Anxiety, depression symptoms, and psychological resilience among hospitalized COVID-19 patients in isolation: A study from Wuhan, China.

OBJECTIVE: To investigate the status of anxiety, depression, and psychological resilience among individuals with COVID-19, and their interrelationships to provide a scientific basis for developing psychological intervention strategies for these patients. METHODS: A total of 126 patients with COVID-19 who were admitted to Wuhan Huoshenshan Hospital were recruited in this study. A comprehensive survey was conducted using a general information questionnaire, the Self-Rating Anxiety Scale, the self-rating depression scale, and the Chinese version of the psychological Connor-Davidson resilience scale; a questionnaire-based survey was conducted. RESULTS: Significant differences in anxiety scores were observed among COVID-19 patients with different education levels and the number of immediate family members. The differences in depression scores were noted among patients of different age groups, and marital statuses were also significant. The total psychological resilience score and the scores of all dimensions are negatively correlated with anxiety and depression. Furthermore, the patient's gender, the number of immediate family members, and the psychological resilience dimensions are associated with the severity anxiety of patients. Patient age and psychological resilience are associated with the depression level of patients. CONCLUSION: Patients with COVID-19 exhibit elevated levels of both anxiety and depression. Notably, psychological resilience emerges as a protective factor against the development of anxiety and depression.

DNA methylation regulator-based signature for predicting clear cell renal cell carcinoma prognosis.

OBJECTIVES: To investigate the role of DNA methylation regulators in the prognosis of clear cell renal cell carcinoma (ccRCC) and to construct a DNA methylation regulator-based signature for predicting patient outcome. METHODS: Data from the TCGA dataset were downloaded and analyzed to identify differentially expressed DNA methylation regulators and their interaction as well as correlation. Consensus clustering was used to establish groups of ccRCC with distinct clinical outcomes. A prognostic signature based on two sets of DNA methylation regulators was established and validated in an independent cohort. RESULTS: Our analysis revealed that the expression levels of DNMT3B, MBD1, SMUG1, DNMT1, DNMT3A, TDG, TET3, MBD2, UHRF2, MBD3, UHRF1, and TET2 were significantly upregulated in ccRCC samples, while UNG, ZBTB4, TET1, ZBTB38, and MECP2 were markedly downregulated. UHRF1 was identified as a hub gene in the DNA methylation regulator interaction network. Significant differences were found regarding overall survival, gender, tumor status, and grade between ccRCC patients in the two risk groups. The prognostic signature, based on two sets of DNA methylation regulators, was an independent prognostic indicator, and these findings were validated in an external, independent cohort. CONCLUSIONS: The study provides evidence that DNA methylation regulators play a significant role in the prognosis of ccRCC and the developed DNA methylation regulator-based signature could effectively predict patient outcome.

Experimental and constitutive model study on the mechanical properties of a structural plane of a rock mass under dynamic disturbance.

An accurate description of the mechanical properties and deformation characteristics of a structural plane of a rock mass with a large chamber or slope under the ultimate stress with periodic stress disturbances is of great significance to ensure the stability and safety of underground rock engineering. By theoretically analysing the strength effect of a structural plane of a rock mass under dynamic disturbance, a criterion for the occurrence of shear damage on a structural plane of a compressed rock mass under dynamic disturbance is proposed. The results of the cyclic disturbance kinetic test show that there is a disturbance threshold for the shear failure of the structural plane under different disturbance stresses. When the disturbance stress is lower than the disturbance threshold, the cumulative plastic strain stabilizes with an increasing number of cycles; when the disturbance stress is higher than the disturbance threshold, an S-shaped curve of cumulative plastic strain versus the number of cycles is observed, revealing the progressive damage process and mechanism of such a rock structure plane under periodic dynamic disturbance. Based on perturbation concept theory, the relationship between the accumulated plastic strain and the number of cyclic loadings is similar to the relationship between strain and time, the creep curve. A new nonlinear viscous element is proposed, and the nonlinear element and the deformation element considering structural plane closure and sliding are combined with the Burgers model to form an 8-element nonlinear viscoelastic‒plastic creep constitutive model. Using the global optimization algorithm of 1stOpt, model validation and parameter identification are performed on the experimental data, and the results show that the model curve has a very good agreement with the experimental data. The model can accurately reflect the deformation characteristics of a structural plane of a rock mass under periodic dynamic disturbance. These research results provide a new idea for analysing disturbance-induced geohazards.

Failure energy evolution of coal-rock combination with different inclinations.

In this paper, in the deformation and damage process under different confining pressures, the energy evolution characteristics and damage mechanism of coal-rock combinations with different inclination angles are studied. Based on the brittleness indexes of coal rock combinations, the evolution rules between brittleness indexes and the inclination are explored, as well as the confining pressure of coal rock combinations; then, the influence mechanism of the inclination angle of coal rock combinations on the plastic yielding degree, energy dissipation level, crack extension and fracture speed in the pre-peak stage is revealed. The composite specimens are mainly damaged due to oblique shear and accompanied by tensile damage; In the deformation and damage, various energies of coal rock composites are distributed as a negative exponential function of the inclination angle, which is significantly affected by the change of the confining pressure.

Structure-switchable aptamer-arranged reconfigurable DNA nanonetworks for targeted cancer therapy.

The structural DNA nanotechnology holds great potential application in bioimaging, drug delivery and cancer therapy. Herein, an intelligent aptamer-incorporated DNA nanonetwork (Apt-Nnes) is demonstrated for cancer cell imaging and targeted drug delivery, which essentially is a micron-scale pattern with the thickness of double-stranded monolayer. Cancer cell-surface receptors can make it perform magical transformation into small size of nanosheet intermediates and specifically enter target cells. The binding affinity of Apt-Nnes is increased by 3-fold due to multivalent binding effect of aptamers and it can maintain the structural integrity in fetal bovine serum (FBS) for 8 h. More interestingly, target cancer cells can cause the structural disassembly, and each resulting unit transports 4963 doxorubicin (Dox) into target cells, causing the specific cellular cytotoxicity. The cell surface receptor-mediated disassembly of large size of DNA nanostructures into small size of fractions provides a valuable insight into developing intelligent DNA nanostructure suitable for biomedical applications.

Severe versus common COVID-19: an early warning nomogram model.

The wide spread of coronavirus disease 2019 is currently the most rigorous health threat, and the clinical outcomes of severe patients are extremely poor. In this study, we establish an early warning nomogram model related to severe versus common COVID-19. A total of 1059 COVID-19 patients were analyzed in the primary cohort and divided into common and severe according to the guidelines on the Diagnosis and Treatment of COVID-19 by the National Health Commission of China (7th version). The clinical data were collected for logistic regression analysis to assess the risk factors for severe versus common type. Furthermore, 123 COVID-19 patients were reviewed as the validation cohort to assess the performance of this model. Multivariate logistic analysis revealed that age, dyspnea, lymphocyte count, C-reactive protein and interleukin-6 were independent factors for prewarning the severe type occurrence. Then, the early warning nomogram model including these risk factors for inferring the severe disease occurrence out of common type of COVID-19 was constructed. The C-index of this nomogram in the primary cohort was 0.863, 95% confidence interval (CI) (0.836-0.889). Meanwhile, in the validation cohort, the C-index of this nomogram was 0.889, 95% CI (0.828-0.950). In both the primary cohort and validation cohorts, the calibration curve showed good agreement between prediction and actual probability. The early warning model shows that data at the very beginning including age, dyspnea, lymphocyte count, CRP, and IL-6 may prewarn the severe disease occurrence to some extent, which could help clinicians early and timely treatment.

A possible dose-response equation: Viral load after plasma infusion in COVID-19 patients and anti-SARS-CoV-2 antibody titers in convalescent plasma.

BACKGROUND: Clinical trials of convalescent plasma therapy for coronavirus disease 2019 (COVID-19) are extensive, but the relationship between antibody titers, infused volume of plasma and virus clearance in patients remains unknown. This study proposed a possible estimating equation for clinical use of high antibody titer convalescent plasma. METHODS: A total of 38 patients were recruited in the Guanggu District Maternal and Child Health Hospital of Hubei Province from March 1 to 30, 2020. COVID-19 convalescent plasma was collected and high-titer (≥1:640) anti-S-RBD units used. The SARS-CoV-2 nucleic acid viral load was measured 24 h before and 72 h after convalescent plasma infusion. RESULTS: Convalescent plasma therapy was associated with reduced viral load in patients with moderate and severe severity. The viral negative rate at 72 h was 65.8%. The disappearance of viral nucleic acid in study patients was positively correlated with infuscate antibody titer and volume (r = 0.3375, p = 0.04). A possible estimation equation was as follows: Log10 (Reduction in viral load) = 0.18 + 0.001 × (Log2 S-RBD antibody titer × Plasma infusion volume) (r = 0.424, p = 0.009). In a single case, the viral nucleic acid persisted 14 days after the fourth plasma infusion. CONCLUSIONS: This study proposes a potential dose-response equation that adds a convenient way to estimate the dose of convalescent plasma product. It is beneficial to facilitate the rational allocation of plasma with high antibody titers and provide an individualised use strategy for convalescent plasma therapy.

Administration Timing and Efficacy of Tocilizumab in Patients With COVID-19 and Elevated IL-6.

BACKGROUND: Tocilizumab (TCZ), an interleukin-6 receptor antibody, has previously been used for treating patients with the coronavirus disease 2019 (COVID-19), but there is a lack of data regarding the administration timing of TCZ. OBJECTIVES: This study aimed to evaluate the timing and efficacy of TCZ in the treatment of patients with COVID-19. METHODS: Laboratory-confirmed patients with COVID-19 with an elevated interleukin-6 (IL-6) level (>10 pg/ml) were offered TCZ intravenously for compassionate use. Clinical characteristics, laboratory tests, and chest imaging before and after the administration of TCZ were retrospectively analyzed. RESULTS: A total of 58 consecutive patients who met the inclusion criteria and with no compliance to the exclusion criteria were included. Of these 58 patients, 39 patients received TCZ treatment, and 19 patients who declined TCZ treatment were used as the control cohort. In the TCZ-treatment group, 6 patients (15.4%) were in mild condition, 16 (41.0%) were in severe condition, and 17 (43.6%) were in critical condition. After TCZ treatment, the condition of 27 patients (69.2%) improved and 12 (30.8%) died. Compared with the improvement group, patients in the death group had higher baseline levels of IL-6 (P = 0.0191) and procalcitonin (PCT) (P = 0.0003) and lower lymphocyte percentage (LYM) (P = 0.0059). Patients receiving TCZ treatment had better prognoses than those without TCZ treatment (P = 0.0273). Furthermore, patients with a baseline IL-6 level of ≥100 pg/ml in the TCZ-treatment group had poorer clinical outcomes than those with an IL-6 level of <100 pg/ml (P = 0.0051). CONCLUSION: The administration of TCZ in an early stage of cytokine storm (IL-6 level < 100 pg/ml) may effectively improve the clinical prognosis of patients with COVID-19 by blocking the IL-6 signal pathway.

Precision-Guided Missile-Like DNA Nanostructure Containing Warhead and Guidance Control for Aptamer-Based Targeted Drug Delivery into Cancer Cells in Vitro and in Vivo.

It is crucial to deliver anticancer drugs to target cells with high precision and efficiency. While nanomaterials have been shown to enhance the delivery efficiency once they reach the target, it remains challenging for precise drug delivery to overcome the nonspecific adsorption and off-target effect. To meet this challenge, we report herein the design of a novel DNA nanostructure to act as a DNA nanoscale precision-guided missile (D-PGM) for highly efficient loading and precise delivery of chemotherapeutic agents to specific target cells. The D-PGM consists of two parts: a warhead (WH) and a guidance/control (GC). The WH is a rod-like DNA nanostructure as a drug carrier, whose trunk is a three-dimensionally self-assembled DNA nanoscale architecture from the programmed hybridization among two palindromic DNA sequences in the x-y dimension and two common DNA oligonucleotides in the z direction, making the WH possess a high payload capacity of drugs. The GC is an aptamer-based logic gate assembled in a highly organized fashion capable of performing cell-subtype-specific recognition via the sequential disassembly, mediated by cell-anchored aptamers. Because of the cooperative effects between the WH and the GC, the GC logic gates operate like the guidance and control system in a precision-guided missile to steer the doxorubicin (DOX)-loaded DNA WH toward target cancer cells, leading to selective and enhanced therapeutic efficacy. Moreover, fluorophores attached to different locations of D-PGM and DOX fluorescence dequenching upon release enable intracellular tracing of the DNA nanostructures and drugs. The results demonstrate that by mimicking the functionalities of a military precision-guided missile to design the sequential disassembly of the GC system in multistimuli-responsive fashion, our intrinsically biocompatible and degradable D-PGM can accurately identify target cancer cells in complex biological milieu and achieve active targeted drug delivery. The success of this strategy paves the way for specific cell identity and targeted cancer therapy.

Simple Self-Assembled Targeting DNA Nano Sea Urchin as a Multivalent Drug Carrier.

An ideal drug delivery platform with high cell selectivity, drug payload capacity, and cellular internalization capability is usually of the essence for targeted cancer chemotherapy. Herein, by combining palindromic DNA strands with a targeting aptamer probe, we demonstrated a self-assembled nanoscale sea urchin-shaped structure (called aptamer-NSU) as a multivalent carrier capable of executing targeted cancer cell imaging and drug delivery. The DNA nanostructure is composed of a spherical trunk and surface-confined spines: the former is assembled from only one biotinylated DNA containing four different palindrome domains, and the latter is a biotinylated aptamer (Sgc8) conjugated to the trunk surface via streptavidin-biotin affinity interaction. The spherical trunk can densely load doxorubicin (Dox), and the surface-confined Sgc8 probes can function as targeting moieties to specifically bind to target cells in a polyvalent-binding fashion. Atomic force microscopy (AFM) and gel electrophoresis show the assembly of Sgc8-NSU. The confocal fluorescence imaging demonstrates that fluorescently labeled Sgc8-NSU can specifically image CEM cells. Flow cytometric analyses indicate that Sgc8-NSU exhibits the multivalent binding effect, achieving the significant improvement in binding affinity and selectivity compared with free Sgc8. Moreover, the CCK-8 assay confirmed that Dox-loaded Sgc8-NSU induces an enhanced cellular cytotoxicity to target cancer cells but not to negative nontarget cells. The developed DNA nanoplatform is expected to provide a valuable insight into constructing structural DNA nanotechnology-based drug delivery nanovehicles suitable for targeted cancer therapy.

DNA nanostructures from palindromic rolling circle amplification for the fluorescent detection of cancer-related microRNAs.

Herein, DNA nanostructures were prepared via a palindromic padlock probe-based rolling circle amplification (called P-RCA) and then employed to implement the sensitive and specific detection of let-7a miRNA extracted from cancer cells without chemical modification. The presence of target let-7a miRNA as a polymerization primer can trigger the P-RCA process, generating a long tandemly repetitive DNA strand. The resulting products can fold into nanostructures via self-hybridization of palindromic regions and possess numerous double-stranded fragments. In this case, the strong fluorescent signal is detected upon exposure to SYBR Green I. As a result, in homogeneous solution, target miRNA can be detected down to 6.4 pM with a wide dynamic range. A high specificity was demonstrated by the excellent discrimination between let-7 miRNA family members, while the applicability of this sensing system in complex biological environments was confirmed by the analysis of target miRNAs extracted from HeLa cells. It should be noted that increasing numbers of palindromic fragments in padlock probe further increases signal amplification efficiency. The experimental results indicate that the newly proposed P-RCA DNA nanostructures have potential to become a promising analytical platform in biomedical research and clinical diagnosis for the miRNA detection with high sensitivity and good specificity.

Autonomous assembly of ordered metastable DNA nanoarchitecture and in situ visualizing of intracellular microRNAs.

Facile assembly of intelligent DNA nanoobjects with the ability to exert in situ visualization of intracellular microRNAs (miRNAs) has long been concerned in the fields of DNA nanotechnology and basic medical study. Here, we present a driving primer (DP)-triggered polymerization-mediated metastable assembly (PMA) strategy to prepare a well-ordered metastable DNA nanoarchitecture composed of only two hairpin probes (HAPs), which has never been explored by assembly methods. Its structural features and functions are characterized by atomic force microscope (AFM) and gel electrophoresis. Even if with a metastable molecular structure, this nanoarchitecture is relatively stable at physiological temperature. The assembly strategy can be expanded to execute microRNA-21 (miRNA-21) in situ imaging inside cancer cells by labelling one of the HAPs with fluorophore and quencher. Compared with the conventional fluorescence probe-based in situ hybridization (FISH) technique, confocal images revealed that the proposed DNA nanoassembly can not only achieve greatly enhanced imaging effect within cancer cells, but also reflect the miRNA-21 expression level sensitively. We believe that the easily constructed DNA nanoarchitecture and in situ profiling strategy are significant progresses in DNA assembly and molecule imaging in cells.

Dual-cyclical nucleic acid strand-displacement polymerization based signal amplification system for highly sensitive determination of p53 gene.

In the present study, we proposed a novel dual-cyclical nucleic acid strand-displacement polymerization (dual-CNDP) based signal amplification system for highly sensitive determination of tumor suppressor genes. The system primarily consisted of a signaling hairpin probe (SHP), a label-free hairpin probe (LHP) and an initiating primer (IP). The presence of target DNA was able to induce one CNDP through continuous process of ligation, polymerization and nicking, leading to extensively accumulation of two nicked triggers (NT1 and NT2). Intriguingly, the NT1 could directly hybridize SHP, while the NT2 could act as the target analog to induce another CNDP. The resulting dual-CNDP contributed the striking signal amplification, and only a very weak blank noise existed since the ligation template of target was not involved. In this case, the target could be detected in a wide linear range (5 orders of magnitude), and a low detection limit (78 fM) was obtained, which is superior to most of the existing fluorescent methods. Moreover, the dual-CNDP sensing system provided a high selectivity towards target DNA against mismatched target and was successfully applied to analysis of target gene extracted from cancer cells or in human serum-contained samples, indicating its great potential for practical applications.

Increasingly branched rolling circle amplification for the cancer gene detection.

An increasingly branched rolling circle amplification (IB-RCA) which contains a padlock probe (PP) and a structurally tailored molecular beacon (MB) was innovatively developed for highly sensitive detection of cancer gene, Kras gene codon 12. In this system, the PP can be circularized after hybridization with the precisely-matched target DNA, while the stem of MB can be also opened by target DNA, resulting in hybridization with the circularized PP to generate a long tandem single-stranded DNA (ssDNA) product. Since the MB is also designed to hybridize with ssDNA product, the newly-opened MBs are able to trigger the next RCA reactions, therapy producing branched rolling circle amplification (RCA) products and in turn leading to the increasingly branched RCA (IB-RCA). This alternately and continuously operates hybridization-based MB opening and opened MBs-triggered RCA. As a result, a great number of MBs are opened that is associated with a dramatically amplified fluorescent signal, enabling to quantify target DNA down to 100 fM. This sensing method demonstrates a new concept of IB-RCA amplification even in a simple way to efficiently transduce the fluorescence signal, accomplishing the highly sensitive and selective detection of cancer gene.

Two-wheel drive-based DNA nanomachine and its sensing potential for highly sensitive analysis of cancer-related gene.

With the biological significance and important advances of nano-scale DNA devices, scientific activities have been directed toward developing molecular machinery. In this work, we present a novel two-wheel drive-based DNA nanomachine composed of one signaling recognition probe (SRP), one label-free recognition probe (LRP), and one driving primer (DP). Target DNA hybridization can activate LRP-based wheel driving by resorting to DP-mediated polymerization/nicking/displacement cycles. This in turn results in the accumulation of nicked strand 1 (NS1) that can initiate extended SRP-based wheel driving. As a result, the hairpin structure of SRP is stretched and pre-quenched fluorescence is restored. Meanwhile, lots of nicked strand 2 (NS2) are produced, which could hybridize perfectly with SRP and lead to further fluorescence amplification. It is worth noting that, because the nanomachine operation relies strongly on inputted target trigger, the unwanted background is completely eliminated. The detection limit of 1 pM and an excellent capability to recognize the single-base mutation were achieved. Significantly, the interrogating of target trigger extracted from cancer cells is already available, reflecting the potential for practical applications. As a proof-of-concept building, the unique analytical properties would significantly benefit the DNA nanomachines and reveal great promise in biochemical and biomedical studies.

Capture and Identification of Heterogeneous Circulating Tumor Cells Using Transparent Nanomaterials and Quantum Dots-Based Multiplexed Imaging.

BACKGROUND: Capture and identification of circulating tumor cells (CTCs) in the blood system can help guide therapy and predict the prognosis of cancer patients. However, simultaneous capture and identification of CTCs with both epithelial and mesenchymal phenotypes remains a formidable technical challenge for cancer research. This study aimed at developing a system to efficiently capture and identify these CTCs with heterogeneous phenotypes using transparent nanomaterials and quantum dots (QDs)-based multiplexed imaging. METHODS: Hydroxyapatite-chitosan (HA-CTS) nanofilm-coated substrates were modified based on our previous work to increase the capture efficiency of cancer cell lines by extending baking and incubating time. QDs-based imaging was applied to detect cytokeratin, epithelial cell adhesion molecule (EpCAM), and vimentin of cancer cells to demonstrate the feasibility of multiplexed imaging. And QDs-based multiplexed imaging of CD45, cytokeratin and vimentin was applied to detect CTCs from different cancer patients that were captured using HA-CTS nanofilm substrates. RESULTS: Comparisons of the capture efficiencies of cancer cells at different baking time of film formation and incubating time of cell capture revealed the optimal baking and incubating time. Optimal time was chosen to develop a modified CTCs capture system that could capture EpCAM-positive cancer cells at an efficiency > 80%, and EpCAM-negative cancer cells at an efficiency > 50%. QDs-based imaging exhibited comparable detection ability but higher photostability compared to organic dyes imaging in staining cells. In addition, QDs-based multiplexed imaging also showed the molecular profiles of cancer cell lines with different phenotypes well. The integrated CTCs capture and identification system successfully captured and imaged CTCs with different sub-phenotypes in blood samples from cancer patients. CONCLUSION: This study demonstrated a reliable capture and detection system for heterogeneous CTCs that combined enrichment equipment based on HA-CTS nanofilm substrates with QDs-based multiplexed imaging.

A Combined Negative and Positive Enrichment Assay for Cancer Cells Isolation and Purification.

Cancer cells that detach from solid tumor and circulate in the peripheral blood (CTCs) have been considered as a new "biomarker" for the detection and characterization of cancers. However, isolating and detecting cancer cells from the cancer patient peripheral blood have been technically challenging, owing to the small sub-population of CTCs (a few to hundreds per milliliter). Here we demonstrate a simple and efficient cancer cells isolation and purification method. A biocompatible and surface roughness controllable TiO2 nanofilm was deposited onto a glass slide to achieve enhanced topographic interactions with nanoscale cellular surface components, again, anti-CD45 (a leukocyte common antigen) and anti-EpCAM (epithelial cell adhesion molecule) were then coated onto the surface of the nanofilm for advance depletion of white blood cells (WBCs) and specific isolation of CTCs, respectively. Comparing to the conventional positive enrichment technology, this method exhibited excellent biocompatibility and equally high capture efficiency. Moreover, the maximum number of background cells (WBCs) was removed, and viable and functional cancer cells were isolated with high purity. Utilizing the horizontally packed TiO2 nanofilm improved pure CTC-capture through combining cell-capture-agent and cancer cell-preferred nanoscale topography, which represented a new method capable of obtaining biologically functional CTCs for subsequent molecular analysis.

Meta-analysis of postoperative adjuvant chemotherapy without radiotherapy in early stage non-small cell lung cancer.

BACKGROUND: Many clinical trials have confirmed that postoperative adjuvant therapy can prolong survival of non-small cell lung cancer. However, the efficiency of postoperative chemotherapy without radiotherapy is unclear, especially in early stage (stages I and II). We aimed to assess the effect of postoperative chemotherapy without radiotherapy in early stage patients. METHODS: Databases and manual searches were adopted to identify eligible randomized control trials. Hazard ratio (HR) was used to assess the advantage of disease-free survival (DFS) and overall survival (OS) by fixed or random-effects models. RESULTS: Fourteen trials with 3,923 patients were included based on inclusion criteria. Compared with surgery alone, postoperative chemotherapy significantly improved DFS and OS with HR of 0.71 (P=0.005) and 0.74 (P<0.00001), respectively. Subgroup analysis showed both cisplatin-based (HR: 0.75, P<0.0001) and single tegafur-uracil (UFT) chemotherapy (HR: 0.72, P=0.002) yielded significant survival benefits, but the latter did not improve DFS (HR: 1.04, P=0.81). Indirect treatment comparison showed cisplatin-based chemotherapy was superior to single UFT in DFS, but comparable in OS. The benefits of postoperative chemotherapy were maintained in patients in stage I (HR: 0.74, P<0.00001) and IB (HR: 0.74, P=0.0003), but not in stage IA, although the trend supported chemotherapy (HR: 0.76, P=0.43). CONCLUSION: This meta-analysis demonstrates that postoperative chemotherapy without radiotherapy improves survival of stage I-II, I, and IB non-small cell lung cancer patients, but not for IA. Meanwhile, efficacy of cisplatin-based chemotherapy is comparable to single UFT in OS, but better in DFS, which should be paid more attention in future clinical practice.

The efficacy and safety of bevacizumab combined with chemotherapy in treatment of HER2-negative metastatic breast cancer: a meta-analysis based on published phase III trials.

Bevacizumab (Bev) combined with chemotherapy significantly improves progression-free survival (PFS) but not overall survival (OS) in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). The efficacy and safety depend on the type of chemotherapy combined with Bev. We performed a meta-analysis of phase III trials to evaluate the efficacy and safety of Bev + standard chemotherapy for HER2-negative MBC. The Cochrane Central Register of Controlled Trials, the Cochrane databases, EMBASE, MEDLINE, and ClinicalTrials.gov were analyzed. The primary outcomes included PFS, OS, and toxicity. Event-based hazard ratios (HRs) and relative risks (RRs) were expressed with the 95% confidence intervals (CIs). Four randomized controlled trials consisting of 3082 patients were included. Bev + standard chemotherapy improved PFS (HR 0.70, CI 0.64-0.77, P = 0.000) but had no effect on OS (HR 0.92, CI 0.82-1.02, P = 0.119). Bev + chemotherapy increased the incidence of febrile neutropenia (RR 1.45, CI 1.00 to 2.09, P = 0.048), proteinuria (RR 11.68, CI 3.72-36.70, P = 0.000), sensory neuropathy (RR 1.33, CI 1.05-1.70, P = 0.020), and grade ≥3 hypertension (RR 13.94, CI 7.06-27.55, P = 0.000). No differences in efficacy were observed between Bev + paclitaxel and Bev + capecitabine (Cape), but Bev + Cape increased the incidence of neutropenia. Bev + standard chemotherapy improved PFS in HER2-negative MBC patients. No benefit in OS was observed. Bev + Cape and Bev + paclitaxel had similar treatment efficacy, but Bev + Cape had a higher incidence of neutropenia.

Bilirubin modulates acetylcholine receptors in rat superior cervical ganglionic neurons in a bidirectional manner.

Autonomic dysfunction as a partial contributing factor to cardiovascular instability in jaundiced patients is often associated with increased serum bilirubin levels. Whether increased serum bilirubin levels could directly inhibit sympathetic ganglion transmission by blocking neuronal nicotinic acetylcholine receptors (nAChRs) remains to be elucidated. Conventional patch-clamp recordings were used to study the effect of bilirubin on nAChRs currents from enzymatically dissociated rat superior cervical ganglia (SCG) neurons. The results showed that low concnetrations (0.5 and 2 µM) of bilirubin enhanced the peak ACh-evoked currents, while high concentrations (3 to 5.5 µM) of bilirubin suppressed the currents with an IC50 of 4 ± 0.5 µM. In addition, bilirubin decreased the extent of desensitization of nAChRs in a concentration-dependent manner. This inhibitory effect of bilirubin on nAChRs channel currents was non-competitive and voltage independent. Bilirubin partly improved the inhibitory effect of forskolin on ACh-induced currents without affecting the action of H-89. These data suggest that the dual effects of enhancement and suppression of bilirubin on nAChR function may be ascribed to the action mechanism of positive allosteric modulation and direct blockade. Thus, suppression of sympathetic ganglionic transmission through postganglionic nAChRs inhibition may partially contribute to the adverse cardiovascular effects in jaundiced patients.