Attributable Causes of Breast Cancer and Ovarian Cancer in China:Reproductive Factors,Oral Contraceptives and Hormone Replacement Therapy

Objective： To provide an evidence-based, consistent assessment of the burden of breast cancer attributable to reproductive factors （RFs, including nulliparity, mean number of children, age at first birth and breastfeeding）, use of oral contraceptives （OCs, restricted to the age group of 15-49 years）, and hormone replacement therapy （HRT）, as well as of the burden of ovarian cancer attributable to the mean number of children in China in 2005. Methods： We derived the prevalence of these risk factors and the relative risk of breast and ovarian cancer from national surveys or large-scale studies conducted in China. In the case of RFs, we compared the exposure distributions in 2001 and counterfactual exposure. Results： Exposure of RFs in 2002 was found to account for 6.74% of breast cancer, corresponding to 9,617 cases and 2,769 deaths, and for 2.78% of ovarian cancer （712 cases, 294 deaths）. The decrease in mean number of children alone was responsible for 1.47% of breast cancer and 2.78% of ovarian cancer. The prevalence of OC use was 1.74% and the population attributable fraction （PAF） of breast cancer was 0.71%, corresponding to 310 cases and 90 deaths. The PAF of breast cancer due to HRT was 0.31%, resulting in 297 cases and 85 deaths. Conclusion： RFs changes in China contributed to a sizable fraction of breast and ovarian cancer incidence and mortality, whereas HRT and OCs accounted for relatively low incidence of breast cancer in China.

Attributable Causes of Cancer in China:Fruit and Vegetable

Objective：To provide an evidence-based and consistent assessment of the burden of cancer attributable to inadequate fruit and vegetable intake in China in 2005.Methods：The proportions of cancers attributable to low consumption of vegetable and fruit were calculated separately to estimate the burden of related cancers for the year 2005 in China.Data on the prevalence of exposure were derived from a Chinese nutrition and health survey.Data on relative risks were mainly derived from meta-analysis.Attributable fractions were calculated based on the counterfactual scenario which was a shift in the exposure distribution.Results：The total cancer burden attributable to inadequate consumption of fruit was up to 233,000 deaths （13.0% of all cancers） and 300,000 cases （11.6% of all cancers） in 2005.Increasing consumption of vegetable to the highest quintile could avoid total cancer deaths and cases by 3.6% （64,000 persons） and 3.4% （88,000 persons）.The contributions to cancer burden were higher in rural areas than in urban areas.They have greater influence on men than on women.The largest proportions of cancer burden attributable to low fruit and vegetable intake were for oral and pharyngeal cancers.Conclusion：This study showed that inadequate intake of fruit and vegetable makes a significant contribution to the cancer burden.Increasing consumption of fruit and vegetable could prevent many cancer deaths and save many lives.Promoting the consumption of fruit and vegetable is an important component in diet-based strategies for preventing cancer.

Age, socioeconomic features, and clinical factors predict receipt of endoscopic retrograde cholangiopancreatography in pancreatic cancer

