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DNA encoded libraries (DEL) have shown promise as a valuable technology for democratizing the hit discovery process. Although DEL provides relatively inexpensive access to libraries of unprecedented size, their production has been hampered by the idiosyncratic needs of the encoding DNA tag relegating DEL compatible chemistry to dilute aqueous environments. Recently reversible adsorption to solid support (RASS) has been demonstrated as a promising method to expand DEL reactivity using standard organic synthesis protocols. Here we demonstrate a suite of on‐DNA chemistries to incorporate medicinally relevant and C−S, C−P and N−S linkages into DELs, which are underrepresented in the canonical methods. [ABSTRACT FROM AUTHOR]

DNA encoded libraries (DEL) have shown promise as a valuable technology for democratizing the hit discovery process. Although DEL provides relatively inexpensive access to libraries of unprecedented size, their production has been hampered by the idiosyncratic needs of the encoding DNA tag relegating DEL compatible chemistry to dilute aqueous environments. Recently reversible adsorption to solid support (RASS) has been demonstrated as a promising method to expand DEL reactivity using standard organic synthesis protocols. Here we demonstrate a suite of on‐DNA chemistries to incorporate medicinally relevant and C−S, C−P and N−S linkages into DELs, which are underrepresented in the canonical methods. [ABSTRACT FROM AUTHOR]

• Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is rare after reduced-intensity conditioning (RIC) transplantation with a cumulative incidence of 1.6% in our large modern cohort. • VOD/SOS continues to be associated with a high nonrelapse mortality (NRM); in our cohort, day 100 NRM was 23% in patients with VOD/SOS compared with 6.4% in patients without VOD/SOS. • VOD/SOS in RIC patients often does not meet classical Baltimore/Seattle criteria and has a later onset, a lower peak bilirubin, and better survival than VOD/SOS in patients with myeloablative conditioning. • VOD/SOS after RIC is strongly associated with higher-dose busulfan (6.4 versus 3.2 mg/kg) in the RIC regimen and use of sirolimus in the graft-versus-host disease prophylaxis regimen. fludarabine with intravenous busulfan at doses of 3.2 mg/kg (Flu/Bu1) or 6.4 mg/kg (Flu/Bu2). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication of hematopoietic stem cell transplantation (HCT) that is felt to be triggered, at least in part, by damage to the liver sinusoidal endothelium from cytotoxic conditioning regimens. Accordingly, the incidence of VOD/SOS after reduced-intensity conditioning (RIC) HCT is low compared with myeloablative transplantation, and the natural history, risk factors, and outcomes of VOD/SOS after RIC have not been well characterized. We retrospectively reviewed 1583 consecutive patients receiving RIC HCT at the Dana-Farber Cancer Institute between 2007 and 2017 and ascertained 26 cases of VOD/SOS. The median day of VOD/SOS onset was 26 days (range, 5 to 48) and the cumulative incidence at day 50 was 1.6% (95% confidence interval [CI], 1.1% to 2.4%). Day 100 nonrelapse mortality rate was 23% in the VOD/SOS cohort compared with 6.4% in patients without VOD/SOS (P =.006). Cumulative incidence of VOD/SOS at day 50 was 3.1% after RIC regimen with Flu/Bu2 ± ATG (fludarabine with two doses of busulfan, total dose 6.4 mg/kg, with or without anti-thymocyte globulin), compared with 0.15% after Flu/Bu1 ± ATG (fludarabine with single busulfan dose 3.2 mg/kg, with or without anti-thymocyte globulin) (P =.0002); the incidence rate was 2.1% after RIC HCT with sirolimus-containing graft-versus-host disease prophylaxis, compared with 0.8% for RIC without sirolimus (P =.06). Significant risk factors identified in multivariable analysis for the development of VOD/SOS were sirolimus use (hazard ratio [HR], 5.1; 95% CI, 1.8 to 14.2; P =.002) and RIC regimen with Flu/Bu2 ± ATG (HR, 34; 95% CI, 4.5 to 252; P <.001) or other (HR, 32; 95% CI, 3.9 to 257; P =.001) compared with Flu/Bu1 ± ATG. Rising serum tacrolimus or sirolimus levels, new acute kidney injury, and increasing platelet transfusion requirements were significant early predictors of onset in the week preceding prior VOD/SOS diagnosis. When compared with a previously published cohort of 76 patients with VOD/SOS who developed VOD/SOS after myeloablative HCT in the same time period, VOD/SOS after RIC occurred later and was associated with a lower peak bilirubin level and better overall survival. The variability in presenting features for RIC VOD/SOS highlights the importance of maintaining a high index of suspicion for this entity in RIC HCT. [ABSTRACT FROM AUTHOR]

Background: Effects of prolonged nevirapine prophylaxis exposure on growth among HIV-exposed uninfected (HEU) infants are unknown. This study examines the impact of extended nevirapine prophylaxis from 6 weeks to 6 months on the growth of HEU infants followed for 18 months and also identifies correlates of incident wasting, stunting, underweight, and low head circumference in the HPTN 046 trial. Methods: Intention-to-treat analysis examined the effect of extended nevirapine exposure on: weight-for-age Z-score, length-for-age Z-score, weight-for-length Z-score, and head circumference for-age Z-score. Multivariable linear mixed-effects and Cox proportional hazard models were used to compare growth outcomes between the study arms and identify correlates of incident adverse growth outcomes, respectively. Results: Compared to placebo, extended prophylactic nevirapine given daily from 6 weeks to 6 months did not affect growth in HEU breastfeeding (BF) infants over time (treatment x time: P > 0.05). However, overall growth declined over time (time effect: P < 0.01) when compared with WHO general population norms. Male sex was associated with higher risk of all adverse growth outcomes (P = 0.05), whereas short BF duration was associated with wasting (P = 0.03). Maternal antiretroviral therapy exposure was protective against underweight (P = 0.02). Zimbabwe tended to have worse growth outcomes especially stunting, compared to South Africa, Uganda and Tanzania (P < 0.05). Conclusions: It is reassuring that prolonged exposure to nevirapine for prevention-of-mother-to-child HIV transmission does not restrict growth. However, targeted interventions are needed to improve growth outcomes among at-risk HEU infants (i.e., male sex, short BF duration, lack of maternal antiretroviral therapy exposure, and resident in Zimbabwe). [ABSTRACT FROM AUTHOR]

Background: Persons who inject drugs (PWID) have high HIV incidence and prevalence, and may have limited access to antiretroviral therapy (ART) in some settings. We evaluated HIV drug resistance in PWID in a randomized clinical trial (HPTN 074). The study intervention included ART at any CD4 cell count with enhanced support for ART and substance use treatment. Methods: HPTN 074 enrolled HIV-infected PWID (index participants) with viral loads ≥1,000 copies/mL and their HIV-uninfected injection-network partners in Indonesia, Ukraine, and Vietnam; the study limited enrollment of people who reported being on ART. HIV drug resistance testing and antiretroviral (ARV) drug testing were performed using samples collected from index participants at study enrollment. Results: Fifty-four (12.0%) of 449 participants had HIV drug resistance; 29 (53.7%) of the 54 participants had multi-class resistance. Prevalence of resistance varied by study site and was associated with self-report of prior or current ART, detection of ARV drugs, and a history of incarceration. Resistance was detected in 10 (5.6%) of 177 newly diagnosed participants. Participants with resistance at enrollment were less likely to be virally suppressed after 52 weeks of follow-up, independent of study arm. Conclusions: In HPTN 074, many of the enrolled index participants had HIV drug resistance and more than half of those had multi-class resistance. Some newly-diagnosed participants had resistance, suggesting that they may have been infected with drug-resistant HIV strains. Behavioral and geographic factors were associated with baseline resistance. Baseline resistance was associated with reduced viral suppression during study follow-up. These findings indicate the need for enhanced HIV care in this high-risk population to achieve sustained viral suppression on ART. [ABSTRACT FROM AUTHOR]

