The mitochondrial NADH shuttle system is a targetable vulnerability for Group 3 medulloblastoma in a hypoxic microenvironment.

Medulloblastoma is a cancerous brain tumor that affects mostly children. Among the four groups defined by molecular characteristics, Group 3, the least well characterized, is also the least favorable, with a survival rate of 50%. Current treatments, based on surgery, radiotherapy, and chemotherapy, are not adequate and the lack of understanding of the different molecular features of Group 3 tumor cells makes the development of effective therapies challenging. In this study, the problem of medulloblastoma is approached from a metabolic standpoint in a low oxygen microenvironment. We establish that Group 3 cells use both the mitochondrial glycerol-3 phosphate (G3PS) and malate-aspartate shuttles (MAS) to produce NADH. Small molecules that target G3PS and MAS show a greater ability to decrease cell proliferation and induce apoptosis specifically of Group 3 cells. In addition, as Group 3 cells show improved respiration in hypoxia, the use of Phenformin, a mitochondrial complex 1 inhibitor, alone or in combination, induced significant cell death. Furthermore, inhibition of the cytosolic NAD+ recycling enzyme lactate dehydrogenase A (LDHA), enhanced the effects of the NADH shuttle inhibitors. In a 3D model using Group 3 human cerebellar organoids, tumor cells also underwent apoptosis upon treatment with NADH shuttle inhibitors. Our study demonstrates metabolic heterogeneity depending on oxygen concentrations and provides potential therapeutic solutions for patients in Group 3 whose tumors are the most aggressive.

HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma.

Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2's transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. Overall, the unique dependence of MB cells, but not normal cells, on HIF-2-mediated anabolic metabolism presents an appealing therapeutic opportunity for treating Group 3 MB patients with minimal toxicity.

Complications associated with submental liposuction: a scoping review.

BACKGROUND: Liposuction is one of the most commonly performed cosmetic procedures worldwide. Complications associated with submental liposuction are rare. However, when they occur they are significant and can cause disfiguring consequences. The objective of this study was evaluated complications from submentual liposuction in literature and description of clinical experience of complication after submentual liposuction. MATERIAL AND METHODS: At first, a scoping review was carried out online search with no time restrictions for complications after submental liposuction was performed in the databases Medline / PubMed, Embase, and Web of Science. The variables analyzed were: age, sex, type of esthetic procedure, anesthesia, complications, time after Procedure, treatment, follow-up care, and sequelae. Then, a case of a patient with submental hematoma after an aesthetic procedure for submental liposuction was described. RESULTS: Firstly, 539 articles were selected, after application of the inclusion criteria, 4 studies were included. Most cases were female (8:1), with a mean age of 55.77 years. Postoperative complications were found, such as submental depression, submental edema, hypertrophic scar formation, scar contracture, cervical necrotizing fasciitis, Cervico-facial dystonia and transient facial nerve paralysis. The follow-up period for cases ranged from 3 to 12 months. The clinical case presented there was no sequelae. CONCLUSIONS: Submental liposuction requires the surgeon's attention. Anatomical knowledge, correct clinical and surgical management, diagnosis, and immediate approach to adverse situations are points that must be respected in this type of esthetic procedure to avoid more serious complications.

Changes in trunk and head acceleration during the 6-minute walk test and its relation to falls risk for adults with multiple sclerosis.

For persons with multiple sclerosis (MS), the general decline in neuromuscular function underlies diminished balance, impaired gait and consequently, increased risk of falling. During gait, optimal control of head motion is an important feature which is achieved partly through control of the trunk-neck region to dampen gait-related oscillations. The primary aim of this study was to examine the effect performing a 6-minute walk test (6MWT) has on head, neck and trunk accelerations in individuals with MS. This was addressed using a repeated measures generalized linear model. We were also interested in assessing whether the 6MWT has an impact on a person's falls risk and specific physiological measures related to falls. Finally the relation between the amplitude (i.e., mean RMS) of head and trunk accelerations and falls risk was examined using linear regression. The main results were that over the course of the 6MWT, individuals progressively slowed down coupled with a concurrent increase in gait-related upper body accelerations (p's > 0.05). Despite the increased acceleration, no significant changes in attenuation from the trunk to the head were observed, indicating that persons were able to maintain an optimal level of control over these oscillations. Performing the 6MWT also had a negative impact on posture, with falls risk significantly increasing following this test (p > 0.05). Interestingly, the overall falls risk values were strongly linked with vertical accelerations about the trunk and head, but not average walking speed during the 6MWT. Overall, performing the 6MWT leads to changes in walking speed, upper body acceleration patterns and increases in overall falls risk.

Head and neck cancer associated with myiasis.

Head and neck cancer patients represent a risk group for the development of fly larvae infestation in neoplastic wounds. This condition can accelerate the disease progression and increase its lethality due to local or systemic complications. The aim of this study was to conduct a scoping review on head and neck cancer associated with myiasis in order to answer the focal question: what are the occurrence, diagnosis, aetiology, treatment and outcomes of head and neck cancer associated with myiasis? This paper was structured based on the five-steps methodology proposed by Arksey and O'Malley (Int J Soc Res Methodol 2005;1:19-32), and followed the PRISMA Extension for Scoping Reviews (PRISMA-ScR), OSF Registries protocol. The electronic search was performed in the MEDLINE/PubMed, Embase and SciELO.org databases for articles published up to 28 February 2021. In total, 38 articles and 56 patients were included. Most patients were male (66%), and the mean age was 66.63 years. Cases were predominantly associated with squamous or basal cell cancer. The most affected anatomical sites were the eyes, scalp, ears and oral cavity, and the most frequent type of larva was Crisomyia (13%). Manual removal of the larvae was considered the standard treatment, associated or not with antibiotics, analgesics and antiparasitic drugs.

Poor patient awareness and frequent misdiagnosis of migraine: findings from a large transcontinental cohort.

BACKGROUND AND PURPOSE: Although migraine is the second most disabling condition worldwide, there is poor awareness of it. The objective was to assess the awareness of migraine and previous diagnostic and therapeutic consultations and treatments in a large international population of migraineurs. METHODS: This was a multicentre study conducted in 12 headache centres in seven countries. Each centre recruited up to 100 patients referred for a first visit and diagnosed with migraine. Subjects were given a structured clinical questionnaire-based interview about the perceptions of the type of headache they suffered from, its cause, previous diagnoses, investigations and treatments. RESULTS: In all, 1161 patients completed the study. Twenty-eight per cent of participants were aware that they suffered from migraine. Sixty-four per cent called their migraine 'headache'; less commonly they used terms such as 'cervical pain' (4%), tension headache (3%) and sinusitis (1%). Eight per cent of general practitioners and 35% of specialists (of whom 51% were neurologists and/or headache specialists) consulted for migraine formulated the correct diagnosis. Before participating in the study, 50% of patients had undergone X-ray, computed tomography and/or magnetic resonance imaging of the cervical spine and 76% underwent brain and/or cervical spine imaging for migraine. Twenty-eight per cent of patients had received symptomatic migraine-specific medications and 29% at least one migraine preventive medication. CONCLUSIONS: Although migraine is a very common disease, poor awareness of it amongst patients and physicians is still an issue in several countries. This highlights the importance of the promotion of migraine awareness to reduce its burden and limit direct and indirect costs and the risk of exposure to useless investigations.

How parked cars affect pollutant dispersion at street level in an urban street canyon? A CFD modelling exercise assessing geometrical detailing and pollutant decay rates.

Computational fluid dynamics (CFD) is a recognised modelling tool for simulating pollutant dispersion in urban street canyons. These studies require accurate street geometry, sufficient modelling experience and access to software to provide reliable outputs. Parked cars are known to act as a passive barrier and affects pollutant dispersion in an urban street canyon. This modelling study examines the impact of accurate geometrical detailing and suitable mesh sizing on air pollution concentrations measured at street level. Mean steady state concentrations of carbon monoxide (CO) were measured in a reference scenario (without parked cars) and three parked car scenarios. A comparison of the results indicated that individual rectangular blocks and generic car scenarios overestimated pollutant concentrations on the footpaths by up to 25% when compared to the results from the five distinct car designs scenario, with the parked cars acting as a passive barrier in each scenario under different wind conditions. The most notable finding demonstrated how the five distinct car designs scenario presented an increase in CO concentrations on the leeward footpath as opposed to a reduction in the results in the other coarser geometrically detailed scenarios. The parked cars trapped pollutants in each scenario with low wind speeds for perpendicular wind conditions, as higher concentrations were measured on the footpaths. A further examination of pollutant decay rates demonstrated how the geometrical detailing of the parked cars also impacted upon the duration taken for pollutants to escape from the footpath zones. These findings demonstrate how parked cars affects pollutant dispersion and concentrations measured on the footpaths at street level, and the adoption of a suitable meshing scheme is vital to capture results in the zone of interest in an urban street canyon.

Complete Genome Sequences of Zika Virus Strains Isolated from the Blood of Patients in Thailand in 2014 and the Philippines in 2012.

Here, we present the complete genome sequences of two Zika virus (ZIKV) strains, Zika virus/Homo sapiens-tc/THA/2014/SV0127-14 and Zika virus/H. sapiens-tc/PHL/2012/CPC-0740, isolated from the blood of patients collected in Thailand, 2014, and the Philippines, 2012, respectively. Sequencing and phylogenetic analysis showed that both strains belong to the Asian lineage.

Corporoplastia ventral de cuerpos cavernosos para el tratamiento de la incurvación severa de pene en Urología Pediátrica / Ventral corpora cavernosa corporoplasty for the treatment of severe penile incurvation in Pediatric Urology

El Hipospadias es una patología congénita de los genitales masculinos que cada día diagnosticamos y tratamos más. Debido a un aumento de la casuística debemos tener a mano un arsenal de técnicas quirúrgicas para su correcto tratamiento. La Corporoplastia Ventral de cuerpos cavernosos es una de ellas que nos ayudara con éxito a tratar los caso más severos dentro de este espectro que es la patología en sí misma. Hablaremos de la técnica y sus indicaciones, además de nuestra experiencia en su utilización en 20 pacientes diferentes con excelentes resultados y sin complicaciones. La corporoplastia es una de las técnicas quirúrgicas con las que podremos tratar los casos más severos de incurvación peneana

Hypospadias is a congenital pathology of the male genitalia that we diagnose and treat more every day. Due to an increase of case load we must have at hand a large quantity of surgical techniques for its correct treatment. Ventral corporoplasty of the corpora cavernosa is one of them that will help us to successfully treat the most severe cases within this variety which is the pathology itself. We performed a prospective study in Malaga, Spain between 2010-2015. We review the technic and its indications, and the authors personal series with 20 cases performed by 2 surgeons using the same protocol and technics. The outcomes showed good results without complications in all cases. Corporoplasty is one of the surgical technique for the treatment of the most sever cases of penile incurvation

[Folic acid: Primary prevention of neural tube defects. Literature Review]. / Ácido fólico: prevención primaria de los defectos del tubo neural. Revisión bibliográfica.

Neural tube defects (NTD) are the most common congenital malformations of the nervous system, they have a multifactorial etiology, are caused by exposure to chemical, physical or biological toxic agents, factors deficiency, diabetes, obesity, hyperthermia, genetic alterations and unknown causes. Some of these factors are associated with malnutrition by interfering with the folic acid metabolic pathway, the vitamin responsible for neural tube closure. Its deficit produce anomalies that can cause abortions, stillbirths or newborn serious injuries that cause disability, impaired quality of life and require expensive treatments to try to alleviate in some way the alterations produced in the embryo. Folic acid deficiency is considered the ultimate cause of the production of neural tube defects, it is clear the reduction in the incidence of Espina Bifida after administration of folic acid before conception, this leads us to want to further study the action of folic acid and its application in the primary prevention of neural tube defects. More than 40 countries have made the fortification of flour with folate, achieving encouraging data of decrease in the prevalence of neural tube defects. This paper attempts to make a literature review, which clarify the current situation and future of the prevention of neural tube defects.

Ácido fólico: prevención primaria de los defectos del tubo neural. Revisión bibliográfica / Folic acid: Primary prevention of neural tube defects. Literature Review

Los defectos en el cierre del tubo neural (DTN) son las malformaciones congénitas más frecuentes del sistema nervioso, van a tener una etiología multifactorial, se producen por la exposición a agentes tóxicos químicos, físicos o biológicos, por factores carenciales, diabetes, obesidad, hipertermia, alteraciones genéticas y causas desconocidas. Algunos de los factores señalados se asocian con la desnutrición por interferir con la vía metabólica del ácido fólico (AF), vitamina encargada del cierre del tubo neural, y cuyo déficit produce las anomalías que pueden ocasionar abortos, mortinatos o lesiones graves del recién nacido que producen incapacidad, alteraciones en la calidad de vida y requieren tratamientos costosos para tratar de paliar en alguna forma las alteraciones producidas en el embrión. El déficit de ácido fólico se considera la causa última de la producción de defectos del tubo neural, la comprobación de la disminución de la incidencia de la Espina Bífida tras la administración preconcepcional de Ácido Fólico es evidente, lo que nos lleva a querer profundizar en el estudio de la acción del AF y su aplicación en la prevención primaria de los DTN. Más de 40 países han realizado la fortificación de harinas con folatos, llegando a conseguir datos esperanzadores de decrecimiento de la prevalencia de los DTN. Este trabajo intenta realizar una revisión bibliográfica que nos clarifique la situación actual y el futuro de la prevención de los DTN

Neural tube defects (NTD) are the most common congenital malformations of the nervous system, they have a multifactorial etiology, are caused by exposure to chemical, physical or biological toxic agents, factors deficiency, diabetes, obesity, hyperthermia, genetic alterations and unknown causes. Some of these factors are associated with malnutrition by interfering with the folic acid metabolic pathway, the vitamin responsible for neural tube closure. Its deficit produce anomalies that can cause abortions, stillbirths or newborn serious injuries that cause disability, impaired quality of life and require expensive treatments to try to alleviate in some way the alterations produced in the embryo. Folic acid deficiency is considered the ultimate cause of the production of neural tube defects, it is clear the reduction in the incidence of Espina Bifida after administration of folic acid before conception, this leads us to want to further study the action of folic acid and its application in the primary prevention of neural tube defects. More than 40 countries have made the fortification of flour with folate, achieving encouraging data of decrease in the prevalence of neural tube defects. This paper attempts to make a literature review, which clarify the current situation and future of the prevention of neural tube defects

Development and psychometric validation of a brief comprehensive health status assessment scale in older patients with hematological malignancies: The GAH Scale.

OBJECTIVES: The purpose of this study was to develop a new brief, comprehensive geriatric assessment scale for older patients diagnosed with different hematological malignancies, the Geriatric Assessment in Hematology (GAH scale), and to determine its psychometric properties. MATERIALS AND METHODS: The 30-item GAH scale was designed through a multi-step process to cover 8 relevant dimensions. This is an observational study conducted in 363 patients aged≥65years, newly diagnosed with different hematological malignancies (myelodysplasic syndrome/acute myeloblastic leukemia, multiple myeloma, or chronic lymphocytic leukemia), and treatment-naïve. The scale psychometric validation process included the analyses of feasibility, floor and ceiling effect, validity and reliability criteria. RESULTS: Mean time taken to complete the GAH scale was 11.9±4.7min that improved through a learning-curve effect. Almost 90% of patients completed all items, and no floor or ceiling effects were identified. Criterion validity was supported by reasonable correlations between the GAH scale dimensions and three contrast variables (global health visual analogue scale, ECOG and Karnofsky), except for comorbidities. Factor analysis (supported by the scree plot) revealed nine factors that explained almost 60% of the total variance. Moderate internal consistency reliability was found (Cronbach's α: 0.610), and test-retest was excellent (ICC coefficients, 0.695-0.928). CONCLUSION: Our study suggests that the GAH scale is a valid, internally reliable and a consistent tool to assess health status in older patients with different hematological malignancies. Future large studies should confirm whether the GAH scale may be a tool to improve clinical decision-making in older patients with hematological malignancies.

Enuresis. Diagnóstico diferencial y tratamiento específico / Enuresis. Differential diagnosis and specific treatment

Introducción. A pesar de su gran prevalencia y antigüedad, esta patología tiene importantes interrogantes etiológicos, diagnósticos y terapéuticos. Hay que partir de dos grupos completamente diferentes: la enuresis (E) monosintomática o no complicada y el síndrome (S) enurético o E complicada con sus respectivos subgrupos, cada uno con etiología diferente que además es multifactorial. Diagnóstico diferencial. Se estructura en 3 niveles: 1º ¿E. monosintomática o S. enurético?; 2º ¿Patalogía o malos hábitos?; 3º ¿Disfunción de llenado o vaciado? Historia. Se describen tratamientos utilizados en diferentes culturas y épocas, demostrando la diversidad y a veces antagonismo que persiste hasta hoy, como demostración de la necesidad de un diagnóstico diferencial y un tratamiento etiológico. Tratamiento actual. Tras estudio de metaanálisis y revisiones sistemáticas se han ordenado por nivel de evidencia (NE) y grado de recomendación (GR) los estudios más válidos de tratamientos de E. monosintomática. La desmopresina, la alarma y la asociación de ambas tienen el máximo NE y GR, mientras que los antidepresivos tienen el mismo NE pero el menor GR por riesgo de efectos adversos. Los anticolinérgicos asociados a desmopresina están en el 2º nivel de NE y GR. Tratamiento personalizado. Se expone un tratamiento integral personalizado multidisciplinar. Se expone un tratamiento integral personalizado y multidisciplinar. Se inicia con diagnóstico diferencial y valoración psicológica. En E. monosintomática se inicia 1º un tratamiento básico conductal, seguido de un 2º paso con desmopresina y/o alarma según características personales. Si el resultado con uno de ellos es insuficiente se aconseja un 3º paso asociando el otro o añadiendo anticolinérgicos. Si es necesario un 4º paso se proponer biofeedback. El soporte psicológico de la familia y del niño es importante para la motivación, adhesión al tratamiento y mantenimiento de éxito. Conclusiones. Cada enurético es distinto y precisa un diagnóstico diferencial adecuado, además de una investigación personalizada, identificando sus factores influyentes. En la E. monosintomática el mejor NE y GR actualmente corresponden a la desmopresina, a la alarma y a ambas juntas. Hay que conocer todos los recursos terapéuticos disponibles, para diseñar un tratamiento lo más individualizado posible. Con frecuencia la combinación de tratamiento es efectiva. En la experiencia de los autores, el tratamiento multidisciplinar en equipo puede ser la mejor opción (AU)

Introduction. In spite of its great prevalence and antiquity, this condition has significant etiological, diagnostic and therapeutic questions. Two completely different groups must be considered: monosymptomatic or uncomplicated enuresis (E) and enuretic or complicated E syndrome (S) with their respective subgroups, each one with different etiology that is also multifactorial. Differential diagnosis. This diagnosis is structured into 3 levels: 1) Monosymptomatic E or enuretic syndrome?; 2) Disease or poor habits?; 3) Filling or emptying dysfunction? History. Treatments used in different cultures and periods that demonstrate the diversity and sometimes antagonisms that persists up to the current date are described as a demonstration of the need for a differential diagnosis and etiological treatment. Current treatment. After the meta-analysis study and systematic reviews, the most valid studies of treatments of monosymptomatic E. were ordered by level of evidence (LE) and recommendation grade (RG). Desmopressin, the alarm and the association of both have a maximum LE and while antidepressants have the same LE, but a lower RG, due to the risk of adverse events. The anticholinergics associated to desmopressin are on the second level of the LE and RG. Personalized treatment. A personalized comprehensive and multidisciplinary treatment is explained. It is begun with the differential diagnosis and psychological evaluation. In monosymptomatic E, a first basic behavioural treatment is initiated followed by a second step with desmopressin and/or o alarm according to personal characteristics. If the result with one of them is insufficient, a third step is recommended by means of associating the other or adding anticholinergics. If a four step is necessary, biofeedback is proposed. The psychological support of the family and of the child is important for motivation, treatment adherence, and maintenance of success. Conclusions. Each enuretic is differential diagnoses in addition to a personalized study, identifying their influencing factors. In Monosymptomatic E, the best LE and RG currently correspond to desmopressin, to the alarm and to both of them. It is necessary to know all the therapeutic resources available to design the most individualized treatment possible. The combination of treatments is frequently effective. In the experience of the authors, team multidisciplinary treatment may be the best option (AU)

Estenosis ppieloureteral de diagnóstico prenatal. Nuestro manejo / Pyeloureteral stenosis of prenatal diagnosis. Our management

La estenosis pieloureteral es la anomalía más frecuente del tracto urinario de diagnóstico prenatal. Actualmente la mayoría de los casos se diagnostican prenatalmente, pero algunos aún se hacen postnatalmente por el desarrollo de síntomas (dolor abdominal, infección urinaria, hematuria, tumoración abdominal o retraso en el desarrollo pondo-estatural). Dilatación no es sinónimo de obstrucción y se requieren estudios seriados con ultrasonidos (US) y renograma diurético (RD) para diferenciar la obstrucción de la dilatación sin patología. Los factores de riesgo de obstrucción se basan en los US y del RD y son: a)hidronefrosis de grado 3 o mayor, B) diámetro antero-posterior de la pelvis renal, medido en el plano transversal, mayor de 20 mm, c) tiempo medio de eliminación mayor de 20 minutos y d) función renal diferencial menor del 40% en el RD. El reflujo vesicoureteral existe en el 15% de los caos por lo que el cistograma suele ser necesario. La técnica operatoria de elección es la plastia desmembrada de Anderson-Hynes, que tiene buenos resultados es más del 95% de los casos. La endopielotomía se reserva para las reestenosis postoperatorias. La laparoscopia es la técnica ideal para niños mayores de una años (AU)

