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Broiler hens consuming feed to appetite (ad libitum; AL) show increased mortality. Feed restriction (R) typically improves reproductive performance and livability of hens. Rapidly growing broilers can exhibit increased mortality due to cardiac insufficiency but it is unknown whether the increased mortality of non-R broiler hens is also due to cardiac compromise. To assess cardiac growth and physiology in fully mature birds, 45-week-old hens were either continued on R rations or assigned to AL feeding for 7 or 21 days. AL hens exhibited increased bodyweight, adiposity, absolute and relative heart weight, ventricular hypertrophy, and cardiac protein/DNA ratio by d 21 (P < 0.05). Increased heart weights due to hypertrophic growth was attributed to enhanced IGF-1-Akt-FoxO1 signaling and its downstream target, translation initiation factor 4E-BP1 in conjunction with down-regulation of ubiquitin ligase atrogin-1/MAFbx (P < 0.05). Reduced activation of cardiac AMPK and downstream activation of ACC-1 in parallel with increased cardiac nitric oxide levels, calcineurin activity, and MAPK activation in AL hens (P < 0.05) suggested that metabolic derangement develops along the cardiovascular remodeling. These indictors of cardiac maladaptive hypertrophic growth were further supported by uregulation of heart failure markers, BNP and MHC-β (P < 0.05). Hens allowed AL feeding for 70 d exhibited a higher incidence of mortality (40% vs. 10%) in association with ascites, pericardial effusion, and ventricle dilation. A higher incidence of irregular ECG patterns and rhythmicity consistent with persistently elevated systolic blood pressure and ventricle fibrosis were observed in AL hens (P < 0.05). These observations support the conclusion that AL feeding in broiler hens results in maladaptive cardiac hypertrophy that progresses to overt pathogenesis in contractility and thereby increases mortality. Feed restriction provides clear physiological benefit to heart function of adult broiler hens. [ABSTRACT FROM AUTHOR]

Summary Signal transducer and activator of transcription 3 (STAT3) and phosphatase and tensin homologue (PTEN) are, respectively, an oncogene and tumour suppressor gene whose dysregulated expression in human prostate cancer is associated with increased malignancy and poor prognosis. Both markers were evaluated in 12 samples of canine benign prostatic hyperplasia (BPH) and 17 canine prostatic carcinomas (PCs) by immunohistochemistry, to understand their possible role in canine prostate carcinogenesis. STAT3 was expressed in 25% and 82.35% of BPH and PC, respectively, with a significantly higher number of STAT3-positive cells in malignant compared with hyperplastic lesions. Three PCs had occasional nuclear expression of STAT3. PTEN was expressed in BPH and PC with a similar distribution and percentage of positive cells; however, four PCs were PTEN negative. Solid PCs contained more STAT3-positive and fewer PTEN-positive cells compared with the other subtypes. A reduced number of PTEN-positive cells was observed in PCs with a high Gleason score (GS10), while no association was demonstrated between STAT3 expression and Gleason score. The data suggest that overexpression of STAT3 and downregulation of PTEN may be an important step in canine prostate carcinogenesis and both markers may be related to the histological subtypes of PC and the degree of differentiation of neoplastic cells. [ABSTRACT FROM AUTHOR]

Nowadays, doctors use electrocardiogram (ECG) to diagnose heart diseases commonly. However, some nonideal effects are often distributed in ECG. Discrete wavelet transform (DWT) is efficient for nonstationary signal analysis. In this paper, the Symlets sym5 is chosen as the wavelet function to decompose recorded ECG signals for noise removal. Soft-thresholding method is then applied for feature detection. To detect ECG features, R peak of each heart beat is first detected, and the onset and offset of the QRS complex are then detected. Finally, the signal is reconstructed to remove high frequency interferences and applied with adaptive searching window and threshold to detect P and T waves. We use the MIT-BIH arrhythmia database for algorithm verification. For noise reduction, the SNR improvement is achieved at least 10 dB at SNR 5 dB, and most of the improvement SNR are better than other methods at least 1 dB at different SNR. When applying to the real portable ECG device, all R peaks can be detected when patients walk, run, or move at the speed below 9 km/h. The performance of delineation on database shows in our algorithm can achieve high sensitivity in detecting ECG features. The QRS detector attains a sensitivity over 99.94%, while detectors of P and T waves achieve 99.75% and 99.7%, respectively. [ABSTRACT FROM AUTHOR]

Introduction The multinucleated syncytiotrophoblast is formed and maintained by cytotrophoblast cell fusion and serves multiple functions to ensure a successful pregnancy. We have previously reported that the proprotein convertase furin is required for trophoblast syncytialization by processing type 1 insulin-like growth factor receptor (IGF1R). Methods Utilizing trophoblast cell fusion models including induced fusion of choriocarcinoma BeWo cells and spontaneous fusion of primary cultured term cytotrophoblast cells, the expression of furin was evaluated by quantitative real-time PCR, Western blotting and immunofluorescence. The key transcription factor regulating the FUR gene promoter and critical responsive elements were identified by luciferase reporter assays, truncated mutants analysis, site-directed mutagenesis and ChIP. Results We demonstrated that the levels of FUR mRNA were significantly stimulated by cAMP/PKA signaling pathway during spontaneous fusion of cytotrophoblast cells and forskolin-induced fusion of BeWo cells. cAMP-responsive element binding protein (CREB) was proven to be the key transcription factor which regulated the FUR P1 promoter during forskolin-induced BeWo cell fusion, and two critical cAMP-responsive elements (CREs) in the P1 promoter were further identified. Finally, we showed that CREB mediated endogenous furin activation and that CREB siRNA attenuated forskolin-induced furin expression and cell fusion in BeWo cells. Discussion This provides the first evidence of the upstream regulator of furin during trophoblast cell fusion. Conclusions The above results suggest that the FUR transcription is activated by CREB-dependent stimulation of the FUR P1 promoter during human trophoblast syncytialization. [ABSTRACT FROM AUTHOR]

Abstract: Furin, a proprotein convertase (PC), is ubiquitously expressed and implicated in many physiological and pathological processes. This study is aimed to identify the role of furin in human trophoblast invasion and migration. Furin was found to be highly expressed in placental villi of both rhesus monkeys and human beings during early pregnancy. Specifically, furin was found in trophoblast column and trophoblast shell, regions where highly invasive cytotrophoblast cells invade the maternal decidua during human placentation. To determine whether furin plays any role in trophoblast invasion and migration, we employed human extravillous HTR8/SVneo cells in Matrigel invasion and transwell migration assays. Knocking-down furin expression by siRNA significantly inhibited invasion and migration of HTR8/SVneo cells (P <0.01), with corresponding decrease of matrix metalloproteinase-9 (MMP-9) activities. In contrast, over-expression of furin markedly increased cell invasion and migration (P <0.01), accompanied by significant increase of MMP-9 activities. Furthermore, furin siRNA significantly increased the levels of both tissue inhibitors of MMPs (TIMP)-1 and -2. Our results suggest that furin may play an important role in the invasion and migration of human trophoblast cells during early pregnancy. [Copyright &y& Elsevier]

The article cites a case of a 51 year old woman who was diagnosed of hyponatremia secondary to cerebral salt wasting (CSW). The patient has an olfactory neuroblastoma history and suffered from cosmetic defects and complicated by wound infections. She was treated with intravenous normal saline with 5% dextrose and with this therapy her serum sodium increases.

DSCR1 (adapt78) is a stress-inducible gene and cytoprotectant. Its protein product, DSCR1 (Adapt78), also referred to as MCIP1, inhibits intracellular calcineurin, a phosphatase that mediates many cellular responses to calcium. Exposure of human U251 and HeLa cells to hydrogen peroxide led to a rapid hyperphosphorylation of DSCR1 (Adapt78). Inhibitor and agonist studies revealed that a broad range of kinases were not responsible for DSCR1 (Adapt78) hyperphosphorylation, including ERK1/2, although parallel activation of the latter was observed. Phosphorylation of both DSCR1 (Adapt78) and ERK1/2 was attenuated by inhibitors of tyrosine phosphatase, suggesting the common upstream involvement of tyrosine dephosphorylation. The hyperphosphorylation electrophoretic shift in DSCR1 (Adapt78) mobility was also observed with other oxidizing agents (peroxynitrite and menadione) but not nonoxidants. Calcium ionophores strongly induced the levels of both hypo- and hyper-phosphorylated DSCR1 (Adapt78) but did not alter phosphorylation status. Calcium-dependent growth factor- and angiotensin II-stimulation also induced both DSCR1 (Adapt78) species. Phosphorylation of either or both serines in a 13-amino acid peptide made to a calcineurin-interacting conserved region of DSCR1 (Adapt78) attenuated inhibition of calcineurin. These data indicate that DSCR1 (Adapt78) protein is a novel, early stage oxidative stress-activated phosphorylation target and newly identified calcium-inducible protein, and suggest that these response mechanisms may contribute to the known cytoprotective and calcineurin-inhibitory activities of DSCR1 (Adapt78). [Copyright &y& Elsevier]

Treatment options for vancomycin-resistant enterococci (VRE) bloodstream infection are limited. Studies comparing daptomycin or linezolid in treating VRE bloodstream infection have conflicting results and suggest daptomycin underdosing. The responses to different daptomycin doses have not been studied. We conducted a multicentre prospective cohort study to compare linezolid and daptomycin (≥6 mg/kg) for the treatment of VRE bloodstream infection. The primary outcome was 14-day mortality. We used multivariate logistic regression analysis for outcome analysis and a generalized additive model for dose-dependent response estimation. Two hundred twelve patients were included (daptomycin, n = 141; linezolid, n = 71). All-cause 14-day mortality was higher in the daptomycin group (36.9% vs. 21.1%; p 0.03). After adjusting for confounders in logistic regression, mortality was lower in the linezolid group (adjusted odds ratio (aOR), 0.45; 95% confidence interval (CI), 0.21–0.96; p 0.04). The generalized additive model showed that higher-dose daptomycin (≥9 mg/kg) was associated with better survival than lower-dose daptomycin (6–9 mg/kg). Logistic regression showed that linezolid (aOR, 0.36; 95% CI, 0.17–0.79; p 0.01) and higher-dose daptomycin (aOR, 0.26; 95% CI, 0.09–0.74; p 0.01) independently predicted lower mortality compared to lower-dose daptomycin. Linezolid was not superior to higher-dose daptomycin in terms of mortality (aOR, 1.40; 95% CI, 0.45–4.37; p 0.57). Higher-dose daptomycin had lower mortality than lower-dose daptomycin. Despite higher mortality for lower-dose daptomycin than linezolid, linezolid conferred no survival benefit compared to higher-dose daptomycin. Our findings suggest that the recommended daptomycin dose is suboptimal for treating VRE bacteraemia. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy is an important modality in treating head and neck cancers. Clinically, predicting radiation response is essential. Stem-like cancer cells have been reported as having a high degree of radiation resistance. However, whether stem cell markers, such as OCT4 and NANOG, can predict clinical outcomes in patients with resected-then-irradiated oral cancer is still unknown. Methods: We established a radioresistant cell subline, OML1_R, from OML-1 oral cancer cells by using sequent 5-Gy irradiations, with a total dose of 50Gy. Between each irradiation, cancer cells were allowed to regrow for 5-7days, then PCR was used to detect mRNA expression of stem cell markers. Paraffin-embedded human tissue sections were used for validation of the role of stem cell markers in predicting post-resection, post-irradiation clinical outcomes. Findings: A 10-Gy radiation stress test confirmed the radioresistance of OML1_R. PCR showed upregulation of OCT4 (4-fold) and NANOG (6-fold) in OML1_R cells compared with their parent OML-1 cells. In 44 patients with resected-but-close-margined oral cancer, higher locoregional control was observed in the low OCT4/NANOG expression group compared with the high OCT4/NANOG expression group (92% versus 62%, p=0.03). Multivariate analysis confirmed that this stem cell marker is an independent factor in predicting locoregional control (adjusted hazard ratio 6.76; 95% confidence interval 1.87-24.43; p=0.04). Interpretation: Our data showed that stem cell markers OCT4 and NANOG are potential bio-predictors in patients with resected-then-irradiated oral cancer. [ABSTRACT FROM AUTHOR]

