NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness.

Adoptive transfer of T cells expressing chimeric antigen receptors (CAR-T) effectively treats refractory hematologic malignancies in a subset of patients but can be limited by poor T-cell expansion and persistence in vivo. Less differentiated T-cell states correlate with the capacity of CAR-T to proliferate and mediate antitumor responses, and interventions that limit tumor-specific T-cell differentiation during ex vivo manufacturing enhance efficacy. NOTCH signaling is involved in fate decisions across diverse cell lineages and in memory CD8+ T cells was reported to upregulate the transcription factor FOXM1, attenuate differentiation, and enhance proliferation and antitumor efficacy in vivo. Here, we used a cell-free culture system to provide an agonistic NOTCH1 signal during naïve CD4+ T-cell activation and CAR-T production and studied the effects on differentiation, transcription factor expression, cytokine production, and responses to tumor. NOTCH1 agonism efficiently induced a stem cell memory phenotype in CAR-T derived from naïve but not memory CD4+ T cells and upregulated expression of AhR and c-MAF, driving heightened production of interleukin-22, interleukin-10, and granzyme B. NOTCH1-agonized CD4+ CAR-T demonstrated enhanced antigen responsiveness and proliferated to strikingly higher frequencies in mice bearing human lymphoma xenografts. NOTCH1-agonized CD4+ CAR-T also provided superior help to cotransferred CD8+ CAR-T, driving improved expansion and curative antitumor responses in vivo at low CAR-T doses. Our data expand the mechanisms by which NOTCH can shape CD4+ T-cell behavior and demonstrate that activating NOTCH1 signaling during genetic modification ex vivo is a potential strategy for enhancing the function of T cells engineered with tumor-targeting receptors.

Excito-repellent and Pesticide-Likeness Properties of Essential Oils on Carpophilus dimidiatus (Fabricius) (Nitidulidae) and Oryzaephilus mercator (L.) (Silvanidae).

Carpophilus dimidiatus (Fabricius) (Nitidulidae) and Oryzaephilus mercator (L.) (Silvanidae) are insect pests that cause severe damage in important walnut growing regions in the northwest of Argentina. The current management approaches for these pests involve the use of unsafe phosphorus pesticides whose overuse have led to farmworker poisoning, pest resistance issues, and environmental contamination. Plant extracts, particularly essential oils, are an alternative source of insect control agents. Excito-repellent essential oils can be used to develop ecofriendly tools for managing the pest population without affecting quality and visual appearance of the stored walnuts. Laboratory studies were conducted to assess the excito-repellent effects of C. dimidiatus and O. mercator of 12 essential oils derived from aromatic plants used as food additives and traditional medicine in Argentina: Aloysia citrodora (AC), Aloysia gratissima (AG), Aloysia gratissima var. Gratissima (AGG), Blepharocalyx salicipholius (BS), Hyptis mutabilis (HM), Lippia junelliana (LJ), Lippia turbinata (LT), Mentha x piperita (MP), Minthostachys mollis (MM), Minthostachys verticillata (MV), Origanum vulgare(OV), and Rosmarinus officinalis (RO). The most bioactive EOs (ERijk ≥ 70%) were Aloysia gratissima var. Gratissima (AGG), Minthostachys verticillata, and Lippia junelliana. Their bioactivity profile and chemical space, characterized from GC-MS measures, Generalized Estimating Equations, and Hierarchical Cluster Analysis, revealed that they are mixtures of very functionalized molecules with physicochemical properties similar to those of insecticides with low residual property that enter the insect body through the respiratory system by inhalation. The AGG, MV, and LJ oils are promising as protective agents of walnut products. In our laboratory, studies of their formulations for use in integrated pest management programs are still ongoing.

Dermoscopic characteristics of cutaneous larva migrans in dark skin: a study from Banjul, The Gambia.

Cutaneous larva migrans (CLM) results from hookworm larvae infestation, mainly Ancylostoma braziliense or Ancylostoma caninum. It is common in Sub-Saharan Africa, often acquired through soil contact, especially in sandy beaches, manifesting as serpiginous, erythematous and intensely pruritic tracts within the epidermis, and presenting with diverse clinical appearances. Diagnosis is mostly clinical; however, dermoscopy can enhance diagnostic accuracy and distinction from mimics. The current body of literature is deficient in its representation of dermoscopic data for CLM in Black patients. This study explores dermoscopy in nine dark-skinned patients with 16 CLM lesions. Distinctive serpiginous structureless areas displaying a range of colours, peripheral scales surrounding brown areas and brown dots were predominant features, whereas vascular characteristics were less evident. This article highlights the presence of distinct reaction patterns, including brown dots, scales, and accentuated, often disrupted brown reticular lines in addition to the characteristic winding tracts in darker skin.

Clinicopathological profile and management challenges of congenital encephaloceles in a tertiary hospital in southwest Nigeria.