The Ureteropelic Junction Obstruction is the most frequent pathology of prenatal diagnosis.l Nowadays, most of the cases are done prenatally, but some of them have to be done after birth because of the symptoms developed/observed (abdominal pain, urinary tract infection, haematuria, abdominal pain, urinary tract infection, haematuria, abdominal mass or failure to thrive). Dilatation is not the same as obstruction, and serial studies with ultrasound (US) and diuretic renogram (DR) are required to make a differential diagnosis between obstruction and dilatation without pathology. The obstruction risk factors are based on US and DR, as follows: a) dilatation grade 3 or higher; b) anteroposterior renal pelvis diameter in transversal plane over 20mmm; c) average half time of elimination of radiotracer (T1/2) greater than 20 minutes; and d) differential renal function less than 40% in the DR. The vesicoureteral reflux is present in 15% of the cases so the voiding cystouretrogram is felt necessary. The gold standard surgical technique is the success. The endopyelothomy is the elective technique for postoperatory restenosis. Laparoscopic approach is ideal for children older than 12 months (AU)

Mitochondrial respiratory uncoupling promotes keratinocyte differentiation and blocks skin carcinogenesis.

Decreased mitochondrial oxidative metabolism is a hallmark bioenergetic characteristic of malignancy that may have an adaptive role in carcinogenesis. By stimulating proton leak, mitochondrial uncoupling proteins (UCP1-3) increase mitochondrial respiration and may thereby oppose cancer development. To test this idea, we generated a mouse model that expresses an epidermal-targeted keratin-5-UCP3 (K5-UCP3) transgene and exhibits significantly increased cutaneous mitochondrial respiration compared with wild type (FVB/N). Remarkably, we observed that mitochondrial uncoupling drove keratinocyte/epidermal differentiation both in vitro and in vivo. This increase in epidermal differentiation corresponded to the loss of markers of the quiescent bulge stem cell population, and an increase in epidermal turnover measured using a bromodeoxyuridine (BrdU)-based transit assay. Interestingly, these changes in K5-UCP3 skin were associated with a nearly complete resistance to chemically-mediated multistage skin carcinogenesis. These data suggest that targeting mitochondrial respiration is a promising novel avenue for cancer prevention and treatment.

The effect of nanoparticles on amyloid aggregation depends on the protein stability and intrinsic aggregation rate.

Nanoparticles interfere with protein amyloid formation. Catalysis of the process may occur due to increased local protein concentration and nucleation on the nanoparticle surface, whereas tight binding or a large particle/protein surface area may lead to inhibition of protein aggregation. Here we show a clear correlation between the intrinsic protein stability and the nanoparticle effect on the aggregation rate. The results were reached for a series of five mutants of single-chain monellin differing in intrinsic stability toward denaturation, for which a correlation between protein stability and aggregation propensity has been previously documented by Szczepankiewicz et al. [Mol. Biosyst.20107 (2), 521-532]. The aggregation process was monitored by thioflavin T fluorescence in the absence and presence of copolymeric nanoparticles with different hydrophobic characters. For mutants with a high intrinsic stability and low intrinsic aggregation rate, we find that amyloid fibril formation is accelerated by nanoparticles. For mutants with a low intrinsic stability and high intrinsic aggregation rate, we find the opposite--a retardation of amyloid fibril formation by nanoparticles. Moreover, both catalytic and inhibitory effects are most pronounced with the least hydrophobic nanoparticles, which have a larger surface accessibility of hydrogen-bonding groups in the polymer backbone.

Darbepoetin alfa for anemia in patients with low or intermediate-1 risk myelodysplastic syndromes and positive predictive factors of response.

