An antioxidant feedforward cycle coordinated by linker histone variant H1.2 and NRF2 that drives nonsmall cell lung cancer progression.

Nonsmall cell lung cancer (NSCLC) is highly malignant with limited treatment options, platinum-based chemotherapy is a standard treatment for NSCLC with resistance commonly seen. NSCLC cells exploit enhanced antioxidant defense system to counteract excessive reactive oxygen species (ROS), which contributes largely to tumor progression and resistance to chemotherapy, yet the mechanisms are not fully understood. Recent studies have suggested the involvement of histones in tumor progression and cellular antioxidant response; however, whether a major histone variant H1.2 (H1C) plays roles in the development of NSCLC remains unclear. Herein, we demonstrated that H1.2 was increasingly expressed in NSCLC tumors, and its expression was correlated with worse survival. When crossing the H1c knockout allele with a mouse NSCLC model (KrasLSL-G12D/+), H1.2 deletion suppressed NSCLC progression and enhanced oxidative stress and significantly decreased the levels of key antioxidant glutathione (GSH) and GCLC, the catalytic subunit of rate-limiting enzyme for GSH synthesis. Moreover, high H1.2 was correlated with the IC50 of multiple chemotherapeutic drugs and with worse prognosis in NSCLC patients receiving chemotherapy; H1.2-deficient NSCLC cells presented reduced survival and increased ROS levels upon cisplatin treatment, while ROS scavenger eliminated the survival inhibition. Mechanistically, H1.2 interacted with NRF2, a master regulator of antioxidative response; H1.2 enhanced the nuclear level and stability of NRF2 and, thus, promoted NRF2 binding to GCLC promoter and the consequent transcription; while NRF2 also transcriptionally up-regulated H1.2. Collectively, these results uncovered a tumor-driving role of H1.2 in NSCLC and indicate an "H1.2-NRF2" antioxidant feedforward cycle that promotes tumor progression and chemoresistance.

Mediation of association between benzo[a]pyrene exposure and lung cancer risk by plasma microRNAs: A Chinese case-control study.

Epidemiologic studies have reported the positive relationship of benzo[a]pyrene (BaP) exposure with the risk of lung cancer. However, the mechanisms underlying the relationship is still unclear. Plasma microRNA (miRNA) is a typical epigenetic biomarker that was linked to environment exposure and lung cancer development. We aimed to reveal the mediation effect of plasma miRNAs on BaP-related lung cancer. We designed a lung cancer case-control study including 136 lung cancer patients and 136 controls, and measured the adducts of benzo[a]pyrene diol epoxide-albumin (BPDE-Alb) and sequenced miRNA profiles in plasma. The relationships between BPDE-Alb adducts, normalized miRNA levels and the risk of lung cancer were assessed by linear regression models. The mediation effects of miRNAs on BaP-related lung cancer were investigated. A total of 190 plasma miRNAs were significantly related to lung cancer status at Bonferroni adjusted P < 0.05, among which 57 miRNAs showed different levels with |fold change| > 2 between plasma samples before and after tumor resection surgery at Bonferroni adjusted P < 0.05. Especially, among the 57 lung cancer-associated miRNAs, BPDE-Alb adducts were significantly related to miR-17-3p, miR-20a-3p, miR-135a-5p, miR-374a-5p, miR-374b-5p, miR-423-5p and miR-664a-5p, which could in turn mediate a separate 42.2%, 33.0%, 57.5%, 36.4%, 48.8%, 32.5% and 38.2% of the relationship of BPDE-Alb adducts with the risk of lung cancer. Our results provide non-invasion biomarker candidates for lung cancer, and highlight miRNAs dysregulation as a potential intermediate mechanism by which BaP exposure lead to lung tumorigenesis.

Inhibition of kinesin family member 20B sensitizes hepatocellular carcinoma cell to microtubule-targeting agents by blocking cytokinesis.

