Cellular models of stress resistance may pave ways to fight neurodegenerative diseases

Alzheimer's disease(AD),the most common form of neurodegeneration,is characterized by selective neuronal vulnerability and brain regionselective neuron demise.The entorhinal cortex and hippoc,ampal CA1 projection neurons are at greater risk in AD whereas other regions display resistance to neurodegeneration.Interestingly,the cerebellum,a phylogenetically very old region,is affected only very late in the disease progression.

Understanding the link between type 2 diabetes mellitus and Parkinson's disease:role of brain insulin resistance

Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular mechanisms.Impaired insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological processes.The contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.

Transient extreme insulin resistance in a critically ill patient:A case report

BACKGROUND Acute hyperglycemia due to insulin resistance is common in critically ill patients,typically managed with insulin infusion.However,the occurrence of transient extreme insulin resistance(EIR)requiring exceptional high-dose insulin is rare.CASE SUMMARY We present the case of a 68-year-old woman with pneumonia who suffered an out-of-hospital cardiac arrest,subsequently developing transient EIR following a new episode of sepsis.Remarkably,insulin resistance rapidly reversed when the insulin infusion rate peaked at 960 units/hour(a total of 18224 units on that day),and it was promptly titrated down to zero upon achieving the target glucose level.CONCLUSION Exceptional high-dose insulin infusion may be required in critically ill patients with stress-related EIR,which is typically transient.Clinicians should be aware of the phenomenon and cautious to avoid hypoglycemia and fluid overload during the steep titration of high-dose insulin infusion.

Microstructure and Wear/corrosion Resistance of Stainless Steel Laser-alloyed with Mn+W_(2)C, Mn+NiWC and Mn+SiC

In-situ formed high Mn steel coating reinforced by carbides was formed by laser surface alloying(LSA).Laser alloyed layers on 1Cr18Ni9Ti steel with Mn+W_(2)C(specimen A),Mn+NiWC(specimen B)and Mn+SiC(specimen C)powders were fabricated to improve the wear and corrosion behavior of 1Cr18Ni9Ti steel blades in high speed mixers.Microstructure evolution,phases,element distribution,microhardness,wear and corrosion behavior of the laser alloyed layers were investigated.Results indicated that high Mn steel matrix composites with undissolved W_(2)C,WC and other in-situ formed carbides were formed by LSA with Mn+W_(2)C and Mn+NiWC while SiC totally dissolved into the high Mn matrix when adding Mn+SiC.Ni as the binding phase in Ni-WC powder decreased the crack sensitivity of the alloyed layer as compared with the addition of W_(2)C powder.An improvement in average microhardness was achieved in the matrix in specimen A,B and C,with the value of 615,602 and 277 HV_(0.5),while that of the substrate was 212 HV_(0.5).The increase of microhardness,wear and corrosion resistance is highly corelated to microstructure,formed phases,type and content of carbides,micro-hardness and toughness of the alloyed layers.

Combined BRAF G469A mutation and echinoderm microtubule associated protein like-4-anaplastic lymphoma kinase rearrangement with resistance:A case report and review of literature

BACKGROUND Through deeper understanding of targetable driver mutations in non-small-cell lung cancer(NSCLC)over the past years,some patients with driver mutations have benefited from the targeted molecular therapies.Although the anaplastic lymphoma kinase and BRAF mutations are not frequent subtypes in NSCLC,the availability of several targeted-drugs has been confirmed through a series of clinical trials.But little is clear about the proper strategy in rare BRAF G469A mutation,not to mention co-exhibition of anaplastic lymphoma kinase and BRAF G469A mutations,which is extremely rare in NSCLC.CASE SUMMARY We present a patient to stage IVA lung adenocarcinoma with coexisting echinoderm microtubule associated protein like-4 rearrangement and BRAF G469A mutation.She received several targeted drugs with unintended resistance and suffered from unbearable adverse events.CONCLUSION Due to the rarity of co-mutations,the case not only enriches the limited literature on NSCLC harbouring BRAF G469A and echinoderm microtubule associated protein like-4 mutations,but also suggests the efficacy and safety of specific multiple-drug therapy in such patients.

