Direct Phenotypical and Functional Dysregulation of Primary Human B Cells by Human Immunodeficiency Virus (HIV) Type 1 In Vitro

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) induces a general dysregulation of immune system. Dysregulation of B cell compartment is generally thought to be induced by HIV-related immune activation and lymphopenia. However, a direct influence of HIV-1 particles on B cells was recently proposed as the third pathway of B cells dysregulation. METHODS/PRINCIPAL FINDINGS: We evaluated the direct and specific consequences of HIV-1 contact on activation, survival, proliferation and phenotype of primary B cells in vitro. Moreover, we examined expression of activation-induced cytidine deaminase (AID) mRNA that is responsible for class switch recombination (CSR) and somatic hypermutation (SHM). Here, we report that changes observed in cellular proliferation, phenotypes and activation of B cells could be caused by direct contact between HIV-1 particles and primary B cells in vitro. Finally, direct HIV-1-derived B cells activation led to the increase of AID mRNA expression and its subsequent CSR function was detected in vitro. CONCLUSION/SIGNIFICANCE: We showed that HIV-1 could directly induce primary B cells dysregulation triggering phenotypical and functional abilities of B cells in vitro that could explain in some extent early B-cell abnormalities in HIV disease

Acyloxylation of Cyclic Enones: Synthesis of Densely Oxygenated Guaianolides

The α′-acyloxylation of cyclic enones with linear carboxylic acids is described. The reaction is promoted by KMnO4 in the presence of a carboxylic acid and its corresponding carboxylic anhydride. The optimization of the reaction has been carried out using the statistical methodology known as design of experiments. The optimized reaction conditions have been evaluated in terms of substrate scope and compatibility with different functional groups. The methodology has been applied to the synthesis of densely oxygenated guaianes and guaianolides

Selection of the appropriate method for the assessment of insulin resistance

Insulin resistance is one of the major aggravating factors for metabolic syndrome. There are many methods available for estimation of insulin resistance which range from complex techniques down to simple indices. For all methods of assessing insulin resistance it is essential that their validity and reliability is established before using them as investigations. The reference techniques of hyperinsulinaemic euglycaemic clamp and its alternative the frequently sampled intravenous glucose tolerance test are the most reliable methods available for estimating insulin resistance. However, many simple methods, from which indices can be derived, have been assessed and validated e.g. homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI). Given the increasing number of simple indices of IR it may be difficult for clinicians and researchers to select the most appropriate index for their studies. This review therefore provides guidelines and advices which must be considered before proceeding with a study

Joint Constraints on Galactic Diffuse Neutrino Emission from the ANTARES and IceCube Neutrino Telescopes

