New Monoterpenoid as the Sex Pheromone of Spanish Populations of the Longtailed Mealybug Pseudococcus Longispinus (Hemiptera: Pseudococcidae).

Pseudococcus longispinus (Targioni-Tozzetti) (Hemiptera: Coccoidea: Pseudococcidae), a polyphagous and cosmopolitan pest native to Australia, is a highly damaging pest for numerous crops of economic importance. The sex pheromone of this species (2-(1,5,5-trimethylcyclopent-2-en-1-yl)ethyl acetate), currently used for pest monitoring purposes, was not attractive to males in field experiments conducted in Spanish persimmon orchards infested with this mealybug. The virgin and mated female volatile profiles of these P. longispinus populations were studied by the volatile collection of effluvia in Porapak-Q. The resulting extracts were analyzed by gas chromatography coupled to mass spectrometry (GC-MS), revealing a new compound specific to virgin females and different from the previously described sex pheromone. Based on GC-MS data and nuclear magnetic resonance experiments, we envisaged monoterpene 2-(1,5-dimethyl-4-methylenecyclopent-2-en-1-yl)ethyl acetate as the new sex pheromone candidate, which was synthesized and shown to be attractive in the field to P. longispinus males of the Spanish population.

The fatty acid omega hydroxylase genes (CYP4 family) in the progression of metabolic dysfunction-associated steatotic liver disease (MASLD): An RNA sequence database analysis and review.

Fatty acid omega hydroxylase P450s consist of enzymes that hydroxylate various chain-length saturated and unsaturated fatty acids (FAs) and bioactive eicosanoid lipids. The human cytochrome P450 gene 4 family (CYP4) consists of 12 members that are associated with several human diseases. However, their role in the progression of metabolic dysfunction-associated fatty liver disease (MASLD) remains largely unknown. It has long been thought that the induction of CYP4 family P450 during fasting and starvation prevents FA-related lipotoxicity through FA metabolism to dicarboxylic acids that are chain-shortened in peroxisomes and then transported to the mitochondria for complete oxidation. Several studies have revealed that peroxisome succinate transported to the mitochondria is used for gluconeogenesis during fasting and starvation, and recent evidence suggests that peroxisome acetate can be utilized for lipogenesis and lipid droplet formation as well as epigenetic modification of gene transcription. In addition, omega hydroxylation of the bioactive eicosanoid arachidonic acid to 20-Hydroxyeicosatetraenoic acid (20-HETE) is essential for activating the GPR75 receptor, leading to vasoconstriction and cell proliferation. Several mouse models of diet-induced MASLD have revealed the induction of selective CYP4A members and the suppression of CYP4F during steatosis and steatohepatitis, suggesting a critical metabolic role in the progression of fatty liver disease. Thus, to further investigate the functional roles of CYP4 genes, we analyzed the differential gene expression of 12 members of CYP4 gene family in datasets from the Gene Expression Omnibus (GEO) from patients with steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. We also observed the differential expression of various CYP4 genes in the progression of MASLD, indicating that different CYP4 members may have unique functional roles in the metabolism of specific FAs and eicosanoids at various stages of fatty liver disease. These results suggest that targeting selective members of the CYP4A family is a viable therapeutic approach for treating and managing MASLD.

Mathematical modeling of brain metastases growth and response to therapies: A review.

Brain metastases (BMs) are the most common intracranial tumor type and a significant health concern, affecting approximately 10% to 30% of all oncological patients. Although significant progress is being made, many aspects of the metastatic process to the brain and the growth of the resulting lesions are still not well understood. There is a need for an improved understanding of the growth dynamics and the response to treatment of these tumors. Mathematical models have been proven valuable for drawing inferences and making predictions in different fields of cancer research, but few mathematical works have considered BMs. This comprehensive review aims to establish a unified platform and contribute to fostering emerging efforts dedicated to enhancing our mathematical understanding of this intricate and challenging disease. We focus on the progress made in the initial stages of mathematical modeling research regarding BMs and the significant insights gained from such studies. We also explore the vital role of mathematical modeling in predicting treatment outcomes and enhancing the quality of clinical decision-making for patients facing BMs.

