Pathogenic Roles for RNASET2 in Clear Cell Renal Cell Carcinoma.

A specific splicing isoform of RNASET2 is associated with worse oncologic outcomes in clear cell renal cell carcinoma (ccRCC). However, the interplay between wild-type RNASET2 and its splice variant and how this might contribute to the pathogenesis of ccRCC remains poorly understood. We sought to better understand the relationship of RNASET2 in the pathogenesis of ccRCC and the interplay with a pathogenic splicing isoform (RNASET2-SV) and the tumor immune microenvironment. Using data from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium, we correlated clinical variables to RNASET2 expression and the presence of a specific RNASET2-SV. Immunohistochemical staining with matched RNA sequencing of ccRCC patients was then utilized to understand the spatial relationships of RNASET2 with immune cells. Finally, in vitro studies were performed to demonstrate the oncogenic role of RNASET2 and highlight its potential mechanisms. RNASET2 gene expression is associated with higher grade tumors and worse overall survival in The Cancer Genome Atlas cohort. The presence of the RNASET2-SV was associated with increased expression of the wild-type RNASET2 protein and epigenetic modifications of the gene. Immunohistochemical staining revealed increased intracellular accumulation of RNASET2 in patients with increased RNA expression of RNASET2-SV. In vitro experiments reveal that this accumulation results in increased cell proliferation, potentially from altered metabolic pathways. RNASET2 exhibits a tumor-promoting role in the pathogenesis of ccRCC that is increased in the presence of a specific RNASET2-SV and associated with changes in the cellular localization of the protein.

Osimertinib vs. afatinib as first-line treatment for patients with metastatic non-small cell lung cancer with an EGFR exon 19 deletion or exon 21 L858R mutation.

Background: The optimal treatment sequencing for patients with metastatic epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) remains a subject of debate. In the United States, osimertinib is the preferred EGFR tyrosine kinase inhibitor (TKI) in the first-line setting. However, small retrospective studies suggest that alternative EGFR TKI sequencing strategies may produce similar outcomes. This study aimed to compare the outcomes of patients with metastatic NSCLC harboring an EGFR exon 19 deletion or exon 21 L858R mutation treated with osimertinib vs. afatinib as first-line therapy. Methods: This retrospective, single-institution study examined 86 patients with metastatic EGFR-mutant NSCLC treated with either afatinib (n=15) or osimertinib (n=71) in the first-line setting. The primary outcome was progression-free survival (PFS), and secondary endpoints included time on EGFR TKI, overall survival (OS), and the incidence of adverse events (AEs). Results: There was no difference in the PFS (median: 27.9 vs. 29.0 months, P=0.75), OS (P=0.18), and the median time on first-line EGFR TKI (23.9 vs. 15.2 months, P=0.10) between the afatinib and osimertinib groups, respectively. The number of AEs was also similar between the two treatment groups (P=0.17). Conclusions: In this real-world retrospective study, there were no differences in PFS or OS between patients treated with afatinib or osimertinib in the first-line setting. These findings should be further investigated in larger prospective studies.

Sparse clusterability: testing for cluster structure in high dimensions.

BACKGROUND: Cluster analysis is utilized frequently in scientific theory and applications to separate data into groups. A key assumption in many clustering algorithms is that the data was generated from a population consisting of multiple distinct clusters. Clusterability testing allows users to question the inherent assumption of latent cluster structure, a theoretical requirement for meaningful results in cluster analysis. RESULTS: This paper proposes methods for clusterability testing designed for high-dimensional data by utilizing sparse principal component analysis. Type I error and power of the clusterability tests are evaluated using simulated data with different types of cluster structure in high dimensions. Empirical performance of the new methods is evaluated and compared with prior methods on gene expression, microarray, and shotgun proteomics data. Our methods had reasonably low Type I error and maintained power for many datasets with a variety of structures and dimensions. Cluster structure was not detectable in other datasets with spatially close clusters. CONCLUSION: This is the first analysis of clusterability testing on both simulated and real-world high-dimensional data.

Early-Stage Primary Lung Neuroendocrine Tumors Treated With Stereotactic Body Radiation Therapy: A Multi-Institution Experience.

