In-and-out Technique: An In-house Efficient Predictive Hole Fabrication Workflow.

Virtual surgical planning (VSP) and three-dimensional (3D) printing can increase precision and reduce surgical time in craniofacial reconstruction. However, the elevated cost and manufacturing time of outsourced workflows is increasing the development of in-house solutions. One of the main challenges in in-house workflows is to create cutting guides that hold plate position information. This is due to the fact that hospitals usually lack the infrastructure required to design and 3D print custom-made plates. Including plate-positioning information in resection guides is especially relevant in complex reconstructions and when tumor extension limits plate placement before resection. Current in-house workflows revolve around the idea of 3D scanning the bent plate's shape and to fuse it with the VSP. The goal of this article is to share our technique to transfer plate position information to resection guides. Our protocol uses a 3D model of the reconstruction as an intermediate step to transfer the plate position of a bent stock reconstruction plate to cutting guides. Two patients who required mandibular reconstruction with fibula flap are presented to illustrate the technique. This workflow requires a 3D-printed model of the desired outcome, cutting guides, and a stock plate. Results were satisfactory in terms of cutting location and angulation, plate adaptation and condylar position. This technique allows for a simple, safe, cheap, and quick alternative to add reconstruction plate information to cutting guides.

UiO-66(Zr) as drug delivery system for non-steroidal anti-inflammatory drugs.

The toxicity for the human body of non-steroidal anti-inflammatory drugs (NSAIDs) overdoses is a consequence of their low water solubility, high doses, and facile accessibility to the population. New drug delivery systems (DDS) are necessary to overcome the bioavailability and toxicity related to NSAIDs. In this context, UiO-66(Zr) metal-organic framework (MOF) shows high porosity, stability, and load capacity, thus being a promising DDS. However, the adsorption and release capability for different NSAIDs is scarcely described. In this work, the biocompatible UiO-66(Zr) MOF was used to study the adsorption and release conditions of ibuprofen, naproxen, and diclofenac using a theoretical and experimental approximation. DFT results showed that the MOF-drug interaction was due to an intermolecular hydrogen bond between protons of the groups in the defect sites, (µ3 - OH, and - OH2) and a lone pair of oxygen carboxyl functional group of the NSAIDs. Also, the experimental results suggest that the solvent where the drug is dissolved affects the adsorption process. The adsorption kinetics are similar between the drugs, but the maximum load capacity differs for each drug. The release kinetics assay showed a solvent dependence kinetics whose maximum liberation capacity is affected by the interaction between the drug and the material. Finally, the biological assays show that none of the systems studied are cytotoxic for HMVEC. Additionally, the wound healing assay suggests that the UiO-66(Zr) material has potential application on the wound healing process. However, further studies should be done.

Does Aesthetic Osseous Genioplasty Impact Upper Airway Volume?

BACKGROUND: Although maxillomandibular advancement is the treatment of choice for obstructive sleep apnea syndrome (OSAS) in the presence of underlying maxillomandibular complex hypoplasia, there is still a gap in the literature regarding the impact of genioplasty upon upper airway volume (UAV). OBJECTIVES: The aim of this study was to evaluate the impact of isolated osseous genioplasty upon UAV. METHODS: A retrospective analysis of all patients subjected to isolated osseous genioplasty between July 2015 and July 2022 was conducted. Cone-beam computed tomography was performed preoperatively and postoperatively to assess the chin and hyoid 3-dimensional (3D) spatial position and UAV changes after surgery. RESULTS: A total of 44 patients were included in the study. Regarding surgical movements of the chin, almost all patients received a sagittal movement (n = 42; 39 forward and 3 backward), while in 8 patients a vertical movement (5 upward and 3 downward) was applied, and in 6 patients the chin was centered. Statistically significant increases in total UAV (P = .014) and at the level of the oropharynx (P = .004) were observed. Specifically, chin centering, upward and forward movements enlarged the oropharynx volume (P = .006, .043 and .065, respectively). Chin advancement enlarged the hypopharynx volume (P = .032), as did upward movement of the hyoid bone (P < .001). CONCLUSIONS: Results of the study suggest that aesthetic osseous genioplasty impacts the UAV: each 3D spatial chin movement differently impacts the upper airway by enlarging or narrowing it. However, further studies addressing the apnea-hypopnea index are required to assess its effectiveness in treating OSAS.

