Dynamic nature of BRAF or KRAS p.G12C mutations in second-line therapy for advanced colorectal cancer patients: do early and late effects exist?

INTRODUCTION: The mitogen-activated protein kinase (MAPK) signalling network aberrations in metastatic colorectal cancer (mCRC) generate intrinsic dynamic effects and temporal variations that are crucial but often overlooked in clinical trial populations. Here, we investigate the time-varying impact of MAPK pathway mutation genotype on each treatment line's contribution to the overall clinical course. METHODS: The PROMETEO study focused on mCRC patients undergoing second-line treatment at 20 hospitals. We evaluated genotypes and employed flexible models to analyse the dynamic effect of each mutation. RESULTS: We examined data derived from 1160 patients. The effects of KRAS G12C or G12V, and BRAF V600E are clearly time-varying, with unexpected consequences such as the deleterious effect of BRAF V600E vs other genotypes dissipating over time when subjects receive antiangiogenics, or KRAS G12V and G12C showing increasing aggressiveness over time. Thus, contrary to expectations, the 12-month survival rate from the second line for those who survived >6 months was 49.9% (95% CI, 32.7-67.3) for KRAS G12C and 59% (95% CI, 38.5-80.6) for BRAF V600E. CONCLUSIONS: The dynamic perspective is essential for understanding the behaviour of tumours with specific genotypes, especially from the second line onward. This may be relevant in patient monitoring and treatment decision-making, particularly in cases with distinct mutations.

Sol-Gel Immobilisation of Lipases: Towards Active and Stable Biocatalysts for the Esterification of Valeric Acid.

Alkyl esters are high added value products useful in a wide range of industrial sectors. A methodology based on a simple sol-gel approach (biosilicification) is herein proposed to encapsulate enzymes in order to design highly active and stable biocatalysts. Their performance was assessed through the optimization of valeric acid esterification evaluating the effect of different parameters (biocatalyst load, presence of water, reaction temperature and stirring rate) in different alcoholic media, and comparing two different methodologies: conventional heating and microwave irradiation. Ethyl valerate yields were in the 80⁻85% range under optimum conditions (15 min, 12% m/v biocatalyst, molar ratio 1:2 of valeric acid to alcohol). Comparatively, the biocatalysts were slightly deactivated under microwave irradiation due to enzyme denaturalisation. Biocatalyst reuse was attempted to prove that good reusability of these sol-gel immobilised enzymes could be achieved under conventional heating.

Potential polyunsaturated aldehydes in the Strait of Gibraltar under two tidal regimes.

Diatoms, a major component of the large-sized phytoplankton, are able to produce and release polyunsaturated aldehydes after cell disruption (potential PUAs or pPUA). These organisms are dominant in the large phytoplankton fraction (>10 µm) in the Strait of Gibraltar, the only connection between the Mediterranean Sea and the Atlantic Ocean. In this area, the hydrodynamics exerts a strong control on the composition and physiological state of the phytoplankton. This environment offers a great opportunity to analyze and compare the little known distribution of larger sized PUA producers in nature and, moreover, to study how environmental variables could affect the ranges and potential distribution of these compounds. Our results showed that, at both tidal regimes studied (Spring and Neap tides), diatoms in the Strait of Gibraltar are able to produce three aldehydes: Heptadienal, Octadienal and Decadienal, with a significant dominance of Decadienal production. The PUA released by mechanical cell disruption of large-sized collected cells (pPUA) ranged from 0.01 to 12.3 pmol from cells in 1 L, and from 0.1 to 9.8 fmol cell⁻¹. Tidal regime affected the abundance, distribution and the level of physiological stress of diatoms in the Strait. During Spring tides, diatoms were more abundant, usually grouped nearer the coastal basin and showed less physiological stress than during Neap tides. Our results suggest a significant general increase in the pPUA productivity with increasing physiological stress for the cell also significantly associated to low nitrate availability.

Polyunsaturated aldehydes from large phytoplankton of the Atlantic Ocean surface (42°n to 33°s).

