bluuebunny/crossref_metadata_2025 huggingface dataset:
The ELiPSE-1 study: A phase 1, multicenter, open-label study of CNTY-101 in subjects with relapsed or refractory CD19-positive B-cell malignancies.
Authors: Patel Krish , Rothman Sarah , Das Poulomee A , Yee Stephanie , Ramachandran Indu , Koumenis Iphigenia , Cook Terry A , Yuan Ying , Trede Nikolaus S. , Mattour Ahmad Hatem
Published: June 2023

TPS7580

Background: Century Therapeutics’ foundational technology is built on induced pluripotent stem cells, differentiated from allogeneic approaches that utilize non-renewable donor-derived cells. This approach allows production of a clonal cell bank of precisely edited cells that can be expanded and differentiated to supply large amounts of homogeneous allogeneic therapeutic products for off-the-shelf use. CNTY-101 is an allogeneic Chimeric Antigen Receptor NK (CAR-NK) cell product with genetic modifications designed to specifically target CD19-expressing B-cell malignancies, reduce allorejection in the recipient allowing for repeat dosing, increase persistence, and enable cell elimination in the event of unexpected adverse events. CNTY-101, as a CAR-NK product, has the potential for improved safety over T-cell based cellular therapies. Methods: This first-in-human study will determine the MTD and recommended Phase 2 regimen (RP2R) of CNTY-101 in combination with subcutaneous (SC) IL-2 in patients with R/R aggressive and indolent CD19-positive B-cell Non-Hodgkin lymphomas including diffuse large B-cell lymphoma, mantle cell lymphoma, primary mediastinal large B-cell lymphoma, follicular lymphoma and marginal zone lymphoma, who are without other treatment options. Part 1 of the study (dose escalation using the BOIN design) will start with a dose of CNTY-101 cells without IL-2 (1 to 3 subjects), followed by dose escalation up to four dose cohorts administering a single dose of CNTY-101 cells in combination with IL-2 daily for 8 days (Sched A). After the single-dose MTD (or the maximal single dose) has been reached, a fractionated schedule of 3 doses per 28-day cycle, administered on Days 1, 8, and 15 (Sched B), will also be explored, starting with approximately one-third the maximum single dose level of CNTY-101, followed by escalation/de-escalation. Subjects in whom CNTY-101 shows signs of clinical benefit (i.e. stable disease or better per Lugano 2014 criteria) may receive additional cycles of CNTY-101 if the Investigator, Sponsor, and appropriate regulatory authorities, as required, concur that the benefit-risk is positive. One overall CNTY-101 RP2R will be declared in Part 1. Part 2, expansion, will further evaluate the safety, pharmacokinetics (PK), and efficacy of the CNTY-101 regimen, treating up to an additional 12 subjects to reach a total of approximately 20 subjects treated at the RP2R. In addition to safety and efficacy endpoints, the trial will evaluate exploratory PK, immunogenicity and pharmacodynamic endpoints including evaluations of tumor cfDNA, iNK tumor trafficking and serum cytokines. Clinical trial information: NCT05336409 .
A phase 1/2 study of STP938, a first-in-class inhibitor of CTP synthase 1, in patients with relapsed/refractory B or T cell lymphoma.
Authors: Patel Manish R. , Ahearne Matthew , Linton Kim , Fox Christopher , Lewis David John , Higgins Maureen , Schwartz Brian E. , Beer Philip A , Tees Michael Timothy
Published: June 2023

TPS7591

Background: The rate limiting step in de novo pyrimidine synthesis is catalyzed by two homologous enzymes, CTPS1 and CTPS2. CTPS1 is essential for lymphocyte proliferation, whereas CTPS2 is sufficient in non-haemopoietic cells. STP938 is a first in class oral CTPS1 inhibitor showing > 1,300-fold selectivity over CTPS2. In preclinical studies, STP938 induced death of cancer cells by apoptosis at nanomolar concentrations, and inhibited tumor growth in in vivo models of hematological malignancies. Methods: The study employs a seamless dose escalation, dose expansion design. The phase 1 dose escalation follows a standard 3+3 approach. Intra-patient dose escalation will be permitted. The recommended phase 2 dose (RP2D) will be nominated based on safety, target engagement and early signs of efficacy. An additional six patients will be treated at the RP2D with a preliminary assessment of food effect. Key phase 1 endpoints are safety and tolerability. Key phase 2 endpoints are objective response rate and duration of response. The study is open to adult patients following at least 2 prior lines of therapy who have no treatment options known to provide clinical benefit. The phase 1 study is recruiting patients with B or T cell lymphoma; the phase 2 study will be limited to cohorts of patients with specific lymphoma subtypes, which may include T cell lymphoma (peripheral or cutaneous), mantle cell lymphoma, indolent B cell lymphoma and diffuse large B cell lymphoma. Standard exclusion criteria apply; patients with ECOG performance score > 2 or known CNS involvement by lymphoma are not eligible. The phase 2 study will follow a Simon two-stage design with an interim analysis for futility based on predefined, lymphoma subtype specific response rates. In the case of STP938 showing promising efficacy, provision is included in the protocol to expand a cohort using an adaptive approach based on early efficacy signals (Mehta and Pocock, 2011). Target engagement is assessed by measuring cytokine release (TNFα, IFNγ, IL2, IL8) from ex vivo stimulated patient T cells. Exploratory studies include pre- and on-treatment lymphoma biopsies to assess biomarkers of response and mechanism of action. Tumor genomics will be assessed by sequencing of circulating tumor DNA prior to treatment and at disease progression using a bespoke genomic assay designed to elucidate biomarkers of response and understand mechanisms of resistance. The phase 1 study (NCT05463263) opened to enrolment in the US and UK in September 2022. No dose limiting toxicities were observed in the first cohort of 3 patients. The phase 2 study will include additional centers in France. Clinical trial information: NCT05463263 .
OMNIA-2: Phase I/II study of ANV419, an IL-2R-βγ targeted antibody-IL-2 fusion protein, in patients with relapsed or refractory multiple myeloma.
Authors: Hess Dagmar , Fladeland Iversen Katrine , Mateos Maria-Victoria , Pabst Thomas , Rosiñol Laura , Kovacikova Jana , Jethwa Schnetzler Sangeeta
Published: June 2023