Estradiol-Induced Epithelial to Mesenchymal Transition and Migration Are Inhibited by Blocking c-Src Kinase in Breast Cancer Cell Lines.

PURPOSE: The epithelial-to-mesenchymal transition (EMT) is the main event that favors cell migration and metastasis in breast cancer. Previously, we demonstrated that 1 nM estradiol (E2) promotes EMT, induced by c-Src kinase, causing changes in the localization of proteins that compose the tight junction (TJ) and adherens junction (AJ). METHODS: The present work highlights the central role of c-Src in the initiation of metastasis, induced by E2, through increasing the ability of MCF-7 and T47-D cells, which express estrogen receptor alpha (ERα), to migrate and invade before they become metastatic. RESULTS: Treatment with E2 can activate two signaling pathways, the first one by the phosphorylated c-Src (p-Src) which forms the p-Src/E-cadherin complex. This phenomenon was completely prevented by incubation with a selective inhibitor of c-Src (5 µM PP2). p-Src then promotes the downregulation of E-cadherin and occludin, which are epithelial phenotype marker proteins of the AJ and TJ, respectively. In the second pathway, E2 binds to ERα, creating a complex that translocates to the nucleus, inducing the synthesis of SNAIL1 and N-cadherin proteins, markers of the mesenchymal phenotype. Both processes increased the migratory and invasive capacities of both cell lines. CONCLUSION: The present study demonstrate that E2 enhance EMT and migration, through c-Src activation, in human breast cancer cells that express ERα and become potential therapeutic targets.

Obtaining polyphenolic extracts from pomegranate peel (Punica granatum) to evaluate the bactericide and antioxidant activity.

Pomegranate (Punica granatum) contains secondary metabolites with antioxidant and bactericide activity; however, the study of the peel in the endemic varieties of Mexico has not been deepened. The polyphenols extraction of peel pomegranate endemic to the state of Michoacan, Mexico could be used in the formlulation of healthy food due contains antioxidant compounds or could be used like drugs due contains antibactericide compunds.In this work 3 varieties of pomegranate were analyzed; Wonderful, Apaseo and Tecozautla harvested in 2017 and 2018, carrying out a physicochemical characterization to establish the ripening, application of an experimental design of response surface for drying the peel and extracting polyphenols using two solvents (acetone and ethanol) by the Soxhlet method. As a result, the pomegranates were in the correct ripening, in the drying an optimal point of operation was found without affecting the metabolites (36 h at 55 °C) and in the extraction, the bactericide and antioxidant activity was evaluated observing that in the ketone extracts the best results were obtained in the Apaseo variety being; ABTS•+ technique of 150.78 ET mM/g, DPPH• 109.8 ET mM/g and 11.82 EAG mg/g in dry extract. For the bactericide activity measured by inhibition halos in S. aureus and E. coli it was had; 20.03 mm and 14.05 mm respectively for the Apaseo variety, which is why it is convenient to extract polyphenols under this method in peel of Mexican pomegranate varieties.

IDENTIFICATION OF ANTHROPOGENIC IMPACT ON NATURAL HABITATS BY ANTIMICROBIAL RESISTANCE QUANTIFICATION IN TWO NEOTROPICAL WILD CATS AND THEIR GEOSPATIAL ANALYSIS.

Human activities such as habitat degradation and fragmentation threaten biodiversity in Neotropical areas. This work proposes an analytical methodology to identify natural areas in Central America with anthropogenic impact, analyzing the presence of antimicrobial resistance genes (ARGs) in accordance with their theoretical relationship with human-related activities. Sixteen ARGs were quantified in feces of different individuals of 13 jaguars (Panthera onca) and 13 pumas (Puma concolor) in three conservation areas in Costa Rica by real-time PCR. At least one ARG was detected in all samples. Of the ARGs encoding tetracycline resistance, the most frequent were tetQ and tetY (85% and 69%, respectively). The sulfonamides (sulI and sulII; 69% each), phenicols (catI and catII; 19% and 54%, respectively), and quinolones (qnrS; 12%) were also detected. The presence of human settlements, livestock farms (pigs, cattle, and poultry), roads, human health centers, flood zones, and rivers were identified within each area to generate an index of human activity. We found no difference between the presence of ARG by roads, agricultural activities, and human settlements (P>0.05). However, tetW showed higher percentages with porcine and bovine farms; both tetY and tetW were more frequent in jaguars than in pumas. Of concern is that many of the most contaminated samples were taken from national parks, such as Braulio Carrillo and Tortuguero, where animals should not have direct contact with humans.

Anatomical Engineering and 3D Printing for Surgery and Medical Devices: International Review and Future Exponential Innovations.

Three-dimensional printing (3DP) has recently gained importance in the medical industry, especially in surgical specialties. It uses different techniques and materials based on patients' needs, which allows bioprofessionals to design and develop unique pieces using medical imaging provided by computed tomography (CT) and magnetic resonance imaging (MRI). Therefore, the Department of Biology and Medicine and the Department of Physics and Engineering, at the Bioastronautics and Space Mechatronics Research Group, have managed and supervised an international cooperation study, in order to present a general review of the innovative surgical applications, focused on anatomical systems, such as the nervous and craniofacial system, cardiovascular system, digestive system, genitourinary system, and musculoskeletal system. Finally, the integration with augmented, mixed, virtual reality is analyzed to show the advantages of personalized treatments, taking into account the improvements for preoperative, intraoperative planning, and medical training. Also, this article explores the creation of devices and tools for space surgery to get better outcomes under changing gravity conditions.

Actividad física y estado nutricional en pacientes reumáticos durante la pandemia de COVID-19 / Physical activity and nutritional status in rheumatic patients during the COVID-19 pandemic

RESUMEN Introducción: El control de las enfermedades reumáticas constituye un reto para los profesionales de la salud. Existen diversos factores que pueden influir en su control, el estado nutricional y la realización de actividades físicas sistemáticamente son algunos de ellos. Objetivo: Evaluar el comportamiento del estado nutricional y la práctica de actividades físicas en pacientes con enfermedades reumáticas durante la pandemia de COVID-19. Métodos: Investigación básica, no experimental, descriptiva y transversal que incluyó como población de estudio una cohorte de 63 pacientes con diagnóstico de enfermedades reumáticas según criterios del Colegio Americano de Reumatología. Se identificaron las características generales de los pacientes, la determinación del estado nutricional y la actividad física, y se utilizó la prueba de correlación de Sperman para identificar la posible relación existente entre las variables de estudio. Resultados: El promedio de edad fue de 53,36 años, con predominio de pacientes femeninas (82,54 %), con artritis reumatoide (53,97 %) y adherentes farmacológicos (96,82 %). Después de terminado el confinamiento existió aumento de pacientes con sobrepeso (41,27 %) y obesidad (9,52 %). Se encontró disminución de la frecuencia de realización de actividades físicas, con predominio de pacientes que realizan actividades físicas menos de tres veces por semana; el 14,28 % refiere que nunca hace ejercicios. Conclusiones: Se identificó que durante el periodo de confinamiento por la COVID-19 existieron variaciones negativas del estado nutricional y de la frecuencia de realización de actividades físicas de los pacientes con ER que pudiera estar relacionado con la actividad clínica de este tipo de enfermedades.

ABSTRACT Introduction: The control of rheumatic diseases constitutes a challenge for health professionals. There are multiple factors that can influence its control, nutritional status and systematic physical activity are some of them. Objective: To evaluate the behavior of the nutritional status and the practice of physical activities in patients with rheumatic diseases during the COVID-19 pandemic. Methods: Basic, non-experimental, descriptive and cross-sectional research that included as a study population a cohort of 63 patients diagnosed with rheumatic diseases according to the criteria of the American College of Rheumatology. The general characteristics of the patients, the rheumatic diseases included in the research, the main digestive manifestations identified, and the Sperman correlation test was used to identify the possible relationship between the study variables. Results: Mean age of 53.36 years, with a predominance of female patients (82.54%), with rheumatoid arthritis (53.97%) and pharmacological adherents (96.82%). After the confinement was over, there was an increase in overweight (41.27%) and obese (9.52%) patients. A decrease in the frequency of physical activities was found with a predominance of patients who perform physical activities less than 3 times a week; 14.28% report that they never exercise. Conclusions: It was identified that during the period of confinement by COVID-19 there were negative variations in the nutritional status and frequency of physical activities of patients with RD that could be related to the clinical activity of this type of disease.

Radiation Oncology Residency Training in Latin America: A Call to Attention.