Summary: Background: Treating severe alcoholic hepatitis involves the exposure of patients to corticosteroids for 7 days to assess "response". Aim: To assess the prognostic and therapeutic implications of baseline neutrophil‐to‐lymphocyte ratio (NLR) in patients with severe alcoholic hepatitis. Methods: Patients recruited to the STOPAH trial and an independent validation group were analysed retrospectively. Area under the receiver operating curve (AUC) analysis was performed. Kaplan‐Meier analysis was used to assess survival. Log‐rank test and odds ratio (OR) were used for comparative analysis. Results: Baseline NLR was available for 789 STOPAH patients. The AUC for NLR was modest for 90‐day outcome (0.660), but was associated with infection, acute kidney injury (AKI) and severity of alcoholic hepatitis. Ninety‐day survival was not affected by prednisolone treatment if NLR < 5 or > 8 but mortality was reduced with prednisolone treatment when the NLR was 5‐8 (21.0% cf. 34.5%; P = 0.012). Prednisolone treatment increased the chance of Lille response if the NLR was  ≥ 5 (56.5% cf. 41.1%: P = 0.01; OR 1.86) but increased the risk of day 7 infection (17.3% cf. 7.4%: P = 0.006; OR 2.60) and AKI (20.8% cf. 7.0%: P = 0.008; OR 3.46) if the NLR was > 8. Incorporation of NLR into a modified Glasgow alcoholic hepatitis score (mGAHS) improved the AUC to 0.783 and 0.739 for 28‐day and 90‐day outcome, respectively. Conclusion: The NLR is associated with AKI and infection in severe alcoholic hepatitis. The NLR identifies those most likely to benefit from corticosteroids at baseline (NLR 5‐8). The mGAHS has a good predictive value for 28‐ and 90‐day outcomes. Linked Content This article is linked to Abdallah and Singal paper. To view this article, visit https://doi.org/10.1111/apt.15399. [ABSTRACT FROM AUTHOR]

The concept of whole genome amplification is something that has arisen in the past few years as the polymerase chain reaction (PCR) has been adapted to replicate regions of genomes that are of biological interest. The applications are many — forensic science, embryonic disease diagnosis, bioterrorism genome detection, ‘immortalization’ of clinical samples, microbial diversity, and genotyping. Several recent papers suggest that whole genomes can be replicated without bias or non-random distribution of the target, these findings open up a new avenue to molecular biology. [Copyright &y& Elsevier]

Successful treatment of solitary bone plasmacytoma and bone remineralisation with novel biological agents leading to new bone formation - a case series GLO:1XW/15may21:bjh17413-fig-0002.jpg PHOTO (COLOR): 2 (A) Magnetic resonance imaging (MRI) assessment of Patient II showed an intermedullary lesion in the proximal right humerus (arrow). Keywords: multiple myeloma; plasmacytoma; immunomodulation; steroids; proteasome inhibitor EN multiple myeloma plasmacytoma immunomodulation steroids proteasome inhibitor e36 e38 3 05/17/21 20210515 NES 210515 Solitary bone plasmacytoma (SBP) is a rare plasma cell disorder that accounts for 1-2% of patients with plasma cell dyscrasias.1 The UK Myeloma Forum Working Group Guidelines endorses optimal dose of radical radiotherapy according to the size of the lesions as identified on magnetic resonance imaging (MRI).2 As only varying benefits have been shown with the use of adjuvant chemotherapy in the pre-novel therapy era,3,4 the optimal management for SBP remains unclear. [Extracted from the article]

Summary: Background: Direct‐acting anti‐viral therapy (DAA) has transformed hepatitis C virus (HCV) care, particularly in patients with decompensated cirrhosis. However, their impact on hepatocellular carcinoma (HCC) remains unclear. Aim: To use a national registry of patients with advanced liver disease to explore the relationship between DAA therapy and HCC. Methods: All patients with de novo HCC post DAA therapy were frequency matched with patients who did not develop HCC. Demographic, clinical and laboratory data were obtained. Cross‐sectional imaging and multidisciplinary team reports were reviewed for dates of HCC diagnosis and HCC progression. Patients were categorised by treatment outcome and time of HCC development. Data were examined by multivariable analysis and Kaplan‐Meier estimation. Results: Eighty patients with HCC were compared with 165 patients without HCC, treated between June 2014 and September 2015. Mean follow‐up from start of DAA therapy was 32.4 months. Twenty‐eight patients were diagnosed with early HCC (within 6 months of therapy) and 52 presented late. Baseline nonmalignant lesions (HR: 1.99), thrombocytopaenia (HR: 1.59) and diabetes (HR: 1.68) increased likelihood of HCC. Response to therapy was reduced in patients who developed liver cancer (SVR in patients with HCC = 54/80 (68%), SVR in patients without HCC = 143/165 (87%), P < 0.001, OR: 3.13, 95% CI: 1.64‐5.99). We found no difference between tumour size, progression or survival between viraemic and nonviraemic patients. Conclusion: There is no alteration in prognosis or cancer progression following HCC development after HCV treatment. However, baseline nonmalignant liver lesions, diabetes and thrombocytopaenia increase the risk of HCC, and HCC is associated with a decreased SVR rate. Linked Content This article is linked to Hollande and Pol paper. To view this article, visit https://doi.org/10.1111/apt.15328. [ABSTRACT FROM AUTHOR]

Background and Aims: Previous studies have shown low rates of diagnosis and treatment of hepatitis C virus (HCV) infection in people who inject drugs (PWID). Our aims were to test the effect of a complex intervention [Hepatitis C Awareness Through to Treatment (HepCATT)] in drug and alcohol clinics—primarily, on engagement of HCV‐positive PWID with therapy and, secondarily, on testing for HCV, referral to hepatology services and start of HCV treatment. Design and setting: A non‐randomized pilot study in three specialist addiction clinics in England comparing an intervention year (starting between September 2015 and February 2016) with a baseline year (2014), together with three control clinics. Participants: Analysis included all attendees at the intervention and control specialist addiction clinics identified as PWID. Intervention: The intervention comprised the placement of a half‐time facilitator in each clinic for 12 months with the brief to increase diagnosis of HCV infection within clients at those services and the engagement of diagnosed individuals with an appropriate care pathway. The facilitator undertook various activities, which could include training of key workers, direct interaction with clients, streamlining and support for hepatology appointments and introduction of dried blood‐spot testing. Measurements For each clinic and period, we obtained the total number of clients and, as relevant, their status as PWID, tested for HCV, known HCV‐positive, engaged with HCV therapy or treated. Findings Compared with baseline, there was strong evidence that engagement with HCV therapy in the intervention year increased (P < 0.001) more in the HepCATT centres than controls, up +31 percentage points [95% confidence interval (CI) = 19–43] versus −12 (CI = –31 to +6) and odds ratio (OR) = 9.99 (CI = 4.42–22.6) versus 0.35 (CI = 0.08–1.56). HepCATT centres also had greater increases in HCV testing (OR = 3.06 versus 0.78, P < 0.001), referral to hepatology (OR = 9.60 versus 0.56, P < 0.001) and treatment initiation (OR = 9.5 versus 0.74, P < 0.001). Conclusions: Introducing a half‐time facilitator into drug and alcohol clinics in England increased engagement of HCV‐positive people who inject drugs with hepatitis C virus care pathways, with increased uptake also of testing, referral to hepatology and initiation of treatment. [ABSTRACT FROM AUTHOR]

The article informs on a study for analysing the impact of Fc gamma receptor polymorphisms on efficacy and safety of daratumumab in relapsed/refractory multiple myeloma. It examines effect of Fc portion of IgG polymorphisms on response, survival, and infusion-related reactions in multiple myeloma patients treated with daratumumab drug as single agent in the GEN501 and SIRIUS studies.

