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Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) has multiple roles in the development and progression of atherosclerosis. Recent studies have indicated an association of PCSK9 with thrombotic process. Purpose We aimed to examine whether there exists a relationship between plasma PCSK9 concentration and the most commonly coagulation parameters including prothrombin time (PT) and activated partial thromboplastin time (APTT). Methods A total of 2293 consecutive patients with angina-like chest pain who had no treatment of lipid-lowering drugs were enrolled in this study. The baseline clinical and laboratory data were collected. PT and APTT tests were performed. Circulating PCSK9 concentrations were determined by ELISA and classified into three subgroups according to their levels of PCSK9 tertiles. The relation of PCSK9 concentration to PT or APTT were analyzed. Results Firstly, we found that the patients with high PCSK9 levels trended to have lower PT and APTT (p Conclusion Circulating PCSK9 concentration was independently negative associated with PT, suggesting a potential link between PCSK9 and PT that may be involved in atherogenesis and atherothrombosis. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences

Objectives For patients with recurrent/metastatic cervical cancer, incorporation of anti-angiogenesis therapy with chemotherapy yields a modest survival benefit of 3.7 months over chemotherapy alone (Tewari et al. NEJM. 2014). The rationale for checkpoint inhibition is supported by programmed death ligand-1 (PD-L1) expression in some cervical cancers (∼70%), with a higher proportion noted in squamous cell carcinoma vs adenocarcinoma. Based on the 14.3% objective response in KEYNOTE-158, the US FDA granted accelerated approval to pembrolizumab for PD-L1–positive cervical cancer for second-line therapy and beyond. Methods KEYNOTE-826 is a phase 3, randomized, double-blind, placebo-controlled, multinational trial of chemotherapy with pembrolizumab or placebo for first-line treatment of recurrent, persistent, or metastatic cervical cancer. Patients not previously treated with chemotherapy for recurrence and not amenable to curative treatment will be randomized 1:1 to chemotherapy + pembrolizumab 200 mg or placebo every 3 weeks. The chemotherapy regimen (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5, with or without bevacizumab 15 mg/kg) will be selected by investigators pre-randomization. Stratification factors include metastatic status at diagnosis (yes/no), bevacizumab use (yes/no), and tumor PD-L1 status (combined positive score

To address high HIV prevalence, the District of Columbia (DC) Department of Health has implemented multiple strategies to increase routine HIV testing since 2006. Examination of delayed HIV diagnosis over time can demonstrate population-level impact of public health strategies to promote HIV testing. Using HIV surveillance data, we examined delayed HIV diagnosis in DC (stage 3 within 90 days of diagnosis), CD4 count at HIV diagnosis, linkage to HIV care, and time to viral suppression among DC residents age 13 and above who were diagnosed from 2006 to 2016. We used the Cochran-Armitage test of trend, Cuzick's test of trend, and Chi-square for univariate analyses, and we examined factors associated with delayed HIV diagnosis using a log-binomial multivariate model. 7,937 DC residents were diagnosed with HIV and had available data. Between 2006 and 2016, delayed HIV diagnoses declined from 36.4% to 25.5%, median CD4 count increased from 190 cells/µl to 426 cells/µl, and median time from HIV diagnosis to viral suppression declined from 1,136 days to 84 days. Women, youth ages 13-29, and men who have sex with men had lower proportions with delayed HIV diagnosis. In the multivariate models, racial/ethnic disparities in delayed HIV diagnoses were apparent during 2006-2008 but not during 2009-2016. Continued efforts around earlier HIV testing are needed in DC.

Objective The study was conducted to inform area-based prevention intervention programs and plan resource allocation to reduce new infections in the District of Columbia (DC), United States of America. Study design The analysis used spatial regression to evaluate the spatial heterogeneity of the new HIV rate and its association with sexually transmitted infection repeaters (STIREPs) and socio-economic as well as demographic characteristics. The HIV and STIREP data were obtained from the DC Department of Health surveillance data (2010–2016). Other covariates were obtained from the American Community Survey, 2016. Methods Ordinary least squares (OLS) and geographically weighted regression (GWR) were used to compare global and local relationships. GWR-computed robust results were compared with other spatial regression methods such as spatial lag or spatial error methods. Results For the OLS model, age, high school dropouts (NHSD), and the black population had an association with new HIV diagnoses (HIVDVi). The results from the GWR model demonstrate spatial variations of association of STIREPs; mean age of each block group; and percentage of female population, NHSD, unemployment, and poverty with HIVDVi. Akaike information criterion (AICc) value for the global model was 2770.99, and R2 was 0.54 (54%). The R2 and AICc of the GWR model was 0.81 (81%) and 2580.84, respectively, where the latter showed a 0.27 (27%) increase in R2 and a decreased AICc. Conclusion These results will assist in planning HIV prevention and intervention strategies. These results will also be used for targeted testing, planning pre-exposure prophylaxis, and access to health care. The results will help plan resource allocation to community-based providers for prevention intervention programs and fund public health programs such as condom distribution, mobile vans, and youth-based sex education.

Background Patients with advanced cervical cancer comprise a high-risk, poor prognostic group. Vascular endothelial growth factor (VEGF) has emerged as a therapeutic target for these patients, though incorporation of the anti-VEGF agent bevacizumab to platinum- and taxane-based chemotherapy (CT) is associated with a modest OS benefit vs CT alone (median OS, 16.8 vs 13.3 mo; hazard ratio, 0.77, 95% CI, 0.62-0.95; P = 0.007; Tewari et al. Lancet. 2017). On the basis of an ORR of 14.3% (95% CI, 7.4-24.1) among 77 pretreated women with PD-L1–positive tumors in the cervical cancer cohort of KEYNOTE-158 (Chung et al. J Clin Oncol. 2019), the PD-1 inhibitor pembrolizumab was granted accelerated approval by the US FDA for patients with PD-L1–positive (combined positive score [CPS] of > 1) cervical cancer who had progressed during or after first-line CT. KEYNOTE-826 (NCT03635567) is a phase 3, randomized, double-blind, multinational study designed to evaluate the efficacy and tolerability of CT with or without pembrolizumab and/or bevacizumab in the first-line setting. Trial design Eligible patients with recurrent, persistent, or metastatic cervical cancer not previously treated with CT in a recurrent or metastatic setting who are not amenable to curative treatment will be randomized 1:1 to CT + pembrolizumab 200 mg or placebo every 3 weeks. The CT regimen (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5, with or without bevacizumab 15 mg/kg) will be selected by the investigator before randomization. Stratification will be performed by metastasis status at diagnosis, planned bevacizumab use (yes/no), and tumor PD-L1 CPS ( Clinical trial identification NCT03635567. Legal entity responsible for the study Merck & Co., Inc. Funding Funding for this study was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure K. Fujiwara: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Merck Sharpe & Dohme Corp.; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Advisory / Consultancy: Takeda; Honoraria (self): Bayer; Honoraria (self): Daiichi Sankyo; Honoraria (self): Janssen Oncology; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Lilly Japan; Honoraria (self): Nippon Kayaku; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Zeria Pharmaceutical; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Kaken Pharmaceutical; Research grant / Funding (institution): Immunogen; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Oncotherapeutics. R. Shapira-Frommer: Honoraria (self): MSD Oncology; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): AstraZeneca; Advisory / Consultancy: Vascular Biogenics; Advisory / Consultancy: Clovis Oncology. J. Alexandre: Honoraria (self): Roche/Genentech; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis ; Honoraria (self): Sanofi/Aventis; Honoraria (self), Advisory / Consultancy: Ipsen; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi; Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen. B. Monk: Advisory / Consultancy: AbbVie; Advisory / Consultancy: Advaxis; Advisory / Consultancy: Agenus; Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Biodesix; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Conjupro; Advisory / Consultancy: Genmab; Advisory / Consultancy: Gradalis; Advisory / Consultancy: ImmunoGen; Advisory / Consultancy: Immunomedics; Advisory / Consultancy: Incyte; Advisory / Consultancy: Janssen/JohnsonJ Advisory / Consultancy: Mateon (formally Oxigene); Advisory / Consultancy: Merck; Advisory / Consultancy: Myriad; Advisory / Consultancy: Perthera; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Precison Oncology. T. Fehm: Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Pfizer. N. Colombo: Honoraria (self), Advisory / Consultancy: Roche/Genentech; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): TESARO, Inc.; Honoraria (self), Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: Takeda; Advisory / Consultancy: TESARO, Inc.; Advisory / Consultancy: BioCad. K. Hasegawa: Honoraria (self), Research grant / Funding (self): Daiichi-Sankyo; Honoraria (self), Advisory / Consultancy: Merck Sharpe & Dohme Corp.; Honoraria (self): Chugai; Honoraria (self): AstraZeneca; Research grant / Funding (self): Yakult Honsha; Research grant / Funding (self): Pfizer. J.J. Li: Travel / Accommodation / Expenses, Full / Part-time employment: Merck & Co., Inc.; Travel / Accommodation / Expenses, Spouse / Financial dependant: Celgene. K. Stein: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.; Shareholder / Stockholder / Stock options: Novartis. S.M. Keefe: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. K. Tewari: Honoraria (self): TESARO, Inc.; Honoraria (self): Clovis Oncology; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Speaker Bureau / Expert testimony: AstraZeneca ; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Morphotek; Research grant / Funding (institution): Regeneron. All other authors have declared no conflicts of interest.

Background Pembro, a PD-1 inhibitor, confers durable benefit in many tumor types but has limited efficacy in non–microsatellite instability–high (MSI-high)/pMMR mCRC. Chemotherapies that include 5-fluorouracil (5-FU), oxaliplatin and irinotecan, which are commonly used to treat mCRC, may modulate intrinsic tumor immunogenicity and sensitize tumors to immunotherapy agents. In the phase 1b KEYNOTE-651 study (NCT03374254), pembro + mFOLFOX7 (cohort B) or pembro + FOLFIRI (cohort D) was evaluated in patients with non–MSI-high/pMMR mCRC. Methods Patients were ≥18 years with non–MSI-high/pMMR mCRC, Eastern Cooperative Oncology Group performance status 0/1, and no prior systemic chemotherapy for stage IV mCRC (cohort B) or 1 prior therapy including a fluoropyrimidine + oxaliplatin-based regimen (cohort D). Patients received pembro 200 mg every 3 weeks (Q3W) + mFOLFOX7 (oxaliplatin [85 mg/m2]; leucovorin [400 mg/m2]; 5-FU [2400 mg/m2]) Q2W (cohort B) or pembro 200 mg Q3W + FOLFIRI (irinotecan [180 mg/m2]; leucovorin [400 mg/m2]; 5-FU [2400 mg/m2]) Q2W (cohort D). Primary objectives were safety/tolerability and establishment of the recommended phase 2 dose (RP2D); the secondary objective was objective response rate. Results At data cutoff (Feb 18, 2019), 15 patients in cohort B and 16 in cohort D started treatment; median follow-up was 6.8 months (cohort B) and 5.7 months (cohort D). Treatment was discontinued in 4 patients (27%) in cohort B (adverse event [AE], n = 1 [7%]; PD, n = 3 [20%]) and 9 patients (56%) in cohort D (AEs, PD, patient withdrawal; n = 3 [19%] each). There was 1 dose-limiting toxicity in cohort D: grade 3 small-intestinal obstruction. See RP2Ds for cohorts B and D in the Methods section. All patients had ≥1 treatment-related AE (TRAE). Grade 3 TRAEs occurred in 8 patients each in cohort B (53%) and cohort D (50%), most commonly anemia and neutropenia (13% each) in cohort B and neutropenia, diarrhea, fatigue, and leukopenia (13% each) in cohort D. There were no grade 4-5 TRAEs. Efficacy results will be presented. Conclusions Pembro in combination with mFOLFOX7 or FOLFIRI was safe and tolerable in patients with mCRC. Clinical trial identification NCT03374254; Release date: December 15, 2017. Editorial acknowledgement Jacqueline Kolston, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA); Funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Array BioPharma. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Array BioPharma. Disclosure R. Kim: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Research grant / Funding (institution): Eisai. J. Kortmansky: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Roche. L. Wong: Research grant / Funding (institution): Astellas Pharma Global Development, Inc./Astellas US, Inc.; Research grant / Funding (institution): BeiGene, Ltd; Research grant / Funding (institution): Exelixis, Inc.; Research grant / Funding (institution): Merck; Research grant / Funding (institution): NovoCure, Inc.; Research grant / Funding (institution): Pierre Fabre Medicament; Research grant / Funding (institution): PledPharma AB; Research grant / Funding (institution): SynCore Biotechnology Co., Ltd.; Research grant / Funding (institution): Halozyme, Inc.; Research grant / Funding (institution): Pharmacyclics, Inc.; Research grant / Funding (institution): TESARO; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Array. M. Tehfe: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Celgene; Honoraria (self): Ipsen; Advisory / Consultancy: BMS; Advisory / Consultancy: Takeda; Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Taisho. J.J. Li: Full / Part-time employment: Merck & Co., Inc. M. Lee: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. C. Mayo: Full / Part-time employment: Merck & Co., Inc. P. Marinello: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. E. Chiorean: Advisory / Consultancy: Ipsen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Halozyme; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Array; Advisory / Consultancy: Five Prime; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Halozyme; Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Ignyta/Roche; Research grant / Funding (institution): Stemline; Research grant / Funding (institution): Macrogenetics. All other authors have declared no conflicts of interest.

This study investigated the effects of angiotensin II (AngII) intervention, using captopril and losartan, on the expression of matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and collagen in rats with pulmonary hypertension, in an effort to understand mechanisms underlying pulmonary vascular remodeling. A total of 40 male Sprague-Dawley rats were randomly divided into normal group, model group, captopril group, and losartan group. After 5 weeks, the mean pulmonary arterial pressure (mPAP), right ventricular index, and neointima formation in each group were determined. Immunohistochemical analysis was performed to determine the degree of pulmonary arterial muscularization as well as MMP-2, MMP-9, and TIMP-1 protein expression in lung tissue. Real-time fluorescent quantitative PCR was used to detect MMP2, MMP9, TIMP1, COL1A1, and COL4A1 mRNA expression. Picro-sirius red staining was performed to detect collagen protein expression. Neointima formation was observed in the model group. Moreover, the mPAP, right ventricular index, degree of arterial muscularization, and collagen deposition, as well as mRNA and protein expression of MMP2, MMP9, and TIMP1 were significantly higher than those in the other groups (P < 0.05). The mPAP, right ventricular index, degree of arterial muscularization, and mRNA and protein expression in the captopril and losartan groups were significantly decreased compared with those of the model group (P < 0.05). AngII regulates MMP-2, MMP-9, and TIMP-1 expression and affects collagen deposition. Thus, this hormone is involved in pulmonary vascular remodeling, indicating a possible mechanism that can be targeted in pulmonary hypertension intervention.

BACKGROUND: New hepatitis C virus (HCV) therapies with pan-genotypic efficacy are needed. The goals of part A of C-CREST-1 and C-CREST-2 were to compare the efficacies of two doses (300 mg or 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with grazoprevir (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ruzasvir (MK-8408; 60 mg once daily), and to evaluate the safety and tolerability of these combination regimens in individuals infected with genotypes 1, 2, or 3.METHODS: Part A of these phase 2, randomised, multicentre, open-label, clinical trials enrolled participants from 11 countries, aged 18 years or older, chronically infected with HCV genotypes 1, 2, or 3, with HCV RNA of at least 10 000 IU/mL, without evidence of cirrhosis, who had not received previous treatment for HCV infection. Within each HCV genotype, participants were randomly assigned (1:1:1:1) with a block size of 4, to open-label treatment to one of four treatment groups: grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (300 mg/day); grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (450 mg/day); grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (300 mg/day); or grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (450 mg/day), according to a computer-generated allocation schedule. Randomisation was centrally implemented using an interactive voice response system and integrated web response system. The primary endpoint was the proportion of participants achieving sustained virological response at 12 weeks (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the end of all study therapy) in the per-protocol analysis set, which included all participants who were randomised and received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT02332707 and NCT02332720.FINDINGS: 241 participants were randomised between Feb 18, 2015, and March 16, 2015. 240 participants completed 8 weeks of treatment and reached follow-up 12 weeks after the end of treatment. Of the four regimens, grazoprevir plus ruzasvir plus uprifosbuvir 450 mg had the most consistently high SVR12 (>90%) for participants infected with genotype 1 (21 [91%] of 23), genotype 2 (15 [94%] of 16), and genotype 3 (20 [91%] of 22). In particular, among those with genotype 2 infection, the grazoprevir plus ruzasvir plus uprifosbuvir 450 mg regimen had a higher SVR12 (15 [94%] of 16) than the grazoprevir plus ruzasvir plus uprifosbuvir 300 mg regimen (ten [71%] of 14), grazoprevir plus elbasvir plus uprifosbuvir 300 mg regimen (11 [69%] of 16), or grazoprevir plus elbasvir plus uprifosbuvir 450 mg regimen (nine [60%] of 15). Overall, the most common adverse events were headache (55 [23%] of 240), fatigue (47 [20%] of 240), and nausea (32 [13%] of 240). Two (INTERPRETATION: These results support further evaluation of the three-drug direct-acting antiviral agent regimen of grazoprevir 100 mg plus ruzasvir 60 mg plus uprifosbuvir 450 mg among a more diverse HCV-infected population, including those with compensated cirrhosis, previous treatment with an interferon-containing regimen, and HCV-HIV co-infection.FUNDING: Merck & Co, Inc.

Background There is a need for hepatitis C virus (HCV) therapies with excellent efficacy across genotypes and in diverse populations. Part A of the C-CREST-1 and C-CREST-2 trials led to the selection of a three-drug regimen of grazoprevir (MK-5172; an HCV NS3/4A protease inhibitor; 100 mg/day) plus ruzasvir (MK-8408; an NS5A inhibitor; 60 mg/day) plus uprifosbuvir (MK-3682; an HCV NS5B polymerase inhibitor; 450 mg/day). Part B of the studies tested this combination as a single formulation in different treatment durations in a broader population. Methods Part B of these randomised, phase 2, open-label clinical trials enrolled individuals from 15 countries who were chronically infected with HCV genotypes 1–6 (HCV RNA ≥10 000 IU/mL) with or without compensated cirrhosis. Those with genotype 1, genotype 2, genotype 4, or genotype 6 were treatment-naive; those with genotype 3 could be treatment-naive or treatment-experienced with pegylated interferon and ribavirin. Randomisation occurred centrally using an interactive voice response system and integrated web response system. Participants were randomly assigned to receive treatment for 8, 12, or 16 weeks with a fixed-dose combination of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin. The primary endpoint was the proportion of participants achieving sustained virological response 12 weeks after the end of all study therapy (SVR12), defined as HCV RNA less than the lower limit of quantification (either target detected unquantifiable or target not detected [

Localized heating during slip avalanches is relevant to the understanding of the transition from shear banding to cracking in bulk metallic glasses (BMGs). Here we focus on the released elastic energies (incorporating the influence of machine stiffness) and avalanche durations for regularly appearing large avalanches to study the maximum temperature increases of a Zr-based BMG compressed at three strain rates of 3 × 10−5, 3 × 10−4, and 3 × 10−3 s−1. The maximum released elastic energies during slip avalanches decrease with the increase of strain rates. The durations of the avalanches are on the scale of tens of milliseconds for each strain rate. As strain rate increases, the maximum temperature rises due to shear-band slips are decreased from 2.6, 2.3 to 1.9 K. Moderate heating during the large slip avalanches for three strain rate implies that thermal softening has only a small effect on the shear-banding instability.

AIMS Application of autochthonous strain Kocuria rosea KDF3 and its protease KP3 as adjuncts for acceleration of Kedong sufu ripening. METHODS AND RESULTS Kedong sufu was manufactured using autochthonous cultures (batch A), K. rosea KDF3 plus autochthonous cultures (batch B) and protease KP3 plus autochthonous cultures (batch C). The effects of certain key factors on the quality of sufu were analysed during a 150-day ripening period. The physicochemical properties of sufu samples from batches B and C after 120 days of ripening met the national standard requirements and samples from batch A after 150 days of ripening. The sensory evaluations of sufu samples from batches B and C after 120 days of ripening and from batch A after 150 days of ripening showed no significant differences (P > 0·05). Furthermore, the mechanism underlying the shorter ripening time and typical sensory quality of sufu prepared with K. rosea KDF3 or protease KP3 was partly revealed by profiles of peptides and free amino acids. The maturation times of Kedong sufu were shortened by 30 days, and the desired characteristics were obtained by adding K. rosea KDF3 or its protease KP3. CONCLUSIONS Kocuria rosea KDF3 or its protease KP3 can hasten sufu maturation. They could be used as adjuncts or additives for accelerating the ripening of Kedong sufu. SIGNIFICANCE AND IMPACT OF THE STUDY This study is the first report of using autochthonous strain K. rosea KDF3 or its protease KP3 as adjuncts for accelerating Kedong sufu ripening. The results are useful for characterizing the ripening of Kedong sufu, and they lay the foundation for pilot plant tests and full-scale plant tests.

O005 RETREATMENT OF PATIENTS WHO FAILED 8 OR 12 WEEKS OF LEDIPASVIR/SOFOSBUVIR-BASED REGIMENS WITH LEDIPASVIR/SOFOSBUVIR FOR 24 WEEKS E. Lawitz, S. Flamm, J.C. Yang, P.S. Pang, Y. Zhu, E. Svarovskaia, J.G. McHutchison, D. Wyles, P. Pockros. Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, Feinberg School of Medicine, Northwestern University, Chicago, IL, Gilead Sciences, Foster City, CA, University of California, San Diego, CA, Scripps Clinic, La Jolla, CA, United States E-mail: jenny.yang@gilead.com

Long-term treatment with cyclosporine A (CsA) is associated with various types of complications; however, CsA-induced anemia has not been reported. The present study examined the impact of CsA on hematopoietic parameters and intrarenal expression of erythropoietin (EPO) and the EPO receptor (EPOR) in a rat model of chronic CsA nephrotoxicity. Sprague-Dawley rats were fed a low-salt diet (0.05% sodium) and were treated daily for 4 weeks with vehicle (olive oil 1 mL/kg subcutaneously) or CsA (15 mg/kg subcutaneously). The expression of EPO and EPOR was evaluated by immunohistochemistry and immunoblotting, and hematopoietic parameters were assessed by measuring blood hemoglobin and hematocrit levels, and these variables were compared between treatment groups. Renal function, oxidative stress, histopathology (tubulointerstitial fibrosis), apoptotic cell death, and expression of transforming growth factor β-inducible gene-h3 (βig-h3) were also compared between treatment groups. In kidneys from vehicle-treated rats, endogenous EPO and EPOR protein were expressed constitutively in the outer stripe of the outer medulla and the cortex. EPO protein expression decreased significantly in kidneys from CsA-treated rats. By contrast, EPOR expression was higher in kidneys from CsA-treated rats than in vehicle-treated rats. These changes were accompanied by decreases in serum hemoglobin and hematocrit levels and correlated with the number of cells positive for terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (r = -0.769, P = .003) and βig-h3 protein expression (r = -0.910, P < .001). Long-term treatment with CsA suppresses renal endogenous EPO expression, resulting in anemia. Increases in apoptotic cell death and βig-h3 expression are closely associated with inhibition of EPO expression in chronic CsA nephrotoxicity.

Portal vein stenosis after liver transplantation is a relatively uncommon vascular complication that may result in graft loss if not promptly treated. The purpose of this study was to evaluate the midterm result of the use of intravascular stents for portal vein stenosis after liver transplantation. From April 2004 to September 2005, percutaneous transhepatic balloon dilation with stent deployment was performed in nine cases. Varices were embolized with stainless steel coils in two cases. No procedure-related complication occurred. Portal venous patency was maintained in all nine patients from 6 to 19 months (mean 10 months). In conclusion, an intravascular stent is an effective treatment for the portal vein stenosis after liver transplantation with excellent midterm patency.

In the USA, Kaposi's sarcoma associated with the acquired immunodeficiency syndrome (AIDS-KS) is ten times more common in homosexual or bisexual men than in heterosexual men with AIDS. One explanation for this finding is that AIDS-KS may be caused by an infectious agent. Because there is a high incidence of human papillomavirus (HPV) infection, especially HPV-16, in homosexual men, we have sought HPV DNA sequences in Kaposi's sarcoma. We used the polymerase chain reaction with a primer pair specific for the highly conserved E6 region of HPV-16 to detect HPV-16 homologous DNA fragments in tumour tissues from 97 patients with KS and in KS-derived cell cultures. HPV DNA sequences were found in 11 of 69 KS skin tumours from homosexual men with AIDS-KS, in 3 of 11 KS biopsy specimens from homosexual men who had no clinical or laboratory evidence of HIV-infection, and in 5 of 17 KS skin lesions from HIV-1-negative elderly men and women with classic KS. The same primer pair amplified HPV-16 homologous fragments from two different continuous cell cultures derived from pleural effusion fluid of patients with pulmonary AIDS-KS and two continuous cell cultures derived from KS skin lesions. The findings suggest that HPV-16-related DNA sequences are associated with different forms of KS and may have a role in the pathogenesis of this neoplasm.