Treatment patterns and outcomes in metastatic castration-resistant prostate cancer patients with and without somatic or germline alterations in homologous recombination repair genes.

BACKGROUND: Although germline BRCA mutations have been associated with adverse outcomes in prostate cancer (PC), understanding of the association between somatic/germline alterations in homologous recombination repair (HRR) genes and treatment outcomes in metastatic castration-resistant PC (mCRPC) is limited. The aim of this study was to investigate the prevalence and outcomes associated with somatic/germline HRR alterations, particularly BRCA1/2, in patients initiating first-line (1L) mCRPC treatment with androgen receptor signalling inhibitors (ARSi) or taxanes. PATIENTS AND METHODS: Data from 729 mCRPC patients were pooled for CAPTURE from four multicentre observational studies. Eligibility required 1L treatment with ARSi or taxanes, adequate tumour samples and biomarker panel results. Patients underwent paired normal and tumour DNA analyses by next-generation sequencing using a custom gene panel including ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2, RAD51B and RAD54L. Patients were divided into subgroups based on somatic/germline alteration(s): with BRCA1/2 mutations (BRCA); with HRR mutations except BRCA1/2 (HRR non-BRCA); and without HRR alterations (non-HRR). Patients without BRCA1/2 mutations were classified as non-BRCA. Radiographic progression-free survival (rPFS), progression-free survival 2 (PFS2) and overall survival (OS) were assessed. RESULTS: Of 729 patients, 96 (13.2%), 127 (17.4%) and 506 (69.4%) were in the BRCA, HRR non-BRCA and non-HRR subgroups, respectively. BRCA patients performed significantly worse for all outcomes than non-HRR or non-BRCA patients (P < 0.05), while PFS2 and OS were significantly shorter for BRCA than HRR non-BRCA patients (P < 0.05). HRR non-BRCA patients also had significantly worse rPFS, PFS2 and OS than non-HRR patients. Exploratory analyses suggested that for BRCA patients, there were no significant differences in outcomes associated with 1L treatment choice (ARSi or taxanes) or with the somatic/germline origin of the alterations. CONCLUSIONS: Worse outcomes were observed for mCRPC patients in the BRCA subgroup compared with non-BRCA subgroups, either HRR non-BRCA or non-HRR. Despite its heterogeneity, the HRR non-BRCA subgroup presented worse outcomes than the non-HRR subgroup. Screening early for HRR mutations, especially BRCA1/2, is crucial in improving mCRPC patient prognosis.

Recommendations for the use of next-generation sequencing (NGS) for patients with advanced cancer in 2024: a report from the ESMO Precision Medicine Working Group.

BACKGROUND: Advancements in the field of precision medicine have prompted the European Society for Medical Oncology (ESMO) Precision Medicine Working Group to update the recommendations for the use of tumour next-generation sequencing (NGS) for patients with advanced cancers in routine practice. METHODS: The group discussed the clinical impact of tumour NGS in guiding treatment decision using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) considering cost-effectiveness and accessibility. RESULTS: As for 2020 recommendations, ESMO recommends running tumour NGS in advanced non-squamous non-small-cell lung cancer, prostate cancer, colorectal cancer, cholangiocarcinoma, and ovarian cancer. Moreover, it is recommended to carry out tumour NGS in clinical research centres and under specific circumstances discussed with patients. In this updated report, the consensus within the group has led to an expansion of the recommendations to encompass patients with advanced breast cancer and rare tumours such as gastrointestinal stromal tumours, sarcoma, thyroid cancer, and cancer of unknown primary. Finally, ESMO recommends carrying out tumour NGS to detect tumour-agnostic alterations in patients with metastatic cancers where access to matched therapies is available. CONCLUSION: Tumour NGS is increasingly expanding its scope and application within oncology with the aim of enhancing the efficacy of precision medicine for patients with cancer.

Application of nanoformulations as a strategy to optimize chemotherapeutic treatment of glioblastoma: a systematic review.