PURPOSE: A congenital encephalocele is the herniation of intracranial contents through skull defects of various sizes. Depending on the site, content, and size, it is associated with significant morbidity and mortality in children. There is a paucity of recent and comprehensive local clinical data regarding this anomaly. Understanding the peculiarities, clinical-pathologic profiles, and management challenges will help prevent and effectively manage congenital encephalocele to improve outcomes. METHODS: This was a retrospective study of all cases of congenital encephalocele managed between July 2000 and December 2023 at a tertiary hospital in the southwest region of Nigeria. Relevant demographic, clinicopathological, and management data were retrieved and analysed. RESULTS: There were 31 females and 11 males. Their ages ranged from 3 hours to 24 years. Sixteen (35.3%) were delivered in a non-health facility. Birth asphyxia was reported in 5 babies. Few mothers (4.8%) used preconception folic acid. Anaemia (n = 5) and sepsis (n = 4) were the common preoperative morbidities. All patients had definitive surgery, with 18 operated on within the first month of life. Cerebrospinal fluid (CSF) leak was the most common postoperative complication and was significantly observed in the sincipital group (p = 0.018). Thirty-one patients (73.8%) presented for follow-up after surgery, and the mean follow-up duration was 26.6 weeks. Mortality was recorded in a patient (2.4%) due to Klebsiella meningitis. CONCLUSION: Congenital encephaloceles are relatively common in our setting. Therefore, there is a need to address the associated poor maternal and neonatal health conditions. Early surgery can be performed with a favourable outcome.

Severity of Rolling Reconstituted High Moisture Barley on Ensiling Characteristics and In Vitro Ruminal Fermentation.

Barley grain sources with variable kernel sizes makes adequate and consistent processing of kernels challenging. This study evaluated how the severity of processing for reconstituted high moisture (65% on DM basis) barley (RHB) affects ensiling characteristics and in vitro ruminal fermentation. Three independent sources of light (<630 g/500 mL) and heavy (>670 g/500 mL) barley were blended to create 4 sources of variable kernel sized barley (646 g/500 mL). Reconstituted barley was rolled through a roller gap width of 1.40 (RHBF), 1.86 (RHBM), or 2.31 mm (RHBC) and ensiled for 1 or 5 mo with dry rolled barley (DRB; roller gap width 1.86 mm) used as a control. The 1-mo RHB and the DRB were further evaluated using the artificial rumen technique (RUSITEC) to investigate the effects of severity of processing for RHB on ruminal fermentation, and gas, methane, and microbial protein production. Using a randomized complete block design (n = 4), 16 fermenters from 2 RUSITEC apparatuses were used to assess the 4 sources and 4 processing treatments. The addition of water increased kernel width before rolling and resulted in increased kernel length, width, and thickness for RHB relative to dry rolled barley. Increasing processing severity for RHB linearly increased kernel width. The percentage of fine particles (<1.18 mm) was greater for DRB than RHBF, but did not differ by processing severity for RHB. Dry matter, organic matter, and starch disappearance were not different between DRB and RHBF, but linearly increased with increasing processing severity for RHB. Fermenter pH tended to be less for DRB relative to RHBF. In conclusion, the reduction in fine particles with the addition of water for RHB may prevent a decline in fermenter pH and when processed to achieve the same PI using a smaller roller gap width, yielded similar DM and OM disappearance suggesting a lesser risk for low ruminal pH without compromising digestibility.

Immunohistochemical Human Epidermal Growth Factor Receptor 2 (HER2) Expression Pattern in Gastric Adenocarcinomas in a Nigerian Tertiary Hospital.

BACKGROUND AND OBJECTIVE: The demonstration of HER2 in gastric adenocarcinoma (GA) tissues by immunohistochemistry assists in deciding whether targeted therapy would optimise the treatment of GA patients who are HER2 positive. However, this has not been extensively studied in our patients hence the need for this study. METHODS: Recipient tissue microarray blocks were constructed from donor archival formalin fixed paraffin embedded gastric tumour tissue from 80 patients seen over a period of 17 years in a retrospective descriptive study. Slides cut from these blocks were stained with antihuman HER2 antibody by immunohistochemistry and scored using the trastuzumab in gastric adenocarcinomas (ToGA) trial criteria. Data on age, gender, site of lesion and histological subtype of the gastric adenocarcinomas were also retrieved and reviewed. RESULTS: Eighty cases (52 males and 28 females; male to female ratio of 1.9:1), 55.65 ±13.50 years (modal age group 60-69 years), were studied. Most tumours (91.2%) involved the distal parts (pylorus, antrum and body) with a few (8.8%) involving the proximal part (cardia and fundus) of the stomach. HER2 was overexpressed in a total of 6 (7.5%) cases only. Two of seven (28.6%) proximal tumours showed HER2 positivity whereas only 4 of 73 (5.5%) of the distal tumours showed HER2 positivity. CONCLUSION: We had only a slightly lower HER2 overexpression rate than in studies from many other parts of the world. The observed overexpression was significantly higher in proximal than distally located tumours suggesting that distal tumours are less likely to respond to Trastuzumab than proximal tumours. The known association of distal gastric tumours with Helicobacter pylori infection probably provides for a possible difference in the molecular aetiopathogenesis of GAs by site of occurrence. The exact mechanisms for proximal gastric carcinogenesis remain to be more clearly elucidated. More studies, including clinical trials with larger sample sizes, are recommended to elucidate this differential expression of HER2 in gastric adenocarcinoma.

