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Objective: Oral cancer examinations seek to clinically identify early oral cancers and discover premalignancies prior to their progression to invasive cancer. Method and materials: A cross-sectional study was conducted between April and August 2017 to explore and quantify the diagnostic approach used by United States (US) general dental practitioners following discovery of an oral lesion suspicious for malignancy/premalignancy. US licensed general dental practitioners who were clinically active members of the US National Dental Practice-Based Research Network were eligible to participate. Data for analysis were obtained via two questionnaires. Results: The majority of participants were males, practiced full-time, had a suburban primary practice, were born during the 1950s, and graduated dental school in the 1980s or 2000s. After identifying an oral lesion suspicious for premalignancy/malignancy, the next action of most general dental practitioner respondents (65.4%) was to refer the patient for consultation/biopsy. Most general dental practitioners (87.2%) referred to an oral and maxillofacial surgeon; 22% of general dental practitioners reported personally biopsying suspicious lesions. There was a relatively weak association between completing an Advanced Education in General Dentistry or General Practice Residency and subsequently personally performing biopsies on patients with oral lesions suspicious for malignancy/premalignancy (OR 1.33, P = .06). Most written referrals took place electronically and often included information, including lesion location (87.0%), lesion sign/symptoms (85.3%), lesion history (83.9%), radiographs (59.3%), medical history (50.6%), dental history (48.8%), and photographs (42.4%). When a referral biopsy was performed, referring clinicians were most frequently informed of the findings via a written report (96.7%, when positive for malignancy/premalignancy, and 95.4% when negative). Conclusion: A snapshot is presented of current actions taken by US general dental practitioners following the discovery of oral abnormalities suspicious for premalignancy/malignancy. [ABSTRACT FROM AUTHOR]

Studying specific subpopulations of cancer-derived extracellular vesicles (EVs) could help reveal their role in cancer progression. In cancer, an increase in reactive oxygen species (ROS) happens which results in lipid peroxidation with a major product of 4-hydroxynonenal (HNE). Adduction by HNE causes alteration to the structure of proteins, leading to loss of function. Blebbing of EVs carrying these HNE-adducted proteins as a cargo or carrying HNE-adducted on EV membrane are methods for clearing these molecules by the cells. We have referred to these EVs as Redox EVs. Here, we utilize a surface tension-mediated extraction process, termed exclusion-based sample preparation (ESP), for the rapid and efficient isolation of intact Redox EVs, from a mixed population of EVs derived from human glioblastoma cell line LN18. After optimizing different parameters, two populations of EVs were analyzed, those isolated from the sample (Redox EVs) and those remaining in the original sample (Remaining EVs). Electron microscopic imaging was used to confirm the presence of HNE adducts on the outer leaflet of Redox EVs. Moreover, the population of HNE-adducted Redox EVs shows significantly different characteristics to those of Remaining EVs including smaller size EVs and a more negative zeta potential EVs. We further treated glioblastoma cells (LN18), radiation-resistant glioblastoma cells (RR-LN18), and normal human astrocytes (NHA) with both Remaining and Redox EV populations. Our results indicate that Redox EVs promote the growth of glioblastoma cells, likely through the production of H2O2, and cause injury to normal astrocytes. In contrast, Remaining EVs have minimal impact on the viability of both glioblastoma cells and NHA cells. Thus, isolating a subpopulation of EVs employing ESP-based immunoaffinity could pave the way for a deeper mechanistic understanding of how subtypes of EVs, such as those containing HNE-adducted proteins, induce biological changes in the cells that take up these EVs. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Plain Language Summary Pexidartinib is effective in patients with tenosynovial giant cell tumor (TGCT) for whom surgery is not feasible. Durability of response after discontinuation of pexidartinib and the safety and efficacy of restarting pexidartinib have not been previously recorded. This phase 4 study was designed to mimic the real‐world experience with pexidartinib to evaluate the effects of discontinuation of and retreatment with pexidartinib in patients with TGCT who previously benefited from the drug.This was a global, multicenter, phase 4 study that enrolled patients with TGCT who were experiencing clinical benefit from pexidartinib in one of four prior phase 1 or phase 3 studies investigating pexidartinib in the disease. Patients could choose to continue pexidartinib at the same dose (the treatment‐continuation cohort) or discontinue treatment with the option to restart pexidartinib (the treatment‐free/retreatment cohort). Tumor progression determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, patient‐reported outcomes (the Patient‐Reported Outcomes Measurement Information System–Physical Function [PROMIS‐PF] questionnaire and the EuroQol 5‐dimension, 5‐level [EQ‐5D‐5L] visual analog scale), and safety were assessed every 3 months. The primary end point was the proportion of patients in the treatment‐free/retreatment cohort who remained treatment‐free at month 12 and 24; this did not depend on disease progression.Thirty‐two patients were enrolled: 21 chose to enter the treatment‐continuation cohort, and 11 entered the treatment‐free/retreatment cohort. During the treatment‐free period, six of 11 (54.5%) patients in the treatment‐free/retreatment cohort had progressive disease (PD) according to RECIST, version 1.1, whereas no patient in the treatment‐continuation cohort had disease progression. Over the 24‐month study, three of 11 (27.3%) patients in the treatment‐free/retreatment cohort restarted treatment because of RECIST version 1.1 PD, symptomatic progression, or both (n = 1 each). The probability of remaining treatment‐free in the treatment‐free/retreatment cohort was 73% (95% confidence interval, 37%–90%). In the treatment‐free/retreatment cohort, the median progression‐free survival of the treatment‐free period was 22.8 months (95% confidence interval, 1.6 months to not estimable). By 6 months of retreatment, all retreated patients achieved new disease stabilization with no new safety concerns; two patients had clinically significant improvements in PROMIS‐PF and EQ‐5D‐5L visual analog scale scores. The mean PROMIS‐PF and EQ‐5D‐5L scores remained stable throughout the study. There was no hepatotoxicity and no new safety signal in either cohort.In this small phase 4 study designed to evaluate outcomes in patients who stopped and restarted pexidartinib, 54.5% of patients who discontinued pexidartinib showed PD, with a median progression‐free survival of 22.8 months. Each of the three patients who restarted pexidartinib stopped progressing, and some reported a new gain in physical function. No PD was detected in patients who remained on treatment, and the safety profile did not indicate long‐term hepatotoxicity or any new safety concerns. Pexidartinib is a medication for people with tenosynovial giant cell tumor (TGCT) for whom surgery is not recommended. This study examined what happens when patients stop taking pexidartinib (after it has helped them) to see whether it is safe and effective to restart if needed. Thirty‐two patients were followed for 2 years: 21 chose to continue pexidartinib and did not experience disease progression, while 11 chose to stop pexidartinib; 54.5% of them had disease progression within 2 years. Three patients who stopped pexidartinib restarted treatment after their tumor size increased or their symptoms worsened. Restarting pexidartinib was safe and effective in these patients. Pexidartinib is a medication for people with tenosynovial giant cell tumor (TGCT) for whom surgery is not recommended.This study examined what happens when patients stop taking pexidartinib (after it has helped them) to see whether it is safe and effective to restart if needed.Thirty‐two patients were followed for 2 years: 21 chose to continue pexidartinib and did not experience disease progression, while 11 chose to stop pexidartinib; 54.5% of them had disease progression within 2 years.Three patients who stopped pexidartinib restarted treatment after their tumor size increased or their symptoms worsened.Restarting pexidartinib was safe and effective in these patients. [ABSTRACT FROM AUTHOR]

ABSTRACT Some cancers such as glioblastoma (GBM), show minimal response to medical interventions, often only capable of mitigating tumor growth or alleviating symptoms. High metabolic activity in the tumor microenvironment marked by immune responses and hypoxia, is a crucial factor driving tumor progression. The many developments in mass spectrometry (MS) over the last decades have provided a pivotal tool for studying proteins, along with their posttranslational modifications. It is known that the proteomic landscape of GBM comprises a wide range of proteins involved in cell proliferation, survival, migration, and immune evasion. Combination of MS imaging and microscopy has potential to reveal the spatial and molecular characteristics of pathological tissue sections. Moreover, integration of MS in the surgical process in form of techniques such as DESI‐MS or rapid evaporative ionization MS has been shown as an effective tool for rapid measurement of metabolite profiles, providing detailed information within seconds. In immunotherapy‐related research, MS plays an indispensable role in detection and targeting of cancer antigens which serve as a base for antigen‐specific therapies. In this review, we aim to provide detailed information on molecular profile in GBM and to discuss recent MS advances and their clinical benefits for targeting this aggressive disease. [ABSTRACT FROM AUTHOR]

Inhibition of CDK4/6 kinases has led to improved outcomes in breast cancer. Nevertheless, only a minority of patients experience long-term disease control. Using a large, clinically annotated cohort of patients with metastatic hormone receptor-positive (HR+) breast cancer, we identify TP53 loss (27.6%) and MDM2 amplification (6.4%) to be associated with lack of long-term disease control. Human breast cancer models reveal that p53 loss does not alter CDK4/6 activity or G1 blockade but instead promotes drug-insensitive p130 phosphorylation by CDK2. The persistence of phospho-p130 prevents DREAM complex assembly, enabling cell-cycle re-entry and tumor progression. Inhibitors of CDK2 can overcome p53 loss, leading to geroconversion and manifestation of senescence phenotypes. Complete inhibition of both CDK4/6 and CDK2 kinases appears to be necessary to facilitate long-term response across genomically diverse HR+ breast cancers. [Display omitted] • TP53 mutation is associated with lack of long-term disease control on CDK4/6i • p53 deficiency suppresses DREAM complex in BC cells, enabling cell-cycle re-entry • Disruption of DREAM complex is sufficient to promote long-term CDK4/6i resistance • Inhibition of CDK2 overcomes p53 loss, promoting geroconversion and disease control Kudo et al. demonstrate that TP53 loss in HR+ breast cancer is clinically associated with long-term failure of CDK4/6i due to cellular escape from quiescence via impaired DREAM complex assembly. Selective CDK2 inhibition is found to reinforce p130 dephosphorylation in p53 mutant models and facilitate durable tumor growth suppression. [ABSTRACT FROM AUTHOR]

