Machine learning algorithms using national registry data to predict loss to follow-up during tuberculosis treatment.

BACKGROUND: Identifying patients at increased risk of loss to follow-up (LTFU) is key to developing strategies to optimize the clinical management of tuberculosis (TB). The use of national registry data in prediction models may be a useful tool to inform healthcare workers about risk of LTFU. Here we developed a score to predict the risk of LTFU during anti-TB treatment (ATT) in a nationwide cohort of cases using clinical data reported to the Brazilian Notifiable Disease Information System (SINAN). METHODS: We performed a retrospective study of all TB cases reported to SINAN between 2015 and 2022; excluding children (< 18 years-old), vulnerable groups or drug-resistant TB. For the score, data before treatment initiation were used. We trained and internally validated three different prediction scoring systems, based on Logistic Regression, Random Forest, and Light Gradient Boosting. Before applying our models we splitted our data into training (~ 80% data) and test (~ 20%) sets, and then compared the model metrics using the test data set. RESULTS: Of the 243,726 cases included, 41,373 experienced LTFU whereas 202,353 were successfully treated. The groups were different with regards to several clinical and sociodemographic characteristics. The directly observed treatment (DOT) was unbalanced between the groups with lower prevalence in those who were LTFU. Three models were developed to predict LTFU using 8 features (prior TB, drug use, age, sex, HIV infection and schooling level) with different score composition approaches. Those prediction scoring systems exhibited an area under the curve (AUC) ranging between 0.71 and 0.72. The Light Gradient Boosting technique resulted in the best prediction performance, weighting specificity and sensitivity. A user-friendly web calculator app was developed ( https://tbprediction.herokuapp.com/ ) to facilitate implementation. CONCLUSIONS: Our nationwide risk score predicts the risk of LTFU during ATT in Brazilian adults prior to treatment commencement utilizing schooling level, sex, age, prior TB status, and substance use (drug, alcohol, and/or tobacco). This is a potential tool to assist in decision-making strategies to guide resource allocation, DOT indications, and improve TB treatment adherence.

Exploring Darunavir, Rilpivirine and Etravirine as Potential Therapies for Bladder Cancer: Efficacy and Synergistic Effects.

This research explores the therapeutic efficacy of Darunavir (DRV), Rilpivirine (RPV), and Etravirine (ETV) against UM-UC-5 bladder cancer cells, addressing the critical need for innovative treatments in bladder cancer research. Through a comprehensive assessment of their individual and combined effects across diverse time intervals, ETV emerges as the most potent drug, with a lowest IC50 of 5.9 µM, closely followed by RPV (lowest IC50 of 9.6 µM), while DRV exhibits the least effectiveness (lowest IC50 of 25.6 µM). Notably, a significant synergistic effect is evident in the ETV and RPV combination, especially at 48 and 72 h for low concentrations. Synergies are also observed with ETV and DRV, albeit to a lesser extent and primarily at 48 h. Conversely, the DRV and RPV combination yields minimal effects, predominantly additive in nature. In summary, this pre-clinical investigation underscores the promising therapeutic potential of ETV and RPV, both as standalone treatments and in combination, hinting at repurposing opportunities in bladder cancer therapy, which could give a new treatment method for this disease that is faster and without as severe side effects as anticancer drugs. These findings represent a substantial stride in advancing personalized medicine within cancer research and will be further scrutinized in forthcoming studies.

Evaluation of the Antiproliferative Potential of Yellow Jaboticaba (Myrciaria glazioviana) Extracts Against Human Cervical Cancer (HeLa cells line) and the Analysis of Their Chemical Composition by HPLC-HRESIMS.

