FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer.

On December 10, 2021, the FDA expanded the indications for ribociclib to include male patients for the treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. Ribociclib is now indicated in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy in adult patients, or with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy (ET), in postmenopausal women or in men. The efficacy of ribociclib + AI for male patients was primarily based on previous favorable benefit-risk assessments of ribociclib from MONALEESA-2 and MONALEESA-7 trials, and supported by COMPLEEMENT-1, an open-label, single-arm, multicenter clinical trial, in which 39 male patients (n = 3,246 total patients) received ribociclib + letrozole + goserelin/leuprolide. The overall response rate (ORR) based on confirmed responses in male patients with measurable disease at baseline was 46.9% [95% confidence interval (CI), 29.1-65.3], consistent with an ORR of 43.6% (95% CI, 41.5-45.8) in the overall population. Overall, adverse reactions occurring in male patients were similar to those occurring in female patients treated with ribociclib + ET. The efficacy of ribociclib + fulvestrant for male patients was primarily based on the previous findings of a favorable benefit-risk assessment from the MONALEESA-3 trial, supported by FDA review of clinical data of a limited number of male patients treated in clinical practice receiving ribociclib + fulvestrant. The known mechanism of action, biologic rationale, and clinical information available adequately demonstrate that the efficacy and safety of ribociclib + AI/fulvestrant are similar in male and female patients. This article summarizes the FDA's decision-making and data supporting the approval of ribociclib in male patients with breast cancer, and discusses regulatory insights.

FDA Approval Summary: Margetuximab plus Chemotherapy for Advanced or Metastatic HER2-Positive Breast Cancer.

On December 16, 2020, the FDA granted regular approval to margetuximab-cmkb (MARGENZA), in combination with chemotherapy, for the treatment of adult patients with HER2-positive (HER2+) metastatic breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. Approval was based on data from SOPHIA, a multicenter, randomized, open-label, active controlled study comparing margetuximab with trastuzumab, in combination with chemotherapy. The primary efficacy endpoint was progression-free survival (PFS) by blinded independent central review. SOPHIA demonstrated a 0.9-month difference in median PFS between the two treatment arms [5.8 vs. 4.9 months, respectively; stratified HR, 0.76 (95% confidence interval: 0.59-0.98; P = 0.0334)]. Overall survival (OS) was immature at the data cut-off date of September 10, 2019. Infusion-related reactions (IRR) are an important safety signal associated with margetuximab plus chemotherapy. In SOPHIA, 13% of patients treated with margetuximab plus chemotherapy reported IRRs, of which 1.5% were grade 3. The most commonly reported adverse drug reactions (>10%) with margetuximab in combination with chemotherapy were fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, IRR, palmar-plantar erythrodysesthesia, and extremity pain. Overall, the favorable risk-benefit profile for margetuximab when added to chemotherapy supported its approval for the intended indication.

Transoral vertical ramus osteotomy fixed with Kirschner pins.

Transoral vertical ramus osteotomy (VRO) has been condemned because the condyle has the potential to sag, and because it needs lengthy maxillomandibular fixation. We have therefore introduced a simple method of fixation, and examined its effectiveness and complications. After the osteotomy, the proximal and distal segments are trimmed to adapt to each other. Four Kirschner (K) pins 0.9mm in diameter are inserted percutaneously from the proximal to the distal segment while the condyle is positioned in the glenoid fossa. This is followed by a brief period of maxillomandibular fixation. We have reviewed the records of 95 patients who had unilateral or bilateral vertical ramus osteotomy fixed with K pins, after which the mean (SD) period of fixation was 19 (11) days. Fixation failed in two patients because excursion of the jaw was either too heavy or too early. The fixations were redone. All other fixations remained stable, including the 20 dual-jaw procedures in which VRO preceded maxillary osteotomy. The mean (SD) maximal mouth opening at final follow-up was 44 (7) mm, and in only one patient was it less than 30mm. Numbness of the lip or chin developed in seven patients, five of whom had other anterior mandibular procedures. Four patients had discomfort on palpation of the site of the pins, and one required removal. The new method was effective, and resulted in few complications within its limitations.

FDA Approval: Ribociclib for the Treatment of Postmenopausal Women with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer.

