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Synthetic lethality by PARP inhibitors: new mechanism uncovered based on unresolved transcription-replication conflicts

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Signal Transduction and Targeted Therapy 2024年第8期9卷 3163-3164页

作者： marina Kolesnichenko Claus Scheidereit Department of Hepatology and Gastroenterology Charite-Universitatsmedizin BerlinBerlinGermany Laboratory for Signal Transduction in Tumor Cells Max Delbruck Center for Molecular Medicine in the Helmholtz Association(MDC)BerlinGermany

In a landmark study recently published in Nature,Petropoulous et *** that synthetic lethality of poly(ADP-ribose)polymerase(PARP)inhibitors in cells with defective homologous recombination repair(HR)results predominantly from transcription replication conflicts(TRC)and not,as previously proposed,from PARP trapping on DNA(Fig.1).The article unveils a new mechanism behind synthetic lethality of PARP inhibitors with relevance for cancer therapy.

关键词： al. PARP mechanism

The bumpy road of purinergic inhibitors to clinical application in immune-mediated diseases

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Neural Regeneration Research 2024年第6期19卷 1206-1211页

作者： Matthias T.Wyss Christine Heuer marina Herwerth Institute of Pharmacology and Toxicology University of ZurichZürichSwitzerland Neuroscience Center Zurich(ZNZ) University of Zurich and ETH ZurichZürichSwitzerland Neurology Department University Hospital of ZurichZürichSwitzerland

Purinergic signaling plays important roles throughout the body in the regulation of organ functions during and following the disruption of *** is also reflected by the widespread expression of two families of purinergic receptors(P1 and P2)with numerous *** the last few decades,there has been increasing evidence that purinergic signaling plays an important role in the regulation of immune ***,signals mediated by P2 receptors have been shown to contribute to immune system-mediated ***,interference with P2 receptors may be a promising strategy for the modulation of immune *** only a few clinical studies have been conducted in isolated entities with limited success,preclinical work suggests that the use of P2 receptor inhibitors may bear some promise in various autoimmune *** the association of P2 receptors with se.e.al disorders from this field,the use of P2 receptor antagonists in clinical therapy is still very *** this narrative review,we briefly review the involvement of the purinergic system in immunological responses and clinical studies on the effect of purinergic inhibition on autoimmune *** then open the aperture a bit and show some preclinical studies demonstrating a potential effect of purinergic blockade on autoimmune *** suramin,a non-specific purinergic inhibitor,as an example,we further show that off-target effects could be responsible for observed effects in immunological settings,which may have interesting ***,we believe that it is worthwhile to further investigate this hitherto underexplored area.

关键词： autoimmune diseases neurological disorders purinergic system P2 receptor inhibitors suramin

Colon and rectal cancer:An emergent public health problem

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World Journal of Gastroenterology 2024年第7期30卷 644-651页

作者： marina Pinheiro David Nascimento Moreira Michele Ghidini LAQV REQUIMTEDepartment of ChemistryFaculty of PharmacyUniversity of Porto4050-313 PortoPortugal Unidade de Saúde Pública Unidade Local de Saúde Barcelos/EsposendeBarcelinhos 4755-069BragaPortugal Medical Oncology Unit Fondazione IRCCS Ca’Granda Ospedale Maggiore PoliclinicoMilan 20122Italy

Colorectal cancer ranks third globally,with a high mortality *** the United States,and different countries in europe,organized population screenings exist and include people between 50 and 74 years of *** screenings have allowed an early diagnosis and consequently an improvement in health *** and rectal cancer(CRC)is a disease of particular interest due to the high global burden associated with it and the role attributed to prevention and early diagnosis in reducing morbidity and *** study is a review of CRC pathology and includes the most recent scientific evidence regarding this pathology,as well as a diagnosis of the epidemiological situation of ***,the recommendation from a public health perspective will be discussed in detail taking into account the context and the most current recommendations.

