Transient receptor potential channels as predictive marker and potential indicator of chemoresistance in colon cancer

Transient receptor potential(TRP)channels are strongly associated with colon cancer development and progression.This study leveraged a multivariate Cox regression model on publicly available datasets to construct a TRP channels-associated gene signature,with further validation of signature in real world samples from our hospital treated patient samples.Kaplan-Meier(K-M)survival analysis and receiver operating characteristic(ROC)curves were employed to evaluate this gene signature’s predictive accuracy and robustness in both training and testing cohorts,respectively.Additionally,the study utilized the CIBERSORT algorithm and single-sample gene set enrichment analysis to explore the signature’s immune infiltration landscape and underlying functional implications.The support vector machine algorithm was applied to evaluate the signature’s potential in predicting chemotherapy outcomes.The findings unveiled a novel three TRP channels-related gene signature(MCOLN1,TRPM5,and TRPV4)in colon adenocarcinoma(COAD).The ROC and K-M survival curves in the training dataset(AUC=0.761;p=1.58e-05)and testing dataset(AUC=0.699;p=0.004)showed the signature’s robust predictive capability for the overall survival of COAD patients.Analysis of the immune infiltration landscape associated with the signature revealed higher immune infiltration,especially an increased presence of M2 macrophages,in high-risk group patients compared to their low-risk counterparts.High-risk score patients also exhibited potential responsiveness to immune checkpoint inhibitor therapy,evident through increased CD86 and PD-1 expression profiles.Moreover,the TRPM5 gene within the signature was highly expressed in the chemoresistance group(p=0.00095)and associated with poor prognosis(p=0.036)in COAD patients,highlighting its role as a hub gene of chemoresistance.Ultimately,this signature emerged as an independent prognosis factor for COAD patients(p=6.48e-06)and expression of model gene are validated by public data and real-world patients.Overall,this bioinformatics study provides valuable insights into the prognostic implications and potential chemotherapy resistance mechanisms associated with TRPs-related genes in colon cancer.

Effects of P301L-TAU on post-translational modifications of microtubules in human iPSC-derived cortical neurons and TAU transgenic mice

TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal function and regulated via a complex set of post-translational modifications,changes of which affect microtubule stability and dynamics,microtubule interaction with other proteins and cellular structures,and mediate recruitment of microtubule-severing enzymes.As impairment of microtubule dynamics causes neuronal dysfunction,we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule dynamics.We therefore aimed to study the effects of a disease-causing mutation of TAU(P301L)on the levels and localization of microtubule post-translational modifications indicative of microtubule stability and dynamics,to assess whether P301L-TAU causes stability-changing modifications to microtubules.To investigate TAU localization,phosphorylation,and effects on tubulin post-translational modifications,we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons(i Neurons)and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU(p R5 mice).Human neurons expressing the longest TAU isoform(2N4R)with the P301L mutation showed increased TAU phosphorylation at the AT8,but not the p-Ser-262 epitope,and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons.P301L-TAU showed pronounced somatodendritic presence,but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU.P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation,but reduced acetylation,of microtubules compared with non-transgenic littermates.In sum,P301L-TAU results in changes in microtubule PTMs,suggestive of impairment of microtubule stability.This is accompanied by missorting and aggregation of TAU in mice but not in i Neurons.Microtubule PTMs/impairment may be of key importance in tauopathies.

The role of LIN28B in tumor progression and metastasis in solid tumor entities

LIN28B is an RNA-binding protein that targets a broad range of microRNAs and modulates their maturation and activity.Under normal conditions,LIN28B is exclusively expressed in embryogenic stem cells,blocking differentiation and promoting proliferation.In addition,it can play a role in epithelial-to-mesenchymal transition by repressing the biogenesis of let-7 microRNAs.In malignancies,LIN28B is frequently overexpressed,which is associated with increased tumor aggressiveness and metastatic properties.In this review,we discuss the molecular mechanisms of LIN28B in promoting tumor progression and metastasis in solid tumor entities and its potential use as a clinical therapeutic target and biomarker.

