Lost in Translation: Multilingual Analysis of Online Breast Cancer Information.

INTRODUCTION: Patients use the internet to learn more about health conditions. Non-English-speaking patients may face additional challenges. The quality of online breast cancer information, the most common cancer in women, is uncertain. This study aims to examine the quality of online breast cancer information for English and non-English-speaking patients. METHODS: Three search engines were queried using the terms: "how to do a breast examination," "when do I need a mammogram," and "what are the treatment options for breast cancer" in English, Spanish, and Chinese. For each language, 60 unique websites were included and classified by type and information source. Two language-fluent reviewers evaluated website quality using the Journal of American Medical Association benchmark criteria (0-4) and the DISCERN tool (1-5), with higher scores representing higher quality. Scores were averaged for each language. Health On the Net code presence was noted. Inter-rater reliability between reviewers was assessed. RESULTS: English and Spanish websites most commonly originated from US sources (92% and 80%, respectively) compared to Chinese websites (33%, P < 0.001). The most common website type was hospital-affiliated for English (43%) and foundation/advocacy for Spanish and Chinese (43% and 45%, respectively). English websites had the highest and Chinese websites the lowest mean the Journal of American Medical Association (2.2 ± 1.4 versus 1.0 ± 0.8, P = 0.002) and DISCERN scores (3.5 ± 0.9 versus 2.3 ± 0.6, P < 0.001). Health On the Net code was present on 16 (8.9%) websites. Inter-rater reliability ranged from moderate to substantial agreement. CONCLUSIONS: The quality of online information on breast cancer across all three languages is poor. Information quality was poorest for Chinese websites. Improvements to enhance the reliability of breast cancer information across languages are needed.

Associations of phthalates with accelerated aging and the mitigating role of physical activity.

Phthalates are positioned as potential risk factors for health-related diseases. However, the effects of exposure to phthalates on accelerated aging and the potential modifications of physical activity remain unclear. A total of 2317 participants containing complete study-related information from the National Health and Nutrition Examination Survey 2007-2010 were included in the current study. We used two indicators, the Klemera-Doubal method biological age acceleration (BioAgeAccel) and phenotypic age acceleration (PhenoAgeAccel), to assess the accelerated aging status of the subjects. Multiple linear regression (single pollutant models), weighted quantile sum (WQS) regression, Quantile g-computation, and Bayesian kernel machine regression (BKMR) models were utilized to explore the associations between urinary phthalate metabolites and accelerated aging. Three groups of physical activity with different intensities were used to evaluate the modifying effects on the above associations. Results indicated that most phthalate metabolites were significantly associated with BioAgeAccel and PhenoAgeAccel, with effect values (ß) ranging from 0.16 to 0.21 and 0.16-0.37, respectively. The WQS indices were positively associated with BioAgeAccel (0.33, 95% CI: 0.11, 0.54) and PhenoAgeAccel (0.50, 95% CI: 0.19, 0.82). Quantile g-computation indicated that phthalate mixtures were associated with accelerated aging, with effect values of 0.15 (95% CI: 0.02, 0.28) for BioAgeAccel and 0.39 (95% CI: 0.12, 0.67) for PhenoAgeAccel respectively. The BKMR models indicated a significant positive association between the concentrations of urinary phthalate mixtures with the two indicators. In addition, we found that most phthalate metabolites showed the strongest effects on accelerated aging in the no physical activity group and that the effects decreased gradually with increasing levels of physical activity (P < 0.05 for trend). Similar results were also observed in the mixed exposure models (WQS and Quantile g-computation). This study indicates that phthalates exposure is associated with accelerated aging, while physical activity may be a crucial barrier against phthalates exposure-related aging.

Beta spending function based on conditional power in group sequential design.

