Chromatin regulation through histone modifications plays an essential role in coordinated expression of multiple genes. Alterations in chromatin induced by histone modifiers and readers regulate ...critical transcriptional programs involved in both normal development and tumor differentiation. Recently, we identified that histone deacetylases HDAC1 and HDAC7 are necessary to maintain cancer stem cells (CSCs) in both breast and ovarian tumors. Here, we sought to investigate the CSC-specific function of HDAC1 and HDAC7 mechanistically by using a stem-like breast cancer (BrCa) cell model BPLER and matched nonstem tumor cell (nsTC)-like HMLER, along with conventional BrCa cell lines with different CSC enrichment levels. We found that HDAC1 and HDAC3 inhibition or knockdown results in HDAC7 downregulation, which is associated with a decrease in histone 3 lysine 27 acetylation (H3K27ac) at transcription start sites (TSS) and super-enhancers (SEs) prominently in stem-like BrCa cells. Importantly, these changes in chromatin landscape also correlate with the repression of many SE-associated oncogenes, including c-MYC, CD44, CDKN1B, SLUG, VDR, SMAD3, VEGFA, and XBP1. In stem-like BrCa cells, HDAC7 binds near TSS and to SEs of these oncogenes where it appears to contribute to both H3K27ac and transcriptional regulation. These results suggest that HDAC7 inactivation, directly or through inhibition of HDAC1 and HDAC3, can result in the inhibition of the CSC phenotype by downregulating multiple SE-associated oncogenes. The CSC selective nature of this mechanism and the prospect of inhibiting multiple oncogenes simultaneously makes development of HDAC7 specific inhibitors a compelling objective.
Antimicrobial stewardship (AMS) initiatives in hospitals often include the implementation of clustered intervention components to improve the surveillance and targeting of antibiotics. However, ...impacts of the individual components of AMS interventions are not well known, especially in low- and lower-middle-income countries (LLMICs).
A scoping review was conducted to summarize evidence from systematic reviews (SRs) on the impact of common hospital-implemented healthcare-worker-targeted components of AMS interventions that may be appropriate for LLMICs.
Major databases were searched systematically for SRs of AMS interventions that were evaluated in hospitals. For SRs to be eligible, they had to report on at least one intervention that could be categorized according to the Effective Practice and Organisation of Care taxonomy. Clinical and process outcomes were considered. Primary studies from LLMICs were consulted for additional information.
Eighteen SRs of the evaluation of intervention components met the inclusion criteria. The evidence shows that audit and feedback, and clinical practice guidelines improved several clinical and process outcomes in hospitals. An unintended consequence of interventions was an increase in the use of antibiotics. There was a cumulative total of 547 unique studies, but only 2% (N=12) were conducted in hospitals in LLMICs. Two studies in LLMICs reported that guidelines and educational meetings were effective in hospitals.
Evidence from high- and upper-middle-income countries suggests that audit and feedback, and clinical practice guidelines have the potential to improve various clinical and process outcomes in hospitals. The lack of evidence in LLMIC settings prevents firm conclusions from being drawn, and highlights the need for further research.
Several studies have shown physiological functions of interleukin (IL)-32, a novel cytokine. However, the role of IL-32 in cancer development has not been reported. In this study, we showed that ...IL-32γ inhibited tumor growth in IL-32γ-overexpressing transgenic mice inoculated with melanoma as well as colon tumor growth in xenograft nude mice inoculated with IL-32γ-transfected colon cancer cells (SW620). The inhibitory effect of IL-32γ on tumor growth was associated with the inhibition of constitutive activated nuclear transcription factor-κB (NF-κB) and of signal transducer and activator of transcription 3 (STAT3). The expression of antiapoptotic, cell proliferation and tumor-promoting genes (bcl-2, X-chromosome inhibitor of apoptosis protein (IAP), cellular IAP and cellular FADD-like IL-1β-converting enzyme-inhibitory protein, cyclin D), cyclin-dependent kinase 4, cycolooxygenase-2 and inducible nitric oxide synthase was decreased, whereas the expression of apoptotic target genes (caspase-3 and -9, bax) increased. In tumor, spleen and blood, the number of cytotoxic CD8(+) T cells and CD57(+) natural killer cells and the levels of IL-10 increased, but that of tumor necrosis factor-α (TNF-α), IL-1β and IL-6 decreased. We also found that forced overexpression of IL-32γ inhibited colon cancer cell (SW620 and HCT116) growth accompanied with the inhibition of activated NF-κB and STAT3 in vitro. In addition, when IL-32γ was knocked down by small interfering RNA (siRNA) or neutralized with an anti-IL-32γ antibody, IL-32γ-induced colon cancer cell growth inhibition, the IL-32γ-induced decrease of TNF-α, IL-1 and IL-6 production, and the increase of IL-10 production were abolished. However, siRNA of NF-κB and STAT3 augmented IL-32γ-induced colon cancer cell growth inhibition. These findings indicate significant pathophysiological roles of IL-32γ in cancer development.
Background
Although numerous multicentre studies have estimated the association between ozone exposure and mortality, there are currently no nationally representative multicentre studies of the ...ozone–mortality relationship in China.
Objective
To investigate the effect on total (nonaccidental) and cause‐specific mortality of short‐term exposure to ambient ozone, and examine different exposure metrics.
Methods
The effects of short‐term exposure to ozone were analysed using various metrics (daily 1‐h maximum, daily 8‐h maximum and daily average) on total (nonaccidental) and cause‐specific (circulatory and respiratory) mortality from 2013 to 2015 in 34 counties in 10 cities across China. We used distributed lag nonlinear models for estimating county‐specific relative risk of mortality and combined the county‐specific relative rates by conducting a random‐effects meta‐analysis.
Results
In all‐year analyses, a 10 μg m−3 increase in daily average, daily 1‐h maximum and daily 8‐h maximum ozone at lag02 corresponded to an increase of 0.6% (95% CI: 0.33, 0.88), 0.26% (95% CI: 0.12, 0.39) and 0.37% (95% CI: 0.2, 0.55) in total (nonaccidental) mortality, 0.66% (95% CI: 0.28, 1.04), 0.31% (95% CI: 0.11, 0.51) and 0.39% (95% CI: 0.16, 0.62) in circulatory mortality, and 0.57% (95% CI: −0.09, 1.23), 0.11% (95% CI: −0.22, 0.44) and 0.22% (95% CI: −0.28, 0.72) in respiratory mortality, respectively. These estimates had a different seasonal pattern by cause of death. In general, the seasonal patterns were consistent with the times of year when ozone concentrations are highest.
Conclusions
Our findings suggest that in China, the acute effects of ozone are more closely related to daily average exposure than any other metric.
While considerable research has investigated the importance of the public’s understanding of the scientific consensus on climate change beliefs and policy support, only recently have scholars begun ...to evaluate the role of
social
consensus perceptions, e.g., what others in the same group think. People receive information about these norms directly from social interactions, such as with neighbors and friends, but also indirectly from media, as in reporting on national public opinion statistics. We assess how well the public understands the level of social consensus across different geographic scales—regional, state, and national—and test whether understanding these norms differentially relates to climate and energy policy support. Among a representative sample of Maryland adults surveyed in 2015 (
n
= 1547), nearly half underestimated the extent of the social consensus about climate change within their region, state, and country. Individuals’ consensus perceptions were significantly related to the true social consensus—estimated through survey data—at the regional scale; however, the size of the relationship was small. We found that consensus perceptions across all geographic levels related to support for climate policy, as mediated by climate belief certainty. But perceptions of social consensus at smaller spatial scales—e.g., regional—appear to have larger effects on public opinion. The results of this study suggest both the importance—and limitations—of geographies of social consensus and the role of attitudinal certainty as a mediator for this relationship. Conveying localized social consensus information may promote public support of climate policy.
Although the proteasome is a validated anticancer target, the clinical application of its inhibitors has been limited because of inherent systemic toxicity. To broaden clinical utility of proteasome ...inhibitors as anticancer agents, it is critical to develop strategies to selectively target proteasomes in cancer cells. The immunoproteasome is an alternative form of the constitutive proteasome that is expressed at high levels in cancer tissues, but not in most normal cells in the body.
To validate the immunoproteasome as a chemotherapeutic target, an immunoproteasome catalytic subunit LMP2-targeting inhibitor and siRNA were used. The sensitivity of PC-3 prostate cancer cells to these reagents was investigated using viability assays. Further, a xenograft model of prostate cancer was studied to test the in vivo effects of LMP2 inhibition.
A small molecule inhibitor of the immunoproteasome subunit LMP2, UK-101, induced apoptosis of PC-3 cells and resulted in significant inhibition (~50-60%) of tumour growth in vivo. Interestingly, UK-101 did not block degradation of IκBα in PC-3 cells treated with TNF-α, suggesting that its mode of action may be different from that of general proteasome inhibitors, such as bortezomib, which block IκBα degradation.
These results strongly suggest that the immunoproteasome has important roles in cancer cell growth and thus provide a rationale for targeting the immunoproteasome in the treatment of prostate cancer.
Background: Bowel cancer is the most prevalent digestive system cancer and is the 4th largest cause of cancer-related death worldwide. In Iraq, colon and rectal cancer (CRC) is the 6th most common ...malignancy in males and the 5th in females. This cancer is sluggish in growth, which gives a window of opportunity to screen for both precursor lesions and early cancer. The Cluster of Differentiation 47 (CD47) protein is a type of transmembrane glycoproteins found on nearly all human cells, including non-hematopoietic and hematopoietic cells. CD47 promotes CRC growth by triggering angiogenesis and apoptosis of tumor cell. Objectives: To evaluate the immunohistochemical expression of (CD47) in various colorectal samples from Iraqi patients with CRC by immunohistochemistry (IHC) assay. Specimens and methods: A total of 45 paraffin-embedded CRC tissue specimens and clinical data were obtained from the Medical City Teaching Hospital in Baghdad and a number of private laboratories in Baghdad, Iraq. In addition, 30 control colon and rectum tissues with no significant pathology were collected from the Forensic Medicine Department for comparison purposes after taking the official approvals. Results: The results revealed a high expression of CD47 in CRC cases, but with no significant correlation with clinicopathological features. Also, the result of figures in this study revealed negative membranous expression of CD47 (score 0), strong membranous expression of CD47 (score 3), moderately membranous expression of CD47 (score 2), and weak membranous expression of CD47 (score 1) Conclusion: Patients with CRC had high CD47 expression, allowing tumor cells to modulate CD47SIRP inhibitory signaling and prevent immune cell attack.
Key points
Adeno‐associated viral vector was used to elevate the expression of muscle specific kinase (MuSK) and rapsyn (a cytoplasmic MuSK effector protein) in the tibialis anterior muscle of ...wild‐type and dystrophic (mdx) mice.
In mdx mice, enhanced expression of either MuSK or rapsyn ameliorated the acute loss of muscle force associated with strain injury.
Increases in sarcolemmal immunolabelling for utrophin and β‐dystroglycan suggest a mechanism for the protective effect of MuSK in mdx muscles.
MuSK also caused subtle changes to the structure and function of the neuromuscular junction, suggesting novel roles for MuSK in muscle physiology and pathophysiology.
Muscle specific kinase (MuSK) has a well‐defined role in stabilizing the developing mammalian neuromuscular junction, but MuSK might also be protective in some neuromuscular diseases. In the dystrophin‐deficient mdx mouse model of Duchenne muscular dystrophy, limb muscles are especially fragile. We injected the tibialis anterior muscle of 8‐week‐old mdx and wild‐type (C57BL10) mice with adeno‐associated viral vectors encoding either MuSK or rapsyn (a cytoplasmic MuSK effector protein) fused to green fluorescent protein (MuSK‐GFP and rapsyn‐GFP, respectively). Contralateral muscles injected with empty vector served as controls. One month later mice were anaesthetized with isoflurane and isometric force‐producing capacity was recorded from the distal tendon. MuSK‐GFP caused an unexpected decay in nerve‐evoked tetanic force, both in wild‐type and mdx muscles, without affecting contraction elicited by direct electrical stimulation of the muscle. Muscle fragility was probed by challenging muscles with a strain injury protocol consisting of a series of four strain‐producing eccentric contractions in vivo. When applied to muscles of mdx mice, eccentric contraction produced an acute 27% reduction in directly evoked muscle force output, affirming the susceptibility of mdx muscles to strain injury. mdx muscles overexpressing MuSK‐GFP or rapsyn‐GFP exhibited significantly milder force deficits after the eccentric contraction challenge (15% and 14%, respectively). The protective effect of MuSK‐GFP in muscles of mdx mice was associated with increased immunolabelling for utrophin and β‐dystroglycan in the sarcolemma. Elevating the expression of MuSK or rapsyn revealed several distinct synaptic and extrasynaptic effects, suggesting novel roles for MuSK signalling in muscle physiology and pathophysiology.
Key points
Adeno‐associated viral vector was used to elevate the expression of muscle specific kinase (MuSK) and rapsyn (a cytoplasmic MuSK effector protein) in the tibialis anterior muscle of wild‐type and dystrophic (mdx) mice.
In mdx mice, enhanced expression of either MuSK or rapsyn ameliorated the acute loss of muscle force associated with strain injury.
Increases in sarcolemmal immunolabelling for utrophin and β‐dystroglycan suggest a mechanism for the protective effect of MuSK in mdx muscles.
MuSK also caused subtle changes to the structure and function of the neuromuscular junction, suggesting novel roles for MuSK in muscle physiology and pathophysiology.
Summary
Characteristics of patients starting oral bisphosphonate therapy changed over time, reflecting trends in osteoporosis management (e.g., new drugs to market), and general healthcare delivery ...(e.g., benzodiazepine use declined, statin use increased). When designing studies that examine osteoporosis drug effects, potential time-related biases must be considered.
Introduction
To describe the type of oral bisphosphonate initiated and characteristics of patients starting oral bisphosphonate therapy over time.
Methods
We identified community-dwelling older adults (ages ≥ 66 years) initiating oral bisphosphonate therapy from April 1996 to March 2016 (1996 to 2015 fiscal years) using healthcare administrative data in Ontario. Patients with conditions other than osteoporosis that may impact bisphosphonate prescribing were excluded. The bisphosphonate initiated and patient characteristics were summarized by fiscal year and stratified by sex.
Results
We identified 560,817 eligible patients (81% women). Most patients initiated cyclical etidronate from 1996 until 2005, and then weekly regimens became dominant. In 2008, risedronate became the main oral bisphosphonate (46% risedronate, 43% alendronate, 11% etidronate); with its use increasing after availability of monthly and delayed-release risedronate formulations. In 2015, 71% of patients started risedronate, 28% started alendronate, and less than 2% started etidronate. Characteristics of patients changed over time, reflecting changes in osteoporosis management and general healthcare delivery. Over time, a larger proportion of men (9% to 28%) and patients with diabetes (women 10% to 17%, men 14% to 22%) initiated therapy; benzodiazepine (women 22% to 13%, men 20% to 10%) and estrogen-based hormone replacement therapy (12% to 15% of women 1996–2002 to 3% since 2008) decreased, while statin use increased (women 15% to 39%, men 14% to 52%).
Conclusions
The characteristics of patients starting oral bisphosphonate therapy have changed over time. Consideration must be given to these time trends when designing studies that examine osteoporosis drug effects.
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