Roles of Optineurin and Extracellular Vesicles in Glaucomatous Retinal Cell Loss

Objective To explore the role of extracellular vesicles(EVs)in the pathogenesis of glaucoma caused by E50K mutation.Methods A photoreceptor cell line,RGC-5,was transfected with empty plasmids and plasmids expressing wild-type(WT)optineurin(OPTN)or E50K OPTN to investigate the effects of OPTN glaucoma as well as to identify the role of EVs in glaucoma pathology.The RGC-5 cells were also stimulated with glutamate,and their viability was evaluated using flow cytometry or CCK-8 assay.EVs were extracted,labeled with PKH-26,and added into the medium for normal RGC-5 culture,and the status of the cells was observed thereafter.Results WT OPTN overexpression,E50K OPTN,and glutamate stimulation induced apoptosis of RGC-5 cells.However,when glutamate stimulation was used as an add-on treatment,the degree of apoptosis in WT OPTN-overexpressing RGC-5 cells was significantly lower than that in E50K OPTN-expressing and normal RGC-5 cells.The viability of normal RGC-5 cells was reduced when co-cultured with WT OPTN-overexpressing RGC-5 or E50K OPTN-overexpressing RGC-5.EVs released by the latter two transfected lines similarly reduced normal RGC-5 survival.Conclusion Our results indicate that WT OPTN overexpression may lead to photoreceptor apoptosis.However,overexpression also confers a degree of protection against high concentrations of extracellular glutamate.Additionally,EVs released by transfected RGC-5 cells may regulate the cell state.These findings may improve our understanding of the mechanisms of cell-cell interactions in pathological conditions,providing a basis for the use of EVs as novel targets for early diagnosis and treatment of glaucoma.

Suppression of mature TAU isoforms prevents Alzheimer's disease-like amyloid-beta oligomer-induced spine loss in rodent neurons

Introduction:TAU isoforms as disease mediators:The microtubule-associated protein TAU is predominantly present in the axons of neurons under physiological conditions.In Alzheimer’s disease(AD)and related tauopathies,TAU also mislocalizes("TAU missorting")to the soma and the dendrites,where it eventually forms aggregates,the so-called neurofibrillary tangles(for review see Zimmer-Bensch and Zempel,2021;Zempel,2023).

Microtubule affinity regulating kinase(MARK/Par1)isoforms differentially regulate Alzheimer-like TAU missorting and Aβ-mediated synapse pathology

Importance of TAU protein for dementia syndromes:Dementia currently affects about 55 million people worldwide,with Alzheimer's disease(AD)being the most prevalent form.The one crucial pathological hallmark of AD that correlates best with loss of synapses and cognitive decline are the so-called intracellular neurofibrillary tangles composed of mislocalized/missorted and hyperphosphorylated TAU protein(Naseri et al.,2019).Many other neurodegenerative diseases,both genetic and nongenetic,are characterized by neurofibrillary ta ngles or pathological accumulation of the protein TAU and are thus termed"tauopathies".

Clinical and economic consequences of pancreatic fistula after elective pancreatic resection

BACKGROUND:Postoperative pancreatic fistula is the main cause of morbidity after pancreatic resection.This study aimed to quantify the clinical and economic consequences of pancreatic fistula in a medium-volume pancreatic surgery center.METHODS:Hospital records from patients who had undergone elective pancreatic resection in our department were identified.Pancreatic fistula was defined according to the International Study Group on Pancreatic Fistula(ISGPF).The consequences of pancreatic fistula were determined by treatment cost,hospital stay,and out-patient follow-up until the pancreatic fistula was completely healed.All costs of the treatment are calculated in Euros.The cost increase index was calculated for pancreatic fistula of grades A,B,and C as multiples of the total cost for the no fistula group.RESULTS:In 54 months,102 patients underwent elective pancreatic resections.Forty patients(39.2%) developed pancreatic fistula,and 54 patients(52.9%) had one or more complications.The median length of hospital stay for the no fistula,grades A,B,and C fistula groups was 12.5,14,20,and 59 days,respectively.The hospital stay of patients with fistula of grades B and C was significantly longer than that of patients with no fistula(P【0.001).The median total cost of the treatment was 4952,4679,8239,and 30 820 Euros in the no fistula,grades A,B,and C fistula groups,respectively.CONCLUSIONS:The grading recommended by the ISGPF is useful for comparing the clinical severity of fistula and for analyzing the clinical and economic consequences of pancreatic fistula.Pancreatic fistula prolongs the hospital stay and increases the cost of treatment in proportion to the severity of the fistula.

Safety and efficacy of surgical hip dislocation in managing femoral head fractures: A systematic review and meta-analysis

BACKGROUND Femoral head fractures(FHFs)are considered relatively uncommon injuries;however,open reduction and internal fixation is preferred for most displaced fractures.Several surgical approaches had been utilized with controversial results;surgical hip dislocation(SHD)is among these approaches,with the reputation of being demanding and leading to higher complication rates.AIM To determine the efficacy and safety of SHD in managing FHFs by reviewing the results reported in the literature.METHODS Major databases including PubMed,Embase,Web of Science,and Cochrane Central Register of Controlled Trials were searched to identify studies reporting on outcomes of SHD utilized as an approach in treating FHFs.We extracted basic studies data,surgery-related data,functional outcomes,radiological outcomes,and postoperative complications.We calculated the mean differences for continuous data with 95%confidence intervals for each outcome and the odds ratio with 95%confidence intervals for binary outcomes.P<0.05 was considered significant.RESULTS Our search retrieved nine studies meeting our inclusion criteria,with a total of 129 FHFs.The results of our analysis revealed that the average operation time was 123.74 min,while the average blood loss was 491.89 mL.After an average followup of 38.4 mo,a satisfactory clinical outcome was achieved in 85%of patients,ranged from 30%to 86%,with avascular necrosis,heterotopic ossification,and osteoarthritis being the most common complications occurring at an incidence of 12%,25%,and 16%,respectively.Trochanteric flip osteotomy nonunion and trochanteric bursitis as a unique complication of SHD occurred at an incidence of 3.4%and 3.8%,respectively.CONCLUSION The integration of SHD approach for dealing with FHFs offered acceptable functional and radiological outcomes with a wide range of safety in regards to the hip joint vascularity and the development of avascular necrosis,the formation of heterotopic ossification,and the development of posttraumatic osteoarthritis;however,it still carries its unique risk of trochanteric flip osteotomy nonunion and persistent lateral thigh pain.

Between evidence and new perspectives on the current state of the multimodal approach to gastric cancer:Is there still a role for radiation therapy?

In patients affected by gastric cancer(GC), especially those in advanced stage, the multidisciplinary app-roach of treatment is fundamental to obtain a good disease control and quality of life. Although many chemotherapeutics in combination to radiotherapy are adopted in the peri- or postoperative setting, the most optimal timing, regimens and doses remains con-troversial. In the era of radical surgery performed with D2-lymphadenectomy, the role of radiation therapy remains to be better defined. Categories of patients, who could benefit more from an intensified local trea-tment rather than more toxic systemic therapy, are still under investigation. Evidence and recent updates of the randomized trials, meta-analysis and prospective trials show that the postoperative radiotherapy plays a fundamental role in reducing the loco-regional recurrence and in turn the disease-free survival in operable advanced GC patients, also after a well performed D2 surgery. Therapeutic decisions should be taken considering the individual patients, but the multimodal approach is necessary to guarantee a longer survival and a good quality of life. Ongoing randomized trials could better define the timing and the combination of radiotherapy and systemic therapy.

Evaluation of different crosslinking methods in altering the properties of extrusion-printed chitosan-basedmulti-material hydrogel composites

Three-dimensional printing technologies exhibit tremendous potential in the advancing fields of tissue engineering and regenerative medicine due to the precise spatial control over depositing the biomaterial.Despite their widespread utilization and numerous advantages,the development of suitable novel biomaterials for extrusion-based 3D printing of scaffolds that support cell attachment,proliferation,and vascularization remains a challenge.Multi-material composite hydrogels present incredible potential in this field.Thus,in this work,a multi-material composite hydrogel with a promising formulation of chitosan/gelatin functionalized with egg white was developed,which provides good printability and shape fidelity.In addition,a series of comparative analyses of different crosslinking agents and processes based on tripolyphosphate(TPP),genipin(GP),and glutaraldehyde(GTA)were investigated and compared to select the ideal crosslinking strategy to enhance the physicochemical and biological properties of the fabricated scaffolds.All of the results indicate that the composite hydrogel and the resulting scaffolds utilizing TPP crosslinking have great potential in tissue engineering,especially for supporting neo-vessel growth into the scaffold and promoting angiogenesis within engineered tissues.

AAV-based gene therapy approaches for genetic forms of tauopathies and related neurogenetic disorders

Tauopathies comprise a spectrum of genetic and sporadic neurodegenerative diseases mainly characterized by the presence of hyperphosphorylated TAU protein aggregations in neurons or glia.Gene therapy,in particular adeno-associated virus(AAV)-based,is an effective medical approach for difficult-to-treat genetic diseases for which there are no convincing traditional therapies,such as tauopathies.Employing AAV-based gene therapy to treat,in particular,genetic tauopathies has many potential therapeutic benefits,but also drawbacks which need to be addressed in order to successfully and efficiently adapt this still unconventional therapy for the various types of tauopathies.In this Viewpoint,we briefly introduce some potentially treatable tauopathies,classify them according to their etiology,and discuss the potential advantages and possible problems of AAV-based gene therapy.Finally,we outline a future vision for the application of this promising therapeutic approach for genetic and sporadic tauopathies.

Differences in Treatment of Schizoaffective Disorder and Schizophrenia in Real Clinical Practice in Slovakia

Background: Schizoaffective Disorder (SAD), similarly to schizophrenia, is a potentially chronic mental disorder that negatively affects the functioning of a patient. Various issues in everyday clinical practice often arise from its diagnostic and therapeutic uncertainty. To date, there is a lack of a well-defined therapeutic algorithm used to treat the simultaneously manifesting schizophrenic and affective components. The aim of this study was to compare the therapeutic approaches in schizophrenia and schizoaffective disorders to identify the need of different treatment strategy for these diseases. Methods: In a retrospective study, we evaluated the therapeutic algorithms used in all patients with SAD (n = 99) hospitalized at the Department of Psychiatry, Comenius University in Bratislava, Faculty of Medicine and University Hospital Bratislava throughout the year 2010 and compared them with the therapeutic procedures used in all schizophrenia patients hospitalized in the same year (n = 120). Results: We found similarities between the groups of patients with schizophrenia and SAD in the number, type and length of hospitalizations and general patient management. Differences were identified in terms of the spectrum of used pharmacotherapy. For the treatment of both mental disorders, atypical antipsychotics were used the most. In the treatment of schizophrenia, we found the most frequent use of combined antipsychotic therapy, meaning oral and long-acting injectable forms. Patients with SAD mostly received antipsychotic monotherapy, but its complex effects were supplemented with other psychotropic drugs, mostly mood-stabilizers and anxiolytics. Conclusion: The results of our study show similarities between schizophrenia and SAD in terms of health care utilization, despite the fact that SAD is generally considered to be a “milder” disorder. On the other hand, this study indicates differences in the spectrum of pharmacotherapy used.

Clinical use of augmented reality,mixed reality,three-dimensionalnavigation and artificial intelligence in liver surgery

A precise knowledge of intra-parenchymal vascular and biliary architecture and the location of lesions in relation to the complex anatomy is indispensable to perform liver surgery.Therefore,virtual three-dimensional(3D)-reconstruction models from computed tomography/magnetic resonance imaging scans of the liver might be helpful for visualization.Augmented reality,mixed reality and 3Dnavigation could transfer such 3D-image data directly into the operation theater to support the surgeon.This review examines the literature about the clinical and intraoperative use of these image guidance techniques in liver surgery and provides the reader with the opportunity to learn about these techniques.Augmented reality and mixed reality have been shown to be feasible for the use in open and minimally invasive liver surgery.3D-navigation facilitated targeting of intraparenchymal lesions.The existing data is limited to small cohorts and description about technical details e.g.,accordance between the virtual 3D-model and the real liver anatomy.Randomized controlled trials regarding clinical data or oncological outcome are not available.Up to now there is no intraoperative application of artificial intelligence in liver surgery.The usability of all these sophisticated image guidance tools has still not reached the grade of immersion which would be necessary for a widespread use in the daily surgical routine.Although there are many challenges,augmented reality,mixed reality,3Dnavigation and artificial intelligence are emerging fields in hepato-biliary surgery.

Functional hyperconnectivity related to brain disease:maladaptive process or element of resilience?

Neuroimaging techniques such as magnetic resonance imaging(MRI)and positron emission tomography provide unique in vivo data to analyze structural and functional connectivity of the whole brain.Recent advances in small animal neuroimaging have opened new opportunities for the study of structure-function interactions in healthy and diseased brain networks,which are essential to develop therapies targeting network reorganization associated with functional improvement.

Understanding genetics, sex and signaling: Implications of sex-dependent APOE4-neutrophil-microglia interactions for Alzheimer’s and tauopathies

A recent study published in Nature Medicine uncovers a novel sex-dependent mechanism involving the apolipoprotein E ε4 (APOE4) and in particular neutrophils and their signaling to microglia, which then would mediate cognitive decline in late-onset Alzheimer’s disease (AD).1 We here put the main findings into perspective with current knowledge about APOE4 genotype and neutrophils in the pathogenesis of AD and related tauopathies, and discuss future research directions and therapeutic implications.

Janus-faced Mitofusin 2 (MFN2): mitochondria-endoplasmic reticulum shaping and tethering functions unveiled

In a recently published study in Science,Naòn et al.report two uncharacterized splice variants of Mitofusin 2(MFN2)that specifically shape and tether the endoplasmic reticulum(ER)to mitochondria.1 This work sheds new light on the pleiotropic effects previously ascribed to MFN2 loss-of-function mutations,and has important implications for associated metabolic and neurological diseases.

