Assessment of the clinical effectiveness and safety of immune checkpoint inhibitors for glioblastoma: A systematic review

Glioblastoma (GBM) is a malignant primary brain tumor which is commonly found in humans. Conventional therapeutic approaches for GBM offer only a short median overall survival (MOS), thereby accentuating its poor clinical outcome. Despite the promising potential shown by use of immune checkpoint inhibitor (ICI) in animal models to treat GBM, human trials result remains inconclusive. This systematic review evaluated the safety and clinical efficacy of ICIs in GBM patients. A literature search from Embase and MEDLINE (Ovid) was completed in October 2023. A total of 10 suitable articles, which encompass 168 patients (164 recurrent and 4 newly-diagnosed GBM), are taken into account. 3 studies assessed the OS, 7 studies assessed the PFS and/or response assessment in neuro-oncology (RANO) criteria and 8 studies assessed the safety, tolerability and/or adverse events. These studies show that the range of MOS of ICI treatments was between 2.6-10.4 months (MOS using current standard treatment for recurrent GBM = 3.5-12.5 months). The median PFS and the median period until patients reach partial response score based on RANO criteria are ranging from 1.5 months to 4.6 months (PFS using current standard treatment is 5.5 months). In conclusion, ICIs are safe in patients with GBM. Reported adverse effects only include mild fatigue, headache, hyperglycemia, and diarrhea. However, ICIs display suboptimal clinical efficacy compared to conventional GBM treatments. Therefore, further research is needed in order to improve the clinical efficacy of ICIs

Explaining racial and ethnic inequalities in postpartum allostatic load: Results from a multisite study of low to middle income woment

AbstractBackgroundRacial and ethnic inequalities in women's health are widely documented, but not for the postpartum period, and few studies examine whether neighborhood, psychosocial, and biological factors explain these gaps in women's health.MethodsUsing prospective longitudinal data collected from 1766 low to middle income women between 2008 and 2012 by the Community Child Health Network (CCHN), we tested the extent to which adjustment for neighborhood, economic, psychological, and medical conditions following a birth explained differences between African American, Latina, and White women in an indicator of physiological dysregulation allostatic load (AL), at one year postpartum as measured by 10 biomarkers: Body Mass Index, Waist Hip Ratio, systolic and diastolic blood pressure, high sensitivity C-reactive protein, Hemoglobin A1c, high-density lipoprotein and cholesterol ratio, and diurnal cortisol.ResultsMean postpartum AL scores were 4.65 for African American, 4.57 for Latina and 3.86 for White women. Unadjusted regression estimates for high AL for African American women (with White as the reference) were 0.80 (SD = 0.11) and 0.53 (SD = 0.15) for Latina women. Adjustment for household poverty, neighborhood, stress, and resilience variables resulted in a reduction of 36% of the excess risk in high AL for African Americans versus Whites and 42% of the excess risk for Latinas compared to Whites.ConclusionsRacial and ethnic inequalities in AL were accounted for largely by household poverty with additional contributions by psychological, economic, neighbourhood and medical variables. There remained a significant inequality between African American, and Latina women as compared to Whites even after adjustment for this set of variables. Future research into health inequalities among women should include a fuller consideration of the social determinants of health including employment, housing and prepregnancy medical conditions

A biochemical approach to define the interactome for calpain2 in endothelial cells

Current repositories for protein-protein interactions and high throughput screening methods focus on individual gene products and do not consider the significance of calcium induced conformational changes. These limitations suggest the need for alternative strategies to better define the calpain2 interactome. Affinity capture coupled with LC-MS/MS and proteomic analysis of the recovered proteins provides a powerful approach to identify protein-protein interactions for the heterodimeric calpain2. CAPN2 (rat) was modified to be catalytically incompetent (C105A) and fused with a C-terminal 15 residue peptide optimized for biotinylation by the biotin protein ligase, BirA. The resulting CAPN2*, heterodimerized with truncated CAPNS1, was purified from E. coli, and biotinylated in vitro. Biotinylated calpain2* served as ‘bait’ for streptavidin affinity capture of calpain2 and its interacting proteins from lysates of bovine aortic (BAEC) and human umbilical vein (HUVEC) endothelial cells (ECs). Protein-calpain2 complexes were formed in the presence of calcium to allow EGTA elution of interacting proteins and LC-MS/MS analysis in the absence of an abundance of bait peptides. Capture of the well characterized calpain inhibitor protein calpastatin (CAST), and a known substrate, vimentin provide proof of concept and validates the conformational integrity of the bait calpain2*. Significant overlap between datasets (two from BAEC and one HUVEC) is also encouraging. Of numerous other proteins including several annexins, ANXA1 was confirmed as a substrate for calpain2. Findings are expected to contribute to continuing efforts in the field to better characterize calpain2’s selection of substrates and may reveal other important clues to calpain’s localization and regulation