The aim of this review was to explore the advances of nanoformulations as a strategy to optimize glioblastoma treatment, specifically focusing on targeting and controlling drug delivery systems to the tumor. This review followed the PRISMA recommendations. The studies were selected through a literature search conducted in the electronic databases PubMed Central, Science Direct, Scopus and Web of Science, in April 2023, using the equation descriptors: (nanocapsule OR nanoformulation) AND (glioblastoma). Forty-seven investigations included were published between 2011 and 2023 to assess the application of different nanoformulations to optimize delivery of chemotherapies including temozolomide, carmustine, vincristine or cisplatin previously employed in brain tumor therapy, as well as investigating another 10 drugs. Data demonstrated the possible application of different matrices employed as nanocarriers and utilization of functionalizing agents to improve internalization of chemotherapeutics. Functionalization was developed with the application of peptides, micronutrients/vitamins, antibodies and siRNAs. Finally, this review demonstrated the practical and clinical application of nanocarriers to deliver multiple drugs in glioblastoma models. These nanomodels might ideally be developed using functionalizing ligand agents that preferably act synergistically with the drug these agents carry. The findings showed promising results, making nanoformulations one of the best prospects for innovation and improvement of glioblastoma treatment.

Efficient photocatalytic activity and selective adsorption of UiO-67 (Zr)/g-C3N4 composite toward a mixture of parabens.

In this study, UiO-67 (Zr)/g-C3N4 composites (U67N) were synthesized at wt.% ratios of 05:95, 15:85, and 30:70 using the solvothermal method at 80 °C for 24 h followed by calcination at 350 °C. The composites were characterized using UV-Vis diffuse reflectance spectroscopy, Fourier-transform infrared spectroscopy, photoluminescence spectroscopy, X-ray photoelectron spectroscopy, X-ray diffraction, scanning electron microscopy-energy-dispersive X-ray spectroscopy, transmission electron microscopy, and nitrogen physisorption analysis. In addition, thermal stability analysis of UiO-67 was conducted using thermogravimetric analysis. The photocatalytic performance of the composites was assessed during the degradation and mineralization of a mixture of methylparaben (MeP) and propylparaben (PrP) under simulated sunlight. The adsorption process of U67N 15:85 was characterized through kinetic studies and adsorption capacity experiments, which were modeled using pseudo-first-order and pseudo-second-order kinetics and Langmuir and Freundlich isotherms, respectively. The influence of pH levels 3, 5, and 7 on the photocatalytic degradation of the mixture was investigated, revealing enhanced degradation and mineralization at pH 3. The U67N composite exhibited dual capability in removing contaminants through adsorption and photocatalytic processes. Among the prepared composites, U67N 15:85 demonstrated the highest photocatalytic activity, achieving removal efficiencies of 96.8% for MeP, 92.5% for PrP, and 45.7% for total organic carbon in 300 kJ/m2 accumulated energy (3 h of reaction time). The detoxification of the effluent was confirmed through acute toxicity evaluation using the Vibrio fischeri method. The oxidation mechanism of the heterojunction formed between UiO-67 (Zr) and g-C3N4 was proposed based on PL analysis, photoelectrochemistry studies (including photocurrent response, Nyquist, and Mott-Schottky analyses), and scavenger assays.

Patterns of kidney function and risk assessment in a nationwide laboratory database: the Brazilian CHECK-CKD study.