TPS8068

Background: ANV419 is a potent, selective IL-2Rβγ targeted antibody IL-2 fusion protein, designed to enable the delivery of high dose interleukin-2 (IL-2) to patients, in order to stimulate anti-tumour response and minimise toxicities. The ANV419-001 first-in-human study (NCT 04855929) demonstrated that ANV419 preferentially stimulates cytotoxic CD8+ T and natural killer (NK) cells over immunosuppressive regulatory T cells, with a significantly longer half-life than that of conventional IL-2. The safety and tolerability data from this study confirmed that ANV419 delivers high molar equivalents of IL-2 in a tolerable and convenient way. In patients with multiple myeloma, the critical role of NK cells has been well described. ANV419 is expected to promote antitumor response via the preferential stimulation of cytotoxic CD8+ T and NK cells. Methods: The OMNIA-2 study (ANV419-102; NCT 05641324) will evaluate safety and preliminary efficacy of ANV419 as monotherapy and in combination with daratumumab (dara), or lenalidomide with low dose dexamethasone (lena/dex), in patients with relapsed or refractory multiple myeloma. OMNIA-2 is a Phase I open-label, multi-center study in adult patients (n = 52) with symptomatic multiple myeloma who responded to previous treatment and received autologous stem cell transplant, or at least 2 lines of therapy including an immunomodulator, proteasome inhibitor, and/or dara. The study is conducted in 2 stages using a Bayesian Optimal Phase 2 approach. Stage 1 consists of a run-in phase with subsequent randomization to ANV419 243mcg/kg or ANV419 108mcg/kg for 8 weeks, followed by a second randomisation to ANV419 108mcg/kg in combination with lena/dex or dara for a further 8 weeks. Stage 2 follows a similar design as stage 1 and consists of a monotherapy run-in phase with either high or low dose ANV419, with a second randomisation to ANV419 108mcg/kg in combination with either lena/dex or dara, according to the safety and efficacy observed in Stage 1. ANV419 is administered intravenously over 15 to 20 minutes every two weeks. Lena, dex and dara are administered at their respective approved dosing regimens. Tumour response is determined using IMWG (2016) response criteria. AEs are assessed according to CTCAE V5.0. OMNIA-2 is being conducted in Denmark, France, Germany, Spain, Switzerland, UK and enrolment began in January 2023 and preliminary data are expected in Q1 2024. Clinical trial information: NCT05641324 .
A phase II study to evaluate the efficacy and safety of combination therapy of durvalumab (MEDI4736) and amrubicin in patients with recurrent small cell lung cancer (SCLC): Aphrodite trial, in progress.
Authors: Kato Yuka , Ohashi Kadoaki , Kozuki Toshiyuki , Kuyama Shoichi , Yamaguchi Kakuhiro , Yokoyama Toshihide , Uno Hideki , Yoshida Michihiro , Hattori Noboru , Hotta Katsuyuki , Kiura Katsuyuki
Published: June 2023

TPS8612

Background: Immunochemotherapy (ICT) is the standard first-line treatment for extensive stage (ES)-SCLC. However, progression-free survival for patients (pts) treated with ICT as first-line therapy is approximately 5 months, and half of the pts will relapse within 6 months. Several drugs have been approved for the treatment after relapse, and amrubicin has been used as a second-line treatment in Japan for 20 years. However, the efficacy of pts treated with amrubicin is unsatisfactory, the median survival was 9.2 months (pts with sensitive relapse (SR-pts)) and 2.6 months (pts with refractory relapse (RR-pts)), indicating an urgent need for new therapeutic strategies in the treatment of post-relapse SCLC pts. A retrospective study showed significant improvement in survival for patients who progress on immunochemotherapy, treated with same ICI plus chemotherapy as second-line therapy (Trans Lung Cancer Rec. 2020). Cytotoxic chemotherapy introduced immunogenic cell death and the addition of chemotherapy to ICI might have a synergistic effect. Based on these assumptions, the combination of amrubicin with ICI may provide additional benefit for post-progression pts and we are therefore initiating this study. Methods: This is an open-label, single-arm, multicenter, physician-initiated Phase 2 study of amrubicin plus durvalumab in Japanese pts with relapsed SCLC. The study is divided into a lead-in cohort (LIC) and a Phase 2 part; the LIC will use a 3+3 design to ensure safety and will proceed to the Phase 2 part if the first 3 pts have no dose limiting toxicity (DLT) or the first 6 pts have only 1 DLT. Eligibility criteria include pts with ES-SCLC who relapse after platinum-containing chemotherapy with durvalumab as first-line therapy, age ≥20, ECOG 0-1. The primary endpoint is 1-year survival. Patients were treated with intravenous amrubicin 40 mg/m2 on day 1-3 and durvalumab 1500 mg/body on day 1 every 3 weeks until PD or unacceptable toxicity. The planned number of pts was 18 each with sensitive relapse (SR-pts) and refractory relapse (RR-pts) which was calculated based on the results of a previous randomized controlled trial (J Clin Oncol. 2008). In this trial, the point estimates and two-sided 90% confidence intervals (Clopper Peason method) for 1-year survival corresponding to the expected 1-year survival were: SR-pts (11/18 patients): 0.611 (90% CI: 0.392-0.801), RR-pts (8/18 0.444 (90% CI: 0.244-0.659). Enrollment began in October 2022, and will be completed by March 2025. Clinical trial information: jRCT2061220036 .
Phase 2 study of telisotuzumab vedotin (Teliso-V) monotherapy in patients with previously untreated MET-amplified locally advanced/metastatic non-squamous non-small cell lung cancer (NSQ NSCLC).
Authors: Horinouchi Hidehito , Shibata Yuji , Looman Jim , Sui Yunxia , Noon Elysa , Lu Shun
Published: June 2023

