Synthesis of novel methyl 3-(Hetero)arylthieno[3,2-b]pyridine-2-carboxylates and antitumor activity evaluation: Studies in vitro and in ovo grafts of chick chorioallantoic membrane (cam) with a triple negative breast cancer cell line

A series of novel functionalized methyl 3-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates 2a–2h were synthesized by C-C Pd-catalyzed Suzuki-Miyaura cross-coupling of methyl 3-bromothie-no[3,2-b]pyridine-2-carboxylate with (hetero)aryl pinacol boranes, trifluoro potassium boronate salts or boronic acids. Their antitumoral potential was evaluated in two triple negative breast cancer (TNBC) cell lines—MDA-MB-231 and MDA-MB-468, by sulforhodamine B assay. Their effects on the non-tumorigenic MCF-12A cells were also evaluated. The results demonstrated that three compounds caused growth inhibition in both TNBC cell lines, with little or no effect against the non-tumorigenic cells. The most promising compound was further studied concerning possible effects on cell viability (by trypan blue exclusion assay), cell proliferation (by bromodeoxyuridine assay) and cell cycle profile (by flow cytometry). The results demonstrated that the GI50 concentration of compound 2e (13 µM) caused a decreased in MDA-MB-231 cell number, which was correlated with a decreased in the % of proliferating cells. Moreover, this compound increased G0/G1 phase and decreased S phases, when compared to control cells (although was not statistic significant). Interestingly, compound 2e also reduced tumor size using an in ovo CAM (chick chorioallantoic membrane) model. This work highlights the potential antitumor effect of a novel methyl 3-arylthieno[3,2-b]pyridine-2-carboxylate derivative.This research was funded by Fundação para a Ciência e Tecnologia (FCT)—Portugal that financially supports CQUM (UID/QUI/686/2019), also financed by European Regional Development Fund (ERDF), COMPETE2020 and Portugal2020, the PTNMR network also supported by Portugal2020. C.P.R.X. is supported through the post-doc grant SFRH/BPD/122871/2016 and J.M.R. through the doctoral grant SFRH/BD/115844/2016, by FCT, ESF (European Social Fund) and HCOP (Human Capital Operational Programme)

Disfunção tiróidea e amiodarona

Although most patients remain clinically euthyroid, some develop amiodarone-induced hyperthyroidism (HPEAI) or hypothyroidism (HPOAI). The authors present a retrospective analysis of ten patients with amiodarone-induced thyroid dysfunction. Six patients were female and mean amiodarone intake was 17.7 months. HPOIA was more common (six patients). From all the patients with HPEAI, two had type 2, one had type 1, and one had type 3 hyperthyroidism. Symptoms suggestive of thyroid dysfunction occurred in five patients, most of them with HPOAI. In HPEAI, the most frequent symptom was exacerbation of arrhythmia (three patients). Discontinuation of amiodarone and treatment with levothyroxine was chosen in 83.3% of the HPOAI cases, while thyonamide treatment with corticosteroids and without amiodarone was the option in 75% of the HPEAI cases. There were three deaths, all in patients with HPEAI. HPEAI is potentially fatal. The clinical picture may be vague, so the thyroid monitoring is mandatory

ATENA–A Novel Rapidly Manufactured Medical Invasive Ventilator Designed as a Response to the COVID-19 Pandemic: Testing Protocol, Safety, and Performance Validation

Background: The urgent need for mechanical ventilators to support respiratory insufficiency due to SARS-CoV-2 led to a worldwide effort to develop low-cost, easily assembled, and locally manufactured ventilators. The ATENA ventilator project was developed in a community-based approach targeting the development, prototyping, testing, and decentralized manufacturing of a new mechanical ventilator. Objective: This article aims to demonstrate ATENA's adequate performance and safety for clinical use. Material: ATENA is a low-cost ventilator that can be rapidly manufactured, easily assembled, and locally produced anywhere in the world. It was developed following the guidelines and requirements provided by European and International Regulatory Authorities (MHRA, ISO 86201) and National Authorities (INFARMED). The device was thoroughly tested using laboratory lung simulators and animal models. Results: The device meets all the regulatory requirements for pandemic ventilators. Additionally, the pre-clinical experiences demonstrated security and adequate ventilation and oxygenation, in vivo. Conclusion: The ATENA ventilator had a good performance in required tests in laboratory scenarios and pre-clinical studies. In a pandemic context, ATENA is perfectly suited for safely treating patients in need of mechanical ventilation.Financial support and sponsorship by CEiiA, INOV4COVID program, donations from scientific patronage, and commercial sales

Autosomal dominant optic atrophy and cataract “plus” phenotype including axonal neuropathy

Objective To characterize the phenotype in individuals with OPA3-related autosomal dominant optic atrophy and cataract (ADOAC) and peripheral neuropathy (PN). Methods Two probands with multiple affected relatives and one sporadic case were referred for evaluation of a PN. Their phenotype was determined by clinical ± neurophysiological assessment. Neuropathologic examination of sural nerve and skeletal muscle, and ultrastructural analysis of mitochondria in fibroblasts were performed in one case. Exome sequencing was performed in the probands. Results The main clinical features in one family (n = 7 affected individuals) and one sporadic case were early-onset cataracts (n = 7), symptoms of gastrointestinal dysmotility (n = 8), and possible/confirmed PN (n = 7). Impaired vision was an early-onset feature in another family (n = 4 affected individuals), in which 3 members had symptoms of gastrointestinal dysmotility and 2 developed PN and cataracts. The less common features among all individuals included symptoms/signs of autonomic dysfunction (n = 3), hearing loss (n = 3), and recurrent pancreatitis (n = 1). In 5 individuals, the neuropathy was axonal and clinically asymptomatic (n = 1), sensory-predominant (n = 2), or motor and sensory (n = 2). In one patient, nerve biopsy revealed a loss of large and small myelinated fibers. In fibroblasts, mitochondria were frequently enlarged with slightly fragmented cristae. The exome sequencing identified OPA3 variants in all probands: a novel variant (c.23T>C) and the known mutation (c.313C>G) in OPA3. Conclusions A syndromic form of ADOAC (ADOAC+), in which axonal neuropathy may be a major feature, is described. OPA3 mutations should be included in the differential diagnosis of complex inherited PN, even in the absence of clinically apparent optic atrophy

Validation of control of allergic rhinitis and asthma test for children (CARATKids)--a prospective multicenter study

BACKGROUND: Control of Allergic Rhinitis and Asthma Test for Children (CARATKids) is the first questionnaire that assesses simultaneously allergic rhinitis and asthma control in children. It was recently developed, but redundancy of questions and its psychometric properties were not assessed. This study aimed to (i) establish the final version of the CARATKids questionnaire and (ii) evaluate its reliability, responsiveness, cross-sectional validity, and longitudinal validity. METHODS: A prospective observational study was conducted in 11 Portuguese centers. During two visits separated by 6 wk, CARATKids, visual analog scale scales and childhood asthma control test were completed, and participant's asthma and rhinitis were evaluated by his/her physician without knowing the questionnaires' results. Data-driven item reduction was conducted, and internal consistency, responsiveness analysis, and associations with external measures of disease status were assessed. RESULTS: Of the 113 children included, 101 completed both visits. After item reduction, the final version of the questionnaire has 13 items, eight to be answered by the child and five by the caregiver. Its Cronbach's alpha was 0.80, the Guyatt's responsiveness index was -1.51, and a significant (p < 0.001) within-patient change of CARATKids score in clinical unstable patients was observed. Regarding cross-sectional validity, correlation coefficients of CARATKids with the external measures of control were between 0.45 and -0.69 and met the a priori predictions. In the longitudinal validity assessment, the correlation coefficients between the score changes of CARATKids and those of external measures of control ranged from 0.34 to 0.46

Using Recombinant Proteins from Lutzomyia longipalpis Saliva to Estimate Human Vector Exposure in Visceral Leishmaniasis Endemic Areas

During the blood meal, female sand flies (insects that transmit the parasite Leishmania) inject saliva containing a large variety of molecules with different pharmacological activities that facilitate the acquisition of blood. These molecules can induce the production of anti-saliva antibodies, which can then be used as markers for insect (vector) biting or exposure. Epidemiological studies using sand fly salivary gland sonicate as antigens are hampered by the difficulty of obtaining large amounts of salivary glands. In the present study, we have investigated the use of two salivary recombinant proteins from the sand fly Lutzomyia longipalpis, considered the main vector of visceral leishmaniasis, as an alternative method for screening of exposure to the sand fly. We primarily tested the suitability of using the recombinant proteins to estimate positive anti-saliva ELISA test in small sets of serum samples. Further, we validated the assay in a large sample of 1,077 individuals from an epidemiological survey in a second area endemic for visceral leishmaniasis. Our findings indicate that these proteins represent a promising epidemiological tool that can aid in implementing control measures against leishmaniasis

The nuclear envelope protein, LAP1B, is a novel protein phosphatase 1 substrate

Protein phosphatase 1 (PP1) binding proteins are quintessential regulators, determining substrate specificity and defining subcellular localization and activity of the latter. Here, we describe a novel PP1 binding protein, the nuclear membrane protein lamina associated polypeptide 1B (LAP1B), which interacts with the DYT1 dystonia protein torsinA. The PP1 binding domain in LAP1B was here identified as the REVRF motif at amino acids 55-59. The LAP1B:PP1 complex can be immunoprecipitated from cells in culture and rat cortex and the complex was further validated by yeast co-transformations and blot overlay assays. PP1, which is enriched in the nucleus, binds to the N-terminal nuclear domain of LAP1B, as shown by immunocolocalization and domain specific binding studies. PP1 dephosphorylates LAP1B, confirming the physiological relevance of this interaction. These findings place PP1 at a key position to participate in the pathogenesis of DYT1 dystonia and related nuclear envelope-based diseases.publishe

Gene expression profiling associated with the progression to poorly differentiated thyroid carcinomas

Poorly differentiated thyroid carcinomas (PDTC) represent a heterogeneous, aggressive entity, presenting features that suggest a progression from well-differentiated carcinomas. To elucidate the mechanisms underlying such progression and identify novel therapeutic targets, we assessed the genome-wide expression in normal and tumour thyroid tissues.info:eu-repo/semantics/publishe