Microgravity, Stem Cells, and Embryonic Development: Challenges and Opportunities for 3D Tissue Generation

Space is a challenging environment for the human body, due to the combined effects of reduced gravity (microgravity) and cosmic radiation. Known effects of microgravity range from the blood redistribution that affects the cardiovascular system and the eye to muscle wasting, bone loss, anemia, and immune depression. About cosmic radiation, the shielding provided by the spaceship hull is far less efficient than that afforded at ground level by the combined effects of the Earth atmosphere and magnetic field. The eye and its nervous layer (the retina) are affected by both microgravity and heavy ions exposure. Considering the importance of sight for long-term manned flights, visual research aimed at devising measures to protect the eye from environmental conditions of the outer space represents a special challenge to meet. In this review we focus on the impact of microgravity on embryonic development, discussing the roles of mechanical forces in the context of the neutral buoyancy the embryo experiences in the womb. At variance with its adverse effects on the adult human body, simulated microgravity may provide a unique tool for understanding the biomechanical events involved in the development and assembly in vitro of three-dimensional (3D) ocular tissues. Prospective benefits are the development of novel safety measures to protect the human eye from cosmic radiation in microgravity during long-term manned spaceflights in the outer space, as well as the generation of human 3D-retinas with its supporting structures to develop innovative and effective therapeutic options for degenerative eye diseases

The Influence of Recurrent Modes of Climate Variability on the Occurrence of Winter and Summer Extreme Temperatures over North America

The influence of the Pacific–North American (PNA) pattern, the northern annular mode (NAM), and the El Ni~no–Southern Oscillation (ENSO) on extreme temperature days and months over North America is examined. Associations between extreme temperature days and months are strongest with the PNA and NAM andweaker for ENSO. In general, the associationwith extremes tends to be stronger onmonthly than daily time scales and for winter as compared to summer. Extreme temperatures are associated with the PNAandNAMin the vicinity of the centers of action of these circulation patterns; however, many extremes also occur on days when the amplitude and polarity of these patterns do not favor their occurrence. In winter, synoptic-scale, transient weather disturbances are important drivers of extreme temperature days; however, many of these smaller-scale events are concurrent with amplified PNA or NAMpatterns. Associations are weaker in summer when other physicalmechanisms affecting the surface energy balance, such as anomalous soilmoisture content, also influence the occurrence of extreme temperatures

Community-based perceptions of emergency care in Kenya

Access to quality emergency services is an essential component of the human right to health, but barriers to emergency care are found throughout Africa and the wider world. Data to support the development of emergency care are essential to improve access to care and further infrastructure development. We undertook this study to understand the community\u27s emergency care needs and the barriers they face when trying to access care and to engage community members with developing high impact solutions to expand access to essential emergency services. To accomplish this, we used a qualitative research methodology to conduct 59 focus groups with 528 total Kenyan community member participants. Data were coded, aggregated, and analysed using the content analysis approach. Participants were uniformly selected from all eight of the historical Kenyan provinces (Central. Coast, Eastern, Nairobi, North Eastern, Nyanza, Rift Valley, and Western), with equal rural and urban community representation. We found that socioeconomic and cultural factors play a major role both in seeking and reaching emergency care. Community members in Kenya experience a wide range of medical emergencies and seem to understand their time-critical nature. They rely on one another for assistance in the face of substantial barriers to care: a lack of a structured system, resources, transportation, trained healthcare providers, and initial care on scene. The results of this study indicate the need for specific interventions to reduce barriers to access essential emergency services in Kenya. Access to emergency care can be improved by encouraging recognition and initial treatment of emergent illness in the community, strengthening the pre­-hospital care system, improving emergency care delivery at health facilities, and creating new policies at both county and national levels

CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail

Mutations in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with Rett syndrome (RTT), West syndrome, and X-linked infantile spasms, sharing the common feature of mental retardation and early seizures. CDKL5 is a rather uncharacterized kinase, but its involvement in RTT seems to be explained by the fact that it works upstream of MeCP2, the main cause of Rett syndrome. To understand the role of this kinase for nervous system functions and to address if molecular mechanisms are involved in regulating its distribution and activity, we studied the ontogeny of CDKL5 expression in developing mouse brains by immunostaining and Western blotting. The expression profile of CDKL5 was compared with that of MeCP2. The two proteins share a general expression profile in the adult mouse brain, but CDKL5 levels appear to be highly modulated at the regional level. Its expression is strongly induced in early postnatal stages, and in the adult brain CDKL5 is present in mature neurons, but not in astroglia. Interestingly, the presence of CDKL5 in the cell nucleus varies at the regional level of the adult brain and is developmentally regulated. CDKL5 shuttles between the cytoplasm and the nucleus and the C-terminal tail is involved in localizing the protein to the cytoplasm in a mechanism depending on active nuclear export. Accordingly, Rett derivatives containing disease-causing truncations of the C terminus are constitutively nuclear, suggesting that they might act as gain of function mutations in this cellular compartment

Long-term efficacy and safety of ibrutinib in the treatment of CLL patients: A real life experience

Ibrutinib has demonstrated a significant clinical impact in patients with de novo and relapsed/refractory chronic lymphocytic leukemia (CLL), even in cases with unfavorable cytogenetics and molecular markers. All CLL patients’ data treated at our Institute with ibrutinib have been retrospectively reviewed. Forty-six patients received ibrutinib either as frontline (10) or second or more advanced treatment (36). Five patients presented with TP53 mutations; 11 had the deletion of chromosome 17p; 17 displayed an unmutated immunoglobulin variable heavy chain status. The median number of cycles administered was 26. Among patients treated frontline, the best overall response rate (ORR) was 90.0%. In patients receiving ibrutinib as a second or later line ORR was 97.2%. Median progression-free survival was 28.8 and 21.1 months for patients treated frontline and as second/later line, respectively. Median overall survival was not reached for those treated frontline and resulted in 4.9 years for patients treated as second/later line. Grade 3–4 hematological toxicities were neutropenia, thrombocytopenia, and anemia. Grade 3–4 extrahematological toxicities included diarrhea, cutaneous rash, utero-vesical prolapse, vasculitis, and sepsis. Ibrutinib is effective and well tolerated in CLL. Responses obtained in a real-life setting are durable and the safety profile of the drug is favorable

Controversies in the Treatment of Peripheral T-cell Lymphoma.