Cervical cancer is a specific type of cancer that affects women around the world, with an incidence of 604 thousand new cases per year and 341 thousand deaths. There is a high demand for new effective antineoplastic drugs with few side effects. In this sense, recent research highlights the potential of compounds of natural origin in treating and preventing different types of cancer. Myrciaria glazioviana is a Brazilian native species belonging to the Myrtaceae family, which has previously described biological activities such as antimicrobial, anti-inflammatory, and antioxidant properties. This study aims to evaluate the anticancer activity of the dichloromethane extract (MGD) and ethyl acetate extract (MGA) of M. glazioviana leaves against human cervical cancer cell line (HeLa), as well as to identify their bioactive compounds. Using HPLC-HRESIMS technique, ten compounds were characterized in both samples: quinic acid, ellagic acid, Tri-O-methyl ellagic acid, two derivatives of Tetra-O-methyl flavellagic acid, quercetrin, Di-O-methyl ellagic acid, and three derivatives of pentamethyl coruleoellagic acid. Through MTT assays using HeLa cells and NIH/3T3 cells, it was observed that MGD and MGA were selective against tumor cells, with IC50 values of 24.31 and 12.62 µg/mL, respectively. The samples induced the tumor cell death by apoptosis, as evidenced by the activation of caspases 3/7, cell shrinkage, and pyknotic nuclei. Both samples were also able to inhibit the migration of HeLa cells after 24 hours of treatment, indicating a potential antimetastatic effect. Therefore, the present research highlights the antiproliferative and antimigratory potential of this species against HeLa cells.

Cisplatin Toxicity Causes Neutrophil-Mediated Inflammation in Zebrafish Larvae.

Cisplatin is an antineoplastic agent used to treat various tumors. In mammals, it can cause nephrotoxicity, tissue damage, and inflammation. The release of inflammatory mediators leads to the recruitment and infiltration of immune cells, particularly neutrophils, at the site of inflammation. Cisplatin is often used as an inducer of acute kidney injury (AKI) in experimental models, including zebrafish (Danio rerio), due to its accumulation in kidney cells. Current protocols in larval zebrafish focus on studying its effect as an AKI inducer but ignore other systematic outcomes. In this study, cisplatin was added directly to the embryonic medium to assess its toxicity and impact on systemic inflammation using locomotor activity analysis, qPCR, microscopy, and flow cytometry. Our data showed that larvae exposed to cisplatin at 7 days post-fertilization (dpf) displayed dose-dependent mortality and morphological changes, leading to a decrease in locomotion speed at 9 dpf. The expression of pro-inflammatory cytokines such as interleukin (il)-12, il6, and il8 increased after 48 h of cisplatin exposure. Furthermore, while a decrease in the number of neutrophils was observed in the glomerular region of the pronephros, there was an increase in neutrophils throughout the entire animal after 48 h of cisplatin exposure. We demonstrate that cisplatin can have systemic effects in zebrafish larvae, including morphological and locomotory defects, increased inflammatory cytokines, and migration of neutrophils from the hematopoietic niche to other parts of the body. Therefore, this protocol can be used to induce systemic inflammation in zebrafish larvae for studying new therapies or mechanisms of action involving neutrophils.

Severe combined immunodeficiency diagnosis and genetic defects.

Severe combined immunodeficiency (SCID) is a rare and life-threatening genetic disorder that severely impairs the immune system's ability to defend the body against infections. Often referred to as the "bubble boy" disease, SCID gained widespread recognition due to the case of David Vetter, a young boy who lived in a sterile plastic bubble to protect him from germs. SCID is typically present at birth, and it results from genetic mutations that affect the development and function of immune cells, particularly T cells and B cells. These immune cells are essential for identifying and fighting off infections caused by viruses, bacteria, and fungi. In SCID patients, the immune system is virtually non-existent, leaving them highly susceptible to recurrent, severe infections. There are several forms of SCID, with varying degrees of severity, but all share common features. Newborns with SCID often exhibit symptoms such as chronic diarrhea, thrush, skin rashes, and persistent infections that do not respond to standard treatments. Without prompt diagnosis and intervention, SCID can lead to life-threatening complications and a high risk of mortality. There are over 20 possible affected genes. Treatment options for SCID primarily involve immune reconstitution, with the most well-known approach being hematopoietic stem cell transplantation (HSCT). Alternatively, gene therapy is also available for some forms of SCID. Once treated successfully, SCID patients can lead relatively normal lives, but they may still require vigilant infection control measures and lifelong medical follow-up to manage potential complications. In conclusion, severe combined immunodeficiency is a rare but life-threatening genetic disorder that severely compromises the immune system's function, rendering affected individuals highly vulnerable to infections. Early diagnosis and appropriate treatment are fundamental. With this respect, newborn screening is progressively and dramatically improving the prognosis of SCID.