TPS9149

Background: Teliso-V is a first-in-class anti–c-Met antibody-drug conjugate composed of the monoclonal antibody telisotuzumab (ABT-700), a cleavable valine-citrulline (dipeptide) linker, and cytotoxic monomethylauristatin E (MMAE; potent microtubule polymerization inhibitor). Direct MMAE payload delivery to c-Met protein overexpressing (OE) cells enables Teliso-V to work independently of c-Met signaling. In NSCLC, while c-Met OE is more common than MET gene amplification (Amp), about 90% of MET Amp tumors will also be c-Met OE. In an ongoing phase 2 trial, Teliso-V showed encouraging efficacy and acceptable safety in previously treated c-Met OE NSQ NSCLC population (Camidge et al. JCO.2022.40.16_suppl.9016). From this study, a retrospective analysis of 10 patients with MET Amp (≥1.8 MET gene to chromosome 7 copy number ratio by fluorescence in situ hybridization [FISH]) demonstrated an objective response rate (ORR) of 80%. Described here is an ongoing phase 2 study evaluating efficacy and safety of Teliso-V monotherapy in patients with previously untreated MET Amp locally advanced/metastatic NSQ NSCLC. Methods: This is a phase 2, single-arm, open-label, global study (NCT05513703). Eligible patients (≥18 years) have histologically documented advanced/metastatic NSQ NSCLC, measurable disease by RECIST v1.1, confirmed MET Amp determined centrally by FISH or locally by FISH, tissue next-generation sequencing (NGS), or plasma NGS using sponsor-approved assays. Additional eligibility criteria include Eastern Cooperative Oncology Group performance status 0 or 1, no alterations in EGFR, ALK, ROS1, or BRAF that predict sensitivity to targeted therapy, no prior systemic therapy for locally advanced or metastatic NSCLC, no prior c-Met–targeted antibody therapy. Teliso-V is administered intravenously at 1.9 mg/kg every 2 weeks until disease progression, intolerable toxicity, or other study drug discontinuation criteria are met. Primary endpoint is ORR assessed by independent central review (ICR). Secondary endpoints include duration of response and disease control rate, progression-free survival per ICR, overall survival, patient-reported outcomes (PROs). Tumor assessments (per RECIST v1.1) are performed at baseline and approx. every 6 (year 1), 8 (year 2), and 12 weeks (year 3 and beyond). PROs are assessed through validated questionnaires (EORTC QLQ-LC13, EORTC QLQ-C30, EQ-5D-5L). Safety and tolerability are evaluated by adverse events, physical examinations, laboratory data, and vital signs. Pharmacokinetic and biomarker evaluations may be used for exploratory analyses. The trial intends to enroll approx. 70 efficacy-evaluable patients, with interim analyses planned after 20 and 50 patients are able to be followed for ≥6 months. The study was open to enrollment as of Nov 2022. Clinical trial information: NCT05513703 .
OMNIA-1: A phase I/II study, an IL-2R-βγ targeted antibody-IL-2 fusion protein, as monotherapy or in combination with anti-PD-1 or anti-CTLA-4 antibodies, in patients with advanced melanoma.
Authors: Ascierto Paolo Antonio , de Velasco Guillermo , Eigentler Thomas , Isambert Nicolas , Mouton Julie , Robert Caroline , Schusterbauer Claudia Michaela , Vijayakumar Jayanthi
Published: June 2023

TPS9599

Background: ANV419 is a potent and selective IL-2Rβγ targeted antibody IL-2 fusion protein, designed to enable the delivery of high dose interleukin-2 (IL-2) to patients in order to stimulate anti-tumour response and minimise toxicities. Recombinant IL-2 (proleukin) induces durable responses in approximately 10% of patients with melanoma. Signalling through IL-2Rα expressing cells is believed to limit its therapeutic potential in cancer. By eliminating binding to IL-2Rα, ANV419 could lead to increased anti-tumor effect while increasing tolerability. The ANV419-001 first-in-human study (NCT 04855929) demonstrated that ANV419 preferentially stimulates cytotoxic CD8+ T and natural killer (NK) cells over immunosuppressive regulatory T cells, with a significantly longer half-life than that of conventional IL-2. The safety and tolerability data from this study confirmed that ANV419 delivers high molar equivalents of IL-2 in a tolerable and convenient way. Methods: ANV419 is being evaluated in a global multicentre, open-label, randomized Phase I/II study in patients with unresectable or metastatic cutaneous melanoma to assess the safety and efficacy of intravenous ANV419 as monotherapy and in combination with anti-PD1 or anti-CTLA-4 antibodies. The OMNIA-1 study leads in with a monotherapy dose expansion part, followed by a combination dose-finding with either anti-PD-1 or anti-CTLA-4 and a combination dose expansion part. ANV419 is administered intravenously every 2 weeks as monotherapy and every 3 weeks when given in combination. Patients with advanced cutaneous melanoma, no active brain metastases and whose disease has progressed on or following at least 1 line of standard of care immunotherapy are eligible. In Part 1, a total of 30 patients will be randomised and evaluated for response to Q2W ANV419 monotherapy (108 µg/kg or 243 µg/kg). In Part 2, escalating doses of Q3W ANV419 are evaluated to define the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) in combination with pembrolizumab (200 mg) or ipilimumab (3 mg/kg). In Part 3, the efficacy and safety of ANV419 in combination with the approved doses pembrolizumab or ipilimumab will be evaluated using a Simon’s 2-stage design. Up to 130 patients are planned to be enrolled. Patients will be stratified according to BRAF mutation status. AEs are assessed according to CTCAE V5.0. Tumour response is determined using RECIST 1.1 criteria. The study is conducted at sites in the US, France, Spain, Germany, Italy, and UK. The first patient was dosed in December 2022. Preliminary monotherapy efficacy data are expected by Q1/2024. Clinical trial information: NCT05578872 .
A randomized phase 2 trial of encorafenib + binimetinib + nivolumab vs ipilimumab + nivolumab in BRAFV600-mutant melanoma brain metastases: SWOG S2000.
Authors: Eroglu Zeynep , Moon James , Najjar Yana G. , Kotecha Rupesh , Spektor Vadim , Wu Michael , Sharon Elad , Grossmann Kenneth F. , Wolchok Jedd D. , Patel Sapna Pradyuman , Tawbi Hussein A.
Published: June 2023

