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Simple Summary: The prognosis of PCa at diagnosis is assessed by classification systems that aim to group homogenous sets of patients. However, great heterogeneity exists within these risk groups, in terms of prognostic factors and treatment options. The aim of this study was to assess the prognostic impact and predictors of adverse tumor grade in very favorable low- and intermediate-risk prostate cancer patients treated with robot-assisted radical prostatectomy at a high-volume tertiary referral center. Objectives: To assess the prognostic impact and predictors of adverse tumor grade in very favorable low- and intermediate-risk prostate cancer (PCa) patients treated with robot-assisted radical prostatectomy (RARP). Methods: Data of low- and intermediate PCa risk-class patients were retrieved from a prospectively maintained institutional database. Adverse tumor grade was defined as pathology ISUP grade group > 2. Disease progression was defined as a biochemical recurrence event and/or local recurrence and/or distant metastases. Associations were assessed by Cox's proportional hazards and logistic regression model. Results: Between January 2013 and October 2020, the study evaluated a population of 289 patients, including 178 low-risk cases (61.1%) and 111 intermediate-risk subjects (38.4%); unfavorable tumor grade was detected in 82 cases (28.4%). PCa progression, which occurred in 29 patients (10%), was independently predicted by adverse tumor grade and biopsy ISUP grade group 2, with the former showing stronger associations (hazard ratio, HR = 4.478; 95% CI: 1.840–10.895; p = 0.001) than the latter (HR = 2.336; 95% CI: 1.057–5.164; p = 0.036). Older age and biopsy ISUP grade group 2 were independent clinical predictors of adverse tumor grade, associated with larger tumors that eventually presented non-organ-confined disease. Conclusions: In a very favorable PCa patient population, adverse tumor grade was an unfavorable prognostic factor for disease progression. Active surveillance in very favorable intermediate-risk patients is still a hazard, so molecular and genetic testing of biopsy specimens is needed. [ABSTRACT FROM AUTHOR]

Simple Summary: In Sri Lanka, the authors are encouraging a cost-effective way to reduce the number of people developing oral cancer, which is a common cancer among men. The authors wanted to find out how well dentists can find signs of oral cancer and potential problems in their patients, and they did this by asking dentists questions in an online survey. Surprisingly, most of the dentists thought it would be better to only check people who are at a higher risk for oral cancer instead of checking everyone. Only about two thirds of the dentists regularly look for signs of oral cancer when people come for dental check-ups. The authors found that these dentists, on average, had noticed about 34 patients with concerning signs in the past year. Almost all the dentists believed that they needed more training to spot these problems. So, while opportunistic screening at the dentist's office is good, dental professionals also need to focus on other ways to prevent oral cancer, like checking high-risk groups and giving dentists more confidence to spot potential issues. In Sri Lanka, opportunistic screening is encouraged as a cost-effective tool to bring down the prevalence of oral cancer, which is the most common cancer among males. The objectives of the study were to determine the practices, attitudes, and level of competency of dental surgeons regarding the early detection of oral cancer and oral potentially malignant disorders (OPMDs) through opportunistic screening. A prospective study was conducted online via a Google form using a pretested, self-administered questionnaire of 22 close-ended questions and 3 open-ended questions. Out of the 137 dental surgeons who responded, 88% (121/137) of the participants believed that screening high-risk target groups would be more effective in the early detection of oral cancer rather than opportunistic screening. Only 64% (88/137) of the participants frequently check for oral cancer and OPMDs when patients visit for dental treatment. Participants recalled an average of 34 patients (4628/137) with clinically suspicious lesions being diagnosed during examination at general dental practice during the past year, and 98% (134/137) of the participants believed that they should receive additional training in order to identify and diagnose clinically suspicious OPMDs and oral cancer. Opportunistic screening in general dental practice as an oral-cancer prevention strategy is appreciable, but due emphasis should be given to other prevention strategies such as population screening and screening high-risk target groups. The level of confidence of general dental practitioners in the early detection of oral cancer has to be raised in order to achieve higher standards in oral cancer prevention through opportunistic screening. [ABSTRACT FROM AUTHOR]