Rapid Antigen-Capture Assay To Detect West Nile Virus in Dead Corvids

The utility of the VecTest antigen-capture assay to detect West Nile virus (WNV) in field-collected dead corvids was evaluated in Manitoba and Ontario, Canada, in 2001 and 2002. Swabs were taken from the oropharynx, cloaca, or both of 109 American Crows, 31 Blue Jays, 6 Common Ravens, and 4 Black-billed Magpies from Manitoba, and 255 American Crows and 28 Blue Jays from Ontario. The sensitivity and specificity of the antigen-capture assay were greatest for samples from American Crows; oropharyngeal swabs were more sensitive than cloacal swabs, and interlaboratory variation in the results was minimal. The sensitivity and specificity of the VecTest using oropharyngeal swabs from crows were 83.9% and 93.6%, respectively, for Manitoba samples and 83.3% and 95.8%, respectively, for Ontario birds. The VecTest antigen-capture assay on oropharyngeal secretions from crows is a reliable and rapid diagnostic test that appears suitable for incorporation into a WNV surveillance program

The acheulean handaxe : More like a bird's song than a beatles' tune?

© 2016 Wiley Periodicals, Inc. KV is supported by the Netherlands Organization for Scientific Research. MC is supported by the Canada Research Chairs Program, the Social Sciences and Humanities Research of Canada, the Canada Foundation for Innovation, the British Columbia Knowledge Development Fund, and Simon Fraser UniversityPeer reviewedPublisher PD

On the differences in the vertical distribution of modeled aerosol optical depth over the southeastern Atlantic

The southeastern Atlantic is home to an expansive smoke aerosol plume overlying a large cloud deck for approximately a third of the year. The aerosol plume is mainly attributed to the extensive biomass burning activities that occur in southern Africa. Current Earth system models (ESMs) reveal significant differences in their estimates of regional aerosol radiative effects over this region. Such large differences partially stem from uncertainties in the vertical distribution of aerosols in the troposphere. These uncertainties translate into different aerosol optical depths (AODs) in the planetary boundary layer (PBL) and the free troposphere (FT). This study examines differences of AOD fraction in the FT and AOD differences among ESMs (WRF-CAM5, WRF-FINN, GEOS-Chem, EAM-E3SM, ALADIN, GEOS-FP, and MERRA-2) and aircraft-based measurements from the NASA ObseRvations of Aerosols above CLouds and their intEractionS (ORACLES) field campaign. Models frequently define the PBL as the well-mixed surface-based layer, but this definition misses the upper parts of decoupled PBLs, in which most low-level clouds occur. To account for the presence of decoupled boundary layers in the models, the height of maximum vertical gradient of specific humidity profiles from each model is used to define PBL heights. Results indicate that the monthly mean contribution of AOD in the FT to the total-column AOD ranges from 44 % to 74 % in September 2016 and from 54 % to 71 % in August 2017 within the region bounded by 25∘ S–0∘ N–S and 15∘ W–15∘ E (excluding land) among the ESMs. ALADIN and GEOS-Chem show similar aerosol plume patterns to a derived above-cloud aerosol product from the Moderate Resolution Imaging Spectroradiometer (MODIS) during September 2016, but none of the models show a similar above-cloud plume pattern to MODIS in August 2017. Using the second-generation High Spectral Resolution Lidar (HSRL-2) to derive an aircraft-based constraint on the AOD and the fractional AOD, we found that WRF-CAM5 produces 40 % less AOD than those from the HSRL-2 measurements, but it performs well at separating AOD fraction between the FT and the PBL. AOD fractions in the FT for GEOS-Chem and EAM-E3SM are, respectively, 10 % and 15 % lower than the AOD fractions from the HSRL-2. Their similar mean AODs reflect a cancellation of high and low AOD biases. Compared with aircraft-based observations, GEOS-FP, MERRA-2, and ALADIN produce 24 %–36 % less AOD and tend to misplace more aerosols in the PBL. The models generally underestimate AODs for measured AODs that are above 0.8, indicating their limitations at reproducing high AODs. The differences in the absolute AOD, FT AOD, and the vertical apportioning of AOD in different models highlight the need to continue improving the accuracy of modeled AOD distributions. These differences affect the sign and magnitude of the net aerosol radiative forcing, especially when aerosols are in contact with clouds.</p

