Treatment-induced neuroendocrine prostate cancer and de novo neuroendocrine prostate cancer:Identification,prognosis and survival,genetic and epigenetic factors

Neuroendocrine prostate cancer(NEPC)shows an aggressive behavior compared to prostate cancer(PCa),also known as prostate adenocarcinoma.Scanty foci in PCa can harbor genetic alternation that can arise in a heterogeneity of prostate cancer.NEPC may arise de novo or develop following androgen deprivation therapy(ADT).NEPC that arise following ADT has the nomenclature“treatmentemerging/induced NEPC(t-NEPC)”.t-NEPC would be anticipated in castration resistant prostate cancer(CRPC)and metastatic PCa.t-NEPC is characterized by low or absent androgen receptor(AR)expression,independence of AR signaling,and gain of neuroendocrine phenotype.t-NEPC is an aggressive metastatic tumor,develops from PCa in response to drug induced ADT,and shows very short response to conventional therapy.t-NEPC occurs in 10%-17%of patients with CRPC.De novo NEPC is rare and is accounting for less than 2%of all PCa.The molecular mechanisms underlying the trans-differentiation from CRPC to t-NEPC are not fully elucidated.Sphingosine kinase 1 plays a significant role in t-NEPC development.Although neuroendocrine markers:Synaptophysin,chromogranin A,and insulinoma associated protein 1(INSM1)are expressed in t-NEPC,they are non-specific for diagnosis,prognosis,and follow-up of therapy.t-NEPC shows enriched genomic alteration in tumor protein P53(TP53)and retinoblastoma 1(RB1).There are evidences suggest that t-NEPC might develop through epigenetic evolution.There are genomic,epigenetic,and transcriptional alterations that are reported to be involved in development of t-NEPC.Knock-outs of TP53 and RB1 were found to contribute in development of t-NEPC.PCa is resistant to immunotherapy,and at present there are running trials to approach immunotherapy for PCa,CRPC,and t-NEPC.

Dominant early heading without yield drag in a sister-line BC breeding progeny DEH_229 is controlled by multiple genetic factors with maineffect loci

Dominant early heading(DEH)in rice(Oryza sativa L.)is of interest in both breeding and genetics.The genetic mechanisms underlying DEH have remained largely unclear.We have developed a near-isogenic DEH line without yield drag named DEH_229 by sister-line backcross(BC)breeding with MH63,a restorer,as the genetic background.We conducted a pilot genetic investigation under both short-day(SD)and long-day(LD)conditions.The DEH line harbored only 1.06%variation in the genome sequence relative to MH63.The variants were distributed throughout the genome.Using QTL mapping by sequencing(QTL-seq)on an F_(2) population derived from a cross of MH63×DEH_229,57 loci were detected under the SD condition.Joint mapping employing a genome-wide association study with accessions from the 3000 rice genome sequencing project(3K-RG),reduced the number of QTL by 43.9%.Using Rice Functional Genomics&Breeding(RFGB)database,the number of SNP cluster regions within the QTL regions reduced by 27.3%.Further comparison of the genome variation between DEH_229 and MH63 in addition to gene annotation information revealed a new DEH allele of DTH3 with multiple variable sites as a possible major factor underlying the early-heading phenotype of DEH_229.An InDel marker,ZMEH_1,was designed based on the variation between DEH_229 and MH63 within this region.It accounted for 86.0%of heading date variation under both SD and LD conditions in 109 randomly chosen progeny derived from extreme lines of the MH63×DEH_229 population.This study reveals the genetic complexity of DEH in the near-isogenic line and may provide useful material and marker information for plant molecular breeding.

