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Simple Summary: This study introduces a CT-based 3D reconstruction algorithm for measuring resection margins post sublobar resection in lung cancer patients. It aims to enhance accuracy and reproducibility, addressing the limitations of gross margin measurement. The findings show feasibility with a target registration error of <2.5 mm. This approach could revolutionize lung cancer treatment, facilitating prompt identification of patients with inadequate resection margins for timely post-operative adjuvant therapies. Sublobar resection has emerged as a standard treatment option for early-stage peripheral non-small cell lung cancer. Achieving an adequate resection margin is crucial to prevent local tumor recurrence. However, gross measurement of the resection margin may lack accuracy due to the elasticity of lung tissue and interobserver variability. Therefore, this study aimed to develop an objective measurement method, the CT-based 3D reconstruction algorithm, to quantify the resection margin following sublobar resection in lung cancer patients through pre- and post-operative CT image comparison. An automated subvascular matching technique was first developed to ensure accuracy and reproducibility in the matching process. Following the extraction of matched feature points, another key technique involves calculating the displacement field within the image. This is particularly important for mapping discontinuous deformation fields around the surgical resection area. A transformation based on thin-plate spline is used for medical image registration. Upon completing the final step of image registration, the distance at the resection margin was measured. After developing the CT-based 3D reconstruction algorithm, we included 12 cases for resection margin distance measurement, comprising 4 right middle lobectomies, 6 segmentectomies, and 2 wedge resections. The outcomes obtained with our method revealed that the target registration error for all cases was less than 2.5 mm. Our method demonstrated the feasibility of measuring the resection margin following sublobar resection in lung cancer patients through pre- and post-operative CT image comparison. Further validation with a multicenter, large cohort, and analysis of clinical outcome correlation is necessary in future studies. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple negative breast cancer is an aggressive breast cancer subtype with limited targeted therapeutic options. As a method of identifying novel therapeutic targets in this disease subtype, we utilize a microRNA that reverses the Epithelial-to-Mesenchymal Transition, which reveals Niemann-Pick C1 (NPC1) as a gene highly expressed in triple negative breast cancer. Silencing of NPC1 causes significant loss of tumor-promoting capabilities of these cell lines. We find that NPC1 promotes cell proliferation in soft agar and invasive capacity, while silencing impairs these functions and leads to mitochondrial dysfunction and suppression of pro-tumorigenic signaling. This work suggests NPC1 as a potential target and a mediator of breast cancer aggression. Triple-negative breast cancer (TNBC) often undergoes at least partial epithelial-to-mesenchymal transition (EMT) to facilitate metastasis. Identifying EMT-associated characteristics can reveal novel dependencies that may serve as therapeutic vulnerabilities in this aggressive breast cancer subtype. We found that NPC1, which encodes the lysosomal cholesterol transporter Niemann–Pick type C1 is highly expressed in TNBC as compared to estrogen receptor-positive (ER+) breast cancer, and is significantly elevated in high-grade disease. We demonstrated that NPC1 is directly targeted by microRNA-200c (miR-200c), a potent suppressor of EMT, providing a mechanism for its differential expression in breast cancer subtypes. The silencing of NPC1 in TNBC causes an accumulation of cholesterol-filled lysosomes, and drives decreased growth in soft agar and invasive capacity. Conversely, overexpression of NPC1 in an ER+ cell line increases invasion and growth in soft agar. We further identified TNBC cell lines as cholesterol auxotrophs, however, they do not solely depend on NPC1 for adequate cholesterol supply. The silencing of NPC1 in TNBC cell lines led to altered mitochondrial function and morphology, suppression of mTOR signaling, and accumulation of autophagosomes. A small molecule inhibitor of NPC1, U18666A, decreased TNBC proliferation and synergized with the chemotherapeutic drug, paclitaxel. This work suggests that NPC1 promotes aggressive characteristics in TNBC, and identifies NPC1 as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Simple Summary: This study included 227 patients, among whom 27.7% (63/227) were diagnosed with tumors spread through air spaces (STASs), which have been shown to be associated with shorter recurrence-free survival and poor prognosis. A prediction model was developed to forecast tumor STAS in early-stage lung adenocarcinoma pathology images. The radiomics prediction model demonstrated good performance, with an AUC value of 0.83. This prediction model can assist pathologists in the diagnostic processes of clinical practice. The presence of spread through air spaces (STASs) in early-stage lung adenocarcinoma is a significant prognostic factor associated with disease recurrence and poor outcomes. Although current STAS detection methods rely on pathological examinations, the advent of artificial intelligence (AI) offers opportunities for automated histopathological image analysis. This study developed a deep learning (DL) model for STAS prediction and investigated the correlation between the prediction results and patient outcomes. To develop the DL-based STAS prediction model, 1053 digital pathology whole-slide images (WSIs) from the competition dataset were enrolled in the training set, and 227 WSIs from the National Taiwan University Hospital were enrolled for external validation. A YOLOv5-based framework comprising preprocessing, candidate detection, false-positive reduction, and patient-based prediction was proposed for STAS prediction. The model achieved an area under the curve (AUC) of 0.83 in predicting STAS presence, with 72% accuracy, 81% sensitivity, and 63% specificity. Additionally, the DL model demonstrated a prognostic value in disease-free survival compared to that of pathological evaluation. These findings suggest that DL-based STAS prediction could serve as an adjunctive screening tool and facilitate clinical decision-making in patients with early-stage lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is a highly aggressive and lethal form of liver cancer, and most patients with HCC die due to HCC-related causes. Although most patients die of HCC-related causes, non–HCC-related death represents a competing event among patients who engage in alcohol use and receive curative treatment and among patients 75 years and older in the hepatitis B virus and all-negative groups who receive curative treatments. All negative was defined as negative for hepatitis C virus, hepatitis B virus, and alcohol-related causes. The results of the current study underscore the importance of assessing and managing underlying comorbidities, especially among certain subgroups of patients with HCC. This study was conducted to determine whether the causes of death among patients with hepatocellular carcinoma (HCC) differ according to chronic liver disease (CLD) etiology. Between 2011 and 2020, 3977 patients who were newly diagnosed with HCC at our institution were enrolled in this study. We determined whether the cause of death was HCC-related and non-HCC-related. For patients with multiple CLD etiologies, etiology was classified using the following hierarchy: hepatitis C virus (HCV) > hepatitis B virus (HBV) > alcohol-related causes > all negative. All negative was defined as negative for HCV, HBV, and alcohol-related causes. Among 3977 patients, 1415 patients were classified as HCV-related, 1691 patients were HBV-related, 145 patients were alcohol-related, and 725 patients were all negative. HCC-related mortality was the leading cause of death, irrespective of etiology. Among patients who underwent curative treatment, HCC-related mortality was the leading cause of death for patients in the HCV, HBV, and all-negative groups, but not for patients in the alcohol-related group. Among patients 75 years and older who underwent curative treatment, HCC-related mortality was the leading cause of death in the HCV but not HBV or all-negative groups. In conclusion, although most patients with HCC die due to HCC-related causes, non-HCC-related mortality represents a competing event in certain patient subgroups. The current study results underscore the importance of assessing and managing underlying comorbidities, particularly among patients with HCC at risk of non-HCC-related mortality. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we demonstrated that overall 51.2% of patients with hepatocellular carcinoma (HCC) had elevated alpha-fetoprotein (AFP) levels. The proportion of patients with elevated AFP levels was stationary in the period from 2011 to 2020. The proportion of patients with Barcelona Clinic Liver Cancer classification (BCLC) stages 0–A HCC decreased from 2011 to 2020, whereas the proportion of patients with non-HBV- and non-HCV (NBNC)-HCC increased in the same period. Furthermore, the proportion of patients with early-stage HCC (i.e., BCLC stages 0–A) was lower for NBNC-HCC than for HBV- or HCV-related HCC. Advanced tumor stage, severe underlying liver disease, viral etiology, and female gender are associated with elevated AFP levels in HCC patients. A recent study from the US showed a decreasing trend in the elevated serum alpha-fetoprotein (AFP) level (i.e., ≥20 ng/mL) in hepatocellular carcinoma (HCC) patients at the time of diagnosis. Furthermore, advanced tumor stage and severe underlying liver disease were associated with elevated AFP levels. We aimed to evaluate this issue in an area endemic for hepatitis B virus (HBV). Between 2011 and 2020, 4031 patients were newly diagnosed with HCC at our institution. After excluding 54 patients with unknown AFP data, the remaining 3977 patients were enrolled in this study. Elevated AFP level was defined as ≥20 ng/mL. Overall, 51.2% of HCC patients had elevated AFP levels; this proportion remained stationary between 2011 and 2020 (51.8% vs. 51.1%). Multivariate analysis showed that female gender (odds ratio (OR) = 1.462; p < 0.001), tumor size per 10 mm increase (OR = 1.155; p < 0.001), multiple tumors (OR = 1.406; p < 0.001), Barcelona Clinic Liver Cancer stages B–D (OR = 1.247; p = 0.019), cirrhosis (OR = 1.288; p = 0.02), total bilirubin > 1.4 mg/dL (OR = 1.218; p = 0.030), and HBV- or hepatitis C virus (HCV)-positive status (OR = 1.720; p < 0.001) were associated with elevated AFP levels. In conclusion, a stationary trend in elevated serum AFP level in HCC patients has been noted in the past 10 years. Advanced tumor stage, severe underlying liver disease, viral etiology, and female gender are associated with elevated AFP levels in HCC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The tumor burden score (TBS) is calculated using the Pythagorean theorem based on the largest tumor size and tumor number (α2 + β2 = γ2, where α is the largest tumor size, β is the tumor number, and γ is the TBS). Patients who underwent liver resection (LR) for Barcelona Clinic Liver Cancer stage 0, A, or B hepatocellular carcinoma (HCC) between 2011 and 2018 were enrolled. Among 743 patients, 193 (26.0%) patients had a low TBS (<2.6), 474 (63.8%) had a moderate TBS (2.6–7.9), and 75 (10.1%) had a high TBS (>7.9). Combining radiographic TBS and alpha-fetoprotein levels could stratify overall survival among HCC patients after LR. We evaluated whether combining the radiographic tumor burden score (TBS) and alpha-fetoprotein (AFP) level could be used to stratify overall survival (OS) among hepatocellular carcinoma (HCC) patients after liver resection (LR). Patients who underwent LR for Barcelona Clinic Liver Cancer stage 0, A, or B HCC between 2011 and 2018 were enrolled. TBS scores were calculated using the following equation: TBS2 = (largest tumor size (in cm))2 + (tumor number)2. Among 743 patients, 193 (26.0%) patients had a low TBS (<2.6), 474 (63.8%) had a moderate TBS (2.6–7.9), and 75 (10.1%) had a high TBS (>7.9). Those with a TBS ≤ 7.9 and AFP < 400 ng/mL had a significantly better OS than those with a TBS > 7.9 and an AFP < 400 ng/mL (p = 0.003) or ≥ 400 ng/mL (p < 0.001). A multivariate analysis using TBS ≤ 7.9 and AFP < 400 ng/mL as the reference values showed that a TBS > 7.9 and an AFP < 400 ng/mL (hazard ratio (HR): 2.063; 95% confidence interval [CI]: 1.175–3.623; p = 0.012) or ≥ 400 ng/mL (HR: 6.570; 95% CI: 3.684–11.719; p < 0.001) were independent predictors of OS. In conclusion, combining radiographic TBSs and AFP levels could stratify OS among HCC patients undergoing LR. [ABSTRACT FROM AUTHOR]

