Total Synthesis of (±)-Welwitindolinone A Isonitrile

A highly stereoselective total synthesis of the alkaloid natural product welwitindolinone A isonitrile has been completed. The synthesis utilizes a chloronium ion mediated semi-pinacol rearrangement to simultaneously install the C10 quaternary center and neopentyl chlorine and a novel anionic cyclization to construct the spiro-oxindole with complete stereocontrol

Evolution of a Synthetic Strategy: Total Synthesis of (±)-Welwitindolinone A Isonitrile

An efficient and highly stereoselective total synthesis of the natural product (±)-welwitindolinone A isonitrile (1) is described. The bicyclo[4.2.0]octane core of 1 was established by a regio- and diastereoselective [2+2] ketene cycloaddition. The C12 quaternary center and vicinal stereogenic chlorine were installed in a single operation with excellent stereocontrol via a chloronium ion mediated semipinacol rearrangement. Described strategies for construction of the spiro-oxinole include a SmI_2−LiCl mediated reductive cyclization and a novel anionic cyclization that simultaneously constructs the spiro-oxindole and vinyl isonitrile moieties

Understanding the transmission dynamics of Leishmania donovani to provide robust evidence for interventions to eliminate visceral leishmaniasis in Bihar, India.

Visceral Leishmaniasis (VL) is a neglected vector-borne disease. In India, it is transmitted to humans by Leishmania donovani-infected Phlebotomus argentipes sand flies. In 2005, VL was targeted for elimination by the governments of India, Nepal and Bangladesh by 2015. The elimination strategy consists of rapid case detection, treatment of VL cases and vector control using indoor residual spraying (IRS). However, to achieve sustained elimination of VL, an appropriate post elimination surveillance programme should be designed, and crucial knowledge gaps in vector bionomics, human infection and transmission need to be addressed. This review examines the outstanding knowledge gaps, specifically in the context of Bihar State, India.The knowledge gaps in vector bionomics that will be of immediate benefit to current control operations include better estimates of human biting rates and natural infection rates of P. argentipes, with L. donovani, and how these vary spatially, temporally and in response to IRS. The relative importance of indoor and outdoor transmission, and how P. argentipes disperse, are also unknown. With respect to human transmission it is important to use a range of diagnostic tools to distinguish individuals in endemic communities into those who: 1) are to going to progress to clinical VL, 2) are immune/refractory to infection and 3) have had past exposure to sand flies.It is crucial to keep in mind that close to elimination, and post-elimination, VL cases will become infrequent, so it is vital to define what the surveillance programme should target and how it should be designed to prevent resurgence. Therefore, a better understanding of the transmission dynamics of VL, in particular of how rates of infection in humans and sand flies vary as functions of each other, is required to guide VL elimination efforts and ensure sustained elimination in the Indian subcontinent. By collecting contemporary entomological and human data in the same geographical locations, more precise epidemiological models can be produced. The suite of data collected can also be used to inform the national programme if supplementary vector control tools, in addition to IRS, are required to address the issues of people sleeping outside

Outcome and biomarker analysis from a multi-centre phase 2 study of ipilimumab in combination with carboplatin and etoposide (ICE) as first line therapy for extensive stage small cell lung cancer.

BACKGROUND: To evaluate safety and efficacy of ipilimumab combined with standard first-line chemotherapy for patients with extensive stage SCLC. METHODS: Chemotherapy-naïve extensive stage SCLC patients were treated with carboplatin and etoposide up to six cycles. Ipilimumab 10 mg/kg was given on day 1 of cycles 3-6 and every 12 weeks. Response was assessed by RECIST v1.0 and immune related response criteria (irRC). The primary endpoint was 1-year progression-free survival (PFS) according to RECIST. Secondary endpoints included PFS by irRC (irPFS) and overall survival (OS). Autoantibody serum levels were evaluated and correlated with clinical outcomes. RESULTS: 42 patients were enrolled between September 2011-April 2014, 39 evaluable for safety and 38 for efficacy. 6/38 patients (15.8% [95% CI: 7.4%-30.4%]) were alive and progression-free at 1-year by RECIST. Median PFS was 6.9 months (95%CI: 5.5-7.9). Median irPFS was 7.3 months (95% CI: 5.5-8.8). Median OS was 17.0 months (95% CI: 7.9-24.3). In patients evaluable for response, 21/29 patients (72.4%) achieved an objective response by RECIST and 28/33 (84.8%) by irRC. All patients experienced at least one adverse event; 35/39 (89.7%) patients developed at least one toxicity ≥ Grade 3; in 27 (69.2%) this was related to ipilimumab. Five deaths were reported to be related to ipilimumab. The positivity of an autoimmune profile at baseline was associated with improved outcomes and severe neurological toxicity. CONCLUSION: Ipilimumab in combination with carboplatin and etoposide might benefit a subgroup of patients with advanced SCLC. Autoantibody analysis correlates with treatment benefit and toxicity and warrants further investigation

Evaluating the potential of ecological niche modelling as a component in marine non-indigenous species risk assessments

Marine biological invasions have increased with the development of global trading, causing the homogenization of communities and the decline of biodiversity. A main vector is ballast water exchange from shipping. This study evaluates the use of ecological niche modelling (ENM) to predict the spread of 18 non-indigenous species (NIS) along shipping routes and their potential habitat suitability (hot/cold spots) in the Baltic Sea and Northeast Atlantic. Results show that, contrary to current risk assessment methods, temperature and sea ice concentration determine habitat suitability for 61% of species, rather than salinity (11%). We show high habitat suitability for NIS in the Skagerrak and Kattegat, a transitional area for NIS entering or leaving the Baltic Sea. As many cases of NIS introduction in the marine environment are associated with shipping pathways, we explore how ENM can be used to provide valuable information on the potential spread of NIS for ballast water risk assessment

Daily use of lateral flow devices by contacts of confirmed COVID-19 cases to enable exemption from isolation compared with standard self-isolation to reduce onward transmission of SARS-CoV-2 in England: a randomised, controlled, non-inferiority trial

BACKGROUND: In the UK, during the study period (April to July, 2021), all contacts of people with COVID-19 were required to self-isolate for 10 days, which had adverse impacts on individuals and society. Avoiding the need to self-isolate for those who remain uninfected would be beneficial. We investigated whether daily use of lateral flow devices (LFDs) to test for SARS-CoV-2, with removal of self-isolation for 24 h if negative, could be a safe alternative to self-isolation as a means to minimise onward transmission of the virus. METHODS: We conducted a randomised, controlled, non-inferiority trial in adult contacts identified by COVID-19 contact tracing in England. Consenting participants were randomly assigned to self-isolation (single PCR test, 10-day isolation) or daily contact testing (DCT; seven LFD tests, two PCR tests, no isolation if negative on LFD); participants from a single household were assigned to the same group. Participants were prospectively followed up, with the effect of each intervention on onward transmission established from routinely collected NHS Test and Trace contact tracing data for participants who tested PCR-positive for SARS-CoV-2 during the study period and tertiary cases arising from their contacts (ie, secondary contacts). The primary outcome of the study was the attack rate, the percentage of secondary contacts (close contacts of SARS-CoV-2-positive study participants) who became COVID-19 cases (tertiary cases) in each group. Attack rates were derived from Bernoulli regression models using Huber-White (robust) sandwich estimator clustered standard errors. Attack rates were adjusted for household exposure, vaccination status, and ability to work from home. The non-inferiority margin was 1·9%. The primary analysis was a modified intention-to-treat analysis excluding those who actively withdrew from the study as data from these participants were no longer held. This study is registered with the Research Registry (number 6809). Data collection is complete; analysis is ongoing. FINDINGS: Between April 29 and July 28, 2021, 54 923 eligible individuals were enrolled in the study, with final group allocations (following withdrawals) of 26 123 (52·6%) participants in the DCT group and 23 500 (47·4%) in the self-isolation group. Overall, 4694 participants tested positive for SARS-CoV-2 by PCR (secondary cases), 2364 (10·1%) in the self-isolation group and 2330 (8·9%) in the DCT group. Adjusted attack rates (among secondary contacts) were 7·5% in the self-isolation group and 6·3% in the DCT group (difference of –1·2% [95% CI –2·3 to –0·2]; significantly lower than the non-inferiority margin of 1·9%). INTERPRETATION: DCT with 24 h exemption from self-isolation for essential activities appears to be non-inferior to self-isolation. This study, which provided evidence for the UK Government's daily lateral flow testing policy for vaccinated contacts of COVID-19 cases, indicated that daily testing with LFDs could allow individuals to reduce the risk of onward transmission while minimising the adverse effects of self-isolation. Although contacts in England are no longer required to isolate, the findings will be relevant for future policy decisions around COVID-19 or other communicable infections. FUNDING: UK Government Department of Health and Social Care

New Approaches to SCLC Therapy: From the Laboratory to the Clinic

The outcomes of patients with SCLC have not yet been substantially impacted by the revolution in precision oncology, primarily owing to a paucity of genetic alterations in actionable driver oncogenes. Nevertheless, systemic therapies that include immunotherapy are beginning to show promise in the clinic. Although, these results are encouraging, many patients do not respond to, or rapidly recur after, current regimens, necessitating alternative or complementary therapeutic strategies. In this review, we discuss ongoing investigations into the pathobiology of this recalcitrant cancer and the therapeutic vulnerabilities that are exposed by the disease state. Included within this discussion, is a snapshot of the current biomarker and clinical trial landscapes for SCLC. Finally, we identify key knowledge gaps that should be addressed to advance the field in pursuit of reduced SCLC mortality. This review largely summarizes work presented at the Third Biennial International Association for the Study of Lung Cancer SCLC Meeting. (C) 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved