[Survival analysis of different kinds of tyrosine kinase inhibitors in the treatment of patients with epidermal growth factor receptor mutated non-small cell lung cancer and leptomeningeal metastasis].

Objective: To explore the prognosis of patients with leptomeningeal metastasis (LM) and epidermal growth factor receptor mutated (EGFRm) non-small cell lung cancer (NSCLC) treated with different kinds of tyrosine kinase inhibitors (TKIs). Methods: From January 2016 to June 2021, the clinicopathological data of 70 patients confirmed by histologically or cytologically EGFRm LM who received different types of TKIs in Cancer Hospital of Chinese Academy of Medical Sciences were retrospectively analyzed. According to treatment patterns, patients were divided into the first-and second-generation EGFR-TKIs treatment group and the third-generation EGFR-TKIs treatment group [Osimertinib 80 mg once a day], and the prognosis and prognostic factors (with Cox proportional hazards model) of patients in different treatment group were assessed. The next-generation sequencing (NGS) of paired samples of cerebrospinal fluid (CSF) and plasma from 64 patients at the time of LM diagnosis was performed simultaneously. Results: There were 20 males and 50 females in 70 EGFRm NSCLC patients with LM. The age ranged from 35 to 69 years, with a median age of 56 years. A total of 24 patients received the first-and second-generation EGFR-TKIs treatment, and 46 received the third-generation EGFR-TKIs treatment. Twenty-four patients developed disease progression on the first-and second EGFR-TKIs treatments, followed by treatment with the third-generation EGFR-TKIs (Osimertinib) in 12 cases, chemotherapy or anti-angiogenesis therapy in 4 cases, and the optimal supportive treatment in 8 cases. Among the 70 patients, 18 had partial response (PR), 48 had stable disease (SD), and 4 had progressive disease (PD). The objective response rate (ORR) and disease control rate (DCR) were 26% (18/70) and 94% (66/70), respectively. The median follow-up time was 16.5 months. The median progression-free survival (PFS) was 5.3 months(95%CI: 2.8-7.8)in the first-and second-generation EGFR-TKIs and 10.8 months (95%CI: 7.9-13.6) in the third-generation EGFR-TKIs, and the difference was statistically significant (P=0.019). The median overall survival (OS) was 14.9 months (95%CI: 9.7-20.0) and 15.7 months (95%CI: 13.3-18.1) in the two groups, respectively, but no statistical differences was observed (P=0.713). Univariate analysis showed that the PFS of patients with EGFRm LM were related to gender and different types of EGFR-TKIs (P˂0.05). Multivariate analysis demonstrated that male (HR=2.30, 95%CI: 1.31-4.03, P=0.004) and the first-and second-generation EGFR-TKIs (HR=2.03, 95%CI: 1.20-3.41, P=0.008) were independent risk factors for PFS in patients with EGFRm LM. The EGFR mutation was detected in 61 (95%) CSF and in 27 (42%) plasma samples. Conclusion: In EGFRm NSCLC patients with LM, the dose of Osimertinib 80 mg (once a day) has a significant PFS benefit compared with the first-and second-generation EGFR-TKIs.

[Study on the prognostic value of preoperative anti hepatitis B virus therapy in patients with hepatocellular carcinoma complicated with microvascular tumor thrombus and establishment of survival prediction model].