Cholesterol is an essential membrane component, and the metabolites from cholesterol play important biological functions to intricately support cancer progression and dampen immune responses. Preclinical and clinical studies have demonstrated the role of cholesterol metabolism regulation on inhibiting tumor growth, remodeling the immunosuppressive tumor microenvironment (TME), and enhancing anti‐tumor immunity. In this minireview, we discuss complex cholesterol metabolism in tumors, its important role in cancer progression, and its influences on immune cells in the TME. We provide an overview of recent advances in cancer treatment through regulating cholesterol metabolism. We discuss the design of cholesterol‐altering multifunctional nanomaterials to regulate oxidative stress, modulate immune checkpoints, manipulate mechanical stress responses, and alter cholesterol metabolic pathways. Additionally, we examine the interactions between cholesterol metabolism regulation and established cancer treatments with the aim of identifying efficient strategies to disrupt cholesterol metabolism and synergistic combination therapies for effective cancer treatment. [ABSTRACT FROM AUTHOR]

We present an intelligent photothermal therapy agents by functionalizing gold nanoparticles with specific nucleic acid sequences. Hairpin nucleic acids are modified to the nanoparticles, forming AuNPs-1 and AuNPs-2. Upon infiltrating cancer cells, these nanoparticles undergo catalytic hairpin assembly in the presence of target miRNA, leading to aggregation and subsequent photothermal conversion. Under near-infrared laser irradiation, aggregated gold nanoparticles exhibit efficient photothermal conversion, selectively damaging cancer cells. This approach offers heightened selectivity, as nanoparticles only aggregate in environments with cancer biomarkers present, sparing normal cells. Cytotoxicity assays confirm minimal toxicity to normal cells. In vivo studies on mice bearing solid tumors validate the system's efficacy in tumor regression. Overall, this study highlights the potential of nucleic acid-functionalized gold nanoparticles in intelligent and selective cancer photothermal therapy, offering insights for targeted diagnosis and treatment development. [ABSTRACT FROM AUTHOR]

The complexity of tumors and the challenges associated with treatment often stem from the limitations of existing models in accurately replicating authentic tumors. Recently, organoid technology has emerged as an innovative platform for tumor research. This bioengineering approach enables researchers to simulate, in vitro, the interactions between tumors and their microenvironment, thereby enhancing the intricate interplay between tumor cells and their surroundings. Organoids also integrate multidimensional data, providing a novel paradigm for understanding tumor development and progression while facilitating precision therapy. Furthermore, advancements in imaging and genetic editing techniques have significantly augmented the potential of organoids in tumor research. This review explores the application of organoid technology for more precise tumor simulations and its specific contributions to cancer research advancements. Additionally, we discuss the challenges and evolving trends in developing comprehensive tumor models utilizing organoid technology. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) is a sexually transmitted virus, whose persistent infection is the main reason for invasive cervical cancer (ICC), which is the fourth most common type of cancer in women, with more than 500 000 new cases every year. After infection, various alterations occur in the host, facilitating the virus's evasion of immune system clearance and promoting its proliferation. Oral probiotic consumption can influence the whole body's immunity, inflammatory reflection, neural, endocrine humoral, metabolic pathways and other organs by adjusting the components of gut microbiota (GM). Some evidence shows there is a tight connection between GM and vaginal microbiota (VM), which is referred to as the gut‐vaginal axis. This review investigates the potential role of probiotics in clearing HPV via the gut‐vagina axis, emphasizing the effectiveness of Lactobacillus in preventing vaginal diseases and suggesting its potential for HPV clearance. Understanding the role of probiotics in the gut‐vagina axis could pave the way for new strategies to reduce and eliminate HPV and related diseases. [ABSTRACT FROM AUTHOR]

Cancer is a multifaceted disease influenced by both intrinsic cellular traits and extrinsic factors, with the tumor microenvironment (TME) being crucial for cancer progression. To satisfy their high proliferation and aggressiveness, cancer cells always plunder large amounts of nutrients and release various signals to their surroundings, forming a dynamic TME with special metabolic, immune, microbial and physical characteristics. Due to the neglect of interactions between tumor cells and the TME, traditional cancer therapies often struggle with challenges such as drug resistance, low efficacy, and recurrence. Importantly, the development of gene editing technologies, particularly the CRISPR‐Cas system, offers promising new strategies for cancer treatment. Combined with nanomaterial strategies, CRISPR‐Cas technology exhibits precision, affordability, and user‐friendliness with reduced side effects, which holds great promise for profoundly altering the TME at the genetic level, potentially leading to lasting anticancer outcomes. This review will delve into how CRISPR‐Cas can be leveraged to manipulate the TME, examining its potential as a transformative anticancer therapy. [ABSTRACT FROM AUTHOR]

The crosstalk between cuproptosis and the tumor immune microenvironment (TIME) is vital during clear cell renal cell carcinoma (ccRCC) malignant progression. However, the underlying molecular mechanisms regulate this cross-talk remain elusive. Through tailored machine learning, we analyze clinical ccRCC data from The Cancer Genome Atlas (TCGA) to explore the critical factors that regulate the interaction among cuproptosis, TIME, and tumor progression. We found that rhomboid-like 2 (RHBDL2), critical gene affecting this process, might inhibit cuproptosis-related genes (CRGs) and promotes ccRCC progression through the Wnt/β-catenin pathway. Next, knocking down RHBDL2 expression increased the cuproptosis-related genes ferredoxin 1 (FDX1) and lipoic acid synthase (LIAS) levels but reduced forkhead box P3 (FOXP3) levels and tumor growth in vivo and in vitro models. By employing HLY78, Wnt/β-catenin pathway activator, we rescued the expression of CRGs and the malignant proliferation and metastasis capacity in ccRCC cells with RHBDL2 knockdown. Mechanistically, RHBDL2 inhibits cuproptosis and promotes malignant progression of ccRCC through the Wnt/β-catenin pathway. Abnormal RHBDL2 expression may cause the suppressive TIME formation by regulating Treg-cell infiltration, thus triggering immune escape. In summary, our results indicated that RHBDL2 is an oncogene that induces tumorigenesis and targeting RHBDL2 may be novel therapeutic direction for metastatic ccRCC. [ABSTRACT FROM AUTHOR]

Patients with advanced and recurrent cervical cancer often lack satisfactory treatment outcomes. Thus, it is necessary to seek reliable biomarkers that provide the ability to identify the disease at an early stage and predict the patient prognosis, providing new strategies for the treatment of cervical cancer. The sequencing data of ITGA3 were retrieved from public datasets. Immune infiltration and sensitivity of potential immunotherapy and chemotherapy have been analyzed between two subgroups. Functional analysis was applied to excavate the related pathways of ITGA3 in cervical cancer. Furthermore, the impact of ITGA3 in tumor progression has been verified in vitro. The results revealed that the level of ITGA3 was upregulated in cervical cancer, and was positively correlated with worse prognosis. The tumor microenvironment of patients in the high-risk group was immunosuppressed. Patients in high-risk group may not benefit from immunotherapy, but be may be sensitive to several chemotherapy drugs. Notably, the angiogenesis, epithelial mesenchymal transition, and PI3K pathway were increased in high-risk group. Collectively, ITGA3 is a marker of poor prognosis and promotes tumor progression by regulating PI3K/AKT pathway in cervical cancer. Our results provide new insights for potential molecular targeted therapy and prognostic prediction of cervical cancer. [ABSTRACT FROM AUTHOR]

Background: SARS-CoV-2, a highly contagious coronavirus, is responsible for the global pandemic of COVID-19 in 2019. Currently, it remains uncertain whether SARS-CoV-2 possesses oncogenic or oncolytic potential in influencing tumor progression. Therefore, it is important to evaluate the clinical and functional role of SARS-CoV-2 on tumor progression. Methods: Here, we integrated bioinformatic analysis of COVID-19 RNA-seq data from the GEO database and performed functional studies to explore the regulatory role of SARS-CoV-2 in solid tumor progression, including lung, colon, kidney and liver cancer. Results: Our results demonstrate that infection with SARS-CoV-2 is associated with a decreased expression of genes associated with cancer proliferation and metastasis in lung tissues from patients diagnosed with COVID-19. Several cancer proliferation or metastasis related genes were frequently downregulated in SARS-CoV-2 infected intestinal organoids and human colon carcinoma cells. In vivo and in vitro studies revealed that SARS-CoV-2 nucleocapsid (N) protein inhibits colon and kidney tumor growth and metastasis through the N-terminal (NTD) and the C-terminal domain (CTD). The molecular mechanism indicates that the N protein of SARS-CoV-2 interacts with YBX1, resulting in the recruitment of PKM mRNA into stress granules mediated by G3BP1. This process ultimately destabilizes PKM expression and suppresses glycolysis. Conclusion: Our study reveals a new function of SARS-CoV-2 nucleocapsid protein on tumor progression. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Materials and Methods Results Conclusion Histone lysine lactylation (Kla) plays a vital role in cancer progression. However, the prognostic value of histone Kla in oral squamous cell carcinoma (OSCC) remains unclear.OSCC RNA expression data were obtained from the TCGA and GEO databases. We explored the prognostic value of histone Kla in OSCC via constructing a Cox model and determined the role of Kla in OSCC drug susceptibility and tumor microenvironment (TME). In addition, the biological roles of candidate biomarkers were identified.A total of 1223 Kla‐specific genes were obtained, with 228 DEKlaGs in OSCC. GO and KEGG enrichment analyses suggested that DEKlaGs contributed to inflammatory and cancer progression. A Cox model in accordance with BCAM, CGNL1, DGKG, and OLR1 could predict OSCC patient prognosis accurately. Subsequently, Kla‐induced prognostic genes were identified to play a crucial role in OSCC drug therapy and TME. Moreover, BCAM was identified as a biomarker that promoted OSCC invasion, angiogenesis, and chemotherapy resistance.Kla was identified to be associated with OSCC prognosis, drug therapy, and TME. Histone Kla‐induced BCAM was identified to play a crucial role during OSCC progression, suggesting that Kla is promising to be a novel therapeutic target for OSCC. [ABSTRACT FROM AUTHOR]

Background: The recurrence of cancer will significantly impact an individual's quality of life (QoL) as they adjust to living with a condition that is often incurable. Patients remain at risk of further progression following recurrence, but fear of cancer progression (FOP) at this time is not commonly examined. Importantly, these fears are known to reach levels in which there are consequences for QoL. Methods: This study sought to explore levels of FOP, health-related QoL, anxiety, and depression in patients after a recurrence of their cancer in a longitudinal manner. With the study taking place throughout the COVID-19 pandemic, an assessment of fears related to cancer and the pandemic was included. A sequential mixed method approach was employed for complementarity and expansion purposes. A questionnaire was administered to 44 participants on three different occasions one month apart. A sub-sample of 10 participants then took part in semi-structured interviews. Findings: FOP was present at moderate levels in patients with a cancer recurrence, with over a third of the sample reaching levels considered dysfunctional. Levels of fear were stable over three months and were not predicted by select demographic or clinical factors. On average, depression was low, but anxiety reached mild levels. Challenges to health-related QoL were evident. Low levels of concern about COVID-19 in relation to cancer were reported. Integrated findings provided more nuanced answers to the research questions, including more specific worries about cancer progression. Implications: Findings support the development of psychosocial interventions to manage FOP, and future recommendations are provided. Identifying the presence of fears not commonly screened for after cancer recurrence adds to the existing knowledge in this area. Through acknowledging and attending to the psychosocial impact of FOP, healthcare professionals can provide tailored support to enhance the well-being of those with a recurrence of their cancer. [ABSTRACT FROM AUTHOR]