On March 13, 2017, the FDA approved ribociclib (KISQALI; Novartis Pharmaceuticals Corp.), a cyclin-dependent kinase 4/6 inhibitor, in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer. The approval was based on a randomized, double-blind, placebo-controlled, international clinical trial (MONALEESA-2). A total of 668 patients were randomized to receive either ribociclib plus letrozole (n = 334) or placebo plus letrozole (n = 334). An improvement in progression-free survival (PFS) was observed in patients receiving ribociclib plus letrozole compared with patients receiving placebo plus letrozole [HR = 0.556; 95% confidence interval (CI), 0.429-0.720]. Overall response rate (ORR) in patients with measurable disease was 52.7% (95% CI, 46.6-58.9) in the ribociclib plus letrozole arm and 37.1% (95% CI, 31.1-43.2) in the placebo plus letrozole arm. Overall survival data were immature. The most common adverse reactions observed in 20% or more of patients taking ribociclib were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain. This article summarizes FDA decision-making and data supporting the approval of ribociclib. Clin Cancer Res; 24(13); 2999-3004. ©2018 AACRSee related commentary by Spring and Bardia, p. 2981.

Antrodia cinnamomea reduces obesity and modulates the gut microbiota in high-fat diet-fed mice.

BACKGROUND: Obesity is associated with gut microbiota dysbiosis, disrupted intestinal barrier and chronic inflammation. Given the high and increasing prevalence of obesity worldwide, anti-obesity treatments that are safe, effective and widely available would be beneficial. We examined whether the medicinal mushroom Antrodia cinnamomea may reduce obesity in mice fed with a high-fat diet (HFD). METHODS: Male C57BL/6J mice were fed a HFD for 8 weeks to induce obesity and chronic inflammation. The mice were treated with a water extract of A. cinnamomea (WEAC), and body weight, fat accumulation, inflammation markers, insulin sensitivity and the gut microbiota were monitored. RESULTS: After 8 weeks, the mean body weight of HFD-fed mice was 39.8±1.2 g compared with 35.8±1.3 g for the HFD+1% WEAC group, corresponding to a reduction of 4 g or 10% of body weight (P<0.0001). WEAC supplementation reduced fat accumulation and serum triglycerides in a statistically significant manner in HFD-fed mice. WEAC also reversed the effects of HFD on inflammation markers (interleukin-1ß, interleukin-6, tumor necrosis factor-α), insulin resistance and adipokine production (leptin and adiponectin). Notably, WEAC increased the expression of intestinal tight junctions (zonula occludens-1 and occludin) and antimicrobial proteins (Reg3g and lysozyme C) in the small intestine, leading to reduced blood endotoxemia. Finally, WEAC modulated the composition of the gut microbiota, reducing the Firmicutes/Bacteroidetes ratio and increasing the level of Akkermansia muciniphila and other bacterial species associated with anti-inflammatory properties. CONCLUSIONS: Supplementation with A. cinnamomea produces anti-obesogenic, anti-inflammatory and antidiabetic effects in HFD-fed mice by maintaining intestinal integrity and modulating the gut microbiota.

Gallstone disease associated with increased risk of arterial stiffness in a Taiwanese population.

Arterial stiffness has similar risk factors to gallstone disease (GSD). However, there are few studies on the association between arterial stiffness and GSD. The aim of this study was to determine the relationship between arterial stiffness and GSD in a Taiwanese population. We enroled 6211 subjects from a health examination centre after excluding those who received medications for diabetes, hypertension and hyperlipidemia or had a history of cardiovascular disease, cerebrovascular disease, cancer, cholecystectomy or ankle-brachial index of ⩽ 0.9 or⩾1.3. Increased arterial stiffness was defined as right brachial-ankle pulse wave velocity (baPWV) ⩾1400 cm s-1. The diagnosis of GSD was based on ultrasonographic findings. The prevalence of increased arterial stiffness was 47.2 and 31.9 % in subjects with and without GSD (P<0.001). A multiple linear regression analysis revealed that GSD, age, systolic blood pressure, fasting plasma glucose and current smoking were positively associated with baPWV, whereas male gender, BMI, habitual exercise and HDL-C were negatively related to baPWV after adjusting for other clinical variables. In conclusion, subjects with GSD are associated with an increased risk of arterial stiffness.

Protective effect and antibody response of DNA vaccine against salmonid alphavirus 3 (SAV3) in Atlantic salmon.