(F)utility of preoperative pulmonary function testing in pectus excavatum to assess severity.

PURPOSE: The utility of pulmonary function testing (PFT) in pectus excavatum (PE) has been subject to debate. Although some evidence shows improvement from preoperative to postoperative values, the clinical significance is uncertain. A high failure-to-completion rate for operative PFT (48%) was identified in our large institutional cohort. With such a high non-completion rate, we questioned the overall utility of PFT in the preoperative assessment of PE and sought to evaluate if other measures of PE severity or cardiopulmonary function could explain this finding. METHODS: Demographics, clinical findings, and results from cardiac MRI, PFT (spirometry and plethysmography), and cardiopulmonary exercise tests (CPET) were reviewed in 270 patients with PE evaluated preoperatively between 2015 and 2018. Regression modeling was used to measure associations between PFT completion and cardiopulmonary function. RESULTS: There were no differences in demographics, symptoms, connective tissue disorders, or multiple indices of pectus severity and cardiac deformation in PFT completers versus non-completers. While regression analysis revealed higher RVEF, LVEF, and LVEF-Z scores, lower RV-ESV/BSA, LV-ESV/BSA, and LV-ESV/BSA-Z scores, and abnormal breathing reserve in PFT completers vs. non-completers, these findings were not consistent across continuous and binary analyses. CONCLUSIONS: We found that PFT completers were not significantly different from non-completers in most structural and functional measures of pectus deformity and cardiopulmonary function. Inability to complete PFT is not an indicator of pectus severity.

Uncovering a novel mechanism: Butyrate induces estrogen receptor alpha activation independent of estrogen stimulation in MCF-7 breast cancer cells.

Butyrate is a promising candidate for an antitumoral drug, as it promotes cancer cell apoptosis and reduces hormone receptor activity, while promoting differentiation and proliferation in normal cells. However, the effects of low-dose butyrate on breast cancer cell cultures are unclear. We explored the impact of sub-therapeutic doses of butyrate on estrogen receptor alpha (ERα) transcriptional activity in MCF-7 cells, using RT-qPCR, Western blot, wound-healing assays, and chromatin immunoprecipitation. Our results showed that sub-therapeutic doses of sodium butyrate (0.1 - 0.2 mM) increased the transcription of ESR1, TFF1, and CSTD genes, but did not affect ERα protein levels. Moreover, we observed an increase in cell migration in wound-healing assays. ChIP assays revealed that treatment with 0.1 mM of sodium butyrate resulted in estrogen-independent recruitment of ERα at the pS2 promoter and loss of NCoR. Appropriate therapeutic dosage of butyrate is essential to avoid potential adverse effects on patients' health, especially in the case of estrogen receptor-positive breast tumors. Sub-therapeutic doses of butyrate may induce undesirable cell processes, such as migration due to low-dose butyrate-mediated ERα activation. These findings shed light on the complex effects of butyrate in breast cancer and provide insights for research in the development of antitumoral drugs.

Training pathologists to assess stromal tumour-infiltrating lymphocytes in breast cancer synergises efforts in clinical care and scientific research.

A growing body of research supports stromal tumour-infiltrating lymphocyte (TIL) density in breast cancer to be a robust prognostic and predicive biomarker. The gold standard for stromal TIL density quantitation in breast cancer is pathologist visual assessment using haematoxylin and eosin-stained slides. Artificial intelligence/machine-learning algorithms are in development to automate the stromal TIL scoring process, and must be validated against a reference standard such as pathologist visual assessment. Visual TIL assessment may suffer from significant interobserver variability. To improve interobserver agreement, regulatory science experts at the US Food and Drug Administration partnered with academic pathologists internationally to create a freely available online continuing medical education (CME) course to train pathologists in assessing breast cancer stromal TILs using an interactive format with expert commentary. Here we describe and provide a user guide to this CME course, whose content was designed to improve pathologist accuracy in scoring breast cancer TILs. We also suggest subsequent steps to translate knowledge into clinical practice with proficiency testing.

