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Radio (chemo) therapy is a crucial treatment modality for head and neck squamous cell carcinoma (HNSCC), but relapse is frequent, and the underlying mechanisms remain largely elusive. Therefore, novel biomarkers are urgently needed. Previously, we identified gains on 16q23-24 to be associated with amplification of the Fanconi anemia A (FancA) gene and to correlate with reduced progression-free survival after radiotherapy. Here, we analyzed the effects of FancA on radiation sensitivity in vitro, characterized the underlying mechanisms, and evaluated their clinical relevance. Silencing of FancA expression in HNSCC cell lines with genomic gains on 16q23-24 resulted in significantly impaired clonogenic survival upon irradiation. Conversely, overexpression of FancA in immortalized keratinocytes conferred increased survival accompanied by improved DNA repair, reduced accumulation of chromosomal translocations, but no hyperactivation of the FA/BRCA-pathway. Downregulation of interferon signaling as identified by microarray analyses, enforced irradiation-induced senescence, and elevated production of the senescence-associated secretory phenotype (SASP) appeared to be candidate mechanisms contributing to FancA-mediated radioresistance. Data of the TCGA HNSCC cohort confirmed the association of gains on 16q24.3 with FancA overexpression and impaired overall survival. Importantly, transcriptomic alterations similar to those observed upon FancA overexpression in vitro strengthened the clinical relevance. Overall, FancA amplification and overexpression appear to be crucial for radiotherapeutic failure in HNSCC. [ABSTRACT FROM AUTHOR]

Summary: For years, the term “apoptosis” was used synonymously with programmed cell death. However, it was recently discovered that receptor interacting protein 3 (RIP3)-dependent “necroptosis” represents an alternative programmed cell death pathway activated in many inflamed tissues. Here, we show in a genetic model of chronic hepatic inflammation that activation of RIP3 limits immune responses and compensatory proliferation of liver parenchymal cells (LPC) by inhibiting Caspase-8-dependent activation of Jun-(N)-terminal kinase in LPC and nonparenchymal liver cells. In this way, RIP3 inhibits intrahepatic tumor growth and impedes the Caspase-8-dependent establishment of specific chromosomal aberrations that mediate resistance to tumor-necrosis-factor-induced apoptosis and underlie hepatocarcinogenesis. Moreover, RIP3 promotes the development of jaundice and cholestasis, because its activation suppresses compensatory proliferation of cholangiocytes and hepatic stem cells. These findings demonstrate a function of RIP3 in regulating carcinogenesis and cholestasis. Controlling RIP3 or Caspase-8 might represent a chemopreventive or therapeutic strategy against hepatocellular carcinoma and biliary disease. [Copyright &y& Elsevier]

Background: Cholangiocarcinoma (CC) is a rare tumour with a dismal prognosis. As conventional medical management offers minimal survival benefit, surgery currently represents the only chance of cure. We evaluated DNA copy number (CN) alterations in CC to identify novel therapeutic targets. Methods: DNA was extracted from 32 CC samples. Bacterial artificial chromosome (BAC) array comparative genomic hybridization was performed using microarray slides containing 3400 BAC clones covering the whole human genome at distances of 1 Mb. Data were analysed within the R statistical environment. Results: DNA CN gains (89 regions) occurred more frequently than DNA CN losses (55 regions). Six regions of gain were identified in all cases on chromosomes 16, 17, 19 and 22. Twenty regions were frequently gained on chromosomes 1, 5, 7, 9, 11, 12, 16, 17, 19, 20 and 21. The BAC clones covering ERBB2, MEK2 and PDGFB genes were gained in all cases. Regions covering MTOR, VEGFR 3, PDGFA, RAF1, VEGFA and EGFR genes were frequently gained. Conclusions: We identified CN gains in the region of 11 useful molecular targets. Findings of variable gains in some regions in this and other studies support the argument for molecular stratification before treatment for CC so that treatment can be tailored to the individual patient. [ABSTRACT FROM AUTHOR]