Polyunsaturated aldehydes (PUAs) are organic compounds mainly produced by diatoms, after cell wounding. These compounds are increasingly reported as teratogenic for species of grazers and deleterious for phytoplanktonic species, but there is still scarce information regarding concentration ranges and the composition of PUAs in the open ocean. In this study, we analyzed the spatial distribution and the type of aldehydes produced by the large-sized (>10 µm) phytoplankton in the Atlantic Ocean surface. Analyses were conducted on PUAs released after mechanical disruption of the phytoplankton cells, referred to here as potential PUAs (pPUAs). Results show the ubiquitous presence of pPUA in the open ocean, including upwelling areas, as well as oligotrophic gyres. Total pPUA concentrations ranged from zero to 4.18 pmol from cells in 1 L. Identified PUAs were heptadienal, octadienal and decadienal, with heptadienal being the most common (79% of total stations). PUA amount and composition across the Atlantic Ocean was mainly related to the nitrogen:phosphorus ratio, suggesting nutrient-driven mechanisms of PUA production. Extending the range of trophic conditions considered by adding data reported for productive coastal waters, we found a pattern of PUA variation in relation to trophic status.

Rechallenge with Anti-EGFR Treatment in RAS/BRAF wt Metastatic Colorectal Cancer (mCRC) in Real Clinical Practice: Experience of the GITuD Group.

BACKGROUND: There are few third- and fourth-line therapeutic options for metastatic colorectal cancer (mCRC). In RAS/BRAF wild-type (wt) mCRC previously treated with anti-epidermal growth factor receptor (anti-EGFR) (first-line) and relapsed after a good response, retreatment with anti-EGFR (rechallenge) emerges as a therapeutic alternative. OBJECTIVE: The aim was to show the activity and safety of anti-EGFR rechallenge in RAS/BRAF wt mCRC in real-world practice. PATIENTS AND METHODS: A multicenter, retrospective, observational study (six hospitals of the Galician Group of Research in Digestive Tumors) was conducted. Adult patients with RAS/BRAF wt mCRC, evaluated by liquid biopsy, were included. They received anti-EGFR rechallenge (cetuximab, panitumumab) as monotherapy, or combined with chemotherapy, in third- or subsequent lines. Efficacy (overall response rate [ORR], disease control rate [DCR], overall survival [OS], and progression-free survival [PFS]) and safety (incidence of adverse events [AEs]) were assessed. RESULTS: Thirty-one patients were analyzed. Rechallenge (median 6 cycles [range 1-27], mainly cetuximab [80.7%]), started at a median anti-EGFR-free time of 18.4 months (1.7-37.5 months) after two (38.7%) or more (61.3%) lines of treatment; 64.5% of patients received a full dose. Median OS and PFS were 9.8 months (95% confidence interval [CI] 8.2-11.4) and 2.6 months (95% CI 1.7-3.4), respectively. ORR was 10%, and DCR was 30%. The most common AEs were diarrhea (35.5%), anemia (29%), emesis (6.4%), and neutropenia (6.4%); < 5% grade ≥ 3; 48.4% of patients reported anti-EGFR-related skin toxicity (grade > 1). Hypomagnesemia required supplements in 29% of patients. Dose delays (≥ 3 days) and reduction (≥ 20%) were reported in 11 (35.5%) and seven patients (22.6%), respectively. CONCLUSIONS: In RAS/BRAF wt mCRC patients, an anti-EGFR rechallenge provides a feasible therapeutic option with clinical benefit (survival) and a manageable safety profile.

Virtual humans for ASD intervention: a brief scoping review.

Individuals with autism spectrum disorder may present social-communicative and behavioral deficits. Recently, research on treatment and diagnosis has shifted its focus to the application of new technologies. Among them is virtual reality, which guarantees a high sense of realism to the experience and allows the implementation of a virtual agent that facilitates the use of the application. In social skills interventions, it has been mostly chosen to implement a virtual agent with a human appearance. Virtual humans guide the user-system interaction through the use of verbal and nonverbal language. They can be equipped with responsiveness: the ability to provide responses to the user based on data recorded during the use of the technology. Responsiveness is functional when the goal is to create an interaction similar to that of everyday life, as it allows for behavioral responses and, at a more sophisticated level, vocal responses. Considering virtual agents capable of holding a conversation with the user, to date three different methods have been implemented that make communication more or less realistic. This brief review proposes a synopsis of relevant virtual humans' features and highlights some key ASD research areas wherein virtual humans are implemented for diagnosis and treatment. A total of 11 studies were selected and their analysis was summarized into 7 main categories. Finally, the clinical and technological implications of the results found were discussed.

