Antineoplastic effect of compounds C14 and P8 on TNBC and radioresistant TNBC cells by stabilizing the K-Ras4BG13D/PDE6δ complex.

Introduction: Breast cancer (BC) is the leading cause of cancer-related deaths among women, with triple-negative breast cancer (TNBC) representing one of the most aggressive and treatment-resistant subtypes. In this study, we aimed to evaluate the antitumor potential of C14 and P8 molecules in both TNBC and radioresistant TNBC cells. These compounds were chosen for their ability to stabilize the complex formed by the overactivated form of K-Ras4BG13D and its membrane transporter (PDE6δ). Methods: The antitumor potential of C14 and P8 was assessed using TNBC cell lines, MDA-MB-231, and the radioresistant derivative MDA-MB-231RR, both carrying the K-Ras4B> G13D mutation. We investigated the compounds' effects on K-Ras signaling pathways, cell viability, and tumor growth in vivo. Results: Western blotting analysis determined the negative impact of C14 and P8 on the activation of mutant K-Ras signaling pathways in MDA-MB-231 and MDA-MB-231RR cells. Proliferation assays demonstrated their efficacy as cytotoxic agents against K-RasG13D mutant cancer cells and in inducing apoptosis. Clonogenic assays proven their ability to inhibit TNBC and radioresistant TNBC cell clonogenicity. In In vivo studies, C14 and P8 inhibited tumor growth and reduced proliferation, angiogenesis, and cell cycle progression markers. Discussion: These findings suggest that C14 and P8 could serve as promising adjuvant treatments for TNBC, particularly for non-responders to standard therapies. By targeting overactivated K-Ras and its membrane transporter, these compounds offer potential therapeutic benefits against TNBC, including its radioresistant form. Further research and clinical trials are warranted to validate their efficacy and safety as novel TNBC treatments.

Multiomic Approaches for Cancer Biomarker Discovery in Liquid Biopsies: Advances and Challenges.

Cancer is a complex and heterogeneous disease that poses a significant threat to global health. Early diagnosis and treatment are critical for improving patient outcomes, and the use of liquid biopsies has emerged as a promising approach for cancer detection and monitoring. Traditionally, cancer diagnosis has relied on invasive tissue biopsies, the collection of which can prove challenging for patients and the results of which may not always provide accurate results due to tumor heterogeneity. Liquid biopsies have gained increasing attention as they provide a non-invasive and accessible source of cancer biomarkers, which can be used to diagnose cancer, monitor treatment response, and detect relapse. The integration of -omics technologies, such as proteomics, genomics, and metabolomics, has further enhanced the capabilities of liquid biopsies by introducing precision oncology and enabling the tailoring of treatment for individual patients based on their unique tumor biology. In this review, we will discuss the challenges and advances in the field of cancer liquid biopsies and the integration of -omics technologies for different types of liquid biopsies, including blood, tear, urine, sweat, saliva, and cerebrospinal fluid.

Synergistic effect of antagonists to KRas4B/PDE6 molecular complex in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among all human cancers as it is highly resistant to chemotherapy. K-Ras mutations usually trigger the development and progression of PDAC. We hypothesized that compounds stabilizing the KRas4B/PDE6δ complex could serve as PDAC treatments. Using in silico approaches, we identified the small molecules C14 and P8 that reduced K-Ras activation in primary PDAC cells. Importantly, C14 and P8 significantly prevented tumor growth in patient-derived xenotransplants. Combined treatment with C14 and P8 strongly increased cytotoxicity in PDAC cell lines and primary cultures and showed strong synergistic antineoplastic effects in preclinical murine PDAC models that were superior to conventional therapeutics without causing side effects. Mechanistically, C14 and P8 reduced tumor growth by inhibiting AKT and ERK signaling downstream of K-RAS leading to apoptosis, specifically in PDAC cells. Thus, combined treatment with C14 and P8 may be a superior pharmaceutical strategy to improve the outcome of PDAC.

Frontiers in páramo water resources research: A multidisciplinary assessment.

