Regulatory feedback loop between circ-EIF4A3 and EIF4A3 Enhances autophagy and growth in colorectal cancer cells.

Recent studies indicate that circular RNAs (circRNAs) are crucial in the progression of colorectal cancer (CRC). Eukaryotic translation initiation factor 4A3 (EIF4A3) has been identified as a promoter of circRNA production. The biological roles and mechanisms of EIF4A3-derived circRNA (circEIF4A3) in CRC cell autophagy remain poorly understood. This study explores the effects of circEIF4A3 on CRC cell growth and autophagy, aiming to elucidate the underlying molecular mechanisms. We discovered that EIF4A3 and circEIF4A3 synergistically enhance CRC cell growth. CircEIF4A3 sequesters miR-3126-5p, consequently upregulating EIF4A3. Further, circEIF4A3 increases EIF4A3 expression, which promotes autophagy by stabilizing ATG5 mRNA and enhances ATG7 protein stability through the stabilization of USP14 mRNA, a deubiquitinating enzyme. Upregulation of ATG5 and ATG7 counteracts the growth-inhibitory effects of EIF4A3 knockdown on CRC cells. Moreover, our findings demonstrate that EIF4A3 induces the formation of circEIF4A3 in CRC cells. In conclusion, a positive feedback loop between circEIF4A3 and EIF4A3 supports CRC cell growth by facilitating autophagy.

Exosomal circ-AHCY promotes glioblastoma cell growth via Wnt/ß-catenin signaling pathway.

BACKGROUND: Glioblastoma (GBM) is the most aggressive brain tumor. Reportedly, circular RNAs (circRNAs) participate in regulation of the development and progression of diverse cancers, including GBM. METHODS: Dysregulated circRNAs in GBM tissues were screened out from GEO database. The expression of candidate circRNAs in GBM cells was measured by qRT-PCR. Loss-of function assays, including colony formation assay, EdU assay, TUNEL assay, and flow cytometry analysis were conducted to determine the effects of circ-AHCY knockdown on GBM cell proliferation and apoptosis. Animal study was further used to prove the inhibitory effect of circ-AHCY silencing on GMB cell growth. Mechanistic experiments like luciferase reporter, RNA pull-down and RNA-binding protein immunoprecipitation (RIP) assays were performed to unveil the downstream molecular mechanism of circ-AHCY. Nanosight Nanoparticle Tracking Analysis (NTA) and PKH67 staining were applied to identify the existence of exosomes. RESULTS: Circ-AHCY was confirmed to be highly expressed in GBM cells. Circ-AHCY silencing suppressed GBM cell proliferation both in vitro and in vivo. Mechanistically, circ-AHCY activates Wnt/ß-catenin signaling pathway by sequestering miR-1294 to up-regulate MYC which activated CTNNB1 transcription. It was also found that circ-AHCY recruited EIF4A3 to stabilize TCF4 mRNA. Enhanced levels of TCF4 and ß-catenin contributed to the stability of TCF4/ß-catenin complex. In turn, TCF4/ß-catenin complex strengthened the transcriptional activity of circ-AHCY. Exosomal circ-AHCY derived from GBM cells induced abnormal proliferation of normal human astrocytes (NHAs). CONCLUSION: Exosomal circ-AHCY forms a positive feedback loop with Wnt/ß-catenin signaling pathway to promote GBM cell growth.

Successful treatment of metastatic vulvar malignant melanoma with toripalimab: A rare case report and review of the literature.

RATIONALE: Vulvar melanoma is a rare and aggressive tumor with a high risk of local recurrence and distant metastasis. The prognosis is poor with a 5-year overall survival rate of only 46.6%. Management of vulvar melanoma remains a clinical challenge. Recent evidences have shown that immune checkpoint inhibitors are effective in the treatment of vulvar melanoma. PATIENT CONCERNS AND DIAGNOSES: A 63-year-old woman with vulvar malignant melanoma suffered inguinal lymph node metastasis after vulvectomy and chemotherapy. She underwent inguinal lymph node dissection and inguinal radiotherapy. The tumor progressed again and she received immunotherapy. INTERVENTIONS: The tumor progressed again, and she was admitted to our hospital and received toripalimab combined with apatinib and abraxane. OUTCOMES: After 6 cycles of immunotherapy, the efficacy achieved partial remission. And with toripalimab as maintenance therapy, the patient achieved durable antitumor efficacy and good safety. LESSONS: In this rare case, the patient with metastatic vulvar malignant melanoma had durable antitumor efficacy and good safety when receiving toripalimab.

