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Background and Objectives: New investigations have detected an enhanced probability for women to develop menstrual cycle alterations after anti-COVID-19 vaccination. Moreover, given that the protective immunity provided by anti-COVID-19 vaccination appears to wane quickly, booster vaccination has been recommended. Nonetheless, whether adverse events arise from such repeated immunization has not been studied. Materials and Methods: We studied the incidence of menstrual cycle alterations, the quantity of menstrual cycle alterations per subject, and of altered menstrual cycles in nonpregnant women of fertile age after anti-COVID-19 vaccination in a cohort of vaccinated female subjects by the means of a standardized questionary that was applied via telephone calls each month. Subjects that received up to four doses were studied for 6 months after each dose. We calculated the odds ratio for enhanced incidence, as well as quadratic functions for the tendencies. A sensitivity analysis excluding subjects taking hormonal birth control and those with polycystic ovary syndrome was performed. Results: Anti-COVID-19 vaccination enhanced the probability to develop menstrual cycle alterations (OR 1.52, CI at 95% 1.2-1.8, p < 0.0001) and, interestingly, such a tendency was enhanced when subjects received more doses (R2 = 0.91). Furthermore, the same trends repeated for the quantity of alterations per subject, and of altered cycles. Such an effect was further demonstrated to be independent upon the vaccine brand being applied, the birth control status, and the diagnosis of polycystic ovary syndrome. Conclusions: Vaccination is the most cost-effective measure for primary prevention and is considered to be safe. Nonetheless, in this article, we show data that suggest that repeated vaccination of adult female subjects may lead to an enhanced incidence of menstrual cycle-related adverse events, quantity of alterations per subject, and altered cycles. We therefore think that the development of new vaccine formulations that produce longer-lasting immunity is of paramount importance to reduce the potential for dose accumulation-dependent enhanced risk.
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Vacinas contra COVID-19 , COVID-19 , Ciclo Menstrual , Humanos , Feminino , Adulto , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/efeitos adversos , Ciclo Menstrual/efeitos dos fármacos , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Vacinação/métodos , Vacinação/efeitos adversos , Distúrbios Menstruais/epidemiologia , Estudos de Coortes , Imunização Secundária/métodos , Incidência , Adulto JovemRESUMO
BACKGROUND: Atrial fibrillation has been associated with higher morbidity and mortality rates in acute ischemic stroke patients (AIS). However, there is scarce information regarding the clinical outcomes and strokes' characteristics among AIS patients with other type of arrhythmias. OBJECTIVE: Our study aims to analyze the hospital mortality rate, stroke characteristics, and clinical and demographical data of patients with any post-stroke arrhythmia. METHODS: Retrospective cohort study of AIS patients with 24h-Holter monitoring during hospital admission recruited between 2015-2020, outcomes were measured using the modified Rankin scale. RESULTS: 597 patients (61.13±13.61 years; 352 men) were included. Arrhythmias were diagnosed in 33 (5.5%), with atrial fibrillation as the most common finding (82%). Age was related to a higher rate of arrhythmia (P = 0.014). A larger prevalence of cardioembolic strokes (69.7% vs 16.6%, P < 0.05) and AIS in the middle cerebral artery's vascular territory (78.8% vs 58.7%, P < 0.05) were found amongst patients with an arrhythmia. No significant association was found between NIHSS at admission with neither incidence of arrhythmia nor mortality. Within the arrhythmia group, three in-hospital deaths were reported: one AF, one ventricular arrhythmia and one second-degree atrioventricular block. In a logistic regression analysis, patients with any kind of arrhythmia had a higher mortality rate (9.1% vs 1.2%, P = 0.011; OR 6.766, 95% CI 1.552 - 29.500). CONCLUSION: Arrhythmia detection after an AIS was associated with increased in-hospital mortality. Risk factors related to arrhythmia detection were a higher mean age, cardioembolic strokes and AIS affecting the middle cerebral artery.
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Arritmias Cardíacas , Mortalidade Hospitalar , AVC Isquêmico , Idoso , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/epidemiologia , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Feminino , Mortalidade Hospitalar/tendências , Humanos , AVC Isquêmico/mortalidade , AVC Isquêmico/terapia , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
Diazenes are valuable compounds that have found broad applicability because of their optical and biological properties. We report the synthesis of alkylaryldiazenes via formal, photoredox-catalyzed, deformylative C-N bond formation. The procedure employs dihydropyridines for the generation of alkyl radicals, which are then trapped by diazonium salts and reduced to the corresponding diazenes. Control experiments were performed to confirm the involvement of radicals in the mechanism. The reaction can be carried out at room temperature and employs readily available reagents; the mild conditions allowed the use of highly functionalized substrates. There was no observed tautomerization of the diazenes to the corresponding arylhydrazones.
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In this communication, the enantioselective synthesis of phthalides and isochromanones is described through a new palladium-catalyzed Heck-Matsuda arylation/NaBH4 -reduction/lactonization sequence of 2,3- and 2,5-dihydrofurans in good overall yields and excellent enantioselectivities (up to 98:2 er). This expeditious synthesis of chiral Heck lactol intermediates allowed the diversification of the strategy to obtain medicinally relevant chiral lactones, amines, and olefins. The natural product 3-butylphthalide was obtained in three steps with an overall yield of 33 % yield in 98:2 er.
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Neoplasias do Endométrio , Instabilidade de Microssatélites , Anticorpos Monoclonais Humanizados , Reparo de Erro de Pareamento de DNA/genética , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Feminino , Humanos , Repetições de Microssatélites , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genéticaRESUMO
S- and P-Stereogenic heterocycles were synthesized by a remarkably simple enantioselective Heck desymmetrization reaction based on the unprecedented noncovalent directing effect of S=O and P=O functionalities. Selected prochiral symmetric substrates were efficiently arylated using the recently disclosed chiral PyraBOx ligand under mild and open-flask reaction conditions. Several five-membered aryl- sulfones, sulfoxides, and phosphine oxides were synthesized in good to excellent yields, in good to high diastereoselectivity, and enantiomeric ratios up to 98:2. Theoretical calculations also support the noncovalent directing effect of the S=O and P=O functionalities during the arylation process.
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New computationally driven protocols for the Heck desymmetrization of 3-cyclopenten-1-ol with aryldiazonium tetrafluoroborates were developed. These new conditions furnished remarkable product selectivity originating from a resident hydroxyl group and the critical choice of the reaction solvent. Mechanistic insights gleaned from theoretical calculations of the putative transition states predicted toluene as an adequate solvent choice to attain high enantioselectivity by strengthening the noncovalent interaction of the substrate hydroxyl group and the chiral cationic palladium catalyst. Laboratory experiments validated the theoretical predictions, and by employing 2% MeOH/toluene as solvent, the Heck-Matsuda reaction provided exclusively the cis-4-arylcyclopentenols 3a-l in good to excellent yields in enantiomeric excesses up to 99%. The performance of the new PyOx ligand (S)-4-tert-butyl-2-(3,5-dichloropyridin-2-yl)-4,5-dihydrooxazole was also successfully evaluated in the Heck-Matsuda desymmetrization of 3-cyclopenten-1-ol. The synthetic potential of these highly functionalized cis-4-arylcyclopentenols is illustrated by a gold-catalyzed synthesis of cyclopenta[b]benzofuran skeletons.
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The boom in visible light photoredox catalysis (VLPC) research has demonstrated that this novel synthetic approach is here to stay. VLPC enables reactive radical intermediates to be catalytically generated at ambient temperature, a feat not generally allowed through traditional pyrolysis- or radical initiator-based methodologies. VLPC has vastly extended the range of substrates and reaction schemes that have been traditionally the domain of radical reactions. In this review the photophysics background of VLPC will be briefly discussed, followed by a report on recent inroads of VLPC into decarboxylative couplings and radical C-H functionalization of aromatic compounds. The bulk of the review will be dedicated to advances in synergistic catalysis involving VLPC, namely the combination of photoredox catalysis with organocatalysis, including ß-functionalization of carbonyl groups, functionalization of weak aliphatic C-H bonds, and anti-Markovnikov hydrofunctionalization of alkenes; dual catalysis with gold or with nickel, photoredox catalysis as an oxidation promoter in transition metal catalysis, and acid-catalyzed enantioselective radical addition to π systems.
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BACKGROUND: Uterine serous carcinomas (USCs) are an aggressive form of uterine cancer that may rely on HER2/neu amplification as a driver of proliferation. The objective of this paper is to assess the sensitivity of USC cell lines with and without HER2/neu gene amplification to afatinib, an irreversible ErbB tyrosine kinase inhibitor, and to test the efficacy of afatinib in the treatment of HER2-amplified USC xenografts. METHODS: Eight of fifteen primary USC cell lines (four with HER2 amplification and four without) demonstrating similar in vitro growth rates were treated with scalar concentrations of afatinib. Effects on cell growth, signalling and cell cycle distribution were determined by flow cytometry assays. Mice harbouring xenografts of HER2/neu-amplified USC were treated with afatinib by gavage to determine the effect on tumour growth and overall survival. RESULTS: Primary chemotherapy-resistant USC cell lines harbouring HER2/neu gene amplification were exquisitely sensitive to afatinib exposure (mean ± s.e.m. IC50=0.0056 ± 0.0006 µM) and significantly more sensitive than HER2/neu-non-amplified USC cell lines (mean ± s.e.m. IC50=0.563 ± 0.092 µM, P<0.0001). Afatinib exposure resulted in abrogation of cell survival, inhibition of HER2/neu autophosphorylation and S6 transcription factor phosphorylation in HER2/neu overexpressing USC and inhibited the growth of HER2-amplified tumour xenografts improving overall survival (P=0.0017). CONCLUSIONS: Afatinib may be highly effective against HER2/neu-amplified chemotherapy-resistant USC. The investigation of afatinib in patients harbouring HER2/neu-amplified USC is warranted.
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Cistadenocarcinoma Seroso/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Quinazolinas/farmacologia , Receptor ErbB-2/metabolismo , Neoplasias Uterinas/tratamento farmacológico , Adulto , Afatinib , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Técnicas In Vitro , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Receptor ErbB-2/genética , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A new enantioselective Heck-Matsuda desymmetrization reaction was accomplished by using 3-cyclopentenol to produce chiral five-membered 4-aryl cyclopentenol scaffolds in good yields and high ee's, together with some 3-aryl-cyclopentanones as minor products. Mechanistically, the hydroxyl group of 3-cyclopentenol acts as a directing group and is responsible for the cis- arrangement in the formation of the 4-aryl-cyclopentenols.
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We describe herein a synthetically useful method for the enantioselective intermolecular Heck-Matsuda arylation of acyclic allylic alcohols. Aryldiazonium tetrafluoroborates were applied as arylating agents in the presence of Pd(TFA)2 and a chiral, commercially available, bisoxazoline ligand. The methodology is straightforward, robust, scalable up to a few grams, and of broad scope allowing the synthesis of a range of ß-aryl-carbonyl compounds in good to high enantioselectivities and yields. This new enantioselective Heck-Matsuda arylation allowed the synthesis of ß-aryl-γ-lactones and ß-aryl aldehydes, which play a vital role as key intermediates in the synthesis of the biologically active compounds, such as (R)-baclofen, (R)-rolipram, (S)-curcumene, (S)-dehydrocurcumene, and (S)-tumerone.
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The "dba-free" Heck-Matsuda reaction was investigated via direct ESI-MS(/MS) monitoring. Palladium species involved in the reduction of Pd(II) during a Wacker type reaction and several "dba-free" arylpalladium transient complexes were detected and characterized. Based on these findings, a more comprehensible catalytic cycle for this pivotal reaction is suggested.
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Compostos Organometálicos/química , Paládio/química , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em TandemRESUMO
BACKGROUND: We evaluated the expression of CD46, CD55 and CD59 membrane-bound complement-regulatory proteins (mCRPs) in primary uterine serous carcinoma (USC) and the ability of small interfering RNA (siRNA) against these mCRPs to sensitise USC to complement-dependent cytotoxicity (CDC) and antibody (trastuzumab)-dependent cellular cytotoxicity (ADCC) in vitro. METHODS: Membrane-bound complement-regulatory proteins expression was evaluated using real-time PCR (RT-PCR) and flow cytometry, whereas Her2/neu expression and c-erbB2 gene amplification were assessed using immunohistochemistry, flow cytometry and fluorescent in-situ hybridisation. The biological effect of siRNA-mediated knockdown of mCRPs on HER2/neu-overexpressing USC cell lines was evaluated in CDC and ADCC 4-h chromium-release assays. RESULTS: High expression of mCRPs was found in USC cell lines when compared with normal endometrial cells (P<0.05). RT-PCR and FACS analyses demonstrated that anti-mCRP siRNAs were effective in reducing CD46, CD55 and CD59 expression on USC (P<0.05). Baseline complement-dependent cytotoxicity (CDC) against USC cell lines was low (mean ± s.e.m.=6.8 ± 0.9%) but significantly increased upon CD55 and CD59 knockdown (11.6 ± 0.8% and 10.7 ± 0.9%, respectively, P<0.05). Importantly, in the absence of complement, both CD55 and CD59, but not CD46, knockdowns significantly augmented ADCC against USC overexpressing Her2/neu. CONCLUSION: Uterine serous carcinoma express high levels of the mCRPs CD46, CD55 and CD59. Small interfering RNA inhibition of CD55 and CD59, but not CD46, sensitises USC to both CDC and ADCC in vitro, and if specifically targeted to tumour cells, may significantly increase trastuzumab-mediated therapeutic effect in vivo.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos , Antígenos CD55/metabolismo , Antígenos CD59/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias do Colo do Útero/metabolismo , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Antígenos CD55/química , Antígenos CD55/genética , Antígenos CD59/química , Antígenos CD59/genética , Ativação do Complemento , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Citotoxicidade Imunológica , Regulação para Baixo , Feminino , Citometria de Fluxo , Humanos , Hibridização in Situ Fluorescente , Proteína Cofatora de Membrana/genética , Proteína Cofatora de Membrana/metabolismo , Pessoa de Meia-Idade , Prognóstico , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor ErbB-2/genética , Trastuzumab , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/imunologiaRESUMO
We describe herein an efficient and diastereoselective substrate-directable Heck-Matsuda reaction with nonactivated five-membered olefins. The carbamate acts as the main directing group in the arylation process allowing the synthesis of several functionalized aryl cyclopentenes in good to excellent diastereoselectivities (>85:15) and in isolated yields ranging from 41 to 90%. No double bond isomerizations were observed in these Heck reactions, and the newly created benzylic centers were preserved in all cases examined. The substrate directable Heck arylation approach was successfully applied in a straightforward total synthesis of the sphingosine 1-phosphate receptor-subtype 1 (S1P(1)) agonist VPC01091 by a concise and practical route involving 5 steps in 40% overall yield.
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Alcenos/síntese química , Ciclopentanos/síntese química , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Receptores de Lisoesfingolipídeo/química , Alcenos/química , Catálise , Ciclopentanos/química , Estrutura Molecular , EstereoisomerismoRESUMO
Like other seafood products, tuna is highly perishable and sensitive to microbial spoilage. Its consumption, whether fresh or canned, can lead to severe food poisoning due to the activity of specific microorganisms, including histamine-producing bacteria. Yet, many grey areas persist regarding their ecology, conditions of emergence, and proliferation in fish. In this study, we used 16S rRNA barcoding to investigate postmortem changes in the bacteriome of fresh and brine-frozen yellowfin tuna (Thunnus albacares), until late stages of decomposition (i.e. 120 h). The results revealed that despite standard refrigeration storage conditions (i.e. 4°C), a diverse and complex spoilage bacteriome developed in the gut and liver. The relative abundance of spoilage bacterial taxa increased rapidly in both organs, representing 82% of the bacterial communities in fresh yellowfin tuna, and less than 30% in brine-frozen tuna. Photobacterium was identified as one of the dominant bacterial genera, and its temporal dynamics were positively correlated with histamine concentration in both gut and liver samples, which ultimately exceeded the recommended sanitary threshold of 50 ppm in edible parts of tuna. The results from this study show that the sanitary risks associated with the consumption of this widely eaten fish are strongly influenced by postcapture storage conditions.
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Microbiota , Atum , Animais , Bactérias/genética , Microbiologia de Alimentos , Histamina/análise , Microbiota/genética , RNA Ribossômico 16S/genética , Sais , Atum/genética , Atum/microbiologiaRESUMO
A dynamic kinetic asymmetric Pd-catalyzed cross-coupling reaction of heterobiaryl bromides with ketone N-tosylhydrazones for the synthesis of heterobiaryl styrenes is described. The combination of Pd(dba)2 as a precatalyst with a TADDOL-derived phosphoramidite ligand provides the corresponding coupling products in good yields and high enantioselectivities under mild conditions. Racemization-free N-oxidation and N-alkylation of the products allowed us to obtain appealing functionalized axially chiral heterobiaryl derivatives.
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Brometos , Paládio , Alquilação , Catálise , LigantesRESUMO
ß,ß-Disubstituted α,ß-unsaturated esters may serve as valuable derivatives for the preparation of other highly functionalized systems found in many natural products and marketed drugs. The stereoselective synthesis of unsymmetrical ß,ß-diarylacrylate compounds possessing two similar aromatic groups remains a substantial challenge. A simple and convenient stereoselective protocol for the preparation of ß,ß-disubstituted acrylates via a Heck-Matsuda reaction is reported. Good to high yields were accomplished by a "ligand-free" Pd-catalyzed arylation reaction of cinnamate esters with arenediazonium tetrafluoroborates. Both electron-deficient and electron-rich arenediazonium salts could be employed as arylating reagents, and cinnamate esters were generally more reactive when substituted with an electron-donating group. The overall methodology is highly stereoselective, and this attribute was taken advantage of in the asymmetric Cu-catalyzed 1,4 reduction reaction to provide ß,ß-diarylpropanoates in high enantioselectivities. The synthesis of a 3-aryl indole and a chiral 4-aryl-2-quinolone from ß,ß-diarylacrylates was achieved by cyclization in the presence of a diphosphine ligated CuH catalyst. A convenient route for the asymmetric formal synthesis of the psychoactive compound (-)-Indatraline is also presented.
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In the title compound, C(24)H(25)NO, the phenyl and diphenyl-methanol substituents are syn to each other. The pyrrolidine ring has an envelope conformation with the flap atom being the C atom bearing the phenyl substituent. The hy-droxy group forms an intra-molecular hydrogen bond with the pyrrolidine N atom, and the phenyl rings lie to same side of the mol-ecule. The crystal packing features C-Hâ¯π inter-actions. Two slightly displaced co-planar orientations were found for one of the phenyl rings; the major component had a site-occupancy factor of 0.782â (15).
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While planktonic viruses have received much attention in recent decades, knowledge of the virome of marine organisms, especially fish, still remains rudimentary. This is notably the case with tuna, which are among the most consumed fish worldwide and represent considerable economic, social and nutritional value. Yet the composition of the tuna virome and its biological and environmental determinants remain unknown. To begin to address this gap, we investigated the taxonomic diversity of viral communities inhabiting the skin mucus, gut and liver of two major tropical tuna species (skipjack and yellowfin) in individuals fished in the Atlantic and Indian Oceans. While we found significant differences in the virome composition between the organs, this was totally independent of the tuna species or sex. The tuna virome was mainly dominated by eukaryotic viruses in the digestive organs (gut and liver), while bacteriophages were predominant in the mucus. We observed the presence of specific viral families in each organ, some previously identified as fish or human pathogens (e.g., Iridoviridae, Parvoviridae, Alloherpesviridae, Papillomaviridae). Interestingly, we also detected a 'core virome' that was shared by all the organs and was mainly composed of Caudovirales, Microviridae and Circoviridae. These results show that tuna host a mosaic of viral niches, whose establishment, role and circulation remain to be elucidated.