Regulation of CD4+NKG2D+ Th1 cells in patients with metastatic melanoma treated with sorafenib : role of IL-15Rα and NKG2D triggering

Beyond cancer-cell intrinsic factors, the immune status of the host has a prognostic impact on patients with cancer and influences the effects of conventional chemotherapies. Metastatic melanoma is intrinsically immunogenic, thereby facilitating the search for immune biomarkers of clinical responses to cytotoxic agents. Here, we show that a multi-tyrosine kinase inhibitor, sorafenib, upregulates interleukin (IL)-15Rα in vitro and in vivo in patients with melanoma, and in conjunction with natural killer (NK) group 2D (NKG2D) ligands, contributes to the Th1 polarization and accumulation of peripheral CD4+NKG2D+ T cells. Hence, the increase of blood CD4+NKG2D+ T cells after two cycles of sorafenib (combined with temozolomide) was associated with prolonged survival in a prospective phase I/II trial enrolling 63 patients with metastatic melanoma who did not receive vemurafenib nor immune checkpoint-blocking antibodies. In contrast, in metastatic melanoma patients treated with classical treatment modalities, this CD4+NKG2D+ subset failed to correlate with prognosis. These findings indicate that sorafenib may be used as an "adjuvant" molecule capable of inducing or restoring IL-15Rα/IL-15 in tumors expressing MHCclass I-related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D+ Th1 cells.peer-reviewe

Encefalopatia hepática etiologia, sintomatologia, fisiopatologia e manejo clínico / Hepatic encephalopathy etiology, symptomatology, pathophysiology and clinical management

A Encefalopatia Hepática (EH) é definida como uma síndrome neuropsiquiátrica de natureza metabólica, potencialmente reversível, que pode surgir em pacientes portadores de hepatopatias crônicas avançadas ou mesmo na insuficiência hepática aguda. A disfunção hepatocelular grave é um elemento primordial para o desenvolvimento da EH, bem como a hipertensão portal em pacientes cirróticos, por promover um desvio do sangue mesentérico para a circulação sistêmica. Caracteriza-se por apresentar alterações do sono e distúrbios psicomotores que progridem desde uma simples letargia a torpor e coma. A neurotoxina protagonista na gênese da EH é a amônia, proveniente dos enterócitos, que realizam o metabolismo da glutamina, de bactérias colônicas, responsáveis pelo catabolismo de proteínas alimentares e da ureia secretada no lúmen intestinal. Ademais, a amônia está associada a diversas outras neurotoxinas e fatores diversos, como a hiperatividade GABAérgica, mercaptanos, octopamina, edema cerebral e microelementos como o manganês. O alvo em comum, por via de regra, é o astrócito do tipo II. A EH é classificada em mínima, esporádica/aguda, espontânea e crônica. A forma mais comum de apresentação, a EH aguda esporádica, está associada a presença de fatores precipitantes, como hemorragia digestiva alta, constipação intestinal, hipocalemia, dieta hiperproteica e alcalose metabólica

Angiogenesis inhibitor therapies for advanced renal cell carcinoma: Toxicity and treatment patterns in clinical practice from a global medical chart review

The aim of this study was to assess the treatment patterns and safety of sunitinib, sorafenib and bevacizumab in real-world clinical settings in US, Europe and Asia. Medical records were abstracted at 18 community oncology clinics in the US and at 21 tertiary oncology centers in US, Europe and Asia for 883 patients ≥18 years who had histologically/cytologically confirmed diagnosis of advanced RCC and received sunitinib (n=631), sorafenib (n=207) or bevacizumab (n=45) as first‑line treatment. No prior treatment was permitted. Data were collected on all adverse events (AEs) and treatment modifications, including discontinuation, interruption and dose reduction. Treatment duration was estimated using Kaplan-Meier analysis. Demographics were similar across treatment groups and regions. Median treatment duration ranged from 6.1 to 10.7 months, 5.1 to 8.5 months and 7.5 to 9.8 months for sunitinib, sorafenib and bevacizumab patients, respectively. Grade 3/4 AEs were experienced by 26.0, 28.0 and 15.6% of sunitinib, sorafenib and bevacizumab patients, respectively. Treatment discontinuations occurred in 62.4 (Asia) to 63.1% (US) sunitinib, 68.8 (Asia) to 90.0% (Europe) sorafenib, and 66.7 (Asia) to 81.8% (US) bevacizumab patients. Globally, treatment modifications due to AEs occurred in 55.1, 54.2 and 50.0% sunitinib, sorafenib and bevacizumab patients, respectively. This study in a large, global cohort of advanced RCC patients found that angiogenesis inhibitors are associated with high rates of AEs and treatment modifications. Findings suggest an unmet need for more tolerable agents for RCC treatment

