Volatile molecules for COVID-19: A possible pharmacological strategy?

COVID-19 is a novel coronavirus disease with a higher incidence of bilateral pneumonia and pleural effusion. The high pulmonary tropism and contagiousness of the virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have stimulated new approaches to combat its widespread diffusion. In developing new pharmacological strategies, the chemical characteristic of volatility can add therapeutic value to the hypothetical drug candidate. Volatile molecules are characterized by a high vapor pressure and are consequently easily exhaled by the lungs after ingestion. This feature could be exploited from a pharmacological point of view, reaching the site of action in an uncommon way but allowing for drug delivery. In this way, a hypothetical molecule for COVID-19 should have a balance between its lung exhalation characteristics and both antiviral and anti-inflammatory pharmacological action. Here, the feasibility, advantages, and disadvantages of a therapy based on oral administration of possible volatile drugs for COVID-19 will be discussed. Both aerosolized antiviral therapy and oral intake of volatile molecules are briefly reviewed, and an evaluation of 1,8-cineole is provided in view of a possible clinical use and also for asymptomatic COVID-19.     

Accuracy of MRI-guided Versus Systematic Prostate Biopsy in Patients Under Active Surveillance: A Systematic Review and Meta-analysis

This meta-analysis focuses on the accuracy of upgrading to clinically significant prostate cancer (PCa) by multiparametric magnetic resonance imaging-targeted biopsy (MRI-TB) versus systematic biopsy (SB). We searched the Medline, Embase, Cochrane Central Register of Controlled Trials, Web of Science, Scopus, and Literatura Latino Americana em Ciências da Saúde databases through January 2020 for comparative, retrospective/prospective, paired-cohort, and randomized clinical trials with paired comparisons. The population consisted of patients with low-risk PCa in active surveillance with at least 1 index lesion on imaging. We evaluated the quality of evidence by using the Quality Assessment of Diagnostic Accuracy Studies-2 score. Group comparisons considered the differences between the area under the curve summary receiver operating characteristic curve in a 2-tailed method. We also compared the positive predictive value of the best single method (MRI-TB or SB) and the referral study test (combined biopsy, a combination of MRI-TB and SB). The meta-analysis included 6 studies enrolling 741 patients. The pooled sensitivity for the 2 groups was 0.79 (95% confidence interval, 0.74-0.83; I² = 75%) and 0.67 (95% confidence interval, 0.63-0.74; I² = 55.4%), respectively. The area under the curve for the MRI-TB and SB groups were 0.99 and 0.92 (P < .001), respectively. The positive predictive value for the MRI-TB and combined biopsy groups were similar. The accumulated evidence suggests better results for MRI-TB compared with SB. Therefore, use of MRI-TB alone may be preferable in patients in active surveillance harboring low-risk PCa.     

Measurement of thorium isotopes and 228Ra in soft tissues and bones of a deceased Thorotrast patient.

The whole body of an individual injected with Thorotrast 36 y prior to her death was analyzed for 232Th, 228Ra, 228Th, and 230Th. Measurement of these isotopes in all tissues of the body will provide data necessary to caculate the radiation dose to individual tissues and to evaluate the risk potential associated with deposition of thorium and progeny in humans. The tissues were ashed, dissolved in acid, and the thorium isolated by ion exchange and electrodeposition. The 228Ra was determined by measuring the 0.991-MeV gamma rays associated with decay of the 228Ac daughter. It was estimated that almost all of the 232Th from the original injection was retained in the body, mostly in the tissues of the reticuloendothelial system. A total of 28 kBq (0.76 microCi) of 232Th was measured in the soft tissues and bones. The body also contained 13 kBq 228Ra, 12 kBq 228Th, and 3.9 kBq 230Th. A Thorotrastoma contained about 3.5% of the total activity. Excluding the Thorotrastoma, approximately 45% of all the activity (232Th, 228Ra, 228Th, and 230Th) was retained in the liver, 13% in the spleen, 2% in muscle, 1% in skin, slightly less than 1% in the respiratory tract, 4% in all other soft tissues, and 33% in the skeleton (bone and bone marrow). Sixty to 80% of the thorium activity in bones containing red marrow was located in the marrow. Bones containing yellow marrow had less than 40% of the thorium activity in the marrow. Highest concentrations were found in the hepatic and other abdominal lymph nodes, spleen, hilar lymph nodes, liver, trachea, and bone. Approximately 60% of the 228Ra formed from the decay of the 232Th had been excreted from the body. The 228Ra and 228Th were in approximate equilibrium throughout the body.     