Investigation of Griffithsin's Interactions with Human Cells Confirms Its Outstanding Safety and Efficacy Profile as a Microbicide Candidate

Many natural product-derived lectins such as the red algal lectin griffithsin (GRFT) have potent in vitro activity against viruses that display dense clusters of oligomannose N-linked glycans (NLG) on their surface envelope glycoproteins. However, since oligomannose NLG are also found on some host proteins it is possible that treatment with antiviral lectins may trigger undesirable side effects. For other antiviral lectins such as concanavalin A, banana lectin and cyanovirin-N (CV-N), interactions between the lectin and as yet undescribed cellular moieties have been reported to induce undesirable side effects including secretion of inflammatory cytokines and activation of host T-cells. We show that GRFT, unlike CV-N, binds the surface of human epithelial and peripheral blood mononuclear cells (PBMC) through an exclusively oligosaccharide-dependent interaction. In contrast to several other antiviral lectins however, GRFT treatment induces only minimal changes in secretion of inflammatory cytokines and chemokines by epithelial cells or human PBMC, has no measureable effect on cell viability and does not significantly upregulate markers of T-cell activation. In addition, GRFT appears to retain antiviral activity once bound to the surface of PBMC. Finally, RNA microarray studies show that, while CV-N and ConA regulate expression of a multitude of cellular genes, GRFT treatment effects only minimal alterations in the gene expression profile of a human ectocervical cell line. These studies indicate that GRFT has an outstanding safety profile with little evidence of induced toxicity, T-cell activation or deleterious immunological consequence, unique attributes for a natural product-derived lectin

Enfuvirtide, an HIV-1 Fusion Inhibitor, for Drug-Resistant HIV Infection in North and South America

Background: The T-20 vs. Optimized Regimen Only Study 1 (TORO 1) was a randomized, open-label, phase 3 study of enfuvirtide (T-20), a human immunodeficiency virus type 1 (HIV-1) fusion inhibitor. Methods: Patients from 48 sites in the United States, Canada, Mexico, and Brazil with at least six months of previous treatment with agents in three classes of antiretroviral drugs, resistance to drugs in these classes, or both, and with at least 5000 copies of HIV-1 RNA per milliliter of plasma were randomly assigned in a 2:1 ratio to receive enfuvirtide plus an optimized background regimen of three to five antiretroviral drugs or such a regimen alone (control group). The primary efficacy end point was the change in the plasma HIV-1 RNA level from base line to week 24. Results: A total of 501 patients underwent randomization, and 491 received at least one dose of study drug and had at least one measurement of plasma HIV-1 RNA after treatment began. The two groups were balanced in terms of the median base-line HIV-1 RNA level (5.2 log10 copies per milliliter in both groups), median CD4+ cell count (75.5 cells per cubic millimeter in the enfuvirtide group, and 87.0 cells per cubic millimeter in the control group), demographic characteristics, and previous antiretroviral therapy. At 24 weeks, the least-squares mean change from base line in the viral load (intention- to-treat, last observation carried forward) was a decrease of 1.696 log10 copies per milliliter in the enfuvirtide group, and a decrease of 0.764 log10 copies per milliliter in the control group (P<0.001). The mean increases in CD4+ cell count were 76 cells per cubic millimeter and 32 cells per cubic millimeter, respectively (P<0.001). Reactions at the site of the injections were reported by 98 percent of patients receiving enfuvirtide. There were more cases of pneumonia in the enfuvirtide group than in the control group. Conclusions: The addition of enfuvirtide to an optimized antiretroviral regimen provided significant antiretroviral and immunologic benefit through 24 weeks in patients who had previously received multiple antiretroviral drugs and had multidrug-resistant HIV-1 infection