CONTEXTE ET OBJECTIF: La démonstration de la présence de HER2 dans les tissus d'adénocarcinome gastrique (AG) par immunohistochimie aide à décider si une thérapie ciblée optimiserait le traitement des patients atteints d'AG HER2 positif. Cependant, cela n'a pas été largement étudié chez nos patients, d'où la nécessité de cette étude. MÉTHODES: Des blocs de microarray de tissus destinataires ont été construits à partir de tissus tumoraux gastriques inclus en paraffine d'archives provenant de 80 patients vus sur une période de 17 ans, dans le cadre d'une étude descriptive rétrospective. Les lames découpées à partir de ces blocs ont été colorées avec un anticorps anti-HER2 humain par immunohistochimie et évaluées selon les critères de l'essai trastuzumab dans les adénocarcinomes gastriques (ToGA). Les données sur l'âge, le sexe, le site de la lésion et le sous-type histologique des adénocarcinomes gastriques ont également été récupérées et examinées. RÉSULTATS: Quatre-vingts cas (52 hommes et 28 femmes ; rapport hommes-femmes de 1,9:1), 55,65 ± 13,50 ans (groupe d'âge modal 60-69 ans), ont été étudiés. La plupart des tumeurs (91,2 %) ont touché les parties distales (pylore, antre et corps) avec quelques-unes (8,8 %) touchant la partie proximale (cardia et fundus) de l'estomac. HER2 a été surexprimé dans un total de 6 cas seulement (7,5 %). Deux des sept tumeurs proximales (28,6 %) ont montré une positivité HER2, tandis que seulement 4 des 73 tumeurs distales (5,5 %) ont montré une positivité HER2. CONCLUSION: Nous avons eu un taux de surexpression de HER2 légèrement inférieur à celui observé dans de nombreuses autres régions du monde. La surexpression observée était significativement plus élevée dans les tumeurs proximales que dans les tumeurs distales, suggérant que les tumeurs distales sont moins susceptibles de répondre au trastuzumab que les tumeurs proximales. L'association connue des tumeurs gastriques distales avec l'infection par Helicobacter pylori fournit probablement une différence potentielle dans l'étiopathogenèse moléculaire des AG par site d'occurrence. Les mécanismes exacts de la carcinogenèse gastrique proximale restent à élucider plus clairement. Davantage d'études, y compris des essais cliniques avec des tailles d'échantillons plus importantes, sont recommandées pour élucider cette expression différentielle de HER2 dans l'adénocarcinome gastrique. MOTS-CLÉS: Adénocarcinome gastrique, expression de HER2, Immunohistochimie, Thérapie ciblée.

Stereotactic body radiotherapy with or without selective dismutase mimetic in pancreatic adenocarcinoma: an adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while reducing normal tissue toxicity. This trial was designed to establish the efficacy and toxicity afforded by the selective dismutase mimetic avasopasem manganese when combined with ablative SBRT for localised pancreatic ductal adenocarcinoma. METHODS: In this adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial, patients aged 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at six academic sites in the USA. Eligible patients were randomly assigned (1:1), with block randomisation (block sizes of 6-12) with a maximum of 24 patients per group, to receive daily avasopasem (90 mg) or placebo intravenously directly before (ie, within 180 min) SBRT (50, 55, or 60 Gy in five fractions, adaptively assigned in real time by Bayesian estimates of 90-day safety and efficacy). Patients and physicians were masked to treatment group allocation, but not to SBRT dose. The primary objective was to find the optimal dose of SBRT with avasopasem or placebo as determined by the late onset EffTox method. All analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT03340974, and is complete. FINDINGS: Between Jan 25, 2018, and April 29, 2020, 47 patients were screened, of whom 42 were enrolled (median age was 71 years [IQR 63-75], 23 [55%] were male, 19 [45%] were female, 37 [88%] were White, three [7%] were Black, and one [2%] each were unknown or other races) and randomly assigned to avasopasem (n=24) or placebo (n=18); the placebo group was terminated early after failing to meet prespecified efficacy parameters. At data cutoff (June 28, 2021), the avasopasem group satisfied boundaries for both efficacy and toxicity. Late onset EffTox efficacy response was observed in 16 (89%) of 18 patients at 50 Gy and six (100%) of six patients at 55 Gy in the avasopasem group, and was observed in three (50%) of six patients at 50 Gy and nine (75%) of 12 patients at 55 Gy in the placebo group, and the Bayesian model recommended 50 Gy or 55 Gy in five fractions with avasopasem for further study. Serious adverse events of any cause were reported in three (17%) of 18 patients in the placebo group and six (25%) of 24 in the avasopasem group. In the placebo group, grade 3 adverse events within 90 days of SBRT were abdominal pain, acute cholangitis, pyrexia, increased blood lactic acid, and increased lipase (one [6%] each); no grade 4 events occurred. In the avasopasem group, grade 3-4 adverse events within 90 days of SBRT were acute kidney injury, increased blood alkaline phosphatase, haematoma, colitis, gastric obstruction, lung infection, abdominal abscess, post-surgical atrial fibrillation, and pneumonia leading to respiratory failure (one [4%] each).There were no treatment-related deaths but one late death in the avasopasem group due to sepsis in the setting of duodenal obstruction after off-study treatment was reported as potentially related to SBRT. INTERPRETATION: SBRT that uses 50 or 55 Gy in five fractions can be considered for patients with localised pancreatic ductal adenocarcinoma. The addition of avasopasem might further enhance disease outcomes. A larger phase 2 trial (GRECO-2, NCT04698915) is underway to validate these results. FUNDING: Galera Therapeutics.

First assessment of atmospheric pollution by trace elements and particulate matter after a severe collapse of a tailings dam, Minas Gerais, Brazil: An insight into biomonitoring with Tillandsia usneoides and a public health dataset.

In this study, samples of bromeliad Tillandsia usneoides (n = 70) were transplanted and exposed for 15 and 45 days in 35 outdoor residential areas in Brumadinho (Minas Gerais state, Brazil) after one of the most severe mining dam collapses in the world. Trace elements aluminum (Al), arsenic (As), chromium (Cr), copper (Cu), iron (Fe), mercury (Hg), manganese (Mn), nickel (Ni) and zinc (Zn) were quantified by atomic absorption spectrometry. Scanning electron microscope generated surface images of T. usneoides fragments and particulate matter (PM2.5, PM10 and PM > 10). Aluminum, Fe and Mn stood out from the other elements reflecting the regional geological background. Median concentrations in mg kg-1 increased (p < 0.05) between 15 and 45 days for Cr (0.75), Cu (1.23), Fe (474) and Mn (38.1), while Hg (0.18) was higher at 15 days. The exposed-to-control ratio revealed that As and Hg increased 18.1 and 9.4-fold, respectively, not showing a pattern associated only with the most impacted sites. The PM analysis points to a possible influence of the prevailing west wind on the increase of total particles, PM2.5 and PM10 in transplant sites located to the east. Brazilian public health dataset revealed increase in cases of some cardiovascular and respiratory diseases/symptoms in Brumadinho in the year of the dam collapse (1.38 cases per 1000 inhabitants), while Belo Horizonte capital and its metropolitan region recorded 0.97 and 0.37 cases, respectively. Although many studies have been carried out to assess the consequences of the tailings dam failure, until now atmospheric pollution had not yet been evaluated. Furthermore, based on our exploratory analysis of human health dataset, epidemiological studies are required to verify possible risk factors associated with the increase in hospital admissions in the study area.

Identification of potential inhibitors of cholinergic and ß-secretase enzymes from phytochemicals derived from Gongronema latifolium Benth leaf: an integrated computational analysis.

Neurodegenerative disorders (NDDs) are associated with increased activities of the brain acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and ß-secretase enzyme (BACE1). Inhibition of these enzymes affords therapeutic option for managing NDDs such as Alzheimer's disease (AD) and Parkinson's disease (PD). Although, Gongronema latifolium Benth (GL) has been widely documented in ethnopharmacological and scientific reports for the management of NDDs, there is paucity of information on its underlying mechanism and neurotherapeutic constituents. Herein, 152 previously reported Gongronema latifolium derived-phytochemicals (GLDP) were screened against hAChE, hBChE and hBACE-1 using molecular docking, molecular dynamics (MD) simulations, free energy of binding calculations and cluster analysis. The result of the computational analysis identified silymarin, alpha-amyrin and teraxeron with the highest binding energies (-12.3, -11.2, -10.5 Kcal/mol) for hAChE, hBChE and hBACE-1 respectively as compared with those of the reference inhibitors (-12.3, -9.8 and - 9.4 for donepezil, propidium and aminoquinoline compound respectively). These best docked phytochemicals were found to be orientated in the hydrophobic gorge where they interacted with the choline-binding pocket in the A-site and P-site of the cholinesterase and subsites S1, S3, S3' and flip (67-75) residues of the pocket of the BACE-1. The best docked phytochemicals complexed with the target proteins were stable in a 100 ns molecular dynamic simulation. The interactions with the catalytic residues were preserved during the simulation as observed from the MMGBSA decomposition and cluster analyses. The presence of these phytocompounds most notably silymarin, which demonstrated dual high binding tendencies to both cholinesterases, were identified as potential neurotherapeutics subject to further investigation.

Impact of a machine learning algorithm on time to palliative care in a primary care population: protocol for a stepped-wedge pragmatic randomized trial.

BACKGROUND: As primary care populations age, timely identification of palliative care need is becoming increasingly relevant. Previous studies have targeted particular patient populations with life-limiting disease, but few have focused on patients in a primary care setting. Toward this end, we propose a stepped-wedge pragmatic randomized trial whereby a machine learning algorithm identifies patients empaneled to primary care units at Mayo Clinic (Rochester, Minnesota, United States) with high likelihood of palliative care need. METHODS: 42 care team units in 9 clusters were randomized to 7 wedges, each lasting 42 days. For care teams in treatment wedges, palliative care specialists review identified patients, making recommendations to primary care providers when appropriate. Care teams in control wedges receive palliative care under the standard of care. DISCUSSION: This pragmatic trial therefore integrates machine learning into clinical decision making, instead of simply reporting theoretical predictive performance. Such integration has the possibility to decrease time to palliative care, improving patient quality of life and symptom burden. TRIAL REGISTRATION: Clinicaltrials.gov NCT04604457 , restrospectively registered 10/26/2020. PROTOCOL: v0.5, dated 9/23/2020.

Nanostructure-Driven Indocyanine Green Dimerization Generates Ultra-Stable Phototheranostics Nanoparticles.

Indocyanine green (ICG) is the only near-infrared (NIR) dye approved for clinical use. Despite its versatility in photonic applications and potential for photothermal therapy, its photobleaching hinders its application. Here we discovered a nanostructure of dimeric ICG (Nano-dICG) generated by using ICG to stabilize nanoemulsions, after which ICG enabled complete dimerization on the nanoemulsion shell, followed by J-aggregation of ICG-dimer, resulting in a narrow, red-shifted (780 nm→894 nm) and intense (≈2-fold) absorbance. Compared to ICG, Nano-dICG demonstrated superior photothermal conversion (2-fold higher), significantly reduced photodegradation (-9.6 % vs. -46.3 %), and undiminished photothermal effect (7 vs. 2 cycles) under repeated irradiations, in addition to excellent colloidal and structural stabilities. Following intravenous injection, Nano-dICG enabled real-time tracking of its delivery to mouse tumors within 24 h by photoacoustic imaging at NIR wavelength (890 nm) distinct from the endogenous signal to guide effective photothermal therapy. The unprecedented finding of nanostructure-driven ICG dimerization leads to an ultra-stable phototheranostic platform.

Multiomics Profiling of Toxins in the Venom of the Amazonian Spider Acanthoscurria juruenicola.

Acanthoscurria juruenicola is an Amazonian spider described for the first time almost a century ago. However, little is known about their venom composition. Here, we present a multiomics characterization of A. juruenicola venom by a combination of transcriptomics, proteomics, and peptidomics approaches. Transcriptomics of female venom glands resulted in 93,979 unique assembled mRNA transcript encoding proteins. A total of 92 proteins were identified in the venom by mass spectrometry, including 14 mature cysteine-rich peptides (CRPs). Quantitative analysis showed that CRPs, cysteine-rich secretory proteins, metalloproteases, carbonic anhydrases, and hyaluronidase comprise >90% of the venom proteome. Relative quantification of venom toxins was performed by DIA and DDA, revealing converging profiles of female and male specimens by both methods. Biochemical assays confirmed the presence of active hyaluronidases, phospholipases, and proteases in the venom. Moreover, the venom promoted in vivo paralytic activities in crickets, consistent with the high concentration of CRPs. Overall, we report a comprehensive analysis of the arsenal of toxins of A. juruenicola and highlight their potential biotechnological and pharmacological applications. Mass spectrometry data were deposited to the ProteomeXchange Consortium via the PRIDE repository with the dataset identifier PXD013149 and via the MassIVE repository with the dataset identifier MSV000087777.

Perfluoroalkylated compounds in the eggs and feathers of resident and migratory seabirds from the Antarctic Peninsula.

