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The Largest Chinese Cohort Study Indicates Homologous Recombination Pathway Gene Mutations as Another Major Genetic Risk Factor for Colorectal Cancer with Heterogeneous Clinical Phenotypes

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Research 2024年第3期6卷 191-203页

作者： Yun Xu Kai Liu Cong Li Minghan Li Fangqi Liu Xiaoyan Zhou Menghong Sun Megha Ranganathan Liying Zhang Sheng Wang Xin Hu Ye Xu Department of Colorectal Surgery Fudan University Shanghai Cancer CenterShanghaiP.R.China Department of pathology Fudan University Shanghai Cancer CenterShanghaiP.R.China Department of pathology Tissue BankFudan University Shanghai Cancer CenterShanghaiP.R.China Department of Medicine Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Department of pathology and Laboratory Medicine David Geffen School of MedicineUniversity of CaliforniaLos AngelesCAUSA Precision Cancer Medical center Fudan University Shanghai Cancer CenterShanghaiP.R.China

While genetic factors were associated with over 30% of colorectal cancer (CRC) patients, mutations in CRC-susceptibility genes were identified in only 5% to 10% of these patients. Besides, previous studies on hereditary CRC were largely designed to analyze germline mutations in patients with single genetic high-risk factor, which limited understanding of the association between genotype and phenotypes. From January 2015 to December 2018, we retrospectively enrolled 2,181 patients from 8,270 consecutive CRC cases, covering 5 categories of genetic high-risk factors. Leukocyte genomic DNA was analyzed for germline mutations in cancer predisposition genes. The germline mutations under each category were detected and analyzed in association with CRC susceptibility, clinical phenotypes, and prognoses. A total of 462 pathogenic variants were detected in 19.3% of enrolled CRC patients. Mismatch repair gene mutation was identified in 9.1% of patients, most prevalent across all high-risk groups. Homologous recombination (HR) gene mutations were detected in 6.5% of cases, penetrated in early-onset and extra-colonic cancer risk groups. Mutations in HR genes, including BARD1, RAD50, and ATM, were found to increase CRC risk with odds ratios of 2.8-, 3.1-, and 3.1-fold, respectively. CRC patients with distinct germline mutations manifested heterogeneous phenotypes in clinicopathology and long-term prognoses. Thus, germline mutation screenings should be performed for CRC patients with any of those genetic risk factors. This study also reveals that HR gene mutations may be another major driver for increased CRC risk.

关键词： susceptibility category Major

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Blastomas of the digestive system in adults:A review

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World Journal of Gastrointestinal Surgery 2024年第4期16卷 1030-1042页

作者： Yu Liu Tony El Jabbour Jonathan Somma Yukihiro Nakanishi Saverio Ligato Hwajeong Lee Zhi-Yan Fu Department of pathology LSU Health Sciences Center School of MedicineNew OrleansLA 70112United States Department of pathology Hartford HealthCareHartfordCT 06102United States Department of pathology Moffitt Cancer CenterTampaFL 33612United States Department of pathology and Laboratory Medicine Albany Medical CenterAlbanyNY 12208United States

Blastomas,characterized by a mixture of mesenchymal,epithelial,and undifferentiated blastematous components,are rare malignant neoplasms originating from precursor blast *** review focuses on digestive system blastomas in adult patients,including gastroblastoma,hepatoblastoma,and *** is a biphasic,epitheliomesenchymal tumor,with only sixteen cases reported to *** addition to the characteristic histology,metastasisassociated lung adenocarcinoma transcript 1-glioma-associated oncogene homolog 1 gene fusion is typical,although recently novel ewing sarcoma breakpoint region 1-c-terminal binding protein 1 and patched 1-glioma-associated oncogene homolog 2 fusions have been *** is exceptionally rare in adults and can show a variety of histologic patterns which may cause diagnostic ***,primarily a pediatric tumor,displays acinar differentiation and squamoid nests with other lines of differentiation also present,especially *** approaches for these blastomas include a combination of imaging modalities,histopathological examination,and molecular *** treatment generally involves surgical resection,which may be supplemented by chemotherapy or radiotherapy in some *** vary with gastroblastoma generally showing favorable outcomes post-surgery whereas hepatoblastoma and pancreatoblastoma often have poorer outcomes,particularly in the setting of *** review highlights the complexity of diagnosing and managing these rare adult blastomas as well as the need for ongoing research to better understand their pathogenesis and improve treatment strategies.