Simple Summary: No measures of the changes occurring in the liver in the case of outflow deprivation during hepatectomies are available. This study investigated four indexes obtained using hyperspectral imaging in a pig model, measured in different liver lobes, before and after hepatic vein occlusion. The variations of StO2% and deoxy-Hb were considerably good markers of venous liver congestion. Introduction. The changes occurring in the liver in cases of outflow deprivation have rarely been investigated, and no measurements of this phenomenon are available. This investigation explored outflow occlusion in a pig model using a hyperspectral camera. Methods. Six pigs were enrolled. The right hepatic vein was clamped for 30 min. The oxygen saturation (StO2%), deoxygenated hemoglobin level (de-Hb), near-infrared perfusion (NIR), and total hemoglobin index (THI) were investigated at different time points in four perfused lobes using a hyperspectral camera measuring light absorbance between 500 nm and 995 nm. Differences among lobes at different time points were estimated by mixed-effect linear regression. Results. StO2% decreased over time in the right lateral lobe (RLL, totally occluded) when compared to the left lateral (LLL, outflow preserved) and the right medial (RML, partially occluded) lobes (p < 0.05). De-Hb significantly increased after clamping in RLL when compared to RML and LLL (p < 0.05). RML was further analyzed considering the right portion (totally occluded) and the left portion of the lobe (with an autonomous draining vein). StO2% decreased and de-Hb increased more smoothly when compared to the totally occluded RLL (p < 0.05). Conclusions. The variations of StO2% and deoxy-Hb could be considered good markers of venous liver congestion. [ABSTRACT FROM AUTHOR]

Simple Summary: The number of pigmented moles is the most important risk factor for melanoma. This "real world" study conducted in 25 Australian childcare centers is the first to show it is possible to prevent a significant proportion of pigmented moles in young Caucasian children by dressing them in UPF 30-50+ clothing that covers at least half their body on a daily basis. Regularly wearing this clothing for 3.5 years was sufficient to prevent almost one-quarter of the pigmented moles that young children developed on their skin. This should, by implication, reduce their risk of developing melanoma in the future. Primary health care providers should stress the importance of garment coverage when recommending sun protection for children and should lobby for all sun-protective clothing standards to assess and report garment coverage, in addition to the transmission of ultraviolet radiation through the fabric (reported as UPF), on clothing labels and packaging for children's clothing, including school uniforms. Numerous pigmented moles are associated with sun exposure and melanomarisk. This cluster randomized controlled trial aimed to determine if sun-protective clothing could prevent a significant proportion of the moles developing in young children (ACTRN12617000621314; Australian New Zealand Clinical Trials Registry. Twenty-five childcare centers in Townsville (19.25° S), Australia, were matched on shade provision and socioeconomic status. One center from each pair was randomized to the intervention arm and the other to the control arm. Children at 13 intervention centers wore study garments and legionnaire hats at childcare and received sun-protective swimwear and hats for home use, while children at the 12 control centers did not. The 1–35-month-old children (334 intervention; 210 control) were examined for moles at baseline (1999–2002) and were re-examined annually for up to 4 years. Both groups were similar at baseline. Children at intervention centers acquired fewer new moles overall (median 12.5 versus 16, p = 0.02; 0.46 versus 0.68 moles/month, p = 0.001) and fewer new moles on clothing-protected skin (6 vs. 8; p = 0.021 adjusted for confounding and cluster sampling) than controls. Intervention children had 24.3% fewer new moles overall (26.5 versus 35) and 31.6% (13 versus 19) fewer moles on clothing-protected skin than controls after 3.5 years. Sunlight's influence on nevogenesis is mitigated when children regularly wear UPF 30-50+ clothing covering half their body, implying that increased clothing cover reduces melanoma risk. Sun-protective clothing standards should mandate reporting of the percentage of garment coverage for childrenswear. [ABSTRACT FROM AUTHOR]

Simple Summary: There is a wide range of choices for combining PD-1/PD-L1 checkpoint inhibitors with other measures in treating tumors, but certain choices of regimens are still controversial. We aimed to investigate the therapeutic efficacy and potential side effects of combination therapy with anti-PD-1/PD-L1 compared to anti-PD-1/PD-L1 monotherapy. Meanwhile, we also explored whether different combination strategies would yield consistent efficacy across different types of tumors. Our study can provide important and useful information for clinicians and encourage the enrollment of more clinical trials for anti-PD-1/PD-L1 combination therapy. Objective: In recent years, the anti-programmed cell death protein-1 and its ligand (PD-1/PD-L1) or combination therapies have been recommended as an alternative emerging choice of treatment for oncology patients. However, the efficacy and adverse events of different combination strategies for the treatment of tumors remain controversial. Methods: PubMed, Embase, Cochrane Library, the American Society of Clinical Oncology (ASCO), and the European Society of Medicine Oncology (ESMO) were searched from database inception until 16 February 2022. The endpoints of objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were analyzed from different treatment schemes and tumor types. The protocol was registered in PROSPERO (CRD42022328927). Results: This meta-analysis included forty-eight eligible studies. Combination therapy has improved ORR (RR = 1.40, p < 0.001), DCR (RR = 1.22, p < 0.001), and PFS (the median survival ratio (MSR) was estimated to be 1.475 p < 0.001) compared to anti-PD-1/PD-L1 but had no significant benefit on OS (MSR was estimated to be 1.086 p = 0.117). Besides, combination treatment strategies are more toxic in any grade AEs (RR = 1.13, p < 0.001) and grade 3–5 AEs (RR = 1.81, p < 0.001). Conclusions: Treatment with PD-1/PD-L1 inhibitors in combination with other antitumor therapies improve patients' ORR, DCR, and PFS compared to anti-PD-1/PD-L1. However, it is regrettable that there is no benefit to OS and an increased risk of AEs in combinatorial therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Different cells present in the tumor microenvironment can deeply influence both cancer spreading and the success of therapy in solid tumors, including colorectal carcinoma (CRC). In particular, tumor-associated fibroblasts (TAF) exert potent immunosuppressive effects leading to the impairment of anti-tumor surveillance and interfering with the function of therapeutic antibodies. Herein, we show that CRC-derived TAF can be turned by zoledronic acid (ZA), in soluble form or as antibody-drug conjugate (ADC), into efficient stimulators of anti-tumor lymphocytes. The ADC, made of the anti-EGFR cetuximab (Cet), used in CRC therapy, and ZA (Cet-ZA) can induce the proliferation of lymphocytes that become able to kill both tumor cells and TAF. The double result is a direct anti-cancer effect and the neutralization of the inhibitory activity exerted by its stroma. The major advantage of the Cet-ZA ADC formulation is the precise delivery of ZA to EGFR+ cells, targeting TAF (potentially immunosuppressive), besides CRC cells. Tumor-associated fibroblasts (TAF) exert immunosuppressive effects in colorectal carcinoma (CRC), impairing the recognition of tumor cells by effector lymphocytes, including Vδ2 T cells. Herein, we show that CRC-derived TAF can be turned by zoledronic acid (ZA), in soluble form or as antibody-drug conjugate (ADC), into efficient stimulators of Vδ2 T cells. CRC-TAF, obtained from patients, express the epidermal growth factor receptor (EGFR) and the butyrophilin family members BTN3A1/BTN2A1. These butyrophilins mediate the presentation of the phosphoantigens, accumulated in the cells due to ZA effect, to Vδ2 T cells. CRC-TAF exposed to soluble ZA acquired the ability to trigger the proliferation of Vδ2 T cells, in part represented by effector memory cells lacking CD45RA and CD27. In turn, expanded Vδ2 T cells exerted relevant cytotoxic activity towards CRC cells and CRC-TAF when primed with soluble ZA. Of note, also the ADC made of the anti-EGFR cetuximab (Cet) and ZA (Cet-ZA), that we recently described, induced the proliferation of anti-tumor Vδ2 T lymphocytes and their activation against CRC-TAF. These findings indicate that ZA can educate TAF to stimulate effector memory Vδ2 T cells; the Cet-ZA ADC formulation can lead to the precise delivery of ZA to EGFR+ cells, with a double targeting of TAF and tumor cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Resistance to standard therapies impose a huge challenge on the treatment for glioblastoma multiforme (GBM), which is often considered as a cell intrinsic property of either GBM or, more significantly, of GBM stem-like cells. Tumor-associated macrophages and microglia (TAMs) take up the majority of the immune population in the tumor microenvironment of GBM and potentially participating in modulating therapy responses. However, little is known about the mechanisms underlying the effect of TAMs on temozolomide (TMZ) induced chemoresistance. Members of the metzincin superfamily such as Matrix Metalloproteases (MMPs) and A Disintegrin and Metalloprotease (ADAM) proteases are important participants in the process of intercellular communications in the tumor microenvironment. Herein, we revealed a novel concept of an intra-tumoral ADAM8 mediated malignant positive feedback loop constituted by the intimate interaction of tumor associated macrophages (TAMs) and GBM cells under TMZ treatment. These findings provide a convincing example and further support the notion that the tumor microenvironment, in addition to GBM cells and GBM stem-like cells, should be considered as an essential modulator of therapy in GBM. In conclusion, our study provides a rational basis for TAM sparing ADAM8-targeting in GBM to optimize standard chemotherapy. Standard chemotherapy of Glioblastoma multiforme (GBM) using temozolomide (TMZ) frequently fails due to acquired chemoresistance. Tumor-associated macrophages and microglia (TAMs) as major immune cell population in the tumor microenvironment are potential modulators of TMZ response. However; little is known about how TAMs participate in TMZ induced chemoresistance. Members of the metzincin superfamily such as Matrix Metalloproteases (MMPs) and A Disintegrin and Metalloprotease (ADAM) proteases are important mediators of cellular communication in the tumor microenvironment. A qPCR screening was performed to identify potential targets within the ADAM and MMP family members in GBM cells. In co-culture with macrophages ADAM8 was the only signature gene up-regulated in GBM cells induced by macrophages under TMZ treatment. The relationship between ADAM8 expression and TAM infiltration in GBM was determined in a patient cohort by qPCR; IF; and IHC staining and TCGA data analysis. Moreover; RNA-seq was carried out to identify the potential targets regulated by ADAM8. CCL2 expression levels were determined by qPCR; Western blot; IF; and ELISA. Utilizing qPCR; IF; and IHC staining; we observed a positive relationship between ADAM8 expression and TAMs infiltration level in GBM patient tissues. Furthermore; ADAM8 induced TAMs recruitment in vitro and in vivo. Mechanistically; we revealed that ADAM8 activated HB-EGF/EGFR signaling and subsequently up-regulated production of CCL2 in GBM cells in the presence of TMZ treatment; promoting TAMs recruitment; which further induced ADAM8 expression in GBM cells to mediate TMZ chemoresistance. Thus; we revealed an ADAM8 dependent positive feedback loop between TAMs and GBM cells under TMZ treatment which involves CCL2 and EGFR signaling to cause TMZ resistance in GBM. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM) is characterized by the presence of systemic clinical manifestations. Among them, pneumonia accounts for a significant cause of morbidity and mortality, highlighting an urgent need to explore possible susceptibility and potential mechanisms of pneumonia in MM. Recently, the gut–lung axis has emphasized the relevance of gut microbiota and pneumonia, indicating that the compromised function of gut microbiota may be susceptible to pneumonia. It has been previously shown that intestinal Klebsiella pneumonia enriches in MM patients and promotes MM progression in our previous work. In addition, host metabolism has been identified as a key regulator of MM. However, what role the altered gut microbiota plays in MM with pneumonia remains unknown. In this study, we explored the association between gut microbiota and MM with pneumonia. This is the first study to identify and elucidate the function of gut microbiota involved in MM with pneumonia. Pneumonia accounts for a significant cause of morbidity and mortality in multiple myeloma (MM) patients. It has been previously shown that intestinal Klebsiella pneumonia (K. pneumonia) enriches in MM and promotes MM progression. However, what role the altered gut microbiota plays in MM with pneumonia remains unknown. Here, we show that