Role of senescence induction in cancer treatment

Cellular senescence is a form of permanent cell cycle arrest that can be triggered by a variety of cell-intrinsic and extrinsic stimuli, including telomere shortening,DNA damage, oxidative stress, and exposure to chemotherapeutic agents and ionizing radiation. Although the induction of apoptotic cell death is a desirable outcome in cancer therapy, mutations and/or deficiencies in the apoptotic signaling pathways have been frequently identified in many human cancer types,suggesting the importance of alternative apoptosis-independent therapeutic approaches for cancer treatment. A growing body of evidence has documented that senescence induction in tumor cells is a frequent response to many anticancer modalities including cyclin-dependent kinases 4/6 small molecule inhibitor-based targeted therapeutics and T helper-1 cytokine-mediated immunotherapy. This review discusses the recent advances and clinical relevance of therapy-induced senescence in cancer treatment.

前列腺癌错配修复基因蛋白MLH1缺失的研究

目的 探讨错配修复基因 (MMR)蛋白MLH1在前列腺癌细胞株及前列腺癌标本的表达及其意义。方法 利用Western印迹法检测了前列腺癌细胞株中错配修复基因蛋白的丢失情况 ;用免疫组织化学法检测前列腺癌标本中错配修复蛋白的表达。结果 在所研究的 8个前列腺癌细胞株中均发现有错配修复基因的缺失 ;前列腺癌标本中也存在错配修复蛋白MLH1表达的减少或消失。结论 前列腺癌中存在错配修复基因的缺失 ,错配修复基因的缺失直接参与了前列腺癌的发生与发展。

Hematopoietic stem cell-derived adipocytes and fibroblasts in the tumor microenvironment

The tumor microenvironment(TME) is complex and constantly evolving. This is due, in part, to the crosstalk between tumor cells and the multiple cell types that comprise the TME, which results in a heterogeneous population of tumor cells and TME cells. This review will focus on two stromal cell types, the cancerassociated adipocyte(CAA) and the cancer-associated fibroblast(CAF). In the clinic, the presence of CAAs and CAFs in the TME translates to poor prognosis in multiple tumor types. CAAs and CAFs have an activated phenotype and produce growth factors, inflammatory factors, cytokines, chemokines, extracellular matrix components, and proteases in an accelerated and aberrant fashion. Through this activated state, CAAs and CAFs remodel the TME, thereby driving all aspects of tumor progression, including tumor growth and survival, chemoresistance, tumor vascularization, tumor invasion, and tumor cell metastasis. Similarities in the tumorpromoting functions of CAAs and CAFs suggest that a multipronged therapeutic approach may be necessary to achieve maximal impact on disease. While CAAs and CAFs are thought to arise from tissues adjacent to the tumor, multiple alternative origins for CAAs and CAFs have recently been identified. Recent studies from our lab and others suggest that the hematopoietic stem cell, through the myeloid lineage, may serve as a progenitor for CAAs and CAFs. We hypothesize that the multiple origins of CAAs and CAFs may contribute to the heterogeneity seen in the TME. Thus, a better understanding of the origin of CAAs and CAFs, how this origin impacts their functions in the TME, and thetemporal participation of uniquely originating TME cells may lead to novel or improved anti-tumor therapeutics.

Enhancer variants reveal a conserved transcription factor network governed by PU.1 during osteoclast differentiation

Genome-wide association studies(GWASs) have been instrumental in understanding complex phenotypic traits. However, they have rarely been used to understand lineage-specific pathways and functions that contribute to the trait. In this study, by integrating lineage-specific enhancers from mesenchymal and myeloid compartments with bone mineral density loci, we were able to segregate osteoblast-and osteoclast(OC)-specific functions. Specifically, in OCs, a PU.1-dependent transcription factor(TF)network was revealed. Deletion of PU.1 in OCs in mice resulted in severe osteopetrosis. Functional genomic analysis indicated PU.1 and MITF orchestrated a TF network essential for OC differentiation. Several of these TFs were regulated by cooperative binding of PU.1 with BRD4 to form superenhancers. Further, PU.1 is essential for conformational changes in the superenhancer region of Nfatc1. In summary, our study demonstrates that combining GWASs with genome-wide binding studies and model organisms could decipher lineage-specific pathways contributing to complex disease states.