Lung cancer risk in never-smokers:An overview of environmental and genetic factors

Lung cancer is the leading cause of cancer-related mortality globally,accounting for 1.8 million deaths in 2020.While the vast majority are caused by tobacco smoking,15%-25%of all lung cancer cases occur in lifelong neversmokers.The International Agency for Research on Cancer(IARC)has classified multiple agents with sufficient evidence for lung carcinogenesis in humans,which include tobacco smoking,as well as several environmental exposures such as radon,second-hand tobacco smoke,outdoor air pollution,household combustion of coal and several occupational hazards.However,the IARC evaluation had not been stratified based on smoking status,and notably lung cancer in never-smokers(LCINS)has different epidemiological,clinicopathologic and molecular characteristics from lung cancer in ever-smokers.Among several risk factors proposed for the development of LCINS,environmental factors have the most available evidence for their association with LCINS and their roles cannot be overemphasized.Additionally,while initial genetic studies largely focused on lung cancer as a whole,recent studies have also identified genetic risk factors for LCINS.This article presents an overview of several environmental factors associated with LCINS,and some of the emerging evidence for genetic factors associated with LCINS.An increased understanding of the risk factors associated with LCINS not only helps to evaluate a never-smoker’s personal risk for lung cancer,but also has important public health implications for the prevention and early detection of the disease.Conclusive evidence on causal associations could inform longer-term policy reform in a range of areas including occupational health and safety,urban design,energy use and particle emissions,and the importance of considering the impacts of second-hand smoke in tobacco control policy.

Genetic pathways in cerebral palsy:a review of the implications for precision diagnosis and understanding disease mechanisms

Ce rebral palsy is a diagnostic term utilized to describe a group of permanent disorders affecting movement and posture.Patients with cerebral palsy are often only capable of limited activity,resulting from non-progressive disturbances in the fetal or neonatal brain.These disturbances severely impact the child’s daily life and impose a substantial economic burden on the family.Although cerebral palsy encompasses various brain injuries leading to similar clinical outcomes,the unde rstanding of its etiological pathways remains incomplete owing to its complexity and heterogeneity.This review aims to summarize the current knowledge on the genetic factors influencing cerebral palsy development.It is now widely acknowledged that genetic mutations and alterations play a pivotal role in cerebral palsy development,which can be further influenced by environmental fa ctors.Des pite continuous research endeavors,the underlying fa ctors contributing to cerebral palsy remain are still elusive.However,significant progress has been made in genetic research that has markedly enhanced our comprehension of the genetic factors underlying cerebral palsy development.Moreove r,these genetic factors have been categorized based on the identified gene mutations in patients through clinical genotyping,including thrombosis,angiogenesis,mitochondrial and oxidative phosphorylation function,neuronal migration,and cellular autophagy.Furthermore,exploring targeted genotypes holds potential for precision treatment.In conclusion,advancements in genetic research have substantially improved our understanding of the genetic causes underlying cerebral palsy.These breakthroughs have the potential to pave the way for new treatments and therapies,consequently shaping the future of cerebral palsy research and its clinical management.The investigation of cerebral palsy genetics holds the potential to significantly advance treatments and management strategies.By elucidating the underlying cellular mechanisms,we can develop to rgeted interventions to optimize outcomes.A continued collaboration between researchers and clinicians is imperative to comprehensively unravel the intricate genetic etiology of cerebral palsy.

Genetic factors contributing to human primary ciliary dyskinesia and male infertility

Primary ciliary dyskinesia （PCD） is an autosomal-recessive disorder resulting from the loss of normal ciliary function. Symptoms include neonatal respiratory distress, chronic sinusitis, bronchiectasis, situs inversus, and infertility. However, only 15 PCD-associated genes have been identified to cause male infertility to date. Owing to the genetic heterogeneity of PCD, comprehensive molecular genetic testing is not considered the standard of care. Here, we provide an update of the progress on the identification of genetic factors related to PCD associated with male infertility, summarizing the underlying molecular mechanisms, and discuss the clinical implications of these findings. Further research in this field will impact the diagnostic strategy for male infertility, enabling clinicians to provide patients with informed genetic counseling, and help to adopt the best course of treatment for developing directly targeted personalized medicine.

