Cldn4 overexpression promotes penile cavernous smooth muscle cell fibrotic response via the JNK signaling pathway.

BACKGROUND: Erectile dysfunction (ED), defined as the inability to achieve or maintain a penile erection sufficient to satisfy sexual behavior, is prevalent worldwide. AIM: Using previous research, bioinformatics, and experimental confirmation, we aimed to discover genes that contribute to ED through regulating hypoxia in corpus cavernosum smooth muscle cells (CCSMCs). METHODS: We used the Gene Expression Omnibus to acquire the sequencing data of the corpus cavernosum transcriptome for diabetic ED and nerve injury type ED rats. We intersected the common differentially expressed genes. Further verification was performed using single cell sequencing. Real-time quantitative polymerase chain reaction and immunofluorescence were used to investigate whether the differentially expressed genes are found in the corpus cavernosum. We used induced hypoxia to assess cell viability changes, and we developed a lentivirus overexpressing Cldn4 for in vitro and in vivo experiments to measure changes in JNK signaling, fibrosis, hypoxia, and erectile function. OUTCOMES: Our results indicate that targeting the JNK pathway and decreasing local hypoxia may be better options for therapeutic intervention to improve erectile function. RESULTS: We identified Cldn4 and found its expression increased in the corpora cavernosa of the 2 datasets. In addition, we found that hypoxia can increase the expression of Cldn4, activate the JNK signaling pathway, and exacerbate fibrosis in CCSMCs. Cldn4 overexpression in CCSMCs activated the JNK signaling pathway and increased fibrotic protein expression. Last, rat corpus cavernosum overexpressing Cldn4 activated the JNK signaling pathway, increased local fibrosis, and impaired erectile function. CLINICAL IMPLICATIONS: Through bioinformatics and in vitro and in vivo experiments, we found that Cldn4 has a negative effect on ED, and targeting Cldn4 may provide new ideas for ED treatment. STRENGTHS AND LIMITATIONS: Although we have identified Cldn4 as a potential target for ED treatment, we have only conducted preliminary validation on CCMSCs, and we still need to further validate in other cell lines. CONCLUSION: CCSMC hypoxia leads to increased Cldn4, in both nerve injury and diabetic ED rat models, and promotes fibrosis by activating the JNK signaling pathway.

Spinal microglial M1 polarization contributes paclitaxel-induced neuropathic pain by triggering cells necroptosis.

Paclitaxel (PTX) is a chemotherapeutic agent that is widely used for the treatment of several types of tumors. However, PTX-induced peripheral neuropathy (PIPN) is an adverse effect generally induced by long-term PTX use that significantly impairs the quality of life. Necroptosis has been implicated in various neurodegenerative disorders. Necroptosis of dorsal root ganglion neurons triggers the pathogenesis of PIPN. Therefore, the present study aims to investigate the role of spinal neuronal necroptosis in PIPN. It also explores the potential role of microglial polarization in necroptosis. We established rat models of PIPN via quartic PTX administration on alternate days (accumulated dose: 8 mg/kg). PTX induced obvious neuronal necroptosis and upregulated the expression of receptor-interacting protein kinase (RIP3) and mixed lineage kinase domain-like protein (MLKL) in the spinal dorsal horn. These effects were inhibited with a necroptosis pathway inhibitor, necrostatin-1 (Nec-1). The effect of microglial polarization on the regulation of spinal necroptosis was elucidated by administering minocycline to inhibit PTX-induced M1 polarization of spinal microglia caused by PTX. We observed a significant inhibitory effect of minocycline on PTX-induced necroptosis in spinal cord cells, based on the downregulation of RIP3 and MLKL expression, and suppression of tumor necrosis factor-α and IL-ß synthesis. Additionally, minocycline improved hyperalgesia symptoms in PIPN rats. Overall, this study suggests that PTX-induced polarization of spinal microglia leads to RIP3/MLKL-regulated necroptosis, resulting in PIPN. These findings suggest a potential target for the prevention and treatment of neuropathic pain.