关键词： Adult blastomas Gastroblastoma Hepatoblastoma Pancreatoblastoma Digestive system

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Microbiome changes in esophageal cancer:implications for pathogenesis and prognosis

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Cancer Biology & Medicine 2024年第2期21卷 163-174页

作者： Yi Li Bing Wei Xia Xue Hongle Li Jun Li Department of Molecular pathology Clinical Pathology CenterAffiliated Cancer Hospital of Zhengzhou University and Henan Cancer HospitalZhengzhou 450003China Henan Key Laboratory of Molecular pathology Zhengzhou 450003China Henan Key Laboratory of Helicobacter pylori&Microbiota and Gastrointestinal Cancer Marshall Medical Research CenterThe Fifth Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China

Esophageal cancer(EC)is an aggressive malignancy with a poor *** factors,including dietary habits,and antacid and antibiotic use,have been shown to influence the esophageal ***,enrichment and diversity of the esophageal microbiome can also impact its *** studies have revealed prevalent changes in the esophageal microbiome among patients with EC,thus suggesting the potential contribution of the esophageal microbiome to EC ***,distinct microbiome compositions have been observed in patients with different responses to radiotherapy and chemotherapy,indicating the role of the esophageal microbiome in modulating treatment *** this review,we have examined previous studies on the esophageal microbiome in healthy individuals and patients with EC or other esophageal diseases,with a focus on identifying microbial communities associated with EC pathogenesis and *** the role of the microbiome in EC may aid in early detection and optimized treatment strategies,ultimately leading to better outcomes for patients.

关键词： Esophageal cancer microbiome dysbiosis microenvironment carcinogenesis

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Liver biopsy in the post-hepatitis C virus era in Japan

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World Journal of Gastroenterology 2024年第14期30卷 1949-1957页

作者： Yoshihiro Ikura Takako Okubo Yasuhiro Sakai Department of pathology Takatsuki General HospitalTakatsuki 569-1192Osaka PrefectureJapan Department of pathology Kansai Medical University Medical CenterMoriguchi 570-8507Japan

In Japan,liver biopsies were previously crucial in evaluating the severity of hepatitis caused by the hepatitis C virus(HCV)and diagnosing HCV-related hepatocellular carcinoma(HCC).However,due to the development of effective antiviral treatments and advanced imaging,the necessity for biopsies has significantly *** change has resulted in fewer chances for diagnosing liver disease,causing many general pathologists to feel less confident in making liver biopsy *** article provides a comprehensive overview of the challenges and potential solutions related to liver biopsies in ***,it highlights the importance of considering steatotic liver diseases as independent conditions that can coexist with other liver diseases due to their increasing ***,it emphasizes the need to avoid hasty assumptions of HCC in nodular lesions,because clinically diagnosable HCCs are not targets for ***,the importance of diagnosing hepatic immune-related adverse events caused by immune checkpoint inhibitors is increasing due to the anticipated widespread use of these *** conclusion,pathologists should be attuned to the changing landscape of liver diseases and approach liver biopsies with care and attention to detail.

关键词： Liver biopsy Alteration Post-hepatitis C virus era Steatotic liver disease Hepatic tumors Immune checkpoint inhibitors

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Targeting stroma and tumor,silencing galectin 1 treats orthotopic mouse hepatocellular carcinoma

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Acta Pharmaceutica Sinica B 2024年第1期14卷 292-303页

作者： Tahereh Setayesh Ying Hu Farzam Vaziri Xin Chen Jinping Lai Dongguang Wei Yu-Jui Yvonne Wan Department of Medical pathology and Laboratory Medicine University of CaliforniaDavisSacramentoCA 95817USA Cancer Biology Program the University of Hawaii Cancer CenterHonoluluHI 96813USA Department of pathology and Laboratory Medicine Kaiser Permanente Sacramento Medical CenterSacramentoCA 95825USA

This study examines inhibiting galectin 1(Gal1)as a treatment option for hepatocellular carcinoma(HCC).Gal1 has immunosuppressive and cancer-promoting *** data showed that Gal1 was highly expressed in human and mouse *** levels of Gal1 positively correlated with the stages of human HCC and negatively with *** roles of Gal1 in HCC were studied using overexpression(OE)or silencing using Igals1 siRNA delivered by *** to HCC initiation induced by RAS and AKT mutations,lgals1-OE and silencing had opposite impacts on tumor *** treatment effect of lgals1 siRNAwas further demonstrated by intersecting HCC at different time points when the tumor load had already reached 9%or even 42%of the body *** spatial transcriptomic profiles of Gal1 silenced and OE HCC,inhibiting matrix formation and recognition of foreign antigen in CD45t cell-enriched areas located at tumor-margin likely contributed to the anti-HCC effects of Gal1 *** the tumors,silencing Gal1 inhibited translational initiation,elongation,and ***,Gal1 silencing increased immune cells as well as expanded cytotoxic T cells within the tumor,and the anti-HCC effect of lgals1 siRNAwas ***,Gal1 silencing has a promising potential for HCC treatment.

