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RANBP9 as potential therapeutic target in non-small cell lung cancer

Journal of Cancer metastasis and Treatment 2020年第1期6卷 177-187页

作者： Anna Tessari Shimaa H.A.Soliman Arturo Orlacchio marina Capece joseph m.amann Rosa Visone David P.Carbone Dario Palmieri Vincenzo Coppola Department of Cancer Biology and Genetics College of MedicineThe Ohio State University and Arthur G.James Comprehensive Cancer CenterColumbusOH 43210USA Department of medicine Dentistry and BiotechnologyG.d’Annunzio University of ChietiChieti 66100Italy Current address:Department of Biochemistry and molecular Genetics Northwestern University Feinberg School of MedicineChicagoIL 60611USA Division of medical Oncology Department of Internal MedicineCollege of MedicineThe Ohio State University and Arthur G.James Comprehensive Cancer CenterColumbusOH 43210USA

Non-small cell lung cancer(NSCLC)remains the leading cause of cancer-related deaths in the Western *** progress made with targeted therapies and immune checkpoint inhibitors,the vast majority of patients have to undergo chemotherapy with platinum-based *** increase efficacy and reduce potential side effects,a more comprehensive understanding of the mechanisms of the DNA damage response(DDR)is *** have shown that overexpressby live cell imaging Incuyion of the scaffold protein RAN binding protein 9(RANBP9)is pervasive in *** importantly,patients with higher levels of RANBP9 exhibit a worse outcome from treatment with platinum-based ***,RANBP9 exists as a target and an enabler of the ataxia telangiectasia mutated(ATm)kinase ***,the depletion of RANBP9 in NSCLC cells abates ATm activation and its downstream targets such as pby live cell imaging Incuy53 ***9 knockout cells are more sensitive than controls to the inhibition of the ataxia and telangiectasia-related(ATR)kinase but not to ATm *** absence of RANBP9 renders cells more sensitive to drugs inhibiting the Poly(ADP-ribose)-Polymerase(PARP)resulting in a“BRCAness-like”*** summary,as a result of increased sensitivity to DNA damaging drugs conferred by its ablation in vitro and in vivo,RANBP9 may be considered as a potential target for the treatment of *** article aims to report the results from past and ongoing investigations focused on the role of RANBP9 in the response to DNA damage,particularly in the context of *** review concludes with future directions and speculative remarks which will need to be addressed in the coming years.

关键词： RANBP9 RANBP10 Scorpins DNA damage DNA repair DNA damage response CTLH complex cisplatin non-small cell lung cancer PARP BRCAness-like phenotype

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monogenic diabetes in children:An underdiagnosed and poorly managed clinical dilemma

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World Journal of Diabetes 2024年第6期15卷 1051-1059页

作者： Saptarshi Bhattacharya joseph m Pappachan Department of Endocrinology Indraprastha Apollo HospitalsDelhi 110076India 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

monogenic diabetes,constituting 1%-2%of global diabetes cases,arises from single gene defects with distinctive inheritance *** over 50 associated genetic disorders,accurate diagnoses and management of monogenic diabetes remain inadequate,underscoring insufficient clinician *** disease spectrum encompasses maturity-onset diabetes of the young(mODY),characterized by distinct genetic mutations affecting insulin secretion,and neonatal diabetes mellitus(NDm)-a heterogeneous group of severe hyperglycemic disorders in *** diabetes,autoimmune monogenic diabetes,genetic insulin resistance and lipodystrophy syndromes further diversify the monogenic diabetes landscape.A tailored approach based on phenotypic and biochemical factors to identify candidates for genetic screening is recommended for suspected cases of *** diagnosis warrants immediate molecular genetic testing for infants under six *** these genetic defects presents a unique opportunity for precision *** research aimed to develop cost-effective genetic testing methods and gene-based therapy can facilitate appropriate identification and optimize clinical *** and study of new genes offer a valuable opportunity to gain deeper insights into pancreatic cell biology and the pathogenic mechanisms underlying common forms of *** clinical review published in the recent issue of World Journal of Diabetes is such an attempt to fill-in our knowledge gap about this enigmatic disease.