PURPOSE: Current guidelines recommend surgery as standard of care for primary lung neuroendocrine tumor (LNET). Given that LNET is a rare clinical entity, there is a lack of literature regarding treatment of LNET with stereotactic body radiation therapy (SBRT). We hypothesized that SBRT could lead to effective locoregional tumor control and long-term outcomes. METHODS AND MATERIALS: We retrospectively reviewed 48 tumors in 46 patients from 11 institutions with a histologically confirmed diagnosis of LNET, treated with primary radiation therapy. Data were collected for patients treated nonoperatively with primary radiation therapy between 2006 and 2020. Patient records were reviewed for lesion characteristics and clinical risk factors. Kaplan-Meier analysis, log-rank tests, and Cox multivariate models were used to compare outcomes. RESULTS: Median age at treatment was 71 years and mean tumor size was 2 cm. Thirty-two lesions were typical carcinoid histology, 7 were atypical, and 9 were indeterminate. The most common SBRT fractionation schedule was 50 to 60 Gy in 5 daily fractions. Overall survival at 3, 6, and 9 years was 64%, 43%, and 26%, respectively. Progression-free survival at 3, 6, and 9 years was 88%, 78%, and 78%, respectively. Local control at 3, 6, and 9 years was 97%, 91%, and 91%, respectively. There was 1 regional recurrence in a paraesophageal lymph node. No grade 3 or higher toxicity was identified. CONCLUSIONS: This is the largest series evaluating outcomes in patients with LNET treated with SBRT. This treatment is well tolerated, provides excellent locoregional control, and should be offered as an alternative to surgical resection for patients with early-stage LNET, particularly those who may not be ideal surgical candidates.

Gestante pretérmino con la COVID-19 asociada a preeclampsia agravada / Preterm pregnant woman with COVID-19 associated with aggravated pre-eclampsia

RESUMEN Introducción: La enfermedad por coronavirus 2019 (COVID-19), es una infección respiratoria aguda causada por el SARS-CoV-2, que potencialmente puede provocar un síndrome respiratorio agudo grave y causar la muerte de la paciente. Objetivo: Presentar una paciente con la COVID -19 asociado a preeclampsia agravada, en una gestante pretérmino. Caso clínico: Paciente de 25 años con gestación de 35,2 semanas, antecedentes de salud aparente que fue recibida desde su llegada a la unidad de cuidados intensivos, remitida por ser positiva a la COVID-19, con síntomas respiratorios de una neumopatía asociada, como cifras tensionales elevadas, sin otra sintomatología. Mediante el examen físico y estudios complementarios humorales se diagnóstica una preeclampsia agravada y un oligoamnios por una rotura de membranas ovulares. Fue tratada y compensada; se inició inducción y durante el procedimiento se diagnostica un riesgo de pérdida de bienestar fetal, por lo que se decidió realizar cesárea urgente. Se recibió recién nacido sano. La paciente no presentó complicaciones postquirúrgicas y se trató acorde a las normas actuales para los casos de madre grave con la COVID-19; tuvo una evolución favorable. Conclusiones: El diagnóstico y tratamiento precoz de una gestante con la COVID- 19 y preeclampsia asociada permite una evolución satisfactoria del binomio madre-feto.

ABSTRACT Introduction: Coronavirus disease 2019 (COVID-19) is an acute respiratory infection caused by SARS-CoV-2, which can potentially cause severe acute respiratory syndrome and cause the death of the patient. Objective: To present a patient with COVID -19 associated with aggravated preeclampsia, in a preterm pregnant woman. Clinical case: A 25-year-old patient with a gestation of 35.2 weeks, a history of apparent health that was received since her arrival at the intensive care unit, referred for being positive for COVID-19, with respiratory symptoms of an associated lung disease, as high blood pressure figures, without other symptoms. Through physical examination and complementary humoral studies, an aggravated preeclampsia and oligohydramnios were diagnosed due to rupture of the ovular membranes. She was treated and compensated; Induction was started and during the procedure a risk of loss of fetal well-being was diagnosed, so it was decided to perform an urgent cesarean section. A healthy newborn was received. The patient did not present post-surgical complications and was treated according to current standards for cases of severe mother with COVID-19; she had a favorable evolution. Conclusions: The early diagnosis and treatment of a pregnant woman with COVID-19 and associated preeclampsia allows a satisfactory evolution of the mother-fetus binomial.

Evaluation of Targeted Next-Generation Sequencing for the Management of Patients Diagnosed with a Cancer of Unknown Primary.