关键词： Liver Hepatocellular carcinoma Carbohydrate-binding lectin Galectin 1 Extracellular matrix Translation Spatial transcriptomics Tumor-margin

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Levisticum officinale extract protects against CCl4-induced hepatotoxicity through anti-inflammatory,anti-fibrotic,and antioxidant properties in rats

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Asian Pacific Journal of Tropical Biomedicine 2024年第8期14卷 331-340页

作者： Nahid Ghaedi Iran Pouraboli Mansour Mirtadzadini Mohammad-mehdi Moeini-aghtaie Department of Biology Faculty of SciencesShahid Bahonar University of KermanKermanIran Department of pathology Pathology and Stem Cell Research CenterAfzalipour Medical FacultyKerman University of Medical SciencesKermanIran

Objective:To investigate the hepatoprotective effects of Levisticum officinale extract on CCl4-induced ***:Different doses of Levisticum officinale extract were given orally to rats for 10 days,then rats received a single dose of CCl4(2.5 mL/kg,50%v/v in liquid paraffin).Biochemical and histopathological assays were performed to assess the effects of the extract on liver function and ***,antioxidant and oxidative markers as well as inflammatory and fibrotic indicators were ***:Pretreatment with Levisticum officinale extract significantly mitigated CCl4-induced damage to liver structure,improved serum levels of alanine aminotransferase,aspartate aminotransferase,alkaline phosphatase,urea,total bilirubin,and total protein,enhanced glutathione content and superoxide dismutase and catalase activities in the liver,as well as decreased plasma and hepatic malondialdehyde *** results demonstrated that the extract reduced Ki-67 andα-SMA expression and Masson’s trichrome staining revealed decreased liver collagen in rats treated with Levisticum officinale ***,Levisticum officinale extract markedly decreased the gene expressions of TNF-α,IL-6,TGF-β1,MCP-1,and ***:Levisticum officinale extract exerts hepatoprotective effects on CCl4-induced hepatotoxicity through antioxidant,anti-inflammatory,and anti-fibrotic activities.

关键词： Levisticum officinale CCl4 Inflammation Liver toxicity Antioxidant

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Mutations in Ras homolog family member A in patients with peripheral T-cell lymphoma and implications for personalized medicine

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Cancer Biology & Medicine 2024年第9期21卷 754-768页

作者： Lina Hu Xuanye Zhang Shengbing Zang Sun Yat-sen University Cancer center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Department of pathology Sun Yat-sen University Cancer Center Department of Medical Oncology Sun Yat-sen University Cancer Center

Genome sequencing has revealed frequent mutations in Ras homolog family member A(RHOA) among various cancers with unique aberrant profiles and pathogenic effects, especially in peripheral T-cell lymphoma(PTCL). The discrete positional distribution and types of RHOA amino acid substitutions vary according to the tumor type, thereby leading to different functional and biological properties, which provide new insight into the molecular pathogenesis and potential targeted therapies for various tumors. However, the similarities and discrepancies in characteristics of RHOA mutations among various histologic subtypes of PTCL have not been fully elucidated. Herein we highlight the inconsistencies and complexities of the type and location of RHOA mutations and demonstrate the contribution of RHOA variants to the pathogenesis of PTCL by combining epigenetic abnormalities and activating multiple downstream pathways. The promising potential of targeting RHOA as a therapeutic modality is also outlined. This review provides new insight in the field of personalized medicine to improve the clinical outcomes for patients.

关键词： Drug target Ras homolog family member A mutation pathogenesis peripheral T-cell lymphoma personalized medicine

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Parasites of the liver:A global problem?

