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Updates in endocrine therapy for metastatic breast cancer

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cancer Biology & Medicine 2022年第2期19卷 202-212页

作者： Poorni M.Manohar Nancy E.Davidson University of Washington/Seattle cancer Care Alliance Seattle 98109WAUSA fred hutchinson cancer Research center Seattle 98109WAUSA

Endocrine therapy(ET)remains the mainstay of treatment for steroid hormone receptor-positive,human epidermal growth factor 2(HER2)-negative metastatic breast cancer(MBC).Tumor resistance to hormone therapy has led to the development of novel endocrine drug combinations,transforming the landscape of MBC *** options for ET are expanding,with promising agents in the *** MBC remains incurable,many patients can enjoy years of survival with good quality of life by cycling through the many available *** the plethora of available agents and rapid approvals,clinicians look to evidencebased guidelines to assist in treatment selection to maximize patient *** this review,we provide a contemporary review of the advances in ET and a suggested algorithm to guide clinicians in daily management of patients with hormone receptor-positive,HER2-negative *** will discuss landmark trials and highlight their impact in reshaping treatment ***,we will provide a glimpse into advances on the horizon and the promise they bring to improve outcomes in patients with advanced breast cancer.

关键词： Endocrine therapy metastatic breast cancer

Finding a role for cancer vaccines in pancreatic cancer:a model of resilience

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Hepatobiliary Surgery and Nutrition 2022年第1期11卷 115-118页

作者： Gentry King Steven Green E.Gabriela Chiorean Department of Medicine Division of Medical OncologyUniversity of Washington School of MedicineSeattleWAUSA Clinical Research Division Fred Hutchinson Cancer Research CenterSeattleWAUSA

Neoadjuvant chemotherapy with folinic acid,5-fluorouracil,irinotecan and oxaliplatin(FOLFIRINOX)or gemcitabine plus nab-paclitaxel(Gem-nabP)for 4 to 6 months,potentially followed by chemoradiotherapy and an attempt for surgical resection for select patients,represents the multidisciplinary care standard for borderline resectable(BRPC)and locally advanced pancreatic ductal adenocarcinoma(LAPC)patients with good performance status(1,2).With neoadjuvant therapy,resection rates average 65%and survival ranges from 22-29 months for BRPC,whereas LAPC patients have resection rates of 15-20%and survival of 16-24 months,respectively(3-5).

关键词： chemotherapy cancer patients

High-throughput quantification of microbial birth and death dynamics using fluorescence microscopy

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Frontiers of Electrical and Electronic Engineering in China 2019年第1期7卷 69-81页

作者： Samuel F. M. Hart David Skelding Adam J. Waite Justin C. Burton Wenying Shou fred hutchinson cancer Research center SeattleWA 98109USA

Background: Microbes live in dynamic environments where nutrient concentrations fluctuate. Quantifying fitness in terms of birth rate and death rate in a wide range of environments is critical for understanding microbial evolution and ecology. Methods^ Here, using high-throughput time-lapse microscopy, we have quantified how Saccharomyces cerevisiae mutants incapable of synthesizing an essential metabolite (auxotrophs) grow or die in various concentrations of the required metabolite. We establish that cells normally expressing fluorescent proteins lose fluorescence upon death and that the total fluorescence in an imaging frame is proportional to the number of live cells even when cells form multiple layers. We validate our microscopy approach of measuring birth and death rates using flow cytometry, cell counting, and chemostat culturing. Results: For lysine-requiring cells, very low concentrations of lysine are not detectably consumed and do not support cell birth, but delay the onset of death phase and reduce the death rate compared to no lysine. In contrast, in low hypoxanthine, hypoxanthine-requiring cells can produce new cells, yet also die faster than in the absence of hypoxanthine. For both strains, birth rates under various metabolite concentrations are better described by the sigmoidal-shaped Moser model than the well-known Monod model, while death rates can vary with metabolite concentration and time. Conclusions: Our work reveals how time-lapse microscopy can be used to discover non-intuitive microbial birth and death dynamics and to quantify growth rates in many environments.