Histamine H3R antagonist counteracts the impaired hippocampal neurogenesis in Lipopolysaccharide-induced neuroinflammation.

Adult neurogenesis in hippocampus dentate gyrus (DG) is associated with numerous neurodegenerative diseases such as aging and Alzheimer's disease (AD). Overactivation of microglia induced neuroinflammation is well acknowledged to contribute to the impaired neurogenesis in pathologies of these diseases and then leading to cognitive dysfunction. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Recently, studies show that H3R are highly expressed not only in neurons but also in microglia to modulate inflammatory response. However, whether inhibition of H3R is responsible for the neurogenesis and cognition in chronic neuroinflammation induced injury and the mechanism remains unclear. In this study, we found that inhibition of H3R by thioperamide reduced the microglia activity and promoted a phenotypical switch from pro-inflammatory M1 to anti-inflammatory M2 in microglia, and ultimately attenuated lipopolysaccharide (LPS) induced neuroinflammation in mice. Additionally, thioperamide rescued the neuroinflammation induced impairments of neurogenesis and cognitive function. Mechanically, the neuroprotection of thioperamide was involved in histamine dependent H2 receptor (H2R) activation, because cimetidine, an H2R antagonist but not pyrilamine, an H1R antagonist reversed the above effects of thioperamide. Moreover, thioperamide activated the H2R downstream phosphorylated protein kinase A (PKA)/cyclic AMP response element-binding protein (CREB) pathway but inhibited nuclear factor kappa-B (NF-κB) signaling. Activation of CREB by thioperamide promoted interaction of CREB-CREB Binding Protein (CBP) to increase anti-inflammatory cytokines (Interleukin-4 and Interleukin-10) and brain-derived neurotrophic factor (BDNF) release but inhibited NF-κB-CBP interaction to decrease pro-inflammatory cytokines (Interleukin-1ß, Interleukin-6 and Tumor necrosis factor α) release. H89, an inhibitor of PKA/CREB signaling, abolished effects of thioperamide on neuroinflammation and neurogenesis. Taken together, these results suggested under LPS induced neuroinflammation, the H3R antagonist thioperamide inhibited microglia activity and inflammatory response, and ameliorated impairment of neurogenesis and cognitive dysfunction via enhancing histamine release. Histamine activated H2R and reinforced CREB-CBP interaction but weakened NF-κB-CBP interaction to exert anti-inflammatory effects. This study uncovered a novel histamine dependent mechanism behind the therapeutic effect of thioperamide on neuroinflammation.

Thioperamide attenuates neuroinflammation and cognitive impairments in Alzheimer's disease via inhibiting gliosis.

Alzheimer's disease (AD) is an age-related neurodegenerative disease, which characterized by deposition of amyloid-ß (Aß) plaques, neurofibrillary tangles, neuronal loss, and accompanied by neuroinflammation. Neuroinflammatory processes are well acknowledged to contribute to the progression of AD pathology. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Recently, studies show that H3R are highly expressed not only in neurons but also in microglia and astrocytes. H3R antagonist has been reported to have anti-inflammatory efficacy. However, whether inhibition of H3R is responsible for the anti-neuroinflammation in glial cells and neuroprotection on APPswe, PSEN1dE9 (APP/PS1 Tg) mice remain unclear. In this study, we found that inhibition of H3R by thioperamide reduced the gliosis and induced a phenotypical switch from A1 to A2 in astrocytes, and ultimately attenuated neuroinflammation in APP/PS1 Tg mice. Additionally, thioperamide rescued the decrease of cyclic AMP response element-binding protein (CREB) phosphorylation and suppressed the phosphorylated P65 nuclear factor kappa B (p-P65 NF-κB) in APP/PS1 Tg mice. H89, an inhibitor of CREB signaling, abolished these effects of thioperamide to suppress gliosis and proinflammatory cytokine release. Lastly, thioperamide alleviated the deposition of amyloid-ß (Aß) and cognitive dysfunction in APP/PS1 mice, which were both reversed by administration of H89. Taken together, these results suggested the H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice via modulation of the CREB-mediated gliosis and inflammation inhibiting, which contributed to Aß clearance. This study uncovered a novel mechanism involving inflammatory regulating behind the therapeutic effect of thioperamide in AD.