BACKGROUND: Chronic kidney disease (CKD) is a global health problem with rising prevalence, morbidity, mortality, and associated costs. Early identification and risk stratification are key to preventing progression to kidney failure. However, there is a paucity of data on practice patterns of kidney function assessment to guide the development of improvement strategies, particularly in lower-income countries. METHODS: A retrospective observational analysis was conducted in a nationwide laboratory database in Brazil. We included all adult patients with at least one serum creatinine assessment between June 2018 and May 2021. Our primary objective was to determine the proportion of patients with estimated glomerular filtration rate (eGFR) evaluations accompanied by predicted levels of urinary albumin-to-creatinine ratio (pACR) assessments within 12 months. RESULTS: Out of 4,5323,332 serum creatinine measurements, 42% lacked pACR measurements within 12 months. Approximately 10.8% of tests suggested CKD, mostly at stage 3a. The proportion of serum creatinine exams paired with pACR assessment varied according to the CKD stage. Internal Medicine, Cardiology, and Obstetrics/Gynecology were the specialties requesting most of the creatinine tests. Nephrology contributed with only 1.1% of serum creatinine requests for testing. CONCLUSION: Our findings reveal that a significant proportion of individuals with a creatinine test lack an accompanying urinary albuminuria measurement in Brazil, contrary to the recommendations of the international guidelines. Non-Nephrologists perform most kidney function evaluations, even among patients with presumable advanced CKD. This highlights the urge to incorporate in clinical practice the early detection of CKD and to encourage more collaborative multidisciplinary care to improve CKD management.

Deep genetic affinity between coastal Pacific and Amazonian natives evidenced by Australasian ancestry.

Different models have been proposed to elucidate the origins of the founding populations of America, along with the number of migratory waves and routes used by these first explorers. Settlements, both along the Pacific coast and on land, have been evidenced in genetic and archeological studies. However, the number of migratory waves and the origin of immigrants are still controversial topics. Here, we show the Australasian genetic signal is present in the Pacific coast region, indicating a more widespread signal distribution within South America and implicating an ancient contact between Pacific and Amazonian dwellers. We demonstrate that the Australasian population contribution was introduced in South America through the Pacific coastal route before the formation of the Amazonian branch, likely in the ancient coastal Pacific/Amazonian population. In addition, we detected a significant amount of interpopulation and intrapopulation variation in this genetic signal in South America. This study elucidates the genetic relationships of different ancestral components in the initial settlement of South America and proposes that the migratory route used by migrants who carried the Australasian ancestry led to the absence of this signal in the populations of Central and North America.

Stress and exhaustion among medical students: a prospective longitudinal study on the impact of the assessment period on medical education.

BACKGROUND: Stress significantly affects both the physical and emotional health of individuals, particularly students in health-related fields. Medical students in Brazil face unique challenges due to the demanding nature of their studies, especially during assessment periods, which heighten academic pressure. These pressures often lead to poor coping strategies and mental health concerns. It is crucial to understand the complex dynamics of stress within medical education to develop strategies that improve student well-being and promote a healthier academic environment. This study aims to investigate the intricate relationship between assessment periods and stress levels among medical students. It seeks to understand how academic demands and sociodemographic factors contribute to stress dynamics during these periods. METHODS: An online observational, longitudinal, and prospective study was conducted from February to October 2022. Medical students were recruited through snowball sampling and participated in surveys administered via Google Forms at two timepoints: before (T1) and during (T2) assessment periods. The surveys collected sociodemographic data and stress symptoms using Lipp's Inventory of Stress Symptoms for Adults (LSSI). RESULTS: The transition from T1 to T2 was defined by a rise in the prevalence of stress from 59.6 to 84.2% (p = 0.001) and a decline in symptom-free students from 40.4 to 15.8% (p = 0.001). There was a significant increase in exhaustion, from 12.3 to 31.6% (p = 0.0001). Higher stress levels were notably more prevalent among younger students (≤ 24 years), females, those from wealthier families, students without scholarships, those without prior degrees, and those in the clinical phase of their studies. However, non significant correlations were found between these sociodemographic and academic factors and the increase in stress. CONCLUSION: The findings highlight significant concerns regarding the mental health of medical students during assessment periods, marked by increased stress and exhaustion levels. These results emphasize the need for proactive interventions to manage stress effectively in medical education, considering its profound impact on students' well-being.

Proteomic Analysis of a Rat Streptozotocin Model Shows Dysregulated Biological Pathways Implicated in Alzheimer's Disease.

