Influence of Smoking Habits on the Efficacy of EGFR-TKI Therapy in Patients with Advanced NSCLC: A Systematic Review and Meta-Analysis.

Background: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are considered as the first-line treatment for advanced EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to analyze the efficacy of EGFR-TKIs treatment in patients with advanced NSCLC of different smoking habits. Methods: We conducted a search for meta-analyses and systematic reviews on the PubMed, MEDLINE, Embase, and the Cochrane Library to address this knowledge gap. Patients were divided into 2 groups: (1) experimental group: treated with EGFR-TKIs or EGFR-TKIs combined with chemotherapy, immunotherapy, antiangiogenesis, radiotherapy and (2) control group: treated with chemotherapy. Progressive-free survival (PFS) and total survival (OS) were adopted for evaluating the efficacy of EGFR-TKIs between experimental group and control group. Results: Eleven studies including 6760 patients were included in the meta-analysis. The results showed that smoking (including previous and current smoking) significantly reduces the PFS and OS in comparison to non-smoking group in the treatment of NSCLC with EGFR-TKIs. In addition, EGFR-TKIs combined with anti-vascular endothelial growth factor therapy can reduce the risk of disease progression in smokers. Conclusions: Our study indicated that smoking significantly reduced the PFS and OS in comparison to non-smoking group in the treatment of NSCLC with EGFR-TKIs.

LncRNA HHIP-AS1 suppresses lung squamous cell carcinoma by stabilizing HHIP mRNA.

AIMS: Lung squamous cell carcinoma (LUSC) causes over 400,000 deaths annually, yet it lacks targeted therapy. A major antagonist of Hedgehog pathway, HHIP (Hedgehog Interacting Protein) plays an important role in LUSC; however, the regulatory mechanism remains unclear. Long non-coding RNA HHIP-AS1 plays suppressive or promotive roles in different cancers, but its role in LUSC remains unknown. This manuscript is to investigate regulatory mechanism of HHIP and the role of HHIP-AS1 in LUSC. MAIN METHODS: Precision-cut lung slices (PCLS) from human LUSC samples are cultured to mimic LUSC growth. Overexpression and knockdown in multiple LUSC cell lines and PCLS are achieved by lentivirus infection. Transcriptome profile and lung cancer activity are evaluated by RNA-sequencing, immunostaining and CCK8 assay etc. KEY FINDINGS: HHIP is regulated independently of Hh pathway in LUSC. Additionally, downregulation of HHIP-AS1 is associated with poor prognosis. Consistently, HHIP-AS1 inhibits LUSC growth by suppressing cell proliferation and migration. Transcriptome profiling of HHIP-AS1 knockdown (KD) cells uncovered HHIP downregulation. Interestingly, a comparison between the transcriptomes of HHIP-AS1 KD or HHIP KD cells manifested high similarity. Subsequently it's confirmed that HHIP-AS1 regulates HHIP in LUSC cells. Notably, HHIP-AS1 regulation on LUSC growth is achieved through stabilizing HHIP mRNA rather than regulating MIR-153-3P/PCDHGA9 or MIR-425-5P/DNYC1I2. Finally, it's confirmed in PCLS from human LUSC samples that HHIP-AS1 suppresses LUSC via regulating HHIP mRNA. SIGNIFICANCE: This study uncovers HHIP-AS1 as a novel tumor suppressor in LUSC and provides new insights into the molecular regulation of LUSC, which will help developing new therapeutic strategies.

Molecular Characteristics and Quantitative Proteomic Analysis of Klebsiella pneumoniae Strains with Carbapenem and Colistin Resistance.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) are usually multidrug resistant (MDR) and cause serious therapeutic problems. Colistin is a critical last-resort therapeutic option for MDR bacterial infections. However, increasing colistin use has led to the emergence of extensively drug-resistant (XDR) strains, raising a significant challenge for healthcare. In order to gain insight into the antibiotic resistance mechanisms of CRKP and identify potential drug targets, we compared the molecular characteristics and the proteomes among drug-sensitive (DS), MDR, and XDR K. pneumoniae strains. All drug-resistant isolates belonged to ST11, harboring blaKPC and hypervirulent genes. None of the plasmid-encoded mcr genes were detected in the colistin-resistant XDR strains. Through a tandem mass tag (TMT)-labeled proteomic technique, a total of 3531 proteins were identified in the current study. Compared to the DS strains, there were 247 differentially expressed proteins (DEPs) in the MDR strains and 346 DEPs in the XDR strains, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that a majority of the DEPs were involved in various metabolic pathways, which were beneficial to the evolution of drug resistance in K. pneumoniae. In addition, a total of 67 DEPs were identified between the MDR and XDR strains. KEGG enrichment and protein-protein interaction network analysis showed their participation in cationic antimicrobial peptide resistance and two-component systems. In conclusion, our results highlight the emergence of colistin-resistant and hypervirulent CRKP, which is a noticeable superbug. The DEPs identified in our study are of great significance for the exploration of effective control strategies against infections of CRKP.