Objective: To explored the effect of preoperative antiviral therapy on the prognosis of microvascular tumor thrombi patients, and to established a prognostic prediction model for these patients after radical resection of liver cancer. Methods: The clinicopathological and survival data of hepatocellular carcinoma patients with microvascular tumor thrombus who underwent radical resection in the Third Affiliated Hospital of Sun Yat-sen University from January 1, 2013 to December 31, 2015 were retrospectively collected. Kaplan-Meier method was used to calculate the survival curve, and log-rank test was used to compare the prognosis of patients with and without antiviral treatment before operation. Univariate and multivariate Cox proportional hazard regression model was used to screen predictive factors. R software was used to make predictive nomogram, and discrimination and calibration degree were used to evaluate the prediction model. Results: Among all 153 patients, 22 were female and 131 were male, aged (51.3±11.7) years. The preoperative antiviral therapy significantly improved overall survival and recurrence-free survival (χ2=41.423, 54.389; both P<0.001). According to the results of multivariate and regression analysis, preoperative antiviral therapy (HR=0.301,95%CI:0.171-0.532,P<0.001), alpha fetoprotein (HR=1.226,95%CI:1.157-1.776,P=0.032) and tumor size (HR=1.008,95%CI:1.001-1.016,P=0.02) were important prognostic factors for overall survival. The area under curve value of 3-year survival prediction model was 0.749(95%CI: 0.712-0.782), and that of 5-year survival prediction model was 0.755(95%CI: 0.724-0.793), with good calibration. Conclusions: Preoperative anti hepatitis B virus(HBV) therapy can significantly improve the prognosis of patients with hepatocellular carcinoma complicated with microvascular tumor thrombus, we develope the prediction models of 3-year and 5-year survival rate that can improve the reference for clinical work and benefit patients.

[Establishment of a predictive model for acute respiratory distress syndrome and analysis of its predictive value in critical burn patients].

Objective: To establish a predictive model for acute respiratory distress syndrome (ARDS) in critical burn patients with the screened independent risk factors, and to validate its predictive value. Methods: Totally 131 critical burn patients (101 males and 30 females, aged 18-84 years) who met the inclusion criteria were admitted to the Department of Burns of the Second Affiliated Hospital of Zhejiang University School of Medicine from January 2018 to December 2019. A retrospective case-control study was conducted. The patients were divided into ARDS group (54 cases) and non-ARDS group (77 cases) according to whether ARDS occurred or not. The statistics of patients in the two groups were recorded including the gender, age, burn index, combination of inhalation injury, smoking history, delayed resuscitation, indwelling nasogastric tube, and complication of sepsis, and the data were statistically analyzed with independent sample t test, chi-square test, and Fisher's exact probability test. The multivariate logistic regression analysis was performed on the indicators with statistically significant differences between the two groups to screen the independent risk factors for developing ARDS in critical burn patients, and the corresponding nomograph prediction model for the risk of ARDS in critical burn patients was established. The risk scores for patients developing ARDS were therefore obtained based on the above-mentioned nomograph, and the corresponding receiver operating characteristic (ROC) curve was drawn to calculate the area under the curve. The internal validation of the above-mentioned ARDS prediction model was performed using the Bootstrap method, and the area under the ROC curve was calculated for modeling group (79 cases) and validation group (52 cases), respectively. A calibration curve was drawn to assess the predictive conformity of the above-mentioned ARDS prediction model for the occurrence of ARDS in critical burn patients. Results: The burn index, proportion of combination of inhalation injury, and proportion of complication of sepsis of patients were significantly higher in ARDS group than in non-ARDS group (t=0.36, χ2=33.78, 49.92, P<0.01). The gender, age, smoking history, delayed resuscitation, and indwelling nasogastric tube of patients in ARDS group were close to those in non-ARDS group (P>0.05). The multivariate logistic regression analysis showed that the burn index, combination of inhalation injury, and complication of sepsis were the independent risk factors for developing ARDS in critical burn patients (odds ratio=1.05, 15.33, 5.02, 95% confidence interval=1.01-1.10, 2.65-88.42, 1.28-19.71, P<0.05 or P<0.01). The overall area under the ROC curve of the above-mentioned ARDS prediction model was 0.92 (95% confidence interval=0.88-0.97), and the area under the ROC curve was 0.95 and 0.91 (95% confidence interval=0.90-1.00, 0.86-0.97) for validation group and modeling group, respectively. When applying the above-mentioned ARDS prediction model for ARDS incidence prediction, there might be some risk of overestimating ARDS incidence when the prediction probability was <35.0% or >85.0%, and some risk of underestimating ARDS incidence when the prediction probability was 35.0%-85.0%. Conclusions: The burn index, inhalation injury, and sepsis are the independent risk factors for the occurrence of ARDS in critical burn patients. The risk prediction model for ARDS based on these three indicators has good predictive ability for ARDS in critical burn patients.