A low-anticoagulant heparin suppresses metastatic dissemination through the inhibition of tumor cell-platelets association.

Metastasis is the leading cause of cancer-related deaths. Despite this relevance, there is no specific therapy targeting metastasis. The interaction of the tumor cell with platelets, forming microemboli is crucial for successful hematogenous dissemination. Heparin disrupts it by a P-selectin-mediated event. However, its clinical use for this purpose is hindered by the requirement of high doses, leading to anticoagulant-related side effects. In this study, we obtained a low-anticoagulant heparin through the fractionation of a pharmaceutical bovine heparin. This derivative was referred to as LA-hep and we investigated its efficacy in inhibiting metastases and explored its capacity of suppressing the interaction between tumor cells and platelets. Our data revealed that LA-hep is as efficient as porcine unfractionated heparin in attenuating lung metastases from melanoma and colon adenocarcinoma cells in an assay with a single intravenous administration. It also prevents platelet arrest shortly after cell injection in wild-type mice and suppresses melanoma-platelets interaction in vitro. Moreover, LA-hep blocks P-selectin's direct binding to tumor cells and platelet aggregation, providing further evidence for the role of P-selectin as a molecular target. Even in P-selectin-depleted mice which developed a reduced number of metastatic foci, both porcine heparin and LA-hep further inhibited metastasis burden. This suggests evidence of an additional mechanism of antimetastatic action. Therefore, our results indicate a dissociation between the heparin anticoagulant and antimetastatic effects. Considering the simple and highly reproducible methodology used to purify LA-hep along with the data presented here, LA-hep emerges as a promising drug for future use in preventing metastasis in cancer patients.

Approaches of marine compounds and relevant immune mediators in Autism Spectrum Disorder: Opportunities and challenges.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that affects social skills, language, communication, and behavioral skills, significantly impacting the individual's quality of life. Recently, numerous works have centered on the connections between the immune and central nervous systems and the influence of neuroinflammation on autism symptomatology. Marine natural products are considered as important alternative sources of different types of compounds, including polysaccharides, polyphenols, sterols, carotenoids, terpenoids and, alkaloids. These compounds present anti-inflammatory, neuroprotective and immunomodulatory activities, exhibiting a potential for the treatment of many diseases. Although many studies address the marine compounds in the modulation of inflammatory mediators, there is a gap regarding their use in the regulation of the immune system in ASD. Thus, this review aims to provide a better understanding regarding cytokines, chemokines, growth factors and immune responses in ASD, as well as the potential of bioactive marine compounds in the immune regulation in ASD. We expect that this review would contribute to the development of therapeutic alternatives for controlling immune mediators and inflammation in ASD.

The Xpert® MTB/RIF cycle threshold value predicts M. tuberculosis transmission to close contacts in a Brazilian prospective multicenter cohort.