TPS9603

Background: While anti-PD-1 and anti-CTLA4 immunotherapies are widely used in the treatment of metastatic melanoma, including melanoma brain metastases (MBM), their efficacy in patients with symptomatic MBM is very limited. In the Checkmate-204 trial of ipilimumab with nivolumab in MBM, the 6-month progression free survival (PFS) rate was 19% with a median PFS of only 1.2 months in symptomatic participants (those with neurological symptoms including steroids up to 4 mg/day of dexamethasone, n=18). (Tawbi, Lancet et al., 2021) In the COMBI-MB study of BRAF/MEK-inhibitors in BRAF-V600 mutant MBM, median PFS was 5.5 months in those with symptomatic metastases (n=17). (Davies et al., Lancet Oncol, 2017) The combination of anti-PD-1/PD-L1 therapy with BRAF/MEK inhibitors has been tested in various trials. The single-arm phase 2 TRICOTEL study explored the triplet regimen of vemurafenib + cobimetinib + atezolizumab in MBM; in the symptomatic brain met cohort, 6-month PFS was 57% (n=24). (Dummer et al., Lancet Oncol 2022). Methods: SWOG S2000 is a randomized phase 2 trial exploring the efficacy of a triplet regimen of BRAF/MEK inhibitors with PD-1 therapy (encorafenib 450 mg qday + binimetinib 30 mg BID + nivolumab 480 mg IV q4 weeks) versus ipilimumab 3 mg/kg + nivolumab 1 mg/kg q3 weeks in patients with symptomatic BRAF-mutant MBM. (The study was amended to exclude patients with asymptomatic MBM.) Eligible patients are ≥18 years old, ECOG 0-2, and prior neoadjuvant or adjuvant anti-PD-1, CTLA-4, or BRAF/MEK-inhibitors is permitted. Steroids up to 8 mg of dexamethasone/day (or equivalent), leptomeningeal spread, and prior local therapy (radiation or surgery) for brain mets are permitted, if a patient has at least one measurable, progressing brain met ≥0.5 cm in size. Primary objective is to compare PFS per (RECIST 1.1) between the two study arms. Secondary objectives include overall survival, toxicity profile, objective tumor response, intracranial response and duration per modified RECIST 1.1, modified RANO-BM, and iRANO criteria, and evaluation of radiographic response criteria by centralized review of banked images. This study is powered to detect an increase in estimated 6-month PFS from 20% to 52% with 80% power and type I error rate of 10%, with 24 eligible patients required. Total sample size is 28 to account for ineligible patients. Available blood, tissue, CSF and stool samples are banked for future correlative studies. The study is currently enrolling patients through SWOG, ECOG and NRG centers. Funding: NIH/NCI grants U10CA180888, U10CA180819, U10CA180820 U10CA180868; and in part by Pfizer, Inc. Clinical trial information: NCT04511013 .
PLUME: A single-arm phase II trial evaluating the combination of pembrolizumab and lenvatinib in metastatic uveal melanoma (mUM) patients (pts) previously treated or not with tebentafusp.
Authors: Rodrigues Manuel , Saint-Ghislain Mathilde , Ramtohul Toulsie , de Koning Leanne , Bouchez Clémentine , Lafite Elsa , Castel Ajgal Zahra , Marret Gregoire , Sanchez Raphaël , Mariani Pascale , Nespoulous Sandra , Gillon Véronique , Servois Vincent , Piperno-Neumann Sophie
Published: June 2023