Alzheimer's Disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and cognitive impairment, affecting 35 million individuals worldwide. Intracerebroventricular (ICV) injection of low to moderate doses of streptozotocin (STZ) in adult male Wistar rats can reproduce classical physiopathological hallmarks of AD. This biological model is known as ICV-STZ. Most studies are focused on the description of behavioral and morphological aspects of the ICV-STZ model. However, knowledge regarding the molecular aspects of the ICV-STZ model is still incipient. Therefore, this work is a first attempt to provide a wide proteome description of the ICV-STZ model based on mass spectrometry (MS). To achieve that, samples from the pre-frontal cortex (PFC) and hippocampus (HPC) of the ICV-STZ model and control (wild-type) were used. Differential protein abundance, pathway, and network analysis were performed based on the protein identification and quantification of the samples. Our analysis revealed dysregulated biological pathways implicated in the early stages of late-onset Alzheimer's disease (LOAD), based on differentially abundant proteins (DAPs). Some of these DAPs had their mRNA expression further investigated through qRT-PCR. Our results shed light on the AD onset and demonstrate the ICV-STZ as a valid model for LOAD proteome description.

[Translated article] Melanoma Registry of the Spanish Academy of Dermatology and Venereology (REGESMEL): Description and Data in its First Year of Operation.

INTRODUCTION: The incidence of melanoma is rising in Spain. The prognostic stages of patients with melanoma are determined by various biological factors, such as tumor thickness, ulceration, or the presence of regional or distant metastases. The Spanish Academy of Dermatology and Venereology (AEDV) has encouraged the creation of a Spanish Melanoma Registry (REGESMEL) to evaluate other individual and health system-related factors that may impact the prognosis of patients with melanoma. The aim of this article is to introduce REGESMEL and provide basic descriptive data for its first year of operation. METHODS: REGESMEL is a prospective, multicentre cohort of consecutive patients with invasive cutaneous melanoma that collects demographic and staging data as well as individual and healthcare-related baseline data. It also records the medical and surgical treatment received by patients. RESULTS: A total of 450 cases of invasive cutaneous melanoma from 19 participant centres were included, with a predominance of thin melanomas≤1mm thick (54.7%), mainly located on the posterior trunk (35.2%). Selective sentinel lymph node biopsy was performed in 40.7% of cases. Most cases of melanoma were suspected by the patient (30.4%), or his/her dermatologist (29.6%). Patients received care mainly in public health centers (85.2%), with tele-dermatology resources being used in 21.6% of the cases. CONCLUSIONS: The distribution of the pathological and demographic variables of melanoma cases is consistent with data from former studies. REGESMEL has already recruited patients from 15 Spanish provinces and given its potential representativeness, it renders the Registry as an important tool to address a wide range of research questions.

Melanoma Registry of the Spanish Academy of Dermatology and Venereology (REGESMEL): Description and Data in its First Year of Operation. / Registro de Melanoma de la Academia Española de Dermatología y Venereología (REGESMEL): descripción y datos en el primer año de funcionamiento.

INTRODUCTION: The incidence of melanoma is rising in Spain. The prognostic stages of patients with melanoma are determined by various biological factors, such as tumor thickness, ulceration, or the presence of regional or distant metastases. The Spanish Academy of Dermatology and Venereology (AEDV) has encouraged the creation of a Spanish Melanoma Registry (REGESMEL) to evaluate other individual and health system-related factors that may impact the prognosis of patients with melanoma. The aim of this article is to introduce REGESMEL and provide basic descriptive data for its first year of operation. METHODS: REGESMEL is a prospective, multicentre cohort of consecutive patients with invasive cutaneous melanoma that collects demographic and staging data as well as individual and healthcare-related baseline data. It also records the medical and surgical treatment received by patients. RESULTS: A total of 450 cases of invasive cutaneous melanoma from 19 participant centres were included, with a predominance of thin melanomas≤1mm thick (54.7%), mainly located on the posterior trunk (35.2%). Selective sentinel lymph node biopsy was performed in 40.7% of cases. Most cases of melanoma were suspected by the patient (30.4%), or his/her dermatologist (29.6%). Patients received care mainly in public health centers (85.2%), with tele-dermatology resources being used in 21.6% of the cases. CONCLUSIONS: The distribution of the pathological and demographic variables of melanoma cases is consistent with data from former studies. REGESMEL has already recruited patients from 15 Spanish provinces and given its potential representativeness, it renders the Registry as an important tool to address a wide range of research questions.

