Passive margins in accreting Archaean archipelagos signal continental stability promoting early atmospheric oxygen rise.

Significant changes in tectonic style and climate occurred from the late Archaean to early Proterozoic when continental growth and emergence provided opportunities for photosynthetic life to proliferate by the initiation of the Great Oxidation Event (GOE). In this study, we report a Neoarchaean passive-margin-type sequence (2560-2500 million years ago) from the Precambrian basement of China that formed in an accretionary orogen. Tectonostratigraphic and detrital zircon analysis reveal that thermal subsidence on the backside of a recently amalgamated oceanic archipelago created a quiet, shallow water environment, marked by deposition of carbonates, shales, and shallow water sediments, likely hosts to early photosynthetic microbes. Distinct from the traditional understanding of passive margins generated by continental rifting, post-collisional subsidence of archipelago margins represents a novel stable niche, signalling initial continental maturity and foreshadowing great changes at the Archaean-Proterozoic boundary.

Cefiderocol for the Treatment of Multidrug-Resistant Gram-Negative Bacteria: A Systematic Review of Currently Available Evidence.

Cefiderocol is a novel synthetic siderophore-conjugated antibiotic that hijacks the bacterial iron transport systems facilitating drug entry into cells, achieving high periplasmic concentrations. This systematic review analyzed the currently available literature on cefiderocol. It summarized in vitro susceptibility data, in vivo antimicrobial activity, pharmacokinetics/pharmacodynamics (PK/PD), clinical efficacy, safety and resistance mechanisms of cefiderocol. Cefiderocol has potent in vitro and in vivo activity against multidrug-resistant (MDR) Gram-negative bacteria, including carbapenem-resistant isolates. But New Delhi Metallo-ß-lactamase (NDM)- positive isolates showed significantly higher MICs than other carbapenemase-producing Enterobacterales, with a susceptible rate of 83.4% for cefiderocol. Cefiderocol is well-tolerated, and the PK/PD target values can be achieved using a standard dose regimen or adjusted doses according to renal function. Clinical trials demonstrated that cefiderocol was non-inferiority to the comparator drugs in treating complicated urinary tract infection and nosocomial pneumonia. Case reports and series showed that cefiderocol was a promising therapeutic agent in carbapenem-resistant infections. However, resistant isolates and reduced susceptibility during treatment to cefiderocol have already been reported. In conclusion, cefiderocol is a promising powerful weapon for treating MDR recalcitrant infections.

Alpine-style nappes thrust over ancient North China continental margin demonstrate large Archean horizontal plate motions.

Whether modern-style plate tectonics operated on early Earth is debated due to a paucity of definitive records of large-scale plate convergence, subduction, and collision in the Archean geological record. Archean Alpine-style sub-horizontal fold/thrust nappes in the Precambrian basement of China contain a Mariana-type subduction-initiation sequence of mid-ocean ridge basalt blocks in a 1600-kilometer-long mélange belt, overthrusting picritic-boninitic and island-arc tholeiite bearing nappes, in turn emplaced over a passive margin capping an ancient Archean continental fragment. Picrite-boninite and tholeiite units are 2698 ± 30 million years old marking the age of subduction initiation, with nappes emplaced over the passive margin at 2520 million years ago. Here, we show the life cycle of the subduction zone and ocean spanned circa 178 million years; conservative plate velocities of 2 centimeters per year yield a lateral transport distance of subducted oceanic crust of 3560 kilometers, providing direct positive evidence for horizontal plate tectonics in the Archean.

Correlation of transrenal DNA with non-small-cell lung cancer in noninvasive disease monitoring.

Background: The study aims to use noninvasive transrenal DNA in advanced non-small-cell lung cancer (NSCLC) patients for treatment monitoring and prognosis. Methods: Urine specimens were collected longitudinally for 103 late-stage NSCLC patients. Detection of targetable mutations in transrenal DNA was achieved by digital droplet PCR. Patients' overall survival outcomes were correlated with levels of transrenal DNA. Results: Corresponding patients' matched tumor results demonstrated concordance rate of 95.6% with transrenal DNA. A significant decline in levels was observed after treatment initiation. We observed changes in transrenal DNA levels to be significantly associated with survival for patients (p < 0.0001). Conclusion: Our results demonstrated strong predictive values of transrenal DNA to better identify patients with poorer survival outcomes and may further complement disease management.

A structurally integrated water environmental modeling system based on dual object structure.

The GIS-based water quantity and water quality model is widely used to provide decision-making supports for water resource and water quality management. However, the existing integration patterns of GIS and model system mainly depend on data communication between themselves which may lead to low operating efficiency and time-consuming model setup. In this paper, a generalized data structure (dual object structure (DOS)) which can store the data of GIS objects and model objects together is proposed and realized for the first time, avoiding frequent data communication during the period of numerical simulation and result expression, realizing the fusion of GIS objects and model objects at the data structure level, improving the operating efficiency of the system. Finally, the water quantity and water quality modeling software (digital basin simulation system (DBSS)) based on DOS was developed by using C++ language. The software has been applied successfully in large-scale river basins of China, and one of the cases was demonstrated to show the application process and the outstanding results.

Downregulation of miR-218 by nicotine promotes cell proliferation through targeting CDK6 in non-small cell lung cancer.

BACKGROUND: Nicotine, an important component of tobacco, is a major risk factor of lung cancer, but the mechanism through which nicotine promotes lung cancer development remains unclear. METHODS: Eighty patients with lung cancer were enrolled in this study, 34 of whom did not smoke and the others did. The expression of miR-218 and CDK6 messenger RNA (mRNA) was measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). A luciferase reporter system was used to identify the direct target of miR-218. The protein expression of CDK6 was analyzed by using Western blotting. Cell proliferation was analyzed using an approach of calculation of cell number under a microscope. RESULTS: Nicotine decreased miR-218 expression in non-small cell lung cancer (NSCLC) cells and promoted proliferation of NSCLC cells. Smoking patients with NSCLC had lower expression of miR-218 in tumor compared with NSCLC patients who did not smoke. We found that miR-218 directly targeted the CDK6 mRNA 3'untranslated region and inhibited its expression in NSCLC cells and also observed a negative correlation between the expression of miR-218 and CDK6 mRNA in lung cancer tissues. Furthermore, miR-218- or nicotine-induced proliferative effects of NSCLC cells were rescued by the recovery of the expression level of CDK6. CONCLUSION: Nicotine promotes proliferation of NSCLC cells through regulating the miR-218/CDK6 axis, which may be a potential therapeutic target for lung cancer.

Antibiotic bedaquiline effectively targets growth, survival and tumor angiogenesis of lung cancer through suppressing energy metabolism.

Tumor angiogenesis plays essential roles during lung cancer progression and metastasis. Therapeutic agent that targets both tumor cell and vascular endothelial cell may achieve additional anti-tumor efficacy. We demonstrate that bedaquiline, a FDA-approved antibiotic drug, effectively targets lung cancer cells and angiogenesis. Bedaquiline dose-dependently inhibits proliferation and induces apoptosis of a panel of lung cancer cell lines regardless of subtypes and molecular heterogeneity. Bedaquiline also inhibits capillary network formation of human lung tumor associated-endothelial cell (HLT-EC) on Matrigel and its multiple functions, such as spreading, proliferation and apoptosis, even in the presence of vascular endothelial growth factor (VEGF). We further demonstrate that bedaquiline acts on lung cancer cells and HLT-EC via inhibiting mitochondrial respiration and glycolysis, leading to ATP reduction and oxidative stress. Consistently, oxidative damage on DNA, protein and lipid were detected in cells exposed to bedaquiline. Importantly, the results obtained in in vitro cell culture are reproducible in in vivo xenograft lung cancer mouse model, confirming that bedaquiline suppresses lug tumor growth and angiogenesis, and increases oxidative stress. Our findings demonstrating that energy depletion is effectively against lung tumor cells and angiogenesis. Our work also provide pre-clinical evidence to repurpose antibiotic bedaquiline for lung cancer treatment.

Benazepril hydrochloride improves diabetic nephropathy and decreases proteinuria by decreasing ANGPTL-4 expression.

BACKGROUND: This study aimed to investigate the effects of benazepril hydrochloride (BH) on proteinuria and ANGPTL-4 expression in a diabetic nephropathy (DN) rat model. METHODS: A total of 72 Wistar male rats were randomly divided into three groups: normal control (NC), DN group and BH treatment (BH) groups. The DN model was induced by streptozotocin (STZ). Weight, glucose, proteinuria, biochemical indicators and the kidney weight index were examined at 8, 12 and 16 weeks. In addition, ANGPTL-4 protein and mRNA expressions were assessed by immunohistochemistry and qRT-PCR, respectively. Relationships between ANGPTL-4 and biochemical indicators were investigated using Spearman analysis. RESULTS: Weight was significantly lower but glucose levels were significantly higher in both the DN and BH groups than in the NC group (P < 0.05). Compared with the DN group, proteinuria, urea, creatinine, triglycerides and total cholesterol levels were decreased, whereas the albumin level was increased after BH treatment (all P < 0.05). Furthermore, BH diminished kidney volume and ameliorated the pathological changes associated with DN. ANGPTL-4 expression was significantly decreased after BH treatment, and ANGPTL-4 expression was highly correlated with biochemical indicators of DN (P < 0.05). CONCLUSIONS: Benazepril hydrochloride improves DN and decreases proteinuria by decreasing ANGPTL-4 expression.

Azithromycin effectively inhibits tumor angiogenesis by suppressing vascular endothelial growth factor receptor 2-mediated signaling pathways in lung cancer.

Tumor angiogenesis is essential during lung cancer development and targeting angiogenesis may possess a potential therapeutic value. The present study demonstrates that azithromycin, a Food and Drug Administration-approved antibiotic drug, is a novel tumor angiogenesis inhibitor. Azithromycin inhibits capillary network formation of human lung tumor associated-endothelial cells (HLT-ECs) in vitro and in vivo. It significantly inhibits HLT-EC adhesion and vascular endothelial growth factor (VEGF)-induced proliferation of HLT-ECs in a dose-dependent manner without affecting migration. In addition, azithromycin induces apoptosis of HLT-ECs even in the presence of VEGF. Notably, azithromycin inhibits proliferation and induces apoptosis in multiple lung cancer cell lines to a significantly reduced extent compared with in HLT-ECs, suggesting that HLT-ECs are more susceptible to azithromycin treatment. In a lung tumor xenograft model, azithromycin significantly inhibits tumor growth and its anti-tumor activities are achieved by suppressing angiogenesis. Notably, the inhibitory effects of azithromycin on angiogenesis are associated with its ability to suppress VEGF-induced activation of VEGF receptor 2 (VEGFR2), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), focal adhesion kinase, and disruption of focal adhesion assembly and actin stress fiber formation in HLT-ECs. The present study identifies that azithromycin targets VEGFR2-mediated focal adhesion and PI3K/Akt signaling pathways in HLT-ECs, leading to the suppression of angiogenesis and lung tumor growth.

Utility of urinary circulating tumor DNA for EGFR mutation detection in different stages of non-small cell lung cancer patients.

PURPOSE: Non-invasive methods of molecular profiling for non-small cell lung cancer (NSCLC) are useful for monitoring disease progression. The aim of the current study was to ascertain if transrenal DNA is sensitive for clinical correlation and EGFR detection in NSCLC patients. METHODS: 160 patients at various stages of the disease participated and samples were collected prospectively at 2-month intervals. A baseline sample was taken before treatment commencement. To ascertain the sensitivity of transrenal DNA, we compared its results with plasma DNA. ddPCR was used to profile the urine and blood samples for key EGFR mutations. RESULTS: Using tumor tissues as references, our study showed good concordance in EGFR mutations with transrenal DNA before treatment. Results were highly matching in late-stage NSCLC patients, with stage III/IV patients yielding an agreement of more than 90%. The assay was also sensitive to detect early-stage patients after surgical procedures. Profiles were highly concordant with results derived from plasma DNA, demonstrating the specificity of transrenal DNA assays. Serial monitoring of these patients showed stable molecular signatures and correlated to different treatments. Survival analysis showed good prognostic utility for late-stage patients with high transrenal DNA variations and patients that acquired T790M mutation. CONCLUSION: The study demonstrated the feasibility of using transrenal DNA in mutation profiling for different stages of NSCLC patients. It highlights the importance of continual monitoring and has potential clinical utility in the clinical management of NSCLC.

Investigation of transrenal KRAS mutation in late stage NSCLC patients correlates to disease progression.

PURPOSE: Using transrenal DNA to detect KRAS mutations in non-small cell lung cancer (NSCLC), the study addressed the clinical impact for longitudinal monitoring and prognostic value for disease outcome. METHODS: Digital droplet PCR was used to detect the mutant DNA. A total of 200 NSCLC patients were recruited with varying molecular profiles. To ascertain the specificity of transrenal DNA to accurately profile the disease, primary tissues were compared. Subsequently, serial samplings were performed at different treatment cycles to gauge the predictive value. RESULTS: Transrenal DNA was successfully detected in all 200 patients. Overall concordance rate for mutant KRAS DNA within urine specimens and primary tissue biopsies was 95% (k = 0.87; 95% CI: 0.82-0.95). Patients with positive results at baseline had lower median overall survival (OS) than the wildtype group. More importantly, longitudinal monitoring of urine specimens showed an increase in the quantity of transrenal DNA, which were highly associated with disease progression and outcome. CONCLUSIONS: Our study showed a highly associative link to the patient's tumor KRAS profile. Monitoring its variations aided in stratifying patients with worse outcome. Urinary specimens that can be extracted non-invasively presents new opportunities to track patients with KRAS mutation undergoing therapy.

Epigallocatechin gallate from green tea exhibits potent anticancer effects in A-549 non-small lung cancer cells by inducing apoptosis, cell cycle arrest and inhibition of cell migration.

PURPOSE: Green tea (Camellia sinensis) is considered as a rich source of epigallocatechin gallate (EGCG) which has been shown to exert impressive pharmacological properties. The anticancer properties of EGCG have been extensively studied however, its anticancer activity has not been explored in lung cancer. The present study was therefore designed to evaluate the anticancer effects of EGCG against non-small cell lung cancer (NSCLC) cell line A-549 and normal human fibroblast FR-2 cells. METHODS: Cell viability was assessed by CCK8 assay, apoptosis by DAPI, annexin V/propidium iodide (PI) and flowcytometery and cell cycle analysis by flow cytometry. Cell migration capacity was investigated by wound-healing assay and protein expression was examined by Western blotting. RESULTS: The results revealed that EGCC could inhibit the proliferation of A-549 cells in a concentration-dependent manner and exhibited an IC50 of 25 µM against the IC50 of 100 µM against the normal human fibroblasts. Further evaluation revealed that EGCG exerts its anticancer effects via induction of apoptosis, modulation of Bax/blc-2 ratio and by triggering G2/M cell cycle arrest. Furthermore, EGCG could also inhibit the migration of A5-49 cells in a concentration-dependent manner. CONCLUSION: In conclusion, based on our results, we believe that EGCG could prove to be an important lead molecule for the treatment of lung cancer.

[Mortality risks of type 2 diabetes mellitus among elderly patients: a 17-year cohort study].

OBJECTIVE: To explore the mortality risks of elders with and without type 2 diabetes mellitus (T2DM) during a fellow-up period of 17 years. METHODS: The subjects were elderly patients (>60 years old) undergoing annual health examinations at our hospital. And the incidence and risk factors were analyzed by Kaplan-Meier method and COX's proportional hazard. RESULTS: A total of 2 142 subjects were divided into T2DM group (DM, n = 746) and non-T2DM group (N-DM, n = 1 396). During a 17-year follow-up, the mortality rate of all causes was 50.9% in DM group versus 32.45% in N-DM group (P < 0.01). The major mortality causes were malignant tumor, respiratory disease and cardiovascular disease. Kaplan-Meier analysis revealed that the accumulative mortality of all causes and cardiovascular with DM was significantly above that of N-DM. The independent mortality risk factors of elders was T2DM (P < 0.01, HR = 1.36, 95% CI: 1.192-1.558) and cardiovascular disease (P < 0.01, HR = 3.26, 95% CI: 2.887-3.690) based upon the COX's proportional hazard analysis. CONCLUSION: Type 2 diabetes mellitus is an independent risk factor for elders with increased mortality risk.

[Association of abdominal fat distribution by computed tomography with body mass index and metabolic syndrome in Chinese elders].

OBJECTIVE: To explore the gender and age difference of abdominal fat distribution in Chinese older adults and examine the effects of metabolic syndrome (MS) on abdominal fat distribution by computed tomography (CT). METHODS: Chinese elders (aged ≥ 65 years old) undergoing abdominal CT scanning at our hospital from January 2009 to December 2010 were collected through retrospective analysis. A total of 52 healthy normal-weight subjects and gender-specific body mass index (BMI)-matched middle-aged adults were selected (28 males, 24 females) to compare the difference of abdominal fat during the same period. Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured at the cross-sections of L4 and L5 intervertebral space. RESULTS: A total of 390 subjects were enrolled. There were 252 males and 138 females. Total abdominal fat (TAF) was not significantly different in both genders [female (323 ± 122 cm²) vs male (303 ± 141 cm²) , P = 0.146]. However, females had higher TAF than males after height correction (128 ± 49 vs 105 ± 49 cm²/m², P = 0.000). VFA and SFA were higher with higher BMI values across lean, normal weight, overweight and obese groups in both genders. VFA and SFA were not significantly different in both genders among 3 different age groups (>65-75, >75-85, >85 years; P > 0.05). Compared with healthy normal weight elders and BMI-matched middle-aged adults, VFA and SFA increased with more components of MS except in only one component group. When the patients were excluded suffering from 2 or more components of MS, VFA was not significantly different between normal weight elders and those with only one component of MS (diabetes/hyperlipidemia/hypertension). Logistic regression analysis showed VFA was a risk factor for elders with MS (male: OR = 1.03, 95%CI: 1.012- 1.047; female: OR = 1.06, 95%CI: 1.026-1.088) . However, SFA and age were not. CONCLUSIONS: The elder females have more TAF than the elder males while abdominal fat does not increase with age in elders. TAF, VFA and SFA have a highly positively correlation with BMI. Visceral fat, not subcutaneous fat, is a risk factor for elders with MS and it increases with an increment of more than 2 components of MS.

[Clinical observation of therapeutic effect of extracorporeal membrane oxygenation in patients with acute respiratory distress syndrome].

OBJECTIVE: To investigate the therapeutic effects and safety of extracorporeal membrane oxygenation (ECMO) in patients with acute respiratory distress syndrome (ARDS). METHODS: ECMO were initiated in 6 patients with ARDS, not responding to conventional mechanical ventilation. Oxygenation status, positive end-expiratory pressure (PEEP) level, and fraction of inspired oxygen [FiO(2)] were compared before and after treatment with ECMO, while the adverse effects of ECMO were recorded. RESULTS: In 6 cases, pulse blood oxygen saturation [SpO(2)] was elevated (0.45-0.92 up to 0.94-1.00), PEEP level [cm H(2)O, 1 cm H(2)O=0.098 kPa] and [FiO(2)] were lowered [PEEP: 10.0-22.0 down to 4.0-15.0; FiO(2): 1.00 down to 0.30-0.60] after treatment with ECMO. Of 6 cases, 2 patients with severe influenza A/H1N1 pneumonia finally died of shock; 1 patient with severe influenza A/H1N1 pneumonia and 1 patient with Klebsiella pneumoniae pneumonia were withdrawn from ECMO treatment because of deterioration of the disease. One patient suffering from Cytomegalovirus pneumonia and another with Acinetobacter baumannii pneumonia were successfully discharged from hospital with recovery. The main complications were bleeding and hemolysis. CONCLUSIONS: ECMO could improve gas exchange, oxygenation and partially replace pulmonary function. Patients with ARDS should be treated with ECMO early if artificial ventilation treatment was unresponsive.