The lncRNA HOTAIR regulates autophagy and affects lipopolysaccharide-induced acute lung injury through the miR-17-5p/ATG2/ATG7/ATG16 axis.

Long non-coding ribonucleic acids (lncRNAs) play critical roles in acute lung injury (ALI). We aimed to explore the involvement of lncRNA HOX transcript antisense intergenic ribonucleic acid (HOTAIR) in regulating autophagy in lipopolysaccharide (LPS)-induced ALI. We obtained 1289 differentially expressed lncRNAs or messenger RNAs (mRNAs) via microarray analysis. HOTAIR was significantly upregulated in the LPS stimulation experimental group. HOTAIR knockdown (si-HOTAIR) promoted cell proliferation in LPS-stimulated A549 and BEAS-2B cells, suppressing the protein expression of autophagy marker light chain 3B and Beclin-1. Inhibition of HOTAIR suppressed LPS-induced cell autophagy, apoptosis and arrested cells in the G0/G1 phase prior to S phase entry. Further, si-HOTAIR alleviated LPS-induced lung injury in vivo. We predicted the micro-ribonucleic acid miR-17-5p to target HOTAIR and confirmed this via RNA pull-down and dual luciferase reporter assays. miR-17-5p inhibitor treatment reversed the HOTAIR-mediated effects on autophagy, apoptosis, cell proliferation and cell cycle. Finally, we predicted autophagy-related genes (ATGs) ATG2, ATG7 and ATG16 as targets of miR-17-5p, which reversed their HOTAIR-mediated protein upregulation in LPS-stimulated A549 and BEAS-2B cells. Taken together, our results indicate that HOTAIR regulated apoptosis, the cell cycle, proliferation and autophagy through the miR-17-5p/ATG2/ATG7/ATG16 axis, thus driving LPS-induced ALI.

Life-threatening hemoptysis accompanied by internal thoracic artery aneurysms in a 28-year-old perinatal woman: a case report.

BACKGROUND: Life-threatening hemoptysis presents an immediate diagnostic and therapeutic challenge, especially during the perinatal period. CASE PRESENTATION: A 28-year-old perinatal woman with no significant past medical or surgical history presented with repeating hemoptysis and respiratory failure. Computed tomography revealed a 2.1 × 3.2  cm2 inhomogeneous tumorous lesion in the right superior mediastinum and a right main bronchus obstruction along with atelectasis of the right lung. Bronchoscopy showed a tumorous protrusion blocking the right main bronchus with active hemorrhage, and malignancy was suspected. Bronchial artery embolization (BAE) was performed to control the bleeding. The arteriogram revealed tortuosity, dilation and hypertrophy of the right bronchial arteries and aneurysms of the internal thoracic artery (ITA). The bleeding completely stopped after BAE. Bronchoscopy was performed again to remove residual blood clots. The patient recovered soon after the procedure and was discharged. CONCLUSIONS: Life-threatening hemoptysis concomitant with ITA aneurysms, which may have a misleading clinical diagnosis and treatment options, has not been reported previously in perinatal women. BAE could be used as a first-line treatment irrespective of the underlying causes.

[Predictive value of glycosylated serum protein combined with glycemic variability on secondary persistent inflammatory immunosuppressed catabolic syndrome prediction in elderly septic patients].

OBJECTIVE: To investigate the predictive value of glycosylated serum protein (GSP) combined with glycemic variability (GV) in persistent inflammation immunosuppressive catabolic syndrome (PICS) in elderly septic patients. METHODS: A retrospective study was conducted. The septic patients aged ≥ 60 years old with 28 days hospitalized duration admitted to geriatric intensive care unit (ICU) of Guangzhou General Hospital of Guangzhou Military Command from January 2014 to December 2017 were enrolled. The patients were divided into two groups according to whether PICS occurred within 14 days after ICU admission according to the PICS diagnostic criteria. General patients' data including gender, age, underlying disease, site of infection, the length of ICU stay were collected, acute physiology and chronic health evaluation II (APACHE II), GSP at 1 day after hospitalization and lymphocyte count (LYM), C-reactive protein (CRP), albumin (ALB), prealbumin (PA) levels at 1 day and 14 days were recorded. The levels of blood glucose on the 1st day and 14th day were observed, the GV was calculated. Data were cross-validated using the random forest method. Receiver operating characteristic (ROC) curve was plotted to evaluate the predictive value of glycemic parameters for PICS. RESULTS: A total of 315 elderly septic patients were included. Patients with malignant tumors, severe autoimmune diseases, and immunosuppressive therapy or dead within 28 days of hospitalization were excluded. A total of 132 patients were enrolled in the analysis, including 45 in the PICS group and 87 in the non-PICS group. The length of ICU stay in the PICS group was significantly longer than that in the non-PICS group [days: 35.0 (22.0, 49.5) vs. 8.0 (5.0, 23.0), P < 0.01]. No significant difference in the baseline data of gender, age, underlying disease, infection site or APACHE II score between the two groups was found. (1) Parameters for PICS diagnosis: with the prolongation of ICU stay, LYM and PA in the non-PICS group were increased and those in the PICS group were decreased, and CRP and ALB levels were decreased in both groups. LYM, ALB and PA levels in the PICS group were significantly lower than those in the non-PICS group at 14 days after ICU admission [LYM (×109/L): 0.6 (0.5, 0.7) vs. 1.1 (0.9, 1.6), ALB (g/L): 25.4±2.7 vs. 29.9±4.3, PA (g/L): 0.08 (0.05, 0.14) vs. 0.11 (0.10, 0.21), all P < 0.01], and CRP level was significantly higher than that in the non-PICS group (mg/L: 87.5±56.3 vs. 49.2±49.1, P < 0.01). (2) Glycemic parameters: the GSP level of the PICS group at 1 day after ICU admission was significantly lower than that of the non-PICS group (mmol/L: 2.3±0.6 vs. 2.7±0.6, P < 0.01), but there was no statistically significant difference in the level of blood glucose or GV at 1 day and 14 days after ICU admission as compared with the non-PICS group [blood glucose (mmol/L): 10.0±3.3 vs. 9.4±3.3 at 1 day, 10.8±3.6 vs. 10.4±3.5 at 14 days; GV: (24.2±1.4)% vs. (23.7±1.2)% at 1 day, (24.8±7.8)% vs. (24.7±7.7)% at 14 days, all P > 0.05]. (3) ROC curve analysis: 1-day GSP as well as 1-day and 14-day GV had certain predictive value for PICS secondary to sepsis in the elderly. The predictive value of 1-day GSP combined with 14-day GV was the highest, its area under ROC curve (AUC) was 0.637, with a sensitivity of 95.8% and a specificity of 25.0%, while the positive likelihood ratio was 1.278, the negative likelihood ratio was 0.167, the positive predictive value was 71.9%, and the negative predictive value was 75.0%. CONCLUSIONS: GSP combined with GV could effectively predict secondary PICS in elderly septic patients.

Eating Centipedes Can Result in Angiostrongylus cantonensis Infection: Two Case Reports and Pathogen Investigation.

Angiostrongyliasis is a food-borne parasitic disease caused by the nematode Angiostrongylus cantonensis that can lead to eosinophilic meningitis (EM) or meningoencephalitis in humans. Angiostrongylus cantonensis is prevalent in the Pacific Islands. In recent years, a large number of outbreaks and severe cases have occurred. Several species of mollusk, such as snails and slugs, act as intermediate and paratenic hosts of A. cantonensis. In this study, two cases of EM were found to have been caused by infection with A. cantonensis due to consumption of raw centipedes. To survey the A. cantonensis infections acquired through centipedes that the patients had bought at a vegetable market, we performed etiological examinations and polymerase chain reaction amplification of A. cantonensis genes. Third-instar larvae of A. cantonensis were detected in the centipedes, and specific genes from A. cantonensis were detected in all the specimens. This indicates that the centipede may act as a competent host for the transmission of A. cantonensis. To our knowledge, this is the first report of A. cantonensis infection through the consumption of centipedes.

Infection by the nematode Angiostrongylus cantonensis induces differential expression of miRNAs in mouse brain.