While immune checkpoint blockade leads to potent antitumor efficacy, it also leads to immune-related adverse events in cancer patients. These toxicities stem from systemic immune activation resulting in inflammation of multiple organs, including the gastrointestinal tract, lung, and endocrine organs. We developed a dual variable domain immunoglobulin of anti-CTLA4 antibody (anti-CTLA4 DVD, where CTLA4 is defined as cytotoxic T lymphocyte-associated antigen-4) possessing an outer tumor-specific antigen-binding site engineered to shield the inner anti-CTLA4-binding domain. Upon reaching the tumor, the outer domain was cleaved by membrane type-serine protease 1 (MT-SP1) present in the tumor microenvironment, leading to enhanced localization of CTLA4 blockade. Anti-CTLA4 DVD markedly reduced multiorgan immune toxicity by preserving tissue-resident Tregs in Rag 1-/- mice that received naive donor CD4+ T cells from WT C57BL/6j mice. Moreover, anti-CTLA4 DVD induced potent antitumor effects by decreasing tumor-infiltrating Tregs and increasing the infiltration of antigen-specific CD8+ T lymphocytes in TRAMP-C2-bearing C57BL/6j mice. Treg depletion was mediated through the antibody-dependent cellular cytotoxicity (ADCC) mechanism, as anti-CTLA4 without the FcγR-binding portion (anti-CTLA4 DANA) spared Tregs, preventing treatment-induced toxicities. In summary, our results demonstrate an approach to anti-CTLA4 blockade that depletes tumor-infiltrating, but not tissue-resident, Tregs, preserving antitumor effects while minimizing toxicity. Thus, our tumor-conditional anti-CTLA4 DVD provides an avenue for uncoupling antitumor efficacy from immunotherapy-induced toxicities. [ABSTRACT FROM AUTHOR]

Highlights • Allogeneic HSCT patients experience elevated tacrolimus levels, renal dysfunction, and become refractory to platelet transfusion in the week before VOD/SOS diagnosis. • These dynamic clinical markers may aid in the earlier diagnosis of VOD/SOS. Abstract Hepatic veno-occlusive disease (VOD), or sinusoidal obstruction syndrome (SOS), is a serious complication of hematopoietic stem cell transplantation (HSCT) with mortality in its severe form exceeding 80%. Although the incidence of VOD/SOS has fallen with contemporary transplantation practices, the increasing use of inotuzumab, the return of gemtuzumab, and the popularity of pharmacokinetic-guided high-dose busulfan may impact incidence. Early intervention with defibrotide improves survival, but prompt diagnosis can be difficult. We aimed to identify clinical parameters that could aid in early detection of VOD/SOS in a large, retrospective, cohort study. Of the 1823 adult patients who underwent myeloablative HSCT between 1996 and 2015 in our center, 205 (11%) developed VOD/SOS, with a median onset of day +14. We compared parameters in the 7 days preceding VOD/SOS onset for cases to 447 randomly selected control subjects in an analogous time frame to determine those with predictive value. Between 7 days before and the day of diagnosis, VOD/SOS patients had higher serum creatinine levels and were more likely to develop acute kidney injury (61% versus 33%, P <.0001), more commonly experienced refractoriness to platelet transfusion (48% versus 24%, P <.0001), and had higher trough serum tacrolimus levels (7 days before VOD/SOS onset: median 8.8 versus 7.3, P =.0002; day of onset: median 9.3 versus 7.2, P <.0001) compared with control subjects. Acute renal dysfunction, platelet refractoriness, and elevated or abnormal tacrolimus levels are dynamic clinical markers that should alert clinicians to the development of VOD/SOS before the presence of classical diagnostic criteria. Using these clinical features to recognize VOD/SOS earlier in its clinical course could promote earlier treatment and lead to improved outcomes of this potentially serious complication. [ABSTRACT FROM AUTHOR]

Background: B-cell maturation antigen (BCMA) is a cell-surface receptor of the tumour necrosis superfamily required for plasma cell survival. BMCA is universally detected on patient-derived myeloma cells and has emerged as a selective antigen to be targeted by novel treatments in multiple myeloma. We assessed the safety, tolerability, and preliminary clinical activity of GSK2857916, a novel anti-BCMA antibody conjugated to microtubule-disrupting agent monomethyl auristatin F, in patients with relapsed and refractory multiple myeloma.Methods: We did an international, multicentre, open-label, first-in-human phase 1 study with dose escalation (part 1) and dose expansion (part 2) phases, at nine centres in the USA, Canada, and the UK. Adults with histologically or cytologically confirmed multiple myeloma, Eastern Cooperative Oncology Group performance status 0 or 1, and progressive disease after stem cell transplantation, alkylators, proteasome inhibitors, and immunomodulators were recruited for this study. In part 1, patients received GSK2857916 (0·03-4·60 mg/kg) through 1 h intravenous infusions once every 3 weeks. In part 2, patients received the selected recommended phase 2 dose of GSK2857916 (3·40 mg/kg) once every 3 weeks. Primary endpoints were maximum tolerated dose and recommended phase 2 dose. Secondary endpoints for part 2 included preliminary anti-cancer clinical activity. All patients who received one or more doses were included in this prespecified administrative interim analysis (data cutoff date June 26, 2017), which was done for internal purposes. This study is registered with ClinicalTrials.gov, number NCT02064387, and is ongoing, but closed for recruitment.Findings: Between July 29, 2014, and Feb 21, 2017, we treated 73 patients: 38 patients in the dose-escalation part 1 and 35 patients in the dose-expansion part 2. There were no dose-limiting toxicities and no maximum tolerated dose was identified in part 1. On the basis of safety and clinical activity, we selected 3·40 mg/kg as the recommended phase 2 dose. Corneal events were common (20 [53%] of 38 patients in part 1 and 22 [63%] of 35 in part 2); most (18 [47%] in part 1 and 19 [54%] in part 2) were grade 1 or 2 and resulted in two treatment discontinuations in part 1 and no discontinuations in part 2. The most common grade 3 or 4 events were thrombocytopenia (13 [34%] of 38 patients in part 1 and 12 [34%] of 35 in part 2) and anaemia (6 [16%] in part 1 and 5 [14%] in part 2). There were 12 treatment-related serious adverse events and no treatment-related deaths. In part 2, 21 (60·0%; 95% CI 42·1-76·1) of 35 patients achieved an overall response.Interpretation: At the identified recommended phase 2 dose, GSK2857916 was well tolerated and had good clinical activity in heavily pretreated patients, thereby indicating that this might be a promising candidate for the treatment of relapsed or refractory multiple myeloma.Funding: GlaxoSmithKline. [ABSTRACT FROM AUTHOR]

In 2007 the members of the ACS Green Chemistry Institute® Pharmaceutical Roundtable assembled a list of key green chemistry research areas to both identify transformations that would benefit from improvements in process greenness and to encourage academic research to this end. The list provided the topics for a review of the literature, published in 2007 in the journal Green Chemistry. As part of the 10th anniversary of the founding of the Roundtable in 2015, the membership revisited the list. This article discusses the selection of the revised list, the updated 10 key green chemistry research areas, 2 solvent themes and the emerging area of medium molecules that resulted from the exercise. [ABSTRACT FROM AUTHOR]

Background: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States. Methods and findings: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18–65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population. Conclusions: In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress. Trial registration: ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800. In a phase 2a trial, Raphael Landovitz and colleagues investigate the safety of injectable cabotegravir in HIV-uninfected people Author summary: Why was this study done?: Daily oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate/emtricitabine is highly effective in preventing HIV infection when taken as prescribed, but adherence challenges have compromised full effectiveness in some populations. Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor in development as a long-acting injectable preparation for HIV treatment and HIV prevention. HIV Prevention Trials Network study 077 (HPTN 077) aimed to establish the safety, tolerability, and pharmacokinetics of 2 dose/interval regimens of long-acting CAB in HIV-uninfected, low-risk individuals globally. What did the researchers do and find?: Participants were randomized to active CAB or placebo. All participants received a 4-week daily oral lead-in of CAB or placebo, followed by a series of injections of CAB or placebo. Participants received either 800 mg as a split 2-ml injection every 12 weeks, or 600 mg as a single 3-ml injection every 8 weeks, after receiving 2 injections 4 weeks apart. We observed frequent injection site reactions (mostly injection site pain), and they were more common with CAB than placebo, but only led to discontinuation of injections in rare cases. No other safety concerns were noted. Pharmacokinetics, using target values from nonhuman primate simian/human immunodeficiency virus challenge prevention studies, support the 600 mg every 8 weeks dose, meeting prespecified targets. What do these findings mean?: We found that CAB was generally well tolerated in HIV-uninfected males and females in diverse geographic locations. Injection site reactions, although frequent, did not deter continued dosing, albeit with short courses. Studies are ongoing to evaluate efficacy in at-risk populations and to further evaluate the safety of the 600 mg every 8 weeks dose. [ABSTRACT FROM AUTHOR]

Background: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States. Methods and findings: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18–65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population. Conclusions: In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress. Trial registration: ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: . [ABSTRACT FROM AUTHOR]

