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Immune checkpoint inhibitors in clinical trials

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Chinese Journal of Cancer 2014年第9期33卷 434-444页

作者： elad sharon Howard Streicher Priscila Goncalves Helen X.Chen Cancer Therapy Evaluation Program Division of Cancer Treatment and DiagnosisNational Cancer Institute Medical Oncology Service Center for Cancer ResearchNational Cancer Institute

Immunology-based therapy is rapidly developing into an effective treatment option for a surprising range of cancers. We have learned over the last decade that powerful immunologic effector cells may be blocked by inhibitory regulatory pathways controlled by specific molecules often called "immune checkpoints." These checkpoints serve to control or turn off the immune response when it is no longer needed to prevent tissue injury and autoimmunity. Cancer cells have learned or evolved to use these mechanisms to evade immune control and elimination. The development of a new therapeutic class of drugs that inhibit these inhibitory pathways has recently emerged as a potent strategy in oncology. Three sets of agents have emerged in clinical trials exploiting this strategy. These agents are antibodybased therapies targeting cytotoxic T-lymphocyte antigen 4(CTLA4), programmed cell death 1(PD-1), and programmed cell death ligand 1(PD-L1). These inhibitors of immune inhibition have demonstrated extensive activity as single agents and in combinations. Clinical responses have been seen in melanoma, renal cell carcinoma, non-small cell lung cancer, and several other tumor types. Despite the autoimmune or inflammatory immune-mediated adverse effects which have been seen, the responses and overall survival benefits exhibited thus far warrant further clinical development.

关键词：临床试验免疫学检查站癌症程序性细胞死亡细胞毒性T淋巴细胞自身免疫性免疫控制

The two sides of chromosomal instability:drivers and brakes in cancer

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1595-1624页

作者： Rendy Hosea sharon Hillary Sumera Naqvi Shourong Wu Vivi Kasim Key Laboratory of Biorheological Science and Technology Ministry of EducationCollege of BioengineeringChongqing UniversityChongqing 400045China The 111 Project Laboratory of Biomechanics and Tissue Repair College of BioengineeringChongqing UniversityChongqing 400044China Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment Chongqing University Cancer HospitalChongqing UniversityChongqing 400030China

Chromosomal instability(CIN)is a hallmark of cancer and is associated with tumor cell malignancy.CIN triggers a chain reaction in cells leading to chromosomal abnormalities,including deviations from the normal chromosome number or structural changes in chromosomes.CIN arises from errors in DNA replication and chromosome segregation during cell division,leading to the formation of cells with abnormal number and/or structure of chromosomes.Errors in DNA replication result from abnormal replication licensing as well as replication stress,such as double-strand breaks and stalled replication forks;meanwhile,errors in chromosome segregation stem from defects in chromosome segregation machinery,including centrosome amplification,erroneous microtubule-kinetochore attachments,spindle assembly checkpoint,or defective sister chromatids cohesion.In normal cells,CiN is deleterious and is associated with DNA damage,proteotoxic stress,metabolic alteration,cell cycle arrest,and senescence.Paradoxically,despite these negative consequences,CiN is one of the hallmarks of cancer found in over 90%of solid tumors and in blood cancers.Furthermore,CiN could endow tumors with enhanced adaptation capabilities due to increased intratumor heterogeneity,thereby facilitating adaptive resistance to therapies;however,excessive CiN could induce tumor cells death,leading to the"just-right"model for CIN in tumors.Elucidating the complex nature of CIN is crucial for understanding the dynamics of tumorigenesis and for developing effective anti-tumor treatments.This review provides an overview of causes and consequences of CIN,as well as the paradox of CIN,a phenomenon that continues to perplex researchers.Finally,this review explores the potential of CIN-based anti-tumor therapy.

关键词： chromosomal consequences thereby

Translating bacteriophage-derived depolymerases into antibacterial therapeutics:Challenges and prospects

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Acta Pharmaceutica Sinica B 2024年第1期14卷 155-169页

作者： Honglan Wang Yannan Liu Changqing Bai sharon Shui Yee Leung School of Pharmacy the Chinese University of Hong KongHong Kong SARChina Emergency Medicine Clinical Research Center Beijing Chao-Yang HospitalCapital Medical UniversityBeijing 100020China Department of Respiratory Shenzhen University General HospitalShenzhen University Clinical Medical AcademyGuangdong 518055China

Predatory bacteriophages have evolved a vast array of depolymerases for bacteria capture and deprotection.These depolymerases are enzymes responsible for degrading diverse bacterial surface carbohydrates.They are exploited as antibiofilm agents and antimicrobial adjuvants while rarely inducing bacterial resistance,making them an invaluable asset in the era of antibiotic resistance.Numerous depolymerases have been investigated preclinically,with evidence indicating that depolymerases with appropriate dose regimens can safely and effectively combat different multidrug-resistant pathogens in animal infection models.Additionally,some formulation approaches have been developed for improved stability and activity of depolymerases.However,depolymerase formulation is limited to liquid dosage form and remains in its infancy,posing a significant hurdle to their clinical translation,compounded by challenges in their applicability and manufacturing.Future development must address these obstacles for clinical utility.Here,after unravelling the history,diversity,and therapeutic use of depolymerases,we summarized the preclinical efficacy and existing formulation findings of recombinant depolymerases.Finally,the challenges and perspectives of depolymerases as therapeutics for humans were assessed to provide insights for their further development.

