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Autologous hematopoietic stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). However, many individuals are unable to collect optimal CD34 + hematopoietic stem and progenitor cell (HSPC) numbers with granulocyte colony-stimulating factor (G-CSF) mobilization. Motixafortide is a novel cyclic-peptide CXCR4 inhibitor with extended in vivo activity. The GENESIS trial was a prospective, phase 3, double-blind, placebo-controlled, multicenter study with the objective of assessing the superiority of motixafortide + G-CSF over placebo + G-CSF to mobilize HSPCs for ASCT in MM. The primary endpoint was the proportion of patients collecting ≥6 × 10 6 CD34 + cells kg –1 within two apheresis procedures; the secondary endpoint was to achieve this goal in one apheresis. A total of 122 adult patients with MM undergoing ASCT were enrolled at 18 sites across five countries and randomized (2:1) to motixafortide + G-CSF or placebo + G-CSF for HSPC mobilization. Motixafortide + G-CSF enabled 92.5% to successfully meet the primary endpoint versus 26.2% with placebo + G-CSF (odds ratio (OR) 53.3, 95% confidence interval (CI) 14.12–201.33, P  < 0.0001). Motixafortide + G-CSF also enabled 88.8% to meet the secondary endpoint versus 9.5% with placebo + G-CSF (OR 118.0, 95% CI 25.36–549.35, P  < 0.0001). Motixafortide + G-CSF was safe and well tolerated, with the most common treatment-emergent adverse events observed being transient, grade 1/2 injection site reactions (pain, 50%; erythema, 27.5%; pruritis, 21.3%). In conclusion, motixafortide + G-CSF mobilized significantly greater CD34 + HSPC numbers within two apheresis procedures versus placebo + G-CSF while preferentially mobilizing increased numbers of immunophenotypically and transcriptionally primitive HSPCs. Trial Registration: ClinicalTrials.gov , NCT03246529 The phase 3 GENESIS trial reports the superiority of the novel CXCR4 inhibitor motixafortide with G-CSF in mobilizing hematopoietic progenitor cells for autologous stem cell transplantation in multiple myeloma.

Lifelong HIV antiretroviral therapy (ART) has prompted an interest in two-drug regimens to minimise cumulative drug exposure and toxicities. The safety, tolerability, and efficacy of dolutegravir and rilpivirine suggest potential compatibility and effectiveness as a two-drug regimen. We aimed to investigate this two-drug regimen in a phase 3 study. We identically designed SWORD-1 and SWORD-2, which were open-label, parallel-group, multicentre, phase 3, randomised, non-inferiority studies in 12 countries evaluating efficacy and safety of once-daily dolutegravir 50 mg plus rilpivirine 25 mg versus current ART regimen (CAR). We included participants aged 18 years or older who were on first or second ART with stable plasma HIV-1 RNA (viral load <50 copies per mL) for 6 months or longer at screening. We randomly assigned participants (1:1) with stratification by third-agent class, age, and planned participation in a bone mineral density substudy. The primary endpoint was proportion of participants with viral load lower than 50 copies per mL at week 48 among those individuals who received one or more doses of study medication. Investigators monitored adverse events to assess safety. These trials are registered with ClinicalTrials.gov, numbers NCT02429791 (SWORD-1) and NCT02422797 (SWORD-2). We screened for participants from April 14, 2015, to Oct 15, 2015, for SWORD-1 and from April 21, 2015, to Sept 25, 2015, for SWORD-2. We randomly assigned 516 participants to dolutegravir-rilpivirine and 512 to continue with CAR. At week 48 (last patient visit was Nov 22, 2016), in the pooled analysis of the intention-to-treat population, 95% of participants had viral loads lower than 50 copies per mL in each group (486 of 513 in the dolutegravir-rilpivirine group vs 485 of 511 in the CAR group), with an adjusted treatment difference of −0·2% (95% CI −3·0 to 2·5) and showed non-inferiority with a predefined margin of −8%. 395 (77%) of 513 participants in the dolutegravir-rilpivirine group and 364 (71%) of 511 participants in the CAR group reported adverse events. The most common adverse events were nasopharyngitis (49 [10%] for dolutegravir-rilpivirine vs 50 [10%] for CAR) and headache (41 [8%] vs 23 [5%]). More participants taking dolutegravir-rilpivirine (17 [3%]) reported adverse events leading to withdrawal than did participants taking CAR (three [<1%]). Dolutegravir-rilpivirine was non-inferior to CAR over 48 weeks in participants with HIV suppression and showed a safety profile consistent with its components. Results support the use of this two-drug regimen to maintain HIV suppression. ViiV Healthcare and Janssen Pharmaceutica NV.

Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms mediating these effects are poorly understood. Here we identify the glucocorticoid receptor (GR) target gene, serum- and glucocorticoid-inducible kinase 1 (SGK1), as one such mechanism. Using a human hippocampal progenitor cell line, we found that a small molecule inhibitor for SGK1, GSK650394, counteracted the cortisol-induced reduction in neurogenesis. Moreover, gene expression and pathway analysis showed that inhibition of the neurogenic Hedgehog pathway by cortisol was SGK1-dependent. SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation. Experiments combining the inhibitor for SGK1, GSK650394, with the GR antagonist, RU486, demonstrated that SGK1 was involved in the cortisol-induced reduction in progenitor proliferation both downstream of GR, by regulating relevant target genes, and upstream of GR, by increasing GR function. Corroborating the relevance of these findings in clinical and rodent settings, we also observed a significant increase of SGK1 mRNA in peripheral blood of drug-free depressed patients, as well as in the hippocampus of rats subjected to either unpredictable chronic mild stress or prenatal stress. Our findings identify SGK1 as a mediator for the effects of cortisol on neurogenesis and GR function, with particular relevance to stress and depression.

Phase 2 studies with upadacitinib, a selective Janus kinase 1 (JAK1) inhibitor, have shown safety and efficacy in the treatment of patients with active rheumatoid arthritis. We did this study to further assess the safety and efficacy of upadacitinib in patients with an inadequate response to biologic disease-modifying anti-rheumatic drugs (bDMARDs). We did this double-blind, randomised controlled phase 3 trial at 153 sites in 26 countries. Patients were aged 18 years or older, had active rheumatoid arthritis and previous inadequate response or intolerance to bDMARDs, and were receiving concomitant background conventional synthetic DMARDS (csDMARDs). We randomly assigned patients (2:2:1:1) by interactive response technology to receive once-daily oral extended-release upadacitinib 15 mg or 30 mg or placebo for 12 weeks, followed by upadacitinib 15 mg or 30 mg from week 12 onwards. The two separate primary endpoints were the proportions of patients achieving a 20% improvement in American College of Rheumatology criteria (ACR20) at week 12 and the proportion of patients achieving a 28-joint disease activity score using C-reactive protein (DAS28[CRP]) of 3·2 or less at week 12. Efficacy and safety analyses were done in the modified intention-to-treat population of all patients who received at least one dose of study drug. Data are presented up to week 24 of this ongoing study. The trial is registered with ClinicalTrials.gov (NCT02706847). Between March 15, 2016, and Jan 10, 2017, 499 patients were randomly assigned (n=165 upadacitinib 15 mg; n=165 upadacitinib 30 mg; n=85 placebo then upadacitinib 15 mg; and n=84 placebo then upadacitinib 30 mg) and one patient was withdrawn from the 15 mg upadacitinib group before the start of study treatment. Mean disease duration was 13·2 years (SD 9·5); 235 (47%) of 498 patients had received one previous bDMARD, 137 (28%) had received two, and 125 (25%) had received at least three; 451 (91%) patients completed treatment up to week 12 and 419 (84%) patients completed treatment up to week 24. At week 12, ACR20 was achieved by 106 (65%; 95% CI 57–72) of 164 patients receiving upadacitinib 15 mg and 93 (56%; 49–64) of 165 patients receiving upadacitinib 30 mg compared with 48 (28%; 22–35) of 169 patients receiving placebo (p<0·0001 for each dose vs placebo). DAS28(CRP) of 3·2 or less was achieved by 71 (43%; 95% CI 36–51) of 164 patients receiving upadacitinib 15 mg and 70 (42%; 35–50) of 165 patients receiving upadacitinib 30 mg versus 24 (14%; 9–20) of 169 patients receiving placebo (p<0·0001 for each dose vs placebo). Up to week 12, overall numbers of patients with adverse events were similar for the placebo group (95 [56%] of 169) and the upadacitinib 15 mg group (91 [55%] of 164), but higher in the upadacitinib 30 mg group (111 [67%] of 165). At week 12, the most common adverse events occurring in at least 5% of patients in any treatment group were upper respiratory tract infection (13 [8%] of 169 in the placebo group; 13 [8%] of 164 in the upadacitinib 15 mg group; ten [6%] of 165 in the upadacitinib 30 mg group), nasopharyngitis (11 [7%]; seven [4%]; nine [5%]), urinary tract infection (ten [6%]; 15 [9%]; nine [5%]), and worsening of rheumatoid arthritis (ten [6%]; four [2%]; six [4%]). The number of patients with serious adverse events was higher in the upadacitinib 30 mg group (12 [7%]) than in the upadacitinib 15 mg group (eight [5%]); no serious adverse events were reported in patients receiving placebo. More patients in the upadacitinib 30 mg group had serious infections, herpes zoster, and adverse events leading to discontinuation than in the upadacitinib 15 mg and placebo groups. During the placebo-controlled phase of the study, one case of pulmonary embolism, three malignancies, one major adverse cardiovascular event, and one death were reported in patients receiving upadacitinib; none were reported in patients receiving placebo. Both doses of upadacitinib led to rapid and significant improvements compared with placebo over 12 weeks in patients with refractory rheumatoid arthritis. AbbVie Inc.