Background: The immunostimulatory monoclonal antibody elotuzumab plus lenalidomide and dexamethasone has been shown to be effective in patients with relapsed or refractory multiple myeloma. The immunomodulatory agent pomalidomide plus dexamethasone has been shown to be effective in patients with multiple myeloma that is refractory to lenalidomide and a proteasome inhibitor.Methods: Patients with multiple myeloma that was refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor were randomly assigned to receive elotuzumab plus pomalidomide and dexamethasone (elotuzumab group) or pomalidomide and dexamethasone alone (control group). The primary end point was investigator-assessed progression-free survival.Results: A total of 117 patients were randomly assigned to the elotuzumab group (60 patients) or the control group (57 patients). After a minimum follow-up period of 9.1 months, the median progression-free survival was 10.3 months in the elotuzumab group and 4.7 months in the control group. The hazard ratio for disease progression or death in the elotuzumab group as compared with the control group was 0.54 (95% confidence interval [CI], 0.34 to 0.86; P=0.008). The overall response rate was 53% in the elotuzumab group as compared with 26% in the control group (odds ratio, 3.25; 95% CI, 1.49 to 7.11). The most common grade 3 or 4 adverse events were neutropenia (13% in the elotuzumab group vs. 27% in the control group), anemia (10% vs. 20%), and hyperglycemia (8% vs. 7%). A total of 65% of the patients in each group had infections. Infusion reactions occurred in 3 patients (5%) in the elotuzumab group.Conclusions: Among patients with multiple myeloma in whom treatment with lenalidomide and a proteasome inhibitor had failed, the risk of progression or death was significantly lower among those who received elotuzumab plus pomalidomide and dexamethasone than among those who received pomalidomide plus dexamethasone alone. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-3 ClinicalTrials.gov number, NCT02654132 .). [ABSTRACT FROM AUTHOR]

Background: The randomized phase 3 ELOQUENT-2 study (NCT01239797) evaluated the efficacy and safety of elotuzumab plus lenalidomide and dexamethasone (ELd) versus lenalidomide and dexamethasone (Ld) in relapsed/refractory multiple myeloma (RRMM), and to date, has the longest follow-up of any monoclonal antibody in patients with RRMM.Methods: In this extended 4-year follow-up of the ELOQUENT-2 trial, the coprimary endpoints of progression-free survival (PFS) and overall response rate as well as the secondary endpoint of overall survival were assessed. In the absence of head-to-head trials comparing Ld-based triplet regimens to guide treatment selection, 4 randomized controlled trials-ELOQUENT-2, ASPIRE, TOURMALINE-MM1, and POLLUX-were indirectly compared to provide insight into the relative efficacy of these regimens in RRMM.Results: Data at 4 years were consistent with 2- and 3-year follow-up data: ELd reduced the risk of disease progression/death by 29% versus Ld (hazard ratio, 0.71) while maintaining safety. The greatest PFS benefit among the assessed subgroups was observed in patients at the median time or further from diagnosis (≥3.5 years) with 1 prior line of therapy, who had a 44% reduction in the risk of progression/death, and in patients in the high-risk category, who had a 36% reduction in favor of ELd. This regimen also showed a relative PFS benefit that was maintained beyond 50 months.Conclusions: The sustained PFS benefit and long-term safety of ELd at 4 years, similar to those observed at 2 and 3 years, support ELd as a valuable therapeutic option for the long-term treatment of patients with RRMM. [ABSTRACT FROM AUTHOR]

Multiple myeloma is the most common plasma cell dyscrasia and causes 2% of all cancer deaths in Western countries. Ovarian carcinosarcomas are very rare gynecological malignancies and account for only 1–2% of all ovarian tumors. In this case, we report a 67-year-old woman with known relapsed ovarian carcinosarcoma who presented with headache and neck pain. She was found to have new lytic lesions in the cranial and thoracic regions. While these lesions were assumed to be metastases, a diligent approach detected an M-spike on serum protein electrophoresis and a monoclonal gammopathy with immunoglobulin G lambda monoclonal immunoglobulin on immunofixation. A bone marrow biopsy confirmed the diagnosis of multiple myeloma. To our knowledge, this is the first ever reported case of concomitant multiple myeloma and ovarian carcinosarcoma. Our case highlights the utmost importance of a systematic approach to lytic lesions and emphasizes the need to consider secondary malignancies in the evaluation of possible metastases. We used the International Myeloma Working Group guidelines for screening and diagnosing multiple myeloma, and we provide a thorough review of this updated approach. [ABSTRACT FROM AUTHOR]

Background: People who inject drugs (PWID) have a high incidence of HIV, little access to antiretroviral therapy (ART) and medication-assisted treatment (MAT), and high mortality. We aimed to assess the feasibility of a future controlled trial based on the incidence of HIV, enrolment, retention, and uptake of the intervention, and the efficacy of an integrated and flexible intervention on ART use, viral suppression, and MAT use.Methods: This randomised, controlled vanguard study was run in Kyiv, Ukraine (one community site), Thai Nguyen, Vietnam (two district health centre sites), and Jakarta, Indonesia (one hospital site). PWID who were HIV infected (index participants) and non-infected injection partners were recruited as PWID network units and were eligible for screening if they were aged 18-45 years (updated to 18-60 years 8 months into study), and active injection drug users. Further eligibility criteria for index participants included a viral load of 1000 copies per mL or higher, willingness and ability to recruit at least one injection partner who would be willing to participate. Index participants were randomly assigned via a computer generated sequence accessed through a secure web portal (3:1) to standard of care or intervention, stratified by site. Masking of assignment was not possible due to the nature of intervention. The intervention comprised systems navigation, psychosocial counselling, and ART at any CD4 count. Local ART and MAT services were used. Participants were followed up for 12-24 months. The primary objective was to assess the feasibility of a future randomised controlled trial. To achieve this aim we looked at the following endpoints: HIV incidence among injection partners in the standard of care group, and enrolment and retention of HIV-infected PWID and their injection partners and the uptake of the integrated intervention. The study was also designed to assess the feasibility, barriers, and uptake of the integrated intervention. Endpoints were assessed in a modified intention-to-treat popualtion after exclusion of ineligible participants. This trial is registered on ClinicalTrials.gov, NCT02935296, and is active but not recruiting new participants.Findings: Between Feb 5, 2015, and June 3, 2016, 3343 potential index participants were screened, of whom 502 (15%) were eligible and enrolled. 1171 injection partners were referred, and 806 (69%) were eligible and enrolled. Index participants were randomly assigned to intervention (126 [25%]) and standard of care (376 [75%]) groups. At week 52, most living index participants (389 [86%] of 451) and partners (567 [80%] of 710) were retained, and self-reported ART use was higher among index participants in the intervention group than those in the standard of care group (probability ratio [PR] 1·7, 95% CI 1·4-1·9). Viral suppression was also higher in the intervention group than in the standard of care group (PR 1·7, 95% CI 1·3-2·2). Index participants in the intervention group reported more MAT use at 52 weeks than those in the standard of care group (PR 1·7, 95% CI 1·3-2·2). Seven incident HIV infections occurred, and all in injection partners in the standard of care group (intervention incidence 0·0 per 100 person-years, 95% CI 0·0-1·7; standard of care incidence 1·0 per 100 person-years, 95% CI 0·4-2·1; incidence rate difference -1·0 per 100 person-years, 95% CI -2·1 to 1·1). No severe adverse events due to the intervention were recorded.Interpretation: This vanguard study provides evidence that a flexible, scalable intervention increases ART and MAT use and reduces mortality among PWID. The low incidence of HIV in both groups impedes a future randomised, controlled trial, but given the strength of the effect of the intervention, its implementation among HIV-infected PWID should be considered.Funding: US National Institutes of Health. [ABSTRACT FROM AUTHOR]