This study aimed to assess the consistency and replicability of treatment recommendations provided by ChatGPT 3.5 compared to gastrointestinal tumor cases presented at multidisciplinary tumor boards (MTBs). It also aimed to distinguish between general and case-specific responses and investigated the precision of ChatGPT's recommendations in replicating exact treatment plans, particularly regarding chemotherapy regimens and follow-up protocols. A retrospective study was carried out on 115 cases of gastrointestinal malignancies, selected from 448 patients reviewed in MTB meetings. A senior resident fed patient data into ChatGPT 3.5 to produce treatment recommendations, which were then evaluated against the tumor board's decisions by senior oncology fellows. Among the examined cases, ChatGPT 3.5 provided general information about the malignancy without considering individual patient characteristics in 19% of cases. However, only in 81% of cases, ChatGPT generated responses that were specific to the individual clinical scenarios. In the subset of case-specific responses, 83% of recommendations exhibited overall treatment strategy concordance between ChatGPT and MTB. However, the exact treatment concordance dropped to 65%, notably lower in recommending specific chemotherapy regimens. Cases recommended for surgery showed the highest concordance rates, while those involving chemotherapy recommendations faced challenges in precision. ChatGPT 3.5 demonstrates potential in aligning conceptual approaches to treatment strategies with MTB guidelines. However, it falls short in accurately duplicating specific treatment plans, especially concerning chemotherapy regimens and follow-up procedures. Ethical concerns and challenges in achieving exact replication necessitate prudence when considering ChatGPT 3.5 for direct clinical decision-making in MTBs. • ChatGPT 3.5 shows promise as a valuable tool in clinical decision-making. • ChatGPT 3.5 provides case-specific recommendations when provided with sufficient information. • In 83% of cases, ChatGPT 3.5 generates conceptual treatment recommendations that align with the MTB. • ChatGPT 3.5 struggles to generate case-specific recommendations, achieving a 65% concordance rate. [ABSTRACT FROM AUTHOR]

Osteosarcomas are genetically complex tumors with abundant structural and numerical alterations. The molecular pathogenesis of the disease is, however, still poorly understood. Aside from various oncogenes and tumor suppressor genes, deregulated microRNAs (miRNAs) are known to influence tumor development and biology. We therefore investigated six well-established osteosarcoma cell lines (HOS58, U2-OS, Saos-2, MNNG/HOS, SJSA-1, and MG-63) for genome-wide miRNA expression (miRBase Version 15.0, http://www.mirbase.org/) and correlated our findings with gene expression. Cultured osteoblasts (hFOB 1.19) and mesenchymal stem cells (L87/4) were used as normal references. Focusing only on miRNAs that were deregulated in the majority of osteosarcoma cell lines, we identified several miRNAs with oncogenic and tumor suppressor properties, including various members of the oncogenic miR-17-92 cluster. In addition, several genes involved in differentiation (RGMB, LRRC17), cell cycle control (CCNE1), and apoptosis (LIMA1, CAMK2N1) were found to be deregulated in osteosarcoma cell lines, most likely due to altered miRNA expression patterns. Our findings indicate a crucial impact of deregulated miRNAs with consecutive changes in gene expression in osteosarcomas, which strongly suggests pathogenetic and potentially therapeutic implications. [ABSTRACT FROM AUTHOR]

Abstract: Thyroid cancer derived from the follicular cell is characterised by specific gene alterations that are closely linked to the various pathological types comprising papillary, follicular and anaplastic thyroid cancer. However, the correlation between molecular biology and pathology is not absolute, since about 30% of cases do not harbour the typical gene alterations. This situation, coupled with the demonstration of genetic heterogeneity in thyroid cancer, is a strong motivation for the search of novel gene alterations. Chromosomal aberrations are a good starting point to initiate this search and therefore the current knowledge on chromosomal alterations in thyroid follicular-cell neoplasia is reviewed in this article. An overview on molecular cytogenetic approaches for this strategy is also provided. The identification of novel genetic markers in thyroid cancer will be further improved by integrative approaches combining data from genomic and expression analyses with clinical data. This approach is powerful to identify genetic markers as well as new therapeutic targets in follicular-cell thyroid cancer. [Copyright &y& Elsevier]