Selenoprotein P1 as a biomarker of insulin resistance in pediatric obesity:Insights and implications

This editorial discusses the findings of Elbarky et al on the role of selenoprotein P1(SEPP1)in pediatric obesity and insulin resistance.Their study uncovered si-gnificantly lower SEPP1 Levels in children who were obese compared with hea-lthy peers,demonstrating a negative correlation between SEPP1 levels and mea-sures of adiposity and insulin resistance.These findings suggest that SEPP1 is a biomarker useful in the early identification of insulin resistance in pediatric populations.This editorial emphasizes the clinical implications of the study and calls for further research to validate and explore the role of SEPP1 in metabolic health.

Efficacy of antimicrobials in preventing resistance in solid organ transplant recipients:A systematic review of clinical trials

BACKGROUND In the absence of effective antimicrobials,transplant surgery is not viable,and antirejection immunosuppressants cannot be administered,as resistant infections compromise the life-saving goal of organ transplantation.AIM To evaluate the efficacy of antimicrobials in preventing resistance in solid organ transplant recipients.METHODS A systematic review was conducted using a search methodology consistent with the preferred reporting items for systematic reviews and meta-analyses.This review included randomized clinical trials that evaluated the efficacy of antimicrobial agents(prophylactic or therapeutic)aimed at preventing antimicrobial resistance.The search strategy involved analyzing multiple databases,including PubMed/MEDLINE,Web of Science,Embase,Scopus,and SciELO,as well as examining gray literature sources on Google Scholar.A comprehensive electronic database search was conducted from the databases’inception until May 2024,with no language restrictions.RESULTS After the final phase of the eligibility assessment,this systematic review ultimate-ly included 7 articles.A total of 2318 patients were studied.The most studied microorganisms were cytomegalovirus,although vancomycinresistant enterococci,Clostridioides difficile,and multidrug-resistant Enterobacterales were also analyzed.The antimicrobials used in the interventions were mainly maribavir,valganciclovir,gancic-lovir,and colistin-neomycin.Of concern,all clinical trials showed significant proportions of resistant microorga-nisms after the interventions,with no statistically significant differences between the groups(mean resistance 13.47%vs 14.39%),except for two studies that demonstrated greater efficacy of maribavir and valganciclovir(mean resistance 22.2%vs 41.1%in the control group;P<0.05).The total reported deaths in three clinical trials were 75,and there were 24 graft rejections in two studies.CONCLUSION All clinical trials reported significant proportions of antimicrobial-resistant microorganisms following interventions.More high-quality randomized clinical trials are needed to corroborate these results.

基于REOF的不同量级降雨侵蚀力时空变化——以重庆市为例

研究重庆市不同地理分区内各量级降雨侵蚀力的时空变化特征,为该地区进行更加精准的区域性水土流失防治工作提供理论依据。选取1981-2020年重庆市31个站点逐日降雨数据,利用旋转经验正交函数(Rotated Empirical Orthogonal Function,REOF)对降雨侵蚀力进行地理分区,并结合R/S、5年滑动平均、Mann-Kendall检验等方法,分析各分区不同量级降雨侵蚀力时空变化。结果表明:①重庆市降雨侵蚀力可分为6个地理区域(Ⅰ-Ⅵ区);②重庆市多年平均降雨侵蚀力为5784.04 MJ·mm/(hm^(2)·h·a),不同降雨侵蚀力从大到小依次为:大雨、暴雨、中雨、大暴雨;③大雨侵蚀力在Ⅰ-Ⅲ区和Ⅴ-Ⅵ区占主导优势,暴雨侵蚀力在Ⅳ区占主导优势。各分区中,中雨、大雨及暴雨侵蚀力主要集中在5-9月,大暴雨侵蚀力集中在6-8月;④各区不同量级降雨侵蚀力年际变化从小到大依次为:中雨、大雨、暴雨、大暴雨;同一量级降雨侵蚀力的整体变化趋势均不显著;Hurst指数表明,中雨侵蚀力在Ⅰ和Ⅴ区、大雨侵蚀力在Ⅱ和Ⅴ区、大暴雨侵蚀力在Ⅰ和Ⅲ区呈强持续上升趋势;⑤中雨、大雨及大暴雨侵蚀力在渝东南、渝东北占主导优势,暴雨侵蚀力在渝西以及重庆中部占主导优势,且Ⅰ区酉阳和秀山、Ⅱ区开州、Ⅲ区北碚和铜梁、Ⅳ区璧山和永川、Ⅴ区巫溪和云阳及Ⅵ区忠县是不同量级降雨侵蚀力的高峰中心。通过对重庆各分区不同量级降雨侵蚀力的分析,明确了可能引起土壤侵蚀的主要雨型、高发时期和潜在风险较高的地区,可为区域水土流失动态监测和水土保持措施的合理制定提供参考。

基于R语言数据挖掘技术的针灸治疗带状疱疹后遗神经痛选穴规律研究

目的应用R语言数据挖掘技术分析针灸治疗带状疱疹后遗神经痛(PHN)的选穴规律。方法检索中国知识资源总库(CNKI)、万方数据知识服务平台(万方数据)、维普中文期刊服务平台(维普网)、中国生物医学文献数据库(CBM)2010年1月1日-2023年7月1日收录的针灸治疗PHN的临床研究文献,利用Excel2016建立数据库,采用R语言对腧穴使用频次、归经、部位、特定穴等进行统计,并进行关联规则分析和聚类分析,得出针灸治疗PHN的选穴特点及规律。结果共纳入198篇文献,包含83个腧穴,总频次为714。高频腧穴为阿是穴、夹脊穴、阳陵泉等,常用经脉为足少阳胆经、足太阴脾经和手阳明大肠经,腧穴多分布于上下肢部,以五输穴、原穴和下合穴居多。核心腧穴为阿是穴、夹脊穴、合谷、曲池,并得到9组关联规则和5个有效聚类。结论针灸治疗带状疱疹后遗神经痛的核心腧穴为阿是穴、夹脊穴、合谷、曲池,主要遵循局部取穴与远端取穴相结合的选穴原则。

语言类型学视角下汉语“看”与现代维吾尔语“kør”的语法化

汉语“看”与现代维吾尔语“kør”属于各自语言体系中的常用基本词汇,它们的使用频率高,语法功能多,在各自语言系统中占比较重要的地位。本文将从汉语“看”和现代维吾尔语“kør”的实义动词用法、体助动词用法及二者语法化三方面进行分析,来探析两种语言之间的共性及各自的独特性,旨在加深“看”和“kør”演变规律的进一步认识。

番茄颈腐根腐病抗性基因Frl的定位研究

番茄颈腐根腐病是近年来极具破坏性的番茄土传病害之一,严重影响番茄的品质和产量。为挖掘番茄颈腐根腐病抗性相关基因,本研究利用全基因关联分析(GWAS)和遗传定位对番茄颈腐根腐病抗性基因进行研究。首先对来自国内外的200份番茄材料进行全基因组关联分析,在番茄9号染色体定位到抗颈腐根腐病的位点,再利用抗病材料KP13及感病材料T15196的双亲群体进行连锁作图,综合GWAS和连锁作图结果,将Frl定位于标记SSR105和FrlSNP20之间,遗传距离约为0.8 cM,物理距离约为93 kb。筛选出4个属于番茄谷胱甘肽硫转移酶(SlGST)家族成员的候选基因Solyc09g011510.2.1、Solyc09g011580.2.1、Solyc09g011600.2.1和Solyc09g011630.2.1。获得1个与抗病性状紧密连锁的标记FrlSNP25,利用该标记对94个番茄材料进行抗性鉴定,样品基因型与颈腐根腐病抗性鉴定表型吻合率92.55%。本研究为番茄抗颈腐根腐病种质创新和揭示番茄抗颈腐根腐病抗性机理奠定了基础。

The influence of resistance exercise training prescription variables on skeletal muscle mass,strength,and physical function in healthy adults:An umbrella review

