Aim
Recent studies have shown that sarcopenia is associated with negative postoperative outcomes. However, none of these studies analysed muscle strength or physical performance, which are also ...important components of sarcopenia. The present study aimed to investigate whether sarcopenia itself, as defined by low muscle mass, strength and physical performance, would predict complications after surgery for colorectal cancer.
Method
We conducted a prospective study of patients who underwent surgery for colorectal cancer at our department between August 2014 and February 2015. Sarcopenia was diagnosed by a combination of third lumbar vertebra muscle index (L3 MI), handgrip strength and 6‐m usual gait speed. Univariate and multivariate analyses evaluating the risk factors for postoperative complications were performed. Only complications classified as Grade II or above according to the Clavien–Dindo classification were analysed in this study.
Results
A total of 142 patients were included in the study, and 17 patients were diagnosed as having sarcopenia. Postoperative complications of Grade II or above occurred in 40 patients, including 10 with sarcopenia and 30 without sarcopenia. Multivariate analysis showed that sarcopenia and previous abdominal surgery were independent risk factors for postoperative complications. Patients with sarcopenia also had an obvious tendency to a higher incidence of infectious complications. By comparing two logistic regression models, sarcopenia showed a better predictive power for postoperative complications than did low muscle mass.
Conclusion
Sarcopenia and previous abdominal surgery are independent risk factors for complications after surgery for colorectal cancer. Including a functional aspect to the definition of sarcopenia may result in a better prediction of postoperative complications.
The invention of bulk metallic glasses has stimulated extensive interest, due to their possible technological applications in a variety of industrial fields and their scientific importance in ...understanding related condensed matter physics. Among all types of BMGs, Fe-based BMGs are a unique yet important family due to their high mechanical strength, good thermal stability, strong corrosion resistance, excellent soft magnetic properties, and relatively low production costs. Since the first synthesis of the Fe-Al-Ga-P-C-B BMG reported in 1995, a vast body of literature regarding Fe-based BMGs has been published. However, until now, a full and systematic description of the development status and future prospects of Fe-based BMGs has been missing. Therefore, this article presents the research development and achievements of Fe-based BMGs in the past few decades, including their preparation, glass-forming ability, crystallization characteristics, mechanical properties, corrosion behaviors, soft and hard magnetic properties, and industrial applications. In addition, future developments of Fe-based BMGs are also proposed.
Dapsone is an important medication for the treatment of leprosy, but a life-threatening drug hypersensitivity syndrome develops in some patients. In this report from China, an
HLA-B
locus is ...identified as a strong genetic risk factor for the syndrome.
Dapsone (4-4′-sulfonyldianiline), which was first synthesized in 1908,
1
is both an antibiotic and an antiinflammatory agent. Dapsone alone or in combination with other drugs has been used for the prevention and treatment of infectious diseases (e.g., leprosy, malaria, and actinomycetoma, as well as
Pneumocystis jirovecii
pneumonia in persons with human immunodeficiency virus HIV infection) and chronic inflammatory diseases characterized by the infiltration of neutrophils or eosinophils (e.g., dermatitis herpetiformis, linear IgA dermatosis, subcorneal pustular dermatosis, and erythema elevatum diutinum).
2
,
3
About 0.5 to 3.6% of persons treated with dapsone have a drug hypersensitivity syndrome,
3
–
5
which was first described by . . .
RNA interference is a naturally occurring endogenous regulatory process where short double-stranded RNA causes sequence-specific posttranscriptional gene silencing. Small interference RNA (siRNA) ...represents a promising therapeutic strategy. Clinical evaluations of siRNA therapeutics in locoregional treatment settings began in 2004. Systemic siRNA therapy is hampered by the barriers for siRNA to reach their intended targets in the cytoplasm and to exert their gene silencing activity. The three goals of this review were to provide an overview of (a) the barriers to siRNA delivery, from the perspectives of physicochemical properties of siRNA, pharmacokinetics and biodistribution, and intracellular trafficking; (b) the non-viral siRNA carriers including cell-penetrating peptides, polymers, dendrimers, siRNA bioconjugates, and lipid-based siRNA carriers; and (c) the current status of the clinical trials of siRNA therapeutics.
In this prospective study, Han Chinese subjects who were candidates for carbamazepine therapy were screened for the HLA-B*1502 allele because of its association with the Stevens–Johnson syndrome and ...toxic epidermal necrolysis.
The Stevens–Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), are two of the most serious adverse reactions caused by drugs. SJS is characterized by high fever, malaise, and a rapidly developing, blistering exanthema of macular papules and target-like lesions, accompanied by mucosal involvement. This condition is associated with a rate of death of approximately 5%. TEN has a similar presentation, with even more extensive skin detachment and a death rate of 25 to 35%.
1
Carbamazepine, an anticonvulsant and specific analgesic agent for trigeminal neuralgia, is the most common cause of SJS–TEN in Southeast Asian countries.
2
We previously . . .
Head and neck squamous cell carcinoma (HNSCC) patients have a poor prognosis, with invasion and metastasis as major causes of mortality. The phosphatidylinositol 3-kinase (PI3K) pathway regulates a ...wide range of cellular processes crucial for tumorigenesis, and PIK3CA amplification and mutation are among the most common genetic alterations in human HNSCC. Compared with the well-documented roles of the PI3K pathway in cell growth and survival, the roles of the PI3K pathway in tumor invasion and metastasis have not been well delineated. We generated a PIK3CA genetically engineered mouse model (PIK3CA-GEMM) in which wild-type PIK3CA is overexpressed in head and neck epithelium. Although PIK3CA overexpression alone was not sufficient to initiate HNSCC formation, it significantly increased tumor susceptibility in an oral carcinogenesis mouse model. PIK3CA overexpression in mouse oral epithelium increased tumor invasiveness and metastasis by increasing epithelial-mesenchymal transition and by enriching a cancer stem cell phenotype in tumor epithelial cells. In addition to these epithelial alterations, we also observed marked inflammation in tumor stroma. AKT is a central signaling mediator of the PI3K pathway. However, molecular analysis suggested that progression of PIK3CA-driven HNSCC is facilitated by 3-phosphoinositide-dependent protein kinase (PDK1) and enhanced transforming growth factor β (TGFβ) signaling rather than by AKT. Examination of human HNSCC clinical samples revealed that both PIK3CA and PDK1 protein levels correlated with tumor progression, highlighting the significance of this pathway. In summary, our results offer significant insight into how PIK3CA overexpression drives HNSCC invasion and metastasis, providing a rationale for targeting PI3K/PDK1 and TGFβ signaling in advanced HNSCC patients with PIK3CA amplification.
The orchestrated action of genes controls complex biological phenotypes, yet the systematic discovery of gene and drug combinations that modulate these phenotypes in human cells is labor intensive ...and challenging to scale. Here, we created a platform for the massively parallel screening of barcoded combinatorial gene perturbations in human cells and translated these hits into effective drug combinations. This technology leverages the simplicity of the CRISPR-Cas9 system for multiplexed targeting of specific genomic loci and the versatility of combinatorial genetics en masse (Combi-GEM) to rapidly assemble barcoded combinatorial genetic libraries that can be tracked with high-throughput sequencing. We applied CombiGEM-CRISPR to create a library of 23,409 barcoded dual guide-RNA (gRNA) combinations and then perform a high-throughput pooled screen to identify gene pairs that inhibited ovarian cancer cell growth when they were targeted. We validated the growth-inhibiting effects of specific gene sets, including epigenetic regulators KDM4C/BRD4 and KDM6B/BRD4, via individual assays with CRISPR-Cas–based knockouts and RNA-interference–based knockdowns. We also tested small-molecule drug pairs directed against our pairwise hits and showed that they exerted synergistic antiproliferative effects against ovarian cancer cells. We envision that the CombiGEM-CRISPR platform will be applicable to a broad range of biological settings and will accelerate the systematic identification of genetic combinations and their translation into novel drug combinations that modulate complex human disease phenotypes.
Psoriasis is a chronic inflammatory skin disorder that affects ~2%–3% of the worldwide population. Inappropriate and excessive activation of endosomal Toll-like receptors 7, 8, and 9 (TLRs 7–9) at ...the psoriatic site has been shown to play a pathogenic role in the onset of psoriasis. Macrophage is a major inflammatory cell type that can be differentiated into phenotypes M1 and M2. M1 macrophages produce proinflammatory cytokines, and M2 macrophages produce anti-inflammatory cytokines. The balance between these two types of macrophages determines the progression of various inflammatory diseases; however, whether macrophage polarization plays a role in psoriatic inflammation activated by endosomal TLRs has not been investigated. In this study, we investigated the function and mechanism of macrophages related to the pathogenic role of TLRs 7–9 in the progression of psoriasis. Analysis of clinical data in database revealed significantly increased expression of macrophage markers and inflammatory cytokines in psoriatic tissues over those in normal tissues. In animal studies, depletion of macrophages in mice ameliorated imiquimod, a TLR 7 agonist-induced psoriatic response. Imiquimod induced expression of genes and cytokines that are signature of M1 macrophage in the psoriatic lesions. In addition, treatment with this TLR 7 agonist shifted macrophages in the psoriatic lesions to a higher M1/M2 ratio. Both of the exogenous and endogenous TLR 7–9 ligands activated M1 macrophage polarization. M1 macrophages expressed higher levels of proinflammatory cytokines and TLRs 7–9 than M2 macrophages. These results suggest that by rendering macrophages into a more inflammatory status and capable of response to their ligands in the psoriatic sites, TLR 7–9 activation drives them to participate in endosomal TLR-activated psoriatic inflammation, resulting in an amplified inflammatory response. Our results also suggest that blocking M1 macrophage polarization could be a strategy which enables inhibition of psoriatic inflammation activated by these TLRs.
Summary
Background
The biological mechanisms of how prenatal smoke exposure leading to atopic disorders remain to be addressed. Whether prenatal smoke exposure affects DNA methylation leading to ...atopic disorders is not clear.
Objective
As most children suffering from atopic dermatitis (AD) continue to develop asthma later in life, we explored whether prenatal smoke exposure induces cord blood DNA methylation.
Methods
Methylation differences associated with smoke exposure were screened by Illumina Infinium 27K methylation arrays for 14 children from the Taiwan birth panel study cohort initially. Information about development of atopic dermatitis (AD) and risk factors was collected. Cord blood cotinine levels were measured to represent prenatal smoke exposure. CpG loci that demonstrated a statistically significant difference in methylation were validated by methylation‐dependent fragment separation (MDFS). Differential methylation in three genes (TSLP, GSTT1, and CYB5R3) was identified through the screen.
Results
Among these, only thymic stromal lymphopoietin (TSLP) gene displayed significant difference in promoter methylation percentage after being validated by MDFS (p = 0.018). TSLP gene was further investigated in a larger sample of 150 children from the cohort who completed the follow‐up study. Methylation status of the TSLP 5′‐CpG island (CGI) was found to be significantly associated with prenatal smoke exposure (OR=3.17, 95% CI=1.63–6.19) and with AD (OR=2.32, 95% CI=1.06–5.11). The degree of TSLP 5′CGI methylation inversely correlated with TSLP protein expression levels (r = −0.45, P = 0.001).
Conclusions & Clinical Relevance
The effect of prenatal tobacco smoke exposure on the risk for AD may be mediated through DNA methylation.
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