Ascites-Derived Organoids to Depict Platinum Resistance in Gynaecological Serous Carcinomas.

Gynaecological serous carcinomas (GSCs) constitute a distinctive entity among female tumours characterised by a very poor prognosis. In addition to late-stage diagnosis and a high rate of recurrent disease associated with massive peritoneal carcinomatosis, the systematic acquisition of resistance to first-line chemotherapy based on platinum determines the unfavourable outcome of GSC patients. To explore the molecular mechanisms associated with platinum resistance, we generated patient-derived organoids (PDOs) from liquid biopsies of GSC patients. PDOs are emerging as a relevant preclinical model system to assist in clinical decision making, mainly from tumoural tissue and particularly for personalised therapeutic options. To approach platinum resistance in a GSC context, proficient PDOs were generated from the ascitic fluid of ovarian, primary peritoneal and uterine serous carcinoma patients in platinum-sensitive and platinum-resistant clinical settings from the uterine aspirate of a uterine serous carcinoma patient, and we also induced platinum resistance in vitro in a representative platinum-sensitive PDO. Histological and immunofluorescent characterisation of these ascites-derived organoids showed resemblance to the corresponding original tumours, and assessment of platinum sensitivity in these preclinical models replicated the clinical setting of the corresponding GSC patients. Differential gene expression profiling of a panel of 770 genes representing major canonical cancer pathways, comparing platinum-sensitive and platinum-resistant PDOs, revealed cellular response to DNA damage stimulus as the principal biological process associated with the acquisition of resistance to the first-line therapy for GSC. Additionally, candidate genes involved in regulation of cell adhesion, cell cycles, and transcription emerged from this proof-of-concept study. In conclusion, we describe the generation of PDOs from liquid biopsies in the context of gynaecological serous carcinomas to explore the molecular determinants of platinum resistance.

Monolayer-to-Mesoscale Modulation of the Optical Properties in 2D CrI_{3} Mapped by Hyperspectral Microscopy.

Magnetic 2D materials hold promise to change the miniaturization paradigm of unidirectional photonic components. However, the integration of these materials in devices hinges on the accurate determination of the optical properties down to the monolayer limit, which is still missing. By using hyperspectral wide-field imaging at room temperature, we reveal a nonmonotonic thickness dependence of the complex optical dielectric function in the archetypal magnetic 2D material CrI_{3} extending across different length scales: onsetting at the mesoscale, peaking at the nanoscale, and decreasing again down to the single layer. These results portray a modification of the electronic properties of the material and align with the layer-dependent magnetism in CrI_{3}, shedding light on the long-standing structural conundrum in this material. The unique modulation of the complex dielectric function from the monolayer up to more than 100 layers will be instrumental for understanding mesoscopic effects in layered materials and tuning light-matter interactions in magnetic 2D materials.

Noninvasive detection of microsatellite instability in patients with endometrial cancer.

The analysis of mismatch repair proteins in solid tissue is the standard of care (SoC) for the microsatellite instability (MSI) characterization in endometrial cancer (EC). Uterine aspirates (UAs) or circulating-DNA (cfDNA) samples capture the intratumor heterogeneity and provide a more comprehensive and dynamic molecular diagnosis. Thus, MSI analysis by droplet-digital PCR (ddPCR) in UAs and cfDNA can provide a reliable tool to characterize and follow-up the disease. The UAs, paraffin-embedded tumor tissue (FFPE) and longitudinal plasma samples from a cohort of 90 EC patients were analyzed using ddPCR panel and compared to the SoC. A high concordance (96.67%) was obtained between the analysis of MSI markers in UAs and the SoC. Three discordant cases were validated as unstable by ddPCR on FFPE samples. Besides, a good overall concordance (70.27%) was obtained when comparing the performance of the ddPCR assay on UAs and cfDNA in high-risk tumors. Importantly, our results also evidenced the value of MSI analysis to monitor the disease evolution. MSI evaluation in minimally invasive samples shows great accuracy and sensitivity and provides a valuable tool for the molecular characterization and follow-up of endometrial tumors, opening new opportunities for personalized management of EC.

Neural predictors of cognitive-behavior therapy outcome in anxiety-related disorders: a meta-analysis of task-based fMRI studies.

