In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy ...or in combination with pembrolizumab.
Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1.
Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs–the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs–the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy.
Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.
•First-in-human phase 1 study in patients with advanced solid tumors who received vibostolimab alone or with pembrolizumab.•Vibostolimab plus pembrolizumab was well tolerated in advanced solid tumors.•Vibostolimab plus pembrolizumab demonstrated antitumor activity in patients with advanced solid tumors.
Summary
Background
There are increasing reports of paradoxical psoriasiform diseases secondary to anti‐tumour necrosis factor (TNF) agents.
Aims
To determine the risks of paradoxical psoriasiform ...diseases secondary to anti‐TNF agents in patients with inflammatory bowel disease (IBD).
Methods
A nationwide population study was performed using the Korea National Health Insurance Claim Data. A total of 50 502 patients with IBD were identified between 2007 and 2016. We compared 5428 patients who were treated with any anti‐TNF agent for more than 6 months (anti‐TNF group) and 10 856 matched controls who had never taken anti‐TNF agents (control group).
Results
Incidence of psoriasis was significantly higher in the anti‐TNF group (36.8 per 10 000 person‐years) compared to the control group (14.5 per 10 000 person‐years) (hazard ratio HR 2.357, 95% confidence interval CI 1.668‐3.331). Palmoplantar pustulosis (HR 9.355, 95% CI 2.754‐31.780) and psoriatic arthritis (HR 2.926, 95% CI 1.640‐5.218) also showed higher risks in the anti‐TNF group. In subgroup analyses, HRs for psoriasis by IBD subtype were 2.549 (95% CI 1.658‐3.920) in Crohn's disease and 2.105 (95% CI 1.155‐3.836) in ulcerative colitis. Interestingly, men and younger (10‐39 years) patients have significantly higher risks of palmoplantar pustulosis (HR 19.682 95% CI 3.867‐100.169 and HR 14.318 95% CI 2.915‐70.315, respectively), whereas women and older (≥40 years) patients showed similar rates between the two groups.
Conclusions
The risks of psoriasiform diseases are increased by anti‐TNF agents in patients with IBD. Among psoriasiform diseases, the risk of palmoplantar pustulosis shows the biggest increase particularly in male and younger patients.
Linked ContentThis article is linked to Pariente and Blondeaux, and Lee et al papers. To view these articles visit https://doi.org/10.1111/apt.14903 and https://doi.org/10.1111/apt.14917.
The purpose of this study was to examine the longitudinal effects of body size over- and underestimation and other psychosocial factors on the risk for onset of overweight (OW) or obesity (OB) 1 year ...later among US adolescents.
Participants with non-missing height and weight were drawn from the first two waves of the National Longitudinal Study of Adolescent to Adult Health (n=13,568). Multinomial logistic regressions were conducted to assess longitudinal risk factors for OW and OB onset, controlling for baseline weight status, age, race/ethnicity, parent education and family structure. Analyses were stratified by sex.
Compared with accurate body size perception, body size overestimation increased the relative risk (RR) of OW onset among women and men (RR=3.34, confidence interval (CI)=2.39-4.68; RR=6.01, CI=4.09-8.83, respectively, P<0.001) in fully adjusted models including body mass index z-scores. Body size underestimation decreased the RR of OW onset among women and men (RR= 0.08, CI=0.03-0.20; RR=0.13, CI=0.06-0.27, respectively) and OB onset (RR=0.05, CI=0.02-0.14; RR=0.19, CI=0.08-0.47, respectively, P<0.001 for all) in fully adjusted models. Dieting, extreme weight loss behaviors and skipping breakfast at Wave 1 increased the risk of OB onset by Wave 2.
Contrary to a common assumption, body size underestimation did not increase, but in fact decreased, the RR for the onset of OW and of OB among adolescents using a prospective longitudinal design. However, body size overestimation predicted onset of OW 1 year later. Body size self-concept and other psychosocial factors have an important role in risk for OW and for OB among both males and females during adolescence.
Anatomy of STEM teaching in North American universities Stains, M; Harshman, J; Barker, M K ...
Science (American Association for the Advancement of Science),
2018-Mar-30, 2018-03-30, 20180330, Letnik:
359, Številka:
6383
Journal Article
Recenzirano
Odprti dostop
Lecture is prominent, but practices vary
A large body of evidence demonstrates that strategies that promote student interactions and cognitively engage students with content (
1
) lead to gains in ...learning and attitudinal outcomes for students in science, technology, engineering, and mathematics (STEM) courses (
1
,
2
). Many educational and governmental bodies have called for and supported adoption of these student-centered strategies throughout the undergraduate STEM curriculum. But to the extent that we have pictures of the STEM undergraduate instructional landscape, it has mostly been provided through self-report surveys of faculty members, within a particular STEM discipline e.g., (
3
–
6
). Such surveys are prone to reliability threats and can underestimate the complexity of classroom environments, and few are implemented nationally to provide valid and reliable data (
7
). Reflecting the limited state of these data, a report from the U.S. National Academies of Sciences, Engineering, and Medicine called for improved data collection to understand the use of evidence-based instructional practices (
8
). We report here a major step toward a characterization of STEM teaching practices in North American universities based on classroom observations from over 2000 classes taught by more than 500 STEM faculty members across 25 institutions.
