Gene expression profiles associated with the presence of a fibrotic focus and the growth pattern in lymph node-negative breast cancer.

PURPOSE: A fibrotic focus, the scar-like area found in the center of an invasive breast tumor, is a prognostic parameter associated with an expansive growth pattern, hypoxia, and (lymph)angiogenesis. Little is known about the molecular pathways involved. EXPERIMENTAL DESIGN: Sixty-five patients were selected of whom microarray data of the tumor and H&E slides for histologic analysis were available. The growth pattern and the presence and size of a fibrotic focus were assessed. Differences in biological pathways were identified with global testing. The correlations of growth pattern and fibrotic focus with common breast cancer signatures and with clinicopathologic variables and survival were investigated. RESULTS: Tumors with a large fibrotic focus showed activation of Ras signaling and of the hypoxia-inducible factor-1alpha pathway. Furthermore, unsupervised hierarchical cluster analysis with hypoxia- and (lymph)angiogenesis-related genes showed that hypoxia-inducible factor-1alpha, vascular endothelial growth factor A, and carbonic anhydrase 9 were overexpressed. The presence of a fibrotic focus, especially a large fibrotic focus, was associated with the basal-like subtype (P = 0.009), an activated wound-healing signature (P = 0.06), and a poor-prognosis 76-gene signature (P = 0.004). The presence of a fibrotic focus (P = 0.02) and especially of a large fibrotic focus (P = 0.004) was also associated with early development of distant metastasis. CONCLUSIONS: Our results sustain the hypothesis that hypoxia-driven angiogenesis is essential in the biology of a fibrotic focus. Ras and Akt might play a role as downstream modulators. Our data furthermore suggest that vascular endothelial growth factor A does not only drive angiogenesis but also lymphangiogenesis in tumors with a fibrotic focus. Our data also show an association between the presence of a fibrotic focus and infaust molecular signatures.     

How an Adolescent's Childbearing Affects Siblings' Pregnancy Risk: A Qualitative Study Of Mexican American Youths

CONTEXT: The siblings of teenage parents are known to be at very high risk of teenage pregnancy, but little is known about how an older sister's childbearing affects a younger sibling's risk. Understanding these influences could help address the very high rates of pregnancy and childbearing among Latino adolescents. METHODS: From 2005 through 2007, a sample of 41 Mexican American 12–18‐year‐olds from southern California completed in‐depth interviews about how an older sister’s teenage childbearing had affected them. Themes that emerged were categorized as risk factors (circumstances that increased youths’ likelihood of becoming involved in a teenage pregnancy) or protective factors (conditions that reduced this likelihood) on the basis of well‐established findings in the literature. RESULTS: Interview data reflected six risk factors and 11 protective factors. The most commonly reported risk factors (discussed by more than a quarter of participants) were that youths did not perceive early parenting as a hardship, had increased difficulties in school and wanted to have a baby too. The most commonly cited protective factors (mentioned by more than half) were an increased motivation to avoid early parenting, an increased appreciation of the difficulties of parenting, mothers' explicitly discouraging early parenting and youths' feeling of greater closeness with their mother. CONCLUSIONS: Interventions that build on the protective factors that result when a youth's older sibling has a teenage birth, while reducing the risk factors, might help families prevent younger children from becoming involved in a teenage pregnancy.     

How do the doping concentrations of N and B in graphene modify the water adsorption?

Understanding the interaction of water and graphene is crucial for various applications such as water purification, desalination, and electrocatalysis. Experimental and theoretical studies have already investigated water adsorption on N- and B-doped graphene. However, there are no reports available that elucidate the influences of the N and B doping content in graphene on the microscopic geometrical structure and the electronic properties of the adsorbed water. Thus, this work is devoted to solving this problem using self-consistent van der Waals density functional theory calculations. The N and B doping contents of 0.0, 3.1, 6.3, and 9.4% were considered. The results showed that the binding energy of water increases almost linearly as a function of doping content at all concentrations for N-doped graphene but below 6.3% for B-doped graphene. In the linear range, the binding energy increases by approximately 30 meV for each increment of the doping ratio. Analyses of the geometric and electronic structures explained the enhancement of the water–graphene interaction with the variation in doping percentage.

N and B doping content in graphene alters the microscopic geometrical structure and electronic properties of adsorbed water.     