Music therapy for tinnitus: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the clinical efficacy of music therapy in the treatment of tinnitus. METHODS: Three English databases (PUBMED, Embase, Web of Science) and three Chinese databases (CNKI, VIP, and Wanfang) were searched, and eligible articles were selected according to the set inclusion criteria. Clinical efficacy was used as the primary outcome, and each score was used as the secondary outcome. Using RevMan5.3 software for statistical analysis. RESULTS: A total of 14 studies involving 1239 tinnitus patients were included. The results of the meta-analysis showed that music therapy had a certain clinical efficacy in the treatment of tinnitus, but there was no significant difference compared with the control group (OR = 1.00, 95%CI =0.83-1.22; P = 1.00). However, music therapy significantly improved THI score (MD = -6.77, 95 % CI = -9.62 to -3.92; P < 0.00001), TSQ (MD = -2.80, 95 % CI = -3.23 to -2.36; P < 0.00001), tinnitus loudness (MD = -3.90, 95 % CI = -6.58 to -1.23; P = 0.004), VAS score (MD = -1.11, 95 % CI = -2.11 to -0.11; P = 0.03) and TQ score (MD = -8.36, 95 % CI = -11.10 to -5.62; P < 0.001). CONCLUSION: Music therapy is an effective method for the treatment of tinnitus, which can improve the THI score, tinnitus severity, VAS score, and TQ score and reduce the loudness of tinnitus. Due to the low quality of the included literature, the current conclusions need to be further verified by more and higher-quality studies.

Transcriptome analysis of response mechanism to Microcystin-LR and microplastics stress in Asian clam (Corbicula fluminea).

In this study, we analyzed the hepatopancreas tissues of Asian Clam (Corbicula fluminea) exposed to three different adverse environmental conditions from the same batch using RNA-seq. The four treatment groups included the Asian Clam group treated with Microcystin-LR (MC), the Microplastics-treated group (MP), the Microcystin-LR and Microplastics-treated group (MP-MC), and the Control group. Our Gene Ontology analysis revealed 19,173 enriched genes, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis identified 345 related pathways. The KEGG pathway analysis demonstrated that the MC vs control group and the MP vs control group were significantly enriched in immune and catabolic pathways such as Antigen processing and presentation, Rheumatoid arthritis, Lysosome pathway, Phagosome pathway, and Autophagy pathway. We also evaluated the effects of Microplastics and Microcystin-LR on the activities of eight antioxidant enzymes and immune enzymes in Asian clams. Our study enriched the genetic resources of Asian clams and provided valuable information for understanding the response mechanism of Asian clams to microplastics and microcystin in the environment, through the identification of differentially expressed genes and related pathway analyses from the large number of transcriptome sequences obtained.

Myelodysplastic Syndrome Treated by Integrated Chinese and Western Medicine: A Case Report.

Context: Myelodysplastic syndrome (MDS) is a group of highly heterogeneous, malignant clonal diseases derived from hematopoietic stem cells. PD-1 monoclonal antibodies can have a synergistic effect with hypomethylating agents (HMAs), especially for patients with drug resistance to demethylation drugs. TCM in the treatment of MDS can improve hematological indexes, and for some patients, control the proliferation of primitive cells and delay or even block the transformation to leukemia. Objective: The study intended to examine the therapeutic effects of programmed cell death-1 (PD-1) inhibitors and azacitidine combined with the Yisuifang Thick Decoction in the treatment of MDS with older, high-risk patients. Design: The research team performed five prospective case studies. Setting: The study took place at the East Hospital affiliated with Beijing University of Chinese Medicine in Beijing, China. Participants: Participants were five older, high-risk MDS patients at the hospital who received PD-1 and azacitidine combined with Yisuifang Thick Decoction between April 2020 and June 2021. Outcome Measures: The research team measured: (1) treatment duration, (2) curative effects, (3) myelosuppression, (4) immune-related adverse reactions, (5) ending outcomes, and (6) progression-free survival (PFS). Results: The male to female ratio for the five participants was 3:2, and the median age was 69 years, with a range from 62 to 79 years. Four participants had refractory HR-MDS and one had primary MDS. The median treatment duration was 3 months, with a range from 2 to 4 months, and the median progression-free survival (PFS) was 5 months, with a range from 3 to 14 months. All participants achieved a partial response (PR) or a complete remission with incomplete count recovery (CRi) and showed improvement in serological indexes. Conclusions: Older, high-risk MDS patients generally have poor physical conditions, often accompanied by a poor karyotype prognosis and a poor prognosis for survival. Therefore, the combination of PD-1, azacytidine, and Yisuifang Thick Decoction may be an effective way to treat HR-MDS.