关键词： Colon and rectal neoplasia Colon and rectal tumor Mortality Morbidity

Periodontitis:An often-neglected complication of diabetes

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World Journal of Diabetes 2024年第3期15卷 318-325页

作者： marina G Kudiyirickal Joseph M Pappachan Primary Care Dental Practice The Smile ClinicPreston PR16PZUnited Kingdom Department of endocrinology and Metabolism Lancashire Teaching Hospitals NHS TrustPreston PR29HTUnited Kingdom Faculty of Science Manchester Metropolitan UniversityManchester M156BHUnited Kingdom Faculty of Biology Medicine and HealthThe University of ManchesterManchester M139PLUnited Kingdom

The bidirectional association between type 2 diabetes mellitus(T2DM)and periodontitis is now well established,resulting in periodontal disease being considered as the 6th major complication of diabetes mellitus(DM)after cardiovascular disease,eye disease,neuropathy,nephropathy,and peripheral vascular *** can worsen the virulence and invasiveness of pathogenic oral microbial flora aggravating the local inflammation and infection in those with periodontal *** the other hand,the chemical and immunological mediators released into the circulation as part of periodontal inflammation worsen the systemic insulin resistance with worsening of *** if undiagnosed or left untreated can also result in eventual tooth loss.A study by Xu et al in the World Journal of Diabetes examined the predictive factors associated with periodontitis in Chinese patients with *** prevalence of periodontitis was found to be 75.7%in this *** on logistic regression analysis,the predictive factors for higher risk were low tooth brushing frequency[odds ratio(OR)=4.3],high triglycerides(TG;OR=3.31),high total cholesterol(TC;OR=2.87),higher glycated hemoglobin(HbA1c;OR=2.55),and higher age(OR=1.05)while higher education level was protective(OR=0.53).However,the most influential variables were HbA1c followed by age,TC,TG,low education level,brushing frequency,and sex on the random forest model(this model showed higher sensitivity for predicting the risk).A good understanding of the predictors for periodontitis in T2DM patients is important in prevention,early detection of susceptible patients,and intervention to improve periodontal health and enable long-term glycaemic control as observed by Xu et al.

关键词： Diabetes mellitus Periodontitis Predictive factors Cardiovascular disease Glycaemic control

Double role of depression in gastric cancer:As a causative factor and as consequence

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World Journal of Gastroenterology 2024年第10期30卷 1266-1269页

作者： Grigorios Christodoulidis Koumarelas Konstantinos-eleftherios Kouliou marina-Nektaria Department of General Surgery University Hospital of LarissaLarissa 41110Greece

In this editorial we comment on the article“Hotspots and frontiers of the rela-tionship between gastric cancer and depression:A bibliometric study”.Gastric cancer(GC)is a common malignancy in the digestive system with increased mortality and morbidity rates *** treatments,such as gastrectomy,negatively impact patients'quality of life and beyond the physical strain,GC patients face psychological challenges,including anxiety and *** prevalence of depression can be as high as 57%,among gastrointestinal cancer *** to the advancements in treatment effectiveness and increased 5-year overall survival rates,attention has shifted to managing psychological ***,the significance of managing the depression doesn’t lie solely in the need for a better psychological *** leads to chronic stress acti-vating the sympathetic nervous system and the hypothalamus-pituitary-adrenal axis,leading release of catecholamines inducing tumor proliferation,migration,and metastasis,contributing to GC *** dysregulation of neurotrans-mitters and the involvement of various signaling pathways underscore the complex interplay between depression and *** strategies are required to address the psychological aspects of GC,including region-specific interventions and increased monitoring for *** the intricate relationship between depression and GC progression is essential for developing effective therapeutic strategies and improving overall outcomes for patients facing this complex *** this editorial we delve into double role of depression in the pathogenesis of GC and as a complication of it.