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World Journal of Gastroenterology 2024年第30期30卷 3554-3559页

作者： Vladislav V Tsukanov Alexander V Vasyutin Julia L Tonkikh Clinical Department of the Digestive System pathology of Adults and Children Federal Research Center“Krasnoyarsk Science Center”of the Siberian Branch of the Russian Academy of SciencesScientific Research Institute of Medical Problems of the NorthKrasnoyarsk 660022Russia

Parasitic liver diseases can be caused by trematodes,cestodes,nematodes,and *** pathology is significant because millions of people in different parts of the world have liver parasites,which can manifest themselves in the development of inflammation,liver cysts,cholecystitis,cholelithiasis,pancreatitis and liver cirrhosis that are often threatening their *** International Agency for Research on Cancer considers three species of trematodes,Schistosoma haematobium,Opisthorchis viverrini and Clonorchis sinensis,to be *** modern examination methods,in some cases including extensive screening of large populations,are required for diagnosing liver *** of parasitic liver diseases is differentiated and can involve a combination of surgical and therapeutic *** is no doubt that the clinical and epidemiological scale allows one to regard parasitic liver diseases as a global healthcare problem.

关键词： Liver Parasites Epidemiology Diagnosis Clinics Treatment Echinococcosis Opisthorchiasis Fascioliasis Schistosomiasis

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The impact of broad glutamine metabolism inhibition on the tumor microenvironment

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Genes & Diseases 2024年第3期11卷 2-4页

作者： Tianhe Li Yun-Ta Chuang Tian-Li Wang Departments of pathology Oncologyand Gynecology and ObstetricsThe Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreMD 21231USA

Glutamine is an importantα-amino acid that provides carbon and nitrogen sources for the biosynthesis of nucleotides,proteins,and *** also generates metabolites that fuel the tricarboxylic acid cycle and maintain intracellular redox *** cells have a heightened metabolic dependence on glutamine to support incessant tumor growth and mitigate tumor microenvironmental stresses including hypoxia,nutrient depletion.

关键词： metabolism tumor microenvironment

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The evolution of cancer genomic medicine in Japan and the role of the National Cancer center Japan

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Cancer Biology & Medicine 2024年第1期21卷 29-44页

作者： Teruhiko Yoshida Yasushi Yatabe Ken Kato Genichiro Ishii Akinobu Hamada Hiroyuki Mano Kuniko Sunami Noboru Yamamoto Takashi Kohno Department of Genetic Medicine and Services National Cancer Center HospitalTokyo 104-0045Japan Department of Diagnostic pathology National Cancer Center HospitalTokyo 104-0045Japan Clinical Research Support Offce Clinical Research Coordinating SectionBiobank Translational Research Support SectionNational Cancer Center HospitalTokyo 104-0045Japan Department of pathology and Clinical Laboratories National Cancer Center Hospital EastChiba 277-8577Japan Division of Molecular Pharmacology National Cancer Center Research InstituteTokyo 104-0045Japan National Cancer center Research Institute Tokyo 104-0045Japan Department of Laboratory Medicine National Cancer Center HospitalTokyo 104-0045Japan Department of Experimental Therapeutics National Cancer Center HospitalTokyo 104-0045Japan Division of Genome Biology National Cancer Center Research InstituteTokyo 104-0045Japan

The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer *** the time,a variety of activating oncogenic alterations and their functional significance were unveiled in cancer cells,which led to the development of molecular targeted therapies in the 2000s and *** CGM is still a relatively new discipline and it is difficult to predict to what extent CGM will benefit the diverse pool of cancer patients,the National Cancer center(NCC)of Japan has already contributed considerably to CGM advancement for the conquest of *** back at these past achievements of the NCC,we predict that the future of CGM will involve the following:1)A biobank of paired cancerous and non-cancerous tissues and cells from various cancer types and stages will be *** quantity and quality of these samples will be compatible with omics *** biobank samples will be linked to longitudinal clinical information.2)New technologies,such as whole-genome sequencing and artificial intelligence,will be introduced and new bioresources for functional and pharmacologic analyses(e.g.,a patient-derived xenograft library)will be systematically deployed.3)Fast and bidirectional translational research(bench-to-bedside and bedside-to-bench)performed by basic researchers and clinical investigators,preferably working alongside each other at the same institution,will be implemented;4)Close collaborations between academia,industry,regulatory bodies,and funding agencies will be established.5)There will be an investment in the other branch of CGM,personalized preventive medicine,based on the individual's genetic predisposition to cancer.

关键词： Cancer genomic medicine biobank patient-derived xenograft multi-gene panel test whole genome sequencing

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