Interdisciplinary knowledge is necessary to achieve sustainable management of natural resources. However, research is still often developed in an exclusively disciplinary manner, hampering the capacity to holistically address environmental issues. This study focuses on páramo, a group of high-elevation ecosystems situated around ∼3000 to ∼5000 m a.s.l. in the Andes from western Venezuela and northern Colombia through Ecuador down to northern Peru, and in the highlands of Panama and Costa Rica in Central America. Páramo is a social-ecological system that has been inhabited and shaped by human activity since ∼10,000 years BP. This system is highly valued for the water-related ecosystem services provided to millions of people because it forms the headwaters of major rivers in the Andean-Amazon region, including the Amazon River. We present a multidisciplinary assessment of peer-reviewed research on the abiotic (physical and chemical), biotic (ecological and ecophysiological), and social-political aspects and elements of páramo water resources. A total of 147 publications were evaluated through a systematic literature review process. We found that thematically 58, 19, and 23 % of the analyzed studies are related to the abiotic, biotic, and social-political aspects of páramo water resources, respectively. Geographically, most publications were developed in Ecuador (71 % of the synthesized publications). From 2010 onwards, the understanding of hydrological processes including precipitation and fog dynamics, evapotranspiration, soil water transport, and runoff generation improved, particularly for the humid páramo of southern Ecuador. Investigations on the chemical quality of water generated by páramo are rare, providing little empirical support to the widespread belief that páramo environments generate water of high quality. Most ecological studies examined the coupling between páramo terrestrial and aquatic environments, but few directly assessed in-stream metabolic and nutrient cycling processes. Studies focused on the connection between ecophysiological and ecohydrological processes influencing páramo water balance are still scarce and mainly related to the dominant vegetation in the Andean páramo, i.e., tussock grass (pajonal). Social-political studies addressed páramo governance and the implementation and significance of water funds and payment for hydrological services. Studies directly addressing water use, access, and governance in páramo communities remain limited. Importantly, we found only a few interdisciplinary studies combining methodologies from at least two disciplines of different nature despite their value in supporting decision-making. We expect this multidisciplinary synthesis to become a milestone to foster interdisciplinary and transdisciplinary dialogue among individuals and entities involved in and committed to the sustainable management of páramo natural resources. Finally, we also highlight key frontiers in páramo water resources research, which in our view need to be addressed in the coming years/decades to achieve this goal.

Protist-Lactic Acid Bacteria Co-Culture as a Strategy to Bioaccumulate Polyunsaturated Fatty Acids in the Protist Aurantiochytrium sp. T66.

Thraustochytrids are aquatic unicellular protists organisms that represent an important reservoir of a wide range of bioactive compounds, such as essential polyunsaturated fatty acids (PUFAs) such as arachidonic acid (ARA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), which are involved in the regulation of the immune system. In this study, we explore the use of co-cultures of Aurantiochytrium sp. and bacteria as a biotechnological tool capable of stimulating PUFA bioaccumulation. In particular, the co-culture of lactic acid bacteria and the protist Aurantiochytrium sp. T66 induce PUFA bioaccumulation, and the lipid profile was evaluated in cultures at different inoculation times, with two different strains of lactic acid bacteria capable of producing the tryptophan dependent auxins, and one strain of Azospirillum sp., as a reference for auxin production. Our results showed that the Lentilactobacillus kefiri K6.10 strain inoculated at 72 h gives the best PUFA content (30.89 mg g-1 biomass) measured at 144 h of culture, three times higher than the control (8.87 mg g-1 biomass). Co-culture can lead to the generation of complex biomasses with higher added value for developing aquafeed supplements.

131I-C19 Iodide Radioisotope and Synthetic I-C19 Compounds as K-Ras4B-PDE6δ Inhibitors: A Novel Approach against Colorectal Cancer-Biological Characterization, Biokinetics and Dosimetry.

In 40-50% of colorectal cancer (CRC) cases, K-Ras gene mutations occur, which induce the expression of the K-Ras4B oncogenic isoform. K-Ras4B is transported by phosphodiesterase-6δ (PDE6δ) to the plasma membrane, where the K-Ras4B-PDE6δ complex dissociates and K-Ras4B, coupled to the plasma membrane, activates signaling pathways that favor cancer aggressiveness. Thus, the inhibition of the K-Ras4B-PDE6δ dissociation using specific small molecules could be a new strategy for the treatment of patients with CRC. This research aimed to perform a preclinical proof-of-concept and a therapeutic potential evaluation of the synthetic I-C19 and 131I-C19 compounds as inhibitors of the K-Ras4B-PDE6δ dissociation. Molecular docking and molecular dynamics simulations were performed to estimate the binding affinity and the anchorage sites of I-C19 in K-Ras4B-PDE6δ. K-Ras4B signaling pathways were assessed in HCT116, LoVo and SW620 colorectal cancer cells after I-C19 treatment. Two murine colorectal cancer models were used to evaluate the I-C19 therapeutic effect. The in vivo biokinetic profiles of I-C19 and 131I-C19 and the tumor radiation dose were also estimated. The K-Ras4B-PDE6δ stabilizer, 131I-C19, was highly selective and demonstrated a cytotoxic effect ten times greater than unlabeled I-C19. I-C19 prevented K-Ras4B activation and decreased its dependent signaling pathways. The in vivo administration of I-C19 (30 mg/kg) greatly reduced tumor growth in colorectal cancer. The biokinetic profile showed renal and hepatobiliary elimination, and the highest radiation absorbed dose was delivered to the tumor (52 Gy/74 MBq). The data support the idea that 131I-C19 is a novel K-Ras4B/PDE6δ stabilizer with two functionalities: as a K-Ras4B signaling inhibitor and as a compound with radiotherapeutic activity against colorectal tumors.

Update on Pediatric Sepsis in Mexico.

The main objective of this work was to determine and update the causal agents' antibiotic sensitivity and resistance patterns on pediatric sepsis in a population of northeast Mexico. It is a cross-sectional study showing the results of blood cultures of pediatric patients with a presumptive diagnosis of sepsis were reviewed according to the SOFA criteria during 2020 in a public hospital in Mexico. A total of 207 blood cultures were performed and analyzed. The main isolated microorganisms were Staphylococcus, followed by Klebsiella and Escherichia. Several microorganisms showed 100% of sensitivity to different antibiotics or antifungals, some of them include Vancomycin, Voriconazole, Meropenem, Ciprofloxacin, and Cefotaxime. Bacteria of genre Staphylococcus showed its highest sensitivity rate to Tigecycline with 63.3%. Too Staphylococcus showed the highest resistance rate to Oxacillin with 50%. Although the patterns of sepsis-causing germs are similar to those previously reported, the development of new drugs with greater efficacy is the main contribution.

Periodic Fever in Children: Etiology and Diagnostic Challenges.

Periodic fever in children is an autoinflammatory illness with an unknown cause. Symptoms include frequent episodes of fever that are followed by an increase in inflammatory markers. A genetic background for periodic fever of unknown origin has been hypothesized, based on its family clustering and parallels to other autoinflammatory illnesses such as familial Mediterranean fever. Genome analysis has been used in studies to look for related gene variations in periodic fever of unknown origin in the pediatric population.  Children with periodic fevers might be a diagnostic challenge. After ruling out the most prevalent causes, a wide variety of other possibilities are investigated. Infectious and noninfectious causes of periodic fever in children are discussed in this article. Inflammasomes (intracellular proteins that activate interleukin (IL)-1b and IL-18) and genetic/hereditary variations are thought to be implicated in the pathogenesis of periodic fever. Evaluation and ruling out possible infective or noninfective causes is vital in the diagnosis of periodic fever in children. Investigations demonstrate that there isn't a single gene linked to it, suggesting that it may have a multifactorial or polygenic origin, with an environmental trigger causing inflammasome activation and fever flares. Treatment is usually symptomatic, with drugs such as colchicine and cimetidine having shown promising results in trials. We explored the literature on periodic fever in children for its epidemiology, pathophysiology, the role of various genes and how they influence the disease and associated complications, and its various treatment modalities.