Upadacitinib is a selective inhibitor of Janus kinase 1 and was efficacious in phase 2 studies in patients with moderate-to-severe rheumatoid arthritis. We aimed to assess the efficacy of upadacitinib in patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). This study is a double-blind, placebo-controlled trial at 150 sites in 35 countries. We enrolled patients aged 18 years or older with active rheumatoid arthritis for 3 months or longer, who had received csDMARDs for at least 3 months with a stable dose for at least 4 weeks before study entry, and had an inadequate response to at least one of the following csDMARDs: methotrexate, sulfasalazine, or leflunomide. Using interactive response technology, we randomly assigned patients receiving stable background csDMARDs (2:2:1:1) to receive a once-daily extended-release formulation of upadacitinib 15 mg or 30 mg, or placebo, for 12 weeks. Patients, investigators, and the funder were masked to allocation. After 12 weeks, patients taking placebo received 15 mg or 30 mg of upadacitinib once daily, according to the prespecified randomisation assignment. The primary endpoints were the proportion of patients at week 12 who achieved 20% improvement in American College of Rheumatology criteria (ACR20), and a 28-joint disease activity score using C-reactive protein (DAS28[CRP]) of 3·2 or less. We did efficacy analyses in the full analysis set of all randomly assigned patients who received at least one dose of study drug, and used non-responder imputation for assessment of the primary outcomes. This study is registered with ClinicalTrials.gov, number NCT02675426. Between Dec 17, 2015, and Dec 22, 2016, 1083 patients were assessed for eligibility, of whom 661 were recruited and randomly assigned to receive upadacitinib 15 mg (n=221), upadacitinib 30 mg (n=219), or placebo (n=221). All patients received at least one dose of study drug, and 618 (93%) completed 12 weeks of treatment. At week 12, ACR20 was achieved by 141 (64%; 95% CI 58–70) of 221 patients receiving upadacitinib 15 mg and 145 (66%; 60–73) of 219 patients receiving upadacitinib 30 mg, compared with 79 (36%; 29–42) of 221 patients receiving placebo (p<0·0001 for each dose vs placebo). DAS28(CRP) of 3·2 or less was met by 107 (48%; 95% CI 42–55) patients receiving upadacitinib 15 mg and 105 (48%; 41–55) patients receiving upadacitinib 30 mg, compared with 38 (17%; 12–22) patients receiving placebo (p<0·0001 for each dose vs placebo). Adverse events were reported in 125 (57%) of 221 patients receiving upadacitinib 15 mg, 118 (54%) of 219 patients receiving upadacitinib 30 mg, and 108 (49%) of 221 patients receiving placebo. The most frequently reported adverse events (≥5% of patients in any group) were nausea (16 [7%] of 221 in the upadacitinib 15 mg group; three [1%] of 219 in the upadacitinib 30 mg group; and seven [3%] of 221 in the placebo group), nasopharyngitis (12 [5%]; 13 [6%]; and nine [4%]), upper respiratory tract infection (12 [5%]; 12 [5%]; and nine [4%]), and headache (nine [4%]; seven [3%]; and 12 [5%]). More infections were reported for upadacitinib (64 [29%] of 221 patients receiving 15 mg and 69 [32%] of 219 patients receiving 30 mg) versus placebo (47 [21%] of 221 patients). There were three herpes zoster infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, and one [<1%] in the upadacitinib 30 mg group) and one primary varicella zoster virus infection (one [<1%] in the upadacitinib 30 mg group), two malignancies (both in the upadacitinib 30 mg group), one adjudicated major adverse cardiovascular event (in the upadacitinib 30 mg group), and five serious infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, three [1%] in the upadacitinib 30 mg group). No deaths were reported during the trial. Patients with moderately to severely active rheumatoid arthritis who received upadacitinib (15 mg or 30 mg) in combination with csDMARDs showed significant improvements in clinical signs and symptoms. AbbVie Inc.

Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficient transgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC.

Standard chemotherapies for diffuse large B-cell lymphoma (DLBCL), based on the induction of exogenous DNA damage and oxidative stress, are often less effective in the presence of increased MYC and BCL-2 levels, especially in the case of double hit (DH) lymphomas harboring rearrangements of the MYC and BCL-2 oncogenes, which enrich for a patient’s population characterized by refractoriness to anthracycline-based chemotherapy. Here we hypothesized that adaptive mechanisms to MYC-induced replicative and oxidative stress, consisting in DNA damage response (DDR) activation and BCL-2 overexpression, could represent the biologic basis of the poor prognosis and chemoresistance observed in MYC/BCL-2-positive lymphoma. We first integrated targeted gene expression profiling (T-GEP), fluorescence in situ hybridization (FISH) analysis, and characterization of replicative and oxidative stress biomarkers in two independent DLBCL cohorts. The presence of oxidative DNA damage biomarkers identified a poor prognosis double expresser (DE)-DLBCL subset, characterized by relatively higher BCL-2 gene expression levels and enrichment for DH lymphomas. Based on these findings, we tested therapeutic strategies based on combined DDR and BCL-2 inhibition, confirming efficacy and synergistic interactions in in vitro and in vivo DH-DLBCL models. These data provide the rationale for precision-therapy strategies based on combined DDR and BCL-2 inhibition in DH or DE-DLBCL.

