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Objectives This study aims to explore the prevalence of sexual satisfaction among Chinese cancer survivors, and explore the association of sexual satisfaction with comorbidity and lifestyle factors. Methods A cross‐sectional study was performed among 3996 Chinese cancer survivors recruited at Shanghai Cancer Rehabilitation Club from March to April 2017. Data were collected through self‐reported questionnaires. The questionnaire includes information about demographic, cancer characteristics, comorbidities, lifestyle factors, and sexual satisfaction. Sexual satisfaction was measured by a single‐item scale. The distribution of sexual satisfaction among different demographic and cancer characteristics was compared using the chi‐squared test. Logistic regression models were conducted to assess the effects of lifestyle factors, comorbidities on sexual satisfaction after adjustment for demographic and cancer characteristics. Results More than 40% of male and female cancer survivors reported no sexual satisfaction. Sexual satisfaction of cancer survivors is significantly associated with both the number and the type of comorbidities. Heart disease, musculoskeletal system disease, diabetes, and hyperlipidemia are the comorbidities significantly associated with sexual satisfaction of cancer survivors. Lifestyle factors other than smoking, including exercise or fitness, drinking alcohol, and eating fruits and vegetables are significantly correlated with sexual satisfaction. Besides, all of the above associations show gender differences. In addition, demographic characteristics include sex, age, marital status, living status, and average monthly income are also significantly associated with sexual satisfaction of cancer survivors. Conclusion Comorbidity and lifestyle factors are associated with sexual satisfaction of cancer survivors, and the associations show gender differences. Improving the lifestyles of cancer survivors, and controlling and reducing their comorbidities are important for improving their sexual satisfaction., This study aims to investigate the prevalence of sexual satisfaction among Chinese cancer survivors, and explore the association of sexual satisfaction with comorbidity and lifestyle factors. Comorbidity and lifestyle factors are associated with sexual satisfaction of cancer survivors, and the associations show gender differences. Improving the lifestyles of cancer survivors, and controlling and reducing their comorbidities are important for improving their sexual satisfaction.

Background To investigate the influence of diabetes duration and glycemic control, assessed by glycated hemoglobin (HbA1c) levels, on risk of incident dementia. Methods The present study is a prospective study of 461 563 participants from the UK Biobank. The age at diabetes diagnosis was determined by self-report. Diabetes duration was calculated as baseline age minus age at diagnosis. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% confidential intervals (CIs). Results During a median follow-up of 8.1 years, 2 233 dementia cases were recorded. As compared with normoglycemic individuals, individuals with diabetes had higher risk of all-cause dementia, and the risk increased with increasing duration of diabetes; compared with participants with diabetes duration of Conclusions Diabetes duration appeared to be associated with the risk of incident dementia due to factors beyond glycemic control. Clinicians should consider not only glycemic control but also diabetes duration in dementia risk assessments for patients with diabetes.

OBJECTIVE The 2017 American College of Cardiology/American Heart Association blood pressure (BP) guidelines lowered the hypertension threshold from a SBP/DBP level of at least 140/90 mmHg to at least 130/80 mmHg. The cardiovascular impact of isolated systolic hypertension (ISH) and isolated diastolic hypertension (IDH) under the new definition remains unclear. METHODS We used data from the UK Biobank study, which is a prospective population-based cohort study. Participants were categorized into five groups: normal BP, normal high BP, ISH, IDH and systolic and diastolic hypertension. The primary endpoint for this study was the composite of nonfatal myocardial infarction (MI), nonfatal ischaemic stroke, nonfatal haemorrhagic stroke and cardiovascular disease (CVD) death. We also explored the results for the above-mentioned CVD outcomes separately. Baseline BP measurements were obtained twice after the participant had been at rest for at least 5 min in a seated position. RESULTS We included 385 955 participants who were not taking antihypertensive medications, were free of CVD at baseline and had available data on BP measurements. During a median follow-up of 8.1 years, 8959 CVD events were recorded, including 4729 nonfatal MIs, 2287 nonfatal ischaemic strokes, 813 nonfatal haemorrhagic strokes, and 1826 CVD deaths. According to the hypertension threshold of at least 130/80 mmHg by the American College of Cardiology/American Heart Association guidelines, both ISH (hazard ratio 1.39; 95% confidence interval 1.27, 1.15) and IDH (hazard ratio 1.28; 95% confidence interval 1.15, 1.43) were significantly associated with a higher overall CVD risk than normal BP. ISH was associated with most CVD risk, except for ischaemic stroke, while the excess CVD risk associated with IDH appeared to be driven mainly by MI and CVD death. We found heterogeneity by sex and age regarding the effects of IDH on overall CVD risk, with significant associations in younger adults (age

Translocator protein 18 kDa (TSPO) is mainly distributed in the outer mitochondrial membrane of steroid-synthesizing cells in the central and peripheral nervous systems. It mediates cholesterol transportation across the phospholipid membrane, which is a prerequisite for neurosteroid synthesis. Though the ligand of TSPO has clinical value in the diagnosis and treatment of neuropsychiatric disorders, the pharmacological study of TSPO for anti-postpartum depression has not been reported. In this study, the classical method of reproductive hormone withdrawal was used to construct a rat model of postpartum depression (PPD). The effect of YL-IPA08, a new ligand compound of TSPO, on PPD was evaluated using multiple behavioral tests at progressive time points. Additionally, real-time quantitative PCR, Western-blotting and an enzyme linked immunosorbent assay were conducted to elucidate the potential molecular mechanism of such effect. We report that the levels of TSPO and neurosteroids in the hippocampus and prefrontal cortex were significantly decreased in PPD rats compared to healthy controls. After 3 weeks of drug treatment, the levels of TSPO and neurosteroids in the hippocampus of PPD rats were increased, and anxiety and depressive like behaviors were alleviated. Meanwhile, compared with sertraline treatment, a positive control in this study, YL-IPA08 treatment had a shorter onset time. Our results suggest that the anxiolytic and anti-depressive activity of YL-IPA08 has significant value in the treatment of PPD and that TSPO may be a potential new target for the treatment of PPD.

Background Physical activity and good nutrition are important behavioral factors in promoting health and preventing disease. It is important to understand the factors affecting physical activity and nutrition. The purpose of this study was to explore whether social capital has an effect on physical activity and nutrition, and whether health literacy plays a mediating role between social capital and physical activity as well as nutrition. Methods This cross-sectional study was performed in a certain district of Shanghai in March and April 2017. Data was collected using a self-reported questionnaire, which included questions on sociodemographic characteristics, social capital, health literacy and health-promoting lifestyle profile-II. Health-promoting lifestyle profile-II measures the behaviours or habits of physical activity and healthy nutrition. An explore factor analysis of the principal components with varimax rotation was carried out on the social capital scale. Descriptive statistics was used to summarize the sociodemographic of participants. Mediation analysis was performed using the bootstrapping tests to examine whether health literacy mediate the relationship between social capital and physical activity as well as nutrition. Results The explore factor analysis results showed that social capital has five dimensions, namely social participation, social support, social network, control over life and feelings about the community. There is a positive correlation between social capital, health literacy, physical activity and nutrition. The correlation coefficient varied from 0.135 to 0.594. Mediation analysis demonstrated health literacy played a partial mediating effect between social capital and physical activity as well as nutrition. In the relationship between physical activity and social capital, the indirect effect of health literacy accounted for 8.20 to 12.65% of the total effect. In the relationship between nutrition and social capital, the mediation effect of health literacy accounted for 4.93 to 12.71% of the total effect. Conclusion Social capital can promote physical activity and nutrition by disseminating health information. Enhancing the social capital of residents will help increase physical activity and develop healthy eating habits. Attention should also be paid to the improvement of residents’ health literacy.

The cause of nuclear shape abnormalities which are often seen in pre-neoplastic and malignant tissues is not clear. In this study we report that deformation of the nucleus can be induced by TGFb1 stimulation in several cell lines including Huh7. In our results, the upregulated histone H3.3 expression downstream of SMAD signaling contributed to TGFb1-induced nuclear deformation, a process of which requires incorporation of the nuclear envelope (NE) proteins lamin B1 and SUN1. During this process, the NE constitutively ruptured and reformed with no observable indications of DNA damage response. Contrast to lamin B1 which was relatively stationary around the nucleus, the upregulated lamin A was highly mobile, shuttling between the nucleus and cytoplasm, and clustering at the nuclear periphery. The chromatin regions that lost NE coverage formed a supra-nucleosomal structure characterized by elevated histone H3K27me3 and histone H1, the formation of which depended on the presence of lamin A. These results provide evidence that shape of the nucleus can be modulated through TGFb1-induced compositional changes in the chromatin and nuclear lamina.

γδ T cells are a unique population of lymphocytes that have regulatory roles in patients with chronic hepatitis B (CHB); however, their role in acute hepatitis B (AHB) infection remains unclear. Phenotype and function of γδ T cells were analyzed in 29 AHB patients, 28 CHB patients, and 30 healthy controls (HCs) using immunofunctional assays. Compared with HCs and CHB patients, decreased peripheral and increased hepatic γδ T cells were found in AHB patients. Increased hepatic γδ T cells in AHB patients were attributed to elevated hepatic chemokine levels. Peripheral γδ T cells exhibited highly activated and terminally differentiated memory phenotype in AHB patients. Consistently, peripheral γδ T cells in AHB patients showed increased cytotoxic capacity and enhanced antiviral activity which was further proved in longitudinal study. Activated γδ T cells in AHB patients exhibited increased cytotoxicity and capacity for viral clearance associated with liver injury and the control of infection.

Background Breast cancer is a common tumor in China and has become a public health problem in modern society. Stress plays an important role in the occurrence and progression of cancer. At present, the current situation of stress on breast cancer survivors (BCSs) in China has not been fully understood. This study aims to explore the stress and coping strategies of Chinese BCSs, which provide suggestions to help BCSs reduce stress. Methods Sixty-three BCSs from the Shanghai Cancer Rehabilitation Club in China were included in this study and were divided into eight focus groups. These were transcribed verbatim, coded using thematic analysis and analyzed using NVivo 11. Results Three themes were extracted from the data to address our research objectives: stress, coping strategies and expectations. The stress of BCSs included psychological stress, stress caused by physical pain, economic stress, stress caused by the change of life status, and stress caused by information overload; the coping strategies included self-strategies and help from others; from the perspective of the survivors, they put forward their expectations for both the society and themselves. Conclusions This study shows that BCSs face a variety of stress. In the face of stress, BCSs need comprehensive support, including social and family support to cope with stressors. The findings from this study provide evidence for improving the quality of life among BCSs.

Background Echinococcosis is considered a neglected zoonotic disease and has been a major worldwide public health problem. Although it is known that health literacy is closely related to health behaviours and health outcomes, few studies have paid attention to echinococcosis related health literacy. This study aims to examine the association between echinococcosis-specific health literacy (ES-HL) and behavioural intention to prevent echinococcosis (BIPE) among herdsmen on the Tibet Plateauin in China. Methods A cross-sectional study of 401 Tibetan herdsmen was conducted in Gande county of Qinghai Province, China. Participants were recruited from August to September 2018 and from February to March 2019. A self-developed questionnaire was used to measure demographic information, ES-HL and BIPE. Hierarchical regression analysis was done to identify the factors associated with BIPE. Results In the hierarchical regression analysis, we entered age, sex, education level, marital state and family monthly income per capita into model 1 which explained a significant amount of variance in BIPE (Adjusted R2 change = 0.029, P = 0.006). Sex (β = − 0.125, P = 0.013) and family monthly income per capita (β = − 0.133, P = 0.009) were found to be associated with BIPE. Subsequently, the three factors of ES-HL were added to Model 1 to create Model 2. In Model 2, the two factors of ES-HL, perceived echinococcosis information support (β = 0.229, P P = 0.089) was not found to be associated with BIPE. The model improved significantly when ES-HL was included (Model 2) explaining the 25.8% of variance of BIPE (Adjust R2 change =0.229, P Conclusions ES-HL is an important predictor of whether individuals take preventive actions against echinococcosis. An ES-HL promotion action project should be developed targeting specific populations to enhance the prevention of echinococcosis.

Introduction The differentiation of benign and malignant sub-centimetre (≤10 mm) lung nodules (SCLNs) is challenging. Computed tomography (CT)-guided biopsy has been widely used for the diagnosis of lung nodules or masses. However, studies regarding CT-guided biopsies for SCLNs are still lacking. Objectives To evaluate the feasibility and diagnostic accuracy of CT-guided biopsies for SCLNs. Methods From December 2011 to October 2017, 102 patients with SCLNs underwent CT-guided lung biopsies. Data on technical success, diagnostic performance and procedure-related complications were collected and analysed. Results The technical success rate of CT-guided biopsy for SCLNs was 99% (101/102). One patient failed to undergo the procedure. A total of 101 SCLNs in 101 patients were examined. The biopsy diagnostic results included 38 malignant cases, 1 suspected malignant case, 5 specific benign cases and 57 non-specific benign cases. The final diagnoses included 49 malignant cases, 49 benign cases and 3 cases of undiagnosed lesions. The sensitivity, specificity and overall diagnostic accuracy were 80% (39/49), 100% (49/49) and 90% (88/98), respectively. Based on the univariate and multivariate logistic regression analyses, the independent risk factors for diagnostic failure were small tissue sample numbers (P = 0.048) and procedure-related hemoptysis (P = 0.004). Pneumothorax was found in 13 patients (13%). Based on the univariate and multivariate logistic regression analyses, the independent risk factor for pneumothorax was the decubitus position (P = 0.011). Hemoptysis was found in seven patients (7%). Conclusions CT-guided biopsy is a safe and highly accurate diagnostic method for SCLNs.

Mutations in lamin A (LMNA) are responsible for a variety of human dystrophic and metabolic diseases. Here, we created a mouse model in which progerin, the lamin A mutant protein that causes Hutchinson–Gilford progeria syndrome (HGPS), can be inducibly overexpressed. Muscle‐specific overexpression of progerin was sufficient to induce muscular dystrophy and alter whole‐body energy expenditure, leading to premature death. Intriguingly, sarcolipin (Sln), an endoplasmic reticulum (ER)‐associated protein involved in heat production, is upregulated in progerin‐expressing and Lmna knockout (Lmna −/−) skeletal muscle. The depletion of Sln accelerated the early death of Lmna −/− mice. An examination at the molecular level revealed that progerin recruits Sln and Calnexin to the nuclear periphery. Furthermore, progerin‐expressing myoblasts presented enhanced store‐operated Ca2+ entry, as well as increased co‐localization of STIM1 and ORAI1. These findings suggest that progerin dysregulates calcium homeostasis through an interaction with a subset of ER‐associated proteins, resulting in thermogenic and metabolic abnormalities., A model for progerin in calcium homeostasis and thermogenesis. In the molecular level, progerin can recruits a subset of endoplasmic reticulum (ER) proteins including Sln and Calnexin, but not SERCA2 or Calreticulin to the nuclear periphery, and may thus induce ER stress and enhance store‐operated calcium entry. The disturbed calcium homeostasis in progeric muscle may trigger transcriptional activation of Sln and ER‐stress associated genes and alter muscle‐based thermogenesis, leading to premature death of the animals. Cyt., cytosolic.

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide. Neuroinflammation is prominent in the short and long-term consequences of neuronal injuries that occur after TBI. Neuroinflammation involves the activation of glia, including microglia and astrocytes, to release inflammatory mediators within the brain, and the subsequent recruitment of peripheral immune cells. Various animal models of TBI have been developed that have proved valuable to elucidate the pathophysiology of the disorder and to assess the safety and efficacy of novel therapies prior to clinical trials. These models provide an excellent platform to delineate key injury mechanisms that associate with types of injury (concussion, contusion, and penetration injuries) that occur clinically for the investigation of mild, moderate, and severe forms of TBI. Additionally, TBI modeling in genetically engineered mice, in particular, has aided the identification of key molecules and pathways for putative injury mechanisms, as targets for development of novel therapies for human TBI. This Review details the evidence showing that neuroinflammation, characterized by the activation of microglia and astrocytes and elevated production of inflammatory mediators, is a critical process occurring in various TBI animal models, provides a broad overview of commonly used animal models of TBI, and overviews representative techniques to quantify markers of the brain inflammatory process. A better understanding of neuroinflammation could open therapeutic avenues for abrogation of secondary cell death and behavioral symptoms that may mediate the progression of TBI.

Methamphetamine (METH)-induced cell death contributes to the pathogenesis of neurotoxicity; however, the relative roles of oxidative stress, apoptosis, and autophagy remain unclear. L-Ascorbate, also called vitamin (Vit.) C, confers partial protection against METH neurotoxicity via induction of heme oxygenase-1. We further investigated the role of Vit. C in METH-induced oxidative stress, apoptosis, and autophagy in cortical cells. Exposure to lower concentrations (0.1, 0.5, 1 mM) of METH had insignificant effects on ROS production, whereas cells exposed to 5 mM METH exhibited ROS production in a time-dependent manner. We confirmed METH-induced apoptosis (by nuclear morphology revealed by Hoechst 33258 staining and Western blot showing the protein levels of pro-caspase 3 and cleaved caspase 3) and autophagy (by Western blot showing the protein levels of Belin-1 and conversion of microtubule-associated light chain (LC)3-I to LC3-II and autophagosome staining by monodansylcadaverine). The apoptosis as revealed by cleaved caspase-3 expression marked an increase at 18 h after METH exposure while both autophagic markers, Beclin 1 and LC3-II, marked an increase in cells exposed to METH for 6 and 24 h, respectively. Treating cells with Vit. C 30 min before METH exposure time-dependently attenuated the production of ROS. Vitamin C also attenuated METH-induced Beclin 1 and LC3-II expression and METH toxicity. Treatment of cells with Vit. C before METH exposure attenuated the expression of cleaved caspase-3 and reduced the number of METH-induced apoptotic cells. We suggest that the protective effect of Vit. C against METH toxicity might be through attenuation of ROS production, autophagy, and apoptosis.

Aging is an evolutionally conserved process that limits life activity. Cellular aging is the result of accumulated genetic damage, epigenetic damage and molecular exhaustion, as well as altered inter-cellular communication; these lead to impaired organ function and increased vulnerability to death. Skeletal muscle constitutes ~40% of the human body’s mass. In addition to maintaining skeletal structure and allowing locomotion, which enables essential daily activities to be completed, skeletal muscle also plays major roles in thermogenesis, metabolism and the functioning of the endocrine system. Unlike many other organs that have a defined size once adulthood is reached, skeletal muscle is able to alter its structural and functional properties in response to changes in environmental conditions. Muscle mass usually remains stable during early life; however, it begins to decline at a rate of ~1% year in men and ~0.5% in women after the age of 50 years. On the other hand, different exercise training regimens are able to restore muscle homeostasis at the molecular, cellular and organismal levels, thereby improving systemic health. Here we give an overview of the molecular factors that contribute to lifespan and healthspan, and discuss the effects of the longevity gene Cisd2 and middle-to-old age exercise on muscle metabolism and changes in the muscle transcriptome in mice during very old age.

Migration and organization of the nucleus are essential for the proliferation and differentiation of cells, including neurons. However, the relationship between the positioning of the nucleus and cellular morphogenesis remains poorly understood. Inherited recessive cerebellar ataxia has been attributed to mutations in SYNE1, a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex. Regardless, Syne1-mutant mice present with normal cerebellar development. The Sad1-Unc-84 homology (SUN)-domain proteins are located at the inner nuclear membrane and recruit Syne proteins through the KASH domain to the outer nuclear membrane. Here, we report an unrecognized contribution of Sun1 and Sun2 to the postnatal development of murine cerebellum. Mice depleted of Sun1 showed a marked reduction in the cerebellar volume, and this phenotype is exacerbated with additional loss of a Sun2 allele. Consistent with these histological changes, Sun1−/− and Sun1−/−Sun2+/− mice exhibited defective motor coordination. Results of immunohistochemical analyses suggested that Sun1 is highly expressed in Purkinje cells and recruits Syne2 to the periphery of the nucleus. Approximately 33% of Purkinje cells in Sun1−/− mice and 66% of Purkinje cells in Sun1−/−Sun2+/− mice were absent from the surface of the internal granule layer (IGL), whereas the proliferation and migration of granule neurons were unaffected. Furthermore, the Sun1−/−Sun2+/− Purkinje cells exhibited retarded primary dendrite specification, reduced dendritic complexity and aberrant patterning of synapses. Our findings reveal a cell-type-specific role for Sun1 and Sun2 in nucleokinesis during cerebellar development, and we propose the use of Sun-deficient mice as a model for studying cerebellar ataxia that is associated with mutation of human SYNE genes or loss of Purkinje cells., Summary: Mice lacking Sun proteins serve as a working model to study SYNE1-associated cerebellar ataxia; they will also be useful in identifying therapeutic targets for neurodegenerative diseases involving Purkinje cell loss.

Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide. Long-term deficits after TBI arise not only from the direct effects of the injury but also from ongoing processes such as neuronal excitotoxicity, inflammation, oxidative stress and apoptosis. Tumor necrosis factor-&alpha, (TNF-&alpha, ) is known to contribute to these processes. We have previously shown that 3,6&prime, dithiothalidomide (3,6&prime, DT), a thalidomide analog that is more potent than thalidomide with similar brain penetration, selectively inhibits the synthesis of TNF-&alpha, in cultured cells and reverses behavioral impairments induced by mild TBI in mice. In the present study, we further explored the therapeutic potential of 3,6&prime, DT in an animal model of moderate TBI using Sprague-Dawley rats subjected to controlled cortical impact. A single dose of 3,6&prime, DT (28 mg/kg, i.p.) at 5 h after TBI significantly reduced contusion volume, neuronal degeneration, neuronal apoptosis and neurological deficits at 24 h post-injury. Expression of pro-inflammatory cytokines in the contusion regions were also suppressed at the transcription and translation level by 3,6&prime, DT. Notably, neuronal oxidative stress was also suppressed by 3,6&prime, DT. We conclude that 3,6&prime, DT may represent a potential therapy to ameliorate TBI-induced functional deficits.

Background: Cistanche deserticola, a traditional Chinese herb medicine, has been widely used for thousands of years with the activities of hormone regulation, immunomodulatory, antioxidative, neuroprotective, anti-inflammatory, and estrogen. Glycosides of Cistanches (GCs) were the main bioactivity components of the herb. Objective: The objective of the study is to study estrogenic activity and the mechanism about estrogen receptors (ERs) of GCs. Materials and Methods: Cell proliferation was measured using the 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyltetrazolium bromide assay for MCF-7 cells. The cell cycle was detected using flow cytometry, and proliferation index was calculated. The mRNA and protein expressions of ERα and ERβ were detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis as the reported method with minor modifications. Results: GCs group at the concentrations of 1.75, 17.5, and 175 μg/mg could enhance proliferation of the MCF-7 cell lines with a time and dosage-dependent manner. Combined medication group (fulvestrant with estradiol [E2] or GCs) could lead to the incline of proliferation rate compared with the individual medication group (P

In recent years, a river-dredging project has been executed in Nantou, Taiwan. A large number of diesel vehicles carrying gravel and sand shuttle back and forth on the main traffic roads (Tai-16 and Tai-21). The purpose of this study is to figure out the levels of metals contributed by those vehicles to the surrounding environment. Eight stations along the roadside of diesel transport routes were selected as exposure sites, while a small village located about 9 km away from the diesel transport routes was selected as the control site. The mass concentrations of coarse and fine particulate matter indicated that contributions from traffic fleets resulted in a higher percentage of coarse particulate matter in the ambient air at exposure sites in comparison with that at control site. Significantly higher values of EC (elemental carbon) concentrations and ratios of EC/OC (organic carbon) at exposure sites indicate that diesel vehicles at exposure sites contributed a greater amount of pollutants than gasoline vehicles. Exposure site concentrations for all metals measured (Fe, Al, Mn, Pb, Zn, Cu, Ni, Mo and As) for fine and coarse particulate matter were all higher than those at the control site. Recorded levels of metal contents in road dust and riverside soil near Tai-16 and Tai-21 showed that while the traffic fleet did not increase the metal contents of crustal elements in the road dust, it did significantly increase the metal contents of traffic-related elements. Enrichment factors (EFs) were calculated with respect to road dust (EFroad) and with respect to the samples of riverside soil (EFriver). Among these metals, Mo was the most highly-enriched metal. The extremely high EFriver value (4300) of Mo indicates that these stations were highly polluted by diesel emission. Whereas the significantly high EFroad value (810) of Mo implies that a considerable of Mo was emitted from tailpipe of diesel vehicles.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Programmed death of neuronal cells plays a crucial role in acute and chronic neurodegeneration following TBI. The tumor suppressor protein p53, a transcription factor, has been recognized as an important regulator of apoptotic neuronal death. The p53 inactivator pifithrin-α (PFT-α) has been shown to be neuroprotective against stroke. A previous cellular study indicated that PFT-α oxygen analogue (PFT-α (O)) is more stable and active than PFT-α. We aimed to investigate whether inhibition of p53 using PFT-α or PFT-α (O) would be a potential neuroprotective strategy for TBI. To evaluate whether these drugs protect against excitotoxicity in vitro, primary rat cortical cultures were challenged with glutamate (50mM) in the presence or absence of various concentrations of the p53 inhibitors PFT-α or PFT-α (O). Cell viability was estimated by LDH assay. In vivo, adult Sprague Dawley rats were subjected to controlled cortical impact (CCI, with 4m/s velocity, 2 mm deformation). Five hours after injury, PFT-α or PFT-α (O) (2 mg/kg, i.v.) was administered to animals. Sensory and motor functions were evaluated by behavioral tests at 24 h after TBI. Apoptotic cells and p53-positive neurons were identified by double staining with cell-specific markers. Levels of mRNA encoding for p53-regulated genes (BAX, PUMA, Bcl-2 and p21) were measured by reverse transcription followed by real time-PCR from TBI animals without or with PFT- α/PFT- α (O) treatment. We found that PFT-α (O) (10uM) enhanced neuronal survival against glutamate-induced cytotoxicity in vitro more effectively than PFT-α (10uM). In vivo PFT-α (O) treatment enhanced functional recovery and decreased contusion volume at 24 h post-injury. Neuroprotection by PFT-α (O) treatment also reduced p53-positive neurons in the cortical contusion region. In addition, p53-regulated PUMA mRNA levels at 8h were significantly reduced by PFT-α (O) administration after TBI. PFT-α (O) treatment also decreased phospho-p53 positive neurons in the cortical contusion region. Our data suggest that PFT-α (O) provided a significant reduction of cortical cell death and protected neurons from glutamate-induced excitotoxicity in vitro, as well as improved neurological functional outcome and reduced brain injury in vivo via anti-apoptotic mechanisms. The inhibition of p53-induced apoptosis by PFT-α (O) provides a useful tool to evaluate reversible apoptotic mechanisms and may develop into a novel therapeutic strategy for TBI.

The objectives of this study were to evaluate qual- ityoflife(QoL)inpatientspresentingtotheJohnsHopkinsPancreas Multidisciplinary Clinic (PMDC), and to examine associations be- tween disease status, performance status, and QoL in order to identify patient subgroups that are most at risk for reduced QoL. Patients and Methods: Data from 77 patients were evalu- ated. At initial presentation, disease and performance status were assessed, as well as QoL, which was obtained with the European Organisation for Research and Treatment of Cancer QLQ-PAN26 questionnaire. Statistical analyses examined asso- ciations between QoL, disease status, and performance status. Results: Digestive symptoms (P.003) significantly differed by pancreatic disease status (resectable, resected, locally ad- vanced, and metastatic). Patients with a worse performance sta- tus, defined as Eastern Cooperative Oncology Group 1, were more likely to report symptomatic pancreatic pain (P.001), digestive symptoms (P.017), cachexia (P.004), and ascites (P.001) compared with patients with a performance status of 0. The majority (92%) of patients reported a significant fear of future health problems, regardless of disease status or perfor- mance status. Conclusion: Although several measures of QoL have been observed in all patients, certain measures appear to correlate specifically with worse disease status. Therefore, routine assess- ment of QoL is suggested in order to guide treatment decisions. Further investigation on optimizing the use of QoL measures and patient-reported outcomes to better tailor management is warranted.

Hutchinson-Gilford progeria syndrome (HGPS) is a human progeroid disease caused by a point mutation on the LMNA gene. We reported previously that the accumulation of the nuclear envelope protein SUN1 contributes to HGPS nuclear aberrancies. However, the mechanism by which interactions between mutant lamin A (also known as progerin or LAΔ50) and SUN1 produce HGPS cellular phenotypes requires further elucidation. Using light and electron microscopy, this study demonstrated that SUN1 contributes to progerin-elicited structural changes in the nuclear envelope and the endoplasmic reticulum (ER) network. We further identified two domains through which full-length lamin A associates with SUN1, and determined that the farnesylated cysteine within the CaaX motif of lamin A has a stronger affinity for SUN1 than does the lamin A region containing amino acids 607 to 656. Farnesylation of progerin enhanced its interaction with SUN1 and reduced SUN1 mobility, thereby promoting the aberrant recruitment of progerin to the ER membrane during postmitotic assembly of the nuclear envelope, resulting in the accumulation of SUN1 over consecutive cellular divisions. These results indicate that the dysregulated interaction of SUN1 and progerin in the ER during nuclear envelope reformation determines the progression of HGPS.

Traumatic brain injury (TBI) is a global health concern that typically causes emotional disturbances and cognitive dysfunction. Secondary pathologies following TBI may be associated with chronic neurodegenerative disorders and an enhanced likelihood of developing dementia-like disease in later life. There are currently no approved drugs for mitigating the acute or chronic effects of TBI.The effects of the drug pomalidomide (Pom), an FDA-approved immunomodulatory agent, were evaluated in a rat model of moderate to severe TBI induced by controlled cortical impact. Post-TBI intravenous administration of Pom (0.5 mg/kg at 5 or 7 h and 0.1 mg/kg at 5 h) was evaluated on functional and histological measures that included motor function, fine more coordination, somatosensory function, lesion volume, cortical neurodegeneration, neuronal apoptosis, and the induction of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6).Pom 0.5 mg/kg administration at 5 h, but not at 7 h post-TBI, significantly mitigated the TBI-induced injury volume and functional impairments, neurodegeneration, neuronal apoptosis, and cytokine mRNA and protein induction. To evaluate underlying mechanisms, the actions of Pom on neuronal survival, microglial activation, and the induction of TNF-α were assessed in mixed cortical cultures following a glutamate challenge. Pom dose-dependently ameliorated glutamate-mediated cytotoxic effects on cell viability and reduced microglial cell activation, significantly attenuating the induction of TNF-α.Post-injury treatment with a single Pom dose within 5 h significantly reduced functional impairments in a well-characterized animal model of TBI. Pom decreased the injury lesion volume, augmented neuronal survival, and provided anti-inflammatory properties. These findings strongly support the further evaluation and optimization of Pom for potential use in clinical TBI.