BACKGROUND: The parasitic nematode Angiostrongylus cantonensis is the primary pathogen causing eosinophilic meningitis and meningoencephalitis in nonpermissive hosts. The larval parasites are eliminated by the host's immune responses in the central nervous system (CNS) through infiltration of eosinophils and lymphocytes. This study aimed to determine primary alterations of microRNA (miRNA) during A. cantonensis infection in mice. METHODS: miRNA array was used to analyze the expression of miRNA in uninfected and A. cantonensis-infected mouse brains at 21 days postinfection (dpi). Target genes were predicted by miRDB software, and protein-protein interaction network was analyzed using STRING v9.1. Expression levels of selected miRNAs and cytokine production were verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Twenty-five mature miRNAs showed differential expression in infected mouse brains, of which 24 were upregulated and one was downregulated compared to the uninfected control. These 25 miRNAs were divided into five clusters, and the first upregulated cluster was selected for further bioinformatics analysis. Target gene prediction and gene ontology (GO) enrichment analysis revealed that the miRNAs were mainly related to the immune response. Furthermore, six target genes of mmu-miR-146a-5p were predicted to interact with tumor necrosis factor alpha (TNF-α). The in vitro study suggested that transfected mmu-miR-146a-5p inhibitor upregulated TNF-α and its target gene Traf6 in microglia following stimulation with A. cantonensis larval antigen. CONCLUSION: This study suggested a critical role of miRNAs in the host defense during A. cantonensis infection, providing new insights into the molecular mechanisms underlying the interaction between mmu-miR-146a-5p and TNF-α in angiostrongyliasis in nonpermissive hosts.

Proteomic Analysis of Differentially Expressed Proteins in Intracranial Angiostrongylus cantonensis Larvae in Permissive and Non-Permissive Hosts.

Angiostrongylus cantonensis infection can lead to severe neuropathological damage caused by the development of these nematodes in the central nervous system after penetrating the blood-brain barrier. They commonly cause eosinophilic meningitis or meningoencephalitis in non-permissive hosts (e.g., mice). It has been shown that differences exist in the brains of permissive and non-permissive hosts during the larval development of A. cantonensis; however, the mechanism underlying the difference is not completely understood. This study analyzed and characterized the differentially expressed proteins in the intracranial A. cantonensis larvae in rat (ILR) and mouse (ILM) brains by using proteomics. We found that 29 proteins were differentially expressed: 12 of these proteins were highly expressed in ILR, whereas the remaining 17 proteins were highly expressed in ILM. Three protein spots were homologous to the actin-2, actin-1, and disorganized muscle protein 1 (dim-1) of Caenorhabditis elegans. In addition, proteomic analyses revealed that act-1 and act-2 were up-regulated in ILM compared to ILR, whereas dim-1 was down-regulated in ILM. Annotation using gene ontology revealed that act-1, act-2, and dim-1 were mainly associated with adenosine triphosphate (ATP) catabolic processes and ATP binding. Quantitative real-time polymerase chain reaction analyses of act-1 and dim-1 using the first internal transcribed spacers of A. cantonensis 18S ribosomal RNA (rRNA) was consistent with 2-dimensional gel electrophoresis (2-DE) and the sizes of these parasites; ILR was longer and wider than ILM. These results indicate that the differentially expressed proteins dim-1 and act-1 could be related to the development and pathogenicity of A. cantonensis in different hosts.

[Severe disease of immune imbalance in ICU: persistent inflammation immunosuppression catabolism syndrome].

OBJECTIVE: Terminology of persistent inflammation immunosuppression and catabolism syndrome (PICS) is developed based on the concept of multiple organ failure (MOF), which reflect that the preponderance is gradually reversed from pro-inflammation to anti-inflammation, and eventually the state of simultaneously persistent inflammation and severe immunosuppression appeared. Although the improvement of rescue technology and management increase the early survival rates of patient with critical illnesses, the long-term outcomes of most patients are not optimistic. The patients with PICS are difficult to treat or prevent, and are likely to indolent death and have a rising incidence, which is an important challenge to the intensive care unit (ICU). The paper review the understanding of PICS, summarize the specific changes of immune system in PICS, and explore the immunological markers for early recognition of PICS and judgment of immune state in order to provide new thinking for prevention and control of PICS.

[Predictive value of SOFA score combined AGI grading system in elderly patients with sepsis: a retrospective analysis with 91 patients].