Summary: Smouldering multiple myeloma (SMM) is associated with increased risk of progression to multiple myeloma within 2 years, with no approved treatments. Elotuzumab has been shown to promote natural killer (NK) cell stimulation and antibody‐dependent cellular cytotoxicity (ADCC) in vitro. CD56dim (CD56dim/CD16+/CD3−/CD45+) NK cells represent the primary subset responsible for elotuzumab‐induced ADCC. In this phase II, non‐randomized study (NCT01441973), patients with SMM received elotuzumab 20 mg/kg intravenously (cycle 1: days 1, 8; monthly thereafter) or 10 mg/kg (cycles 1, 2: weekly; every 2 weeks thereafter). The primary endpoint was the relationship between baseline proportion of bone marrow‐derived CD56dim NK cells and maximal M protein reduction; secondary endpoints included overall response rate (ORR) and progression‐free survival (PFS). Fifteen patients received 20 mg/kg and 16 received 10 mg/kg; combined data arepresented. At database lock (DBL, September 2014), no association was found between baseline CD56dim NK cell proportion and maximal M protein reduction. With minimum 28 months' follow‐up (DBL: January 2016), ORR (90% CI) was 10% (2·7–23·2) and 2‐year PFS rate was 69% (52–81%). Upper respiratory tract infections occurred in 18/31 (58%) patients. Four (13%) patients experienced infusion reactions, all grade 1–2. Elotuzumab plus lenalidomide/dexamethasone is under investigation for SMM. [ABSTRACT FROM AUTHOR]

Abstract: We sought a regimen that incorporates optimal novel agents and balances efficacy with toxicity in transplant‐ineligible multiple myeloma (MM) patients. Our study evaluated modified lenalidomide‐bortezomib‐dexamethasone (RVD lite) in this population and was administered over a 35‐day cycle. Lenalidomide 15 mg was given orally on days 1–21; bortezomib 1·3 mg/m2 weekly subcutaneously on days 1, 8, 15 and 22; and dexamethasone 20 mg orally was given on the day of and day after bortezomib for 9 cycles followed by 6 cycles of consolidation with lenalidomide and bortezomib. The primary objective was to evaluate the overall response rate (ORR); secondary objectives included safety, progression‐free survival (PFS) and overall survival (OS). Fifty‐three eligible patients were screened between April 2013 and May 2015; 50 received at least one dose of therapy. Median age at study entry was 73 years (range 65–91). The ORR was 86% and 66% of patients achieved a very good partial response or better. Median PFS was 35·1 months (95% confidence interval 30·9–not reached) and median OS was not reached at a median follow‐up of 30 months. Peripheral neuropathy was reported in 31 (62%) patients with only 1 patient experiencing grade 3 symptoms. RVD lite is a well‐tolerated and highly effective regimen, with robust PFS and OS, in the transplant‐ineligible MM population. [ABSTRACT FROM AUTHOR]

DNA-encoded libraries (DEL)-based discovery platforms have recently been widely adopted in the pharmaceutical industry, mainly due to their powerful diversity and incredible number of molecules. In the two decades since their disclosure, great strides have been made to expand the toolbox of reaction modes that are compatible with the idiosyncratic aqueous, dilute, and DNA-sensitive parameters of this system. However, construction of highly important C(sp³)-C(sp³) linkages on DNA through cross-coupling remains unexplored. In this article, we describe a systematic approach to translating standard organic reactions to a DEL setting through the tactical combination of kinetic analysis and empirical screening with information captured from data mining. To exemplify this model, implementation of the Giese addition to forge high value C-C bonds on DNA was studied, which represents a radical-based synthesis in DEL. [ABSTRACT FROM AUTHOR]

Summary: Hepatic veno‐occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life‐threatening complication of haematopoietic stem cell transplant (HSCT) conditioning and chemotherapy. Defibrotide is approved for treatment of hepatic VOD/SOS with pulmonary or renal dysfunction [i.e., multi‐organ dysfunction (MOD)] after HSCT in the United States and severe VOD/SOS after HSCT in patients aged older than 1 month in the European Union. Defibrotide was available as an investigational drug by an expanded‐access treatment programme (T‐IND; NCT00628498). In the completed T‐IND, the Kaplan–Meier estimated Day +100 survival for 1000 patients with documented defibrotide treatment after HSCT was 58·9% [95% confidence interval (CI), 55·7–61·9%]. Day +100 survival was also analysed by age and MOD status, and post hoc analyses were performed to determine Day +100 survival by transplant type, timing of VOD/SOS onset (≤21 or >21 days) and timing of defibrotide treatment initiation after VOD/SOS diagnosis. Day +100 survival in paediatric patients was 67·9% (95% CI, 63·8–71·6%) and 47·1% (95% CI, 42·3–51·8%) in adults. All patient subgroups without MOD had higher Day +100 survival than those with MOD; earlier defibrotide initiation was also associated with higher Day +100 survival. The safety profile of defibrotide in the completed T‐IND study was similar to previous reports. [ABSTRACT FROM AUTHOR]

Bacteriophages are viruses that only infect bacterial cells and can be used to treat antibiotic resistant bacterial infections. This study focused on the isolation and characterization of bacteriophages lytic to Staphylococcus aureus at Coastal Carolina University (CCU) in Conway, South Carolina, as a means to isolate bacteriophages that can potentially be used to treat methicillin-resistant Staphylococcus aureus (MRSA), an antibiotic-resistant S. aureus variant. From 2014 to 2018, collection of ear and nose samples from 225 randomly selected CCU volunteers was conducted. Filter sterilization, amplification, microbial tests, and PCR analyses were performed in order to identify and characterize bacteriophages. Coliphage populations were also monitored as an indicator of temporal competition and fecal contamination. A pilot study was initiated in 2017 in which 15 CCU volunteers were sampled once a month from October 2017 through March 2018 in order to investigate coliphage and S. aureus phage population dynamics. The purpose of this study was to gain insight into the lytic Staphylococcus aureus phage repository found in the CCU community, and to explore S. aureus phage dynamics amongst the CCU populace. Results indicated that a considerable S. aureus and E. coli phage reservoir exists amongst the CCU population. Most phages could not be characterized via PCR analysis, suggesting high diversity. The preliminary study indicated that S. aureus and E. coli hosts potentially exhibit temporal competition, of which might be explanatory of phage population fluctuations. [ABSTRACT FROM AUTHOR]

The treatment of multiple myeloma (MM) has gone through several major advances over the last 5 years with the introduction of next generation proteasome inhibitors (PI; carfilzomib, ixazomib) and immunomodulatory derivatives (IMiD; pomalidomide), with these new agents having a substantial impact on patient outcome. However, despite these advances, MM remains a highly resistant disease given its propensity for clonal heterogeneity and its complex interaction with the surrounding bone marrow microenvironment. Almost all patients eventually relapse despite therapeutic responses to a PI, IMiD or both. With the regulatory approval of the monoclonal antibodies Daratumumab and Elotuzumab in 2015, impressive and durable responses are being observed, even in heavily pre-treated patients who have exhausted other therapeutic options, suggesting immunological approaches in this setting have real merit. This review will focus on newer monoclonal antibodies and chimericantigen receptor (CAR) T cell strategies currently under investigation and in various stages of clinical development. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is the second most common haematological malignancy after non-Hodgkin lymphoma. Despite the improvement in outcomes over the last decade with the introduction of novel therapies, such as immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs), MM remains an incurable disease. Patients who are both refractory to IMiDs and PIs carry a particularly dismal prognosis. The development of targeted therapy in the form of monoclonal antibodies has shifted the treatment paradigm of this disease, resulting in unprecedented response rates, even among the highest-risk patients. In this review, we will summarize the mechanism of action and provide an overview of the clinical trials that have led to the US Food and Drug Administration approval of Daratumumab and Elotuzumab, and their current use in the treatment of MM. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to understand the influence of disease and patient characteristics on exposure to daratumumab, an immunoglobulin Gκ (IgGκ) monoclonal antibody, and clinical outcomes in relapsed or refractory multiple myeloma (MM).Patients and Methods: Baseline myeloma type, albumin levels, renal/hepatic function, age, sex, race, weight, Eastern Cooperative Oncology Group (ECOG) status, refractory status, and number of prior therapies were evaluated using data from two clinical studies-GEN501 (N = 104) and SIRIUS (N = 124).Results: Daratumumab clearance was approximately 110% higher in IgG myeloma patients than non-IgG myeloma patients, leading to significantly lower exposure in IgG myeloma patients based on maximum trough serum concentrations (p < 0.0001). However, the overall response rate was similar for IgG and non-IgG myeloma patients (odds ratio 1.08, 95% confidence interval 0.54-2.17, p = 0.82). For a given exposure, the drug effect was significantly higher (approximately two times) in IgG versus non-IgG patients (p = 0.03). The influence of other patient and disease characteristics on daratumumab exposure was minimal and no significant effect on efficacy was observed (p ≥ 0.1). The incidences of infections and overall grade 3 or higher adverse events in subpopulations were generally consistent with that of the overall population.Conclusion: Due to competition with the MM-produced IgG M-protein for neonatal Fc receptor protection from clearance, IgG-based monoclonal antibodies in general may have significantly higher clearance and lower concentrations in IgG MM patients compared with non-IgG MM patients. Careful evaluation of the impact of exposure and patient and disease characteristics on safety and efficacy is warranted for all IgG-based monoclonal antibodies used in MM. [ABSTRACT FROM AUTHOR]