This work reports the effect of two DNA vaccines against salmonid alphavirus 3 (SAV3) in Atlantic salmon. Presmolts were vaccinated by intramuscular injection of plasmids encoding the SAV3 structural polyprotein C-E3-E2-6K-E2 (pCSP), E2 only (pE2), or plasmid without insert (pcDNA3.3). E2 is expressed at the surface of cells transfected with pCSP and internally in cells transfected with pE2. A commercial vaccine based on inactivated SAV (NCPD) was used for comparison. At 10 weeks post-vaccination, only fish vaccinated with pCSP showed antibody against E2 and virus-neutralizing activity. Vaccinated fish were infected with SAV3 to determine protection by virus quantitation in serum after 7 days and scoring of pathological changes after 21 days. Fish vaccinated with both pCSP and NCPD vaccines showed significant virus reduction in serum, while fish vaccinated with pE2 did not. All fish vaccinated with pcDNA3.3 and pE2 showed pathological changes in organs typical of PD, 60% of fish vaccinated with NCPD showed PD pathology, while fish vaccinated with pCSP did not show PD pathology. Taken together, DNA vaccination with pCSP provided strong protection for salmon against SAV3 infection, which in part may be due to production of virus-neutralizing antibodies.

Retinoic acid directs breast cancer cell state changes through regulation of TET2-PKCζ pathway.

The key molecular mechanism governing the cancer cell state (stem cell-like state vs differentiation state) to control the cancer stem cell (CSC) pool remains elusive. This study provides the first evidence showing that all-trans retinoic acid (ATRA) induces the interaction and chromatin recruitment of a novel RARß-TET2 complex to epigenetically activate a specific cohort of gene targets, including MiR-200c. TET2-activated miR-200c further targets and suppresses PKCζ, a cell polarity protein that has a pivotal role in directing asymmetric division of mammalian stem cells to sustain the stem cell pool. Our data reveal that pharmacological concentration of ATRA effectively downregulates PKCζ through activation of miR-200c, leading to a decrease of the stem cell-like populations from non-tumorigenic mammary epithelial cells and non-aggressive breast cancer cells. However, aggressive breast cancer cells that manifest TET2-miR-200c dysregulation sustain a CSC pool highly resistant to ATRA, where inhibition of PKCζ directs the resistant CSCs to the luminal cell-like state and sensitization to tamoxifen, resulting in abrogation of mammary tumor growth and progression. Together, these findings elucidate a novel RARß-TET2-miR-200c-PKCζ signaling pathway that directs cancer cell state changes and also provide previously unidentified therapeutic implications for PKCζ inhibitors in diminishment of breast CSCs to eradicate breast cancer.

Pre-operative serum albumin level substantially predicts post-operative morbidity and mortality among patients with colorectal cancer who undergo elective colectomy.

The quantitative relationship between serum albumin level and surgical outcomes has not been clearly established. This study included 3732 patients with colon cancer who underwent a potentially curative colectomy. Post-operative mortality and morbidity were analysed according to the patients' demographic data, pre-operative comorbidities, and tumour-related factors. Age, asthma, renal impairment, and albumin level were significantly associated with post-operative morbidity and mortality in the multivariate analyses. Logistic regression analysis revealed linear relationships of post-operative morbidity and mortality with albumin level. The morbidity and mortality rates decreased by 7.3% and 15.6%, respectively, for each 0.1 g/dL increase in albumin level. This finding remained significant in the hypoalbuminaemia subgroup but not in the normoalbuminaemia subgroup. That is, the morbidity and mortality rates significantly decreased by 8.7% and 17.7%, respectively (both P < 0.001), in the former group and decreased by 2.7% (P = 0.112) and 11.6% (P = 0.092), respectively, in the latter group. This study demonstrated that serum albumin level linearly predicted the post-operative morbidity and mortality among the colorectal cancer patients. Pre-operative serum albumin level may therefore be used as a continuous rather than a categorical marker of disease severity, especially among patients with hypoalbuminaemia.

Activation of salt-inducible kinase 2 promotes the viability of peritoneal mesothelial cells exposed to stress of peritoneal dialysis.

