Federated learning for predicting histological response to neoadjuvant chemotherapy in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a rare cancer, characterized by high metastatic potential and poor prognosis, and has limited treatment options. The current standard of care in nonmetastatic settings is neoadjuvant chemotherapy (NACT), but treatment efficacy varies substantially across patients. This heterogeneity is still poorly understood, partly due to the paucity of curated TNBC data. Here we investigate the use of machine learning (ML) leveraging whole-slide images and clinical information to predict, at diagnosis, the histological response to NACT for early TNBC women patients. To overcome the biases of small-scale studies while respecting data privacy, we conducted a multicentric TNBC study using federated learning, in which patient data remain secured behind hospitals' firewalls. We show that local ML models relying on whole-slide images can predict response to NACT but that collaborative training of ML models further improves performance, on par with the best current approaches in which ML models are trained using time-consuming expert annotations. Our ML model is interpretable and is sensitive to specific histological patterns. This proof of concept study, in which federated learning is applied to real-world datasets, paves the way for future biomarker discovery using unprecedentedly large datasets.

How Can Digital Mental Health Enhance Psychiatry?

The use of digital technologies is constantly growing around the world. The wider-spread adoption of digital technologies and solutions in the daily clinical practice in psychiatry seems to be a question of when, not if. We propose a synthesis of the scientific literature on digital technologies in psychiatry and discuss the main aspects of its possible uses and interests in psychiatry according to three domains of influence that appeared to us: 1) assist and improve current care: digital psychiatry allows for more people to have access to care by simply being more accessible but also by being less stigmatized and more convenient; 2) develop new treatments: digital psychiatry allows for new treatments to be distributed via apps, and practical guidelines can reduce ethical challenges and increase the efficacy of digital tools; and 3) produce scientific and medical knowledge: digital technologies offer larger and more objective data collection, allowing for more detection and prevention of symptoms. Finally, ethical and efficacy issues remain, and some guidelines have been put forth on how to safely use these solutions and prepare for the future.

Lithium effects on serine-threonine kinases activity: High throughput kinomic profiling of lymphoblastoid cell lines from excellent-responders and non-responders bipolar patients.

Objectives: Lithium is the leading mood stabiliser for maintenance treatment in bipolar disorder (BD). However, response to lithium is heterogeneous with more than 60% of patients experiencing partial or no response. In vitro and in vivo molecular studies have reported the implication of kinases in the pathophysiology of BD.Methods: Since kinases are putative targets for lithium therapeutic action, we conducted the first pilot study using kinase array technology to evaluate the global serine/threonine kinases (STK) profiles in cell lines from BD I subtype patients classified as lithium excellent-responders (ER) and non-responder (NR) to lithium treatment.Results: We found significant differences in the basal STK profiles between ER and NR to lithium. We also tested lithium influence on the global STK profile and found no significant difference between ER vs NR cell lines.Conclusions: The results obtained in this exploratory study suggest that multiplex kinase activity profiling could provide a complementary approach in the study of biomarkers of therapeutic response in BD.

Lithium response in bipolar disorders and core clock genes expression.

OBJECTIVES: We examine whether the lithium response is associated with changes in the expression of core clock genes. METHODS: The effect of a therapeutic concentration of lithium (1 mM) on the expression levels of 17 circadian genes was examined in lymphoblastoid cell lines (LCLs) derived from two well-characterized groups of bipolar disorder patients, defined as lithium non-responders (NR, n = 20) or excellent responders (ER, n = 16). Quantitative real-time PCR (qRT-PCR) was conducted at 2, 4 and 8 days (d2, d4 and d8) with and without lithium exposure. RESULTS: At d2, in ER only, BHLHE41, RORA, PER1, ARNTL, CRY2, BHLHE40 and CSNK1D were upregulated, whereas NR1D1 was downregulated. At d4, in ER only, CRY1 was downregulated. At d8, in NR only, GSK3ß was upregulated and DBP, TIMELESS and CRY1 were downregulated. Significant Group × Lithium interactions existed for NR1D1 at d2 (P = 0.02), and CRY1 at d4 (P = 0.02). Longitudinal analyses showed differential temporal evolutions between NR and ER (significant Time × Group interaction) for PER3, NR1D1, DBP, RORA, CSNK1D and TIMELESS; and a significant Time × Lithium interaction for NR1D1. Coexpression data analyses suggested distinct groups of circadian genes concurrently modulated by lithium. CONCLUSIONS: In LCLs, lithium influences expression of circadian genes with differences in amplitude and kinetics according to the patient's lithium response status.

