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We identified factors associated with willingness to participate in HIV vaccine trials among HIV-negative injection drug users (IDU) and young men having sex with men (MSM) enrolled in prospective cohort studies in Vancouver. Of 435 IDU and 330 MSM, 83% and 63% were willing to participate in HIV vaccine trials, respectively. In both samples, greater willingness was associated with high perceived HIV threat, and with initiating injection or first having sex with men at younger ages. Among IDU, frequent needle exchange programs attenders were more willing to participate than infrequent attenders (p = .004). Among MSM, those with a higher depression score were more willing to participate (p < .001). In logistic regression models, independent predictors of willingness to participate included frequent needle exchange attendance among IDU, and high depression score and high perceived HIV threat among MSM. This suggests that needle exchange programs are ideal venues for recruiting high-risk IDU into HIV vaccine trials. Since MSM reporting more depressive symptoms were more willing to participate, HIV vaccine trials should provide appropriate counseling to safeguard participants' psychological and physical health. [ABSTRACT FROM AUTHOR]

In patients who progress from acute hepatitis B virus (HBV) infection to a chronic HBV (CHB) infection, CD8+ T cells fail to eliminate the virus and become impaired. A functional cure of CHB likely requires CD8+ T cell responses different from those induced by the infection. Here we report preclinical immunogenicity and efficacy of an HBV therapeutic vaccine that includes herpes simplex virus (HSV) glycoprotein D (gD), a checkpoint modifier of early T cell activation, that augments CD8+ T cell responses. The vaccine is based on a chimpanzee adenovirus serotype 6 (AdC6) vector, called AdC6-gDHBV2, which targets conserved and highly immunogenic regions of the viral polymerase and core antigens fused to HSV gD. The vaccine was tested with and without gD in mice for immunogenicity, and in an AAV8-1.3HBV vector model of antiviral efficacy. The vaccine encoding the HBV antigens within gD stimulates potent and broad CD8+ T cell responses. In a surrogate model of HBV infection, a single intramuscular injection achieved pronounced and sustained declines of circulating HBV DNA copies and HBV surface antigen; both inversely correlated with HBV-specific CD8+ T cell frequencies in spleen and liver.

Condensates have emerged as a new way to understand how cells are organized, and have been invoked to play crucial roles in essentially all cellular processes. In this view, the cell is occupied by numerous assemblies, each composed of member proteins and nucleic acids that preferentially interact with each other. However, available visual representations of condensates fail to communicate the growing body of knowledge about how condensates form and function. The resulting focus on only a subset of the potential implications of condensates can skew interpretations of results and hinder the generation of new hypotheses. Here we summarize the discussion from a workshop that brought together cell biologists, visualization and computation specialists, and other experts who specialize in thinking about space and ways to represent it. We place the recent advances in condensate research in a historical perspective that describes evolving views of the cell; highlight different attributes of condensates that are not well-served by current visual conventions; and survey potential approaches to overcome these challenges. An important theme of these discussions is that the new understanding on the roles of condensates exposes broader challenges in visual representations that apply to cell biological research more generally.

Aberrant formation of biomolecular condensates has been proposed to play a role in several cancers. The oncogenic fusion protein BRD4-NUT forms condensates and drives changes in gene expression in Nut Carcinoma. Here we sought to understand the molecular elements of BRD4-NUT and its associated histone acetyltransferase (HAT), p300, that promote these activities. We determined that a minimal fragment of NUT (MIN) in fusion with BRD4 is necessary and sufficient to bind p300 and form condensates. Furthermore, a BRD4-p300 fusion protein also forms condensates and drives gene expression similarly to BRD4-NUT(MIN), suggesting the p300 fusion may mimic certain features of BRD4-NUT. The intrinsically disordered regions, transcription factor-binding domains, and HAT activity of p300 all collectively contribute to condensate formation by BRD4-p300, suggesting that these elements might contribute to condensate formation by BRD4-NUT. Conversely, only the HAT activity of BRD4-p300 appears necessary to mimic the transcriptional profile of cells expressing BRD4-NUT. Our results suggest a model for condensate formation by the BRD4-NUT:p300 complex involving a combination of positive feedback and phase separation, and show that multiple overlapping, yet distinct, regions of p300 contribute to condensate formation and transcriptional regulation., (© 2023. The Author(s).)

Bempegaldesleukin (BEMPEG), a CD122-preferential IL2 pathway agonist, has been shown to induce proliferation and activation of NK cells. NK activation is dependent on the balance of inhibitory and excitatory signals transmitted by NK receptors, including Fc-gamma receptors (FCγRs) and killer immunoglobulin-like receptors (KIRs) along with their KIR-ligands. The repertoire of KIRs/KIR-ligands an individual inherits and the single-nucleotide polymorphisms (SNPs) of FCγRs can influence NK function and affect responses to immunotherapies. In this retrospective analysis of the single-arm PIVOT-02 trial, 200 patients with advanced solid tumors were genotyped for KIR/KIR-ligand gene status and FCγR SNP status and evaluated for associations with clinical outcome. Patients with inhibitory KIR2DL2 and its ligand (HLA-C1) observed significantly greater tumor shrinkage (TS, median change -13.0 vs. 0%) and increased PFS (5.5 vs. 3.3 months) and a trend toward improved OR (31.2 vs. 19.5%) compared to patients with the complementary genotype. Furthermore, patients with KIR2DL2 and its ligand together with inhibitory KIR3DL1 and its ligand (HLA-Bw4) had improved OR (36.5 vs. 19.6%), greater TS (median change -16.1 vs. 0%), and a trend toward prolonged PFS (8.4 vs. 3.6 months) as compared to patients with the complementary genotype. FCγR polymorphisms did not influence OR/PFS/TS.These data show that clinical response to BEMPEG plus nivolumab treatment in the PIVOT-02 trial may be associated with the repertoire of KIR/KIR-ligands an individual inherits. Further investigation and validation of these results may enable KIR/KIR-ligand genotyping to be utilized prospectively for identifying patients likely to benefit from certain cancer immunotherapy regimens., (© 2023. The Author(s).)

Many biomolecular condensates appear to form through liquid-liquid phase separation (LLPS). Individual condensate components can often undergo LLPS in vitro, capturing some features of the native structures. However, natural condensates contain dozens of components with different concentrations, dynamics, and contributions to compartment formation. Most biochemical reconstitutions of condensates have not benefited from quantitative knowledge of these cellular features nor attempted to capture natural complexity. Here, we build on prior quantitative cellular studies to reconstitute yeast RNA processing bodies (P bodies) from purified components. Individually, five of the seven highly concentrated P-body proteins form homotypic condensates at cellular protein and salt concentrations, using both structured domains and intrinsically disordered regions. Combining the seven proteins together at their cellular concentrations with RNA yields phase-separated droplets with partition coefficients and dynamics of most proteins in reasonable agreement with cellular values. RNA delays the maturation of proteins within and promotes the reversibility of, P bodies. Our ability to quantitatively recapitulate the composition and dynamics of a condensate from its most concentrated components suggests that simple interactions between these components carry much of the information that defines the physical properties of the cellular structure.