Enhanced Production of Active Photosynthetic and Biochemical Molecules in Silybum marianum L. Using Biotic and Abiotic Elicitors in Hydroponic Culture.

Elicitors are stressors that activate secondary pathways that lead to the increased production of bioactive molecules in plants. Different elicitors including the fungus Aspergillus niger (0.2 g/L), methyl jasmonate (MeJA, 100 µM/L), and silver nanoparticles (1 µg/L) were added, individually and in combination, in a hydroponic medium. The application of these elicitors in hydroponic culture significantly increased the concentration of photosynthetic pigments and total phenolic contents. The treatment with MeJA (methyl jasmonate) (100 µM/L) and the co-treatment of MeJA and AgNPs (silver nanoparticles) (100 µM/L + 1 µg/L) exhibited the highest chlorophyll a (29 µg g-1 FW) and chlorophyll b (33.6 µg g-1 FW) contents, respectively. The elicitor MeJA (100 µM/L) gave a substantial rise in chlorophyll a and b and total chlorophyll contents. Likewise, a significant rise in carotenoid contents (9 µg/g FW) was also observed when subjected to meJA (100 µM/L). For the phenolic content, the treatment with meJA (100 µM/L) proved to be very effective. Nevertheless, the highest production (431 µg/g FW) was observed when treated with AgNPs (1 µg/L). The treatments with various elicitors in this study had a significant effect on flavonoid and lignin content. The highest concentration of flavonoids and lignin was observed when MeJA (100 mM) was used as an elicitor, following a 72-h treatment period. Hence, for different plant metabolites, the treatment with meJA (100 µM/L) and a co-treatment of MeJA and AgNPs (100 µM/L + 1 µg/L) under prolonged exposure times of 120-144 h proved to be the most promising in the accretion of valuable bioactive molecules. The study opens new insights into the use of these elicitors, individually or in combination, by using different concentrations and compositions.

Curcumin Improves Human Umbilical Cord-Derived Mesenchymal Stem Cell Survival via ERK1/2 Signaling and Promotes Motor Outcomes After Spinal Cord Injury.

Human umbilical cord-derived mesenchymal stem cell (hUC-MSC) transplantation is thought to be a promising strategy for treating spinal cord injury (SCI). However, the low survival rate of transplanted hUC-MSCs limits their clinical application in cell replacement therapy. Curcumin can suppress inflammation after SCI; however, it remains unknown whether curcumin can modulate the survival of transplanted hUC-MSCs. In this study, to investigate whether curcumin could strengthen the therapeutic effects of hUC-MSC transplantation on SCI, we induced hUC-MSC apoptosis with TNF-α, transplanted hUC-MSC into SCI rats, and assessed the antiapoptotic effect and mechanism of curcumin. LDH release analysis and flow cytometry demonstrated that TNF-α led to hUC-MSC apoptosis and that curcumin increased the hUC-MSC survival rate in a dose-dependent manner. In addition, we showed that the phosphorylation levels of ERK1/2, JNK, and P38 were upregulated in apoptotic hUC-MSCs, while curcumin increased the phosphorylation of ERK1/2 but did not activate JNK or P38, and these effects were reversed by the p42/44 antagonist U0126. Furthermore, we found that the motor function scores and number of surviving HNA-positive cells were significantly increased after curcumin and hUC-MSC transplantation therapy 8 weeks post-SCI, while U0126 markedly attenuated these effects. These data confirmed that curcumin suppressed hUC-MSC apoptosis through the ERK1/2 signaling pathway and that combined curcumin and hUC-MSC treatment improved motor function in rats after SCI. The current research provides a strong basis for hUC-MSC replacement therapy in conjunction with curcumin in the treatment and management of SCI in humans.

Eudragit S100 prepared pH-responsive liposomes-loaded betulinic acid against colorectal cancer in vitro and in vivo.