Conditional power (CP) serves as a widely utilized approach for futility monitoring in group sequential designs. However, adopting the CP methods may lead to inadequate control of the type II error rate at the desired level. In this study, we introduce a flexible beta spending function tailored to regulate the type II error rate while employing CP based on a predetermined standardized effect size for futility monitoring (a so-called CP-beta spending function). This function delineates the expenditure of type II error rate across the entirety of the trial. Unlike other existing beta spending functions, the CP-beta spending function seamlessly incorporates beta spending concept into the CP framework, facilitating precise stagewise control of the type II error rate during futility monitoring. In addition, the stopping boundaries derived from the CP-beta spending function can be calculated via integration akin to other traditional beta spending function methods. Furthermore, the proposed CP-beta spending function accommodates various thresholds on the CP-scale at different stages of the trial, ensuring its adaptability across different information time scenarios. These attributes render the CP-beta spending function competitive among other forms of beta spending functions, making it applicable to any trials in group sequential designs with straightforward implementation. Both simulation study and example from an acute ischemic stroke trial demonstrate that the proposed method accurately captures expected power, even when the initially determined sample size does not consider futility stopping, and exhibits a good performance in maintaining overall type I error rates for evident futility.

Apelin-13 Improves Cognitive Impairment and Repairs Hippocampal Neuronal Damage by Activating PGC-1α/PPARγ Signaling.

Alzheimer's disease (AD) is a complex neurodegenerative disease that is prevalent around the world. Both Apelin-13 and proliferator-activated receptor-γ (PPARγ)/PPARγ co-activator 1α (PGC-1α) are regarded as candidate targets for treating AD. The investigation examined whether Apelin-13 exerts neuroprotective effects via PGC-1α/PPARγ signaling. In this study, Apelin-13 improved cognitive deficits in AD mice, while SR-18,292 (a PGC-1α inhibitor) interfered with the therapeutic effects of Apelin-13. Mechanistically, Apelin-13, PGC-1α and PPARγ were decreased in AD mice and oxygen-glucose deprivation (OGD)-induced neuronal cells. Apelin-13 bound to PGC-1α and negatively regulated the expression of PGC-1α and PPARγ. In turn, PGC-1α accelerated the accumulation of Apelin-13 and PPARγ. Additionally, neuronal apoptosis was inhibited, and the abundance of apoptosis-related proteins (Bax, Bcl-2, and cleaved caspase 3) was induced. The content of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) fluctuated. The level of inflammatory factors (interleukin-6, IL-6, IL-10, tumor necrosis factor-α, TNF-α) was regulated. In short, Apelin-13 exerted anti-apoptosis, anti-oxidant stress and anti-inflammatory effects. Interestingly, PGC-1α silencing promoted neuronal apoptosis, oxidant stress and inflammation, and overexpression of PGC-1α exhibited the opposite. More importantly, inhibition of PGC-1α attenuated Apelin-13-enhanced cognitive impairment and neuronal damage. Therefore, our findings suggested that Apelin-13 exerted neuroprotective effects in part via the PGC-1α/PPARγ pathway.

Glial fibrillary acidic protein astrocytopathy and tuberculous meningoencephalitis occurring in a patient with Legionella pneumonia: a case report.

BACKGROUND: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a recently identified recurrent meningoencephalomyelitis with GFAP immunoglobulin G presence in the serum or cerebrospinal fluid (CSF) as a specific biomarker. GFAP astrocytopathy is closely associated with the occurrence of some tumors and often coexists with other antibodies, such as the N-methyl-D-aspartate receptor and aquaporin-4 antibodies. However, GFAP astrocytopathy complicated by central nervous system infection is rare. CASE PRESENTATION: Here, we present the case of a patient admitted to a local hospital due to a prominent fever and cough. The patient had a 1-month history of headaches before admission that were not considered serious at the time. Metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid revealed a high sequence number of Legionella pneumophila and a few mycobacteria. His cough and fever improved significantly after antibiotic treatment. Still, a slight headache remained. Subsequently, his condition worsened, and he visited our hospital with a disturbance of consciousness. Mycobacterium tuberculosis was detected with mNGS of the CSF, while the CSF and serum were also positive for GFAP antibodies. Following anti-tuberculosis and steroid therapy, the patient's symptoms improved, and he tested negative for the GFAP antibody. CONCLUSION: This is the first reported case of GFAP astrocytopathy complicated by tuberculous meningoencephalitis. Due to overlaps in the clinical manifestations of the two diseases, GFAP astrocytopathy is sometimes misdiagnosed as tuberculous meningoencephalitis. Therefore, in addition to ensuring careful identification of the two diseases, clinicians need to be aware of their possible co-existence.

Risk difference, relative risk, and odds ratio for non-inferiority clinical trials with risk rate endpoint.

Non-inferiority (NI) clinical trials are widely used to evaluate whether the new experimental treatment is not unacceptably worse than the current active-control treatment by more than a pre-specified non-inferiority margin (NI margin). However, choosing either an absolute difference [risk difference (RD)] or a relative difference [relative risk (RR) and odds ratio (OR)] to evaluate efficacy in NI clinical trials is still controversial. In this study, we aim to evaluate the performance of abovementioned three metrics for testing NI clinical trials with risk rate endpoint. Herein, extensive Monte Carlo simulations based on various parameter settings (NI margin as well as risk rates in the experimental group and active-control group) are conducted to compare the Type I error rate, statistical power, and the necessary sample size to achieve a desired power for testing NI using RD, RR, and OR. We show that testing NI using RD not only controls well the Type I error and achieves the highest statistical power but also requires the smallest sample size compared to RR and OR. In practice, however, the choice among three metrics still needs to be based upon clinical interpretations and regulatory perspectives.

Thromboelastography (TEG) parameters as potential predictors of malignancy and tumor progression in colorectal cancer.

PURPOSE: The purpose of this study was to investigate the use of thromboelastography (TEG) in patients with colorectal cancer and to examine whether the TEG parameters can be used as potential markers for disease screening and prediction of disease severity. METHODS: One-hundred fifteen healthy controls (HC), 43 patients with benign adenoma (BA), and 387 patients with colorectal cancers (CRC) were included in the study. TEG parameters (reaction time, R; clot kinetics, K; alpha angle, α-angle; maximum amplitude, MA), conventional laboratory parameters, and clinical information were collected and analyzed among the HC, BA, and CRC groups. Receiver operating characteristics (ROC) were used for differential analysis. The correlation between TEG parameters and pathological information of CRC (differentiation degree, vaso-nerve infiltration, TNM stage) was analyzed. The differences in TEG parameters at different stages of disease and pre-/post operation were compared. RESULTS: Shorter K and higher α-angle/MA were found in patients with CRC compared with HC and BA (P < 0.001). TEG parameters demonstrated moderate diagnostic value (distinguish CRC from HC + BA: K-AUC = 0.693, α-angle-AUC = 0.687, MA-AUC = 0.700) in CRC but did not outperform traditional laboratory parameters. TEG hypercoagulability was closely associated with tumor markers (carcinoma embryonic antigen and carbohydrate antigen 19-9) and pathological information (differentiation degree, vaso-nerve infiltration, and TNM stage) (P < 0.05). Trend analysis showed that K decreased, but α-angle/MA increased gradually as the tumor progressed (P < 0.001). K- and α-angle showed slightly better sensitivity in predicting advanced tumors compared to traditional laboratory parameters. In CRC patients, 3-6 months after tumor resection, K [from 1.8 (1.5, 2.3) to 1.9 (1.6, 2.6)], α-angle [from 65.3 (59.0, 68.6) to 63.7 (56.6, 68.5)], and MA [from 61.0 (58.2, 66.0) to 58.9 (55.8, 61.3)] exhibited modest improvements compared to their preoperative values (P < 0.05). CONCLUSION: TEG parameters possess moderate diagnostic value in CRC diagnosis and predicting advanced tumors, and they are closely linked to surgical interventions. Although TEG parameters do not significantly outperform traditional laboratory parameters, they still hold promise as potential alternative indicators in CRC patients.