Severe immune-related hyperthermia followed by immune-related pneumonitis with PD-1 inhibitor (sintilimab) in small cell lung cancer: A case report.

Immune checkpoint inhibitors (ICIs) have achieved prominent efficacy in the treatment of numerous cancers, which is the most significant breakthrough in cancer therapy in recent years. However, ICIs are associated with a series of immune-related adverse events (irAEs). Pneumonitis is an uncommon but potentially fatal irAE. In the case reported here, a patient with advanced small cell lung cancer (SCLC) had rapid progression of disease following chemotherapy and received ICIs. The patient experienced severe immune-related hyperthermia followed by immune-related pneumonitis. Fortunately, a good clinical response was achieved after the patient received corticosteroids and tocilizumab.

Characterization of the weathered basement rocks in the Dongping field from the Qaidam Basin, Western China: significance as gas reservoirs.

Reservoir quality is a critical risk factor in basement reservoirs. Researches into basement reservoirs by petrographic analysis combined with X-ray diffraction, log identification, electron microscopy, field emission scanning electron microscopy, porosity and pulse-decay permeability and core analysis have provided insights into the characterization of the commonality, diversity and difference of the weathered basement rocks as gas reservoirs in the Dongping field. Geological structures, lithology and near-surface processes control the reservoir physical property together. From Wellblock Dp 3 to Wellblock Dp 17, the high uplift gradually transforms into the low slope area towards the center of basin, with the lithology changing as well, which results in different degrees of fracture development in the bedrock in different wellblocks. The basement lithologies are granite, granitic gneiss, and limestone with slate in Wellblock Dp3, Dp1 and Dp17, respectively. Though they all provide effective reservoir space for gas accumulation, the productivity of nature gas shows significant differences. Fractures are the main store space in the three wellblocks. The development of fractures gives rise to secondary porosity around them because of physical weathering and chemical dissolution, but they generate many inhomogeneous fractures and secondary solution pores, whether on the planar distribution or in vertical. In Wellblock Dp3, high angle fractures were generated under the action of structural stress mechanism, with a large number of secondary pores. The porosity is between 0.1 and 23.2%. In Wellblock Dp 1, low angle fractures were the main storage space, with plenty of solution pores mainly in melanocratic minerals. The porosity is between 0.1 and 18.8%. In Wellblock Dp 17, where short and dense fractures developed, the porosity is between 0.1 and 10.3%. The data indicate that the granite in the uplift in Wellblock Dp3 has better reservoir properties due to the stronger physical weathering and chemical dissolution. As the porosity gradually decreases towards the slope and low-lying area, the more favorable exploration area should be the uplift and slope area in the depression area. However, the effective caprock developed locally in Wellblock Dp3, which affected the gas accumulation. Meanwhile, the reservoirs' petrophysical properties showed distintive variation with different depths in different wellblocks. High productivity layers are under the 200 m, 100 m and 200 m depths from the top of the basement rocks in Wellblock Dp 3, Wellblock Dp 1 and Wellblock Dp 17, respectively. This suggestion in this study will be of significance for guiding oil and gas exploration in front of the Altun Mountains.

[Research Progress of New Generation EGFR-TKIs after Third-generation].

