Modelling the habitat of the endangered Carpentarian Grasswren (Amytornis dorotheae): The importance of spatio-temporal habitat availability in a fire prone landscape

Species distribution modelling (SDM), a tool increasingly adopted to quantify geographic range size, often predicts species’ distributions as static. However, habitat availability may exhibit spatial and temporal variation when dynamic processes, such as fire, determine suitability. Static SDM approaches may not satisfactorily represent this dynamic process. We investigated the potential use of SDM to quantify dynamic habitat availability by applying the MaxEnt SDM technique to model the habitat of the Carpentarian Grasswren (Amytornis dorotheae), an endangered Australian passerine dependent on long unburnt vegetation in a fire prone system. By adjusting a typical SDM approach to incorporate the dynamic nature of fire, we modelled the spatio-temporal variation of suitable habitat over 12 years and compared it to a static modelling approach. Incorporating fire as a dynamic process increased the importance of the fire variable to models (from 35% permutation importance) and improved model performance, as evaluated by the AUC using cross-validation. Our dynamic model revealed sizeable temporal variation in the area and spatial arrangement of suitable habitat that was not apparent in the static model. This result may partly solve the mystery of why the species occurs as widely separated populations despite the presence of seemingly suitable intervening habitat. In areas where the species is no longer found, habitat availability was less consistent due to frequent fire, and fire refugia was more limited and isolated, when compared to sites with recent records. These results demonstrate that, when compared to a static approach, a dynamic SDM approach can lead to improved understanding of dynamic ecological processes, and their impact on a species

A practical guide to the handling and administration of talimogene laherparepvec in Europe.

Talimogene laherparepvec is a herpes simplex virus-1-based intralesional oncolytic immunotherapy and is the first oncolytic virus to be approved in Europe. It is indicated for the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (stage IIIB, IIIC, and IVM1a) with no bone, brain, lung, or other visceral disease. Talimogene laherparepvec is a genetically modified viral therapy, and its handling needs special attention due to its deep freeze, cold-chain requirements, its potential for viral shedding, and its administration by direct intralesional injection. This review provides a practical overview of handling, storage, and administration procedures for this agent in Europe. Talimogene laherparepvec vials should be transported/stored frozen at a temperature of -90°C to -70°C, and once thawed, vials must not be refrozen. Universal precautions for preparation, administration, and handling should be followed to avoid accidental exposure. Health care providers should wear personal protective equipment, and materials that come into contact with talimogene laherparepvec should be disposed of in accordance with local institutional procedures. Individuals who are immunocompromised or pregnant should not prepare or administer this agent. Talimogene laherparepvec is administered by intralesional injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound. Treatment should be continued for ≥6 months. As with other immunotherapies, patients may experience an increase in the size of existing lesion(s) or the appearance of new lesions (ie, progression) prior to achieving a response ("pseudo-progression"). As several health care professionals (eg, physicians [dermatologists, surgeons, oncologists, radiologists], pharmacists, nurses) are involved in different stages of the process, there is a need for good interdisciplinary collaboration when using talimogene laherparepvec. Although there are specific requirements for this agent's storage, handling, administration, and disposal, these can be effectively managed in a real-world clinical setting through the implementation of training programs and straightforward standard operating procedures

HOX transcription factors are potential targets and markers in malignant mesothelioma