关键词： Saccharomyces cerevisiae fluorescence microscopy microbial growth birth rate death rate

CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts human mesenchymal stem cell senescence

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Science China(Life Sciences) 2024年第3期67卷 460-474页

作者： Daoyuan Huang Qian Zhao Kuan Yang Jinghui Lei Ying Jing Hongyu Li Chen Zhang Shuai Ma Shuhui Sun Yusheng Cai Guibin Wang Jing Qu Weiqi Zhang Si Wang Guang-Hui Liu Advanced Innovation centerfor Human Brain Protection National Clinical Research Centerfor Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational Medicinecenter International Centerfor Aging and CancerBejing Municipal GeriatricMedical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Beijing Institute for Stem Cell and Regenerative Medicine Beijing100101China CAS Key Laboratory of Genomic and Precision Medicine Bejing Institute of Genomics and China National Center for BioinformationChinese Academy of SciencesBeijing 100101China Institute for Stem Cell and Regeneration CASBeijing 100101China The Fifth People's Hospital of Chongqing Chongqing 400062China Sino-Danish Cllege University of Chinese Academy of SciencesBeijing101408China National Laboratory of Biomacromolecules CAS Center for Excelence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing100101China State Key Laboratory of Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijing 102206China

Cullin-RING E3 ubiquitin ligases(CRLs),the largest family of multi-subunit E3 ubiquitin ligases in eukaryotic cells,represent core cellular machinery for executing protein degradation and maintaining ***,we asked what roles Cullin proteins play in human mesenchymal stem cell(hMSC)homeostasis and *** this end,we conducted a comparative aging phenotype analysis by individually knocking down Cullin members in three senescence models:replicative senescent hMSCs,hutchinson-Gilford Progeria Syndrome hMSCs,and Werner syndrome *** all family members,we found that CUL2 deficiency rendered hMSCs the most susceptible to *** investigate CUL2-specific underlying mechanisms,we then applied CRISPR/Cas9-mediated gene editing technology to generate CUL2-deficient human embryonic stem cells(hESCs).When we differentiated these into h MSCs,we found that CUL2 deletion markedly accelerates hMSC ***,we identified that CUL2 targets and promotes ubiquitin proteasome-mediated degradation of TSPYL2(a known negative regulator of proliferation)through the substrate receptor protein APPBP2,which in turn downregulates one of the canonical aging marker-P21^(waf1/cip1),and thereby delays *** work provides important insights into how CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts hMSC senescence,providing a molecular basis for directing intervention strategies against aging and aging-related diseases.

关键词： Cullins stem cell senescence aging proteostasis ubiquitination APPBP2 TSPYL2

Nutritional epidemiology methods and related statistical challenges and opportunities

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Statistical Theory and Related Fields 2018年第1期2卷 2-10页

作者： Ross L.Prentice Ying Huang fred hutchinson cancer Research center and University of Washington SeattleWAUSA

The public health importance of nutritional epidemiology research is discussed,along withmethodological challenges to obtaining reliable information on dietary approaches to chronicdisease *** issues in assessing dietary intake need to be addressed toobtain reliable disease association ***-reported dietary data typically incorporatemajor random and systematic *** biomarkers offer potential for more reliable analyses,but biomarkers have been established only for a few dietary variables,and these may be tooexpensive to apply to all participants in large epidemiologic cohorts.A possible way forwardinvolves additional nutritional biomarker development using high-dimensional metabolomicprofiling,using blood and urine specimens,in conjunction withfurther development of statisticalapproaches for accommodating measurement error with failure time response *** the opportunity to contribute greatly to worldwide public health through the development of statistical methods to address these nutritional epidemiology research challenges,asis elaborated in this contribution.

关键词： Chronic disease epidemiology failure time data hazard ratio measurement error metabolomics nutritional biomarker regression calibration

The MYC transcription factor network： balancing metabolism, proliferation and oncogenesis

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Frontiers of Medicine 2018年第4期12卷 412-425页

作者： Patrick A. Carroll Brian W. Freie Haritha Mathsyaraja Robert N. Eisenman Division of Basic Sciences Fred Hutchinson Cancer Research Center 1100 Fairview Ave. N. Seattle WA 90109 USA

Transcription factor networks have evolved in order to control, coordinate, and separate, the functions of distinct network modules spatially and temporally. In this review we focus on the MYC network （also known as the MAX-MLX Network）, a highly conserved super-family of related basic-helix-loop-helix-zipper （bHLHZ） proteins that functions to integrate extracellular and intracellular signals and modulate global gene expression. Importantly the MYC network has been shown to be deeply involved in a broad spectrum of human and other animal cancers. Here we summarize molecular and biological properties of the network modules with emphasis on functional interactions among network members. We suggest that these network interactions serve to modulate growth and metabolism at the transcriptional level in order to balance nutrient demand with supply, to maintain growth homeostasis, and to influence cell fate. Moreover, oncogenic activation of MYC and/or loss of a MYC antagonist, results in an imbalance in the activity of the network as a whole, leading to tumor initiation, progression and maintenance.

关键词： network transcription cancer MYC MAX MLX

GDF15 promotes prostate cancer bone metastasis and colonization through osteoblastic CCL2 and RANKL activation

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Bone Research 2022年第1期10卷 150-164页

作者： Jawed Akhtar Siddiqui Parthasarathy Seshacharyulu Sakthivel Muniyan Ramesh Pothuraju Parvez Khan Raghupathy Vengoji Sanjib Chaudhary Shailendra Kumar Maurya Subodh Mukund Lele Maneesh Jain Kaustubh Datta Mohd Wasim Nasser Surinder Kumar Batra Department of Biochemistry and Molecular Biology University of Nebraska Medical CenterOmahaNEUSA Department of Pathology and Microbiology University of Nebraska Medical CenterOmahaNEUSA fred&Pamela Buffett cancer center University of Nebraska Medical CenterOmahaNE 68198-5870USA Eppley Institute for Research in cancer and Allied Diseases University of Nebraska Medical CenterOmahaNEUSA

Bone metastases occur in patients with advanced-stage prostate cancer(PCa). The cell-cell interaction between PCa and the bone microenvironment forms a vicious cycle that modulates the bone microenvironment, increases bone deformities, and drives tumor growth in the bone. However, the molecular mechanisms of PCa-mediated modulation of the bone microenvironment are complex and remain poorly defined. Here, we evaluated growth differentiation factor-15(GDF15) function using in vivo preclinical PCa-bone metastasis mouse models and an in vitro bone cell coculture system. Our results suggest that PCa-secreted GDF15 promotes bone metastases and induces bone microarchitectural alterations in a preclinical xenograft model. Mechanistic studies revealed that GDF15 increases osteoblast function and facilitates the growth of PCa in bone by activating osteoclastogenesis through osteoblastic production of CCL2 and RANKL and recruitment of osteomacs. Altogether, our findings demonstrate the critical role of GDF15 in the modulation of the bone microenvironment and subsequent development of PCa bone metastasis.

关键词： GDF15 metastasis RANKL

Determinants of prognosis in metastatic urothelial carcinoma:a review of the literature

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Journal of cancer Metastasis and Treatment 2022年第1期8卷 240-252页

作者： Gavin Hui Ali Raza Khaki Petros Grivas Department of Medicine Stanford UniversityStanfordCA 94304USA Division of Oncology Department of MedicineStanford UniversityStanfordCA 94304USA Division of Medical Oncology Department of MedicineUniversity of WashingtonFred Hutchinson Cancer CenterSeattleWA 98109USA

The treatments for metastatic urothelial carcinoma(mUC)have advanced substantially since *** tools have been used to inform clinical trial designs and treatment ***,prognostic tools were developed for mUC based on older clinical trials involving cytotoxic *** novel therapies emerged,there are studies investigating prognostic factors in the era of immune checkpoint inhibitors(ICI),antibody-drug conjugates,and targeted *** review aims to highlight prognostic factors in mUC and their potential in clinical decision-making and *** the setting of chemotherapy,patient performance status,site of metastatic burden,and specific laboratory findings were found to have prognostic value in *** the era of ICI,newer models identified variables such as neutrophil to lymphocyte ratio,platelet count,and lactate dehydrogenase to also have potential prognostic *** addition to clinical biomarkers,molecular biomarkers,such as PD-L1 assay and fibroblast growth factor receptor 2 and 3 genomic testings,may have promising prognostic and predictive *** methods of identifying clinical and molecular prognostic factors involve clinician *** large complex datasets emerge,machine learning and artificial intelligence may help data analysis and detect important prognostic *** careful validation,such machine learning-based strategies may help create more robust prognostic and/or predictive models in the future.

关键词： Bladder cancer biomarkers health outcomes nomogram prediction prognosis urothelial carcinoma urinary tract cancers

Response to discussion of‘Nutritional epidemiology methods and related statistical challenges and opportunities’

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Statistical Theory and Related Fields 2018年第1期2卷 23-26页

作者： Ross L.Prentice Ying Huang fred hutchinson cancer Research center and University of Washington Seattle WAUSA

We very much appreciate each of the three sets of comments on our *** manuscript argued thatthe nutritional epidemiology research area,which is soimportant to worldwide public health,is burdened withchallenges in estimating dietary intakes,both shortterm intakes and intakes over the years or decades thatmay be relevant to chronic disease *** nutritional epidemiology literature having chronic diseaseoutcomes mostly relies on dietary self-report *** few dietary variables having an established objective measure(biomarker),comparison with self-reportdata suggests that the data include not only a large‘noise’component,which available statistical methods can typically accommodate,but frequently also alarge systematic bias component that,for example,maydepend on such study subject body mass index(BMI),age and ethnicity,among other *** is the needto address this systematic bias component of dietaryintake assessment that stimulates our call for additionalreliance on biomarkers,for additional biomarker development,and for the development of novel and flexible statistical methods for use in disease associationanalyses.

关键词： intake epidemiology mostly