Lithium response in bipolar disorder: No difference in GADL1 gene expression between cell lines from excellent-responders and non-responders.

Previous association studies have shown mixed results between glutamic acid decarboxylase like-1 (GADL1) gene polymorphism and prophylactic lithium response in bipolar disorder (BD) patients. In the present study, GADL1 gene expression was investigated in regard to lithium response, using Alda scale, in lymphoblastoid cells (LCLs) of 36 Caucasian BD patients. No difference in GADL1 expression was observed among LCLs from excellent-responders, non-responders or controls. Furthermore, lithium did not induce significant changes in GADL1 expression levels after 4 or 8 days. These results did not support an association of GADL1 expression in the determination of a lithium response in BD patients.

Lithium and bipolar disorder: Impacts from molecular to behavioural circadian rhythms.

Bipolar disorder (BD) is a severe and common psychiatric disorder. BD pathogenesis, clinical manifestations and relapses are associated with numerous circadian rhythm abnormalities. Lithium (Li) is the first-line treatment in BD, and its therapeutic action has been related to its ability to alter circadian rhythms. We systematically searched the PubMed database until January 2016, aiming to critically examine published studies investigating direct and indirect effects of Li on circadian rhythms. The results, from the 95 retained studies, indicated that Li: acts directly on the molecular clocks; delays the phase of sleep-wakefulness rhythms and the peak elevation of diurnal cycle body temperature; reduces the amplitude and shortens the duration of activity rhythms and lengthens free-running rhythms. Chronic Li treatment stabilizes free-running activity rhythms, by improving day-to-day rhythmicity of the activity, with effects that appear to be dose related. Pharmacogenetics demonstrate several associations of Li's response with circadian genes (NR1D1, GSK3ß, CRY1, ARNTL, TIM, PER2). Finally, Li acts on the retinal-hypothalamic pineal pathway, influencing light sensitivity and melatonin secretion. Li is a highly investigated chronobiologic agent, and although its chronobiological effects are not completely understood, it seems highly likely that they constitute an inherent component of its therapeutic action in the treatment of mood disorders.

Influence of Mikania laevigata Extract over the Genotoxicity Induced by Alkylating Agents.

Medicinal plants are still widely used worldwide; yet for some species, little or no information is available concerning their biological activity, specially their genotoxic and antimutagenic potential. Mikania laevigata (Asteraceae) is a native plant from South America, and its extracts are largely used to treat respiratory complaints. The aim of the present work was then to evaluate, in vivo, the potential biological activity of M. laevigata on the genotoxicity induced by methyl methanesulfonate (MMS) and cyclophosphamide (CP), using the comet assay. Male CF1 mice were divided into groups of 5-6 animals, received by gavage 0.1 mL/10 g body wt of water, Mikania laevigata extract (MLE), MMS, and CP. Results showed that treatment with 200 mg/kg of the MLE previously to MMS and CP administration, respectively, reduced the damage index (DI) in 52% and 60%, when compared to DI at 24 h. Pretreatment also reduced the damage frequency (DF) in 56% (MMS) and 58% (CP), compared to DF at 24 h. MLE administration has been shown to protect mouse DNA from damage induced by alkylating agents; this corroborates to the biological activities of M. laevigata and points towards the need of plant compounds isolation to proceed with further studies.

Anti-hyperalgesic activity of corilagin, a tannin isolated from Phyllanthus niruri L. (Euphorbiaceae).