Simple Summary: To forecast the invasiveness of the increasingly detected pure ground glass nodules, 338 cases were included in this study. Among them, 22.8% (77/338) of patients with pGGN were diagnosed with invasive adenocarcinoma. There were no nodal metastases or recurrence during a mean 78-month follow-up. A radiomic prediction model was constructed to predict the tumor's invasiveness. The radiomic prediction model achieved good performance with an AUC of 0.7676. The prediction model can be used clinically in the treatment selection process. It remains a challenge to preoperatively forecast whether lung pure ground-glass nodules (pGGNs) have invasive components. We aimed to construct a radiomic model using tumor characteristics to predict the histologic subtype associated with pGGNs. We retrospectively reviewed clinicopathologic features of pGGNs resected in 338 patients with lung adenocarcinoma between 2011–2016 at a single institution. A radiomic prediction model based on forward sequential selection and logistic regression was constructed to differentiate adenocarcinoma in situ (AIS)/minimally invasive adenocarcinoma (MIA) from invasive adenocarcinoma. The study cohort included 133 (39.4%), 128 (37.9%), and 77 (22.8%) patients with AIS, MIA, and invasive adenocarcinoma (acinar 55.8%, lepidic 33.8%, papillary 10.4%), respectively. The majority (83.7%) underwent sublobar resection. There were no nodal metastases or tumor recurrence during a mean follow-up period of 78 months. Three radiomic features—cluster shade, homogeneity, and run-length variance—were identified as predictors of histologic subtype and were selected to construct a prediction model to classify the AIS/MIA and invasive adenocarcinoma groups. The model achieved accuracy, sensitivity, specificity, and AUC of 70.6%, 75.0%, 70.0%, and 0.7676, respectively. Applying the developed radiomic feature model to predict the histologic subtypes of pGGNs observed on CT scans can help clinically in the treatment selection process. [ABSTRACT FROM AUTHOR]