Los individuos con trastorno del espectro autista pueden presentar déficits socio-comunicativos y conductuales. Recientemente, la investigación sobre el tratamiento y el diagnóstico se ha centrado en la aplicación de nuevas tecnologías. Entre ellas se encuentra la realidad virtual, que garantiza un alto sentido de realismo a la experiencia y permite la implementación de un agente virtual que facilite el uso de la aplicación. En las intervenciones de habilidades sociales, se ha optado mayoritariamente por implementar un agente virtual con apariencia humana. Los humanos virtuales guían la interacción usuario-sistema mediante el uso de lenguaje verbal y no verbal. Estos pueden estar dotados de responsividad: la capacidad de proporcionar respuestas al usuario basadas en los datos registrados durante el uso de la tecnología. La responsividad es funcional cuando el objetivo es crear una interacción similar a la de la vida cotidiana, ya que permite dar respuestas conductuales y, a un nivel más sofisticado, respuestas vocales. Considerando los agentes virtuales capaces de mantener una conversación con el usuario, hasta la fecha se han implementado tres métodos diferentes que hacen que la comunicación sea más o menos realista. Esta breve revisión propone una sinopsis de las características de los humanos virtuales relevantes y destaca algunas áreas de investigación clave del TEA en las que se implementan humanos virtuales para el diagnóstico y el tratamiento. Se seleccionó un total de 11 estudios y su análisis se resumió en 7 categorías principales. Por último, se discuten las implicaciones clínicas y tecnológicas de los resultados encontrados.

The whole-body motor skills of children with autism spectrum disorder taking goal-directed actions in virtual reality.

Many symptoms of the autism spectrum disorder (ASD) are evident in early infancy, but ASD is usually diagnosed much later by procedures lacking objective measurements. It is necessary to anticipate the identification of ASD by improving the objectivity of the procedure and the use of ecological settings. In this context, atypical motor skills are reaching consensus as a promising ASD biomarker, regardless of the level of symptom severity. This study aimed to assess differences in the whole-body motor skills between 20 children with ASD and 20 children with typical development during the execution of three tasks resembling regular activities presented in virtual reality. The virtual tasks asked to perform precise and goal-directed actions with different limbs vary in their degree of freedom of movement. Parametric and non-parametric statistical methods were applied to analyze differences in children's motor skills. The findings endorsed the hypothesis that when particular goal-directed movements are required, the type of action could modulate the presence of motor abnormalities in ASD. In particular, the ASD motor abnormalities emerged in the task requiring to take with the upper limbs goal-directed actions with low degree of freedom. The motor abnormalities covered (1) the body part mainly involved in the action, and (2) further body parts not directly involved in the movement. Findings were discussed against the background of atypical prospective control of movements and visuomotor discoordination in ASD. These findings contribute to advance the understanding of motor skills in ASD while deepening ecological and objective assessment procedures based on VR.

Cribriform morular thyroid carcinoma: a case report with pathological, immunohistochemical, and molecular findings suggesting an origin from follicular cells (or their endodermal precursors).

Cribriform morular thyroid carcinoma (CMTC) is a rare malignant thyroid tumor with a peculiar growth pattern secondary to permanent activation of the WNT/ß-catenin pathway. CMTC may be associated with familial adenomatous polyposis or sporadic; it shares morphological features with papillary thyroid carcinoma (PTC) and was considered a variant of PTC in the 2017 WHO classification of tumors of endocrine organs. The new 5th edition of the WHO classification of endocrine and neuroendocrine tumors considered CMTC an independent thyroid neoplasm of uncertain histogenesis. A thymic/ultimobranchial pouch-related differentiation in CMTC has been recently postulated. We, however, have used the pathological and immunohistochemical features of this case of CMTC with 2 novel oncogenic somatic variants (c.3428_3429insA, p.(Tyr1143Ter) and c.3565del, p. (Ser1189Hisfs*76) of the APC gene to propose an origin from follicular cells (or their endodermal precursors). As usual in CMTC, the morular component of this tumor was positive for CDX2. Given the fact that WNT/ß-catenin signaling, through CDX2, activates large intestine and small intestine gene expression, we postulate that in CMTC, the tumor cells have their terminal differentiation blocked, thus showing a peculiar primitive endodermal (intestinal-like) phenotype negative for sodium-iodide symporter, thyroperoxidase, and thyroglobulin. Establishing the histogenesis of CMTC is very relevant for the development of appropriate therapies of redifferentiation, particularly in patients where the tumor cannot be controlled by surgery.