Population Histories and Genomic Diversity of South American Natives.

South America is home to one of the most culturally diverse present-day native populations. However, the dispersion pattern, genetic substructure, and demographic complexity within South America are still poorly understood. Based on genome-wide data of 58 native populations, we provide a comprehensive scenario of South American indigenous groups considering the genomic, environmental, and linguistic data. Clear patterns of genetic structure were inferred among the South American natives, presenting at least four primary genetic clusters in the Amazonian and savanna regions and three clusters in the Andes and Pacific coast. We detected a cline of genetic variation along a west-east axis, contradicting a hard Andes-Amazon divide. This longitudinal genetic variation seemed to have been shaped by both serial population bottlenecks and isolation by distance. Results indicated that present-day South American substructures recapitulate ancient macroregional ancestries and western Amazonia groups show genetic evidence of cultural exchanges that led to language replacement in precontact times. Finally, demographic inferences pointed to a higher resilience of the western South American groups regarding population collapses caused by the European invasion and indicated precontact population reductions and demic expansions in South America.

Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial.

BACKGROUND: Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2). PATIENTS AND METHODS: Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed. RESULTS: Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed. CONCLUSIONS: MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.

Germline-focused analysis of tumour-detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations.

BACKGROUND: The European Society for Medical Oncology Precision Medicine Working Group (ESMO PMWG) was reconvened to update its 2018/19 recommendations on follow-up of putative germline variants detected on tumour-only sequencing, which were based on an analysis of 17 152 cancers. METHODS: We analysed an expanded dataset including 49 264 paired tumour-normal samples. We applied filters to tumour-detected variants based on variant allele frequency, predicted pathogenicity and population variant frequency. For 58 cancer-susceptibility genes, we then examined the proportion of filtered tumour-detected variants of true germline origin [germline conversion rate (GCR)]. We conducted subanalyses based on the age of cancer diagnosis, specific tumour types and 'on-tumour' status (established tumour-gene association). RESULTS: Analysis of 45 472 nonhypermutated solid malignancy tumour samples yielded 21 351 filtered tumour-detected variants of which 3515 were of true germline origin. 3.1% of true germline pathogenic variants were absent from the filtered tumour-detected variants. For genes such as BRCA1, BRCA2 and PALB2, the GCR in filtered tumour-detected variants was >80%; conversely for TP53, APC and STK11 this GCR was <2%. CONCLUSION: Strategic germline-focused analysis can prioritise a subset of tumour-detected variants for which germline follow-up will produce the highest yield of most actionable true germline variants. We present updated recommendations around germline follow-up of tumour-only sequencing including (i) revision to 5% for the minimum per-gene GCR, (ii) inclusion of actionable intermediate penetrance genes ATM and CHEK2, (iii) definition of a set of seven 'most actionable' cancer-susceptibility genes (BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6 and RET) in which germline follow-up is recommended regardless of tumour type.

Buthionine sulfoximine and chemoresistance in cancer treatments: a systematic review with meta-analysis of preclinical studies.

Buthionine sulfoximine (BSO) is a synthetic amino acid that blocks the biosynthesis of reduced glutathione (GSH), an endogenous antioxidant cellular component present in tumor cells. GSH levels have been associated with tumor cell resistance to chemotherapeutic drugs and platinum compounds. Consequently, by depleting GSH, BSO enhances the cytotoxicity of chemotherapeutic agents in drug-resistant tumors. Therefore, the aim of this study was to conduct a systematic review with meta-analysis of preclinical studies utilizing BSO in cancer treatments. The systematic search was carried out using the following databases: PubMed, Web of Science, Scopus, and EMBASE up until March 20, 2023, in order to collect preclinical studies that evaluated BSO, alone or in association, as a strategy for antineoplastic therapy. One hundred nine investigations were found to assess the cytotoxic potential of BSO alone or in combination with other compounds. Twenty-one of these met the criteria for performing the meta-analysis. The evidence gathered indicated that BSO alone exhibits cytotoxic activity. However, this compound is generally used in combination with other antineoplastic strategies, mainly chemotherapy ones, to improve cytotoxicity to carcinogenic cells and treatment efficacy. Finally, this review provides important considerations regarding BSO use in cancer treatment conditions, which might optimize future studies as a potential adjuvant antineoplastic therapeutic tool.