Análisis de la evolución del conocimiento preventivo y su práctica entre la población de Colombia hacia la enfermedad por Coronavirus (Covid-19)

La presente investigación muestra la evolución que ha presentado el conocimiento y práctica de las recomendaciones dadas por la Organización Mundial de la Salud para la prevención de la Covid-19 en comparación al estudio realizado por Rivera-Diaz et al. Se encuetaron 478 personas, los resultados mostraron que un alto porcentaje conoce y pone en práctica las recomendaciones de la OMS indistintamente del sexo del individuo. Además, el estudio evidencia la problemática relacionada con el consumo de sustancias o medicamentos para la prevención de la Covid-19, que pueden poner en serios riesgos la salud de quien los consume; de otro lado, el uso de plantas medicinales también demuestra ser una práctica muy común en la población.

SUMMARY This research shows the evolution that has been presented by the knowledge and practice by part of the people of the recommendations given by the World Health Organization for the prevention of Covid-19 compared to the study carried out by Rivera-Diaz et al. 478 people were surveyed, the results showed that a high percentage knows and puts into practice the WHO recommendations regardless of the sex of the individual. In addition, the study shows the problems related to the consumption of substances and / or medications for the prevention of Covid-19, which can put the health of those who consume them at serious risk; on the other hand, the use of medicinal plants also proves to be a very common practice in the population.

A presente investigação mostra a evolução que tem apresentado o conhecimento e prática das recomendações da Organização Mundial da Saúden para a prevenção do Covid-19 em comparação com o estudo realizado por Rivera-Diaz et ai. 478 pessoas foram entrevistadas, os resultados mostraram que uma alta porcentagem conhece e coloca em prática as recomendações da OMS, independentemente da sexo do indivíduo. Além disso, o estudo destaca o problema relacionado à consumo de substâncias ou medicamentos para a prevenção da Covid-19, que podem colocar em sério risco a saúde de quem os consome; Por outro lado, o uso de As plantas medicinais também se revelam uma prática muito comum na população.

Combined treatment of graft versus host disease using donor regulatory T cells and ruxolitinib.

Donor derived regulatory T lymphocytes and the JAK1/2 kinase inhibitor ruxolitinib are currently being evaluated as therapeutic options in the treatment of chronic graft versus host disease (cGvHD). In this work, we aimed to determine if the combined use of both agents can exert a synergistic effect in the treatment of GvHD. For this purpose, we studied the effect of this combination both in vitro and in a GvHD mouse model. Our results show that ruxolitinib favors the ratio of thymic regulatory T cells to conventional T cells in culture, without affecting the suppressive capacity of these Treg. The combination of ruxolitinib with Treg showed a higher efficacy as compared to each single treatment alone in our GvHD mouse model in terms of GvHD incidence, severity and survival without hampering graft versus leukemia effect. This beneficial effect correlated with the detection in the bone marrow of recipient mice of the infused donor allogeneic Treg after the adoptive transfer.

Effects of heavy grazing on the microclimate of a humid grassland mountain ecosystem: Insights from a biomass removal experiment.

In high-altitude Andean grasslands (páramo), overgrazing leads to alterations in both vegetation and microclimate. These alterations need to be identified to devise land management strategies that will preserve and enhance ecosystem processes. To elucidate this issue, we designed an overgrazing experiment: we selected two plots covered with native grass (pajonal), in one of which we mowed to the ground surface. We left the second plot undisturbed to serve as a control. For both plots, we continuously monitored albedo and ancillary energetic components to generate quarterly and yearly comparisons for the following parameters: (a) impacts on albedo and resilience of grass; (b) radiative forcing of albedo; and (c) land surface temperature feedback during the recovery period. In the first quarter following removal, when the soil was covered with light litter, median albedo increased 38.81% (0.16 ± 0.02), then began a gradual decrease, which continued until its full recovery 1.75 years later (0.10 ± 0.01). During the first year of the experiment, a strong mean negative instantaneous radiative forcing was observed (-7.08 ± 6.03 Wm-2), signifying a reduction in net shortwave energy. This forcing returned to normal, pre-intervention conditions (-0.55 ± 0.97 Wm-2) after 1.75 years, equal to the energetic recovery period of the grass. Both the amount (from 133.0 ± 44.72 to 119.67 ± 39.30 Wm-2) and the partitioning (net shortwave decreased 5%; net longwave increased 9.7%) of net energy were altered after removal, evidence of cooling feedback during the recovery period. This feedback indicated that the decrease in albedo (1.25%) or instantaneous radiative forcing (-4.67 Wm-2) resulted in a decrease in land surface temperature of 1 °C. Thus, our overgrazing experiment without soil destruction followed by a natural recovery time has identified the energetic recovery period for grass in the páramos; suggesting the albedo as a good indicator of grass resilience.