OBJECTIVE: To explore the predictive value of sequential organ failure assessment (SOFA) score combined the acute gastrointestinal injury (AGI) grading system in critical elderly patients with sepsis. METHODS: A retrospective analysis was conducted. Elderly patients with sepsis aged > 60 years admitted to medical intensive care unit (MICU) of General Hospital of Guangzhou Military Command from March 2014 to December 2015 and experiencing critical care over 48 hours were enrolled. Age, gender, acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score and AGI score at admission (SOFAinitial, AGIinitial), the highest SOFA score and AGI score within the first week (SOFAmax, AGImax), serum procalcitonin (PCT), C-reactive protein (CRP), albumin (ALB), platelet (PLT), hemoglobin (Hb) and lactate (Lac) levels, length of ICU stay, usage of mechanical ventilation and renal replacement therapy were recorded. The primary end point was 28-day mortality. To extract factors affecting 28-day mortality, the risk factor of death of the senile sepsis patients were analyzed by binary logistic regression analysis (stepwise method). Fitness of the model was assessed by the Hosmer-Lemeshow test and calibration plot (P > 0.05). Receiver operating characteristic (ROC) analysis was performed for APACHE II score, SOFAinitial score, SOFAmax score, AGIinitial score, AGImax score and SOFAmax and combined AGImax score. RESULTS: Ninety-one patients were enrolled, the incidence of AGI in elderly patients with sepsis was 100%; 34 patients died 28 days after the admission, and the 28-day mortality rate was 37.4%. Non-survivors presented a higher APACHE II score, SOFAinitial score, SOFAmax score, AGIinitial score, AGImax score and longer usage of mechanical ventilation and renal replacement therapy. SOFAmax score [odds ratio (OR) = 1.576] and AGImax score (OR = 5.695) were associated with 28-day mortality in binary logistic regression analysis (both P < 0.01). The area under the curve (AUC) and 95% confidence interval (95%CI) of SOFAmax score combined AGImax score was significantly higher than that of SOFAinitial score, SOFAmax score, AGIinitial score, AGImax score and APACHE II score [0.806 (0.710-0.881) vs. 0.723 (0.619-0.812), 0.786 (0.688-0.865), 0.641 (0.533-0.739), 0.633 (0.526-0.881), 0.638 (0.531-0.736), all P < 0.05]. The Youden index (55.37) and positive predict value (5.51) of SOFAmax score combined AGImax score were the largest. When its cut-off value reached 14, the sensitivity and specificity was 67.65% and 87.72%, respectively. According to score of APACHE II, SOFAinitial, SOFAmax or AGImax, the higher of each score, the higher mortality rate could be. CONCLUSIONS: The combination of SOFAmax score and AGImaxscore enable accurate prediction in elderly patients with sepsis.

[Progress in circulating microRNAs as biomarkers of sepsis].

OBJECTIVE: Sepsis is as life-threatening organ failure caused by a dysregulated host response to infection, with urgent onset, complex mechanism and high mortality. Its early diagnosis and treatment is particularly important. However, the sensitivity and specificity of current laboratory markers for the diagnosis of sepsis is not ideal. MicroRNAs represent a novel group of small RNA molecules that do not encode for proteins. MicroRNAs are synthesized in the cytoplasm and transferred to circulation primarily by micro-vesicles, and they are stable in circulation and can be rapidly detected. The researches regarding circulating miRNA as biomarkers of sepsis were collected to analyze the characteristics of differential expression of miRNAs including miR-150, miR-133a, miR-122, miR-223, miR-4772, miR-297 and miR-574-5p etc. in the pathogenesis of sepsis, which suggest that they can be used as biomarkers for the diagnosis and prognosis of sepsis.

[Analysis of larval excretory-secretory antigen and its immunodiagnosis of Angiostrongyliasis cantonensis infection].

OBJECTIVE: To analyze the diagnostic value of larval excretory-secretory antigen in Angiostrongylus cantonensis (LESA) infection. METHODS: A.cantonensis larvae harvested from mice brain were cultured in vitro. The LESA and the adult worm antigens of A.cantonensis (AWA) were collected and analyzed using SDS-PAGE and Western blotting. Two ELISA systems were established using the two antigens (LESA-ELISA and AWA-ELISA) to detect the serum spectra from different sources. RESULTS: SDS-PAGE and Western blotting displayed fewer protein and antigen bands for LESA than for the adult antigen. Two distinct bands of LESA (with relative molecular masses of 40 000 and 26 000) showed reactivity with the sera from patients with A. cantonensis infection. The serum levels of IgG and IgM antibodies to LESA increased at the beginning of infection in mice, reaching the peak on day 5 after infection and decreased on day 10. Compared with AWA-ELISA, LESA-ELISA showed a lower seropositive ratio in suspected patients with A.cantonensis, with also a lower cross-positive ratio in patients with schistosomiasis and clonorchis sinensis. CONCLUSION: LESA possesses fewer antigen reaction bands than AWA. Although with a slightly lower positive ratio than AWA, LESA has a higher specificity for detecting serum antibodies in suspected cases of A.cantonensis infection, and therefore shows a potential for the diagnosis of angiostrongyliasis especially in the early stage and in current infection.