Life underneath the VCA umbrella: Perspectives from the US Uterus Transplant Consortium

The parallel emergence of uterus transplantation (UTx) and other transplantation innovations including face and hand transplantation led to the categorization of the uterus as a vascular composite allograft (VCA). With >60 transplants and >20 births worldwide, UTx is transitioning rapidly from a research endeavor to an effective treatment option for women with uterine factor infertility. While it originally made sense to group the innovations under one umbrella, it is time to revisit the designation of UTx as a VCA. We describe how UTx needs unique policy, procedural codes, insurance contracts, and educational initiatives. We contend that separating UTx from VCAs may become necessary in the future to avoid hindering the growth and regulation of this field.     

Observations on the arterial baroreflex in neurally mediated vasodepressor syncope

The arterial baroreflex was studied in subjects who had recently had an episode of vasodepressor syncope. This was determined using 2–3 mcg/kg intravenous boluses of phenylephrine and assessing the bradycardic response. The values were measured in ms/mmHg and expressed as the angular coefficient of the regression line between the increase in R—R interval on the electrocardiograph and the systolic arterial pressure. In subjects examined immediately after the vasodepressor syncope episode the bradycardic response was much more marked than in controls (p < 0.01) and in the subjects themselves 6 months after the episode, provided that they were symptom-free (p < 0.01). It is concluded that in vasodepressor syncope there is a phase in which the baroreflex is highly sensitive and that this is due not to a lowering of the stimulation threshold but to a gain in the efferent arc, which explains a vagotonic response.     

Effect of Helicobacter pylori infection, age and epithelial cell turnover in a general population at high risk for gastric cancer

BACKGROUND: H. pylori and age are two known risk factors for atrophic gastritis and high epithelial cell turnover may be an indicator for preneoplastic changes in the stomach. We searched for an association between H. pylori, age and gastritis in the general population together with the proliferative state into the antral mucosa. METHODS: We examined gastric biopsies from antrum and corpus of 117 consecutive volunteers which were endoscoped during a population study in San Marino. H. pylori status was determined by serum IgG antibodies, rapid urease test on biopsies and histology. Presence of gastritis and grading of inflammation, activity, intestinal metaplasia and atrophy were ascertained using Sydney System. On a subsample of 36 subjects without endoscopic lesions we performed an immunohistochemical study on gastric cell proliferation using PCNA. A computer-aided count was made on stained epithelial cells to evaluate labeling index. Statistical analysis was performed using chi 2 test and linear regression. RESULTS: Inflammatory infiltrate (both activity and mononuclear cells), (p < 0.0001) and intestinal metaplasia (p < 0.004) were significantly higher in H. pylori positive subjects. Atrophic gastritis was present in 82% H. pylori positive subjects vs 17.6% (p < 0.0001). Labeling Index was significantly higher in H. pylori positive subjects (p < 0.005) and it was correlated with inflammation and atrophy (p = 0.001). Elderly H. pylori negative subjects have a lower cell turnover (p = 0.006) but H. pylori infected subjects do not show any decrease of Labeling Index with age. CONCLUSIONS: In the general population of an area with high gastric cancer rate, H. pylori infection is associated with atrophic gastritis and with hyperproliferative gastric cell state. These conditions are present either in young and old age and increase the neoplastic risk of gastric mucosa.     

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.     

Chimeric antigen receptor-modified human regulatory T cells that constitutively express IL-10 maintain their phenotype and are potently suppressive

Clinical trials of Treg therapy in transplantation are currently entering phases IIa and IIb, with the majority of these employing polyclonal Treg populations that harbor a broad specificity. Enhancing Treg specificity is possible with the use of chimeric antigen receptors (CARs), which can be customized to respond to a specific human leukocyte antigen (HLA). In this study, we build on our previous work in the development of HLA-A2 CAR-Tregs by further equipping cells with the constitutive expression of interleukin 10 (IL-10) and an imaging reporter as additional payloads. Cells were engineered to express combinations of these domains and assessed for phenotype and function. Cells expressing the full construct maintained a stable phenotype after transduction, were specifically activated by HLA-A2, and suppressed alloresponses potently. The addition of IL-10 provided an additional advantage to suppressive capacity. This study therefore provides an important proof-of-principle for this cell engineering approach for next-generation Treg therapy in transplantation.