Interleukin-1β:Friend or foe for gastrointestinal cancers

Gastrointestinal(GI)cancer is a malignancy arising in the digestive system and accounts for approximately a third of increasing global cancer-related mortality,especially in the colorectum,esophagus,stomach,and liver.Interleukin-1β(IL-1β)is a leukocytic pyrogen recognized as a tumor progression-related cytokine.IL-1βsecretion and maturation in inflammatory responses could be regulated by nuclear factor-kappaB-dependent expression of NLR family pyrin domain containing 3,inflammasome formation,and activation of IL-1 converting enzyme.Several studies have documented the pro-tumorigenic effects of IL-1β in tumor microenvironments,promoting proliferation and metastatic potential of cancer cells in vitro and tumorigenesis in vivo.The application of IL-1β inhibitors is also promising for targeted therapy development in some cancer types.However,as a leukocytic pro-inflammatory cytokine,IL-1β may also possess anti-tumorigenic effects and be type-specific in different cancers.This editorial discusses the up-to-date roles of IL-1β in GI cancers,including underlying mechanisms and down-stream signaling pathways.Understanding and clarifying the roles of IL-1β would significantly benefit future therapeutic targeting and help improve therapeutic outcomes in patients suffering from GI cancer.

Impact of Social Determinants of Health on Self-Perceived Resilience: An Exploratory Study of Two Cohorts of Adults with Congenital Heart Disease

Social determinants of health(SDOH)affect quality of life.We investigated SDOH impacts on self-perceived resilience among people with adult congenital heart disease(ACHD).Secondary analysis of data from two com-plementary studies:a survey study conducted May 2021–June 2022 and a qualitative study conducted June 2020–August 2021.Resilience was assessed through CD-RISC10 score(range 0–40,higher scores reflect greater self-perceived resilience)and interview responses.Sociodemographic and SDOH(education,employment,living situa-tion,monetary stability,financial dependency,area deprivation index)data were collected by healthcare record review and self-report.We used linear regression with robust standard errors to analyze survey data and performed a thematic analysis of interview data.Survey participants(N=127)mean age was 42±14 years;51%were female,87%white.ACHD was moderate(75%)or complex(25%);41%functional class C or D.Resilience(mean 30±7)varied by monetary stability:compared to people with difficulty paying bills,resilience was 15.0 points higher(95%CI:6.9–23.1,p<0.001)for people reporting having enough money and 14.2 points higher(95%CI:5.9–22.4,p=0.001)for those reporting just enough money.Interview participants’(N=25)mean age was 32 years(range 22–44);52%were female,72%white.ACHD was moderate(56%)or complex(44%);76%functional class C or D.Participants discussed factors affecting resilience aligned with each of the major SDOH,prominently,economic stability and healthcare access and quality.Financial stability may be important for supporting self-perceived resi-lience in ACHD.This knowledge can inform the development of resilience interventions for this population.

Systemic inflammation in colorectal cancer: Underlying factors,effects, and prognostic significance

Systemic inflammation is a marker of poor prognosis preoperatively present in around 20%-40%of colorectal cancer patients.The hallmarks of systemic inflammation include an increased production of proinflammatory cytokines and acute phase proteins that enter the circulation.While the low-level systemic inflammation is often clinically silent,its consequences are many and may ultimately lead to chronic cancer-associated wasting,cachexia.In this review,we discuss the pathogenesis of cancer-related systemic inflammation,explore the role of systemic inflammation in promoting cancer growth,escaping antitumor defense,and shifting metabolic pathways,and how these changes are related to less favorable outcome.

Toll-like receptor signaling in colorectal cancer:carcinogenesis to cancer therapy

Toll-like receptors(TLRs)are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins,and signal expression of major histocompatibility complex proteins,costimulatory molecules,and inflammatory mediators by macrophages,neutrophils,dendritic cells,and other cell types.These protein receptors are characterized by their ability to respond to invading pathogens promptlyby recognizing particular TLR ligands,including flagellin and lipopolysaccharide of bacteria,nucleic acids derived from viruses,and zymosan of fungi.There are2 major TLR pathways;one is mediated by myeloid differentiation factor 88(MYD88)adaptor proteins,and the other is independent of MYD88.The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1(NF-κB1)and all the TLRs,except TLR3,have been shown to activate this pathway.TLR3and TLR4 act via MYD88-independent pathways with delayed activation of NF-κB signaling.TLRs play a vital role in activating immune responses.TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis,and are highly likely to be involved in the activation of a number of pathways following cancer therapy.Colorectal cancer(CRC)is one of the most common cancers,and accounts for almost half a million deaths annually worldwide.Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum.The key molecules involved in inflammation-driven carcinogenesis include TLRs.As sensors of cell death and tissue remodeling,TLRs may have a universal role in cancer;stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years.TLRs 3/4/7/8/9 are all validated targets for cancer therapy,and a number of companies are developing agonists and vaccine adjuvants.On the other hand,antagonists may favor inhibition of signaling responsible for autoimmune responses.In this paper,we review TLR signaling in CRC from carcinogenesis to cancer therapy.