Purpose: Despite the call to increase the number of radiation oncologists in Latin America, the quality, similarity, and number of residency training programs are unknown. We seek to describe the current state of residency programs in radiation oncology in Latin America. Methods and Materials: Latin American Residents in Radiation Oncology performed a cross-sectional analysis of universities and training centers for radiation oncologists in Latin America. Latin American Residents in Radiation Oncology members identified and contacted current residents and specialists at each center to obtain information and documents that described their training curricula. Results: As of 2020, 13 of 23 (56.5%) Latin American countries have radiation oncology training. Seventy-three training centers were identified (59 active and 14 inactive), associated with 28 universities. On average, each active center trains 2.6 new residents per year, and in total, 156 residents are trained annually. The average length of training programs is 3.6 years. Brazil and Mexico comprise 31 (52.5%) and 7 (11.9%) of active programs, respectively, and 64 (41.8%) and 50 (32.7%) residents, respectively. Training is available in 38 cities in 13 countries, and outside Brazil and Mexico, only 13 cities in 11 countries (9 capitals and 4 noncapital cities). Individualized curriculum documents were provided by 20 (83.3%) of 24 non-Brazilian programs, while 1 standardized guideline was provided for Brazilian training programs. These demonstrated variation between subjects taught, their devoted time, outside specialty rotations, and experiences in modern techniques. Seventy-five percent include volumetric modulated arc therapy, 70% stereotactic radiosurgery, and 55% stereotactic body radiation therapy training. One-hundred percent include gynecologic brachytherapy education and <50% brachytherapy education in other disease sites. Conclusions: Training is highly centralized in capital cities. The number of trainees is insufficient to close the current human resource divide but is limited by available job openings. Over 50% of training programs now include technological training in stereotactic radiosurgery, stereotactic body radiation therapy, or volumetric modulated arc therapy; however, substantial variation still exists. The development of radiation oncology specialists must be improved and modernized to address the escalating demand for cancer care.

The Human Dermis as a Target of Nanoparticles for Treating Skin Conditions.

Skin has a preventive role against any damage raised by harmful microorganisms and physical and chemical assaults from the external environment that could affect the body's internal organs. Dermis represents the main section of the skin, and its contribution to skin physiology is critical due to its diverse cellularity, vasculature, and release of molecular mediators involved in the extracellular matrix maintenance and modulation of the immune response. Skin structure and complexity limit the transport of substances, promoting the study of different types of nanoparticles that penetrate the skin layers under different mechanisms intended for skin illness treatments and dermo-cosmetic applications. In this work, we present a detailed morphological description of the dermis in terms of its structures and resident cells. Furthermore, we analyze the role of the dermis in regulating skin homeostasis and its alterations in pathophysiological conditions, highlighting its potential as a therapeutic target. Additionally, we describe the use of nanoparticles for skin illness treatments focused on dermis release and promote the use of metal-organic frameworks (MOFs) as an integrative strategy for skin treatments.

Transplantation of hematopoietic progenitors in myelofibrosis.

The objective of this work is to generate recommendations on the management of allogeneic stem cell transplantation (allo-SCT) in primary myelofibrosis (PMF). A comprehensive systematic review of articles published between 1999 and 2015 (January) was used as a source of scientific evidence. The recommendations were produced through a Delphi process involving a panel of 23 experts appointed by the European LeukemiaNet and the European Blood and Marrow Transplantation Group. Key questions included patient selection, donor selection, pre-transplant management, conditioning regimen, post-transplant management, prevention, and management of post-transplant relapse. Patients with intermediate-2 or high-risk disease and age < 70 years should be considered candidates for allo-SCT. Patients with intermediate-risk 1 disease and age < 65 years should be considered candidates if they have refractory transfusion-dependent anemia, or a peripheral blood (PB) blast percentage > 2%, or adverse cytogenetics. Splenectomy before transplantation must be decided on a case-by-case basis. Patients with intermediate-2 or high-risk disease who lack a human leukocyte antigen (HLA)-matched sibling or unrelated donor should be enrolled in a protocol that uses HLA non-identical donors. PB was considered the most appropriate source of hematopoietic stem cells for transplants from HLA-matched unrelated donors and siblings. The optimal intensity of the conditioning regimen has yet to be defined. Strategies such as discontinuation of immunosuppressive drugs, infusion of donor lymphocytes, or both were considered adequate to prevent clinical relapse. In conclusion, we provide consensus-based recommendations aimed at optimizing allo-SCT in PMF. Unmet clinical needs were highlighted.

