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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 roles.Our data showed that Gal1 was highly expressed in human and mouse HCC.The levels of Gal1 positively correlated with the stages of human HCC and negatively with survival.The roles of Gal1 in HCC were studied using overexpression(OE)or silencing using Igals1 siRNA delivered by AAV9.Prior to HCC initiation induced by RAS and AKT mutations,lgals1-OE and silencing had opposite impacts on tumor load.The 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 weight.Comparing 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 silencing.Within the tumors,silencing Gal1 inhibited translational initiation,elongation,and termination.Furthermore,Gal1 silencing increased immune cells as well as expanded cytotoxic T cells within the tumor,and the anti-HCC effect of lgals1 siRNAwas CD8-dependent.Overall,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

Single nucleotide polymorphism within chromosome 8q24 is associated with prostate cancer development in Saudi Arabia

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Asian Journal of Urology 2024年第1期11卷 26-32页

作者： Awad Elsid Osman Sahar Alharbi Atif Ali Ahmed Asim Ali Elbagir pathology and Clinical laboratory Management department(PCLM) King Fahad Medical CityRiyadhSaudi Arabia department of pathology and laboratory medicine University of Missouri at Children's Mercy HospitalKansas CityMOUSA

Objective: Genome-wide association studies have demonstrated that single nucleotide polymorphisms (SNPs) are important risk factors for the development of prostate cancer (PCa). Preliminary studies have suggested that the incidence of PCa in Saudi males is low but is probably familial or genetically related.Methods: To identify any possible association of SNP with PCa development in Saudi patients, we investigated a group of SNPs in Saudi PCa patients (n=85) and compared the outcomes to healthy normal controls (n=115) and nodular hyperplasia patients (n=120). DNA was extracted from paraffin-embedded formalin fixed tissue or whole blood from both patients’ groups and healthy control group. A total of thirteen SNPs were genotyped using TaqMan® minor groove binder polymerase chain reaction assay.Results: The rs16901979A, s629242T and rs1447295A alleles were found at significantly higher frequency in PCa patients than controls (p< 0.05). The rs16901979 CA genotype was found at significantly greater frequency in PCa patients than in healthy controls (43% vs. 14%, odds ratio=4.6, p=0.0001) and benign hyperplasia group (43% vs. 25%, odds ratio=2.2, p=0.009).Conclusion: Our study has highlighted the association of rs16901979 SNP with PCa in Saudi males. Such findings have important implications in the PCa diagnosis and in screening unaffected family members of Saudi patients.

关键词： Prostatecancer Saudi Singlenucleotide polymorphism Allele

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抗PD-1治疗相关肝损伤的组织学模式

Gastroenterology Report 2020年第1期8卷 50-55,I0002页

作者： Dongwei Zhang John Hart Xianzhong Ding Xuchen Zhang Michael Feely Lindsay Yassan Lindsay Alpert Consuelo Soldevila-Pico Xuefeng Zhang Xiuli Liu Jinping Lai department of pathology Immunology and Laboratory of MedicineUniversity of Florida College of MedicineGainesvilleFLUSA department of pathology and laboratory medicine University of Rochester Medical CenterRochesterNYUSA department of pathology University of Chicago Pritzker School of MedicineChicagoILUSA department of pathology and laboratory of medicine Loyola University Medical CenterMaywoodILUSA department of pathology Yale School of MedicineNew HavenCTUSA department of medicine University of Florida College of MedicineGainesvilleFLUSA department of pathology Duke University Medical CenterDurhamNCUSA department of pathology Kaiser Permanente Sacramento Medical CenterSacramentoCAUSA

背景:Nivolumab和pembrolizumab是两种PD-1受体阻断性单克隆抗体,已成功用于多种晚期恶性肿瘤的治疗。抗PD-1治疗诱发的肝脏毒性的组织学变化尚未被深入研究,因此,本研究旨在评估这一组织学模式。方法:回顾性分析来自5个医疗中心(佛罗... 详细信息