This study aimed to develop polymer Eudragit S100 for preparing pH-responsive liposomes-loaded betulinic acid (pH-BA-LP) to improve the therapeutic index of chemotherapy for colorectal cancer. BA-loaded liposomes were coated with Eudragit S100 by a thin film dispersion and easily scalable pH-driven method. The prepared liposomes were evaluated for size, surface morphology, entrapment efficiency, stability, in vitro drug release, and antitumor activity. In particular, pH-BA-LP showed advantages such as lower size (<100 nm), encapsulation efficiency of 90%, high stability, and stably cumulative release. By detecting the antitumor effects of pH-BA-LP in vivo, it showed that the tumor proliferation and cell migration were significantly inhibited in colorectal cancer. The pH-BA-LP also inhibited tumor growth via the regulation of Akt/TLR-mediated signalling and significantly down-regulated the expression of NFAT1 and NFAT4 proteins. It was found that pH-BA-LP can increase NK cells and CD3+ cells in tumor tissues, and the proportion of CD8+ cells in CD3+ cells was also increased, which proved that pH-BA-LP can play an antitumor effect by enhancing the autoimmunity level in tumor-bearing mice. The positive infiltration rates of CD8 and CD68 were increased and CD163 was relatively decreased by using pH-BA-LP, which proved that pH-BA-LP can regulate the immune infiltration levels in tumor-bearing mice. Therefore, the present work provides an effective method to prepare pH-responsive polymer-coated liposomes for colonic delivery with biologically active compounds.

Community structure of bacterioplankton and its relationship with environmental factors in the upper reaches of the Heihe River in Qinghai Plateau.

Planktonic microorganisms play a key role in the biogeochemical processes of the aquatic system, and they may be affected by many factors. High-throughput sequencing technology was used in this study to investigate and study the bacterioplankton community of water bodies in the upper reaches of the Heihe River Basin in Qinghai Plateau. Results showed that Proteobacteria, Firmicutes, Bacteroidetes and Actinobacteria are the predominant phyla in this river section, while the main genera are Thiomonas, Acidibacillus, Acidocella, Rhodanobacter, Acidithiobacter and Gallionella, which are autochthonous in the acid-mine drainage. Additionally, total nitrogen, total phosphorus, permanganate index and pH are significantly correlated with the bacterioplankton abundance and are the main limiting factors for the spatial distribution of the bacterioplankton. PICRUSt inferred that the mainstream microbial assemblages had a higher abundance of KOs belong to metabolism of terpenoids and polyketides, while the tributary had higher abundance of KOs belong to the immune system. The relationship between bacterioplankton community composition and environmental factors in the Heihe River basin was discussed for the first time in this study, which provides a theoretical basis for the healthy, orderly development of the water environment in the Heihe River Basin.

One-thousandth-level laser power stabilization based on optical feedback from a well-designed high-split-ratio and nonpolarized beam splitter.

Laser power stabilization plays a significant role in atomic and molecular physics, quantum precision measurement, and optical sensing and measurement. In the classical method of using a feedback control loop to stabilize the laser power, the beam splitter is the conjunction element to connect the feedback beam inside the loop and the output beam outside the loop. The stability of its split ratio will directly affect the result of power stabilization, especially in demand of high split ratios for high-efficiency output. For the compatibility of a high split ratio and high stability in a power-stabilized system, we designed and manufactured a high-split-ratio nonpolarized plate beam splitter, whose split ratio was insensitive to variations of beam intensity, polarization, and ambient temperature. Based on the optical feedback of the designed beam splitter, the light intensity was closed-loop controlled by an acousto-optic modulator; finally, the power outside the loop was stabilized as well. The output power was stabilized at 537 mW and a 6 h long-term test was performed. The relative stability of laser power outside the loop in terms of root mean square and peak to peak was 2.72×10-4 and 1.60×10-3, respectively. The relative Allan standard deviation reached 2.78×10-5 at an average time of 200 s. These results will greatly benefit many practical fields that require laser power stabilization with high split ratios and one-thousandth-level stability.

HCV core antigen plays an important role in the fight against HCV as an alternative to HCV-RNA detection.

OBJECTIVE: To discuss the clinical significance of HCV-cAg testing in the diagnosis, activity determination, and monitoring of therapeutic effectiveness of HCV infection and its advantages compared with HCV-RNA and anti-HCV antibodies detection. METHODS: By summarizing the published literature, the advantages and significance of HCV core antigen detection were sought. RESULTS: The expression of HCV-cAg is highly consistent with that of HCV-RNA, but compared with HCV-RNA, detection of HCV-cAg is easy to operate, time saving, and low cost. HCV-cAg can be detected within 12~15 days after infection, and the window period can be shortened by5~7 weeks. HCV-cAg is a serological indicator of virus replication, which can distinguish previous infection of HCV or current infection. HCV-cAg detection is more suitable for immunocompromised, hemodialysis, organ transplant patients. HCV-cAg also can be used to monitor antiviral efficacy and predict sustained virological response (SVR). CONCLUSION: HCV core antigen has similar clinical sensitivity to NAT and can be used as a substitute for HCV-RNA in the diagnosis of virus infection. Combined detection of HCV-cAg and antibody serology can help doctors detect HCV infection earlier, accurately diagnose different stages of HCV infection, and evaluate the therapeutic effect of antiviral drugs, which are beneficial in the prevention and treatment of hepatitis C.