Lung cancer has the highest mortality rate in the world. The first- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) greatly improve the survival time and quality of life of patients with non-small cell lung cancer (NSCLC) to some extent. However, after a period of progression-free survival, most patients develop drug resistance, in which T790M mutation is the mainly resistance mechanism. The third-generation EGFR-TKIs, represented by osimertinib, are found to have significant effect on this resistance. The effect is remarkable, but drug resistance is still inevitable. For example, C797S mutation, mesenchymal-epithelial transition (MET), RAS mutation, BRAF mutation, transformation of small cell lung cancer (SCLC), transformation of epithelial mesenchymal transition (EMT), etc. But, there is no standard and effective treatment after the third-generation EGFR-TKIs resistance. In this view, we summarize the research progress in the new generation EGFR-TKIs after third-generation, in order to provide some reference for the follow-up research and treatment.
.

Induction of breast cancer stem cells by M1 macrophages through Lin-28B-let-7-HMGA2 axis.

Proinflammatory macrophage (M1) is now being suggested as a potential therapeutic strategy for cancer because of its tumoricidal capacity. However, few studies have been focused directly on the effects of M1 macrophages on cancer cells. Here, we found that M1 induced a subpopulation of CD44high/CD24-/low or ALDH1+ cells with CSC-like phenotypes from different types of breast cancer cells (BCCs) in a paracrine manner. Stat3/NF-κB pathways in BCCs were activated by proinflammatory cytokines, igniting Lin-28B-let-7-HMGA2 axis to induce CSC through epithelial-mesenchymal transition (EMT). Previously, we reported that Stat3-coordinated Lin-28B-let-7-HMGA2 axis initiated EMT in BCCs. Here, inhibition of Stat3/NF-κB pathways or Lin-28B-let-7-HMGA2 axis suppressed EMT/CSCs program. Notably, HMGA2 knockdown directly repressed M1-induced CSC formation and expression of Klf-4 and Nanog. Meanwhile, prolonged coculture with BCCs endowed M1 with M2 properties. M1 supernatant induced CSC from non-stem cancer cells, while M2 supernatant sustained a higher proportion of ALDH1+ cells. Our data suggest that macrophages might modulate CSC formation and maintenance by transferring between M1/M2 phenotype. Given that M1 are being considered as a promising immunotherapy tool, it is important to inhibit their CSC-inducing potential by targeting key molecules and pathways.

Comparison of apatinib and capecitabine (Xeloda) with capecitabine (Xeloda) in advanced triple-negative breast cancer as third-line therapy: A retrospective study.

The treatment of advanced triple-negative breast cancer, which failed in first-line or second-line therapy, is a significant challenge. We conducted this retrospective study to explore the efficacy and safety of apatinib and capecitabine as the third-line treatment for advanced triple-negative breast cancer.This retrospective study involved 44 advanced triple-negative breast cancer patients who failed in first-line or second-line therapy in Tangshan People's Hospital from January 2016 to February 2017. Twenty-two patients received apatinib and capecitabine, while 22 patients were treated with capecitabine monotherapy as third-line therapy. The progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events were compared between 2 groups.The apatinib and capecitabine group exhibited a higher PFS than capecitabine group (P = .001). Meanwhile, ORR and DCR in apatinib and capecitabine group were better than in capecitabine group (P = .042; .016). The 2 groups showed no significant difference in adverse events except degree I-II bleeding (P = .021). Both the apatinib and capecitabine and the capecitabine regimens revealed good tolerability.The apatinib and capecitabine regimen can achieve a better efficacy and similar serious adverse events compared with capecitabine regimen as the third-line treatment for advanced triple-negative breast cancer.

Antioxidant and DNA damage protecting potentials of polysaccharide extracted from Phellinus baumii using a delignification method.

A delignification method was employed to extract the polysaccharide from the fruiting body of Phellinus baumii. The three parameters, processing temperature, ratio of water to raw material and amount of acetic acid every time were optimized using the Box-Behnken design. As a result, the optimal extraction conditions were: processing temperature 70.3°C, ratio of water to raw material of 34.7mL/g and amount of acetic acid of 0.32mL every time. Under these conditions, the highest yield of polysaccharide (10.28%) was obtained. The main fraction (PPB-2) purified from PPB was composed of fucose, arabinose, galactose, glucose, xylose and mannose, while glucose was the predominant monosaccharide. PPB-2 exhibited noticeable antioxidant activity and strong protection against oxidative DNA damage. These findings implied that acid-chlorite delignification was a superior method to extract the polysaccharide from P. baumii and PPB-2 may be useful for cancer chemoprevention.

[Expression of BTG1 protein in laryngeal squamous cell carcinoma and its clinical significance].

OBJECTIVE: To investigate the expression of B-cell translocation gene 1 (BTG1) and to determine the relationship between BTG1 expression and clinicopathological features, biological behaviors in laryngeal squamous cell carcinoma. METHOD: Immunohistochemistry and Western blot were used to analyze BTG1 protein expression in 70 cases of laryngeal cancer and 35 cases of adjacent corresponding laryngeal mucosal tissues to illuminate the relationship between BTG1 expression and clinical factors. RESULT: The positive rate of BTG1 protein expression was 31.43% in laryngeal carcinoma tissues, significantly lower than 91.43% in the adjacent laryngeal tissues (P < 0.05). Western blot showed the relative expression of BTG1 protein between cancer lesion and adjacent tissue were 0.217 ± 0.032 and 0.918 ± 0.081, showing the difference with statistical significance (P < 0.05). The expression of protein was significantly correlated with the tumor invasion, lymph node metastasis, clinic stage and histological grade (P < 0.05 or P < 0.01), but not with sex, age and tumor location (P > 0.05) of patients with laryngeal cancer. CONCLUSION: The expression of BTG1 protein was decreased in laryngeal squamous cell carcinoma, suggesting that BTG1 gene may be closely associated with the carcinogenesis and the degree of malignancy. Detection of BTG1 expression may be useful in diagnosis, treatment and prognosis of laryngeal carcinoma.

Combined therapy against recurrent and intracranial invasion of sinonasal hemangiopericytoma: A case report.

Sinonasal hemangiopericytoma (HPC) is a soft tissue tumor of vascular origin. Open surgical methods and endoscopic techniques are considered the standard treatments for sinonasal HPC. However, local recurrences resulting from residual tumors are common. Adjuvant radiotherapy and chemotherapy have also been used to treat HPC, however, the number of studies which have investigated effective adjuvant treatments in the literature are limited. The current study reports a 42-year-old male with recurrent and intracranial invasion of sinonasal HPC, diagnosed in Xuanwu Hospital (Beijing, China). The patient underwent multiple surgeries to remove the tumors, however, no adjuvant therapy was adopted during this period and the tumors reoccurred within 1 year. On admittance to Tangshan People's Hospital (Tangshan, China), the patient presented with limited mouth opening and chewing ability, and hearing loss. Under observation using an electron microscope, HPC usually consists of spindle-shaped cells with elongated nuclei and displays characteristic staghorn-like vascular channels. In the present case, immunohistochemical studies were performed on paraffin-embedded sections of the tumor. The tumor cells expressed CD34, CD68(+/-), epithelial membrane antigen, CD31, α-actin, desmin, CD99, S-100, B-cell lymphoma-2 and Ki-67 (30%), but were negative for creatine kinase. The patient was treated with intensity-modulated radiotherapy and adjuvant chemotherapy, which demonstrated efficacy. No recurrence and metastasis was observed at the 1 year follow-up subsequent to the combined therapy.

Quantitative analysis of the association between CRP rs2808630 and rs1417938 polymorphisms and cancer risk.

Accumulating evidence indicates that polymorphisms in the CRP gene are important in the development of cancer. The current meta-analysis was performed to investigate the association between CRP polymorphisms 3407 A>G (rs2808630) and 29 A>T (rs1417938), and the risk of developing cancer. A search of the relevant literature was conducted using the PubMed database to identify eligible studies published up until March 25, 2014. Five case-control studies involving 888 cases and 3,167 controls for the 3407 A>G polymorphism, and six case-control studies involving 3,110 cases and 5,951 controls for the 29 A>T polymorphism were included in the current meta-analysis. The pooled odds ratios with 95% confidence intervals were calculated using the fixed- or random-effects model. Meta-analysis identified no association between the CRP 3407 A>G and 29 A>T polymorphisms, and overall cancer risk. Additional stratified analysis by cancer type did not reveal any significant associations in the genetic models investigated. The findings of the present study indicated that CRP 3407 A>G and 29 A>T polymorphisms are not associated with cancer risk.