Genome-Wide Association Study Reveals Host Genetic Factors for Liver Diseases

A number of disease-associated genetic markers for common liver diseases have been identified using genome-wide association studies (GWASs). The GWAS strategy is based on genome-wide single-nucleotide polymorphism typing technologies, which are now commercially available, accom-panied by statistical methods to identify host genetic factors that are associated with target diseases or complex genetic traits. One of the most striking features of the GWAS strategy is the ability to identify unexpected disease-associated genetic markers across the entire human genome. Here, we describe the technological aspects of the GWAS strategy with examples from actual GWAS reports related to hepatitis research, including drug response for patients with chronic hepatitis C, susceptibility to primary biliary cirrhosis, and hepatitis-B-related hepatocellular carcinoma.

Host/genetic factors associated with COVID-19 call for precision medicine

If the current rate of infection are to be better managed,and future waves of infection kept at bay,it is absolutely necessary that the conditions and mechanisms of exposure to Severe Acute Respiratory Syndrome-Coronavirus 2(SARS-CoV-2)be better understood,as well as the downstream severe or lethal clinical complications.While the identification of notable comorbidities has now helped to define broad risk groups,the idiosyncratic responses of individual patients can generate unexpected clinical deterioration that is difficult to predict from initial clinical features.Thus,physicians caring for patients with COVID-19 face clinical dilemmas on a daily basis.The ability to decipher individual predispositions to SARS-CoV-2 infection or severe illness,in light of variations in host immunological and inflammatory responses,in particular as a result of genetic variations,would be of great benefit in infection management.To this end,this work associates the description of COVID-19 clinical complications,comorbidities,sequelae,and environmental and genetic factors.We also give examples of underlying genomic susceptibility to COVID-19,especially with regard to the newly reported link between the disease and the unbalanced formation of neutrophil extracellular traps.As a consequence,we propose that the host/genetic factors associated with COVID-19 call for precision medicine in its treatment.This is to our knowledge the first article describing elements towards precision medicine for patients with COVID-19.

Genetic factors in intervertebral disc degeneration

Low back pain(LBP)is a major cause of disability and imposes huge economic burdens on human society worldwide.Among many factors responsible for LBP,intervertebral disc degeneration(IDD)is the most common disorder and is a target for intervention.The etiology of IDD is complex and its mechanism is still not completely understood.Many factors such as aging,spine deformities and diseases,spine injuries,and genetic factors are involved in the pathogenesis of IDD.In this review,we will focus on the recent advances in studies on the most promising and extensively examined genetic factors associated with IDD in humans.A number of genetic defects have been correlated with structural and functional changes within the intervertebral disc(IVD),which may compromise the disc’s mechanical properties and metabolic activities.These genetic and proteomic studies have begun to shed light on the molecular basis of IDD,suggesting that genetic factors are important contributors to the onset and progression of IDD.By continuing to improve our understanding of the molecular mechanisms of IDD,specific early diagnosis and more effective treatments for this disabling disease will be possible in the future.

Host Genetic Background Impacts Microbiome Composition in Newborn Alligator

Genetic factors play a key role in determination of the structure of the cloacal flora for newborn Chinese Alligators.We collected the cloacal microbiomes for 24 newborn Chinese Alligators from three different genetic backgrounds for 16S gene amplicon sequencing.The number of cloacal flora for the Chinese Alligators from different groups was comparable but differed structurally.There were variations in proportions of floral compositions at the phylum and family levels;however,the main difference was at the genus level.There were two significant differences in richness and evenness among the three groups.Non-metric multidimensional scaling NMDS analysis revealed that the 24 samples could be clearly divided into three categories based on their genetic backgrounds(stress=0.0244).Thus,we postulated that newborn Chinese Alligators with different genetic backgrounds have different immune strengths,which affects individual responses to environmental microorganisms.In summary,newborn Chinese Alligators from different genetic backgrounds exhibit variations in cloacal microbiome.