Long-wavelength-infrared laser filamentation in solids in the near-single-cycle regime.

We experimentally demonstrate long-wavelength-infrared (LWIR) femtosecond filamentation in solids. Systematic investigations of supercontinuum (SC) generation and self-compression of the LWIR pulses assisted by laser filamentation are performed in bulk KrS-5 and ZnSe, pumped by ${\sim}{145}\;{\rm fs}$∼145fs, 9 µm, 10 µJ pulses from an optical parametric chirped-pulse amplifier operating at 10 kHz of repetition rate. Multi-octave SC spectra are demonstrated in both materials. While forming stable single filament, 1.5 cycle LWIR pulses with 4.5 µJ output pulse energy are produced via soliton-like self-compression in a 5 mm thick KrS-5. The experimental results quantitatively agree well with the numerical simulation based on the unidirectional pulse propagation equation. This work shows the experimental feasibility of high-energy, near-single-cycle LWIR light bullet generation in solids.

[Study on anti-osteoporosis effect of Eucommiae Cortex based on GC-MS metabonomics].

Based on GC-MS metabolomics and biochemical index analysis, the mechanism of bone mass loss in osteoporosis and the evaluation of anti-osteoporosis in Eucommiae Cortex were studied. The OVX rats model was established by bilateral ovariectomized. The routine indexes such as BMC, BMD, BGP and TRAP5 b were determined. The GC-MS technique was used to analyze the metabolism profile of serum samples between the control group, model group and medicine group, and multiple statistical analysis methods including principal component analysis(PCA), partial least squares-linear discriminant analysis(PLS-LDA) and subwindow rearrangement analysis(SPA) were used to screen and identify biomarkers. Five metabolites were selected as potential biomarkers, glycine, lysine, tryptophan, docosahexaenoic acid and glucose. Except for the significant increase of tryptophan in serum of OVX rats, the other four metabolites were significantly decreased. Moreover, the five biomarkers of the medicine group had a trend of returning to rats in control group. The significantly altered metabolite levels indicated that Eucommiae Cortex may relieve the symptoms of osteoporosis by regulating amino acid metabolism and oxidative stress.

[Protoplast and its application in molecular mechanism of quality formation of traditional Chinese medicine].

Since the first separation, protoplasts have played an important role in basic and applied research of plant biology and molecular biology. There are a lot of reports on protoplast preparation and transformation, especially in the selection of explants, enzymatic environment and transformation mode. Protoplasts have also been widely used in gene expression and regulation, especially in subcellular localization, protein interaction and promoter activity. In this paper, the preparation and transformation of protoplasts and the related research reports in gene expression and regulation are reviewed. The research status of protoplast in the molecular mechanism analysis of quality formation of traditional Chinese medicine is summarized. At the same time, the researches of protoplast in the molecular mechanism research of quality formation of traditional Chinese medicine are prospected. Firstly, we should further strengthen the exploration of protoplast preparation and transformation conditions of different traditional Chinese medicine resources. Secondly, we should further strengthen the research on quality formation related functional genes by using protoplast. Third, we should further make the study on the molecular regulation of quality formation of traditional Chinese medicine by protoplast. This paper attempts to provide a new way of thinking and technical method for the analysis of molecular mechanism of traditional Chinese medicine quality formation in the future.

[Application research of entropy weight-based grey systematic theory in quality evaluation of Angelicae Sinensis Radix slices].