Impact of a Novel Social Work Program on Access to Tertiary Care.

Background: In the movement for global health equity, increased research and funding have not yet addressed a shortage of evidence on effectively implementing context-specific interventions; one unmet need is facilitating access to specialty care within the public health sector in Mexico. Compañeros en Salud has been piloting a novel program, called Right to Healthcare (RTHC), to increase access to specialty care for the rural poor in Chiapas, Mexico. The RTHC program incorporates social work, patient navigation, referrals, direct economic support, and accompaniment for patients. Objectives: This study evaluates the effectiveness of the RTHC program. Primary outcomes analyzed included acceptance of any referral and attendance of any appointment. Secondary outcomes included acceptance of the first referral and rate of appointment attendance for patients with an accepted referral. Methods: Using referral process data for the years 2014 to 2019 from a public tertiary care hospital in Chiapas, 91 RTHC patients were matched using 2:1 optimal pair matching with a control cohort balancing covariates of patient age, sex, specialty referred to, level of referring hospital, and municipality. Findings: RTHC patients were more likely to have had an accepted referral (OR 17.42, 95% CI 3.68 to 414.16) and to have attended an appointment (OR 5.49, 95% CI 2.93 to 11.60) compared to the matched control group. RTHC patients were also more likely to have had their first referral accepted (OR 2.78, 95% CI 1.29 to 6.73). Among patients with an accepted referral, RTHC patients were more likely to have attended an appointment (OR 3.86, 95% CI 1.90 to 8.57). Conclusions: The results demonstrate that the RTHC model is successful in increasing access to specialty care by both increasing referral acceptance and appointment attendance.

Gestão e ambientes de trabalho na atenção primária à saúde: revisão de escopo / Gestión y entornos de trabajo en la atención primaria de salud: revisión del alcance / Management and work environments in primary health care: scope review

RESUMO Objetivo: identificar subsídios teóricos e empíricos sobre ambientes de trabalho na atenção primária à saúde (APS) em sua relação à saúde do trabalhador (questão preliminar) que indiquem elementos relativos à gestão (questão específica). Métodos: Scoping Review de seis etapas com consulta aos sujeitos, busca na literatura do período de 2010 a 2019 em seis bases de dados e bibliotecas virtuais com seleção de 21 artigos. A etapa complementar, de consulta, operacionalizou grupo focal com 14 trabalhadores da APS em um município do Sul do Brasil. Resultados: foram organizados em três categorias temáticas: i) Aspectos administrativos no ambiente de trabalho: dificuldades relacionadas à gestão; ii) Percepções sobre as relações de trabalho: barreiras entre equipe e gestão; e iii) Conflitos no ambiente de trabalho: estratégias de enfrentamento. Considerações finais: questões de ordem burocrática e de rotina da APS influenciam as relações interpessoais e os resultados alcançados, sendo fundamentais para o alcance de ambientes saudáveis de trabalho dos atores em cena. O suporte institucional, o diálogo e a possibilidade de exercer um trabalho pleno de sentido e valor é direito do trabalhador, reafirmando a promoção de ambientes de trabalho saudáveis na APS como prioridade ético-política.