Nutrigenomics is the study of how food and associated nutrients affect gene expression. This field sits at the intersection of diet, the genome and health with the ultimate goal of exploiting its understanding to design a precision nutrition strategy for humans. We have studied diet and nutrigenomics in the context of something we call "dietary rational gene targeting." Here, healthy diet is used to alter disease-causing gene expression back toward the normal to treat various diseases and conditions while lowering treatment cost and toxicity. In this paper, we discuss the use of this strategy to modulate the expression of redox-associated genes to improve human health. Most human disorders are associated, at least to some extent, with oxidative stress and so treatments (including diet) that target redox-related genes have major potential clinical significance. Healthy dietary options here are wide-ranging and include whole foods and botanical-based beverages. In some cases, botanical supplements may also be useful gene modulators although their health benefits are less clear. Key redox gene targets for these dietary agents include antioxidant genes, related transcription factors, detoxification genes, and DNA repair genes. Other important considerations include bioavailability, the contribution of the microbiome, and advancing technologies. In this review, specific examples of redox associated genes and pathologies and their potential treatment with healthy diet are presented to illustrate our approach. This will also serve as a foundation for the design of future clinical studies to improve diet-related health. [Display omitted] • Dietary targeting of redox genes has therapeutic value. • Diet options are whole foods, healthy beverages and supplements. • Targeted redox genes are key drivers of disease. • Bioavailability is a major challenge. • Suggested studies and directions are proposed. [ABSTRACT FROM AUTHOR]