Background: CDK7 has been demonstrated to play a crucial role in the initiation and progression of malignancy. Therefore, targeting CDK7, which regulates the transcription process, has emerged as a new promising approach for treating cancer. Research on CDK7 inhibitors has significantly increased over the past 2 decades, with almost 600 related papers in the Web of Science Core Collection database. To effectively identify future research hotspots and potential future directions, it is crucial to systematically review and visually present the research on this topic from a comprehensive viewpoint, ensuring scientific reliability. Methods: This study performed bibliometric analysis via CiteSpace and VOSviewer scientometrics analysis software to examine data on the publication of articles on CDK7 inhibitors over the past 2 decades; the data included country of publication, author names, institution names, scientific categories, cited journals, and keywords related to the field of CDK7 inhibitors. Results: This bibliometric analysis included 426 publications from 41 different nations, referencing a total of 15,892 sources. Research associated with CDK7 inhibitors has rapidly expanded since 2016, and the US and China are the two countries with the highest publication output among the countries and institutes that produce literature on CDK7 inhibitors. Furthermore, the US is the country that most frequently engages in international cooperation. The evolution of keywords identifying antitumor strategies related to CDK7-mediated cellular transcription processes has been the research focus in recent years. Conclusion: In this study, we identified research efforts and their evolving patterns and predicted advances in the CDK7 inhibitor field. The knowledge structure of CDK7 inhibitors encompasses pharmacological mechanisms, therapeutic targets, and cancer treatment strategies. The primary objectives of contemporary research are to discover the processes underlying cancer progression, identify specific signaling pathways, and develop effective clinical medicines. [ABSTRACT FROM AUTHOR]

Autophagy plays a crucial role in cancer cell survival by facilitating the elimination of detrimental cellular components and the recycling of nutrients. Understanding the molecular regulation of autophagy is critical for developing interventional approaches for cancer therapy. In this study, we report that migfilin, a focal adhesion protein, plays a novel role in promoting autophagy by increasing autophagosome-lysosome fusion. We found that migfilin is associated with SNAP29 and Vamp8, thereby facilitating Stx17-SNAP29-Vamp8 SNARE complex assembly. Depletion of migfilin disrupted the formation of the SNAP29- mediated SNARE complex, which consequently blocked the autophagosome-lysosome fusion, ultimately suppressing cancer cell growth. Restoration of the SNARE complex formation rescued migfilin-deficiency-induced autophagic flux defects. Finally, we found depletion of migfilin inhibited cancer cell proliferation. SNARE complex reassembly successfully reversed migfilin-deficiency-induced inhibition of cancer cell growth. Taken together, our study uncovers a new function of migfilin as an autophagy-regulatory protein and suggests that targeting the migfilin-SNARE assembly could provide a promising therapeutic approach to alleviate cancer progression. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) play a significant role in the occurrence and development of malignant tumours. However, ceRNAs, which are significantly associated with the prognosis of breast cancer (BC), need to be further investigated. Therefore, the current study aimed to investigate the effect of the lncRNA DDX11-AS1 on BC progression. Bioinformatics analysis via a public microarray revealed that DDX11-AS1 was upregulated in BC. The above findings were verified via RT‒qPCR analysis of BC tissues. Additionally, our study revealed that the expression levels of DDX11-AS1 increased with increasing pathological grade and lymph node metastasis. Furthermore, DDX11-AS1 knockdown markedly inhibited the proliferation, migration and invasion abilities of BC cells. Mechanistically, DDX11-AS1 could prevent the degradation of MTDH in BC via competitively binding with miR-30c-5p, which could act as a tumour promoter factor. Additionally, miR-30c-5p was downregulated and MTDH was upregulated in BC cells and tissues. The promoting effect of DDX11-AS1 on BC cells was enhanced by miR-30c-5p silencing and reduced by treatment with MTDH inhibitors. Collectively, the above results suggest that the DDX11-AS1/miR-30c-5p/MTDH axis could be associated with the progression of BC and that DDX11-AS1 could be a potential biomarker and therapeutic target for BC. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the malignant tumor with the highest mortality rate in gynecology. We aimed to identify novel genes that promote ovarian cancer progression and epithelial-mesenchymal transition under hypoxic conditions. We screened SVIL as a hypoxia-associated target in ovarian cancer and explored the related molecular mechanisms. We assessed the effects of SVIL on ovarian cancer progression and metastasis in clinical samples and cellular hypoxia models. Further, we investigated the relevant pathways of SVIL and confirmed the effects of SVIL on ovarian cancer progression by using nude mouse in situ tumor models. We found that SVIL was significantly highly expressed in the hypoxic environment of ovarian cancer, and SVIL expression correlated with patient prognosis.CCK8, Wound-healing assay, Transwell assay, Western Blot, and apoptosis assays revealed that knockdown of SVIL inhibited the activation of the TGFβ1/smad2/3 pathway, which attenuated the progression and epithelial-mesenchymal transition(EMT) of ovarian cancer and alleviated cisplatin resistance by increasing cisplatin-induced apoptosis. Furthermore, in a nude mouse ovarian cancer in situ model, we found that the knockdown of SVIL significantly inhibited tumor growth and metastasis. SVIL highly expressed in the hypoxic microenvironment can increase ovarian cancer progression and cisplatin resistance by activating TGFβ1/smad2/3 pathway. Our study demonstrated that SVIL may be a novel target for the treatment of ovarian cancer. [Display omitted] • SVIL was overexpressed in ovarian cancer and correlated with patient prognosis. • Knockdown of SVIL inhibited the activation of the TGFβ1/smad2/3 pathway. • SVIL attenuated the resistant progression and EMT of ovarian cancer. • Knockdown of SVIL significantly inhibited tumor growth and metastasis. • SVIL is a novel target for the treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Integrin alpha 5 (ITGA5) was previously confirmed to be related to prognosis in several cancer types; however, its function in clear cell renal cell carcinoma (ccRCC) and how this molecule regulates tumor progression and the tumor microenvironment (TME) remain to be elucidated. Methods: We investigated the prognostic implications of ITGA5 with a machine learning model and evaluated biological behaviors of different levels of ITGA5 expression in vitro. Bioinformatic analysis was performed to explain the comprehensive effect of ITGA5 on the TME and drug sensitivity. Results: We constructed a machine learning model to elaborate the prognostic implication of ITGA5. As tumorigenesis of ccRCC was tightly relevant with several mutant genes, we investigated the correlation between ITGA5 expression and frequent mutations and found ITGA5 upregulation in VHL mutant ccRCC (P = 0.016). Through overexpressing, silencing, and blocking ITGA5, we verified the role of ITGA5 in promoting ccRCC adverse biological activities; and the potential functions of ITGA5 in ccRCC were bioinformatically demonstrated, summarizing as cell proliferation, migration, and angiogenesis. The localization of ITGA5 primarily in endothelia and macrophages further verified its magnitude in angiogenesis and aroused our excavation in ITGA5 regulation of immune infiltration landscape. Generally, ITGA5-high ccRCC presented an immunosuppressive TME by inducing a lower level of CD8 + T cell infiltration. For the last part we predicted drug sensitivity relevant to ITGA5 and concluded that a joint medication of ITGA5 inhibitors and VEGFR-target drugs (including sunitinib, axitinib, pazopanib, and motesanib) might be a promising therapeutic strategy. Conclusion: Our findings clarified the adverse outcome induced by high expression of ITGA5 in ccRCC patients. In vitro experiments and bioinformatical analysis identified ITGA5 function as predominantly cell proliferation, migration, angiogenesis, and macrophage recruitment. Further, we predicted immune infiltration and medication sensitivity regulation by ITGA5 and proposed a joint use of ITGA5 inhibitors and anti-angiogenetic drugs as a potential potent therapeutic strategy. [ABSTRACT FROM AUTHOR]

MicroRNA‐21 (MiR‐21) has been confirmed to be upregulated in tumors, and its abnormal expression is closely associated with tumor occurrence. However, the traditional imaging methods are limited to qualitative imaging of miR‐21, and no effective strategy has been developed for monitoring its concentration in vivo during cancer initiation and progression. Herein, a biosensor is created utilizing a NIR‐II ratiometric fluorescent nanoprobe to quantitatively monitor dynamic alterations in miR‐21 levels in vivo. The nanoprobe (termed DCNP@DNA2@IR806) is constructed by introducing IR806 as a donor and down‐conversion nanoparticles (DCNP) as the acceptor, using DNA as linkers. Upon miR‐21‐responsive initiation of the nanoprobe, the 1550 nm fluorescent signal of DCNP stimulated by a 808 nm laser (F1550, 808Ex) increased because of the close proximity of IR806 to the DCNP and the subsequent non‐radiative energy transfer (NRET). Meanwhile, the 1550 nm fluorescent signal of DCNP stimulated by a 980 nm laser (F1550, 980Ex) remained stable because of the absence of NRET. This ratiometric NIR‐II fluorescent signal has been confirmed to be a reliable indicator of miR‐21 concentration in vivo. The strategy holds promise for further enhancing the understanding of microRNAs‐based molecular mechanisms underlying cancer progression, laying a foundation for the early diagnosis of microRNAs‐related diseases. [ABSTRACT FROM AUTHOR]

Gas therapy has emerged as a promising approach for treating cancer, with gases like NO, H2S, and CO showing positive effects. Among these, NO is considered a key gas molecule with significant potential in stopping cancer progression. However, due to its high reactivity and short half-life, delivering NO directly to tumors is crucial for enhancing cancer treatment. NO-driven nanomedicines (NONs) have been developed to effectively deliver NO donors to tumors, showing great progress in recent years. This review provides an overview of the latest advancements in NO-based cancer nanotherapeutics. It discusses the types of NO donors used in current research, the mechanisms of action behind NO therapy for cancer, and the different delivery systems for NO donors in nanotherapeutics. It also explores the potential of combining NO donors with other treatments for enhanced cancer therapy. Finally, it examines the future prospects and challenges of using NONs in clinical settings for cancer treatment. Highlights: A thorough and detailed overview of NO-based therapy, including information on its various donor types, mechanisms of NO release, and the underlying mechanisms of its anticancer effects. An overview of the NO-driven delivery system is provided, covering both covalent and non-covalent approaches, with a particular emphasis on the latest progress. This review delves into the current clinical treatments for cancer based on NO. It also highlights the ongoing and potential challenges in NO-driven anticancer therapy, along with discussions on optimizing advanced multi-synergistic treatments for cancer. [ABSTRACT FROM AUTHOR]