背景:Nivolumab和pembrolizumab是两种PD-1受体阻断性单克隆抗体,已成功用于多种晚期恶性肿瘤的治疗。抗PD-1治疗诱发的肝脏毒性的组织学变化尚未被深入研究,因此,本研究旨在评估这一组织学模式。方法:回顾性分析来自5个医疗中心(佛罗里达大学医学院、芝加哥大学Pritzker医学院、Loyola大学医学中心、耶鲁大学医学院、杜克大学医学中心)的8例接受Nivolumab或pembrolizumab治疗的晚期恶性肿瘤患者。这些患者既往均无肝病史,病毒性肝炎检测均为阴性。结果:抗PD-1治疗后,8例患者中有7例出现轻中度的胃肠道症状,如腹痛、疲乏、恶心、呕吐及黄疸。所有患者肝脏化学检测指标均显著升高。6例患者的肝损伤表现为急性小叶性肝炎,另外2例不同的损伤模式分别为脂肪性肝炎合并轻度胆汁淤积和急性胆汁淤积性损伤。无一例出现自身免疫性肝炎的典型特征。所有患者在中止抗PD-1治疗并予以免疫抑制治疗后,肝功能均恢复正常。结论:本研究结果显示,在抗PD-1治疗前对肝功能异常者进行筛选并在治疗期间定期监测肝功能指标,有助于预防严重肝损伤的发生。PD-1抑制剂并不会导致自身免疫性肝炎,而仅仅是引起免疫介导的急性非特异性肝炎。对于部分肝损伤患者,只要中止抗PD-1治疗即可,不必采用类固醇治疗。

关键词： nivolumab pembrolizumab anti-PD-1 liver injury histology hepatitis

The CUL4A ubiquitin ligase is a potential therapeutic target in skin cancer and other malignancies

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Chinese Journal of Cancer 2013年第9期32卷 478-482页

作者： Jeffrey Hannah Peng-Bo Zhou department of pathology and laboratory medicine Weill Cornell Medical College and Weill Cornell Graduate School of Medical Sciences department of pathology and laboratory medicine Weill Cornell Medical College

Cullin 4A(CUL4A)is an E3 ubiquitin ligase that directly affects DNA repair and cell cycle progression by targeting substrates including damage-specific DNA-binding protein 2(DDB2),xeroderma pigmentosum complementation group C(XPC),chromatin licensing and DNA replication factor 1(Cdt1),and p21.Recent work from our laboratory has shown that Cul4a-deficient mice have greatly reduced rates of ultraviolet-induced skin carcinomas.On a cellular level,Cul4a-deficient cells have great capacity for DNA repair and demonstrate a slow rate of proliferation due primarily to increased expression of DDB2 and p21,respectively.This suggests that CUL4A promotes tumorigenesis(as well as accumulation of skin damage and subsequent premature aging)by limiting DNA repair activity and expediting S phase entry.In addition,CUL4A has been found to be up-regulated via gene amplification or overexpression in breast cancers,hepatocellular carcinomas,squamous cell carcinomas,adrenocortical carcinomas,childhood medulloblastomas,and malignant pleural mesotheliomas.Because of its oncogenic activity in skin cancer and up-regulation in other malignancies,CUL4A has arisen as a potential candidate for targeted therapeutic approaches.In this review,we outline the established functions of CUL4A and discuss the E3ligase’s emergence as a potential driver of tumorigenesis.