Purpose:The aim of this umbrella review was to determine the impact of resistance training(RT)and individual RT prescription variables on muscle mass,strength,and physical function in healthy adults.Methods:Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)guidelines,we systematically searched and screened eligible systematic reviews reporting the effects of differing RT prescription variables on muscle mass(or its proxies),strength,and/or physical function in healthy adults aged>18 years.Results:We identified 44 systematic reviews that met our inclusion criteria.The methodological quality of these reviews was assessed using A Measurement Tool to Assess Systematic Reviews;standardized effectiveness statements were generated.We found that RT was consistently a potent stimulus for increasing skeletal muscle mass(4/4 reviews provide some or sufficient evidence),strength(4/6 reviews provided some or sufficient evidence),and physical function(1/1 review provided some evidence).RT load(6/8 reviews provided some or sufficient evidence),weekly frequency(2/4 reviews provided some or sufficient evidence),volume(3/7 reviews provided some or sufficient evidence),and exercise order(1/1 review provided some evidence)impacted RT-induced increases in muscular strength.We discovered that 2/3 reviews provided some or sufficient evidence that RT volume and contraction velocity influenced skeletal muscle mass,while 4/7 reviews provided insufficient evidence in favor of RT load impacting skeletal muscle mass.There was insufficient evidence to conclude that time of day,periodization,inter-set rest,set configuration,set end point,contraction velocity/time under tension,or exercise order(only pertaining to hypertrophy)influenced skeletal muscle adaptations.A paucity of data limited insights into the impact of RT prescription variables on physical function.Conclusion:Overall,RT increased muscle mass,strength,and physical function compared to no exercise.RT intensity(load)and weekly frequency impacted RT-induced increases in muscular strength but not muscle hypertrophy.RT volume(number of sets)influenced muscular strength and hypertrophy.

Biomass-enhanced Janus sponge-like hydrogel with salt resistance and highstrength for efficient solar desalination

Interfacial solar-driven evaporation technology shows great potential in the field of industrial seawater desalination, and the development ofefficient and low-cost evaporation materials is key to achieving large-scale applications. Hydrogels are considered to be promising candidates;however, conventional hydrogel-based interfacial solar evaporators have difficulty in simultaneously meeting multiple requirements, including ahigh evaporation rate, salt resistance, and good mechanical properties. In this study, a Janus sponge-like hydrogel solar evaporator (CPAS) withexcellent comprehensive performance was successfully constructed. The introduction of biomass agar (AG) into the polyvinyl alcohol (PVA)hydrogel backbone reduced the enthalpy of water evaporation, optimized the pore structure, and improved the mechanical properties. Meanwhile, by introducing hydrophobic fumed nano-silica aerogel (SA) and a synergistic foaming-crosslinking process, the hydrogel spontaneouslyformed a Janus structure with a hydrophobic surface and hydrophilic bottom properties. Based on the reduction of the evaporation enthalpy andthe modulation of the pore structure, the CPAS evaporation rate reached 3.56 kg m^(-2) h^(-1) under one sun illumination. Most importantly, owingto the hydrophobic top surface and 3D-interconnected porous channels, the evaporator could work stably in high concentrations of salt-water(25 wt% NaCl), showing strong salt resistance. Efficient water evaporation, excellent salt resistance, scalable preparation processes, and low-costraw materials make CPAS extremely promising for practical applications.

Gingipain from Porphyromonas gingivalis causes insulin resistance by degrading insulin receptors through direct proteolytic effects

Periodontitis is a critical risk factor for the occurrence and development of diabetes.Porphyromonas gingivalis may participate in insulin resistance(IR)caused by periodontal inflammation,but the functional role and specific mechanisms of P.gingivalis in IR remain unclear.In the present study,clinical samples were analysed to determine the statistical correlation between P.gingivalis and IR occurrence.Through culturing of hepatocytes,myocytes,and adipocytes,and feeding mice P.gingivalis orally,the functional correlation between P.gingivalis and IR occurrence was further studied both in vitro and in vivo.Clinical data suggested that the amount of P.gingivalis isolated was correlated with the Homeostatic Model Assessment for IR score.In vitro studies suggested that coculture with P.gingivalis decreased glucose uptake and insulin receptor(INSR)protein expression in hepatocytes,myocytes,and adipocytes.Mice fed P.gingivalis tended to undergo IR.P.gingivalis was detectable in the liver,skeletal muscle,and adipose tissue of experimental mice.The distribution sites of gingipain coincided with the downregulation of INSR.Gingipain proteolysed the functional insulin-binding region of INSR.Coculture with P.gingivalis significantly decreased the INSR–insulin binding ability.Knocking out gingipain from P.gingivalis alleviated the negative effects of P.gingivalis on IR in vivo.Taken together,these findings indicate that distantly migrated P.gingivalis may directly proteolytically degrade INSR through gingipain,thereby leading to IR.The results provide a new strategy for preventing diabetes by targeting periodontal pathogens and provide new ideas for exploring novel mechanisms by which periodontal inflammation affects the systemic metabolic state.