TPS9613

Background: Up to 50% of pts with uveal melanoma (UM) develop metastases, mainly hepatic, with poor overall survival and limited treatment options as response rate to first-line immune checkpoint inhibitors (ICI) is low in mUM pts. Tebentafusp, a bispecific T-cell engager, was recently approved in this setting but only in HLA A*02-01+ mUM patients. Lenvatinib is a tyrosine kinase inhibitor targeting multiple growth factor receptors including vascular endothelial growth factor receptors (VEGFRs), fibroblast growth factor receptors (FGFRs) and colony-stimulating factor receptor (CSF1-R), which are key pathways in UM. Lenvatinib showed an immune-modulating effect in preclinical models. The combination demonstrated synergic clinical anti-tumor activity in various tumor types including microsatellite-stable endometrial cancers, kidney cancers and ICI-resistant skin melanomas. We hypothesize that combining pembrolizumab with lenvatinib in mUM may lead to an improved immune response in mUM patients. Methods: Fifty-four, ICI-naïve, metastatic UM pts will be enrolled in this monocentric, single-arm phase II trial at Institut Curie, Paris, France. Because previous exposure to tebentafusp might increase the activity of subsequent ICI, the combination will be assessed in two independent cohorts: cohort 1 with HLA A*02-01neg, tebentafusp-naive patients (22 assessable patients), and cohort 2 with HLA A*02-01pos pts previously treated with tebentafusp (28 assessable patients). Up to 54 patients may be included according to an 8% drop-out rate. Each participant will receive pembrolizumab (200 mg Q3W, maximum of 35 cycles) plus lenvatinib (starting at 20mg QD) until reaching a discontinuation criterion. Liver MRI and chest-abdomen-pelvis CT will be performed every 9 weeks until progressive disease. Primary objective is to evaluate the progression-free survival (PFS) after nine cycles of treatment (27 weeks) as assessed by the investigator using the RECIST v1.1. Secondary objectives include PFS according to immune RECIST (iRECIST), overall survival, overall response rate, safety and tolerability, quality of life. Inclusion period started mid-July 2022 for two years. To date, twenty-four (21 in cohort 1, 3 in cohort 2) of planned 54 pts have been enrolled in six months. Biospecimens (longitudinal blood samples and tumor tissue at inclusion) will be collected during the study to allow biomarker research. Clinical trial information: NCT05282901 .
A 3D adipogenesis platform to study the fate of fibro/adipogenic progenitors in muscular dystrophies
Authors: Reggio Alessio , De Paolis Francesca , Bousselmi Salma , Cicciarelli Felice , Bernardini Sergio , Rainer Alberto , Seliktar Dror , Testa Stefano , Cirillo Carmine , Grumati Paolo , Cannata Stefano , Fuoco Claudia , Gargioli Cesare
Published: June 2023

In human dystrophies, progressive muscle wasting is exacerbated by ectopic deposition of fat and fibrous tissue originating from fibro/adipogenic progenitors (FAPs). In degenerating muscles, the ability of these cells to promote successful healing is attenuated, and FAPs aberrantly expand and differentiate into adipocytes and fibroblasts. Thus, arresting the fibro/adipogenic fate of FAPs, without affecting their physiological role, represents a valuable therapeutic strategy for patients affected by muscle diseases. Here, using a panel of adipose progenitor cells, including human-derived FAPs, coupled with pharmacological perturbations and proteome profiling, we report that LY2090314 interferes with a genuine adipogenic program acting as WNT surrogate for the stabilization of a competent β-catenin transcriptional complex. To predict the beneficial impact of LY2090314 in limiting ectopic deposition of fat in human muscles, we combined a poly-ethylene-glycol-fibrinogen biomimetic matrix with these progenitor cells to create a miniaturized 3D model of adipogenesis. Using this scalable system, we demonstrated that a two-digit nanomolar dose of this compound effectively represses adipogenesis at higher 3D scale, thus indicating the potential for LY2090314 to limit FAP-derived fat infiltrates in dystrophic muscles.
From mechanisms of heart failure to clinical heart success
Authors: Bakkers Jeroen , Bellin Milena , Hmeljak Julija , Karra Ravi
Published: June 2023

Summary: This Editorial introduces DMM's new Special Issue on ‘Moving heart failure to heart success’. The Guest Editors reflect on how articles in the issue advance the cardiac research field.
Sovereign Debt in the Twenty-first Century
Authors: Mitchener Kris James , Trebesch Christoph
Published: June 2023

How will sovereign debt markets evolve in the twenty-first century? We survey how the literature has responded to the eurozone debt crisis, placing “lessons learned” in historical perspective. The crisis featured: (i) the return of debt problems to advanced economies, (ii) a bank–sovereign “doom loop” and the propagation of sovereign risk to households and firms, (iii) rollover problems and self-fulfilling crisis dynamics, (iv) severe debt distress without outright sovereign defaults, (v) large-scale sovereign bailouts from abroad, and (vi) creditor threats to litigate and hold out in a debt restructuring. Many of these characteristics were already present in historical debt crises and are likely to remain relevant in the future. Looking forward, our survey points to a growing role of sovereign bank linkages, legal risks, domestic debt and default, and of official creditors, due to new lenders such as China as well as the increasing dominance of central banks in global debt markets. Questions of debt sustainability and default will remain acute in both developing and advanced economies. (JEL E58, F33, F34, G01, G21, H63, N20)
What is Certain about Uncertainty?
Authors: Cascaldi-Garcia Danilo , Sarisoy Cisil , Londono Juan M. , Sun Bo , Datta Deepa D. , Ferreira Thiago , Grishchenko Olesya , Jahan-Parvar Mohammad R. , Loria Francesca , Ma Sai , Rodriguez Marius , Zer Ilknur , Rogers John
Published: June 2023

This paper provides a comprehensive survey of existing measures of uncertainty, risk, and volatility, noting their conceptual distinctions. It summarizes how they are constructed, their relative advantages in usage, and their effects on financial market and economic outcomes. The measures are divided into four categories based on the construction methodology: news-based, survey-based, econometric-based, and market-based measures. While heightened uncertainty is typically associated with negative real and financial outcomes, the magnitude of these effects and the interpretation of transmission channels crucially depend on identification considerations.(JEL C83, D81, E10, E52, E60, F10, G10)
Case Report: A prenatal diagnosis of osteogenesis imperfecta in a patient with a novel pathogenic variant in COL1A2
Authors: Peláez Chomba Melissa Sindy , Vásquez Gómez Guillermo Raúl , Sullcahuaman Allende Yasser Ciro , Mendoza Fernández Julio Cesar , Purizaca Rosillo Nelson David , Zevallos Alejandra , Cruzate Cabrejos Vicente Leandro
Published: June 2023

Osteogenesis imperfecta is considered a rare genetic condition which is characterized by bone fragility. In 85% of cases, it is caused by mutations in COL1A1 and COL1A2 genes which are essential to produce type I collagen. We report the case of a female neonate delivered to a 27-year-old women at San Bartolomé Teaching Hospital with a family history of clavicle fracture. A prenatal control with ultrasound was performed to the mother at 29 weeks. A fetus with altered morphology and multiple fractures was found. Therefore, a prenatal diagnosis of osteogenesis imperfecta was performed. The neonate was born with a respiratory distress syndrome and an acyanotic congenital heart disease. Therefore, she remained in NICU until her death. We highlight the importance of prenatal diagnosis, genetic counseling and a multidisciplinary evaluation in this type of pathologies and report a new probably pathogenic variant in the COL1A2 gene detected by exomic sequencing in amniotic fluid.
An empirical investigation on the impact of attitudes towards organ donation in India
Authors: Nayak Vinod C. , Nayak Smitha
Published: June 2023

Background: Organ shortage is a global issue and it is imperative to take steps to bridge this gap. In the Indian context, despite its demographic dividend, the rate of organ donation has been abysmally low. This emphasizes a need to demystify the antecedents of organ donation intention among the Indian population.

Methods: Using a cross-sectional research design and adopting a post-positivism research philosophy, this study identified 259 respondents by adopting a purposive sampling approach and data on knowledge of organ donation was collected using a structured, pretested questionnaire.

Results: Awareness of organ donation law in India is low on specific issues and respondents from the health science & medicine discipline scored better on knowledge about organ donation. The findings show that most participants had heard about organ donation and had a favourable attitude toward it. The primary sources of information on organ donation were television and newspapers, and healthcare service providers. A complementary partial median is established (β = .217, t = 5.889, p < .001) which implies that willingness to discuss with family significantly mediates the association between attitude towards organ & tissue donation and willingness to sign the donor card.

Conclusion: This study revealed that there is a general awareness of organ and tissue donation among the Indian population, but they lack clarity on certain specific issues. Mass media has to be effectively used to build awareness campaigns revolving around enhancing knowledge on a specific issue and building acceptance of the concept of organ and tissue donation.
Historical changes in baby names in China
Authors: Ogihara Yuji
Published: June 2023

Based on previous research on names and naming practices, I propose three suggestions to Bao et al. (2021), which investigated historical changes in given names of Han Chinese in China between 1920 and 2005. Their study analyzed a one-shot cross-sectional survey conducted in 2005 and reported that unique names increased from 1920 to 2005. The authors concluded that China became more individualistic over time for the period. However, three questions have remained unanswered in Bao et al. (2021). First, were the samples of older birth cohorts truly representative? Second, did unique names increase only after the 1970s? Third, how are the historical changes in average name length interpreted? Answering these three questions would contribute to a further understanding of the historical changes in given names and their underlying psychological/cultural shifts in China.
COVID-19 vaccinations and their side effects: a scoping systematic review
Authors: Monadhel Hind , Abbas Ayad , Mohammed Athraa
Published: June 2023

Introduction: The COVID-19 virus has impacted people worldwide, causing significant changes in their lifestyles. Since the emergence of the epidemic, attempts have begun to prepare a vaccine that can eliminate the virus and restore balance to life in the entire world. Over the past two years, countries and specialized companies have competed to obtain a license from the World Health Organization for the vaccines that were discovered. After the appearance of vaccines in the health community, comparisons and fears of their side effects began, but people don’t get an answer to the question of which is the best vaccine.

Methods: IEEE Xplore, ScienceDirect, the New England Journal of Medicine, Google Scholar, and PubMed databases were searched for literature on the COVID-19 vaccine and its side effects. we surveyed the literature on the COVID-19 vaccine’s side effects and the sorts of side effects observed after vaccination. Depending on data from the literature, we compared these vaccines in terms of side effects, then we analyzed the gaps and obstacles of previous studies and made proposals to process these gaps in future studies.

Results: Overall, 17 studies were included in this scoping systematic review as they fulfilled the criteria specified, the majority of which were cross-sectional and retrospective cross-sectional studies. Most of the side effects were mild, self-limiting, and common. Thus, they usually resolve within 1–3 days after vaccination. Factors associated with higher side effects included advanced age, allergic conditions, those taking other medications (particularly immunosuppressive ones), those with a history of type II diabetes, heart disease, hypertension, COVID-19 infection, and female sex. Our meta‐analyses also found that mRNA vaccines looked to be more effective, while inactivated vaccinations had fewer side effects.

Conclusion: This review shows that the COVID-19 vaccine is safe to administer and induces protection.
General public awareness, knowledge and attitude toward COVID-19 infection and prevention: a cross-sectional study from Pakistan
Authors: Alam Beenish Fatima , Almojaibel Abdullah A. , Aziz Ansari Khalid , Haroon Mohammad , Noreen Sara , Tauqir Saman , Almas Khalid , Farooqi Faraz A. , Ali Saqib
Published: June 2023

Background: The aim of this study is to evaluate the knowledge, perceptions, and attitude of the public in Pakistan (using social media) towards COVID-19.

Methods: A cross-sectional study was conducted amongst 1120 individuals nationwide. A self-developed, pre-tested questionnaire was used that comprised of sections covering demographic characteristics, medical history, hygiene awareness, COVID-19-related knowledge, and learning attitude. Descriptive statistics were used for frequencies, percentages, averages and standard deviations. Inferential statistics were done using the Student’s t-test and ANOVA.

Results: The average age of participants was 31 years (range 18-60 years). In total 56 individuals (5%) had completed primary or secondary school education; 448 (40%) were employed (working from home) and 60% were jobless due to the COVID-19 crisis. Almost all the study subjects (1030 (92%)) were washing their hands multiple times a day. A total of 83% had awareness regarding quarantine time, 82% used face masks whenever they left their homes, 98% were aware of the origin of the disease, and 70% had knowledge regarding the most common symptoms of COVID-19.

Conclusion: It can be concluded from the current study that female participants had higher level of education, and more awareness regarding the coronavirus. The majority of the participants followed proper hand washing regimes and washed their faces. Further knowledge and awareness should be promoted.
Evaluation of awake prone positioning effectiveness in moderate to severe COVID-19
Authors: Truong Nguyen Thanh , Phong Nguyen Thanh , Nguyen Nguyen Thanh , Khanh Le Thuy Thuy , Tran Luu Hoai Bao , Linh Nguyen Thi My , Thao Dang Phuong , Trinh Nguyen Thi Diem , Kieu Pham Tieu , Thao Nguyen Thi Phuong , Hoang Vo Tan , Ngoc Nguyen Thanh , Oanh Pham Kieu Nguyet , Vien Tran Thi Dong , Tung Nguyen Le Nhu , Ly Vo Trieu , Khoa Tran Dang , Phu Nguyen Hoan , Van Cao Thi Cam , Duc Tran Minh , Beane Abigail , Khoa Le Dinh Van , Clifton David , Kestelyn Evelyne , Hai Ho Bich , Yen Lam Minh , Tan Le Van , Glover Guy , Thwaites Guy E , Geskus Ronald , Duc Du Hong , Dung Nguyen Thanh , Thwaites C Louise
Published: June 2023

Evidence mainly from high income countries suggests that lying in the prone position may be beneficial in patients with COVID-19 even if they are not receiving invasive ventilation. Studies indicate that increased duration of prone position may be associated with improved outcomes, but achieving this requires additional staff time and resources. Our study aims to support prolonged (≥ 8hours/day) awake prone positioning in patients with moderate to severe COVID-19 disease in Vietnam. We use a specialist team to support prone positioning of patients and wearable devices to assist monitoring vital signs and prone position and an electronic data registry to capture routine clinical data.
Pemberdayaan Masyarakat Melalui Peningkatan Pengetahuan Dasar Metalurgi Terapan dan Ketrampilan Pengelasan Bagi Generasi Muda Desa Sebalor, Kec. Bandung, Kab. Tulungagung
Authors: Purniawan Agung , Jatimurti Wikan , Sutarsis Sutarsis , Altama Alfreda Krisna
Published: June 2023

Pengabdian Kepada Masyarakat adalah salah satu dari Tri Dharma Perguruan Tinggi yang dilaksanakan dalam rangka untuk meningkatkan partisipasi atau pemberdayaan masyarakat di sektor ekonomi dan industri terutama generasi mudanya. Salah satu sektor industri yang cukup menjanjikan dan sangat mungkin dilaksanakan adalah unit usaha pengelasan. Hal ini dikarenakan keterampilan bidang las mampu menghasilkan produk yang sesuai standar sehingga kualitasnya dapat dipertanggungjawabkan. Namun kelemahan unit usaha di daerah adalah belum adanya kemampuan terkait teori, ketrampilan dan inspeksi atau evaluasi terhadap hasil las yang sesuai dengan standar. Kondisi ini mengakibatkan unit usaha tersebut tidak memiliki standar produk yang memadai. Berdasarkan kondisi ini maka tujuan umum program pengabdian masyarakat ini adalah menghasilkan unit usaha las yang berkompeten dan memiliki standar produk, melalui pemberdayaan kelompok karang taruna Desa Sebalor, Kec. Bandung, Kabupaten Tulungagung dengan pelatihan keterampilan las. Sekitar sepuluh orang anggota Karang Taruna mengikuti pelatihan tersebut dari pemaparan dasar teori sampai praktik pengelasannya. Dalam pelatihan tersebut beberapa peserta sudah memiliki dasar mengelas dan mendapatkan pengetahuan dasar tentang teori pengelasan yang standar, pemilihan material, dan cara sederhana untuk mengevaluasi hasil lasan.
Minimally invasive laparoscopic methods of biopsy in small animal practice
Authors: Tapia-Araya Angelo , Monti Simone , Sampayo José , Gomariz Francisco Martinez , Ortega Juan Granados , Enciso Silvia , Sánchez-Margallo Francisco
Published: June 2023

Laparoscopic surgery has benefitted from many technical advances, achieving better results and reduced complications in comparison to conventional surgical techniques. Specialist equipment has been developed to better aid the minimally invasive approach, allowing for more precision, becoming a method of choice for biopsy. It is of particular value in patients where the sites are small or present in locations unsuitable for image-guided biopsy, or where adequate tissue cannot be obtained by image-guided biopsy. Laparoscopy has been proven to offer several benefits to the patient both intraoperatively and postoperatively, therefore, it can be said that laparoscopy provides a safe and effective means of obtaining biopsies in small animal practice.
Conscientious, competent and caring: producing the junior doctor of the future
Authors: McLachlan John C , Sawdon Marina , Finn Gabrielle , Fleming Karen
Published: June 2023

