Results and lessons learnt from the WISTERIA phase I trial combining AZD1775 with cisplatin pre- or post-operatively in head and neck cancer.

Background: Pre-clinical studies suggest AZD1775, a WEE1 kinase inhibitor, potentiates the activity of various chemotherapeutic agents.

Methods: WISTERIA was a prospective, parallel two-group, open-label, dose-finding, phase I clinical trial. Eligible patients had histologically confirmed oral, laryngeal, or hypopharyngeal squamous cell carcinoma, ECOG performance status 0/1, and aged ≥18-to-≤70 years.

Evaluation of hypofractionated adaptive radiotherapy using the MR Linac in localised pancreatic cancer: protocol summary of the Emerald-Pancreas phase 1/expansion study located at Oxford University Hospital, UK.

Introduction: Online adaptive MR-guided radiotherapy allows for dose escalation to pancreatic cancer while sparing surrounding critical organs. We seek to evaluate the safety of delivering hypofractionated five-fraction, three-fraction and single-fraction MR-guided stereotactic ablative radiotherapy (SABR) to the pancreas.

Methods And Analysis: This is a single-centre three-arm phase 1 non-randomised safety study.

Design, Synthesis, and Evaluation of Novel Δ-Thiazolino 2-Pyridone Derivatives That Potentiate Isoniazid Activity in an Isoniazid-Resistant Mutant.

() drug resistance poses an alarming threat to global tuberculosis control. We previously reported that , a ring-fused thiazolo-2-pyridone, inhibits respiration, blocks biofilm formation, and restores the activity of the antibiotic isoniazid (INH) in INH-resistant isolates. This discovery revealed a new strategy to address INH resistance.

The oligometastatic paradigm and the role of radiotherapy.

Most cancer-related deaths are due to metastatic disease. There is now an emerging evidence base suggesting that a subgroup of metastatic patients benefit significantly from local resection (surgery) or ablation (stereotactic ablative body radiation, SABR) of their metastatic sites. These patients are in what has been termed the 'oligometastatic state', a transitional window between local and disseminated disease where locally ablative, metastasis-directed therapy prolongs progression-free survival, improves overall survival and sometimes achieves cure.

FLASHlab@PITZ: New R&D platform with unique capabilities for electron FLASH and VHEE radiation therapy and radiation biology under preparation at PITZ.

At the Photo Injector Test facility at DESY in Zeuthen (PITZ), an R&D platform for electron FLASH and very high energy electron radiation therapy and radiation biology is being prepared (FLASHlab@PITZ). The beam parameters available at PITZ are worldwide unique. They are based on experiences from 20 + years of developing high brightness beam sources and an ultra-intensive THz light source demonstrator for ps scale electron bunches with up to 5 nC bunch charge at MHz repetition rate in bunch trains of up to 1 ms length, currently 22 MeV (upgrade to 250 MeV planned).

Implementation of Stereotactic MRI-Guided Adaptive Radiotherapy (SMART) for Hepatobiliary and Pancreatic Cancers in the United Kingdom - Fifty in Five.

The first MRIdian® MR linear accelerator (MR-Linac; ViewRay, Oakwood Village, Ohio) in the United Kingdom went live in December 2019 following a record installation time. Stereotactic MRI-guided Adaptive Radiotherapy (SMART) has since been implemented and has advantages of excellent soft tissue definition of both target and organs at risk (OARs), real-time target and OAR visualisation on cine-MRI, daily recontouring of target and critical OARs with live online plan adaptation/re-optimisation, and automatic respiratory-gated treatment delivery. We present a multi-disciplinary narrative and technical description of how this innovative technique was implemented for hepatobiliary (HPB) cancers.

Safety and Treatment Outcomes of Nivolumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Retrospective Multicenter Cohort Study.

Nivolumab is an anti-PD-1 monoclonal antibody currently used as immunotherapy for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with evidence of disease progression after platinum-based chemotherapy. This study evaluates real-world safety and treatment outcomes of non-trial nivolumab use. A retrospective multicenter cohort study of patients with recurrent/metastatic HNSCC treated with nivolumab between January 2017 and March 2020 was performed.

Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion.

RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC of 1.

Sprouty2 positively regulates T cell function and airway inflammation through regulation of CSK and LCK kinases.

The function of Sprouty2 (Spry2) in T cells is unknown. Using 2 different (inducible and T cell-targeted) knockout mouse strains, we found that Spry2 positively regulated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling by modulating the activity of LCK. Spry2-/- CD4+ T cells were unable to activate LCK, proliferate, differentiate into T helper cells, or produce cytokines.

Considerations for the treatment of pancreatic cancer during the COVID-19 pandemic: the UK consensus position.

The coronavirus disease 2019 (COVID-19) pandemic epicentre has moved to the USA and Europe, where it is placing unprecedented demands on healthcare resources and staff availability. These service constraints, coupled with concerns relating to an increased incidence and severity of COVID-19 among patients with cancer, should lead to re-consideration of the risk-benefit balance for standard treatment pathways. This is of particular importance to pancreatic cancer, given that standard diagnostic modalities such as endoscopy may be restricted, and that disease biology precludes significant delays in treatment.

A phase 1 trial of the safety, tolerability and biological effects of intravenous Enadenotucirev, a novel oncolytic virus, in combination with chemoradiotherapy in locally advanced rectal cancer (CEDAR).

Background: Chemoradiotherapy remains the standard of care for locally advanced rectal cancer. Efforts to intensify treatment and increase response rates have yet to yield practice changing results due to increased toxicity and/or absence of increased radiosensitization. Enadenotucirev (EnAd) is a tumour selective, oncolytic adenovirus which can be given intravenously.

Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based inhibitors.

infections are a global health problem and new approaches to treat with drugs of high specificity would be valuable. A library of substituted ring fused 2-pyridones has been synthesized and evaluated for their ability to attenuate infectivity. pharmacokinetic studies were performed, with the best candidates demonstrating that a C8-methylsulfonamide substituent improved pharmacokinetic properties important for oral administration.

Phase I trial of WEE1 inhibition with chemotherapy and radiotherapy as adjuvant treatment, and a window of opportunity trial with cisplatin in patients with head and neck cancer: the trial protocol.

Introduction: Patients with head and neck squamous cell carcinoma with locally advanced disease often require multimodality treatment with surgery, radiotherapy and/or chemotherapy. Adjuvant radiotherapy with concurrent chemotherapy is offered to patients with high-risk pathological features postsurgery. While cure rates are improved, overall survival remains suboptimal and treatment has a significant negative impact on quality of life.

Optimal identification of human conventional and nonconventional (CRTH2IL7Rα) ILC2s using additional surface markers.

Background: Human type 2 innate lymphoid cells (ILC2s) are identified by coupled detection of CRTH2 and IL7Rα on lineage negative (Lin) cells. Type 2 cytokine production by CRTH2IL7Rα innate lymphoid cells (ILCs) is unknown.

Objective: We sought to identify CRTH2IL7Rα type 2 cytokine-producing ILCs and their disease relevance.

Chemical disarming of isoniazid resistance in .

() killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of that are resistant to frontline antibiotics.

Durvalumab for recurrent or metastatic head and neck squamous cell carcinoma: Results from a single-arm, phase II study in patients with ≥25% tumour cell PD-L1 expression who have progressed on platinum-based chemotherapy.

Background: Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) progressing on platinum-based chemotherapy have poor prognoses and limited therapeutic options. Programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) are frequently upregulated in HNSCC. The international, multi-institutional, single-arm, phase II HAWK study (NCT02207530) evaluated durvalumab monotherapy, an anti-PD-L1 monoclonal antibody, in PD-L1-high patients with platinum-refractory R/M HNSCC.

State of the Art in Respiratory Syncytial Virus Drug Discovery and Development.

Respiratory syncytial virus (RSV) is a globally prevalent viral infection with limited treatment options which hospitalizes millions each year. Treatment options have been limited to palivizumab, a monoclonal antibody, approved for prophylaxis in high-risk infants and ribavirin with very limited efficacy and significant safety concerns. This Perspective surveys the range of direct acting antiviral agents (DAAs) that target key steps in the viral life cycle.

Observation of High Transformer Ratio Plasma Wakefield Acceleration.

Particle-beam-driven plasma wakefield acceleration (PWFA) enables various novel high-gradient techniques for powering future compact light-source and high-energy physics applications. Here, a driving particle bunch excites a wakefield response in a plasma medium, which may rapidly accelerate a trailing witness beam. In this Letter, we present the measurement of ratios of acceleration of the witness bunch to deceleration of the driver bunch, the so-called transformer ratio, significantly exceeding the fundamental theoretical and thus far experimental limit of 2 in a PWFA.

New insights in the diagnosis of chronic refractory cough.

Background: Chronic Refractory Cough (CRC) is a common condition that significantly impairs patients' quality of life. Unfortunately, in many situations patients continue to experience CRC in spite of following published guidelines for diagnosis and treatment.

Methods: 99 patients were referred to National Jewish Health (NJH), a specialty respiratory center for evaluation of CRC (cough ≥ 8 weeks duration).

The Clinical Utility of Cell-Free DNA Measurement in Differentiated Thyroid Cancer: A Systematic Review.

Background: Cell-free DNA (cfDNA) can be detected in the circulation of healthy individuals, but is found in higher concentrations in cancer patients. Furthermore, mutations in tumor cells can be identified in circulating DNA fragments. This has been the subject of significant interest in the field of cancer research, but little has been published in thyroid cancer.

Thiazolino 2-Pyridone Amide Isosteres As Inhibitors of Chlamydia trachomatis Infectivity.

Chlamydia trachomatis is a global health burden due to its prevalence as a sexually transmitted disease and as the causative agent of the eye infection trachoma. We recently discovered 3-amido thiazolino 2-pyridones which attenuated C. trachomatis infectivity without affecting host cell or commensal bacteria viability.

Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: The role of thymic stromal lymphopoietin.

Background: Type 2 innate lymphoid cells (ILC2s) represent an important type 2 immune cell. Glucocorticoid regulation of human ILC2s is largely unknown.

Objective: We sought to assess steroid resistance of human blood and airway ILC2s from asthmatic patients and to examine its mechanism of induction.

Airway and serum biochemical correlates of refractory neutrophilic asthma.

Background: Despite progress in the diagnosis and management of asthma, many patients have poorly controlled or refractory asthma (RA). The mechanism of this RA is not well understood.

Objective: We sought to explore the relationship between neutrophils and other biomarkers of RA.

Mechanism of T2/T17-predominant and neutrophilic T2/T17-low subtypes of asthma.

Background: The mechanism of T2/T17-predominant and T2/T17-low asthma is unknown.

Objective: We sought to study the immune mechanism of T2/T17-predominant and T2/T17-low asthma.

Methods: In a previously reported cohort of 60 asthmatic patients, 16 patients were immunophenotyped with T2/T17-predominant asthma and 22 patients with T2/T17-low asthma.