Background: Despite recent changes in the treatment landscape, there remains an unmet need for effective, tolerable, chemotherapy-free treatments for patients with advanced/metastatic urothelial carcinoma (mUC), especially cisplatin-ineligible patients., Objective: To evaluate the immunostimulatory interleukin-2 cytokine prodrug bempegaldesleukin (BEMPEG) plus nivolumab in patients with advanced/mUC from the phase 2 multicenter PIVOT-02 study., Design, Setting, and Participants: This open-label, multicohort phase 1/2 study enrolled patients with previously untreated locally advanced/surgically unresectable or mUC (N = 41)., Intervention: Patients received BEMPEG 0.006 mg/kg plus nivolumab 360 mg intravenously every 3 wk., Outcome Measurements and Statistical Analysis: The primary objectives were safety and the objective response rate (ORR) in patients with measurable disease at baseline and at least one postbaseline tumor response assessment (response-evaluable). Secondary objectives were overall survival (OS) and progression-free survival (PFS). Exploratory biomarker analyses via univariate logistic regression were performed to test the association between potential biomarkers (CD8 + tumor-infiltrating lymphocytes, tumor mutational burden, and IFN-γ gene expression profile) and response., Results and Limitations: The ORR was 35% (13/37 evaluable patients) and the complete response rate was 19% (7/37 patients); the median duration of response was not reached. Median PFS was 4.1 mo (95% confidence interval [CI] 2.1-8.7) and median OS was 23.7 mo (95% CI 15.8-not reached). Overall, 40/41 patients (98%) experienced at least one treatment-related adverse event (TRAE); grade 3/4 TRAEs occurred in 11 patients (27%), most commonly pyrexia (4.9%; 2 patients). Exploratory biomarker analyses showed no association between biomarkers and response. Limitations include the small sample size and single-arm design., Conclusions: BEMPEG plus nivolumab was well tolerated and showed antitumor activity as first-line treatment in patients with locally advanced/mUC., Patient Summary: We investigated an immune-stimulating prodrug called bempegaldesleukin plus the antibody nivolumab as the first therapy for patients with advanced or metastatic cancer of the urinary tract. This combination had manageable treatment-related side effects and was effective in a subset of patients. This trial is registered at ClinicalTrials.gov as NCT02983045., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Competing Interests: HE has the following disclosures: Co-founder of Virion Therapeutics, Advisor roles (board or consultancy) with: Freelance, Inc, Takeda, Biogen (board), Regenxbio, Ring Therapeutics (board), Canine Rabies Treatment Initiative (board). SC has the following disclosures: COO, Virion Therapeutics, Stock, Nektar Therapeutics. AL has the following disclosures: CEO, Virion Therapeutics.

Importance: Patients with breast cancer and brain metastases (BM) have a poor prognosis and high clinical need for novel treatments; however, historically, studies have often excluded these patients. Although the BEACON study did not meet its primary end point, treatment with etirinotecan pegol vs chemotherapy of the physician's choice for patients with advanced breast cancer demonstrated a significant improvement in overall survival (OS) for the prespecified patient subgroup with preexisting, pretreated, and nonprogressive BM., Objective: To compare clinical outcomes in patients with BM treated with etirinotecan pegol vs chemotherapy of the physician's choice in a confirmatory trial., Design, Setting, and Participants: This study was a phase 3, open-label, randomized clinical trial (ATTAIN) in patients with metastatic breast cancer and a history of stable pretreated BM who experienced disease progression while receiving chemotherapy in the metastatic setting. The trial took place at 47 sites in 10 countries, and patients were enrolled between March 7, 2017, and November 6, 2019., Interventions: Patients were randomized to receive etirinotecan pegol, 145 mg/m2, every 21 days or chemotherapy (eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel)., Main Outcomes and Measures: The primary end point was OS. Key secondary end points included progression-free survival, objective response rate, duration of response, and the clinical benefit rate., Results: A total of 178 female patients (9 [5.1%] Asian, 8 [4.5%] Black or African American, and 123 [69.1] White individuals) were randomized to receive treatment with etirinotecan pegol (92 [51.7%]; median [range] age, 53 [27-79] years) or chemotherapy (86 [48.3%]; median [range] age, 52 [24-77] years). Median OS was similar in both groups (etirinotecan pegol, 7.8 months; chemotherapy, 7.5 months; hazard ratio [HR], 0.90; 95% CI, 0.61-1.33; P = .60). Median progression-free survival for non-central nervous system metastases per blinded independent central review for etirinotecan pegol vs chemotherapy was 2.8 and 1.9 months (HR, 0.72; 95% CI, 0.45-1.16; P = .18) and 3.9 vs 3.3 months, respectively, for central nervous system metastases (HR, 0.59; 95% CI, 0.33-1.05; P = .07). Safety profiles between the groups were largely comparable., Conclusions and Relevance: The results of the ATTAIN randomized clinical trial found no statistically significant difference in outcomes between treatment with etirinotecan pegol and chemotherapy in patients with BM. However, this study represents one of the largest published trials dedicated to patients with breast cancer and BM and may help to inform further research., Trial Registration: ClinicalTrials.gov Identifier: NCT02915744.

Competing Interests: HE has the following disclosures: Co-founder of Virion Therapeutics, Advisor roles (board or consultancy) with: Freelance, Inc, Takeda, Biogen (board), Regenxbio, Ring Therapeutics (board), Canine Rabies Treatment Initiative (board). DL has the following disclosures: Advisory roles (board or consultancy): Accelerate, Antabio, Centauri, Entasis, GenPax, GSK, Meiji, Menarini, Mutabilis, Nordic, Paion, ParaPharm, ParaGraf, Pfizer, QPEX, Shionogi, Summit/Discuva, Sumitovant, T.A.Z., VenatoRx, Wockhardt, Zambon; was on the Russian Direct Investment Fund's Advisory Board for the Sputnik V but resigned following the invasion of the Ukraine. Paid lectures: bioMérieux, Beckman Coulter, Cardiome, GSK, Hikma, Merck/MSD, Menarini, Nordic, Pfizer and Shionogi. Relevant shareholdings: Dechra, GSK, Merck, Pfizer and Perkin Elmer amounting to <10% of portfolio value; Share options: T.A.Z. He also has nominated holdings in Avacta, Diaceutics, Destiny, Evgen, Faron, Genedrive, Poolbeg, Renalytics, Saietta, Synairgen and Verici through Enterprise Investment Schemes but has no authority to trade these shares directly. SC has the following disclosures: COO, Virion Therapeutics, Stock, Nektar Therapeutics.