Absence of diabetic retinopathy in a patient who has had diabetes mellitus for 69 years, and inadequate glycemic control: case presentation

The main risk factors for the development and progression of diabetic retinopathy (DR) are chronic hyperglycemia, disease duration and systemic blood pressure. So far chronic hyperglycemia is the strongest evidence concerning the risk of developing DR. However there are some patients with poor metabolic control who never develop this diabetic complication. We present a case of a 73-year-old woman with type 1 diabetes mellitus, diagnosed 69 years ago. The patient is 73 years old, with no evidence of DR, despite poor glycemic control and several risk factors for DR. This case suggests the presence of a possible protection factor, which could be genetic

Test of protected silver coating on aluminum samples of ARIEL main telescope mirror substrate material

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Hematopoietic cell transplantation in severe combined immunodeficiency : The SCETIDE 2006-2014 European cohort

Publisher Copyright: © 2021 The AuthorsBackground: Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. Objective: We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. Methods: HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. Results: Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P 0.5 × 10e3/μL at +1 year were identified as independent predictors of favorable clinical and immunologic outcome. Conclusion: Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration.Peer reviewe

Btk regulates macrophage polarization in response to lipopolysaccharide

Bacterial Lipopolysaccharide (LPS) is a strong inducer of inflammation and does so by inducing polarization of macrophages to the classic inflammatory M1 population. Given the role of Btk as a critical signal transducer downstream of TLR4, we investigated its role in M1/M2 induction. In Btk deficient (Btk (−\−)) mice we observed markedly reduced recruitment of M1 macrophages following intraperitoneal administration of LPS. Ex vivo analysis demonstrated an impaired ability of Btk(−/−) macrophages to polarize into M1 macrophages, instead showing enhanced induction of immunosuppressive M2-associated markers in response to M1 polarizing stimuli, a finding accompanied by reduced phosphorylation of STAT1 and enhanced STAT6 phosphorylation. In addition to STAT activation, M1 and M2 polarizing signals modulate the expression of inflammatory genes via differential activation of transcription factors and regulatory proteins, including NF-κB and SHIP1. In keeping with a critical role for Btk in macrophage polarization, we observed reduced levels of NF-κB p65 and Akt phosphorylation, as well as reduced induction of the M1 associated marker iNOS in Btk(−/−) macrophages in response to M1 polarizing stimuli. Additionally enhanced expression of SHIP1, a key negative regulator of macrophage polarisation, was observed in Btk(−/−) macrophages in response to M2 polarizing stimuli. Employing classic models of allergic M2 inflammation, treatment of Btk (−/−) mice with either Schistosoma mansoni eggs or chitin resulted in increased recruitment of M2 macrophages and induction of M2-associated genes. This demonstrates an enhanced M2 skew in the absence of Btk, thus promoting the development of allergic inflammation

Effect of Photobiomodulation Combined with Physiotherapy on Functional Performance in Children with Myelomeningo-Cele-Randomized, Blind, Clinical Trial.

peer reviewed[en] BACKGROUND: This study aimed to evaluate the electrical activity of the rectus femoris, tibialis anterior, and lateral gastrocnemius muscles during the sit-to-stand task and functional mobility after a neurofunctional physiotherapy protocol associated with PBM. METHODS: Twenty-five children were randomly allocated to either Active PBM + physiotherapy (n = 13) or PBM sham + physiotherapy (n = 12). PBM was carried out with a LED device (850 nm, 25 J, 50 s per point and 200 mW) at four points over the area with absence of a spiny process. Both groups completed a twelve-week supervised program with two weekly 45-60 min sessions. Pre-training and post-training assessments involved the Pediatric Evaluation of Disability Inventory (PEDI). Muscle activity was assessed using portable electromyography (BTS Engineering) and the electrodes were positioned on the lateral gastrocnemius, anterior tibialis, and rectus femoris muscles. The RMS data were recorded and analyzed. RESULTS: After 24 sessions of the treatment protocol, improvements were found in the PEDI score. The participants presented greater independence in performing the tasks, requiring less assistance from their caregivers. More significant electrical activity was found in the three muscles evaluated between the rest period and execution of the sit-to-stand tasks, both in the more compromised or less compromised lower limbs. CONCLUSION: Neurofunctional physiotherapy with or without PBM improved functional mobility and electrical muscle activity in children with myelomeningocele