Genetic and environmental control of rice tillering

Increasing tiller number is a target of high-yield rice breeding. Identification of tiller-defect mutants and their corresponding genes is helpful for clarifying the molecular mechanism of rice tillering. Summarizing research progress on the two processes of rice tiller formation, namely the formation and growth of axillary meristem, this paper reviews the effects of genetic factors, endogenous hormones, and exogenous environment on rice tillering, finding that multiple molecular mechanisms and signal pathways regulating rice tillering cooperate rice tillering, and discusses future research objectives and application of its regulatory mechanism. Elucidation of theis mechanism will be helpful for breeding high-yielding rice cultivars with ideal plant type via molecular design breeding.

The dorsal root ganglion as a target for neurorestoration in neuropathic pain

Neuropathic pain is a severe and chronic condition widely found in the general population.The reason for this is the extensive variety of damage or diseases that can spark this unpleasant constant feeling in patients.During the processing of pain,the dorsal root ganglia constitute an important region where dorsal root ganglion neurons play a crucial role in the transmission and propagation of sensory electrical stimulation.Furthermore,the dorsal root ganglia have recently exhibited a regenerative capacity that should not be neglected in the understanding of the development and resolution of neuropathic pain and in the elucidation of innovative therapies.Here,we will review the complex interplay between cells(satellite glial cells and inflammatory cells)and factors(cytokines,neurotrophic factors and genetic factors)that takes place within the dorsal root ganglia and accounts for the generation of the aberrant excitation of primary sensory neurons occurring in neuropathic pain.More importantly,we will summarize an updated view of the current pharmacologic and nonpharmacologic therapies targeting the dorsal root ganglia for the treatment of neuropathic pain.

Oxidative stress factors in Parkinson's disease

Parkinson's disease(PD) is the second most common cause of neurodegeneration.Over the last two decades, various hypotheses have been proposed to explain the etiology of PD.Among these is the oxidant-antioxidant theory, which asserts that local and systemic oxidative damage triggered by reactive oxygen species and other free radicals may promote dopaminergic neuron degeneration.Excessive reactive oxygen species formation, one of the underlying causes of pathology in the course of PD has been evidenced by various studies showing that oxidized macromolecules including lipids, proteins, and nucleic acids accumulate in brain tissues of PD patients.DNA oxidation may produce various lesions in the course of PD.Mutations incurred as a result of DNA oxidation may further enhance reactive oxygen species production in the brains of PD patients, exacerbating neuronal loss due to defects in the mitochondrial electron transport chain, antioxidant depletion, and exposure to toxic oxidized dopamine.The protein products of SNCA, PRKN, PINK1, DJ1, and LRRK2 genes are associated with disrupted oxidoreductive homeostasis in PD.SNCA is the first gene linked with familial PD and is currently known to be affected by six mutations correlated with the disorder: A53T, A30P, E46K, G51D, H50Q and A53E.PRKN encodes Parkin, an E3 ubiquitin ligase which mediates the proteasome degradation of redundant and disordered proteins such as glycosylated α-synuclein.Over 100 mutations have been found among the 12 exons of PRKN.PINK1, a mitochondrial kinase highly expressed in the brain, may undergo loss of function mutations which constitute approximately 1–8% of early onset PD cases.More than 50 PD-promoting mutations have been found in PINK1.Mutations in DJ-1, a neuroprotective protein, are a rare cause of early onset PD and constitute only 1% of cases.Around 20 mutations have been found in DJ1 among PD patients thus far.Mutations in the LRRK2 gene are the most common known cause of familial autosomal dominant PD and sporadic PD.Treatment of PD patients, especially in the advanced stages of the disease, is very difficult.The first step in managing progressive PD is to optimize dopaminergic therapy by increasing the doses of dopamine agonists and L-dopa.The next step is the introduction of advanced therapies, such as deep brain stimulation.Genetic factors may influence the response to L-dopa and deep brain stimulation therapy and the regulation of oxidative stress.Consequently, research into minimally invasive surgical interventions, as well as therapies that target the underlying etiology of PD is warranted.

