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Comprehensive molecular characterization to predict immunotherapy response in advanced biliary tract cancer: a phase II trial of pembrolizumab

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oncology research 2025年第1期33卷 57-65页

作者： Ryul Kim Joo Kyung Park Minsuk Kwon Minae An Jung Yong Hong Joon Oh Park Sung Hee Lim Seung Tae Kim division of hematology-oncology Department of Medicine Samsung Medical Center Sungkyunkwan University School of Medicine Seoul Korea. division of Gastroenterology Department of Medicine Samsung Medical Center Sungkyunkwan University School of Medicine Seoul Korea. department of hematology-oncology Ajou University School of Medicine Suwon-si Gyeonggi-do Korea. Samsung Advanced Institute of Health Science and Technology Sungkyunkwan University School of Medicine Seoul Korea.

Background:Immune checkpoint inhibitors (ICIs) are effective in a subset of patients with metastatic solid tumors. However, the patients who would benefit most from ICIs in biliary tract cancer (BTC) are still controversial.Materials and methods:We molecularly characterized tissues and blood from 32 patients with metastatic BTC treated with the ICI pembrolizumab as second-line therapy.Results:All patients had microsatellite stable (MSS) type tumors. Three of the 32 patients achieved partial response (PR), with an objective response rate (ORR) of 9.4% (95% confidence interval [CI], 2.0-25.2) and nine showed stable disease (SD), exhibiting a disease control rate (DCR) of 37.5% (95% CI, 21.1-56.3). For the 31 patients who had access to PD-1 ligand 1 (PD-L1) combined positive score (CPS) testing (cut-off value ≥1%), the ORR was not different between those who had PD-L1-positive (PD-L1+; 1/11, 9.1%) and PDL1-(2/20, 10.0%) tumors ( = 1.000). The tumor mutational burden (TMB) of PD-L1+ BTC was comparable to that of PD-L1-BTC ( = 0.630). TMB and any exonic somatic mutations were also not predictive of pembrolizumab response. Molecular analysis of blood and tumor samples demonstrated a relatively high natural killer (NK) cell proportion in the peripheral blood before pembrolizumab treatment in patients who achieved tumor response. Moreover, the tumors of these patients presented high enrichment scores for NK cells, antitumor cytokines, and Th1 signatures, and a low enrichment score for cancer-associated fibroblasts.Conclusions:This study shows the molecular characteristics associated with the efficacy of pembrolizumab in BTC of the MSS type.

关键词： Biliary tract cancer Pembrolizumab Whole-exome sequencing Whole-transcriptome sequencing

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Proton pump inhibitors and all-cause mortality risk among cancer patients

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World Journal of Clinical oncology 2025年第1期16卷 34-42页

作者： Arunkumar Krishnan Carolin Victoria Schneider Declan Walsh department of Supportive oncology Atrium Health Levine CancerCharlotteNC 28204United States department of medicine Section of Hematology and OncologyWake Forest University School of MedicineWinston-SalemNC 27101United States department of medicine Ⅲ GastroenterologyMetabolic Diseasesand Intensive CareUniversity Hospital RWTH AachenAachen 52074Germany

BACKGROUND Proton pump inhibitors(PPIs)are widely used,including among cancer patients,to manage gastroesophageal reflux and other gastric acid-related *** evidence suggests associations between long-term PPI use and higher risks for various adverse health outcomes,including greater *** To investigate the association between PPI use and all-cause mortality among cancer patients by a comprehensive analysis after adjustment for various confounders and a robust methodological approach to minimize *** This retrospective cohort study used data from the TriNetX research network,with electronic health records from multiple healthcare *** study employed a new-user,active comparator design,which compared newly treated PPI users with non-users and newly treated histamine2 receptor antagonists(H2RA)users among adult cancer *** prescribed PPIs(esomeprazole,lansoprazole,omeprazole,pantoprazole,or rabeprazole)users were compared to non-users or newly prescribed H2RAs(cimetidine,famotidine,nizatidine,or ranitidine)*** primary outcome was all-cause *** patient in the main group was matched to a patient in the control group using 1:1 propensity score matching to reduce confounding *** Cox regression models were used to estimate hazard ratios(HRs)and 95% confidence interval(CI).RESULTS During the follow-up period(median 5.4±1.8 years for PPI users and 6.5±1.0 years for non-users),PPI users demonstrated a higher all-cause mortality rate than non-users after 1 year,2 years,and at the end of follow up(HRs:2.34-2.72).Compared with H2RA users,PPI users demonstrated a higher rate of all-cause mortality HR:1.51(95%CI:1.41-1.69).Similar results were observed across sensitivity analyses by excluding deaths from the first 9 months and 1-year post-exposure,confirming the robustness of these *** a sensitivity analysis,we analyzed all-cause mortality outcomes between former PPI users and individual