Multicomponent Exercise Program to Improve the Immediate Sequelae of COVID-19: A Prospective Study with a Brief Report of 2-Year Follow-Up.

COVID-19 placed teams of professionals in a hostile and unfamiliar environment where the lack of knowledge of its pathology led to the adaptation of programs used so far for other conditions to try to address the immediate sequelae of COVID-19 infection. That is why the aim of this study was to assess the effects of a multicomponent exercise program (MEP) in improving cardio-respiratory performance, health status, disability due to dyspnea, aerobic capacity and endurance, and the immediate sequelae of COVID-19. Thirty-nine patients referred from different hospital services were included in this study. An intervention of seven weeks with sessions twice a week was carried out, where patients underwent intervallic training sessions followed by strengthening exercises and individualized respiratory physiotherapy exercises. The results of this study show a significant improvement in cardio-respiratory performance, health status, disability due to dyspnea, and aerobic capacity and endurance after intervention; and an increase in health status and reduction in disability due to dyspnea at the 2-year follow-up. In addition, none of the patients had any adverse effects either pre-post treatment or at the 2-year follow-up. Individualized and monitored MEP in survivors of COVID-19 showed positive effects in a pre-post evaluation and the 2-year follow up, improving the immediate sequelae of post-COVID-19 patients. This highlights the importance of the professional background of the rehabilitation teams in adapting to an unknown clinical environment.

Susceptibility Genes and Chromosomal Regions Associated With Non-Syndromic Familial Non-Medullary Thyroid Carcinoma: Some Pathogenetic and Diagnostic Keys.

Thyroid cancer is the malignant tumor that is increasing most rapidly in the world, mainly at the expense of sporadic papillary thyroid carcinoma. The somatic alterations involved in the pathogenesis of sporadic follicular cell derived tumors are well recognized, while the predisposing alterations implicated in hereditary follicular tumors are less well known. Since the genetic background of syndromic familial non-medullary carcinoma has been well established, here we review the pathogenesis of non-syndromic familial non-medullary carcinoma emphasizing those aspects that may be useful in clinical and pathological diagnosis. Non-syndromic familial non-medullary carcinoma has a complex and heterogeneous genetic basis involving several genes and loci with a monogenic or polygenic inheritance model. Most cases are papillary thyroid carcinoma (classic and follicular variant), usually accompanied by benign thyroid nodules (follicular thyroid adenoma and/or multinodular goiter). The possible diagnostic and prognostic usefulness of the changes in the expression and/or translocation of various proteins secondary to several mutations reported in this setting requires further confirmation. Given that non-syndromic familial non-medullary carcinoma and sporadic non-medullary thyroid carcinoma share the same morphology and somatic mutations, the same targeted therapies could be used at present, if necessary, until more specific targeted treatments become available.

Efficacy and safety of FOLFIRI/aflibercept (FA) in an elderly population with metastatic colorectal cancer (mCRC) after failure of an oxaliplatin-based regimen.

BACKGROUND: The VELOUR study showed the benefit of FOLFIRI-Aflibercept (FA) versus FOLFIRI in patients with metastatic colorectal cancer (mCRC) in second-line treatment. However, only 36% of the included patients were ≥65 years. Thus, we seek to evaluate the efficacy and safety of FA in the elderly population in the context of routine practice. MATERIALS AND METHODS: We conducted an observational, retrospective, multicenter, observational study of patients ≥70 years with mCRC treated with FA after progression to oxaliplatin chemotherapy in routine clinical practice in 9 hospitals of the GITuD group. RESULTS: Of 388 patients treated with FA between June 2013 and November 2018, 75 patients ≥70 years were included. The median number of cycles was 10 and the objective response (ORR) and disease control rates (DCR) were 33.8% and 72.0%, respectively. With a median follow-up of 27.1 months, median Progression-free survival (PFS) was 6.6 months and median Overall Survival (OS) was 15.1 months. One third fewer metastasectomies were performed in the ≥75 years' subgroup (24 vs. 52%, p = 0.024) and more initial FOLFIRI dose reductions (68 vs. 36%, p = 0.014). ORR (23.8% vs. 38.3%), DCR (42.8% vs. 85.1%), and PFS (4 vs. 7.8 months; p = 0.017) were significantly less, without difference in OS (9.9 vs. 17.1 months; p = 0.129). The presence of prior hypertension (HT) (PFS 7.9 vs. 5.7 months, p = 0.049) and HT ≥ grade 3 during treatment (PFS 7.6 vs. 6.6 months, p = 0.024) were associated with longer PFS. The most frequent grade 3/4 adverse events were: asthenia (21.3%), neutropenia (14.7%), and diarrhea (14.7%). 57.3% required FOLFIRI dose reduction; 34.7% of aflibercept, including discontinuation (5.3% and 18.7%, respectively). CONCLUSIONS: FA combination is effective in patients ≥70 years. The occurrence of HT is predictive of efficacy. Close monitoring of toxicity and initial dose adjustment is recommended.