关键词： Gastric cancer Depression Anxiety Chronic stress Pathogenesis of gastric cancer

Immune signature of small bowel adenocarcinoma and the role of tumor microenvironment

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World Journal of Gastroenterology 2024年第8期30卷 794-798页

作者： Grigorios Christodoulidis marina Nektaria Kouliou Konstantinos eleftherios Koumarelas Department of General Surgery University Hospital of LarissaLarissa 41110Greece

In this editorial we comment on the article published“Clinical significance of programmed cell death-ligand expression in small bowel adenocarcinoma is determined by the tumor microenvironment”.Small bowel adenocarcinoma(SBA)is a rare gastrointestinal neoplasm and despite the small intestine's significant surface area,SBA accounts for less than 3%of such *** detection is challenging and the reason arises from its asymptomatic nature,often leading to late-stage discovery and poor *** involves platinum-based chemotherapy with a 5-fluorouracil combination,but the lack of effective chemotherapy contributes to a generally poor *** are linked to genetic disorders and risk factors,including chronic inflammatory *** unique characteristics of the small bowel,such as rapid cell renewal and an active immune system,contributes to the rarity of these tumors as well as the high intratumoral infiltration of immune cells is associated with a favorable *** cell death-ligand 1(PD-L1)expression varies across different cancers,with potential discrepancies in its prognostic *** instability(MSI)in SBA is associated with a high tumor mutational burden,affecting the prognosis and response to *** presence of PD-L1 and programmed cell death 1,along with tumor-infiltrating lymphocytes,plays a crucial role in the complex microenvironment of SBA and contributes to a more favorable prognosis,especially in the context of high MSI *** tumor-infiltrating lymphocytes are identified as independent prognostic indicators and the association between MSI status and a favorable prognosis,emphasizes the importance of evaluating the immune status of tumors for treatment decisions.

关键词： Programmed cell death 1 Programmed cell death-ligand 1 Programmed death ligand Small bowel adenocarcinoma Tumor infiltrating lymphocytes Tumor microenvironment Microsatellite instability

Revolutionizing gastric cancer treatment:The potential of immunotherapy

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World Journal of Gastroenterology 2024年第4期30卷 286-289页

作者： Grigorios Christodoulidis Konstantinos eleftherios Koumarelas marina Nektaria Kouliou Department of General Surgery University Hospital of LarissaLarissa 41110Greece

Gastric cancer,a prevalent malignancy worldwide,ranks sixth in terms of frequency and third in fatality,causing over a million new cases and 769000 annual *** in eastern europe and eastern Asia,risk factors include family medical history,dietary habits,tobacco use,Helicobacter pylori,and epstein-Barr virus ***,gastric cancer is often diagnosed at an advanced stage,leading to a grim prognosis,with a 5-year overall survival rate below 5%.Surgical intervention,particularly with D2 Lymphadenectomy,is the mainstay for early-stage cases but offers limited *** advanced cases,the National Comprehensive Cancer Network recommends chemotherapy,radiation,and targeted *** immunotherapy presents promise,especially for unresectable or metastatic cases,with strategies like immune checkpoint inhibitors,tumor vaccines,adoptive immunotherapy,and nonspecific *** this editorial,with regards to the article“Advances and key focus areas in gastric cancer immunotherapy:A comprehensive scientometric and clinical trial review”,we address the advances in the field of immunotherapy in gastric cancer and its future prospects.

关键词： Immunotherapy Adaptive immunotherapy Tumor vaccines Chimeric antigen receptor therapy Tumor-infiltrating lymphocytes therapy Natural killer therapy Cytokine-induced killer therapy engineered T cell receptor therapy Immune checkpoint inhibitors

Understanding autoimmune pancreatitis: Clinical features, management challenges, and association with malignancies

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World Journal of Gastroenterology 2024年第15期30卷 2091-2095页

作者： Grigorios Christodoulidis marina Nektaria Kouliou Konstantinos eleftherios Koumarelas Department of General Surgery University Hospital of LarissaUniversity of ThessalyLarissa 41110Greece