ETHNOPHARMACOLOGICAL RELEVANCE: Corilagin (ß-1-O-galloyl-3,6-(R)-hexahydroxydiphenoyl-D-glucose) is a tannin isolated from Phyllanthus niruri (Euphorbiaceae). This plant is well known for their therapeutic purposes to treat several diseases associated with dolorous process and are used in several ethno-medicines in tropical and subtropical countries. AIM OF THE STUDY: This study was designed to evaluate the anti-hyperalgesic activity of corilagin using chemically and thermally based nociception models in mice. MATERIALS AND METHODS: Corilagin was isolated from Phyllanthus niruri (Euphorbiaceae) by extraction and chromatographic procedures and the anti-hyperalgesic activity was evaluated by using writhing, formalin, capsaicin, glutamate and hot plate tests in mice. RESULTS: Corilagin presented activity in acetic acid model with the ID50 calculated value of 6.46 (3.09-13.51) being about 20.6 fold more potent than acetylsalicylic acid. It also exhibited activity against the first phase of formalin test with ID50 value of 18.38 (15.15-22.59) µmol/kg. In the capsaicin and glutamate models, corilagin demonstrated significant activity at the 3 mg/kg. CONCLUSION: The experimental data demonstrated that corilagin exhibits anti-hyperalgesic activity that may be due to interaction with the glutamatergic system.

Epidemiologic and clinical characteristics of pregnant women living with HIV/AIDS in a region of Southern Brazil where the subtype C of HIV-1 infection predominates.

UNLABELLED: Southern Brazil has the highest prevalence rate of AIDS in the country and is the only region in the Americas where HIV-1 subtype C prevails. OBJECTIVE: We evaluated the epidemiologic and clinical characteristics of pregnant women living with HIV/AIDS in the South region of Santa Catarina, Brazil. METHODS: All pregnant women with HIV infection attending the obstetric outpatient clinic of Criciúma, State of Santa Catarina, in 2007 (n = 46) were invited to participate. Data of 36 eligible participants were obtained through a standardized questionnaire. RESULTS: The great majority were young, with a steady partner, low family income, low education level and referring early first sexual intercourse. Many reported use of illicit non-injecting drugs (55.5%) and unprotected sex with partners that were HIV-positive (57.7%), injecting drug user (22.2%), male inmate (19.4%), truck driver (13.8%), with history of sexually transmitted disease (11.1%) or men who have sex with men (MSM) (2.8%). Most (66.7%) of the participants had their HIV diagnosis done during the pregnancy, 7 (19.4%) had a previous history of HIV mother-to-child transmission. Therapy based on highly active antiretroviral therapy (94%) was initiated at 19.3 weeks on average and 33% showed irregular antiretroviral adherence. CONCLUSION: These results confirm previous data on HIV epidemiology in Brazil and suggest that the women partners' sexual behavior and unprotected sexual intercourse are important aspects of HIV epidemic. Additional efforts in education, prophylaxis and medication adherence are needed.

Perfil dos efeitos adversos e contra indicações dos fármacos moduladores do apetite: uma revisão sistemática / Side effects and contraindications of anti-obesity drugs: a systematic review

Anti-obesity drugs such as mazindol and beta-phenylethylamine derivatives induce their therapeutic effects by inhibiting noradrenaline and dopamine reuptake. In the hypothalamus, noradrenaline and dopamine play an important role in the control of appetite. Sibutramine reduces food intake due to a mechanism of action discretely distinct from beta-phenylethylamine products. In fact, this drug also decreases serotonin reuptake, which is a neurotransmitter quite related to satiety. Rimonabant was considered anovelty on the treatment of obesity, mainly due to its quite new mechanism of action, which is based on the blockade of CB1 receptors. Thus, considering a recent increase in the consumption of such anti-obesity drugs, this study aimed to perform a systematic review about the safety of these drugs. Based on literature, this study concluded that beta-phenylethylaminic drugs and mazindol show many side effects, mainly due to the activation of the sympathetic system (i.e. cardiovascular and gastrointestinal effects, and also central side effects, such as anxiety, and insomnia). Despite sibutramine is well tolerated by patients, clinical studies show that this drugis able to evoke similar sympathetic central and peripheral effects. Regarding rimonabant, the clinical use of this drug was linked to an increase in the incidence of major depression. In conclusion, despite most of the side effects evoked by anti-obesity drugs are classified as of low to moderate intensity, physicians must be aware of such effects upon prescription. In addition, they have to pay attention to the contraindications of such anti-obesity drugs in order to avoid health complications.