小麦抗条锈基因Yr5、Yr9和Yr18分子标记的特异性评估

Yr5、Yr9(1B/1R)、Yr18基因的自身性状或连锁性状在中国小麦育种中具有重要的应用前景。本研究运用以Avocet S为背景的单基因近等基因系及其对应基因的载体品种,对Yr5基因的连锁标记STS9/10,Yr9(1B/1R)基因的分子标记AF1/4、D15、20H,Yr18基因的分子标记csLV34、cssfr1~cssfr5进行有效性验证。结果表明,Yr5基因的特异性分子标记STS9/10、Yr9(1B/1R)基因的特异性分子标记AF1/4、D15和20H均能够准确识别不同遗传背景材料中的相应抗性基因;Yr18基因分子标记cssfr2能够准确检测Yr18的非载体材料,并检测出Avocet S*6/Yr5、Avocet S*6/Yr24、Avocet S*6/Yr27三个材料具有Yr18的等位变异。这说明Yr5基因的连锁标记STS9/10,Yr9(1B/1R)基因的分子标记AF1/4、D15、20H能对目的基因进行有效检测,Yr18基因的几个分子标记结合使用不仅能够对目的基因进行有效检测,而且能够识别该位点的等位变异。

基于R语言数据挖掘间质性肺病(肺痹)的古代源流与方药规律

目的通过系统梳理间质性肺病(肺痹)的中医理论源流,并基于R语言数据挖掘分析中医古籍治疗肺痹的用药规律,为现代中医临床诊疗提供参考。方法通过查阅专业书籍,确定以“肺痹”为检索词,对第5版《中华医典》《中医药古籍数据库》及《广中医古籍数据库》中符合纳入标准的条文进行提取,探讨肺痹的理论发展源流,基于R语言平台(V4.2.3)对中药处方进行频次分析、关联规则分析以及聚类分析、Phi相关性分析等。结果肺痹的中医病名及病因病机制论首见于《黄帝内经》,隋唐时期沿袭其理论并继承发展,宋朝《圣济总录》首次单列肺痹章节,并提出治法方药,进一步发展了肺痹理论,明清时期记载的肺痹条文占80%以上,理法方药趋于完善。筛选得到治疗肺痹的方剂45首,中药112味,中药频次居于前五位依次为杏仁、陈皮、瓜蒌、人参和茯苓,关联规则分析得到最为常用的药对:郁金-杏仁,瓜蒌-杏仁,瓜蒌-郁金-杏仁等,聚类分析得到2个核心药物组方:瓜蒌-郁金-杏仁-栀子-贝母-桑叶,陈皮-茯苓-半夏-人参-白术-甘草-紫菀-桔梗。结论古籍论治肺痹的病机关键是“郁、痰、瘀、虚”,形成的核心处方用药符合以行气开痹、化痰祛瘀、补虚通络的治疗原则,可为肺痹分期的临床诊治、后续开展临床研究及新药研发提供参考。

Insulin resistance as the molecular link between diabetes and Alzheimer's disease

Diabetes mellitus(DM)and Alzheimer's disease(AD)are two major health concerns that have seen a rising prevalence worldwide.Recent studies have indicated a possible link between DM and an increased risk of developing AD.Insulin,while primarily known for its role in regulating blood sugar,also plays a vital role in protecting brain functions.Insulin resistance(IR),especially prevalent in type 2 diabetes,is believed to play a significant role in AD's development.When insulin signalling becomes dysfunctional,it can negatively affect various brain functions,making individuals more susceptible to AD's defining features,such as the buildup of beta-amyloid plaques and tau protein tangles.Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD.This review aims to explore the relationship between DM and AD,with a focus on the role of IR.It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR.Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.