This article is based on the Association for the Study of Medical Education Gold Medal Plenary for 2022, given by the first author. It outlines different ways in which medical training can be approached, based on his career and his work with colleagues. Among the attributes that it would be desirable to promote in future doctors are conscientiousness, competence and care for patients as individuals. This article explores each of these in separate sections. The first demonstrates that the trait of conscientiousness can be observed in first and second year medical students by their compliance in routine low level tasks such as attendance and submission of required work on time. A ‘conscientiousness index’ calculated on this basis is a statistically significant predictor of later events such as performance in exams, the prescribing safety assessment, and the UK situational judgement test in subsequent years, and also in postgraduate assessments such as Royal college exams and the annual reviews of competence progression. The second proposes that competence in tasks undertaken by junior doctors is better achieved by teaching on medical imaging, clinical skills and living anatomy than by cadaveric dissection. The final section argues that the incorporation of arts and humanities teaching into medical education is likely to lead to better understanding of the patient perspective in later practice.
Providing effective supervision for staff working in a care home setting
Authors: Ashurst Adrian M
Published: June 2023

Adrian Ashurst reflects on the importance of regular supervision and provides some useful tips to support supervisors when conducting a supervision meeting.
Similarities and Dissimilarities in Student Grades Distributions, Over Time and by Gender
Authors: Ferreira Pedro , Canto-e-Castro Luísa , Silva Carina
Published: June 2023

The focus of this article is to analyze the distribution patterns of student grades over time for different subjects and by gender. Specifically, we examined the final term grades of upper secondary students in Portuguese public schools across four subjects (Mathematics, Portuguese Language, Philosophy, and Physical Education) from the academic years 2013-2014 to 2017-2018. These grades reflect the teachers' perceptions of the students' knowledge gained throughout the academic year. We expected to see some regularity in the grade distributions over time for a particular subject. However, we found that the similarity of grades across subjects and time was so striking that differences were barely noticeable by visual inspection. Due to the very large sample sizes (in the order of tens of thousands), the quantification of similarities and dissimilarities was done through distribution’s proximity statistics and not by classic statistical methods, like Chi-Square or comparison of means tests. Additionally, we applied a methodology of multiple equivalence tests to globally compare the relative frequencies of each of the grades in pairs of independent samples. Our analysis showed that there was a high level of similarity in grades for the same subject over time, but we also found differences between subjects and between genders.
Enhancing Student Performance during Online Learning with Psychosocial Processes and Information and Communication Technology Competence: The Role of Psychological Engagement as Mediator
Authors: Uyun Muhamad , Bahriah Yuli , Zulhijra Zulhijra , Utia Ike , Fitriani Fitriani
Published: June 2023

Some Indonesians may still regard online education as a novel, although they frequently engage in online-related activities without even realizing it. The quality of learning, satisfaction, achievement, retention, and, more broadly, personal growth are all favorably correlated with student engagement. For students to provide their best effort and succeed in online learning, it is crucial to have good psychological engagement in them. This engagement will help their psychological processes and dispositions to improve. The quantitative research methodology was utilized in this research. In addition, 800 high school students from South Sumatra participated in this research as a sample. The structural equation model is analyzed (SEM). The findings indicated that 85.9 percent of the time, a psychological commitment is influenced by information communications technology (ICT) proficiency, psychosocial processes, and student performance. Thus, the value of .713 indicates that psychological involvement, psychosocial processes, and ICT proficiency all impact student performance. This study demonstrates that every hypothesis has a favorable and significant impact. These circumstances suggest that students who are proficient in ICT and psychosocial processes will be able to enhance their performance through challenging and dry learning. The interaction between students while learning strengthens this condition.
Sohanjana Antibullying Intervention: Culturally and Socially Targeted Intervention for Teachers in Pakistan to Take Actions Against Bullying
Authors: Siddiqui Sohni , Schultze-Krumbholz Anja , Kamran Mahwish
Published: June 2023

Several studies have demonstrated that bullying and cyberbullying are prevalent in Pakistani educational institutions, negatively affecting students' physical and mental health. Literature has revealed that it has not always been successful to prevent bullying in Pakistani educational institutions by adapting or adopting antibullying interventions from other countries. Sohanjana Antibullying Intervention is the first contextualized antibullying intervention designed specifically for Pakistani teachers. Assisting teachers in identifying bullying and victimization issues prevalent in educational institutions, intervening quickly to assist pupils, and creating a conducive school environment are the main goals of this program. A description of the Sohanjana intervention program, its modules, and its design is presented in the current study. After a comprehensive literature review on bullying in Pakistan, and conducting a baseline survey for need assessment, the program’s content and activities have been developed. In this 32-hour professional development program, teachers are trained on eight different themes over the course of eight modules. In the present paper, the design, the theoretical background, details of the different modules and preliminary evaluation data of the Sohanjana intervention program are presented. A pilot study of the intervention so far has produced successful results and gathered positive feedback from participants. As a result of the feedback, several recommendations and suggestions are discussed in the study.
The Moderating Role of Entrepreneurial Self-Efficacy and Locus of Control on the Effect of the University Environment and Program on Entrepreneurial Intention and Attitudes
Authors: Sekerbayeva Aigerim , Tamenova Saltanat , Tarman Bulent , Demir Servet , Baizyldayeva Uldana , Yussupova Saule
Published: June 2023

This article examines the influence of the university environment and learning programs on students' entrepreneurial intentions and attitudes, considering the moderating roles of entrepreneurial self-efficacy and locus of control. The empirical analysis employs a multilevel (hierarchical) linear model, utilizing responses from 713 students across 30 universities in Kazakhstan who participated in the GUESSS 2021 project survey. Our findings reveal that students' entrepreneurial intentions are directly influenced by entrepreneurial self-efficacy and locus of control. However, the locus of control is also indirectly influenced by the university environment and learning program. The learning program's effect on both entrepreneurial aspirations and attitudes is mediated by self-efficacy. Locus of control, conversely, negatively affects both entrepreneurial attitudes and intentions in program learning. The study's results underscore that student entrepreneurship is shaped by personal factors such as self-efficacy and locus of control, alongside the university context. Interestingly, the findings also indicate interdependencies between these factors, further influencing students' entrepreneurial intentions and attitudes.