Kinesin family member 20B (KIF20B, also known as MPHOSPH1) is a kinesin protein that plays a critical role in cytokinesis. Previously, we and others have demonstrated the oncogenic role of KIF20B in several cancers; however, the exact mechanisms underlying its tumorigenic effects remain unclear. Herein, we showed overexpression of KIF20B in human hepatocellular carcinoma (HCC) and reported a negative correlation between KIF20B level and prognosis of patients. Mechanistically, reducing KIF20B blockades mitotic exit of HCC cells at telophase in a spindle assembly checkpoint independent way. Importantly, reducing KIF20B acts synergistically with three microtubule-associated agents (MTA) to p53- or p14ARF-dependently suppress p53-wt or p53-null HCC cells. In addition to taxol, reducing KIF20B also enhanced the toxicity of two chemotherapeutic drugs, hydroxycamptothecin and mitomycin C. In conclusion, we found a novel mechanism in that blocking cytokinesis by KIF20B inhibition increases the efficacy of MTA; our results thus suggested a dual-mitotic suppression approach against HCC by combining MTA with KIF20B inhibition, which simultaneously blocks mitosis at both metaphase and telophase.

Glyceraldehyde-3-phosphate dehydrogenase promotes liver tumorigenesis by modulating phosphoglycerate dehydrogenase.

Up-regulated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is observed in multiple cancers with unclear mechanism. Using GAPDH transgenic mouse and a mouse model of diethylnitrosamine-induced hepatocellular carcinoma (HCC), here we show that GAPDH overexpression aggravated tumor development by activating cell proliferation and inflammation. In cultured hepatic cells, overexpression of GAPDH or a catalytic domain-deleted GAPDH (GAPDHΔCD ) affected metabolism, up-regulated phosphoglycerate dehydrogenase (PHGDH), increased histone methylation levels, and promoted proliferation. Consistently, inhibition of GAPDH by short hairpin RNA reprogrammed metabolism down-regulated PHGDH and histone methylation, and inhibited proliferation. The xenograft study suggested that HepG2 cells overexpressing GAPDH or GAPDHΔCD similarly promoted tumor development, whereas knockdown PHGDH in GAPDH overexpressing cells significantly inhibited tumor development. In liver sections of HCC patients, increased GAPDH staining was found to be positively correlated with PHGDH and histone methylation staining. CONCLUSION: GAPDH increases histone methylation levels by up-regulating PHGDH, promoting diversion from glycolysis to serine biosynthesis, and consequently accelerating HCC development. (Hepatology 2017;66:631-645).

Genetic variant rs16430 6bp > 0bp at the microRNA-binding site in TYMS and risk of sporadic breast cancer risk in non-Hispanic white women aged ≤ 55 years.

Thymidylate synthase (TYMS) is involved in the folate metabolism and provision of nucleotides needed for DNA synthesis and repair. Thus, functional genetic variants in TYMS may alter cancer risk. In the study, we evaluated associations of three germline variants (rs2790 A > G, rs16430 6 bp > 0 bp, and rs1059394 C > T) in the predicted miRNA-binding sites of TYMS with risk of sporadic breast cancer in non-Hispanic white women aged ≤ 55. We found that carriers of the rs16430 0 bp variant allele had an increased risk of breast cancer [adjusted odd ratio (OR) = 1.37, 95% confidence interval (CI): 1.08-1.73; P = 0.010], compared with carriers of the 6 bp/6 bp genotype. This increased risk was more evident in older subjects (OR = 1.47, 95% CI = 1.06-2.03, P = 0.022), never smokers (OR = 1.67, 95% CI = 1.23-2.25, P < 0.001), never drinkers (OR = 1.44, 95% CI = 1.01-2.05, P = 0.043), and estrogen receptor-positive patients (OR = 1.46, 95% CI = 1.11-1.92, P = 0.006), regardless of tumor stages. The results are consistent with the functional analyses of rs16430 as previously reported, which showed that the 0 bp allele had a decrease in both luciferase activity by ∼ 70% and mRNA levels by ∼ 50% compared with the 6bp allele. Additionally, the rs16430 variant was predicted to influence the binding activity of miR-561. Taken together, these findings indicate that the TYMS rs16430 may contribute to the etiology of sporadic breast cancer in non-Hispanic white women aged ≤ 55 yr. Further validation in large population-based or cohort studies is needed.

