Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant

BackgroundDiffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.MethodsImmunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models, and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.ResultsGD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo, and in vivo.ConclusionOur study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG.     

Early SARS-CoV-2 Reinfections within 60 Days and Implications for Retesting Policies

Illustrated by a clinical case supplemented by epidemiologic data, early reinfections with SARS-CoV-2 Omicron BA.1 after infection with Delta variant, and reinfection with Omicron BA.2 after Omicron BA.1 infection, can occur within 60 days, especially in young, unvaccinated persons. The case definition of reinfection, which influences retesting policies, should be reconsidered.     

Pulmonary Function in Scleroderma

Pulmonary function tests were performed in 45 patients with scleroderma. Thirteen patients (29%) were found to have restrictive disease, 12 patients (27%) were found to have obstructive disease, and 19 patients (42%) had small airway disease (SAD). Smoking did not seem to be a factor underlying either obstructive or small airway disease in these patients. A low diffusing capacity was most common in patients with restrictive disease and rarely the only abnormality in pulmonary function. SAD was usually found in patients who had normal chest radiographs and no pulmonary symptoms and was often the only abnormality. SAD is therefore an early and sensitive indicator of pulmonary involvement in scleroderma.     

Short-term perioperative outcomes after robot-assisted and laparoscopic distal pancreatectomy

Robotic surgery offers potential technical advantages that may facilitate pancreatic resection. The aim of this study was to evaluate the learning curve and short-term perioperative outcomes in patients who underwent laparoscopic and robot-assisted distal pancreatectomy. All perioperative variables were evaluated and compared retrospectively between laparoscopic (LDP) (n = 23) and robot-assisted (RDP) (n = 11) distal pancreatectomy. The mean total operative time was shorter in LDP (194 vs. 225 min; p = 0.017). All other perioperative criteria were similar between LDP and RDP patients (blood loss, transfusion rate, conversion, pancreatic fistula, postoperative morbidity, and duration of hospitalization). Non-adjusted CUSUM curve for composite events including operative time, conversion, postoperative morbidity and reoperation rates showed that the RDP learning curve corresponded to the first seven consecutive patients. During early experience, RDP was associated with longer operative time but similar short-term perioperative outcomes compared to conventional distal pancreatectomy.     

The State of Information and Communication Technology and Health Informatics in Ghana

Information and Communication Technology (ICT) has become a major tool in delivery of health services and has had an innovative impact on quality of life. ICT is affecting the way healthcare is delivered to clients. In this paper, we discuss the state of ICT and health informatics in Ghana. We also discuss the state of various relevant infrastructures for the successful implementation of ehealth projects. We analyse the past and present state of health informatics in Ghana, in comparison to other African countries. We also review the challenges facing successful implementation of health informatics projects in Ghana and suggest possible solutions.     

Leptospirosis among zebu cattle in farms in Kaduna State,Nigeria

ObjectiveTo assess the occurrence of Leptospira spp serovar Hardjo among Zebu cattle in some livestock producing areas of Kaduna State, Nigeria.MethodsSera samples were obtained from 164 Zebu breed of cattle above one year osf age in seven cattle farms were screened for antibodies to Leptospira spp. serovar Hardjo using Enzyme linked immunosorbent assay (ELISA).ResultsAntibodies to Leptospira spp. serovar Hardjo were detected in eighteen (10.98%) out of the 164 animals sampled. There was no significant difference (P>0.05) in seropositivity between the different age groups or between different Zebu breeds.ConclusionThe presence of Leptospirosis among the Zebu breeds of cattle may poses a threat to livestock production and has public health implication due to its zoonotic potential.     

Review

Abstract

Neuroanatomical and functional studies in the eating disorders (ED) are reviewed. Typically, anorexia nervosa (AN) is associated with cerebral spinal fluid spaces enlargement which generally recover as a function of re-feeding. However, specific cortical areas fail to correct in weight restored anorectic patients suggesting trait-related abnormalities. Functional changes in AN associated with starvation reverse with weight recovery, however, reduced 5-HT2A receptor binding may be fundamental to the pathophysiology of AN since this remains after long term weight restoration. Structural studies of bulimia nervosa (BN) provide evidence of brain atrophy, in the absence of significant weight loss but potentially related to chronic dietary restriction. Functional investigations reveal reduced thalamic and hypothalamic serotonin transporter availability in BN which increases with longer illness duration. Thus, BN is associated with substantial structural and functional alterations despite normal weight. Recent advances in neuroimaging techniques and their interpretation are increasing our understanding of normal processes in the control of food intake including neuroanatomical correlates of hunger and satiety. Taken together with the structural and functional changes observed in the ED, neuroimaging provides a powerful platform to identify the underlying trait-related pathophysiological mechanisms in the aetiology and maintenance of AN and BN.