Propuesta de incorporación de competencias de formación en ingeniería

El presente artículo presenta una propuesta a partir de un análisis sobre las competencias en Ingeniería que se proponen en diferentes modelos de competencias en Educación Superior, tales como el modelo norteamericano que propone ABET Accreditation Board for Engineering and Technology) y el modelo de competencias establecidas por El Ministerio de Educación Superior en España y se establece una comparación con las competencias que define el ICFES para las evaluaciones SABER PRO, a partir de las evaluaciones diseñadas para medir los logros y competencias de los próximos a graduarse de los diferentes programas académicos, a través de los diferentes módulos que se diseñan de acuerdo a la profesión de la Ingeniería de Sistemas, para identificar qué tanto se aproximan a los modelos más elaborados y conocidos en el mundo

Translational Studies Using the MALT1 Inhibitor (S)-Mepazine to Induce Treg Fragility and Potentiate Immune Checkpoint Therapy in Cancer

INTRODUCTION: Regulatory T cells (Tregs) play a critical role in the maintenance of immune homeostasis but also protect tumors from immune-mediated growth control or rejection and pose a significant barrier to effective immunotherapy. Inhibition of MALT1 paracaspase activity can selectively reprogram immune-suppressive Tregs in the tumor microenvironment to adopt a proinflammatory fragile state, which offers an opportunity to impede tumor growth and enhance the efficacy of immune checkpoint therapy (ICT). METHODS: We performed preclinical studies with the orally available allosteric MALT1 inhibitor (S)-mepazine as a single-agent and in combination with anti-programmed cell death protein 1 (PD-1) ICT to investigate its pharmacokinetic properties and antitumor effects in several murine tumor models as well as patient-derived organotypic tumor spheroids (PDOTS). RESULTS: (S)-mepazine demonstrated significant antitumor effects and was synergistic with anti-PD-1 therapy in vivo and ex vivo but did not affect circulating Treg frequencies in healthy rats at effective doses. Pharmacokinetic profiling revealed favorable drug accumulation in tumors to concentrations that effectively blocked MALT1 activity, potentially explaining preferential effects on tumor-infiltrating over systemic Tregs. CONCLUSIONS: The MALT1 inhibitor (S)-mepazine showed single-agent anticancer activity and presents a promising opportunity for combination with PD-1 pathway-targeted ICT. Activity in syngeneic tumor models and human PDOTS was likely mediated by induction of tumor-associated Treg fragility. This translational study supports ongoing clinical investigations (ClinicalTrials.gov Identifier: NCT04859777) of MPT-0118, (S)-mepazine succinate, in patients with advanced or metastatic treatment-refractory solid tumors

Propuesta de incorporación de competencias de formación en ingeniería

El presente artículo presenta una propuesta a partir de un análisis sobre las competencias en Ingeniería que se proponen en diferentes modelos de competencias en Educación Superior, tales como el modelo norteamericano que propone ABET Accreditation Board for Engineering and Technology) y el modelo de competencias establecidas por El Ministerio de Educación Superior en España y se establece una comparación con las competencias que define el ICFES para las evaluaciones SABER PRO, a partir de las evaluaciones diseñadas para medir los logros y competencias de los próximos a graduarse de los diferentes programas académicos, a través de los diferentes módulos que se diseñan de acuerdo a la profesión de la Ingeniería de Sistemas, para identificar qué tanto se aproximan a los modelos más elaborados y conocidos en el mundo

Human immune disorder associated with homozygous hypomorphic mutation affecting MALT1B splice variant

Seeholzer, Thomas/0000-0002-1115-3358; Gewies, Andreas/0000-0002-7606-6482WOS:000616665800049PubMed: 32858082[No Abstract Available]Jeffrey Modell Foundation; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [SFB 1054/A04, SFB 1335/P07]We thank Caspar Ohnmacht for technical support. Our work in Turkey was supported by the Jeffrey Modell Foundation. The work by D.K. was supported by the Deutsche Forschungsgemeinschaft (grants SFB 1054/A04 and SFB 1335/P07)

Companion Rescue and Risk Management of Trekkers on the Everest Trek, Solo Khumbu Region, Nepal

Background: Trekking to high-altitude locations presents inherent health-related hazards, many of which can managed with specific first aid (FA) training. This study evaluates the trip preparation, FA knowledge, and FA self-assessment of trekkers (organized by tour operators vs. individually planned tours). Data obtained shall be used for specific FA trip preparation and management of emergencies en route for this population. Methods: A total of 366 trekkers on the Everest Base Camp Trek, Nepal, were interviewed using a questionnaire specifically designed to evaluate their FA knowledge and management of emergencies. Data evaluation was performed using descriptive statistics. Results: A total of 40.5% of trekkers experienced at least one medical incident during their trip, of which almost 50% were due to acute mountain sickness (AMS). There was more AMS in commercially organized groups than in individually planned ones (55% vs. 40%). For more than 50%, no medical care was available during their trip. A total of 80% could answer only 3/21 FA questions completely correctly. Only 1% showed adequate knowledge concerning FA strategies. A total of 70% were willing to enroll in an FA class specialized towards the needs of trekkers. Conclusions: The importance of high-altitude FA knowledge and trip preparation is widely underestimated. There is an unmet demand amongst trekkers for specific wilderness FA classes

Translational Studies Using the MALT1 Inhibitor (S)-Mepazine to Induce Treg Fragility and Potentiate Immune Checkpoint Therapy in Cancer

Introduction: Regulatory T cells (Tregs) play a critical role in the maintenance of immune homeostasis but also protect tumors from immune-mediated growth control or rejection and pose a significant barrier to effective immunotherapy. Inhibition of MALT1 paracaspase activity can selectively reprogram immune-suppressive Tregs in the tumor microenvironment to adopt a proinflammatory fragile state, which offers an opportunity to impede tumor growth and enhance the efficacy of immune checkpoint therapy (ICT). Methods: We performed preclinical studies with the orally available allosteric MALT1 inhibitor (S)-mepazine as a single-agent and in combination with anti-programmed cell death protein 1 (PD-1) ICT to investigate its pharmacokinetic properties and antitumor effects in several murine tumor models as well as patient-derived organotypic tumor spheroids (PDOTS). Results: (S)-mepazine demonstrated significant antitumor effects and was synergistic with anti-PD-1 therapy in vivo and ex vivo but did not affect circulating Treg frequencies in healthy rats at effective doses. Pharmacokinetic profiling revealed favorable drug accumulation in tumors to concentrations that effectively blocked MALT1 activity, potentially explaining preferential effects on tumor-infiltrating over systemic Tregs. Conclusions: The MALT1 inhibitor (S)-mepazine showed single-agent anticancer activity and presents a promising opportunity for combination with PD-1 pathway-targeted ICT. Activity in syngeneic tumor models and human PDOTS was likely mediated by induction of tumor-associated Treg fragility. This translational study supports ongoing clinical investigations (ClinicalTrials.gov Identifier: NCT04859777) of MPT-0118, (S)-mepazine succinate, in patients with advanced or metastatic treatment-refractory solid tumors

Cardiovascular Risk Profiles and Pre-Existing Health Conditions of Trekkers in the Solu-Khumbu Region, Nepal

Background: High-altitude tourist trekking continues to grow in popularity on the Everest Trek in Nepal. We examined which pre-existing cardiovascular and health conditions these global trekkers had and what health issues they encountered during the trek, be it exacerbations of pre-existing conditions, or new acute ones. Method: Trekkers (n = 350) were recruited from guesthouses along the Everest Trek, mostly at Tengboche (3860 m). After completing a questionnaire on their health and travel preparation, they underwent a basic physical examination with an interview. Results: Almost half (45%) had pre-existing conditions, mostly orthopaedic and cardiovascular diseases. The average age was 42.7 years (range 18–76). The average BMI was 23.4 kg/m2, but 21% were overweight. A third were smokers (30%), and 86% had at least one major cardiovascular risk factor. A quarter (25%) were suffering from manifest acute mountain sickness (AMS), and 72% had at least one symptom of AMS. Adequate pre-travel examination, consultation, and sufficient personal preparation were rarely found. In some cases, a distinct cardiovascular risk profile was assessed. Hypertensive patients showed moderately elevated blood pressure, and cholesterol levels were favourable in most cases. No cardiovascular emergencies were found, which was fortunate as timely, sufficient care was not available during the trek. Conclusion: The results of earlier studies in the Annapurna region should be revalidated. Every trekker to the Himalayas should consult a physician prior to departure, ideally a travel medicine specialist. Preventative measures and education on AMS warrant special attention. Travellers with heart disease or with a pronounced cardiovascular risk profile should be presented to an internal medicine professional. Travel plans must be adjusted individually, especially with respect to adequate acclimatisation time and no physical overloading. With these and other precautions, trekking at high altitudes is generally safe and possible, even with significant pre-existing health conditions. Trekking can lead to invaluable personal experiences. Since organized groups are limited in their flexibility to change their itinerary, individual trekking or guided tours in small groups should be preferred

XIAP loss triggers RIPK3- and caspase-8-driven IL-1β activation and cell death as a consequence of TLR-MyD88-induced cIAP1-TRAF2 degradation

X-linked Inhibitor of Apoptosis (XIAP) deficiency predisposes people to pathogen-associated hyperinflammation. Upon XIAP loss, Toll-like receptor (TLR) ligation triggers RIPK3-caspase-8-mediated IL-1β activation and death in myeloid cells. How XIAP suppresses these events remains unclear. Here, we show that TLR-MyD88 causes the proteasomal degradation of the related IAP, cIAP1, and its adaptor, TRAF2, by inducing TNF and TNF Receptor 2 (TNFR2) signaling. Genetically, we define that myeloid-specific cIAP1 loss promotes TLR-induced RIPK3-caspase-8 and IL-1β activity in the absence of XIAP. Importantly, deletion of TNFR2 in XIAP-deficient cells limited TLR-MyD88-induced cIAP1-TRAF2 degradation, cell death, and IL-1β activation. In contrast to TLR-MyD88, TLR-TRIF-induced interferon (IFN)β inhibited cIAP1 loss and consequent cell death. These data reveal how, upon XIAP deficiency, a TLR-TNF-TNFR2 axis drives cIAP1-TRAF2 degradation to allow TLR or TNFR1 activation of RIPK3-caspase-8 and IL-1β. This mechanism may explain why XIAP-deficient patients can exhibit symptoms reminiscent of patients with activating inflammasome mutations