Genetic variants involved in gallstone formation and capsaicin metabolism,and the risk of gallbladder cancer in Chilean women

AIM:To determine the effects of genetic variants associated with gallstone formation and capsaicin (a pungent component of chili pepper) metabolism on the risk of gallbladder cancer (GBC).METHODS: A total of 57 patients with GBC, 119 patients with gallstones, and 70 controls were enrolled in this study. DNA was extracted from their blood or paraffi n block sample using standard commercial kits. The statuses of the genetic variants were assayed using Taqman SNP Genotyping Assays or Custom Taqman SNP Genotyping Assays.RESULTS:The non-ancestral T/T genotype of apolipoprotein B rs693 polymorphism was associated with a decreased risk of GBC (OR:0.14,95% CI:0.03-0.63). The T/T genotype of cholesteryl ester transfer protein (CETP) rs708272 polymorphism was associated with an increased risk of GBC (OR:5.04,95% CI:1.43-17.8).CONCLUSION: Genetic variants involved in gallstone formation such as the apolipoprotein B rs693 and CETP rs 708272 polymorphisms may be related to the risk of developing GBC in Chilean women.

Traumatic brain injury Nature and genetic influences

At present, much evidence indicates that TBI is similar in pathology and severity during the acute stage, yet may result in varied outcomes. Known prognostic factors, such as age and severity of injury and treatments, only partially explain this variability. In addition, it has been demonstrated that genetic polymorphisms may play an important role in TBI susceptibility, as well as outcome following TBI.

Progress and challenges in genome-wide studies to understand the genetics of diabetic retinopathy

There are many advantages to understanding the genetics of human disease.Genetic markers can be used to calculate the risk of developing a disease,and elucidation of genetic risk factors can pinpoint the molecular aetiology of disease,which can facilitate the development of targeted therapies.Diabetic retinopathy(DR)is a common complication of diabetes that has a significant impact on quality of life.It has a clear genetic component,but determination of the genetic risk factors has proven difficult.To date,genome-wide studies for DR have been conducted on relatively small patient cohorts compared to other complex eye diseases and replication of genetic findings has been limited.The disease is highly heterogeneous,confounding attempts to classify patients into appropriate groups for genetic analysis and making direct comparisons between studies challenging.Future studies to determine the genetic causes of DR will need to focus on larger sample sizes,detailed phenotyping and appropriate classification of patients.Global co-operation and meta-analyses combining data from multiple studies will be critical to the discovery of genetic risk loci for DR.

Nonalcoholic steatohepatitis and hepatocellular carcinoma: Beyond the boundaries of the liver

The burden of non-alcoholic steatohepatitis (NASH) related hepatocellularcarcinoma (HCC) is drawing attention due to the emerging epidemic of obesityand metabolic syndrome and is expected to increase in the near future.Antidiabetic medications, air pollutants, and newer genetic mutations are latestconcerns as risk factors for HCC development in patients with NASH. Althoughmolecular signatures are very accurate, they are not cost-effective and cannot beapplied in larger population due to logistic issues. We need multicentric longitudinalstudies including diverse geographical areas to evaluate the complexinterplay of different risk factors and genetics in these patients.

Insulin resistance in diabetes: The promise of using induced pluripotent stem cell technology

Insulin resistance(IR)is associated with several metabolic disorders,including type 2 diabetes(T2D).The development of IR in insulin target tissues involves genetic and acquired factors.Persons at genetic risk for T2D tend to develop IR several years before glucose intolerance.Several rodent models for both IR and T2D are being used to study the disease pathogenesis;however,these models cannot recapitulate all the aspects of this complex disorder as seen in each individual.Human pluripotent stem cells(hPSCs)can overcome the hurdles faced with the classical mouse models for studying IR.Human induced pluripotent stem cells(hiPSCs)can be generated from the somatic cells of the patients without the need to destroy a human embryo.Therefore,patient-specific hiPSCs can generate cells genetically identical to IR individuals,which can help in distinguishing between genetic and acquired defects in insulin sensitivity.Combining the technologies of genome editing and hiPSCs may provide important information about the genetic factors underlying the development of different forms of IR.Further studies are required to fill the gaps in understanding the pathogenesis of IR and diabetes.In this review,we summarize the factors involved in the development of IR in the insulin-target tissues leading to diabetes.Also,we highlight the use of hPSCs to understand the mechanisms underlying the development of IR.