Service Utilization Patterns and Direct Medical Costs of Hospitalization in Patients With Renal Failure Before and After Initiating Home Peritoneal Dialysis.

OBJECTIVES: This study aimed to determine the hospital service utilization patterns and direct healthcare hospital costs before and during peritoneal dialysis (PD) at home. METHODS: A retrospective cohort study of patients with kidney failure (KF) was conducted at a Mexican Social Security Institute hospital for the year 2014. Cost categories included inpatient emergency room stays, inpatient services at internal medicine or surgery, and hospital PD. The study groups were (1) patients with KF before initiating home PD, (2) patients with less than 1 year of home PD (incident), and (3) patients with more than 1 year of home PD (prevalent). Costs were actualized to international dollars (Int$) 2023. RESULTS: We found that 53% of patients with KF used home PD services, 42% had not received any type of PD, and 5% had hospital dialysis while waiting for home PD. The estimated costs adjusting for age and sex were Int$5339 (95% CI 4680-9746) for patients without home PD, Int$17 556 (95% CI 15 314-19 789) for incident patients, and Int$7872 (95% CI 5994-9749) for prevalent patients; with significantly different averages for the 3 groups (P < .001). CONCLUSIONS: Although the use of services and cost is highest at the time of initiating PD, over time, using home PD leads to a significant reduction in use of hospital services, which translates into institutional cost savings. Our findings, especially considering the high rates of KF in Mexico, suggest a pressing need for interventions that can reduce healthcare costs at the beginning of renal replacement therapy.

Neuroendocrine Tumor Presented With Axillary Mass: A Case Report.

ABSTRACT: A 79-year-old man presented with a palpable left axillary mass and ultrasonography findings of conglomerate lymph nodes. The initial clinical suspicion was a lymphoproliferative disorder, but histopathological results revealed a grade 3 neuroendocrine tumor. The mass showed somatostatin receptor overexpression in 99m Tc-HYNIC-TOC scintigraphy and high uptake in 18 F-FDG PET/CT. Bilateral hypermetabolic adrenal nodes suggestive of metastases were also detected. The patient was treated with chemotherapy and immunotherapy, and PET/CT scan showed a partial metabolic response after 4 cycles. According to this case, neuroendocrine tumor should be considered in the differential diagnosis of axillary masses.

Chromosomal instability in aneuploid acute lymphoblastic leukemia associates with disease progression.

Chromosomal instability (CIN) lies at the core of cancer development leading to aneuploidy, chromosomal copy-number heterogeneity (chr-CNH) and ultimately, unfavorable clinical outcomes. Despite its ubiquity in cancer, the presence of CIN in childhood B-cell acute lymphoblastic leukemia (cB-ALL), the most frequent pediatric cancer showing high frequencies of aneuploidy, remains unknown. Here, we elucidate the presence of CIN in aneuploid cB-ALL subtypes using single-cell whole-genome sequencing of primary cB-ALL samples and by generating and functionally characterizing patient-derived xenograft models (cB-ALL-PDX). We report higher rates of CIN across aneuploid than in euploid cB-ALL that strongly correlate with intraclonal chr-CNH and overall survival in mice. This association was further supported by in silico mathematical modeling. Moreover, mass-spectrometry analyses of cB-ALL-PDX revealed a "CIN signature" enriched in mitotic-spindle regulatory pathways, which was confirmed by RNA-sequencing of a large cohort of cB-ALL samples. The link between the presence of CIN in aneuploid cB-ALL and disease progression opens new possibilities for patient stratification and offers a promising new avenue as a therapeutic target in cB-ALL treatment.

Volumetric analysis: Rethinking brain metastases response assessment.

Background: The Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) criteria are the gold standard for assessing brain metastases (BMs) treatment response. However, they are limited by their reliance on 1D, despite the routine use of high-resolution T1-weighted MRI scans for BMs, which allows for 3D measurements. Our study aimed to investigate whether volumetric measurements could improve the response assessment in patients with BMs. Methods: We retrospectively evaluated a dataset comprising 783 BMs and analyzed the response of 185 of them from 132 patients who underwent stereotactic radiotherapy between 2007 and 2021 at 5 hospitals. We used T1-weighted MRIs to compute the volume of the lesions. For the volumetric criteria, progressive disease was defined as at least a 30% increase in volume, and partial response was characterized by a 20% volume reduction. Results: Our study showed that the proposed volumetric criteria outperformed the RANO-BM criteria in several aspects: (1) Evaluating every lesion, while RANO-BM failed to evaluate 9.2% of them. (2) Classifying response effectively in 140 lesions, compared to only 72 lesions classified by RANO-BM. (3) Identifying BM recurrences a median of 3.3 months earlier than RANO-BM criteria. Conclusions: Our study demonstrates the superiority of volumetric criteria in improving the response assessment of BMs compared to the RANO-BM criteria. Our proposed criteria allow for evaluation of every lesion, regardless of its size or shape, better classification, and enable earlier identification of progressive disease. Volumetric criteria provide a standardized, reliable, and objective tool for assessing treatment response.

Beyond the Scalpel: Assessing ChatGPT's potential as an auxiliary intelligent virtual assistant in oral surgery.

AI has revolutionized the way we interact with technology. Noteworthy advances in AI algorithms and large language models (LLM) have led to the development of natural generative language (NGL) systems such as ChatGPT. Although these LLM can simulate human conversations and generate content in real time, they face challenges related to the topicality and accuracy of the information they generate. This study aimed to assess whether ChatGPT-4 could provide accurate and reliable answers to general dentists in the field of oral surgery, and thus explore its potential as an intelligent virtual assistant in clinical decision making in oral surgery. Thirty questions related to oral surgery were posed to ChatGPT4, each question repeated 30 times. Subsequently, a total of 900 responses were obtained. Two surgeons graded the answers according to the guidelines of the Spanish Society of Oral Surgery, using a three-point Likert scale (correct, partially correct/incomplete, and incorrect). Disagreements were arbitrated by an experienced oral surgeon, who provided the final grade Accuracy was found to be 71.7%, and consistency of the experts' grading across iterations, ranged from moderate to almost perfect. ChatGPT-4, with its potential capabilities, will inevitably be integrated into dental disciplines, including oral surgery. In the future, it could be considered as an auxiliary intelligent virtual assistant, though it would never replace oral surgery experts. Proper training and verified information by experts will remain vital to the implementation of the technology. More comprehensive research is needed to ensure the safe and successful application of AI in oral surgery.

Does the distribution of musculoskeletal pain shape the fate of long-term sick leave? A prospective cohort study with register follow-up.

ABSTRACT: Although multisite pain can markedly reduce work ability, the relevance of the bodily pain distribution as a predictor of long-term sick leave is still unknown. This study aimed to investigate the association between musculoskeletal pain distributions and long-term sick leave in the general working population of Denmark and included 66,177 currently employed wage earners without long-term sick leave during the prior 52 weeks. Participants reported whether they had pain in the lower extremity (hips/knees), upper extremity (neck/shoulders), or the low back. The analysis controlled for age, sex, year of survey reply, educational level, occupational group, psychosocial work factors, body max index, smoking, leisure-time physical activity, and mental health confounders. The results demonstrated that the risk of long-term sick leave increased with the number of pain sites. Compared with no pain, localized pain in any body region increased the risk/hazard by 25% to 29% (HR [95% CI]: 1.29 [1.07-1.54] for pain only in the low back), whereas pain in 2 regions increased the risk by 39% to 44% (HR [95% CI]: 1.41 [1.18-1.69] for pain in the low back + hips/knees). Workers reporting pain in all 3 regions experienced a 72% increased risk (HR [95% CI]: 1.72 [1.55-1.91]). Thus, the number of pain regions seems to matter more than the exact pain location. The spatial extension of musculoskeletal pain in workers functions as a gradient system, where pain spread throughout the body is an independent indicator of the high risk of long-term sick leave.

Radiation necrosis after radiation therapy treatment of brain metastases: A computational approach.

Metastasis is the process through which cancer cells break away from a primary tumor, travel through the blood or lymph system, and form new tumors in distant tissues. One of the preferred sites for metastatic dissemination is the brain, affecting more than 20% of all cancer patients. This figure is increasing steadily due to improvements in treatments of primary tumors. Stereotactic radiosurgery (SRS) is one of the main treatment options for patients with a small or moderate number of brain metastases (BMs). A frequent adverse event of SRS is radiation necrosis (RN), an inflammatory condition caused by late normal tissue cell death. A major diagnostic problem is that RNs are difficult to distinguish from BM recurrences, due to their similarities on standard magnetic resonance images (MRIs). However, this distinction is key to choosing the best therapeutic approach since RNs resolve often without further interventions, while relapsing BMs may require open brain surgery. Recent research has shown that RNs have a faster growth dynamics than recurrent BMs, providing a way to differentiate the two entities, but no mechanistic explanation has been provided for those observations. In this study, computational frameworks were developed based on mathematical models of increasing complexity, providing mechanistic explanations for the differential growth dynamics of BMs relapse versus RN events and explaining the observed clinical phenomenology. Simulated tumor relapses were found to have growth exponents substantially smaller than the group in which there was inflammation due to damage induced by SRS to normal brain tissue adjacent to the BMs, thus leading to RN. ROC curves with the synthetic data had an optimal threshold that maximized the sensitivity and specificity values for a growth exponent ß* = 1.05, very close to that observed in patient datasets.

The Potential Utility of 18 F-FDG PET/CT in Monitoring Corticosteroid Therapy in Inflammatory Pseudotumor.

ABSTRACT: A 69-year-old man with suspected gastrointestinal stromal tumor was referred to 18 F-FDG PET/CT. Images showed increased metabolism in a jejunal wall thickening, 2 liver lesions, and hepatic lymph nodes. The patient underwent wedge biopsy of the liver, which revealed inflammatory pseudotumor. The patient was treated with 20 mg/d prednisone, with a gradual dose reduction. A partial metabolic response was achieved after 2 months of therapy, and a final PET/CT showed complete metabolic response after 9 months. This clinical case shows the potential role of PET/CT in the assessment of the response of the inflammatory pseudotumor to corticosteroid therapy.

Outcomes From a Nurse Practitioner Led Dynamic Compression System Bracing Program for Pectus Carinatum.

BACKGROUND: Dynamic compression system (DCS) is often effective at treating pectus carinatum (PC). However, some patients will fail therapy. This study reports outcomes from a nurse-practitioner led bracing program, and evaluates what factors are predictive of successful therapy. METHODS: We performed a retrospective cohort study involving all patients treated with DCS bracing at our institution between February 2018 and February 2022. Patients with at least three visits were included. The primary outcome was achieving neutral chest. Factors considered potentially predictive included patient age, sex, initial pressure of correction (PIC), and the change in pressure of correction between the first two visits (deltaPC1). A Cox proportional hazards model was used for analysis, and Kaplan-Meier analyses estimated the median time to correction. RESULTS: 283 patients were evaluated. The median age was 14 (IQR 12-15), the majority were male (90.1 %) and white (92.6 %). The median PIC and deltaPC1was 4.13 PSI (IQR 3.17-5.3), and 1.34 PSI (IQR 0.54-2.25), respectively. 117 patients achieved correction. The median estimated time to correction was 7.5 months (95 % CI 5.9-10.1). In the final Cox model, greater deltaPC1 was associated with increased risk of correction (HR: 2.46; 95 % CI 2.03-2.98), and increased PIC was associated with decreased risk of correction up to one year of therapy (0-3 months HR 0.62, 95 % CI 0.50-0.78; 3-12 months HR 0.62; 95 % CI 0.45-0.85). CONCLUSIONS: DCS bracing administered by advanced care providers in collaboration with surgeons can effectively treat PC. The deltaPC1 and PIC are the factors most predictive of successful therapy. LEVEL OF EVIDENCE: Level III.

Intrahepatic Cholangiolitis in Cystic Fibrosis (ICCF): An Under-Appreciated Cause of Persistent Cholestasis in Infancy.

Liver histology in infants with cystic fibrosis (CF) and persistent cholestasis is seldom reported in detail. We extend previous observation of a distinctive intrahepatic cholangiopathy (ICCF) to 3 additional infants homozygous for CFTR pathological variants and a fourth infant with a heterozygous CFTR variant, summarizing our experience in 10 infants with CFTR variants and persistent cholestasis. Cholangiograms demonstrate abnormal extrahepatic ducts in 2 infants with CF, 1 with uniform dilatation interpreted as a choledochal cyst and the other with narrow patent ducts. Liver histology in 3 CF homozygotes had prominent ductular reaction with a focally destructive cholangiolitis (inflammation of small bile ducts). The CFTR heterozygote had generalized portal edema with ductular reaction and paucity but no cholangitis. Cholestasis slowly subsided in all infants. ICCF is characterized by severe ductular reaction, prominent cholangiocyte injury, and multifocal necrotizing cholangiolitis. Local aggregates of portal ceroid might suggest previous bile leakage from damaged ducts. ICCF in liver biopsies from infants with cystic fibrosis and persistent cholestasis is unrelated to the specific CFTR genotype. Liver biopsy findings and intraoperative cholangiogram help rule out biliary atresia. ICCF is an early manifestation of CF, a likely prototype for pathogenesis of cystic fibrosis liver disease later in life.

Effects of Chemical inhibition of histone deacetylase proteins in the growth and virulence of Macrophomina phaseolina (Tassi) Goid / Efectos de la inhibición química de las proteínas desacetilasas de histonas en el crecimiento y la virulencia de Macrophomina phaseolina (Tassi) Goid

Abstract Chromatin remodeling enzymes are important "writers'', "readers'' and "erasers'' of the epigenetic code. These proteins are responsible for the placement, recognition, and removal of molecular marks in histone tails that trigger structural and functional changes in chromatin. This is also the case for histone deacetylases (HDACs), i.e., enzymes that remove acetyl groups from histone tails, signaling heterochromatin formation. Chromatin remodeling is necessary for cell differentiation processes in eukaryotes, and fungal pathogenesis in plants includes many adaptations to cause disease. Macrophomina phaseolina (Tassi) Goid. is a nonspe-cific, necrotrophic ascomycete phytopathogen that causes charcoal root disease. M. phaseolina is a frequent and highly destructive pathogen in crops such as common beans (Phaseolus vulgaris L.), particularly under both water and high temperature stresses. Here, we evaluated the effects of the classical HDAC inhibitor trichostatin A (TSA) on M. phaseolina in vitro growth and virulence. During inhibition assays, the growth of M. phaseolina in solid media, as well as the size of the microsclerotia, were reduced (p <0.05), and the colony morphology was remark-ably affected. Under greenhouse experiments, treatment with TSA reduced (p <0.05) fungal virulence in common bean cv. BAT 477. Tests of LIPK, MAC1 and PMK1 gene expression during the interaction of fungi with BAT 477 revealed noticeable deregulation. Our results provide additional evidence about the role of HATs and HDACs in important biological processes of M. phaseolina.

Resumen Las enzimas remodeladoras de la cromatina son «escritores¼, «lectores¼ y «borradores¼ importantes del código epigenético. Estas proteínas son responsables de la localización, el reconocimiento y la remoción de las marcas moleculares sobre las terminaciones de las histonas que desencadenan cambios funcionales y estructurales en la cromatina. Es el caso de las desacetilasas de histonas (HDAC), enzimas que remueven grupos acetilo de las «colas¼ de las histonas, señalizando la formación de heterocromatina. La anterior es una actividad necesaria en los procesos de diferenciación celular de los eucariotas, y se conoce que la patogénesis fúngica en las plantas requiere de adaptaciones diversas para ocasionar enfermedad. Macrophomina phaseolina (Tassi) Goid. es un ascomiceto fitopatógeno, necrótrofo e inespecífico, causante de la pudrición carbonosa. Este es un hongo frecuente y altamente destructivo en cultivos como fríjol común (Phaseolus vulgaris L.), particularmente bajo estrés hídrico y térmico. En este trabajo evaluamos los efectos del inhibidor de HDAC clásicas tricostatina A (TSA) sobre el crecimiento in vitro y la virulencia de M. phaseolina. El TSA redujo el crecimiento de M. phaseolina en medio sólido y el tamano de los microesclerocios (p < 0,05), lo que afectó la morfología colonial. En invernadero, el tratamiento con TSA disminuyó (p<0,05) la gravedad de la infección en la variedad de frijol BAT 477. La expresión de los genes de patogenicidad LIPK, MAC1 y PMK1 durante la interacción del hongo con la planta reveló una desregulación importante. Estos resultados proporcionan evidencia adicional del papel que cumplen las HDAC en la regulación de procesos biológicos fundamentales de M. phaseolina. © 2023 Asociación Argentina de Microbiología. Publicado por Elsevier Espana, S.L.U.

Use of probiotics in the catfish Sorubim cuspicaudus larviculture

Sorubim cuspicaudus, a migratory catfish distributed in the Magdalena, Sinú, and Catatumbo river basins, is categorized as vulnerable to extinction. Production of fingerlings in controlled environments stands as a strategic conservation approach, and larviculture is a critical phase in rearing this species. Probiotics are used for improvement in the critical stages of fingerling production. The study aimed to evaluate the use of probiotics (Bacillus subtilis and Bacillus licheniformis) during the larviculture phase of S. cuspicaudus. Larvae at 42 hours post-hatching (1.5±0.1mg, total length 5.7±0.4mm) were treated with four levels of probiotic inclusion in the water: 0, 5, 10, and 20ppm for 22 days. Water quality remained within suitable ranges for neotropical catfish species larviculture and the parameters assessed were weight gain (Gw), length gain (Gl), specific growth rate (G), survival rate (S), stress resistance (Sr), intestinal fold length (LF), and colony-forming units (CFU) count. Results showed higher Gl (22.23±3.5mm), Gw (40.0±12.6mg), G (14.9±1.5%/day), LP (205±72.7µm), and CFU (118.7±80.9) were found at 20 ppm (p0.05). The findings of this study suggest that probiotics (Bacillus subtilis and Bacillus licheniformis) could be used as an alternative to advance in the S. cuspicaudus larviculture.

Sorubim cuspicaudus, un bagre migratorio distribuido en las cuencas de los ríos Magdalena, Sinú y Catatumbo, se encuentra catalogado como una especie vulnerable a la extinción. La producción de alevinos en ambientes controlados es considerada como una estrategia crucial para su conservación, y la larvicultura es una fase crítica en la cría de esta especie. Para mejorar esta fase crítica de producción de alevinos se utilizan probióticos. El estudio tenía como objetivo evaluar el uso de probióticos (Bacillus subtilis y Bacillus licheniformis) durante la fase de larvicultura de S. cuspicaudus. Las larvas, a las 42 horas post eclosión (1,5±0,1mg, longitud total 5,7±0,4mm) fueron tratadas con cuatro niveles de inclusión de probióticos en el agua: 0, 5, 10 y 20ppm durante 22 días. La calidad del agua se mantuvo dentro de los rangos adecuados para la larvicultura de especies neotropicales de bagre y los parámetros evaluados fueron el aumento de peso (Gw), el aumento de longitud (GL), la tasa específica de crecimiento (G), la tasa de supervivencia (S), la resistencia al estrés (Sr), la longitud del pliegue intestinal (LF) y el recuento de unidades formadoras de colonias (UFC). Los resultados mostraron mayores GL (22,23±3,5 mm), Gw (40,0±12,6 mg), G (14,9±1,5%/día), LP (205±72,7 µm) y UFC (118,7±80,9) a 20 ppm (p0,05). Los resultados de este estudio sugieren que los probióticos (Bacillus subtilis y Bacillus licheniformis) podrían utilizarse como alternativa para avanzar en la larvicultura de S. cuspicaudus.

Overcoming chemotherapy resistance in low-grade gliomas: A computational approach.

Low-grade gliomas are primary brain tumors that arise from glial cells and are usually treated with temozolomide (TMZ) as a chemotherapeutic option. They are often incurable, but patients have a prolonged survival. One of the shortcomings of the treatment is that patients eventually develop drug resistance. Recent findings show that persisters, cells that enter a dormancy state to resist treatment, play an important role in the development of resistance to TMZ. In this study we constructed a mathematical model of low-grade glioma response to TMZ incorporating a persister population. The model was able to describe the volumetric longitudinal dynamics, observed in routine FLAIR 3D sequences, of low-grade glioma patients acquiring TMZ resistance. We used the model to explore different TMZ administration protocols, first on virtual clones of real patients and afterwards on virtual patients preserving the relationships between parameters of real patients. In silico clinical trials showed that resistance development was deferred by protocols in which individual doses are administered after rest periods, rather than the 28-days cycle standard protocol. This led to median survival gains in virtual patients of more than 15 months when using resting periods between two and three weeks and agreed with recent experimental observations in animal models. Additionally, we tested adaptive variations of these new protocols, what showed a potential reduction in toxicity, but no survival gain. Our computational results highlight the need of further clinical trials that could obtain better results from treatment with TMZ in low grade gliomas.

Initial interactions with the FDA on developing a validation dataset as a medical device development tool.

Quantifying tumor-infiltrating lymphocytes (TILs) in breast cancer tumors is a challenging task for pathologists. With the advent of whole slide imaging that digitizes glass slides, it is possible to apply computational models to quantify TILs for pathologists. Development of computational models requires significant time, expertise, consensus, and investment. To reduce this burden, we are preparing a dataset for developers to validate their models and a proposal to the Medical Device Development Tool (MDDT) program in the Center for Devices and Radiological Health of the U.S. Food and Drug Administration (FDA). If the FDA qualifies the dataset for its submitted context of use, model developers can use it in a regulatory submission within the qualified context of use without additional documentation. Our dataset aims at reducing the regulatory burden placed on developers of models that estimate the density of TILs and will allow head-to-head comparison of multiple computational models on the same data. In this paper, we discuss the MDDT preparation and submission process, including the feedback we received from our initial interactions with the FDA and propose how a qualified MDDT validation dataset could be a mechanism for open, fair, and consistent measures of computational model performance. Our experiences will help the community understand what the FDA considers relevant and appropriate (from the perspective of the submitter), at the early stages of the MDDT submission process, for validating stromal TIL density estimation models and other potential computational models. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.