A smart diagnostic tool based on deep kernel learning for on-site determination of phosphate,calcium, and magnesium concentration in a hydroponic system

Calcium, phosphate, and magnesium are essential nutrients for plant growth. The in situ determination of these nutrients is an important task for monitoring them in a closed hydroponic system where the nutrient elements need to be individually quantified based on ion-selective electrode (ISE) sensing. The accuracy issue of calcium ISEs due to interference, drift, and ionic strength, and the unavailability of phosphate and magnesium ISEs makes the development of these ion detecting tools hard to set up in a hydroponic system. This study modeled and evaluated a smart tool for recognising three ions (calcium, phosphate, and magnesium) based on the automatic multivariate standard addition method (AMSAM) and deep kernel learning (DKL) model. The purpose was to improve the accuracy of calcium ISEs, determining phosphate through cobalt electrochemistry, and soft sensing of magnesium ions. The model provided better performance in on-site detecting and measuring those ions in a lettuce hydroponic system achieving root mean square errors (RMSEs) of 12.5, 12.1, and 7.5 mg L⁻¹ with coefficients of variation (CVs) below 5.0%, 7.0%, and 10% for determining Ca²⁺, H₂PO₄⁻, and Mg²⁺ in the range of 150–250, 100–200, and 20–70 mg L⁻¹ respectively. Furthermore, the DKL was implemented for the first time in the third platform (LabVIEW) and deployed to determine three ions in a real on-site hydroponic system. The open architecture of the SDT allowed posting the measured results on a cloud computer. This would help growers monitor their plants'' nutrients conveniently. The informative data about the three mentioned ions that have no commercial sensors so far, could be adapted to the other components to develop a fully automated fertigation system for hydroponic production.

A smart diagnostic tool based on deep kernel learning for on-site determining phosphate, calcium, and magnesium concentration in a hydroponic system.     

Selected compounds derived from Moutan Cortex stimulated glucose uptake and glycogen synthesis via AMPK activation in human HepG2 cells

Aim of the study

To evaluate the effect of selected compounds derived from Moutan Cortex on glucose uptake and glycogen synthesis associated with AMPK activation in insulin-resistant human HepG2 cell.

Materials and methods

The effect of isolated compounds (1-16) on glucose uptake and glycogen synthesis was performed using HepG2 cells. The western blot was used to determine the expression of AMPK and its downstream substrates, ACC, p-ACC, and p-GSK-3β.

Results

The effects of the 16 compounds from Moutan Cortex on glucose metabolism in HepG2 cells under high glucose conditions were evaluated. Compounds 2, 3, and 6 displayed highly potent effects on the stimulation of glucose uptake and glycogen synthesis in human HepG2 cells under high glucose conditions. Compounds 2, 3, and 6 phosphorylate AMPK (AMP-activated protein kinase), and resulted in increased phosphorylation of GSK-3β and suppression of lipogenic expression (ACC and FAS) in a dose-dependent manner. Compounds 2, 3, and 6 also demonstrated interesting, strong eNOS phosphorylation in human umbilical vein endothelial cells (HUVECs). Compounds 1, 4, 5-12, and 14 displayed considerable effects on hepatic glucose production, AMPK activation, and phosphorylation of GSK-3β in HepG2 cells under high glucose conditions.

Conclusions

These effects may indicate that the activation of AMPK by the active compounds from Moutan Cortex has considerable potential for reversing the metabolic abnormalities associated with type-2 diabetes.     

Signals of Significantly Increased Vaccine Breakthrough,Decreased Hospitalization Rates,and Less Severe Disease in Patients with Coronavirus Disease 2019 Caused by the Omicron Variant of Severe Acute Respiratory Syndrome Coronavirus 2 in Houston, Texas

Genetic variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to dramatically alter the landscape of the coronavirus disease 2019 (COVID-19) pandemic. The recently described variant of concern designated Omicron (B.1.1.529) has rapidly spread worldwide and is now responsible for the majority of COVID-19 cases in many countries. Because Omicron was recognized recently, many knowledge gaps exist about its epidemiology, clinical severity, and disease course. A genome sequencing study of SARS-CoV-2 in the Houston Methodist health care system identified 4468 symptomatic patients with infections caused by Omicron from late November 2021 through January 5, 2022. Omicron rapidly increased in only 3 weeks to cause 90% of all new COVID-19 cases, and at the end of the study period caused 98% of new cases. Compared with patients infected with either Alpha or Delta variants in our health care system, Omicron patients were significantly younger, had significantly increased vaccine breakthrough rates, and were significantly less likely to be hospitalized. Omicron patients required less intense respiratory support and had a shorter length of hospital stay, consistent with on average decreased disease severity. Two patients with Omicron stealth sublineage BA.2 also were identified. The data document the unusually rapid spread and increased occurrence of COVID-19 caused by the Omicron variant in metropolitan Houston, Texas, and address the lack of information about disease character among US patients.