Simple Summary: tRF-27 has been identified as upregulated in both naïve trastuzumab-resistant HER2-positive breast cancer cells and patient samples, positioning it as a potential biomarker. However, the underlying mechanisms of this upregulation remain unclear. This study proposes that the abnormal transcription of specific tRNA-Cys-GCA isodecoders in naïve trastuzumab-resistant cells might contribute to the accumulation of tRF-27. Additionally, the reduction in H3K27me3 modifications at these tRNA genes, attributed to imbalances in histone modification enzymes, appears to influence tRNA transcription alterations. Building upon these findings, our research demonstrates that the application of a demethylase inhibitor may offer a potential strategy to overcome trastuzumab resistance. tRNA-derived fragments (tRFs) play crucial roles in cancer progression. Among them, tRF-27 has been identified as a key factor in promoting naïve trastuzumab resistance in HER2-positive breast cancer. However, the origin of tRF-27 remains uncertain. In this study, we propose that the upregulated expression of specific cysteine tRNAs may lead to the increased accumulation of tRF-27 in trastuzumab-resistant JIMT1 cells. Mechanistically, the reduced inhibitory H3K27me3 modification at the promoter regions of tRF-27-related tRNA genes in JIMT1 cells, potentially resulting from decreased EZH2 and increased KDM6A activity, may be a critical factor stimulating the transcriptional activity of these tRNA genes. Our research offers fresh insights into the mechanisms underlying elevated tRF-27 levels in trastuzumab-resistant breast cancer cells and suggests potential strategies to mitigate trastuzumab resistance in clinical treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: High-Z gold nanoparticles show potential as radiosensitizers in the radiotherapy of cancer. In this paper, we introduce the benefits and procedures for the application of gold nanoparticles in targeted cancer radiotherapy. Based on microscopic images of the distribution of antibody-conjugated nanoparticles, we established pharmacokinetic models simulating the biodistribution of nanoparticle conjugates in the tumor and tumor environment in preclinical models. This information has been implemented in radiation transport Monte Carlo simulation codes for further investigating physical and chemical enhancement and radiobiological effects, such as DNA strand breaks and cell survival. Future perspectives and challenges of translating this promising gold nanoparticle-aided radiotherapy into clinical practice are also discussed. High-Z gold nanoparticles (AuNPs) conjugated to a targeting antibody can help to improve tumor control in radiotherapy while simultaneously minimizing radiotoxicity to adjacent healthy tissue. This paper summarizes the main findings of a joint research program which applied AuNP-conjugates in preclinical modeling of radiotherapy at the Klinikum rechts der Isar, Technical University of Munich and Helmholtz Zentrum München. A pharmacokinetic model of superparamagnetic iron oxide nanoparticles was developed in preparation for a model simulating the uptake and distribution of AuNPs in mice. Multi-scale Monte Carlo simulations were performed on a single AuNP and multiple AuNPs in tumor cells at cellular and molecular levels to determine enhancements in the radiation dose and generation of chemical radicals in close proximity to AuNPs. A biologically based mathematical model was developed to predict the biological response of AuNPs in radiation enhancement. Although simulations of a single AuNP demonstrated a clear dose enhancement, simulations relating to the generation of chemical radicals and the induction of DNA strand breaks induced by multiple AuNPs showed only a minor dose enhancement. The differences in the simulated enhancements at molecular and cellular levels indicate that further investigations are necessary to better understand the impact of the physical, chemical, and biological parameters in preclinical experimental settings prior to a translation of these AuNPs models into targeted cancer radiotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The abundance of microbial species residing within tumors is correlated to cancer progression across many different cancers, including bladder cancer. However, links between the intratumor microbiome of muscle invasive bladder cancer (MIBC) and specific mechanisms of cancer progression have not been well studied. In this paper, we aim to uncover the relationship between microbial abundance in the MIBC intratumor microbiome and epithelial–mesenchymal transition (EMT), one key feature of cancer progression. By comparing the gene expression of EMT-associated genes to the abundance of intratumor microbes in MIBC patients, we found significant correlations between the abundance of microbes and either the upregulation or downregulation of EMT-associated genes. Our findings call for an investigation of possible mechanisms through which the microbiome may regulate EMT in MIBC patients. With further investigation, our findings can be used to provide a new, microbial approach in the diagnosis and therapy of MIBC. The intra-tumor microbiome has recently been linked to epithelial–mesenchymal transition (EMT) in a number of cancers. However, the relationship between EMT and microbes in bladder cancer has not been explored. In this study, we profiled the abundance of individual microbe species in the tumor samples of over 400 muscle invasive bladder carcinoma (MIBC) patients. We then correlated microbe abundance to the expression of EMT-associated genes and genes in the extracellular matrix (ECM), which are key players in EMT. We discovered that a variety of microbes, including E. coli, butyrate-producing bacterium SM4/1, and a species of Oscillatoria, were associated with expression of classical EMT-associated genes, including E-cadherin, vimentin, SNAI2, SNAI3, and TWIST1. We also found significant correlations between microbial abundance and the expression of genes in the ECM, specifically collagens and elastin. Lastly, we found that a large number of microbes exhibiting significant correlations to EMT are also associated with clinical prognosis and outcomes. We further determined that the microbes we profiled were likely not environmental contaminants. In conclusion, we discovered that the intra-tumoral microbiome could potentially play a significant role in the regulation of EMT in MIBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Current means of bladder cancer diagnosis are invasive or lack sensitivity. Dysbiosis of the urinary microbiome has been implicated in the development of bladder cancer, though its potential as a diagnostic tool is unknown. This study attempts to characterize bladder cancer-specific dysbiosis of the urinary microbiome to explore its diagnostic potential. Numerous species were observed to be differentially abundant between the urine samples of patients with bladder cancer and healthy individuals. Specific immune modulations were observed with respect to these species, as was the enrichment of select pathways known to be implicated in the progression of bladder cancer. The study suggests that the urinary microbiome may reflect dysregulations of the tumor microenvironment. Further investigation may reveal the potential of the identified species as urinary biomarkers of this disease. In this way, the urinary microbiome may allow for the noninvasive and earlier detection of bladder cancer, regardless of stage or subtype. There are a total of 82,290 new cases and 16,710 deaths estimated for bladder cancer in the United States in 2023. Currently, urine cytology tests are widely used for bladder cancer diagnosis, though they suffer from variable sensitivity, ranging from 45 to 97%. More recently, the microbiome has become increasingly recognized for its role in human diseases, including cancers. This study attempts to characterize urinary microbiome bladder cancer-specific dysbiosis to explore its diagnostic potential. RNA-sequencing data of urine samples from patients with bladder cancer (n = 18) and matched controls (n = 12) were mapped to bacterial sequences to yield species-level abundance approximations. Urine samples were analyzed at both the population and species level to reveal dysbiosis associated with bladder cancer. A panel of 35 differentially abundant species was discovered, which may be useful as urinary biomarkers for this disease. We further assessed whether these species were of similar significance in a validation dataset (n = 81), revealing that the genera Escherichia, Acinetobacter, and Enterobacter were consistently differentially abundant. We discovered distinct patterns of microbial-associated immune modulation in these samples. Several immune pathways were found to be significantly enriched with respect to the abundance of these species, including antigen processing and presentation, cytosolic DNA sensing, and leukocyte transendothelial migration. Differential cytokine activity was similarly observed, suggesting the urinary microbiome's correlation to immune modulation. The adherens junction and WNT signaling pathways, both implicated in the development and progression of bladder cancer, were also enriched with these species. Our findings indicate that the urinary microbiome may reflect both microbial and immune dysregulations of the tumor microenvironment in bladder cancer. Given the potential biomarker species identified, the urinary microbiome may provide a non-invasive, more sensitive, and more specific diagnostic tool, allowing for the earlier diagnosis of patients with bladder cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Palbociclib is one of the preferred treatments for hormone-receptor-positive, HER2-negative metastatic breast cancer in women; its effectiveness and safety in the Chinese real-world population require further investigation. Our study aimed to identify the clinical outcomes of patients who received palbociclib in combination with endocrine therapy (ET) in China. The effectiveness of palbociclib plus ET in treating metastatic breast cancer was confirmed in 397 Chinese patients across eight clinical sites. The regimens were well tolerated by both the general and elderly groups. However, some factors were identified as potential hindrances to the therapy's benefits, including higher Ki-67 expression, primary resistance to ETs, liver metastases, more metastatic sites, later line of therapy, and the use of fulvestrant instead of aromatase inhibitors. Palbociclib is useful for treatment of metastasis breast cancer, and our study may provide a basis for further research. Background: Palbociclib has been approved for marketing in China. However, its effectiveness, safety, and latent variables in the Chinese population require further investigation. Methods: Information was retrieved from 397 patients with metastatic breast cancer (mBC) who received at least two cycles of palbociclib plus endocrine therapy (PAL plus ET) at eight clinical sites in China. The patients' demographic characteristics, treatment patterns, and adverse events (AEs) were analyzed. Results: The objective response rate (ORR) and clinical benefit rate (CBR) for PAL plus ET were 28.97% and 66.25%, respectively. The median PFS was 14.2 months in the whole population. In addition to protein Ki-67 status and sensitivity to ETs, no liver metastases, fewer metastatic sites, an earlier line of therapy, and treatment combined with AI instead of FUL were also considered as independent prognostic factors for PAL treatment. Administration of PAL was generally well tolerated in patients with hormone-receptor-positive and human-epidermal-growth-factor-receptor-2-negative (HR+/HER2−) advanced breast cancer (ABC). The therapy was safe in the elderly population, which is consistent with the outcomes of the whole population and previous reports. Conclusions: In this most widely distributed study in China to date, palbociclib combined with ET proved its effectiveness for HR+/HER2− ABC treatment, and adverse events were manageable. Here, we identified some independent prognosis factors, but the mechanism by which these factors influence effectiveness requires further verification. [ABSTRACT FROM AUTHOR]

Immunotherapy has emerged in recent years as arguably the most effective treatment for advanced hepatocellular carcinoma (HCC), but the failure of a large percentage of patients to respond to immunotherapy remains as the ultimate obstacle to successful treatment. Etiology-associated dysregulation of immune-associated (IA) genes may be central to the development of this differential clinical response. We identified immune-associated genes potentially dysregulated by alcohol or viral hepatitis B in HCC and validated alcohol-induced dysregulations in vitro while using large-scale RNA-sequencing data from The Cancer Genome Atlas (TCGA). Thirty-four clinically relevant dysregulated IA genes were identified. We profiled the correlation of all genomic alterations in HCC patients to IA gene expression while using the information theory-based algorithm REVEALER to investigate the molecular mechanism for their dysregulation and explore the possibility of genome-based patient stratification. We also studied gene expression regulators and identified multiple microRNAs that were implicated in HCC pathogenesis that can potentially regulate these IA genes' expression. Our study identified potential key pathways, including the IL-7 signaling pathway and TNFRSF4 (OX40)- NF-κB pathway, to target in immunotherapy treatments and presents microRNAs as promising therapeutic targets for dysregulated IA genes because of their extensive regulatory roles in the cancer immune landscape. [ABSTRACT FROM AUTHOR]

Papillary thyroid carcinoma (PTC) variants exhibit different prognosis, but critical characteristics of PTC variants that contribute to differences in pathogenesis are not well-known. This study aims to characterize dysregulated immune-associated and cancer-associated genes in three PTC subtypes to explore how the interplay between cancer and immune processes causes differential prognosis. RNA-sequencing data from The Cancer Genome Atlas (TCGA) were used to identify dysregulated genes in each variant. The dysregulation profiles of the subtypes were compared using functional pathways clustering and correlations to relevant clinical variables, genomic alterations, and microRNA regulation. We discovered that the dysregulation profiles of classical PTC (CPTC) and the tall cell variant (TCPTC) are similar and are distinct from that of the follicular variant (FVPTC). However, unique cancer or immune-associated genes are associated with clinical variables for each subtype. Cancer-related genes MUC1, FN1, and S100-family members were the most clinically relevant in CPTC, while APLN and IL16, both immune-related, were clinically relevant in FVPTC. RAET-family members, also immune-related, were clinically relevant in TCPTC. Collectively, our data suggest that dysregulation of both cancer and immune associated genes defines the gene expression landscapes of PTC variants, but different cancer or immune related genes may drive the phenotype of each variant. [ABSTRACT FROM AUTHOR]

Simple Summary: This study proposed the "Residual-Dense-Attention" (RDA) U-Net model architecture to automatically segment organs and lesions in computed tomography (CT) images. The RDA U-Net used ResBlock and DenseBlock at the encoder. Attention gates were used at the decoder position to help the model suppress irrelevant areas of the CT image. Forty-one patients' bladder images were provided for training. The RDA U-Net provided faster but satisfactory segmentation results for bladder cancers and lesions. In today's high-order health examination, imaging examination accounts for a large proportion. Computed tomography (CT), which can detect the whole body, uses X-rays to penetrate the human body to obtain images. Its presentation is a high-resolution black-and-white image composed of gray scales. It is expected to assist doctors in making judgments through deep learning based on the image recognition technology of artificial intelligence. It used CT images to identify the bladder and lesions and then segmented them in the images. The images can achieve high accuracy without using a developer. In this study, the U-Net neural network, commonly used in the medical field, was used to extend the encoder position in combination with the ResBlock in ResNet and the Dense Block in DenseNet, so that the training could maintain the training parameters while reducing the overall identification operation time. The decoder could be used in combination with Attention Gates to suppress the irrelevant areas of the image while paying attention to significant features. Combined with the above algorithm, we proposed a Residual-Dense Attention (RDA) U-Net model, which was used to identify organs and lesions from CT images of abdominal scans. The accuracy (ACC) of using this model for the bladder and its lesions was 96% and 93%, respectively. The values of Intersection over Union (IoU) were 0.9505 and 0.8024, respectively. Average Hausdorff distance (AVGDIST) was as low as 0.02 and 0.12, respectively, and the overall training time was reduced by up to 44% compared with other convolution neural networks. [ABSTRACT FROM AUTHOR]