In order to discuss the "entropy weight method" for weighting various indicators in the comprehensive evaluation of Angelicae Sinensis Radix slices(ASR), the quality of ASR was comprehensively evaluated by entropy weight-based gray systematic theory and cluster analysis. In this study, the contents of ferulic acid, volatile oil, polysaccharide, alcohol extract, water extract, moisture, total ash and acid-insoluble ash in 44 batches of ASR from different sources were determined. The entropy weight method was used for objective weighting. With relative correlation(r_i) as a measure, a multi-index comprehensive evaluation model was constructed for the quality of ASR. The results showed that the relative correlation value of 44 batches of ASR ranged from 0.301 9 to 0.662 9. There were certain differences in the quality of ASR from different sources. The ASR S1-S8, traceable and standardized in processing techno-logy, showed a high relative correlation degree and high quality ranking, indicating that the implementation of systemic management of the production chain of Chinese herbal pieces was beneficial to the quality control of ASR. The quality evaluation results of 44 batches of ASR were consistent with those of traditional geo-authentic habitats for ASR and the mainstream varieties of ASR on market, and basically consistent with the results of cluster analysis. This study suggests that the gray systematic theory based on the entropy weighting method can be used for the quality evaluation of ASR. The objective weighting of the entropy weight method improves the reliability of the gray correlation method and the scientificity of ASR quality evaluation.

[Establishment of concentration process and physical property parameter model of Carthami Flos extract based on quality by design].

To explore the potential of "physical property model" based on the concept of quality by design(QbD),during the application of process analysis technology(PAT) in the concentration process. The Carthami Flos was used as a model drug. Firstly, the total flavonoid retention rate and the hydroxysafflor yellow A(HSYA) retention rate of the concentrated solution were used as indicators to determine the concentration temperature range of the Carthami Flos extract. Then different concentrations were prepared at the optimal concentration temperature, and the corresponding viscosity(η) and electrical conductivity(σ) at different concentrations and temperatures were measured. Data processing software such as Excel, 1 stOpt, SPSS, and MATLAB were used to establish Carthami Flos extract's mathematical model of physical parameters: ρ-C, η-C, η-T, η-C-T, σ-T, σ-C-T. The results showed that the best concentration temperature of the Carthami Flos extract should not exceed 60 ℃, and the R~2 of the exponential equation and Arrhenius equation established based on physical parameters was all greater than 0.9, indicating that such model had better predictive ability. The mathematical model:η=14.465 1 exp(-0.019 8T+ 0.771 1C-0.058 3C~2), σ=4.061 0 + 0.004 3T +(-1.104 1 +0.950 9T)C-0.556 9TC~2 can be used to reflect the comprehensive effect of concentration and temperature on viscosity or conductance, laying foundation for the establishment of an online monitoring system for the viscosity or conductivity of the extraction liquid in the concentration step, rapid prediction of the concentration status, and control of the concentration endpoint. This study has initially proved the feasibility of using the physical property model as the core of the research idea in application of PAT for intelligent quality control of traditional Chinese medicine concentration links, providing a reference for the online intelligent monitoring of concentration steps of traditional Chinese medicine extracts.

An Industrial Micro-Defect Diagnosis System via Intelligent Segmentation Region.

In the field of machine vision defect detection for a micro workpiece, it is very important to make the neural network realize the integrity of the mask in analyte segmentation regions. In the process of the recognition of small workpieces, fatal defects are always contained in borderline areas that are difficult to demarcate. The non-maximum suppression (NMS) of intersection over union (IOU) will lose crucial texture information especially in the clutter and occlusion detection areas. In this paper, simple linear iterative clustering (SLIC) is used to augment the mask as well as calibrate the score of the mask. We propose an SLIC head of object instance segmentation in proposal regions (Mask R-CNN) containing a network block to learn the quality of the predict masks. It is found that parallel K-means in the limited region mechanism in the SLIC head improved the confidence of the mask score, in the context of our workpiece. A continuous fine-tune mechanism was utilized to continuously improve the model robustness in a large-scale production line. We established a detection system, which included an optical fiber locator, telecentric lens system, matrix stereoscopic light, a rotating platform, and a neural network with an SLIC head. The accuracy of defect detection is effectively improved for micro workpieces with clutter and borderline areas.

Analyzing the molecular mechanism of the tissue specificity of gastrointestinal stromal tumors by using bioinformatics approaches.

PURPOSE: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. About 70% of GIST occur in the stomach, 20% in the small intestine and less than 10% in the esophagus. This study aimed to explore the difference of gene expression profile of GIST between different tumor sites. METHODS: Microarray data GSE8167 (accession number of the microarray data) were available from Gene Expression Omnibus (GEO) which included 23 gastric and 9 small intestine untreated GIST samples, and then the differentially expressed genes (DEGs) between these samples were identified using t-test. Furthermore, pathway enrichment analysis was performed to these DEGs and one protein-protein interaction network was constructed by STRING. Additionally, BioNet in R was used to establish a sub-network with false discovery rate < 0.001, and genes in this sub-network were further subjected to gene ontology (GO) and pathway analyses. RESULTS: A total 730 genes were differentially expressed between gastric samples and small intestine samples, indicating the tissue specifity of GIST. Pathway analysis suggested these DEGs disturbed ECM-receptor interaction, gap junction and colorectal cancer. Moreover, some nodes (such as PLAT, VEGFC, PGF and CHD7) in the sub-network were significantly enriched in blood vessel development (p=4.58E-06), appendage development (p=9.54E-06) and skeletal system development (p=2.40E-04), respectively. Finally, several DEGs in the sub-network, including VEGFC and PGF, mainly affected pathways in cancer, focal adhesion, bladder cancer and cytokine-cytokine receptor interaction. CONCLUSIONS: Our results suggest that molecular mechanisms of GIST originating in different site were different. Our findings are helpful for physicians and researchers to study the tissue specificity of GIST.

Randomized controlled trial of endostar combined with cisplatin/ pemetrexed chemotherapy for elderly patients with advanced malignant pleural effusion of lung adenocarcinoma.

PURPOSE: To evaluate the clinical efficacy and safety of endostar combined with cisplatin/pemetrexed (CP) chemotherapy for elderly patients with advanced malignant pleural effusion (MPE) of lung adenocarcinoma. METHODS: A total of 128 lung adenocarcinoma patients with MPE were randomly divided into two groups. Patients in the treatment group were treated with pemetrexed 500 mg/m2, i.v., d 1, cisplatin intracavitary administration with a total dose of 75 mg/m2, d 2, 5 and 8, and endostar intracavitary administration 45 mg, d 1, 4 and 7. Patients in the control group were treated with chemotherapy alone (pemetrexed and cisplatin and mode of administration were the same as for the treatment group. RESULTS: The effective rates (ER) of the treatment group and control group were 81.82 and 64.52%, respectively (x2=4.906, p=0.027). The MPE control rates (DCRs) were 93.94 and 79.03%, respectively (x2=6.168, p=0.013). The control rate of the treatment group was higher compared with the control group (p<0.05), especially during the first period when it was 54.55% (p=0.019); in addition, the recurrence rate was lower (9.68 vs 30.61%, p=0.005). Dyspnea, mood and overall health improved significantly in the treatment group patients. No statistically significant differences in side effects between the groups were noticed. CONCLUSION: Intracavity endostar combined with intracavitary and i.v. pemetrexed and cisplatin had a significant effect on advanced MPE of lung adenocarcinoma. In addition, the quality of life (QoL) was significantly improved and the side effects were tolerable.

Hydrostatic pressure and muscarinic receptors are involved in the release of inflammatory cytokines in human bladder smooth muscle cells.

AIMS: Abnormal intravesical pressure results in a series of pathological changes. We investigated the effects of hydrostatic pressure and muscarinic receptors on the release of inflammatory cytokines in rat and human bladder smooth muscle cells (HBSMCs). METHODS: Animal model of bladder outlet obstruction was induced by urethra ligation. HBSMCs were subjected to elevated hydrostatic pressure and/or acetylcholine (Ach). Macrophage infiltration in the bladder wall was determined by immunohistochemical staining. The expression of inflammatory genes was measured by RT-PCR, ELISA and immunofluorescence. RESULTS: In obstructed bladder, inflammatory genes and macrophage infiltration were remarkably induced. When HBSMCs were subjected to 200-300 cm H2 O pressure for 2-24 h in vitro, the expressions of IL-6 and RANTES were significantly increased. Hydrostatic pressure promoted the protein levels of phospho-NFκB p65 and phospho-ERK1/2 as well as muscarinic receptors. Moreover, NFκB or ERK1/2 inhibitors suppressed pressure-induced inflammatory genes mRNA. When cells were treated with 1 µM acetylcholine for 6 h, a significant increase in IL-6 mRNA expression was detected. Acetylcholine also enhanced pressure-induced phospho-NFκB p65 and IL-6 protein expression. Additionally, pressure-induced IL-6 was partially suppressed by muscarinic receptors antagonists. CONCLUSIONS: Hydrostatic pressure and muscarinic receptors were involved in the secretion of inflammatory cytokines in HBSMCs, indicating a pro-inflammatory effect of the two factors in the pathological process of BOO.