BACKGROUND: Cognitive-behavior therapy (CBT) is a well-established first-line intervention for anxiety-related disorders, including specific phobia, social anxiety disorder, panic disorder/agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder. Several neural predictors of CBT outcome for anxiety-related disorders have been proposed, but previous results are inconsistent. METHODS: We conducted a systematic review and meta-analysis of task-based functional magnetic resonance imaging (fMRI) studies investigating whole-brain predictors of CBT outcome in anxiety-related disorders (17 studies, n = 442). RESULTS: Across different tasks, we observed that brain response in a network of regions involved in salience and interoception processing, encompassing fronto-insular (the right inferior frontal gyrus-anterior insular cortex) and fronto-limbic (the dorsomedial prefrontal cortex-dorsal anterior cingulate cortex) cortices was strongly associated with a positive CBT outcome. CONCLUSIONS: Our results suggest that there are robust neural predictors of CBT outcome in anxiety-related disorders that may eventually lead (probably in combination with other data) to develop personalized approaches for the treatment of these mental disorders.

Red Blood Cells Protein Profile Is Modified in Breast Cancer Patients.

Metastasis is the primary cause of death for most breast cancer (BC) patients who succumb to the disease. During the hematogenous dissemination, circulating tumor cells interact with different blood components. Thus, there are microenvironmental and systemic processes contributing to cancer regulation. We have recently published that red blood cells (RBCs) that accompany circulating tumor cells have prognostic value in metastatic BC patients. RBC alterations are related to several diseases. Although the principal known role is gas transport, it has been recently assigned additional functions as regulatory cells on circulation. Hence, to explore their potential contribution to tumor progression, we characterized the proteomic composition of RBCs from 53 BC patients from stages I to III and IV, compared with 33 cancer-free controls. In this work, we observed that RBCs from BC patients showed a different proteomic profile compared to cancer-free controls and between different tumor stages. The differential proteins were mainly related to extracellular components, proteasome, and metabolism. Embryonic hemoglobins, not expected in adults' RBCs, were detected in BC patients. Besides, lysosome-associated membrane glycoprotein 2 emerge as a new RBCs marker with diagnostic and prognostic potential for metastatic BC patients. Seemingly, RBCs are acquiring modifications in their proteomic composition that probably represents the systemic cancer disease, conditioned by the tumor microenvironment.

Content agreement of depressive symptomatology in children and adolescents: a review of eighteen self-report questionnaires.

Identifying major depression in children and adolescents is more challenging than in adults. Questionnaires are often used for screening or guiding clinical assessment. Several instruments of different lengths are used as equivalent measures in diagnostic decisions. In this paper, we explore to what extent 18 commonly used depression scales for children and adolescents explore depression clinical symptoms as established by standard DSM-5 diagnosis criteria. We analyzed scale content adequacy by examining the overlap between scale contents and consensus clinical symptoms, the diagnostic time frame for active symptom assessment, and readability for the target age group. The 18 scales encompassed 52 distinct symptoms. These scales included just 50% of clinical symptoms required for diagnosis. The content overlap was low; on average, 29% of symptoms coincide across scales. Half of the scales did not use the standard period for active symptom appraisal, and some did not include a period for assessment. The reading levels on six scales were inappropriate for the scale's target population age group. The substantial heterogeneity in defining the depressive syndrome, the low overlap among scales, different periods of a positive diagnosis, and mismatch of reading competence for detecting may lead to heterogeneity in clinical diagnoses when using different scales. Improving the content of self-report in terms of homogeneity of diagnostic criteria would lead to better diagnostic decisions and patient management.

Improving the Management of Endometrial Cancer Patients through the Use of Liquid Biopsy Analyses: A Case Report.

Endometrial cancer (EC) is the 4th most common neoplasm of the female genital tract, with 15-20% of patients being of high risk of recurrence which leads to a significant decrease in patient survival. Current therapeutic options for patients with EC are poor, being the combined therapy of carboplatin and paclitaxel the standard of care, with limited efficacy. Therefore, new therapeutic options and better monitoring tools are needed to improve the management of the disease. In the current case report, we showcase the value of liquid biopsy analyses in a microsatellite instability EC patient with initially good prognosis that however underwent rapid progression disease within 6 months post-surgery; through the study of plasma cfDNA/ctDNA dynamics to assess the tumour evolution during treatment, as well as the study of the uterine aspirate as a valuable sample that captures the intra-tumour heterogeneity that allows a comprehensive genomic profiling of the disease to identify potential therapeutic options. Furthermore, preclinical models were generated at the time of tumour progression to assess the efficacy of the identified targeted therapies.

Evaluation of Adverse Effects in Nursing Mothers and Their Infants After COVID-19 mRNA Vaccination.

Background and Objectives: Breastfeeding women are generally excluded from clinical trials with new vaccines. The objective of the study was to explore whether the BNT162b2 mRNA and mRNA-1273 COVID-19 vaccines are safe for breastfeeding mothers and their breastfed infants. Methods: A convenience sample prospective cohort single institution study was performed on breastfeeding health care professionals, who were exposed to second dose of SARS-CoV2 vaccine at the beginning of the study period. They and their breastfed children's symptoms were followed up through online questionnaires for 14 days. Results: Of the 95 finally included participants, only 1 was lost to follow-up on day 7. Mean age of the mothers was 35.9 ± 3.9 years and that of their infants was 14.6 ± 12.1 months. At least one adverse event was reported by 85% (95% confidence interval [CI]: 76-91.5%) of the mothers. The most frequent was injection site pain in 81% of cases. Moreover, 31% (95% CI: 22-41%) observed some event in their breastfed children. Most frequently, 19% (95% CI: 13-30%) of the children were irritable. During the 14 days of follow-up, 36% of the children (95% CI: 27-46%) were diagnosed with respiratory infection. Conclusions: Most mothers' reactions were mild and transitory, generally limited to the first 3 days after vaccination. Many children's events were associated with concomitant infectious processes and we did not detect a notable peak on any particular day of follow-up. Neither mothers nor their infants developed serious adverse events nor were they diagnosed with COVID-19 within the study period.

SARS-CoV-2 Antibodies in Breast Milk After Vaccination.

BACKGROUND AND OBJECTIVES: Passive and active immunity transfer through human milk (HM) constitutes a key element in the infant's developing immunity. Certain infectious diseases and vaccines have been described to induce changes in the immune components of HM. METHODS: We conducted a prospective cohort single-institution study from February 2 to April 4, 2021. Women who reported to be breastfeeding at the time of their coronavirus disease 2019 (COVID-19) vaccination were invited to participate. Blood and milk samples were collected on day 14 after their second dose of the vaccine. Immunoglobulin G (IgG) antibodies against nucleocapsid protein as well as IgG, immunoglobulin M and immunoglobulin A (IgA) antibodies against the spike 1 protein receptor-binding domain against severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2 RBD-S1) were analyzed in both serum and HM samples. RESULTS: Most of the participants (ie, 94%) received the BNT162b2 messenger RNA COVID-19 vaccine. The mean serum concentration of anti-SARS-CoV-2 RBD-S-IgG antibodies in vaccinated individuals was 3379.6 ± 1639.5 binding antibody units per mL. All vaccinated study participants had anti-SARS-CoV-2 RBD-S1-IgG, and 89% of them had anti-SARS-CoV-2 RBD-S-IgA in their milk. The antibody concentrations in the milk of mothers who were breastfeeding 24 months were significantly higher than in mothers with breastfeeding periods <24 months (P < .001). CONCLUSIONS: We found a clear association between COVID-19 vaccination and specific immunoglobulin concentrations in HM. This effect was more pronounced when lactation periods exceeded 23 months. The influence of the lactation period on immunoglobulins was specific and independent of other variables.

M-TRAP: Safety and performance of metastatic tumor cell trap device in advanced ovarian cancer patients.

OBJECTIVE: Despite radical surgery and chemotherapy, most patients with ovarian cancer die due to disease progression. M-Trap is an implantable medical device designed to capture peritoneal disseminated tumor cells with the aim to focalize the disease. This trial analyzed the safety and performance of the device. METHODS: This first-in-human prospective, multi-center, non-blinded, single-arm study enrolled 23 women with high-grade serous advanced ovarian cancer. After primary or interval debulking surgery, 3 M-Trap devices were placed in the peritoneum of the abdominal cavity. 18-months post-implantation or at disease progression, devices were initially removed by laparoscopy. The primary safety endpoint was freedom from device and procedure-related major adverse events (MAEs) through 6-months post-implantation compared to an historical control. The primary performance endpoint was histopathologic evidence of tumor cells capture. RESULTS: Only one major adverse event was attributable to the device. 18 women were free of device and procedure related MAEs (78.3%). However, the primary safety endpoint was not achieved (p = 0.131), primarily attributable to the greater surgical complexity of the M-Trap patient population. 62% of recurrent patients demonstrated tumor cell capture in at least one device with a minimal tumor cell infiltration. No other long-term device-related adverse events were reported. The secondary performance endpoint demonstrated a lack of disease focalization. CONCLUSIONS: The M-Trap technology failed to meet its primary safety objective, although when adjusted for surgical complexity, the study approved it. Likewise, the devices did not demonstrate the anticipated benefits in terms of tumor cell capture and disease focalization in recurrent ovarian cancer.

Genomic Profiling of Uterine Aspirates and cfDNA as an Integrative Liquid Biopsy Strategy in Endometrial Cancer.

The incidence and mortality of endometrial cancer (EC) have risen in recent years, hence more precise management is needed. Therefore, we combined different types of liquid biopsies to better characterize the genetic landscape of EC in a non-invasive and dynamic manner. Uterine aspirates (UAs) from 60 patients with EC were obtained during surgery and analyzed by next-generation sequencing (NGS). Blood samples, collected at surgery, were used for cell-free DNA (cfDNA) and circulating tumor cell (CTC) analyses. Finally, personalized therapies were tested in patient-derived xenografts (PDXs) generated from the UAs. NGS analyses revealed the presence of genetic alterations in 93% of the tumors. Circulating tumor DNA (ctDNA) was present in 41.2% of cases, mainly in patients with high-risk tumors, thus indicating a clear association with a more aggressive disease. Accordingly, the results obtained during the post-surgery follow-up indicated the presence of ctDNA in three patients with progressive disease. Moreover, 38.9% of patients were positive for CTCs at surgery. Finally, the efficacy of targeted therapies based on the UA-specific mutational landscape was demonstrated in PDX models. Our study indicates the potential clinical applicability of a personalized strategy based on a combination of different liquid biopsies to characterize and monitor tumor evolution, and to identify targeted therapies.

Risk and protective factors for anxiety and obsessive-compulsive disorders: an umbrella review of systematic reviews and meta-analyses.

BACKGROUND: A multitude of risk/protective factors for anxiety and obsessive-compulsive disorders have been proposed. We conducted an umbrella review to summarize the evidence of the associations between risk/protective factors and each of the following disorders: specific phobia, social anxiety disorder, generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder, and to assess the strength of this evidence whilst controlling for several biases. METHODS: Publication databases were searched for systematic reviews and meta-analyses examining associations between potential risk/protective factors and each of the disorders investigated. The evidence of the association between each factor and disorder was graded into convincing, highly suggestive, suggestive, weak, or non-significant according to a standardized classification based on: number of cases (>1000), random-effects p-values, 95% prediction intervals, confidence interval of the largest study, heterogeneity between studies, study effects, and excess of significance. RESULTS: Nineteen systematic reviews and meta-analyses were included, corresponding to 216 individual studies covering 427 potential risk/protective factors. Only one factor association (early physical trauma as a risk factor for social anxiety disorder, OR 2.59, 95% CI 2.17-3.1) met all the criteria for convincing evidence. When excluding the requirement for more than 1000 cases, five factor associations met the other criteria for convincing evidence and 22 met the remaining criteria for highly suggestive evidence. CONCLUSIONS: Although the amount and quality of the evidence for most risk/protective factors for anxiety and obsessive-compulsive disorders is limited, a number of factors significantly increase the risk for these disorders, may have potential prognostic ability and inform prevention.

Extracellular Vesicles-Based Biomarkers Represent a Promising Liquid Biopsy in Endometrial Cancer.

Tumor-derived extracellular vesicles (EVs) are secreted in large amounts into biological fluids of cancer patients. The analysis of EVs cargoes has been associated with patient´s outcome and response to therapy. However, current technologies for EVs isolation are tedious and low cost-efficient for routine clinical implementation. To explore the clinical value of circulating EVs analysis we attempted a proof-of-concept in endometrial cancer (EC) with ExoGAG, an easy to use and highly efficient new technology to enrich EVs. Technical performance was first evaluated using EVs secreted by Hec1A cells. Then, the clinical value of this strategy was questioned by analyzing the levels of two well-known tissue biomarkers in EC, L1 cell adhesion molecule (L1CAM) and Annexin A2 (ANXA2), in EVs purified from plasma in a cohort of 41 EC patients and 20 healthy controls. The results demonstrated the specific content of ANXA2 in the purified EVs fraction, with an accurate sensitivity and specificity for EC diagnosis. Importantly, high ANXA2 levels in circulating EVs were associated with high risk of recurrence and non-endometrioid histology suggesting a potential value as a prognostic biomarker in EC. These results also confirmed ExoGAG technology as a robust technique for the clinical implementation of circulating EVs analyses.

Risk factors for posttraumatic stress disorder: An umbrella review of systematic reviews and meta-analyses.

Approximately one third of individuals who experience a severe traumatic event will develop posttraumatic stress disorder (PTSD). It is crucial to identify what factors may be associated with increased or decreased risk for PTSD. We conducted an umbrella review of systematic reviews and meta-analyses of risk/protective factors for PTSD and assessed and graded the evidence of the association between each factor and PTSD. Thirty-three systematic reviews and meta-analyses were included and 130 potential risk factors were identified. Of those, 57 showed a significant association with PTSD. Being female or being indigenous people of the Americas, among the sociodemographic factors; history of physical disease and family history of psychiatric disorder, among the pretrauma factors; and cumulative exposure to potentially traumatic experiences, trauma severity, and being trapped during an earthquake, among the peritrauma factors, showed convincing or highly suggestive evidence of an association with PTSD. Data from prospective studies were less conclusive. Our results have the potential of helping refine PTSD prediction models and contributing to the design of prevention strategies.

Translational research in psychiatry: The Research Domain Criteria Project (RDoC). / Investigación traslacional en psiquiatría: el marco Research Domain Criteria (RDoC).

Despite the consensus achieved in the homogenization of clinical criteria by categorical psychiatric classification systems (DEM and CIE), they are criticized for a lack of validity and inability to guide clinical treatment and research. In this review article we introduce the Research Domain Criteria (RDoC) framework as an alternative framework for translational research in psychiatry. The RDOC framework systematizes both research targets and methodology for research in psychiatry. RDoC is based on a catalogue of neurobiological and neurocognitive evidence of behaviour, and conceives psychopathology as the phenotypic expression of alterations of functional domains that are classified into 5psychobiological systems. The RdoC framework also proposes that domains must be validated with evidence in 7levels of analysis: genes, molecules, cells, nerve circuits, physiology, behaviour and self-reports. As opposed to categorical systems focused on diagnosis, RDoC focuses on the study of psychopathology as a correlate of detectable functional, biological and behavioural disruption of normal processes. In order to build a useful psychiatric nosology for guiding clinical interventions, the RDoC research framework links the neurobiological basis of mental processes with phenotypical manifestations. Although the RDoC findings have not yet been articulated into a specific model for guiding clinical practice, they provide a useful transition system for creating clinical, basic and epidemiological research hypotheses.

Spatial cluster analysis for bovine paratuberculosis in Paraiba State, Northeastern Brazil / Análise de aglomerados espaciais para paratuberculose bovina no Estado da Paraíba, Nordeste do Brasil

The aim of this survey was to identify spatial clustering of bovine paratuberculosis positive herds in the State of Paraíba, Northeastern Brazil. The state was divided into three sampling groups: sampling stratum 1 (mesoregion of Sertão), sampling stratum 2 (mesoregion of Borborema), and sampling stratum 3 (mesoregions of Zona da Mata and Agreste). Ten animals were sampled in herds with up to 99 cows aged over 24 months; 15 animals were sampled in herds with 100 or more cows aged over 24 months; and all animals were sampled in those with up to 10 cows aged over 24 months. In total, 2504 cows aged ≥ 24 months were sampled from 480 herds. Indirect enzyme-linked immunosorbant assay (ELISA) test kits were used for Mycobacterium avium subsp. paratuberculosis (MAP) antibody detection. A herd was deemed positive for paratuberculosis if it included at least one positive animal in herds of up to 24 females, and two positive animals in herds with more than 24 females. Spatial clustering was assessed using the Cuzick-Edwards' k-nearest neighbor method and spatial scan statistics. Two significant clustering of positive herds were detected in Northern part of Borborema mesoregion, a border region with the State of Rio Grande do Norte, in which there is a large animal movement from different locations without knowing the sanitary condition of animals. As serological tests for MAP diagnosis are not widely available and are very expensive, as well as replacement or maintenance of livestock by animal purchasing is common in the region, it is concluded that prevention measures should be applied at herd level.(AU)

O objetivo deste estudo foi identificar agrupamentos espaciais de rebanhos positivos para paratuberculose bovina no Estado da Paraíba, Nordeste do Brasil. O estado foi dividido em três grupos amostrais: estrato amostral 1 (mesorregião do Sertão), estrato amostral 2 (mesorregião da Borborema), e estrato amostral 3 (mesorregiões da Zona da Mata e Agreste). Dez animais foram amostrados em rebanhos com até 99 vacas com idade maior ou igual a 24 meses; 15 animais foram amostrados em rebanhos com 100 ou mais vacas com idade maior ou igual a 24 meses; e todos os animais foram amostrados naqueles rebanhos com até 10 vacas. No total, foram amostradas 2504 vacas com idade ≥24 meses de 480 rebanhos. Para a detecção de anticorpos anti-Mycobacterium avium subsp. paratuberculosis (MAP) foram utilizados kits do teste imunoenzimático indireto (ELISA). Um rebanho foi considerado positivo para paratuberculose se apresentasse pelo menos um animal positivo em rebanhos de até 24 fêmeas, e dois animais positivos em rebanhos com mais de 24 fêmeas. Os agrupamentos espaciais foram avaliados com o uso da metodologia k-vizinhos mais próximos de Cuzick-Edwards e estatística espacial de varredura. Dois agrupamentos significativos de rebanhos positivos foram detectados na parte norte da mesorregião da Borborema, uma região de fronteira com o Estado do Rio Grande do Norte onde há intenso movimento de animais de diferentes locais sem o conhecimento do estado sanitário desses animais. Tendo em vista que os testes sorológicos para diagnóstico de MAP não são amplamente disponíveis e muito caros, bem como é comum na região a reposição e manutenção dos rebanhos por compra de animais, conclui-se que medidas de prevenção devem ser aplicadas em nível de rebanho.(AU)

High Levels of Hemoglobin Promote Carotid Adventitial Vasa Vasorum Neoangiogenesis in Chronic Kidney Disease.

Chronic kidney disease (CKD) patients, characterized by traditional and nontraditional risk factors, are prone to develop atheromatosis and thus cardiovascular events and mortality. The angiogenesis of the adventitial vasa vasorum (aVV) surrounding the carotid has been described as the atheromatosis initiator. Therefore, the aim of the study was to (1) evaluate if the carotid aVV in CKD patients increases in comparison to its physiological value of healthy patients; (2) explore which traditional or nontraditional risk factor including inflammation, bone and mineral metabolism, and anemia could be related to the aVV angiogenesis. CKD patients without previous cardiovascular events (44, stages 3-4; 37, stage 5D) and 65 healthy subjects were compared. The carotid aVV and the intima-media thickness (cIMT) were evaluated by ultrasound. CKD patients at stages 3-4 showed higher aVV of the right carotid artery even after adjusting for age. Importantly, a multiple linear regression model showed hemoglobin levels > 12.5 g/dL as the factor for an estimated higher aVV of the right carotid artery. In conclusion, the association of hemoglobin with higher aVV could suggest the role of high hemoglobin in the higher incidence of adverse cardiovascular outcomes in CKD patients.