BACKGROUND: The Xpert® MTB/RIF rapid molecular test provides a quantitative measure of Mycobacterium tuberculosis (Mtb) DNA in the form of cycle threshold (Ct) values. This information can be translated into mycobacterial load and used as a potential risk measure of bacterial spread for tuberculosis cases, which can impact infection control. However, the role of Ct values in assessing Mtb transmission to close contacts has not yet been demonstrated. METHODS: A prospective study was performed to investigate the association between Xpert® MTB/RIF Ct values and Mtb transmission to close contacts of patients with culture-confirmed pulmonary TB in a multi-center Brazilian cohort. We evaluated clinical and laboratory data, such as age, sex, race, smoking habits, drug use, alcohol use, chest radiograph, Xpert® MTB/RIF results among pulmonary tuberculosis cases, and QuantiFERON(QFT)-Plus results at baseline and after six months for close contacts who had a negative result at baseline. RESULTS: A total of 1,055 close contacts of 382 pulmonary tuberculosis cases were included in the study. The median Ct values from pulmonary tuberculosis cases of QFT-Plus positive (at baseline or six months) close contacts were lower compared with those who were QFT-Plus negative. An adjusted logistic regression demonstrated that reduced Ct values from the index cases were independently associated with QFT-Plus conversion from negative to positive (OR: 1.61, 95% CI: 1.12-2.32) after adjusting for clinical characteristics. CONCLUSION: Close contacts of pulmonary TB index cases exhibiting low Xpert MTB/RIF Ct values displayed higher rates of TB infection, reflecting Mtb transmission.

TP53-mutated acute myeloid leukemia and myelodysplastic syndrome: biology, treatment challenges, and upcoming approaches.

Improved understanding of TP53 biology and the clinicopathological features of TP53-mutated myeloid neoplasms has led to the recognition of TP53-mutated acute myeloid leukemia/myelodysplastic syndrome (TP53m AML/MDS) as a unique entity, characterized by dismal outcomes following conventional therapies. Several clinical trials have investigated combinations of emerging therapies for these patients with the poorest molecular prognosis among myeloid neoplasms. Although some emerging therapies have shown improvement in overall response rates, this has not translated into better overall survival, hence the notion that p53 remains an elusive target. New therapeutic strategies, including novel targeted therapies, immune checkpoint inhibitors, and monoclonal antibodies, represent a shift away from cytotoxic and hypomethylating-based therapies, towards approaches combining non-immune and novel immune therapeutic strategies. The triple combination of azacitidine and venetoclax with either magrolimab or eprenetapopt have demonstrated safety in early trials, with phase III trials currently underway, and promising interim clinical results. This review compiles background on TP53 biology, available and emerging therapies along with their mechanisms of action for the TP53m disease entity, current treatment challenges, and recently published data and status of ongoing clinical trials for TP53m AML/MDS.

Decoding the Influence of Obesity on Prostate Cancer and Its Transgenerational Impact.

In recent decades, the escalating prevalence of metabolic disorders, notably obesity and being overweight, has emerged as a pressing concern in public health. Projections for the future indicate a continual upward trajectory in obesity rates, primarily attributable to unhealthy dietary patterns and sedentary lifestyles. The ramifications of obesity extend beyond its visible manifestations, intricately weaving a web of hormonal dysregulation, chronic inflammation, and oxidative stress. This nexus of factors holds particular significance in the context of carcinogenesis, notably in the case of prostate cancer (PCa), which is a pervasive malignancy and a leading cause of mortality among men. A compelling hypothesis arises from the perspective of transgenerational inheritance, wherein genetic and epigenetic imprints associated with obesity may wield influence over the development of PCa. This review proposes a comprehensive exploration of the nuanced mechanisms through which obesity disrupts prostate homeostasis and serves as a catalyst for PCa initiation. Additionally, it delves into the intriguing interplay between the transgenerational transmission of both obesity-related traits and the predisposition to PCa. Drawing insights from a spectrum of sources, ranging from in vitro and animal model research to human studies, this review endeavors to discuss the intricate connections between obesity and PCa. However, the landscape remains partially obscured as the current state of knowledge unveils only fragments of the complex mechanisms linking these phenomena. As research advances, unraveling the associated factors and underlying mechanisms promises to unveil novel avenues for understanding and potentially mitigating the nexus between obesity and the development of PCa.

An approach to generate synthetic 4DCT datasets to benchmark Mid-Position implementations.

PURPOSE: The Mid-Position image is constructed from 4DCT data using Deformable Image Registration and can be used as planning CT with reduced PTV volumes. 4DCT datasets currently-available for testing do not provide the corresponding Mid-P images of the datasets. This work describes an approach to generate human-like synthetic 4DCT datasets with the associated Mid-P images that can be used as reference in the validation of Mid-P implementations. METHODS: Twenty synthetic 4DCT datasets with the associated reference Mid-P images were generated from twenty clinical 4DCT datasets. Per clinical dataset, an anchor phase was registered to the remaining nine phases to obtain nine Deformable Vector Fields (DVFs). These DVFs were used to warp the anchor phase in order to generate the synthetic 4DCT dataset and the corresponding reference Mid-P image. Similarly, a reference 4D tumor mask dataset and its corresponding Mid-P tumor mask were generated. The generated synthetic datasets and masks were used to compare and benchmark the outcomes of three independent Mid-P implementations using a set of experiments. RESULTS: The Mid-P images constructed by the three implementations showed high similarity scores when compared to the reference Mid-P images except for one noisy dataset. The biggest difference in the estimated motion amplitudes (-2.6 mm) was noticed in the Superior-Inferior direction. The statistical analysis showed no significant differences among the three implementations for all experiments. CONCLUSION: The described approach and the proposed experiments provide an independent method that can be used in the validation of any Mid-P implementation being developed.

Acute myeloid leukaemia relapse after allogeneic haematopoietic stem cell transplantation: Mechanistic diversity and therapeutic directions.

Emerging biological and clinical data, along with advances in new technologies, have exposed the mechanistic diversity in post-haematopoietic stem cell transplant (HCT) relapse. Post-HCT relapse mechanisms are relevant for guiding sophisticated selection of therapeutic interventions and identification of areas for further research. Clonal evolution and emergence of resistant leukemic strains is a common mechanism shared by relapse post-chemotherapy and post-HCT, other mechanisms such as leukemic immune escape and donor T cell exhaustion are unique entities to post-HCT relapse. Due to diversity in the mechanisms behind post-HCT relapse, the subsequent clinical approach relies on clinician discretion, rather than objective evidence. Lack of standardized selection based on post-HCT relapse mechanism(s) could be a contributing factor to observed poor outcomes. Therapeutic strategies including donor lymphocyte infusion (DLI), second transplant, immunotherapies, hypomethylating agents, and targeted strategies are supported options and efficacy may be enhanced when post-HCT AML relapse mechanism is established and guides treatment selection. This review aims, through compilation of supporting studies, to describe mechanisms of post-HCT relapse and their implications for subsequent treatment selection and inspiration for future research.

Systemic Inflammatory Disorders, Immunosuppressive Treatment and Increase Risk of Head and Neck Cancers-A Narrative Review of Potential Physiopathological and Biological Mechanisms.

Head and neck cancers (HNCs) are known to present multiple factors likely to influence their development. This review aims to provide a comprehensive overview of the current scientific literature on the interplay between systemic inflammatory disorders, immunosuppressive treatments and their synergistic effect on HNC risk. Both cell-mediated and humoral-mediated systemic inflammatory disorders involve dysregulated immune responses and chronic inflammation and these inflammatory conditions have been associated with an increased risk of HNC development, primarily in the head and neck region. Likewise, the interaction between systemic inflammatory disorders and immunosuppressive treatments appears to amplify the risk of HNC development, as chronic inflammation fosters a tumor-promoting microenvironment, while immunosuppressive therapies further compromise immune surveillance and anti-tumor immune responses. Understanding the molecular and cellular mechanisms underlying this interaction is crucial for developing targeted prevention strategies and therapeutic interventions. Additionally, the emerging field of immunotherapy provides potential avenues for managing HNCs associated with systemic inflammatory disorders, but further research is needed to determine its efficacy and safety in this specific context. Future studies are warranted to elucidate the underlying mechanisms and optimize preventive strategies and therapeutic interventions.

Choosing Between Older Matched Sibling Donor and Younger Matched Unrelated Donor in Allogeneic Hematopoietic Cell Transplantation: Comparison of Clinical Outcomes in Acute Myeloid Leukemia and Myelodysplastic Syndrome.

The choice between an older matched sibling donor (MSD) and a younger matched unrelated donor (MUD) in allogeneic hematopoietic cell transplantation (HCT) remains a subject of ongoing debate. In this single-center retrospective study of 377 patients who received peripheral blood stem cell (PBSC) transplants for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), we compared outcomes of 85 patients who received grafts from MSDs age >60 years and 292 patients who received grafts from MUDs age <30 years. Compared to recipients of MSD transplants, recipients of MUD transplants were younger and more likely to receive dual T cell depletion (TCD), a higher CD34+ cell dose, and a fresh graft. Recipients of MSD transplants were maintained on immunosuppressive therapy longer than those who received MUD grafts. We found no differences in overall survival, relapse-free survival, graft-versus-host disease (GVHD)-free and relapse-free survival, nonrelapse mortality, relapse, engraftment, graft failure, and acute GVHD between recipients of MSD grafts and recipients of MUD grafts. We report a higher 30-day incidence, but not 1-year incidence, of bloodstream infections among recipients of MUD transplants compared to subjects who received their grafts from a MSD. The incidence of moderate-severe chronic GVHD was higher in MSD graft recipients compared with MUD graft recipients in univariate analysis, but not in multivariate analysis. Although this difference could reflect the greater use of dual TCD, known to be associated with very low rates of chronic GVHD in MUD transplant recipients, the incidence of moderate-severe chronic GVHD was no different between MSD and MUD transplant recipients following propensity score matching, suggesting that other variables could be responsible. Taken together, our data suggest that in patients with AML or MDS who receive PBSC transplants, such factors as convenience, ease of access, and costs should be considered when selecting an older MSD over a younger MUD.

Milk kefir alters fecal microbiota impacting gut and brain health in mice.

Kefir is a fermented beverage made of a symbiotic microbial community that stands out for health benefits. Although its microbial profile is still little explored, its effects on modulation of gut microbiota and production of short-chain fatty acids (SCFAs) seems to act by improving brain health. This work aimed to analyze the microbiota profile of milk kefir and its effect on metabolism, oxidative stress, and in the microbiota-gut-brain axis in a murine model. The experimental design was carried out using C57BL-6 mice (n = 20) subdivided into groups that received 0.1 mL water or 0.1 mL (10% w/v) kefir. The kefir proceeded to maturation for 48 h, and then it was orally administered, via gavage, to the animals for 4 weeks. Physicochemical, microbiological, antioxidant analyzes, and microbial profiling of milk kefir beverage were performed as well as growth parameters, food intake, serum markers, oxidative stress, antioxidant enzymes, SCFAs, and metabarcoding were analyzed in the mice. Milk kefir had 76.64 ± 0.42% of free radical scavenging and the microbiota composed primarily by the genus Comamonas. Moreover, kefir increased catalase and superoxide dismutase (colon), and SCFAs in feces (butyrate), and in the brain (butyrate and propionate). Kefir reduced triglycerides, uric acid, and affected the microbiome of animals increasing fecal butyrate-producing bacteria (Lachnospiraceae and Lachnoclostridium). Our results on the brain and fecal SCFAs and the antioxidant effect found were associated with the change in the gut microbiota caused by kefir, which indicates that kefir positively influences the gut-microbiota-brain axis and contributes to the preservation of gut and brain health. KEY POINTS: • Milk kefir modulates fecal microbiota and SCFA production in brain and colon. • Kefir treatment increases the abundance of SCFA-producing bacteria. • Milk kefir increases antioxidant enzymes and influences the metabolism of mice.

Impact of waitlist time on post-HSCT survival: a cohort study at a hospital in southern Brazil.

INTRODUCTION: The time elapsed from diagnosis to hematopoietic stem cell transplantation (HSCT) is influenced by numerous factors. In Brazil, patients using the public health system are also dependent on the availability of HSCT-specific beds in the hematology ward. OBJECTIVE AND METHODS: We conducted a cohort study of listed patients who underwent allogeneic HSCT at a Brazilian public hospital to investigate the impact of the waitlist time on post-HSCT survival. RESULTS: The median time from diagnosis to HSCT was 19 months (IQR, 10 - 43), of which 6 months (IQR, 3 - 9) were spent on the waitlist. The time on the waitlist for HSCT appeared to influence mainly the survival of adult patients (≥ 18 years), with an increasing risk according to this time (RR, 3.53 and 95%CI, 1.81 - 6.88 for > 3 and ≤ 6 months; RR 5.86 and 95%CI, 3.26 - 10.53 for > 6 and ≤ 12 months, and; RR 4.24 and 95%CI, 2.32 - 7.75 for > 12 months). CONCLUSION: Patients who remained on the waitlist for less than 3 months had the highest survival (median survival, 856 days; IQR, 131 - 1607). The risk of reduced survival was about 6-fold higher (95%CI, 2.8 - 11.5) in patients with malignancies.

Positive maternal affect during mother-litter interaction is reduced in new mother rats exhibiting a depression-like phenotype.

The experience of positive affect during new motherhood is considered essential for a healthy mother-infant relationship, with life-long consequences for both mother and child. Affective availability and contingent responsiveness are often compromised in mothers experiencing postpartum depression, yet how maternal affect impacts parenting is not fully understood. In this study, we used the Wistar-Kyoto (WKY) rat model of depression and ultrasonic vocalizations to examine the relationship between maternal affect and parenting. We examined the affective and behavioral response of WKY and control new mother rats during social interactions with their offspring. Our results show that WKY mothers displayed altered USV signaling accompanying substantial disturbances in their maternal caregiving. In addition, WKY mothers failed to adjust vocal frequency in coordination with offspring proximity and interaction compared to control mothers. A follow up experiment demonstrated that the administration of the adenosine A2A receptor antagonist MSX-3 ameliorated both maternal behavioral deficits and low positive affect in WKY mothers. Together, our results highlight the importance of maternal positive affect in the dyad relationship and suggest a role for the striatopallidal pathway in the affective processing of parenting.

Creatinine Clearance in Acute Brain Injury: A Comparison of Methods.

BACKGROUND: Currently, the measurement of glomerular filtration rate is very complex and costly, so its daily evaluation is performed using endogenous markers, of which creatinine is the most frequently used. It allows the estimation of glomerular filtration rate by means of its clearance or by formulas based on its serum and urine concentration. Augmented renal clearance (ARC) is frequent among critically ill patients and is defined as creatinine clearance (CrCl) > 130 ml/min/1.73 m2. The aim of this study was to compare measured CrCl (MCC) and estimated CrCl obtained with the Cockcroft-Gault formula (CG), the Modification of Diet in Renal Disease Study equation (MDRD), and the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) in patients with severe traumatic brain injury and nontraumatic subarachnoid hemorrhage. The second aim was to assess the incidence of ARC in this population of neurocritical patients. METHODS: This was a prospective, observational, single center study from a cohort of 74 patients admitted to the neurocritical intensive care unit due to traumatic brain injury or subarachnoid hemorrhage. Serum creatinine (at 7 a.m.) and a 6-h urine collection were analyzed, and CrCl was measured and estimated by using CG, MDRD, and CKD-EPI. The intraclass correlation coefficient (ICC) was evaluated for each pair, and Bland-Altman plots were used to assess clinical significance. RESULTS: Among 74 patients, the median age was 53 (interquartile range [IQR] 36-65), and the median Glasgow Coma Scale score at admission was 6. The median MCC at admission was 176 (IQR 135-214). The medians of CG, MDRD and CKD-EPI were, respectively, 129 ml/min/1.73 m2 (IQR 95-176), 158 (IQR 115-202), and 116 (97-132). An ICC was applied to evaluate the correlation between MCC and estimated methods and showed a weak correlation between MCC and estimated CrCl obtained with the three different methods. The strongest ICC statistical correlation was found between MCC and MDRD, and the weakest correlation was found between MCC and CKD-EPI. Bland-Altman plots showed that differences between each pair were not clinically acceptable. ARC was present in 78% of measurements, using MCC. A weak correlation was observed between MCC and calculated CrCl. CG, MDRD, and CKD-EPI overestimated MCC when MCC ≤ 130 ml/min/1.73 m2 and underestimated it when MCC > 130 ml/min/1.73 m2. CONCLUSIONS: In this population, there was a weak statistical correlation between measured and estimated methods. In patients with ARC, formulas underestimated MCC. MCC should probably be the preferred methodology for renal function assessment in the clinical setting to better adjust drug dosage and guarantee drug effectiveness.

Repurposing Benztropine, Natamycin, and Nitazoxanide Using Drug Combination and Characterization of Gastric Cancer Cell Lines.

Gastric cancer (GC) ranked as the fifth most incident cancer in 2020 and the third leading cause of cancer mortality. Surgical prevention and radio/chemotherapy are the main approaches used in GC treatment, and there is an urgent need to explore and discover innovative and effective drugs to better treat this disease. A new strategy arises with the use of repurposed drugs. Drug repurposing coupled with drug combination schemes has been gaining interest in the scientific community. The main objective of this project was to evaluate the therapeutic effects of alternative drugs in GC. For that, three GC cell lines (AGS, MKN28, and MKN45) were used and characterized. Cell viability assays were performed with the reference drug 5-fluororacil (5-FU) and three repurposed drugs: natamycin, nitazoxanide, and benztropine. Nitazoxanide displayed the best results, being active in all GC cells. Further, 5-FU and nitazoxanide in combination were tested in MKN28 GC cells, and the results obtained showed that nitazoxanide alone was the most promising drug for GC therapy. This work demonstrated that the repurposing of drugs as single agents has the ability to decrease GC cell viability in a concentration-dependent manner.

Atorvastatin and Nitrofurantoin Repurposed in the Context of Breast Cancer and Neuroblastoma Cells.

Chemotherapy still plays a central role in the treatment of cancer. However, it is often accompanied by off-target effects that result in severe side-effects and development of drug resistance. The aim of this work was to study the efficacy of different repurposed drugs on the viability of MCF-7 and SH-SY5Y breast cancer and neuroblastoma cells, respectively. In addition, combinations of these repurposed drugs with a classical chemotherapeutic drug (doxorubicin) were also carried out. The cytotoxic effects of the repurposed drugs were evaluated individually and in combination in both cancer cell lines, assessed by MTT assays and morphological evaluation of the cells. The results demonstrated that atorvastatin reduced the viability of both cell lines. However, nitrofurantoin was able to induce cytotoxic effects in MCF-7 cells, but not in SH-SY5Y cells. The combinations of the repurposed drugs with doxorubicin induced a higher inhibition on cell viability than the repurposed drugs individually. The combination of the two repurposed drugs demonstrated that they potentiate each other. Synergism studies revealed that the combination of doxorubicin with the two repurposed drugs was more effective in SH-SY5Y cells, compared to MCF-7 cells. Taken together, our preliminary study highlights the potential use of atorvastatin and nitrofurantoin in the context of breast cancer and neuroblastoma.