Regional efficacy evaluation in multi-regional clinical trials using a discounting factor weighted Z test.

Multi-regional clinical trial (MRCT) is an efficient design to accelerate drug approval globally. Once the global efficacy of test drug is demonstrated, each local regulatory agency is required to prove effectiveness of test drug in their own population. Meanwhile, the ICH E5/E17 guideline recommends using data from other regions to help evaluate regional drug efficacy. However, one of the most challenges is how to manage to bridge data among multiple regions in an MRCT since various intrinsic and extrinsic factors exist among the participating regions. Furthermore, it is critical for a local agency to determine the proportion of information borrowing from other regions given the ethnic differences between target region and non-target regions. To address these issues, we propose a discounting factor weighted Z statistic to adaptively borrow information from non-target regions. In this weighted Z statistic, the weight is derived from a discounting factor in which the discounting factor denotes the proportion of information borrowing from non-target regions. We consider three ways to construct discounting factors based on the degree of congruency between target and non-target regions either using control group data, or treatment group data, or all data. We use the calibrated power prior to construct discounting factor based on scaled Kolmogorov-Smirnov statistic. Comprehensive simulation studies show that our method has desirable operating characteristics. Two examples are used to illustrate the applications of our proposed approach.

Effects of Microplastic (MP) Exposure at Environmentally Relevant Doses on the Structure, Function, and Transcriptome of the Kidney in Mice.

As a common emerging environmental pollutant, microplastics (MPs) have been detected in a variety of environmental media and human bodies. The potential toxic effects and mechanisms of MPs need to be revealed urgently. MPs can be deposited in the kidney, and exposure to high doses of MPs can cause nephrotoxicity in experimental animals. In this study, we investigated the effects of exposure to polystyrene microplastics (PS-MPs) at environmentally relevant doses (0.1 and 1 mg/L) on kidney structure, function, and transcriptome in mice. We found that mice exposed to PS-MPs in drinking water for eight weeks had no change in body weight or kidney coefficient. PS-MPs administration decreased the levels of blood urea nitrogen (BUN) in mice, while serum creatinine (CRE) and uric acid (UA) concentrations were unaffected. Through using periodic acid-Schiff (PAS) and Masson staining, we discovered that the glomerular tuft area increased in the PS-MP-treated mice, while the degree of renal fibrosis remained unchanged. Furthermore, renal cortex transcriptomic analysis identified 388 and 303 differentially expressed genes (DEGs) in the 0.1 and 1 mg/L dose groups, respectively. The DEGs were highly enriched in mitochondrial-related terms and pathways of thermogenesis and oxidative phosphorylation. Moreover, protein-protein interaction (PPI) network analysis revealed that cytochrome b-c1 complex subunit 10 (UQCR11) and cytochrome c oxidase subunit 3 (MT-CO3) were important node proteins. These findings suggest that environmental exposure to MPs can cause abnormalities in renal structure and filtration function and that long-term exposure to MPs may be a risk factor for renal disease.

Electrospun membranes filtering 100 nm particles from air flow by means of the van der Waals and Coulomb forces.

Nonwoven fibrous filter membranes are widely used in filtration because of their low cost. They are less effective in intercepting airborne particles of the order of 100 nm, which is of the SARS-CoV-2 (COVID-19) virus's size. Many diseases, including COVID-19, predominantly spread by droplets released by breathing, coughing, sneezing, or medical procedures. It was shown that the smallest droplets can evaporate in air before settling, thus, making viruses airborne and easily penetrating even the best masks and filters. As a result, air-filtering membranes, which are capable of effective interception of ∼100 nm nanoparticles are highly desirable. A traditional way to improve filtration efficiency by overlapping several layers of nonwoven fabrics increases the required pressure drop, and thus, should be avoided as much as possible. Here, we propose and demonstrate an innovative approach to enhance performance of filtration membranes based on (i) a dramatic reduction in the fiber size, and (ii) metal coating of the fibers. The first component of this approach allows one to incorporate a novel physical mechanism of filtration, the short-range van der Waals forces, whereas the second one adds the long-range electric Coulomb forces if the oncoming nanoparticles are pre-charged and the metal-plated membrane grounded. In the present work, the ∼100 nm aluminum nanoparticles are filtered as a model of commensurate airborne single COVID-19 viruses, and Platinum is used as the sputter-coated material for the fiber coating. The resulting filtration efficiency enhanced by the electric Coulomb forces alone is increased by the factor of 1.77, while the filtration efficiency additionally facilitated by the van der Waals forces increased by the factor of 2.44. In comparison to the filter membranes with ∼500 nm fibers without the electric forces involved, the van-der-Waals-electric filter membrane with fibers ∼90 nm is 2.24 × 1.77 = 3.96 times more effective. The quality factor of a membrane which combines the van der Waals and Coulomb forces is 10.6 psi-1, which is almost three times that of a comparable membrane without the electric Coulomb force (with only van der Waals forces being used).

A single-cell survey unveils cellular heterogeneity and sensitive responses in mouse cortices induced by oral exposure to triphenyl phosphate.

Triphenyl phosphate (TPhP) is a non-halogenated organophosphorus flame retardant, and there is a higher exposure risk in children. TPhP has been found to be neurotoxic upon developmental exposure, yet the specific mechanism remains unclear. To characterize the cellular responses underlying TPhP-induced developmental neurotoxicity, we administered TPhP (0.5, 5 or 50 mg/kg/day) to neonatal mice from postnatal day 10 (P10)-P70. A total of 17,229 cells and 26,338 genes were identified in cortical samples from control and low-dose (the internal doses of metabolite DPhP comparable to human exposure level) groups using single-cell RNA sequencing (scRNA-seq). TPhP exposure led to heterogeneous transcriptional alterations and intercellular crosstalk among neurons, neural stem/progenitor cells (NSPCs), endothelial cells, and immunocytes. Deprivation of NSPCs, loss of mature neurons, and concomitant neuroinflammation mediated by extrinsic and intrinsic immunocytes were found in TPhP-exposed cortices. In addition, we observed blood-brain barrier destruction prior to the anxiety/depression-like neurobehavioral changes. These results reveal the distinctive cellular processes in TPhP's neurodevelopmental toxicity and uncover that the impeded neurogenesis, disrupted vascular barrier, and concomitant neuroinflammation are the sensitive responses to TPhP exposure. Our study paves the way for the application of scRNA-seq in toxicity assessments for emerging neurotoxic pollutants.

Screening rate and influential factors of lung cancer with low-dose computed tomography in Asian population: a systematic review and meta-analysis.

BACKGROUND: There are currently no studies synthesizing the screening rate and influential factors of low-dose computed tomography (LDCT)-screened lung cancer in Asian population. METHODS: A systematic review was conducted, using both English and Chinese language databases on March, 2019. The pooled screening rate and estimated odds ratios (ORs) of influential factors were analyzed using random effects models. Subgroup and meta-regression analyses were also employed to explore the heterogeneity. RESULTS: The pooled LDCT lung cancer screening rate was 1.12% (95% confidence interval (CI): 0.94%, 1.32%), and increased with age. Adenocarcinoma and stage I lung cancer had higher screening rates. Analysis of influential factors in the general population showed that female and elder age (≥50 years) were significantly influencing LDCT lung cancer screening rate (for female, OR = 1.32, 95% CI: 1.15-1.52; for adults ≥ 50 years, OR = 1.94, 95% CI: 1.52-2.49). Meta-regression analysis indicated that the heterogeneity maybe significantly correlated with the sample size, risk population and source of population. CONCLUSIONS: Unlike European and American populations, female and adults > 50 years rather than smoking adults were positively associated with screening rate in Asian populations. It is important to further study the benefits of lung cancer screening with LDCT in Asian populations.

Obesity affects outcomes of pancreatoduodenectomy.

BACKGROUND: Obesity is a major global health problem, and it has reached epidemic proportions worldwide. Therefore, surgeons will confront an increasingly larger proportion of obese candidates for pancreatoduodenectomy (PD) in the future. Several small retrospective studies have been conducted to evaluate the role of Body Mass Index (BMI) in postoperative surgical complications after PD, with conflicting results. The aim of this study was to use a large multi-institutional database to clarify the impact of different levels of obesity after PD. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database was queried for patients who underwent PD from 2014 to 2016. Patients were categorized in the following six BMI groups: <18.5 (Underweight), 18.5-24.9 (Normal Weight), 25-29.9 (Overweight), 30-34.9 (Class I obesity), 35-39.9 (Class II Obesity) and >40 (Class III Obesity). The primary outcomes of interest were 30-day mortality and morbidity after PD among the six BMI groups. RESULTS: The final population consists of 10,316 patients. Class III is associated with higher risk of 30-day mortality (OR 2.56, 95% CI 1.25-5.25, p = 0.011), major complications (OR 2.23, 95% CI 1.54-3.22, p < 0.001), clinically relevant postoperative pancreatic fistula (OR 2.48, 95% CI 1.89-3.24, p < 0.001), surgical site infections (OR 2.06, 95% CI 1.61-2.65, p < 0.001) and wound dehiscence (OR 3.47, 95% CI 1.7-7.1, p < 0.001) in multivariable analysis. CONCLUSIONS: In conclusion, our study shows that obesity is significantly associated with higher risk of postoperative complications in patients undergoing PD and patients with BMI≥40 have increased risk of mortality after PD.

Opioid Use as a Predictor of Pain Outcomes in Iraq and Afghanistan Veterans with Chronic Pain: Analysis of a Randomized Controlled Trial.

OBJECTIVE: Our objectives were to: 1) assess the relationship between self-reported opioid use and baseline demographics, clinical characteristics and pain outcomes; and 2) examine whether baseline opioid use moderated the intervention effect on outcomes at 9 months. DESIGN: We conducted a secondary analysis of data from the Evaluation of Stepped Care for Chronic Pain (ESCAPE) trial, which found stepped-care to be effective for chronic pain in military veterans. SETTING: A post-deployment clinic and five general medicine clinics at a Veteran Affairs Medical Center. SUBJECTS: In total 241 veterans with chronic musculoskeletal pain; 220 with complete data at 9 months. METHODS: Examination of baseline relationships and multivariable linear regression to examine baseline opioid use as a moderator of pain-related outcomes including Roland Morris Disability Questionnaire (RMDQ), Brief Pain Inventory (BPI) Interference scale, and Graded Chronic Pain Scale (GCPS) at 9 months. RESULTS: Veterans reporting baseline opioid use (n = 80) had significantly worse RMDQ (16.0 ± 4.9 vs. 13.4 ± 4.2, P < .0001), GCPS (68.7 ± 12.0 vs. 65.0 ± 14.4, P = .049), BPI Interference (6.2 ± 2.2 vs. 5.0 ± 2.1, P < .0001), and depression (PHQ-9 12.5 ± 6.2 vs. 10.6 ± 5.7, P = .016) compared to veterans not reporting baseline opioid use. Using multivariable modeling we found that baseline opioid use moderated the intervention effect on pain-related disability (RMDQ) at 9 months (interaction Beta = -3.88, P = .0064) but not pain intensity or interference. CONCLUSIONS: In a stepped-care trial for pain, patients reporting baseline opioid use had greater improvement in pain disability at 9 months compared to patients not reporting opioid use.

Multifocal Pain as a Predictor of Pain Outcomes in Military Veterans with Chronic Musculoskeletal Pain: A Secondary Data Analysis of a Randomized Controlled Trial.

OBJECTIVE: We aimed to examine 1) the relationship between multifocal pain and clinical characteristics, including demographics, pain outcomes, somatic symptoms, health-related quality of life, depression, and anxiety, and 2) whether multifocal pain was independently associated with treatment response. METHODS: We conducted a secondary data analysis on veterans with chronic pain enrolled in the Evaluation of Stepped Care for Chronic Pain (ESCAPE) trial with complete data at 9 months (n = 222). We examined baseline relationships and used multivariable linear regression to examine whether multifocal pain was independently associated with outcomes that included Brief Pain Inventory (BPI) Interference scale and Graded Chronic Pain Scale (GCPS) scores between baseline and 9 months. RESULTS: The sample had a mean BPI Interference score of 5.3 ± 2.2 and a mean GCPS score of 65.6 ± 13.7, 55% had significant depression (Patient Health Questionnaire 9-item depression scale [PHQ-9] score of ≥10), and 42% had significant anxiety (Generalized Anxiety Disorder Scale [GAD-7] score of ≥10). Veterans reporting three or more pain sites (the "more diffuse pain" group) had significantly less improvement on GCPS (b = 4.6, standard error [SE] = 2.3, P = 0.045), BPI Interference (b = 1.0, SE = 0.2, P = 0.0011), and health-related quality of life (Short-Form 36-item scale, Physical Component Summary) (b = 4.1, SE = 1.0, P < 0.0001) than did veterans reporting fewer than three pain sites (the "less diffuse pain" group). More diffuse pain was not associated with changes in PHQ-9 or GAD-7 scores. CONCLUSIONS: Multifocal pain predicted worse pain outcomes between baseline and 9 months in veterans enrolled in a trial for treating chronic musculoskeletal pain.

Exploring the dynamic mechanism of allosteric drug SHP099 inhibiting SHP2E69K.

The E69K mutation is one of the most frequent protein tyrosine phosphatase-2 (SHP2) mutations in leukemia, and it can cause the increase in the protein activity. Recent studies have shown that the E69K mutation was fairly sensitive to the allosteric inhibitor of SHP2 (SHP099). However, the molecular mechanism of the allosteric drug SHP099 inhibiting SHP2E69K remains unclear. Thus, the molecular dynamic simulations and the post-dynamics analyses (RMSF, PCA, DCCM, RIN and the binding free energies) for SHP2WT, SHP2WT-SHP099, SHP2E69K and SHP2E69K-SHP099 were carried out, respectively. Owing to the strong binding affinity of SHP099 to residues Thr219 and Arg220, the flexibility of linker region (residues Val209-Arg231) was reduced. Moreover, the presence of SHP099 kept the autoinhibition state of the SHP2 protein through enhancing the interactions between the linker region and Q loop in PTP domain, such as Thr219/Val490, Thr219/Asn491, Arg220/Ile488 and Leu254/Asn491. In addition, it was found that the residues (Thr219, Arg220, Leu254 and Asn491) might be the key residues responsible for the conformational changes of protein. Overall, this study may provide an important basis for understanding how the SHP099 effectively inhibited the SHP2E69K activity at the molecular level.

LncRNA FGF14-AS2 represses growth of prostate carcinoma cells via modulating miR-96-5p/AJAP1 axis.

OBJECTIVE: This investigation devoted to lncRNA FGF14 antisense RNA 2 (FGF14-AS2) in prostate carcinoma progression. METHODS: The levels of lncRNA FGF14-AS2, miR-96-5p, and Adherens junction-associated protein-1 (AJAP1) in prostate carcinoma were tested by Western blot and qRT-PCR. How these two genes interacted was confirmed by RNA immunoprecipitation and dualluciferase gene methods. The effect of FGF14-AS2/miR-96-5p/AJAP1 axis in prostate carcinoma progression was determined by MTT, Transwell, and nude mice tumor model. RESULTS: FGF14-AS2 was a downregulated lncRNA in prostate carcinoma tissue and cells. FGF14-AS2 could restrain miR-96-5p expression while miR-96-5p hampered AJAP1. FGF14-AS2 could effectively decrease the biological behaviors of prostate carcinoma cells, while knock-down of FGF14-AS2 triggered opposite results. Moreover, miR-96-5p mimic presented a cancer promoter role in prostate carcinoma cells. AJAP1 expression level could affect levels of proteins related to epithelial-mesenchymal transition. In vivo experiment suggested that overexpressing FGF14-AS2 could reverse the promotion of silenced AJAP1 on prostate carcinoma cell metastasis, thus to inhibit tumor growth. CONCLUSION: lncRNA FGF14-AS2 was a downregulated lncRNA in prostate carcinoma and influenced cell proliferation and metastasis. The influence relied on modulating miR-96-5p and its target gene AJAP1.

Identification of protein tyrosine phosphatase 1B (PTP1B) inhibitors through De Novo Evoluton, synthesis, biological evaluation and molecular dynamics simulation.

Protein tyrosine phosphatase 1B (PTP1B) is a widely expressed 50 kDa enzyme and the first intracellular PTP to be purified from human placental tissue. It has been proved that protein tyrosine phosphatase 1B played a significant role in the negative regulation of insulin signaling pathway and overexpression of PTP1B could lead to the decrease of insulin resistance. Therefore PTP1B has emerged as a novel promising therapeutic target for the treatment of type-2 diabetes mellitus. Computer aided drug design (CADD), chemical synthesis and biological activity assay resulted in the identification of a novel potent PTP1B inhibitor, compound 1a, which shared an IC50 value of 4.46 µM. Finally, the analysis of molecular dynamics simulation provided the theoretical basis for favorable activity of compound 1a.

Optimal, minimax and admissible two-stage design for phase II oncology clinical trials.

BACKGROUND: The article aims to compare the efficiency of minimax, optimal and admissible criteria in Simon's and Fleming's two-stage design. METHODS: Three parameter settings (p1-p0 = 0.25-0.05, 0.30-0.10, 0.50-0.30) are designed to compare the maximum sample size, the critical values and the expected sample size for minimax, optimal and admissible designs. Type I & II error constraints (α, ß) vary across (0.10, 0.10), (0.05, 0.20) and (0.05, 0.10), respectively. RESULTS: In both Simon's and Fleming's two-stage designs, the maximum sample size of admissible design is smaller than optimal design but larger than minimax design. Meanwhile, the expected samples size of admissible design is smaller than minimax design but larger than optimal design. Mostly, the maximum sample size and expected sample size in Fleming's designs are considerably smaller than that of Simon's designs. CONCLUSIONS: Whenever (p0, p1) is pre-specified, it is better to explore in the range of probability q, based on relative importance between maximum sample size and expected sample size, and determine which design to choose. When q is unknown, optimal design may be more favorable for drugs with limited efficacy. Contrarily, minimax design is recommended if treatment demonstrates impressive efficacy.

Septic Systems and Rainfall Influence Human Fecal Marker and Indicator Organism Occurrence in Private Wells in Southeastern Pennsylvania.

In the United States, approximately 48 million people are served by private wells. Unlike public water systems, private well water quality is not monitored, and there are few studies on the extent and sources of contamination of private wells. We extensively investigated five private wells to understand the variability in microbial contamination, the role of septic systems as sources of contamination, and the effect of rainfall on well water quality. From 2016 to 2017, weekly or biweekly samples (n = 105) were collected from five private wells in rural Pennsylvania. Samples were tested for general water quality parameters, conventional and sewage-associated microbial indicators, and human pathogens. Total coliforms, human Bacteroides (HF183), and pepper mild mottle virus were detected at least once in all wells. Regression revealed significant relationships between HF183 and rainfall 8-14 days prior to sampling and between total coliforms and rainfall 8-14 or 0-14 days prior to sampling. Dye tracer studies at three wells confirmed the impact of household septic systems on well contamination. Microbiological measurements, chemical water quality data, and dye tracer tests provide evidence of human fecal contamination in the private wells studied, suggesting that household septic systems are the source of this contamination.