An assessment of racial differences in epidemiological, clinical and psychosocial factors among head and neck cancer patients at the time of surgery

Objective:Racial disparities have been well characterized and African American(AA)patients have 30%lower 5-year survival rates than European Americans(EAs)for head and neck squamous carcinoma(HNSCC).This poorer survival can be attributed to a myriad of different factors.The purpose of this study was to characterize AA-EA similarities and differences in sociodemographic,lifestyle,clinical,and psychosocial characteristics in HNSCC patients near the time of surgery.Methods:Setting:Single tertiary care center.Participants:Thirty-nine newly diagnosed,untreated HNSCC patients(n=24 EAs,n=15 AAs)who were to undergo surgery were recruited.Study Design:Cross-sectional study Sociodemographic,lifestyle factors,and disease factors(cancer site,AJCC clinical and pathologic stage,and HPV status)were assessed.Risk factors,leisure time,quality of life and social support were also assessed using validated questionnaires.Exposures:EA and AA patients were similar in the majority of sociodemographic factors assessed.AAs had a higher trend toward pathologically later stage disease compared to EAs and significantly increased time to treatment.Results:EA and AA patients were similar in the majority of sociodemographic factors assessed.AAs had a higher trend toward pathologically later stage disease compared to EAs.AAs also had significantly increased time to treatment(P=0.05).The majority of AA patients(62%)had later stage pathologic disease.AA were less likely to complete high school or college(P=0.01)than their EA counterparts.Additionally,AAs were more likely to report having a gap in health insurance during the past decade(37%vs.15%).Conclusions:This preliminary study demonstrates a similar profile of demographics,clinical and psychosocial characteristics preoperatively for AAs and EAs.Key differences were AAs tending to have later pathologic stage disease,educational status,delays in treatment initiation,and gaps in health insurance.

Changes in otolaryngology application requirements and match outcomes:Are we doing any better?

Objectives:Otolaryngology-specific requirements were piloted to minimize applicant and program burdens.We investigated the impact of introducing and then removing these requirements on Match outcomes.Methods:2014-2021 National Resident Matching Program?data were examined.The primary outcome was the impact of Otolaryngology Resident Talent Assessment(ORTA;prematch 2017,postmatch 2019)and Program-Specific Paragraph(PSP;implemented 2016,optional 2018)on applicant numbers and match rates.Secondary survey analysis assessed candidate perceptions of PSP/ORTA.Results:Applicant numbers declined significantly during PSP/ORTA(18.9%;p=0.001).With the optional PSP and postmatch ORTA,applicant numbers increased significantly(39.0%;p=0.002).Examined individually,mandatory PSP was associated with a significant decline in applicants(p=0.007),whereas postmatch ORTA was associated with significant increases in applicants(p=0.010).ORTA and PSP negatively impacted the decision to apply to otolaryngology in 59.8%and 51.3%of applicants,respectively.Conversely,match rate success improved significantly from 74.8%to 91.2%during PSP/ORTA(p=0.014),followed by a significant decline to 73.1%after PSP was made optional and ORTA moved to postmatch(p=0.002).Conclusions:ORTA and PSP correlated with decreased applicant numbers and increased match rate success.As programs seek ways to remove barriers to applying to otolaryngology,the potential consequences of an increasing pool of unmatched candidates must also be considered.

引入市场资金建设肿瘤防治医疗实体的探讨

中国目前面临提高癌症防治质量,加快癌症医学研究发展速度,加快培养新一代癌症防治工作者的挑战,迅速扩大高水平肿瘤防治中心的建设显得尤为重要。建立一个新的肿瘤中心是一项非常昂贵的投资,在目前国家资金对公立医院投入有限的严峻形势下,引进私人资金来设立肿瘤中心已迫在眉睫。文章建议以公私合作的模式来建立新的私立肿瘤中心——市场投资与公立肿瘤中心共同管理的结合体。对于服务质量的评估,公立癌症中心与公私合作的癌症中心应该使用同一标准。我们提出的公私合作模式还有助于解除公众和国家决策者对私立肿瘤中心可能引起当地入院难和治疗水平下降问题的后顾之忧。此外,进一步深化医疗体制改革将是保障私立肿瘤中心顺利筹建和运行的关键。

Dermal fibroblast expression of stromal cellderived factor-1 （SDF-1） promotes epidermal keratinocyte proliferation in normal and diseased skin

Stromal cells provide a crucial microenvironment for overlying epithelium. Here we investigated the expression and function of a stromal cell-specific protein, stromal cell-derived factor-1 （SDF-1）, in normal human skin and in the tissues of diseased skin. Immunohistology and laser capture microdissection （LCM）-coupled quantitative real- time RT-PCR revealed that SDF-1 is constitutively and predominantly expressed in dermal stromal cells in nor- mal human skin in vivo. To our surprise, an extremely high level of SDF-1 transcription was observed in the dermis of normal human skin in vivo, evidenced by much higher mRNA expression level than type I collagen, the most abundant and highly expressed protein in human skin. SDF-1 was also upregulated in the tissues of many human skin disorders including psoriasis, basal cell carcinoma （BCC）, and squamous cell carcinoma （SCC）. Double immunostaining for SDF-1 and HSP47 （heat shock protein 47）, a marker of fibroblasts, revealed that fibroblasts were the major source of stroma-cell-derived SDF-1 in both normal and diseased skin. Functionally, SDF-1 activates the ERK （extracellular-signal-regulated kinases） pathway and functions as a mitogen to stimulate epidermalkeratinocyte proliferation. Both overexpression of SDF-1 in dermal fibroblasts and treatment with rhSDF-1 to the skin equivalent cultures significantly increased the number of keratinocyte layers and epidermal thickness. Con- versely, the stimulative function of SDF-1 on keratinocyte proliferation was nearly completely eliminated by inter- fering with CXCR4, a specific receptor of SDF-1, or by knock-down of SDF-1 in fibroblasts. Our data reveal that extremely high levels of SDF-1 provide a crucial microenvironment for epidermal keratinocyte proliferation in both physiologic and pathologic skin conditions.

Neuron specific enolase is a potential target for regulating neuronal cell survival and death: implications in neurodegeneration and regeneration

Enolase is a multifunctional enzyme primarily involved in catalyzing the conversion of 2-phosphoglycerate to phosphoenolpyruvate during glycolysis and the reverse reaction during gluconeogenesis[1-4].Though typically expressed in the cytosol,enolase has been shown to migrate to the cell surface upon inflammatory signal[3].

hnRNP E1 at the crossroads of translational regulation of epithelial-mesenchymal transition

The epithelial-mesenchymal transition(EMT),in which cells undergo a switch from a polarized,epithelial phenotype to a highly motile fibroblastic or mesenchymal phenotype is fundamental during embryonic development and can be reactivated in a variety of diseases including cancer.Spatio-temporally-regulated mechanisms are constantly orchestrated to allow cells to adapt to their constantly changing environments when disseminating to distant organs.Although numerous transcriptional regulatory factors are currently well-characterized,the post-transcriptional control of EMT requires continued investigation.The hnRNP E1 protein displays a major role in the control of tumor cell plasticity by regulating the translatome through multiple non-redundant mechanisms,and this role is exemplified when E1 is absent.hnRNP E1 binding to RNA molecules leads to direct or indirect translational regulation of specific sets of proteins:(1)hnRNP E1 binding to specific targets has a direct role in translation by preventing elongation of translation;(2)hnRNP E1-dependent alternative splicing can prevent the generation of a competing long non-coding RNA that acts as a decoy for microRNAs(miRNAs)involved in translational inhibition of EMT master regulators;(3)hnRNP E1 binding to the 3'untranslated region of transcripts can also positively regulate the stability of certain mRNAs to improve their translation.Globally,hnRNP E1 appears to control proteome reprogramming during cell plasticity,either by direct or indirect regulation of protein translation.

S1P/S1PR1 signaling differentially regulates the allogeneic response of CD4 and CD8 T cells by modulating mitochondrial fission

Graft-versus-host disease (GVHD) significantly contributes to patient morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HSCT). Sphingosine-1-phosphate (S1P) signaling is involved in the biogenetic processes of different immune cells. In the current study, we demonstrated that recipient sphingosine kinase 1 (Sphk1), but not Sphk2, was required for optimal S1PR1-dependent donor T-cell allogeneic responses by secreting S1P. Using genetic and pharmacologic approaches, we demonstrated that inhibition of Sphk1 or S1PR1 substantially attenuated acute GVHD (aGVHD) while retaining the graft-versus-leukemia (GVL) effect. At the cellular level, the Sphk1/S1P/S1PR1 pathway differentially modulated the alloreactivity of CD4+ and CD8+ T cells;it facilitated T-cell differentiation into Th1/Th17 cells but not Tregs and promoted CD4+ T-cell infiltration into GVHD target organs but was dispensable for the CTL activity of allogeneic CD8+ T cells. At the molecular level, the Sphk1/S1P/S1PR1 pathway augmented mitochondrial fission and increased mitochondrial mass in allogeneic CD4+ but not CD8+ T cells by activating the AMPK/AKT/mTOR/Drp1 pathway, providing a mechanistic basis for GVL maintenance when S1P signaling was inhibited. For translational purposes, we detected the regulatory efficacy of pharmacologic inhibitors of Sphk1 and S1PR1 in GVHD induced by human T cells in a xenograft model. Our study provides novel mechanistic insight into how the Sphk1/S1P/S1PR1 pathway modulates T-cell alloreactivity and validates Sphk1 or S1PR1 as a therapeutic target for the prevention of GVHD and leukemia relapse. This novel strategy may be readily translated into the clinic to benefit patients with hematologic malignancies and disorders.

STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function

Stimulator of interferon genes(STING)-mediated innate immune activation plays a key role in tumor-and self-DNA-elicited antitumor immunity and autoimmunity.However,STING can also suppress tumor immunity and autoimmunity.STING signaling In host nonhematopoietic cells was reported to either protect against or promote graft-versus-host disease(GVHD),a major complication of allogeneic hematopoietic cell transplantation(allo-HCT).Host hematopoietic antigen-presenting cells(APCs)play key roles in donor T-cell priming during GVHD initiation.However,how STING regulates host hematopoietic APCs after allo-HCT remains unknown.We utilized murine models of allo-HCT to assess the role of STING in hematopoietic APCs.STING-deficient recipients developed more severe GVHD after major histocompatibility complex-mismatched allo-HCT.Using bone marrow chimeras,we found that STING deficiency in host hematopoietic cells was primarily responsible for exacerbating the disease.Furthermore,STING on host CD11c+cells played a dominant role in suppressing allogeneic T-cell responses.Mechanistically,STING deficiency resulted in increased survival,activation,and function of APCs,including macrophages and dendritic cells.Consistently,constitutive activation of STING attenuated the survival,activation,and function of APCs isolated from STING V154M knock-in mice.STING-deficient APCs augmented donor T-cell expansion,chemokine receptor expression,and migration into intestinal tissues,resulting in accelerated/exacerbated GVHD.Using pharmacologic approaches,we demonstrated that systemic administration of a STING agonist(bis-(3'-5')-cyclic dimeric guanosine monophosphate)to recipient mice before transplantation significantly reduced GVHD mortality.In conclusion,we revealed a novel role of STING in APC activity that dictates T-cell allogeneic responses and validated STING as a potential therapeutic target for controlling GVHD after allo-HCT.