Weight regain after bariatric surgery: Promoters and potential predictors

Obesity is globally viewed as chronic relapsing disease.Bariatric surgery offers the most efficient and durable weight loss approach.However,weight regain after surgery is a distressing issue as obesity can revert.Surgical procedures were originally designed to reduce food intake and catalyze weight loss,provided that its role is marginalized in long-term weight maintenance.Consequently,it is essential to establish a scientifically standardized applicable definitions for weight regain,which necessitates enhanced comprehension of the clinical situation,as well as have realistic expectations concerning weight loss.Moreover,several factors are proposed to influence weight regain as psychological,behavioral factors,hormonal,metabolic,anatomical lapses,as well as genetic predisposition.Recently,there is a growing evidence of utilization of scoring system to anticipate excess body weight loss,along with characterizing certain biomarkers that identify subjects at risk of suboptimal weight loss after surgery.Furthermore,personalized counseling is warranted to help select bariatric procedure,reinforce self-monitoring skills,motivate patient,encourage mindful eating practices,to avoid recidivism.

Structural brain volume differences between cognitively intact ApoE4 carriers and non-carriers across the lifespan

Apolipoprotein E4（ApoE4） is a prominent genetic risk factor for Alzheimer＇s disease. The purpose of this review is to explore differences in structural brain volume detected by magnetic resonance imaging between cognitively intact ApoE4 carriers and non-carriers across the lifespan（i.e., older adults, middle-aged adults, young adults, children and adolescents, and neonates）. Consistent findings are found throughout various developmental stages. This area of research may elucidate the mechanisms by which ApoE4 influences risk of developing Alzheimer＇s disease. It could also inform potential treatment strategies and interventions for carriers of the ApoE4 allele.

inMTSCCA:An Integrated Multi-task Sparse Canonical Correlation Analysis for Multi-omic Brain Imaging Genetics

Identifying genetic risk factors for Alzheimer's disease(AD)is an important research topic.To date,different endophenotypes,such as imaging-derived endophenotypes and proteomic expression-derived endophenotypes,have shown the great value in uncovering risk genes compared to case-control studies.Biologically,a co-varying pattern of different omics-derived endophenotypes could result from the shared genetic basis.However,existing methods mainly focus on the effect of endophenotypes alone;the effect of cross-endophenotype(CEP)associations remains largely unexploited.In this study,we used both endophenotypes and their CEP associations of multi-omic data to identify genetic risk factors,and proposed two integrated multi-task sparse canonical correlation analysis(inMTSCCA)methods,i.e.,pairwise endophenotype correlationguided MTSCCA(pcMTSCCA)and high-order endophenotype correlation-guided MTSCCA(hocMTSCCA).pcMTSCCA employed pairwise correlations between magnetic resonance imaging(MRI)-derived,plasma-derived,and cerebrospinal fluid(CSF)-derived endophenotypes as an additional penalty.hocMTSCCA used high-order correlations among these multi-omic data for regularization.To figure out genetic risk factors at individual and group levels,as well as altered endophenotypic markers,we introduced sparsity-inducing penalties for both models.We compared pcMTSCCA and hocMTSCCA with three related methods on both simulation and real(consisting of neuroimaging data,proteomic analytes,and genetic data)datasets.The results showed that our methods obtained better or comparable canonical correlation coefficients(CCCs)and better feature subsets than benchmarks.Most importantly,the identified genetic loci and heterogeneous endophenotypic markers showed high relevance.Therefore,jointly using multi-omic endophenotypes and their CEP associations is promising to reveal genetic risk factors.