关键词： All-cause mortality Cancer Histamine-2 receptor antagonists Mortality Malignancy Proton pump inhibitors Carcinoma Outcome

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FHL2 deficiency aggravates Candida albicans infection through decreased myelopoiesis

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Science China Life Sciences 2025年

作者： Rongmei Gao Kanchao Chen Yimin Wang Rongxia Guo Xiaoyu Zhang Peng Wu Weili Wang Qingxiang Huang Xuemei Xie Shangda Yang Yanling Lü Qian Ren Fei Liu Song Chen Fengxia Ma Tao Cheng Hui Cheng State Key Laboratory of Experimental hematology National Clinical Research Center for Blood Diseases Haihe Laboratory of Cell Ecosystem Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Sciences & Peking Union Medical College CAMS Center for Stem Cell medicine PUMC Department of Stem Cell and Regenerative Medicine

Hematopoiesis is a finely tuned process that generates all blood cell types through self-renewal and differentiation, which is crucial for maintaining homeostasis. Acute infections can prompt a hematopoietic response known as emergency myelopoiesis. In this study, using a Candida albicans (C. albicans) infection model, we demonstrated for the first time that disruption of Fhl2 led to increased fungal burden,heightened inflammatory response and reduced survival rates. Impaired myeloid hematopoiesis and immune cell production were evident, as proved by the decreased numbers of hematopoietic stem and progenitor cells (HSPCs) and granulocytes in the bone marrow of Fhl2-deficient mice. In conclusion, FHL2 regulated emergency myelopoiesis in response to C. albicans, affecting the host’s defense against pathogens.

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Acquired sensorineural hearing loss,oxidative stress,and microRNAs

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Neural Regeneration Research 2025年第9期20卷 2513-2519页

作者： Desmond A.Nunez Ru C.Guo division of Otolaryngology–Head&Neck Surgery Department of SurgeryFaculty of MedicineThe University of British ColumbiaVancouverBCCanada division of Otolaryngology–Head&Neck Surgery Gordon&Leslie Diamond Health Care CentreVancouver General HospitalVancouverBCCanada Faculty of medicine–The University of British Columbia VancouverBCCanada

Hearing loss is the third leading cause of human ***-related hearing loss,one type of acquired sensorineural hearing loss,is largely responsible for this escalating global health ***-induced,ototoxic,and idiopathic sudden sensorineural are other less common types of acquired hearing *** etiology of these conditions is complex and multi-fa ctorial involving an interplay of genetic and environmental *** stress has recently been proposed as a likely linking cause in most types of acquired sensorineural hearing *** non-coding RNA sequences known as microRNAs(miRNAs)have increasingly been shown to play a role in cellular hypoxia and oxidative stress responses including promoting an apoptotic *** hair cell death is a central histopathological finding in sensorineural hearing *** these cells do not regenerate in humans,it underlies the irreversibility of human age-related hearing *** EMBASE,Ovid MEDLINE,Web of Science Core Collection,and *** databases over the period August 1,2018 to July 31,2023 were searched with"hearing loss,""hypoxamiRs,""hypoxia,""microRNAs,""ischemia,"and"oxidative stress"text words for English language primary study publications or registered clinical *** red clinical trials known to the senior author we re also assessed.A total of 222studies were thus *** excluding duplicates,editorials,retra ctions,secondary research studies,and non-English language articles,39 primary studies and clinical trials underwent full-text *** resulted in 11 animal,in vitro,and/or human subject journal articles and 8 registered clinical trial database entries which form the basis of this narrative *** miR-34a and miR-29b levels increase with age in *** miRNAs were demonstrated in human neuroblastoma and murine cochlear cell lines to target Sirtuin 1/peroxisome proliferato r-activated receptor gamma coactivator-1-alpha(SIRT1/P GC-1α),SIRT