In this study, we investigated factors that influence the differences in exposure of perfluoroalkyl acids (PFAAs) from eight species of Antarctic seabirds, including Pygoscelis penguins, Stercorarius maccormicki, and Macronectes giganteus. We analyzed the relationship between foraging ecology (based on δ13C, δ15N, and δ34S values) and PFAAs accumulated in eggs and breast feathers. Ten out of 15 targeted PFAAs were detected in eggs compared to eight in feathers. Mean ∑PFAA concentrations in feathers ranged from 0.47 in P. antarcticus to 17.4 ng/g dry weight (dw) in S. maccormicki. In eggs, ∑PFAA concentrations ranged from 3.51 in P. adeliae to 117 ng/g dw in S. maccormicki. The highest concentrations of most PFAAs were found in trans-equatorial migrators such as S. maccormicki, probably due their high trophic position and higher concentrations of PFAAs in the Northern Hemisphere compared to the Southern Hemisphere. Based on stable isotopes correlations, our results suggest that the trophic position (δ15N) and the foraging area (δ13C and δ34S) influence PFAAs concentrations in Antarctic seabirds. Our results point to the possibility that long-distance migratory birds may have as bio-vectors in the transport of pollutants, including PFCAs, in Antarctic environments, although this must be further confirmed in future studies using a mass balanced approach, such as extractable organofluorine (EOF).

γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma.

B-cell maturation antigen (BCMA) is a validated target for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM). Despite promising objective response rates, most patients relapse, and low levels of BCMA on a subset of tumor cells has been suggested as a probable escape mechanism. BCMA is actively cleaved from the tumor cell surface by the ubiquitous multisubunit γ-secretase (GS) complex, which reduces ligand density on tumor cells for CAR T-cell recognition and releases a soluble BCMA (sBCMA) fragment capable of inhibiting CAR T-cell function. Sufficient sBCMA can accumulate in the bone marrow of MM patients to inhibit CAR T-cell recognition of tumor cells, and potentially limit efficacy of BCMA-directed adoptive T-cell therapy. We investigated whether blocking BCMA cleavage by small-molecule GS inhibitors (GSIs) could augment BCMA-targeted CAR T-cell therapy. We found that exposure of myeloma cell lines and patient tumor samples to GSIs markedly increased surface BCMA levels in a dose-dependent fashion, concurrently decreased sBCMA concentrations, and improved tumor recognition by CAR T cells in vitro. GSI treatment of MM tumor-bearing NOD/SCID/γc-/- mice increased BCMA expression on tumor cells, decreased sBCMA in peripheral blood, and improved antitumor efficacy of BCMA-targeted CAR T-cell therapy. Importantly, short-term GSI administration to MM patients markedly increases the percentage of BCMA+ tumor cells, and the levels of BCMA surface expression in vivo. Based on these data, a US Food and Drug Administration (FDA)-approved clinical trial has been initiated, combining GSI with concurrent BCMA CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT03502577.

BKCa Channel Activation Attenuates the Pathophysiological Progression of Monocrotaline-Induced Pulmonary Arterial Hypertension in Wistar Rats.

PURPOSE: In the present study, the therapeutic efficacy of a selective BKCa channel opener (compound X) in the treatment of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) was investigated. METHODS: PAH was induced in male Wistar rats by a single injection of MCT. After two weeks, the MCT-treated group was divided into two groups that were either treated with compound X or vehicle. Compound X was administered daily at 28 mg/kg. Electrocardiographic, echocardiographic, and haemodynamic analyses were performed; ex vivo evaluations of pulmonary artery reactivity, right ventricle (RV) and lung histology as well as expression levels of α and ß myosin heavy chain, brain natriuretic peptide, and cytokines (TNFα and IL10) in heart tissue were performed. RESULTS: Pulmonary artery rings of the PAH group showed a lower vasodilatation response to acetylcholine, suggesting endothelial dysfunction. Compound X promoted strong vasodilation in pulmonary artery rings of both control and MCT-induced PAH rats. The untreated hypertensive rats presented remodelling of pulmonary arterioles associated with increased resistance to pulmonary flow; increased systolic pressure, hypertrophy and fibrosis of the RV; prolongation of the QT and Tpeak-Tend intervals (evaluated during electrocardiogram); increased lung and liver weights; and autonomic imbalance with predominance of sympathetic activity. On the other hand, treatment with compound X reduced pulmonary vascular remodelling, pulmonary flow resistance and RV hypertrophy and afterload. CONCLUSION: The use of a selective and potent opener to activate the BKCa channels promoted improvement of haemodynamic parameters and consequent prevention of RV maladaptive remodelling in rats with MCT-induced PAH.

Clinicopathologic Features of Childhood Rhabdomyosarcoma and Treatment Outcomes in Ibadan, Nigeria: A 10-year Review.