intestinal K. pneumonia is significantly enriched in MM with pneumonia. This enriched intestinal K. pneumonia links to the incidence of pneumonia in MM, and intestinal colonization of K. pneumonia contributes to pneumonia in a 5TGM1 MM mice model. Further targeted metabolomic assays reveal the elevated level of glutamine, which is consistently increased with the enrichment of K. pneumonia in MM mice and patients, is synthesized by K. pneumonia, and leads to the elevated secretion of TNF-α in the lung normal fibroblast cells for the higher incidence of pneumonia. Inhibiting glutamine synthesis by establishing glnA-mutated K. pneumonia alleviates the incidence of pneumonia in the 5TGM1 MM mice model. Overall, our work proposes that intestinal K. pneumonia indirectly contributes to pneumonia in MM by synthesizing glutamine. Altogether, we unveil a gut–lung axis in MM with pneumonia and establish a novel mechanism and a possible intervention strategy for MM with pneumonia. [ABSTRACT FROM AUTHOR]

Simple Summary: This work focuses on the peculiar contribution made by molecular dynamics simulation and in silico tools, in the choice of an effective second line therapy for a BRAF-mutated melanoma patient who developed resistance to the undergoing targeted therapy with BRAF/MEK inhibitors. Among the MEK inhibitors, we identified a drug alternative to trametinib, able to block the target even in the presence of a damaging mutation, and supported these findings, gathered by an in silico approach, with a liquid biopsy tracking of the response to treatment. The evolution of the disease, before and after the therapy change, was followed by analysis of the circulating tumor DNA and circulating melanoma cells. The systemic treatment of metastatic melanoma has radically changed, due to an improvement in the understanding of its genetic landscape and the advent of targeted therapy. However, the response to BRAF/MEK inhibitors is transitory, and big efforts were made to identify the mechanisms underlying the resistance. We exploited a combined approach, encompassing liquid biopsy analysis and molecular dynamics simulation, for tracking tumor evolution, and in parallel defining the best treatment option. The samples at different time points were collected from a BRAF-mutant melanoma patient who developed an early resistance to dabrafenib/trametinib. The analysis of the circulating tumor DNA (ctDNA) identified the MEK1 p.P124L mutation that confers resistance to trametinib. With an in silico modeling, we identified cobimetinib as an alternative MEK inhibitor, and consequently suggested a therapy switch to vemurafenib/cobimetinib. The patient response was followed by ctDNA tracking and circulating melanoma cell (CMC) count. The cobimetinib administration led to an important reduction in the BRAF p.V600E and MEK1 p.P124L allele fractions and in the CMC number, features suggestive of a putative response. In summary, this study emphasizes the usefulness of a liquid biopsy-based approach combined with in silico simulation, to track real-time tumor evolution while assessing the best treatment option. [ABSTRACT FROM AUTHOR]

Simple Summary: Epigenetic modification plays an important regulatory role in breast cancer progression. However, the relationship between epigenetic modification with tumor metabolism has not yet been fully elucidated. PDK1, as a key enzyme in glucose metabolism, mediates multiple tumors development. But, the mechanism of epigenetic modification in regulating PDK1 remains unclear in breast cancer. Here, we demonstrated that HDAC2 and EZH2 upregulated PDK1 expression through inhibiting miR-148a. Importantly, miR-148a targeting PDK1 regulated breast cancer cells glycolysis, invasion, epithelial-mesenchymal transition (EMT) and Adriamycin resistance. Our results suggested that the HDAC2/EZH2/miR-148a/PDK1 axis may be a promising potential therapeutic strategy. Background: Breast cancer has one of highest morbidity and mortality rates for women. Abnormalities regarding epigenetics modification and pyruvate dehydrogenase kinase 1 (PDK1)-induced unusual metabolism contribute to breast cancer progression and chemotherapy resistance. However, the role and mechanism of epigenetic change in regulating PDK1 in breast cancer remains to be elucidated. Methods: Gene set enrichment analysis (GSEA) and Pearson's correlation analysis were performed to analyze the relationship between histone deacetylase 2 (HDAC2), enhancer of zeste homologue 2 (EZH2), and PDK1 in database and human breast cancer tissues. Dual luciferase reporters were used to test the regulation between PDK1 and miR-148a. HDAC2 and EZH2 were