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Bidirectional effect of Wnt signaling antagonist DKK1 on the modulation of anthrax toxin uptake

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Science China(Life Sciences) 2014年第5期57卷 469-481页

作者： QIAN LiLi CAI ChangZu YUAN PengFei JEONG Sun-Young YANG XiaoZhou DEALMEIDA Venita ERNST James COSTA Michael COHEN Stanley N. WEI WenSheng College of Life Sciences and State Key Laboratory of Protein and Plant Gene Research Peking University Department of Genetics Stanford University School of Medicine Department of Cancer Targets GenentechInc.South San Francisco Department of Protein Chemistry and Protein Engineering GenentechInc.South San Francisco Department of Medicine Stanford University School of Medicine

LRP6, a co-receptor for the morphogen Wnt, aids endocytosis of anthrax complexes. Here we report that Dickkopfl （DKK1） protein, a secreted LRP6 ligand and antagonist, is also a modulator of anthrax toxin sensitivity, shRNA-mediated gene silencing or TALEN-mediated gene knockout of DKK1 reduced sensitivity of cells to PA-dependent hybrid toxins. However, unlike the solely inhibitory effect on Wnt signaling, the effects of DKK1 overexpression on anthrax toxicity were bidirectional, depending on its endogenous expression and cell context. Fluorescence microscopy and biochemical analyses showed that DKK1 facilitates internalization of anthrax toxins and their receptors, an event mediated by DKK1-LRP6-Kremen2 complex. Monoclonal antibodies against DKK1 provided dose-dependent protection to macrophages from killing by anthrax lethal toxin （LT）. Our discovery that DKK1 forms ternary structure with LRP6 and Kremen2 in promoting PA-mediated toxin internalization provides a paradigm for bacterial exploitation of mechanisms that host cells use to internalize signaling proteins.

关键词： DKK1 anthrax toxin LRP6 TALENs internalization Kremen2 receptor Wnt

DEM analysis of the influence of stirrer design on die filling with forced powder feeding

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Particuology 2024年第5期88卷 107-115页

作者： Chao Zheng Edward Yost Ariel R.Muliadi Nicolin Govender Ling Zhang Chuan-Yu Wu School of Chemistry and Chemical Engineering University of SurreyGuildfordGU2 7XHUnited Kingdom Small Molecule Pharmaceutics GenentechInc.One DNA WaySouth San FranciscoCA94080USA

Die filling is a critical stage during powder compaction,which can significantly affect the product quality and *** this paper,a forced feeder is introduced attempting to improve the filling performance of a lab-scale die filling *** die filling process is analysed with a graphics processing units(GPU)enhanced discrete element method(DEM).Various stirrer designs are assessed for a wide range of process settings(i.e.,stirrer speed,filling speed)to explore their influence on the die filling performance of free-flowing *** results show that die filing with the novel helical-ribbon(i.e.,type D)stirrer design exhibits the highest filling ratio,implying that it is the most robust stirrer design for the feeder configuration ***,die filling performance with the type D stirrer design is a function of the stirrer speed and the filling speed.A positive variation of filling ratio(ηf>0%)can be ensured over the whole range of filling speed by adjusting the stirrer speed(i.e.,inc.easing the stirrer speed).The approach used in this study can not only help understand how the stirrer design affects the die filling performance but also guide the optimization of feeder system and process settings.

关键词： Discrete element method Die filling Forced feeding Stirrer design GPU computing

Overall Survival and Health Care Costs of Medicare Patients with Previously Treated Chronic Lymphocytic Leukemia

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Journal of Cancer Therapy 2018年第7期9卷 576-587页

作者： Carolina Reyes Genevieve Gauthier Sherry Shi Annie Guerin genentech inc. South San Francisco CA USA Analysis Group inc. Montreal Canada

Background: Bendamustine-based regimens are often used in the management of patients with chronic lymphocytic leukemia (CLL) but few studies have analyzed the comorbidity- and/or adverse event (CAE)-related healthcare costs in patients receiving these regimens in a real-world setting. Aims: To describe all-cause and CAE-related healthcare costs in relapse/refractory (R/R) elderly patients with CLL treated with bendamustine-based regimens in a real-world setting. Methods: Adult patients with R/R CLL who received bendamustine-based regimens on/after January 2010 were selected from the Medicare Limited Data Set (LDS) 5% Standard Analytic Files. Selected patients were classified into cohorts based on the two most prevalent bendamustine-based regimens observed (index treatment): 1) bendamustine + rituximab (BR cohort) and 2) bendamustine monotherapy (B-mono cohort). For each cohort, all-cause and CAE-related healthcare costs, while on treatment, were reported per-patient-per-month (PPPM). Overall survival (OS) rates following initiation of the index treatment were described using age- and gender-adjusted Kaplan-Meier curves. Results: A total of 275 patients were inc.uded in the BR cohort and 100 patients in the B-mono cohort. Most patients were male and the mean age was approximately 75 years old. During treatment, total all-cause healthcare costs were $14,520 PPPM for the BR cohort and $13,125 PPPM for the B-mono cohort—outpatient costs (mainly driven by CLL-drug costs) represented 86.1% of the total all-cause healthcare costs for the BR cohort and 69.8% for the B-mono cohort. CAE costs accounted for 58.3% of the total all-cause healthcare costs for the BR cohort and 66.9% for the B-mono cohort. Median OS was 35 months in the BR cohort and 21 months in the B-mono cohort. Conclusion: In this population of elderly patients with R/R CLL treated with bendamustine-based regimens, CAEs were common and translated into important medical costs. Median OS was also relatively shor

关键词： Chronic Lymphocytic Leukemia Relapse/Refractory Bendamustine Economic Burden Overall Survival Adverse Events

The Unmet Need in Chronic Lymphocytic Leukemia: Impact of Comorbidity Burden on Treatment Patterns and Outcomes in Elderly Patients

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Journal of Cancer Therapy 2013年第8期4卷 1321-1329页

作者： Sacha Satram-Hoang Carolina Reyes Khang Q. Hoang Faiyaz Momin Sandra Skettino genentech Inc. South San Francisco USA Q. D. Research Inc. Granite Bay USA

Introduction: Chronic lymphocytic leukemia (CLL) is a disease of the elderly. Elderly patients often have inc.eased comorbidity burden and loss of organ reserve that may impact their ability to tolerate cancer therapy. We described realworld characteristics of typical CLL patients and identified factors predictive of receiving treatment. Methods: A retrospective cohort analysis of 8343 first primary CLL patients was performed using the linked Surveillance, Epidemiology, and End Results-Medicare database. Patients were diagnosed from 1/1/1998 to 12/31/2007, >66 years, and continuously enrolled in Medicare Parts A and B in the year prior to diagnosis. Comorbidity was examined using the National Cancer Institute comorbidity index and the Cumulative Illness Rating Scale. Cox and Logistic regression modeling assessed patient characteristics predictive of receiving treatment within the first year after diagnosis. Results: Median follow-up time from diagnosis was 782 days. During the study time period, there were 3366 (40%) treated patients and 4977 (60%) untreated. Even among those diagnosed with advanced stage (n = 4213), 57% were not treated. Treated patients were younger at diagnosis compared to untreated (76 vs. 79;p inc.eased, the inc.dence and severity of comorbidities inc.eased. In multivariate regression analyses, the treatment rate was significantly lower among patients >80 years, females, and with early stage disease;and significantly decreased with inc.easing comorbidity burden. Conclusions: Age, gender, comorbidity and stage were predictive of receiving treatment. Among patients with advanced stage, 57% were not being treated possibly due to older age and/or higher comorbidity burden.

关键词： Chronic Lymphocytic Leukemia Elderly Patients Comorbidities Treatment Survival

Treatment Patterns and Mortality Risk among Elderly Patients with Metastatic Triple Negative Breast Cancer in the United States: An Observational Cohort Study Using SEER-Medicare Data

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Journal of Cancer Therapy 2019年第2期10卷 117-133页

作者： Sacha Satram-Hoang Preeti Bajaj Alisha Stein Patricia Cortazar Faiyaz Momin Carolina Reyes Q.D. Research Inc. Granite Bay CA USA genentech Inc. South San Francisco CA USA

Purpose: Triple negative breast cancer is more aggressive than other breast cancer subtypes and accounts for up to 20% of all breast cancers. Despite the poorer prognosis, there are no approved targeted treatments available and chemotherapy remains the only choice. We examined treatment patterns and outcomes among elderly metastatic triple-negative breast cancer (mTNBC) patients in routine clinical practice. Methods: Patients were identified from the linked SEER-Medicare database between 1/1/2001 and 12/31/2013 and inc.uded de novo Stage IV (n = 776) and patients with distant metastasis followed an initial diagnosis of Stage I - III disease (n = 1851). Kaplan-Meier analyses and time-varying Cox proportional hazards regression were used to assess overall survival (OS). Results: The mean age at metastatic diagnosis was 77.6 years and 1259 (48%) patients received chemotherapy. Compared to inc.eased OS compared to untreated patients, and the survival advantage was more pronounced in the -month longer unadjusted OS compared to the ≥70 cohort (log rank p inc.eased risk of death for untreated patients in the inc.eased risk of death for untreated patients in the ≥70 year olds (vs. treated). Conclusions: In this real-world analysis, 48% of elderly mTNBC patients did not receive chemotherapy and a greater proportion were untreated in the ≥70 year old cohort (55%). Although the survival benefits of chemotherapy were greater in the younger cohort, the benefits of treatment persisted in ≥70 year olds. These findings suggest opportunities exist to improve the clinical treatment of elderly mTNBC patients.

关键词： Triple Negative Breast Cancer Elderly Patients Chemotherapy Survival

Differences in Treatment Patterns and Health Care Costs among Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia Patients Receiving Rituximab in the Hospital Outpatient Setting versus the Office/Clinic Setting

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Journal of Cancer Therapy 2014年第2期5卷 208-216页

作者： Stacey DaCosta Byfield Art Small Laura K. Becker Carolina M. Reyes genentech inc. South San Francisco USA Optum Eden Prairie USA

Objective: To examine whether differences in treatment patterns and health care costs exist among chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL) patients receiving rituximab in a hospital outpatient setting versus those receiving rituximab in a physician office/community clinic setting. Methods: This retrospective database study used medical and pharmacy claims (1/2007-7/2012) from a large US health plan. Patients ≥18 years with ≥2 rituximab claims and ≥2 claims for either NHL or CLL were identified. The date of the first rituximab claim were set as the index date, and differences in treatment patterns and health care costs were examined during the period following the index date. Costs were adjusted for patient characteristics using a multivariate regression model. Results: A total of 4441 patients were identified;3167 received rituximab in the office/clinic setting, and 1274 in the hospital outpatient setting. From 2007 to 2012, the percentage of patients receiving rituximab in the hospital outpatient setting inc.eased from 22% to 39%. Patients treated in the hospital outpatient setting vs. the office/clinic setting had fewer average counts of rituximab infusions (5.60 vs. 7.49, p 0.001), higher total health care costs (cost ratio = 1.325, p 0.001), higher infusion day drug and administration costs (cost ratio = 1.509, p 0.001), and higher rates of ER visits and inpatient stays (both p 0.001). Conclusions: These findings suggest that site of care may impact treatment patterns and costs of patients receiving rituximab, and additional research is needed to better understand the reason(s) for these differences by site of service.

关键词： Lymphoma Leukemia Rituximab Treatment Setting Costs

inc.eased Mortality Risk among Early Stage Hormone Receptor Positive Breast Cancer Patients Who Did Not Receive Adjuvant or Neoadjuvant Therapy

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Journal of Cancer Therapy 2019年第1期10卷 1-20页

作者： Sacha Satram-Hoang Alisha Stein Patricia Cortazar Faiyaz Momin Carolina Reyes Q.D. Research Inc. Granite Bay CA USA genentech Inc. South San Francisco CA USA

Background: Hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) is the most common biologic subtype of breast cancer. Although adjuvant therapy has demonstrated a survival benefit in clinical trials, its use is poorly understood in the real-world among elderly breast cancer patients sinc. age is a barrier to receiving adjuvant therapy. An examination of treatment patterns and outcomes associated with receipt of adjuvant/neoadjuvant therapy among elderly HR + HER2-breast cancer patients was undertaken. Methods: There were 18,470 HR + HER2-breast cancer patients from the linked SEER-Medicare database. Patients were diagnosed with stage I-III disease between 1/1/2007-12/31/2011, ≥66 years, enrolled in Medicare Parts A, B and D, and underwent breast cancer surgery after diagnosis. Time-varying Cox proportional hazards regression assessed overall survival. Results: There were 13,670 (74%) patients treated with adjuvant/neoadjuvant therapy and 4800 (26%) untreated. Compared to treated patients, untreated patients were older, had earlier stage, lower grade, smaller tumors, poorer performance, higher comorbidity score, and less use of a 21-gene recurrence score (RS) assay (p inc.easing age, stage, tumor size, tumor grade, comorbidity score and poor performance were significantly associated with higher mortality risks, while use of an RS assay was associated with lower risks. The Cox model showed a 48% higher risk of death in untreated compared to treated patients. In a subset of 8967 patients with stage I disease, tumor size < 2.0 cm and grade 1/2;untreated patients had a 22% higher risk of death compared to treated patients. Conclusions: Older patients with favorable clinical characteristics (earlier stage, smaller tumor, lower grade) are less likely to be treated and have a higher risk of death compared to adjuvant/neoadjuvant treated patients. An unmet need among older breast cancer patients persist

关键词： Hormone Receptor Positive Breast Cancer Elderly Patients Adjuvant Therapy Survival

Reversible phosphorylation of the 26S proteasome

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Protein & Cell 2017年第4期8卷 255-272页

作者： Xing Guo Xiuliang Huang Mark J. Chen The Life Sciences Institute of Zhejiang University Hangzhou 310058 China Ministry of Education Key Laboratory of Protein Science School of Life Sciences Tsinghua University Beijinq 100084 China Department of Bioinformatics and Computational Biology Genentech Inc. South San Francisco CA 94080 USA

The 26S proteasome at the center of the ubiquitin- proteasome system （UPS） is essential for virtually all cellular processes of eukaryotes. A common miscon- ception about the proteasome is that, once made, it remains as a static and uniform complex with sponta- neous and constitutive activity for protein degradation. Recent discoveries have provided compelling evidence to support the exact opposite insomuch as the 26S proteasome undergoes dynamic and reversible phos- phorylation under a variety of physiopathological con- ditions. In this review, we summarize the history and current understanding of proteasome phosphorylation, and advocate the idea of targeting proteasome kinases/ phosphatases as a new strategy for clinical interven- tions of several human diseases.

关键词： proteasome phosphorylation kinase,phosphatase protein degradation

Treatment Patterns and Clinical Characteristics of Patients with Advanced Basal Cell Carcinoma in the Community Oncology Setting

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Journal of Cancer Therapy 2013年第6期4卷 24-31页

作者： Mark S. Walker Lee S. Schwartzberg Diana M. Chen D. Devi Ramanan Arthur C. Houts Carolina Reyes ACORN Research LLC Memphis USA genentech Inc. South San Francisco USA The West Clinic Memphis USA

Advanced basal cell carcinoma (aBCC) inc.udes metastatic and locally advanced BCC that is inoperable (or with surgery contraindicated). We describe patient characteristics and treatment history for aBCC cases from community oncology. Nine cases of aBCC were found within the ACORN Data Warehouse, a community oncology database of >180,000 cancer patients. Data were summarized descriptively. Three illustrative case histories are presented. Patients were predominantly Caucasian (8/9), male (6/9), and over 60 (6/9). Four had metastatic disease;five had aBCC without metastasis. Five had a history of treatment for early stage BCC, inc.uding surgery (5/5), radiation (1/5), and none had chemotherapy. Those with history of early stage BCC had periods of apparent lack of follow-up and treatment. One had chemotherapy for aBCC (platinum based with radiation) and eight had radiation without chemotherapy. Patients had multiple comorbid serious medical conditions. Six were deceased, but only one was documented to have aBCC as cause of death. Advanced BCC is rare in community oncology settings. There appear to be gaps in the care and follow-up of patients with initial early stage BCC. More data and larger samples are needed from multi-specialty databases such as dermatology and head and neck surgery.

关键词： Advanced Basal Cell Carcinoma Community Oncology Treatment Patterns Observational Study Long Term Follow Up