Potentially functional variants in the core nucleotide excision repair genes predict survival in Japanese gastric cancer patients.

Functional genetic variants of DNA repair genes may alter the host DNA repair capacity, and thus influence efficiency of therapies. We genotyped eight potentially functional single nucleotide polymorphisms (SNPs) in genes (i.e. ERCC1, XPA, XPC, XPD and XPG) involved in the nucleotide excision repair (NER) pathway in 496 Japanese gastric cancer patients, and assessed overall survival and recurrence-free survival. The combined effects of risk genotypes of these eight SNPs in Japanese patients were further replicated in 356 North-American gastric cancer patients. In Japanese patients, we found that the XPC rs2228000 TT genotype was associated with shorter overall survival [hazards ratio (HR) = 1.75, 95% confidence interval (95% CI) = 1.07-2.86] and recurrence-free survival (HR = 2.17, 95% CI = 1.19-3.95), compared with CC/CT genotypes, and the XPG rs17655 CC genotype was associated with shorter overall survival (HR = 1.60, 95% CI = 1.08-2.36), compared with GG/CG genotypes. The number of observed risk genotypes in the combined analysis was associated with shorter overall survival and recurrence-free survival in a dose-response manner (P(trend) = 0.006 and P(trend) < 0.000) in Japanese patients; specifically, compared with those with ≤1 risk genotypes, those with ≥2 risk genotypes showed markedly shorter overall survival (HR = 1.79, 95% CI = 1.18-2.70) and recurrence-free survival (HR = 2.80, 95% CI = 1.66-4.73). The association between ≥2 risk genotypes and shorter overall survival was not significant (HR = 1.26, 95% CI = 0.82-1.94) in North-American patients, but the trends were similar in these two groups of patients. These data show that functional SNPs in NER core genes may impact survival in Japanese gastric cancer patients.

Strategies and influencing factors for the treatment of advanced non-small cell lung cancer based on epidermal growth factor receptor tyrosine kinase inhibitors: a narrative review.

Background and Objective: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the primary treatment for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations, significantly enhancing patient prognosis. Despite the efficacy of EGFR-TKIs, monotherapy faces challenges such as variability among individuals and early drug resistance. This article aims to explore the treatment strategies and influencing factors for advanced NSCLC patients treated with EGFR-TKIs, optimize treatment plans, and improve the prognosis of patients with advanced NSCLC. Methods: We undertook a comprehensive, narrative review of the latest literature to define the current application and progress of EGFR-TKIs in treating patients with advanced NSCLC. Key Content and Findings: The efficacy and promise of EGFR-TKIs, both as monotherapy and combined with other agents, for treating patients with advanced NSCLC are outlined. The study delves into the mechanisms of resistance and the ongoing development of EGFR-TKIs. Various factors influencing the treatment of advanced NSCLC patients with EGFR-TKIs are also examined. Conclusions: EGFR-TKIs alone improve survival in patients with advanced NSCLC. Combined with other agents, some regimens have shown improved benefits in overcoming drug resistance and prolonging patient survival. It is imperative to focus on developing novel EGFR-TKIs and investigate innovative combination therapies to maximize patient benefit.

Linker histone variant H1.2 is a brake on white adipose tissue browning.

Adipose-tissue is a central metabolic organ for whole-body energy homeostasis. Here, we find that highly expressed H1.2, a linker histone variant, senses thermogenic stimuli in beige and brown adipocytes. Adipocyte H1.2 regulates thermogenic genes in inguinal white-adipose-tissue (iWAT) and affects energy expenditure. Adipocyte H1.2 deletion (H1.2AKO) male mice show promoted iWAT browning and improved cold tolerance; while overexpressing H1.2 shows opposite effects. Mechanistically, H1.2 binds to the promoter of Il10rα, which encodes an Il10 receptor, and positively regulates its expression to suppress thermogenesis in a beige cell autonomous manner. Il10rα overexpression in iWAT negates cold-enhanced browning of H1.2AKO male mice. Increased H1.2 level is also found in WAT of obese humans and male mice. H1.2AKO male mice show alleviated fat accumulation and glucose intolerance in long-term normal chow-fed and high fat diet-fed conditions; while Il10rα overexpression abolishes these effects. Here, we show a metabolic function of H1.2-Il10rα axis in iWAT.

The elevation of salinity above 1% deteriorated nitrification performance and reshaped nitrifier community of an MBR: An often overlooked factor in the treatment of high-strength ammonium wastewater.

The effects of synchronous variations of influent salinity with the elevation of NH4+-N concentration on nitrification performance and microbial community structure of bioreactor are often ignored. In this study, we investigated the dynamic response of nitrifying activated sludge to synchronously increased salinity and ammonia loading rate (ALR) in a nitrification membrane bioreactor (MBR). We found that the increase in influent salinity above 1% (from 0.91 to 1.32%) led to the deterioration of the nitrification performance of the MBR. The combined inhibition effect of salinity (1.32%), free ammonia (FA, an average of 1.37 mg/L), and free nitrous acid (FNA, an average of 0.155 mg/L) on nitrite-oxidizing bacteria (NOB) resulted in long-term (35 days) nitrite accumulation. The further increase of salinity and ALR exhibited little influence on the nitrification performance of MBR after the activated sludge had adapted to high salinity (>1%), effective nitrification performance was achieved at high ALR up to 1.71 kg NH4+-N/m3·d and high salinity (2.13%). The microbial analysis showed that the elevated salinity and accumulation of FNA reshaped the microbial community structure of ammonia-oxidizing bacteria (AOB) and NOB. The dominant species of AOB and NOB shifted from the salinity-resistant species Nitrosomonas aestuarii to the species Nitrosomonas mobilis with dual resistant to salinity and FNA, and from non-salinity-resistant species Candidatus Nitrospira defluvii to salinity-resistant species Nitrobacter winogradskyi and Nitrospira marina, respectively. Therefore, the salinity of 1% may be a critical level for the nitrification performance and the shift in the nitrifier community of activated sludge without salinity acclimation.

EGFR transcriptionally upregulates UTX via STAT3 in non-small cell lung cancer.

BACKGROUND: Histone demethylase UTX has been reported to participate in the occurrence and development of many cancers in tissue-specific manners. However, the role of UTX in non-small cell lung cancer (NSCLC) and exactly what regulates the expression of UTX remains unclear. Here, we analyzed the role of UTX in NSCLC in association with the widely recognized tumor driver epidermal growth factor receptor (EGFR). METHODS: UTX levels in clinical samples were detected by immunohistochemistry staining, western blotting and real-time quantitative PCR. The expression of UTX in tumor tissue was correlated with the phosphorylation of EGFR. Cell proliferation and migration were evaluated by MTT and wound-healing assays. The impact of EGFR and its downstream pathways on UTX was explored with corresponding inhibitors, and examined by western blotting and real-time quantitative PCR. RESULTS: In this study, we found that the expression of UTX in cancer tissues of patients with NSCLC was significantly higher than that in paracancerous tissues, and positively associated with EGFR phosphorylation levels. In addition, in NSCLC cell lines, UTX can promote proliferation and migration, while inhibition of its enzyme activity suppressed cell growth. Moreover, UTX expression was significantly upregulated when EGFR signaling pathway was activated, and vice versa when EGFR pathway was inhibited by tyrosine kinase inhibitor. Further mechanistic studies suggested that the activation of EGFR activated its downstream JAK/STAT3 signaling pathway and promoted STAT3 phosphorylation; the phosphorylated STAT3 transcriptionally promoted the levels of UTX. CONCLUSIONS: These results suggest an "EGFR-STAT3-UTX" axis that plays an oncogenic role in NSCLC.

A functional methylation signature to predict the prognosis of Chinese lung adenocarcinoma based on TCGA.

BACKGROUND: Lung cancer is the leading cause of cancer morbidity and mortality worldwide, however, the individualized treatment is still unsatisfactory. DNA methylation can affect gene regulation and may be one of the most valuable biomarkers in predicting the prognosis of lung adenocarcinoma. This study was aimed to identify methylation CpG sites that may be used to predict lung adenocarcinoma prognosis. METHODS: The Cancer Genome Atlas (TCGA) database was used to detect methylation CpG sites associated with lung adenocarcinoma prognosis and construct a methylation signature model. Then, a Chinese cohort was carried out to estimate the association between methylation and lung adenocarcinoma prognosis. Biological function studies, including demethylation treatment, cell proliferative capacity, and gene expression changes in lung adenocarcinoma cell lines, were further performed. RESULTS: In the TCGA set, three methylation CpG sites were selected that were associated with lung adenocarcinoma prognosis (cg14517217, cg15386964, and cg18878992). The risk of mortality was increased in lung adenocarcinoma patients with the gradual increase level of methylation signature based on three methylation sites levels (HR = 45.30, 95% CI = 26.69-66.83; p < 0.001). The C-statistic value increased to 0.77 when age, gender, and other clinical variables were added to the signature to prediction model. A similar situation was confirmed in Chinese lung adenocarcinoma cohort. In the biological function studies, the proliferative capacity of cell lines was inhibited when the cells were demethylated with 5-aza-2'-deoxycytidine (5-aza-2dC). The mRNA and protein expression levels of SEPT9 and HIST1H2BH (cg14517217 and cg15386964) were downregulated with different concentrations of 5-aza-2dC treatment, while cg18878992 showed the opposite result. CONCLUSION: This study is the first to develop a three-CpG-based model for lung adenocarcinoma, which is a practical and useful tool for prognostic prediction that has been validated in a Chinese population.

Epigenome-wide DNA methylation signature of plasma zinc and their mediation roles in the association of zinc with lung cancer risk.

Essential trace element zinc is associated with decreased lung cancer risk, but underlying mechanisms remain unclear. This study aimed to investigate role of DNA methylation in zinc-lung cancer association. We conducted a case-cohort study within prospective Dongfeng-Tongji cohort, including 359 incident lung cancer cases and a randomly selected sub-cohort of 1399 participants. Epigenome-wide association study (EWAS) was used to examine association of plasma zinc with DNA methylation in peripheral blood. For the zinc-related CpGs, their mediation effects on zinc-lung cancer association were assessed; their diagnostic performance for lung cancer was testified in the case-cohort study and further validated in another 126 pairs of lung cancer case-control study. We identified 28 CpGs associated with plasma zinc at P < 1.0 × 10-5 and seven of them (cg07077080, cg01077808, cg17749033, cg15554270, cg26125625, cg10669424, and cg15409013 annotated to GSR, CALR3, SLC16A3, PHLPP2, SLC12A8, VGLL4, and ADAMTS16, respectively) were associated with incident risk of lung cancer. Moreover, the above seven CpGs were differently methylated between 126 pairs of lung cancer and adjacent normal lung tissues and had the same directions with EWAS of zinc. They could mediate a separate 7.05%∼22.65% and a joint 29.42% of zinc-lung cancer association. Compared to using traditional factors, addition of methylation risk score exerted improved discriminations for lung cancer both in case-cohort study [area under the curve (AUC) = 0.818 vs. 0.738] and in case-control study (AUC = 0.816 vs. 0.646). Our results provide new insights for the biological role of DNA methylation in the inverse association of zinc with incident lung cancer.

A new minimally invasive technique for correction of pectus carinatum.

BACKGROUND: The Abramson technique for the correction of pectus carinatum (PC) is commonly performed worldwide. However, the postoperative complications of this technique related to bar fixation, including wire breakage and bar displacement, are relatively high. In this study, a new minimally invasive technique for correction of PC is described, in which the pectus bar is secured by bilateral selected ribs, and for which no special fixation to the rib is needed. METHODS: The procedure was performed by placing the pectus bar subcutaneously over the sternum with both ends of the bar passing through the intercostal space of the selected rib at the anterior axillary line. The protruding sternum was depressed by the bar positioned in this 2 intra- and 2 extra-thorax manners. Between October 2011 and September 2019, 42 patients with PC underwent this procedure. RESULTS: Satisfactory cosmetic results were obtained in all the patients. The mean operation time was 87.14 min, and the mean postoperative stay was 4.05 days. Wound infection occurred in 3 patients, 2 were cured by antibiotics, and 1 received bar removal 4 months after the initial operation due to the exposure of the implant resulting from uncontrolled infection. Mild pneumothorax was found in 3 patients and cured by conservative treatment. One patient suffered from hydropneumothorax, which was treated with chest drainage. The bars were removed at a mean duration of 24.4 months since primary repair in 20 patients without recurrence. CONCLUSIONS: This new technique for minimally invasive correction of PC deformity is a safe and feasible procedure yielding good results and minimal complications.

DNA methylome analysis identifies BMI-related epigenetic changes associated with non-small cell lung cancer susceptibility.

BACKGROUND: Body mass index (BMI) has been reported to be inversely associated with incident risk of non-small cell lung cancer (NSCLC). However, the underlying mechanism is still unclear. This study aimed to investigate the role of DNA methylation in the relationship between BMI and NSCLC. METHODS: We carried out a genome-wide DNA methylation study of BMI in peripheral blood among 2266 Chinese participants by using Illumina Methylation arrays. For the BMI-related DNA methylation changes, their associations with NSCLC risk were further analyzed and their mediation effects on BMI-NSCLC association were also evaluated. RESULTS: The methylation levels of four CpGs (cg12593793, cg17061862, cg11024682, and cg06500161, annotated to LMNA, ZNF143, SREBF1, and ABCG1, respectively) were found to be significantly associated with BMI. Methylation levels of cg12593793, cg11024682, and cg06500161 were observed to be inversely associated with NSCLC risk [OR (95%CI) =0.22 (0.16, 0.31), 0.39 (0.30, 0.50), and 0.66 (0.53, 0.82), respectively]. Additionally, cg11024682 in SREBF1 and cg06500161 in ABCG1 mediated 45.3% and 19.5% of the association between BMI and decreased NSCLC risk, respectively. CONCLUSIONS: In this study, we identified four DNA methylation sites associated with BMI in the Chinese populations at the genome-wide significant level. We also found that the BMI-related methylations of SREBF1 and ABCG1 could mediate about a quintile-to-half of the effect of BMI on reduced NSCLC risk, which adds a potential mechanism underlying this association.

Epigenome-wide DNA methylation signature of benzo[a]pyrene exposure and their mediation roles in benzo[a]pyrene-associated lung cancer development.

Benzo[a]pyrene (B[a]P) is a typical carcinogen associated with increased lung cancer risk, but the underlying mechanisms remain unclear. This study aimed to investigate epigenome-wide DNA methylation associated with B[a]P exposure and their mediation effects on B[a]P-lung cancer association in two lung cancer case-control studies of 462 subjects. Their plasma levels of benzo[a]pyrene diol epoxide-albumin (BPDE-Alb) adducts and genome-wide DNA methylations were separately detected in peripheral blood by using enzyme-linked immunosorbent assay (ELISA) and genome-wide methylation arrays. The epigenome-wide meta-analysis was performed to analyze the associations between BPDE-Alb adducts and DNA methylations. Mediation analysis was applied to assess effect of DNA methylation on the B[a]P-lung cancer association. We identified 15 CpGs associated with BPDE-Alb adducts (P-meta < 1.0 × 10-5), among which the methylation levels at five loci (cg06245338, cg24256211, cg15107887, cg02211741, and cg04354393 annotated to UBE2O, SAMD4A, ACBD6, DGKZ, and SLFN13, respectively) mediated a separate 38.5%, 29.2%, 41.5%, 47.7%, 56.5%, and a joint 58.2% of the association between BPDE-Alb adducts and lung cancer risk. Compared to the traditional factors [area under the curve (AUC) = 0.788], addition of these CpGs exerted improved discriminations for lung cancer, with AUC ranging 0.828-0.861. Our results highlight DNA methylation alterations as potential mediators in lung tumorigenesis induced by B[a]P exposure.

Clinical and Transmission Characteristics of Covid-19 - A Retrospective Study of 25 Cases from a Single Thoracic Surgery Department.

The outbreak of corona virus disease 2019 (Covid-19) imposes a major challenge in managing patients undergoing surgical operation. In this study, we analyzed clinical and transmission features of 25 cases of Covid-19 from a single thoracic department, including 13 patients and 12 health care staff. There were 13 males and 12 females. The median age of the patients was 61 (range: 51 to 69) years. The median age of the health care staff was 35 (range: 22 to 51) years. By the end of follow-up date (Mar. 3, 2020), there were 16 non-severe cases (64%) and 9 severe cases (36%), 5 cases were dead (20%). Nineteen (76%) of the infected cases were confirmed by SARS-CoV-2 nucleic acid test, the rest were clinically diagnosed as suspected Covid-19 cases, and 19 (76%) of the infected cases had positive exposure history. We found that COPD was significantly associated with severity and death (P=0.040, and P=0.038, respectively), and chest operation was significantly associated with death for Covid-19 patients (P=0.039). A potential "super spreader" may be the source of the transmission before the implementation of quarantine and comprehensive protection. It was concluded that Covid-19 is associated with poor prognosis for patients undergoing thoracic operation, especially for those with COPD. Implementation of comprehensive protective measures is important to control nosocomial infection.

Fat-Specific Knockout of Mecp2 Upregulates Slpi to Reduce Obesity by Enhancing Browning.

Abnormalities of methyl-CpG binding protein 2 (Mecp2) cause neurological disorders with metabolic dysfunction; however, its role in adipose tissues remains unclear. Here, we report upregulated Mecp2 in white adipose tissues (WAT) of obese humans, as well as in obese mice and during in vitro adipogenesis. Normal chow-fed adipocyte-specific Mecp2 knockout mice (Mecp2 Adi KO mice) showed a lean phenotype, with downregulated lipogenic genes and upregulated thermogenic genes that were identified using RNA sequencing. Consistently, the deficiency of Mecp2 in adipocytes protected mice from high-fat diet (HFD)-induced obesity and inhibited in vitro adipogenesis. Furthermore, Mecp2 Adi KO mice showed increased browning under different stimuli, including cold treatment. Mechanistically, Mecp2 bound to the promoter of secretory leukocyte protease inhibitor (Slpi) and negatively regulated its expression. Knockdown of Slpi in inguinal WAT of Mecp2 Adi KO mice prevented cold-induced browning. Moreover, recombinant SLPI treatment reduced the HFD-induced obesity via enhancing browning. Together, our results suggest a novel non-central nervous system function of Mecp2 in obesity by suppressing browning, at least partially, through regulating adipokine Slpi.

Loss of histone lysine methyltransferase EZH2 confers resistance to tyrosine kinase inhibitors in non-small cell lung cancer.

Tyrosine kinase inhibitor (TKI) treatment is the first-line therapy for non-small cell lung cancer (NSCLC) caused by activating mutations of epidermal growth factor receptor (EGFR). However, acquired resistance to EGFR-TKI occurs almost inevitably. Aberrant activation of proto-oncogene MET has been known to confer EGFR-TKI resistance; however, the mechanisms involved remains unclear. Recent evidence implicates epigenetic heterogeneity as playing roles in cancer drug resistance, whereas links involving epigenetic heterogeneity and MET in NSCLC remain poorly understood. We found that expression of EZH2, a histone methyltransferase, was negatively correlated with MET activation and EGFR-TKI resistance in NSCLC cells and clinical samples, suggesting the potential for EZH2 to be used as a biomarker for EGFR-TKI sensitivity. Knockdown or inhibition of EZH2 up-regulated MET expression and phosphorylation, and elevated proliferation and EGFR-TKI resistance of cells in vitro. Meanwhile, inhibition of MET or PI3K/AKT enhanced EZH2 levels and restored sensitivity to EGFR-TKI. These findings indicate a "MET-AKT-EZH2" feedback loop regulating EGFR-TKI-resistance. Furthermore, combination therapy of PI3K/AKT inhibition and EGFR-TKI, which interrupts the loop, enhanced tumor-suppressive effects in an EGFR-TKI-resistant xenograft model, indicating a potential approach against drug resistance in NSCLC.

Hydrophobic melamine foam as the solvent holder for liquid-liquid microextraction.

In this study, the hydrophobic melamine foam (HMF) was proposed as the solvent holder for liquid-liquid microextraction (LLME) purpose. The HMF contained 3D mesh structure with ultralight, compressible and hydrophobic properties. When it was used as the solvent holder, it had merits of convenient collection of the extractant phase by compressing the foam, enhanced extraction efficiency because of the large contact area between the extractant phase and sample solution, and reusability of the foam. The HMF-LLME combined with gas chromatography-mass spectrometry (GC-MS) was applied for the determination of polycyclic aromatic hydrocarbons (PAHs) in environmental water samples. Under the optimized conditions, the proposed method showed linear ranges of 0.01-50.00 ng mL-1 with good correlation coefficients (r > 0.99), low limits of detection (0.4-3.0 pg mL-1), and good precision with intra-day and inter-day relative standard deviations in the range of 6.1-13.7% and 5.3-15.0%, respectively. The HMF retained good performance after 10 cycles' usages, demonstrating excellent reusability. The proposed HMF-LLME method provided comparable results with the traditional liquid-liquid extraction of PAHs based on United States Environmental Protection Agency Method 3510C on real water samples but with more operational convenience, less consumption of organic solvent and low cost. The HMF was suitable as the solvent holder for LLME purpose with accurate, convenient, rapid, eco-friendly and reusable properties.

Targeting mitosis exit: A brake for cancer cell proliferation.

The transition from mitosis to interphase, referred to as mitotic exit, is a critical mitotic process which involves activation and inactivation of multiple mitotic kinases and counteracting protein phosphatases. Loss of mitotic exit checkpoints is a common feature of cancer cells, leading to mitotic dysregulation and confers cancer cells with oncogenic characteristics, such as aberrant proliferation and microtubule-targeting agent (MTA) resistance. Since MTA resistance results from cancer cells prematurely exiting mitosis (mitotic slippage), blocking mitotic exit is believed to be a promising anticancer strategy. Moreover, based on this theory, simultaneous inhibition of mitotic exit and additional cell cycle phases would likely achieve synergistic antitumor effects. In this review, we divide the molecular regulators of mitotic exit into four categories based on their different regulatory functions: 1) the anaphase-promoting complex/cyclosome (APC/C, a ubiquitin ligase), 2) cyclin B, 3) mitotic kinases and phosphatases, 4) kinesins and microtubule-binding proteins. We also review the regulators of mitotic exit and propose prospective anticancer strategies targeting mitotic exit, including their strengths and possible challenges to their use.