Stereotactic radiotherapy for prostate cancer:A review and future directions

Prostate cancer affects over 200000 men annually in the United States alone.The role of conventionally fractionated external beam radiation therapy (RT) is well established as a treatment option for eligible prostate cancer patients; however,the use of stereotactic body radiotherapy (SBRT) in this setting is less well defined.Within the past decade,there have been a number of studies investigating the feasibility of SBRT as a potential treatment option for prostate cancer patients.SBRT has been well studied in other disease sites,and the shortened treatment course would allow for greater convenience for patients.There may also be implications for toxicity as well as disease control.In this review we present a number of prospective and retrospective trials of SBRT in the treatment of prostate cancer.We focus on factors such as biochemical progression-free survival,prostate specific antigen (PSA) response,and toxicity in order to compare SBRT to established treatment modalities.We also discuss future steps that the clinical community can take to further explore this new treatment approach.We conclude that initial studies examining the use of SBRT in the treatment of prostate cancer have demonstrated impressive rates of biochemical recurrencefree survival and PSA response,while maintaining a relatively favorable acute toxicity profile,though long-term follow-up is needed.

Deep UV Microscopy Identifies Prostatic Basal Cells:An Important Biomarker for Prostate Cancer Diagnostics

Objective and Impact Statement.Identifying benign mimics of prostatic adenocarcinoma remains a significant diagnostic challenge.In this work,we developed an approach based on label-free,high-resolution molecular imaging with multispectral deep ultraviolet(UV)microscopy which identifies important prostate tissue components,including basal cells.This work has significant implications towards improving the pathologic assessment and diagnosis of prostate cancer.Introduction.One of the most important indicators of prostate cancer is the absence of basal cells in glands and ducts.However,identifying basal cells using hematoxylin and eosin(H&E)stains,which is the standard of care,can be difficult in a subset of cases.In such situations,pathologists often resort to immunohistochemical(IHC)stains for a definitive diagnosis.However,IHC is expensive and time-consuming and requires more tissue sections which may not be available.In addition,IHC is subject to false-negative or false-positive stains which can potentially lead to an incorrect diagnosis.Methods.We leverage the rich molecular information of label-free multispectral deep UV microscopy to uniquely identify basal cells,luminal cells,and inflammatory cells.The method applies an unsupervised geometrical representation of principal component analysis to separate the various components of prostate tissue leading to multiple image representations of the molecular information.Results.Our results show that this method accurately and efficiently identifies benign and malignant glands with high fidelity,free of any staining procedures,based on the presence or absence of basal cells.We further use the molecular information to directly generate a high-resolution virtual IHC stain that clearly identifies basal cells,even in cases where IHC stains fail.Conclusion.Our simple,low-cost,and label-free deep UV method has the potential to improve and facilitate prostate cancer diagnosis by enabling robust identification of basal cells and other important prostate tissue components.

柚皮素：新一代免疫调节剂

大量研究表明,植物来源的黄酮类化合物具有广泛的生理活性和药理作用,日常摄取适量的黄酮类化合物能够显著降低许多疾病的发生.柚皮素作为一种自然界分布广泛的黄酮类化合物富含于水果、蔬菜、坚果、咖啡、茶和红酒等日常饮食中,与其他黄酮类化合物相比柚皮素易于胃肠道吸收、生物利用度高且安全剂量大.自2004年起我们对柚皮素调节免疫的分子机制进行了深入系统的研究.本文将重点介绍柚皮素作为一种新型免疫调节剂的研究进展.

A novel preoperative inflammatory marker prognostic score in patients with localized and metastatic renal cell carcinoma

Objective:Several inflammatory markers have been studied as potential biomarkers in renal cell carcinoma(RCC),however few reports have analyzed their prognostic value in aggregate and in non-clear cell histologies.We hypothesize that a combination of specific inflammatory markers into an RCC Inflammatory Score(RISK)could serve as a rigorous prognostic indicator of overall survival(OS)in patients with clear cell and non-clear cell RCC.Methods:Combination of preoperative C-reactive protein(CRP),albumin,erythrocyte sedimentation rate(ESR),corrected calcium,and aspartate transaminase to alanine transaminase(AST/ALT)ratio was used to develop RISK.RISK was developed using grid-search methodology,receiver-operating-characteristic(ROC)analysis,and sensitivity-specificity trade-off analysis.Prognostic value of RISK was analyzed using the KaplaneMeier method and Cox proportional regression models.Predictive accuracy was compared with RISK to Size,Size,Grade,and Necrosis(SSIGN)score,University of California-LOS Angeles(UCLA)Integrated Staging System(UISS),and Leibovich Prognosis Score(LPS).

Taking early preventive interventions to manage the challenging issue of acquired resistance to third-generation EGFR inhibitors

Although the clinical efficacies of third-generation epidermal growth factor receptor(EGFR)-tyrosine kinase in-hibitors(TKIs)such as osimertinib in the treatment of non-small cell lung cancer(NSCLC)with EGFR-activating mutations are promising,drug-acquired resistance inevitably occurs whether they are used as first-line or second-line treatment.Therefore,managing the acquired resistance to third-generation EGFR-TKIs is crucial in the clinic for improving patient survival.Great efforts have been made to develop potentially effective strategies or regimens for the treatment of EGFR-mutant NSCLC patients after relapse following these TKIs therapies with the hope that patients will continue to benefit from treatment through overcoming acquired resistance.Although this approach,which aims to overcome drug-acquired resistance,is necessary and important,it is a passive practice.Taking pre-ventive action early before disease progression to manage the unavoidable development of acquired resistance offers an equally important and efficient approach.We strongly believe that early preventive interventions using effective and tolerable combination regimens that interfere with the process of developing acquired resistance may substantially improve the outcomes of EGFR-mutant NSCLC treatment with third-generation EGFR-TKIs.Thus,this review focuses on discussing the scientific rationale and mechanism-driven strategies for delaying and even preventing the emergence of acquired resistance to third-generation EGFR-TKIs,particularly osimertinib.

The heterogeneity of CAFs and immune cell populations in the tumor microenvironment of pancreatic adenocarcinoma

Over the past decade,researchers have identified and characterized the diverse cell populations within the tumor microenvironment of pancreatic cancer.The interplay between these cells in the TME either promotes or inhibits the malignant behavior of pancreatic cancer cells.Cancer-associated fibroblasts,previously thought to be one main subset,can now be broadly subclassified into three main types:inflammatory,myofibroblastic,and antigen-presenting,with the former and the latter two exerting pro-tumoral and anti-tumoral functions,respectively.Myeloid cells include myeloid-derived suppressor cells and tumor-associated macrophages.Myeloid-derived suppressor cells can be further divided into polymorphonuclear and monocytic and exhibit pro-tumoral activities.Tumor-associated macrophages exhibit M1(anti-tumoral)or M2(pro-tumoral)phenotypes,which are present in a dynamic fashion between the two phenotypes.Other constituents of the immune make-up of the tumor microenvironment include T and B cells and less described subsets which include natural killer cells,γδT cells,and group 2 innate lymphoid cells.This review provides an overview of the studies that lead to the discovery of those cellular populations and highlights the recent efforts to utilize them as therapeutic targets in pancreatic cancer.

TMPRSS2 and SARS-CoV-2 SPIKE interaction assay for uHTS

SARS-CoV-2,the coronavirus that causes the disease COVID-19,has claimed millions of lives over the past 2 years.This demands rapid development of effective therapeutic agents that target various phases of the viral replication cycle.The interaction between host transmembrane serine protease 2(TMPRSS2)and viral SPIKE protein is an important initial step in SARS-CoV-2 infection,offering an opportunity for therapeutic development of viral entry inhibitors.Here,we report the development of a time-resolved fluorescence/Förster resonance energy transfer(TR-FRET)assay for monitoring the TMPRSS2–SPIKE interaction in lysate from cells co-expressing these proteins.The assay was configured in a 384-well-plate format for high-throughput screening with robust assay performance.To enable large-scale compound screening,we further miniaturized the assay into 1536-well ultrahigh-throughput screening(uHTS)format.A pilot screen demonstrated the utilization of the assay for uHTS.Our optimized TR-FRET uHTS assay provides an enabling platform for expanded screening campaigns to discover new classes of small-molecule inhibitors that target the SPIKE and TMPRSS2 protein–protein interaction.

Targeting apoptosis to manage acquired resistance to third generation EGFR inhibitors

A significant clinical challenge in lung cancer treatment is management of the inevitable acquired resistance to third-generation epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(EGFR-TKIs),such as osimertinib,which have shown remarkable success in the treatment of advanced NSCLC with EGFR activating mutations,in order to achieve maximal response duration or treatment remission.Apoptosis is a major type of programmed cell death tightly associated with cancer development and treatment.Evasion of apoptosis is considered a key hallmark of cancer and acquisition of apoptosis resistance is accordingly a key mechanism of drug acquired resistance in cancer therapy.It has been clearly shown that effective induction of apoptosis is a key mechanism for third generation EGFR-TKIs,particularly osimertinib,to exert their therapeutic efficacies and the development of resistance to apoptosis is tightly associated with the emergence of acquired resistance.Hence,restoration of cell sensitivity to undergo apoptosis using various means promises an effective strategy for the management of acquired resistance to third generation EGFR-TKIs.