关键词： hearing loss hypoxia microRNAs oxidative stress sensorineural

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Ubiquitin-specific protease 1 facilitates tumor immune escape from natural killer cells and predicts the prognosis in small cell lung cancer

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oncology research 2025年第1期33卷 213-224页

作者： Shiqin Jiang Yichun Tang Feng Ma Yuchun Niu Lei Sun department of Clinical Pharmacy Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine Shenzhen 518104 China. department of Pathology Zhujiang Hospital Southern Medical University Guangzhou 510280 China. department of Radiation oncology The First People's Hospital of Foshan Foshan 528000 China. department of oncology The First Affiliated Hospital of Jinan University Jinan University Guangzhou 510630 China. department of oncology The First Dongguan Affiliated Hospital Guangdong Medical University Dongguan 523721 China.

Objective:Small cell lung cancer (SCLC) is commonly recognized as the most fatal lung cancer type. Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers, their benefits are limited to a minority of patients with SCLC. In the present study, novel indicators for predicting the outcomes and molecular targets for SCLC treatment were elucidated.Methods:We conducted bioinformatics analysis to identify the key genes associated with tumor-infiltrating lymphocytes in SCLC. The functional role of the key gene identified in SCLC was determined both and .Results:A significant correlation was observed between patient survival and CD56dim natural killer (NK) cell proportion. Furthermore, we noted that the hub gene ubiquitin-specific protease 1 (USP1) is closely correlated with both CD56dim NK cells and overall survival in SCLC. Bioinformatics analysis revealed that USP1 is upregulated in SCLC. In addition, gene set enrichment analysis revealed that USP1 overexpression hinders NK cell-mediated immune responses. By co-cultivating NK-92 cells with SCLC cells, we demonstrated that NK cell cytotoxicity against SCLC could be improved either via USP1 knock-down or pharmacological inhibition. Furthermore, using a nude-mice xenograft tumor model, we noted that USP1 inhibition effectively suppressed tumor proliferation and increased the expression of NK cell-associated markers.Conclusions:Our study findings highlight the importance of NK cells in regulating SCLC. USP1 overexpression can inhibit NK cell-mediated immunity; therefore, USP1 may serve not only as a prognostic biomarker but also as a potential molecular target of SCLC therapy.

关键词： Immune escape Natural killer (NK) cell Prognosis Small cell lung cancer (SCLC) Ubiquitin-specific protease 1 (USP1)

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Lighting the shades of hidden pain:a role for spinal cord neurons and microglia in vestibulodynia

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Neural Regeneration Research 2025年第10期20卷 2898-2900页

作者： Rosmara Infantino Francesca Gargano Serena Boccella Carmela Belardo Andrea Maria Morace Francesca Guida Sabatino Maione Livio Luongo department of Experimental medicine Division of PharmacologyUniversitàdegli Studi della Campania“L.Vanvitelli”Italy UniversitàCampus Bio-medico di Roma RomeItaly

Vulvodynia,a chronic pain disorder affecting the vulvar region,represents a significant challenge in both diagnosis and treatment within the field of women’s *** condition is characterized by chronic pain that significantly affects the quality of life of afflicted *** present perspective paper examines the role of spinal sensitization and microglial activation in vulvodynia.

关键词： pain diagnosis activation

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Inflammasome links traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease

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Neural Regeneration Research 2025年第6期20卷 1644-1664页

作者： Gabriela Seplovich Yazan Bouchi Juan Pablo de Rivero Vaccari Jennifer C.Munoz Pareja Andrew Reisner Laura Blackwell Yehia Mechref Kevin K.Wang J.Adrian Tyndall Binu Tharakan Firas Kobeissy department of Surgery Morehouse School of MedicineAtlantaGAUSA department of Neurobiology Center for NeurotraumaMultiomics&Biomarkers(CNMB)Neuroscience InstituteMorehouse School of MedicineAtlantaGAUSA department of Neurological Surgery and the Miami Project to Cure Paralysis University of Miami Miller School of MedicineMiamiFLUSA division of Pediatric Critical Care Department of PediatricsUniversity of Miami Miller School of MedicineMiamiFLUSA department of Pediatrics Emory UniversityAtlantaGAUSA department of Neurosurgery Children’s Healthcare of AtlantaAtlantaGAUSA department of Chemistry and Biochemistry Texas Tech UniversityLubbockTXUSA Morehouse School of medicine AtlantaGAUSA

Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasomedependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.