关键词： Phage-derived polysaccharide depolymerases Bacteriophage proteins Bacterial capsules Polysaccharide capsules Antibiotic resistance Biofilms Antibacterial therapy Antimicrobial adjuvants Combination treatment

Grafts in Peyronie’s surgery without the use ofprostheses:a systematic review and meta-analysis

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Asian Journal of Andrology 2024年第3期26卷 250-259页

作者： Anastasios Natsos Vasileios Tatanis Stavros Kontogiannis sharon Waisbrod Kristiana Gkeka Mohamed Obaidad Angelis Peteinaris Konstantinos Pagonis Costas Papadopoulos Panagiotis Kallidonis Evangelos Liatsikos Petros Drettas Department of Urology University of PatrasPatras 26500Greece Uroclinic Pfaeffikon 8808Switzerland Department of Medical Physics University of PatrasPatras26500Greece Department of Urology Medical University of ViennaVienna 1090Austria.

Peyronie’s disease(PD)is characterized by abnormal penile curvature,and various surgical methods have been developed usingdifferent graft materials.However,there is currently no universal agreement on which type of graft is the best.The objective of thisreview was to evaluate the available literature and identify the most effective graft material for penile curvature correction in PD.A literature search was conducted using electronic databases,including PubMed,Scopus,and the Cochrane Library.The patients,intervention,comparison,and outcome(PICO)approach was used to define the eligibility of studies.Two authors independentlyselected studies,evaluated them,and extracted data.Random-effect models using the DerSimonian–Laird method were used.Moststudies were single-arm studies and had a high risk of bias.Buccal mucosa grafts(BMG)were found to result in the highest penilestraightening rates and were associated with the least de novo erectile dysfunction.TachoSil grafts demonstrated a high successrate in straightening despite a higher mean preoperative curvature,while Tutoplast grafts had a higher incidence of postoperativeerectile dysfunction.BMG had the highest percentage of postoperative penile straightening.Overall,the TachoSil graft showed thebest performance when preoperative curvature is taken into account.Based on the available literature,BMG appear to be the mosteffective for penile curvature correction in PD,but this is offset by the requirement for low preoperative curvature.The TachoSilgraft shows the best overall performance when preoperative curvature is considered.Comparative randomized clinical trials arestill needed to determine graft superiority.

关键词： erectile function penile curvature penile grafts Peyronie’s disease

Propagation and Pinning of Travelling Wave for Nagumo Type Equation

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Journal of Applied Mathematics and Physics 2024年第3期12卷 861-869页

作者： sharon-Yasotha Veerayah-Mcgregor Valipuram Manoranjan Department of Mathematics Washington State University Pullman Washington USA

In this paper, we study the propagation and its failure to propagate (pinning) of a travelling wave in a Nagumo type equation, an equation that describes impulse propagation in nerve axons that also models population growth with Allee effect. An analytical solution is derived for the traveling wave and the work is extended to a discrete formulation with a piecewise linear reaction function. We propose an operator splitting numerical scheme to solve the equation and demonstrate that the wave either propagates or gets pinned based on how the spatial mesh is chosen.

关键词： Operator Splitting Travelling Wave Piecewise Reaction Nagumo Equation Pinning Finite Differences

Maternal Group B Streptococcus Infection Correlates Inversely With Preeclampsia in Pregnant African American Women

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Maternal-Fetal Medicine 2024年第1期6卷 23-28页

作者： Keun Soo Kwon Tzu Hsuan Cheng Simone A。Reynolds Jordan Zhou Huchong Cai sharon Lee Ivan Velickovic Mudar Dalloul David Wlody Ming Zhang Department of Anesthesiology State University of New York-Downstate Health Sciences UniversityNew York 11203USA Department of Epidemiology and Biostatistics School of Public HealthState University of New York-Downstate Health Sciences UniversityNew York 11203USA Department of Obstetrics and Gynecology State University of New York-Downstate Health Sciences UniversityNew York 11203USA