[Cyto-inactivation instantly induced by microwave ablation on thyroid nodules].

Objective: To explore the effect of microwave ablation on thyroid nodules cell activity by the reaction of key enzyme of cell activation. Methods: From November 2017 to February 2018, 104 patients with 120 thyroid nodules underwent ultrasound-guided microwave ablation at Super-minimally Invasive Medicals, Shanghai International Medical Center, aged 14-55 years, 42 males and 62 females.Twice core needle biopsy were performed before and after thermal ablation.The specimen were using hematoxylin and eosin (HE) staining and enzyme histochemical staining with include succinate dehydrogenase (SDH) and nicotinamide adeninedinucleotide phosphate diaphorase (NADPH-d), respectively, and observe under microscope. Results: Enzyme histochemical staining showed that the positive rate of SDH and NADPH-d in the marginal region and transitional region were 100% before ablation, and were 0% immediately after ablation.The positive rate of SDH and NADPH-d histochemical staining in the same area before and immediately after ablation was statistically significant (P<0.05). Shortly after microwave ablation, the tissue structure and cell morphology showed no obvious alteration in HE stained sections, but in sections with enzyme histochemical staining, the activity of SDH and NADPH-d in ablated tissue disappeared.The accuracy rate of pathologic diagnosis was 100% after ablation. Conclusions: SDH and NADPH-d enzyme activity may be better in evaluating the short-term efficacy of microwave ablation of thyroid nodules than HE staining.

Placenta percreta with colon involvement in a twin pregnancy: case report and literature review.

A case of a woman with twin pregnancy having placenta percreta involving the colon, showed hematochezia symptoms, experienced bleeding which caused the patient's mortality. Placenta percreta with bowel involvement is a very serious complication of pregnancy. Symptoms are very atypical and it is very difficult to diagnose.

[Effect of cetylpyridinium chloride Buccal Tablets on perioperative application of OSAHS patients].

Objective:To investigate the effect of Cetylpyridinium Chloride Buccal Tablets on perioperative application of OSAHS patients.Method:Sixty patients of OSAHS were randomly divided into treatment group and control group according to the ratio of 1:1, using randomized single-blind controlled trial. The treatment group was treated with Cetylpyridinium Chloride Buccal Tablets in perioperative period and the control group was not. All patients accepted UPPP. Pharyngeal pain, pharyngeal edema, levels of IL-1, IL-8 and TNF-α in saliva were analyzed on the first day, third day and fifth day after surgery.Result:Compared with control group, the pharyngeal pain of treatment group was slighter on the third day and fifth day (P< 0.05). The levels of IL-1ß, IL-8 and TNF-α in saliva were lower on the third day and fifth day (P< 0.05).Conclusion:Applying Cetylpyridinium Chloride Buccal Tablets during perioperative period can effectively relieve postoperative pharyngeal pain and inflammatory response in patients with OSAHS.

Laparoscopic subtotal hysterectomy due to giant uterine fibroids: a case report.

The laparoscopic subtotal hysterectomy (LSH) was given to a patient whose uterus was about seven-month pregnanacy because of fibroids. The biggest problem was the operation space and visual field was too narrow. Different from the usual procedure we do, we morcellated the uterus at the beginning to expand the space. Loop ligature of the uterine isthmus was adopted to block uterine ateries before morcellating the uterus. After the adnexa exposed totally, we started to cut off the round ligaments, proper ligaments and fallopian tubes like usual. It was the first time we did LSH for so giant uterus in our hospital, although which was usually suitable for the uterus smaller than four-month pregnancy. But if the uterine ateries can be blocked effectively at the beginning, the uterus can be morcellated and the space will be enlarged. The laparoscopic subtotal hysterectomy will also be completed successfully.