Background HLX07 is a fully-humanised anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) with re-engineered Fab rendering its less immunogenic and better binding affinity than cetuximab. In-vivo studies of HLX07 demonstrated either equal or superior efficacy to cetuximab at the same dose level. Here, we present the data from the phase 1 study of HLX07 in advanced solid tumours. Methods We conducted an open-label, dose-escalation study to evaluate the safety, maximum tolerated dose (MTD), PK and clinical response of HLX07 in subjects with recurrent or metastatic solid tumours unamendable to standard therapy. Subjects received once weekly intravenous infusion of HLX07 at doses of 50, 100, 200, 400, 600 and 800 mg until disease progression, withdrawal of consent or development of toxicities. Dose-limiting toxicities (DLTs) were evaluated within 28 days after the first dose and CT/MRI scans were evaluated every 8 weeks after the first infusion for treatment response. Safety, immunogenicity, PK and clinical response evaluations were performed throughout the study period. Results HLX07 was first approved to initiate clinical trial by the Taiwan and US FDAs; subject recruitment began in late 2016. As of 13-June-2019, 19 subjects received HLX07 in the study with the longest follow-up period of over 224 days. Among the 16 subjects who had been evaluated for efficacy, 1 subject with advanced colon cancer in 600 mg cohort achieved partial response and 5 subjects in different cohorts achieved stable disease status. Particularly at the 400 mg dose level, 30% of patients were in stable disease status at week 16 evaluation. Possibly related to HLX07 AEs with grade >2 severity included skin rashes (10.6%), hypophosphatemia (5.3%), hypomagnesemia (5.3%) and hypocalcemia (5.3%). No novel safety signal was identified; no DLT was noted up to 800 mg cohort. The PK data up to 600 mg was described in the following table. Table: 68P PK parameter of HLX07 at 50, 100, 200, 400 and 600 mg dose levels Dose (mg)  Cmax (×μg/mL)   AUC0-t (×h*μg/mL)   t1/2 (MEAN CV%)(h)   -  1st dose  4th dose  1st dose  4th dose  1st dose  4th dose  50  15.0  15  351  311  31.08 (14.12%)  23.11(32.61%)  100  43.2  41  2067  3110  39.70 (37.61%)  55.87 (11.98%)  200  76.1  99  5793  9541  74.61 (12.49%)  154.56 (38.73%)  400  119  216  9085  23274  106.60 (19.68%)  131.28 (57.48%)  600  158  311  14278  69567  138.64 (10.49%)  210.27 (26.59%)  Dose (mg)  Cmax (×μg/mL)   AUC0-t (×h*μg/mL)   t1/2 (MEAN CV%)(h)   -  1st dose  4th dose  1st dose  4th dose  1st dose  4th dose  50  15.0  15  351  311  31.08 (14.12%)  23.11(32.61%)  100  43.2  41  2067  3110  39.70 (37.61%)  55.87 (11.98%)  200  76.1  99  5793  9541  74.61 (12.49%)  154.56 (38.73%)  400  119  216  9085  23274  106.60 (19.68%)  131.28 (57.48%)  600  158  311  14278  69567  138.64 (10.49%)  210.27 (26.59%)  Table: 68P PK parameter of HLX07 at 50, 100, 200, 400 and 600 mg dose levels Dose (mg)  Cmax (×μg/mL)   AUC0-t (×h*μg/mL)   t1/2 (MEAN CV%)(h)   -  1st dose  4th dose  1st dose  4th dose  1st dose  4th dose  50  15.0  15  351  311  31.08 (14.12%)  23.11(32.61%)  100  43.2  41  2067  3110  39.70 (37.61%)  55.87 (11.98%)  200  76.1  99  5793  9541  74.61 (12.49%)  154.56 (38.73%)  400  119  216  9085  23274  106.60 (19.68%)  131.28 (57.48%)  600  158  311  14278  69567  138.64 (10.49%)  210.27 (26.59%)  Dose (mg)  Cmax (×μg/mL)   AUC0-t (×h*μg/mL)   t1/2 (MEAN CV%)(h)   -  1st dose  4th dose  1st dose  4th dose  1st dose  4th dose  50  15.0  15  351  311  31.08 (14.12%)  23.11(32.61%)  100  43.2  41  2067  3110  39.70 (37.61%)  55.87 (11.98%)  200  76.1  99  5793  9541  74.61 (12.49%)  154.56 (38.73%)  400  119  216  9085  23274  106.60 (19.68%)  131.28 (57.48%)  600  158  311  14278  69567  138.64 (10.49%)  210.27 (26.59%)  Conclusions HLX07 is generally well tolerated without reaching the MTD up to 800 mg weekly cohort and exhibits antitumour activity with durable objective responses at various doses. These findings support the initiation of a phase 1b/2 study of HLX07 plus chemotherapy in advanced solid tumours with the longest follow-up time of over 275 days as of 20-June-2019. Additionally, HLX07 is currently under safety and efficacy investigation combined with anti-PD-1 antibody, HLX10, in squamous cell carcinoma of head and neck. Clinical trial identification HLX07-001 Phase 1 study (NCT02648490); HLX07-002 Phase 1b/2 study (NCT03577704). Legal entity responsible for the study Shanghai Henlius Biotech, Inc.; Taiwan Henlix Biotech Co. Ltd. Funding Shanghai Henlius Biotech, Inc. Disclosure M.M. Hou: Research grant / Funding (institution): Taiwan Henlix Biotech Co. Ltd. C.L. Ho: Research grant / Funding (institution): Taiwan Henlix Biotech Co. Ltd. H.Y. Lin: Research grant / Funding (institution): Taiwan Henlix Biotech Co. Ltd. W. Jiang: Full / Part-time employment: Shanghai Henlius Biotech, Inc. S. Liu: Full / Part-time employment: Shanghai Henlius Biotech,Inc. Y. Hong: Full / Part-time employment: Shanghai Henlius Biotech, Inc. A. LUK: Full / Part-time employment: Shanghai Henlius Biotech, Inc. S.F. Lin: Full / Part-time employment: Taiwan Henlix Biotech Co. Ltd. T.C. Hsieh: Full / Part-time employment: Taiwan Henlix Biotech Co. Ltd. E. Liu: Full / Part-time employment: Taiwan Henlix Biotech Co. Ltd. [ABSTRACT FROM AUTHOR]

Background The survival advantage of induction chemotherapy (IC) followed by locoregional treatment is controversial in locally advanced head and neck squamous cell carcinoma (LAHNSCC). We previously showed feasibility and safety of cetuximab-based IC (paclitaxel/carboplatin/cetuximab—PCC, and docetaxel/cisplatin/5-fluorouracil/cetuximab—C-TPF) followed by local therapy in LAHNSCC. The primary end point of this phase II clinical trial with randomization to PCC and C-TPF followed by combined local therapy in patients with LAHNSCC stratified by human papillomavirus (HPV) status and T-stage was 2-year progression-free survival (PFS) compared with historical control. Patients and methods Eligible patients were ≥18 years with squamous cell carcinoma of the oropharynx, oral cavity, nasopharynx, hypopharynx, or larynx with measurable stage IV (T0–4N2b–2c/3M0) and known HPV by p16 status. Stratification was by HPV and T-stage into one of the two risk groups: (i) low-risk: HPV-positive and T0–3 or HPV-negative and T0–2; (ii) intermediate/high-risk: HPV-positive and T4 or HPV-negative and T3–4. Patient reported outcomes were carried out. Results A total of 136 patients were randomized in the study, 68 to each arm. With a median follow up of 3.2 years, the 2-year PFS in the PCC arm was 89% in the overall, 96% in the low-risk and 67% in the intermediate/high-risk groups; in the C-TPF arm 2-year PFS was 88% in the overall, 88% in the low-risk and 89% in the intermediate/high-risk groups. Conclusion The observed 2-year PFS of PCC in the low-risk group and of C-TPF in the intermediate/high-risk group showed a 20% improvement compared with the historical control derived from RTOG-0129, therefore reaching the primary end point of the trial. [ABSTRACT FROM AUTHOR]

Background: We investigated the expression of CXCR4, CCR7, estrogen receptor (ER), progesterone receptor (PR) and HER2-neu in human metastatic breast cancers to determine whether these biological biomarkers were preferentially expressed in any organ-specific metastases. [ABSTRACT FROM PUBLISHER]

Abstract: Introduction: Living donor liver transplantation (LDLT) is now widely performed for patients to resolve the critical shortage of organs from cadavers. Despite rapid implementation and expansion of the procedure, both outcome and complication analyses of LDLT are still incomplete. Objectives: To analyze the outcome of LDLT, with particular reference to complications of those in need of surgical or radiological intervention. Methods: Forty-eight LDLTs performed at National Taiwan University Hospital between December 1997 and April 2003 were reviewed retrospectively. Results: Forty-two (87.5%) patients survived the operation. The 1-year graft and patient survival rate was 81.5%. Seventeen of the 48 LDLT patients had at least one postoperative complication, which needed surgical or radiological intervention. The complications included bile leakage (n = 3), biliary stricture (n = 4), internal bleeding (n = 7), intra-abdominal abscess (n = 2), liver abscess (n = 1), hepatic artery thrombosis (n = 2), duodenal ulcer bleeding (n = 1), jejunal perforation (n = 1), adhesion ileus (n = 1), and intracranial hemorrhage (n = 1). Nine of the 17 patients with complications died. In contrast, only 2 of the other 31 patients died. Seven of the mortalities were related to the complications. All survivors received only one definite intervention early after the complications were diagnosed. However, the others received an average of 1.71 ± 0.95 (0 to 3) interventions. Conclusions: Complications requiring surgical or radiological treatment caused major mortality of LDLT. Early and definite treatment of these complications is important to improve the patient''s outcome. [Copyright &y& Elsevier]

Abstract: Background: Liver transplantation (LT) has been advocated as a salvage treatment for unresectable hepatocellular carcinoma (HCC). Selection criteria still need to be developed in Taiwan. Objectives: The purpose of our study was to assess the clinical findings and outcome of cirrhotic patients with HCC undergoing liver transplantation. Methods: Our study consisted of 13 HCC patients who underwent liver transplantation during October 1996 to March 2003. The medical records and pathologic reports were analyzed retrospectively. Results: Overall survival rates at 1 and 3 years were 86% and 61%, respectively. HCC recurrences occurred in three patients, one of whom is still alive with HCC recurrence 2 years after LT. The other two patients died of HCC recurrence 1 and 2 years after LT, respectively. Pretransplant α-fetoprotein (AFP) levels of >200 ng/mL were noted in all three patients with HCC recurrence. In contrast, only one of the ten patients without HCC recurrence had pretransplant AFP >200 ng/mL (P = .003). Four patients did not meet Milan criteria, two of whom had HCC recurrence. However, the other two patients with microscopic vascular invasion survived and were free of HCC. The only one patient, who had histologic grade 4 HCC, died of recurrence, although his tumor was AJCC stage 1. Conclusions: High AFP level is a risk factor for HCC recurrence after LT. In addition to Milan criteria, histologic tumor grading should be considered in patient selection. Microscopic vascular invasion may not affect the outcome of the patients with early HCC. [Copyright &y& Elsevier]