BACKGROUND: Cancer of unknown primary (CUP) comprises a heterogeneous collection of malignancies that are typically associated with a poor prognosis and a lack of effective treatment options. We retrospectively evaluated the clinical utility of targeted next-generation sequencing (NGS) among CUP patients to assist with diagnosis and identify opportunities for molecularly guided therapy. PATIENTS AND METHODS: Patients with a CUP at Moffitt Cancer Center who underwent NGS between January 1, 2014 and December 31, 2019, were eligible for study inclusion. Next-generation sequencing results were assessed to determine the frequency of clinically actionable molecular alterations, and chart reviews were performed to ascertain the number of patients receiving molecularly guided therapy. RESULTS: Ninety-five CUP patients were identified for analysis. Next-generation sequencing testing identified options for molecularly guided therapy for 55% (n = 52) of patients. Among patients with molecularly guided therapy options, 33% (n = 17) were prescribed a molecularly guided therapy. The median overall survival for those receiving molecularly guided therapy was 23.6 months. Among the evaluable patients, the median duration of treatment for CUP patients (n = 7) receiving molecular-guided therapy as a first-line therapy was 39 weeks. The median duration of treatment for CUP patients (n = 8) treated with molecularly guided therapy in the second- or later-line setting was 13 weeks. Next-generation sequencing results were found to be suggestive of a likely primary tumor type for 15% (n = 14) of patients. CONCLUSION: Next-generation sequencing results enabled the identification of treatment options in a majority of patients and assisted with the identification of a likely primary tumor type in a clinically meaningful subset of patients.

Preoperative immunonutrition and carbohydrate loading associated with improved bowel function after radical cystectomy.

BACKGROUND: Preoperative malnourishment has been consistently associated with poor outcomes after radical cystectomy and other major abdominal surgeries. Most enhanced recovery after surgery (ERAS) studies have examined preoperative nutrition and its relationship to outcomes after gastrointestinal surgery. Although numerous studies have demonstrated the benefits of using an ERAS protocol, this study in unique in comparing 2 ERAS protocols, with and without a nutrition component. METHODS: A formalized preoperative nutrition protocol (PNP) recommending use of preoperative immunonutrition and carbohydrate drink was introduced in June 2018. A total of 78 consecutive patients who drank both beverages were compared with 92 historical controls. Multivariable logistic regression analyses were sequentially performed to determine if preoperative nutrition was associated with binary outcome variables (30-day complication, infectious complication, and readmission within 30 days). RESULTS: The preoperative nutrition group and control group were statistically similar in distribution of age, sex, American Society of Anesthesiologists physical status classification, clinical stage, and body mass index. Return of bowel function was found to occur earlier in the preoperative nutrition group than in the control group (3.12 vs 3.74 days; relative risk, 0.82; CI, 0.73-0.93; P = .0029). Complications within 30 days were similar in both groups (63.6% vs 55.4%; P = 0.36). Infectious complications (42.9% vs 37%; P = .53) and readmission within 30 days (22.1% vs 15.2%; P = .34) were also similar in both groups. CONCLUSIONS: Use of a PNP including immunonutrition and carbohydrate drink may be associated with earlier return of bowel function after radical cystectomy.

A Retrospective Analysis of Patients Undergoing Telemedicine Evaluation in the PreAnesthesia Testing Clinic at H. Lee Moffitt Cancer Center.

BACKGROUND: Telemedicine for preanesthesia evaluation can decrease access disparities by minimizing commuting, time off work, and lifestyle disruptions from frequent medical visits. We report our experience with the first 120 patients undergoing telemedicine preanesthesia evaluation at Moffitt Cancer Center. METHODS: This is a retrospective analysis of 120 patients seen via telemedicine for preanesthesia evaluation compared with an in-person cohort meeting telemedicine criteria had it been available. Telemedicine was conducted from our clinic to a patient's remote location using video conferencing. Clinic criteria were revised to create a tier of eligible patients based on published guidelines and anesthesiologist consensus. RESULTS: Day-of-surgery cancellation rate was 1.67% in the telemedicine versus 0% in the in-person cohort. The two telemedicine group cancellations were unrelated to medical workup, and cancellation rate between the groups was not statistically significant (P = .49). Median round trip distance and time saved by the telemedicine group was 80 miles [range 4; 1180] and 121 minutes [range 16; 1034]. Using the federal mileage rate, the median cost savings was $46 [range $2.30; 678.50] per patient. Patients were similar in gender and race in both groups (P = .23 and .75, respectively), but the in-person cohort was older and had higher American Society of Anesthesiologists physical status classification (P = .0003). CONCLUSIONS: Telemedicine preanesthesia evaluation results in time, distance, and financial savings without increased day-of-surgery cancellations. This is useful in cancer patients who travel significant distances to specialty centers and have a high frequency of health care visits. American Society of Anesthesiologists Physical Status classification and age differences between cohorts indicate possible patient or provider selection bias. Randomized controlled trials will aid in further exploring this technology.

Studying the spatial temporal spread of the citrus tristeza virus through ODEs and Bernoulli trials.

The Citrus tristeza virus (CTV) is one of the most economically devastating citrus diseases worldwide. The spread of CTV in eastern Spain was studied by Gottwald et al. with the goal of determining the spatio-temporal mechanisms of spread. Since the subjects in this study are individual trees, it is natural to think of infections as Bernoulli trials. This approach is difficult however, due to the spatial and temporal dependence of the observations. Consequently, a system of ordinary differential equations (ODE) was used to model the probabilities of infection as well as the spatial and temporal dependence. Given the parameters in the ODE, the probabilities of infection are treated as conditionally independent. Using the conditional independence we then specify the joint likelihood function as a Poisson binomial distribution. For the purpose of model selection and hypothesis testing we, employed accumulated prediction error (APE) which has connections to both Bayesian and frequentist frameworks. We demonstrated the robustness of our method in accounting for spatio-temporal dependencies in the data by accurately predicting the spatial distribution of the disease through Join Counts.

Correction: Modelling the effects of quadrivalent Human Papillomavirus (HPV) vaccination in Puerto Rico.

[This corrects the article DOI: 10.1371/journal.pone.0184540.].

Modelling the effects of quadrivalent Human Papillomavirus (HPV) vaccination in Puerto Rico.

BACKGROUND: No study has estimated the potential impact of Human Papillomavirus (HPV) vaccination in Puerto Rico, a population with considerable burden of HPV-related morbidities. We evaluated the health and economic impacts of implementing a vaccination strategy for females and males in Puerto Rico, with the quadrivalent HPV (HPV4) vaccine, under different vaccination scenarios. METHODS: We adapted a mathematical model which estimates the direct and indirect health benefits and costs of HPV4 vaccination in a dynamic population. The model compared three vaccination scenarios against screening only (no-vaccination) for three doses of HPV4 vaccine among individuals aged 11-15 years in Puerto Rico: 1) 34% for females and 13% for males (34%F/13%M), 2) 50% for females and 40% for males (50%F/40%M), and 3) 80% for female and 64% for male (80%F/64%M). Data specific to Puerto Rico was used. When not available, values from the United States were used. Input data consisted of demographic, behavioral, epidemiological, screening, and economic parameters. RESULTS: The model predicted decreases in: 1) HPV infection prevalence for females and males, 2) cervical intraepithelial neoplasia and cervical cancer incidence for females, 3) genital warts incidence for females and males, and 4) cervical cancer deaths among females, when various vaccination program scenarios were considered. In addition, when the vaccination percentage was increased in every scenario, the reduction was greater and began earlier. The analysis also evidenced an incremental cost effectiveness ratio (ICER) of $1,964 per quality-adjusted life year gained for the 80%F/64%M uptake scenario. CONCLUSIONS: HPV vaccine can prove its cost effectiveness and substantially reduce the burden and costs associated to various HPV-related conditions when targeted to the adequate population together with an organized HPV vaccination program.

Eddy covariance captures four-phase crassulacean acid metabolism (CAM) gas exchange signature in Agave.

Mass and energy fluxes were measured over a field of Agave tequilana in Mexico using eddy covariance (EC) methodology. Data were gathered over 252 d, including the transition from wet to dry periods. Net ecosystem exchanges (FN,EC ) displayed a crassulacean acid metabolism (CAM) rhythm that alternated from CO2 sink at night to CO2 source during the day, and partitioned canopy fluxes (FA,EC ) showed a characteristic four-phase CO2 exchange pattern. Results were cross-validated against diel changes in titratable acidity, leaf-unfurling rates, energy exchange fluxes and reported biomass yields. Projected carbon balance (g C m(-2) year(-1) , mean ± 95% confidence interval) indicated the site was a net sink of -333 ± 24, of which contributions from soil respiration were +692 ± 7, and FA,EC was -1025 ± 25. EC estimated biomass yield was 20.1 Mg (dry) ha(-1) year(-1) . Average integrated daily FA,EC was -234 ± 5 mmol CO2 m(-2) d(-1) and persisted almost unchanged after 70 d of drought conditions. Regression analyses were performed on the EC data to identify the best environmental predictors of FA . Results suggest that the carbon acquisition strategy of Agave offers productivity and drought resilience advantages over conventional semi-arid C3 and C4 bioenergy candidates.

RASS: a web server for RNA alignment in the joint sequence-structure space.

Comparison of ribonucleic acid (RNA) molecules is important for revealing their evolutionary relationships, predicting their functions and predicting their structures. Many methods have been developed for comparing RNAs using either sequence or three-dimensional (3D) structure (backbone geometry) information. Sequences and 3D structures contain non-overlapping sets of information that both determine RNA functions. When comparing RNA 3D structures, both types of information need to be taken into account. However, few methods compare RNA structures using both sequence and 3D structure information. Recently, we have developed a new method based on elastic shape analysis (ESA) that compares RNA molecules by combining both sequence and 3D structure information. ESA treats RNA structures as 3D curves with sequence information encoded on additional coordinates so that the alignment can be performed in the joint sequence-structure space. The similarity between two RNA molecules is quantified by a formal distance, geodesic distance. In this study, we implement a web server for the method, called RASS, to make it publicly available to research community. The web server is located at http://cloud.stat.fsu.edu/RASS/.

Association between obesity and symptoms of depression of adults in Puerto Rico.

OBJECTIVE: This study was aimed at determining the prevalence of overweight; of class 1 and class 2/3 obesity; and of the symptoms of depression in adults in Puerto Rico. The study also evaluated the relationship between the symptoms of depression and weight status. METHODS: The sample for this study consists of 6,025 adults (3,851 females and 2,174 males) who lived in Puerto Rico at the time of and who participated in either the 2006 or the 2010 BRFSS. RESULTS: In this sample 70.0% of the respondents were either overweight or obese. About 39.6% of them were considered overweight, while 18.1% were obese class 1 and 12.3% were obese class 2 or 3. When compared by gender, the prevalence rate of overweight was higher for males (46.9%) than it was for females (35.5%), but females (14.1%) had a higher rate of class 2/3 obesity than did males (9.2%). There were no significant gender-based differences in the class 1 (BMI between 30 and 35) obesity group. According to the study's findings, depression symptoms and class 1 obesity are not strongly associated. A positive relationship between depression and weight was found only in women with class 2/3 obesity (BMI>35). CONCLUSION: In summary, the results of this study show that depressive symptoms are associated with obesity, and this correlation seems to be more significant in women, especially those with severe obesity, less education, and lower incomes. Findings point to the existence of a high risk of comorbid obesity and depression of adults in Puerto Rico.

RNA global alignment in the joint sequence-structure space using elastic shape analysis.

The functions of RNAs, like proteins, are determined by their structures, which, in turn, are determined by their sequences. Comparison/alignment of RNA molecules provides an effective means to predict their functions and understand their evolutionary relationships. For RNA sequence alignment, most methods developed for protein and DNA sequence alignment can be directly applied. RNA 3-dimensional structure alignment, on the other hand, tends to be more difficult than protein structure alignment due to the lack of regular secondary structures as observed in proteins. Most of the existing RNA 3D structure alignment methods use only the backbone geometry and ignore the sequence information. Using both the sequence and backbone geometry information in RNA alignment may not only produce more accurate classification, but also deepen our understanding of the sequence-structure-function relationship of RNA molecules. In this study, we developed a new RNA alignment method based on elastic shape analysis (ESA). ESA treats RNA structures as three dimensional curves with sequence information encoded on additional dimensions so that the alignment can be performed in the joint sequence-structure space. The similarity between two RNA molecules is quantified by a formal distance, geodesic distance. Based on ESA, a rigorous mathematical framework can be built for RNA structure comparison. Means and covariances of full structures can be defined and computed, and probability distributions on spaces of such structures can be constructed for a group of RNAs. Our method was further applied to predict functions of RNA molecules and showed superior performance compared with previous methods when tested on benchmark datasets. The programs are available at http://stat.fsu.edu/ ∼jinfeng/ESA.html.

Evolución y creatividad / Evolution and creativity

Este artículo pretende mostrar que el conflicto es natural e inherente a la naturaleza humana. Se plantea que el conflicto es una manifestación de la capacidad de adaptación limitada que posee el cerebro humano; por lo que necesita transformar al medio y a los demás para su supervivencia. Por otro lado, la cultura como creación humana impone reglas que no todos comparten. Entonces, las claves de un manejo funcional de los conflictos se pueden encontrar en el mejoramiento de los hábitos de crianza como solución a largo plazo, y en la transformación de la educación, orientada ahora hacia la convivencia, la creatividad y la aceptación de la diferencia.

This article pretends to show conflict as natural and proper of human nature. The author thinks the conflict is a manifestation of the limited adaptation ability the human brain has; thus, it needs to transform the environment and the others to survive. On the other hand, culture as a human creation settles rules not shared by all people. Then, the keys for a functional handling of conflicts can be found in the improvement of raising habits as a long- term solution, and in the transformation of education, oriented now to live in community, creativity and difference acceptance.