The scarcity of complex intermediates in pharmaceutical research motivates the pursuit of reaction optimization protocols on submilligram scales. We report here the development of an automated flow-based synthesis platform, designed from commercially available components, that integrates both rapid nanomole-scale reaction screening and micromole-scale synthesis into a single modular unit. This system was validated by exploring a diverse range of reaction variables in a Suzuki-Miyaura coupling on nanomole scale at elevated temperatures, generating liquid chromatography–mass spectrometry data points for 5760 reactions at a rate of >1500 reactions per 24 hours. Through multiple injections of the same segment, the system directly produced micromole quantities of desired material. The optimal conditions were also replicated in traditional flow and batch mode at 50- to 200-milligram scale to provide good to excellent yields. [ABSTRACT FROM AUTHOR]

Summary: Patients with multiple myeloma (MM) have improved treatment options, including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Despite their efficacy, increased rates of cardiovascular (CV) complications occur in patients exposed to some of these therapies. While previous research has focused on identifying the toxicities inherent to each specific agent, the CV side effects may be potentiated by the combination of PIs and IMiDs plus dexamethasone. We present a patient with MM with recurrent cardiotoxicity only when exposed to combination PI and IMiD‐based therapy. We also review the literature in this context, and propose a potential algorithm for cardiotoxicity prevention in this population. [ABSTRACT FROM AUTHOR]

IL-36 cytokines signal through the IL-36 re-ceptor (IL-36R) and a shared subunit, IL-1 receptor accessory protein (IL-1RAcP). The activation mechanism for the IL-36 pathway is proposed to be similar to that of IL-1 in that an IL-36R agonist (IL-36α, IL-36β, or IL-36γ) forms a binary complex with IL-36R, which then recruits IL-1RAcP. Recent studies have shown that IL-36R interacts with IL-1RAcP even in the absence of an agonist. To elucidate the IL-36 activation mechanism, we considered all possible binding events for IL-36 ligands/receptors and examined these events in direct binding assays. Our results indicated that the agonists bind the IL-36R extracellular domain with micromolar affinity, but do not detectably bind IL-1RAcP. Using surface plasmon resonance (SPR), we found that IL-1RAcP also does not bind IL-36R when no agonist is present. In the presence of IL-36α, however, IL-1RAcP bound IL-36R strongly. These results suggested that the main pathway to IL-36R/IL-36α/IL-1RAcP ternary complex is through the IL-36R/IL-36α binary complex, which recruits IL-1RAcP. We could not measure the binding affinity of IL-36R to IL-1RAcP directly, so we engineered a fragment crystallizable (Fc) linked construct to induce IL-36R-IL-1RAcP heterodimerization and predicted the binding affinity during a complete thermodynamic cycle to be 74 μM. The SPR analysis also indicated that the IL-36R antagonist IL-36Ra binds IL-36R with higher affinity and a much slower off rate than the IL-36R agonists, shedding light on IL-36 pathway inhibition. Our results reveal the landscape of IL-36 ligand and receptor interactions, improving our understanding of IL-36 pathway activation and inhibition. [ABSTRACT FROM AUTHOR]

Marizomib ( MRZ) is an irreversible, pan-subunit proteasome inhibitor ( PI) in clinical development for relapsed/refractory multiple myeloma ( RRMM) and glioma. This study analysed MRZ, pomalidomide ( POM) and low-dose dexamethasone (Lo- DEX) [ PMD] in RRMM to evaluate safety and determine the maximum tolerated dose ( MTD) and/or recommended Phase 2 dose ( RP2D). Intravenous MRZ (0·3-0·5 mg/m2) was administered over 2 h on days 1, 4, 8, 11; POM (3-4 mg) on days 1-21; and Lo- DEX (5 or 10 mg) on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22 and 23 of every 28-day cycle. Thirty-eight patients were enrolled that had received a median of 4 (range 1-10) prior lines of therapy; all patients received prior lenalidomide and bortezomib. No dose-limiting toxicities ( DLTs) were observed and 0·5 mg/m2 MRZ was determined to be the RP2D. The most common treatment-related ≥Grade 3 adverse events were: neutropenia (11/38 patients: 29%), pneumonia (4/38 patients 11%), anaemia (4/38 patients; 11%) and thrombocytopenia (4/38 patients; 11%). The overall response rate and clinical benefit rate was 53% (19/36) and 64% (23/36), respectively. In conclusion, PMD was well tolerated and demonstrated promising activity in heavily pre-treated, high-risk RRMM patients. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM), a B cell malignancy characterized by clonal proliferation of plasma cells in the bone marrow, remains incurable despite the use of novel and conventional therapies. In this study, we demonstrated MM cell cytotoxicity triggered by realgar (REA; As4S4) nanoparticles (NREA) versus Arsenic trioxide (ATO) against MM cell lines and patient cells. Both NREA and ATO showed in vivo anti-MM activity, resulting in significantly decreased tumour burden. The anti-MM activity of NREA and ATO is associated with apoptosis, evidenced by DNA fragmentation, depletion of mitochondrial membrane potential, cleavage of caspases and antiapoptotic proteins. NREA induced 2G/M cell cycle arrest and modulation of cyclin B1, p53 (TP53), p21 (CDKN1A), Puma (BBC3) and Wee-1 (WEE1). Moreover, NREA induced modulation of key regulatory molecules in MM pathogenesis including JNK activation, c-Myc (MYC), BRD4, and histones. Importantly, NREA, but not ATO, significantly depleted the proportion and clonogenicity of the MM stem-like side population, even in the context of the bone marrow stromal cells. Finally, our study showed that both NREA and ATO triggered synergistic anti-MM activity when combined with lenalidomide or melphalan. Taken together, the anti-MM activity of NREA was more potent compared to ATO, providing the preclinical framework for clinical trials to improve patient outcome in MM. [ABSTRACT FROM AUTHOR]

Background: Maraviroc (MVC) is a candidate drug for HIV preexposure prophylaxis (PrEP).Objective: To assess the safety and tolerability of MVC-containing PrEP over 48 weeks in U.S. women at risk for HIV infection.Design: Phase 2 randomized, controlled, double-blinded study of 4 antiretroviral regimens used as PrEP. (ClinicalTrials.gov: NCT01505114).Setting: 12 clinical research sites of the HIV Prevention Trials Network and AIDS Clinical Trials Group.Participants: HIV-uninfected women reporting condomless vaginal or anal intercourse with at least 1 man with HIV infection or unknown serostatus within 90 days.Intervention: MVC only, MVC-emtricitabine (FTC), MVC-tenofovir disoproxil fumarate (TDF), and TDF-FTC (control).Measurements: At each visit, clinical and laboratory (including HIV) assessments were done. Primary outcomes were grade 3 and 4 adverse events and time to permanent discontinuation of the study regimen. All randomly assigned participants were analyzed according to their original assignment.Results: Among 188 participants, 85% completed follow-up, 11% withdrew early, and 4% were lost to follow-up; 19% discontinued their regimen prematurely. The number discontinuing and the time to discontinuation did not differ among regimens. Grade 3 or 4 adverse events occurred in 5 (MVC), 13 (MVC-FTC), 9 (MVC-TDF), and 8 (TDF-FTC) participants; rates did not differ among regimens. One death (by suicide) occurred in the MVC-TDF group but was judged not to be related to study drugs. Of available plasma samples at week 48 (n = 126), 60% showed detectable drug concentrations. No new HIV infections occurred.Limitations: Participants were not necessarily at high risk for HIV infection. The regimen comprised 3 pills taken daily. The study was not powered for efficacy.Conclusion: Maraviroc-containing PrEP regimens were safe and well-tolerated compared with TDF-FTC in U.S. women. No new HIV infections occurred, although whether this was due to study drugs or low risk in the population is uncertain. Maraviroc-containing PrEP for women may warrant further study.Primary Funding Source: National Institutes of Health. [ABSTRACT FROM AUTHOR]