Extracellular vesicles in anti-tumor drug resistance: Mechanisms and therapeutic prospects

Drug resistance presents a significant challenge to achieving positive clinical outcomes in anti-tumor therapy.Prior research has illuminated reasons behind drug resistance,including increased drug efflux,alterations in drug targets,and abnormal activation of oncogenic pathways.However,there's a need for deeper investigation into the impact of drug-resistant cells on parental tumor cells and intricate crosstalk between tumor cells and the malignant tumor microenvironment(TME).Recent studies on extracellular vesicles(EVs)have provided valuable insights.EVs are membrane-bound particles secreted by all cells,mediating cell-to-cell communication.They contain functional cargoes like DNA,RNA,lipids,proteins,and metabolites from mother cells,delivered to other cells.Notably,EVs are increasingly recognized as regulators in the resistance to anti-cancer drugs.This review aims to summarize the mechanisms of EV-mediated anti-tumor drug resistance,covering therapeutic approaches like chemo-therapy,targeted therapy,immunotherapy and even radiotherapy.Detecting Ev-based biomarkers to predict drug resistance assists in bypassing anti-tumor drug resistance.Additionally,targeted inhibition of EV biogenesis and secretion emerges as a promising approach to counter drug resistance.We highlight the importance of conducting in-depth mechanistic research on EVs,their cargoes,and functional ap-proaches specifically focusing on EV subpopulations.These efforts will significantly advance the devel-opment of strategies to overcome drug resistance in anti-tumor therapy.

Reversal of tamoxifen resistance by artemisinin in ER+breast cancer:bioinformatics analysis and experimental validation

Breast cancer is the leading cause of cancer-related deaths in women worldwide,with Hormone Receptor(HR)+being the predominant subtype.Tamoxifen(TAM)serves as the primary treatment for HR+breast cancer.However,drug resistance often leads to recurrence,underscoring the need to develop new therapies to enhance patient quality of life and reduce recurrence rates.Artemisinin(ART)has demonstrated efficacy in inhibiting the growth of drug-resistant cells,positioning art as a viable option for counteracting endocrine resistance.This study explored the interaction between artemisinin and tamoxifen through a combined approach of bioinformatics analysis and experimental validation.Five characterized genes(ar,cdkn1a,erbb2,esr1,hsp90aa1)and seven drug-disease crossover genes(cyp2e1,rorc,mapk10,glp1r,egfr,pgr,mgll)were identified using WGCNA crossover analysis.Subsequent functional enrichment analyses were conducted.Our findings confirm a significant correlation between key cluster gene expression and immune cell infiltration in tamoxifen-resistant and-sensitized patients.scRNA-seq analysis revealed high expression of key cluster genes in epithelial cells,suggesting artemisinin’s specific impact on tumor cells in estrogen receptor(ER)-positive BC tissues.Molecular target docking and in vitro experiments with artemisinin on LCC9 cells demonstrated a reversal effect in reducing migratory and drug resistance of drug-resistant cells by modulating relevant drug resistance genes.These results indicate that artemisinin could potentially reverse tamoxifen resistance in ER-positive breast cancer.

Drug resistance mechanisms in cancers:Execution of prosurvival strategies

One of the quintessential challenges in cancer treatment is drug resistance.Several mechanisms of drug resistance have been described to date,and new modes of drug resistance continue to be discovered.The phenomenon of cancer drug resistance is now widespread,with approximately 90% of cancer-related deaths associated with drug resistance.Despite significant advances in the drug discovery process,the emergence of innate and acquired mechanisms of drug resistance has impeded the progress in cancer therapy.Therefore,understanding the mechanisms of drug resistance and the various pathways involved is integral to treatment modalities.In the present review,I discuss the different mechanisms of drug resistance in cancer cells,including DNA damage repair,epithelial to mesenchymal transition,inhibition of cell death,alteration of drug targets,inactivation of drugs,deregulation of cellular energetics,immune evasion,tumor-promoting inflammation,genome instability,and other contributing epigenetic factors.Furthermore,I highlight available treatment options and conclude with future directions.