关键词： monogenic diabetes maturity-onset diabetes of the young Neonatal diabetes mitochondrial diabetes Insulin resistance syndromes Genetic testing Next generation sequencing

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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

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Elucidating the Degradation Pathways of Human Insulin in the Solid State

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Journal of Analysis and Testing 2024年第03期8卷 288-299页

作者： Andrew Fagan Lorraine m.Bateman joseph P.O'Shea Abina m.Crean SSPC the SFI Centre for Pharmaceutical Research School of Pharmacy University College Cork School of Pharmacy University College Cork Analytical and Biological Chemistry Research Facility (ABCRF) University College Cork School of Chemistry University College Cork

While there have been significant advances in the development of peptide oral dosage forms in recent years, highlighted by the clinical and commercial success of approved peptides such as Rybelsus?, there remain several barriers in the way of broad range applicability of this approach to peptide delivery. One such barrier includes the poor physical and chemical stability inherent to their structures, which persists in the solid state although degradation typically occurs at different rates and via different pathways in comparison to the solution state. Using insulin as a model peptide, this work sought to contribute to the development of analytical techniques for investigating common insulin degradation pathways. Chemically denatured,deamidated and aggregated samples were prepared and used to benchmark circular dichroism spectroscopy, reverse phase HPLC and size exclusion chromatography methods for the investigation of unfolding, chemical modifications and covalent aggregation of the insulin molecule respectively. Solid state degraded samples were prepared by heating insulin powder at 60 °C and 75% relative humidity for 1, 3, 5 and 7 d, and the degradation profiles of the samples were evaluated and compared with those observed in solution. While no unfolding was observed to occur, significant deamidation and covalent aggregation were detected. Reductive disulfide bond cleavage using dithiothreitol allowed for separation of the insulin A-and B-chains,offering a facile yet novel means of assessing the mechanisms of deamidation and covalent aggregation occurring in the solid state.

关键词： Biopharmaceutical analysis Covalent aggregation Deamidation Disulfide cleavage Insulin Solid state Stability

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Acute worsening of microvascular complications of diabetes mellitus during rapid glycemic control:The pathobiology and therapeutic implications

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World Journal of Diabetes 2024年第3期15卷 311-317页

作者： Dania Blaibel Cornelius James Fernandez joseph m Pappachan Department of Endocrinology and metabolism Lancashire Teaching Hospitals NHS TrustPreston PR29HTUnited Kingdom Department of Endocrinology and metabolism Pilgrim HospitalUnited Lincolnshire Hospitals NHS TrustBoston PE219QSUnited Kingdom Faculty of Science Manchester Metropolitan UniversityManchester M156BHUnited Kingdom Faculty of Biology Medicine and HealthThe University of ManchesterManchester M139PLUnited Kingdom

While chronic hyperglycaemia resulting from poorly controlled diabetes mellitus(Dm)is a well-known precursor to complications such as diabetic retinopathy,neuropathy(including autonomic neuropathy),and nephropathy,a paradoxical intensification of these complications can rarely occur with aggressive glycemic management resulting in a rapid reduction of glycated ***,acute onset or worsening of retinopathy and treatment induced neuropathy of diabetes are more common among these complications,rarely other problems such as albuminuria,diabetic kidney disease,Charcot’s neuroarthropathy,gastroparesis,and urinary bladder dysfunction are also *** World Journal of Diabetes recently published a rare case of all these complications,occurring in a young type 1 diabetic female intensely managed during pregnancy,as a case report by Huret et *** is essential to have a comprehensive understanding of the pathobiology,prevalence,predisposing factors,and management strategies for acute onset,or worsening of microvascular complications when rapid glycemic control is achieved,which serves to alleviate patient morbidity,enhance disease management compliance,and possibly to avoid medico-legal issues around this rare clinical *** editorial delves into the dynamics surrounding the acute exacerbation of microvascular complications in poorly controlled Dm during rapid glycaemic control.

关键词： Diabetes mellitus microvascular complications Diabetic retinopathy Treatment induced neuropathy of diabetes Diabetic nephropathy Charcot’s neuropathy

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Non-pharmacological interventions for diabetic peripheral neuropathy:Are we winning the battle?