Introduction: This study aims to investigate the role of the m6A regulatory factor METTL3 in LUAD. Methods: By examining the expression of METTL3 in LUAD and conducting cellular functional experiments, the biological functions of METTL3 were discussed. mRNA-seq and MeRIP-qPCR were used to identify downstream target genes and pathways. Results: The expression level of METTL3 in LUAD is lower than that in the control group. The downregulation of METTL3 promoted the proliferation, migration, and invasion of LUAD cells, while overexpression of METTL3 results in the opposite effects. Furthermore, we found that FGF2 was negatively regulated by METTL3. Inhibiting FGF2 reversed the tumor-promoting effects caused by METTL3 downregulation in LUAD cells. Silencing METTL3 enhanced the stability of FGF2 mRNA. Silencing FGF2 resulted in reduced activity of the PI3K/AKT/mTOR signaling pathway in METTL3 knockdown LUAD cells. Discussion: In summary, our findings unveil an intricate signaling network involving METTL3/FGF2/PI3K/AKT/mTOR in LUAD and provide valuable insights into the molecular mechanisms underlying tumor progression, thus holding significant implications for targeted therapy and advancing LUAD research. [ABSTRACT FROM AUTHOR]

Objective: Gastric cancer (GC) is one of the most prevalent malignant tumors of the digestive system. The advanced metastasis of gastric cancer severely limits the conventional approaches for its treatment, while certain traditional Chinese medicinal compounds have been reported to possess promising abilities in inhibiting tumor metastasis. Such as Poria (PA), known as Fu Ling in Chinese, is a commonly used traditional Chinese medicinal herb derived from Poria cocos, a fungus belonging to the polyporaceae family. Methods: The proliferation capacity of cells was measured using the MTT assay, while the invasion and migration abilities of cells after treatment with different concentrations of PA were evaluated through wound healing assay and Transwell assay. The differential expression of mRNA was analyzed using qPCR. The in vivo growth of tumors was assessed by subcutaneous tumor formation in mice. Results: Both in vivo and in vitro experiments have demonstrated that PA significantly inhibits the proliferation of GC. Moreover, in vitro experiments have revealed that PA not only suppresses the invasion and migration of GC cells but also reverses TNF-β-induced EMT. Further experiments have revealed that PA inhibits cell invasion, migration and EMT by inducing ferroptosis in GC cells. Conclusion: In brief, the present study shows that PA inhibits tumor metastasis by inducing ferroptosis in GC cells. Our findings suggest that PA may have therapeutic potential in GC. [ABSTRACT FROM AUTHOR]

We utilize patient tumor material to generate short-term bladder cancer patient–derived organoid (PDO) cultures for ex vivo drug testing, show that these PDOs retain the molecular and cellular characteristics of the primary tissue, and identify a multiomic signature for gemcitabine response. Predicting response to therapy for each patient's tumor is critical to improving long-term outcomes for muscle-invasive bladder cancer. This study aims to establish ex vivo bladder cancer patient–derived organoid (PDO) models that are representative of patients' tumors and determine the potential efficacy of standard of care and curated experimental therapies. Tumor material was collected prospectively from consented bladder cancer patients to generate short-term PDO models, which were screened against a panel of clinically relevant drugs in ex vivo three-dimensional culture. Multiomic profiling was utilized to validate the PDO models, establish the molecular characteristics of each tumor, and identify potential biomarkers of drug response. Gene expression (GEX) patterns between paired primary tissue and PDO samples were assessed using Spearman's rank correlation coefficients. Molecular correlates of therapy response were identified using Pearson correlation coefficients and Kruskal-Wallis tests with Dunn's post hoc pairwise comparison testing. A total of 106 tumors were collected from 97 patients, with 65 samples yielding sufficient material for complete multiomic molecular characterization and PDO screening with six to 32 drugs/combinations. Short-term PDOs faithfully represent the tumor molecular characteristics, maintain diverse cell types, and avoid shifts in GEX-based subtyping that accompany long-term PDO cultures. Utilizing an integrative approach, novel correlations between ex vivo drug responses and genomic alterations, GEX, and protein expression were identified, including a multiomic signature of gemcitabine response. The positive predictive value of ex vivo drug responses and the novel multiomic gemcitabine response signature need to be validated in future studies. Short-term PDO cultures retain the molecular characteristics of tumor tissue and avoid shifts in expression-based subtyping that have plagued long-term cultures. Integration of multiomic profiling and ex vivo drug screening data identifies potential predictive biomarkers, including a novel signature of gemcitabine response. Better models are needed to predict patient response to therapy in bladder cancer. We developed a platform that uses short-term culture to best mimic each patient's tumor and assess potential sensitivity to therapeutics. [ABSTRACT FROM AUTHOR]

Background: Ubiquitination is an important post-transcriptional modification crucial for maintaining cell homeostasis. As a deubiquitination enzyme, ubiquitin-specific protease 1 (USP1) is associated with tumor progression; however, its role in bladder cancer is unknown. This study aimed to analyze USP1 expression and study its roles in bladder cancer. Methods: The web server GEPIA was used to analyze the USP1 expression. To explore USP1's function in bladder cancer, we constructed USP1-knockout cell lines in UMUC3 cells. A FLAG-USP1 (WT USP1) plasmid and a plasmid FLAG-USP1 C90S (catalytic–inactive mutant) were used to overexpress USP1 in T24 cells. CCK8, colony formation, and Transwell assays were used to assess cell viability, proliferation, and migration. RNA-sequencing (RNA-seq) and dual-luciferase reporter assays were performed to screen the pathway. Co-immunoprecipitation and immunofluorescence were used to explore the interaction between USP1 and c-MYC. A xenograft mouse model was used to study the role of USP1 in bladder cancer. Results: USP1 expression was upregulated in human bladder cancer cells and correlated with poor patient prognosis. USP1 overexpression promoted cell proliferation, clone formation, and migration, and this was attenuated by genetic ablation of USP1. Furthermore, we observed that USP1 deficiency inhibited tumor formation in vivo. Mechanistically, the c-MYC pathway was remarkably activated compared with the other pathways. Furthermore, USP1 could interact with c-MYC and increase c-MYC's stability depending on the catalytic activity of USP1. Conclusions: Our results suggested that high expression of USP1 promotes bladder cancer progression by stabilizing c-MYC; hence, USP1 may serve as a novel therapeutic target for treating bladder cancer. [ABSTRACT FROM AUTHOR]

Bladder cancer remains a prevalent and challenging malignancy. Myeloid-derived suppressor cells (MDSCs) have emerged as key contributors to the immunosuppressive tumor microenvironment, facilitating tumor progression, immune evasion, and resistance to therapies. This review explores the role of MDSC in bladder cancer, highlighting their involvement in immune regulation; tumor progression; and resistance to therapies such as bacillus Calmette–Guérin (BCG) therapy, chemotherapy, and immune checkpoint inhibitors (ICIs). We also discuss their potential as biomarkers and therapeutic targets, with current evidence suggesting that targeting MDSCs, either alone or in combination with existing treatments such as BCG and ICIs, may enhance anti-tumor immunity and improve clinical outcomes. However,, challenges remain, particularly regarding the identification and therapeutic modulation of MDSC subpopulations. Further research is warranted to fully elucidate their role in bladder cancer and to optimize MDSC-targeted therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Although the zinc finger transcription factor 281 (ZNF281)/ZBP-99 protein has been shown to promote tumor progression, its role in the development of cervical cancer remains unclear. We find that its level is higher in cervical cancer tissues than in normal cervical tissues. And it promotes metastasis in HeLa cell lines by facilitating the epithelial-mesenchymal transition process, thereby enhancing the migration of HeLa cells in vivo. Our research might provide a new marker for predicting the development of cervical cancer. Background: Cervical cancer is the fourth most common cancer among women worldwide. The zinc finger transcription factor 281 (ZNF281)/ZBP-99 protein specifically binds to GC-rich DNA sequences and regulates gene expression, and it has been shown to promote tumor progression. In this study, we aim to investigate the function and molecular mechanism of ZNF281 in uterine cervical carcinoma. Methods: We conducted immunohistochemistry and Western blot assays to determine the expression of ZNF281 in eight human cervical cancer tissues. And, xenograft experiments involving the injection of HeLa cells into nude mice was used to determine the function of ZNF281 on proliferation. Transwell assays were used to detect the migration and invasion of HeLa cells after indicated that ZNF281 overexpression. Results: Our results indicated that ZNF281 protein levels were higher in cervical cancer tissues compared to normal cervical tissues. Additionally, ZNF281 was expressed in human cervical carcinoma cell lines, including HeLa, SiHa, C-33 A, CaSki, and HT-3, and is localized in both the cell nucleus and cytoplasm. ZNF281 overexpression did not influence HeLa cell proliferation or tumor size in situ. Moreover, nude mice injected with ZNF281-overexpressing cell lines developed more tumor lesions in the lungs compared to those injected with control cell lines. Conclusions: These findings suggest that ZNF281 is associated with tumor metastasis without affecting cell proliferation, both in vivo and in vitro. [ABSTRACT FROM AUTHOR]