[Clinical research of ulnar styloid fracture complicated with wrist dorsal branch of ulnar nerve injury].

OBJECTIVE: To analyze the therapy and effectiveness of ulnar styloid fracture complicated with wrist dorsal branch of ulnar nerve injury. METHODS: Between October 2005 and October 2012, 16 cases of ulnar styloid fracture complicated with wrist dorsal branch of ulnar nerve injury were treated. There were 14 males and 2 females with an average age of 42 years (range, 22-58 years). Fracture was caused by traffic accident in 8 cases, by mechanical crush in 5 cases, and by falling in 3 cases. According to the anatomical features of the ulnar styloid and imaging findings, ulnar styloid fractures were classified as type I (ulnar styloid tip fracture) in 1 case and type II (ulnar styloid base fracture) in 15 cases. The skin sensation of ulnar wrist was S0 in 5 cases, S1 in 1 case, S2 in 7 cases, and S3 in 3 cases according to the criteria of the British Medical Research Council in 1954 for the sensory functions of the ulnar wrist. The time from injury to operation was 6-72 hours (mean, 18 hours). Fracture was treated by operative fixation, and nerve was repaired by epineurium neurolysis in 13 cases of nerve contusion and by sural nerve graft in 3 cases of complete nerve rupture. RESULTS: All incisions healed by first intention. Sixteen patients were followed up for an average time of 14 months (range, 6-24 months). The X-ray films showed that all of them achieved bone union at 4-10 weeks after operation (mean, 6 weeks). No patient had complications such as ulnar wrist chronic pain and an inability to rotate. According to Green-O'Brien wrist scoring system, the results were excellent in 13 cases and good in 3 cases; according to the criteria of the British Medical Research Council in 1954 for the sensory functions of the ulnar wrist, the results were excellent in all cases, including 11 cases of S4 and 5 cases of S3+. Two-point discrimination of the ulnar wrist was 5-9 mm (mean, 6.6 mm). CONCLUSION: For patients with ulnar styloid fracture complicated with wrist dorsal branch of ulnar nerve injury, internal fixation and nerve repair should be performed. It can prevent ulnar wrist pain and promote sensory recovery.

[Application of ethylene oxide standard sampling subpackage].

Using the all closed covering low-temperature method, we successfully made the packaging and sampling of ethylene oxide standard.

Doxazosin gastrointestinal therapeutic system versus tamsulosin for the treatment of benign prostatic hyperplasia: a study in Chinese patients.

AIM: The efficacy and safety profiles of two alpha1-adrenoceptor antagonists, doxazosin gastrointestinal therapeutic system, a controlled-release formulation of doxazosin, and tamsulosin, were compared in Chinese men with confirmed benign prostatic hyperplasia. METHODS: After a 2-week placebo run-in phase, 117 patients were randomized to daily treatment with doxazosin gastrointestinal therapeutic system (4 mg doxazosin) (n = 60) or 0.2 mg tamsulosin (n = 57) for 6 weeks with no titration of study medications. Efficacy was measured by the International Prostate Symptom Score, maximum urinary flow rate, postvoid residual urine volume, and quality-of-life score from the International Prostate Symptom Score. Adverse events were recorded. RESULTS: Both drugs significantly improved the International Prostate Symptom Score (total, irritative subscore and obstructive subscore) and maximum urinary flow rate. Doxazosin gastrointestinal therapeutic system reduced postvoid residual urine volume significantly more than tamsulosin (-25 +/- 5 mL vs 2 +/- 5 mL, P = 0.041) in patients with residual volume >0 mL at baseline. Other differences between groups were not statistically significant. CONCLUSIONS: The doxazosin gastrointestinal therapeutic system and tamsulosin were effective and well tolerated for the treatment of benign prostatic hyperplasia in Chinese men.