RESUMEN Objetivo: identificar subsidios teóricos y empíricos sobre ambientes de trabajo en APS en su relación con la salud de los trabajadores (cuestión preliminar) que indiquen elementos relacionados con la gestión (cuestión específica). Métodos: Scoping Review de seis etapas con consulta a los sujetos, búsqueda bibliográfica en el período de 2010 a 2019 en seis bases de datos y bibliotecas virtuales con selección de 21 artículos. La fase complementaria, de consulta, consistió en un grupo de reflexión con 14 trabajadores de Atención Primaria de Salud en un municipio del Sur de Brasil. Resultados: organizados en tres categorías temáticas: Aspectos administrativos en el entorno laboral: dificultades relacionadas con la gestión; Percepciones sobre las relaciones laborales: barreras entre el equipo y la dirección; Conflictos en el entorno laboral: estrategias de afrontamiento. Consideraciones finales: las cuestiones burocráticas y rutinarias de la APS influyen en las relaciones interpersonales y en los resultados alcanzados, siendo fundamentales para el logro de ambientes de trabajo saludables de los actores en escena. El apoyo institucional, el diálogo y la posibilidad de ejercer un trabajo lleno de sentido y valor es un derecho del trabajador, reafirmando la promoción de ambientes de trabajo saludables en la APS como una prioridad ético-política.

ABSTRACT Objective: to identify theoretical and empirical subsidies on work environments in primary health care (PHC) in relation to workers' health (preliminary question) that indicate elements related to management (specific question). Methods: six-step Scoping Review with consultation with the subjects, literature search from 2010 to 2019 in six databases and virtual libraries with selection of 21 articles. The complementary stage, consultation, operated a focus group with 14 PHC workers in a municipality in southern Brazil. Results: they were organized into three thematic categories: i) Administrative aspects in the work environment: difficulties related to management; ii) Perceptions about labor relations: barriers between staff and management; and iii) Conflicts in the workplace: coping strategies. Final considerations: bureaucratic and routine PHC issues influence interpersonal relationships and the results achieved, being fundamental for achieving healthy work environments for the actors on the scene. Institutional support, dialogue and the possibility of carrying out work full of meaning and value are workers' rights, reaffirming the promotion of healthy work environments in PHC as an ethical-political priority.

Healthy work environment in primary health care: integrative literature review / Ambiente de trabajo saludable en atención primaria: revisión bibliográfica integradora / Ambiente de trabalho saudável na atenção primária à saúde: revisão integrativa da literatura

Objective: to identify, in the scientific production, constituent elements of a healthy work environment in Primary Health Care for workers' health. Method: integrative literature review, conducted from June to August 2019, according to a search protocol built with eligibility parameters for the definition of a sample of 35 studies, to answer the guiding question: Which elements of the work environment in primary care refer to workers' health? Results: the analysis resulted in the elaboration of categories about illness and stress as repercussions of the subjective experience of work and the protective alternatives, education and transformation of work environments. Conclusion: in the scientific production studied, the constituent elements of a healthy work environment in Primary Health Care, related to workers' health, are generators of illness and stress and are in constant association with the context of this level of care, with the political management and the health work process, and with subjective experiences at work.

Objetivo: identificar, en la producción científica, los elementos constitutivos de un ambiente de trabajo saludable en Atención Primaria de la Salud para la salud de los trabajadores. Método: revisión bibliográfica integradora, realizada de junio a agosto de 2019, según un protocolo de búsqueda construido con parámetros de elegibilidad para la definición de una muestra de 35 estudios, para responder a la pregunta guía: ¿Qué elementos constitutivos del ambiente de trabajo en atención primaria hacen referencia a la salud de los trabajadores? Resultados: el análisis dio lugar a la elaboración de categorías sobre la enfermedad y el estrés como repercusiones de la experiencia subjetiva del trabajo y las alternativas de protección, educación y transformación de los ambientes de trabajo. Conclusión: en la producción científica estudiada, los elementos constitutivos del ambiente de trabajo saludable en la Atención Primaria de Salud, relacionados con la salud de los trabajadores, son generadores de enfermedad y estrés y están en constante asociación con el contexto de este nivel de atención, la gestión política y el proceso de trabajo en salud y las experiencias subjetivas en el trabajo.

Objetivo: identificar, na produção científica, elementos constituintes do ambiente de trabalho saudável na Atenção Primária à Saúde para a saúde dos trabalhadores. Método: revisão integrativa da literatura, realizada no período de junho a agosto de 2019, conforme protocolo de busca construído com parâmetros de elegibilidade para a definição de uma amostra de 35 estudos, para responder à questão norteadora: Quais elementos constituintes do ambiente de trabalho na atenção primária referem-se à saúde dos trabalhadores? Resultados: a análise resultou na elaboração das categorias acerca do adoecimento e do estresse como repercussões da vivência subjetiva do trabalho e das alternativas protetivas, de educação e de transformação dos ambientes de trabalho. Conclusão: na produção científica estudada, os elementos constituintes do ambiente de trabalho saudável na Atenção Primária à Saúde, relacionados à saúde dos trabalhadores, são geradores de adoecimento e estresse e estão em constante associação ao contexto desse nível de atenção, à gestão política e do processo de trabalho na saúde e às vivências subjetivas no trabalho.