Simple Summary: This study analyzes real-world outcomes for advanced, non-oncogene addicted non-small cell lung cancer patients treated with atezolizumab monotherapy following platinum-based chemotherapy, based on data from two academic institutions in Serbia. Progression-free survival did not significantly differ between patients receiving atezolizumab as a second, third, or later line of therapy, indicating consistent efficacy across treatment lines. Additionally, the number of prior chemotherapy cycles had no significant impact on progression-free survival, suggesting that a higher prior treatment burden did not compromise atezolizumab effectiveness. Importantly, a good ECOG performance status emerged as the strongest predictor of prolonged progression-free survival, highlighting the importance of patients' health status at treatment initiation. Immune checkpoint inhibitors (ICIs) like atezolizumab have improved outcomes in advanced non-small cell lung cancer (NSCLC) patients, especially in the second-line setting after progression on platinum-based chemotherapy. However, access to ICIs remains limited in many developing nations. This study evaluated the efficacy of atezolizumab as a second-line versus later-line treatment for advanced NSCLC patients in Serbia. Methods: This retrospective study involved 147 advanced NSCLC patients treated with atezolizumab following progression on prior platinum-based chemotherapy at two academic centers in Serbia. Data on demographics and clinical, pathological, and molecular characteristics were collected. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method, and multivariable Cox proportional hazards regression identified outcome predictors. Results: The median PFS was 7.13 months, and median OS was 38.6 months. The overall response rate (ORR) was 15%, with a disease control rate (DCR) of 57.9%. No significant PFS differences were observed between patients treated with atezolizumab in the second line versus later lines. Patients with good performance status (ECOG 0–1) had significantly better PFS compared to those with poorer status (12.03 vs. 1.63 months, p < 0.0001). Conclusions: Atezolizumab is effective in both second-line and later-line settings for advanced NSCLC, particularly in patients with good performance status. This highlights the importance of patient selection based on performance status, as well as the need for wider access to ICIs in resource-limited regions. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with the head and neck region being the most common location. Perineural invasion (PNI), or the invasion of cancer into and around nerves, is a high-risk factor in cSCC associated with poor outcomes. The mechanisms of PNI in cSCC are poorly understood, but recent studies suggest that cross-communication between nerve components and cancer is a contributing factor. A better understanding of the mechanisms that promote PNI may lead to new therapies that improve outcomes in cSCC patients. Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with a lifetime risk of 14–20% that is rising every year. Although prognosis for cSCC is generally good, certain high-risk features of cSCC portend increased rates of nodal and distant metastasis, recurrence, and disease-specific mortality. One such high-risk factor is perineural invasion (PNI), which is broadly defined as the invasion of cancer into and around nerves. Compared to other high-risk factors, PNI presence is associated with the highest risk for locoregional and distant metastasis. Still, the mechanisms underlying the pathogenesis of PNI remain poorly understood. Recent studies suggest the migration and invasion of tumors into nerves is a result of complex molecular crosstalk within the tumor-nerve microenvironment, wherein the milieu of signaling molecules simultaneously promote neuronal growth and tumor cell invasion. Methods: Understanding the molecular and cellular mechanisms that promote PNI will lead to future developments of targeted therapies that may improve locoregional control and survival. Results/Conclusions: In our article, we aim to provide a comprehensive review of recent findings about the pathogenesis of PNI, clinical implications of PNI-positive disease in cSCC, available treatment modalities, and potential future therapeutic targets. [ABSTRACT FROM AUTHOR]

Simple Summary: CD59 prevents the formation of membrane attack complex, enabling tumor cells to escape complement-mediated cytotoxicity. It appears that the expression of CD59 significantly impacts survival outcomes due to its interaction with immune cells. The associations between CD59 and immune suppressive cells such as T-regulatory cells, myeloid derived suppressor cells, and macrophage create an immune suppressive environment in cervical, brain, head and neck, and stomach cancers. However, kidney cancer has less or no association, leading to better survival outcomes. Thus, assessing the levels of CD59 and its immune cell associations is crucial as it plays a predictive role in deciding prognostic outcomes. Background: CD59, a GPI-anchored membrane protein, protects cancer cells from complement-dependent cytotoxicity (CDC) by inhibiting the formation of the membrane attack complex (MAC). It has been demonstrated to be overexpressed in most solid tumors, where it facilitates tumor cell escape from complement surveillance. The role of CD59 in cancer growth and interactions between CD59 and immune cells that modulate immune evasion has not been well explored. Methods: Using cancer patient database from The Cancer Genome Atlas (TCGA) and other public databases, we analyzed CD59 expression, its prognostic significance, and its association with immune cell infiltration in the tumor microenvironment, identifying associated genomic and functional networks and validating findings with invitro cell-line experimental data. Results: This article describes the abundant expression of CD59 in multiple tumors such as cervical squamous cell carcinoma (CESC), kidney renal cell carcinoma (KIRC), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), and stomach adenocarcinoma (STAD), as well as in pan-cancer, using The Cancer Genome Atlas (TCGA) database and confirmed using multiple cancer cell lines. The expression of CD59 significantly alters the overall survival (OS) of patients with multiple malignancies such as CESC, GBM, HNSC, and STAD. Further, the correlation between CD59 and Treg and/or MDSC in the tumor microenvironment (TME) has shown to be strongly associated with poor outcomes in CESC, GBM, HNSC, and STAD as these tumors express high FOXP3 compared to KIRC. Moreover, unfavorable outcomes were strongly associated with the expression of CD59 and M2 tumor-associated macrophage infiltration in the TME via the IL10/pSTAT3 pathway in CESC and GBM but not in KIRC. In addition, TGFβ1-dominant cancers such as CESC, GBM, and HNSC showed a high correlation between CD59 and TGFβ1, leading to suppression of cytotoxic T cell activity. Conclusion: Overall, the correlation between CD59 and immune cells predicts its prognosis as unfavorable in CESC, GBM, HNSC, and STAD while being favorable in KIRC. [ABSTRACT FROM AUTHOR]

Simple Summary: A CRISPR knockout screen was performed targeting all genes of the human genome with about 12 knockout sgRNAs each. By comparing pancreatic cancer cells with high or low metastatic capacity, genes were identified that affect the viability of metastatic cells while not affecting cell viability of non-metastatic cells. Further functional studies looked at some of the identified candidate genes. For one of the metastasis-related genes—MYBL2—a change in its interaction with another regulator gene was found to be implicated in metastasis. Background/Objectives: Early and aggressive metastasis is a major feature of pancreatic ductal adenocarcinoma. Understanding the processes underlying metastasis is crucial for making a difference to disease outcome. Towards these ends, we looked in a comprehensive manner for genes that are metastasis-specific. Methods: A genome-wide CRISPR-Cas9 gene knockout screen with 259,900 single guide RNA constructs was performed on pancreatic cancer cell lines with very high or very low metastatic capacity, respectively. Functional aspects of some of the identified genes were analysed in vitro. The injection of tumour cells with or without a gene knockout into mice was used to confirm the effect on metastasis. Results: The knockout of 590 genes—and, with higher analysis stringency, 67 genes—affected the viability of metastatic cells substantially, while these genes were not vital to non-metastasizing cells. Further evaluations identified different molecular processes related to this observation. One of the genes was MYBL2, encoding for a well-known transcription factor involved in the regulation of cell survival, proliferation, and differentiation in cancer tissues. In our metastasis-focussed study, no novel functional activity was detected for MYBL2, however. Instead, a metastasis-specific transformation of its genetic interaction with FOXM1 was observed. The interaction was synergistic in cells of low metastatic capacity, while there was a strong switch to a buffering mode in metastatic cells. In vivo analyses confirmed the strong effect of MYBL2 on metastasis. Conclusions: The genes found to be critical for the viability of metastatic cells form a basis for further investigations of the processes responsible for triggering and driving metastasis. As shown for MYBL2, unexpected processes of regulating metastasis might also be involved. [ABSTRACT FROM AUTHOR]

Simple Summary: Integrin α6β4 makes triple-negative breast cancer (TNBC) more aggressive by controlling genes that drive tumor invasion and metastasis. PTPRZ1 is linked to cancer relapse, but its role in TNBC is not well understood. We discovered that PTPRZ1 expression is significantly increased by integrin α6β4 in TNBC. We also found that integrin β4 gene expression correlates with PTPRZ1 in breast cancer patient samples. Importantly, we found that integrin α6β4 controls PTPRZ1 through UCHL1, which in turn stabilized Hif-1α. When UCHL1 or PTPRZ1 are blocked, the aggressiveness driven by integrin β4 signaling decreased substantially. Data analysis showed that high levels of these genes (ITGB4, UCHL1, Hif1α, PTPRZ1) are linked to worse survival rates, especially in patients who received chemotherapy treatment. Our findings suggest that integrin α6β4 helps TNBC become invasive through UCHL1-Hif-1α regulation of PTPRZ1, pointing to a new approach to targeting integrin α6β4 signaling using PTPRZ1 and UCHL1 inhibitors. Integrin α6β4 drives triple-negative breast cancer (TNBC) aggressiveness through the transcriptional regulation of key genes. Here, we investigated how integrin α6β4 regulates protein tyrosine phosphatase receptor type Z1 (PTPRZ1). Using stable re-expression of integrin β4 (ITGB4) in cells naturally devoid of integrin α6β4 or knockdown or knockout (KO) of ITGB4, we found that integrin α6β4 regulates PTPRZ1 expression. To gain mechanistic insight, we focused on Hif-1α due to the impact of integrin α6β4 on a hypoxia-associated signature. We found that nuclear localization of Hif-1α, but not Hif-2α, was substantially enhanced with integrin α6β4 signaling. Hif-1α knockdown by shRNA or chemical inhibition decreased PTPRZ1 expression, while chemical activation of Hif-1α increased it. Upstream of Hif-1α, integrin α6β4 upregulates UCHL1 to stabilize Hif-1α and ultimately regulate PTPRZ1. Inhibition of UCHL1 and PTPRZ1 dramatically decreases integrin α6β4-mediated cell migration and three-dimensional invasive growth. Finally, public breast cancer database analyses demonstrated that ITGB4 correlates with PTPRZ1 and that high expression of ITGB4, UCHL1, HIF1A, and PTPRZ1 associated with decreased overall survival, distant metastasis free survival, post progression survival, and relapse-free survival. In summary, these findings provide a novel function of integrin α6β4 in promoting tumor invasive phenotypes through UCHL1-Hif-1α-mediated regulation of PTPRZ1. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most common cancer type and the leading cause of mortality for women worldwide. The microbiome influences various cancer therapies, including radiotherapy. Thus, radiotherapy-derived metabolites and microbiome composition may affect cancer progression and treatment response, and vice versa. This review explores this bidirectional relationship as well as providing current evidence and future perspectives in this field. The gut microbiome has emerged as a crucial player in modulating cancer therapies, including radiotherapy. In the case of breast cancer, the interplay between the microbiome and radiotherapy-derived metabolites may enhance therapeutic outcomes and minimize adverse effects. In this review, we explore the bidirectional relationship between the gut microbiome and breast cancer. We explain how gut microbiome composition influences cancer progression and treatment response, and how breast cancer and its treatments influence microbiome composition. A dual role for radiotherapy-derived metabolites is explored in this article, highlighting both their therapeutic benefits and potential hazards. By integrating genomics, metabolomics, and bioinformatics tools, we present a comprehensive overview of these interactions. The study provides real-world insight through case studies and clinical trials, while therapeutic innovations such as probiotics, and dietary interventions are examined for their potential to modulate the microbiome and enhance treatment effectiveness. Moreover, ethical considerations and patient perspectives are discussed, ensuring a comprehensive understanding of the subject. Towards revolutionizing treatment strategies and improving patient outcomes, the review concludes with future research directions. It also envisions integrating microbiome and metabolite research into personalized breast cancer therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: While tumor cell invasion beyond the surgically resectable "margin" of glioblastoma is thought to be associated with nearly 100% of recurrences and poor survival, no reliable methods exist for mapping the location of invading tumor cells within the human brain. Building on prior work demonstrating the ability of Q-space magnetic resonance imaging (QSI) to highlight structural alterations in tissue architecture, we hypothesized that using this imaging method to construct tumor-associated tractography might identify tumor-specific structures that underlie cellular invasion. Our results demonstrate that such tractography patterns can be observed in a tumor-specific manner, and provide preliminary evidence that those patterns may colocalize with invading tumor cells, and metrics derived from them may be associated with patient survival time. Background: The invasion of glioblastoma cells beyond the visible tumor margin depicted by conventional neuroimaging is believed to mediate recurrence and predict poor survival. Radiomic biomarkers that are associated with the direction and extent of tumor infiltration are, however, non-existent. Methods: Patients from a single center with newly diagnosed glioblastoma (n = 7) underwent preoperative Q-space magnetic resonance imaging (QSI; 3T, 64 gradient directions, b = 1000 s/mm2) between 2018 and 2019. Tumors were manually segmented, and patterns of inter-voxel coherence spatially intersecting each segmentation were generated to represent tumor-associated tractography. One patient additionally underwent regional biopsy of diffusion tract- versus non-tract-associated tissue during tumor resection for RNA sequencing. Imaging data from this cohort were compared with a historical cohort of n = 66 glioblastoma patients who underwent similar QSI scans. Associations of tractography-derived metrics with survival were assessed using t-tests, linear regression, and Kaplan–Meier statistics. Patient-derived glioblastoma xenograft (PDX) mice generated with the sub-hippocampal injection of human-derived glioblastoma stem cells (GSCs) were scanned under high-field conditions (QSI, 7T, 512 gradient directions), and tumor-associated tractography was compared with the 3D microscopic reconstruction of immunostained GSCs. Results: In the principal enrollment cohort of patients with glioblastoma, all cases displayed tractography patterns with tumor-intersecting tract bundles extending into brain parenchyma, a phenotype which was reproduced in PDX mice as well as in a larger comparison cohort of glioblastoma patients (n = 66), when applying similar methods. Reconstructed spatial patterns of GSCs in PDX mice closely mirrored tumor-associated tractography. On a Kaplan–Meier survival analysis of n = 66 patients, the calculated intra-tumoral mean diffusivity predicted the overall survival (p = 0.037), as did tractography-associated features including mean tract length (p = 0.039) and mean projecting tract length (p = 0.022). The RNA sequencing of human tissue samples (n = 13 tumor samples from a single patient) revealed the overexpression of transcripts which regulate cell motility in tract-associated samples. Conclusions: QSI discriminates tumor-specific patterns of inter-voxel coherence believed to represent white matter pathways which may be susceptible to glioblastoma invasion. These findings may lay the groundwork for future work on therapeutic targeting, patient stratification, and prognosis in glioblastoma. [ABSTRACT FROM AUTHOR]

Simple Summary: The prognostic value of lymphovascular or perineural invasion in prostate cancer specimens regarding oncological outcomes after radical prostatectomy is unclear. Within a contemporary study cohort of 822 prostate cancer patients, 78 (9%) exhibited lymphovascular invasion and 633 (77%) exhibited perineural invasion in RP specimens. In univariable Cox regression models, lymphovascular invasion and perineural invasion were both associated with higher rates of biochemical recurrence (BCR). However, after multivariable adjustment for standard pathologic tumor characteristics, lymphovascular or perineural invasion was not found to be an independent predictor for BCR. These phenomes may be explained by the strong association between the Gleason Grade Group and pathologic tumor stage with lymphovascular as well as perineural invasion. Objective: The aim of this study was to test for the association between lymphovascular invasion or perineural invasion in radical prostatectomy (RP) specimens and biochemical recurrence (BCR). Methods: Relying on a tertiary-care database, we identified prostate cancer patients treated with RP between January 2014 and June 2023. Of these, the majority underwent robotic-assisted RP (81%). Kaplan–Meier survival analyses and Cox regression models addressed BCR according to either lymphovascular invasion or perineural invasion in RP specimens. Additionally, the linear trend test assessed the association between the Gleason Grade Group or pathologic tumor stage and lymphovascular or perineural invasion. Results: Of 822 patients, 78 (9%) exhibited lymphovascular invasion and 633 (77%) exhibited perineural invasion in RP specimens. In survival analyses, the five-year BCR-free survival rates were 62% in patients with lymphovascular invasion vs. 70% in patients without lymphovascular invasion (p = 0.04) and 64% in patients with perineural invasion vs. 82% in patients without perineural invasion (p = 0.01). In univariable Cox regression models, lymphovascular invasion (hazard ratio 1.58, 95% confidence interval 1.01–2.47; p = 0.045) and perineural invasion (hazard ratio 1.77, 95% confidence interval 1.13–2.77; p = 0.013) were both associated with a higher BCR rate. After accounting for age at surgery, PSA value, pathologic tumor stage, Gleason Grade Group, lymph node invasion, positive surgical margin, surgical approach, and adjuvant radiation therapy, lymphovascular (p = 0.740) or perineural invasion (p = 0.341) were not significantly associated with a higher BCR since the Gleason Grade Group and pathologic tumor stage highly correlated with lymphovascular as well as perineural invasion. Conclusions: In univariable models, lymphovascular or perineural invasion is associated with BCR. After adjustment for standard pathologic tumor characteristics, lymphovascular or perineural invasion is not an independent predictor for BCR. [ABSTRACT FROM AUTHOR]

Simple Summary: Inter-alpha-trypsin inhibitor-5 (ITIH5), a class II tumor suppressor gene, encodes a protein that is lost during tumor progression in many solid cancers. Unexpectedly, however, ITIH5 is significantly upregulated in cholangiocarcinoma (CCA), making it a potential liquid biopsy marker for early CCA detection, as recently shown. Indeed, CCA is the first tumor entity described in which ITIH5 is upregulated rather than downregulated in the tumor compared to normal tissue. In our study, we demonstrate that CCAs with abundant ITIH5 protein expression have favorable survival, a low UICC stage and the absence of perineural invasion. The re-expression of ITIH5 impairs the colony growth of cholangiocarcinoma cell lines. Although ITIH5 is upregulated in the tumor, it retains its tumor-suppressive function in CCA, similar to other tumor entities such as breast cancer and pancreatic cancer, where it is downregulated. Thus, ITIH5 may have both diagnostic and prognostic biomarker potential in CCA. The mechanisms of ITIH5 upregulation, particularly in intrahepatic CCAs, during oncogenic transformation remain unclear, but their elucidation could improve future CCA therapies. Background: Cholangiocarcinoma (CCA) are aggressive bile duct cancers with a poor prognosis for which there are only few established prognostic biomarkers and molecular targets available. The gene ITIH5, a known class II tumor suppressor gene (C2TSG), encodes a secreted protein of the extracellular matrix mediating tumor suppressive properties. Recently, it was surprisingly found that the ITIH5 protein is specifically upregulated in CCAs and that ITIH5 detection in blood could be an excellent liquid biopsy marker for indicating the presence of a CCA tumor in a patient. We therefore investigated whether patients with CCAs with abundant versus low ITIH5 protein expression also differ in their prognosis. Methods: To clarify this question, a large CCA cohort (n = 175) was examined using immunohistochemistry on a tissue microarray (TMA). Results: Abundant ITIH5 expression in CCA was associated with favorable survival, a low UICC stage and the absence of perineural invasion (PNI). Conclusions: ITIH5 has biomarker potential not only for the early detection of CCA from blood-based liquid biopsies but also as a prognostic tissue biomarker for risk stratification. Our results suggest that the upregulation of ITIH5 is particularly abundant in intrahepatic CCAs (iCCA). The mechanisms mediating the strong initial upregulation of ITIH5 during the oncogenic transformation of bile duct cells are still unclear. [ABSTRACT FROM AUTHOR]

Simple Summary: Our study examined PD-L1 expression in advanced Thyroid Cancer (TC) and its relationship with histological subtypes, molecular mutations, and progression-free survival (PFS). Analyzing data from 176 patients with advanced TC, our study found significant variability in PD-L1 expression with Oncocytic Thyroid Cancer (OTC) and Anaplastic Thyroid Cancer (ATC) exhibiting the highest frequencies of PD-L1 expression, while Medullary TC (MTC) and Papillary TC Follicular Variant (PTCFV) did not show any PD-L1 expression. Notably, PD-L1 positivity correlated with shorter progression-free survival (PFS) in ATC and was associated with TP53 mutation. These findings suggest that PD-L1 expression, combined with genetic profiling could inform personalized immunotherapy strategies for aggressive forms of TC, emphasizing the need for further research to validate these biomarkers and enhance treatment efficacy. Background: Thyroid cancer (TC) remains a significant clinical challenge worldwide, with a subset of patients facing aggressive disease progression and therapeutic resistance. Immune checkpoint inhibitors targeting programmed death-ligand 1 (PD-L1) have emerged as promising therapeutic approaches for various malignancies, yet their efficacy in TC remains uncertain. The objective of this study was to investigate PD-L1 expression in aggressive TC and its association with histological subtypes, molecular mutation, and progression-free survival. Methods: This is a retrospective study of patients with advanced TC seen in two tertiary health care centers. Included in this study were patients with advanced TC with recurrence or progression on therapy for whom tumor molecular profiling and PD-L1 status were available. Kaplan–Meier estimators were utilized to analyze the progression-free survival (PFS) between patients with PD-L1 positive and negative status in Anaplastic TC (ATC) subgroup. Results: A total of 176 patients with advanced thyroid cancer were included (48.9% female). Of the patients, 13 had ATC, 11 Medullary TC (MTC), 81 Papillary TC Classic Variant (PTCCV), 20 Follicular TC (FTC), 8 Oncocytic TC (OTC), 10 Poorly Differentiated TC (PDTC), and 30 had the Papillary TC Follicular Variant (PTCFV). BRAF mutation was present in 41%, TERT in 30%, RAS in 19%, TP53 in 10%, and RET in 8.6% of patients. PD-L1 positivity was significantly different across different TC types and histological subtypes (p < 0.01): Patients with OTC had the highest frequency of PD-L1 positivity (71%), followed by ATC (69%), PTCCV (28.5%), and FTC (11%). Patients with MTC and PTCFV did not exhibit any PD-L1 positivity. TP53 mutation was positively associated with PD-L1 expression (21.6% vs. 7.5%, p = 0.03), and RAS mutation was negatively associated with PD-L1 expression (8.1% vs. 24.2% p = 0.04). Among patients with ATC, positive PD-L1 expression was associated with lower PFS (p = 0.002). Conclusions: PD-L1 expression varies across different TC types and histological subtypes and may be modulated by the mutational landscape. PD-L1 expression in ATC is associated with shorter PFS. Follow up studies are warranted to elucidate the molecular mechanism driving the observed differences in immune pathways, potentially paving the way for the development of more effective and personalized immune therapies for patients with aggressive TC. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GBM) is the deadliest form of primary brain cancer, and the survival of patients is only about 15 months after diagnosis, even with aggressive treatment. Many cellular factors that are used by GBM cells to divide abnormally and invade brain tissue to result in patient death are unknown. Here, we investigated the potential role of the cellular enzyme QSOX1, which creates specific bonds within proteins, in GBM cell proliferation, migration in a dish, and invasion into brain tissue in our chick embryo brain tumor model system. By experimentally reducing QSOX1 protein production in GBM cells, we found that this reduction resulted in less proliferation, slower migration, and less invasion into brain tissue. These results show the importance of the QSOX1 enzyme in GBM cells in order for them to exhibit their abnormal aggressive behavior that drives this incurable cancer. Background: Quiescin Sulfhydryl Oxidase 1 (QSOX1) is an enzyme that catalyzes the oxidation of free thiols to generate disulfide bonds in a variety of proteins, including the cell surface and extracellular matrix. QSOX1 has been reported to be upregulated in a number of cancers, and the overexpression of QSOX1 has been correlated with aggressive cancers and poor patient prognosis. Glioblastoma (GBM) brain cancer has been practically impossible to treat effectively, with cells that rapidly invade normal brain tissue and escape surgery and other treatment. Thus, there is a crucial need to understand the multiple mechanisms that facilitate GBM cell invasion and to determine if QSOX1 is involved. Methods and Results: Here, we investigated the function of QSOX1 in human glioblastoma cells using two cell lines derived from T98G cells, whose proliferation, motility, and invasiveness has been shown by us to be dependent on disulfide bond-containing adhesion and receptor proteins, such as L1CAM and the FGFR. We lentivirally introduced shRNA to attenuate the QSOX1 protein expression in one cell line, and a Western blot analysis confirmed the decreased QSOX1 expression. A DNA content/cell cycle analysis using flow cytometry revealed 27% fewer knockdown cells in the S-phase of the cell cycle, indicating a reduced proliferation. A cell motility analysis utilizing our highly quantitative SuperScratch time-lapse microscopy assay revealed that knockdown cells migrated more slowly, with a 45% decrease in migration velocity. Motility was partly rescued by the co-culture of knockdown cells with control cells, indicating a paracrine effect. Surprisingly, knockdown cells exhibited increased motility when assayed using a Transwell migration assay. Our novel chick embryo orthotopic xenograft model was used to assess the in vivo invasiveness of knockdown vs. control cells, and tumors developed from both cell types. However, fewer invasive knockdown cells were observed after about a week. Conclusions: Our results indicate that an experimental reduction in QSOX1 expression in GBM cells leads to decreased cell proliferation, altered in vitro migration, and decreased in vivo invasion. [ABSTRACT FROM AUTHOR]

Simple Summary: Serous ovarian carcinoma (SOC) is the most common type of ovarian cancer, but predicting its behaviour and patient outcomes has been challenging. This research is the first to comprehensively assess histopathological features such as lymphovascular space invasion, tumour budding, the tumour–stroma ratio, the stromal type, microvessel density, tumour-infiltrating lymphocytes, and tertiary lymphoid structures in the same cohort of both primary and metastatic SOC cases. By simultaneously evaluating these features, our study provides new insights into the tumour microenvironment and its role in disease progression. This comprehensive approach highlights the prognostic value of these features and offers a straightforward method for assessing tumour aggressiveness in routine clinical practice. These findings could lead to better risk stratification and personalised treatment strategies for SOC patients, particularly in settings where access to advanced molecular testing is limited. Background/Objectives: Serous ovarian carcinoma (SOC) is the most common subtype of epithelial ovarian cancer, with high-grade (HGSOC) and low-grade (LGSOC) subtypes presenting distinct clinical behaviours. This study aimed to evaluate histopathologic features in SOC, correlating these with prognostic outcomes, and explore the potential clinical implications. Methods: We analysed 51 SOC cases for lymphovascular space invasion (LVSI), tumour border configuration (TBC), microvessel density (MVD), tumour budding (TB), the tumour–stroma ratio (TSR), the stromal type, tumour-infiltrating lymphocytes (TILs), and tertiary lymphoid structures (TLSs). A validation cohort of 54 SOC cases from The Cancer Genome Atlas (TCGA) was used for comparison. Results: In the discovery set, significant predictors of aggressive behaviour included LVSI, high MVD, high TB, and low TILs. These findings were validated in the validation set where the absence of TLSs, lower peritumoural TILs, immature stromal type, and low TSR were associated with worse survival outcomes. The stromal type was identified as an independent prognostic predictor in SOC across both datasets. Inter-observer variability analysis demonstrated substantial to almost perfect agreement for these features, ensuring the reproducibility of the findings. Conclusions: The histopathological evaluation of immune and stromal features, such as TILs, TLSs, TB, TSR, and stromal type, provides critical prognostic information for SOC. Incorporating these markers into routine pathological assessments could enhance risk stratification and guide treatment, offering practical utility, particularly in low-resource settings when molecular testing is not feasible. [ABSTRACT FROM AUTHOR]

Simple Summary: Receptor for hyaluronan-mediated motility (RHAMM) is a hyaluronan receptor involved in various functions, including in breast cancer. Chemoresistance in breast cancer is a major clinical issue, and the role of RHAMM and hyaluronan in this process is not well understood. Our study found that RHAMM and hyaluronan are linked to increased aggressiveness and recurrence in breast cancer after chemotherapy. In lab experiments, epirubicin-resistant breast cancer cells had higher RHAMM levels than non-resistant cells. Knockdown of RHAMM decreased the growth and migration of both cell types. It also lowered CD44 levels, a marker of cancer stem cells, and changed N-cadherin and E-cadherin, resulting in more typical epithelial cell behavior. These findings suggest that abnormal RHAMM activity contributes to chemoresistance by enhancing cancer stem cell properties and altering cell characteristics, promoting cancer growth and spread. This research could lead to new ways to combat breast cancer chemoresistance. Background/Objectives: Receptor for hyaluronan-mediated motility (RHAMM) is a hyaluronan (HA) receptor, which exerts diverse biological functions in not only physiological but also pathological conditions in human malignancies, including breast cancer. Although chemoresistance is a significant clinical challenge in breast cancer, a possible contribution of RHAMM and hyaluronan to breast cancer chemoresistance has remained unclear. Methods: We immunolocalized RHAMM and HA in breast carcinoma tissues. Also, we utilized epirubicin-sensitive (parental) and rpirubicin-resistant (EPIR) breast cancer cell lines to explore the role of RHAMMM in breast cancer progression. Results: We found out that RHAMM and HA were cooperatively correlated with breast cancer aggressiveness and recurrence after chemotherapy. In vitro studies demonstrated that RHAMM was overexpressed in EPIR cells compared to parental cells. In addition, the knockdown of RHAMM significantly suppressed proliferation and migration of both parental and EPIR cells. On the other hand, the expression level of cancer stem cell marker CD44, which was overexpressed in M-EPIR (epirubicin-resistant MCF-7 subline) compared to MCF-7, was significantly suppressed by knockdown of RHAMM. In addition, the knockdown of RHAMM significantly altered the expression of N-cadherin and E-cadherin, leading to an epithelial phenotype. Conclusions: Aberrant RHAMM signaling were considered to cause chemoresistance related to cancer stemness and epithelial to mesenchymal transition, and increased cell proliferation and migration of both chemo-sensitive and chemo-resistant breast cancer cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Rectal cancer (RC) is the third most common gastrointestinal malignancy, with a rising incidence, particularly among the population under 50 years old. Extramural venous invasion (EMVI) is defined as the presence of malignant cells in veins beyond the muscularis propria near the primary colorectal tumor. The aim of our retrospective study was to assess the prognostic value of separate pathological EMVI reporting in operative RC samples and to determine its relationship with standard pathohistological and surgical parameters among a selected cohort of RC patients from our institution. Finally, EMVI is proved not only to be a feature of aggressive tumor behavior, but also as a separate and independent parameter in patients with rectal cancer. The results we obtained strongly suggest the importance of separately reporting extramural vascular invasion (EMVI) from lymphovascular invasion (LVI) in daily practice, as well as that EMVI could be a good addition to TNM staging. Background/Objectives: Vascular invasion, especially extramural vascular invasion (EMVI), has emerged as a prognostic parameter for rectal cancer (RC) in recent years. Prediction of recurrence and metastasis development poses a significant challenge for oncologists, who need markers for prediction of adverse outcome. The aim of this study was to examine the prognostic significance of pathohistologically detected EMVI in untreated rectal cancer and its implications in separate reporting. Methods: We examined 100 untreated RC patients who underwent curative resection from January 2016 to June 2018 with a follow-up of 5 years. Patients were divided into equal EMVI− and EMVI+ groups based on histological re-examination of H&E-stained postoperative surgical samples. Results: The presence of EMVI within the selected cohort was significantly associated with female gender, T3/T4 and N1/N2 post-operative stages, positive lymph nodes, lymph node ratio LNR2 and LNR3 groups, abundant tumor-infiltrating lymphocytes, positive lympho-vascular invasion (LVI), perineural (PNI), and circumferential resection margin (CRM) (p < 0.05 in all tests). Within EMVI+ patients, local recurrences and/or metastases and death outcomes were more frequent events (p = 0.029 and p = 0.035, respectively), while survival analyses revealed that EMVI+ patients had significantly shorter overall survival (OS, p = 0.040) and disease-free survival (DFS, p = 0.028). Concerning LVI, differences in OS between LVI+ and LVI− patients were not statistically significant (p = 0.068), while LVI+ patients had significantly shorter DFS (p = 0.024). Moreover, univariate COX regression analysis demonstrated the negative impact of EMVI on OS (HR: 2.053, 95% CI: 1.015–4.152; p = 0.045) and DFS (HR: 2.106, 95% CI: 1.066–4.870; p = 0.038), which was not the case for LVI + RC patients. Conclusions: The obtained results strongly suggest the significance of separate reporting of EMVI from lympho-vascular invasion, as it is potentially a surrogate marker for adverse prognosis and outcome. [ABSTRACT FROM AUTHOR]

