To date, the association between phospholipase C epsilon 1 (PLCE1) rs2274223 A>G and risk of digestive tract cancer (DTC) remains inconclusive. To derive a more precise estimation of the association, we conducted a meta-analysis on all eligible case–control studies involving 8281 cases and 10,532 controls.
A comprehensive search was conducted to identify all eligible studies of PLCE1 rs2274223 polymorphism and digestive tract cancer risk. The pooled odds ratio (OR) and the 95% confidence interval (95% CI) were calculated using a fixed or random effect model. Heterogeneity, publication bias, and sensitivity analysis were also explored.
Overall, the PLCE1 rs2274223 A>G polymorphism was associated with risk of DTC in all genetic models (GA vs. AA: OR = 1.21, 95% CI = 1.14–1.29, P<0.001; GG vs. AA: OR = 1.30, 95% CI = 1.06–1.60, P = 0.012; GG/GA vs. AA: OR = 1.20, 95% CI = 1.10–1.32, P<0.001; GG vs. GA/AA: OR = 1.21, 95% CI = 1.01–1.46, P = 0.040). The recessive model did not reach statistically significance when the P values were Bonferroni corrected to 0.0125. In the stratified analysis by cancer type, ethnicity, and source of controls, significantly increased risk was observed for esophagus cancer, Asians in three genetic models (heterozygote comparison, homozygote comparison and dominant model), population-based studies in all genetic models, and for gastric cancer in the heterozygote comparison and dominant model after Bonferroni correction. However, in the subsite of gastric cancer, no significant association was found either in cardia or non-cardia gastric cancer.
Our study indicated that PLCE1 rs2274223 A>G polymorphism was significantly associated with increased risk of DTC, especially among Asian populations. Due to some minor limitations, our findings should be confirmed in further studies.
High sensitivity photodetectors in ultraviolet (UV) and infrared (IR) range have broad civilian and military applications. Here we report on an un-cooled solution-processed UV-IR photon counter based on modified organic field-effect transistors. This type of UV detectors have light absorbing zinc oxide nanoparticles (NPs) sandwiched between two gate dielectric layers as a floating gate. The photon-generated charges on the floating gate cause high resistance regions in the transistor channel and tune the source-drain output current. This “super-float-gating” mechanism enables very high sensitivity photodetectors with a minimum detectable ultraviolet light intensity of 2.6 photons/μm2s at room temperature as well as photon counting capability. Based on same mechansim, infrared photodetectors with lead sulfide NPs as light absorbing materials have also been demonstrated.
Budd-Chiari syndrome (BCS) is defined as hepatic venous outflow obstruction at any level from the small hepatic veins to the junction of the inferior vena cava (IVC) and the right atrium, regardless of the cause of obstruction. We present two cases of acute iatrogenic BCS and our clinical management of these cases. The first case was a 43-year-old woman who developed acute BCS following the implantation of an IVC stent for the correction of stenosis in the IVC after hepatectomy for hepatolithiasis. The second case was a 61-year-old woman with complete obstruction of the outflow of hepatic veins during bilateral hepatectomy for hepatolithiasis. Acute iatrogenic BCS should be considered a rare complication following hepatectomy for hepatolithiasis. Awareness of potential hepatic outflow obstructions and timely management are critical to avoid poor outcomes when performing hepatectomy for hepatolithiasis.
Acute iatrogenic Budd-Chiari syndrome; Hepatolithiasis; Hepatectomy; Inferior vena cava
Neuroendocrine tumors (NETs) are tumors originated from neuroendocrine cells in the body. The localization and the detection of the extent of NETs are important for diagnosis and treatment, which should be individualized according to the tumor type, burden, and symptoms. Molecular imaging of NETs with high sensitivity and specificity is achieved by nuclear medicine method using single photon-emitting and positron-emitting radiopharmaceuticals. Somatostatin receptor imaging (SRI) using SPECT or PET as a whole-body imaging technique has become a crucial part of the management of NETs. The radiotherapy with somatostatin analogues labeled with therapeutic beta emitters, such as lutetium-177 or yttrium-90, has been proved to be an option of therapy for patients with unresectable and metastasized NETs. Molecular imaging can deliver an important message to improve the outcome for patients with NETs by earlier diagnosis, better choice of the therapeutic method, and evaluation of the therapeutic response.
This study aimed to evaluate the preliminary clinical and radiographic outcomes of acute displaced femoral neck fracture treated by closed reduction and internal fixation (CRIF) with free iliac bone block grafting with comparison to a routine protocol of CRIF without bone grafting.
From December 2008 to February 2010, 220 adult patients with acute displaced femoral neck fractures were enrolled in this study. In study group, there were 124 patients (57 males, 67 females) with a mean age of 44.8 years (range, 20-64 years). There were 70 transcervical fractures and 54 subcapital fractures. The patients were treated by CRIF and free iliac bone block grafting. The control group consisted of 96 adult patients (46 males, 50 females) with a mean age of 46.3 years (range, 23-64 years). There were 61 transcervical fractures and 35 subcapital fractures. The patients in control group were treated by CRIF without bone grafting.
In study group, 112 patients were followed up for an average of 27.4 months (range, 24-34 months). All fractures healed within 5 months. However, 10 patients presented AVN of the femoral heads. The mean Harris score was 88.6 (range, 41-100). In control group, 68 patients were followed up for an average of 31.2 months (range, 24-42 months). The rates of AVN of the femoral head and fracture nonunion in control group were 26.5% (18/68) and 16.2% (11/68), respectively, significantly higher than those in study group (both P<0.05). The mean Harris score in control group was 83.8 (41–100), significantly lower than that in study group (P<0.05).
Acute displaced femoral neck fractures can be treated by CRIF and free iliac bone block grafting in a minimally invasive manner. This technique can guarantee uneventful fracture healing and significantly reduce the rate of femoral head osteonecrosis.
Fluorescence polarization (FP) has become a powerful technique to quantitatively analyze the binding of a small soluble fluorescence-labeled probe to a larger soluble protein and its displacement by other molecules. Here, we describe a detailed protocol to identify small molecules capable of targeting p53-MDM2/ MDMX interactions using a fluorescence polarization assay with Rhodamine-labeled p53 peptides.
Fluorescence polarization; p53; MDM2; MDMX; Small molecules
Nephrolithiasis is a common disorder worldwide. E-cadherin (CDH1) is involved in epithelial cell-cell interactions and plays important roles in the etiology of nephrolithiasis. We hypothesized that variants in the CDH1 gene are associated with risk of nephrolithiasis. In a hospital-based case-control study of 127 nephrolithiasis patients and 152 controls frequency matched by age and sex, we genotyped the functional -160C>A (rs16260) polymorphism and assessed its associations with risk of nephrolithiasis in a Chinese population. We found that the CA/AA genotypes were associated with a significantly decreased risk of nephrolithiasis (OR = 0.53, 95%CI = 0.32-0.87), compared with the CC genotype, particularly among subgroups of BMI > 24 kg/m2 (OR = 0.38, 95%CI = 0.17-0.85), age ≤ 57 years (OR = 0.47, 95%CI = 0.24-0.93), and men (OR = 0.56, 95%CI = 0.29-0.99). Our results suggest that the CDH1 polymorphism is involved in the etiology of nephrolithiasis and thus may be a marker for genetic susceptibility to nephrolithiasis.
AIM: To identify the role of human development in the incidence and mortality rates of gastrointestinal cancers worldwide.
METHODS: The age-standardized incidence and mortality rates for gastrointestinal cancers, including cancers of the esophagus, stomach, pancreas, liver, gallbladder, and colorectum, were obtained from the GLOBOCAN 2008 database and United States Cancer Statistics (USCS) report. The human development index (HDI) data were calculated according to the 2011 Human Development Report. We estimated the mortality-to-incidence ratios (MIRs) at the regional and national levels, and explored the association of the MIR with development levels as measured by the HDI using a modified “drug dose to inhibition response” model. Furthermore, countries were divided into four groups according to the HDI distribution, and the MIRs of the four HDI groups were compared by one-way ANOVA followed by the Tukey-Kramer post-hoc test. State-specific MIRs in the United States were predicted from the estimated HDI using the fitted non-linear model, and were compared with the actual MIRs calculated from data in the USCS report.
RESULTS: The worldwide incidence and mortality rates of gastrointestinal cancers were as high as 39.4 and 54.9 cases per 100000 individuals, respectively. Linear and non-linear regression analyses revealed an inverse correlation between the MIR of gastrointestinal cancers and the HDI at the regional and national levels (β < 0; P = 0.0028 for regional level and < 0.0001 for national level, ANOVA). The MIR differed significantly among the four HDI areas (very high HDI, 0.620 ± 0.033; high HDI, 0.807 ± 0.018; medium HDI, 0.857 ± 0.021; low HDI, 0.953 ± 0.011; P < 0.001, one-way ANOVA). Prediction of the MIRs for individual United States states using best-fitted non-linear models showed little deviation from the actual MIRs in the United States. Except for 28 data points (9.93% of 282), the actual MIRs of all gastrointestinal cancers were mostly located in the prediction intervals via the best-fit non-linear regression models.
CONCLUSION: The inverse correlation between HDI and MIR demonstrates that more developed areas have a relatively efficacious healthcare system, resulting in low MIRs, and HDI can be used to estimate the MIR.
Gastrointestinal neoplasms; Mortality-to-incidence ratio; Human development index; Healthcare disparities; Socioeconomic factors
CD4+ T helper (Th)1 and Th17 cells both can cause autoimmune diseases either alone or collaboratively, if left unchecked. However, what determines the dominant Th effector phenotype in a specific autoimmune disease remains ill understood. Our present investigation shows that null mutation of immediate early response gene X-1 (IEX-1) promotes differentiation of Th17 cells, but compromising the survival of Th1 cells. The differential effect gave rise to a greater number of Th17 cells, a higher level of IL-17 production, and severer arthritis in IEX-1 knockout (KO) mice than in wild type (WT) mice after immunizations with collagen. IEX-1 deficiency-facilitated Th17 cell differentiation was mediated by increased formation of reactive oxygen species (ROS) at mitochondria following T cell activation, as suggested by marked inhibition of Th17 induction with ROS scavenger N-acetylcysteine (NAC) or mitoquinone (MitoQ), a specific inhibitor for mitochondrial ROS production. Mitochondrial ROS augmented the expression of B-cell activating transcription factor (Batf) that may contribute to increased IL-17 production in the absence of IEX-1 in light of its importance in IL-17 transcription. The results demonstrate that mitochondrial ROS contribute significantly to the dominant Th effector phenotype in autoimmunity in addition to the milieu of cytokines.
Th1/17 cell balance; mitochondria; ROS; IEX-1; arthritis
To explore the distribution of etiologies and risk factors of upper gastrointestinal hemorrhage (UGH) in the context of new pharmacologic therapies that may alter risk of UGH.
Retrospective study was performed on eligible UGH inpatients at two academic medical centers, between July 1, 2001-June 30, 2003. Administrative data and chart review were used to identify demographics, UGH risk factors and etiologies. Bivariate and multivariate analyses were performed to describe distributions and associations of risk factors and etiologies.
UGH was identified in 227 subjects, with erosive disease (n=99, 44%), peptic ulcer disease (n=75, 33%) and variceal bleeds (n=39, 17%) accounting for the majority of bleeds. Known risk factors for UGH occurred in 70% (n=156) of subjects (prior UGH 43% (n=90), NSAID use 23% (n=52), ASA use 25% (n=57), NSAID + ASA use 6.6%(n=15)), while 19%(n=42) were using a proton-pump inhibitor and 5% (n=11) a cyclooxygenase-2 inhibitor. Subjects at site 1 were more likely to have erosive disease (OR 7.1, P<0.001) and less likely to have variceal bleeding (OR 0.12, P=0.009) in multivariate analyses. Preventive therapy did not differ between sites.
Unlike older studies, peptic ulcer disease was not the most common etiology, suggesting that advances in H pylori eradication may affect the epidemiology of UGH. Despite advances in therapeutics of acid-related disease, erosive disease accounted for the majority of UGH. Most subjects had risk factors for UGH and most were not receiving protective therapy. Large between site differences in the distribution of etiologies existed.
Gastrointestinal hemorrhage; epidemiology
The MDM2-p53 feedback loop is crucially important for restricting p53 level and activity during normal cell growth and proliferation, and is thus subjected to dynamic regulation in order for cells to activate p53 upon various stress signals. Several ribosomal proteins, such as RPL11, RPL5, RPL23, RPL26, or RPS7, have been shown to play a role in regulation of this feedback loop in response to ribosomal stress. Here, we identify another ribosomal protein S14, which is highly associated with 5q-syndrome, as a novel activator of p53 by inhibiting MDM2 activity. We found that RPS14, but not RPS19, binds to the central acidic domain of MDM2, like RPL5 and RPL23, and inhibits its E3 ubiquitin ligase activity toward p53. This RPS14-MDM2 binding was induced upon ribosomal stress caused by actinomycin D or mycophenolic acid. Overexpression of RPS14, but not RPS19, elevated p53 level and activity, leading to G1 or G2 arrest. Conversely, knockdown of RPS14 alleviated p53 induction by these two reagents. Interestingly, knockdown of either RPS14 or RPS19 caused a ribosomal stress that led to p53 activation, which was impaired by further knocking down the level of RPL11 or RPL5. Together, our results demonstrate that RPS14 and RPS19 play distinct roles in regulating the MDM2-p53 feedback loop in response to ribosomal stress.
RPS14; p53; MDM2; RPL11; RPL5; RPS19; ribosomal stress
B7-H3 is a member of the B7-family of co-stimulatory molecules, which has been shown to be broadly expressed in various tumor tissues, and which plays an important role in adaptive immune responses. The role of B7-H3 in osteosarcoma, however, remains unknown. In this study we used immunohistochemistry to analyze B7-H3 expression in 61 primary osteosarcoma tissues with case-matched adjacent normal tissues, and 37 osteochondroma and 20 bone fibrous dysplasia tissues. B7-H3 expression was expressed in 91.8% (56/61) of the osteosarcoma lesions, and the intensity of B7-H3 expression in osteosarcoma was significantly increased compared with adjacent normal tissues, osteochondroma and bone fibrous dysplasia tissues (p<0.001). Patients with high tumor B7-H3 levels had a significantly shorter survival time and recurrence time than patients with low tumor B7-H3 levels (p<0.001). Moreover, tumor B7-H3 expression inversely correlated with the number of tumor-infiltrating CD8+ T cells (p<0.05). In vitro, increasing expression of B7-H3 promotes osteosarcoma cell invasion, at least in part by upregulating matrix metalloproteinase-2 (MMP-2). In conclusion, our study provides the first evidence of B7-H3 expression in osteosarcoma cells as a potential mechanism controlling tumor immunity and invasive malignancy, and which is correlated with patients’ survival and metastasis.
Several proteins have been suggested in promoting tumor formation in numerous human tissues by inactivating the tumor suppressor p53. This has generated interest in the development of small molecules to block these inhibitors of p53 and to regain p53 activity. Recently, we identified a small molecule, Inauhzin, which can inhibit SIRT1 activity and activate p53. SIRT1 is a deacetylase that deacetylates p53 and facilitates Mdm2 mediated p53 destabilization. In this study, we tested if combining Inauhzin with Nutlin-3, an inhibitor of MDM2-p53 binding, might synergistically activate p53 to suppress tumor growth. Indeed, at lower doses, combination of Inauhzin and Nutlin-3 exhibited a synergistic effect on inhibiting cell growth and promoting apoptosis in human colon and lung cancer cell lines in a p53-dependent fashion. Minimal effects were observed with treatment of either compound alone. Using a xenograft tumor model, we also showed a synergistic effect with both compounds. Thus, to fully regain p53 activity, targeting its multiple inhibitory proteins might be a better approach. Our study provides evidence supporting this concept for achieving better therapeutic efficacy in tumors that possess wild type p53.
MDM2; Nutlin-3; acetylation; apoptosis; deacetylation; inauhzin; p53; small molecule inhibitor; xenograft tumor
The less invasive stabilization system (LISS) can effectively treat tibial fractures. However, the LISS is technically demanding, has a long learning curve, and presents a heavy economic burden to patients. The U-grooved locking compression plate (U-LCP), characterized by a U-groove at each end, is designed to treat tibial fractures. This paper reports the outcomes of tibial fractures treated using the U-LCP compared with the LISS.
Seventy-eight patients with unilateral tibial fractures treated with either the U-LCP (group I) or LISS (group II) were enrolled. In group I, a U-LCP was inserted subcutaneously with two Kirschner wires embedded into the U-grooves to temporarily secure the plate. A second identical plate was placed over the first to guide screw insertion. In group II, the LISS was used to fix the tibial fractures. Patient age, sex, fracture type, severity of soft tissue injury, operative time, fluoroscopic time, complications, and functional recovery of affected limbs were recorded.
The two groups were comparable in age, sex, fracture type, and severity of soft tissue injury (p > 0.05). The average operation and fluoroscopic times in group I were significantly less than those in group II (p < 0.05). At follow-up, all fractures healed. There were no significant differences between both groups in time to bony union, wound complication rate, or functional recovery of injured limbs (p > 0.05).
The U-LCP can yield good outcomes in the treatment of proximal tibial fractures, with less radiation exposure, a shorter operation time, and a sustainable price compared with the LISS.
Objective: Coronary collateral circulation is an alternative source of blood supply to myocardium in the presence of advanced coronary artery disease. We sought to determine which clinical and angiographic variables are associated with collateral development in patients with stable angina and chronic total coronary occlusion. Methods: Demographic variables, biochemical measurements, and angiographic findings were collected from 478 patients with stable angina and chronic total coronary occlusion. The presence and extent of collaterals supplying the distal aspect of a total coronary occlusion from the contra-lateral vessel were graded from 0 to 3 according to the Rentrop scoring system. Results: Low (Rentrop score of 0 or 1) and high (Rentrop score of 2 or 3) coronary collateralizations were detected in 186 and 292 patients, respectively. Despite similar age, cigarette smoking, and medical treatment, patients with low collateralization were female in a higher proportion and less hypertensive, and had higher rates of type 2 diabetes and dyslipidemia than those with high collateralization (for all comparisons, P<0.05). In addition, patients with low collateralization exhibited more single-vessel disease, less right coronary artery occlusion, more impaired renal function, and higher serum levels of high-sensitivity C-reactive protein (hsCRP) compared with those with high collateralization. Multivariate analysis revealed that age of ≥65 years, female gender, diabetes, no history of hypertension, dyslipidemia, moderate to severe renal dysfunction, single-vessel disease, and elevated hsCRP levels were independently associated with low coronary collateralization. Conclusions: Coronary collateralization was reduced in almost 40% of stable angina patients with chronic total occlusion, which was related to clinical and angiographic factors. The impact of coronary collateralization on outcomes after revascularization needs further investigation.
Stable angina; Coronary collateral circulation; Risk factors; Angiography; Chronic total coronary occlusion
To develop a pharmacokinetic-pharmacodynamic disease progression (PK/PD/DIS) model to characterize the effect of etanercept in collagen-induced arthritis (CIA) rats on rheumatoid arthritis (RA) progression.
The CIA rats received either 5 mg/kg intravenous (IV), 1 mg/kg IV, or 5 mg/kg subcutaneous (SC) etanercept at day 21 post-disease induction. Effect on disease progression was measured by paw swelling. Plasma concentrations of etanercept were assayed by enzyme-linked immunosorbent assay (ELISA). PK profiles were fitted first; parameter estimates were applied to fit paw edema data for PD and DIS-related parameter estimation using ADAPT 5 software.
The model contained a two-compartment PK model with Michaelis-Menten elimination. For SC administration, two additional mathematical functions for absorption were added. The disease progression component was an indirect response model with a time-dependent change in paw edema production rate constant (kin) assumed to be inhibited by etanercept.
Etanercept has modest effects on paw swelling in CIA rats. The PK and PD profiles were well described by the developed PK/PD/DIS model, which may be used for other anti-cytokine biologic agents for RA.
arthritis; etanercept; model; pharmacodynamics; pharmacokinetics
In most metazoans, early embryonic development is characterized by rapid mitotic divisions that are controlled by maternal mRNAs and proteins that accumulate during oogenesis . These rapid divisions pause at the Mid-Blastula Transition (MBT), coinciding with a dramatic increase in gene transcription and the degradation of a subset of maternal mRNAs [2, 3]. In Drosophila, the cell cycle pause is controlled by inhibitory phosphorylation of Cdk1, which in turn is driven by down-regulation of the activating Cdc25 phosphatases [4, 5]. Here, we show that the two Drosophila Cdc25 homologues, String and Twine, differ in their dynamics and that, contrary to current models , their down-regulations are not controlled by mRNA degradation but through different post-translational mechanisms. The degradation rate of String protein gradually increases during the late syncytial cycles in a manner dependent on the nuclear-to-cytoplasmic ratio and on the DNA replication checkpoints. Twine, on the other hand, is targeted for degradation at the onset of the MBT through a switch-like mechanism controlled like String by the nuclear-to-cytoplasmic ratio, but not requiring the DNA replication checkpoints. We demonstrate that post-translational control of Twine degradation ensures that the proper number of mitoses precede the MBT.
Objectives. To investigate how Xiao-Ai-Ping injection, a traditional Chinese medicine and an ancillary drug in tumor treatment, enhances the antitumor effects of cisplatin on Lewis lung cancer (LLC) cells. Methods. LLC-bearing mice were daily intraperitoneally injected with various doses of cisplatin, Xiao-Ai-Ping, or cisplatin plus Xiao-Ai-Ping, respectively. Body weight and tumor volumes were measured every three days. Results. Combination of Xiao-Ai-Ping and cisplatin yielded significantly better antigrowth and proapoptotic effects on LLC xenografts than sole drug treatment did. In addition, we found that Xiao-Ai-Ping triggered the infiltration of CD8+ T cells, a group of cytotoxic T cells, to LLC xenografts. Furthermore, the mRNA levels of interferon-γ (ifn-γ), perforin-1 (prf-1), and granzyme B (gzmb) in CD8+ T cells were significantly increased after combination treatment of Xiao-Ai-Ping and cisplatin. In vitro studies showed that Xiao-Ai-Ping markedly upregulated the mRNA levels of ifn-γ, prf-1, and gzmb in CD8+ T cells in a concentration-dependent manner, suggesting that Xiao-Ai-Ping augments the function of CD8+ T cells. Conclusions. Xiao-Ai-Ping promotes the infiltration and function of CD8+ T cells and thus enhances the antigrowth effects of cisplatin on LLC xenografts, which provides new evidence for the combination of Xiao-Ai-Ping and cisplatin in clinic in China.
This study compared the effects of ten types of traditional Chinese medicines (TCMs) and six different antibiotics on E. coli O157:H7 Shiga toxin gene (stx2) mRNA expression level based on real-time PCR and the expression level of Stx toxin using an ELISA quantitative assay. We also compared their effects on the induction of the SOS response. The results clearly indicated that all ten TCMs had negative results in the SOS response induction test, while most TCMs did not increase the levels of stx2 mRNA and the Stx toxin. Some TCMs did increase the mRNA levels of the stx2 gene and the Stx toxin level, but their increases were much lower than those caused by antibiotics. With the exception of cefotaxime, the six antibiotics increased the Stx toxin level and increased the stx2 gene mRNA level. With the exceptions of cefotaxime and tetracycline, the antibiotics increased the SOS induction response. These results suggest that TCMs may have advantages compared with antibiotics, when treating E. coli O157:H7; TCMs did not greatly increase Stx toxin production and release.
The phytohormone abscisic acid ((+)-ABA) plays a key role in many processes. The biological and biochemical activities of unnatural (−)-ABA have been extensively investigated since 1960s. However, the recognition mechanism by which only a few members among PYR/PYL/RCAR (PYLs) family can bind (−)-ABA remains largely unknown. Here we systematically characterized the affinity of PYLs binding to the (−)-ABA and reported the crystal structures of apo-PYL5, PYL3-(−)-ABA and PYL9-(+)-ABA. PYL5 showed the strongest binding affinity with (−)-ABA among all the PYLs. PYL9 is a stringently exclusive (+)-ABA receptor with interchangeable disulfide bonds shared by a subclass of PYLs. PYL3 is a dual receptor to both ABA enantiomers. The binding orientation and pocket of (−)-ABA in PYLs are obviously different from those of (+)-ABA. Steric hindrance and hydrophobic interaction are the two key factors in determining the stereospecificity of PYLs binding to (−)-ABA, which is further confirmed by gain-of-function and loss-of-function mutagenesis. Our results provide novel insights of the bioactivity of ABA enantiomers onto PYLs, and shed light on designing the selective ABA receptors agonists.
Lung cancer is the leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Most lung cancer is caused by the accumulation of genomic alterations due to tobacco exposure. To uncover its mutational landscape, we performed whole-exome sequencing in 31 NSCLCs and their matched normal tissue samples. We identified both common and unique mutation spectra and pathway activation in lung adenocarcinomas and squamous cell carcinomas, two major histologies in NSCLC. In addition to identifying previously known lung cancer genes (TP53, KRAS, EGFR, CDKN2A and RB1), the analysis revealed many genes not previously implicated in this malignancy. Notably, a novel gene CSMD3 was identified as the second most frequently mutated gene (next to TP53) in lung cancer. We further demonstrated that loss of CSMD3 results in increased proliferation of airway epithelial cells. The study provides unprecedented insights into mutational processes, cellular pathways and gene networks associated with lung cancer. Of potential immediate clinical relevance, several highly mutated genes identified in our study are promising druggable targets in cancer therapy including ALK, CTNNA3, DCC, MLL3, PCDHIIX, PIK3C2B, PIK3CG and ROCK2.
We present a compact and highly-sensitive fiber-optic refractometer based on a high-Q π-phase-shifted fiber-Bragg-grating (πFBG) that is chemically etched to the core of the fiber. Due to the π phase-shift, a strong πFBG forms a high-Q optical resonator and the reflection spectrum features an extremely narrow notch that can be used for highly sensitivity refractive index measurement. The etched πFBG demonstrated here has a diameter of ∼9.3 μm and a length of only 7 mm, leading to a refractive index responsivity of 2.9 nm/RIU (RIU: refractive index unit) at an ambient refractive index of 1.318. The reflection spectrum of the etched πFBG features an extremely narrow notch with a linewidth of only 2.1 pm in water centered at ∼1,550 nm, corresponding to a Q-factor of 7.4 × 105, which allows for potentially significantly improved sensitivity over refractometers based on regular fiber Bragg gratings.
fiber gratings; optical fiber sensors; optical resonators; refractive index
Preterm delivery (PTD) is the leading cause of neonatal morbidity and mortality. Epidemiologic studies indicate recurrence of PTD is maternally inherited creating a strong possibility that mitochondrial variants contribute to its etiology. This study examines the association between mitochondrial genotypes with PTD and related outcomes.
This study combined, through meta-analysis, two case-control, genome-wide association studies (GWAS); one from the Danish National Birth Cohort (DNBC) Study and one from the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health. The outcomes of PTD (≤36 weeks), very PTD (≤32 weeks) and preterm prelabor rupture of membranes (PPROM) were examined. 135 individual SNP associations were tested using the combined genome from mothers and neonates (case vs. control) in each population and then pooled via meta-analysis.
After meta-analysis there were four SNPs for the outcome of PTD below p≤0.10, and two below p≤0.05. For the additional outcomes of very PTD and PPROM there were three and four SNPs respectively below p≤0.10.
Given the number of tests no single SNP reached study wide significance (p=0.0006). Our study does not support the hypothesis that mitochondrial genetics contributes to the maternal transmission of PTD and related outcomes.
Surgical intervention-related trauma contributes largely to the development of postoperative immunosuppression, with reduced resistance to secondary bacterial infection. This study compared the impact of laparotomy versus laparoscopy on macrophage-associated bactericidal ability and examined whether laparotomy renders the host more susceptible to microbial infection.
BALB/c mice were randomized into control, laparotomy, and laparoscopy groups. Laparotomy, but not laparoscopy, significantly downregulated CR3 expression on macrophages, diminished macrophage-induced uptake and phagocytosis of E. coli and S. aureus, and impaired macrophage-mediated intracellular bacterial killing. Consistent with this, mice that underwent laparotomy displayed substantially higher bacterial counts in the blood and visceral organs as well as a significantly enhanced mortality rate following bacterial infection, whereas mice subjected to laparoscopy did not show any defects in their bacterial clearance.
Laparotomy has an adverse effect on host innate immunity against microbial infection by impairing macrophage-mediated phagocytosis and killing of the invaded bacteria. By contrast, laparoscopy appears to preserve macrophage-associated bactericidal ability, thus alleviating the development of postoperative immunosuppression.
Laparotomy; Laparoscopy; Phagocytosis; Bactericidal activity; Innate immunity; Macrophages