Background: Immune checkpoint inhibitor-based combinations have expanded the treatment options for patients with renal cell carcinoma (RCC); however, tolerability remains challenging. The aim of this study was to evaluate the safety and efficacy of the immunostimulatory interleukin-2 cytokine prodrug bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) as first-line therapy in patients with advanced clear-cell RCC., Methods: This was an open-label multicohort, multicenter, single-arm phase 1/2 study; here, we report results from the phase 1/2 first-line RCC cohort (N=49). Patients received BEMPEG 0.006 mg/kg plus NIVO 360 mg intravenously every 3 weeks. The primary objectives were safety and objective response rate (ORR; patients with measurable disease at baseline and at least one postbaseline tumor response assessment). Secondary objectives included overall survival (OS) and progression-free survival (PFS). Exploratory biomarker analyses: association between baseline biomarkers and ORR., Results: At a median follow-up of 32.7 months, the ORR was 34.7% (17/49 patients); 3/49 patients (6.1%) had a complete response. Of the 17 patients with response, 14 remained in response for >6 months, and 6 remained in response for >24 months. Median PFS was 7.7 months (95% CI 3.8 to 13.9), and median OS was not reached (95% CI 37.3 to not reached). Ninety-eight per cent (48/49) of patients experienced ≥1 treatment-related adverse event (TRAE) and 38.8% (19/49) had grade 3/4 TRAEs, most commonly syncope (8.2%; 4/49) and increased lipase (6.1%; 3/49). No association between exploratory biomarkers and ORR was observed. Limitations include the small sample size and single-arm design., Conclusions: BEMPEG plus NIVO showed preliminary antitumor activity as first-line therapy in patients with advanced clear-cell RCC and was well tolerated. These findings warrant further investigation., Competing Interests: Competing interests: AOS-R received research funding from BioClin Therapeutics, Bristol Myers Squibb, Janssen, Merck Sharp & Dohme, Michael and Sherry Sutton Fund for Urothelial Cancer, Nektar Therapeutics, US National Institutes of Health, and Takeda. She has also served as an advisor/consultant to AstraZeneca, Bavarian Nordic, BioClin Therapeutics, Bristol Myers Squibb, EMD Serono, Genentech, Inovio Pharmaceuticals, Janssen, Merck, US National Comprehensive Cancer Network, Nektar Therapeutics, and Seattle Genetics. DCC has received consulting fees from Pfizer, Nectar, Torque, and Puretech. AD has been an advisory board member for Nektar Therapeutics. MS has served as a consultant/advisor for Genentech-Roche, Bristol Myers Squibb, AstraZeneca/MedImmune, Pfizer, Novartis, Kyowa-Kirin, Amgen, Merus, Seattle Genetics, Immune Design, Prometheus, Anaeropharma, Astellas-Agensys, Immunova, Nektar Therapeutics, Neostem, Pierre-Fabre, Eli Lilly, Symphogen, Lion Biotechnologies, Amphivena, and Adaptive Biotechnologies. MAB has acted as a paid consultant for, and/or as a member of the advisory boards of, Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Genomic Health, Nektar Therapeutics, and Sanofi and has received grants to his institution from Xencor, Bayer, Bristol Myers Squibb, Genentech/Roche, Seattle Genetics, Incyte, Nektar Therapeutics, AstraZeneca, Tricon Pharmaceuticals, Peleton Therapeutics, and Pfizer for work performed as outside of the current study. AVB has received institutional research funding from AstraZeneca/MedImmune, F Hoffmann–La Roche/Genentech, Merck, and Seattle Genetics; and honoraria from AstraZeneca/MedImmune, F Hoffmann–La Roche/Genentech and Merck. He has also served as an advisor/consultant to AstraZeneca/MedImmune, Cerulean Pharma, F Hoffmann–La Roche/Genentech, Incyte, Merck, Nektar Therapeutics, Pfizer/EMD Serono, and Seattle Genetics/Astellas. GG has received grants and personal fees from PharmaMar, grants from Novartis, and personal fees from Lilly, Pfizer, Bayer, and Eisai, outside the submitted work. EP, LT, DC, UH, AC, and DY are employees of, and have ownership interest (eg, stock) in, Nektar Therapeutics. SLC is a former employee of, and has ownership interest (eg, stock) in, Nektar Therapeutics. MAT is the chief medical officer at Nektar Therapeutics and has ownership interest (eg, stock) in the company. JZ is the chief research and development officer at Nektar Therapeutics and has ownership interest (eg, stock) in the company. MEH has had a consulting or advisory Role with Nektar Therapeutics, Janssen, Crispr Therapeutics, Bristol Myers Squibb/Celgene, and Exelixis; and has received research funding from Apexigen, Astellas Pharma, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Corvus Pharmaceuticals, Lilly, Endocyte, Genentech, Genmab, Innocrin Pharma, Iovance Biotherapeutics, Merck, Nektar Therapeutics, Novartis, Pfizer, Progenics, Sanofi/Aventis, Seattle Genetics, Torque, Unum Therapeutics, and Achilles Therapeutics. NMT has received grant support, consulting fees, and honoraria from Bristol Myers Squibb; grant support from Epizyme and Mirati Therapeutics; grant support, consulting fees, and honoraria from, and served on an advisory board for, Exelixis and Novartis; received consulting fees and honoraria from Argos Therapeutics and Pfizer; and received consulting fees and honoraria from, and served on an advisory board for, Eisai, Nektar Therapeutics, and Oncorena., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Bempegaldesleukin (BEMPEG: NKTR-214) is an immunostimulatory IL-2 cytokine prodrug engineered to deliver a controlled, sustained and preferential IL-2 pathway signal. Nivolumab (NIVO), a PD-1 inhibitor, has been shown to prolong survival in patients with advanced melanoma and recurrence-free survival in the adjuvant setting. PIVOT-02 showed that BEMPEG plus NIVO was well-tolerated and demonstrated clinical activity as first-line therapy in metastatic melanoma. PIVOT-12 is a randomized, phase III, global, multicenter, open-label study comparing adjuvant therapy with BEMPEG plus NIVO versus NIVO alone in adult and adolescent patients with completely resected cutaneous stage III/IV melanoma at high risk of recurrence. The primary objective is to compare the efficacy, as measured by recurrence-free survival, of BEMPEG plus NIVO versus NIVO.