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World Journal of Diabetes 2024年第4期15卷 579-585页

作者： Dania Blaibel Cornelius James Fernandez joseph m Pappachan Department of Endocrinology and metabolism Lancashire Teaching Hospitals NHS TrustPreston PR29HTUnited Kingdom Department of Endocrinology&metabolism Pilgrim HospitalUnited Lincolnshire Hospitals NHS TrustBoston PE219QSUnited Kingdom Faculty of Science Manchester Metropolitan UniversityManchester M156BHUnited Kingdom Faculty of Biology Medicine&HealthThe University of ManchesterManchester M139PLUnited Kingdom

Despite the advent of relatively reliable modalities of diagnosing diabetic peripheral neuropathy(DPN),such as nerve conduction studies,there is still a knowledge gap about the pathophysiology,and thus limited available in-terventions for symptom control and curtailing disease *** pharma-cologic aspect of management is mainly centred on pain control,however,there are several important aspects of DPN such as loss of vibration sense,pressure sense,and proprioception which are associated with risks to lower limb health,which pharmacotherapy does not ***,published evidence suggests non-pharmacologic interventions such as glycaemic control through dietary modification and exercise need to be combined with other measures such as psychotherapy,to reach a desired,however modest *** is emerging as an important treatment modality for several chronic medical conditions including neuropathic and other pain *** their study published in the World Journal of Diabetes on the potential of acupuncture to reduce DPN symptoms and enhance nerve conduction parameters,Hoerder et al have been able to demonstrate that acupuncture improves sensory function and that this effect is likely sustained two months after treatment *** previous studies also support these findings,larger multi-center randomized control trials including a sham-controlled arm accounting for a placebo effect are ***,given the satisfactory safety profile and the positive results found in these studies,it is likely that acupuncture may become an important aspect of the repertoire of effective DPN management.

关键词： Diabetic peripheral neuropathy Diabetes mellitus Pharmacotherapy Acupuncture Neuropathic pain Nonpharmacological intervention

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Diabetic cardiomyopathy:Emerging therapeutic options

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World Journal of Diabetes 2024年第8期15卷 1677-1682页

作者： Cornelius James Fernandez Sahana Shetty joseph m Pappachan Department of Endocrinology&metabolism Pilgrim HospitalUnited Lincolnshire Hospitals NHS TrustBoston PE219QSUnited Kingdom Department of Endocrinology Kasturba Medical CollegeManipal Academy of Higher EducationManipal 576104KarnatakaIndia 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

Diabetic cardiomyopathy(DbCm)is a common but underrecognized complication of patients with diabetes mellitus(Dm).Although the pathobiology of other cardiac complications of diabetes such as ischemic heart disease and cardiac autonomic neuropathy are mostly known with reasonable therapeutic options,the mechanisms and management options for DbCm are still not fully *** its early stages,DbCm presents with diastolic dysfunction followed by heart failure(HF)with preserved ejection fraction that can progress to systolic dysfunction and HF with reduced ejection fraction in its advanced stages unless appropriately *** from prompt control of Dm with lifestyle changes and antidiabetic medications,disease-modifying therapy for DbCm includes prompt control of hypertension and dyslipidemia inherent to patients with Dm as in other forms of heart diseases and the use of treatments with proven efficacy in HF.A basic study by Zhang et al,in a recent issue of the World Journal of Diabetes elaborates the potential pathophysiological alterations and the therapeutic role of teneligliptin in diabetic mouse models with *** this preliminary basic study might help to improve our understanding of DbCm and offer a potential new management option for patients with the disease,the positive results from such animal models might not always translate to clinical practice as the pathobiology of DbCm in humans could be ***,such experimental studies can encourage more scientific efforts to find a better solution to treat patients with this enigmatic disease.

关键词： Diabetic cardiomyopathy Diabetic cardiomyopathy Heart failure Pathobiology Teneligliptin

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Diabetes and tuberculosis:An emerging dual threat to healthcare

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World Journal of Diabetes 2024年第7期15卷 1409-1416页

作者： Sahana Shetty joseph m Pappachan Cornelius James Fernandez Department of Endocrinology Kasturba Medical CollegeManipalManipal Academy of Higher EducationManipal 576104KarnatakaIndia 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 Department of Endocrinology&metabolism Pilgrim HospitalUnited Lincolnshire Hospitals NHS TrustBoston PE219QSUnited Kingdom

Tuberculosis(TB)remains a huge global healthcare challenge even in the 21^(st) century though the prevalence has dropped in developed countries in recent *** mellitus(Dm)is an important risk factor for the development and perpetuation of TB owing to the immune dysfunction in patients with *** coexistence of both diseases in the same individual also aggravates disease severity,complications,and chance of treatment failure because of gross immune alterations posed by Dm as well as *** complex cellular and humoral immunological factors are involved in the dangerous interaction between TB and Dm,some of which remain unknown even *** is highly important to identify the risk factors for TB in patients with Dm,and vice versa,to ensure early diagnosis and management to prevent complications from this ominous *** their research study published in the recent issue of the World Journal of Diabetes,Shi et al elaborate on the factors associated with the development of TB in a large cohort of Dm patients from *** such research output from different regions of the world is expected to improve our knowledge to fight the health devastation posed by TB in patients with diabetes.