found to regulate miR-148a expression through Western blotting assays, qRT-PCR and co-immunoprecipitation assays. The effects of PDK1 and miR-148a in breast cancer were investigated by immunofluorescence (IF) assay, Transwell assay and flow cytometry assay. The roles of miR-148a/PDK1 in tumor growth were investigated in vivo. Results: We found that PDK1 expression was upregulated by epigenetic alterations mediated by HDAC2 and EZH2. At the post-transcriptional level, PDK1 was a new direct target of miR-148a and was upregulated in breast cancer cells due to miR-148a suppression. PDK1 overexpression partly reversed the biological function of miR-148a—including miR-148a's ability to increase cell sensitivity to Adriamycin (ADR) treatment—inhibiting cell glycolysis, invasion and epithelial–mesenchymal transition (EMT), and inducing apoptosis and repressing tumor growth. Furthermore, we identified a novel mechanism: DNMT1 directly bound to EZH2 and recruited EZH2 and HDAC2 complexes to the promoter region of miR-148a, leading to miR-148a downregulation. In breast cancer tissues, HDAC2 and EZH2 protein expression levels also were inversely correlated with levels of miR-148a expression. Conclusion: Our study found a new regulatory mechanism in which EZH2 and HDAC2 mediate PDK1 upregulation by silencing miR-148a expression to regulate cancer development and Adriamycin resistance. These new findings suggest that the HDAC2/EZH2/miR-148a/PDK1 axis is a novel mechanism for regulating cancer development and is a potentially promising target for therapeutic options in the future. [ABSTRACT FROM AUTHOR]

Mesenchymal cells employ actin-based membrane protrusions called podosomes and invadopodia for cross-tissue migration during normal human development such as embryogenesis and angiogenesis, and in diseases such as atherosclerosis plaque formation and cancer cell metastasis. The Akt isoforms, downstream effectors of phosphatidylinositol 3 kinase (PI3K), play crucial roles in cell migration and invasion, but their involvement in podosome formation and cell invasion is not known. In this study, we have used Akt1 and/or Akt2 knockout mouse embryonic fibroblasts and Akt3-targeted shRNA to determine the roles of the three Akt isoforms in Src and phorbol ester-induced podosome formation, and extracellular matrix (ECM) digestion. We found that deletion or knockdown of Akt1 significantly reduces Src-induced formation of podosomes and rosettes, and ECM digestion, while suppression of Akt2 has little effect. In contrast, Akt3 knockdown by shRNA increases Src-induced podosome/rosette formation and ECM invasion. These data suggest that Akt1 promotes, while Akt3 suppresses, podosome formation induced by Src, and Akt2 appears to play an insignificant role. Interestingly, both Akt1 and Akt3 suppress, while Akt2 enhances, phorbol ester-induced podosome formation. These data show that Akt1, Akt2 and Akt3 play different roles in podosome formation and ECM invasion induced by Src or phorbol ester, thus underscoring the importance of cell context in the roles of Akt isoforms in cell invasion. [ABSTRACT FROM AUTHOR]

Hereditary Tyrosinemia type 1 (HT1) is a metabolic liver disease caused by genetic defects of fumarylacetoacetate hydrolase (FAH), an enzyme necessary to complete the breakdown of tyrosine. The severe hepatic dysfunction caused by the lack of this enzyme is prevented by the therapeutic use of NTBC (2-[2-nitro-4-(trifluoromethyl)benzoyl] cyclohexane-1,3-dione). However despite the treatment, chronic hepatopathy and development of hepatocellular carcinoma (HCC) are still observed in some HT1 patients. Growing evidence show the important role of heat shock proteins (HSPs) in many cellular processes and their involvement in pathological diseases including cancer. Their survival-promoting effect by modulation of the apoptotic machinery is often correlated with poor prognosis and resistance to therapy in a number of cancers. Here, we sought to gain insight into the pathophysiological mechanisms associated with liver dysfunction and tumor development in a murine model of HT1. Differential gene expression patterns in livers of mice under HT1 stress, induced by drug retrieval, have shown deregulation of stress and cell death resistance genes. Among them, genes coding for HSPB and HSPA members, and for anti-apoptotic BCL-2 related mitochondrial proteins were associated with the hepatocarcinogenetic process. Our data highlight the variation of stress pathways related to HT1 hepatocarcinogenesis suggesting the role of HSPs in rendering tyrosinemia-affected liver susceptible to the development of HCC. [ABSTRACT FROM AUTHOR]