Invasive pulmonary fungal infections in patients with connective tissue disease: a retrospective study from northern China

Invasive pulmonary fungal infection (IPFI) is a potentially fatal complication in patients with connective tissue disease (CTD). The current study aimed to uncover the clinical characteristics and risk factors of patients with IPFI-CTD. The files of 2186 CTD patients admitted to a single center in northern China between January 2011 and December 2013 were retrospectively reviewed. A total of 47 CTD patients with IPFI were enrolled into this study and assigned to the CTD-IPFI group, while 47 uninfected CTD patients were assigned to the control group. Clinical manifestations were recorded, and risk factors of IPFI were calculated by stepwise logistical regression analysis. Forty-seven (2.15%) CTD patients developed IPFI. Systemic lupus erythematosus patients were responsible for the highest proportion (36.17%) of cases with IPFI. Candida albicans (72.3%) accounted for the most common fungal species. CTD-IPFI patients had significantly elevated white blood cell count, erythrocyte sedimentation rate, C-reactive protein and fasting glucose values compared to controls (P<0.05). Cough, sputum and blood in phlegm were the most common symptoms. Risk factors of IPFI in CTD included maximum prednisone dose ≥30 mg/day within 3 months prior to infection, anti-microbial drug therapy, and interstitial pneumonia. CTD patients who have underlying interstitial pneumonia, prior prednisone or multiple antibiotics, were more likely to develop IPFI.

LHX6 acts as a novel potential tumour suppressor with epigenetic inactivation in lung cancer.

LIM homeobox domain 6 (LHX6) is a putative transcriptional regulator that controls the differentiation and development of neural and lymphoid cells. However, the function of LHX6 in cancer development remains largely unclear. Recently, we found that LHX6 is hypermethylated in lung cancer. In this study, we analysed its epigenetic regulation, biological functions, and related molecular mechanisms in lung cancer. Methylation status was evaluated by methylation-specific PCR and bisulfite genomic sequencing. LHX6 mRNA levels were measured in relation to the methylation status. The effects of LHX6 expression on tumourigenesis were studied in vitro and in vivo. LHX6 was readily expressed in normal lung tissues without methylation, but was downregulated or silenced in lung cancer cell lines and tissues with hypermethylation status. Treatment of lung cancer cells with the demethylating agent 5-aza-2'-deoxycytidine restored LHX6 expression. Moreover, LHX6 hypermethylation was detected in 56% (52/93) of primary lung cancers compared with none (0/20) of the tested normal lung tissues. In lung cancer cell lines 95D and H358, forced expression of LHX6 suppressed cell viability, colony formation, and migration, induced apoptosis and G1/S arrest, and inhibited their tumorigenicity in nude mice. On the other hand, knockdown of LHX6 expression by RNA interference increased cell proliferation and inhibited apoptosis and cell cycle arrest. These effects were associated with upregulation of p21 and p53, and downregulation of Bcl-2, cyclinD1, c-myc, CD44, and MMP7. In conclusion, our results suggest that LHX6 is a putative tumour suppressor gene with epigenetic silencing in lung cancer.

IL-10 treatment is associated with prohibitin expression in the Crohn's disease intestinal fibrosis mouse model.

Prohibitin, which can inhibit oxidative stress and mitochondrial dysfunction, has been shown to have significant anti-inflammatory activities. Here, we investigate the effects of altering prohibitin levels in affected tissues in the interleukin-10 knockout (IL-10KO) mouse model with intestinal fibrosis. The aim of this study is to investigate the effects of IL-10 on prohibitin and the role of prohibitin in intestinal fibrosis of murine colitis. After the mice were treated with IL-10, prohibitin expression and localization were evaluated in IL-10KO and wild-type (WT, 129/SvEv) mice. The colon tissue was then investigated and the potential pathogenic molecular mechanisms were further studied. Fluorescence-based quantitative polymerase chain reaction (FQ-PCR) and immunohistochemistry assays revealed a significant upregulation of prohibitin with IL-10 treatment. Furthermore, IL-10 decreases inflammatory cytokines and TGF-ß1 in the IL-10KO model of Crohn's disease and demonstrates a promising trend in decreasing tissue fibrosis. In conclusion, we hypothesize that IL-10 treatment is associated with increased prohibitin and would decrease inflammation and fibrosis in an animal model of Crohn's disease. Interestingly, prohibitin may be a potential target for intestinal fibrosis associated with inflammatory bowel disease (IBD).

Adjuvant chemotherapy in oesophageal cancer: a meta-analysis and experience from the Shanghai Cancer Hospital.

Whether adjuvant chemotherapy increases survival of oesophageal cancer patients has been widely debated. The present study used meta-analysis software to combine data from six studies up to July 2007 that were found and selected as suitable, comprising a total of 1001 oesophageal cancer patients. The results indicated that adjuvant chemotherapy did not significantly improve outcome in oesophageal cancer patients. A trend towards improved outcome from adjuvant chemotherapy was found in lymph node-positive patients, but did not reach significance. In our own study including 270 oesophageal cancer patients, adjuvant chemotherapy did not improve overall patient survival, but did improve survival for patients with metastases in cervical and/or celiac lymph nodes (stage IVa). Although our study had the largest patient sample, more prospective clinical trials with large numbers of patients are necessary to confirm the value of adjuvant chemotherapy in stage IVa patients.

A new method to induce multi-drug resistance to carboplatin in a mouse model of human tongue squamous cell carcinoma.

Multi-drug resistance (MDR) in human head and neck squamous cell carcinoma (HNSCC) constitutes a major obstacle to the effectiveness of chemotherapy. In previous studies, MDR was mainly induced in vitro. The authors report a novel in vivo method of inducing MDR in nude mice with xenotransplanted Tca8113 cells. Carboplatin, a chemotherapeutic agent used to treat HNSCC, was injected around the tumors for 10 weeks. A subsequent cell survival assay of dissociated tumor cells suggested that MDR had been induced successfully. Immunocytochemistry, reverse transcription polymerase chain reaction and Western blot analysis showed that the expression levels of MDR-related proteins, including topoisomerase II, MRP and glutathione transferase, were elevated in the induction group. The authors conclude that in vivo induction of MDR provides a useful method for establishing animal models of MDR.

Mechanical strain induces osteogenic differentiation: Cbfa1 and Ets-1 expression in stretched rat mesenchymal stem cells.

Distraction osteogenesis is an active process of bone regeneration under controlled mechanical stimulation. Osteogenic differentiation of mesenchymal stem cells (MSCs) is essential for bone formation during this process. Cbfa1 and Ets-1 (core binding factor alpha 1 and v-ets erythroblastosis virus E26 oncogene homolog 1) are transcription factors that play important roles in the differentiation of MSCs to osteoblasts. In order to mimic a single activation of a clinical distraction device, a short period of cyclic mechanical strain (40 min and 2,000 microstrains) was applied to rat MSCs. Cellular proliferation and alkaline phosphatase (ALP) activity were examined. The mRNA expression of Cbfa1 and Ets-1, as well as ALP, a specific osteoblast marker, was detected using real-time quantitative reverse transcription polymerase chain reaction. The results showed that mechanical strain can promote MSC proliferation, increase ALP activity and up-regulate the expression of Cbfa1 and Ets-1. A significant increase in Ets-1 expression was detected immediately after mechanical stimulation, but Cbfa1 expression was elevated later. The temporal expression pattern of ALP coincided perfectly with that of Cbfa1. Mechanical strain may act as a stimulator to induce differentiation of mesenchymal stem cells into osteoblasts, which is vital for bone formation in distraction osteogenesis.

GTP-binding protein-independent potentiation by mastoparan of IL-1beta-induced nitric oxide release from insulin-secreting HIT-T15 cells.

Our recent data implicated small molecular weight G-proteins (e.g., H-Ras) in interleukin 1beta (IL 1beta)-induced metabolic dysfunction and apoptotic demise of the islet beta cell (Tannous et al., Biochem Pharmacol 2001; 62:1459-1468, Kowluru and Morgan, Biochem Pharmacol, 2002; 63:1027-1035, Chen et al. Biochem Pharmacol, 2003; 66:1681-1694). Recently, we have shown that mastoparan, a tetradecapeptide from wasp venom, has been shown to directly activate islet endogenous G-proteins and regulate islet function (Amin et al., Endocrinology 2003; 144: 4508-4518). Herein, we investigated potential contributory roles, if any, of mastoparan (Mas)-sensitive G-proteins in IL-induced nitric oxide (NO) release from insulin-secreting HIT-T15 cells. While, ineffective by itself, Mas significantly potentiated IL-induced NO release from HIT-T15 cells. Interestingly, Mas-17, an inactive analog of Mas, also potentiated IL-induced NO release, suggesting that the potentiating effect of Mas may not involve activation of specific G-proteins. Such potentiating effects on IL-induced NO release were also demonstrable in the presence of another polycationic compound, melittin. Together, these findings suggest that Mas-induced potentiation of IL-induced NO release may in part be due to its amphiphilic and polycationic nature. These data also warrant caution in the use of Mas to study its regulation of cellular function without the use of an appropriate negative control, such as Mas-17.

Hrs interacts with sorting nexin 1 and regulates degradation of epidermal growth factor receptor.

Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is a mammalian homologue of yeast vacuolar protein sorting (Vps) protein Vps27p; however, the role of Hrs in lysosomal trafficking is unclear. Here, we report that Hrs interacts with sorting nexin 1 (SNX1), a recently identified mammalian homologue of yeast Vps5p that recognizes the lysosomal targeting code of epidermal growth factor receptor (EGFR) and participates in lysosomal trafficking of the receptor. Biochemical analyses demonstrate that Hrs and SNX1 are ubiquitous proteins that exist in both cytosolic and membrane-associated pools, and that the association of Hrs and SNX occurs on cellular membranes but not in the cytosol. Furthermore, endogenous SNX1 and Hrs form a approximately 550-kDa complex that excludes EGFR. Immunofluorescence and subcellular fractionation studies show that Hrs and SNX1 colocalize on early endosomes. By using deletion analysis, we have mapped the binding domains of Hrs and SNX1 that mediate their association. Overexpression of Hrs or its SNX1-binding domain inhibits ligand-induced degradation of EGFR, but does not affect either constitutive or ligand-induced receptor-mediated endocytosis. These results suggest that Hrs may regulate lysosomal trafficking through its interaction with SNX1.

Adsorptive and electrochemical behaviors of estradiol valerate at a mercury electrode.

It was found that estradiol valerate could be adsorbed at a mercury electrode under open circuit. The adsorptive and electrochemical behaviors of estradiol valerate on a static mercury electrode were investigated by cyclic voltammetry, linear scan voltammetry and chronocoulometry. Based on this, a sensitive and selective adsorptive stripping square-wave voltammetric method was developed for the determination of estradiol valerate based on the optimization of solution conditions and electrochemical parameters. It was found that in a Britton-Robinson buffer solution containing 18% alcohol (pH 9.5), estradiol valerate gave a sensitive reductive peak at potential -1.29 V (vs. SCE) and the peak current was linear with the concentration of estradiol valerate in the range 2.0 x 10(-8)-2.5 x 10(-6) mol L-1. The detection limit was 1.1 x 10(-8) mol L-1. The interference of some common steroid estrogens was examined and it was found that they did not interfere in the determination of estradiol valerate in the present system.

Characterization and cytokine stimulating activities of heteroglycans from Tremella fuciformis.

Three heteroglycans, T1a, T1b, and T1c, have been isolated from the body of Tremella fuciformis Berk. They are composed of mannose (Man), xylose (Xyl), glucose (Glc), fucose (Fuc), and glucuronic acid (GlcA). According to methylation analysis and partial acidic hydrolysis the main chains of T1a, T1b, and T1c consisted of (1-->3)-linked Man, which was branched at the 2, 4, or 6 positions. The branching points were linked with nonreducing terminal GIcA-residues or (1-->6)-linked glucan-chains. Molecular weights of the three heteroglycans are 53,000, 18,000, and 12,000 D respectively, but they undergo self-aggregation in water. T1a-T1c induce human monocytes to produce interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) in vitro. Acidic hydrolysate fractions of T1a (T1a-1, 2, 3, 4, 5) with molecular weight from 53,000 to 1,000 D, also induce human monocytes to produce IL-6 as efficient as T1a.