Immune checkpoint inhibitors in Cancer patients with rheumatologic preexisting autoimmune diseases: a systematic review and meta-analysis.

BACKGROUND: Patients with rheumatologic preexisting autoimmune disease (PAD) have not been enrolled in clinical trials of immune checkpoint inhibitors (ICIs). Therefore, the risks and benefits of ICI therapy in such patients are unclear. Herein, we investigated the safety and efficacy of ICIs in rheumatologic PAD patients through a meta-analysis. METHODS: The PubMed, Cochrane Library, Embase and Web of Science databases were searched for additional studies. We analyzed the following data through Stata software: incidence of total irAEs (TirAEs), rate of flares, incidence of new on-set irAEs, rate of discontinuation, objective response rate (ORR) and disease control rate (DCR). RESULTS: We identified 23 articles including 643 patients with rheumatologic PAD. The pooled incidences of TirAEs, flares and new-onset irAEs were 64% (95% CI 55%-72%), 41% (95% CI 31%-50%), and 33% (95% CI 28%-38%), respectively. In terms of severity, the incidences were 7% (95% CI 2%-14%) for Grade 3-4 flares and 12% (95% CI 9%-15%) for Grade 3-4 new-onset irAEs. Patients with RA had a greater risk of flares than patients with other rheumatologic PADs did (RR = 1.35, 95% CI 1.03-1.77). The ORR and DCR were 30% and 44%, respectively. Baseline anti-rheumatic treatment was not significantly associated with the frequency of flares (RR = 1.05, 95% CI 0.63-1.77) or the ORR (RR = 0.45, 95% CI 0.12-1.69). CONCLUSIONS: Patients with rheumatologic PAD, particularly those with RA, are susceptible to relapse of their rheumatologic disease following ICI therapy. ICIs are also effective for treating rheumatologic PAD patients. PROSPECTIVE REGISTER OF SYSTEMATIC REVIEWS (PROSPERO): number CRD 42,023,439,702.

Efficacy and safety of VEGF/VEGFR inhibitors for platinum-resistant ovarian cancer: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Almost all patients with ovarian cancer will experience relapse and eventually develop platinum-resistant. The poor prognosis and limited treatment options have prompted the search for novel approaches in managing platinum-resistant ovarian cancer (PROC). Therefore, a meta-analysis was conducted to evaluate the efficacy and safety of combination therapy with vascular endothelial growth factor (VEGF) /VEGF receptor (VEGFR) inhibitors for PROC. METHODS: A comprehensive search of online databases was conducted to identify randomized clinical trials published until December 31, 2022. Pooled hazard ratios (HR) was calculated for overall survival (OS) and progression-free survival (PFS), while pooled odds ratio (OR) was calculated for objective response rate (ORR) and treatment-related adverse events (TRAEs). Subgroup analysis was further performed to investigate the source of heterogeneity. RESULTS: In total, 1097 patients from eight randomized clinical trials were included in this meta-analysis. The pooled HRs of OS (HR = 0.72; 95% CI: 0.62-0.84, p < 0.0001) and PFS (HR = 0.52; 95% CI: 0.45-0.59, p < 0.0001) demonstrated a significant prolongation in the combination group compared to chemotherapy alone for PROC. In addition, combination therapy demonstrated a superior ORR compared to monotherapy (OR = 2.34; 95%CI: 1.27-4.32, p < 0.0001). Subgroup analysis indicated that the combination treatment of VEGF/VEGFR inhibitors and chemotherapy was significantly more effective than monochemotherapy in terms of OS (HR = 0.71; 95% CI: 0.61-0.84, p < 0.0001), PFS (HR = 0.49; 95% CI: 0.42-0.57, p < 0.0001), and ORR (OR = 2.97; 95% CI: 1.89-4.67, p < 0.0001). Although the combination therapy was associated with higher incidences of hypertension, mucositis, proteinuria, diarrhea, and hand-foot syndrome compared to monochemotherapy, these toxicities were manageable and well-tolerated. CONCLUSIONS: The meta-analysis demonstrated that combination therapy with VEGF/VEGFR inhibitors yielded better clinical outcomes for patients with PROC compared to monochemotherapy, especially when combined with chemotherapy. This analysis provides more treatment options for patients with PROC. SYSTEMATIC REVIEW REGISTRATION: [ https://www.crd.york.ac.uk/PROSPERO ], Prospective Register of Systematic Reviews (PROSPERO), identifier: CRD42023402050.

Comparison of endoscopic resection therapies for rectal neuroendocrine tumors.

AIMS: This study was to evaluate and compare the efficacy and safety of endoscopic mucosal resection (EMR), clip-and-snare assisted endoscopic mucosal resection (CS-EMR), and endoscopic submucosal dissection (ESD) for the endoscopic resection of rectal NETs. MATERIAL AND METHODS: A retrospective analysis was performed on 47 patients with rectal NETs who underwent endoscopic treatment in The Second Affiliated Hospital of Soochow University. Manifestations of clinic pathological characteristics, complications, procedure time and hospitalization costs were studied. RESULTS: The complete resection rates with CS-EMR and ESD were significantly higher than those with EMR (CS-EMR vs. EMR, p = 0.038; ESD vs. EMR, p = 0.04), but no significant difference was found between the CS-EMR and ESD groups (p = 0.383). The lateral margin was less distant in the CS-EMR group than in the ESD group and there was no difference with regard to vertical margin (lateral margin distance, 1500 ± 3125 vs.3000 ± 3000 µm; vertical margin distance, 400 ± 275 vs.500 ± 500 µm). Compared to ESD, CS-EMR required less operation time (p < 0.01) and money (p < 0.01) and reduced the length of hospital stays (p < 0.01). CONCLUSIONS: The CS-EMR technique is more effective and efficient than EMR for small rectal NETs. In addition, CS-EMR reduces procedure time, duration of post-procedure hospitalization and decreases patients' cost compared to ESD while ensuring sufficient vertical margin distances.

A chromosome-level genome of Syringa oblata provides new insights into chromosome formation in Oleaceae and evolutionary history of lilacs.

Lilacs (Syringa L.), a group of well-known ornamental and aromatic woody plants, have long been used for gardening, essential oils and medicine purposes in East Asia and Europe. The lack of knowledge about the complete genome of Syringa not only hampers effort to better understand its evolutionary history, but also prevents genome-based functional gene mining that can help in the variety improvement and medicine development. Here, a chromosome-level genome of Syringa oblata is presented, which has a size of 1.12 Gb including 53 944 protein coding genes. Synteny analysis revealed that a recent duplication event and parallel evolution of two subgenomes formed the current karyotype. Evolutionary analysis, transcriptomics and metabolic profiling showed that segment and tandem duplications contributed to scent formation in the woody aromatic species. Moreover, phylogenetic analysis indicated that S. oblata shared a common ancestor with Osmanthus fragrans and Olea europaea approximately 27.61 million years ago (Mya). Biogeographic reconstruction based on a resequenced data set of 26 species suggested that Syringa originated in the northern part of East Asia during the Miocene (approximately 14.73 Mya) and that the five Syringa groups initially formed before the Late Miocene (approximately 9.97 Mya). Furthermore, multidirectional dispersals accompanied by gene introgression among Syringa species from Northern China during the Miocene were detected by biogeographic reconstruction. Taken together, the results showed that complex gene introgression, which occurred during speciation history, greatly contributed to Syringa diversity.

Efficacy and safety of PD-1/PD-L1 inhibitors combined with anti-angiogenic therapy for the unresectable hepatocellular carcinoma and the benefit for hepatitis B virus etiology subgroup: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death, worldwide. The predominant causative factor for HCC is hepatitis B virus (HBV) infection. We conducted a meta-analysis to estimate the efficacy and safety of PD-1/PD-L1 inhibitors combined with anti-angiogenic therapy for the first-line treatment of the unresectable HCC and to evaluate the benefits of different geographic regions and etiology stratifications. METHODS: Randomized clinical trials published up to 12th November 2022 were searched by online databases. Moreover, effects of hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) were extracted from included studies. Pooled odds ratio (OR) and 95% CI for objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs) were calculated. RESULTS: A total of 3057 patients from five phase III randomized clinical trials were collected and reviewed for this meta-analysis. The pooled HR of OS (HR = 0.71; 95% CI: 0.60-0.85) and PFS (HR = 0.64; 95% CI: 0.53-0.77) demonstrated significantly better benefit in PD-1/PD-L1 inhibitors combination group than targeted monotherapy to treat unresectable HCC. In addition, combination therapy showed better ORR and DCR, with ORs of 3.29 (95% CI: 1.92-5.62) and 1.88 (95% CI: 1.35-2.61), respectively. The subgroup analysis indicated that PD-1/PD-L1 inhibitors combination therapy was significantly superior to anti-angiogenic monotherapy for HBV-related HCC in terms of OS (HR = 0.64; 95% CI: 0.55-0.74) and PFS (HR = 0.53; 95% CI:0.47-0.59), while there was no significant difference in patients with HCV (OS, HR = 0.81, p = 0.1) or non-viral (OS, HR = 0.91, p = 0.37; PFS, HR = 0.77, p = 0.05). CONCLUSIONS: Meta-analysis revealed for the first-time that PD-1/PD-L1 inhibitors combination therapy for unresectable HCC was associated with better clinical outcomes than anti-angiogenic monotherapy, especially for HBV infection and Asian population.

Three-Dimensional Speckle-Tracking Echocardiography to Evaluate Left Ventricular Function of Patients with Breast Cancer After Anthracycline Chemotherapy.

Objective: To explore the use of 3-dimensional speckle-tracking echocardiography (3DSTE) to evaluate changes in left ventricular function in patients with breast cancer after anthracycline chemotherapy. Methods: The clinical data of 30 patients with breast cancer diagnosed by pathology at The Third Affiliated Hospital of Qiqihar Medical University from December 2020 to December 2022 were collected for retrospective analysis. All patients received anthracycline chemotherapy, and serum cardiac troponin T (cTnT) concentrations were measured within 24 to 48 hours before chemotherapy and after 1 cycle and 4 cycles of chemotherapy. Then, conventional ultrasonography, routine echocardiography, and 3DSTE were performed to obtain dynamic images and parameters such as left ventricular global longitudinal strain, global area strain, global circumferential strain, global radial strain, and twist values. The myocardial comprehensive index was calculated to compare changes before and after anthracycline chemotherapy. A receiver operating characteristic curve was created for each parameter, and the areas under the curves were calculated. Results: Except for left ventricular end-diastolic diameter and end-diastolic interventricular septum thickness, the other conventional ultrasonography parameters differed at the 3 chemotherapy time points tested (all P < .001). The parameters as measured by 3DSTE decreased with an increased cumulative dose of anthracycline drugs, and the values differed at the different time points (all P < .001); the MCI value decreased the most. The serum cTnT concentrations of 9 patients after 4 cycles of chemotherapy were higher than the normal range, and the serum cTnT concentrations differed at the different chemotherapy time points (P < .001). Receiver operating characteristic curve analysis showed that the area under the curve value for MCI was higher than other quantitative parameters of imaging; for MCI, the area under the curve was 0.799, the Youden index was 0.683, the sensitivity was 77.80%, and the specificity was 90.50%. Conclusion: 3DSTE is helpful for early detection of damage to left ventricular function in patients with breast cancer treated with anthracycline drugs, and MCI is the most sensitive observation index among the parameters tested.

The prognostic role of tumor mutation burden on survival of breast cancer: a systematic review and meta-analysis.

BACKGROUND: As a potential genetic biomarker, tumor mutation burden (TMB) has made progress in numerous tumors. There are limited data regarding TMB and its prognostic role is controversial in breast cancer. This systematic review and meta-analysis were conducted to assess the prognostic value of TMB on survival of breast cancer. METHODS: The databases PubMed, Embase, Web of Science, and Cochrane Library were searched for articles published through May 31, 2022. Moreover, effective data were extracted from included studies and calculated pooled effects of hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) by STATA 16.0. Heterogeneity was conducted by the I2 statistic and p-value. Using publication bias evaluation, sensitivity analysis, and subgroup analysis, the origin of heterogeneity was further investigated. RESULTS: They were up to 1,722 patients collected from sixteen cohorts for this analysis. The pooled effects of HR for both OS (HR: 1.14, 95% CI: 0.83,1.58, p > 0.01) and PFS (HR: 0.96, 95% CI: 0.53,1.71, p > 0.01) indicated no statistically significant difference in the high TMB and low TMB group. In immune checkpoint inhibitors (ICIs) subgroup, high TMB patients demonstrated benefit of OS (HR: 0.72, 95% CI: 0.59,0.87, p = 0.001) and PFS (HR: 0.52, 95% CI: 0.35,0.77, p < 0.001), whereas difference was not statistically significant in the non-ICIs subgroup (OS, HR:1.76, 95% CI: 0.97,3.20, p = 0.062; PFS, HR:2.31, 95% CI: 0.89,5.97, p = 0.086). In addition, sensitivity analysis revealed that the pooled effects were stable. The funnel plot and Begg's test suggested the absence of publication bias. CONCLUSION: Meta-analysis revealed that the prognostic relevance of TMB in breast cancer is limited in scope. High TMB may be associated with longer survival only in ICIs-based treatment, but the association is not evident in non-ICIs-based treatment. TRIAL REGISTRATION: [ https://www.crd.york.ac.uk/PROSPERO ], Prospective Register of Systematic Reviews (PROSPERO), identifier: CRD42022342488.

Design, synthesis and activity evaluation of prodrug form JBP485 and Vitamin E for alleviation of NASH.

Non-alcoholic steatohepatitis (NASH) is a serious form of non-alcoholic fatty liver disease (NAFLD) characterized by liver steatosis with lobular inflammation, hepatocyte injury and pericellular fibrosis. JBP485 is a hydrophilic dipeptide with protective effects on liver through alleviation of oxidative stress and inhibition of hepatocyte apoptosis and ICAM-1 expression. Vitamin E (VE), as a powerful biological antioxidant, exerts a certain protective effect on cell membranes and lipoproteins from lipid peroxidation. In this study, on the basis of the structural characteristics of two agents, the prodrug form target of JBP485 and VE (JBP485-VE) was designed and synthesized via succinic acid linker. The synthesized compound significantly reduced the degree of inflammation and fibrosis according to hematoxylin-eosin (H&E) and sirius red staining assay for the liver tissue in CCl4-induced NASH mouse model. The clear reduction of TG, T-CHO and ALT, AST content also demonstrated its efficacy in the treatment of NASH. In addition, JBP485-VE also reduced the expression of the inflammatory markers IL-2, IL-17A and malondialdehyde (MDA) in liver tissue, which indicated its higher anti-inflammatory and anti-oxidative stress activity. All these evaluated biological properties suggest that the strategy of prodrug design provided an effective method for the treatment of NASH.

Unraveling the Biosynthesis of Carvacrol in Different Tissues of Origanum vulgare.

Origanum vulgare, belonging to the Lamiaceae family, is a principal culinary herb used worldwide which possesses great antioxidant and antibacterial properties corresponding to various volatile organic components (VOCs). However, the metabolite profiles and underlying biosynthesis mechanisms of elaborate tissues (stems, leaves, bracts, sepals, petals) of Origanum vulgare have seldom been reported. Here, solid-phase microextraction-gas chromatography/mass spectrometry results showed that Origanum vulgare 'Hot and Spicy' (O. vulgare 'HS') was extremely rich in carvacrol and had the tissue dependence characteristic. Moreover, a full-length transcriptome analysis revealed carvacrol biosynthesis and its tissue-specific expression patterns of 'upstream' MVA/MEP pathway genes and 'downstream' modifier genes of TPSs, CYPs, and SDRs. Furthermore, the systems biology method of modular organization analysis was applied to cluster 16,341 differently expressed genes into nine modules and to identify significant carvacrol- and peltate glandular trichome-correlated modules. In terms of these positive and negative modules, weighted gene co-expression network analysis results showed that carvacrol biosynthetic pathway genes are highly co-expressed with TF genes, such as ZIPs and bHLHs, indicating their involvement in regulating the biosynthesis of carvacrol. Our findings shed light on the tissue specificity of VOC accumulation in O. vulgare 'HS' and identified key candidate genes for carvacrol biosynthesis, which would allow metabolic engineering and breeding of Origanum cultivars.

Rapid Detection of Five Estrogens Added Illegally to Dietary Supplements by Combining TLC with Raman Imaging Microscope.

Estrogens added illegally to dietary supplements are hazardous to human health. Traditional detection and analysis methods have many limitations, and we have developed an assay that combines thin-layer chromatography with Raman imaging microscopy (TLC-RIM). The five estrogens (estrone, estradiol, estriol, ethinyl estradiol, and diethylstilbestrol) were initially separated by TLC, then detected by area scanning Raman imaging with a 532 nm laser under a microscope. Raman spectra were obtained for each estrogen, which were used for detecting estrogen illegally added to botanical dietary supplements. The LOD of each estrogen was 0.4, 1.0, 0.8, 0.2, and 0.2 mg/mL, respectively. The matrix in the real sample did not interfere with the detection of estrogens. The method was fast, sensitive, stable, specific, and reliable.

A Phenothiazine-HPQ Based Fluorescent Probe with a Large Stokes Shift for Sensing Biothiols in Living Systems.

Due to the redox properties closely related to numerous physiological and pathological processes, biothiols, including cysteine (Cys), homocysteine (Hcy) and glutathione (GSH), have received considerable attention in biological science. On account of the important physiological roles of these biothiols, it is of profound significance to develop sensitive and selective detection of biothiols to understand their biological profiles. In this work, we reported an efficient fluorescent probe, PHPQ-SH, for detecting biothiols in vitro and vivo, based on the phenothiazine-HPQ skeleton, with DNBS (2,4-dinitrobenzenesulfonate) as the response unit. Probe PHPQ-SH exhibited brilliant sensing performances toward thiols, including a large Stokes shift (138 nm), excellent sensitivity (for GSH, LOD = 18.3 nM), remarkable fluorescence enhancement (163-fold), low cytotoxicity, rapid response (8 min), and extraordinary selectivity. Finally, the probe PHPQ-SH illustrated herein was capable of responding and visualizing biothiols in MCF-7 cells and zebrafish.

Clinicopathological evidence of hepatitis B virus infection in the development of gastric adenocarcinoma.

Gastric cancer (GC) is one of the infection-related cancers. Helicobacter pylori and Epstein-Barr virus (EBV) were established risk factors for GC. Recently, there are several reports showing the inconsistent association between hepatitis B virus (HBV) infection and the development of GC. To explore the relationship between HBV infection and the development of GC, we designed a meta-analysis of previous epidemiological studies, a hospital-based case-control study, followed by an immunohistochemistry (IHC) assay of HBV-exposed GC samples. We found that HBV infection was associated with an increased risk of GC based on the meta-analysis. No significant association between HBV infection and GC was detected according to our hospital-based case-control study. Histological examination showed that the gastric epithelium positive for HBx demonstrated a higher nuclear-cytoplasmic ratio compared to those HBx-negative cells. HBx and HBcAg were expressed more in tumors than those in normal counterparts in HBV-exposed subjects, and PD-L1 was lower in GC tissues from HBV carriers than those in HBV clearances. In conclusion, HBV infection may contribute to a higher risk for GC based on the meta-analysis and to the morphological atypia of gastric epithelium by the histological assessment, and GC patients among HBV carriers showed lower expression of PD-L1 may lose the chance for immune checkpoint blockade therapy.

Fenretinide-polyethylene glycol (PEG) conjugate with improved solubility enhanced cytotoxicity to cancer cell and potent in vivo efficacy.

Fenretinide (4-HPR), a synthetic retinoid, has shown its antitumor activity in many tumor types with low cytotoxicity to normal cells and high clinical safety. However, the low water solubility limits its further biological applications. To increase solubility, 4-HPR was conjugated with methoxy polyethylene glycol carboxylic acid (mPEG2K-COOH) by an ester linkage between the phenol hydroxyl of 4-HPR and the carboxyl of mPEG2K-COOH. The 4-HPR-PEG2K conjugate micelles had mean size of 76.70 ± 1.248 nm with a narrow distribution and a low critical micelle concentration. In vitro cytotoxicity studies showed the micelles have higher cytotoxicity to A2780s and MCF-7 cells. Its IC50 was 4.7 and 4.1-fold lower than the free 4-HPR, respectively. Importantly, in vivo pharmacokinetic studies, the AUC of 4-HPR was found to be 2.3-fold higher in 4-HPR-PEG2K micelles compared to free 4-HPR. And the 4-HPR-PEG2K micelles had higher antitumor activity. Meanwhile, the histopathology analysis exhibited that the micellar treatment decreased the viability of A2780s cells and increased the level of induced apoptosis. Therefore, the enhanced activity of 4-HPR by the method of conjugation with mPEG2K-COOH could hopefully provide new insights into the matter of ovarian cancer and breast cancer treatment.

ErbB4 acts as a suppressor in colitis and its associated carcinoma by negatively regulating cholesterol metabolism.

Previously we reported that ErbB4 played a protective role in chronic liver injury and hepatocellular carcinoma. Herein, we examined the role of ErbB4 in the development of colitis-associated cancer (CAC) in ErbB4 knockout mice models, in vitro cell lines and clinical samples. We found that ErbB4 deficiency may lead to more severe inflammation, slower recovery and the development of CAC. Further, loss of ErbB4 could activate Kras by upregulating rate-limiting enzymes in cholesterol metabolism pathway through interacting with the transcription factor Srebf1. In clinic samples, ErbB4 is downregulated in colonic tissues from patients with Crohn's disease. And data from The Cancer Genome Atlas also showed significant negative correlation between ErbB4 and several cholesterol metabolic enzymes. In summary, our study uncovers ErbB4 as a protector in the development of CAC, for its loss could activate Kras by upregulating cholesterol metabolism.

Time-series transcriptome provides insights into the gene regulation network involved in the volatile terpenoid metabolism during the flower development of lavender.

BACKGROUND: Essential oils (EOs) of Lavandula angustifolia, mainly consist of monoterpenoids and sesquiterpenoids, are of great commercial value. The multi-flower spiciform thyrse of lavender not only determines the output of EOs but also reflects an environmental adaption strategy. With the flower development and blossom in turn, the fluctuation of the volatile terpenoids displayed a regular change at each axis. However, the molecular mechanism underlying the regulation of volatile terpenoids during the process of flowering is poorly understood in lavender. Here, we combine metabolite and RNA-Seq analyses of flowers of five developmental stages at first- and second-axis (FFDSFSA) and initial flower bud (FB0) to discover the active terpenoid biosynthesis as well as flowering-related genes. RESULTS: A total of 56 mono- and sesquiterpenoids were identified in the EOs of L. angustifolia 'JX-2'. FB0' EO consists of 55 compounds and the two highest compounds, ß-trans-ocimene (20.57%) and (+)-R-limonene (17.00%), can get rid of 74.71 and 78.41% aphids in Y-tube olfactometer experiments, respectively. With sequential and successive blossoms, temporally regulated volatiles were linked to pollinator attraction in field and olfaction bioassays. In three characteristic compounds of FFDSFSA' EOs, linalyl acetate (72.73%) and lavandulyl acetate (72.09%) attracted more bees than linalool (45.35%). Many transcripts related to flowering time and volatile terpenoid metabolism expressed differently during the flower development. Similar metabolic and transcriptomic profiles were observed when florets from the two axes were maintained at the same maturity grade. Besides both compounds and differentially expressed genes were rich in FB0, most volatile compounds were significantly correlated with FB0-specific gene module. Most key regulators related to flowering and terpenoid metabolism were interconnected in the subnetwork of FB0-specific module, suggesting the cross-talk between the two biological processes to some degree. CONCLUSIONS: Characteristic compounds and gene expression profile of FB0 exhibit ecological value in pest control. The precise control of each-axis flowering and regular emissions at transcriptional and metabolic level are important to pollinators attraction for lavender. Our study sheds new light on lavender maximizes its fitness from "gene-volatile terpenoid-insect" three layers.

Effect of Deubiquitinase Ovarian Tumor Domain-Containing Protein 5 (OTUD5) on Radiosensitivity of Cervical Cancer by Regulating the Ubiquitination of Akt and its Mechanism.

BACKGROUND The aim of this study was to investigate the role of deubiquitinase [ovarian tumor domain-containing protein 5 (OTUD5)] in regulating Akt ubiquitination and its effect on the radiosensitivity of cervical cancer. MATERIAL AND METHODS Cervical cancer C33A cells were cultured, and then 2 groups of cells (overexpressed cells and silenced cells) were established by overexpressing and silencing OTUD5 gene. Next, quantitative polymerase chain reaction (qPCR) was employed to detect the expression level of OTUD5 in cells in each group. Co-immunoprecipitation and Western blot (WB) analysis were applied to measure the expression level of phosphorylated protein kinase B (Akt) and the level of ubiquitination. The sensitivity of cells to radiotherapy in each group was detected via clone-forming efficiency assay. After that, Statistical Product and Service Solutions (SPSS) 17.0 software was employed for analyses. The t test, one-way analysis of variance (ANOVA), and p test were used. P<0.05 suggested that a difference was statistically significant. RESULTS The levels of phosphorylated Akt and ubiquitination in OTUD5-overexpressed C33A cells were lower than those in the OTUD5-silenced group and control group. The sensitivity of OTUD5-overexpressed C33A cells to radiotherapy was higher than that of the OTUD5-silenced group and control group. CONCLUSIONS OTUD5 affects the radiosensitivity of cervical cancer through the regulation of Akt deubiquitination.

Evolution of leaf structure and drought tolerance in species of Californian Ceanothus.

PREMISE OF THE STUDY: Studies across diverse species have established theory for the contribution of leaf traits to plant drought tolerance. For example, species in more arid climates tend to have smaller leaves of higher vein density, higher leaf mass per area, and more negative osmotic potential at turgor loss point (πTLP ). However, few studies have tested these associations for species within a given lineage that have diversified across an aridity gradient. METHODS: We analyzed the anatomy and physiology of 10 Ceanothus (Rhamnaceae) species grown in a common garden for variation between and within "wet" and "dry" subgenera (Ceanothus and Cerastes, respectively) and analyzed a database for 35 species for leaf size and leaf mass per area (LMA). We used a phylogenetic generalized least squares approach to test hypothesized relationships among traits, and of traits with climatic aridity in the native range. We also tested for allometric relationships among anatomical traits. KEY RESULTS: Leaf form, anatomy, and drought tolerance varied strongly among species within and between subgenera. Cerastes species had specialized anatomy including hypodermis and encrypted stomata that may confer superior water storage and retention. The osmotic potentials at turgor loss point (πTLP ) and full turgor (πo ) showed evolutionary correlations with the aridity index (AI) and precipitation of the 10 species' native distributions, and LMA with potential evapotranspiration for the 35 species in the larger database. We found an allometric correlation between upper and lower epidermal cell wall thicknesses, but other anatomical traits diversified independently. CONCLUSIONS: Leaf traits and drought tolerance evolved within and across lineages of Ceanothus consistently with climatic distributions. The πTLP has signal to indicate the evolution of drought tolerance within small clades.

ERBB4 acts as a suppressor in the development of hepatocellular carcinoma.

ERBB4, one member of the epidermal growth factor receptor (EGFR) family, plays a key role in physiological and pathological processes. Recently, we identified that ERBB4 played a protective role from chronic hepatitis B virus infection. However, the role of ERBB4 in hepatocellular carcinoma (HCC) is still unclear. Here, we explore the role of ERBB4 in the development of HCC using in vitro models, in vivo animal models and clinical samples of HCC. Liver-specific ERBB4 knockout alleles and full ERBB4 except heart knockout mice were used in this study. Liver inflammation and tumor models of mice were produced by carbon tetrachloride (CCl4) and diethylnitrosamine (DEN) administration, respectively. Commercial tissue arrays of 90 HCC patients with paired counterparts were used to evaluate the expression and the prognostic value of ERBB4. Genes altered in the setting of ERBB4 loss was studied by microarray analysis and further validated by real-time PCR. We have found that depletion of ERBB4 in mice leads to more severe injury and liver tumor formation and loss of ERBB4 contributes to the development of hepatocellular tumor. In clinic samples of HCC, ERBB4 is down-regulated and exhibit prognostic value of HCC patients. Mechanistically, loss of ERBB4 suppressed p53 expression by inhibiting the expression of the tumor suppressor tp53inp1. Our study uncovers ERBB4 as a suppressor in the development of HCC and implies an ERBB4-TP53INP1-P53 axis in HCC.

[Effect of lupeol on migration and invasion of human breast cancer MDA-MB-231 cells and its mechanism].

In this study, we examined the inhibitory effects of lupeol, an extract of Euphorbia fischerana Steud, on human breast cancer MDA-MB-231 cells migration and invasion. Lupeol was found to inhibit the invasion of MDA-MB-231 in the cell adhesion assay, transwell test and wound healing assay. The expression of cyclooxygenase-2 (COX-2), matrix metalloproteinase-2 (MMP-2), -9 (MMP-9) and nuclear transcription factor-kappa B (NF-κB) p65 in breast cancer following treatment with different concentrations of lupeol was analyzed with Western blot. Lupeol inhibited the migration and invasion of MDA-MB-231 cells in a dose- dependent manner in vitro (P < 0.05). The expression of COX-2, MMP-2, MMP-9 and NF-κB p65 levels was significantly down-regulated. These observations suggest that lupeol can inhibit the abilities of invasion of MDA-MB-231 cells by inhibiting the protein expression of COX-2, MMP-2 and MMP-9. Its mechanism may be related to inhibition of the nuclear NF-κB signal pathway.

[Effect of ethyl gallate on invasion abilities and its mechanism of breast cancer MDA-MB-231 cells].

This study is to investigate the effect of ethyl gallate on invasion capabilities and its mechanism of breast cancer MDA-MB-231 cells. Using cell adhesion and transwell assay, separately, the effects of ethyl gallate on the invasion of MDA-MB-231 cells were measured. The Akt-NF-κB signal pathway protein expressions were analyzed with Western blot. Also, the mRNA levels of MMP-9 and MMP-2 were analyzed by RT-PCR. Ethyl gallate inhibited the abilities of motility, adhesion and invasion of breast cancer MDA-MB-231 cells in vitro (P<0.05), inhibited the mRNA levels of MMP-9, MMP-2, phosphorylation of AKt and protein expression of NF-κB. It is concluded that ethyl gallate can inhibit the abilities of invasion of breast cancer in vitro by inhibiting the mRNA levels of MMP-9/MMP-2, phosphorylation of Akt and protein expression of NF-κB.