Simple Summary: While the prognosis of hormone receptor-positive (HR+) breast cancer has been significantly improved, tamoxifen resistance remains a challenge in the treatment of HR+ breast cancer. This study identified that tRF-16-K8J7K1B, a novel small ncRNA derived from the 3′-end of tRNAAla-TGC, was highly expressed in tamoxifen-resistant cells compared to parental cells. Moreover, extracellular tRF-16-K8J7K1B confers tamoxifen resistance via incorporation into exosomes and then degrades the expression of apoptosis-related proteins, reducing the proportion of drug-induced cell apoptosis. Therefore, we propose that exosomal tRF-16-K8J7K1B could be a potential predictive biomarker and therapeutic target for overcoming tamoxifen resistance. Tamoxifen resistance remains a challenge in hormone receptor-positive (HR+) breast cancer. Recent evidence suggests that transfer ribonucleic acid (tRNA)-derived fragments play pivotal roles in the occurrence and development of various tumors. However, the relationship between tRNA-derived fragments and tamoxifen resistance remains unclear. In this study, we found that the expression of tRF-16-K8J7K1B was upregulated in tamoxifen-resistant cells in comparison with tamoxifen-sensitive cells. Higher levels of tRF-16-K8J7K1B were associated with shorter disease-free survival in HR+ breast cancer. Overexpression of tRF-16-K8J7K1B promotes tamoxifen resistance. Moreover, extracellular tRF-16-K8J7K1B could be packaged into exosomes and could disseminate tamoxifen resistance to recipient cells. Mechanistically, exosomal tRF-16-K8J7K1B downregulates the expression of apoptosis-related proteins, such as caspase 3 and poly (ADP-ribose) polymerase, by targeting tumor necrosis factor-related apoptosis-inducing ligand in receptor cells, thereby reducing drug-induced cell apoptosis. Therapeutically, the inhibition of exosomal tRF-16-K8J7K1B increases the sensitivity of breast cancer cells to tamoxifen in vivo. These data demonstrate that exosomal tRF-16-K8J7K1B may be a novel therapeutic target to overcome tamoxifen resistance in HR+ breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Hypopharyngeal squamous cell carcinoma (HSCC) is a type of cancer with poor prognosis in head and neck tumors. More studies have shown that abnormal expression of lncRNA plays a crucial role in HSCC. Through RIP experiments, we confirmed that NR120519 interacts with KRT17, and the expression of both is closely related to the overall survival of HSCC. Subsequent experiments showed that both NR120519 and KRT17 could regulate the AKT/mTOR pathway and lead to EMT transformation, promoting the progression of HSCC. Therefore, NR120519/KRT17/AKT/mTOR axis has been identified as a new pathway, providing a feasible preliminary basis for future studies. Background: Hypopharyngeal carcinoma is the worst type of head and neck squamous cell carcinoma. It is necessary to identify the key molecular targets related to the carcinogenesis and development of hypopharyngeal carcinoma. Methods: Differentially expressed lncRNAs in hypopharyngeal carcinoma were selected by microarray, and lncRNA-associated proteins were found by RIP assay. Colony formation, CCK-8, wound healing and Transwell assays were performed to detect the effects of lncRNA and its associated protein on cell proliferation and migration in vitro. Downstream pathways of lncRNA and its associated protein were detected by WB. Through a subcutaneous tumor model, the effects of lncRNA and its associated protein on cell proliferation were detected. The expressions of lncRNA and its associated protein in hypopharyngeal cancer tissues were detected by qRT-PCR and immunohistochemistry assays, respectively, and survival analyses were performed by Kaplan-Meier curve. Results: A total of 542 and 265 lncRNAs were upregulated and downregulated in microarrays, respectively. LncRNA NR120519 was upregulated and promoted cell proliferation and migration of hypopharyngeal carcinoma in vitro and cell proliferation in vivo. RIP and WB assays showed that KRT17 was associated with and blocked by NR120519.The silencing of KRT17 promoted cell proliferation and the migration of hypopharyngeal carcinoma in vitro and cell proliferation in vivo by activating the AKT/mTOR pathway and epithelial-mesenchymal transformation (EMT). Finally, the NR120519 high expression and KRT17 low expression groups showed shorter overall survival. Conclusion: NR120519 activated the AKT/mTOR pathway and EMT by blocking KRT17 to promote cell proliferation and the migration of hypopharyngeal carcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Although multiple actionable genes have been identified in melanoma, 38–42% of patients are still not druggable based on current research. In our study, DNA-NGS and RNA-NGS were utilized to construct molecular profiles of a Chinese cohort of 469 melanoma patients. Up to 11.7% (7/60) of patients in the undruggable group could be recognized as actionable by DNA and RNA sequential sequencing. Additionally, the use of RNA-NGS enhanced the proportion of druggable fusions from 2.56% to 17.27%. In total, the use of RNA-NGS increased the druggable proportion from 75% to 78%. Our study systemically analyzed the genetic landscape of Asian melanoma and demonstrated how DNA and RNA sequential sequencing is essential in bringing clinical benefits to more melanoma patients. Background: In contrast to Caucasian melanoma, which has been extensively studied, there are few studies on melanoma in Asian populations. Sporadic studies reported that only 40% of Asian melanoma patients could be druggable, which was much lower than that in Caucasians. More studies are required to refine this conclusion. Methods: Chinese melanoma patients (n = 469) were sequentially sequenced by DNA-NGS and RNA-NGS. The genomic alterations were determined, and potentially actionable targets were investigated. Results: Patients with potential druggable targets were identified in 75% of Chinese melanoma patients by DNA-NGS based on OncoKB, which was much higher than in a previous Asian study. NRG1 fusions were first identified in melanoma. In addition, up to 11.7% (7/60) of patients in the undruggable group could be recognized as actionable by including RNA-NGS analysis. By comparing the fusion detection rate between DNA-NGS and RNA-NGS, all available samples after DNA-NGS detection were further verified by RNA-NGS. The use of RNA-NGS enhanced the proportion of druggable fusions from 2.56% to 17.27%. In total, the use of RNA-NGS increased the druggable proportion from 75% to 78%. Conclusions: In this study, we systemically analyzed the actionable landscape of melanoma in the largest Asian cohort. In addition, we first demonstrated how DNA and RNA sequential sequencing is essential in bringing clinical benefits to more patients with melanoma. [ABSTRACT FROM AUTHOR]

Simple Summary: At present, the immunotherapy and immune microenvironment of bladder cancer have attracted more and more attention from clinicians and researchers. In this study, the high expression of SULF2 by RNA sequencing of tissues from 90 bladder cancer patients was associated with poor prognosis in patients. We further found that a high expression of SULF2 can promote the polarization of macrophages to M2. In mechanistic studies, we found that SULF2 can promote the secretion of IL-8 through Wnt/β-catenin. IL-8 promotes the transcription of CD163 and CD206 in the microenvironment, ultimately leading to the polarization of macrophages to M2 macrophages. This study elucidates the effect of SULF2 on the polarization of macrophages in the tumor microenvironment. Sulfatase 2 (SULF2) affects the occurrence and development of cancer by regulating HSPG-binding factors. However, the mechanism of SULF2 in bladder cancer (BCa) is unknown. To determine this, we analyzed the RNA sequencing of 90 patients with BCa. The results showed that the expression of SULF2 was closely related to the prognosis of BCa. Moreover, in vivo and in vitro experiments revealed that SULF2 promotes tumor proliferation and invasion. Furthermore, using a mouse orthotopic BCa model and flow cytometric analysis, we identified that SULF2 affects the polarization of macrophages. Mechanism studies clarified that SULF2 promoted the release of HSPG-binding factors, such as IL-8, in the microenvironment through β-catenin. Meanwhile, IL-8 activated the JAK2/STAT3 pathway of macrophages to promote the expression of CD163 and CD206, thereby regulating the polarization of macrophages to the M2-type. Conclusively, these results indicate that SULF2 plays an important role in regulating the microenvironment of BCa and promotes the polarization of macrophages to the M2-type by secreting IL-8, which further deepens the malignant progression of BCa. [ABSTRACT FROM AUTHOR]