El objetivo de este trabajo es generar recomendaciones sobre el manejo del trasplante alogénico de células madre (alo-SCT) en la mielofibrosis primaria (MFP). Se utilizó una revisión sistemática integral de artículos publicados entre 1999 y 2015 (enero) como fuente de evidencia científica. Las recomendaciones se produjeron mediante un proceso Delphi en el que participó un panel de 23 expertos designados por la European LeukemiaNet y el European Blood and Marrow Transplantation Group. Las preguntas clave incluyeron la selección de pacientes, la selección de donantes, el manejo previo al trasplante, el régimen de acondicionamiento, el manejo posterior al trasplante, la prevención y el manejo de la recaída después del trasplante. Los pacientes con enfermedad de riesgo intermedio 2 o alto y edad < 70 años deben ser considerados candidatos para alo-SCT. Los pacientes con enfermedad de riesgo intermedio 1 y edad < 65 años deben ser considerados candidatos si presentan anemia refractaria dependiente de transfusiones, o un porcentaje de blastos en sangre periférica > 2%, o citogenética adversa. La esplenectomía previa al trasplante debe decidirse caso por caso. Los pacientes con enfermedad de riesgo intermedio 2 o alto que carecen de un hermano compatible con el antígeno leucocitario humano (HLA) o de un donante no emparentado deben inscribirse en un protocolo que utilice donantes no idénticos de HLA. PB se consideró la fuente más apropiada de células madre hematopoyéticas para trasplantes de hermanos y donantes no emparentados compatibles con HLA. La intensidad óptima del régimen de acondicionamiento aún debe definirse. Se consideraron adecuadas estrategias como la suspensión de los fármacos inmunosupresores, la infusión de linfocitos del donante o ambas para evitar la recaída clínica. En conclusión, proporcionamos recomendaciones basadas en consenso destinadas a optimizar el alo-SCT en MFP. Se destacaron las necesidades clínicas insatisfechas.

Essential thrombocythaemia.

Essential thrombocythemia (ET) is a chronic Philadelphia-negative myeloproliferative neoplasm that has its main involvement in the megakaryopoietic lineage, generating sustained thrombocytosis in peripheral blood and an increase in the number of mature megakaryocytes in the bone marrow. In addition to marked thrombocytosis, it is characterized by increased thrombotic or hemorrhagic risk and the presence of constitutional symptoms. Patients with ET have a low but known risk of disease progression to myelofibrosis and/or acute leukemia. The diagnosis is made based on the 2016 WHO criteria. At present, available treatments for patients with ET are mainly aimed at minimizing the risk of thrombosis and/or bleeding.

La trombocitemia esencial (TE) es una neoplasia mieloproliferativa crónica Filadelfia negativa que tiene su principal involucro en la línea megacariopoyética, generando trombocitosis sostenida en la sangre periférica y un incremento en el número de megacariocitos maduros en médula ósea. Además de una marcada trombocitosis, se caracteriza por un mayor riesgo trombótico o hemorrágico y la presencia de síntomas constitucionales. Los pacientes con TE tienen un riesgo bajo, pero conocido, de evolución de la enfermedad a mielofibrosis y/o leucemia aguda. El diagnóstico se realiza con base en los criterios de la Organización Mundial de la Salud del 2016. Los tratamientos actualmente disponibles para los pacientes con TE están dirigidos principalmente a minimizar el riesgo de trombosis y/o hemorragia.

Pregnancy in myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPN) are associated with a significant risk of thrombosis and the hypercoagulable environment of pregnancy increases this risk. The most frequent gestational complications consist of spontaneous abortion, thrombosis, bleeding, and hypertensive disease of pregnancy. Treatment depends on thrombotic risk, gestational trimester, and myeloproliferative neoplasm.

Las neoplasias mieloproliferativas (NMP) están asociadas a un riesgo notable de trombosis y el entorno de hipercoagulabilidad propio del embarazo aumenta este riesgo. Las complicaciones gestacionales más frecuentes consisten en: aborto espontáneo, trombosis, sangrado y enfermedad hipertensiva del embarazo. El tratamiento depende del riesgo trombótico, trimestre gestacional y neoplasia mieloproliferativa.

Polycythemia vera.

Polycythemia vera (PV) is mainly characterized by erythrocytosis, thrombotic and hemorrhagic predisposition, a variety of symptoms, and cumulative risks of fibrotic progression and/or leukemic evolution over time. The diagnosis is made based on the 2016 WHO criteria. The treatment of PV focuses on rapidly reducing the erythrocyte mass, either by means of phlebotomies or with cytoreductive treatment, and the reduction of thrombotic risk by correcting cardiovascular risk factors and the use of platelet antiaggregants.