Mutations in the mouse diabetes (db) gene result in obesity and diabetes in a syndrome resembling morbid human obesity. Previous data suggest that the db gene encodes the receptor for the obese (ob) ...gene product, leptin. A leptin receptor was recently cloned from choroid plexus and shown to map to the same 6-cM interval on mouse chromosome 4 as db. This receptor maps to the same 300-kilobase interval as db, and has at least six alternatively spliced forms. One of these splice variants is expressed at a high level in the hypothalamus, and is abnormally spliced in C57BL/Ks db/db mice. The mutant protein is missing the cytoplasmic region, and is likely to be defective in signal transduction. This suggests that the weight-reducing effects of leptin may be mediated by signal transduction through a leptin receptor in the hypothalamus.
Superelastic conducting fibers with improved properties and functionalities are needed for diverse applications. Here we report the fabrication of highly stretchable (up to 1320%) sheath-core ...conducting fibers created by wrapping carbon nanotube sheets oriented in the fiber direction on stretched rubber fiber cores. The resulting structure exhibited distinct short- and long-period sheath buckling that occurred reversibly out of phase in the axial and belt directions, enabling a resistance change of less than 5% for a 1000% stretch. By including other rubber and carbon nanotube sheath layers, we demonstrated strain sensors generating an 860% capacitance change and electrically powered torsional muscles operating reversibly by a coupled tension-to-torsion actuation mechanism. Using theory, we quantitatively explain the complementary effects of an increase in muscle length and a large positive Poisson's ratio on torsional actuation and electronic properties.
Background and purpose
We investigated changes in deep gray matter (DGM) volume and its relationship to cognition and clinical factors in a large cohort of patients with neuromyelitis optica spectrum ...disorder (NMOSD) and compared them with results from multiple sclerosis (MS).
Methods
Brain magnetic resonance imaging (3 Tesla) and clinical data from 91 patients with NMOSD, 52 patients with MS and 44 healthy controls (HCs) were prospectively evaluated. Differences in DGM volumes were compared among groups. The relationships between DGM atrophy and clinical variables were also analysed.
Results
Patients with NMOSD exhibited significantly reduced thalamic volumes compared with HCs (P = 0.029), although this atrophy was less severe than that seen in patients with MS (P < 0.001). DGM atrophy was restricted to the thalamus in NMOSD, but it was broadly distributed in MS. Patients with NMOSD with cognitive impairment (CI) exhibited more severe thalamic atrophy than those with cognitive preservation (P = 0.017) and HCs (P = 0.003), whereas patients with MS with CI revealed DGM atrophy across the entire structure, with the exception of the bilateral pallidum, left hippocampus and amygdala, relative to HCs. The Expanded Disability Status Scale score was correlated with thalamic atrophy in both NMOSD and MS. Patients with NMOSD with brain lesions demonstrated more severe thalamic atrophy than did those without brain lesions and HCs (P < 0.001).
Conclusions
The DGM atrophy was less severe and more selectively distributed in NMOSD than in MS. Thalamic atrophy was associated with clinical disability, including CI, in both NMOSD and MS.
Adjuvant chemotherapy and chemoradiotherapy are some of the standards of care for gastric cancer (GC). The Adjuvant chemoRadioTherapy In Stomach Tumors (ARTIST) 2 trial compares two adjuvant ...chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II or III, node-positive GC.
The ARTIST 2 compared, in a 1:1:1 ratio, three adjuvant regimens: oral S-1 (40-60 mg twice daily 4 weeks on/2 weeks off) for 1 year, S-1 (2 weeks on/1 week off) plus oxaliplatin 130 mg/m2 every 3 weeks (SOX) for 6 months, and SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to surgery type (total or subtotal gastrectomy), pathologic stage (II or III), and Lauren histologic classification (diffuse or intestinal/mixed). The primary endpoint was disease-free survival (DFS) at 3 years; a reduction of 33% in the hazard ratio (HR) for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful. The trial is registered at clinicaltrials.gov (NCT0176146).
A total of 546 patients were recruited between February 2013 and January 2018 with 182, 181, and 183 patients in the S-1, SOX, and SOXRT arms, respectively. Median follow-up period was 47 months, with 178 DFS events observed. Estimated 3-year DFS rates were 64.8%, 74.3%, and 72.8% in the S-1, SOX, and SOXRT arms, respectively. HR for DFS in the control arm (S-1) was shorter than that in the SOX and SOXRT arms: S-1 versus SOX, 0.692 (P = 0.042) and S-1 versus SOXRT, 0.724 (P = 0.074). No difference in DFS was found between SOX and SOXRT (HR 0.971; P = 0.879). Adverse events were as anticipated in each arm, and were generally well-tolerated and manageable.
In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy. The addition of radiotherapy to SOX did not significantly reduce the rate of recurrence after D2 gastrectomy.
•In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy.•The addition of radiotherapy to chemotherapy did not significantly reduce the rate of recurrence after D2 gastrectomy.•DFS between patients treated with adjuvant chemotherapy and chemoradiotherapy was similar across all subgroups, including Lauren classification.
Collagen is the primary component of the extracellular matrix in the human body. It has proved challenging to fabricate collagen scaffolds capable of replicating the structure and function of tissues ...and organs. We present a method to 3D-bioprint collagen using freeform reversible embedding of suspended hydrogels (FRESH) to engineer components of the human heart at various scales, from capillaries to the full organ. Control of pH-driven gelation provides 20-micrometer filament resolution, a porous microstructure that enables rapid cellular infiltration and microvascularization, and mechanical strength for fabrication and perfusion of multiscale vasculature and tri-leaflet valves. We found that FRESH 3D-bioprinted hearts accurately reproduce patient-specific anatomical structure as determined by micro-computed tomography. Cardiac ventricles printed with human cardiomyocytes showed synchronized contractions, directional action potential propagation, and wall thickening up to 14% during peak systole.
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