Objective:To determine whether an association exists between group B Streptococcus(GBS)colonization and preeclampsia among pregnant Black women.Methods:This retrospective cross-sectional study involved Black women who gave birth at State University of New York Downstate Hospital between January 2010 and December 2017.Data were collected from the Obstetric Department,including delivery date,time,mode of delivery,age of the mother,weeks of gestation at delivery,and antepartum complications.The GBS test results were originally determined using the eSwab transport system.Preeclampsia was defined based on the American College of Obstetricians and Gynecologists criteria for the periods 2010–2012 and 2013–2017.The primary outcome was whether GBS was associated with the outcome of preeclampsia in the population of Black women.Covariates,including smoking status,gestational age,parity,body mass index,maternal age,and presence of herpes simplex virus(HSV)and human immunodeficiency virus(HIV)were examined as potential confounders.Chi-squared test and logistic regression model were used,presenting odds ratios with 95%confidence intervals(P<0.050),analyzed with SAS on Demand for Academics(SAS Institute,Inc.,NY).Results:Among the 8,019 Black women included in this study,GBS-positive women(n=977)had a 53%reduction in the likelihood of being diagnosed with preeclampsia compared to GBS-negative women(adjusted odds ratio,0.47;95%confidence interval,0.32–0.70).We did not find evidence of differences in the distribution of smoking habits(P=0.783)or maternal age(P=0.107)between GBS-positive and GBS-negative women.However,the GBS-positive women tended to be less likely to have a preterm delivery(9.62%(94/977)vs.24.24%(1707/7042),P<0.001),less likely to be nulliparous(33.37%(326/977)vs.37.87%(2667/7042),P=0.006),and less likely to be obese(51.38%(502/977)vs.55.30%(3894/7042),P<0.001)compared with GBS-negative women.In contrast,GBS-positive women were more likely to have a comorbid infection than their counterparts:HSV(5.94%(58/977)vs.2

关键词： Pregnancy outcome Preeclampsia GBS colonization African American Afro-Caribbean

Acceptability of Caesarean Section among Pregnant Women Seeking Antenatal Care at Women and Newborn Hospital-University Teaching Hospitals, Lusaka Zambia

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Open Journal of Obstetrics and Gynecology 2024年第5期14卷 721-743页

作者： Huhenya sharon Chongo Maureen Masumo Namayipo Nankamba Lusaka College of Nursing and Midwifery University Teaching Hospital Lusaka Zambia Department of Midwifery Women and Child Health School of Nursing Sciences University of Zambia Lusaka Zambia

Caesarean section remains one of the most common obstetric and major operations performed on women during pregnancy and has contributed to improving maternal and foetal health. Consequently, significant mortality and morbidity from pregnancy and labour-related causes can be eliminated by a timely caesarean section. The acceptance of the life-saving procedure remains unsatisfactory in most sub-Saharan nations. The study aimed to assess the acceptability of caesarean section and associated factors among pregnant women seeking antenatal care at Women and Newborn Hospital-University Teaching Hospitals in Lusaka Zambia. The study utilised a quantitative cross-sectional analytical study design involving 420 pregnant women selected using systematic random sampling at Women and Newborn Hospital-University Teaching Hospitals Lusaka Zambia. Data was obtained using an Interview schedule and analysed using R software version 4.3.2. Chi-square, Fisher’s exact test, Wilcoxon rank sum test and binary logistic regression for statistical analysis at a 5% level of significance. The study found that the acceptability of Caesarean section as a mode of delivery was low (29%) among respondents at Women and Newborn Hospital-University Teaching Hospitals. This was influenced by marital status (P = 0.002), socioeconomic status (P = 0.050), parity (P = 0.004), gestation age (P = 0.008), previous history of caesarean section (P = 0.003), knowledge (P < 0.001), attitude (P < 0.001), and sociocultural beliefs (P = 0.045). Low acceptability of Caesarean section delivery is common among women at Women and Newborn Hospital-University Teaching Hospitals, despite its potential benefits for maternal and neonatal health. Socio-demographic and maternal characteristics, knowledge, attitude, perception, and socio-cultural beliefs play a major role in determining acceptability. Therefore, efforts to enhance acceptability should focus on improving knowledge, enhancing positive perceptions and attitudes, and allaying negative socio-cultural beliefs towar

关键词： Caesareans Section Acceptability Knowledge Attitude Perception

Immunoregulatory and Anti-cancer Activities of Combination Treatment of Novel Four-Herb Formula and Doxorubicin in 4T1-Breast Cancer Bearing Mice

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Chinese Journal of Integrative Medicine 2024年第4期30卷 311-321页

