Search

Abstract TL-895 (formerly known as M7583) is a potent, highly selective, adenosine triphosphate (ATP)-competitive, second-generation, irreversible inhibitor of Bruton’s tyrosine kinase (BTK). We characterized its biochemical and cellular effects in in vitro and in vivo models. TL-895 was evaluated preclinically for potency against BTK using IC50 concentration–response curves; selectivity using a 270-kinase panel; BTK phosphorylation in Ramos Burkitt’s lymphoma cells by ProteinSimple Wes analysis of one study; anti-proliferative effects in primary chronic lymphocytic leukemia (CLL) blasts; cell viability effects in diffuse large B-cell lymphoma (DLBCL) and mantle-cell lymphoma (MCL) cell lines; effects on antibody-dependent cell-mediated cytotoxicity (ADCC) from Daudi cells and chromium-51 release from human tumor cell lines; and efficacy in vivo using four MCL xenograft model and 21 DLBCL patient-derived xenograft (PDX) models (subtypes: 9 ABC, 11 GCB, 1 Unclassified). TL-895 was active against recombinant BTK (average IC50 1.5 nM) and inhibited only three additional kinases with IC50 within tenfold of BTK activity. TL-895 inhibited BTK auto-phosphorylation at the Y223 phosphorylation site (IC50 1–10 nM). TL-895 inhibited the proliferation of primary CLL blasts in vitro and inhibited growth in a subset of activated DLBCL and MCL cell lines. TL-895 inhibited the ADCC mechanism of therapeutic antibodies only at supra-clinical exposure levels. TL-895 significantly inhibited tumor growth in the Mino MCL xenograft model and in 5/21 DLBCL PDX models relative to vehicle controls. These findings demonstrate the potency of TL-895 for BTK and its efficacy in models of B-cell lymphoma despite its refined selectivity.

Abstract In the first millennia of the Holocene, human communities in the Fertile Crescent experienced drastic cultural and technological transformations that modified social and human-environments interactions, ultimately leading to the rise of complex societies. The potential influence of climate on this “Neolithic Revolution” has long been debated. Here we present a speleothem record from the Kurdistan Region of Iraq, covering from Early Neolithic to Early Chalcolithic periods (~ 11 to 7.3 ka, 9000–5300 BCE). The record reveals the influence of the Siberian High on regional precipitation, and shows large hydroclimatic variability at the multicentennial scale. In particular, it highlights wetter conditions between 9.7 and 9.0 ka, followed by an abrupt reduction of precipitation between 9.0 and 8.5 ka, and a wetter interval between 8.5 and 8.0 ka. A comparison with regional and local archaeological data demonstrates an influence of recorded hydroclimatic changes on settlement patterns (size, distribution, permanent vs. seasonal occupation) and on the exploitation of water resources by Neolithic to Chalcolithic populations. Our record does not show prominent hydroclimatic changes at 9.3 and 8.2 ka, thus not supporting direct influence of such rapid and widespread events on the process of Neolithization and its cultural dispersal.

Abstract The lakeshore site of La Marmotta is one of the most important Early Neolithic sites of Mediterranean Europe. The site is famous for the exceptional preservation of organic materials, including numerous wooden artefacts related to navigation, agriculture, textile production, and basketry. This article presents interdisciplinary research on three of the most complete and well-preserved sickles recovered from the site, yet unpublished. All the components of the tools are analysed: the stone inserts, the wooden haft and the adhesive substances used to fix the stones inside the haft. Our innovative methodology combines use-wear and microtexture analysis of stone tools through confocal microscopy, taxonomical and technological analysis of wood, gas chromatography–mass spectrometry analysis of the adhesive substances, and pollen, non-pollen palynomorphs, and phytolith analysis of the remains incorporated within the adhesive. This multiproxy approach provides a significant insight into the life of these tools, from their production to their use and abandonment, providing evidence of the species of harvested plants and the conditions of the field during the harvesting.

Abstract This study aimed to determine the changes of lipidome in obese women undergoing combined physical exercise training. Fourteen adult women with obesity (mean BMI and age, 33 kg/m2 and 34 ± 5 years), were submitted to combined physical training (aerobic and strength exercises, alternately, 55 min at 75–90% of the maximum heart rate, 3 times a week) for 8 weeks. All participants were evaluated before and after the training intervention for lipidome, anthropometric measurements, muscle strength, and maximum oxygen consumption (VO2max). Untargeted liquid chromatography-mass spectrometry analyses allowed the identification of 1252 variables, of which 160 were significant (p

AIMS: The main objective of this study was to describe patients who were involuntarily admitted to the emergency department of Lausanne University Hospital on involuntary admission in 2018 in terms of age, gender, emergency department length of stay, the motive for involuntary admission, use of psychoactive substances, diagnosis, and destination at emergency department discharge, with or without discontinuation of involuntary admission. METHODS: This retrospective, observational, and monocentric study included patients 18 years and older admitted to the emergency department of Lausanne University Hospital on involuntary admission from January 1, 2018, to December 31, 2018. Patients were identified by the Cantonal Medical Office of Vaud. The emergency department length of stay and patient destination on discharge from the emergency department were extracted from the patient flow database, and discharge letters and involuntary admission were extracted from the electronic archiving software. Descriptive statistics were processed by using means and standard deviations for quantitative variables with a normal distribution and median and interquartile range for non-normally distributed data. RESULTS: During the study period, 83 patients were admitted on involuntary admission to the emergency department. The majority of the patients were male (58%) with a mean age of 55 (±20) years. The median emergency department length of stay of patients with an involuntary admission was between 9 and 16 hours, depending on whether the involuntary admission was confirmed or discontinued after patient assessment in the emergency department. In comparison, the median emergency department length of stay was 6 hours for patients overall. The two principal diagnoses described were psychiatric (schizophrenia) and mental and behavioural disorders due to psychoactive substance use. Half of the patients on involuntary admission consumed psychoactive substances, primarily alcohol, and had a mean ethanolaemia of 53 (±32) mmol/l. CONCLUSIONS:Only a third of patients admitted on involuntary admission saw this measure confirmed after their assessment in the emergency department. Involuntary admissions with admission to the emergency department is used to force patients to be examined by an emergency physician or even a psychiatrist. On-call and primary care physicians seemed to lack the time or resources to set up alternatives to emergency department admissions on involuntary admission, especially in situations in which the involuntary admission was discontinued after an emergency department assessment. This demonstrates the inappropriate use of this measure because a patient cannot be involuntarily hospitalised in an emergency department.

Humans and dogs commonly share the same domestic environment. Europe, and Italy specifically, have a substantial and growing dog population. Potentially zoonotic parasites may be harbored even by dogs receiving regular veterinary care. Thus, transmission of zoonotic or potentially zoonotic parasites to owners and their families should not be underestimated. Frequently, endoparasite infections occur as a subclinical infection and clinicopathological alterations have been documented including anemia, hypoalbuminemia, and eosinophilia. The aim of this large retrospective secondary data study was to analyze coprological endoparasite results and putative risk factors obtained from owned dogs, through a 9-year-period (2011-2019). Possible associations between diagnosed endoparasites and sex, age, seasonality, and year of examination were evaluated. Additionally, parasitological diagnoses were combined to complete blood count parameters and biochemical profiles, when available, to check for any possible hematological alteration from parasitism. A total of 1,972 dogs were evaluated for endoparasites using common fecal diagnostic tests over a 9-year period. The overall proportion of endoparasite-positive animals was 10%. The most common endoparasites detected were Cystoisospora spp. (3%), Toxocara canis (2.8%), Giardia duodenalis (1.6%), and Trichuris vulpis (1.2%). Of these parasites detected, Toxocara poses the greatest zoonotic risk, while Giardia species are considered to have a low potential to be zoonotic. There was no significant diagnostic trend across the years through the study period. Dogs were more frequently diagnosed endoparasite-positive when young and during cold seasons compared to the baselines of mature dogs and warm seasons. The clinicopathological profiles indicated that parasitized dogs had mild hematological alterations. The frequency of detected potentially zoonotic endoparasites in this study highlights that the risk should not be underestimated. Parasitic infection was found to be mostly dependent on age and season. Having this information may help clinicians to develop anthelmintic protocols to reduce the risk of transmission.

The control of non-coding repeated DNA by DNA methylation plays an important role in genomic stability, contributing to health and healthy aging. Mind-body practices can elicit psychophysical wellbeing via epigenetic mechanisms, including DNA methylation. However, in this context the effects of movement meditations have rarely been examined. Consequently, the current study investigates the effects of a specifically structured movement meditation, called the Quadrato Motor Training (QMT) on psychophysical wellbeing and on the methylation level of repeated sequences. An 8-week daily QMT program was administered to healthy women aged 40-60 years and compared with a passive control group matched for gender and age. Psychological well-being was assessed within both groups by using self-reporting scales, including the Meaning in Life Questionnaire [MLQ] and Psychological Wellbeing Scale [PWB]). DNA methylation profiles of repeated sequences (ribosomal DNA, LINE-1 and Alu) were determined in saliva samples by deep-sequencing. In contrast to controls, the QMT group exhibited increased Search for Meaning, decreased Presence of Meaning and increased Positive Relations, suggesting that QMT may lessen the automatic patterns of thinking. In the QMT group, we also found site-specific significant methylation variations in ribosomal DNA and LINE-1 repeats, consistent with increased genome stability. Finally, the correlations found between changes in methylation and psychometric indices (MLQ and PWB) suggest that the observed epigenetic and psychological changes are interrelated. Collectively, the current results indicate that QMT may improve psychophysical health trajectories by influencing the DNA methylation of specific repetitive sequences.

Abstract Background Human milk is a vehicle for bioactive compounds and beneficial bacteria which promote the establishment of a healthy gut microbiome of newborns, especially of preterm infants. Pasteurized donor human milk (PDHM) is the second-best option when preterm mother’s own milk is unavailable. Since pasteurization affect the microbiological quality of donor milk, PDHM was inoculated with different preterm milk samples and then incubated, in order to evaluate the effect in terms of bacterial growth, human milk microbiome and proteolytic phenomena. Methods In an in-vitro study PDHM was inoculated at 10% v/v using ten preterm milk samples. Microbiological, metataxonomic and peptidomic analyses, on preterm milk samples at the baseline (T0), on PDHM and on inoculated milk (IM) samples at T0, after 2 h (T1) and 4 h (T2) of incubation at 37 °C, were conducted. Results IM samples at T2 showed a Total Bacterial Count not significantly different (p > 0.01) compared to preterm milk samples. At T2 lactic acid bacteria level was restored in all IM. After inoculation, metataxonomic analysis in IM samples showed that Proteobacteria remained the predominant phylum while Firmicutes moved from 3% at T1 to 9.4% at T2. Peptidomic profile of IM resembled that of PDHM, incubated for the same time, in terms of number and type of peptides. Conclusion The study demonstrated that inoculation of PDHM with mother’s own milk could restore bacterial growth and personalize human milk microbiome in PDHM. This effect could be beneficial because of the presence of maternal probiotic bacteria which make PDHM more similar to mother’s own milk.

Introduction. As part of the holistic concept of health, mental health can be focused on prevention of contagion and coping with the disease and its consequences in the context of the current COVID-19 pandemic. The present study describes, compares, and analyzes the association of the impact of the event, perceived stress, coping strategies, emotional regulation, and sociodemographic characteristics during the quarantine in various countries. Material and methods. This research is a multicentric and epidemiological study with a convenience online snowball sampling of the general population and university students. Results. 1.179 participants from Colombia, Brazil, Mexico, Italy, and Spain responded to the survey. Most of them included students and workers, with a high educational level and living with family during the quarantine. There are significant differences in the medians of all variables among countries and sociodemographic characteristics. The variables positively and significantly associated with the impact of the event during quarantine included the perceived stress, the coping strategies of alcohol/drug use, planning and active coping, focus on emotions and vent, the emotional regulation strategy expressive suppression, and living in Italy. Conclusions. These results have contributed to the understanding of mental, emotional, and behavioral response to quarantine, as well as underline the urgency of monitoring mental health among the vulnerable groups, in order to design specific prevention and intervention programs.

La cirugía del cáncer de recto y ano se ha desarrollado considerablemente en las últimas décadas. En función de dichos avances, se ha observado una disminución en la morbimortalidad operatoria, así como también una mejoría en el pronóstico de estos pacientes. El objetivo del presente estudio es exponer y analizar los resultados del tratamiento quirúrgico del cáncer de recto y ano en un servicio universitario. Se realizó un estudio observacional, descriptivo y retrospectivo de todos los pacientes intervenidos por cáncer de recto y ano en el Hospital Español entre 2016 y 2020. Las variables registradas fueron: variables demográficas, clínico-oncológicas, relacionadas a la morbimortalidad operatoria y a la recidiva locorregional, y la sobrevida a 5 años. El procedimiento más realizado fue la resección anterior de recto (RAR) en 11 intervenciones (58%), mientras que las 8 restantes correspondieron a amputaciones abdominoperineales (AAP) (42%). Se diagnosticaron un total de 6 complicaciones intraoperatorias en 5 pacientes, siendo la perforación del tumor la más frecuente, y un total de 18 complicaciones postoperatorias en 11 pacientes, siendo la más frecuente la infección de la herida quirúrgica abdominal. La morbilidad operatoria mayor fue de 31,6% y la mortalidad operatoria a 90 días fue de 0%. La sobrevida global a 5 años fue de 63,2%. Los resultados quirúrgicos en la presente casuística fueron comparables con los de la bibliografía consultada. Destacamos la nula mortalidad a 90 días, con resultados oncológicos similares a los reportados en la literatura.

Introdução: O hipertireoidismo decorre da elevação sérica dos hormônios tireoidianos, secundário a hiperfunção da glândula tireoide. As causas mais prevalentes são a Doença de Graves (DG) e os Bócios Nodulares Tóxicos (BNT). As principais formas de tratamento são as drogas anti-tireoideanas (DAT), ablação com iodo radioativo (DTI131) e a tireoidectomia. Métodos: Estudo transversal, descritivo, com inclusão de pacientes com diagnóstico de hipertireoidismo por DG e BNT; foram coletados dados epidemiológicos, clínicos, laboratoriais e de tratamento. Resultados: A maioria dos pacientes foi referenciada pela atenção primária e encontrava-se em uso prévio de DAT. A variável idade obteve diferença estatisticamente significativa entre as etiologias de DG e BNT, e em ambas, houve predomínio de incidência no sexo feminino. A DG apresentou maior frequência de sinais e sintomas de tireotoxicose, ao passo que o BNT mostrou mais sinais e sintomas de compressão. Houve remissão da doença em 23,2% dos pacientes com DG. Em 23,2% dos pacientes optou-se pela manutenção de metimazol em baixa dose por mais de 36 meses e em 16,1% foi realizado tratamento definitivo. No BNT foram preferidas terapias definitivas, principalmente a tireoidectomia em 27,5% dos pacientes. Doses baixas de metimazol por mais de 36 meses foram utilizados também no BNT, em 22,5% dos pacientes. Conclusão: O hipertireoidismo é uma doença heterogênea, desde a clínica inicial até a terapêutica, entre suas etiologias mais prevalentes. Observou-se uma tendência de priorizar as terapias medicamentosas em longo prazo com baixas doses tanto na DG, quanto no BNT.

The Lombardy region has been one of the areas most affected by the COVID-19 pandemic since the first months of 2020, providing real-life experiences in the acute phase. It is unclear how the respiratory rehabilitation network responded to this emergency. The aims of this retrospective study were: i) to analyze clinical, functional, and disability data at admission; ii) describe assessment tools and rehabilitative programs; iii) evaluate improvement after rehabilitation. The study was conducted on data collected from ten pulmonary rehabilitation centers in Lombardy, between the period of March 1st 2020 to March 1st 2021, in patients with respiratory failure recovering from COVID-19 both at admission and discharge. The study included demographics, comorbidities, nutritional status, risk of falls, disability status (Barthel index; Short Physical Performance Battery (SPPB); 6 minutes walking test (6MWT), symptoms (dyspnoea with Barthel Dyspnoea and MRC Dyspnoea Scale), length of stay, discharge destination, need for mechanical ventilation, respiratory function, assessment/outcomes indices, and prescribed rehabilitative programs. 413 patients were analyzed. Length of stay in acute and rehabilitative units was less than 30 days. Fifty % of patients used non-invasive ventilation during their stay. Functional status was mildly compromised for forced volumes and oxygenation, while severely compromised for diffusion capacity. Independency was low while physical performance status very low. At discharge, 318 (77%) patients were sent home, 83 (20.1%) were transferred to an acute unit and 12 (2.9%) passed away. Barthel Index and 6MWT were the most used, while MRC score was the least used outcome parameter. The 5 main rehabilitative activities were walking (90.8 %), transfer from bed to armchair (77.5%), limb mobilization in bed (76%), balance (71.2%), and cycle-ergometer or treadmill (43.1%). A huge difference was found in admission, discharge, and delta change among different rehabilitative centers. When available, all outcomes showed a significant improvement. With the limitation of a retrospective study with a clear amount of missing data, COVID-19 subjects admitted to rehabilitative centers presented a reduced physical performance, symptoms of dyspnoea, and severe disability. The 6MWT and Barthel index were the most used measurement.

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by the degeneration of the second motor neuron. The phenotype ranges from very severe to very mild forms. All patients have the homozygous loss of the SMN1 gene and a variable number of SMN2 (generally 2–4 copies), inversely related to the severity. The amazing results of the available treatments have made compelling the need of prognostic biomarkers to predict the progression trajectories of patients. Besides the SMN2 products, few other biomarkers have been evaluated so far, including some miRs. Methods: We performed whole miRNome analysis of muscle samples of patients and controls (14 biopsies and 9 cultures). The levels of muscle differentially expressed miRs were evaluated in serum samples (51 patients and 37 controls) and integrated with SMN2 copies, SMN2 full-length transcript levels in blood and age (SMA-score). Results: Over 100 miRs were differentially expressed in SMA muscle; 3 of them (hsa-miR-181a-5p, -324-5p, -451a; SMA-miRs) were significantly upregulated in the serum of patients. The severity predicted by the SMA-score was related to that of the clinical classification at a correlation coefficient of 0.87 (p

BackgroundManaging HIV infection as a chronic condition includes encouraging adoption of healthy behaviors and promotion of physical activity (PA). However, people living with HIV (PLH) are often under social and programmatic vulnerability that may compromise behavior change. Understanding such barriers is crucial for successful incorporation of PA in their comprehensive care.Methods and findingsIn this study, we describe PA, energy intake from diet, and anthropometry of a cohort of PLH starting antiretroviral therapy (ART) at a Brazilian reference clinic, report how PA was addressed in routine care and investigate association between PA, energy intake and psychosocial constructs that may facilitate PA (social support and self-efficacy for PA). Among 61 PLH (86.9% males, mean age = 32.5 years) anthropometry was normal, but 47.5% reported PA below recommendations. Despite presenting high social support scores, family encouragement for PA was low, and self-efficacy classified as medium. Chart reviews yielded infrequent reports concerning PA. After adjusting for gender and age, we found a negative association between energy intake from diet and self-efficacy, but none between PA and energy intake or between PA and psychosocial constructs.ConclusionsWe conclude that patients in our cohort were insufficiently active when starting ART, and that PA was poorly addressed by caretakers in routine HIV care. Nevertheless, social support and self-efficacy scores suggest potential for behavioral change. Caregivers should therefore start considering patients' vulnerabilities and establishing strategies to help them overcome barriers to incorporate PA in their comprehensive care effectively.

BackgroundThe notion that smoking cannabis may damage the respiratory tract has been introduced in recent years but there is still a paucity of studies on this subject. The aim of this study was to investigate the relationship between cannabis smoking, pneumothorax and bullous lung disease in a population of operated patients.Methods and findingsWe performed a retrospective study on patients operated on for spontaneous pneumothorax. Patients were divided into three groups according to their smoking habit: cannabis smokers, only-tobacco smokers and nonsmokers. Cannabis lifetime exposure was expressed in dose-years (1d/y = 1 gram of cannabis/week for one year). Clinical, radiological and perioperative variables were collected. The variables were analyzed to find associations with smoking habit. The impact of the amount of cannabis consumption was also investigated by ROC curves analysis. Of 112 patients, 39 smoked cannabis, 23 smoked only tobacco and 50 were nonsmokers. Median cannabis consumption was 28 dose/years, median tobacco consumption was 6 pack/years. Cannabis smokers presented with more severe chronic respiratory symptoms and bullous lung disease and with a higher incidence of tension pneumothorax than both tobacco smokers and nonsmokers. Cannabis smokers also developed a larger pneumothorax, experienced prolonged postoperative stay and demonstrated a higher incidence of pneumothorax recurrence after the operation than nonsmokers did. The risk of occurrence of chronic respiratory symptoms and bullous lung disease in cannabis smokers was dose-related.ConclusionsCannabis smoking seems to increase the risk of suffering from respiratory complaints and can have detrimental effects on lung parenchyma, in a dose-dependent manner. Cannabis smoking also negatively affected the outcome of patients operated for spontaneous pneumothorax. A history of cannabis abuse should always be taken in patients with pneumothorax. There may be need for a specific treatment for pneumothorax in cannabis smokers.

Joint repair: Growing new cartilage from placental stem cells Stem cells derived from placental tissue may help in treating damaged joints, thanks to an improved method for encouraging them to form cartilage. Placenta-derived stem cells are readily available, as the placenta is usually discarded after birth. These stem cells can easily be grown into cartilage tissue in a laboratory, but not when transplanted. Researchers led by Yufeng Dong (Louisiana State University Health Sciences Center, Shreveport, USA) and Xifu Shang (Anhui Provincial Hospital, Hefei, China) treated stem cells with a naturally occurring protein, JAG1, which blocks the signal that prevents them from forming cartilage. They found that JAG1 increased the stem cells’ capacity for cartilage formation. When JAG1-stimulated stem cells were injected into a mouse model of joint disease, cartilage formation was improved, and joint inflammation was reduced.

Saprolegnia infections are among the main parasitic diseases affecting farmed salmonids. The distribution and potential transfer of Saprolegnia spp. between farms and the natural environment has been scarcely investigated. Therefore, this work aimed to study the diversity and abundance of oomycete species in salmonid farms, tributary water, and effluent water systems. Four trout farms in Italy and two Atlantic salmon farms in Scotland were considered. In Italian farms, 532 isolates of oomycetes were obtained from fish and water, at upstream, inside, and downstream the farms. In Scottish farms, 201 oomycetes isolates were obtained from water outside the farm and from fish and water inside the farming units. Isolates were identified to the species level through amplification and sequencing of the ITS rDNA region. In Italy, S. parasitica was significantly more present in farmed than in wild fish, while in water it was more frequently isolated from the wild, particularly in effluent systems, not associated with more frequent isolation of S. parasitica in wild fish downstream the farm. In Scotland, S. parasitica was the most prevalent species isolated from fish, while isolates from water were mostly Pythium spp. with few S. parasitica isolates from upstream and downstream the farms.

Abstract To determine whether cell sheets generated with long-term passaged (P10) aging human mesenchymal stromal cells (MSCs) could be used for bone tissue regeneration as tissue engineered periosteum in a femoral allograft mouse model similar to fresh passaged (P3) young MSCs. At 3 weeks after transplantation of MSC sheets, results showed more bony callus formed between allograft and host bone ends in both young P3 MSC and aged P10 MSC sheet-wrapped groups when compared to allograft alone. At 6 weeks, while both MSC sheet-wrapped allografts showed more bony callus formation when compared to allograft alone groups, the bony callus size in aged P10 MSC sheet groups was significantly less than young P3 MSC sheet groups. Biomechanical testing confirmed that P3 MSC sheet-grafted femurs had the highest biomechanical strength in the three groups. Histology sections showed that the area of the chondriod callus in the aged P10 MSC sheet groups was significantly larger than in P3 MSC sheet groups. Finally, a significant increase of chondro-osteoclast activity was observed in the P3 MSC sheet-grafted femur. Our data demonstrates that extensive long-term culture-induced MSC aging impaired their osteogenic ability and subsequent bony callus formation, and could be used to induce cartilaginous callus formation.

Abstract Oleanolic acid (OA), a pentacyclic triterpenoid, has been shown to modulate multiple signaling pathways in a variety of cell linages. But the mechanisms underlying OA-mediated mesenchymal stromal cell (MSC) osteogenic differentiation are not known. In this study, we examined effects of OA on cell viability, osteogenic differentiation in MSCs, and the involvement of Notch and BMP signaling. OA induced bone marrow derived MSC differentiation towards osteoprogenitor cells and inhibited Notch signaling in a dose dependent manner. Constitutive activation of Notch signaling fully blocked OA induced MSC osteogenic differentiation. The expression level of early osteogenic marker genes, ALP, Runx2, and type I collagen, which play a critical role in MSC to osteoblast transition and servers as a downstream target of BMP signaling, was significantly induced by OA. Furthermore, BMP2 mediated MSC osteogenic differentiation was significantly enhance by OA treatment, indicating a synergistic effect between BMP2 and OA. Our results suggest that OA is a promising bioactive agent for bone tissue regeneration, and inhibition of Notch signaling is required for its osteogenic effects on MSCs.

Abstract Background Oral squamous cell carcinoma (OSCC) is usually diagnosed at an advanced stage and is commonly preceded by oral premalignant lesions. The mortality rates have remained unchanged (50% within 5 years after diagnosis), and it is related to tobacco smoking and alcohol intake. Novel molecular markers for early diagnosis are urgently needed. The purpose of this study was to evaluate the diagnostic value of methylation level in a set of 18 genes by bisulfite next-generation sequencing. Methods With minimally invasive oral brushing, 28 consecutive OSCC, one squamous cell carcinoma with sarcomatoid features, six high-grade squamous intraepithelial lesions (HGSIL), 30 normal contralateral mucosa from the same patients, and 65 healthy donors were evaluated for DNA methylation analyzing 18 target genes by quantitative bisulfite next-generation sequencing. We further evaluated an independent cohort (validation dataset) made of 20 normal donors, one oral fibroma, 14 oral lichen planus (OLP), three proliferative verrucous leukoplakia (PVL), and two OSCC. Results Comparing OSCC with normal healthy donors and contralateral mucosa in 355 CpGs, we identified the following epigenetically altered genes: ZAP70, ITGA4, KIF1A, PARP15, EPHX3, NTM, LRRTM1, FLI1, MIR193, LINC00599, PAX1, and MIR137HG showing hypermethylation and MIR296, TERT, and GP1BB showing hypomethylation. The behavior of ZAP70, GP1BB, H19, EPHX3, and MIR193 fluctuated among different interrogated CpGs. The gap between normal and OSCC samples remained mostly the same (Kruskal-Wallis P values

Background: Previous studies on breast cancer (BC), underarm cosmetic products (UCP) and aluminum salts have shown conflicting results. We conducted a 1:1 age-matched case-control study to investigate the risk for BC in relation to self-reported UCP application. Methods: Self-reported history of UCP use was compared between 209 female BC patients (cases) and 209 healthy controls. Aluminum concentration in breast tissue was measured in 100 cases and 52 controls. Multivariable conditional logistic regression analysis was performed to estimate odds ratios (ORs) with 95% confidence intervals (CIs), adjusting for established BC risk factors. Findings: Use of UCP was significantly associated with risk of BC (p = 0.036). The risk for BC increased by an OR of 3.88 (95% CI 1.03–14.66) in women who reported using UCP's several times daily starting at an age earlier than 30 years. Aluminum in breast tissue was found in both cases and controls and was significantly associated to self-reported UCP use (p = 0.009). Median (interquartile) aluminum concentrations were significantly higher (p = 0.001) in cases than in controls (5.8, 2.3–12.9 versus 3.8, 2.5–5.8 nmol/g). Interpretation: Frequent use of UCPs may lead to an accumulation of aluminum in breast tissue. More than daily use of UCPs at younger ages may increase the risk of BC.

Abstract Background A small number of patients affected by Neutral Lipid Storage Diseases (NLSDs: NLSD type M with Myopathy and NLSD type I with Ichthyosis) have been described in various ethnic groups worldwide. However, relatively little is known about the progression and phenotypic variability of the disease in large specific populations. The aim of our study was to assess the natural history, disability and genotype-phenotype correlations in Italian patients with NLSDs. Twenty-one patients who satisfied the criteria for NLSDs were enrolled in a retrospective cross-sectional study to evaluate the genetic aspects, clinical signs at onset, disability progression and comorbidities associated with this group of diseases. Results During the clinical follow-up (range: 2–44 years, median: 17.8 years), two patients (9.5%, both with NLSD-I) died of hepatic failure, and a further five (24%) lost their ability to walk or needed help when walking after a mean period of 30.6 years of disease. None of the patients required mechanical ventilation. No patient required a heart transplant, one patient with NLSD-M was implanted with a cardioverter defibrillator for severe arrhythmias. Conclusion The genotype/phenotype correlation analysis in our population showed that the same gene mutations were associated with a varying clinical onset and course. This study highlights peculiar aspects of Italian NLSD patients that differ from those observed in Japanese patients, who were found to be affected by a marked hypertrophic cardiopathy. Owing to the varying phenotypic expression of the same mutations, it is conceivable that some additional genetic or epigenetic factors affect the symptoms and progression in this group of diseases.

Introducción: las bicicletas son un medio de transporte popular que trae beneficios para la salud, cuando son utilizadas regularmente. Sin embargo, son frecuentes los accidentes que se presentan en sus usuarios. El objetivo de este trabajo fue evaluar la prevalencia de accidentes y el uso de equipos de protección individual (EPI) en usuarios de bicicletas en São Paulo (Brasil), por medio de formularios. Además, la población estudiada fue orientada sobre la importancia del uso de EPI. Materiales y métodos: ciclistas de diferentes regiones de São Paulo respondieron a las preguntas hechas en un formulario y fueron orientados sobre el correcto uso de los EPI. Resultados: la muestra total fue de 608 personas, evaluadas y entrevistadas (210 mujeres y 398 hombres). El porcentaje mayor de entrevistados tenía entre 20 y 40 años. Los EPI más usados fueron casco, tenis y señalización de pedales. El 48% de los encuestados dijo que había sufrido accidentes usando este medio de transporte. Gran parte de los accidentes ocurrieron en momentos de ocio, durante las mañanas y en días de sol. El 69.5 % de las personas entrevistadas escucharon las indicaciones. Conclusiones: la mayoría de los ciclistas de la ciudad de São Paulo son jóvenes, varones y no utilizan los EPI obligatorios. Los accidentes sufridos, relatados por la población encuestada, no estuvieron relacionados con las condiciones meteorológicas ni con el consumo de alcohol. En este estudio, se observó que solo los ciclistas que ya usaban los EPI estaban interesados en las directrices sobre su importancia y uso correcto.

Squamous cell carcinoma is the most common malignant oral tumor in cats. The late presentation is one of the factors contributing to the detrimental prognosis of this disease. The immunohistochemical expression of the p53 tumor suppressor protein has been reported in 24% to 65% of feline oral squamous cell carcinomas, but no study has systematically evaluated in this tumor the presence of p53 encoding gene (TP53) mutations. The aim of this retrospective study was to determine whether p53 immunohistochemistry accurately reflects the mutational status of the TP53 gene in feline oral squamous cell carcinoma. Additionally, the prevalence of p53 dysregulation in feline oral squamous cell carcinoma was compared with that of feline non-neoplastic oral mucosa, in order to investigate the relevance of these dysregulations in cancer development. The association between p53 dysregulations and exposure to environmental tobacco smoke and tumor characteristics was further assessed. Twenty-six incisional biopsies of oral squamous cell carcinomas and 10 cases each of lingual eosinophilic granuloma, chronic gingivostomatitis and normal oral mucosa were included in the study. Eighteen squamous cell carcinomas (69%) expressed p53 and 18 had mutations in exons 5-8 of TP53. The agreement between immunohistochemistry and mutation analysis was 77%. None of non-neoplastic oral mucosa samples had a positive immunohistochemical staining, while one case each of eosinophilic granuloma and chronic gingivostomatitis harbored TP53 mutations. Unlike previously hypothesized, p53 dysregulations were not associated with exposure to environmental tobacco smoke. These results suggest an important role of p53 in feline oral tumorigenesis. Additionally, the immunohistochemical detection of p53 expression appears to reflect the presence of TP53 mutations in the majority of cases. It remains to be determined if the screening for p53 dysregulations, alone or in association with other markers, can eventually contribute to the early detection of this devastating disease.

BACKGROUND:Next generation sequencing methods are widely adopted for a large amount of scientific purposes, from pure research to health-related studies. The decreasing costs per analysis led to big amounts of generated data and to the subsequent improvement of software for the respective analyses. As a consequence, many approaches have been developed to chain different software in order to obtain reliable and reproducible workflows. However, the large range of applications for NGS approaches entails the challenge to manage many different workflows without losing reliability. METHODS:We here present a high-throughput sequencing pipeline (HaTSPiL), a Python-powered CLI tool designed to handle different approaches for data analysis with a high level of reliability. The software relies on the barcoding of filenames using a human readable naming convention that contains any information regarding the sample needed by the software to automatically choose different workflows and parameters. HaTSPiL is highly modular and customisable, allowing the users to extend its features for any specific need. CONCLUSIONS:HaTSPiL is licensed as Free Software under the MIT license and it is available at https://github.com/dodomorandi/hatspil.

Neuroblastoma is the most common extracranial pediatric solid tumor with a heterogeneous clinical course, ranging from spontaneous regression to metastatic disease and death, irrespective of intensive chemotherapeutic regimen. On the basis of several parameters, children affected by neuroblastoma are stratified into low, intermediate and high risk. At present, more than 50% of high-risk patients with metastatic spread display an overall poor long-term outcome also complicated by devastating long-term morbidities. Thus, novel and more effective therapies are desperately needed to improve lifespan of high-risk patients. In this regard, adoptive cell therapy holds great promise and several clinical trials are ongoing, demonstrating safety and tolerability, with no toxicities. Starting from the immunological and clinical features of neuroblastoma, we here discuss the immunotherapeutic approaches currently adopted for high-risk patients and different innovative therapeutic strategies currently under investigation. The latter are based on the infusion of natural killer (NK) cells, as support of consolidation therapy in addition to standard treatments, or chimeric antigen receptor (CAR) T cells directed against neuroblastoma associated antigens (e.g., disialoganglioside GD2). Finally, future perspectives of adoptive cell therapies represented by γδ T lymphocyes and CAR NK cells are envisaged.

Anatomical atlases have been developed to improve the targeting of basal ganglia in deep brain stimulation. However, the sole anatomy cannot predict the functional outcome of this surgery. Deep brain stimulation is often a compromise between several functional outcomes: motor, fluency and neuropsychological outcomes in particular. In this study, we have developed anatomo-clinical atlases for the targeting of subthalamic and medial globus pallidus deep brain stimulation. The activated electrode coordinates of 42 patients implanted in the subthalamic nucleus and 29 patients in the medial globus pallidus were studied. The atlas was built using the representation of the volume of tissue theoretically activated by the stimulation. The UPDRS score was used to represent the motor outcome. The Stroop test was represented as well as semantic and phonemic fluencies. For the subthalamic nucleus, best motor outcomes were obtained when the supero-lateral part of the nucleus was stimulated whereas the semantic fluency was impaired in this same region. For the medial globus pallidus, best outcomes were obtained when the postero ventral part of the nucleus was stimulated whereas the phonemic fluency was impaired in this same region. There was no significant neuropsychological impairment. We have proposed new anatomo-clinical atlases to visualize the motor and neuropsychological consequences at 6 months of subthalamic nucleus and pallidal stimulation in patients with Parkinson's disease.