关键词：泛素连接酶恶性肿瘤皮肤癌治疗 DNA修复 DNA结合蛋白靶点细胞水平

Update on hepatocellular carcinoma: Pathologists' review

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World Journal of Gastroenterology 2019年第14期25卷 1653-1665页

作者： Tony El Jabbour Stephen M Lagana Hwajeong Lee department of pathology and laboratory medicine Albany Medical College department of pathology and Cell Biology College of Physicians and Surgeons Columbia University

Histopathologic diversity and several distinct histologic subtypes of hepatocellular carcinoma(HCC) are well-recognized. Recent advances in molecular pathology and growing knowledge about the biology associated with distinct histologic features and immuno-profile in HCC allowed pathologists to update classifications. Improving sub-classification will allow for more clinically relevant diagnoses and may allow for stratification into biologically meaningful subgroups. Therefore, immuno-histochemical and molecular testing are not only diagnostically useful, but also are being incorporated as crucial components in predicting prognosis of the patients with HCC. Possibilities of targeted therapy are being explored in HCC, and it will be important for pathologists to provide any data that may be valuable from a theranostic perspective. Herein, we review and provide updates regarding the pathologic sub-classification of HCC.Pathologic diagnostic approach and the role of biomarkers as prognosticators are reviewed. Further, the histopathology of four particular subtypes of HCC:Steatohepatitic, clear cell, fibrolamellar and scirrhous-and their clinical relevance, and the recent consensus on combined HCC-cholangiocarcinoma is summarized. Finally, emerging novel biomarkers and new approaches to HCC stratification are reviewed.

关键词： Hepatocellular carcinoma Subtype Classification Review Update

Regulation of hematopoietic stem cells in the niche

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Science China(Life Sciences) 2015年第12期58卷 1209-1215页

作者： ZHAO Meng LI LinHeng Stowers Institute for medical Research department of pathology & laboratory medicine University of Kansas Medical Center

Hematopoiesis provides a suitable model for understanding adult stem cells and their niche. Hematopoietic stem cells(HSCs) continuously produce blood cells through orchestrated proliferation, self-renewal, and differentiation in the bone marrow(BM). Within the BM exists a highly organized microenvironment termed "niche" where stem cells reside and are maintained. HSC niche is the first evidence that a microenvironment contributes to protecting stem cell integrity and functionality in mammals. Although multiple models exist, recent progress has principally elucidated the cellular complexity of the HSC niche that maintains and regulates HSCs in BM. Here we introduce the development and summarize the achievements of HSC niche studies.

关键词：造血干细胞小生境调控成体干细胞自我更新哺乳动物研究成果 HSC

Coexisting tubular adenoma with a neuroendocrine carcinoma of colon allowing early surgical intervention and implicating a shared stem cell origin

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World Journal of Gastroenterology 2017年第6期23卷 1106-1112页

作者： Mahmoud L Soliman Ashish Tiwari Qing Zhao department of pathology and laboratory medicine Boston University Medical Center department of Gastroenterology Boston University Medical Center

High-grade colonic neuroendocrine carcinomas (NECs) are uncommon but extremely aggressive. Their co-existence with tubular adenoma (TA) has rarely been reported. We present a 68-year-old man who was found on routine colonoscopy to have multiple colorectal TAs and an ulcerated lesion in the ascending colon. Microscopically, a poorly-differentiated invasive carcinoma juxtaposed with a TA was identified. Differential diagnosis included a poorly-differentiated adenocarcinoma, medullary carcinoma, high-grade NEC and lymphoma. The immunohistochemical profile showed positive staining for keratins, synaptophysin and chromogranin but negative for LCA, CDX2, CK7, CK20, TTF-1 and PSA, supporting the NEC diagnosis. Upon subsequent laparoscopic right hemicolectomy, the tumor was identified as a 3.0 cm umbilicated and ulcerated mass with an adjacent TA. Both TA and NEC showed positive staining for β-catenin indicating a shared colonic origin. The mitotic counts (77/10 high power fields) and a high proliferation rate (75% by Ki-67) corroborated a high-grade stratification. Mutational analysis indicated a wild-type BRAF and KRAS with mismatch repair proficiency. The AJCC(7th edition) pathologic stage is p T3, p N0, p Mx. The patient received adjuvant chemotherapy with cisplatin/etoposides for three cycles and will be followed up for a year to detect recurrence. In conclusion, the co-existence of TA with high grade-NEC in our case allowed early identificationand intervention of the otherwise asymptomatic but aggressive tumor. In addition, the finding of a highgrade NEC within a large TA in this case suggests a link between the two lesions and could represent a shared stem cell origin.