Treatment-related gastrointestinal toxicities and advanced colorectal or pancreatic cancer:A critical update

Gastrointestinal toxicities(GIT), including oral mucositis,nausea and vomiting, and diarrhea, are common side effects of chemotherapy and targeted agents in patients with advanced colorectal cancer and pancreatic cancer. Being often underreported, it is still difficult to precisely establish their burden in terms of both patient's quality of life and cancer care costs. Moreover, with the use of more intensive upfront combination regimens, the frequency of these toxicities is rapidly growing with a potential negative effect also on patient's outcome, as a result of dose reductions, delays or even discontinuation of active treatments. Thus, identifying patients at higher risk of developing GIT as well as an optimal management are paramount in order to improve patient's compliance and outcome. After the description of the main treatment-induced GIT, we discuss the current knowledge on the pathophysiology of these side effects and comment the scales commonly used to assess and grade them. We then provide a critical update on GIT incidence based on the results of key randomized trials conducted in patients with metastatic colorectal cancer and advanced pancreatic cancer.

Current trends in the development and application of molecular technologies for cancer epigenetics

Current progress in epigenetic research supports the view that diet and dietary components are important in cancer etiology by enhancing or inhibiting carcinogenesis.Since diet and dietary factors may significantly contribute to the causation and progression of many cancers,it is important to find the molecular mechanisms of action of such dietary factors for cancer prevention and treatment.Recently,the role of epigenetic mechanisms in the cancer development and progression has attracted more attention as additional evidence along with traditional DNA sequence based mechanisms such as mutations and structural re-arrangements.Such an increasing interest in cancer epigenetics has also accelerated the development and application of molecular assays and tools for DNA methylation detection and histone modification enrichment analysis.In this paper,key assays and methods for epigenetic research are reviewed and discussed in terms of their utility and usability.In addition,more advanced methods for genome-wide analysis are introduced as part of upcoming research trends and directions.

Current debate in the oncologic management of rectal cancer

Despite the considerable amount of research in the field,the management of locally advanced rectal cancer remains a subject to debate.To date,effective treatment centers on surgical resection with the standard approach of total mesorectal resection.Radiation therapy and chemotherapy have been incorporated in order to decrease local and systemic recurrence.While it is accepted that a multimodality treatment regimen is indicated,there remains significant debate for how best to accomplish this in regards to order,dosing,and choice of agents.Preoperative radiation is the standard of care,yet remains debated with the option for chemoradiation,short course radiation,and even ongoing studies looking at the possibility of leaving radiation out altogether.Chemotherapy was traditionally incorporated in the adjuvant setting,but recent reports suggest the possibility of improved efficacy and tolerance when given upfront.In this review,the major studies in the management of locally advanced rectal cancer will be discussed.In addition,future directions will be considered such as the role of immunotherapy and ongoing trials looking at timing of chemotherapy,inclusion of radiation,and nonoperative management.

Estrogen receptor alpha gene amplification in breast cancer:25 years of debate

Twenty-five years ago,Nembrot and colleagues reported amplification of the estrogen receptor alpha gene(ESR1) in breast cancer,initiating a broad and still ongoing scientific debate on the prevalence and clinical significance of this genetic aberration,which affects one of the most important genes in breast cancer.Since then,a multitude of studies on this topic has been published,covering a wide range of divergent results and arguments.The reported prevalence of this alteration in breast cancer ranges from 0% to 75%,suggesting that ESR1 copy number analysis is hampered by technical and interpreter issues.To date,two major issues related to ESR1 amplification remain to be conclusively addressed:(1) The extent to which abundant amounts of messenger RNA can mimic amplification in standard fluorescence in situ hybridization assays in the analysis of strongly expressed genes like ESR1,and(2) the clinical relevance of ESR1 amplification:Such relevance is strongly disputed,with data showing predictive value for response as well as for resistance of the cancer to anti-estrogen therapies,or for subsequent development of cancers in the case of precursor lesions that display amplification of ESR1.This review provides a comprehensive summary of the various views on ESR1 amplification,and highlights explanations for the contradictions and conflicting data that could inform future ESR1 research.

What is the most cost-effective strategy to screen for second primary colorectal cancers in male cancer survivors in Korea?