Maintaining mesothelial cell viability is critical to long-term successful peritoneal dialysis (PD) treatment. To clarify the viability mechanism of peritoneal mesothelial cells under PD solutions exposure, we examined the mechanisms of cellular response to this stress conditions. Here we report that the proteasome activity is inhibited when treated with PD solutions. Proteasome inhibition-mediated activation of salt-inducible kinase 2 (SIK2), an endoplasmic reticulum-resident protein, is important for mesothelial cell viability. SIK2 is mobilized to promote autophagy and protect the cells from apoptosis under PD solution or MG132 treatment. Immunofluorescence staining showed that SIK2 is colocalized with LC3B in the autophagosomes of mesothelial cells treated with PD solution or derived from patients undergoing PD treatment. SIK2 activation is likely via a two-step mechanism, upstream kinases relieving the autoinhibitory conformation of SIK2 molecule followed by autophosphorylation of Thr175 and activation of kinase activity. These results suggest that activation of SIK2 is required for the cell viability when proteasome activity is inhibited by PD solutions. Maintaining or boosting the activity of SIK2 may promote peritoneal mesothelial cell viability and evolve as a potential therapeutic target for maintaining or restoring peritoneal membrane integrity in PD therapy.

Accuracy and Trending of Continuous Noninvasive Hemoglobin Monitoring in Patients Undergoing Liver Transplantation.

BACKGROUND: Shift in large fluid volumes and massive blood loss during liver transplantation frequently leads to rapid changes in hemoglobin (Hb) concentration; thus, to ensure adequate tissue oxygenation, accurate and rapid determination of Hb concentration is essential in transplant recipients. The Radical-7 Pulse CO-Oximeter provides a noninvasive and continuous way to monitor Hb concentration (SpHb) in real time and is an ideal candidate for use during liver transplantation. In this study, we assessed the relationship between SpHb and total Hb (tHb) obtained from arterial blood samples during surgery. METHODS: Forty patients undergoing liver transplantation were enrolled in this study. tHb and time-matched SpHb were measured at 5 different phases throughout surgery. Paired SpHb and tHb levels were assessed using linear regression, Bland-Altman analysis, and the Critchley polar plot method. RESULTS: A total of 161 paired measurements with sufficient signal quality were analyzed. The correlation between SpHb and tHb was 0.59 (P < .001). Bland-Altman analysis revealed that a bias between SpHb and tHb was 2.28 g/dL, and limits of agreement (LoA) were from -0.78 to 5.34 g/dL. Trending analysis showed that 87% of data were located within the acceptable trending area, indicating that the trending ability was not satisfied. CONCLUSIONS: The Radical-7 Pulse CO-Oximeter was not sufficient to monitor Hb levels and trends during liver transplantation surgery in our cohort. In particular, in critical patients and in those with low Hb levels, invasive Hb measurement should be used for assessment.

Cardiac Output Assessed by the Fourth-Generation Arterial Waveform Analysis System Is Unreliable in Liver Transplant Recipients.

BACKGROUND: Liver transplant recipients often have violent hemodynamic fluctuation during surgery that may be related to perioperative and postoperative morbidity. Because there are some considerations for the risk of the pulmonary arterial catheter (PAC), the conventional invasive device for cardiac output (CO) measurement, a reliable and minimally invasive alternative is required. We validated the reliability of CO measurements with the use of a minimally invasive FloTrac system with the latest fourth-generation algorithm in liver transplant recipients. METHODS: Forty liver transplant recipients without atrial fibrillation, valvular pathology, or intracardiac shunt were recruited in this prospective, observational study. CO values measured by use of PAC with continuous thermodilution method (COTh) and FloTrac devices (COFT) were collected simultaneously throughout the operation for reliability validation. RESULTS: Four hundred pairs of CO data points were collected in total. The linear regression analysis showed a high correlation coefficient (73%, P < .001). However, the percent error between COTh and COFT was 42.2%, which is worse than the established interchangeability criterion of 30%. The concordance rates were calculated at 89% and 59% by 4-quadrant plot and polar plot analysis, respectively. Neither met the preset validation criteria (>92% for the 4-quadrant plot and >90% for polar plot analyses). CONCLUSIONS: Our study demonstrates that the CO measurements in liver transplant recipients by the latest FloTrac system and the PAC do not meet the recognized interchangeability criterion. Although the result showed improvement in linear regression analysis, it failed to display a qualified trending ability.

Higher serum uric acid level increases risk of prehypertension in subjects with normal glucose tolerance, but not pre-diabetes and diabetes.