α-tocopherol as a selective modulator of toxicogenic damage induced by antineoplastic agents cyclophosphamide and doxorubicin.

The aim of this study was to determine the oxidative/antioxidative effects, modulatory and selective potential of α-tocopherol (vitamin E) on antineoplastic drug-induced toxicogenetic damage. The toxicity, cytotoxicity and genotoxicity induced by antineoplastic agents cyclophosphamide (CPA) and doxorubicin (DOX) was examined utilizing as models Saccharomyces cerevisiae, Allium cepa, Artemia salina and human peripheral blood mononuclear cells (PBMCs) in the presence of α-tocopherol. For these tests, concentrations of α- tocopherol 100 IU/ml (67mg/ml), CPA 20 µg/ml, DOX 2 µg/ml were used. The selectivity of α-tocopherol was assessed by the MTT test using human mammary gland non-tumor (MCF10A) and tumor (MCF-7) cell lines. Data showed cytoplasmic and mitochondrial oxidative damage induced by CPA or DOX was significantly diminished by α-tocopherol in S. cerevisiae. In addition, the toxic effects on A. salina and cytotoxic and mutagenic effects on A. cepa were significantly reduced by α-tocopherol. In PBMCs, α-tocopherol alone did not markedly affect these cells, and when treated in conjunction with CPA or DOX, α-tocopherol reduced the toxicogenetic effects noted after antineoplastic drug administration as evidenced by decreased chromosomal alterations and lowered cell death rate. In human mammary gland non-tumor and tumor cell lines, α-tocopherol produced selective cytotoxicity with 2-fold higher effect in tumor cells. Evidence indicates that vitamin E (1) produced anti-cytotoxic and anti-mutagenic effects against CPA and DOX (2) increased higher selectivity toward tumor cells, and (3) presented chemoprotective activity in PBMCs.

Genomic insight into the origins and dispersal of the Brazilian coastal natives.

In the 15th century, ∼900,000 Native Americans, mostly Tupí speakers, lived on the Brazilian coast. By the end of the 18th century, the coastal native populations were declared extinct. The Tupí arrived on the east coast after leaving the Amazonian basin ∼2,000 y before present; however, there is no consensus on how this migration occurred: toward the northern Amazon and then directly to the Atlantic coast, or heading south into the continent and then migrating to the coast. Here we leveraged genomic data from one of the last remaining putative representatives of the Tupí coastal branch, a small, admixed, self-reported Tupiniquim community, as well as data of a Guaraní Mbyá native population from Southern Brazil and of three other native populations from the Amazonian region. We demonstrated that the Tupiniquim Native American ancestry is not related to any extant Brazilian Native American population already studied, and thus they could be considered the only living representatives of the extinct Tupí branch that used to settle the Atlantic Coast of Brazil. Furthermore, these data show evidence of a direct migration from Amazon to the Northeast Coast in pre-Columbian time, giving rise to the Tupí Coastal populations, and a single distinct migration southward that originated the Guaraní people from Brazil and Paraguay. This study elucidates the population dynamics and diversification of the Brazilian natives at a genomic level, which was made possible by recovering data from the Brazilian coastal population through the genomes of mestizo individuals.

Toxicogenetic profile of the monoterpene alpha-terpineol on normal and tumor eukaryotic cells.