La policitemia vera (PV) se caracteriza principalmente por eritrocitosis, predisposición trombótica y hemorrágica, una variedad de síntomas y riesgos acumulativos de progresión fibrótica y/o evolución leucémica a lo largo del tiempo. El diagnóstico se realiza con base en los criterios de la Organización Mundial de la Salud del 2016. El tratamiento de la PV se centra en reducir rápidamente la masa eritrocitaria, ya sea por medio de flebotomías o con tratamiento citorreductor, y la disminución del riesgo trombótico mediante la corrección de factores de riesgo cardiovascular y el uso de antiagregantes plaquetarios.

Risks in invasive procedures.

Patients with myeloproliferative neoplasms have an increased risk of thrombosis and bleeding. This risk must be identified, as well as individualizing the therapeutic strategy before invasive procedures; adequate cytoreduction reduces the risk of complications.

Los pacientes con neoplasias mieloproliferativas tienen un riesgo incrementado de trombosis y sangrado. Se debe identificar dicho riesgo, así como individualizar la estrategia terapéutica previo a los procedimientos invasivos; una adecuada citorreducción disminuye el riesgo de complicaciones.

Symptom control.

In addition to symptoms secondary to splenomegaly, microvascular abnormalities, and thrombohemorrhagic complications, patients with MPN may experience a significant symptom burden attributed to an increase in circulating inflammatory cytokines. These symptoms can be severe and limit quality of life. Therefore, in addition to the prevention of complications, one of the objectives of the treatment of MPN is the control of symptoms.

Además de la sintomatología secundaria a la esplenomegalia, a las alteraciones microvasculares y a las complicaciones trombohemorrágicas, los pacientes con neoplasias mieloproliferativas (NMP) pueden experimentar una importante carga sintomática atribuida a un aumento de citocinas inflamatorias circulantes. Estos síntomas pueden ser severos y limitar la calidad de vida. Por ello, además de la prevención de las complicaciones, uno de los objetivos del tratamiento de las NMP es el control de los síntomas.

Thrombotic events.

Major thrombotic complications in myeloproliferative neoplasms (MPNs) represent an important clinical problem due to their high morbidity, the complexity of their management, and their associated mortality. The appearance of a thrombosis implies a high thrombotic risk stratification of the MPN and determines the initiation or optimization of cytoreductive treatment and the use of antiplatelet or anticoagulant therapy as secondary prophylaxis. The incidence of thrombosis at the time of diagnosis is higher than during the course of the disease, being located in the arterial territory in 60-70% of cases. Once thrombosis has occurred, up to 20-33% of patients experience thrombotic recurrence in the same initial vascular territory.

Las complicaciones trombóticas mayores en las neoplasias mieloproliferativas (NMP) representan un importante problema clínico debido a su elevada morbilidad, la complejidad de su manejo y su mortalidad asociada. La aparición de una trombosis comporta una estratificación de alto riesgo trombótico de la NMP y determina el inicio o la optimización del tratamiento citorreductor y el uso de terapia antiplaquetaria o anticoagulante como profilaxis secundaria. La incidencia de trombosis en el momento del diagnóstico es mayor que durante la evolución de la enfermedad, localizándose en territorio arterial en el 60-70% casos. Una vez se ha producido una trombosis, hasta el 20-33% de los pacientes sufre una recurrencia trombótica en el mismo territorio vascular inicial.

First inter-institutional consensus on Chronic Myeloproliferative Neoplasms.

The objective of the consensus is to make available to the professionals of the different public health institutions in our country, who are in charge of these diseases, the most relevant and up-to-date information about their diagnosis and treatment in clinical practice. With this inter-institutional consensus we hope to contribute to improving the quality of care for patients with chronic myeloproliferative neoplasms throughout the Mexican Republic, to unify criteria in both diagnosis and treatment of the different myeloproliferative diseases.

OBJETIVO: El objetivo del consenso es poner a disposición de los profesionales de las diferentes instituciones de salud pública en nuestro país, quienes se encuentran a cargo de estas enfermedades, la información más relevante y actualizada acerca de su diagnóstico y tratamiento en la práctica clínica. Con este consenso interinstitucional esperamos contribuir a mejorar la calidad de la atención de los pacientes con neoplasias mieloproliferativas crónicas a todo lo ancho y largo de la República Mexicana, con el fin de unificar criterios tanto en diagnóstico como en tratamiento de las diferentes enfermedades mieloproliferativas.