Over the past 14 months, the Alpha and Delta variants of concern (VOCs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused two distinct coronavirus disease 2019 (COVID-19) surges in the United States, Southeast Asia, Europe, and elsewhere (https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html, last accessed December 30, 2021; https://www.gov.uk/government/collections/new-sars-cov-2-variant, last accessed December 30, 2021), and remodeled the landscape of human behavior and many societies. Delta replaced the Alpha variant as the cause of virtually all COVID-19 in many countries (https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---13-july-2021, last accessed August 18, 2021; https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/coronaviruscovid19infectionsurveypilot/9july2021, last accessed August 18, 2021).At the start of the pandemic almost 2 years ago, the Houston Methodist health care system instituted a comprehensive and integrated population genomics project designed to sequence all SARS-CoV-2 samples causing COVID-19 in patients cared for at our facilities, which include eight hospitals located throughout the metroplex. The project was implemented when the initial Houston Methodist COVID-19 case was diagnosed at the end of February 2020, and has continued unabated.1, 2, 3, 4, 5, 6, 7 This project was facilitated by the existence of a single large diagnostic laboratory that serves the entire system and is seamlessly integrated with a research institute with extensive genomics expertise and capacity. A key goal was to comprehensively map the population genomics, trajectory, and other features of the pandemic in metropolitan Houston, Texas, with a population size of approximately 7.2 million. Houston is the fourth largest city in the United States, is the most ethnically diverse metropolitan area in the country, and is a major port of entry. To date, SARS-CoV-2 genomes have been sequenced from >70,000 patient samples. Many features of four distinct SARS-CoV-2 waves in Houston have been described.2, 3, 4, 5, 6The successes of rapid SARS-CoV-2 vaccine development and documented efficacy, coupled with the significant downturn of the disease wave caused by Delta in Houston and elsewhere in fall 2021,⁶ suggested that the pandemic was abating. However, the identification of a new VOC designated B.1.1.529 and known as Omicron that has spread rapidly in South Africa and the United Kingdom has tempered this optimism.8, 9, 10 Inasmuch as Omicron was recognized recently, and much is not known about its epidemiology and clinical characteristics and course, we used our integrated infrastructure in an effort to address the lack of information available for US Omicron patients. Genome sequencing identified 4468 COVID-19 patients with symptomatic disease caused by Omicron in the Houston Methodist health care system beginning in late November 2021 and ending January 5, 2022. In 3 weeks, Omicron spread throughout the Houston metropolitan region to become the cause of 90% of new COVID-19 cases, and at the end of the study period caused 98% of all new cases. Compared with patients infected with either Alpha or Delta variant and cared for in our system, significantly fewer Omicron patients were hospitalized, and those who were hospitalized required significantly less intense respiratory support and had a shorter length of stay. Our findings are consistent with decreased disease severity among Houston Methodist Omicron patients. Many factors undoubtedly have contributed, including but not limited to increased vaccination uptake, population immunity, and patient demographics, such as younger age. The extent to which our findings translate to other cities and other patient populations, including children, is unknown. These data expand on our initial Omicron work⁷ and address the lack of information about disease character among US patients with COVID-19 caused by this VOC.     

Multiple dose study of interactions between artesunate and artemisinin in healthy volunteers

AIMS: To investigate whether coadministration of the antimalarials artesunate and artemisinin alters the clearance of either drug. METHODS: Ten healthy Vietnamese males (Group AS) were randomized to receive a single dose of 100 mg oral artesunate (pro-drug of dihydroartemisinin) on day -5 and then once daily for 5 consecutive days (days 1-5). Oral artemisinin (500 mg) was coadministered on days 1 and 5. Another 10 subjects (Group AM) were given 500 mg oral artemisinin on day -5 and then further doses on days 1-5. Artesunate 100 mg was given on days 1 and 5. Artemisinin and dihydroartemisinin plasma concentrations on days -5, 1 and 5 were quantified by h.p.l.c. with on-line postcolumn derivatization and u.v. detection. RESULTS: In Group AS, dihydroartemisinin oral clearance values (mean (95% CI)) were similar on day 1 (32 (22, 47)) l h(-1) and day 5 (38 (28, 51)) l h(-1) of daily artesunate administration but these mean values were approximately three fold higher compared with day -5 after a single dose (95 (56, 159)). In this group, artemisinin oral clearance increased from 196 (165, 232) l h(-1) on day 1-315 (241, 410) l h(-1) on day 5. In Group AM, dihydroartemisinin oral clearance on day 1 was 39 (34, 46) l h(-1) and increased 1.6 fold to 64 (48, 85) l h(-1) on day 5. In this group, artemisinin oral clearance increased sequentially (1.5 and 4.7 fold, respectively) from 207 (151, 285) l h(-1) on day -5-308 (257, 368) l h(-1) on day 1 and to 981 (678, 1420) l h(-1) on day 5. The increase in artemisinin oral clearance between days -5 and 1 (in the absence of artesunate) was similar to that between days 1 and 5 in Group AS subjects who took daily artesunate. Dihydroartemisinin was not a significant metabolite of artemisinin. CONCLUSIONS: Artesunate (dihydroartemisinin) did not alter the elimination of artemisinin. However, dihydroartemisinin elimination was inhibited by artemisinin. Artemisinin induced its own elimination even 5 days after a single oral dose. There was no evidence for the formation of dihydroartemisinin from artemisinin.     

Disease-free survival as a surrogate for overall survival in upper tract urothelial carcinoma

Objectives

The primary endpoint in trials of perioperative systemic therapy for urothelial carcinoma is 5-year overall survival (OS). A shorter-term endpoint could significantly speed the translation of advances into practice. We hypothesized that disease-free survival (DFS) could be a surrogate endpoint for OS in upper tract urothelial carcinoma (UTUC) patients treated with radical nephroureterectomy (RNU).

Patients and methods

The study included 2,492 patients treated with RNU with curative intent for UTUC.

Results

2/3-year DFS estimates were 78/73 %, and the 5-year OS estimate was 64 %. The overall agreements between 2- and 3-year DFS with 5-year OS were 85 and 87 %, respectively. Agreements were similar when analyzed in subgroups stratified by pathological stages, lymph node status, and adjuvant chemotherapy. The kappa statistic was 0.59 (95 % CI 0.55–0.63) for 2-year DFS/5-year OS and 0.64 (95 % CI 0.61–0.68) for 3-year DFS/5-year OS, indicating moderate reliability. The hazard ratio for DFS as a time-dependent variable for predicting OS was 11.5 (95 % CI 9.1–14.4), indicating a strong relationship between DFS and OS.

Conclusions

In patients treated with RNU for UTUC, DFS and OS are highly correlated, regardless of tumor stage and adjuvant chemotherapy. While significant differences in DFS, assessed at 2 and 3 years, are highly likely to persist in OS at 5 years, marginal DFS advantages may not translate into OS benefit. External validation is necessary before accepting DFS as an appropriate surrogate endpoint for clinical trials investigating advanced UTUC patients.     

Perioperative outcomes of robot-assisted radical prostatectomy compared with open radical prostatectomy: results from the nationwide inpatient sample

Background

Prior to the introduction and dissemination of robot-assisted radical prostatectomy (RARP), population-based studies comparing open radical prostatectomy (ORP) and minimally invasive radical prostatectomy (MIRP) found no clinically significant difference in perioperative complication rates.

Objective

Assess the rate of RARP utilization and reexamine the difference in perioperative complication rates between RARP and ORP in light of RARP's supplanting laparoscopic radical prostatectomy (LRP) as the most common MIRP technique.

Design, setting, and participants

As of October 2008, a robot-assisted modifier was introduced to denote robot-assisted procedures. Relying on the Nationwide Inpatient Sample between October 2008 and December 2009, patients treated with radical prostatectomy (RP) were identified. The robot-assisted modifier (17.4x) was used to identify RARP (n = 11 889). Patients with the minimally invasive modifier code (54.21) without the robot-assisted modifier were classified as having undergone LRP and were removed from further analyses. The remainder were classified as ORP patients (n = 7389).

Intervention

All patients underwent RARP or ORP.

Measurements

We compared the rates of blood transfusions, intraoperative and postoperative complications, prolonged length of stay (pLOS), and in-hospital mortality. Multivariable logistic regression analyses of propensity score–matched populations, fitted with general estimation equations for clustering among hospitals, further adjusted for confounding factors.

Results and limitations

Of 19 462 RPs, 61.1% were RARPs, 38.0% were ORPs, and 0.9% were LRPs. In multivariable analyses of propensity score–matched populations, patients undergoing RARP were less likely to receive a blood transfusion (odds ratio [OR]: 0.34; 95% confidence interval [CI], 0.28–0.40), to experience an intraoperative complication (OR: 0.47; 95% CI, 0.31–0.71) or a postoperative complication (OR: 0.86; 95% CI, 0.77–0.96), and to experience a pLOS (OR: 0.28; 95% CI, 0.26–0.30). Limitations of this study include lack of adjustment for tumor characteristics, surgeon volume, learning curve effect, and longitudinal follow-up.

Conclusions

RARP has supplanted ORP as the most common surgical approach for RP. Moreover, we demonstrate superior adjusted perioperative outcomes after RARP in virtually all examined outcomes.