Los fármacos antiobesidad tales como el mazindoly los derivados de la beta-feniletilamina actúan inhibiendo la recaptación de la noradrenalinay de la dopamina, neurotransmisores que en el hipotálamo desenvuelven papel importante en el control del apetito. La sibutramina presenta mecanismo de acción discretamente diferente porque disminuye también la recaptación deserotonina, lo cual es positivo porque la activación del sistema serotoninérgico provoca saciedad. El rimonabanto surgió como una novedad para el tratamiento de la obesidad debido a su mecanismo de acción por medio del bloqueo de receptores cannabinoides CB1. Así, considerando el uso creciente y indiscriminado de moduladores del apetito este estudio tiene como principal objetivo realizar una revisión sistemática de la literatura sobre los efectos adversos de estos fármacos. De acuerdo con la literatura, este estudio concluyó que los fármacos beta-feniletilamínicos y el mazindol provocan varios efectos adversos derivados dela activación del sistema simpático, como sonlos efectos gastrointestinales y cardiovasculares, además de algunos efectos secundarios centrales, tales como ansiedad e insomnio. A pesar de la sibutramina ser mejor tolerada por los pacientes, los estudios clínicos muestran que este fármaco es responsable de varios efectos centrales y periféricos simpáticos. Con relación al rimonabanto, a pesar de la expectativa en relación a su mecanismo de acción innovador, su uso clínico demostró efectos adversos graves, como una depresión mayor. Enconclusión, aun cuando la mayor parte de los efectos secundarios provocados por los fármacos anti-obesidad fueron clasificados como de bajao moderada intensidad, los médicos deben estar conscientes de tales efectos secundarios en el momento de la prescripción de un fármaco anorexígeno. Además, deben estar atentos a las contra indicaciones de los tratamientos para la obesidad, a fin de evitar complicaciones mayores.

Fármacos anorexígenos como o mazindole os derivados da beta-feniletilamina ageminibindo a recaptação de noradrenalina edopamina, cujos neuro transmissores estão envolvidos em nível hipotalâmico no controle do apetite. A sibutramina possui mecanismo de ação ligeiramente diverso, pois também inibe a recaptação de serotonina, sendo um ponto positivo, visto que a ativação do sistema serotoninérgico promove a saciedade. O rimonabanto despontou como uma novidade no tratamento da obesidade, graças ao seu mecanismo de ação baseado no bloqueio de receptores canabinoides CB1. Considerando o uso crescente e indiscriminado de moduladores do apetite, o presente estudo visa fazer uma revisão sistemática da literatura sobre os efeitos adversos e as contraindicações do uso desses fármacos. Com base na literatura, este estudo concluiu que os fármacos beta-feniletilamínicos e o mazindol apresentam muitos efeitos adversos decorrentes da ativação do sistema simpático, como distúrbios gastrintestinais e cardiovasculares, além de alguns efeitos centrais, como ansiedade e insônia. Apesar de a sibutramina ser mais bem tolerada, os estudos clínicos mostram que este fármaco é também responsável por sintomas relacionados à ativação simpática periférica e a estimulação do sistema nervoso central. O rimonabanto, apesar das expectativas com relação ao seu mecanismo de ação inovador, mostrou efeitos adversos graves, como depressão maior. Em conclusão, muito embora os efeitos adversos fossem considerados de intensidade leve ou moderada, o médico precisa ter em mente tais situações no momento da prescrição de um fármaco anorexígeno. Além disso, deve estaratento às contraindicações dos tratamentos para obesidade, a fim de evitar maiores complicações.

Epidemiologic and clinical characteristics of pregnant women living with HIV/AIDS in a region of Southern Brazil where the subtype C of HIV-1 infection predominates

Southern Brazil has the highest prevalence rate of AIDS in the country and is the only region in the Americas where HIV-1 subtype C prevails. OBJECTIVE: We evaluated the epidemiologic and clinical characteristics of pregnant women living with HIV/AIDS in the South region of Santa Catarina, Brazil. METHODS: All pregnant women with HIV infection attending the obstetric outpatient clinic of Criciúma, State of Santa Catarina, in 2007 (n = 46) were invited to participate. Data of 36 eligible participants were obtained through a standardized questionnaire. RESULTS: The great majority were young, with a steady partner, low family income, low education level and referring early first sexual intercourse. Many reported use of illicit non-injecting drugs (55.5 percent) and unprotected sex with partners that were HIV-positive (57.7 percent), injecting drug user (22.2 percent), male inmate (19.4 percent), truck driver (13.8 percent), with history of sexually transmitted disease (11.1 percent) or men who have sex with men (MSM) (2.8 percent). Most (66.7 percent) of the participants had their HIV diagnosis done during the pregnancy, 7 (19.4 percent) had a previous history of HIV mother-to-child transmission. Therapy based on highly active antiretroviral therapy (94 percent) was initiated at 19.3 weeks on average and 33 percent showed irregular antiretroviral adherence. CONCLUSION: These results confirm previous data on HIV epidemiology in Brazil and suggest that the women partners' sexual behavior and unprotected sexual intercourse are important aspects of HIV epidemic. Additional efforts in education, prophylaxis and medication adherence are needed.

Evaluation of the genotoxic and antigenotoxic potential of Melissa officinalis in mice.

Melissa officinalis (L.) (Lamiaceae), a plant known as the lemon balm, is native to the east Mediterranean region and west Asia. Also found in tropical countries, such as Brazil, where it is popularly known as "erva-cidreira" or "melissa", it is widely used in aqueous- or alcoholic-extract form in the treatment of various disorders. The aim was to investigate in vivo its antigenotoxicity and antimutagenicity, as well as its genotoxic/mutagenic potential through comet and micronucleus assaying. CF-1 male mice were treated with ethanolic (Mo-EE) (250 or 500 mg/kg) or aqueous (Mo-AE) (100 mg/kg) solutions of an M. officinalis extract for 2 weeks, prior to treatment with saline or Methyl methanesulfonate (MMS) doses by intraperitoneal injection. Irrespective of the doses, no genotoxic or mutagenic effects were observed in blood and bone-marrow samples. Although Mo-EE exerted an antigenotoxic effect on the blood cells of mice treated with the alkylating agent (MMS) in all the doses, this was not so with Mo-AE. Micronucleus testing revealed the protector effect of Mo-EE, but only when administered at the highest dose. The implication that an ethanolic extract of M. officinalis has antigenotoxic/antimutagenic properties is an indication of its medicinal relevance.

Non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine inhibit cytochrome C oxidase in mouse brain regions.

The highly active antiretroviral therapy completely changed the clinical evolution of HIV infection, reducing the morbidity and mortality among human immunodeficiency virus (HIV)-1 infected patients. Therefore, in the present study we evaluated the effect of chronic efavirenz (EFV) and nevirapine (NVP) administration on mitochondrial respiratory chain complexes activities (I, II, II-III, IV) in different brain regions of mice. Mice were orally administered via gavage with EFV 10 mg/kg, NVP 3.3 mg/kg or vehicle (controls) once a day for 36 days. We observed that the complex IV activity was inhibited by both EFV and NVP in cerebral cortex, striatum and hippocampus of mice, but not in cerebellum, as compared to control group. In contrast, chronic EFV and NVP administration did not alter complexes I, II and II-III. We speculated that brain energy metabolism dysfunction could be involved in the CNS-related adverse effects.

Anti-HIV drugs nevirapine and efavirenz affect anxiety-related behavior and cognitive performance in mice.

Nevirapine (NVP) and efavirenz (EFV) belong to the class of anti-HIV drugs called non-nucleoside reverse transcriptase inhibitors (NNRTIs), commonly used as part of highly active antiretroviral therapy (HAART). Although the HAART is able to bring down viral load to undetectable levels and restore immune function, their prolonged use causes several adverse effects. It has been demonstrated that both NVP and EFV are able to cross the blood-brain barrier, causing important central nervous system-related side effects. Thus, this study investigated the effects of chronic administration of EFV (10 mg/kg) and NVP (3.3 mg/kg) in mice submitted to two distinct series of experiments, which aimed to evaluate: (1) the emotional behavior (elevated plus-maze, forced swimming, and open-field test) and (2) the cognitive performance (object recognition and inhibitory avoidance test) of mice. Our results demonstrated that EFV, but not NVP, reduced the exploration to open arms in the elevated plus-maze test. Neither NVP nor EFV altered mouse behavior in the forced swimming and open-field tests. Both drugs reduced the recognition index in the object recognition test, but only EFV significantly impaired the aversive memory assessed in the inhibitory avoidance test 24 h after training. In conclusion, our findings point to a genuine anxiogenic-like effect to EFV, since it reduced exploration to open arms of elevated plus-maze test without affecting spontaneous locomotion. Additionally, both drugs impaired recognition memory, while only the treatment with EFV impaired significantly aversive memory.

Evaluation of the genotoxic and antigenotoxic potential of Melissa officinalis in mice

Melissa officinalis (L.) (Lamiaceae), a plant known as the lemon balm, is native to the east Mediterranean region and west Asia. Also found in tropical countries, such as Brazil, where it is popularly known as "erva-cidreira" or "melissa", it is widely used in aqueous- or alcoholic-extract form in the treatment of various disorders. The aim was to investigate in vivo its antigenotoxicity and antimutagenicity, as well as its genotoxic/mutagenic potential through comet and micronucleus assaying. CF-1 male mice were treated with ethanolic (Mo-EE) (250 or 500 mg/kg) or aqueous (Mo-AE) (100 mg/kg) solutions of an M. officinalis extract for 2 weeks, prior to treatment with saline or Methyl methanesulfonate (MMS) doses by intraperitoneal injection. Irrespective of the doses, no genotoxic or mutagenic effects were observed in blood and bone-marrow samples. Although Mo-EE exerted an antigenotoxic effect on the blood cells of mice treated with the alkylating agent (MMS) in all the doses, this was not so with Mo-AE. Micronucleus testing revealed the protector effect of Mo-EE, but only when administered at the highest dose. The implication that an ethanolic extract of M. officinalis has antigenotoxic/antimutagenic properties is an indication of its medicinal relevance.

Effects of the HIV treatment drugs nevirapine and efavirenz on brain creatine kinase activity.

Nevirapine (NVP) and efavirenz (EFV) are antiretroviral drugs belonging to potent class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) widely used for the treatment human immunodeficiency virus (HIV) infection. It has been demonstrated that NVP and EFV are able to cross the blood-brain barrier and arrive at the central nervous system (CNS), causing important adverse effects related to their presence within this tissue. Considering that the exact mechanisms responsible for CNS toxicity associated with NVP and EFV remain unknown and that creatine kinase (CK) plays an important role in cell energy homeostasis, in the present work we evaluated CK activity in brain of mice after chronic administration of these drugs. Our results demonstrated that NVP and EFV significantly inhibited CK activity in cerebellum, hippocampus, striatum and cortex of mice. Although it is difficult to extrapolate our findings to the human condition, the inhibition of brain CK activity by NVP and EFV may be associated with neurological adverse symptoms of these drugs.