To assess the cytocompatibility of five commercially available xenogenic barrier membranes used for oral regenerative procedures and to determine the growth factor content of these membranes in-vitro. Human mesenchymal stem cells (hMSCs) and immortalized periodontal ligament stem cells (PDL-hTERTs) were used to determine the cytocompatibility of xenogenic barrier membranes made of collagen (Biogide, BG, Geistlich Pharma AG, Switzerland; Biomend, BM, Zimmer Biomet, USA; Osseoguard OG, Zimmer Biomet, USA; OssixPlus, OX, Datum Dental, Israel) or extracellular matrix (ECM) (Dynamatrix, DM, Keystone Dental, USA) and of their eluates obtained by washing. Cells were cultured with previously washed and unwashed membranes (n=4) and in the medium used for washing (eluate). Cell proliferation at 3 days (eluates) and at 7 days (membranes) was assessed using the WST-1 cell proliferation kit. Growth factor content of the membranes was measured using multiplex ELISA. The eluate of BG and BM significantly inhibited proliferation of hMSCs, whereas DM and OX showed stimulating effects. The highest impact was observed for DM, its eluate doubled the cell proliferation of adherent cells when compared to the control (p<0.001). The eluate of OG did not influence eluate cell cultures (p>0.05). The presence of membranes had different impact on hMSCs and PDLs. hMSCs seem to be more resistant to the inhibitory effects of BG, OG and BM. hMSCs are only affected by OX, which actually stimulates hMSCs when the specimens are not washed previously. PDLs however proliferate significantly less once they are placed into culture with BM and OG as well as BG-not washed. Once BG is washed no inhibitory effect on PDLs was observed, however overall the washing of membrane samples prior to the placement into the cell culture did hardly have any effect on the outcome. The strongest inhibition of proliferation was shown with the BM and OG membrane in PDL-hTERTs (p<0.001). Growth factor contents were quite similar quantitatively and qualitatively among the tested membranes with concentrations in the range of 50-500 pg/ml. Intriguingly DM contained considerably higher amounts of bFGF with up to 8000 pg/ml. The collagen membranes cross-linked with aldehydes show poor outcomes in PDLs while the collagen membrane cross-linked with polysaccharides generally shows promising results similar to the ECM-membrane DM in both membrane and eluate tests. The findings may be due to various factors, especially differences observed in composition, processing and bFGF content. [ABSTRACT FROM AUTHOR]

Summary Hepatocellular carcinoma (HCC) represents a classic example of inflammation-linked cancer. To characterize the role of the immune system in hepatic injury and tumor development, we comparatively studied the extent of liver disease and hepatocarcinogenesis in immunocompromised versus immunocompetent Fah-deficient mice. Strikingly, chronic liver injury and tumor development were markedly suppressed in alymphoid Fah − / − mice despite an overall increased mortality. Mechanistically, we show that CD8 + T cells and lymphotoxin β are central mediators of HCC formation. Antibody-mediated depletion of CD8 + T cells as well as pharmacological inhibition of the lymphotoxin-β receptor markedly delays tumor development in mice with chronic liver injury. Thus, our study unveils distinct functions of the immune system, which are required for liver regeneration, survival, and hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

Non-alcoholic steatotic liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD has a major effect on the intrinsic proliferative properties of hepatocytes. Here, we investigated the mechanisms underlying the activation of DNA damage response during NAFLD. Proliferating mouse NAFLD hepatocytes harbor replication stress (RS) with an alteration of the replication fork's speed and activation of ATR pathway, which is sufficient to cause DNA breaks. Nucleotide pool imbalance occurring during NAFLD is the key driver of RS. Remarkably, DNA lesions drive cGAS/STING pathway activation, a major component of cells' intrinsic immune response. The translational significance of this study was reiterated by showing that lipid overload in proliferating HepaRG was sufficient to induce RS and nucleotide pool imbalance. Moreover, livers from NAFLD patients displayed nucleotide pathway deregulation and cGAS/STING gene alteration. Altogether, our findings shed light on the mechanisms by which damaged NAFLD hepatocytes might promote disease progression. [Display omitted] • Proliferating NAFLD hepatocytes harbor replication stress • Defective replication fork dynamic induces DNA damage signaling • Nucleotide pool imbalance promotes replication stress in NAFLD hepatocytes • The cGAS-STING pathway connects DNA damage to the interferon pathway in NAFLD hepatocytes Donne et al. find that non-alcoholic steatotic liver disease (NAFLD) hepatocytes display hallmarks of replication stress due to a nucleotide pool imbalance. Replication stress is sufficient to elicit NAFLD hepatocyte DNA lesions and to drive the activation of the DNA-sensing pathway cGAS-STING. [ABSTRACT FROM AUTHOR]

Abstract: Papillary thyroid cancer is unusual among epithelial malignancies in that it is associated with a number of chromosomal rearrangements. The most common of these is the Ret oncogene, normally silent in the follicular cell, but which has been shown to be rearranged to the promoter region of a variety of different genes, all of which are constituently expressed in the thyroid follicular cell. It has been suggested that chromosomes in the thyroid cell are arranged within the nucleus in such a way as to predispose the cell to inappropriate fusion in the advent of DNA double-strand breakage. The presence of tumour specific fusion genes, and their transcribed proteins, presents a possible therapeutic target for thyroid cancer, but the relative contribution of the gene rearrangement in the growth and development of the tumour will need careful evaluation before clinical studies could take place. [Copyright &y& Elsevier]