Many recent thrust fault earthquakes have involved coseismic surface faulting and surface folding strains. This multifaceted nature of active thrust sheet deformation can make attempts to quantify slip and slip rates from surface strains challenging and uncertain. We present new methods for integrating records of surface deformation, subsurface structure, and geochronology to investigate active deformation over multiple rupture cycles across the Southern Junggar Thrust in the southern Junggar Basin, NW China, from ~225 ka to present. Fluvial terraces preserve records of surface faulting as a prominent fault scarp where the Southern Junggar Thrust is surface-emergent. Terraces also exhibit progressive folding strains across fold scarps that are spatially coincident with subsurface fault-bend folds--constrained by seismic reflection data--along the Southern Junggar Thrust. We quantify the fault slip at depth implied by fold scarp relief along Holocene-aged terraces, and the results are corroborated by independent estimates of slip implied by fault scarp relief for the same terraces. Older terraces exhibit a distinct fanning of dips across fold scarps, suggesting active fault-bend folding kinematics involving a component of limb rotation. We developed quantitative relations for fault-bend folds between fault slip and fold dip using a mechanical, forward modeling approach. Using this novel method, we show how Southern Junggar Thrust slip rate has decelerated markedly, from ~4.1 mm/yr in the middle Quaternary to ~1.2 mm/yr throughout the Holocene. These results provide new insight into natural fault-bend folding kinematics and define innovative methods for elucidating accurate estimates of fault slip and slip rates from terrace folds in active thrust sheets. [ABSTRACT FROM AUTHOR]

Peripheral neuropathy ( PN) is the most troublesome adverse event associated with the proteasome inhibitor bortezomib. Studies suggest an inflammatory aetiology for bortezomib-induced PN (Bi PN) and it has been hypothesized that reducing inflammation with concomitant dexamethasone may reduce Bi PN incidence and/or severity. We retrospectively analysed PN rates from 32 studies (2697 patients with previously untreated multiple myeloma) incorporating bortezomib and differing dexamethasone schedules: partnered dosing (days of and after bortezomib), weekly dosing, and other dosing schedules (e.g. days 1-4, 8-11). Pooled overall PN rates were 45·5%, 63·9%, and 47·5%, respectively, with 5·3%, 11·0%, and 9·6% grade ≥3. Adjusting for potential confounders (age, gender, presence of thalidomide, bortezomib treatment duration), PN rates in patients on partnered dosing schedules appeared lower than in patients on weekly or other dosing schedules. Analyses conducted using patient-level data suggest that cumulative dexamethasone dose, a potential confounding factor, is unlikely to have influenced the analyses. Findings were similar in a separate pooled analysis excluding data from regimens incorporating thalidomide, when pooled overall PN rates were 50·1%, 63·9%, and 48·3%, respectively, with 4·2%, 11·0%, and 8·6% grade ≥3. These findings suggest that partnered dexamethasone dosing may result in less severe Bi PN compared with alternative dexamethasone dosing schedules. [ABSTRACT FROM AUTHOR]

Given the importance of amines in a large number of biologically active natural products, active pharmaceutical ingredients, agrochemicals, and functional materials, the development of efficient C-N bond-forming methods with wide substrate scope continues to be at the frontier of research in synthetic organic chemistry. Here, we present a general and fundamentally new synthetic approach for the direct, transition-metal-free preparation of symmetrical and unsymmetrical diaryl-, arylalkyl-, and dialkylamines that relies on the facile single or double addition of readily available C-nucleophiles to the nitrogen atom of bench-stable electrophilic aminating agents. Practical single and double polarity reversal (i.e., umpolung) of the nitrogen atom is achieved using sterically and electronically tunable ketomalonate-derived imines and oximes. Overall, this novel approach represents an operationally simple, scalable, and environmentally friendly alternative to transition-metal-catalyzed C-N cross-coupling methods that are currently used to access structurally diverse secondary amines. [ABSTRACT FROM AUTHOR]

The oral proteasome inhibitor ixazomib is approved in the United States, European Union and other countries, in combination with oral lenalidomide and dexamethasone (Rd), for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was based on the global, randomised, double-blind, placebo-controlled Phase III TOURMALINE- MM1 study of ixazomib-Rd ( IRd) versus placebo-Rd in patients with relapsed/refractory multiple myeloma. IRd resulted in a significant improvement in progression-free survival versus placebo-Rd (median: 20·6 vs. 14·7 months; hazard ratio 0·74). Common toxicities observed more commonly with IRd versus placebo-Rd were thrombocytopenia, nausea, vomiting, diarrhoea, constipation, rash, peripheral neuropathy, peripheral oedema and back pain; these were generally grade 1/2 in severity except for thrombocytopenia (19% vs. 9% grade 3/4), which appeared manageable and reversible, with no differences between arms in significant bleeding or dose discontinuations. No cumulative toxicities were observed, indicating the potential feasibility of long-term IRd treatment. Safety data from TOURMALINE- MM1 are reviewed and guidance for managing clinically relevant adverse events associated with IRd is provided. Most toxicities were manageable with supportive care and dose delays or reductions as needed. Clinicians should be aware of and understand these potential side effects to optimise and prolong patient benefit. [ABSTRACT FROM AUTHOR]

Objective: Alcohol-related liver disease (ARLD) is the leading cause of alcohol-related mortality in the UK. Helping patients with ARLD to stop drinking is an important treatment goal. The aim of this study is to explore baclofen's utility in maintaining abstinence.Methods-A Prospective Cohort Study: Patients with ARLD were commenced on baclofen; the dose was titrated according to tolerability and response up to 30 mg three times daily. Severity of physical dependence and biochemical markers of liver injury were assessed at baseline, 3 months, and 12 months.Results: Length of follow-up differed. Of 219 patients in the original cohort, 186 and 113 were evaluated at 3 months and 12 months, respectively. Loss to follow-up was due to death, baclofen non-adherence, and failure to attend appointments. Comparison of baseline and 1-year biochemical markers showed significant reductions in GGT (median change = 82.0; 95% CI = -149.0 to -40.0; p < 0.0005), ALT (-10.5; 95% CI = -16.5 to -5.0; p = 0.001), and bilirubin (-4.5; 95% CI = -7.0 to -2.0; p < 0.001). The proportion of eligible patients reporting complete abstinence at 3 and 12 months was 55% and 53%, respectively. A significant reduction in alcohol consumption and Severity of Alcohol Dependence Questionnaire score was observed at both follow-up time points.Conclusion: Adherence to the baclofen was good, and it had a positive impact on measures of alcohol consumption. A limitation of our study is its observational nature. Further randomized studies alongside investigation of dosing strategies are required. [ABSTRACT FROM AUTHOR]

With the development of ever-expanding synthetic methodologies, a medicinal chemist's toolkit continues to swell. However, with finite time and resources as well as a growing understanding of our field's environment impact, it is critical to refine what can be made to what should be made. This review seeks to highlight multiple cheminformatic approaches in drug discovery that can influence and triage design and execution impacting the likelihood of rapidly generating high-value molecules in a more sustainable manner. This strategy gives chemists the tools to design and refine vast libraries, stress "druglikeness", and rapidly identify SAR trends. Project success, i.e., identification of a clinical candidate, is then reached faster with fewer molecules with the farther-reaching ramification of using fewer resources and generating less waste, thereby helping "green" our field. [ABSTRACT FROM AUTHOR]