Simple Summary: Human Papilloma Virus (HPV) is known to affect thousands globally. HPV infection can act carcinogenically on host cells with expression of the virus's E6 and E7 oncoproteins. Within the United States, roughly 70% of oropharyngeal cancers are thought to be HPV induced. Viral genome integration has been well studied, yet genomic effects of the E6 and E7 proteins on other genetic regions remain relatively unidentified. This study characterizes genomic mutation in HPV-infected HNSCC patients with specific regard to host E6 and E7 expression. Individuals with greater presence of these oncoproteins were found to exhibit a greater average of point mutations, particularly on chromosomes 1, 11, and 17. Greater expression of E6 and E7 also correlates to a lesser number of clustered variation events and fewer repeats of copy number segments. Analysis of the genomic effects of HPV may provide additional insight into the pathogenesis of HNSCC. Human Papilloma Virus (HPV) is highly prevalent within the U.S., with studies estimating that over 80% of individuals will contract the virus in their lifetime. HPV is considered a primary risk factor for the development and progression of oropharyngeal cancers. The impact of the HPV virus's E6 and E7 oncoproteins on cellular signaling pathways and genomic integration has been extensively characterized. Indirect genomic effects; however, remain relatively unidentified. In this study, we analyzed 83 HPV+ Head and Neck Squamous Cell Carcinoma (HNSCC) patients of varying HPV types. Expression counts of the HPV E6 and E7 oncogenes were estimated across samples and correlated with genomic mutational classes. High expression of E6 and E7 oncoproteins was associated with a greater number of total point mutations, especially on chromosomes 1, 11, and 17, which have been implicated in HPV-mediated cancers in previous studies. Samples with high E6 and E7 expression also exhibited more frequent non-clustered structural variation and a lack of clustered variation altogether. Copy number segments were present with fewer number of repeats in high E6 and E7 expression samples, which is known to correlate with decreased expression of affected genes. E6 and E7 expression was associated with increased activity of several cellular pathways associated in oncogenesis and telomere maintenance. In comprehensively characterizing the effects of the HPV oncoproteins on the human genome, potential mechanisms of HNSCC pathogenesis may be further elucidated. [ABSTRACT FROM AUTHOR]

Simple Summary: To date, there has not been adequate research conducted on prostate cancer tumor stem cells, which play an important role in tumor recurrence, invasion, and drug resistance. In this study, we innovatively used a tumor stem cell-associated index (mRNAsi), calculated by a single-class logistic regression machine learning algorithm (OCRL), in combination with multiple databases to identify MBNL1-AS1 as a key lncRNA for prostate cancer stem cells and elucidated via in vivo and in vitro experiments. In addition, the experiments showed that the down-regulation of MBNL1-AS1 promotes the malignance of prostate cancer cell lines through the miR-221-3p/CDKN1B/C-myc axis by stimulating the stemness of tumor stem cells. This provides the basis for theoretical studies of prostate cancer and provides targets for precision therapy. The recurrence, progression, and drug resistance of prostate cancer (PC) is closely related to the cancer stem cells (CSCs). Therefore, it is necessary to find the key regulators of prostate cancer stem cells (PCSCs). Here, we analyzed the results of a single-class logistic regression machine learning algorithm (OCLR) to identify the PCSC-associated lncRNA MBNL1-AS1. The effects of MBNL1-AS1 on the stemness of CSCs was assessed using qPCR, western blot and sphere-forming assays. The role of MBNL1-AS1 in mediating the proliferation and invasion of the PC cell lines was examined using Transwell, wounding-healing, CCK-8, EdU and animal assays. Dual-luciferase and ChIRP assays were used to examine the molecular mechanism of MBNL1-AS1 in PCSCs. MBNL1-AS1 was shown to be negatively correlated with stemness index (mRNAsi), and even prognosis, tumor progression, recurrence, and drug resistance in PC patients. The knockdown of MBNL1-AS1 significantly affected the stemness of the PC cells, and subsequently their invasive and proliferative abilities. Molecular mechanism studies suggested that MBNL1-AS1 regulates CDKN1B through competitive binding to miR-221-3p, which led to the inhibition of the Wnt signaling pathway to affect PCSCs. In conclusion, our study identified MBNL1-AS1 as a key regulator of PCSCs and examined its mechanism of action in the malignant progression of PC. [ABSTRACT FROM AUTHOR]

Simple Summary: The sabizabulin agent represses tumor cell growth, cell migration, and colony formation, and induces cell death in HER2+ breast cancer models. Sabizabulin is comparable to paclitaxel to suppress HER2+ xenograft growth and to inhibit lung metastasis in a HER2+ patient-derived xenograft (PDX) model. Sabizabulin is a promising orally available agent as an alternative to taxanes to target tubulin in breast cancer patients, including the HER2+ breast cancer molecular subtype. HER2+ breast cancer accounts for 15% of all breast cancer cases. Current frontline therapy for HER2+ metastatic breast cancer relies on targeted antibodies, trastuzumab and pertuzumab, combined with microtubule inhibitors in the taxane class (paclitaxel or docetaxel). It is well known that the clinical efficacy of taxanes is limited by the development of chemoresistance and hematological and neurotoxicities. The colchicine-binding site inhibitors (CBSIs) are a class of promising alternative agents to taxane therapy. Sabizabulin (formerly known as VERU-111) is a potent CBSI that overcomes P-gp-mediated taxane resistance, is orally bioavailable, and inhibits tumor growth and distant metastasis in triple negative breast cancer (TNBC). Herein, we demonstrate the efficacy of sabizabulin in HER2+ breast cancer. In vitro, sabizabulin inhibits the proliferation of HER2+ breast cancer cell lines with low nanomolar IC50 values, inhibits clonogenicity, and induces apoptosis in a concentration-dependent manner. In vivo, sabizabulin inhibits breast tumor growth in the BT474 (ER+/PR+/HER2+) xenograft model and a HER2+ (ER-/PR-) metastatic patient-derived xenograft (PDX) model, HCI-12. We demonstrate that sabizabulin is a promising alternative agent to target tubulin in HER2+ breast cancer with similar anti-metastatic efficacy to paclitaxel, but with the advantage of oral bioavailability and lower toxicity than taxanes. [ABSTRACT FROM AUTHOR]

Simple Summary: There are limited treatments for patients with HER2-negative breast cancer, especially for patients with metastatic breast cancer. This study aimed to observe the efficacy and safety of low-dose apatinib combined with chemotherapy in real-world clinical diagnosis and treatment of HER2-negative metastatic breast cancer. A total of 128 patients were treated with 250 mg apatinib, and we observed the median progression-free survival (PFS) and overall survival (OS) were 4.7 months and 15.3 months, respectively. This observation also indicated that the breast cancer susceptibility gene (BRCA) mutation predicted a better response to apatinib and that combination of immunotherapy or paclitaxel-platinum regimens might be an optimal treatment option. Importantly, a lower dose of apatinib showed mild side effects that improved the patients' life quality. Treatment options for human epidermal growth factor receptor (HER2)-negative breast cancer patients are limited in comparison to the HER2-positive patients, particularly for metastatic breast cancer patients. Apatinib is a small-molecule tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor 2 (VEGFR-2). Here, we reported the apatinib-based therapy data in HER2-negative metastatic breast cancer. Apatinib was taken at a dose of 250 mg orally once per day and combined with standard chemotherapy regimens. The PFS and OS of 128 patients were 4.7 months and 15.3 months, respectively. The objective response rate (ORR) and the disease control rate (DCR) were 22.7% and 80.5%, respectively. Patients with breast cancer susceptibility gene (BRCA) mutations were found to have a longer PFS and OS. Moreover, combination immunotherapy or paclitaxel-platinum regimens shared an improved response to other regimens. Most of the adverse effects (hypertension, anaemia, and hand-foot syndrome) were grade 1 to 2. Metastatic breast cancer patients could benefit from apatinib therapy at a low dosage, and the adverse effects are mild in real-world clinical practice. Furthermore, BRCA may be a putative biomarker for apatinib in HER2-negative breast cancer. Immunotherapy or paclitaxel-platinum regimens may be recommended to combine with apatinib therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Upper tract urothelial carcinoma (UTUC) is a rare malignancy that occurs mostly in elderly individuals with a high prevalence of comorbidities. However, the prognostic impact of comorbidities in these patients is not well evaluated. The aim of this retrospective study was to assess the significance of Adult Comorbidity Evaluation-27 (ACE-27) grade on the clinical outcomes of 409 patients with non-metastatic UTUC who underwent radical nephroureterectomy. We found that a high ACE-27 grade was an independent risk factor for UTUC progression, UTUC-specific death, and all-cause mortality in multivariate analyses. A prognostic model combining ACE-27 grade, tumor stage, and tumor grade showed good predictive performance and accuracy. Integrating the ACE-27 grade with standard pathological features can help physicians in clinical decision-making and risk stratification. Patients with upper tract urothelial carcinoma (UTUC) have a high prevalence of comorbidities. However, the prognostic impact of comorbidities in these patients is not well studied. We aimed to outline the comorbidity burden in UTUC patients and investigate its relationship with overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS). We retrospectively reviewed the clinicopathological data of 409 non-metastatic UTUC patients who received radical nephroureterectomy between 2000 and 2015. The comorbidity burden was evaluated using the Adult Comorbidity Evaluation-27 (ACE-27). Kaplan-Meier survival analysis showed that high ACE-27 grade was significantly associated with worse PFS, CSS, and OS. In multivariate Cox regression and competing risk analyses, we found that ACE-27 grade, tumor stage, and tumor grade were independent prognosticators of OS, CSS, and PFS. We combined these three significant factors to construct a prognostic model for predicting clinical outcomes. A receiver operating characteristic curve revealed that our prognostic model had high predictive performance. The Harrel's concordance indices of this model for predicting OS, CSS, and PFS were 0.81, 0.85, and 0.85, respectively. The results suggest that the UTUC patient comorbidity burden (ACE-27) provides information on the risk for meaningful clinical outcomes of OS, CSS, and PFS. [ABSTRACT FROM AUTHOR]