关键词： Alzheimer's disease caspase-1 chronic traumatic encephalopathy inflammasomes neurodegeneration neuroinflammation NLRP1 NLRP3 pyroptosis tauopathy traumatic brain injury

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Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery

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Neural Regeneration Research 2025年第1期20卷 224-233页

作者： Yi Zhang Zhongwu Liu Michael Chopp Michael Millman Yanfeng Li Pasquale Cepparulo Amy Kemper Chao Li Li Zhang Zheng Gang Zhang department of Neurology Henry Ford HospitalDetroitMIUSA department of Physics Oakland UniversityRochesterMIUSA department of Pathology Henry Ford HospitalDetroitMIUSA division of Pharmacology Department of NeuroscienceReproductive and Dentistry SciencesSchool of MedicineUniversity of Naples“Federico Ⅱ”NaplesItaly

Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional *** previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic *** the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression *** EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a *** male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or *** array of behavior assays was used to measure neurological *** with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological *** vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal *** analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct *** of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of *** data provide evidence that 27a-sEVs have

关键词： axonal remodeling cerebral endothelial cells exosomes miR-27a mitochondria Semaphorin 6A small extracellular vesicles stroke

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Inhibiting SHP2 reduces glycolysis, promotes microglial M1 polarization, and alleviates secondary inflammation following spinal cord injury in a mouse model

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Neural Regeneration Research 2025年第3期20卷 858-872页

作者： Xintian Ding Chun Chen Heng Zhao Bin Dai Lei Ye Tao Song Shuai Huang Jia Wang Tao You department of Orthopedics The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui ProvinceChina department of Orthopedics Provincial Hospital Affiliated to Anhui Medical UniversityHefeiAnhui ProvinceChina

Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2(SHP2), encoded by PTPN11, is widely expressed in the human body and plays a role in inflammation through various mechanisms. Therefore, SHP2 is considered a potential target for the treatment of inflammation-related diseases. However, its role in secondary inflammation after spinal cord injury remains unclear. In this study, SHP2 was found to be abundantly expressed in microglia at the site of spinal cord injury. Inhibition of SHP2 expression using siRNA and SHP2 inhibitors attenuated the microglial inflammatory response in an in vitro lipopolysaccharide-induced model of inflammation. Notably, after treatment with SHP2 inhibitors, mice with spinal cord injury exhibited significantly improved hind limb locomotor function and reduced residual urine volume in the bladder. Subsequent in vitro experiments showed that, in microglia stimulated with lipopolysaccharide, inhibiting SHP2 expression promoted M2 polarization and inhibited M1 polarization. Finally, a co-culture experiment was conducted to assess the effect of microglia treated with SHP2 inhibitors on neuronal cells. The results demonstrated that inflammatory factors produced by microglia promoted neuronal apoptosis, while inhibiting SHP2 expression mitigated these effects. Collectively, our findings suggest that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. Therefore, inhibiting SHP2 alleviates the inflammatory response in mice with spinal cord injury and promotes functional recovery postinjury.

关键词： apoptosis glycolysis inflammatory response microglia neurons polarization spinal cord injury Src homology 2-containing protein tyrosine phosphatase 2

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Apples to oranges:environmentally derived,dynamic regulation of serotonin neuron subpopulations in adulthood?

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Neural Regeneration Research 2025年第9期20卷 2596-2597页

作者： Christopher J.O’Connell Matthew J.Robson department of Genetics College of MedicineHarvard UniversityBostonMAUSA James L.Winkle College of Pharmacy Division of Pharmaceutical SciencesUniversity of CincinnatiCincinnatiOHUSA Neuroscience Graduate Program College of MedicineUniversity of CincinnatiCincinnatiOHUSA

Traumatic brain injury(TBI)is a public health problem with an undue economic burden that impacts nearly every age,ethnic,and gender group across the globe(Capizzi et al.,2020).TBIs are often sustained during a dynamic range of exposures to energetic environmental forces and as such outcomes are typically heterogeneous regarding severity and pathology(Capizzi et al.,2020).

关键词： sustained orange dynamic

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