Many biomolecular condensates are thought to form via liquid-liquid phase separation (LLPS) of multivalent macromolecules. For those that form through this mechanism, our understanding has benefitted significantly from biochemical reconstitutions of key components and activities. Reconstitutions of RNA-based condensates to date have mostly been based on relatively simple collections of molecules. However, proteomics and sequencing data indicate that natural RNA-based condensates are enriched in hundreds to thousands of different components, and genetic data suggest multiple interactions can contribute to condensate formation to varying degrees. In this Perspective, we describe recent progress in understanding RNA-based condensates through different levels of biochemical reconstitutions as a means to bridge the gap between simple in vitro reconstitution and cellular analyses. Complex reconstitutions provide insight into the formation, regulation, and functions of multicomponent condensates. We focus on two RNA-protein condensate case studies: stress granules and RNA processing bodies (P bodies), and examine the evidence for cooperative interactions among multiple components promoting LLPS. An important concept emerging from these studies is that composition and stoichiometry regulate biochemical activities within condensates. Based on the lessons learned from stress granules and P bodies, we discuss forward-looking approaches to understand the thermodynamic relationships between condensate components, with the goal of developing predictive models of composition and material properties, and their effects on biochemical activities. We anticipate that quantitative reconstitutions will facilitate understanding of the complex thermodynamics and functions of diverse RNA-protein condensates., (© 2022 Currie and Rosen; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

Purpose: Therapies that produce deep and durable responses in patients with metastatic melanoma are needed. This phase II cohort from the international, single-arm PIVOT-02 study evaluated the CD122-preferential interleukin-2 pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in first-line metastatic melanoma., Methods: A total of 41 previously untreated patients with stage III/IV melanoma received BEMPEG 0.006 mg/kg plus NIVO 360 mg once every 3 weeks for ≤ 2 years; 38 were efficacy-evaluable (≥ 1 postbaseline scan). Primary end points were safety and objective response rate (blinded independent central review); other end points included progression-free survival, overall survival (OS), and exploratory biomarkers., Results: At 29.0 months' median follow-up, the objective response rate was 52.6% (20 of 38 patients), and the complete response rate was 34.2% (13 of 38 patients). Median change in size of target lesions from baseline was -78.5% (response-evaluable population); 47.4% (18 of 38 patients) experienced complete clearance of target lesions. Median progression-free survival was 30.9 months (95% CI, 5.3 to not estimable). Median OS was not reached; the 24-month OS rate was 77.0% (95% CI, 60.4 to 87.3). Grade 3 and 4 treatment-related and immune-mediated adverse events occurred in 17.1% (7 of 41) and 4.9% (2 of 41) of patients, respectively. Increased polyfunctional responses in CD8+ and CD4+ T cells were seen in blood after treatment, driven by cytokines with effector functions. Early on-treatment blood biomarkers (CD8+ polyfunctional strength difference and eosinophils) correlated with treatment response., Conclusion: BEMPEG in combination with NIVO was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging antitumor activity in first-line metastatic melanoma, including an extended median progression-free survival. Exploratory analyses associated noninvasive, on-treatment biomarkers with response, before radiologic evidence was observed., Competing Interests: Adi DiabHonoraria: Array BioPharmaConsulting or Advisory Role: Nektar, CureVac, Celgene, IderaResearch Funding: Nektar, Idera, Celgene, Pfizer, Merck, ApexigenTravel, Accommodations, Expenses: Nektar Scott S. TykodiConsulting or Advisory Role: Merck, Intellisphere LLC, Natera, Bristol Myers Squibb, ExelixisResearch Funding: Genentech, Bristol Myers Squibb, Merck Sharp & Dohme, Calithera Biosciences, Pfizer, Jounce Therapeutics, Nektar, Exelixis, Clinigen GroupPatents, Royalties, Other Intellectual Property: Patent pending Gregory A. DanielsHonoraria: Sanofi/RegeneronConsulting or Advisory Role: Sanofi/RegeneronSpeakers' Bureau: Regeneron, Array BioPharma, Sanofi/RegeneronResearch Funding: Bristol Myers Squibb, Amgen, Viralytics, Nektar, Merck Michele MaioStock and Other Ownership Interests: Theravance, Epigen TherapeuticsHonoraria: Bristol Myers Squibb, AstraZeneca, Roche, MSD, Merck, Amgen, Pierre Fabre, Alfasigma, Sanofi, LillyConsulting or Advisory Role: Bristol Myers Squibb, Roche, AstraZeneca, MSD, Merck, Pierre Fabre, AlfasigmaPatents, Royalties, Other Intellectual Property: DNA hypomethylating agents for cancer therapyTravel, Accommodations, Expenses: Bristol Myers Squibb, AstraZeneca, Roche, MSD, Merck, Amgen, Pierre Fabre, Alfasigma Brendan D. CurtiHonoraria: Clinigen Group, NektarConsulting or Advisory Role: MerckResearch Funding: Bristol Myers Squibb, Galectin Therapeutics, Clinigen GroupPatents, Royalties, Other Intellectual Property: Biomarkers for OX40 responseTravel, Accommodations, Expenses: Agonox Karl D. LewisHonoraria: Array BioPharma, Iovance BiotherapeuticsConsulting or Advisory Role: Array BioPharma, Merck, Roche, Regeneron, Sanofi, Iovance BiotherapeuticsResearch Funding: Roche/Genentech, Merck, Array BioPharma, Incyte, Nektar, Iovance Biotherapeutics, Bristol Myers Squibb, Kartos Therapeutics, OncoSec, Regeneron, Alkermes, Neon Therapeutics, Ultimovacs, Senhwa Biosciences, Replimune, AmgenTravel, Accommodations, Expenses: Merck, Roche/Genentech, Regeneron, Neon Therapeutics, AlkermesUncompensated Relationships: Roche/Genentech, Regeneron Sekwon JangConsulting or Advisory Role: Bristol Myers Squibb, EMD Serono, Novartis, Sanofi, Sun Biopharma, Genentech Ewa KalinkaHonoraria: Bristol Myers Squibb, MSD, AstraZeneca, Regeneron, Nektar, RocheConsulting or Advisory Role: Bristol Myers SquibbSpeakers' Bureau: Bristol Myers Squibb, RocheResearch Funding: Bristol Myers Squibb, Merck Sharp & Dohme, Nektar, AstraZeneca, RocheTravel, Accommodations, Expenses: Roche Igor PuzanovStock and Other Ownership Interests: CelldexConsulting or Advisory Role: Amgen, Iovance Biotherapeutics, Merck, Roche, Nouscom, Seneca Therapeutics Alexander I. SpiraStock and Other Ownership Interests: LillyHonoraria: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol Myers Squibb, BayerConsulting or Advisory Role: Array BioPharma, Incyte, Amgen, Novartis, AstraZeneca/MedImmune, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Merck, Bristol Myers SquibbResearch Funding: Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone Oncology, Plexxikon, Amgen, Daiichi Sankyo, ADC Therapeutics, Janssen Oncology, Mirati Therapeutics, Rubius Therapeutics Daniel C. ChoConsulting or Advisory Role: Nektar, Pfizer, Werewolf TherapeuticsExpert Testimony: Genentech, Abbott/AbbVie Shanhong GuanEmployment: Nektar TherapeuticsStock and Other Ownership Interests: Nektar Therapeutics Erika PuenteEmployment: NektarStock and Other Ownership Interests: Nektar Tuan NguyenEmployment: Nektar, Theravance TherapeuticsStock and Other Ownership Interests: Nektar, Theravance Ute HochOther Relationship: Nektar Sue L. CurrieEmployment: NektarStock and Other Ownership Interests: Nektar Wei LinEmployment: Erasca Inc, NektarLeadership: Erasca IncStock and Other Ownership Interests: Nektar, Erasca IncTravel, Accommodations, Expenses: Nektar, Erasca Inc Mary A. TagliaferriEmployment: NektarLeadership: Nektar, ENZO BiochemStock and Other Ownership Interests: NektarPatents, Royalties, Other Intellectual Property: US 10576121Travel, Accommodations, Expenses: Nektar Jonathan ZalevskyEmployment: NektarLeadership: NektarStock and Other Ownership Interests: NektarTravel, Accommodations, Expenses: Nektar Mario SznolStock and Other Ownership Interests: Amphivena, Intensity Therapeutics, Adaptive Biotechnologies, Actym Therapeutics, Torque, Nextcure, EvolveImmune Therapeutics, Johnson & Johnson/Janssen, GlaxoSmithKlineConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca/MedImmune, Nektar, Lilly, Adaptimmune, Seattle Genetics, Pierre Fabre, Molecular Partners, AbbVie, Pieris Pharmaceuticals, Innate Pharma, Immunocore, Genocea Biosciences, Anaeropharma, Zelluna, Boston Pharmaceuticals, Alligator Bioscience, Servier, Dragonfly Therapeutics, Verastem, Boehringer Ingelheim, Agenus, Numab, BioNTech AG, Genentech/Roche, Gilead Sciences, Jazz Pharmaceuticals, Targovax, Sapience Therapeutics, Pfizer, Tessa Therapeutics, OncoSec, Trillium Therapeutics, StCube, Simcha, ITeos TherapeuticsOther Relationship: Haymarket Media, Physicians' Education Resource, DAVAOncology, CEC Oncology Michael E. HurwitzEmployment: Pfizer, Gamida Cell, ArvinasConsulting or Advisory Role: Nektar, Janssen, Crispr Therapeutics, Bristol Myers Squibb/Celgene, ExelixisResearch Funding: Apexigen, Astellas Pharma, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Corvus Pharmaceuticals, Lilly, Endocyte, Genentech, Genmab, Innocrin Pharma, Iovance Biotherapeutics, Merck, Nektar, Novartis, Pfizer, Progenics, Sanofi/Aventis, Seattle Genetics, Torque, Unum Therapeutics, Achilles TherapeuticsNo other potential conflicts of interest were reported.

