Long Term Cell Immune Response to COVID-19 Vaccines Assessment Using a Delayed-Type Hypersensitivity (DTH) Cutaneous Test.

OBJECTIVE: As we progress with mass vaccination against SARS-CoV-2, there are key questions about the immunogenicity of COVID-19 vaccines that still are not answered. Conventional methods to measure cellular immune responses are complex and expensive in a pandemic situation. PATIENTS AND METHODS: Forty healthy healthcare workers accepted to participate during the vaccination schedule with a mRNA vaccine against SARS-CoV-2. Measurement of Delayed-Type Hypersensitivity (DTH) cutaneous response after intradermal test of protein S of SARS-CoV-2 at day 35 and day 200 was performed. At the same time, a specific anti-RBD IgG using a classic ELISA before vaccination, and on days 0, 35, and 200 was performed. RESULTS: All 40 individuals had a positive DTH skin response at day 35, whereas 39 participants had a positive skin test at day 200. Moreover, although all 40 individuals showed a positive humoral response of specific IgG against spike protein at day 35, with most of them having significantly lower levels at day 200. CONCLUSION: DTH could be proposed as an ideal and easy method to predict cellular immunity response to mRNA vaccines 200 days after starting an immunization schedule with mRNA vaccine for COVID-19.

Multicenter Phase II Study of Lurbinectedin in BRCA-Mutated and Unselected Metastatic Advanced Breast Cancer and Biomarker Assessment Substudy.

PURPOSE: This multicenter phase II trial evaluated lurbinectedin (PM01183), a selective inhibitor of active transcription of protein-coding genes, in patients with metastatic breast cancer. A unicenter translational substudy assessed potential mechanisms of lurbinectedin resistance. PATIENTS AND METHODS: Two arms were evaluated according to germline BRCA1/2 status: BRCA1/2 mutated (arm A; n = 54) and unselected ( BRCA1/2 wild-type or unknown status; arm B; n = 35). Lurbinectedin starting dose was a 7-mg flat dose and later, 3.5 mg/m2 in arm A. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST). The translational substudy of resistance mechanisms included exome sequencing (n = 13) and in vivo experiments with patient-derived xenografts (n = 11) from BRCA1/2-mutated tumors. RESULTS: ORR was 41% (95% CI, 28% to 55%) in arm A and 9% (95% CI, 2% to 24%) in arm B. In arm A, median progression-free survival was 4.6 months (95% CI, 3.0 to 6.0 months), and median overall survival was 20.0 months (95% CI, 11.8 to 26.6 months). Patients with BRCA2 mutations showed an ORR of 61%, median progression-free survival of 5.9 months, and median overall survival of 26.6 months. The safety profile improved with lurbinectedin dose adjustment to body surface area. The most common nonhematologic adverse events seen at 3.5 mg/m2 were nausea (74%; grade 3, 5%) and fatigue (74%; grade 3, 21%). Neutropenia was the most common severe hematologic adverse event (grade 3, 47%; grade 4, 10%). Exome sequencing showed mutations in genes related to the nucleotide excision repair pathway in four of seven tumors at primary or acquired resistance and in one patient with short-term stable disease. In vivo, sensitivity to cisplatin and lurbinectedin was evidenced in lurbinectedin-resistant (one of two) and cisplatin-resistant (two of three) patient-derived xenografts. CONCLUSION: Lurbinectedin showed noteworthy activity in patients with BRCA1/2 mutations. Response and survival was notable in those with BRCA2 mutations. Additional clinical development in this subset of patients with metastatic breast cancer is warranted.

The cost of surviving nitrogen excess: energy and protein demand in the lichen Cladonia portentosa as revealed by proteomic analysis.

MAIN CONCLUSION: Different nitrogen forms affect different metabolic pathways in lichens. In particular, the most relevant changes in protein expression were observed in the fungal partner, with NO 3- mostly affecting the energetic metabolism and NH 4+ affecting transport and regulation of proteins and the energetic metabolism much more than NO 3- did. Excess deposition of reactive nitrogen is a well-known agent of stress for lichens, but which symbiont is most affected and how, remains a mystery. Using proteomics can expand our understanding of stress effects on lichens. We investigated the effects of different doses and forms of reactive nitrogen, with and without supplementary phosphorus and potassium, on the proteome of the lichen Cladonia portentosa growing in a 'real-world' simulation of nitrogen deposition. Protein expression changed with the nitrogen treatments but mostly in the fungal partner, with NO3- mainly affecting the energetic metabolism and NH4+ also affecting the protein synthesis machinery. The photobiont mainly responded overexpressing proteins involved in energy production. This suggests that in response to nitrogen stress, the photobiont mainly supports the defensive mechanisms initiated by the mycobiont with an increased energy production. Such surplus energy is then used by the cell to maintain functionality in the presence of NO3-, while a futile cycle of protein production can be hypothesized to be induced by NH4+ excess. External supply of potassium and phosphorus influenced differently the responses of particular enzymes, likely reflecting the many processes in which potassium exerts a regulatory function.

Echocardiographic assessment of the aortic root dilatation in adult patients after tetralogy of Fallot repair.

INTRODUCTION: Transthoracic echocardiography is an important tool after tetralogy of Fallot repair, of which aortic root dilatation is a recognized complication. In this study we aimed to assess its prevalence and potential predictors. METHODS: We consecutively assessed adult patients by transthoracic echocardiography after tetralogy of Fallot repair, and divided them into two groups based on the maximum internal aortic diameter at the sinuses of Valsalva in parasternal long-axis view: group 1 with aortic root dilatation (≥38 mm) and group 2 without dilatation (<38 mm). RESULTS: A total of 53 patients were included, mean age 32±10 years, with a mean time since surgery of 23±7 years. An aortopulmonary shunt had been performed prior to complete repair in 25 patients, and a transannular patch was used in 19 patients. Aortic root measurement was possible in all patients. Aortic root dilatation was identified in eight patients (15%), all male. Male gender (p=0.001), body surface area (1.93±0.10 vs. 1.70±0.20 m(2), p=0.03) and increased left ventricular end-diastolic diameter (p=0.005) were predictors of aortic root dilatation. None of the surgical variables studied were predictors of aortic root dilatation. CONCLUSIONS: The prevalence of aortic root dilatation in this cohort was low and male gender was a predictor of its occurrence. The type of repair and time to surgery did not influence its occurrence. Quantification of aortic root diameter is possible by transthoracic echocardiography; we suggest indexing it to body surface area in clinical practice.

Nitrogen deposition effects on Mediterranean-type ecosystems: an ecological assessment.

We review the ecological consequences of N deposition on the five Mediterranean regions of the world. Seasonality of precipitation and fires regulate the N cycle in these water-limited ecosystems, where dry N deposition dominates. Nitrogen accumulation in soils and on plant surfaces results in peaks of availability with the first winter rains. Decoupling between N flushes and plant demand promotes losses via leaching and gas emissions. Differences in P availability may control the response to N inputs and susceptibility to exotic plant invasion. Invasive grasses accumulate as fuel during the dry season, altering fire regimes. California and the Mediterranean Basin are the most threatened by N deposition; however, there is limited evidence for N deposition impacts outside of California. Consequently, more research is needed to determine critical loads for each region and vegetation type based on the most sensitive elements, such as changes in lichen species composition and N cycling.