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Glioma is the most common primary brain tumor in the human brain. The present study was designed to explore the expression of PIMREG in glioma and its relevance to the clinicopathological features and prognosis of glioma patients. The correlations of PIMREG with the infiltrating levels of immune cells and its relevance to the response to immunotherapy were also investigated. PIMREG expression in glioma was analyzed based on the GEO, TCGA, and HPA databases. Kaplan–Meier survival analysis was used to examine the predictive value of PIMREG for the prognosis of patients with glioma. The correlation between the infiltrating levels of immune cells in glioma and PIMREG was analyzed using the CIBERSORT algorithm and TIMRE database. The correlation between PIMREG and immune checkpoints and its correlation with the patients’ responses to immunotherapy were analyzed using R software and the GEPIA dataset. Cell experiments were conducted to verify the action of PIMREG in glioma cell migration and invasion. We found that PIMREG expression was upregulated in gliomas and positively associated with WHO grade. High PIMREG expression was correlated with poor prognosis of LGG, prognosis of all WHO grade gliomas, and prognosis of recurrent gliomas. PIMREG was related to the infiltration of several immune cell types, such as M1 and M2 macrophages, monocytes and CD8+ T cells. Moreover, PIMREG was correlated with immune checkpoints in glioma and correlated with patients’ responses to immunotherapy. KEGG pathway enrichment and GO functional analysis illustrated that PIMREG was related to multiple tumor- and immune-related pathways. In conclusion, PIMREG overexpression in gliomas is associated with poor prognosis of patients with glioma and is related to immune cell infiltrates and the responses to immunotherapy.

Stroke is a disease with high incidence, mortality and disability rates. It is also the main cause of adult disability in developed countries. Stroke is often caused by small emboli on the inner wall of the blood vessels supplying the brain, which can lead to arterial embolism, and can also be caused by cerebrovascular or thrombotic bleeding. With the exception of recombinant tissue plasminogen activator (rt-PA), which is a thrombolytic drug used to recanalize the occluded artery, most treatments have been demonstrated to be ineffective. Stroke can also induce peripheral organ damage. Most stroke patients have different degrees of injury to one or more organs, including the lung, heart, kidney, spleen, gastrointestinal tract and so on. In the acute phase of stroke, severe inflammation occurs in the brain, but there is strong immunosuppression in the peripheral organs, which greatly increases the risk of peripheral organ infection and aggravates organ damage. Nonneurological complications of stroke can affect treatment and prognosis, may cause serious short-term and long-term consequences and are associated with prolonged hospitalization and increased mortality. Many of these complications are preventable, and their adverse effects can be effectively mitigated by early detection and appropriate treatment with various medical measures. This article reviews the pathophysiological mechanism, clinical manifestations and treatment of peripheral organ injury after stroke.

Cyclin-dependent kinase regulatory subunit 2 (CKS2) is a potential prognostic marker and is overexpressed in various cancers. This study analyzed sequencing and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus, with external validation using the Chinese Glioma Genome Atlas (CGGA) data. CKS2 expression in the normal brain and tumor tissue was compared. cBioPortal and MethSurv were utilized to scrutinize the prognostic value of CKS2 methylation. Gene set enrichment examination and single-sample gene set enrichment analysis were employed to explore the potential biological functions of CKS2. Cell viability, colony formation, and transwell assays were conducted to evaluate the influence of CKS2 on glioma cell proliferation and invasion. Compared with normal brain tissue, the expression of CKS2 was upregulated in glioma samples (p < 0.001). Multivariate data analysis from TCGA and CGGA indicated that increased expression of CKS2 was an independent risk factor for the prognosis of overall survival in glioma patients. CKS2 methylation was negatively associated with CKS2 expression. Patients with CKS2 hypomethylation had worse overall survival compared with patients with CKS2 methylation, as suggested by the analysis of both TCGA and CGGA datasets. The expression level of CKS2 is closely related to tumor immunity, including the correlation of tumor immune cell infiltration, immune score, and co-expression of multiple immune-related genes. In addition, CKS2 is associated with several immune checkpoints and responses to the chemotherapy drug cisplatin. CKS2 knockdown impeded the expansion and aggression of glioma cell lines. The changes in CKS2 expression may provide a novel prognostic biomarker that can be used to improve patient overall survival rates.

The clinical success of cisplatin ushered in a new era of the application of metallodrugs. When it comes to practice, however, drug resistance, tumor recurrence, and drug systemic toxicity make it implausible to completely heal the patients. Herein, we successfully transform an electron acceptor [1, 2, 5]thiadiazolo[3,4

Background. Collagen type V alpha 1 chain (COL5A1) is a hypoxia-related gene (a collagen family protein) and participates in the formation of the extracellular matrix. Although some evidence supports a significant role for COL5A1 in the progression of several cancers, a pan-cancer analysis of COL5A1 is not currently available. Herein, we aimed to assess the prognostic value of COL5A1 in 33 human cancers and to investigate its underlying immunological function. Methods. Through multiple bioinformatics methods, we analyzed the data from Oncomine, TCGA, CCLE, HPA, DNMIVD, and cBioPortal database to explore the potential underlying carcinogenic effect of COL5A1, including the relevance of COL5A1 to the outcome, DNA methylation, tumor microenvironment, immune cells infiltration, and drug sensitivity in 33 human cancers. The effects of COL5A1 on glioma cell proliferation, migration, and invasion were verified in cellular experiments. Results. Our findings indicated that COL5A1 was expressed at high levels in 13 cancers and was negatively related to the prognosis of 11 cancers. Additionally, COL5A1 was coexpressed with genes encoding the major histocompatibility complex, immune activators, immune suppressors, chemokines, chemokine receptors, mismatch repair genes, and immune checkpoints. We also identified different roles for COL5A1 in the immunocyte infiltration in different cancers. The correlation between COL5A1 and drug sensitivity was found in several cancers. COL5A1 potentially influenced the tumor progression through immune-related pathways, negative regulation of immune system processes, chemokine signaling pathways, JAK-STAT pathways, T cell receptor pathways, lymphocyte migration, and antigen processing and presentation, among other processes. Conclusions. Based on our study, COL5A1 may be employed as a prognostic marker in different malignancies because of its impact on tumorigenesis and immune cell infiltration and have implications for cancer immune checkpoint inhibitors and chemotherapy.

Ischemic stroke is one of the main issues threatening human health worldwide, and it is also the main cause of permanent disability in adults. Energy consumption and hypoxia after ischemic stroke leads to the death of nerve cells, activate resident glial cells, and promote the infiltration of peripheral immune cells into the brain, resulting in various immune-mediated effects and even contradictory effects. Immune cell infiltration can mediate neuronal apoptosis and aggravate ischemic injury, but it can also promote neuronal repair, differentiation and regeneration. The central nervous system (CNS), which is one of the most important immune privileged parts of the human body, is separated from the peripheral immune system by the blood-brain barrier (BBB). Under physiological conditions, the infiltration of peripheral immune cells into the CNS is controlled by the BBB and regulated by the interaction between immune cells and vascular endothelial cells. As the immune response plays a key role in regulating the development of ischemic injury, neutrophils have been proven to be involved in many inflammatory diseases, especially acute ischemic stroke (AIS). However, neutrophils may play a dual role in the CNS. Neutrophils are the first group of immune cells to enter the brain from the periphery after ischemic stroke, and their exact role in cerebral ischemia remains to be further explored. Elucidating the characteristics of immune cells and their role in the regulation of the inflammatory response may lead to the identification of new potential therapeutic strategies. Thus, this review will specifically discuss the role of neutrophils in ischemic stroke from production to functional differentiation, emphasizing promising targeted interventions, which may promote the development of ischemic stroke treatments in the future.

The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome is a member of the NLR family of inherent immune cell sensors. The NLRP3 inflammasome can detect tissue damage and pathogen invasion through innate immune cell sensor components commonly known as pattern recognition receptors (PRRs). PRRs promote activation of nuclear factor kappa B (NF-κB) pathways and the mitogen-activated protein kinase (MAPK) pathway, thus increasing the transcription of genes encoding proteins related to the NLRP3 inflammasome. The NLRP3 inflammasome is a complex with multiple components, including an NAIP, CIITA, HET-E, and TP1 (NACHT) domain; apoptosis-associated speck-like protein containing a CARD (ASC); and a leucine-rich repeat (LRR) domain. After ischemic stroke, the NLRP3 inflammasome can produce numerous proinflammatory cytokines, mediating nerve cell dysfunction and brain edema and ultimately leading to nerve cell death once activated. Ischemic stroke is a disease with high rates of mortality and disability worldwide and is being observed in increasingly younger populations. To date, there are no clearly effective therapeutic strategies for the clinical treatment of ischemic stroke. Understanding the NLRP3 inflammasome may provide novel ideas and approaches because targeting of upstream and downstream molecules in the NLRP3 pathway shows promise for ischemic stroke therapy. In this manuscript, we summarize the existing evidence regarding the composition and activation of the NLRP3 inflammasome, the molecules involved in inflammatory pathways, and corresponding drugs or molecules that exert effects after cerebral ischemia. This evidence may provide possible targets or new strategies for ischemic stroke therapy.

Objective: The current study was to explore whether meisoindigo was effective in suppressing proliferation and inducing apoptosis of human glioblastoma multiforme U87 cells and to explore its possible mechanisms. Method: Morphological changes were observed by light microscopy. Cell counting kit-8 (CCK-8) assay was performed to detect cellular proliferation. Apoptosis was monitored by flow cytometry. Akt, phospho-Akt, PI3K, p65, phospho-p65 and apoptosis-related proteins caspase-3 and caspase-9 were examined by Western blotting assays. Immunofluorescence was used to evaluate level of P65 expression in cells. Result: Meisoindigo inhibited the proliferation of U87 cells, and the inhibitory effect increased in a dose dependent manner. Moreover, meisoindigo exposure triggered an increase in the level of caspase-3 and caspase-9, supporting its role in the activation of apoptosis. Furthermore, meisoindigo reduced the expression of PI3K, Akt, phospho-Akt, NF-κB, p65 and phospho-p65 in U87 cells, and displacement of p65 from the nucleus to the cytoplasm. Conclusion: Meisoindigo inhibits proliferation and induces apoptosis of U87 cells, probably through down-regulating the PI3K/Akt pathway and reducing nuclear translocation of NF-κB p65.

Background The importance of social and economic capital as predictors of health is widely documented, yet the complexity of interactions between them and effects on older people’s health is still unclear. Combining the material and psychosocial explanations of health, this study explores the potential interactions between social and economic capital in influencing older adults’ health in urban and rural China. Methods Using data from the China Family Panel Survey, physical and mental health in 2018 were regressed on social and economic capital indicators in 2016, controlling for sociodemographic characteristics of 3535 respondents aged 65 and older. Rothman’s synergy index was calculated to investigate potential interaction effects. Results Economic hardships were significantly related to both self-reported health and mental health. Neighborhood cohesion and social participation were significantly associated with mental health for all, bonding trust was significantly associated with mental health for urban older people. We found no significant associations between social capital components and self-reported health. There was an interaction effect between low neighborhood cohesion and economic hardships, and between low social participation and economic hardships, creating an increased burden of poor mental health. The interaction effect between low bonding trust and economic hardships on mental health was apparent only among urban older people. Conclusions Geographical settings are important factors in the complexity between social and economic capital in affecting older health. Intervention efforts directed towards reducing simultaneously multiple dimensions of deprivation, such as poverty, social exclusion, social isolation, could be helpful in improving older people’s health. In materially deprived places, policies to promote health equity by improving social capital but without eliminating poverty may be less effective.

Through considerable effort in research and clinical studies, the immune system has been identified as a participant in the onset and progression of brain injury after ischaemic stroke. Due to the involvement of all types of immune cells, the roles of the immune system in stroke pathology and associated effects are complicated. Past research concentrated on the functions of monocytes and neutrophils in the pathogenesis of ischaemic stroke and tried to demonstrate the mechanisms of tissue injury and protection involving these immune cells. Within the past several years, an increasing number of studies have elucidated the vital functions of T cells in the innate and adaptive immune responses in both the acute and chronic phases of ischaemic stroke. Recently, the phenotypes of T cells with proinflammatory or anti-inflammatory function have been demonstrated in detail. T cells with distinctive phenotypes can also influence cerebral inflammation through various pathways, such as regulating the immune response, interacting with brain-resident immune cells and modulating neurogenesis and angiogenesis during different phases following stroke. In view of the limited treatment options available following stroke other than tissue plasminogen activator therapy, understanding the function of immune responses, especially T cell responses, in the post-stroke recovery period can provide a new therapeutic direction. Here, we discuss the different functions and temporal evolution of T cells with different phenotypes during the acute and chronic phases of ischaemic stroke. We suggest that modulating the balance between the proinflammatory and anti-inflammatory functions of T cells with distinct phenotypes may become a potential therapeutic approach that reduces the mortality and improves the functional outcomes and prognosis of patients suffering from ischaemic stroke.

Investigating the spatial epidemic dynamics of COVID-19 is crucial in understanding the routine of spatial diffusion and in surveillance, prediction, identification and prevention of another potential outbreak. However, previous studies attempting to evaluate these spatial diffusion dynamics are limited. Using city as the research unit and spatial association analysis as the primary strategy, this study explored the changing primary risk factors impacting the spatial spread of COVID-19 across Chinese cities under various diffusion assumptions and throughout the epidemic stage. Moreover, this study investigated the characteristics and geographical distributions of high-risk areas in different epidemic stages. The results empirically indicated rapid intercity diffusion at the early stage and primarily intracity diffusion thereafter. Before countermeasures took effect, proximity, GDP per capita, medical resources, outflows from Wuhan and intercity mobility significantly affected early diffusion. With speedily effective countermeasures, outflows from the epicenter, proximity, and intracity outflows played an important role. At the early stage, high-risk areas were mainly cities adjacent to the epicenter, with higher GDP per capita, or a combination of higher GDP per capita and better medical resources, with more outflow from the epicenter, or more intercity mobility. After countermeasures were effected, cities adjacent to the epicenter, or with more outflow from the epicenter or more intracity mobility became high-risk areas. This study provides an insightful understanding of the spatial diffusion of COVID-19 across cities. The findings are informative for effectively handling the potential recurrence of COVID-19 in various settings.

Background. CYP39A1 is a poorly characterized metabolic enzyme that has been investigated in a few tumors. However, the role of CYP39A1 in hepatocellular carcinoma (HCC) has not yet been clarified. In this study, the expression and clinical significance of CYP39A1 in HCC were explored. Methods. CYP39A1 protein expression was detected in Akt/c-Met-induced HCC mice and 14 paired fresh HCC samples as well as another 159 HCC and matched noncancerous tissues. Meanwhile, the mRNA expression was analyzed by GEO and TCGA analysis and validated in 14 paired fresh HCC tissues. Furthermore, the relationships between CYP39A1 expression and clinicopathologic features as well as prognosis were analyzed. HCC cell growth changes were analyzed by cell viability assays after CYP39A1 overexpression and then validated after CYP39A1 knockout by DepMap database analysis. Results. CYP39A1 protein expression was lower expressed in HCC mouse models, and its mRNA and protein expression were also downregulated in HCC compared with noncancerous liver tissues. Higher CYP39A1 expression was associated with well differentiation. Moreover, survival analysis indicated that lower CYP39A1 expression was associated with poorer overall survival. In addition, HepG2 and SMMC-7721 cell viability were inhibited after CYP39A1 overexpression. Genome-wide CRISPR/Cas9 proliferation screening indicated that knockout of CYP39A1 could promote HCC cell growth. Likewise, p-NF-κB and Nrf2 were suppressed after CYP39A1 overexpression. It is worth mentioning that total bile acid, total bilirubin, and direct bilirubin were significantly increased in the patients with low CYP39A1 expression. Conclusions. Downregulation of CYP39A1 is associated with HCC carcinogenesis, tumor differentiation, and poor overall survival, suggesting that CYP39A1 may serve as a tumor suppressor gene and novel biomarker for HCC patients.

The Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway, a well-conserved and basic intracellular signaling cascade, is mostly inactivated under basal conditions, although it can be phosphorylated under extracellular stimulation; in addition, it can influence the transcription and expression of multiple genes involved in biological processes such as cellular growth, metabolism, differentiation, degradation and angiogenesis. The inflammatory response, apoptosis, oxidative stress and angiogenesis are the main factors involved in the pathogenesis of ischemic stroke. Numerous studies have confirmed that the JAK2/STAT3 axis can be activated rapidly by ischemic stress, which is closely related to the regulation of these important pathological processes. However, different opinions on the specific role of this signaling pathway remain. In this paper, we review and summarize previous studies on the JAK2/STAT3 pathway in ischemic stroke.

Ischemia/reperfusion injury (IRI) occurs commonly during renal transplantation. It has been well demonstrated that the inflammatory response has an important role in the pathogenesis and pathological processes of IRI. However, the signaling events that trigger the activation of the inflammatory response are less clear. Accumulated evidence has identified the role of various injury factors released from or exposed in ischemic, damaged, or dying cells, which serve as initiators of the inflammatory response and exacerbate kidney injury after renal IRI. Signaling pathways triggered by these endogenous molecules that activate different pathogen recognition receptors have also been widely investigated. Here, we review the molecular signaling molecules that initiate the inflammatory response during renal IRI and that provide potential therapeutic options for the disease.

Background Asthma exacerbations commonly lead to unplanned health care utilization and are costly. Early identification of children at increased risk of asthma exacerbations would allow a proactive management approach. Objective We evaluated common asthma risk factors to predict the probability of exacerbation for individual children aged 0-21 years using data from the electronic medical record (EMR). Methods We analyzed longitudinal EMR data for over 3000 participants with asthma seen at Cincinnati Children's Hospital Medical Center over a 7-year period. The study population was divided into 3 age groups: 0-4, 5-11, and 12-21 years. Each age group was divided into a derivation cohort and a validation cohort, which were used to build a risk score model. We predicted risk of exacerbation in the next 12 months, validated the scores by risk stratum, and developed a clinical tool to determine the risk level based on this model. Results Risk model results were confirmed with validation cohorts by calendar year and age groups. Race, allergic sensitization, and smoke exposure were each important risk factors in the 0-4 age group. Abnormal spirometry and obesity were more sensitive predictors of exacerbation in children >12 years. For each age group, a higher expanded score was associated with a higher predicted probability of an asthma exacerbation in the subsequent year. Conclusion This asthma exacerbation prediction model, and the associated clinical tool, may assist clinicians in identifying children at high risk for exacerbation that may benefit from more aggressive management and targeted risk mitigation.

China’s rapid socioeconomic growth in recent years and the simultaneous increase in many forms of pollution are generating contradictory pictures of residents’ well-being. This paper applies multilevel analysis to the 2013 China General Social Survey data on social development and health to understand this twofold phenomenon. Multilevel models are developed to investigate the impact of socioeconomic development and environmental degradation on self-reported health (SRH) and self-reported happiness (SRHP), differentiating among lower, middle, and higher income groups. The results of the logit multilevel analysis demonstrate that income, jobs, and education increased the likelihood of rating SRH and SRHP positively for the lower and middle groups but had little or no effect on the higher income group. Having basic health insurance had an insignificant effect on health but increased the likelihood of happiness among the lower income group. Provincial-level pollutants were associated with a higher likelihood of good health for all income groups, and community-level industrial pollutants increased the likelihood of good health for the lower and middle income groups. Measures of community-level pollution were robust predictors of the likelihood of unhappiness among the lower and middle income groups. Environmental hazards had a mediating effect on the relationship between socioeconomic development and health, and socioeconomic development strengthened the association between environmental hazards and happiness. These outcomes indicate that the complex interconnections among socioeconomic development and environmental degradation have differential effects on well-being among different income groups in China.

Neurological function deficits due to cerebral ischemia or neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) have long been considered a thorny issue in clinical treatment. Recovery after neurologic impairment is fairly limited, which poses a major threat to health and quality of life. Accumulating evidences support that ROS and autophagy are both implicated in the onset and development of neurological disorders. Notably, oxidative stress triggered by excess of ROS not only puts the brain in a vulnerable state but also enhances the virulence of other pathogenic factors, just like mitochondrial dysfunction, which is described as the culprit of nerve cell damage. Nevertheless, autophagy is proposed as a subtle cellular defense mode against destructive stimulus by timely removal of damaged and cytotoxic substance. Emerging evidence suggests that the interplay of ROS and autophagy may establish a determinant role in the modulation of neuronal homeostasis. However, the underlying regulatory mechanisms are still largely unexplored. This review sets out to afford an overview of the crosstalk between ROS and autophagy and discusses relevant molecular mechanisms in cerebral ischemia, AD, and PD, so as to provide new insights into promising therapeutic targets for the abovementioned neurological conditions.

After ischemic stroke, the integrity of the blood-brain barrier is compromised. Peripheral immune cells, including neutrophils, T cells, B cells, dendritic cells, and macrophages, infiltrate into the ischemic brain tissue and play an important role in regulating the progression of ischemic brain injury. In this review, we will discuss the role of different immune cells after stroke in the secondary inflammatory reaction and focus on the phenotypes and functions of macrophages in ischemic stroke, as well as briefly introduce the anti-ischemic stroke therapy targeting macrophages.

Empirical studies of the socio-economic determinants of the wellbeing of the oldest-old in China including the role of geography and spatial factors are rare. This paper applies binary logistic regression analysis to data on the oldest-old aged 80 years old and higher from the 2011 Chinese Longitudinal Healthy Longevity Study (CLHLS). Socioeconomic determinants of the self-reported quality of life (QoL) and self-reported health (SRH) of the oldest-old population are explored, with special attention paid to the role of residence and region. The results indicate that, after controlling for individual demographic and health behavior variables, both economic status and social welfare have a significant effect on self-reported QoL and SRH. There are also significant differences in self-reported QoL among cities, towns and rural areas, with the oldest-old respondents living in Central rural, Western town and Western rural areas being significantly less likely to report good QoL, compared to the oldest-old living in Eastern cities. Significant differences in SRH exist among Eastern China, Western China and Northeastern China, with the oldest-old from Western towns being significantly less likely to report good health, and the oldest-old from Northeastern cities being significantly more likely to report good health than those from Eastern cities. The results of this study indicate that socioeconomic factors that explain self-reported QoL and SRH of the older population are in general factors that explain the self-reported QoL and SRH of the oldest-old cohorts. The interaction effect of residence and region matters more than each of the individual factors, in providing us with more detailed information on the role of geography in explaining QoL and health of the oldest-old. At a time when the oldest-old cohorts in China are at the beginning of their projected growth, these findings are vital for providing policy makers with more information on the urgency of making more geographically targeted policy to improve more effectively the self-reported QoL and SRH of the oldest-old population.

Ubiquitin-specific protease 10 (USP10), a novel deubiquitinating enzyme, is associated with androgen receptor transcriptional activity and pathological processes of tumor. However, information between USP10 and the adrenal gland is limited. In particular, the role of USP10 in adrenal tumors has not been elucidated yet. This study aims to investigate the expression of USP10 in the human normal adrenal gland and various adrenal tumors. Tissue samples were obtained from 30 adrenocortical adenomas, nine adrenocortical adenocarcinomas, and 20 pheochromocytomas following laparoscopic surgery. Twenty normal adrenal glands were obtained from kidney surgical resection conducted due to renal cell carcinomas. USP10 expression was investigated on protein levels using immunohistochemistry and on mRNA levels using bioinformatics analysis in the Gene Expression Omnibus (GEO) Datasets. In the 20 cases of normal adrenal glands analyzed, USP10 protein was constantly expressed in situ in the cortex of the adrenal glands, but in the medulla of the gland, only the sustentacular cells were detected positive. In adrenal tumors, detectable levels of USP10 protein were found in 100 % (30/30) adrenocortical adenomas, 88.89 % (8/9) adrenocortical carcinomas, and 10 % (2/20) pheochromocytomas. Bioinformatics analysis did not show a significant difference in USP10 messenger RNA (mRNA) expression between adrenal tumors and normal adrenal gland tissues. A positive USP10 immunoreaction can be useful in distinguishing adrenal cortical tumors from pheochromocytoma.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients with GBM have poor outcomes, even with the current gold-standard first-line treatment: maximal safe resection combined with radiotherapy and temozolomide chemotherapy. Accumulating evidence suggests that advances in antigen-specific cancer vaccines and immune checkpoint blockade in other advanced tumors may provide an appealing promise for immunotherapy in glioma. The future of therapy for GBM will likely incorporate a combinatorial, personalized approach, including current conventional treatments, active immunotherapeutics, plus agents targeting immunosuppressive checkpoints.

Measurement of the changes in intracellular Ca2+ levels is an important assay for drug discovery. In this report, we describe a novel Ca2+ indicator, dCys-GCaMP, based on the green fluorescent protein and the development of a rapid and simple cell-based functional assay using this new Ca2+ indicator. We demonstrated the sensitivity and reliability of the assay by measuring the cellular responses to the agonists, antagonists, channel blockers, and modulators of the ionotropic N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. HEK293 cells coexpressing the NMDA receptor and dCys-GCaMP displayed a strong increase in fluorescence intensity when stimulated with the agonist glutamate. This increase in the fluorescence signal was agonist concentration dependent and could be blocked by NMDAR antagonists and channel blockers. The pharmacological parameters measured with the dCys-GCaMP assay are in close agreement with those derived from conventional assays with synthetic dye fluo-4 and literature values. In addition, we showed that this assay could be used on G protein-coupled receptors as well, as exemplified by studies on the α1A adrenergic receptor. A limited scale evaluation of the assay performance in a 96-well compound screening format suggests that the dCys-GCaMP assay could be easily adapted to a high-throughput screening environment. The most important advantage of this new assay over the conventional fluo-4 and aequorin assays is the elimination of the dye-loading or substrate-loading process.

Background In the transitional stage of socioeconomic development, the traditional practice of home-based care in China is being tested. The evolution and factors of home-based care utilization are the prerequisites for the formulation of a support policy. However, no extant research has studied home-based elder care on a national scale. Aim This paper aims to examine changing caregiving relationships nationwide for home-based elderly individuals and investigate the changing factors of care utilization in a ten-year period, with special attention to the effects of “location” on care patterns. Methods The data come from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Andersen and Newman's behavioral model is employed as the theoretical framework for this research. The trends in care use from 2002 to 2011 are explored and multilevel multinomial analyses are performed to investigate the changing factors of care patterns between 2002 and 2011. Results From 2002 to 2011, China saw a sharp decrease in children as caregivers, a significant increase in spousal caregivers, and a gradual decrease in other caregivers. Compared to 2002, the effects of the predisposing and enabling factors are more important than the need factors in 2011. Location and the interactions of the north-south divide and the urban-rural divide had a significant effect on care patterns. Conclusions From 2002 to 2011, there was a decline in the traditional values-advocated care system and the elderly had to rely more on their own resources to find caregivers. In the design of a support program, there is an urgent need for policy makers to take social inequality among elderly individuals and the effects of location into consideration.

To investigate the clinical value of acoustic radiation force impulse (ARFI) elastography in the differential diagnosis of focal liver lesions.ARFI elastography was performed for 169 lesions from 163 patients with focal liver lesions and 15 healthy volunteers, and the virtual touch tissue imaging (VTI) findings and measured value of shear wave velocity (SWV) of liver lesions were obtained and compared between groups. The t-test was applied for comparison of means between two groups; the one-way analysis of variance was applied for comparison of means between multiple groups, and the Student-Newman-Keuls test was applied for further comparison between any two groups.Benign focal liver lesions were stiffer or softer than or had the same stiffness as the surrounding liver parenchyma. These lesions had a uniform texture, and the ratio between their diameters on elastographic images and two-dimensional images was close to 1. The typical VTI finding of hemangioma lesions was"honeycomb"pattern. Most malignant focal liver lesions were stiffer than the surrounding liver parenchyma, and the ratio between their diameters on elastographic images and two-dimensional images was greater than 1. The typical VTI finding of metastatic lesions was"bull's eye"sign. With a measured SWV of 2.08 m/s as the diagnostic threshold for malignant liver lesions, its sensitivity, specificity, and accuracy were 90.3%, 76.9%, and 84.2%, respectively. Poorly differentiated hepatocellular carcinoma (HCC) showed a significant increase in stiffness compared with moderately differentiated HCC (t = 5.319, P = 0.025) and well-differentiated HCC (t = 6.372, P = 0.011).ARFI elastography can reflect changes in the stiffness of focal liver lesions accurately, and is useful for the differential diagnosis of benign and malignant focal liver lesions.

Cellular heterogeneity is a fundamental characteristic of many cancers. A lack of cellular homogeneity contributes to difficulty in designing targeted oncological therapies. Therefore, the development of novel methods to determine and characterize oncologic cellular heterogeneity is a critical next step in the development of novel cancer therapies. Single-cell sequencing (SCS) technology has been recently employed for analyzing the genetic polymorphisms of individual cells at the genome-wide level. SCS requires (1) precise isolation of the single cell of interest; (2) isolation and amplification of genetic material; and (3) descriptive analysis of genomic, transcriptomic, and epigenomic data. In addition to targeted analysis of single cells isolated from tumor biopsies, SCS technology may be applied to circulating tumor cells, which may aid in predicting tumor progression and metastasis. In this paper, we provide an overview of SCS technology and review the current literature on the potential application of SCS to clinical oncology and research.

ObjectiveTo investigate the role of large decompressive craniectomy (LDC) in the management of severe and very severe traumatic brain injury (TBI) and compare it with routine decompressive craniectomy (RDC).MethodsThe clinical data of 263 patients with severe TBI (GCS≤8) treated by either LDC or RDC in our department were studied retrospectively in this article. One hundred and thirty-five patients with severe TBI, including 54 patients with very severe TBI (GCS≤5), underwent LDC (LDC group). The other 128 patients with severe TBI, including 49 patients with very severe TBI, underwent RDC (RDC group). The treatment outcome and postoperative complications of the two treatment methods were compared and analyzed in a 6-month follow-up period.ResultsNinety-six patients (71.7%) obtained satisfactory treatment outcome in the LDC group, while only 75 cases (58.6%) obtained satisfactory outcome in the RDC group (P

The platelet-derived growth factor (PDGF) A-chain gene is a developmentally regulated gene that is expressed in high levels in a limited number of normal and transformed cell lines and in cells stimulated by cytokines, including PDGF itself. We have now analyzed potential regulatory elements in 3.6 kilobase pairs (kb) of the 5'-flanking sequences of the human PDGF A-chain gene using reporter gene constructs and transient transfection analyses. The region between base pairs (bp) -618 and +392 (relative to the transcription initiation site) is sufficient for optimal promoter activity. A highly G + C region containing three contiguous Sp1 binding sites between bp -150 and -33 contributes over 80% of promotor activity. DNase I footprinting analyses indicates that Sp1 binds to and protects over 57 bp of this G + C region. A functional serum response element is located within bp -477 and -468 and positively regulates induction of PDGF A by PDGF. A negative regulatory (silencer) element is located from -1.9 to -0.9 kb. The results suggest that the major constitutive expression of the PDGF A-chain gene requires a highly G + C-rich region containing three Sp1 binding sites and that induction of the PDGF A-chain gene by PDGF is mediated by a SRE located at bp -477 to -468.