关键词： Tuberculosis Diabetes mellitus Immune dysfunction Treatment failure multi-drug resistant tuberculosis

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Prevalence and intensity of urinary schistosomiasis and soil-transmitted helminths among women of reproductive age in mwaluphamba,Kwale

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Asian Pacific Journal of Tropical medicine 2024年第2期17卷 71-83页

作者： Samuel m.Ngui joseph m.mwangangi Joachim Richter josephine W.Ngunjiri Department of Biological Sciences University of EmbuKenya medical Entomology Kenya Medical Research Institute(KEMRI)Center for Geographic Medicine Research Coast KilifiKenya Institute of International Health Global Health CenterCharitéUniversity MedicineBerlinCorporate Member of Free University and Humboldt University and Berlin Institute of HealthBerlinGermany Swiss Tropical and Public Health Institute BaselSwitzerland Tropical and Infectious Diseases Department of Biological sciencesUniversity of EmbuKenya

Objective:To assess the epidemiology of urinary schistosomiasis and soil-transmitted helminthiasis among women of reproductive age in mwaluphamba,Kwale County,***:A community-based cross-sectional study design was employed to randomly sample 422 women of reproductive age(15-m four villages in mwaluphamba *** specimens were collected and examined using the Kato-Katz method,while filtration technique was used to analyze urine ***’sociodemographic details were obtained using a standardized ***:Urinary schistosomiasis prevalence was at 4.7%(20/422,95%CI 2.8%-6.9%)while the prevalence of soil-transmitted helminthiasis infection was 4.5%(19/422,95%CI 2.6%-6.7%).The infection intensities of urinary schistosomiasis among the study participants ranged from 1 to 120 eggs/10 mL of urine with median egg count of 18.45 eggs/10 *** patients were diagnosed with light infection,of 56.16 egg/gram and 48.48 egg/gram for Trichuris trichiura and hookworms,*** without latrines had 15.7 times higher risk of having urinary schistosomiasis compared to those with a ***,use of surface water(aOR=1.0,95%CI 0.2-1.4,P=0.010)and crossing the river to go to a place(aOR=1.1,95%CI 0.3-1.6,P=0.009)were statistically significant risk factors for getting urinary *** bivariable regression analysis,defecating around the water source(OR=4.3,95%CI 1.5-12.9)had a statistically significant association with the prevalence of soil-transmitted helminthiasis(P=0.008).Conclusions:This study has given an insight on the prevalence and intensity of urinary schistosomiasis and soil-transmitted helminthiasis in mwaluphamba location that form a basis for strengthening the control and elimination programmes for these neglected tropical diseases.

关键词： Urinary schistosomiasis Prevalence Soiltransmitted helminths mwaluphamba

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Rising tide: The global surge of type 2 diabetes in children and adolescents demands action now

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World Journal of Diabetes 2024年第5期15卷 797-809页

作者： joseph m Pappachan Cornelius James Fernandez Ambika P Ashraf Department of Endocrinology and metabolism Lancashire Teaching Hospitals NHS TrustPreston PR29HTUnited Kingdom Faculty of Science Manchester Metropolitan UniversityManchester M156BHUnited Kingdom Faculty of Biology Medicine&HealthThe University of ManchesterManchester M139PLUnited Kingdom Department of Endocrinology&metabolism Pilgrim HospitalUnited Lincolnshire Hospitals NHS TrustBoston PE219QSUnited Kingdom Division of Pediatric Endocrinology and Diabetes Department of PediatricsUniversity of Alabama at BirminghamBirminghamAL 35233United States

Childhood-onset obesity has emerged as a major public healthcare challenge across the globe,fueled by an obesogenic environment and influenced by both genetic and epigenetic *** has led to an exponential rise in the incidence of type 2 diabetes mellitus in children and *** looming wave of diabetes-related complications in early adulthood is anticipated to strain the healthcare budgets in most *** there is a collective global effort to curb the devastation caused by the situation,the impact is poised to be pro-found.A multifaceted research effort,governmental legislation,and effective social action are crucial in attaining this *** article delves into the current epidemiological landscape,explores evidence concerning potential risks and consequences,delves into the pathobiology of childhood obesity,and discusses the latest evidence-based management strategies for diabesity.

关键词： Childhood obesity Diabesity Type 2 diabetes mellitus Adolescence Cardiovascular disease Pharmacotherapy

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