BACKGROUND: Current guidelines support the use of erythropoiesis-stimulating agents for the treatment of anemia associated with low-risk myelodysplastic syndromes (MDS). DESIGN AND METHODS: Single-arm, open-label, multi-center, phase 2 trial that evaluated the efficacy and safety of darbepoetin alfa (DA) in patients with low or intermediate-risk MDS, hemoglobin <100 g/L, erythropoietin (EPO) levels <500 IU/L and transfusion requirements <2 units/month over the preceding 2 months. Erythroid response (major [MaR] or minor [MiR]) and fatigue (Functional Assessment of Cancer Therapy-Fatigue [FACT-F]) were evaluated at 8, 16 and 24 weeks. DA was initiated at 300 µg weekly. For patients who did not achieve MaR by 8 weeks, filgrastim 300 µg weekly was added. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01039350. RESULTS: Forty-four patients (72.7% transfusion independent) were included. Median age was 76.0 years (range 41.3-92.4), 54.5% were male, and 90.9% presented ECOG Status (0-1). Eighteen patients received filgrastim. An erythroid response was achieved by 31 of 44 patients (70.5%) at week 8 (47.7% MaR, 22.7% MiR), 31 of 44 patients (70.5%) at week 16 (61.4% MaR, 9.1% MiR), and 32 of 44 patients (72.7%) at week 24 (61.3% MaR, 11.4% MiR). Mean (95% CI) change in FACT-F at week 24 was 3.61 (0.72 to 6.51). Baseline EPO levels <100 IU/L were a predictive factor of response. DA was well tolerated. Four mild (two iron deficiencies, flu syndrome and headache) and one fatal (thromboembolic event) adverse events were considered related to darbepoetin alfa. CONCLUSIONS: A fixed dose of 300 µg of darbepoetin alfa weekly (with or without filgrastim) seems to be an effective and safe treatment for anemic patients with low or intermediate-risk MDS, low transfusion burden and EPO levels <500 IU/L. Results may not be extrapolable to unselected MDS patients.

Solvolysis of substituted benzoyl chlorides in nonionic and mixed micellar solutions.

The solvolysis of substituted benzoyl chlorides is sensitive both to substituent electronic effects and to medium effects. The solvolysis reactions of substituted benzoyl chlorides have been analyzed in the presence of nonionic micelles. The reaction is inhibited or catalyzed depending on the reaction mechanism, dissociative or associative, respectively. The micellar effects observed can be related to the low water content and low polarity of the interface as well as an increase of the nucleophilic character of the interfacial water. Moreover, the effect of the micellar surface charge on the solvolysis mechanism with high associative character was systematically studied. Mixed micelles of nonionic-ionic surfactants with a variable ionic content were prepared and characterized regarding charge and polarity. A correlation between the net charge of the micelles and the rate constants at the micellar interface was observed. The results suggest that the transient state for this mechanism is highly stabilized in a positively charged environment while the negative surface given by anionic micelles strongly inhibit the solvolysis reaction.

Inhibition of IAPP and IAPP(20-29) fibrillation by polymeric nanoparticles.

The fibrillation process of the islet amyloid polypeptide (IAPP) and its fragment (IAPP(20-29)) was studied by means of Thioflavin T (ThT) fluorescence and transmission electron microscopy in the absence and presence of N-isopropylacrylamide:N-tert-butylacrylamide (NiPAM:BAM) copolymeric nanoparticles. The process was found to be strongly affected by the presence of the nanoparticles, which retard protein fibrillation as a function of the chemical surface properties of the nanoparticles. The NiPAM:BAM ratio was varied from 50:50 to 100:0. The nanoparticles with higher fraction of NiPAM imposed the strongest retardation of IAPP and IAPP(20-29) fibrillation. These particles have the strongest hydrogen bonding capacity due to the less bulky N-isopropyl group and thus less steric hindrance of the hydrogen-bonding groups of the nanoparticle polymer backbone. Kinetic fibrillation data, as monitored by ThT fluorescence and supported by surface plasmon resonance experiments, suggest that the peptide is strongly absorbed onto the surface of the nanoparticles. This interaction reduces the concentration of peptide free in solution available to proceed to fibrillation which results in an increased lag time of fibrillation, observed as a delayed onset of ThT fluorescence increase, plus a reduction of the amount of fibrils formed as indicated by the equilibrium values at the end of the fibrillation reaction. For the fragment (IAPP(20-29)), the presence of nanoparticles changes the mechanism of association from monomers to fibrils, by interfering with early oligomeric species along the fibrillation pathway.