The objectives of this study were to describe the clinicopathologic features and treatment outcomes of childhood rhabdomyosarcoma in a resource-constrained setting. All cases of childhood rhabdomyosarcoma seen over a 10-year period (July 2006 to June 2016) at the University College Hospital, Ibadan, Nigeria were reviewed. Data were extracted from the database of the pediatric Hematology/Oncology Unit of the hospital and analyzed. Ethical approval was obtained from the Institutional Ethics Committee. Fifty children were seen comprising 30 men and 20 women with bimodal ages of 4 and 5 years. Median duration of illness was 16 weeks and the most common primary tumor site was the head-and-neck region in 27 (54%) of cases. The histologic subtypes were embryonal in 30 (60%), alveolar in 9 (18%), and not specified in 11 (22%). The Intergroup Rhabdomyosarcoma Study group TNM Pretreatment stages were stage I in 15 (30%), stage III in 17 (34%), and stage IV in 18 (36%). Treatment included chemotherapy, surgery, and radiotherapy and abandoned in 20 (40%) cases. Median survival was 45 weeks (95% confidence interval: 16.4-73.6) and 5 (10%) patients were alive and disease free, 4 years or more after diagnosis. Outcome of childhood rhabdomyosarcoma is poor and early diagnosis and improved access to treatment are recommended.

First year after the Brumadinho tailings' dam collapse: Spatial and seasonal variation of trace elements in sediments, fishes and macrophytes from the Paraopeba River, Brazil.

On January 2019, the B1 iron ore tailings' dam collapsed in Brumadinho, Brazil, being one of the worst mining-related disasters, with 270 human deaths (11 of them still missing) and 12.106 m3 of tailings released to the environment. The tailings devastated the Córrego do Feijão brook and reached the adjacent Paraopeba River, the region's main watercourse and a major tributary of the São Francisco basin. Although physicochemical parameters of the river were strongly impacted, and acute toxicological effects have been reported from exposure experiments, contamination of aquatic biota had not yet been assessed. Therefore, the aim of this study was to evaluate contamination by trace elements (As, Al, Cd, Co, Cr, Cu, Fe, Hg, Mn, Ni, Pb and Zn) in sediment, fish and macrophytes along the Paraopeba River, upstream and downstream from the dam failure site, during the dry and wet season. With the exception of Cd and Hg, all elements in sediment samples had lower median concentrations downstream. An inverse pattern was observed for the aquatic biota, with significant higher concentrations of Fe, Mn, Ni and Zn in fishes, and increased concentrations of most elements in macrophytes, indicating an increase in element bioavailability. A significant seasonal variation was observed with increased concentrations of As (dry season) and Pb (wet season) in fish samples, with the same trend occurring in macrophytes. Concentrations of potentially toxic elements in fish samples in wet weight (Cr: 1.80 ± 1.31 mg kg-1, Hg: 0.21 ± 0.11 mg kg-1 and Pb: 0.79 ± 0.80 mg kg-1) were lower than those reported before the disaster. Furthermore, As and Pb concentrations exceeded the safety threshold for fish consumption in 3% and 41% of samples, respectively, representing a matter of concern for public health.

Paediatric soft tissue sarcomas in a resource constraint setting: Grade and stage at presentation and at oncologic intervention are usually of poor prognostic characteristics.

AIM: To describe the pattern of paediatric Rhabdomyosarcomas (RMS) and Non-Rhabdomyosarcomas (NRMS) with emphasis on the indices that affect survival outcomes. METHODS: We reviewed all patients with histologically confirmed RMS and NRMS in the Departments of Pathology and Paediatrics, University College Hospital (UCH), Ibadan, Nigeria; in children aged 0-14 years. The study period was January 1991 to December 2016. Information obtained included age, gender, morphology and site of the tumours. The tumour grade and pathologic/clinical staging of all patients were also obtained and verified by the clinical records. Tumour grading was carried out using the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) Sarcoma group grading system and staging was done using TNM. Follow up, survival information and final outcome were retrieved. RESULTS: The 104 patients included in the study had almost equal male-to-female ratio, age ranged between 5 months and 14 years (median 8.2 years). Rhabdomyosarcoma had mean age of 5.6 (±3.8) years while that of NRMS was 9.2(±4.1) years. Overall, the modal age group was 5-9 years. Rhabdomyosarcoma was the commonest histological type (76%), undifferentiated sarcomas (6.7%), fibrosarcoma (3.8%) and 2.9% each for synovial sarcoma and dermatofibrosarcoma protuberans. The common primary sites were the head and neck (including the orbit) 49 (47.1%), and the abdominopelvic 26 (25%) regions. Majority (89%) had histologic grade 3 at presentation. Seventy per cent and 64% of patients with RMS and NRMS, respectively, had high stage tumour at presentation. Median survival for all patients with Rhabdomyosarcoma was 45 weeks with a 1-year survival of 43% and 2-year survival of 25%. Non-RMS (Dermatofibrosarcoma protuberans and Solitary fibrous tumours) had survival of over 4 year's duration. CONCLUSION: Majority of our patients presented at a late stage with histologic high grade which confers poor prognosis and reduced chances for good overall survival outcome.

Rapid situational assessment of people who inject drugs (PWID) in Nairobi and coastal regions of Kenya: a respondent driven sampling survey.