Purpose: Craniopharyngioma is a tumor derived from the squamous epithelium of Rathke's pouch. Despite successful excision, recurrence is common, typically occurring at the original tumor site. More rarely, recurrences can manifest at distant locations. This article reports on three distinct types of ectopic recurrence and reviews the existing literature. Methods: We reviewed clinical records and neuroimaging data of craniopharyngioma patients at our institution, identifying three cases of ectopic recurrence. Additionally, we conducted a literature review of similar cases published between 1975 and 2023, focusing on historical background, pathophysiology, clinical and radiological features, and treatment options. Results: We identified nineteen articles detailing ectopic recurrence of craniopharyngiomas in pediatric patients. The right frontal lobe was the most frequently reported site of recurrence. The shortest interval to recurrence was 11 months, while the longest was 14 years. Most cases were managed with surgical resection, yielding positive outcomes. In our cases, the recurrence sites were temporal intraparenchymal, intraosseous orbital, and occipital intraventricular. All were successfully treated with surgery, with no subsequent recurrences. Conclusion: Although craniopharyngiomas are histologically benign, they can recur locally and, more rarely, at distant sites. Surgical intervention is generally well-tolerated. Further research into tumor cell dissemination mechanisms is essential to develop strategies for preventing ectopic recurrence. [ABSTRACT FROM AUTHOR]

To examine whether the endometrial cancer (EC) survival disadvantage among Black populations is US-specific, a comparison between African-descent populations from different countries with a high development index is warranted. We analyzed 28 213 EC cases from cancer registries in Florida (2005-2018) and the French Caribbean islands of Martinique (2005-2018) and Guadeloupe (2008-2018) combined. Kaplan-Meier and all-cause Cox proportional hazards models were used to compare survival. Models were stratified by EC histology type and the main predictor examined was race/ethnicity (non-Hispanic White [NHW] and no-Hispanic Black [NHB] women in the United States versus Black women residing in the Caribbean). For endometrioid and nonendometrioid EC, after adjusting for age, histology, stage at diagnosis, receipt of surgery, period of diagnosis, and poverty level, US NHB women and Caribbean Black women had a higher risk of death relative to US NHW women. There was no difference between US NHB and Caribbean Black women (hazard ratio [HR] = 1.07; 95% CI, 0.88-1.30) with endometrioid EC. However, Caribbean Black women with nonendometrioid carcinomas had a 40% higher risk of death (HR = 1.40; 95% CI, 1.13-1.74) than US NHB women. The low EC survival among US Black women extends to foreign populations of African descent. For the aggressive nonendometrioid ECs, survival among Caribbean Black women outside of the United States is considerably worse. This article is part of a Special Collection on Gynecological Cancers. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Prostatic carcinosarcoma comprises <1% of all prostate neoplasms. The literature on this disease is limited to a few case studies, primarily due to the rarity of this malignancy. We aimed to investigate the demographic, clinical, and histologic factors, prognosis, and survival of prostatic carcinosarcoma. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients with prostatic carcinosarcoma from 2000-2018. Demographic and clinical data, including age, race, sex, tumor grade, stage, tumor size, lymph node status, metastasis, and treatment modalities, were recorded. RESULTS: Patients with prostatic carcinosarcoma had a median age of 72 years at diagnosis, most cases among White individuals (93%). When reported, the histologic grade comprised moderately differentiated (3.3%), poorly differentiated (56.7%), and undifferentiated/anaplastic (40%) subtypes. In patients with reported data, tumor size varied between 2-5 cm (15.8%) and >5 cm (84.2%). Distant metastasis most commonly occurred in the liver (12.5%) and lung (12.5%), followed by the bone (8.3%). The most common treatment performed was surgery with radiation (32.4%). The five-year overall survival was 11.9%. CONCLUSIONS: Prostatic carcinosarcoma affects men in the seventh decade of life. Regional and distant tumor stage is considered an indicator of survival. Prostate carcinosarcoma is rare; due to its aggressive nature, a deeper understanding, and an improved personalized therapeutic approach are necessary for improving patient outcomes in this challenging arena of oncology. [ABSTRACT FROM AUTHOR]

The PIM kinase family, consisting of PIM1, PIM2, and PIM3, is a group of serine/threonine protein kinases crucial for cellular growth, immunoregulation, and oncogenesis. PIM1 kinase is often overexpressed in solid and hematopoietic malignancies, promoting cell survival, proliferation, migration, and senescence by activating key genes. In vitro and in vivo studies have established the oncogenic potential of PIM1 kinases. These kinases have been implicated in tumor progression, metastasis, and resistance to chemotherapy, underscoring their potential as a therapeutic target for cancer therapy. This review delves into the intricate molecular mechanisms through which PIM1 interacts with specific substrates in different tumor tissues, leading to diverse outcomes in various human cancers. Over the past decade, the inhibition of PIM1 in cancers has garnered significant attention as a potential standalone treatment. Various in vitro, in vivo, and early clinical trial data have provided support for this approach to varying extents. Novel compounds that inhibit PIM1 kinase have shown effectiveness and a favorable toxicity profile in preclinical studies. Several of these substances are now being studied in clinical trials due to their promising outcomes. This article provides a thorough examination of the PIM1 kinase pathways and the recent advancements in producing PIM1 kinase inhibitors for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) play a critical role in resistance to immunotherapy. In this study, we identified epidermal growth factor-like 6 (Egfl6) as a regulator of myeloid cell functions. Our analyses indicated that Egfl6, via binding with β3 integrins and activation of p38 and SYK signaling, acts as a chemotactic factor for myeloid cell migration and promotes their differentiation toward an immunosuppressive state. In syngeneic mouse models of ovarian cancer (OvCa), tumor expression of Egfl6 increased the intratumoral accumulation of polymorphonuclear (PMN) MDSCs and TAMs and their expression of immunosuppressive factors, including CXCL2, IL-10, and PD-L1. Consistent with this, in an immune 'hot' tumor model, Egfl6 expression eliminated response to anti-PD-L1 therapy, while Egfl6 neutralizing antibody decreased the accumulation of tumor-infiltrating CD206+ TAMs and PMN-MDSCs and restored the efficacy of anti-PD-L1 therapy. Supporting a role in human tumors, in human OvCa tissue samples, areas of high EGFL6 expression colocalized with myeloid cell infiltration. scRNA-Seq analyses revealed a correlation between EGFL6 and immune cell expression of immunosuppressive factors. Our data provide mechanistic insights into the oncoimmunologic functions of EGFL6 in mediating tumor immune suppression and identified EGFL6 as a potential therapeutic target to enhance immunotherapy in patients with OvCa. [ABSTRACT FROM AUTHOR]

Background: A multicenter database was utilized to examine the current treatment landscape and clinical outcomes among patients with metastatic hormone‐sensitive prostate cancer (mHSPC) following approval of upfront androgen receptor signaling inhibitors (ARSIs). Methods: We retrospectively analyzed patients with mHSPC who commenced treatment between February 2018 and June 2023. The Kaplan–Meier method was used to assess oncological outcomes, including time to castration‐resistant prostate cancer (CRPC), progression‐free survival 2 (PFS2, duration from initial treatment to tumor progression during second‐line treatment), cancer‐specific survival (CSS), and overall survival (OS). Cox regression analyses were performed to determine the impact of treatment choices on oncological outcomes. In addition, the incidence rate of adverse events was assessed. Results: In total, 829 patients were analyzed; 42.5% received ARSIs with androgen deprivation therapy (ADT), 44.0% received combined androgen blockade (CAB), and 13.5% received ADT alone. Kaplan–Meier curves and multivariate Cox regression analyses indicated higher rates of CRPC and shorter PFS2 in patients treated with CAB versus ARSIs with ADT. By contrast, CSS and OS were not significantly different between the ARSI with ADT group and the CAB group. Grades 3–4 adverse events occurred in 1.9% of patients receiving CAB and 6.0% of those receiving ARSIs with ADT. Conclusions: Initial treatment with ARSIs in combination with ADT resulted in a longer time to CRPC and longer PFS2 compared to CAB. Although CAB and ADT alone were associated with fewer adverse events, ARSIs with ADT should be considered a first‐line treatment option given its superior oncological outcomes. [ABSTRACT FROM AUTHOR]

This study develops a prognostic model to predict metastasis and prognosis in colorectal cancer liver metastases by identifying distinct macrophage subsets. Using scRNA-seq data from primary colorectal cancer and liver metastases, we dissected the cellular landscape to find unique macrophage subpopulations, particularly EEF1G + macrophages, which were prevalent in liver metastases. The study leveraged data from GSE231559, TCGA, and GEO databases to construct an 8-gene risk model named EMGS, based on the EEF1G + macrophage gene signature. Patients were divided into high-risk and low-risk groups using the median EMGS score, with the high-risk group showing significantly worse survival. This group also demonstrated upregulated pathways associated with tumor progression, such as epithelial-mesenchymal transition and angiogenesis, and downregulated metabolic pathways. Moreover, the high-risk group presented an immunosuppressive microenvironment, with a higher TIDE score indicating lower effectiveness of immunotherapy. The study identifies potential drugs targeting the high-risk group, suggesting therapeutic avenues to improve survival. Conclusively, the EMGS score identifies colorectal cancer patients at high risk of liver metastases, highlighting the role of specific macrophage subsets in tumor progression and providing a basis for personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Gastric foveolar type neoplasia is a rare histological variant of gastric tumors. It is very difficult to differentiate between benign and malignant intraepithelial foveolar neoplasia (IFN). Although limited molecular alterations have been identified in IFNs, somatic copy number alterations (SCNAs), which are linked to tumor progression, have not been systematically evaluated in IFN. Methods: The aim of the present study was to comprehensively examine SCNAs using a SNP array in 37 cases of IFN, compared with intestinal type dysplasia, including 39 low grade (LGD) and 32 high grade dysplasia (HGD) cases. In addition, gene mutations were evaluated using a gene panel. Finally, we attempted to determine molecular profiles using a hierarchical clustering analysis. Results: Two patterns could be categorized according to the SCNAs in 108 tumors examined: high (subgroup 1) and low (subgroup 2) frequencies of SCNAs. Although IFN and LGD were associated with subgroup 2, HGD was found in both subgroups. The median numbers of total SCNAs and copy number gains were higher in IFN or HGD than in LGD. In addition, the IFN genotype was characterized by altered genes located at 4p13–4q35.2, including RAP1GDS1 and LEF1, which may be associated with IFN development. Finally, no significant mutations were found in IFNs using a gene panel. Conclusions: The current molecular profiles of IFN may help elucidate the mechanisms of IFN development. [ABSTRACT FROM AUTHOR]