Background: Recombinant human growth hormone (rhGH) treatment in children is usually prescribed using actual body weight. This may result in inappropriately high doses in obese children. Methods: Retrospective audit of all paediatric patients treated with rhGH 2010–14 at a tertiary paediatric hospital in the UK. Change in height SDS and IGF-I SDS during the first year of treatment was stratified by initial BMI SDS in a mixed cohort, and a subgroup of GH deficient (GHD) patients. Alternative doses for those BMI SDS ≥2.0 (Obese) were calculated using BSA, IBW and LBW. Results: 354 patients (133 female) received rhGH, including 213 (60.2%) with GHD. Obesity was present in 40 patients (11.3%) of the unselected cohort, and 32 (15.0%) of the GHD cohort. For GHD patients, gain in height SDS was directly related to BMI SDS, except in obese patients (p<0.05). For both the entire cohort, and GHD patients only, IGF-1 SDS was significantly higher in obese patients (p<0.0001 for both groups). Cross sectional data identified 265 children receiving rhGH, 81 (30.5%) with a BMI-SDS ≥1.75. Alternate prescribing strategies for rhGH prescribing in obese patients suggest a saving of 27% - 38% annually. Conclusions: Gain in IGF-I SDS is greater in obese children, and is likely to be related to relatively higher doses of rhGH. Additional gain in height was not achieved at the higher doses administered to obese children. Alternative dosing strategies in the obese patient population should be examined in rigorous clinical trials. [ABSTRACT FROM AUTHOR]

Background: The China Continuation study was a separate regional expansion of the global, double-blind, placebo-controlled, randomized phase III TOURMALINE-MM1 study of ixazomib plus lenalidomide-dexamethasone (Rd) in patients with relapsed/refractory multiple myeloma (RRMM) following one to three prior therapies. Methods: Patients were randomized (1:1) to receive ixazomib 4.0 mg or placebo on days 1, 8, and 15, plus lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg on days 1, 8, 15, and 22, in 28-day cycles. Randomization was stratified according to number of prior therapies, disease stage, and prior proteasome inhibitor exposure. The primary endpoint was progression-free survival (PFS). In total, 115 Chinese patients were randomized (57 ixazomib-Rd, 58 placebo-Rd). Results: At the preplanned final analysis for PFS, after median PFS follow-up of 7.4 and 6.9 months, respectively, PFS was improved with ixazomib-Rd versus placebo-Rd (median 6.7 vs 4.0 months; HR 0.598; p = 0.035). At the preplanned final analysis of overall survival (OS), after median follow-up of 20.2 and 19.1 months, respectively, OS was improved with ixazomib-Rd versus placebo-Rd (median 25.8 vs 15.8 months; HR 0.419; p = 0.001). On the ixazomib-Rd and placebo-Rd arms, respectively, 38 (67%) and 43 (74%) patients reported grade ≥3 adverse events (AEs), 19 (33%) and 18 (31%) reported serious AEs, and 4 (7%) and 5 (9%) died on-study. The most frequent grade 3/4 AEs were thrombocytopenia (18%/7% vs 14%/5%), neutropenia (19%/5% vs 19%/2%), and anemia (12%/0 vs 26%/2%). Conclusions: This study demonstrated that PFS and OS were significantly improved with ixazomib-Rd versus placebo-Rd, with limited additional toxicity, in patients with RRMM. [ABSTRACT FROM AUTHOR]

Marizomib, a natural marine product, is an irreversible proteasome inhibitor currently under investigation in relapsed-refractory multiple myeloma ( RRMM) and malignant glioma. Central nervous system-multiple myeloma ( CNS- MM) is a rare manifestation of extra-medullary disease with few therapeutic options, highlighting the unmet clinical need in these patients. Marizomib demonstrated encouraging activity in RRMM and has emerging clinical activity in glioma, making it a potential CNS- MM therapeutic intervention. Herein, we present two patients with RRMM and CNS involvement who benefited from marizomib-based therapy. These cases provide the first proof of principle for further exploring marizomib in CNS- MM patients. [ABSTRACT FROM AUTHOR]

Herein we disclose SAR studies of a series of dimethylamino pyrrolidines which we recently reported as novel inhibitors of the PRC2 complex through disruption of EED/H3K27me3 binding. Modification of the indole and benzyl moieties of screening hit 1 provided analogs with substantially improved binding and cellular activities. This work culminated in the identification of compound 2 , our nanomolar proof-of-concept (PoC) inhibitor which provided on-target tumor growth inhibition in a mouse xenograft model. X-ray crystal structures of several inhibitors bound in the EED active-site are also discussed. [ABSTRACT FROM AUTHOR]

p53-related protein kinase (TP53RK, also known as PRPK) is an upstream kinase that phosphorylates (serine residue Ser15) and mediates p53 activity. Here we show that TP53RK confers poor prognosis in multiple myeloma (MM) patients, and, conversely, that TP53RK knockdown inhibits p53 phosphorylation and triggers MM cell apoptosis, associated with downregulation of c-Myc and E2F-1-mediated upregulation of proapoptotic Bim. We further demonstrate that TP53RK downregulation also triggers growth inhibition in p53-deficient and p53-mutant MM cell lines and identify novel downstream targets of TP53RK including ribonucleotide reductase-1, telomerase reverse transcriptase, and cyclin-dependent kinase inhibitor 2C. Our previous studies showed that immunomodulatory drugs (IMiDs) downregulate p21 and trigger apoptosis in wild-typep53 MM.1S cells, Importantly, we demonstrate by pull-down, nuclear magnetic resonance spectroscopy, differential scanning fluorimetry, and isothermal titration calorimetry that IMiDs bind and inhibit TP53RK, with biologic sequelae similar to TP53RK knockdown. Our studies therefore demonstrate that either genetic or pharmacological inhibition of TP53RK triggers MM cell apoptosis via both p53-Myc axis-dependent and axis-independent pathways, validating TP53RK as a novel therapeutic target in patients with poor-prognosis MM. [ABSTRACT FROM AUTHOR]

p53-related protein kinase (TP53RK, also known as PRPK) is an upstream kinase that phosphorylates (serine residue Ser15) and mediates p53 activity. Here we show that TP53RK confers poor prognosis in multiple myeloma (MM) patients, and, conversely, that TP53RK knockdown inhibits p53 phosphorylation and triggers MM cell apoptosis, associated with downregulation of c-Myc and E2F-1-mediated upregulation of pro-apoptotic Bim. We further demonstrate that TP53RK downregulation also triggers growth inhibition in p53-deficient and p53-mutant MM cell lines and identify novel downstream targets of TP53RK including ribonucleotide reductase-1, telomerase reverse transcrip-tase, and cyclin-dependent kinase inhibitor 2C. Our previous studies showed that immunomodulatory drugs (IMiDs) downregulate p21 and trigger apoptosis in wild-type-p53 MM. 1S cells, Importantly, we demonstrate by pull-down, nuclear magnetic resonance spectroscopy, differential scanning f luorimetry, and isothermal titration calorimetry that IMiDs bind and inhibit TP53RK, with biologic sequelae similar to TP53RK knockdown. Our studies therefore demonstrate that either genetic or pharmacological inhibition of TP53RK triggers MM cell apoptosis via both p53-Myc axis-dependent and axis-independent pathways, validating TP53RK as a novel therapeutic target in patients with poor-prognosis MM. [ABSTRACT FROM AUTHOR]

Background: Maraviroc (MVC) is a candidate for human immunodeficiency virus (HIV) pre-exposure prophylaxis.Methods: Phase 2 48-week safety/tolerability study was conducted, comparing 4 regimens: MVC alone, MVC plus emtricitabine (FTC), MVC plus tenofovir disoproxil fumarate (TDF), and TDF plus FTC. Eligible participants were HIV-uninfected men and transgender women reporting condomless anal intercourse with ≥1 HIV-infected or unknown-serostatus man within 90 days. At each visit, assessments, laboratory testing, and counseling were done. Analyses were intention to treat.Results: Among 406 participants, 84% completed follow-up, 7% stopped early, and 9% were lost to follow-up; 9% discontinued their regimen early. The number discontinuing and the time to discontinuation did not differ among study regimens (P = .60). Rates of grade 3-4 adverse events did not differ among regimens (P = .37). In a randomly selected subset, 77% demonstrated detectable drug concentrations at week 48. Five participants acquired HIV infection (4 MVC alone, 1 MVC + TDF; overall annualized incidence, 1.4% [95% confidence interval, .5%-3.3%], without differences by regimen; P = .32); 2 had undetectable drug concentrations at every visit, 2 had low concentrations at the seroconversion visit, and 1 had variable concentrations.Conclusions: MVC-containing regimens were safe and well tolerated compared with TDF + FTC; this study was not powered for efficacy. Among those acquiring HIV infection, drug concentrations were absent, low, or variable. MVC-containing regimens may warrant further study for pre-exposure prophylaxis.Clinical Trials Registration: NCT01505114. [ABSTRACT FROM AUTHOR]