Endothelial and platelet markers in diabetes mellitus type 2

Diabetes mellitus(DM) is an extremely common disorder which carries a risk of vascular impairment.DM type 2(DM2) can be characterized by the dysfunction of haemostasis manifesting by stimulated coagulation process,disorder of platelet function and decreased fibrinolytic activity.These all are the reasons why DM2 is the most common acquired thrombophilia.Endothelial dysfunction along with platelet hyperactivity are unquestionably involved in the hyperactivation of platelets and clotting factors in DM.As a natural consequence of continuous investigation,many markers of endothelial dysfunction and diabetic thrombocytopathy have been identified and considered for implementation in clinical practice.Endothelial function can be assessed by the evaluation of endothelial markers,circulating molecules synthesised in various amounts by the endothelium.These markers precede the signs of evident microangiopathy.Platelets have an ethiopathogenic relation to the microangiopathy in DM.Their increased activity was confirmed in both types of DM.Predictors of endothelial and platelet disorder could improve the screening of individuals at increased risk,thus leading to the early diagnosis,appropriate treatment,as well as to the effective prevention of the complications of DM2.In the article we deal with the mechanisms involved in the pathogenesis of endothelial and platelet functional abnormalities,endothelial and platelet markers of DM2 considered for implementation in clinical practice and possibilities of their detection.

Structural integrity and remodeling underlying functional recovery after stroke

Stroke is the second leading cause of death worldwide with about 50% of survivors being chronically disabled(Donkor,2018).The behavioral improvement seen in stroke patients in the first weeks after a stroke is contributed by behavioral compensation, reorganization in somatotopic maps and activity in peri-infarct but also distant regions which are connected to the stroke area as supported by animal studies.

Buying Time for an Effective Epidemic Response: The Impact of a Public Holiday for Outbreak Control on COVID-19 Epidemic Spread

在新发突发传染病的早期阶段,快速应对对于疫情防控至关重要。用于控制疫情的公共假期能为大规模、迅速地进行社会隔离和其他举措提供关键的时间窗口期。本研究的目的是探讨抗疫假期的起始时间节点和持续时间对中国早期新冠病毒肺炎疫情传播的影响。我们开发了一个房室模型来模拟从2020年1月开始中国新冠病毒肺炎疫情的动态传播;预测并比较了春节期间在有抗疫假期和没有抗疫假期下的疫情传播;考虑了抗疫假期在不同持续时间、不同起始时间节点,以及在关于病毒传播率的不同假设下的多种情况;估计了在不同情况下达到某些感染阈值所需的天数延迟。结果表明,中国的抗疫假期使新冠病毒肺炎疫情的传播停滞了许多天。与不设抗疫假期的场景相比,基础场景的抗疫假期(湖北省为21 d,中国所有其他省为10 d)可使确诊感染100000例的时间延迟7.54 d。持续时间更长的抗疫假期会对疫情防控产生更大的影响。为期21 d的全国性抗疫假期可使确诊感染100000例的时间延迟近10 d。此外,研究发现,在新发突发传染病较早阶段实施抗疫假期比较晚阶段实施对遏制疫情蔓延更有效,抗疫假期期间采取额外的控制措施可以增强疫情控制效果。总之,抗疫假期能够通过有效地减少人群的社交接触频率及范围,从而减缓疫情的传播。抗疫假期使得新冠病毒肺炎传播暂时停滞,为疫情防控争取了时间,科学家可用争取的时间来发现传播途径并确定有效的公共卫生干预措施,政府可用争取的时间来完善基础设施、调配医疗用品、培训和部署专业人力资源,从而为长期防控做好准备。

Long-term survival of a patient after resection of a gastrointestinal stromal tumor arising from the pancreas

BACKGROUND:Gastrointestinal stromal tumors (GISTs) may arise in any part of the gastrointestinal tract;extragastrointestinal locations are extremely rare.Only a few cases of extragastrointestinal stromal tumor arising from the pancreas were reported.None of the reports described a long-term follow-up of the patients.METHOD:This report describes an interesting and unusual case of GIST arising from the pancreas.RESULTS:A 74-year-old female presented with a palpable abdominal mass.CT scan showed a large mass 11×8×4 cm originating from the tail of the pancreas.Percutaneous biopsy revealed a GIST predominantly with spindle cells,but some parts also contained epitheloid cells.The patient was treated by distal pancreatic resection with splenectomy.Immunohistochemistry of the tumor showed a staining pattern characteristic of GIST.The patient has achieved a long-term survival of five years and six months without any sign of recurrence of the disease.CONCLUSION:This is the first reported case of an extragastrointestinal stromal tumor arising from the pancreas treated surgically,with a long-term survival.