作者： Lea Ling-Yu Kan Ben Chung-Lap Chan Grace Gar-Lee Yue LI Pei-ting sharon Sze-Man Hon HUANG Dan-qi Miranda Sin-Man Tsang Clara Bik-San Lau Ping-Chung Leung Chun-Kwok Wong Institute of Chinese Medicine The Chinese University of Hong KongHong Kong SARChina State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants The Chinese University of Hong KongHong KongChina Department of Chemical Pathology The Chinese University of Hong KongHong Kong SARChina China-Australia International Research Centre for Chinese Medicine School of Health and Biomedical SciencesSTEM CollegeRMIT UniversityBundooraVictoriaAustralia Li Dak Sum Yip Yio Chin R&D Centre for Chinese Medicine The Chinese University of Hong Kong SARHong KongChina

Objective To investigate the in vivo immunomodulatory and anti-tumor mechanisms of the combined treatment of novel Four-Herb formula(4HF)and doxorubicin in triple-negative breast cancer(TNBC).Methods Murine-derived triple-negative mammary carcinoma cell line,4T1 cells,was cultured and inoculated into mouse mammary glands.Sixty-six mice were randomly assigned into 6 groups(n=11 in ench):naive,control,LD 4HF(low dose 4HF),HD 4HF(high dose 4HF),LD 4HF+D(low dose and doxorubicin),and D(doxorubicin).Apart from the naive group,each mouse received subcutaneous inoculation with 5×10^(5)4T1 cells resuspended in 100µL of normal saline in the mammary fat pads.Starting from the day of tumor cell inoculation,tumors were grown for 6 days.The LD and HD groups received daily oral gavage of 658 and 2,630 mg/kg 4HF,respectively.The LD 4HF+D group received daily oral gavage of 658 mg/kg 4HF and weekly intraperitoneal injection of doxorubicin(5 mg/kg).The D group received weekly intraperitoneal injections of doxorubicin(5 mg/kg).The treatment naive mice received daily oral gavage of 0.2 mL double distilled water and 0.1 mL normal saline via intraperitoneal injection once a week.The control group received daily oral gavage of 0.2 mL double-distilled water.The treatment period was 30 days.At the end of treatment,mice organs were harvested to analyze immunological activities via immunophenotyping,gene and multiplex analysis,histological staining,and gut microbiota analysis.Results Mice treated with the combination of 4HF and doxorubicin resulted in significantly reduced tumor and spleen burdens(P<0.05),altered the hypoxia and overall immune lymphocyte landscape,and manipulated gut microbiota to favor the anti-tumor immunological activities.Moreover,immunosuppressive genes,cytokines,and chemokines such as C-C motif chemokine 2 and interleukin-10 of tumors were significantly downregulated(P<0.05).4HF-doxorubicin combination treatment demonstrated synergetic activities and was most effective in activating the anti-tumor immune response(P<

关键词： adjunctivetherapy breast cancer cytokines Chinese medicine tumor microenvironment

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有压差下全接触刷式密封迟滞特性数值研究

兵器装备工程学报 2024年第1期45卷 180-187,222页

作者：刘美红汤俊锋康宇驰许嘉辉李川 sharon Kao-Walter 昆明理工大学机电工程学院昆明650000 布莱金厄理工学院数学和自然科学系瑞典卡尔斯克鲁纳SE-37179

刷式密封迟滞特性引起的泄漏问题、摩擦磨损问题及流动换热问题较为突出。刷式密封迟滞特性数值模型呈现接触对多、刷丝大变形的特点,存在非线性程度较高、收敛性较差的问题。提出了基于有限元软件ABAQUS的刷式密封迟滞特性求解模型,考... 详细信息

刷式密封迟滞特性引起的泄漏问题、摩擦磨损问题及流动换热问题较为突出。刷式密封迟滞特性数值模型呈现接触对多、刷丝大变形的特点,存在非线性程度较高、收敛性较差的问题。提出了基于有限元软件ABAQUS的刷式密封迟滞特性求解模型,考虑刷丝之间接触、刷丝与背板接触、刷丝与转子之间接触,引入阻尼提高模型收敛性。在数值计算与实验结果、理论计算对比验证的基础上,研究了刷丝自由端长度、刷丝直径、刷丝倾斜角度以及上下游压差对迟滞特性和接触力最大值的影响程度。研究结果表明:随着上下游压差、直径的增大,刷式密封迟滞特性呈现增加的趋势,而刷丝倾角的增加导致迟滞特性呈现递减的趋势,刷丝自由端长度的改变对迟滞特性的影响较小;刷丝直径是影响刷丝与转子之间接触力最大值的主要因素,刷丝倾斜角度对接触力最大值有一定程度影响。上述研究为分析刷式密封迟滞特性提供了理论依据,为降低迟滞特性提供了参考。

关键词：刷式密封迟滞特性几何参数迟滞能接触力