Alpha-terpineol is a monoterpene alcohol found in essential oils from medicinal plants with some well-known pharmacological activities and widely used in cosmetics. However, the toxicological effects and additional pharmacological activities need to be clarified. Thus, the study evaluated the toxic, cytotoxic, genotoxic, hemolytic, and oxidative potential of alpha-terpineol in non-clinical bioassays. Different concentrations of alpha-terpineol were used in bioassays, including MTT (50, 100, 200, and 400 µg/mL), Artemia salina (6.25-400 µg/mL), Allium cepa (10, 50, and 100 µg/mL), comet assay (100, 200, and 500 µg/mL), cytokinesis-block micronucleus (100, 250, and 500 µg/mL), confocal microscopy for apoptosis quantification (100 and 500 µg/mL), hemolysis and Saccharomyces cerevisiae central disk test (10, 35, and 75 µg/mL). For the MTT test, alpha-terpineol was more cytotoxic on melanoma murine B16-F10 cells rather than macrophages. For A. salina test, alpha-terpineol showed LC50 of 68.29 and 76.36 µg/mL for 24 h and 48 h of exposure time, respectively. Meanwhile, alpha-terpineol was also cytotoxic to meristematic cells, which revealed inhibition of cellular division and mutagenic action by formation of bridges and delayed anaphases. The compound increased damage index and frequency of damage corroborated by the presence of micronuclei, bridges and nuclear buds at 500 µg/mL, but it caused neither hemolysis, oxidative damage on the S. cerevisiae nor cell death in normal fibroblasts. The findings indicate alpha-terpineol has cytotoxic potential by cytogenetic and molecular mechanisms associated with apoptosis and probable target effects against melanoma cells.

Environmental spreading of clinically relevant carbapenem-resistant gram-negative bacilli: the occurrence of blaKPC-or-NDM strains relates to local hospital activities.

BACKGROUND: Aquatic matrices impacted by sewage may shelter carbapenem-resistant (CR) Gram-negative bacilli (GNB) harboring resistance genes of public health concern. In this study, sewage treatment plants (STPs) servicing well-defined catchment areas were surveyed for the presence of CR-GNB bearing carbapenemase genes (blaKPC or blaNDM). RESULTS: A total of 325 CR-GNB were recovered from raw (RS) and treated (TS) sewage samples as well as from water body spots upstream (UW) and downstream (DW) from STPs. Klebsiella-Enterobacter (KE) group amounted to 116 isolates (35.7%). CR-KE isolates were recovered from TS, DW (35.7%) and RS samples (44.2%) (p = 0.001); but not from UW samples. KE isolates represented 65.8% of all blaKPC or blaNDM positive strains. The frequency of blaKPC-or-NDM strains was positively associated with the occurrence of district hospitals located near STPs, as well as with the number of hospitalizations and of sewer connections serviced by the STPs. blaKPC-or-NDM strains were recovered from ST samples in 7 out of 14 STPs, including four tertiary-level STPs; and from 6 out of 13 DW spots whose RS samples also had blaKPC-or-NDM strains. CONCLUSIONS: Clinically relevant GNB bearing blaKPC-or-NDM resist sewage treatments and spread into environmental aquatic matrices mainly from STPs impacted by hospital activities.

Evaluation of mutagenesis, necrosis and apoptosis induced by omeprazole in stomach cells of patients with gastritis.