[EN] The existence of diffuse Galactic neutrino production is expected from cosmic-ray interactions with Galactic gas and radiation ¿elds. Thus, neutrinos are a unique messenger offering the opportunity to test the products of Galactic cosmic-ray interactions up to energies of hundreds of TeV. Here we present a search for this production using ten years of Astronomy with a Neutrino Telescope and Abyss environmental RESearch (ANTARES) track and shower data, as well as seven years of IceCube track data. The data are combined into a joint likelihood test for neutrino emission according to the KRAg model assuming a 5 PeV per nucleon Galactic cosmic-ray cutoff. No signi¿cant excess is found. As a consequence, the limits presented in this Letter start constraining the model parameter space for Galactic cosmic-ray production and transport.Albert, A.; Andre, M.; Anghinolfi, M.; Ardid Ramírez, M.; Aubert, J-.; Aublin, J.; Avgitas, T.... (2018). Joint Constraints on Galactic Diffuse Neutrino Emission from the ANTARES and IceCube Neutrino Telescopes. The Astrophysical Journal. 868(2):1-7. https://doi.org/10.3847/2041-8213/aaeecfS178682Aartsen, M. G., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., Ahrens, M., … Anderson, T. (2017). Search for Astrophysical Sources of Neutrinos Using Cascade Events in IceCube. The Astrophysical Journal, 846(2), 136. doi:10.3847/1538-4357/aa8508Aartsen, M. G., Abraham, K., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., … Archinger, M. (2015). A COMBINED MAXIMUM-LIKELIHOOD ANALYSIS OF THE HIGH-ENERGY ASTROPHYSICAL NEUTRINO FLUX MEASURED WITH ICECUBE. The Astrophysical Journal, 809(1), 98. doi:10.1088/0004-637x/809/1/98Aartsen, M. G., Abraham, K., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., … Anderson, T. (2017). All-sky Search for Time-integrated Neutrino Emission from Astrophysical Sources with 7 yr of IceCube Data. The Astrophysical Journal, 835(2), 151. doi:10.3847/1538-4357/835/2/151Aartsen, M. G., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., Ahrens, M., … Anderson, T. (2017). Constraints on Galactic Neutrino Emission with Seven Years of IceCube Data. The Astrophysical Journal, 849(1), 67. doi:10.3847/1538-4357/aa8dfbAartsen, M. G., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., Ahrens, M., … Ansseau, I. (2017). The IceCube Neutrino Observatory: instrumentation and online systems. Journal of Instrumentation, 12(03), P03012-P03012. doi:10.1088/1748-0221/12/03/p03012Ackermann, M., Ajello, M., Atwood, W. B., Baldini, L., Ballet, J., Barbiellini, G., … Berenji, B. (2012). FERMI-LAT OBSERVATIONS OF THE DIFFUSE γ-RAY EMISSION: IMPLICATIONS FOR COSMIC RAYS AND THE INTERSTELLAR MEDIUM. The Astrophysical Journal, 750(1), 3. doi:10.1088/0004-637x/750/1/3Adrián-Martínez, S., Ageron, M., Aguilar, J. A., Samarai, I. A., Albert, A., André, M., … Ardid, M. (2012). The positioning system of the ANTARES Neutrino Telescope. Journal of Instrumentation, 7(08), T08002-T08002. doi:10.1088/1748-0221/7/08/t08002Ageron, M., Aguilar, J. A., Al Samarai, I., Albert, A., Ameli, F., André, M., … Ardid, M. (2011). ANTARES: The first undersea neutrino telescope. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 656(1), 11-38. doi:10.1016/j.nima.2011.06.103Ahn, H. S., Allison, P., Bagliesi, M. G., Beatty, J. J., Bigongiari, G., Childers, J. T., … Zinn, S. Y. (2010). DISCREPANT HARDENING OBSERVED IN COSMIC-RAY ELEMENTAL SPECTRA. The Astrophysical Journal, 714(1), L89-L93. doi:10.1088/2041-8205/714/1/l89Albert, A., André, M., Anghinolfi, M., Anton, G., Ardid, M., Aubert, J.-J., … Basa, S. (2017). New constraints on all flavor Galactic diffuse neutrino emission with the ANTARES telescope. Physical Review D, 96(6). doi:10.1103/physrevd.96.062001Antoni, T., Apel, W. D., Badea, A. F., Bekk, K., Bercuci, A., Blümer, J., … Zabierowski, J. (2005). KASCADE measurements of energy spectra for elemental groups of cosmic rays: Results and open problems. Astroparticle Physics, 24(1-2), 1-25. doi:10.1016/j.astropartphys.2005.04.001Apel, W. D., Arteaga-Velázquez, J. C., Bekk, K., Bertaina, M., Blümer, J., Bozdog, H., … Cossavella, F. (2013). KASCADE-Grande measurements of energy spectra for elemental groups of cosmic rays. Astroparticle Physics, 47, 54-66. doi:10.1016/j.astropartphys.2013.06.004Gaggero, D., Grasso, D., Marinelli, A., Taoso, M., & Urbano, A. (2017). Diffuse Cosmic Rays Shining in the Galactic Center: A Novel Interpretation of H.E.S.S. and Fermi-LAT γ -Ray Data. Physical Review Letters, 119(3). doi:10.1103/physrevlett.119.031101Gaggero, D., Grasso, D., Marinelli, A., Urbano, A., & Valli, M. (2015). THE GAMMA-RAY AND NEUTRINO SKY: A CONSISTENT PICTURE OF FERMI -LAT, MILAGRO, AND ICECUBE RESULTS. The Astrophysical Journal, 815(2), L25. doi:10.1088/2041-8205/815/2/l25Gaggero, D., Urbano, A., Valli, M., & Ullio, P. (2015). Gamma-ray sky points to radial gradients in cosmic-ray transport. Physical Review D, 91(8). doi:10.1103/physrevd.91.083012Vladimirov, A. E., Digel, S. W., Jóhannesson, G., Michelson, P. F., Moskalenko, I. V., Nolan, P. L., … Strong, A. W. (2011). GALPROP WebRun: An internet-based service for calculating galactic cosmic ray propagation and associated photon emissions. Computer Physics Communications, 182(5), 1156-1161. doi:10.1016/j.cpc.2011.01.01

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication

Background: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade 653 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design

Outcomes from elective colorectal cancer surgery during the SARS-CoV-2 pandemic

This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic