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Among genetically engineered mouse models of breast cancer, MMTV-PyVT is a mouse strain in which the oncogenic polyoma virus middle T antigen is driven by the mouse mammary tumor virus promoter. The aim of the present study was to perform morphologic and genetic analyses of mammary tumors arising from MMTV-PyVT mice. To this end, mammary tumors were obtained at 6, 9, 12, and 16 weeks of age for histology and whole-mount analyses. We conducted whole-exome sequencing to identify constitutional and tumor-specific mutations, and genetic variants were identified using the GRCm38/mm10 mouse reference genome. Using hematoxylin and eosin analysis and whole-mount carmine alum staining, we demonstrated the progressive proliferation and invasion of mammary tumors. Frameshift insertions/deletions (indels) were noted in the Muc4. Mammary tumors showed small indels and nonsynonymous single-nucleotide variants but no somatic structural alterations or copy number variations. In summary, we validated MMTV-PyVT transgenic mice as a multistage model for mammary carcinoma development and progression. Our characterization may be used as a reference for guidance in future research.

Background/Aim: A recent study suggested that solute carrier family 35 member A2 (SLC35A2) is related to poor prognosis in patients with breast cancer. SLC35A2 transports uridine diphosphate-galactose from the cytosol to the lumen of the endoplasmic reticulum and Golgi. Materials and Methods: Immunohistochemical expression of SLC35A2 was evaluated using tissue microarrays. Cell growth, migration, and invasion of breast cancer cells were examined following loss- and gain-of-expression of SLC35A2. Results: Normal breast tissue exhibited SLC35A2 immunoreactivity in the nucleus. A progressive increase in cytoplasmic expression from in situ carcinoma to invasive carcinoma was observed. There was a correlation between cytoplasmic SLC35A2 expression and breast cancer stage (p

Case Serious complications of severe coronavirus disease 2019 (COVID-19) include subcutaneous emphysema (SE) and pneumomediastinum, which are complicated to treat with conventional Western medicine. We report how combining Chinese herbal medicine (CHM) with Western medicine quickly resolved a patient's COVID-19-associated pulmonary complications, shortened hospital stay and improved quality of life. Clinical features and outcome A 59-year-old male with a history of smoking and tumors was diagnosed with COVID-19 in May 2021. At hospitalization, his oxygen saturation (SpO2) was 80%, he had a continuous severe cough, rapid shallow breathing, spontaneous SE and pneumomediastinum. By Day 4 of hospitalization, his condition was worsening despite standard care, so CHM was added. After 3–5 days, his coughing had lessened and supplementary oxygen therapy was de-escalated. Nine days after starting CHM, the SE had completely resolved and the patient avoided intubation. His WHO OS 10-point Scale score had fallen from 6 to 3 points and the modified Medical Research Council Dyspnea Scale score from 4 to 2 points. He was hospitalized for 19 days. At 1 week post-discharge, the patient could handle most of his daily activities and experienced minor shortness of breath only when performing labor-intensive tasks. At 1 month, his work output was restored to pre-COVID-19 levels. Conclusion CHM combined with standard Western medicine improved pulmonary function, respiratory rate, blood oxygen saturation and shortened the hospital stay of a patient with severe COVID-19 complicated by SE and pneumomediastinum.

Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

PURPOSE Combining standard of care (pertuzumab-trastuzumab [PH], chemotherapy) with cancer immunotherapy may potentiate antitumor immunity, cytotoxic activity, and patient outcomes in high-risk, human epidermal growth factor receptor 2 (HER2)–positive early breast cancer. We report the phase III IMpassion050 primary analysis of neoadjuvant atezolizumab, PH, and chemotherapy in these patients. METHODS Patients with a primary tumor of > 2 cm and histologically confirmed, positive lymph node status (T2-4, N1-3, M0) were randomly assigned 1:1 to atezolizumab/placebo with dose-dense doxorubicin/cyclophosphamide, followed by paclitaxel, and PH. After surgery, patients were to continue atezolizumab/placebo and PH (total: 1 year of HER2-targeted therapy); those with residual disease could switch to ado-trastuzumab emtansine with atezolizumab/placebo. Coprimary efficacy end points were pathologic complete response (pCR; ypT0/is ypN0) rates in intention-to-treat (ITT) and programmed cell death-ligand 1 (PD-L1)–positive populations. RESULTS At clinical cutoff (February 5, 2021), pCR rates in the placebo and atezolizumab groups in the ITT populations were 62.7% (n = 143/228) and 62.4% (n = 141/226), respectively (difference –0.33%; 95% CI, –9.2 to 8.6; P = .9551). The pCR rates in the placebo and atezolizumab groups in patients with PD-L1–positive tumors were 72.5% (n = 79/109) and 64.2% (n = 70/109), respectively (difference –8.26%; 95% CI, –20.6 to 4.0; P = .1846). Grade 3-4 and serious adverse events were more frequent in the atezolizumab versus placebo group. Five grade 5 adverse events occurred (four neoadjuvant, one adjuvant; two assigned to study treatment), all with atezolizumab. Overall, the safety profile was consistent with that of atezolizumab in other combination studies. CONCLUSION Atezolizumab with neoadjuvant dose-dense doxorubicin/cyclophosphamide–paclitaxel and PH for high-risk, HER2-positive early breast cancer did not increase pCR rates versus placebo in the ITT or PD-L1–positive populations. PH and chemotherapy remains standard of care; longer follow-up may help to inform the long-term impact of atezolizumab.

Iliac vein compression syndrome (IVCS, or May–Thurner syndrome) occurs due to the compression of the left common iliac vein between the lumbar spine and right common iliac artery. Because most patients with compression are asymptomatic, the syndrome is difficult to diagnose based on the degree of anatomical compression. In this study, we investigated how the tilt angle of the left common iliac vein affects the flow patterns in the compressed blood vessel using three-dimensional computational fluid dynamic (CFD) simulations to determine the flow fields generated after compression sites. A patient-specific iliac venous CFD model was created to verify the boundary conditions and hemodynamic parameter set in this study. Thirty-one patient-specific CFD models with various iliac venous angles were developed using computed tomography (CT) angiograms. The angles between the right or left common iliac vein and inferior vena cava at the confluence level of the common iliac vein were defined as α1 and α2. Flow fields and vortex locations after compression were calculated and compared according to the tilt angle of the veins. Our results showed that α2 affected the incidence of flow field disturbance. At α2 angles greater than 60 degrees, the incidence rate of blood flow disturbance was 90%. In addition, when α2 and α1 + α2 angles were used as indicators, significant differences in tilt angle were found between veins with laminar, transitional, and turbulent flow (p < 0.05). Using this mathematical simulation, we concluded that the tilt angle of the left common iliac vein can be used as an auxiliary indicator to determine IVCS and its severity, and as a reference for clinical decision making.

There is little research about the stress, quality of life (QOL) and gut microbiota in newly diagnosed breast cancer patients. We sought to determine the relationship of distress scale and FACT-B different domain and fecal microbial composition among newly diagnosed breast cancer patients. Total 82 newly diagnosed breast cancer patients were enrolled in this prospective, observational study. The mean score of the FACT-B was 104.5 (SD, 19.76). The mean DT score was 4.43, with 53.7% (44/82) of the patients reporting moderate to severe distress (score 5 or above). Several associations between distress, FACT-B different domain and microbial taxa were observed among this sample of breast cancer patients. Specifically, Alcaligenaceae and Sutterella were significantly more abundant in individuals with higher scores on the DT scale at the family and genus level, respectively (p = 0.017), while Streptococcaceae (p = 0.028) at the family level and Streptococcus (p = 0.023) at the genus level were significantly more abundant in individuals with lower scores on the DT scale. This study defines the relationships among stress, QOL and gut microbiota in newly diagnosed breast cancer patients and provides many useful information to find potential probiotics for decreasing stress and improving QOL in breast cancer patients.

The purpose of this study was to investigate the performance of different lubricated and protective conditions of wire ropes. The failure behaviors of wire ropes under different surface conditions were evaluated by using salt spray, wear, and tensile testing. The four surface conditions of the test wire ropes included naked wire and wires coated with wire rope oil, 85W/140 gear oil, and grease, respectively. The potentiodynamic polarization curves revealed that the naked wire was more easily corroded in 3.5% aqueous NaCl solution than in 5%. The results indicated that only the specimen coated with wire rope oil showed no corrosion in the 5% aqueous solution after nine days of the salt spray, and likewise this specimen was not characterized by long distance scratches in a starvation lubrication condition, causing the wire’s tensile strength underwent almost no degradation. Furthermore, the uncertain performance of grease restricted the applications of wire ropes in corrosive environment.

Purpose:This study reports the MTD, recommended phase 2 dose (RP2D), and preliminary efficacy of alpelisib or buparlisib used in combination with tamoxifen plus goserelin in premenopausal patients with hormone receptor–positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC).Patients and Methods:This study enrolled premenopausal women with HR+, HER2− ABC. Patients received tamoxifen (20 mg once daily) and goserelin acetate (3.6 mg every 28 days) with either alpelisib (350 mg once daily; n = 16) or buparlisib (100 mg once daily; n = 13) in 28-day cycles until MTD was observed.Results:The criteria for MTD were not met for both alpelisib and buparlisib. The RP2D of alpelisib and buparlisib in combination with tamoxifen and goserelin were 350 mg and 100 mg, respectively. Both combinations met protocol-specified criteria for tolerability. The most common grade 3/4 treatment-emergent adverse events (TEAE) were hypokalemia (12.5%), hyperglycemia (6.3%), and rash (6.3%) for alpelisib and alanine aminotransferase increase (30.8%), aspartate aminotransferase increase (23.1%), and anxiety (15.4%) for buparlisib. TEAEs led to treatment discontinuation in 18.8% and 53.8% of alpelisib- and buparlisib-treated patients, respectively. Progression-free survival was 25.2 months in the alpelisib group and 20.6 months in the buparlisib group.Conclusions:The RP2Ds of alpelisib and buparlisib were 350 mg and 100 mg, respectively. No unexpected safety findings were reported. Although an early-phase study, data suggest that alpelisib plus endocrine therapy may be a potentially efficacious treatment that warrants further evaluation for premenopausal patients with HR+, HER2− ABC.See related commentary by Clark et al., p. 371

Supplementary Appendix

Supplementary Figure S1. The mRNA expression of MAP4K5, TRIO, EPHA4, DGKA and MAPK7 in TNBC cells Supplementary Figure S2. Inhibition of PKC-alpha, MET, and CDK6 reduced stem cell-like population.

This work uses molecular dynamics to simulate the grooving behavior of optical silica glass. The amorphous SiO2 (silica glass) was fabricated using a melting-quenching process, and the critical cut depth, and mechanism of the chip formation, were explored using a molecular dynamics simulation. The analytical results indicated that the tool edge radius affected the critical cut depth and roughness of the machined surface. A larger tool edge radius had a larger equivalent negative rake angle at the same depth of cut, causing a larger critical cut depth, while producing a smoother machined surface. In addition, the uncut chip thickness affected the tangential force and thrust force distribution weighting of the tool. The temperature field analysis revealed that a groove formed by the chip formation mechanism resulted in a higher workpiece temperature, causing the brittle material to exhibit ductile cutting behavior during the nanogrooving process. However, grooves formed by the scratching-indenting mechanism had a lower workpiece temperature.

Purpose Breast cancer is increasing around the globe, including Asia. We aimed to examine the survival and risk of contralateral breast cancer (CBC) in Asian breast cancer patients with BRCA mutations. MethodsA total of 128 breast cancer patients with germline BRCA mutations and 4,754 control breast cancer patients were enrolled. Data on clinical pathologic characteristics, survival and CBC were collected from the medical record. The rates of survival and CBC were estimated by Kaplan-Meier method. Results The mean age of onset in BRCA mutation carriers was significantly younger than control patients (BRCA vs. Non-BRCA: 43.9 vs. 53.2 years-old). BRCA mutation carriers had a higher proportion of triple-negative breast cancer (TNBC) (52%) than control patients (12%, pBRCA mutation patients than in control cases (hazard ratio (HR) = 3.95, 95% CI 2.71-5.75); when stratified by genotype, the HRs (95%CI) were 4.84 (3.00-7.82) for BRCA1 and 3.13 (1.78-5.49) for BRCA2 carriers, respectively. Moreover, BRCA1 mutation patients with triple-negative breast cancer (TNBC) as their first breast cancer had the highest risk of CBC (HR = 5.55, 95% CI 3.29-9.34). However, we did not observe any differences in relapse-free survival and overall survival between mutation carriers and control patients. ConclusionOur study suggest that BRCA patients had a significantly higher risk of developing CBC, particularly for BRCA1 mutation carriers with TNBC as the first breast cancer.

As a special activity of the Student Cluster Competition at SC19 conference, we made an attempt to reproduce the scalability evaluations of a highly paralleled polynomial filtering eigensolver for computing planetary interior normal modes. Our experiments were conducted on a Mars dataset using a small scale 4-node cluster with Intel Skylake CPU architecture, while the original article’s were conducted on a Moon dataset using a large scale 256-node supercomputer with Intel CPU Skylake and KNL architectures. This article shares our experiences and observations from our reproducibility activity and discusses our findings on three main sections: the weak scalability, the strong scalability, and the relationships between variables. The results of weak scalability and strong scalability were successfully reproduced. But due to the differences on the problem scale, input dataset, and system architecture, different behaviors regarding the polynomial degree were observed.

The mechanism of annealing-induced amorphization of metallic glass is investigated in this study via molecular dynamics simulation. Spherical nucleuses of Cu–Ni–Al alloy with a face-centered cubic structure are embedded to simulate nanograins in Cu–Ni–Al amorphous alloy; subsequently, the material is annealed at different temperatures. The results show that the critical radius for nucleation at temperatures above the glass transition temperature (Tg) affected the behavior, grain growth, and annihilation of nanograins in the Cu–Ni–Al amorphous alloy during annealing. When the temperature increased, the critical radius for nucleation increased as well. This causes the small nanograins to annihilate quickly and the large nanograins to develop rapidly. When the annealing temperature is higher than Tg, part of the crystal nuclei, which is smaller than the critical radius, can be eliminated. The crystallinity of the metallic glass decreased, and the minimum crystallinity is attained after a period of annealing simulation. Subsequently, as the residual effective nanograins began developing, the crystallinity of the amorphous metal increased again. Therefore, the annealing duration time is critical to the crystallinity of the amorphous alloy after annealing.

Aims and objectives The aims of the study were to (i) estimate the prevalence of frailty among older adults with type 2 diabetes, and (ii) investigate risk factors associated with frailty in the study group. Background The high prevalence of frailty among older adults and its adverse health impacts including higher risks for physical disabilities and a higher mortality rate is quickly evolving to become an important public health issue. Design A cross-sectional design. Methods Data were collected from the Clinical Diabetes Centre of our study group. Frailty was assessed using the Chinese version of the Tilburg frailty indicator. Other questionnaires included Activities of Daily Living, Mini-Mental State Examination, Taiwan Geriatric Depression Scale and Instrumental Activities of Daily Living. Multivariable logistic regression was established to identify factors associated with frailty. The STrengthening the Reporting of OBservational studies in Epidemiology checklist was used preparing the manuscript. Results A total of 248 subjects were recruited in this study, a total of 66 participants had frailty (26.6%). Our results showed that factors including age, number of chronic diseases, cerebrovascular accident, renal diseases, frequency of falling, frequency of hyperglycaemia, Activities of Daily Living, depression, Mini-Mental State Examination, and Instrumental Activities of Daily Living ≧1 task disability were correlated with frailty in older adults with type 2 diabetes. After adjusting for confounding factors, multivariate logistic regression analyses showed a significant increase in the probability of frailty by 1.72-times when comparing type 2 diabetes subjects with depression to those without depression. Conclusion This study revealed that depression is a significant factor associated with the occurrence of frailty among older adults with type 2 diabetes. Relevance to clinical practice Our results provided strong clinical evidence showing depression as an important factor associated with the risk of frailty in older individuals with type 2 diabetes. We recommend early detection via routine screenings for symptoms of depression during diabetes care to achieve early prevention or the delay of frailty and its implicated adverse health consequences.

Breast cancer is the most common invasive cancer in women worldwide. Next-generation sequencing (NGS) provides a high-resolution profile of cancer genome. Our study ultimately gives the insight for genetic screening to identify the minority of patients with breast cancer with a poor prognosis, who might benefit from the most intensive possible treatment. The detection of mutations can polish the traditional method to detect high-risk patients who experience poor prognosis, recurrence and death early. In total, 147 breast cancer tumors were sequenced with targeted sequencing using a RainDance Cancer Hotspot Panel. The average age of all 147 breast cancer patients in the study was 51.7 years, with a range of 21–77 years. The average sequencing depth was 5,222x (range 2,900x-8,633x), and the coverage was approximately 100%. A total of 235 variants in 43 genes were detected in 147 patients by high-depth Illumina sequencing. A total of 219 single nucleotide variations were found in 42 genes from 147 patients, and 16 indel mutations were found in 13 genes from 84 patients. After filtering with the 1000 Genomes database and for synonymous SNPs, we focused on 54 somatic functional point mutations. The functional point mutations contained 54 missense mutations in 22 genes. Additionally, mutation of genes within the RET, PTEN, CDH1, MAP2K4, NF1, ERBB2, RUNX1, PIK3CA, FGFR3, KIT, KDR, APC, SMO, NOTCH1, and FBXW7 in breast cancer patients were with poor prognosis. Moreover, TP53 and APC mutations were enriched in triple-negative breast cancer. APC mutations were associated with a poor prognosis in human breast cancer (log-rank P

Vitamin D is a steroid hormone that confers anti-proliferative and anti-inflammatory properties in prostate cells. Vitamin D deficiency is associated with advanced prostate cancer (PCa) stage, grade, and increased mortality. Since AA men are more likely to be vitamin D deficient compared to EA men, elucidating the pleiotropic effects of vitamin D may provide additional drug targets to mitigate disparate outcomes for AA men with PCa. Total RNA sequencing (RNAseq) was performed on an AA prostate cell line, RC-77N/E, derived from non-malignant epithelial tissue obtained from a PCa patient. We compared untreated RC-77N/E cells with RC-77N/E cells treated with 10 nM of vitamin D3 metabolite, 1α,25(OH)2D3 at 24h. Bioinformatic analysis, public cohort data mining, and RT-qPCR was performed to filter and validate selected statistically significant differentially expressed genes from RNAseq analysis. Our comparison of 1α,25(OH)2D3 treated versus untreated control RC-77N/E cell replicates revealed, 1601 significantly differentially expressed genes (DEGs) (FDR p < 0.05). Ingenuity Pathway Analysis software was used to conduct pathway enrichment analysis, which predicted repression of signaling pathways involved in actin cytoskeleton organization, epithelial-mesenchymal transitioning, adherens junction pathway, and RhoA pathway signaling with high enrichment z-score and statistically significant p-value. We additionally report predicted repression of PCa cell viability, invasion, cell proliferation and organismal death, for disease and function. We prioritized differentially expressed genes by identifying genes with 1) vitamin D response elements (VDREs) and 2) predicted poor prognosis, by performing overall survival analyses using The Cancer Genome Atlas (TCGA) Prostate Adenocarcinoma (PRAD) Cohort. We identified ANLN (Anillin) and ECT2 (Epithelial Cell Transforming 2), which were further validated using an AA tumor/benign contralateral matched clinical cohort, and a public cohort study using a non-malignant European prostate cell line, RWPE1. Our data suggest 1α,25(OH)2D3 significantly downregulates ANLN and ECT2 (FDR p < 0.05) in the RC-77N/E cell line, where survival analyses in the TCGA PRAD cohort show low expression of both ANLN and ECT2 are associated with significantly better overall survival outcome (p < 0.05). In our clinical cohort validations, both ANLN and ECT2 also show significantly decreased expression in non-malignant compared to tumor (p < 0.05). In conclusion, our study provides more insight of vitamin D3 regulation of PCa biomarkers and their potential roles in AA prostate cancer prevention, adjuvant treatment, as well as improving cancer survivor outcome Citation Format: Jabril R. Johnson, Rachel N. Martini, Yate Yuan-Ching, Leanne Woods-Burnham, Mya Walker, Greisha L. Ortiz-Hernandez, Dorothy Galloway, Melissa B. Davis, Sean K. Kimbro, Adam B. Murphy, Rick A. Kittles. 1,25-dihydroxyvitamin D3-mediated suppression of genes associated with cell cycle regulation and actin organization in a non-malignant African American prostate cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3509.

Background Human 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1) is an enzyme associated with steroidogenesis, however its' role in hepatocellular carcinoma (HCC) biology is unknown. Trilostane is an inhibitor of HSD3B1 and has been tested as a treatment for patients with breast cancer but has not been studied in patients with HCC. Methods and Results The expression of HSD3B1 in HCC tumors in 57 patients were examined. A total of 44 out of 57 tumors (77.2%) showed increased HSD3B1 expression. The increased HSD3B1 in tumors was significantly associated with advanced HCC. In vitro, the knockdown of HSD3B1 expression in Mahlavu HCC cells by a short hairpin RNA (shRNA) led to significant decreases in colony formation and cell migration. The suppression of clonogenicity in the HSD3B1-knockdown HCC cells was reversed by testosterone and 17β-estradiol. Trilostane-mediated inhibition of HSD3B1 in different HCC cells also caused significant inhibition of clonogenicity and cell migration. In subcutaneous HCC Mahlavu xenografts, trilostane (30 or 60 mg/kg, intraperitoneal injection) significantly inhibited tumor growth in a dose-dependent manner. Furthermore, the combination of trilostane and sorafenib significantly enhanced the inhibition of clonogenicity and xenograft growth, surpassing the effects of each drug used alone, with no documented additional toxicity to animals. HSD3B1 blockade was found to suppress the phosphorylation of extracellular signal-regulated kinase (ERK). The decreased ERK phosphorylation was reversed by testosterone or 17b-estradiol. Conclusions Trilostane significantly inhibited the growth of HCC by inhibiting HSD3B1 function and augmenting the efficacy of sorafenib.

Evacuated tube solar collector (ETSC) is widely used for domestic and industrial applications. Using reflective coating in an ETSC to realize concentration is a method to heighten the thermal efficiency due to solar irradiation could be reflected by the coating on the lower half of the outer glass tube and concentrated to the eccentric inner absorber. In this paper, an evacuated tube solar collector with inner concentrating (ETSC-IC) by reflective coating was proposed and fabricated. A series of experimental tests of the ETSC-IC was conducted to investigate the thermal performance. In addition, the mathematical model of the novel collector with inner concentrating was developed, and the structural parameters of the inner reflective concentrating evacuated tube, including the coating angel and the eccentric distance, have been analyzed. The optical and thermal analysis revealed that the best coating angle of the evacuated tube was 180°, and the thermal performance of the ETSC-IC enhanced with the increase of the eccentric distance under the best coating angle. The thermal efficiency of the ETSC-IC could reach 0.65 to 0.72 on the condition that the solar irradiation was around 950 W/m2 and the temperature of inlet water varied between 45 °C and 70 °C, and the ambient temperature was 31.2 °C. The thermal efficiency of the ETSC-IC was improved by approximately 10% compared with the conventional evacuated tube due to the enhanced irradiation concentrating and the reduction of heat loss caused by the coating on the outer glass tube.

ObjectiveWe aimed to investigate the efficacy and tolerability of cranial electrotherapy stimulation (CES) for patients with anxiety symptoms.MethodWe searched the Pubmed, Cochrane Central Register of Controlled Trials (CENTRAL), Embase and Medline for randomized control trials (RCTs) from the time of inception until November 15, 2021, following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data were pooled using a random-effects model. The primary outcomes were the mean change scores for anxiety symptoms. The secondary outcomes were the mean change scores for depressive symptoms.ResultsEleven RCTs were eligible (n = 794, mean age: 41.4, mean population of female: 64.8%). CES significantly reduced the anxiety symptoms compared to the control group [k = 11, n = 692, Hedge's g = −0.625, 95% confidence intervals (CIs) = −0.952 to −0.298, P < 0.001] with moderate effect size. The subgroup analysis showed that CES reduced both primary and secondary anxiety (primary anxiety, k =3, n = 288, Hedges' g = −1.218, 95% CIs = −1.418 to −0.968, P = 0.007; secondary anxiety, k = 8, n = 504, Hedges' g = −0.334, 95% CIs = −0.570 to −0.098, P = 0.006). After performing between group analysis, we found CES has significant better efficacy for patients with primary anxiety than those with secondary anxiety (P < 0.001). For secondary outcome, CES significantly reduced depressive symptoms in patients with anxiety disorders (k = 8, n = 552, Hedges' g = −0.648, 95% CIs = −1.062 to −0.234, P = 0.002). No severe side effects were reported and the most commonly reported adverse events were ear discomfort and ear pain.ConclusionWe found CES is effective in reducing anxiety symptoms with moderate effect size in patients with both primary and secondary anxiety. Furthermore, CES was well-tolerated and acceptable.Systematic Review Registration: PROSPERO, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021267916.

ObjectiveThis study aimed to investigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) in treating suicidal ideation in patients with mental illness.MethodWe followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Major electronic databases were systematically searched from the time of their inception until July 22, 2021. The primary outcome was the mean change in the scores for suicidal ideation. The secondary outcome was the mean change in depression severity.ResultsTen randomized controlled trials were eligible with 415 participants in the active treatment group (mean age = 53.78 years; mean proportion of women = 54.5%) and 387 participants in the control group (mean age = 55.52 years; mean proportion of women = 51.78%). rTMS significantly reduced suicidal ideation (k = 10, n = 802, Hedges' g = −0.390, 95% confidence interval [CI] = −0.193 to −0.588, p n = 761, Hedges' g = −0.698, 95% CI = −1.023 to −0.372, p < 0.001) in patients with major mental disorders. In the subgroup analysis, rTMS reduced suicidal ideation among patients with non-treatment-resistant depression (non-TRD) (−0.208) but not in those with TRD. rTMS as combination therapy had a larger effect than did monotherapy (−0.500 vs. −0.210). Suicidal ideation significantly reduced in patients receiving more than ten treatment sessions (-0.255). Importantly, the rTMS group showed favorable tolerability without major adverse events.ConclusionThe study showed that rTMS was effective and well-tolerated in reducing suicidal ideation and depression severity in patients with major mental disorders.

Biosolids that are applied to agricultural soil as an organic fertilizer are frequently contaminated with pharmaceutical residues that have persisted during wastewater treatment and partitioned into the organic phase. Macrolide antibiotics, which serve as a critically important human medicine, have been detected within biosolids. To determine the impacts of macrolide antibiotics on soil bacteria, every year for a decade, a series of replicated field plots received an application of a mixture of erythromycin, clarithromycin, and azithromycin at a realistic (0.1 mg kg soil(−1)) or an unrealistically high (10 mg kg soil(−1)) dose or were left untreated. The effects of repeated antibiotic exposure on the soil bacterial community, resistome, mobilome, and integron gene cassette content were evaluated by 16S rRNA and integron gene cassette amplicon sequencing, as well as whole-metagenome sequencing. At the unrealistically high dose, the overall diversity of the resistome and mobilome was altered, as 21 clinically important antibiotic resistance genes predicted to encode resistance to 10 different antibiotic drug classes were increased and 20 mobile genetic element variants (tnpA, intI1, tnpAN, and IS91) were increased. In contrast, at the realistic dose, no effect was observed on the overall diversity of the soil bacterial community, resistome, mobilome, or integron gene cassette-carrying genes. Overall, these results suggest that macrolide antibiotics entrained into soil at concentrations anticipated with biosolid applications would not result in major changes to these endpoints. IMPORTANCE Biosolids, produced from the treatment of sewage sludge, are rich in plant nutrients and are a valuable alternative to inorganic fertilizer when applied to agricultural soil. However, the use of biosolids in agriculture, which are frequently contaminated with pharmaceuticals, such as macrolide antibiotics, may pose a risk to human health by selecting for antibiotic resistance genes that could be transferred to plant-based food destined for human consumption. The consequences of long-term, repeated macrolide antibiotic exposure on the diversity of the soil bacterial community, resistome, and mobilome were evaluated. At unrealistically high concentrations, macrolide antibiotics alter the overall diversity of the resistome and mobilome, enriching for antibiotic resistance genes and mobile genetic elements of concern to human health. However, at realistic antibiotic concentrations, no effect on these endpoints was observed, suggesting that current biosolids land management practices are unlikely to pose a risk to human health due to macrolide antibiotic contamination alone.

Purpose: This study reports the MTD, recommended phase 2 dose (RP2D), and preliminary efficacy of alpelisib or buparlisib used in combination with tamoxifen plus goserelin in premenopausal patients with hormone receptor–positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC). Patients and Methods: This study enrolled premenopausal women with HR+, HER2− ABC. Patients received tamoxifen (20 mg once daily) and goserelin acetate (3.6 mg every 28 days) with either alpelisib (350 mg once daily; n = 16) or buparlisib (100 mg once daily; n = 13) in 28-day cycles until MTD was observed. Results: The criteria for MTD were not met for both alpelisib and buparlisib. The RP2D of alpelisib and buparlisib in combination with tamoxifen and goserelin were 350 mg and 100 mg, respectively. Both combinations met protocol-specified criteria for tolerability. The most common grade 3/4 treatment-emergent adverse events (TEAE) were hypokalemia (12.5%), hyperglycemia (6.3%), and rash (6.3%) for alpelisib and alanine aminotransferase increase (30.8%), aspartate aminotransferase increase (23.1%), and anxiety (15.4%) for buparlisib. TEAEs led to treatment discontinuation in 18.8% and 53.8% of alpelisib- and buparlisib-treated patients, respectively. Progression-free survival was 25.2 months in the alpelisib group and 20.6 months in the buparlisib group. Conclusions: The RP2Ds of alpelisib and buparlisib were 350 mg and 100 mg, respectively. No unexpected safety findings were reported. Although an early-phase study, data suggest that alpelisib plus endocrine therapy may be a potentially efficacious treatment that warrants further evaluation for premenopausal patients with HR+, HER2− ABC. See related commentary by Clark et al., p. 371

BACKGROUND In the Phase II NeoSphere study (NCT00545688), dual HER2 blockade with pertuzumab (P) + trastuzumab (H), + docetaxel (D) significantly increased pathologic complete response (pCR) vs. H+D in the neoadjuvant setting for HER2-positive early breast cancer (EBC), locally advanced (LA) BC, or inflammatory BC, with supportive progression- and disease-free survival (DFS) data. Consistently, the randomized, multicenter, double-blind, placebo (Pla)-controlled Phase III PEONY trial (NCT02586025) significantly improved total pCR (tpCR; primary endpoint) with P+H+D vs. H+D in an Asian population, and safety data were in-line with the known P safety profile. We present the final analysis of long-term efficacy (at 3 and 5 years) and safety from the study. METHODS Patients had centrally confirmed HER2-positive EBC (T2–3, N0–1) or LABC (T2–3, N2 or N3; T4, any N) and were randomized 2:1 to four neoadjuvant P+H+D or Pla+H+D cycles every 3 weeks. P: 840 mg loading/420 mg maintenance doses (or Pla); H: 8 mg/kg loading/6 mg/kg maintenance; D: 75 mg/m2. Patients then received three fluorouracil, epirubicin, and cyclophosphamide cycles, followed by 13 of P+H or Pla+H in the adjuvant setting for up to 1 year. Long-term outcomes (event-free survival [EFS], DFS, overall survival [OS]; all secondary endpoints) were assessed by Kaplan–Meier methods, Cox proportional hazards models, and a two-sided log-rank test (stratified by disease category and hormone receptor status). RESULTS Data cut-off was Mar 14, 2022, and 329 patients were randomized; 219 to P; 110, to Pla. Safety populations were 218 and 110 patients, respectively. Baseline characteristics were well balanced. Most patients received the full HER2-targeted cycles. Median follow-up was 62.9 months. Long-term efficacy data are shown in the table. During the overall treatment period, 70.6% of patients in the P+H+D arm and 68.2% in the Pla+H+D arm experienced grade ≥3 adverse events (AEs); the most common (in ≥5% of patients in either arm) being neutropenia (59.2% vs. 55.5%), leukopenia (34.4% vs. 34.5%), and febrile neutropenia (5.0% vs. 3.6%). Of the most common any-grade AEs (in ≥30% of patients in either arm), diarrhea was more common in the P+H+D arm (40.8% vs. 17.3% in the Pla+H+D arm). Serious AEs were reported in 17.0% and 13.6% of patients, respectively. No primary cardiac events (heart failure [New York Heart Association grade III or IV] or significant decline of left ventricular ejection fraction) or secondary cardiac events occurred during any study periods. CONCLUSIONS Long-term efficacy endpoints (EFS, DFS, and OS) were supportive of the primary endpoint results (tpCR) and suggested a clinically meaningful improvement with P+H vs. Pla+H when administered before and after surgery for one year of anti-HER2- therapy. Safety data were in-line with the known P safety profile and generally comparable between arms, with the exception of diarrhea. PEONY adds to the totality of data showing the benefit of the P+H+D regimen in HER2-positive EBC. Table 1: Long-term efficacy data Citation Format: Zhi-Ming Shao, Da Pang, Hongjian Yang, Wei Li, Shusen Wang, Shude Cui, Ning Liao, Yong-Sheng Wang, Chuan Wang, Yuan-Ching Chang, Hwei-Chung Wang, Seok Yun Kang, Jae Hong Seo, Kunwei Shen, Suphawat Laohawiriyakamol, Zefei Jiang, Liang Huang, Haiyan Wang, François Lamour, Grace Song, Eleonora Restuccia. Final analysis of the Phase III PEONY trial: long-term efficacy and safety of neoadjuvant–adjuvant pertuzumab or placebo, plus trastuzumab and docetaxel, in patients with HER2-positive early or locally advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-03.

To date, there is limited evidence on the antidepressant effects of memantine in patients with major mental diseases. We conducted a systematic review and meta-analysis to assess the efficacy of memantine in such populations.A literature search was performed for randomized controlled trials (RCTs) from the date of their inception until September 28, 2021, using PubMed, Medline, Embase, and the Cochrane Library. Changes in depression scores were the primary outcome. The response rate and remission rate to the treatment were secondary outcomes. We also assessed the dropout rate for tolerance.Eleven double-blind RCTs were included with 899 participants. Memantine significantly reduced depressive symptom scores compared with the control group (k = 11, n = 899, Hedges' g = -0.17, 95% confidence interval [CI] = -0.30 to -0.04, p = 0.009) with a small effect size. For secondary outcomes, memantine did not show a significant effect on response rate nor remission rate. In the subgroup analysis, memantine significantly reduced depressive symptom scores in patients with mood disorders (k = 8, n = 673, Hedges' g = -0.17, 95% CI = -0.32 to -0.01, p = 0.035) with a small effect size, but not in patients with schizophrenia.The present meta-analysis indicates that memantine effectively alleviates depressive symptoms in patients with mood disorders with a small effect size. Furthermore, memantine is well-tolerated and acceptable.

The present study evaluated if enteric bacteria or antibiotic resistance genes carried in fecal amendments contaminate the hay at harvest, representing a potential route of exposure to ruminants that consume the hay. In the field experiments, dairy manure was applied to a hay field for three successive growing seasons, and biosolids were applied to a hay field for one growing season. Various enteric bacteria in the amendments were enumerated by viable plate count, and selected gene targets were quantified by qPCR. Key findings include the following: at harvest, hay receiving dairy manure or biosolids did not carry more viable enteric bacteria than hay from unamended control plots. The fermentation of hay did not result in a detectable increase in viable enteric bacteria. The application of dairy manure or biosolids resulted in a few gene targets being more abundant in hay during the first harvest. Fermentation of hay resulted in an increase in the abundance of gene targets, but this occurred with hay from both the amended and control plots. Overall, the application of fecal amendments resulted in an increase in the abundance of some gene targets associated with antibiotic resistance in the first cut hay.

Additional file 1. NIH

This in-situ experimental study reports the long-term monitoring results of an earth air heat exchanger (EAHE) used to provide ventilation in a cafeteria building, in Nantou, Taiwan. The EAHE consisted of 7 parallel buried pipes with a length of 50 m and a diameter of 0.25 m. The energy performance of the system was analyzed based on data of both sensible and latent heat exchange. The monitored results have been compared with other previous cases presented in the literature to clarify the effect of various climates and design conditions on the EAHE application. The results show that despite relatively high soil temperatures underground compared with the previous case study in temperate regions, the visible temperature difference between inlet air and outlet supply air was recorded in the summer. The annual COP can reach 27.2 while the specific surface area is 0.039 m2(m3hr−1)−1, which represents a relatively low heat transfer area compared with other cases. The conclusion is that considering uncontrollable soil temperatures, the use of a relatively low specific surface area is suitable for great cooling demand in a hot and humid climate, while the design target is on maximizing the heat transfer rate rather than a higher temperature difference.

The molecular dynamic (MD) method is utilized to investigate the mechanical properties and deformation mechanism of [0001] and $$ \left[\overline{1}2\overline{1}0\right] $$ Ti nanowires at a high tensile strain rate. The simulation results reveal that the yield behavior of the [0001] Ti nanowire was dominated by a transition phase and led to like twinning deformation. The deformation twin led to a crystal rotation with a large angle. The $$ \left[\overline{1}2\overline{1}0\right] $$ Ti nanowires yielded through dislocation slip by a pyramidal plane of the HCP crystal structure. Therefore, the yield strength of the $$ \left[\overline{1}2\overline{1}0\right] $$ Ti nanowires was lower than that of the [0001] Ti nanowires. The broken strain of the $$ \left[\overline{1}2\overline{1}0\right] $$ Ti nanowire was also lower than that of the [0001] Ti nanowire. After yielding, the Ti nanowires plastically deformed through the slipping of an extended dislocation (a pair of partial dislocations), such that an FCC stacking fault was formed in the HCP crystal structure between the partial dislocations. Another extended dislocation in the FCC stacking fault was formed and moved by the slipping mechanism, causing further plastic deformation and reducing the flow stress.

Background Coprescription is a potential medical problem for older adults that could induce polypharmacy and subsequent complications. In Taiwan, Chinese herbal medicine (CHM) is popular among the older adults. Investigating the coprescription trends in Western medicine, CHM and dental medicine is important to avoid possible polypharmacy. Methods We analyzed data from the Longitudinal Health Insurance Database 2000 (LHID 2000) in Taiwan. Patients ≥ 60 years old who received coprescription of Western medicine, Chinese herbal medicine and drugs for dental care from 1997 to 2013 were included. The odds ratio (OR) and 95% confidence interval (95% CI) were estimated by a logistic regression model for evaluating the correlation between baseline characteristics and coprescription. Results A total of 233,594 patients were included for the analysis. Most patients receiving coprescriptions live in the northern Taiwan and with a monthly income lower than 20,000 new Taiwan dollars. The trends in older adults using Western medicine alone or CHM alone decreased over time, but the cohort using dental medicine alone had the opposite result. Decreased trends in coprescription with age were noted. The trends in the proportion of coprescription and the number of days of coprescription increased with the calendar year. Increased trends in the proportion of patients with coprescription were also found, except for the cohort of patients who used both Western medicine and CHM. Patients who were female, aged 70-79 years and residents from the outside islands of Taiwan were prone to receive coprescription. Conclusions Coprescription in older patients is not uncommon in Taiwan. Healthcare providers and policymakers should be aware of the complex coprescription pattern in the older adults.

Aberrant lipid metabolism provides bioenergetic, biosynthetic, and redox supplies to cancer cells. Previous studies have reported differential lipid profiling in thyroid malignancies. Sterol regulatory element-binding protein 1 (SREBP1), encoded by the SREBF1 gene, is a master regulator of cellular lipid homeostasis. The clinical and functional significance of SREBP1 in thyroid cancer is not well understood. Here, we showed that SREBP1 expression is significantly upregulated in invasive thyroid cancer than in normal thyroid tissue or benign thyroid nodules. High tumoral SREBP1 expression was associated with extrathyroidal extension, advanced disease stage, and shorter disease-specific survival in patients with differentiated thyroid cancer. SREBP1 overexpression significantly increased the oxygen consumption rate, filopodia formation, and migratory and invasive capacities of thyroid cancer cells. Knockdown of SREBF1 or treatment with an SREBP1 activation inhibitor fatostatin had the opposite effect. RNA-Seq analysis showed that modulation of SREBP1 expression was accompanied by corresponding changes in the expression of epithelial–mesenchymal transition markers and CYR61/CTGF. SREBP1-facilitated cell invasion could be abrogated by treatment with a YAP inhibitor such as verteporfin or genetic silencing of CYR61 or CTGF. In summary, SREBP1 upregulation can be used as a prognostic indicator for thyroid cancer and SREBP1 overexpression is involved in cancer invasiveness, at least partly, through upregulation of CYR61/CTGF via the Hippo-YAP pathway.

Representing a text as a graph for obtaining automatic text summarization has been investigated for over ten years. With the development of attention or Transformer on natural language processing (NLP), it is possible to make a connection between the graph and attention structure for a text. In this paper, an attention matrix between the sentences of the whole text is adopted as a weighted adjacent matrix of a fully connected graph of the text, which can be produced through the pre-training language model. The GCN is further applied to the text graph model for classifying each node and finding out the salient sentences from the text. It is demonstrated by the experimental results on two typical datasets that our proposed model can achieve a competitive result in comparison with sate-of-the-art models.

Background Although the powerful clinical effects of radiofrequency and microwave ablation have been established, such ablation is associated with several limitations, including a small ablation size, a long ablation time, the few treatment positioning, and biosafety risks. To overcome these limitations, biosafe and efficient magnetic ablation was achieved in this study by using biocompatible liquid gallium as an ablation medium and a contrast medium for imaging. Results Magnetic fields with a frequency (f) lower than 200 kHz and an amplitude (H) × f value lower than 5.0 × 109 Am−1 s−1 were generated using the proposed method. These fields could generate an ablation size of 3 cm in rat liver lobes under a temperature of approximately 300 °C and a time of 20 s. The results of this study indicate that biomedical gallium can be used as a contrast medium for the positioning of gallium injections and the evaluation of ablated tissue around a target site. Liquid gallium can be used as an ablation medium and imaging contrast medium because of its stable retention in normal tissue for at least 3 days. Besides, the high anticancer potential of gallium ions was inferred from the self-degradation of 100 µL of liquid gallium after around 21 days of immersion in acidic solutions. Conclusions The rapid wireless ablation of large or multiple lesions was achieved through the simple multi-injection of liquid gallium. This approach can replace the currently favoured procedure involving the use of multiple ablation probes, which is associated with limited benefits and several side effects. Methods Magnetic ablation was confirmed to be highly efficient by the consistent results obtained in the simulation and in vitro tests of gallium and iron oxide as well as the electromagnetic specifics and thermotherapy performance comparison detailed in this study Ultrasound imaging, X-ray imaging, and magnetic resonance imaging were found to be compatible with the proposed magnetic ablation method. Self-degradation analysis was conducted by mixing liquid gallium in acidic solutions with a pH of approximately 5–7 (to imitate a tumour-containing microenvironment). X-ray diffraction was used to identify the gallium oxides produced by degraded gallium ions.

BackgroundNumerous prospective studies, predominantly in the Caucasian population, have proven the clinical utility of using multigene expression tests to prevent overtreatment in early-stage breast cancer patients with early-stage disease. In this study, we used an Asian population to validate a clinical-genomic assay (RecurIndex®) for estimating the risk of distant recurrence and relapse in early-stage breast cancer patients. MethodsA total of 298 patients with early-stage breast cancer, luminal-like subtype (85.6%) and HER2-enriched/ triple-negative subtype (14.4%), was enrolled in a retrospective study across five participating medical centers in Taiwan. The inclusion criteria were as follows: women (1) who underwent primary surgery without prior induction treatments, (2) with an early pathologic N stage and (3) who received either mastectomy or breast-conserving surgery. Kaplan Meier method and Cox proportional hazards model were used to, respectively, identify independent prognostic factors and calculate the 5- and 10-year survival rates of patients in the low- and high-risk groups assigned by the diagnostic test. A forest plot was produced to assess hazard ratios and 95% confidence intervals. The primary endpoint was distant recurrence-free survival (DRFS) and the secondary endpoint was relapse-free survival (RFS).ResultsThe 10-year DRFS rate was significantly higher in the good prognosis group than in the poor prognosis group (91.9% [95% CI, 86.1-98.1%] versus 62.9% [95% CI, 49.8-79.4%]). The overall hazard ratio for distant recurrence was 1.031 [95% CI, 1.017 - 1.046] per unit Recurrence index-distant recurrence (RI-DR) score increment. ConclusionsThe present study provides robust evidence of the clinical utility of using the RI-DR score to accurately predict clinical outcomes. RecurIndex® could be used to determine the utility of adjuvant chemotherapy in Asian patients, especially those having hormone-receptor positive tumors, leading to a meaningful reduction in adjuvant chemotherapy recommendations.

The present study investigated the impact of on-farm anaerobic digestion on the abundance of enteric bacteria, antibiotic resistance-associated gene targets, and the horizontal transfer potential of extended-spectrum β-lactamase (ESBL) genes. Samples of raw and digested manure were obtained from six commercial dairy farms in Ontario, Canada. Digestion significantly abated populations of viable coliforms in all six farms. Conjugative transfer of plasmids carrying β-lactamase genes from manure bacteria enriched overnight with buffered peptone containing 4 mg/liter cefotaxime into a β-lactam-sensitive green fluorescent protein (GFP)-labeled Escherichia coli recipient strain was evaluated in patch matings. Digestion significantly decreased the frequency of the horizontal transfer of ESBL genes. Twenty-five transconjugants were sequenced, revealing six distinct plasmids, ranging in size from 40 to 180 kb. A variety of ESBL genes were identified: bla(CTX-M-1), bla(CTX-M-14), bla(CTX-M-15), bla(CTX-M-27), bla(CTX-M-55), and bla(PER-1). bla(CTX-M-15) was the most prevalent ESBL gene detected on plasmids harbored by transconjugants. Various mobile genetic elements were found located proximal to resistance genes. Ten gene targets, including sul1, str(A), str(B), erm(B), erm(F), intI1, aadA, incW, bla(PSE), and bla(OXA-20), were quantified by quantitative PCR on a subset of 18 raw and 18 digested samples. Most targets were significantly more abundant in raw manure; however, erm(B) and erm(F) targets were more abundant in digested samples. Overall, on-farm digestion of dairy manure abated coliform bacteria, a number of antibiotic resistance-associated gene targets, and the potential for in vitro conjugation of plasmids conferring resistance to extended-spectrum β-lactams and other classes of antibiotics into E. coli CV601. IMPORTANCE Using livestock manure for fertilization can entrain antibiotic-resistant bacteria into soil. Manure on some dairy farms is anaerobically digested before being land applied. Recommending the widespread implementation of the practice should be founded on understanding the impact of this treatment on various endpoints of human health concern. Although lab-scale anaerobic treatments have shown potential for reducing the abundance of antibiotic resistance genes, there are very few data from commercial farms. Anaerobic digestion of manure on six dairy farms efficiently abated coliform bacteria, E. coli, and a majority of antibiotic resistance-associated gene targets. In addition, the conjugation potential of plasmids carrying ESBL genes into introduced E. coli strain CV601 was reduced. Overall, anaerobic digestion abated coliform bacteria, the genes that they carry, and the potential for ESBL-carrying plasmid transfer.

Objective: Chinese herbal medicine (CHM) is quite popular in Asia. The purpose of this study is to investigate the benefits of decreasing the risk of cirrhosis in patients with non-alcoholic fatty ...

In recent years, indoor positioning system employing Bluetooth has attracted tremendous attention. However, it is investigated that its received channel information is significantly affected by hardware configuration and wireless environments, especially the received dataset of angle of arrival (AOA), which leads to inaccurate channel estimation and positioning. Further-more, AOA estimation at larger angle direction is severely influenced by the variant wireless environment and signal distortion, which has not been resolve in existing literature. In this paper, we propose an advanced I/Q density-based AOA estimation (IQDAE) to deal with the above-mentioned problem, which consists of two sub-schemes. We firstly employ the designed phase difference (PD) filter to convert I/Q signals to phase information and then select the candidate sets by eliminating outliers. Afterward, we conceive a PD density-based classification algorithm to estimate AOA. The experimental results show that the mean absolute error of proposed IQDAE algorithm is comparably smaller than that from the other schemes, including commercial solutions, especially at larger angles. The results indicate that we can effectively increase the service range for the Bluetooth positioning system by adopting the proposed algorithm.

This study analyzed the body composition of individuals with type 2 diabetes (T2DM). In this retrospective chart review study, body composition was measured through multifrequency bioelectrical impedance analysis (InBody 770). Body composition assessments were conducted in individuals with T2DM, who were aged ≥18 years. The parameters included body mass index (BMI), body fat mass (BFM), fat-free mass (FFM), visceral fat area, percent body fat (PBF), appendicular skeletal muscle mass (ASM), and skeletal muscle index (SMI). One-way ANOVA and independent t-tests were used to calculate differences in body composition distribution by age and sex. A total of 2404 participants were recruited. The prevalence of overall low muscle mass and sarcopenic obesity was 28.0% and 18.7%, respectively, which increased with age. The overall prevalence of obesity when PBF was used was 71.5%, which was higher than that when BMI was applied (32.4%). The normal BMI group exhibited a prevalence of low muscle mass of 55.6% and sarcopenic obesity of 34.8%. For both men and women, bodyweight, BFM, FFM, ASM, and SMI all decreased with age. The prevalence of low muscle mass and sarcopenic obesity was high in older adults and people with normal BMI. Using BMI to assess obesity and determine insufficient muscle mass underestimates the prevalence of obesity and neglects the problems of sarcopenia and high body fat in people with normal BMI.

BackgroundEndosperm is a triploid tissue in seed resulting from a sperm nucleus fused with the binucleate central cell after double fertilization. Endosperm may be involved in metabolite production, solute transport, nutrient storage, and germination. In the legume family (Fabaceae), with the greatest number of domesticated crops, approximately 60% of genera contain well-differentiated endosperm in mature seeds. Soybean seeds, the most important legume crop in the worlds, have endosperm surrounding embryos during all stages of seed development. However, the function of soybean endosperm is still unknown.ResultsFlow cytometry assay confirmed that soybean endosperm was triploid. Cytobiological observation showed that soybean endosperm cells were alive with zigzag-shape cell wall. Soybean endosperm cells allowed fusion proteins (42 kDa) to move from bombarded cells to adjacent unbombarded-cells. Such movement is not simple diffusion because the fusion proteins failed to move into dead cells. We used symplastic tracers to test the transport potential of soybean endosperm. Small organic dye and low-molecular-weight symplastic tracers revealed fast symplastic transport. After a treatment of an inhibitor of ATPase,N,N′-dicyclohexylcarbodiimide (DCCD), symplastic transport was blocked, but all tracers still showed fast apolopastic transport. The transport speed of 8-hydroxypyrene-1,3,6-trisulfonic acid in endosperm was 1.5 to 3 times faster than in cotyledon cells or Arabidopsis embryos.ConclusionsSoybean endosperm is a membrane-like, semi-transparent, and fully active tissue located between the seed coat and cotyledon. Soybean endosperm cells allowed macromolecules to move fast via plasmodesmata transport. The size exclusion limit is larger for soybean endosperm cells than its cotyledon or even Arabidopsis embryo cells. Soybean endosperm may be involved in fast and horizontal transport during the mid-developmental stage of seeds.

In this study, molecular dynamics (MD) are used to simulate the nanoimprinting behaviors of (001) Ni thin films using 3×3 array cuboid diamond punch. Different pitch of the punches was used to investigate the effect of the interaction among the forming pattern and the quality of the formed holes. Forming force was evaluated including normal and tractional force of the punch during pressing process. The dislocation behavior was also monitoring during the holes forming. The result showed that the pitch of the punch was 2w could get the best forming pattern.

A variety of epigenetic dysregulations are observed in thyroid malignancies. EZH2, the catalytic subunit of polycomb repressive complex 2, is upregulated in advanced thyroid cancers. EZH2 can catalyze trimethylation of histone H3 at lysine 27 (H3K27me3) and contribute to transcriptional silencing of target genes. Here, we investigated the immunohistochemical expression of H3K27me3 in neoplastic and normal thyroid tissues. Normal thyroid epithelial cells typically exhibited nuclear staining of moderate intensity. A similar expression pattern was observed in nodular goiters and follicular adenomas. By contrast, strong H3K27me3 expression was evident in 80% (8/10) lymphocytic thyroiditis, 63% (80/127) papillary thyroid cancer, 41% (7/17) follicular thyroid cancer, and 73% (8/11) poorly differentiated and anaplastic thyroid cancer. In differentiated thyroid cancer, strong H3K27me3 expression was associated with extrathyroidal extension (p

Background The information of Oncotype DX applied in Asian breast cancer patients is limited. A recurrence index for distant recurrence (RI-DR) has been developed for early-stage breast cancer (EBC) from tumor samples in Chinese patients. In this study, we compared the prognostic performance of the Oncotype DX (ODx) recurrence score (RS) with the RI-DR for any recurrence risk type. Materials and methods One hundred thirty-eight (138) patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative EBC who were previously tested with ODx were included for testing with the RI-DR. The cutoff score to partition the low- and high-risk patients was 26 for RS and 36 for RI-DR. The primary endpoint was recurrence-free survival (RFS). Results The concordance between the RI-DR and RS was 83% in N0 patients and 81% in node-positive patients when the RS score cutoff was set at 26. With a median follow-up interval of 36.8 months, the 4-year RFS for the high- and low-risk groups categorized by the RS were 61.9% and 95.0%, respectively (hazard ratio: 10.6, 95.0% confidence interval [CI]: 1.8–62.9). The 4-year RFS in the high- and low-risk groups categorized by the RI-DR were 72.6% and 98.5%, respectively (hazard ratio: 18.9, 95% CI: 1.8–138.8). Conclusion This paper illustrated the performance of RI-DR and ODx RS in breast cancer women in Taiwan. There was high concordance between the RI-DR and RS. The RI-DR is not inferior to the RS in predicting RFS in EBC patients. This study will fill the gap between the current and best practice in Chinese patients., Utilization of Oncotype DX is uncommon in Asia due to lack of clinical data. We compare a clinical-genomic model, developed from Taiwan, to Oncotype 21-gene panel in Chinese patients.

A four-path filter/mixer for surface acoustic wave (SAW)-less frequency division duplex (FDD) radio receivers is proposed, targeting high linearity and compression requirements. A bottom-plate mixing technique improves linearity by reducing the gate-source voltage modulation of the MOSFET switches. Differential bottom-plate mixing allows for switch sharing which halves the effective switch resistance to reduce drain-source voltage modulation. The first four-path switch-RC filter stage with bottom-plate mixing and a shared switch renders 2nd-order voltage-domain RF-bandpass filtering around the LO frequency. Extra out-of-band rejection is implemented combined with $V$ – $I$ conversion and zero-IF frequency down-conversion in the second cross-coupled switch-RC four-path stage, which offers a low-ohmic high-linearity current path for out-of-band interferers. A prototype chip fabricated in a 28-nm CMOS technology achieves an out-of-band IIP3 of +44 dBm, IIP2 of +90 dBm and blocker 1-dB gain-compression point of +13 dBm for a blocker frequency offset of 80 MHz. At this offset frequency, the measured desensitization is only 0.6 dB for a 0-dBm blocker, and 3.5 dB for a 10-dBm blocker at 0.7-GHz LO (i.e., 6- and 9-dB blocker noise figure). The chip consumes 38–96 mW for LO-frequencies of 0.1–2 GHz and occupies an active area of 0.49 mm2.

Background A cationic liposome-PEG-PEI complex (LPPC) was employed as a carrier for achieving targeted delivery of drug to human epidermal growth factor receptor-2 (HER2/neu)-expressing breast cancer cells. LPPC can be easily loaded with an anti-tumor drug and non-covalently associated with an anti-tumor antibody such as Herceptin that is clinically used to rapidly form immunoparticles within 1 h. Results Drug-loaded LPPC have an average size about 250 nm and a zeta potential of about 40 mV. Herceptin was complexed onto surface of the LPPC to form the drug/LPPC/Herceptin complexes. The size of curcumin/LPPC/Herceptin complexes were 280 nm and the zeta potentials were about 23 mV. Targeting ability of this delivery system was demonstrated through specific binding on surface of cells and IVIS images in vivo, which showed specific binding in HER2-positive SKBR3 cells as compared to HER2-negative Hs578T cells. Only the drug/LPPC/Herceptin complexes displayed dramatically increased the cytotoxic activity in cancer cells. Both in vitro and in vivo results indicated that Herceptin adsorbed on LPPC directed the immunocomplex towards HER2/neu-positive cells but not HER2/neu-negative cells. The complexes with either component (curcumin or doxorubicin) used in the LPPC-delivery system provided a better therapeutic efficacy compared to the drug treatment alone and other treatment groups, including clinical dosages of Herceptin and LipoDox, in a xenografted model. Conclusions LPPC displays important clinical implications by easily introducing a specific targeting characteristic to drugs utilized for breast cancer therapy. Electronic supplementary material The online version of this article (10.1186/s12951-019-0457-3) contains supplementary material, which is available to authorized users.

Biosolids were obtained from four Ontario municipalities that vary in how the sewage sludge is treated. These included a Class B biosolids that was anaerobically digested, a Class A biosolids that were heat treated and pelletized (Propell), and two Class A biosolids that were stabilized using either the N-Viro (N-Rich) or Lystek (LysteGro) processes. Viable enteric indicator or pathogenic bacteria in the biosolids were enumerated by plate count, gene targets associated with antibiotic resistance or horizontal gene transfer were detected by PCR, and a subset of these gene targets were quantified by qPCR. Following application at commercial rates to field plots, the persistence of enteric bacteria and gene targets in soil was followed during the growing season. Carrots, radishes and lettuce were sown into the amended and unamended control plots, and the diversity and abundance of gene targets they carried at harvest determined. All three Class A biosolids carried fewer and less abundant antibiotic resistance genes than did the Class B biosolids, in particular the very alkaline N-Viro product (N-Rich). Following application, some gene targets (e.g. int1, sul1, strA/B, aadA) that are typically associated with mobile gene cassettes remained detectable throughout the growing season, whereas others (e.g. ermB, ermF, blaOXA20) that are not associated with cassettes became undetectable within three weeks or less. At harvest a larger number of gene targets were detected on the carrots and radishes than in the lettuce. Overall, land application of Class A biosolids will entrain fewer viable bacteria and genes associated with antibiotic resistance into crop ground than will amendment with Class B biosolids.