[Influence of genetic variation of programmed death-ligand 1 (PD-L1) on the prognosis of patients with non-small cell lung cancer who received platinum-based adjuvant chemotherapy].

Objective: The aim of present study was to investigate the influence of genetic variation of programmed death-ligand 1 (PD-L1) on the prognosis of patients with non-small cell lung cancer (NSCLC) who received platinum-based adjuvant chemotherapy. Methods: This study was designed as a retrospective analysis, and a total of 278 patients with postoperative NSCLC who received platinum-based adjuvant chemotherapy from January 2012 to December 2018 in the Department of Respiratory Medicine of the First affiliated Hospital of Zhengzhou University were included in this study. Biological specimens of the patients were collected during hospitalization. Recurrence status and adverse reactions were evaluated in the hospital during adjuvant chemotherapy. Survival data of the patients were obtained through telephone follow-up after completing the fixed cycle of adjuvant chemotherapy. DNA extracted from the collected hematological specimens was genotyped for PD-L1 gene polymorphism. Additionally, postoperative cancer tissue specimens from 68 patients were collected for RNA extraction in order to perform the PD-L1 mRNA expression analysis. The univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis. Results: Prognostic results indicated that the median disease-free survival (DFS) of the 278 patients with NSCLC was 3.2 years and the median overall survival (OS) was 4.9 years. The prevalence of -1813G>C polymorphism were: GG genotype 173 cases (62.23%), GC genotype 92 cases (33.09%), CC genotype 13 cases (4.68%), the minor allele frequency was 0.21, the distribution of the three genotypes was in accordance with Hardy-Weinberg Equilibrium (P=0.864). In view of the rare frequency of CC genotype, GC and CC genotype were merged in the following analysis. The survival analysis results of the two genotype groups suggested that the median DFS of patients with GG and GC/CC genotype was 2.7 and 4.0 years, which was statistically significant (P=0.013). Furthermore, the median OS of patients with GG and GC/CC was 4.0 and 5.4 years respectively, which was statistically significant as well (P=0.009). However, the safety analysis failed to find the significant association between the polymorphism and adverse events (P>0.05). Interestingly, expression analysis of RNA extracted from cancer tissues specimens indicated that the PD-L1 mRNA expression of the patients with GG genotype were significantly higher than those of the GC/CC genotype (3.67±0.65 vs 2.69±0.78, P<0.001). Conclusion: The prognosis of patients with postoperative non-small cell lung cancer who received platinum-based adjuvant chemotherapy is influenced by -1813G>C polymorphism of PD-L1 gene.

Risk factors and patterns of household clusters of respiratory viruses in rural Nepal.

Viral pneumonia is an important cause of death and morbidity among infants worldwide. Transmission of non-influenza respiratory viruses in households can inform preventative interventions and has not been well-characterised in South Asia. From April 2011 to April 2012, household members of pregnant women enrolled in a randomised trial of influenza vaccine in rural Nepal were surveyed weekly for respiratory illness until 180 days after birth. Nasal swabs were tested by polymerase chain reaction for respiratory viruses in symptomatic individuals. A transmission event was defined as a secondary case of the same virus within 14 days of initial infection within a household. From 555 households, 825 initial viral illness episodes occurred, resulting in 79 transmission events. The overall incidence of transmission was 1.14 events per 100 person-weeks. Risk of transmission incidence was associated with an index case age 1-4 years (incidence rate ratio (IRR) 2.35; 95% confidence interval (CI) 1.40-3.96), coinfection as initial infection (IRR 1.94; 95% CI 1.05-3.61) and no electricity in household (IRR 2.70; 95% CI 1.41-5.00). Preventive interventions targeting preschool-age children in households in resource-limited settings may decrease the risk of transmission to vulnerable household members, such as young infants.

The role of recombination in evolutionary adaptation of Escherichia coli to a novel nutrient.

The benefits and detriments of recombination for adaptive evolution have been studied both theoretically and experimentally, with conflicting predictions and observations. Most pertinent experiments examine recombination's effects in an unchanging environment and do not study its genomewide effects. Here, we evolved six replicate populations of either highly recombining R+ or lowly recombining R- E. coli strains in a changing environment, by introducing the novel nutrients L-arabinose or indole into the environment. The experiment's ancestral strains are not viable on these nutrients, but 130 generations of adaptive evolution were sufficient to render them viable. Recombination conferred a more pronounced advantage to populations adapting to indole. To study the genomic changes associated with this advantage, we sequenced the genomes of 384 clones isolated from selected replicates at the end of the experiment. These genomes harbour complex changes that range from point mutations to large-scale DNA amplifications. Among several candidate adaptive mutations, those in the tryptophanase regulator tnaC stand out, because the tna operon in which it resides has a known role in indole metabolism. One of the highly recombining populations also shows a significant excess of large-scale segmental DNA amplifications that include the tna operon. This lineage also shows a unique and potentially adaptive combination of point mutations and DNA amplifications that may have originated independently from one another, to be joined later by recombination. Our data illustrate that the advantages of recombination for adaptive evolution strongly depend on the environment and that they can be associated with complex genomic changes.

Myelotomy reduces spinal cord edema and inhibits aquaporin-4 and aquaporin-9 expression in rats with spinal cord injury.

OBJECTIVE: Spinal cord edema contributes to the pathophysiological mechanisms underlying spinal cord injury (SCI) and is associated with functional recovery after SCI. Early myelotomy may be a promising surgical intervention for reducing SCI-induced edema. However, it remains unclear whether myelotomy can reduce SCI-induced edema. In addition, aquaporin-4 (AQP4) and aquaporin-9 (AQP9) have important roles in the regulation of water homeostasis. Here, we aimed to determine the effects of myelotomy on AQP4 and AQP9 expression and spinal cord edema in a rat model of moderate SCI. METHODS: Rats were randomly assigned to three groups: the sham control group (n=22) receiving laminectomy alone; the contusion group (n=44) receiving laminectomy plus contusion; and the myelotomy group (n=44) receiving laminectomy plus contusion followed by myelotomy at 24 h. Functional recovery was estimated by the open-field and inclined plane tests. Spinal cord edema was determined by measuring the water content. The expression of AQP4 and AQP9 was determined by western blot. RESULTS: Compared with the contusion group, myelotomy significantly improved the Basso, Beattie and Bresnahan scores in the open-field test and resulted in a higher mean angle value in the incline plane test. Myelotomy significantly reduced SCI-induced edema at 4 and 6 days after SCI, which was accompanied by downregulation of AQP4 and AQP9 expression. CONCLUSION: Myelotomy improves locomotor function, reduces edema in rats with SCI and is associated with decreased expression of AQP4 and AQP9.

Optimal time window of myelotomy in rats with acute traumatic spinal cord injury: a preliminary study.

OBJECTIVES: Pathophysiological mechanisms underlying spinal cord injury (SCI) partially involve edema and formation of a hematoma. Myelotomy seems to be a promising intervention. However, the appropriate timing of myelotomy is still unknown in SCI. Here we aimed to determine the timing of microsurgical myelotomy in an animal model of SCI. METHODS: The SCI model was contusion-induced with a new york university impactor. Sixty-five adult female rats were randomly divided into the following groups: laminectomy alone (the 'sham group', SG), laminectomy plus contusion (the 'contusion group', CG) or laminectomy plus contusion followed by myelotomy at 8, 24 or 48 h (8 h-MTG [myelotomy-treated group], 24 h-MTG or 48 h-MTG). Functional recovery was evaluated via the open field test and the inclined plane test every week after SCI. The percentage of spared white matter area (SWMA) and ultrastructure characteristics of the injured dorsolateral spinal cord were determined on the 42nd day after SCI. RESULTS: Compared with the CG, myelotomy at 8 h-MTG or 24 h-MTG greatly improved the BASSO-BEATTIE- BRESNAHAN scores (P<0.008), whereas the 48 h-MTG showed less efficacy (P=0.023). All myelotomy groups showed higher mean angle values in an inclined plane test (P<0.005) and had greater percentages of SWMA than the CG. Rats in the 24 h-MTG showed a higher intra-axonal fraction and myelin fraction than those in 48 h-MTG (P<0.005). CONCLUSION: Myelotomy up to 48 h after SCI improves recovery in rats. The potential time window of myelotomy may be between 8 and 24 h after SCI.

Meta-analysis demonstrates lack of association of the hOGG1 Ser326Cys polymorphism with bladder cancer risk.

The functional polymorphism Ser326Cys (rs1052133) in the human 8-oxoguanine DNA glycosylase (hOGG1) gene has been implicated in bladder cancer risk. However, reports of this association between the Ser326Cys polymorphism and bladder cancer risk are conflicting. In order to help clarify this relationship, we made a meta-analysis of seven case-control studies, summing 2521 cases and 2408 controls. We used odds ratios (ORs) with 95% confidence intervals (95%CIs) to assess the strength of the association. Overall, no significant association between the hOGG1 Ser326Cys polymorphism and bladder cancer risk was found for Cys/Cys vs Ser/Ser (OR = 1.10, 95%CI = 0.74-1.65), Ser/Cys vs Ser/Ser (OR = 1.07, 95%CI = 0.81-1.42), Cys/Cys + Ser/Cys vs Ser/Ser (OR = 1.08, 95%CI = 0.87-1.33), and Cys/Cys vs Ser/Cys + Ser/Ser (OR = 1.04, 95%CI = 0.65-1.69). Even when stratified by ethnicity, no significant association was observed. We concluded that the hOGG1 Ser326Cys polymorphism does not contribute to susceptibility to bladder cancer.

Profound thrombocytopenia associated with piperacillin in a hemodialysis patient.

Piperacillin-induced thrombocytopenia, albeit reversible, is a life-threatening hematological emergency but easily overlooked. We describe a 78-year-old uremic man on regular hemodialysis who received intravenous administration of piperacillin (2 g) 3 times a day to treat nosocomial pneumonia. On the eighth day of therapy, isolated profound thrombocytopenia with a nadir value of 3 x 103/mm3 was noticed. Physical examination revealed multiple bruises over puncture sites and petechiae over bilateral lower extremities. An exhaustive search for potential causes of thrombocytopenia was unrevealing. Upon withdrawal of piperacillin and immediate high-flux hemodialysis, platelet count rapidly normalized up to 215 x 103/ mm3 in 3 days. With the widespread use of piperacillin, early recognition of piperacillin-induced immune thrombocytopenia and prompt withdrawal of the causative antibiotic may achieve less morbidity.

Effects of piroxicam-beta-cyclodextrin sachets on abnormal postural sway in patients with chronic low back pain.

BACKGROUND: The clinical effects of piroxicam-beta-cyclodextrin (PBC) in sachet form have been surveyed in patients with osteoarthritic or acute pain in western countries, but scarcely studied in those with chronic low back pain (LBP), and never investigated in the field of postural sway. The aim of this study was to evaluate the clinical effects of PBC in sachet form prescribed in patients with chronic backache in local Asian when compared with those of plain piroxicam. METHODS: After randomized allocation and experimental exclusion, a total of 42 eligible patients were randomized into two groups, the sachet group (n = 23) and the piroxicam tablet group (n = 19). Both groups were administered the same dosage, orally per day (daily dose = 20 mg). The duration of trial was 28 days. Efficacy was assessed with pain score, disability index and postural sway. RESULTS: The patients in sachet group showed greater improvement in pain score and disability index than those who took piroxicam tablets. There were significantly lower sway velocity and intensity at almost all different conditions than baseline profiles in both groups (P < 0.05). However, there was no significant difference of sway velocity and intensity in the piroxicam tablets group with regard to eyes open or eyes closed in 20 degrees dorsiflexion. CONCLUSIONS: Piroxicam-beta-cyclodextrin (PBC) sachet may have greater improvement in the treatment of chronic LBP and possess the extended effects on postural abnormality relevant to chronic LBP.

Low sensitivity of T-cell based detection of tuberculosis among HIV co-infected Tanzanian in-patients.

OBJECTIVE: To evaluate the performance of QuantiFERON-TB GOLD (QFTG) in a resource-poor setting among patients with and without HIV infection. DESIGN: Cross-sectional study. SETTING: Two hospitals in Northern Tanzania. SUBJECTS: Eighty three adult male and female inpatients. INTERVENTION: All patients were screened for HIV infection and underwent tuberculin skin test (TST) and QFTG. RESULTS: Eighty-three subjects were enrolled, and 29 (35%) of 83 were HIV-infected. QFTG yielded indeterminate results in 12 (22%; 95% CI 12%-34%) of 54 HIV-uninfected and 13 (45%; 95% CI 26%-64%) of 29 HIV-infected subjects (p = 0.0323). Among those with smear-positive pulmonary tuberculosis, TST was positive in 40 (100%; 95% CI 91%-100%) of 40 HIV-uninfected subjects compared with seven (54%; 95% CI 25%-81%) of 13 HIV-infected subjects (p < 0.0001), and QFTG was positive in 28 (70%; 95% CI 53%-83%) of 40 HIV-uninfected subjects compared with three (23%; 95% CI 5%-54%) of 13 HIV-infected subjects (p = 0.0029). Among medical inpatients at risk for latent tuberculosis infection, TST was positive in seven (50%) of 14 HIV-uninfected patients and three (19%) of 16 HIV-infected patients (p = 0.0701) and QFTG was positive among two (14%) of 14 HIV-uninfected patients and three (19%) of 16 HIV-infected patients (p = 0.7437). CONCLUSIONS: The presence of HIV co-infection was associated with a significant reduction in sensitivity of both the TST (p < 0.0001) and QFTG (p = 0.0029) for the diagnosis of active M. tuberculosis infection. The high proportion of indeterminate QFTG and lack of sensitivity, particularly among HIV-infected patients, may limit its applicability in settings like Tanzania. Larger studies in resource-poor settings are required.

[Effect of IL-11 on the invasive and metastatic abilities of anaplastic thyroid carcinoma cells].

Objective: To explore the effect of hematopoietic cytokines IL-11 on invasion and metastasis abilities of anaplastic thyroid cacinoma(ATC) cells. Methods: Real-time PCR was performed for examining the IL-11 mRNA expression in thyroid carcinoma cell lines, and IL-11 protein expression in the supernament of thyroid carcinoma cell lines was detected by ELISA. Molecular cloning was employed to construct IL-11 stable knockdown cell line; MTT assay was used to analyze the effect of IL-11 on the proliferation of ATC cells; Transwell and wound healing assays were employed to analyze the abilities of migration and invasion in ATC cells. Western blotting was used to detect the relative pathway proteins. SPSS statistical package 19.0 was used to analyze the date, and Student's t test was used for multiple comparisons. Results: The protein level of IL-11 were significantly lower in knock-down cell lines than that in negative control cell lines(21.55±1.69, 16.18±0.85, 26.37±2.00 vs 54.54±3.99, all P<0.05). Colony formation assays reveal that colony number between knock-down cells and negative control cells has no significance(P>0.05). Meanwhile, MTT assays show that there is no significance between knock-down cell lines and negative control cell line(P>0.05). However, Transwell invasion and migration assays show that number of migrated cells is increased when ATC cells were treated with rhIL-11(0-100 ng/ml)at increasing concentrations. Conclusion: IL-11 improves the migratory and invasive abilities of ATC cells via inducing EMT of ATC cells, and it can be used as a potential target for ATC molecular targeted therapy.

Curcuminoids purified from turmeric powder modulate the function of human multidrug resistance protein 1 (ABCC1).

Multidrug resistance is a major cause of chemotherapy failure in cancer patients. One of the resistance mechanisms is the overexpression of drug efflux pumps such as P-glycoprotein and multidrug resistance protein 1 (MRP1, (ABCC1)). In this study, curcumin mixture and three major curcuminoids purified from turmeric (curcumin I, II, and III) were tested for their ability to modulate the function of MRP1 using HEK293 cells stably transfected with MRP1-pcDNA3.1 and pcDNA3.1 vector alone. The IC(50) of curcuminoids in these cell lines ranged from 14.5-39.3 microM. Upon treating the cells with etoposide in the presence of 10 microM curcuminoids, the sensitivity of etoposide was increased by several folds only in MRP1 expressing and not in pcDNA3.1-HEK 293 cells. Western blot analysis showed that the total cellular level of MRP1 protein level was not affected by treatment with 10 microM curcuminoids for three days. The modulatory effect of curcuminoids on MRP1 function was confirmed by the inhibition of efflux of two fluorescent substrates, calcein-AM and fluo4-AM. Although all the three curcuminoids increased the accumulation of fluorescent substrates in a concentration-dependent manner, curcumin I was the most effective inhibitor. In addition, curcuminoids did not affect 8-azido[alpha-(32)P]ATP binding, however they did stimulate the basal ATPase activity and inhibited the quercetin-stimulated ATP hydrolysis of MRP1 indicating that these bioflavonoids interact most likely at the substrate-binding site(s). In summary, these results demonstrate that curcuminoids effectively inhibit MRP1-mediated transport and among curcuminoids, curcumin I, a major constituent of curcumin mixture, is the best modulator.

Effect of retinoic acid isomers on proliferation, differentiation and PML relocalization in the APL cell line NB4.

Retinoic acids exert a wide physiological role in development and differentiation. Retinoic acids have also been used in the treatment of human cancers, particularly in acute promyelocytic leukemia (APL). A structure-function relationship of the RA isomers in terms of clinical effect has been observed since all-trans retinoic acid (ATRA) induces a high complete remission rate while 13-cis retinoic acid (13-cis RA) shows much poorer effect. In this study, we examined the effect of RA isomers, including ATRA, 13-cis RA and 9-cis RA, on the proliferation and differentiation of NB4 cells. A number of parameters such as cell growth curve, dynamics of cell cycle, expression of clusters of differentiation and reduction of nitro blue tetrazolium (NBT) as well as immunofluorescence staining of PML were used to evaluate the effects of three isomers at two concentrations (10(-8) M and 10(-7) M). It has been shown that during the first 48 h of RA treatment, the APL cell differentiation was coupled with the cell proliferation. Although similar effects of proliferation inhibition and differentiation induction were observed among the three isomers at 10(-7) M, significant differences appeared at a concentration of 10(-8) M, 9-cis RA showed a higher activity than that of ATRA, while ATRA showed better results than 13-cis RA. Our results provide further evidence that 9-cis RA could be a promising molecule in differentiation induction of malignant cells.

Sociodemographic and clinical characteristics of clients presenting for HIV voluntary counselling and testing in Moshi, Tanzania.

HIV voluntary counselling and testing (VCT) reduces high-risk sexual behaviour. Factors associated with HIV infection in VCT clients have not been well characterized in northern Tanzania. We prospectively surveyed 813 VCT clients in Moshi, Tanzania. Clients were administered a questionnaire on sociodemographic characteristics, sexual behaviour, and health status. Blood was taken for rapid HIV antibody testing. Factors associated with HIV seropositivity were identified using multivariate logistic regression analysis. Of 813 clients, the seroprevalence was 16.7%. The strongest associations with seropositivity were reporting diarrhoea (odds ratio [OR] 10.4, 95% confidence interval [CI] 3.6-29.9), an ill sexual partner (OR 6.3, 95% CI 3.0-12.9), or being a woman (OR 3.5, 95% CI 2.0-6.3). In a separate regression, the number of symptoms also predicted HIV infection (OR 2.1, 95% CI 1.6-2.6). VCT clients who tested positive had more HIV-related symptoms suggesting presentation at a later stage of HIV infection.

Hibiscus protocatechuic acid protects against oxidative damage induced by tert-butylhydroperoxide in rat primary hepatocytes.

Hibiscus protocatechuic acid (PCA), a simple phenolic compound isolated from Hibiscus sabdariffa L., was studied for its protective effects against oxidative damage induced by tert-butylhydroperoxide (t-BHP) in a primary culture of rat hepatocytes. It had been reported that exposure of isolated hepatocytes to t-BHP results in leakage of lactate dehydrogenase (LDH) and alanine transaminase (ALT), peroxidation of cellular lipids, and depolarization of mitochondria. The present investigations showed that PCA at concentrations of 0.05 mg/ml and 0.10 mg/ml significantly decreased the leakage of LDH (P < 0.01) and ALT (P < 0.05 and P < 0.01) and the formation of malondialdehyde (MDA; P < 0.05 and P < 0.01) induced by 30-min treatment with t-BHP (1.5 mM) in primary cultured rat hepatocytes. PCA also attenuated t-BHP (0.10 mM) induced mitochondrial depolarization as determined by a retention test of rhodamine 123 and DNA repair synthesis as evidenced by unscheduled DNA synthesis (UDS). In addition, PCA exhibited an effective ability to quench 1,1-diphenyl-2-picrylhydrazyl radicals (DPPH). In conclusion, PCA demonstrated protective effects against cytotoxicity and genotoxicity of hepatocytes induced by t-BHP. One of mechanisms of PCA's protective effect may be associated with its property of scavenging free radicals.

Cytotoxicity of release products from magnetic nanocomposites in targeted drug delivery.

The efficacy of chemotherapy can be significantly improved if the therapeutic agent remains localized at the afflicted area and released at controlled rates. Such a targeted drug delivery can be achieved using magnetic nanocomposite (MNC), which incorporates drug and magnetic nanoparticles in biodegradable polymer microspheres. Reported here are results from an in vitro study on drug release rate and cytotoxicity of other release products from MNC. The model system contains an anti-cancer chemotherapy agent 5-flurouracil (5-FU) and (Co(0.5)Zn(0.5))Fe(2)O(4) in poly(lactic-co-glycolic acid) (PLGA) matrix produced by an oil/oil emulsion technique. Cell proliferation data indicate a sustained release of 5-FU for mouse macrophage cell eradication, whereas other microsphere components of magnetic nanoparticles and PLGA have little cytotoxic effects.

Morbidity and mortality among a cohort of HIV-infected adults in a programme for community home-based care, in the Kilimanjaro Region of Tanzania (2003-2005).

Community home-based care (CHBC) plays an integral role in the care of HIV-infected patients living in resource-limited regions. A longitudinal cohort study has recently been conducted, in the Kilimanjaro Region of northern Tanzania, in order to identify the components of an effective CHBC programme. Structured questionnaires were administered to clients over two census rounds, one in October 2003-February 2004 and the other in January 2005-October 2005. In the second round, follow-up interviews were completed for 226 (87.9%) of the 257 clients included in the first round. The clients included in the first round had a median (range) age of 38 (20-66) years and 182 (75.2%) of them were female. Although only 27 (12.9%) of them were using antiretroviral therapy (ART) when first interviewed, 108 (44.6%) were taking trimethoprim-sulfamethoxazole (SXT) prophylaxis. By the time of the follow-up interviews, 102 (45.1%) of the clients included in the first round had died, giving a mortality of 51/100 person-years of observation. The primary cause of death for 87 (85.3%) of the clients who had died was respiratory and/or gastro-intestinal infection, and the most common contributory causes of death were malnutrition (81.4%) and anaemia (42.2%). On bivariable analysis, the following first-round conditions were found to be significantly associated with death by the second census round: weakness for >1 month [odds ratio (OR)=2.64; P=0.008]; oral thrush (OR=2.31; P=0.015); painful swallowing (OR=2.02; P=0.036); staying in bed for part of the day over most of the previous month (OR=1.94; P=0.017); fever for >1 month (OR=1.95; P=0.016); and severe bacterial infections (OR=1.80; P=0.036). The high mortality was associated with advanced, symptomatic HIV disease for which antiretroviral therapy was indicated. Clients who were in the advanced stages of HIV disease (as defined by the World Health Organization's criteria) in the first census round were significantly more likely to have died by the time of the second round than the other clients investigated (log-rank chi(2)=8.115; P=0.044). The high level of morbidity observed in this study, and the causes of mortality that were identified, emphasise the need for CHBC programmes to provide HIV-infected patients with improved access to basic resources such as SXT and isoniazid prophylaxis, clean water, oral rehydration therapy, and micronutrient supplementation, in addition to increased access to ART.

Phytotoxicity of lanthanum in rice in haplic acrisols and cambisols.

Growth and physiological responses of rice to lanthanum were studied to elucidate the function of lanthanum in plants and its critical concentration relative to environmental safety. Shoot La content increased with the increasing added La concentrations. When shoot La content exceeded a toxic value, plant growth and chlorophyll a/b decreased and peroxidase (POD) activity, cell membrane permeability, and content of proline in the leaf increased. Leaf chlorophyll a/b and POD activity might provide useful criteria for early diagnoses of phytotoxicity of soil contaminated by La. In the present study, the critical concentration of La for rice relative to environmental safety was suggested to be 42.03 mg kg(-1) in red soil and 83.33 mg kg(-1) in paddy soil.