BACKGROUND Endoscopic retrograde cholangiopancreatography(ERCP) is the recommended technique for biliary decompression in pancreatic cancer. Previous studies have suggested racial, socioeconomic and geographic differences in diagnosis,treatment and outcomes of pancreatic cancer patients.AIM To examine geographic, racial, socioeconomic and clinical factors associated with utilization of ERCP.METHODS Surveillance, Epidemiology and End Results and linked Medicare claims data were used to identify pancreatic cancer patients between 2000-2011. Claims data were used to identify patients who had ERCP and other treatments. The primary outcome was receipt of ERCP. Chi-squared analyses were used to compare demographic information. Trends in use of ERCP over time were assessed using Cochran Armitage test. Adjusted odds ratios(aORs) and 95% confidence intervals(CIs) for receipt ERCP were calculated using logistic regression,controlling for other characteristics.RESULTS Among 32510 pancreatic cancer patients, 14704(45.2%) underwent ERCP.Patients who had cancer located in the head of the pancreas(aOR 3.27, 95%CI:2.99-3.57), had jaundice(aOR 7.59, 95%CI: 7.06-8.17), cholangitis(aOR 4.22,95%CI: 3.71-4.81) or pruritus(aOR 1.42, 95%CI: 1.22-1.66) and lived in lower education zip codes(aOR 1.14, 95%CI: 1.04-1.24) were more likely to receive ERCP. In contrast, patients who were older(aOR 0.88, 95%CI: 0.83, 0.94), not married(aOR 0.92, 95%CI: 0.86, 0.98), and lived in a non-metropolitan area(aOR0.89, 95%CI: 0.82, 0.98) were less likely to receive ERCP. Compared to white patients, non-white/non-black patients(aOR 0.83, 95%CI: 0.70-0.97) were less likely to receive ERCP. Patients diagnosed later in the study period were less likely to receive ERCP(aOR 2004-2007 0.85, 95%CI: 0.78-0.92; aOR 2008-2011 0.76,95%CI: 0.70-0.83). After stratifying by indications for ERCP including jaundice,racial differences persisted(aOR black patients 0.80, 95%CI: 0.67-0.95,nonwhite/nonblack patients 0.73, 95%CI: 0.58-0.91). Among patients with jaundice, those who underwent surgery were less likely to undergo ERCP(aOR0.60, 95%CI: 0.52, 0.69).CONCLUSION ERCP utilization in pancreatic cancer varies based on patient age, marital status,and factors related to where the patient lives. Further studies are needed to guide appropriate biliary intervention for these patients.

The metastatic castration-resistant prostate cancer treatment paradigm： more choices, more questions

The world of prostate cancer has dramatically changed in the last few years. The original paradigm that metastatic castration-resistant prostate cancer （mCRPC） is untreatable is clearly wrong.

Examining heterogeneity of stromal cells in tumor microenvironment based on pan-cancer single-cell RNA sequencing data

Tumor tissues contain both tumor and non-tumor cells,which include infiltrated immune cells and stromal cells,collectively called the tumor microenvironment(TME).Single-cell RNA sequencing(sc RNAseq)enables the examination of heterogeneity of tumor cells and TME.In this review,we examined sc RNAseq datasets for multiple cancer types and evaluated the heterogeneity of major cell type composition in different cancer types.We further showed that endothelial cells and fibroblasts/myofibroblasts in different cancer types can be classified into common subtypes,and the subtype composition is clearly associated with cancer characteristic and therapy response.

Baseline neutrophil-lymphocyte ratio and platelet-lymphocyte ratio appear predictive of immune treatment related toxicity in hepatocellular carcinoma

BACKGROUND A well-recognized class effect of immune checkpoint inhibitors(ICI)is immune-related adverse events(IrAEs)ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI.Deaths are reported in<5%of patients treated with ICI.There are,however,no reliable markers to predict the onset and severity of IrAEs.We tested the association between neutrophil-lymphocyte ratio(NLR)and platelet-lymphocyte ratio(PLR)at baseline with development of clinically significant IrAEs(grade≥2)in hepatocellular carcinoma(HCC)patients treated with ICI.AIM To test the association between NLR and PLR at baseline with development of clinically significant IrAEs(grade≥2)in HCC patients treated with ICI.METHODS Data was extracted from an international database from a consortium of 11 tertiary-care referral centers.NLR=absolute neutrophil count/absolute lymphocyte count(ALC)and PLR=platelet count/ALC.Cutoff of 5 was used for NLR and 300 for PLR based on literature.We also tested the association between RESULTS Data was collected from 361 patients treated between 2016-2020 across the United States(67%),Asia(14%)and Europe(19%).Most patients received Nivolumab(n=255,71%).One hundred sixty-seven(46%)patients developed at least one IrAE,highest grade 1 in 80(48%),grade≥2 in 87(52%)patients.In a univariable regression model PLR>300 was significantly associated with a lower incidence of grade≥2 IrAEs(OR=0.40;P=0.044).Similarly,a trend was observed between NLR>5 and lower incidence of grade≥2 IrAEs(OR=0.58;P=0.097).Multivariate analyses confirmed PLR>300 as an independent predictive marker of grade≥2 IrAEs(OR=0.26;P=0.011),in addition to treatment with programmed cell death ligand 1(PD-1)/cytotoxic T lymphocyte-associated protein-4(OR=2.57;P=0.037)and PD-1/tyrosine kinase inhibitor(OR=3.39;P=0.01)combinations.Antibiotic use was not associated with IrAE incidence(OR=1.02;P=0.954).Patients treated with steroids had a>2-fold higher incidence of grade≥2 IrAEs(OR=2.74;P<0.001),although 74%were prescribed steroids for the treatment of IrAEs.CONCLUSION Given that high baseline NLR and PLR are associated with a decreased incidence of IrAEs,lower baseline NLR and PLR may be predictive biomarkers for the appearance of IrAEs in HCC treated with ICI.This finding is in keeping with several studies in solid tumors that have shown that baseline NLR and PLR appear predictive of IrAEs.