In this editorial we comment on the article by Jaber et *** pancreatitis(AIP)represents a distinct form of pancreatitis,categorized into AIP-1 and AIP-2,characterized by obstructive jaundice,lymphoplasmacytic infiltrate,and ***-1,associated with elevated immunoglobulin G4(IgG4)levels,exhibits higher relapse rates,affecting older males,while AIP-2 is less common and linked to inflammatory bowel *** is considered a manifestation of IgG4-related systemic disease,sharing characteristic histological *** are the primary treatment,with emerging biomarkers like interferon alpha and *** poses an increased risk of various malignancies,and the assoc-iation with pancreatic cancer is *** is reserved for severe cases,necessitating careful evaluation due to diagnostic *** patients may have concurrent PanINs but display favorable long-term outcomes compared to pancreatic cancer *** diagnostic assessment,including biopsy and steroid response,is crucial for informed surgical decisions in AIP.

关键词： Autoimmune pancreatitis Immunoglobulin G4-related disease Pancreatic cancer Surgery

Prognosis value of heat-shock proteins in esophageal and esophagogastric cancer:A systematic review and meta-analysis

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World Journal of Gastrointestinal Oncology 2024年第4期16卷 1578-1595页

作者： eric Toshiyuki Nakamura Amanda Park marina Alessandra Pereira Daniel Kikawa Francisco Tustumi Department of Gastroenterology Instituto do CâncerHospital das Clínicas da Universidade de São PauloFaculdade de MedicinaUniversidade de São PauloSão Paulo 01246000Brazil Department of Scientific Initiation Universidade Mogi das CruzesSão Paulo 08780911Brazil Department of evidence-Based Medicine Centro Universitário LusíadaCentre for Evidence-Based MedicineCentro Universitário Lusíada(UNILUS)SantosBrazil Department of Surgery Hospital Israelita Albert EinsteinSão Paulo 05652900Brazil

BACKGROUND Heat shock proteins(HSPs)are molecular chaperones that play an important role in cellular protection against stress events and have been reported to be overex-pressed in many *** prognostic significance of HSPs and their regulatory factors,such as heat shock factor 1(HSF1)and CHIP,are poorly *** To investigate the relationship between HSP expression and prognosis in esophageal and esophagogastric *** A systematic review was conducted in accordance with PRISMA recommend-ations(PROSPeRO:CRD42022370653),on embase,PubMed,Cochrane,and ***,case-control,and cross-sectional studies of patients with eso-phagus or esophagogastric cancer were ***-positive patients were compared with HSP-negative,and the endpoints analyzed were lymph node metastasis,tumor depth,distant metastasis,and overall survival(OS).HSPs were stratified according to the HSP family,and the summary risk difference(RD)was calculated using a random-effect *** The final selection comprised 27 studies,including esophageal squamous cell carcinoma(21),esophagogastric adenocarcinoma(5),and mixed neoplasms(1).The pooled sample size was 3465 ***40 and 60 were associated with a higher 3-year OS[HSP40:RD=0.22;95%confidence interval(CI):0.09-0.35;HSP60:RD=0.33;95%CI:0.17-0.50],while HSF1 was associated with a poor 3-year OS(RD=-0.22;95%CI:-0.32 to-0.12).The other HSP families were not associated with long-term ***1 was associated with a higher probability of lymph node metastasis(RD=-0.16;95%CI:-0.29 to-0.04).HSP40 was associated with a lower probability of lymph node dissemination(RD=0.18;95%CI:0.03-0.33).The expression of other HSP families was not significantly related to tumor depth and lymph node or distant *** The expression levels of certain families of HSP,such as HSP40 and 60 and HSF1,are associated with long-term survival and lymph node dissemination in patients with esophageal and esophagogastric cancer.

关键词： Heat-shock proteins Heat-shock response Prognosis esophageal neoplasms Meta-analysis