Peripheral T-cell lymphomas are a heterogeneous group of rare diseases with an aggressive behavior and dismal prognosis. Their classification is complex and still evolving, and several biomolecular markers now help refine the prognosis of specific disease entities, although still have limited impact in tailoring the treatment. First-line treatment strategies can cure only a minority of patients and relapsed-refractory disease still represents the major cause of failure. Frontline autologous transplantation may have an impact in the consolidation of response; however, its role is still questioned as far as complete responses obtained after induction chemotherapy are concerned. Newer drugs are now being evaluated in clinical trials, but effective salvage strategies for those who experience treatment failures are lacking. Here we review and discuss the most controversial aspects of diagnosis and treatment of peripheral T-cell lymphomas

Prognostic value of interim positron emission tomography in patients with peripheral T-cell lymphoma

The definition of the role of positron emission tomography (PET) in peripheral T-cell lymphomas (PTCLs) is still under investigation. The purpose of the present observational retrospective study was to assess the early prognostic value of PET after the first three cycles of therapy (PET+3), evaluating visual data in de novo PTCL patients treated in first line with standard chemotherapy and followed by both PET and computed tomography scan. Of 27 PET+3-negative patients, 19 also had a negative PET at the end of treatment (PET+6), whereas 8 of 27 had a positive final one; 6 of 7 PET+3-positive patients had a positive PET+6, whereas only 1 patient had a negative PET+6. Estimated overall survival plotted according to PET+3 results showed 78.6% for negative patients and 21.4% for positive patients at 88.7 months with a significant difference. Patients with negative PET+3 had superior progression-free survival of 72.6% compared with 16.7% of PET+3-positive patients. At the time of this analysis, 17 of 19 (89.5%) patients with negative PET+3 are in continuous complete response (CCR) and only 1 of 7 (14.2%) patients with positive PET+3 is still in CCR. In conclusion, our results indicate that positive PET+3 is predictive of a worse outcome in PTCL, and this significant statistical difference between the two curves could be clinically informative. Larger and prospective studies and harmonization of PET reading criteria are needed

CARACTERIZACIÓN ZOOMÉTRICA DE BOVINOS CRIOLLOS: PATAGÓNICOS VS. NOROESTE ARGENTINO

Objetivo. Evaluar las diferencias zoométricas entre machos y hembras adultas de bovinos criollos del mismo tronco racial entre las regiones del Noreste Argentino (NOA) y la Patagonia Argentina (PA). Materiales y métodos. Se dispuso de una muestra de 259 bovinos adultos de las siguientes poblaciones: Hembras NOA (NH=80), Machos NOA (NM=33), Hembras PAT (PH=115) y Machos PAT (PM=31). Se midieron nueve variables zoométricas: Largo de cabeza (LC); ancho de cabeza (AC); perímetro torácico (PT); largo total (LT); ancho anterior de la grupa (AAG), ancho posterior de la grupa (APG); largo de la grupa (LG); alzada a la cruz (ACR) y alzada a la grupa (AGR). Estas medidas fueron ajustadas por edad y según sexo. Sobre la base de cinco factores asociados a las variables, los animales fueron agrupados en 3 conglomerados homogéneos (C1, C2 y C3) con el propósito de comparar las cuatro poblaciones. Resultados. Los conglomerados presentaron diferencias significativas (

Genetics and clinical phenotype of Erdheim–Chester disease: A case report of constrictive pericarditis and a systematic review of the literature

Background: Erdheim–Chester disease (ECD) is a rare form of histiocytosis. An increasing number of genetic mutations have been associated with this syndrome, confirming its possible neoplastic origin. Recently, a connection between the BRAF mutational status and a specific phenotype was described; however, no studies have yet evaluated the correlations between other mutations and the clinical features of the disease. Objectives: This study aims to clarify the association between the clinical phenotype and genetic mutations identified in the neoplastic cell lines of ECD. Methods: We describe a case of ECD characterized by pericardial involvement and a KRAS mutation shared with chronic myelomonocytic leukemia. Hence, through a meta-analysis of individual participant data of all genetically and clinically described cases of ECD in the literature, we aimed to elucidate the association between its clinical phenotype and baseline genetic mutations. Results: Of the 760 studies screened, our review included 133 articles published from 2012 to April 2021. We identified 311 ECD patients whose genotype and phenotype were described. We found five main genes (BRAF, KRAS, NRAS, PIK3CA, and MAP2K1) whose mutation was reported at least three times. Mutation of BRAF led to a neurological disease (183 of 273 patients, 67%; p < 0.001); KRAS- and NRAS-mutated patients mainly showed cutaneous (five of six patients, 83.3%, p < 0.004) and pleural (four of nine patients, 44%, p = 0.002) involvement, respectively; PIK3CA was not associated with specific organ involvement; and MAP2K1 mutations caused the disease to primarily involve the peritoneum and retroperitoneum (4 of 11, 36.4%, p = 0.01). Conclusion: This work implies a possible influence of baseline mutation over the natural history of ECD, underscoring the importance of a thorough genetic analysis in all cases with the ultimate goal of identifying a possible targeted therapy for each patient