Effect of Aspergillus and Bacillus Concentration on Cotton Growth Promotion.

There are no studies in literature on the effect of inoculant concentrations on plant growth promotion. Therefore, in the present study, two experiments were carried out, one under pot conditions and the other in the field with cotton crop, in order to verify the effect of Aspergillus and Bacillus concentrations on the biometric and nutritional parameters of plant and soil, in addition to yield. The pot experiment evaluated the effect of different concentrations, ranging from 1 × 104 to 1 × 1010 colony-forming units per milliliter (CFU mL-1) of microorganisms Bacillus velezensis (Bv188), Bacillus subtilis (Bs248), B. subtilis (Bs290), Aspergillus brasiliensis (F111), Aspergillus sydowii (F112), and Aspergillus sp. versicolor section (F113) on parameters plant growth promotion and physicochemical and microbiological of characteristics soil. Results indicated that the different parameters analyzed are influenced by the isolate and microbial concentrations in a different way and allowed the selection of four microorganisms (Bs248, Bv188, F112, and F113) and two concentrations (1 × 104 and 1 × 1010 CFU mL-1), which were evaluated in the field to determine their effect on yield. The results show that, regardless of isolate, inoculant concentrations promoted the same fiber and seed cotton yield. These results suggest that lower inoculant concentrations may be able to increase cotton yield, eliminating the need to use concentrated inoculants with high production cost.

Raman Spectroscopy and Machine Learning Reveals Early Tumor Microenvironmental Changes Induced by Immunotherapy.

Cancer immunotherapy provides durable clinical benefit in only a small fraction of patients, and identifying these patients is difficult due to a lack of reliable biomarkers for prediction and evaluation of treatment response. Here, we demonstrate the first application of label-free Raman spectroscopy for elucidating biomolecular changes induced by anti-CTLA4 and anti-PD-L1 immune checkpoint inhibitors (ICI) in the tumor microenvironment (TME) of colorectal tumor xenografts. Multivariate curve resolution-alternating least squares (MCR-ALS) decomposition of Raman spectral datasets revealed early changes in lipid, nucleic acid, and collagen content following therapy. Support vector machine classifiers and random forests analysis provided excellent prediction accuracies for response to both ICIs and delineated spectral markers specific to each therapy, consistent with their differential mechanisms of action. Corroborated by proteomics analysis, our observation of biomolecular changes in the TME should catalyze detailed investigations for translating such markers and label-free Raman spectroscopy for clinical monitoring of immunotherapy response in cancer patients. SIGNIFICANCE: This study provides first-in-class evidence that optical spectroscopy allows sensitive detection of early changes in the biomolecular composition of tumors that predict response to immunotherapy with immune checkpoint inhibitors.

Longitudinal monitoring of tumor response to immune checkpoint inhibitors using noninvasive diffuse reflectance spectroscopy.

Immune checkpoint inhibitors have revolutionized cancer treatment. However, there are currently no methods for noninvasively and nondestructively evaluating tumor response to immune checkpoint inhibitors. We used diffuse reflectance spectroscopy to monitor in vivo tumor microenvironmental changes in response to immune checkpoint inhibitors in a CT26 murine colorectal cancer model. Mice growing CT26 tumor xenografts were treated with either anti-PD-L1, anti-CTLA-4, a combination of both inhibitors, or isotype control on 3 separate days. Monotherapy with either anti-PD-L1 or anti-CTLA-4 led to a large increase in tumor vascular oxygenation within the first 6 days. Reoxygenation in anti-CTLA-4-treated tumors was due to a combination of increased oxygenated hemoglobin and decreased deoxygenated hemoglobin, pointing to a possible change in tumor oxygen consumption following treatment. Within the anti-PD-L1-treated tumors, reoxygenation was primarily due to an increase in oxygenated hemoglobin with the minimal change in deoxygenated hemoglobin, indicative of a likely increase in tumor perfusion. The tumors in the combined treatment group did not show any significant changes in tumor oxygenation following therapy. These studies demonstrate the sensitivity of diffuse reflectance spectroscopy to tumor microenvironmental changes following immunotherapy and the potential of such non-invasive techniques to determine early tumor response to immune checkpoint inhibitors.