The intra-tumor microbiota has been increasingly implicated in cancer pathogenesis. In this study, we aimed to examine the microbiome in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) and determine its compositional differences with relation to age and gender. After grouping 497 LUAD and 433 LUSC patients by age and gender and removing potential contaminants, we identified differentially abundant microbes in each patient cohort vs. adjacent normal samples. We then correlated dysregulated microbes with patient survival rates, immune infiltration, immune and cancer pathways, and genomic alterations. We found that most age and gender cohorts in both LUAD and LUSC contained unique, significantly dysregulated microbes. For example, LUAD-associated Escherichia coli str. K-12 substr. W3110 was dysregulated in older female and male patients and correlated with both patient survival and genomic alterations. For LUSC, the most prominent bacterial species that we identified was Pseudomonas putida str. KT2440, which was uniquely associated with young LUSC male patients and immune infiltration. In conclusion, we found differentially abundant microbes implicated with age and gender that are also associated with genomic alterations and immune dysregulations. Further investigation should be conducted to determine the relationship between gender and age-associated microbes and the pathogenesis of lung cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: The Derlin-1 protein, encoded by DERL1, is located in the endoplasmic reticulum membrane and is responsible for the unfolded protein response. Derlin-1 has recently drawn lots of attention with regard to cancer pathogenesis. The purpose of this study is to examine its role and molecular mechanism in upper tract urothelial carcinoma (UTUC). The protein levels of Derlin-1 in human UTUC specimens are observed by immunohistochemistry. Derlin-1 overexpression is evidently associated with cancer stage, distant metastasis, recurrence, and poor prognosis in patients with UTUC. In an in vitro study, the knockdown of Derlin-1 represses, while over-expression of Derlin-1 increases migration and invasion of UTUC cells significantly. We identify the microRNA-375-3p (miR-375-3p) as one of the potential candidate microRNAs and then examine the relationship between Derlin-1 and miR-375-3p. The dual-luciferase reporter assay confirms that miR-375-3p directly targets Derlin-1. Furthermore, we reveal that miR-375-3p modulate Derlin-1 and epithelial–mesenchymal transition (EMT) marker protein levels. However, the above effects are reversed by the restoration of Derlin-1. Our study clarifies that miR-375-3p represses invasion and migration by directly targeting Derlin-1 and regulating the expression of EMT-associated proteins in UTUC cells, suggesting Derlin-1 may act as a useful predictor of prognosis and that both Derlin-1 and miR-375-3p could be potential therapeutic targets in UTUC. Little is known regarding the molecular characterization of upper tract urothelial carcinoma (UTUC). Novel therapeutic targets and prognostic predictors are imminent. In the present study, we aim to examine the oncogenic function and molecular mechanism of Derlin-1 in UTUC. Derlin-1 overexpression is significantly associated with poor prognosis in patients with UTUC. In vitro, knockdown or over-expression of Derlin-1 markedly regulated UTUC cell invasion and migration. We further discovered miR-375-3p suppresses cell invasion and migration by inversely regulating Derlin-1 and blocking EMT in UTUC cells. Taking this together, miR-375-3p functions as a tumor suppressive microRNA by directly targeting Derlin-1 and blocking epithelial–mesenchymal transition (EMT) in UTUC. [ABSTRACT FROM AUTHOR]

Simple Summary: Atezolizumab plus bevacizumab has been approved as the first-line systemic treatment for unresectable hepatocellular carcinoma (uHCC) patients. However, the real-world practice of this combination is limited. We reported 48 uHCC patients who received atezolizumab plus bevacizumab, the median progression-free survival (PFS) was 5.0 months, and the objective response rate and disease control rate were 27.1% and 68.8%, respectively. The severity of most adverse events was predominantly grade 1–2, and most patients tolerated the toxicities. We also used inflammatory biomarkers to predict PFS, including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Univariate and multivariate analyses revealed NLR and PLR were independent prognostic factors for superior PFS. The significance of our study is the first research to investigate the prognostic value of NLR and PLR among uHCC patients receiving atezolizumab plus bevacizumab. It would bring more information to physicians about the efficacy and safety of atezolizumab plus bevacizumab in real-world clinical practice. Atezolizumab plus bevacizumab has been approved as the first-line systemic treatment for patients with unresectable hepatocellular carcinoma (uHCC). This study was designed to assess the clinical impact of atezolizumab plus bevacizumab in uHCC patients. A total of 48 uHCC patients receiving atezolizumab plus bevacizumab were identified, including first-line, second-line, third-line, and later-line settings. In these patients, the median progression-free survival (PFS) was 5.0 months, including 5.0 months for the first-line treatment, not reached for the second-line treatment, and 2.5 months for the third line and later line treatment. The objective response rate and disease control rate to atezolizumab plus bevacizumab were 27.1% and 68.8%, respectively. The severity of most adverse events was predominantly grade 1–2, and most patients tolerated the toxicities. The ratios of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte (PLR) were used to predict PFS in these patients. The optimal cutoff values of NLR and PLR were 3 and 230, and NLR and PLR were independent prognostic factors for superior PFS in the univariate and multivariate analyses. Our study confirms the efficacy and safety of atezolizumab plus bevacizumab in uHCC patients in clinical practice and demonstrates the prognostic role of NLR and PLR for PFS in these patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Recurrence of cancer on the opposite side after the removal of primary upper tract urothelial carcinoma (UTUC) is uncommon, but the risk of subsequent deterioration of kidney function may be severe and result in the need for permanent dialysis. There is a clear correlation between inflammation and tumor development in patients with cancer. As the presence of white blood cells (WBC) in urine is an indicator of local inflammation and a biomarker for bladder recurrence of UTUC, we hypothesized that systemic inflammation is involved in the occurrence of contralateral lesions. We proved that elevated serum WBC, late chronic kidney disease, and multiple tumors are independent prognostic factors for contralateral recurrence. Moreover, in a subgroup analysis, the importance of chronic kidney disease in contralateral recurrence was demonstrated for the first time in a non-Asian population. It is recommended that high-risk patients be closely followed up to monitor the opposite upper urinary tract. This study aimed to examine the prognostic significance of preoperative inflammation-associated blood cell markers in the metachronous contralateral recurrence of upper tract urothelial carcinoma (UTUC). Patients with nonmetastatic UTUC treated in Taiwan and the U.S. between 1990 and 2017 were included. The Kaplan–Meier method was used to calculate the contralateral recurrence rate, and multivariate logistic regression was performed to study the association of blood cell markers and clinicopathological characteristics with contralateral recurrence. Overall, a total of 1039 patients were included in this study, 52 of whom (5.0%) developed metachronous recurrence of the contralateral side. Kaplan–Meier analysis indicated that a history of bladder cancer (p = 0.006), multiple tumors (p = 0.016), advanced chronic kidney disease (CKD; p < 0.001), elevated serum white blood cell (WBC) count (p < 0.001), and decreased hemoglobin levels (p = 0.001) significantly reduced the contralateral recurrence-free survival. Multivariate analysis showed that multiple tumors (hazard ratio (HR), 1.87; p = 0.030), advanced CKD (HR, 2.63; p = 0.002) and increased WBC count (HR, 2.60; p = 0.001) were independent risk factors for higher contralateral recurrence rate. Notably, advanced CKD was a significant factor regardless of the patient's region. In summary, multiple tumors, advanced CKD and elevated serum WBC count are independent predictors of contralateral recurrence in patients with UTUC. It is recommended that patients with these adverse characteristics be closely followed up to monitor the opposite upper urinary tract. [ABSTRACT FROM AUTHOR]