[Reinterpretation of the Malpighian body in light of the existence of a single glomerular arteriole (Trabucco and Marquez)]. / Reinterpretación de la estructura del corpúsculo de Malpighi en función de la existencia de una sola arteriola glomerular (Trabucco y Márquez).

INTRODUCTION: In 1842 William Bowman described the microvascular system of the Malpighian body. Electron microscopic studies definitively revealed the spatial structure of its mesangial-capillary-epithelial component. In 1952-54 Trabucco and Marquez challenged the ideas of Bowman, demonstrating the existence of a single glomerular arteriole. Our study supports the finding of a single glomerular arteriole, leading to a definitive interpretation of the Malpighian body structure. MATERIALS AND METHODS: Serial histological studies were carried out of the vascular pole in a case of oligomeganephrotic renal hypoplasia and the immunohistochemical study of embryonal glomerular development (15 embryos aged between 7 and 11weeks), with alpha-actin (smooth muscle marker), CD31 and CD34 (endothelial markers) and CD10 (podocyte marker). RESULTS: The study of the glomerular vascular pole in the case of oligomeganephrotic renal hypoplasia supports the existence of a single glomerular arteriole. Our immunohistochemical study confirmed this finding and provided data on the morphogenesis of the mesangial-capillary-epithelial component of the Malpighian body. CONCLUSIONS: There exist a single glomerular arteriole. Mesangial and endothelial cells originating from a single glomerular arteriole interact with an epithelial component derived from the nephrogenic vesicle which then generate the lobular glomerular tuft, providing the basis for a definitive interpretation of the structure of the Malpighian body. There is no scientific base to the interpretation of the glomerular microvascular system as having two glomerular arterioles with an intercalated capillary network.

PD-L1 expression and immune cells in anaplastic carcinoma and poorly differentiated carcinoma of the human thyroid gland: A retrospective study.

Anaplastic thyroid carcinoma (ATC) and poorly differentiated thyroid carcinoma (PDTC) have limited treatment options, and immune profiling may help select patients for immunotherapy. The prevalence and relevance of programmed death-1 ligand (PD-L1) expression and the presence of immune cells in ATC and PDTC has not yet been well established. The present study investigated PD-L1 expression (clone 22C3) and cells in the tumor microenvironment (TME), including tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs) and dendritic cells, in whole tissue sections of 15 cases of ATC and 13 cases of PDTC. Immunohistochemical PD-L1 expression using a tumor proportion score (TPS) with a 1% cut-off was detected in 9/15 (60%) of ATC cases and 1/13 (7.7%) of PDTC cases (P=0.006). PD-L1 expression in TILs was limited to the ATC group (73.3 vs. 0% in ATC and PDTC, respectively). In the ATC group, the TPS for tumor positive PD-L1 expression revealed a non-significant trend towards worse survival, but no difference was observed when investigating PD-L1 expression in TILs and TAMs. In addition to increased PD-L1 expression, all ATC cases exhibited significantly increased CD3+ and CD8+ T cells, CD68+ and CD163+ macrophages, and S100+ dendritic cells compared with the PDTC cases. Loss of mutL homolog 1 and PMS1 homolog 2 expression was observed in one ATC case with the highest PD-L1 expression, as well as in the only PDTC case positive for PD-L1. Notably, the latter was the only PDTC case exhibiting positivity for p53 and a cellular microenvironment similar to ATC. The current results indicated that PD-L1 expression was frequent in ATC, but rare in PDTC. In addition to PD-L1, the present study suggested that microsatellite instability may serve a role in both the TME and the identification of immunotherapy candidates among patients with PDTC.

Systemic thrombosis in a large cohort of COVID-19 patients despite thromboprophylaxis: A retrospective study.

BACKGROUND: Incidence of thrombotic events associated to Coronavirus disease-2019 (COVID-19) is difficult to assess and reported rates differ significantly. Optimal thromboprophylaxis is unclear. OBJECTIVES: We aimed to analyze the characteristics of patients with a confirmed thrombotic complication including inflammatory and hemostatic parameters, compare patients affected by arterial vs venous events and examine differences between survivors and non-survivors. We reviewed compliance with thromboprophylaxis and explored how the implementation of a severity-adjusted protocol could have influenced outcome. METHODS: Single-cohort retrospective study of COVID-19 patients admitted, from March 3 to May 3 2020, to the Infanta Leonor University Hospital in Madrid, epicenter of the Spanish outbreak. RESULTS: Among 1127 patients, 80 thrombotic events were diagnosed in 69 patients (6.1% of the entire cohort). Forty-three patients (62%) suffered venous thromboembolism, 18 (26%) arterial episodes and 6 (9%) concurrent venous and arterial thrombosis. Most patients (90%) with a confirmed thrombotic complication where under low-molecular-weight heparin treatment. Overt disseminated intravascular coagulation (DIC) was rare. Initial ISTH DIC score and pre-event CRP were significantly higher among non-survivors. In multivariate analysis, arterial localization was an independent predictor of mortality (OR = 18, 95% CI: 2.4-142, p < .05). CONCLUSIONS: Despite quasi-universal thromboprophylaxis, COVID-19 lead to a myriad of arterial and venous thrombotic events. Considering the subgroup of patients with thrombotic episodes, arterial events appeared earlier in the course of disease and conferred very poor prognosis, and an ISTH DIC score ≥ 3 at presentation was identified as a potential predictor of mortality. Severity-adjusted thromboprophylaxis seemed to decrease the number of events and could have influenced mortality. Randomized controlled trials are eagerly awaited.

Sustained Stable Disease with Capecitabine plus Bevacizumab in Metastatic Appendiceal Adenocarcinoma: A Case Report.

In a patient who had been diagnosed in 2006 with appendiceal adenocarcinoma with peritoneal metastases after an incomplete surgery, palliative chemotherapy was administered. First-line treatment with 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) and second-line treatment including 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) plus panitumumab showed inefficiency in controlling disease progression. Third-line chemotherapy combining capecitabine plus bevacizumab was started, achieving good control of the tumour growth and a minor response in the second computed tomography scan. We decided to maintain the treatment, although forced bevacizumab "breaks" were necessary due to unexpected adverse events, with the patient suffering disease progression every time bevacizumab was stopped and reaching minor response again once the antiangiogenic treatment was reintroduced. During more than 10 years after starting third-line treatment, the patient maintained good performance status and disease stability with this "up and down" management until January 2019, when a neurological adverse event during bevacizumab infusion drove us to abandon it definitely.

The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals.

INTRODUCTION AND OBJECTIVES: Up to 50% of patients with hypertrophic cardiomyopathy (HCM) show no disease-causing variants in genetic studies. Mutations in CSRP3 have been associated with HCM, but evidence supporting pathogenicity is inconclusive. In this study, we describe an HCM cohort with a missense variant in CSRP3 (p.Cys150Tyr) with supporting evidence for pathogenicity and a description of the associated phenotype. METHODS: CSRP3 was sequenced in 6456 index cases with a diagnosis of HCM and in 5012 probands with other cardiomyopathies. In addition, 3372 index cases with hereditary cardiovascular disorders other than cardiomyopathies (mainly channelopathies and aortopathies) were used as controls. RESULTS: The p.(Cys150Tyr) variant was identified in 11 unrelated individuals of the 6456 HCM probands, and it was not identified in patients with other cardiomyopathies (p < 0.0001) or in our control population (p < 0.0001). Ten of the index cases were heterozygous and one was homozygous. Homozygous had a more severe phenotype. Family screening identified 17 other carriers. Wild-type individuals showed no signs of disease. The mean age at diagnosis of affected individuals was 55 ±â€¯13 years, and the mean left ventricular wall thickness was 18 ±â€¯3 mm. The variant showed highly age-dependent penetrance. After a mean follow-up of 11 (±8) years, no adverse events were reported in any of the HCM patients. CONCLUSIONS: The p.(Cys150Tyr) variant in CSRP3 causes late-onset and low risk form of hypertrophic cardiomyopathy in heterozygous carriers.

Reducing sexual risk behavior among steady heterosexual serodiscordant couples in a testing and counseling program.

OBJECTIVE: To assess the effect of an HIV counseling and testing program targeting steady heterosexual serodiscordant couples. METHODS: We studied 564 couples who attended a sexually transmitted infections/HIV clinic in Madrid in the period 1989 to 2007 and participated in couples counseling and testing. Sociodemographic, epidemiologic, clinical, and behavioral information of both partners was obtained before testing the nonindex partner. Sexual practices reported in the first (preintervention) and second visit were compared, as well those reported in 4 additional visits. RESULTS: Among the 399 couples who returned for a second visit (71%), the median number of sexual risk practices in the previous 6 months decreased (26.9-0; P <0.001) and the percentage of couples who had not engaged in sexual risk behavior increased (46.1-66.7; P <0.001). This reduction was maintained by the 143 couples who had 4 return visits. The diagnosis of HIV-infection in the index case previous to entering the program was associated with a lower frequency of sexual risk behavior. Independent predictors of postintervention risky sexual behavior included preintervention sexual risk behavior (odds ratio [OR]: 2.8, 95% confidence interval: 1.7-4.4), index case aged over 35 (OR: 2.0, 1.2-3.3), and a recent pregnancy (OR: 3.1, 1.6-6.3). The incidence of HIV seroconversion was 3.9 per 1000 couple-years (1.4-9.7). CONCLUSION: The diagnosis of HIV-infection and counseling appears to provide complementary reductions in sexual risk behaviors among serodiscordant steady heterosexual couples at follow-up, but the risk of transmission was not totally eliminated.

Primary malignant melanoma of the biliary tract: A case report and literature review.

BACKGROUND: Primary malignant melanoma of the biliary tract (MBT) is a rare condition whose diagnosis requires excluding a primary origin in another location. This paper reviews the most important characteristics of MBT cases published in the literature and reports a new case. The patient reported here is the first case of primary malignant melanoma of the biliary tract with pulmonary metastasis treated with immunotherapy. This patient remains disease-free 36 mo after the treatment of metastatic lung lesions. CASE SUMMARY: A 51-year-old man was admitted to the gastrointestinal department to study obstructive jaundice of a 1 wk clinical course. Magnetic resonance cholangiopancreatography revealed dilatation of the intrahepatic biliary tract and stenosis of the common hepatic duct. Given the suspicion of biliary tract neoplasia, cholecystectomy and resection of the common hepatic duct were performed with hepatic jejunostomy free of complications. Anatomo-pathological diagnosis was melanoma. After intervention, the patient was referred to the Department of Medical Oncology, where a primary origin was excluded in the skin, mucosa, and eyes. This confirmed diagnosis of primary biliary tract melanoma. Computed tomography was performed 12 mo after the procedure revealed several subcentimetric lung nodules. Wedge resection was performed. After confirming the diagnosis of pulmonary metastasis of primary melanoma of the biliary tract, the patient was started on immunotherapy with nivolumab. Tolerance to treatment was excellent. The patient remains disease-free 36 mo after the treatment of metastatic lung lesions. CONCLUSION: The patient reported here is the first case of primary malignant melanoma of the biliary tract with lung metastases successfully treated with immunotherapy.

Ultrasound-Assisted Esterification of Valeric Acid to Alkyl Valerates Promoted by Biosilicified Lipases.

A novel, environmentally friendly, and sustainable ultrasound-assisted methodology in the valorization of valeric acid to alkyl valerate using a biosilicified lipase from Candida antarctica is reported. This one-pot room temperature methodology of enzyme biosilicification leads to biosilicified lipases with improved activity and reaction efficiency as compared to free enzymes. Yields in the ultrasound-promoted esterification of valeric acid was ca. 90% in 2 h with 15% m/v of biosilicified lipase (Bio-lipase; 616 U/g biocatalyst enzymatic activity) and a molar ratio 1:2 (valeric acid:ethanol), slightly superior to that observed by the free enzyme (75% conversion, 583U/g biocatalyst enzymatic activity). The reuse of enzymes in these conditions was tested and the results show a relatively good reusability of these biosilicified enzymes under the investigated conditions, particularly preserving fairly stable specific activities (616 vs. 430 U/g biocatalyst after four reuses).