YesBackground The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development and which are dys-regulated in some cancers. In this study we examined the expression and oncogenic function of HOX genes in mesothelioma, a cancer arising from the pleura or peritoneum which is associated with exposure to asbestos. Methods We tested the sensitivity of the mesothelioma-derived lines MSTO-211H, NCI-H28, NCI-H2052, and NCI-H226 to HXR9, a peptide antagonist of HOX protein binding to its PBX co-factor. Apoptosis was measured using a FACS-based assay with Annexin, and HOX gene expression profiles were established using RT-QPCR on RNA extracted from cell lines and primary mesotheliomas. The in vivo efficacy of HXR9 was tested in a mouse MSTO-211H flank tumor xenograft model. Results We show that HOX genes are significantly dysregulated in malignant mesothelioma. Targeting HOX genes with HXR9 caused apoptotic cell death in all of the mesothelioma-derived cell lines, and prevented the growth of mesothelioma tumors in a mouse xenograft model. Furthermore, the sensitivity of these lines to HXR9 correlated with the relative expression of HOX genes that have either an oncogenic or tumor suppressive function in cancer. The analysis of HOX expression in primary mesothelioma tumors indicated that these cells could also be sensitive to the disruption of HOX activity by HXR9, and that the expression of HOXB4 is strongly associated with overall survival. Conclusion HOX genes are a potential therapeutic target in mesothelioma, and HOXB4 expression correlates with overall survival.The authors gratefully acknowledge the support of the British Lung Foundation, grant number ICAPPG10-1. KJH acknowledges support from the ICR/RM NIHR Biomedical Research Centre

Nivolumab versus investigator's choice in patients with recurrent or metastatic squamous cell carcinoma of the head and neck : efficacy and safety in CheckMate 141 by age

Objectives: Many patients with squamous cell carcinoma of the head and neck (SCCHN) are 6565 years old; comorbidities and other age-related factors may affect their ability to tolerate traditional chemotherapy. Nivolumab is the only immunotherapy to significantly improve overall survival (OS) versus investigator's choice (IC) of single-agent chemotherapy at primary analysis in a phase 3 trial (CheckMate 141) in patients with recurrent/metastatic SCCHN post-platinum therapy. In this post hoc analysis, we report efficacy and safety by age. Patients and methods: Eligible patients were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks (n = 240) or IC (methotrexate, docetaxel, or cetuximab n = 121). The primary endpoint of the trial was OS. For this analysis, outcomes were analyzed by age < 65 and 6565 years. The data cut-off date was September 2017 (minimum follow-up 24.2 months). Results: At baseline, 68 patients (28.3%) receiving nivolumab and 45 patients (37.2%) receiving IC were 6565 years. Baseline characteristics were generally similar across age groups. OS and tumor response benefits with nivolumab versus IC were maintained regardless of age. The 30-month OS rates of 11.2% (<65 years) and 13.0% ( 6565 years) with nivolumab were more than tripled versus corresponding IC rates of 1.4% and 3.3%, respectively. The nivolumab arm had a lower rate of treatment-related adverse events versus IC regardless of age, consistent with the overall patient population. Conclusion: In CheckMate 141, nivolumab resulted in a higher survival versus IC in patients <65 and 6565 years, with a manageable safety profile in both age groups. ClinicalTrials.gov: NCT02105636

Pembrolizumab for recurrent head and neck squamous cell carcinoma (HNSCC): Post hoc analyses of treatment options from the phase III KEYNOTE-040 trial

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The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC)

Head and neck cancers, including those of the lip and oral cavity, nasal cavity, paranasal sinuses, oropharynx, larynx and nasopharynx represent nearly 700,000 new cases and 380,000 deaths worldwide per annum, and account for over 10,000 annual deaths in the United States alone. Improvement in outcomes are needed for patients with recurrent and or metastatic squamous cell carcinoma of the head and neck (HNSCC). In 2016, the US Food and Drug Administration (FDA) granted the first immunotherapeutic approvals - the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab - for the treatment of patients with recurrent squamous cell carcinoma of the head and neck (HNSCC) that is refractory to platinum-based regimens. The European Commission followed in 2017 with approval of nivolumab for treatment of the same patient population, and shortly thereafter with approval of pembrolizumab monotherapy for the treatment of recurrent or metastatic HNSCC in adults whose tumors express PD-L1 with a 65 50% tumor proportion score and have progressed on or after platinum-containing chemotherapy. Then in 2019, the FDA granted approval for PD-1 inhibition as first-line treatment for patients with metastatic or unresectable, recurrent HNSCC, approving pembrolizumab in combination with platinum and fluorouracil for all patients with HNSCC and pembrolizumab as a single agent for patients with HNSCC whose tumors express a PD-L1 combined positive score 65 1. These approvals marked the first new therapies for these patients since 2006, as well as the first immunotherapeutic approvals in this disease. In light of the introduction of these novel therapies for the treatment of patients with head and neck cancer, The Society for Immunotherapy of Cancer (SITC) formed an expert committee tasked with generating consensus recommendations for emerging immunotherapies, including appropriate patient selection, therapy sequence, response monitoring, adverse event management, and biomarker testing. These consensus guidelines serve as a foundation to assist clinicians' understanding of the role of immunotherapies in this disease setting, and to standardize utilization across the field for patient benefit. Due to country-specific variances in approvals, availability and regulations regarding the discussed agents, this panel focused solely on FDA-approved drugs for the treatment of patients in the U.S

Identification and mitigation of a vibrational telescope systematic with application to spitzer

We observed Proxima Centauri with the Spitzer Space Telescope Infrared Array Camera five times in 2016 and 2017 to search for transits of Proxima Centauri b. Following standard analysis procedures, we found three asymmetric, transit-like events that are now understood to be vibrational systematics. This systematic is correlated with the width of the point-response function (PRF), which we measure with rotated and nonrotated-Gaussian fits with respect to the detector array. We show that the systematic can be removed with a novel application of an adaptive elliptical-aperture photometry technique, and compare the performance of this technique with fixed and variable circular-aperture photometry, using both BiLinearly Interpolated Subpixel Sensitivity (BLISS) maps and nonbinned Pixel-Level Decorrelation (PLD). With BLISS maps, elliptical photometry results in a lower standard deviation of normalized residuals, and reduced or similar correlated noise when compared to circular apertures. PLD prefers variable, circular apertures, but generally results in more correlated noise than BLISS. This vibrational effect is likely present in other telescopes and Spitzer observations, where correction could improve results. Our elliptical apertures can be applied to any photometry observations, and may be even more effective when applied to more circular PRFs than Spitzer's.The authors acknowledge support from the following: CATA-Basal/Chile PB06 Conicyt and Fondecyt/Chile project #1161218 (J.S.J.). Spanish MINECO programs AYA2016-79245-C03-03-P, ESP2017-87676-C05-02-R (E.R.), ESP2016-80435-C2-2-R (E.P.) and through the “Centre of Excellence Severo Ochoa” award SEV-2017-0709 (P.J.A.,C.R.-L., E.R.). STFC Consolidated Grant ST/P000592/1 (G.A.E.). NASA Planetary Atmospheres Program grant NNX12AI69G and NASA Astrophysics Data Analysis Program grant NNX13AF38G (R.C., J.H., K.M., M.H.). Spanish Ministry of Science, Innovation and Universities and the Fondo Europeo de Desarrollo Regional (FEDER) through grant ESP2016-80435-C2-1-R and PGC2018-098153-B-C33 (I.R.)

PATRIOT: A phase I study to assess the tolerability, safety and biological effects of a specific ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) as a single agent and in combination with palliative radiation therapy in patients with solid tumours.

PATRIOT is a phase I study of the ATR inhibitor, AZD6738, as monotherapy, and in combination with palliative radiotherapy. Here, we describe the protocol for this study, which opened in 2014 and is currently recruiting and comprises dose escalation of both drug and radiotherapy, and expansion cohorts

Measurement of the p-pbar -> Wgamma + X cross section at sqrt(s) = 1.96 TeV and WWgamma anomalous coupling limits

The WWgamma triple gauge boson coupling parameters are studied using p-pbar -> l nu gamma + X (l = e,mu) events at sqrt(s) = 1.96 TeV. The data were collected with the DO detector from an integrated luminosity of 162 pb^{-1} delivered by the Fermilab Tevatron Collider. The cross section times branching fraction for p-pbar -> W(gamma) + X -> l nu gamma + X with E_T^{gamma} > 8 GeV and Delta R_{l gamma} > 0.7 is 14.8 +/- 1.6 (stat) +/- 1.0 (syst) +/- 1.0 (lum) pb. The one-dimensional 95% confidence level limits on anomalous couplings are -0.88 < Delta kappa_{gamma} < 0.96 and -0.20 < lambda_{gamma} < 0.20.Comment: Submitted to Phys. Rev. D Rapid Communication