BACKGROUND: A Cross-sectional Rapid Situational Assessment of People Who Inject Drug (PWIDs) applying Respondent Driven sampling techniques (RDS) was used to recruit subjects/participants in a study aimed at assessing HIV prevalence and risk behaviors among injecting drug users in Nairobi and Coastal regions of Kenya. There is paucity of data and information on injecting drug use in sub-Saharan Africa and there is sufficient evidence of existence of the environment for development and growth of injecting drug use. Past studies on PWID and its association to HIV and AIDS that have been conducted in Kenya do not provide sufficient information to support effective planning and comprehensive national response to the HIV and AIDS epidemic. METHODS: A cross-sectional study design was adopted in which a set of initial subjects referred to as 'seeds' were first identified from which an expanding chain of referrals were obtained, with subjects from each wave referring subjects of subsequent waves. The seeds were drawn randomly from the population and interviewed to pick the one with the largest network and other unique characteristics. A maximum of twelve seeds were recruited. The second stage involved conducting assessment visits to the sites to identify potential collaborators that included non-governmental organizations (NGOs), drug treatment centres, health facilities, community based organizations (CBO's) among others. Three NGOs located in the coast region and one in Nairobi region were identified to assist in identifying drug injection locations and potential participants. Key informant interviews (KIIs) and Focus Group Discussions (FGDs) were also conducted using interview guides. RESULTS: A total of 646 individuals (344 in Nairobi and 302 at the coast) were recruited for the study between January and March 2010. Of these 590 (91%) were male and 56 (9%) were female. Findings showed that most PWIDs initiated injecting drug use between the ages of 20-29 years, with the youngest age of initiation being 11 years and oldest age being 53 years. Most commonly injected drug was heroin (98%), with a small (2%) percentage injecting cocaine. Other non-injecting methods such as smoking or combining these two drugs with other drugs such as cannabis or Rohypnol were also common. Most PWIDs used other substances (cigarettes, alcohol, and cannabis) before initiating injecting drug use. The adjusted national HIV prevalence of PWIDs was 18.3% (19.62% unadjusted) with PWIDs in Nairobi region registering 18.33% (20.58% unadjusted) compared PWIDs for Coastal region indicating 18.27% (18.59% - unadjusted). The gender based HIV prevalence showed that women were more at risk of acquiring HIV (44.51%-adjusted) compared to men (15.97%-adjusted). The age specific HIV prevalence showed that PWIDs who initiated injecting at 11-19 years (44.7% adjusted) were most at risk in Nairobi compared to those who initiated injecting at age 20-24 years (23.2% - adjusted) in the coastal region. While all PWIDs continue to be at risk in the two regions, those from the Western parts of Nairobi, Kenya were at a relatively higher risk given their increased propensity for sharing injecting equipment and solutions. CONCLUSIONS: Compared to the national HIV prevalence of (4.9%), the results show that People Who Inject Drugs (PWIDs) are at particularly high risk of infection in Kenya and there is urgent need for intervention (KenPHIA, 2018). This study also showed clear evidence that 70% of PWIDs are primary school educated, engage in high risk injecting and sexual behaviors comprising sharing of injecting equipment, unprotected heterosexual and homosexual sex. Given that initiation of injecting drug use begins early and peaks after formal school years (20-29 years), prevention programmes should be targeted at primary and secondary school students, college and out of school youth. Further, to protect People who inject drugs (PWIDs) from HIV infection, the country should introduce free Needle Syringe Programs (NSP) with provision of condoms and Methadone Assisted Therapy (MAT) as a substitute for drug use.

Virulence of Five Phytophthora Species Causing Rhododendron Root Rot in Oregon.

Phytophthora root rot is a destructive disease of rhododendron that causes substantial losses of this nursery crop in infested field and container production areas. Historically, Phytophthora cinnamomi was considered the main causal agent of the disease. However, a recent survey of soilborne Phytophthora species from symptomatic rhododendrons in Oregon revealed that P. plurivora is more common than P. cinnamomi, and that several other Phytophthora species may be involved. We investigated the ability of the five most abundant species from the survey to cause root rot: P. plurivora, P. cinnamomi, P. pini, P. pseudocryptogea, and P. cambivora. Three to four isolates were selected for each species from across six Oregon nurseries. Media of containerized Rhododendron catawbiense 'Boursault' was infested with single isolates in a randomized complete block design in a greenhouse. Phytophthora cinnamomi, P. pini, and P. plurivora rapidly caused ≥90% of severe root rot, whereas P. pseudocryptogea caused more moderate disease (46% of severe root rot). Phytophthora cambivora failed to produce enough inoculum and was used at a lower inoculum density than the other four species; however, occasionally, it caused severe root rot (5% incidence). No differences in virulence were observed among isolates of the same species, except for one isolate of P. plurivora that caused less disease than other P. plurivora isolates. This study demonstrates that all five Phytophthora species, which were representative of 94% of the survey isolates, are capable of causing severe root rot and plant death, but that not all species are equally virulent.