BACKGROUND: Gastritis is a superficial and prevalent inflammatory lesion that is considered a public health concern once can cause gastric ulcers and gastric cancer, especially when associated with Helicobacter pylori infection. Proton pump inhibitors, such as omeprazole, are the most widely used drugs to treat this illness. The aim of the study was evaluate cytogenetic effects of omeprazole in stomach epithelial cells of patients with gastritis in presence and absence of H. pylori, through cytogenetic biomarkers and catalse and superoxide dismutase analysis. METHODS: The study included 152 patients from the Gastroenterology Outpatient Clinic of Hospital Getúlio Vargas, Teresina-Brazil, that reported continuous and prolonged omeprazole use in doses of 20, 30 and 40 mg/kg. The participants were divided into groups: (1) patients without gastritis (n = 32); (2) patients without gastritis but with OME use (n = 24); (3) patients with gastritis (n = 26); (4) patients with gastritis undergoing OME therapy (n = 26); (5) patients with gastritis and H. pylori (n = 22) and (6) patients with gastritis and H. pylori on OME therapy (n = 22). RESULTS: OME induced cytogenetic imbalance in the stomach epithelium through the formation of micronuclei (group 6 > 1, 2, 3, 4, 5; group 5 > 1, 2, 3; group 4 > 1, 2, 3); bridges (groups 4 and 6 > 1, 2, 3, 5 and group 2 > 3, 5); buds (groups 2,4,6 > , 1, 3, 5); binucleated cells (group 6 > 1, 2, 3, 4, 5; group 4 > 1, 2, 3); (groups 2 and 3 > 1); picnoses (group 6 > 1, 2, 3, 4, 5), groups 2 and 5 > 1, 3; group 4 > 1, 2, 3, 5); cariorrexis (groups 6 and 4 > 1, 2, 3, 5; groups 2, 3, 5 > 1) and karyolysis (groups 2, 4, and 6 > 1, 3, 5; groups 3 and 5 > 1). The OME cytogenetic instability was associated with H. pylori infection, indicating clastogenic/aneugenic effects, chromosomes alterations, gene expression changes, cytotoxicity and apoptosis. CONCLUSIONS: The cytogenetic changescan be attributed to several mechanisms that are still unclear, including oxidative damage, as observed by increased catalase and superoxide dismutase expresion. Positive correlations between antioxidant enzymes were found with micronuclei formation, and were negative for picnoses. Thus, the continuous and prolonged omeprazole use induces genetic instability, which can be monitored through cytogenetic analyzes, as precursor for gastric cancer.

Antimitotic and toxicogenetic action of Stevia urticifolia aerial parts on proliferating vegetal and mammalian cells: in vitro and in vivo traditional and replacement methods.

Stevia urticifolia Thunb. is an underexploited herb possessing bioactive flavonoids, saponins, and terpenoids. The aim of this study was to examine the antiproliferative and toxicogenetic properties of the ethyl acetate extract from Stevia urticifolia aerial parts (EtAcSur) upon Artemia salina, erythrocytes, Allium cepa and sarcoma 180 cells and fibroblasts, as well as in vivo studies on mice to determine systemic, macroscopic, and behavioral alterations and bone marrow chromosomal damage. The assessment using A. salina larvae and mouse blood cells revealed LC50 and EC50 values of 68.9 and 113.6 µg/ml, respectively. Root growth and mitosis were inhibited by EtAcSur, and chromosomal aberrations were detected only at 100 µg/ml. EtAcSur exhibited potent concentration-dependent viability reduction of S180 and L-929 cells and antioxidant capacity employing ABTS• and DPPH•. No previous in vivo studies were performed before with the EtAcSur. Signals of acute toxicity were not observed at 300 mg/kg. Physiological and toxicological investigations at 25 and 50 mg/mg/day i.p. for 8 days did not markedly change body or organ relative weights, nor patterns of spontaneous locomotor and exploratory activities. In contrast, clastogenic effects on bone marrow were found at 50 mg/mg/day. EtAcSur was found to (1) produce toxicity in microcrustaceans, (2) capacity as free radical scavenger, (3) antimitotic, cytotoxic and clastogenic activties upon vegetal and mammalian cells, and (4) lethality on both tumor and normal murine cells indistinctly. In vivo damage systemic effects were not remarkable and clinical signals of toxicity were not observed, suggesting the significant pharmacological potential of S. urticifolia for the development of antineoplastic agents.Abbreviations: ABTS: 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid); DMSO: dimethylsulfoxide; DPPH: 1,1-diphenyl-2-picrylhydrazyl; EC50: effective concentration 50%; EtAcSur: ethyl acetate extract from Stevia urticifolia aerial parts; Hb, hemoglobin; IC50: inhibitory concentration 50%; LC50,: lethal concentration 50%; MI: mitotic index; RBC, red blood cells; Trolox: 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid.