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ERJ Open Res 2022 Apr 16;8(2). Epub 2022 May 16.

Asthma UK Centre for Applied Research; Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

https://bit.ly/3J43Ouo. Read More

Antimicrob Agents Chemother 2022 May 18:e0013622. Epub 2022 May 18.

Division of Clinical Pharmacology, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa.

Ritonavir-boosted darunavir (DRV/r) and dolutegravir (DTG) are affected by induction of metabolizing enzymes and efflux transporters caused by rifampicin (RIF). This complicates the treatment of people living with HIV (PLWH) diagnosed with tuberculosis. Recent data showed that doubling DRV/r dose did not compensate for this effect, and hepatic safety was unsatisfactory. Read More

Infect Dis Ther 2022 May 17. Epub 2022 May 17.

Medigen Vaccine Biologics Corporation, Taipei, Taiwan.

Introduction: MVC-COV1901 is a protein subunit COVID-19 vaccine based on the stable prefusion spike protein S-2P adjuvanted with CpG 1018 and aluminum hydroxide. Interim results of a phase 2 clinical trial demonstrated favorable safety profile and immunogenicity and the vaccine has been authorized for use in Taiwan. However, waning antibody levels after immunization and variants of concern (VoC) could negatively impact vaccine-induced neutralization of virus. Read More

Invest New Drugs 2022 May 17. Epub 2022 May 17.

Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.

Poor tolerance to standard therapies and multi-drug resistance complicate treatment of elderly patients with acute myeloid leukemia (AML). It is therefore imperative to explore novel tolerable agents and target alternative pathways. KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization. Read More

J Immunother Cancer 2022 May;10(5)

Drug Development Department, Gustave Roussy Institute, Villejuif, France.

Background: This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs).

Methods: Emactuzumab (500-1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Read More

Blood 2022 May 16. Epub 2022 May 16.

NHLBI / NIH, Bethesda, Maryland, United States.

Polymerization of deoxygenated hemoglobin S (HbS) underlies the pathophysiology of sickle cell disease (SCD). In activating red blood cell pyruvate kinase and glycolysis, mitapivat (AG-348) increases adenosine triphosphate (ATP) levels and decreases the 2,3-diphosphoglycerate (2,3-DPG) concentration, an upstream precursor in glycolysis. Both changes have therapeutic potential for patients with SCD. Read More

Expert Opin Investig Drugs 2022 May 18:1-8. Epub 2022 May 18.

Clinical Trial Unit, First Hospital, Jilin UniversityPhase I , Changchun, Jilin, China.

Background: This is the first-in-human study to evaluate the pharmacokinetics, safety, and tolerability of TQC3564 (a novel CRTh2 receptor antagonist) in healthy Chinese subjects.

Research Design And Methods: This project was a phase Ia clinical study of TQC3564 as a single-ascending dose (SAD) (25 to 1200 mg) and a multiple-ascending dose (MAD) (100 or 500 mg, QD) as well as a two-period crossover food-effect study (300 mg).

Results:     In the SAD and MAD study, TQC3564 were found to be safe and well tolerated, without dose-dependent adverse events (AEs), and all AEs were mild or moderate in severity. Read More

Front Oncol 2022 26;12:811411. Epub 2022 Apr 26.

Division of Hematology/Oncology-The University of Cincinnati, Augusta, GA, United States.

Background: Autophagy is a catabolic process that is triggered in cells during periods of metabolic or hypoxic stress, which enables their survival during this challenge. Autophagy may also impart survival advantage to tumors cells undergoing attack from chemotherapy or radiation. Inhibition of early-stage autophagy can rescue cancer cells, while inhibition of late-stage autophagy enhances cell death due to accumulation of damaged organelles. Read More

Lancet Infect Dis 2022 May 11. Epub 2022 May 11.

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Background: Western (WEEV), eastern (EEEV), and Venezuelan (VEEV) equine encephalitis viruses are mosquito-borne pathogens classified as potential biological warfare agents for which there are currently no approved human vaccines or therapies. We aimed to evaluate the safety, tolerability, and immunogenicity of an investigational trivalent virus-like particle (VLP) vaccine, western, eastern, and Venezuelan equine encephalitis (WEVEE) VLP, composed of WEEV, EEEV, and VEEV VLPs.

Methods: The WEVEE VLP vaccine was evaluated in a phase 1, randomised, open-label, dose-escalation trial at the Hope Clinic of the Emory Vaccine Center at Emory University, Atlanta, GA, USA. Read More

Eur J Cancer 2022 May 11;169:135-145. Epub 2022 May 11.

Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.

Background: S81694 is an inhibitor of monopolar spindle 1 kinase, a target expressed in proliferating cells. CL1-81694-001 was the first-in-human study aiming at identifying a safe dosing schedule in solid tumour patients.

Patients And Methods: This trial was based on inter-individual dose-escalation of single agent S81694 in cohorts of ≥3 patients to assess the safety and tolerability and determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase II dose (RP2D), with S81694 given on days 1,8,15 of a 28-day cycle as 1-h infusion. Read More

J Clin Med 2022 May 5;11(9). Epub 2022 May 5.

Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA 23226, USA.

This study investigates plan quality generated by an MR-Linac (MRL) treatment planning system (TPS) for 5-fraction stereotactic body radiation therapy (SBRT) of primary pancreatic cancer (PCa). In addition, an isotoxic dose escalation was investigated with the MRL TPS based on stereotactic MR-guided adaptive radiation therapy (SMART) trial constraints. A clinical workflow was developed for adaptive and non-adaptive treatments with the MRL, on which a time-driven activity-based costing (TDABC) analysis was performed to quantify clinical efficacy. Read More

Trials 2022 May 13;23(1):401. Epub 2022 May 13.

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK.

Background: Mesenchymal stromal cells (MSCs) may be of benefit in ARDS due to immunomodulatory and reparative properties. This trial investigates a novel CD362 enriched umbilical cord derived MSC product (REALIST ORBCEL-C), produced to Good Manufacturing Practice standards, in patients with moderate to severe ARDS due to COVID-19 and ARDS due to other causes.

Methods: Phase 1 is a multicentre open-label dose-escalation pilot trial. Read More

BMC Med Imaging 2022 May 13;22(1):86. Epub 2022 May 13.

College of Radiology, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117, Jinan, China.

Purpose: To analyse the changes in brain white matter before and after radiotherapy (RT) by applying multisequence MR radiomics features and to establish a relationship between the changes in radiomics features and radiation dose.

Methods: Eighty-eight patients with brain tumours who had undergone RT were selected in this study, and MR images (T1, T1+C, T2FLAIR, T2, DWI, and ASL) before and after RT were obtained. The brain white matter was delineated as an ROI under dose gradients of 0-5 Gy, 5-10 Gy, 10-15 Gy, 15-20 Gy, 20-30 Gy, 30-40 Gy, and 40-50 Gy. Read More

Clin Ther 2022 May 10. Epub 2022 May 10.

Clinical Trial Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing, China; Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Purpose: CN-105 is an IV, apolipoprotein E-mimetic pentapeptide. Preclinical studies have reported that CN-105 effectively down-regulates neuroinflammatory responses in microglia and mitigates neuronal excitotoxicity following acute brain injury. The CN-105 Phase I and II trials that have been done in the United States have demonstrated that CN-105 was well tolerated in US participants. Read More

Clin Cancer Res 2022 May 12. Epub 2022 May 12.

Franciszek Lukaszczyk Oncology Center, Bydgoszcz, Poland.

Purpose: Dual timepoint FET-PET acquisition (10 and 60 minutes after FET injection) improves the definition of glioblastoma location and shape. Here we evaluated the safety and efficacy of simultaneous integrated boost (SIB) planned using dual FET-PET for postoperative glioblastoma treatment.

Experimental Design: In this prospective pilot study (March 2017-December 2020), 17 patients qualified for FET-PET-based SIB intensity-modulated radiotherapy after resection. Read More

Strahlenther Onkol 2022 May 12. Epub 2022 May 12.

Department of Radiation Oncology, University of Wuerzburg, Josef-Schneider-Str. 11, 97080, Würzburg, Germany.

Purpose: Dose-escalated external beam radiation therapy (EBRT) and EBRT + high-dose-rate brachytherapy (HDR-BT) boost are guideline-recommended treatment options for localized prostate cancer. The purpose of this study was to compare long-term outcome and toxicity of dose-escalated EBRT versus EBRT + HDR-BT boost.

Methods: From 2002 to 2019, 744 consecutive patients received either EBRT or EBRT + HDR-BT boost, of whom 516 patients were propensity score matched. Read More

Nat Med 2022 May 12. Epub 2022 May 12.

Houston AIDS Research Team, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, USA.

HIV-1 therapy with single or dual broadly neutralizing antibodies (bNAbs) has shown viral escape, indicating that at least a triple bNAb therapy may be needed for robust suppression of viremia. We performed a two-part study consisting of a single-center, randomized, double-blind, dose-escalation, placebo-controlled first-in-human trial of the HIV-1 V2-glycan-specific antibody PGDM1400 alone or in combination with the V3-glycan-specific antibody PGT121 in 24 adults without HIV in part 1, as well as a multi-center, open-label trial of the combination of PGDM1400, PGT121 and the CD4-binding-site antibody VRC07-523LS in five viremic adults living with HIV not on antiretroviral therapy (ART) in part 2 ( NCT03205917 ). The primary endpoints were safety, tolerability and pharmacokinetics for both parts and antiviral activity among viremic adults living with HIV and not on ART for part 2 of the study. Read More

Gynecol Oncol 2022 May 9. Epub 2022 May 9.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, United States of America.

Purpose: The management of vulvar cancer with clinically negative groin lymph nodes but with positive sentinel lymph node biopsy (SLNB) is controversial, with options including inguinofemoral lymphadenectomy (IFL) and/or adjuvant chemotherapy and radiotherapy. We used the National Cancer Database (NCDB) to examine trends in the management of clinically node negative, pathologically node positive (cN-/pN+) patients.

Methods: The NCDB was used to identify cN-/pN+ vulvar cancer patients. Read More

Platelets 2022 May 13:1-7. Epub 2022 May 13.

Department of Pharmacy, Peking University First Hospital, Beijing, China.

The thrombopoietin mimetic peptide for injection is a second-generation thrombopoietin receptor agonist (TPO-RA) used in the treatment of patients with immune thrombocytopenia. The aim of the present study was to assess the safety, tolerance, pharmacokinetic and pharmacodynamic properties of thrombopoietin mimetic peptide for injection in Chinese healthy volunteers. A randomized, placebo-controlled, double-blind, dose-escalation study was conducted in healthy Chinese subjects aged 18-50 years. Read More

Anesth Analg 2022 May 12. Epub 2022 May 12.

Department of Anesthesiology, Duke University, Durham, North Carolina.

Background: Intraperitoneal chloroprocaine has been used during cesarean delivery to supplement suboptimal neuraxial anesthesia for decades. The short in vitro half-life of chloroprocaine (11-21 seconds) has been cited to support the safety of this approach. However, there are no data regarding the rate of absorption, representing patient drug exposure, through this route of administration. Read More

Lancet Microbe 2021 Jul 15;2(7):e291-e299. Epub 2021 Apr 15.

Tropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia; Infectious Diseases Unit, Department of General Medicine, Royal Children's Hospital Melbourne, Melbourne, VIC, Australia.

Background: Streptococcus pyogenes is a leading cause of infection-related morbidity and mortality. A reinvigorated vaccine development effort calls for new clinically relevant human S pyogenes experimental infection models to support proof of concept evaluation of candidate vaccines. We describe the initial Controlled Human Infection for Vaccination Against S pyogenes (CHIVAS-M75) study, in which we aimed to identify a dose of emm75 S pyogenes that causes acute pharyngitis in at least 60% of volunteers when applied to the pharynx by swab. Read More

Lancet Microbe 2021 Sep 25;2(9):e429-e440. Epub 2021 Jun 25.

Division of Mucosal Immunology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Medicine, School of Medicine and CU-UCSD Center for Mucosal Immunology, Allergy and Vaccine, University of California, San Diego, San Diego, CA, USA. Electronic address:

Background: There are an estimated 1·3-4·0 million cases of cholera and 20 000-140 000 cholera-related deaths worldwide each year. The rice-based cholera toxin B subunit (CTB) vaccine, MucoRice-CTB, is an oral candidate vaccine that does not require a cold chain, has shown efficacy in animal models, and could be of benefit in places where there is a paucity of medical infrastructure. We aim to assess the safety, tolerability, and immunogenicity of MucoRice-CTB in humans. Read More

Lancet Microbe 2022 Feb 6;3(2):e113-e123. Epub 2021 Dec 6.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands.

Background: A recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP) vaccine has been reported as safe, immunogenic, and highly protective in a ring vaccination trial. We aimed to identify transcriptomic immune response biomarker signatures induced by vaccination and associated signatures with its immunogenicity and reactogenicity to better understand the potential mechanisms of action of the vaccine.

Methods: 354 healthy adult volunteers were vaccinated in randomised, double-blind, placebo-controlled trials in Europe (Geneva, Switzerland [November, 2014, to January, 2015]) and North America (USA [Dec 5, 2014, to June 23, 2015]), and dose-escalation trials in Africa (Lambaréné, Gabon [November, 2014, to January, 2015], and Kilifi, Kenya [December, 2014, to January, 2015]) using different doses of the recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP; 3 × 10 to 1 × 10 plaque-forming units [pfu]). Read More

Clinicoecon Outcomes Res 2022 3;14:357-369. Epub 2022 May 3.

Analysis Group, Inc., Boston, MA, USA.

Purpose: Current pharmacologic management of paroxysmal nocturnal hemoglobinuria (PNH) consists of C5 inhibitors, eculizumab and ravulizumab; however, because patients experience incomplete symptom control, off-label doses may be utilized. We conducted a retrospective, longitudinal cohort study of provider-based claims data to assess the real-world eculizumab dosing patterns in PNH patients.

Patients And Methods: Patients were ≥12 years, received ≥2 eculizumab infusions between January 1, 2015 and September 30, 2019, and had ≥3 months of continuous clinical activity prior to index. Read More

Med Phys 2022 May 9. Epub 2022 May 9.

Department of Radiation Oncology, Emory University, Atlanta, Georgia, USA.

Purpose: Dose escalation to dominant intraprostatic lesions (DILs) is a novel treatment strategy to improve the treatment outcome of prostate radiation therapy. Treatment planning requires accurate and fast delineation of the prostate and DILs. In this study, a 3D cascaded scoring convolutional neural network is proposed to automatically segment the prostate and DILs from MRI. Read More

J Drugs Dermatol 2022 May;21(5):472-477

This single-center, open label, dose escalation cohort study evaluated the safety and efficacy of various doses of intralesional injections of TGF-β1/COX-2 combined with histidine-lysine polypeptide (siRNA/HKP) nanoparticle silencing therapeutic in patients with cutaneous in situ squamous cell carcinoma. Twenty-five patients (mean age: 67, SD: 10 years; 52% men) with cutaneous in situ squamous cell carcinoma participated. TGF-β1/COX-2 siRNA/HKP nanoparticle therapeutic was injected weekly for up to 6 weeks based on the following dosing cohorts: 10 μg/treatment, 20 μg/treatment, 30 μg/treatment, 60 μg/treatment, and 120 μg/treatment. Read More

JAMA Neurol 2022 May 9. Epub 2022 May 9.

Department of Neuroscience, University of California, San Diego, San Diego.

Importance: Individuals with Down syndrome (DS) are at high risk of developing Alzheimer disease due to an increased dose of the amyloid precursor protein gene, APP, which leads to increased levels of full-length APP and its products, including amyloid-β (Aβ). The liposome-based antiamyloid ACI-24 vaccine is intended to treat neurological disorders caused by misfolded Aβ pathological protein. However, the safety, tolerability, and immunogenicity of the ACI-24 vaccine among adults with DS have not been fully examined. Read More

ESMO Open 2022 May 5;7(3):100473. Epub 2022 May 5.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing. Electronic address:

Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) resistance frequently occurs in patients with non-small-cell lung cancer (NSCLC). EGFR Thr790Met mutation (T790M+) is seen in ∼50% of patients. We assessed the safety, tolerability, and pharmacokinetics (PK) of BPI-15086, a novel, ATP-competitive, irreversible, third-generation, mutation-selective EGFR-TKI in patients with EGFR T790M-mutated NSCLC. Read More

BMC Cancer 2022 May 6;22(1):511. Epub 2022 May 6.

Department of Medical Oncology, Leiden University, Leiden, The Netherlands.

Background: Acquired resistance to approved tyrosine kinase inhibitors limits their clinical use in patients with gastrointestinal stromal tumor (GIST). This study investigated the safety, tolerability and efficacy of alpelisib, a phosphatidylinositol 3-kinase inhibitor, used in combination with imatinib in patients with advanced GIST who had failed prior therapy with both imatinib and sunitinib.

Methods: This phase 1b, multicenter, open-label study consisted of 2 phases: dose escalation and dose expansion. Read More

BMJ Open 2022 May 6;12(5):e056264. Epub 2022 May 6.

Department of Cardiothoracic Surgery, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China

Introduction: Heart failure (HF) is a growing global public health burden. However, due to the very limited regenerative capacity of mature cardiomyocytes in the adult mammalian heart, conventional treatments can only improve the symptoms of HF but fail to restore cardiac function. Heart transplantation is limited by a severe shortage of donors. Read More