AIM:To identify a cost-effective strategy of second primary colorectal cancer (CRC) screening for cancer survivors in Korea using a decision-analytic model.METHODS: A Markov model estimated the clinical and economic consequences of a simulated 50-year-old male cancer survivors' cohort, and we compared the results of eight screening strategies: no screening, fecal occult blood test (FOBT) annually, FOBT every 2 years, sigmoidoscopy every 5 years, double contrast barium enema every 5 years, and colonoscopy every 10 years (COL10), every 5 years (COL5), and every 3 years (COL3). We included only direct medical costs, and our main outcome measures were discounted lifetime costs, life expectancy, and incremental cost-effectiveness ratio (ICER).RESULTS: In the base-case analysis, the non-dominated strategies in cancer survivors were COL5, and COL3. The ICER for COL3 in cancer survivors was $5593/life-year saved (LYS), and did not exceed $10000/LYS in one-way sensitivity analyses. If the risk of CRC in can- cer survivors is at least two times higher than that in the general population, COL5 had an ICER of less than $10500/LYS among both good and poor prognosis of index cancer. If the age of cancer survivors starting CRC screening was decreased to 40 years, the ICER of COL5 was less than $7400/LYS regardless of screening compliance.CONCLUSION: Our study suggests that more strict and frequent recommendations for colonoscopy such as COL5 and COL3 could be considered as economically reasonable second primary CRC screening strategies for Korean male cancer survivors.

Retinoblastoma tumor suppressor functions shared by stem cell and cancer cell strategies

Carcinogenic transformation of somatic cells resembles nuclear reprogramming toward the generation of pluripotent stem cells.These events share eternal escape from cellular senescence,continuous self-renewal in limited but certain population of cells,and refractoriness to terminal differentiation while maintaining the potential to differentiate into cells of one or multiple lineages.As represented by several oncogenes those appeared to be first keys to pluripotency,carcinogenesis and nuclear reprogramming seem to share a number of core mechanisms.The retinoblastoma tumor suppressor product retinoblastoma(RB)seems to be critically involved in both events in highly complicated manners.However,disentangling such complicated interactions has enabled us to better understand how stem cell strategies are shared by cancer cells.This review covers recent findings on RB functions related to stem cells and stem cell-like behaviors of cancer cells.

Approaches to quantify axonal morphology for the analysis of axonal degeneration

Morphological hallmarks of axonal degeneration(AxD):Axons transmit signals from one neuron to another and a re crucial for the proper communication in the nervous system.Therefore,the disintegration of axons,a process named AxD,has detrimental consequences and plays a key role in many neurological diseases.

B7-1与B7-2对调节人IL-2基因的转录因子NF-κB和AP-1的相同作用

为了解B7共刺激对细胞因子 ,特别是对IL 2mRNA及转录因子NF κB和AP 1的影响 ,探讨B7介导的IL 2调节的分子机制 ,在异基因混合淋巴细胞反应 (MLR)体系中分别或联合加入抗B7 1、抗B7 2单克隆抗体和CTLA 4Ig以阻断B7/CD2 8信号传导 ,通过竞争性PCR定量检测其对IL 2和IL 4mRNA的影响 ,并初步测定IFN γmRNA的改变 ,同时用转染MHCⅡ类分子及联合转染等量B7 1或B7 2的NIH3T3转基因细胞tDR7,tDR7/B7 1和tDR7/B7 2刺激CD2 8+ T细胞 ,通过DNA 蛋白结合实验观察B7对IL 2转录因子NF κB和AP 1的影响。结果表明 :抗B7 2单抗和CTLA 4Ig可明显抑制B7介导的IL 2和IL 4mRNA合成 ,而抗B7 1单抗仅有轻度抑制作用 ,2种或 3种抗体联合应用时抑制作用相加。MLR 1 - 6小时 ,单独tDR7即可诱导NF κB的表达 ,联合转染B7早期对其结合活力无明显影响 ,6小时后tDR7诱导作用减弱 ,B7却可显著延长tDR7的诱导作用至 72小时。tDR7早期同样可诱导AP 1的表达 ,联合转染B7分子在 2 4小时内对其有一定的抑制作用 ,而在反应后期可延长tDR7对AP 1的上调作用 ,B7 1与B7 2间作用未见明显不同。结论 :B7通过减少IL 2mRNA降解和影响基因转录而上调IL 2分泌 ,并可同时影响多种细胞因子分泌 ;在转录水平B7 1与B7 2作用未见明显不同 。

MUC1及其C端活性片段突变体具有抑制肿瘤的活性

MUC1蛋白翻译后成为一条多肽链,它很快在内质网被切割成2个亚基,形成稳定的异源二聚体.Cys-Gln-Cys(CQC)3个氨基酸位于MUC1C端亚基跨膜结构域与胞内结构域的连接处.研究发现,MUC1C端的CQCRRK结构域突变成AQARRK或使其缺失,突变体的致瘤性明显降低.表明:通过突变CQC→AQA来阻碍与C端亚基相关的二聚体化,可能成为肿瘤治疗的新途径.