Myelofibrosis: diagnosis and treatment.

Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm characterized by clonal myeloproliferation, dysregulated kinase signaling, and release of abnormal cytokines. In recent years, important progress has been made in the knowledge of the molecular biology and the prognostic assessment of MF. Conventional treatment has limited impact on the patients' survival; it includes a wait-and-see approach for asymptomatic patients, erythropoiesis-stimulating agents, androgens, or immunomodulatory agents for anemia, cytoreductive drugs such as hydroxyurea for the splenomegaly and constitutional symptoms, and splenectomy or radiotherapy in selected patients. The discovery of the Janus kinase (JAK) 2 mutation triggered the development of molecular targeted therapy of MF. The JAK inhibitors are effective in both JAK2-positive and JAK2-negative MF; one of them, ruxolitinib, is the current best available therapy for MF splenomegaly and constitutional symptoms. Although ruxolitinib has changed the therapeutic scenario of MF, there is no clear indication of a disease-modifying effect. Allogeneic stem cell transplantation remains the only curative therapy of MF, but due to its associated morbidity and mortality, it is usually restricted to eligible high- and intermediate-2-risk MF patients. To improve current therapeutic results, the combination of JAK inhibitors with other agents is currently being tested, and newer drugs are being investigated.

La mielofibrosis (MF) es una neoplasia mieloproliferativa negativa para BCR-ABL1 caracterizada por mieloproliferación clonal, señalización de cinasa desregulada y liberación de citocinas anormales. En los últimos años se han realizado importantes avances en el conocimiento de la biología molecular y la valoración pronóstica de la MF. El tratamiento convencional tiene un impacto limitado en la supervivencia de los pacientes; incluye un enfoque de espera para pacientes asintomáticos, agentes estimulantes de la eritropoyesis, andrógenos o agentes inmunomoduladores para la anemia, fármacos citorreductores como la hidroxiurea para la esplenomegalia y los síntomas constitucionales, y esplenectomía o radioterapia en pacientes seleccionados. El descubrimiento de la mutación Janus cinasa (JAK) 2 desencadenó el desarrollo de la terapia dirigida molecular de la MF. Los inhibidores de JAK son efectivos tanto en MF con JAK2 positivo como con JAK2 negativo; uno de ellos, el ruxolitinib, es la mejor terapia disponible actualmente para la esplenomegalia y los síntomas constitucionales de la MF. Sin embargo, aunque el ruxolitinib ha cambiado el escenario terapéutico de la MF, no hay indicios claros de un efecto modificador de la enfermedad. El alotrasplante de células madre sigue siendo la única terapia curativa de la MF, pero debido a su morbilidad y mortalidad asociadas, generalmente se restringe a pacientes elegibles con MF de riesgo alto e intermedio 2. Para mejorar los resultados terapéuticos actuales, actualmente se está probando la combinación de inhibidores de JAK con otros agentes y se están investigando fármacos más nuevos.

The Role of Key Amino Acids in the Antimicrobial Mechanism of a Bacteriocin Model Revealed by Molecular Simulations.

The AS-48 bacteriocin is a potent antimicrobial polypeptide with enhanced stability due to its circular sequence of peptidic bonds. The mechanism of biological action is still not well understood in spite of both the elucidation of the molecular structure some years ago and several experiments performed that yielded valuable information about the AS-48 bacterial membrane poration activity. In this work, we present a computational study at an atomistic scale to analyze the membrane disruption mechanism. The process is based on the two-stage model: (1) peptide binding to the bilayer surface and (2) membrane poration due to the surface tension exerted by the peptide. Indeed, the induced membrane tension mechanism is able to explain stable formation of pores leading to membrane disruption. The atomistic detail obtained from the simulations allows one to envisage the contribution of the different amino acids during the poration process. Clustering of cationic residues and hydrophobic interactions between peptide and lipids seem to be essential ingredients in the process. GLU amino acids have shown to enhance the membrane disrupting ability of the bacteriocin. TRP24-TRP24 interactions make also an important contribution in the initial stages of the poration mechanism. The detailed atomistic information obtained from the simulations can serve to better understand bacteriocin structural characteristics to design more potent antimicrobial therapies.