关键词： Neuroendocrine 癌管状的腺瘤 Colorectal Colocalization

Understanding axon guidance: attraction, repulsion, and statistical physics

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Neural Regeneration Research 2015年第2期10卷 176-179页

作者： William G.Wadsworth Rutgers Robert Wood Johnson medical School Department of Pathology and Laboratory Medicine

Understanding axon guidance is important for developing therapies to restore neuronal connections damaged by injury or disease. Axons migrate in response to extraceUular guidance molecules that induce or inhibit axon outgrowth activity within the axon. The direction of guidance is determined by the attractive and repulsive responses that the axon has to the guidance cues. In a deterministic model of guidance, the direction of guidance can be precisely determined if the attractive and repulsive effect that each cue has on the axon is known. But what if there are numerous attractive and repulsive responses induced by multiple guidance cues, and the direction of the attractive and repulsive events fluctuates？ If the effect that each attractive and repulsive event has on guidance becomes too complex to measure then understand- ing how each molecular cue influences the guidance decision becomes impossible.

关键词： and statistical physics Understanding axon guidance UNC

Emerging chemical engineering of exosomes as“bioscaffolds”in diagnostics and therapeutics

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Genes & Diseases 2023年第4期10卷 1494-1512页

作者： Jianwei Wang Meijiao Wang Ning Jiang Shijia Ding Qiling Peng Lei Zheng School of Basic medical Science Chongqing Medical UniversityChongqing 400016China Molecular medicine Diagnostic and Testing Center Chongqing Medical UniversityChongqing 400016China department of pathology Chongqing Medical UniversityChongqing 400016China College of laboratory medicine Chongqing Medical UniversityChongqing 400016China department of laboratory medicine Nanfang HospitalSouthern Medical University/The First School of Clinical MedicineSouthern Medical UniversityGuangzhouGuangdong 510515China

All cells release extracellular vesicles(EVs)as part of their normal physiology.As one of the subtypes,exosomes(EXOs)have an average size range of approximately 40 nm e160 nm in diameter.Benefiting from their inherent immunogenicity and biocompatibility,the utility of autologous EXOs has the potential for both disease diagnosis/treatment.EXOs are generally employed as“bioscaffolds”and the whole diagnostic and therapeutic effects are mainly ascribed to exogenous cargos on the EXOs,such as proteins,nucleic acids,and chemotherapeutic agents and fluorophores delivered into specific cells or tissues.Surface en-gineering of EXOs for cargo loadings is one of the prerequisites for EXO-mediated diagnosis/treatment.After revisiting EXO-mediated diagnosis/treatment,the most popular strategies to directly undertake loadings of exogenous cargos on EXOs include genetic and chemical en-gineering.Generally,genetically-engineered EXOs can be merely produced by living organisms and intrinsically face some drawbacks.However,chemical methodologies for engineered EXOs diversify cargos and extend the functions of EXOs in the diagnosis/treatment.In this review,we would like to elucidate different chemical advances on the molecular level of EXOs along with the critical design required for diagnosis/treatment.Besides,the prospects of chemical engineering on the EXOs were critically addressed.Nevertheless,the superiority of EXO-medi-ated diagnosis/treatment via chemical engineering remains a challenge in clinical translation and trials.Furthermore,more chemical crosslinking on the EXOs is expected to be explored.Despite substantial claims in the literature,there is currently no review to exclusively summa-rize the chemical engineering to EXOs for diagnosis/treatment.We envision chemical engi-neering of EXOs will encourage more scientists to explore more novel technologies for a wider range of biomedical applications and accelerate the successful translation of EXO-based drug“bioscaffolds”from bench to bedside.

关键词： Chemical engineering Diagnostics Exosomes Extracellular vesicles Theranostics Therapeutics