p21-Activated Kinase 1 Promotes Breast Tumorigenesis via Phosphorylation and Activation of the Calcium/Calmodulin-Dependent Protein Kinase II.

p21-Activated kinase-1 (Pak1) is frequently overexpressed and/or amplified in human breast cancer and is necessary for transformation of mammary epithelial cells. Here, we show that Pak1 interacts with and phosphorylates the Calcium/Calmodulin-dependent Protein Kinase II (CaMKII), and that pharmacological inhibition or depletion of Pak1 leads to diminished activity of CaMKII. We found a strong correlation between Pak1 and CaMKII expression in human breast cancer samples, and combined inhibition of Pak1 and CaMKII with small-molecule inhibitors was synergistic and induced apoptosis more potently in Her2 positive and triple negative breast cancer (TNBC) cells. Co-adminstration of Pak and CaMKII small-molecule inhibitors resulted in a dramatic reduction of proliferation and an increase in apoptosis in a 3D cell culture setting, as well as an impairment in migration and invasion of TNBC cells. Finally, mice bearing xenografts of TNBC cells showed a significant delay in tumor growth when treated with small-molecule inhibitors of Pak and CaMKII. These data delineate a signaling pathway from Pak1 to CaMKII that is required for efficient proliferation, migration and invasion of mammary epithelial cells, and suggest new therapeutic strategies in breast cancer.

Conocimiento preventivo y su práctica entre la población de Colombia hacia la enfermedad por Coronavirus (COVID-19): una perspectiva de género / Preventive knowledge and its practice among Colombian population towards coronavirus disease (COVID-19): A Gender-Based Perspective

RESUMEN Este estudio investiga el conocimiento existente de la COVID-19 en ambos sexos y propone una práctica para prevenir la COVID-19. Se realizó un estudio transversal con una encuesta en línea recopilando datos en diferentes regiones de Colombia, a través de un cuestionario validado estructurado y de diseño propio basado en el asesoramiento público general de la Organización Mundial de la Salud (OMS) sobre la prevención de la COVID-19. Este estudio ha empleado la técnica de muestreo de bola de nieve, y contó con 445 participantes (46,5% hombres y 53,5% mujeres). Se identificó que las mujeres no solo tienen un mejor conocimiento, sino que su comportamiento en la práctica es mucho mejor que sus contrapartes masculinas. Aunque los resultados entre hombres y mujeres son muy similares, la pregunta de quedarse en casa es bastante concluyente a favor de las mujeres, quienes son más responsables. Finalmente, el estudio demuestra que las mujeres corren menos riesgo en comparación con los hombres, porque estas tienen mejores prácticas de prevención, como lo indican las estadísticas. Este estudio destaca aún más la idea de que las mujeres son menos propicias para contraer la infección de covid-19 debido a su mejor comportamiento de práctica que los hombres.

SUMMARY This study investigates the existing knowledge of covid-19 among both genders and a likely use of it in practice to combat COVID-19. Cross sectional study with an online survey and data was collected from Colombia, through a structured, self-design validated questionnaire was created based on the World Health Organization (WHO) general public advice towards COVID-19 prevention. This study has employed snow-ball sampling technique, counted on 445 participants (46.5% male and 53.5% female). This study has found out that women not only carry better knowledge, but their practicing behavior is far better than their male counterparts. Although the results between men and women are very similar, the question about staying at home is quite conclusive in favor of women, who are more responsible. Finally his study proves that women are on a less risk in comparison to men on the basis of prevention practices exercised better as the prevailing statistics indicate. This study highlighted the notion further that women are less conducive to infection of COVID-19 due to their better practicing behavior than men.