ETS transcription factors from the ERG and ETV1/4/5 subfamilies are overexpressed in the majority of prostate cancer patients and contribute to disease progression. Here, we have developed two in vitro assays for the interaction of ETS transcription factors with DNA that are amenable to high-throughput screening. Using ETS1 as a model, we applied these assays to screen 110 compounds derived from a high-throughput virtual screen. We found that the use of lower-affinity DNA binding sequences, similar to those that ERG and ETV1 bind to in prostate cells, allowed for higher inhibition from many of these test compounds. Further pilot experiments demonstrated that the in vitro assays are robust for ERG, ETV1, and ETV5, three of the ETS transcription factors that are overexpressed in prostate cancer.

Many different transcription factors (TFs) regulate gene expression in a combinatorial fashion, often by binding in close proximity to each other on composite cis- regulatory DNA elements. Here, we investigated how ETS TFs bind with the AP1 TFs JUN-FOS at composite DNA-binding sites. DNA-binding ability with JUN-FOS correlated with the phenotype of ETS proteins in prostate cancer. We found that the oncogenic ETS-related gene (ERG) and ETS variant (ETV) 1/4/5 subfamilies co-occupy ETS-AP1 sites with JUN-FOS in vitro , whereas JUN-FOS robustly inhibited DNA binding by the tumor suppressors ETS homologous factor (EHF) and SAM pointed domain-containing ETS TF (SPDEF). EHF bound ETS-AP1 DNA with tighter affinity than ERG in the absence of JUN-FOS, possibly enabling EHF to compete with ERG and JUN-FOS for binding to ETS-AP1 sites. Genome-wide mapping of EHF- and ERG-binding sites in prostate epithelial cells revealed that EHF is preferentially excluded from closely spaced ETS-AP1 DNA sequences. Structural modeling and mutational analyses indicated that adjacent positively charged surfaces from EHF and JUN-FOS use electrostatic repulsion to disfavor simultaneous DNA binding. Conservation of positive residues on the JUN-FOS interface identified E74-like ETS TF 1 (ELF1) as an additional ETS TF exhibiting anticooperative DNA binding with JUN-FOS, and we found that ELF1 is frequently down-regulated in prostate cancer. In summary, divergent electrostatic features of ETS TFs at their JUN-FOS interface enable distinct binding events at ETS-AP1 DNA sites, which may drive specific targeting of ETS TFs to facilitate distinct transcriptional programs., (© 2018 Madison et al.)

Liquid-liquid phase separation (LLPS) is thought to contribute to the establishment of many biomolecular condensates, eukaryotic cell structures that concentrate diverse macromolecules but lack a bounding membrane. RNA granules control RNA metabolism and comprise a large class of condensates that are enriched in RNA-binding proteins and RNA molecules. Many RNA granule proteins are composed of both modular domains and intrinsically disordered regions (IDRs) having low amino acid sequence complexity. Phase separation of these molecules likely plays an important role in the generation and stability of RNA granules. To understand how folded domains and IDRs can cooperate to modulate LLPS, we generated a series of engineered proteins. These were based on fusions of an IDR derived from the RNA granule protein FUS (fused in sarcoma) to a multivalent poly-Src homology 3 (SH3) domain protein that phase-separates when mixed with a poly-proline-rich-motif (polyPRM) ligand. We found that the wild-type IDR promotes LLPS of the polySH3-polyPRM system, decreasing the phase separation threshold concentration by 8-fold. Systematic mutation of tyrosine residues in Gly/Ser-Tyr-Gly/Ser motifs of the IDR reduced this effect, depending on the number but not on the position of these substitutions. Mutating all tyrosines to non-aromatic residues or phosphorylating the IDR raised the phase separation threshold above that of the unmodified polySH3-polyPRM pair. These results show that low-complexity IDRs can modulate LLPS both positively and negatively, depending on the degree of aromaticity and phosphorylation status. Our findings provide plausible mechanisms by which these sequences could alter RNA granule properties on evolutionary and cellular timescales., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

The recruitment of transcriptional cofactors by sequence-specific transcription factors challenges the basis of high affinity and selective interactions. Extending previous studies that the N-terminal activation domain (AD) of ETV5 interacts with Mediator subunit 25 (MED25), we establish that similar, aromatic-rich motifs located both in the AD and in the DNA-binding domain (DBD) of the related ETS factor ETV4 interact with MED25. These ETV4 regions bind MED25 independently, display distinct kinetics, and combine to contribute to a high-affinity interaction of full-length ETV4 with MED25. High-affinity interactions with MED25 are specific for the ETV1/4/5 subfamily as other ETS factors display weaker binding. The AD binds to a single site on MED25 and the DBD interacts with three MED25 sites, allowing for simultaneous binding of both domains in full-length ETV4. MED25 also stimulates the in vitro DNA binding activity of ETV4 by relieving autoinhibition. ETV1/4/5 factors are often overexpressed in prostate cancer and genome-wide studies in a prostate cancer cell line indicate that ETV4 and MED25 occupy enhancers that are enriched for ETS-binding sequences and are both functionally important for the transcription of genes regulated by these enhancers. AP1-motifs, which bind JUN and FOS transcription factor families, were observed in MED25-occupied regions and JUN/FOS also contact MED25; FOS strongly binds to the same MED25 site as ETV4 AD and JUN interacts with the other two MED25 sites. In summary, we describe features of the multivalent ETV4- and AP1-MED25 interactions, thereby implicating these factors in the recruitment of MED25 to transcriptional control elements., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Giardiasis is a treatable disease, caused by the flagellated protozoan parasite, Giardia duodenalis (G. duodenalis). It is one of the most common enteric parasites found globally to cause gastrointestinal disturbances, and infections may result in long-term irritable bowel syndrome-like symptoms. It is a common misconception that giardiasis is associated with foreign travel, which results in locally acquired cases in the UK being underdiagnosed. This report highlights the findings from one large Scottish Health Board, arising from a change in testing methodology, which resulted in the screening of all stools submitted for enteric investigations for G. duodenalis. Previous selection criteria were restricted to patients with a travel history to specific regions of the world, or on the basis of certain clinical details. In this report, clinical details were recorded from samples shown to be positive using two methods: an ELISA-based antigen detection assay and microscopy. Clinical details were assessed for a total of 28 laboratory-confirmed positive cases against the original selection criteria. Twenty-six cases (93%) would have been excluded from Giardia testing if the previous selection criteria had been applied. Although nine cases stated foreign travel, only two had been to regions deemed to be 'high risk'. Therefore, those seven cases that travelled to perceived 'low-risk' regions would have been excluded from testing for this reason. This summary highlights the need for significant improvements to the selection criteria for Giardia testing. Laboratories should be encouraged towards the testing of all routinely submitted stools for this neglected pathogen to ensure cases that are acquired locally are properly identified and treated effectively.

Autoinhibition enables spatial and temporal regulation of cellular processes by coupling protein activity to surrounding conditions, often via protein partnerships or signaling pathways. We report the molecular basis of DNA-binding autoinhibition of ETS transcription factors ETV1, ETV4 and ETV5, which are often overexpressed in prostate cancer. Inhibitory elements that cooperate to repress DNA binding were identified in regions N- and C-terminal of the ETS domain. Crystal structures of these three factors revealed an α-helix in the C-terminal inhibitory domain that packs against the ETS domain and perturbs the conformation of its DNA-recognition helix. Nuclear magnetic resonance spectroscopy demonstrated that the N-terminal inhibitory domain (NID) is intrinsically disordered, yet utilizes transient intramolecular interactions with the DNA-recognition helix of the ETS domain to mediate autoinhibition. Acetylation of selected lysines within the NID activates DNA binding. This investigation revealed a distinctive mechanism for DNA-binding autoinhibition in the ETV1/4/5 subfamily involving a network of intramolecular interactions not present in other ETS factors. These distinguishing inhibitory elements provide a platform through which cellular triggers, such as protein-protein interactions or post-translational modifications, may specifically regulate the function of these oncogenic proteins., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Histone H3 lysine 4 (H3K4) methylation is a dynamic modification. In budding yeast, H3K4 methylation is catalyzed by the Set1-COMPASS methyltransferase complex and is removed by Jhd2, a JMJC domain family demethylase. The catalytic JmjC and JmjN domains of Jhd2 have the ability to remove all three degrees (mono-, di-, and tri-) of H3K4 methylation. Jhd2 also contains a plant homeodomain (PHD) finger required for its chromatin association and H3K4 demethylase functions. The Jhd2 PHD finger associates with chromatin independent of H3K4 methylation and the H3 N-terminal tail. Therefore, how Jhd2 associates with chromatin to perform H3K4 demethylation has remained unknown. We report a novel interaction between the Jhd2 PHD finger and histone H2A. Two residues in H2A (Phe-26 and Glu-57) serve as a binding site for Jhd2 in vitro and mediate its chromatin association and H3K4 demethylase functions in vivo. Using RNA sequencing, we have identified the functional target genes for Jhd2 and the H2A Phe-26 and Glu-57 residues. We demonstrate that H2A Phe-26 and Glu-57 residues control chromatin association and H3K4 demethylase functions of Jhd2 during positive or negative regulation of transcription at target genes. Importantly, we show that H2B Lys-123 ubiquitination blocks Jhd2 from accessing its binding site on chromatin, and thereby, we have uncovered a second mechanism by which H2B ubiquitination contributes to the trans-histone regulation of H3K4 methylation. Overall, our study provides novel insights into the chromatin binding dynamics and H3K4 demethylase functions of Jhd2., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Human disease caused by Legionella species is dominated by Legionella pneumophila, the main causative agent in cases of Legionnaires' disease. However, other species are known to cause infection, for example, Legionella longbeachae causes an equivalent number of cases of disease as L. pneumophila in Australia and New Zealand. Infection with L. longbeachae is commonly associated with exposure to composts and potting soils, and cases of infection with this organism have been increasing in Europe over the past ten years. The increase in incidence may be linked to factors such as increased awareness of clinical presentation, or due to changing formulation of growing media, although it should be noted that the presence of Legionella species in growing media does not correlate with the number of cases currently seen. This is likely due to the variables associated with infection, for example, host factors such as smoking or underlying health conditions, or difference in growing media storage or climate, especially warm humid conditions, which may affect survival and growth of these organisms in the growing media environment. There are numerous unknowns in this area and collaboration between growing media manufacturers and researchers, as well as more awareness among diagnosing clinicians, laboratory staff and the general public is necessary to reduce risk. More research is needed before definitive conclusions can be drawn: L. pneumophila research currently dominates the field and it is likely that the overreliance on diagnostic techniques such as the urinary antigen test, which is specific for L. pneumophila Sg 1, is detrimental to the diagnosis of L. longbeachae infection., (© Royal Society for Public Health 2015.)

The E26 transformation-specific (Ets-1) transcription factor is autoinhibited by a conformationally disordered serine-rich region (SRR) that transiently interacts with its DNA-binding ETS domain. In response to calcium signaling, autoinhibition is reinforced by calmodulin-dependent kinase II phosphorylation of serines within the SRR. Using mutagenesis and quantitative DNA-binding measurements, we demonstrate that phosphorylation-enhanced autoinhibition requires the presence of phenylalanine or tyrosine (ϕ) residues adjacent to the SRR phosphoacceptor serines. The introduction of additional phosphorylated Ser-ϕ-Asp, but not Ser-Ala-Asp, repeats within the SRR dramatically reinforces autoinhibition. NMR spectroscopic studies of phosphorylated and mutated SRR variants, both within their native context and as separate trans-acting peptides, confirmed that the aromatic residues and phosphoserines contribute to the formation of a dynamic complex with the ETS domain. Complementary NMR studies also identified the SRR-interacting surface of the ETS domain, which encompasses its positively charged DNA-recognition interface and an adjacent region of neutral polar and nonpolar residues. Collectively, these studies highlight the role of aromatic residues and their synergy with phosphoserines in an intrinsically disordered regulatory sequence that integrates cellular signaling and gene expression.

Over the past 5 years, a number of cases of legionellosis in Scotland have been associated with compost use; however, studies investigating sources of infection other than water systems remain limited. This study delivers the first comprehensive survey of composts commonly available in the UK for the presence of Legionella species. Twenty-two store-bought composts, one green-waste compost and one home-made compost were tested for Legionella by culture methods on BCYE-α medium, and the findings were confirmed by macrophage infectivity potentiator (mip) speciation. Twenty-two of the samples were retested after an enrichment period of 8 weeks. In total, 15 of 24 composts tested positive for Legionella species, a higher level of contamination than previously seen in Europe. Two isolates of Legionella pneumophila were identified, and Legionella longbeachae serogroup 1 was found to be one of the most commonly isolated species. L. longbeachae infection would not be detected by routine Legionella urinary antigen assay, so such testing should not be used as the sole diagnostic technique in atypical pneumonia cases, particularly where there is an association with compost use. The occurrence of Legionella in over half of the samples tested indicates that compost could pose a public health risk. The addition of general hygiene warnings to compost packages may be beneficial in protecting public health., (© 2013 The Authors Clinical Microbiology and Infection © 2013 European Society of Clinical Microbiology and Infectious Diseases.)

Background: Studies of the retreatment with consensus interferon (CIFN) and ribavirin (RBV) of hepatitis C virus (HCV)-infected patients who failed prior pegylated interferon alfa/ribavirin (PEG-IFN/RBV) have found quite variable efficacy and tolerability of this therapy. As such, CIFN/RBV use and efficacy in clinical practice were evaluated within the Department of Veterans Affairs (VA), the largest national, integrated system for HCV care., Aims: The purpose of this study was to determine rates of sustained virologic response (SVR) and patterns of CIFN/RBV use in the VA. Methods included retrospective review of national VA data in HCV-infected patients who had previously failed≥12 weeks of PEG-IFN/RBV and were prescribed CIFN/RBV between October 1, 2003 and September 30, 2006., Results: A total of 597 patients met the study criteria. CIFN was primarily dosed as 15 mcg subcutaneously daily combined with standard doses of RBV. Mean treatment duration was 21 weeks; CIFN was discontinued within 4 weeks in 24%. Hematological growth factors were used in 49%. Post-treatment viral loads were available in 385 patients. SVR to CIFN/RBV was achieved in 11%, and was significantly higher in prior PEG-IFN/RBV relapsers compared with nonresponders (31% vs. 6%, respectively; P<0.0001). A 2-log10 or greater drop in HCV RNA after 24 weeks of PEG-IFN/RBV was a predictor of subsequent SVR to CIFN/RBV., Conclusions: CIFN/RBV was used frequently in clinical practice for retreatment of PEG-IFN/RBV. In this setting, early treatment discontinuation was common. Overall SVR was low, although response was significantly better in prior PEG-IFN/RBV relapsers and those who had a 2-log(10) or greater decline than in nonresponders.

Using a sample of Canadian Forces personnel (N = 490) returning from deployment in Afghanistan, we tested a model of reintegration experiences, with a focus on affective organizational commitment, support factors, posttraumatic stress symptoms, changes in alcohol use, and turnover intentions. The model provided an excellent fit to the data, although homecoming experiences were not associated with commitment as predicted. No differences emerged between novice (single tour) and experienced (multiple tours) personnel, although the number of tours was associated with increased affective commitment as expected.

Background: Many HCV-infected persons with recent or ongoing injection drug use (IDU) do not receive HCV treatment due to the perceived risk of HCV reinfection. There are few prospective studies investigating HCV reinfection among IDUs., Methods: Two hundred and twenty-four persons with past or ongoing IDU were followed from 1997 to 2007. Baseline and every 6-month follow-up data were collected including demographics, IDU, and sexual behaviors. Serum was tested for the presence of HCV antibody and serially for HCV RNA. Resolvers were defined as HCV antibody and RIBA positive and RNA negative at two consecutive time points or as becoming HCV RNA negative after HCV antiviral treatment. Reinfection was defined by the presence of HCV RNA at > or =2 visits., Results: One hundred and eighty-six persons had chronic HCV and 38 had resolved HCV. The resolvers were followed for a total of 214 person-years. Forty-two percent of resolvers reported ongoing IDU, representing 58 person-years of IDU. Only one reinfection occurred in the resolvers, for a reinfection rate of 0.47 cases/100 person-years of follow-up. The single reinfection, which occurred in a person who continued to inject drugs, represents a reinfection rate of 1.75 cases/100 person-years of IDU., Conclusion: These data suggest that despite ongoing IDU, persistent HCV reinfection is lower than previously published. This can be attributed to a more clinically relevant definition of reinfection. This information will better help clinicians make informed decisions regarding HCV treatment options for patients who may continue to inject illicit drugs.

Background/goals: Many patients with a history of injection drug use (IDU) are excluded from hepatitis C virus (HCV) treatment. This prospective multicenter study aimed to determine the impact of IDU history on HCV treatment candidacy and outcomes., Study: Between 1999 and 2001, 4318 HCV-infected patients seen at 24 VA Medical Centers were evaluated for HCV treatment candidacy and followed prospectively. Univariate and multivariate logistic regression analyses were used to determine whether an IDU history was associated with HCV treatment candidacy, HCV treatment acceptance, early treatment discontinuation, and virologic response., Results: Of 4318 participants, 2611 (61%) reported an IDU history. IDU history was not significantly associated with HCV treatment candidacy, acceptance, early discontinuation of therapy, or virologic response (all P values nonsignificant). Instead, reduced HCV treatment candidacy was independently associated with low-income [odds ratio (OR)=1.46, 95% confidence interval (CI)=1.22-1.74), education < or = 12 years (OR=1.23, 95% CI=1.03-1.46), and alcohol consumption > or = 3 drinks/d (OR=2.08, 95% CI=1.68-2.57), whereas early discontinuation of HCV therapy was independently associated with low-income and consuming > or = 3 alcoholic drinks/d., Conclusions: A history of IDU was not associated with HCV treatment candidacy or outcomes, supporting national guidelines to evaluate former IDUs on a case-by-case basis for HCV treatment.

Studies have indicated a high prevalence of hepatic steatosis in patients with chronic hepatitis C (CHC). To address the impact of steatosis on the clinical course of CHC and treatment response requires large multicenter studies. The present study analyzed hepatitis C virus (HCV)-infected veterans enrolled in a U.S. Veteran Administration multicenter study of the epidemiology and response to interferon alpha-2b and ribavirin treatment. Of the 357 patients, 97.1% were males, with a mean age of 48.7+/-6.4 years, and 184 (51.5%) had hepatic steatosis. The mean body mass index (BMI) was 29.3+/-5.2 kg/m(2), including 37.1% who were obese (BMI, > or =30 kg/m(2)). Stage III-IV fibrosis was present in 111 of 334 (33.3%) of the patients. After adjusting for age, race, and history of alcohol use in the past 12 months, only stage III-IV fibrosis was independently and significantly associated with hepatic steatosis (P=0.03). There was a trend of association between obesity and steatosis independent of the other factors. Only HCV genotype was independently associated with a sustained virological response (SVR) to interferon alpha-2b and ribavirin treatment after adjusting for age, alcohol use, steatosis, BMI, stage III-IV fibrosis, serum AFP, and HCV load. In conclusion, analyses of our multicenter trial data demonstrated that the prevalence of hepatic steatosis is 51.5% in HCV-infected U.S. veterans. We found that steatosis is independently associated with stage III-IV fibrosis. However, only HCV genotype, and not steatosis, obesity, or stage III-IV fibrosis, was associated with SVR to interferon alpha-2b and ribavirin treatment.

Chronic hepatitis C virus (HCV) infection affects approximately 1.3% of the general U.S. population and 5-10% of veterans who use Department of Veterans Affairs medical services. Chronic HCV is clearly linked to the development of cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver disease requiring liver transplantation. The consequences of HCV infection constitute a significant disease burden and demonstrate the need for effective medical care. Treatment of chronic HCV is aimed at slowing disease progression, preventing complications of cirrhosis, reducing the risk of HCC, and treating extrahepatic complications of the virus. As part of a comprehensive approach to HCV management, antiviral therapy with peginterferon alfa combined with ribavirin is the current standard of care. Antiviral therapy should be provided to those individuals who meet criteria for treatment and who are at greatest risk for progressive liver disease. Many of these patients may have comorbid medical and psychiatric conditions, which may worsen while on antiviral therapy. Current antiviral regimens are associated with significant adverse effects that can lead to noncompliance, dose reduction, and treatment discontinuation. To overcome these barriers and to address these issues, it has become crucial to facilitate a multidisciplinary team who can respond to and provide HCV-specific care and treatment. Screening for HCV, preventing transmission, delaying disease progression, ensuring appropriate antiviral therapy, and managing treatment-related adverse effects can improve patient quality of life, treatment adherence, and ultimately, improve patient outcomes.

Background: Although HIV testing is recommended for persons with hepatitis C virus (HCV) infection who are at risk for HIV, little is known about HIV testing in this population., Methods: Data were prospectively collected in 4364 HCV-infected patients at 24 Veterans Affairs medical centers across the United States, including demographics, risk factors for HIV infection, and self-reported information on HIV testing., Results: Overall, 76.8% had been tested for HIV at least once, 14.8% were never tested, 6.6% did not know if they were tested, and 1.8% declined to answer. Multivariable analysis identified injection drug use, needlestick injury, sex with a same-sex partner, a greater number of lifetime sexual partners, and sex with an injection drug user as factors that were independently associated with HIV testing. At least one risk factor for HIV infection was present in 84.5% of the 646 patients who were never HIV tested. Among the 3350 subjects who were tested for HIV, 8.4% were positive, 88.3% were negative, 2.4% did not know the results of their test, and 0.9% declined to answer. Multivariable analysis identified African American and Hispanic race/ethnicity, income < or = 10,000 dollars, sex with a same-sex partner, and sex with an injection drug user as the only variables that were independently associated with HIV seropositivity., Conclusions: Although a substantial proportion of HCV-infected patients have been tested for HIV, missed opportunities for early diagnosis of HIV infection exist. Public health strategies to improve HIV testing among patients with chronic HCV infection are needed.

Background: Incarcerated populations are at high risk for hepatitis C virus (HCV) infection, yet prisoners are not routinely screened or treated for HCV infection. Understanding the risk factors of HCV infection among prisoners could help improve HCV interventions., Methods: Prevalence and risk of HCV infection among 469 prisoners entering California State correctional facilities were assessed using HCV antibody screening, HCV RNA measurement, and structured interviews. Multivariate logistic regression analysis was used to identify independent correlates of HCV infection., Results: The prevalence of HCV infection was 34.3% overall (95% confidence interval [CI], 30%-38%) and was 65.7% among those with a history of injection drug use (IDU), compared with 10.2% among those with no history of IDU (odds ratio [OR], 17.24; 95% CI, 10.52-28.25). Significant differences in HCV antibody positivity were found in association with age at first detention but not with the nature of the crime. Independent correlates of HCV infection included age, history of IDU, cumulative time of incarceration, biological sex (OR for females subjects compared with males subjects, 0.35; 95% CI, 0.13-0.96), and a history of having sex with a male IDU (OR, 4.42; 95% CI, 1.46-13.37). We identified significant differences in risk factors between male and female subjects--notably, that the risk of HCV infection was significantly elevated among female non-IDUs who reported having sexual partners with a history of IDU. Among non-IDUs, correlates of HCV infection included history of receipt of blood products and cumulative years of incarceration., Conclusions: HCV infection is pervasive among the California prison population, including prisoners who are non-IDUs and women with high-risk sexual behavior. These results should promote consideration of routine HCV antibody screening and behavioral interventions among incarcerated men and women.

Objective: To describe prevalence and incidence of HIV-1, hepatitis C virus (HCV) and risk behaviours in a prospective cohort of injecting drugs users (IDU)., Setting: Vancouver, which introduced a needle exchange programme (NEP) in 1988, and currently exchanges over 2 million needles per year., Design: IDU who had injected illicit drugs within the previous month were recruited through street outreach. At baseline and semi-annually, subjects underwent serology for HIV-1 and HCV, and questionnaires on demographics, behaviours and NEP attendance were completed. Logistic regression analysis was used to identify determinants of HIV prevalence., Results: Of 1006 IDU, 65% were men, and either white (65%) or Native (27%). Prevalence rates of HIV-1 and HCV were 23 and 88%, respectively. The majority (92%) had attended Vancouver's NEP, which was the most important syringe source for 78%. Identical proportions of known HIV-positive and HIV-negative IDU reported lending used syringes (40%). Of HIV-negative IDU, 39% borrowed used needles within the previous 6 months. Relative to HIV-negative IDU, HIV-positive IDU were more likely to frequently inject cocaine (72 versus 62%; P < 0.001). Independent predictors of HIV-positive serostatus were low education, unstable housing, commercial sex, borrowing needles, being an established IDU, injecting with others, and frequent NEP attendance. Based on 24 seroconversions among 257 follow-up visits, estimated HIV incidence was 18.6 per 100 person-years (95% confidence interval, 11.1-26.0)., Conclusions: Despite having the largest NEP in North America, Vancouver has been experiencing an ongoing HIV epidemic. Whereas NEP are crucial for sterile syringe provision, they should be considered one component of a comprehensive programme including counselling, support and education.