Simple Summary: Growing evidence has reported the role of sorafenib in hepatocellular carcinoma (HCC) patients with liver transplantation (LT). However, the clinical impact of lenvatinib in this population is limited. Our study enrolled 10 HCC patients who received lenvatinib after LT in our institute. Partial response was 20% and disease control rate was 70%. The median progression-free survival and overall survival were 3.7 and 16.4 months, respectively. Adverse events (AEs) were predominantly grade 1–2 in severity, and the majority of patients tolerated. Additionally, 25 HCC patients without LT who underwent lenvatinib treatment were identified as the control group; there was no significant difference in survival or AEs between these two groups. The significance of our study is that it is the first to investigate the efficacy and safety of lenvatinib among HCC patients with LT. It provides more information to physicians about the role of lenvatinib in this special population in clinical practice. Tumor recurrence is the most common cause of death in hepatocellular carcinoma (HCC) patients who received liver transplantation (LT). Recently, lenvatinib was approved for the systemic treatment of unresectable HCC patients; however, the role of lenvatinib in HCC patients after LT remains unclear. There were 56 patients with recurrent HCC after LT from 2008 to 2018 in our institute, and 10 patients who received lenvatinib were identified. Additionally, to understand the difference in the clinical impact of lenvatinib in the LT and non-LT settings, 25 HCC patients without LT who underwent lenvatinib treatment were identified from our HCC database and regarded as the control group. In the LT group, partial response was 20% and stable disease was 50%, resulting in a disease control rate of 70%; the median progression-free survival (PFS), time to treatment failure (TTF) and overall survival (OS) were 3.7, 3.6 and 16.4 months, respectively. Adverse events (AEs) were predominantly grade 1–2 in severity, and the majority of patients tolerated the side effects. There was no significant difference in PFS/OS, and we observed a similar pattern of AEs between these two groups. Our study confirms the comparable efficacy and safety of lenvatinib in HCC patients with LT and non-LT in clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: It is well established that tobacco smoke is the key player in lung squamous cell carcinoma (LUSC) pathogenesis, and there is growing evidence that electronic cigarette (e-cigarette) vapor may also cause LUSC. Recently, several studies have associated tobacco smoke with differential enhancer RNA (eRNA) expression. However, the effects of tobacco smoke and e-cigarette vapor on eRNA expression in correlation to LUSC outcomes have not been fully elucidated. This study demonstrates that tobacco smoke and e-cigarette vapor may decrease DNA methylation and increase chromosomal alterations at key sites, which ultimately upregulate the expression of oncogenic eRNAs and downregulate the expression of tumor-suppressing eRNAs. Subsequently, we demonstrate that these eRNAs may have altered interactions with immune cells to promote LUSC pathogenesis and reduced patient survival. We hope our results can be validated in future studies, and the key eRNAs we identified may be used as effective targets for more specialized treatments for smoking-mediated LUSC. Tobacco is the primary etiologic agent in worsened lung squamous cell carcinoma (LUSC) outcomes. Meanwhile, it has been shown that etiologic agents alter enhancer RNAs (eRNAs) expression. Therefore, we aimed to identify the effects of tobacco and electronic cigarette (e-cigarette) use on eRNA expression in relation to LUSC outcomes. We extracted eRNA counts from RNA-sequencing data of tumor/adjacent normal tissue and before/after e-cigarette tissue from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), respectively. Tobacco-mediated LUSC eRNAs were correlated to patient survival, clinical variables, and immune-associated elements. eRNA expression was also correlated to mutation rates through the Repeated Evaluation of Variables Conditional Entropy and Redundance (REVEALER) algorithm and methylated sites through methylationArrayAnalysis. Differential expression analysis was then completed for the e-cigarette data to compare with key tobacco-mediated eRNAs. We identified 684 downregulated eRNAs and 819 upregulated eRNAs associated with tobacco-mediated LUSC, specifically, with the cancer pathological stage. We also observed a decrease in immune cell abundance in tobacco-mediated LUSC. Yet, we found an increased association of eRNA expression with immune cell abundance in tobacco-mediated LUSC. We identified 16 key eRNAs with significant correlations to 8 clinical variables, implicating these eRNAs in LUSC malignancy. Furthermore, we observed that these 16 eRNAs were highly associated with chromosomal alterations and reduced CpG site methylation. Finally, we observed large eRNA expression upregulation with e-cigarette use, which corresponded to the upregulation of the 16 key eRNAs. Our findings provide a novel mechanism by which tobacco and e-cigarette smoke influences eRNA interactions to promote LUSC pathogenesis and provide insight regarding disease progression at a molecular level. [ABSTRACT FROM AUTHOR]

Simple Summary: Poorly differentiated and anaplastic thyroid cancers respond poorly to surgery, radiation, and hormone therapy. Cancer stem cells play an important role in tumor growth, drug resistance, and recurrence. This study focuses on how the sonic hedgehog (Shh) pathway maintains thyroid cancer stem cell self-renewal and whether it can be targeted for anticancer therapy. The authors report that the Shh pathway regulates the expression of BMI1 and SOX2, two genes involved in stem cell self-renewal, and that targeting the Shh pathway has little effect on thyroid tumor xenografts but can inhibit the growth of tumor xenografts derived from thyroid cancer stem cells. This study advances the knowledge on how thyroid cancer stem cells regenerate and highlights the potential therapeutic values of targeting the Shh pathway. The sonic hedgehog (Shh) pathway plays important roles in tumorigenesis, tumor growth, drug resistance, and metastasis. We and others have reported earlier that this pathway is highly activated in thyroid cancer. However, its role in thyroid cancer stem cell (CSC) self-renewal and tumor development remains incompletely understood. B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and SRY-Box Transcription Factor 2 (SOX2) are two CSC-related transcription factors that have been implicated in promoting CSC self-renewal. The objective of our current investigation was to determine the role of the Shh pathway in regulating BMI1 and SOX2 expression in thyroid cancer and promoting thyroid tumor growth and development. Here we report that inhibition of the Shh pathway by Gli1 siRNA or by cyclopamine and GANT61 reduced BMI1 and SOX2 expression in SW1736 and KAT-18 cells, two anaplastic thyroid cancer cell lines. The opposite results were obtained in cells overexpressing Gli1 or its downstream transcription factor Snail. The Shh pathway regulated SOX2 and BMI1 expression at a transcriptional and post-transcriptional level, respectively. GANT61 treatment suppressed the growth of SW1736 CSC-derived tumor xenografts but did not significantly inhibit the growth of tumors grown from bulk tumor cells. Clinicopathological analyses of thyroid tumor specimens by immunohistochemical (IHC) staining revealed that BMI1 and SOX2 were highly expressed in thyroid cancer and correlated with Gli1 expression. Our study provides evidence that activation of the Shh pathway leads to increased BMI1 and SOX2 expression in thyroid cancer and promotes thyroid CSC-driven tumor initiation. Targeting the Shh pathway may have therapeutic value for treating thyroid cancer and preventing recurrence. [ABSTRACT FROM AUTHOR]

Simple Summary: The cancer microbiome has been suggested to be closely involved in the immune dysregulation that leads to carcinogenesis. Given that pancreatic adenocarcinoma (PAAD) is one of the most lethal cancers, it is important to identify features of the microbiome that may contribute to more deadly PAAD tumors. In this study, we analyzed PAAD patient RNA-sequencing data from The Cancer Genome Atlas (TCGA) to correlate abundance of intra-pancreatic microbes to dysregulation of immune and cancer-associated genes and pathways. We discovered that the presence of several bacteria species within PAAD tumors is linked to metastasis and immune suppression. Furthermore, we found that the increased prevalence and poorer prognosis of PAAD in males and smokers are linked to the presence of potentially cancer-promoting or immune-inhibiting microbes. Further study into the roles of these microbes in PAAD is imperative for understanding how a pro-tumor microenvironment may be treated to limit cancer progression. An intra-pancreatic microbiota was recently discovered in several prominent studies. Since pancreatic adenocarcinoma (PAAD) is one of the most lethal cancers worldwide, and the intratumor microbiome was found to be a significant contributor to carcinogenesis in other cancers, this study aims to characterize the PAAD microbiome and elucidate how it may be associated with PAAD prognosis. We further explored the association between the intra-pancreatic microbiome and smoking and gender, which are both risk factors for PAAD. RNA-sequencing data from The Cancer Genome Atlas (TCGA) were used to infer microbial abundance, which was correlated to clinical variables and to cancer and immune-associated gene expression, to determine how microbes may contribute to cancer progression. We discovered that the presence of several bacteria species within PAAD tumors is linked to metastasis and immune suppression. This is the first large-scale study to report microbiome-immune correlations in human pancreatic cancer samples. Furthermore, we found that the increased prevalence and poorer prognosis of PAAD in males and smokers are linked to the presence of potentially cancer-promoting or immune-inhibiting microbes. Further study into the roles of these microbes in PAAD is imperative for understanding how a pro-tumor microenvironment may be treated to limit cancer progression. [ABSTRACT FROM AUTHOR]