Although the association between serum uric acid (SUA) levels and prehypertension has been reported in previous studies, it is unknown whether their relationship is similar in subjects with diabetes, pre-diabetes and normal glucose tolerance (NGT). This study thus aimed to investigate the relationship between SUA and prehypertension in subjects with different glycemic status, including NGT, pre-diabetes and diabetes. A total of 12 010 participants were included after excluding subjects with blood pressure ⩾140/90 mm Hg, history of hypertension, leukaemia, lymphoma, hypothyroidism, medication for hypertension and hyperuricemia and missing data. Subjects were divided into four groups based on SUA quartiles (male Q1: ⩽345.0, Q2: 345.0-392.6, Q3: 392.6-440.2, Q4: ⩾440.2 µmol l(-1) and female Q1: ⩽249.8, Q2: 249.8-285.5, Q3: 285.5-333.1, Q4: ⩾333.1 µmol l(-1)). Diabetes, pre-diabetes and NGT were assessed according to the 2010 American Diabetes Association diagnostic criteria. Normotension and prehypertension were defined according to the JNC-7 (The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) criteria. The SUA was significantly higher in prehypertensive subjects as compared with normotensive subjects. SUA, as a continuous variable, was positively associated with prehypertension in subjects with NGT but not pre-diabetes and diabetes. Besides, NGT subjects with the highest quartile of SUA exhibited a higher risk of prehypertension after adjustment for other confounding factors. In pre-diabetes and diabetes groups, none of SUA quartiles was significantly related to prehypertension. SUA was significantly associated with an increased risk of prehypertension in subjects with NGT but insignificantly in subjects with pre-diabetes and diabetes.

FDA Approval: Ibrutinib for Patients with Previously Treated Mantle Cell Lymphoma and Previously Treated Chronic Lymphocytic Leukemia.

On November 13, 2013, the FDA granted accelerated approval to ibrutinib (IMBRUVICA capsules; Pharmacyclics, Inc.) for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. On February 12, 2014, the FDA granted accelerated approval for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. Ibrutinib is a first-in-class Bruton's tyrosine kinase (BTK) inhibitor that received all four expedited programs of the FDA: Fast-Track designation, Breakthrough Therapy designation, Priority Review, and Accelerated Approval. Both approvals were based on overall response rate (ORR) and duration of response (DOR) in single-arm clinical trials in patients with prior treatment. In MCL (N = 111), the complete and partial response rates were 17.1% and 48.6%, respectively, for an ORR of 65.8% [95% confidence interval (CI), 56.2%-74.5%]. The median DOR was 17.5 months (95% CI, 15.8-not reached). In CLL (N = 48), the ORR was 58.3% (95% CI, 43.2%-72.4%), and the DOR ranged from 5.6 to 24.2 months. The most common adverse reactions (≥ 30% in either trial) were thrombocytopenia, diarrhea, neutropenia, bruising, upper respiratory tract infection, anemia, fatigue, musculoskeletal pain, peripheral edema, and nausea.

Hepatitis C viral infection and the risk of dementia.

BACKGROUND AND PURPOSE: Hepatitis C virus (HCV) infection may cause cognitive impairment, but no studies have focused specifically on cognitive impairment stemming from HCV. The purpose of this study was to investigate the potential increased risk for dementia in HCV-infected patients. METHODS: A population-based cohort study based on the Taiwan National Health Insurance Research Database was conducted. From all potential participants aged 50 years or more, a total of 58,570 matched (1:1) pairs of HCV-infected patients and non-HCV-infected patients were included. Each subject was individually tracked from 1997 to 2009 to identify incident cases of dementia (onset in 1999 or later). Cox proportional hazards regressions were employed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between HCV infection and dementia. RESULTS: There were 2989 dementia cases from the HCV-infected cohort during the follow-up period of 533,861.1 person-years; the overall incidence rates of dementia differed from the non-HCV cohort (56.0 vs. 47.7 cases per 10,000 person-years, P < 0.05). The adjusted HR for dementia was 1.36 (95% CI 1.27-1.42) for HCV-infected patients after adjusting for alcohol-related disease, liver cirrhosis, hepatic encephalopathy and hepatocellular carcinoma. CONCLUSIONS: HCV infection may increase the risk for dementia. Further mechanistic research is needed.

The ratio of plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury in patients undergoing liver transplantation.

BACKGROUND: Postoperative acute kidney injury (AKI) is associated with high morbidity and mortality after liver transplantation (OLT). Previous studies have shown the value of plasma neutrophil gelatinase-associated lipocalin (NGAL) taken 2 hours after reperfusion of the liver graft as an early marker predicting AKI. The study was performed to determine whether plasma NGAL concentrations obtained as early as 1 hour after reperfusion was predictive of AKI and whether the NGAL ratio was an early predictor for AKI in the first 48 hours after OLT. METHODS: Twenty-six liver transplant recipients donated plasma samples for NGAL determinations at induction (T1), at graft reperfusion (T3) as well as after 1 (T4) and hours 2 (T5), and at the end of the surgery (T7). AKI was defined at 48 hours after liver transplantation according to the acute kidney injury network criteria. Predictive ability was assessed using areas under the curve of receiver operator characteristic analyses. RESULTS: The area under the curve of the receiver operator characteristics curve of (plasma NGAL concentration at T4)/(plasma NGAL concentration at T1) to predict AKI was 0.717 at T5, 0.765 at T7, 0.714 at T8 (24 hours post-OLT), and 0.781 at T9 (48 hours post-OLT). CONCLUSION: The plasma NGAL concentrations taken 1 hour after reperfusion of the liver graft seem to be predictive of AKI; the NGAL changing ratio may be an early predictor for AKI in the first 48 hours after OLT.

Ceramide accumulation and up-regulation of proinflammatory interleukin-1ß exemplify lipotoxicity to mediate declines of reproductive efficacy of broiler hens.

The study was conducted to delineate fundamental mechanisms that initiate the deleterious effect of fuel overloading on reproductive efficacy of broiler breeder hens. Sixty hens at age 26 wk were fed recommended amounts of feed (160 g/d per hen) or allowed voluntary feeding (approximately 30% more than restriction). At age 35 and 50 wk, hens were sampled for further analyzes. Voluntary feeding resulted in poor egg production, high rate of mortality, and abnormal ovarian structure (mainly overt hierarchical follicle atresia at age 35 wk and ovarian involution at age 50 wk). In contrast to feed-restricted hens, voluntary feeding also induced metabolic dysregulations that comprised enhanced adiposity; hepatic triacylglycerol accumulation; and elevated concentrations of plasma glucose, NEFAs, very low density lipoprotein, triacylglycerol, phospholipids, and sphingomyelin (P < 0.05). Furthermore, hepatic and circulating ceramide and sphingomyelin accumulation, and up-regulation of proinflammatory IL-1ß expression in liver and adipose tissues (P < 0.05) systemically manifested the development of lipotoxicity in feed-satiated hens. Lipotoxicity leading to impaired ovarian dysfunctions, including follicle atresia, ovarian regression, and a decline of circulating estradiol levels (P < 0.05) in feed-satiated hens, was further exemplified by ceramide accumulation and up-regulation of IL-1ß, serine palmitoyltransferase, and sphingomyelinase transcript abundance, but suppressed protein kinase Akt activation (P < 0.1 to 0.05) within the hierarchical follicles. This study provides the first in vivo evidence of the actions of ceramide and IL-1ß in mediating overfeeding-induced follicle atresia and progression of ovarian involution in broiler hens.

The role of EZH2 in tumour progression.

Accumulated evidence shows that EZH2 is deregulated in a wide range of cancer types, and it has a crucial role in stem cell maintenance and tumour development. Therefore, blocking EZH2 expression or activity may represent a promising strategy for anticancer treatment. In this review, we address the current understanding of the mechanisms underlying EZH2 regulation alongside the function of EZH2 gene targets that are involved in cancer progression. Finally, we will describe cancer therapies that target EZH2 or its downstream cascades, which could potentially reverse the oncogenic and stemness properties of the tumour cells to suppress cancer progression and recurrence.

Age factor and implication of human papillomavirus type-specific prevalence in women with normal cervical cytology.

The prevalence and genotype distribution of human papillomavirus (HPV) infection in women with normal cervical cytology varies widely according to the population studied. Two non-overlapping population-based cohort studies of women aged ≥30 years for the periods 2008-2009 (n=5026) and 2004-2005 (n=10 014) were analysed. The prevalence rate of HPV was 11·0% (95% CI 10·5-11·6). HPV infection was significantly associated with age, menopausal status, and inversely associated with hormone replacement therapy. There was an increasing trend of α3/α15, α5/α6, and multiple HPV infections with increasing age. The five most common types were HPV52, 18, 53, 58 and 70, while HPV16, 31, 33 ranked 21st, 25th, and 16th, respectively, in the merged cohort with normal cytology (n=14 724). HPV16, 31, and 33 were significantly associated with abnormal cytology, which could have resulted in their rarity in the total merged cohort (n=15 040).