Molecular prognostic prediction in liver cirrhosis

The natural history of cirrhosis varies and therefore prognostic prediction is critical given the sizable patient population. A variety of clinical prognostic indicators have been developed and enable patient risk stratification although their performance is somewhat limited especially within relatively earlier stage of disease. Molecular prognostic indicators are expected to refine the prediction,and potentially link a subset of patients with molecular targeted interventions that counteract poor prognosis. Here we overview clinical and molecular prognostic indicators in the literature,and discuss critical issues to successfully define,evaluate,and deploy prognostic indicators as clinical scores or tests. The use of liver biopsy has been diminishing due to sampling variability on fibrosis assessment and emergence of imaging- or lab testbased fibrosis assessment methods. However,recent rapid developments of genomics technologies and selective molecular targeted agents has highlighted the need for biopsy tissue specimen to explore and establish molecular information-guided personalized/stratified clinical care,and eventually achieve "precision medicine".

mRNA delivery in cancer immunotherapy

Messenger RNA(mRNA)has drawn much attention in the medical field.Through various treatment approaches including protein replacement therapies,gene editing,and cell engineering,mRNA is becoming a potential therapeutic strategy for cancers.However,delivery of mRNA into targeted organs and cells can be challenging due to the unstable nature of its naked form and the low cellular uptake.Therefore,in addition to mRNA modification,efforts have been devoted to developing nanoparticles for mRNA delivery.In this review,we introduce four categories of nanoparticle platform systems:lipid,polymer,lipid-polymer hybrid,and protein/peptide-mediated nanoparticles,together with their roles in facilitating mRNA-based cancer immunotherapies.We also highlight promising treatment regimens and their clinical translation.

Novel Non-Protein Biomarkers for Early Detection of Hepatocellular Carcinoma

Early detection of hepatocellular carcinoma(HCC)while in its early stages is critical for reducing HCC mortality in high-risk patients.However,highly sensitive and specific surveillance biomarkers for early-stage HCC detection are still lacking.In recent years,great efforts have been made to research tumor-derived molecular features that are detectable in circulation,such as circulating tumor deoxyribonucleic acid and circulating tumor ribonucleic acid,in order to explore their potential as noninvasive biomarker candidates in many tumor types.In this review,we summarize current studies on these new approaches and their application in early HCC detection.

Circulating and non-circulating proteins and nucleic acids as biomarkers and therapeutic molecules in ovarian cancer

Ovarian cancer is the second most fatal gynecological cancer. For the last decade or so significant use of non-circulating and circulating biomarkers has been highlighted. However, the study of such biomarkers at nanovesicle technology such as exosomes, proteomic and genomics studies could further contribute to better identification of anomalous protein and networks which could act as potential targets for biomarker and immunotherapy development. This review provides an overview of the circulating and non-circulating biomarkers with the aim of addressing the current challenges and potential biomarkers that could lead to early ovarian cancer diagnosis and better management. By means of this review we also lay a hypothesis that characterization of exosomal protein, nucleic acid content from body fluids (serum, plasma, urine, etc.) can decode the secret of disease and potentially improve diagnostic sensitivity which could further lead to more effective screening and early detection of the disease.

Biomarkers for therapy selection in metastatic urothelial cancer

The treatment of metastatic urothelial cancer(mUC)has been transformed by recent progress in clinical trials and drug development.There are now three therapeutic classes with proven benefits in mUC:chemotherapy,immunotherapy,and targeted therapy.The optimal sequence and combination of these classes remain to be defined.Biomarker development is essential to guide treatment selection at each therapeutic juncture.Two biomarkers,programmed death-ligand 1 expression and fibroblast growth factor receptor alterations,have been incorporated into the mUC treatment paradigm thus far.This review discusses predictive biomarkers in development and their potential to influence mUC treatment selection moving forward.

用于精准蛋白降解和癌症治疗的刺激响应型PROTAC进展

刺激响应型蛋白质降解靶向嵌合体(PROTAC)前药可在特定刺激条件下激活PROTAC分子,实现特定区域和细胞的靶蛋白降解,从而克服不可控蛋白降解导致的毒副作用,是改善PROTAC疗效和成药性的有效策略.本文系统总结了目前用于特异性降解病灶组织目标蛋白从而精准治疗肿瘤的各种刺激响应型PROTAC前药策略.首先,本文介绍了PROTAC的发展历程和作用原理,以及目前进入临床试验阶段的PROTAC分子;然后,介绍了细胞内原位生成PROTAC的前药策略,以及各种刺激手段激活的PROTAC前药,包括外源性的光、X-射线以及内源性的肿瘤微环境的乏氧、活性氧和酶等;接着,概括了配体修饰型的主动靶向PROTAC前药,包括抗体、叶酸、适配体等修饰策略.本文重点强调了基于纳米递药系统的PROTAC前药策略,其可实现特异性肿瘤组织药物递送和精准蛋白降解.最后,本文对PROTAC的未来发展进行了探讨和展望.

IFN-γ^(+) cytotoxic CD4^(+) T lymphocytes are involved in thepathogenesis of colitis induced by IL-23 and the foodcolorant Red 40

The food colorant Red 40 is an environmental risk factor for colitis development in mice with increased expression of interleukin(IL)-23.This immune response is mediated by CD4^(+)T cells,but mechanistic insights into how these CD4^(+)T cells trigger andperpetuate colitis have remained elusive.Here,using single-cell transcriptomic analysis,we found that several CD4^(+)T-cell subsetsare present in the intestines of colitic mice,including an interferon(IFN)-γ-producing subset.In vivo challenge of primed mice withRed 40 promoted rapid activation of CD4^(+)T cells and caused marked intestinal epithelial cell(IEC)apoptosis that was attenuated bydepletion of CD4^(+)cells and blockade of IFN-γ.Ex vivo experiments showed that intestinal CD4^(+)T cells from colitic mice directlypromoted apoptosis of IECs and intestinal enteroids.CD4^(+)T cell-mediated cytotoxicity was contact-dependent and required FasL,which promoted caspase-dependent cell death in target IECs.Genetic ablation of IFN-γconstrained IL-23-and Red 40-inducedcolitis development,and blockade of IFN-γinhibited epithelial cell death in vivo.These results advance the understanding of themechanisms regulating colitis development caused by IL-23 and food colorants and identify IFN-γ^(+)cytotoxic CD4^(+)T cells as a newpotential therapeutic target for colitis.

Treatment of unresectable malignant pleural mesothelioma in 2021: emerging standards in immunotherapy

Patients with unresectable malignant pleural mesothelioma(MPM)have historically poor outcomes and treatment,and their treatments have been limited to palliative chemotherapy.Recent efforts to improve prognosis for these patients by adding angiogenesis inhibitors to chemotherapy led to significant benefits.However,the emergence of immunotherapy combinations for the front-line treatment has upended the standard of care and has led to the first new FDA approvals for the treatment of MPM in nearly two decades.This review aims to cover the main clinical trials in unresectable MPM with VEGF inhibitors and immunotherapy which have led to paradigm shifts in current practice.Ongoing clinical trials exploring the combination of chemo and immunotherapies show a great deal of promise,and continued support for ambitious,large-scale well-designed trials remain vital for defining the future outcomes of patients diagnosed with MPM.