Simple Summary: While the intratumor microbiome has been largely unexplored in relation to prostate cancer development, our research shows that microbes may play an anti-tumor or pro-tumor role to significantly alter clinical course in prostate cancer patients. We found that the presence and absence of specific microbes are strongly correlated with known biomarkers of prostate cancer, including increased androgen receptor expression, prostate-specific antigen level, immune-associated gene dysregulation, stem-cell related gene overexpression, cancer pathways, and known chromosomal alterations. Our results provide important insight on potential mechanisms by which intratumor microbes may greatly contribute to prostate cancer progression and prognosis. We hope our results can be validated in future studies, and the key microbes that we identified can be used as effective targets for more specialized prebiotic and probiotic treatments for prostate cancer. Although 1 in 9 American men will receive a diagnosis of prostate cancer (PC), most men with this diagnosis will not die from it, as most PCs are indolent. However, there is a subset of patients in which the once-indolent PC becomes metastatic and eventually, fatal. In this study, we analyzed microbial compositions of intratumor bacteria in PC to determine the influence of the microbiome on metastatic growth. Using large-scale RNA-sequencing data and corresponding clinical data, we correlated the abundance of microbes to immune pathways and PC risk factors, identifying specific microbes that either significantly deter or contribute to cancer aggressiveness. Interestingly, most of the microbes we found appeared to play anti-tumor roles in PC. Since these anti-tumor microbes were overrepresented in tumor samples, we believe that microbes thrive in the tumor microenvironment, outcompete cancer cells, and directly mitigate tumor growth by recruiting immune cells. These include Listeria monocytogenes, Methylobacterium radiotolerans JCM 2831, Xanthomonas albilineans GPE PC73, and Bradyrhizobium japonicum, which are negatively correlated with Gleason score, Tumor-Node-Metastasis (TNM) stage, prostate-specific antigen (PSA) level, and Androgen Receptor (AR) expression, respectively. We also identified microbes that contribute to tumor growth and are positively correlated with genomic alterations, dysregulated immune-associated (IA) genes, and prostate cancer stem cells (PCSC) genes. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world. Previous studies have identified the importance of alcohol and hepatitis B (HBV) infection on HCC carcinogenesis, indicating synergy in the methods by which these etiologies advance cancer. However, the specific molecular mechanism behind alcohol and HBV-mediated carcinogenesis remains unknown. Because the microbiome is emerging as a potentially important regulator of cancer development, this study aims to classify the effects of HBV and alcohol on the intratumoral liver microbiome. RNA-sequencing data from The Cancer Genome Atlas (TCGA) were used to infer microbial abundance. This abundance was then correlated to clinical variables and to cancer and immune-associated gene expression, in order to determine how microbial abundance may contribute to differing cancer progression between etiologies. We discovered that the liver microbiome is likely oncogenic after exposure to alcohol or HBV, although these etiological factors could decrease the abundance of a few oncogenic microbes, which would lead to a tumor suppressive effect. In HBV-induced tumors, this tumor suppressive effect was inferred based on the downregulation of microbes that induce cancer and stem cell pathways. Alcohol-induced tumors were observed to have distinct microbial profiles from HBV-induced tumors, and different microbes are clinically relevant in each cohort, suggesting that the effects of the liver microbiome may be different in response to different etiological factors. Collectively, our data suggest that HBV and alcohol operate within a normally oncogenic microbiome to promote tumor development, but are also able to downregulate certain oncogenic microbes. Insight into why these microbes are downregulated following exposure to HBV or alcohol, and why the majority of oncogenic microbes are not downregulated, may be critical for understanding whether a pro-tumor liver microbiome could be suppressed or reversed to limit cancer progression. [ABSTRACT FROM AUTHOR]

The 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) is a potential regulatory node in the mevalonate pathway that is frequently dysregulated in tumors. This study found that HMGCS1 expression is upregulated in stomach adenocarcinoma samples of patients and tumorspheres of gastric cancer cells. HMGCS1 elevates the expression levels of the pluripotency genes Oct4 and SOX-2 and contributes to tumorsphere formation ability in gastric cancer cells. HMGCS1 also promotes in vitro cell growth and progression and the in vivo tumor growth and lung metastasis of gastric cancer cells. After blocking the mevalonate pathway by statin and dipyridamole, HMGCS1 exerts nonmetabolic functions in enhancing gastric cancer progression. Furthermore, the level and nuclear translocation of HMGCS1 in gastric cancer cells are induced by serum deprivation. HMGCS1 binds to and activates Oct4 and SOX-2 promoters. HMGCS1 also enhances the integrated stress response (ISR) and interacts with the endoplasmic reticulum (ER) stress transducer protein kinase RNA-like endoplasmic reticulum kinase (PERK). Our results reveal that HMGCS1 contributes to gastric cancer progression in both metabolic and nonmetabolic manners. [ABSTRACT FROM AUTHOR]

Monomethyl auristatin E (MMAE) is the most popular and widely used cytotoxin in the development of antibody-drug conjugates (ADCs). However, current MMAE-based ADCs are all constructed using cleavable linkers, and this design concept still has insurmountable drawbacks. Their potential instabilities and lipophilic MMAE-induced "bystander effect" inevitably increase the toxicity to normal tissues. Herein, we overturn previous negative views of MMAE-based ADCs with non-cleavable linkers and propose using ionized L-Cysteine (Cys)-linker-MMAE as a novel payload, which can ingeniously enrich and enter tumor cells through receptor-mediated endocytosis of antibodies while its lower permeability helps to avoid further off-target toxicity. We demonstrate that Cys-linker-MMAE maintains high potency similar to free MMAE at the tubulin molecular level and can also be efficiently released in target cells. As a result, the preferred ADC (mil40-15) not only exhibits ideal plasma stability and maintains potent cytotoxicity as MMAE (IC50: 10−11 M), but also shows improved safety with lower bystander toxicity (IC50: 10−9 M), its maximum tolerated dose approaching the level of the naked antibody (160 mg/kg). This study indicated that Cys-linker-MMAE has the potential as a potent payload for ADCs, which is expected to provide novel strategies for the development of MMAE-based ADCs. [ABSTRACT FROM AUTHOR]

We sought to examine the relationship between microtubule-associated proteins (MAPs) and the prognosis of urothelial carcinoma by assessing the microtubule bundle formation genes using a reappraisal transcriptome dataset of urothelial carcinoma (GSE31684). The result revealed that microtubule-associated protein 1b (MAP1B) is the most significant upregulated gene related to cancer progression. Real-time reverse-transcription polymerase chain reaction was used to measure MAP1B transcription levels in urothelial carcinoma of the upper tract (UTUC) and the bladder (UBUC). Immunohistochemistry was conducted to detect MAP1B protein expression in 340 UTUC and 295 UBUC cases. Correlations of MAP1B expression with clinicopathological status, disease-specific survival, and metastasis-free survival were completed. To assess the oncogenic functions of MAP1B, the RTCC1 and J82 cell lines were stably silenced against their endogenous MAP1B expression. Study findings indicated that MAP1B overexpression was associated with adverse clinical features and could independently predict unfavorable prognostic effects, indicating its theranostic value in urothelial carcinoma. [ABSTRACT FROM AUTHOR]

CD133, known as prominin1, is a penta-span transmembrane glycoprotein presumably a cancer stem cell marker for carcinomas, glioblastomas, and melanomas. We showed that CD133(+) 'melanoma-initiating cells' are associated with chemoresistance, contributing to poor patient outcome. The current study investigates the role(s) of CD133 in invasion and metastasis. Magnetic-activated cell sorting of a melanoma cell line (BAKP) followed by transwell invasion assays revealed that CD133(+) cells are significantly more invasive than CD133(−) cells. Conditional reprogramming of BAKP CD133(+) cells maintained stable CD133 overexpression (BAK-R), and induced cancer stem cell markers, melanosphere formation, and chemoresistance to kinase inhibitors. BAK-R cells showed upregulated CD133 expression, and consequently were more invasive and metastatic than BAK-P cells in transwell and zebrafish assays. CD133 knockdown by siRNA or CRISPR-Cas9 (BAK-R-T3) in BAK-R cells reduced invasion and levels of matrix metalloproteinases MMP2/MMP9. BAK-R-SC cells, but not BAK-R-T3, were metastatic in zebrafish. While CD133 knockdown by siRNA or CRISPR-Cas9 in BAK-P cells attenuated invasion and diminished MMP2/MMP9 levels, doxycycline-induced CD133 expression in BAK-P cells enhanced invasion and MMP2/MMP9 concentrations. CD133 may therefore play an essential role in invasion and metastasis via upregulation of MMP2/MMP9, leading to tumor progression, and represents an attractive target for intervention in melanoma. [ABSTRACT FROM AUTHOR]

Antibody-drug conjugate (ADC) is a novel efficient drug delivery system that has been successfully used in clinical practice, and it has become a research hotspot in the anti-tumor drug field. Acid-cleavable linkers were first used in clinical ADCs, but their structural variety (e.g., hydrazone and carbonate) is still limited, and their stability is usually insufficient. Designing novel acid-cleavable linkers for the conjugation of the popular cytotoxin monomethyl auristatin E (MMAE) has always been a significant topic. In this paper, we generate a novel, silyl ether-based acid-cleavable antibody-MMAE conjugate, which skillfully achieves efficient combination of amino-conjugated MMAE with the acid-triggered silyl ether group by introducing p-hydroxybenzyl alcohol (PHB). The stability, acid-dependence cleavage, effective mechanism, efficacy and safety of the resulting ADC were systematically studied; the results show that it exhibits a significant improvement in stability, while maintaining appropriate efficacy and controlled therapeutic toxicity. This strategy is expected to expand a new type of acid-cleavable linkers for the development of ADCs with highly potent payloads. [ABSTRACT FROM AUTHOR]

Among all breast cancer types, basal-like breast cancer (BLBC) represents an aggressive subtype that lacks targeted therapy. We and others have found that receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in BLBC and other types of cancer and that ROR1 is significantly correlated with patient prognosis. In addition, using primary patient-derived xenografts (PDXs) and ROR1-knockout BLBC cells, we found that ROR1+ cells form tumors in immunodeficient mice. We developed an anti-ROR1 immunotoxin and found that targeting ROR1 significantly kills ROR1+ cancer cells and slows down tumor growth in ROR1+ xenografts. Our bioinformatics analysis revealed that ROR1 expression is commonly associated with the activation of FGFR-mediated signaling pathway. Further biochemical analysis confirmed that ROR1 stabilized FGFR expression at the posttranslational level by preventing its degradation. CRISPR/Cas9-mediated ROR1 knockout significantly reduced cancer cell invasion at cellular levels by lowering FGFR protein and consequent inactivation of AKT. Our results identified a novel signaling regulation from ROR1 to FGFR and further confirm that ROR1 is a potential therapeutic target for ROR1+ BLBC cells. [ABSTRACT FROM AUTHOR]