Current treatments for clear cell renal cell cancer (ccRCC) are insufficient because two-thirds of patients with metastases progress within two years. Here we report the identification and characterization of a cancer stem cell (CSC) population in ccRCC. CSCs are quantitatively correlated with tumor aggressiveness and metastasis. Transcriptional profiling and single cell sequencing reveal that these CSCs exhibit an activation of WNT and NOTCH signaling. A significant obstacle to the development of rational treatments has been the discrepancy between model systems and the in vivo situation of patients. To address this, we use CSCs to establish non-adherent sphere cultures, 3D tumor organoids, and xenografts. Treatment with WNT and NOTCH inhibitors blocks the proliferation and self-renewal of CSCs in sphere cultures and organoids, and impairs tumor growth in patient-derived xenografts in mice. These findings suggest that our approach is a promising route towards the development of personalized treatments for individual patients. Cancer stem cells are thought to be largely resistant to treatment and can be responsible for tumour recurrence. Here, using renal cancer organoids, self-renewing sphere cultures and PDX from patients, the authors show that the proliferation of stem cells within organoids, PDX and spheres can be blocked by the concomitant inhibition of the NOTCH and WNT pathways.

Dezocine is considered to be an alternative medication for managing postoperative pain. The aim of this study was to assess the efficacy and safety of this drug in this regard. Medline, EMBASE and the Cochrane Central Register of Control Trials (CENTRAL) were searched to identify all randomized controlled trials (RCTs) that compare dezocine with placebo or dezocine with morphine on postoperative pain. The data were extracted and pooled using Mantel-Haenszel random effects model. Heterogeneity was tested using the I2 statistic with values >50% and Chi2 test with P ≤ 0.05 indicating obvious heterogeneity between the studies. Seven trials evaluating 665 patients were included. The number of patients with at least 50% pain relief was increased (N = 234; RR 3.04, 95% CI 2.27 to 4.08) and physician (N = 465; RR 2.84, 95% CI 1.66 to 4.84) and patient satisfaction (N = 390; RR 2.81, 95% CI 1.85 to 4.26) were improved following the administration of dezocine compared with the placebo. The effects of dezocine were similar to those of morphine in terms of the number of patients reporting at least 50% pain relief within 2-6 h after surgery (N = 235; RR 1.29, 95% CI 1.15 to 1.46) and physician (N = 234; RR 1.18, 95% CI 0.93 to 1.49) and patient (N = 158; RR 1.33, 95% CI 0.93 to 1.92) satisfaction. While, the number of patients with at least 50% pain relief within 0-1 h after surgery increased following dezocine compared with morphine treatment (N = 79; RR 1.45, 95% CI 1.18 to 1.77). There was no difference in the incidence of postoperative nausea and vomiting (PONV) following dezocine treatment compared with the placebo (N = 391; RR 1.06, 95% CI 0.42 to 2.68) or morphine treatment (N = 235; RR 0.65, 95% CI 0.14 to 2.93). Dezocine is a promising analgesic for preventing postoperative pain, but further studies are required to evaluate its safety.

The objective of this study was to evaluate the longitudinal effect of enrofloxacin or tulathromycin use in calves at high risk of bovine respiratory disease (BRD) on antimicrobial resistance genes and mutation in quinolone resistance-determining regions (QRDR) in fecal E. coli . Calves at high risk of developing BRD were randomly enrolled in one of three groups receiving: (1) enrofloxacin (ENR; n = 22); (2) tulathromycin (TUL; n = 24); or (3) no treatment (CTL; n = 21). Fecal samples were collected at enrollment and at 7, 28, and 56 days after beginning treatment, cultured for Escherichia coli (EC) and DNA extracted. Isolates were screened for cephalosporin, quinolone and tetracycline resistance genes using PCR. QRDR screening was conducted using Sanger sequencing. The only resistance genes detected were aac(6′)Ib-cr (n = 13), bla -CTX-M (n = 51), bla -TEM (n = 117), tet A (n = 142) and tet B (n = 101). A significantly higher detection of gyr A mutated at position 248 at time points 7 (OR = 11.5; P value = 0.03) and 28 (OR = 9.0; P value = 0.05) was observed in the ENR group when compared to calves in the control group. Our findings support a better understanding of the potential impacts from the use of enrofloxacin in calves on the selection and persistence of resistance.