SHIV1157ipd3N4小量多次阴道粘膜感染中国猕猴的初步研究

目的建立R5-SHIV1157ipd3N4病毒中国猕猴阴道粘膜小剂量多次感染模型，为我国艾滋病疫苗有效性评价提供新的模型构建、应用策略。方法选用10—20TCID50剂量的SHIV1157ipd3N4病毒阴道黏膜途径感染6只雌性中国猕猴，共感染11次，每次攻毒间隔4～7d。定期测定血浆病毒载量和外周血CD4＋：CD8＋。结果6只中国猕猴经11次病毒攻击后，均建立系统性感染，血浆病毒载量呈阳性；CD4＋：CD8＋均有下降。结论初步建立了R5-SHIV1157ipd3N4中国猕猴阴道黏膜小剂量多次感染模型，为艾滋病研究提供了更接近于自然感染状态的模型建立模式。

基于网络药理学的转化医学平台与个体化治疗方案发现

网络药理学作为一门交叉学科，旨在深入理解药物与分子网络的相互作用、试图建立药物对细胞网络的时空调节模型，用于在人体病理生理学与临床用药等层面上理解药物的作用特征。笔者所在课题组与团队进行了一系列理论与方法学探索，本文综合介绍了该方面的最新进展。通过集成大规模癌症组学数据构建网络药理学模型，展示了该研究策略在转化医学（提出新治疗靶标、药物重定位）以及个体化治疗方面的应用前景。主要内容包括：

Classification,clinicopathologic features and treatment of gastric neuroendocrine tumors

Gastric neuroendocrine tumors(GNETs)are rare lesions characterized by hypergastrinemia that arise from enterochromaffin-like cells of the stomach.GNETs consist of a heterogeneous group of neoplasms comprising tumor types of varying pathogenesis,histomorphologic characteristics,and biological behavior.A classification system has been proposed that distinguishes four types of GNETs;the clinicopathological features of the tumor,its prognosis,and the patient’s survival strictly depend on this classification.Thus,correct management of patients with GNETs can only be proposed when the tumor has been classified by an accurate pathological and clinical evaluation of the patient.Recently developed cancer therapies such as inhibition of angiogenesis or molecular targeting of growth factor receptors have been used to treat GNETs,but the only definitive therapy is the complete resection of the tumor.Here we review the literature on GNETs,and summarize the classification,clinicopathological features(especially prognosis),clinical presentations and current practice of management of GNETs.We also present the latest findings on new gene markers for GNETs,and discuss the effective drugs developed for the diagnosis,prognosis and treatment of GNETs.

Computed tomography scans of paranasal sinuses before functional endoscopic sinus surgery

This review aims to familiarize the radiologist with the common types of sinus surgery including their indications and techniques.We also illustrate how surgeons interpret 3D sinus anatomy when evaluating computed tomography(CT)studies.Preoperative evaluation by CT is mandatory for all patients undergoing functional endoscopic sinus surgery(FESS).In the past decade in particular,CT of the paranasal sinuses has become a roadmap for FESS.The radiologist's goal is to report on five key points:the extent of sinus opacification,opacification of sinus drainage pathways,anatomical variants,critical variants,and condition of surrounding soft tissues of the neck,brain and orbits.We present a systematic approach to the use of coronal,axial,and sagittal images in CT evaluation before FESS.

Retroviral integrase protein and intasome nucleoprotein complex structures

Retroviral replication proceeds through the integration of a DNA copy of the viral RNA genome into the host cellular genome, a process that is mediated by the viral integrase(IN) protein. IN catalyzes two distinct chemical reactions: 3'-processing, whereby the viral DNA is recessed by a di- or trinucleotide at its 3'-ends, and strand transfer, in which the processed viral DNA ends are inserted into host chromosomal DNA. Although IN has been studied as a recombinant protein since the 1980 s, detailed structural understanding of its catalytic functions awaited high resolution structures of functional IN-DNA complexes or intasomes, initially obtained in 2010 for the spumavirus prototype foamy virus(PFV). Since then, two additional retroviral intasome structures, from the α-retrovirus Rous sarcoma virus(RSV) and β-retrovirus mouse mammary tumor virus(MMTV), have emerged. Here, we briefly review the history of IN structural biology prior to the intasome era, and then compare the intasome structures of PFV, MMTV and RSV in detail. Whereas the PFV intasome is characterized by a tetrameric assembly of IN around the viral DNA ends, the newer structures harbor octameric IN assemblies. Although the higher order architectures of MMTV and RSV intasomes differ from that of the PFV intasome, they possess remarkably similar intasomal core structures. Thus, retroviral integration machineries have adapted evolutionarily to utilize disparate IN elements to construct convergent intasome core structures for catalytic function.