Progress of studies on natural products for glioblastoma therapy.

Glioblastoma (GBM) is the most common, malignant, and lethal primary brain tumor in adults. Up to now, the chemotherapy approaches for GBM are limited. Therefore, more studies on identifying and exploring new chemotherapy drugs or strategies overcome the GBM are essential. Natural products are an important source of drugs against various human diseases including cancers. With the better understanding of the molecular etiology of GBM, the development of new anti-GBM drugs has been increasing. Here, we summarized recent researches of natural products for the GBM therapy and their potential mechanisms in details, which will provide new ideas for the research on natural products and promote developing drugs from nature products for GBM therapy.

S670, an amide derivative of 3-O-acetyl-11-keto-ß-boswellic acid, induces ferroptosis in human glioblastoma cells by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome.

Glioblastoma (GBM) is the most common malignant tumor in the brain with temozolomide (TMZ) as the only approved chemotherapy agent. GBM is characterized by susceptibility to radiation and chemotherapy resistance and recurrence as well as low immunological response. There is an urgent need for new therapy to improve the outcome of GBM patients. We previously reported that 3-O-acetyl-11-keto-ß-boswellic acid (AKBA) inhibited the growth of GBM. In this study we characterized the anti-GBM effect of S670, a synthesized amide derivative of AKBA, and investigated the underlying mechanisms. We showed that S670 dose-dependently inhibited the proliferation of human GBM cell lines U87 and U251 with IC50 values of around 6 µM. Furthermore, we found that S670 (6 µM) markedly stimulated mitochondrial ROS generation and induced ferroptosis in the GBM cells. Moreover, S670 treatment induced ROS-mediated Nrf2 activation and TFEB nuclear translocation, promoting protective autophagosome and lysosome biogenesis in the GBM cells. On the other hand, S670 treatment significantly inhibited the expression of SXT17, thus impairing autophagosome-lysosome fusion and blocking autophagy flux, which exacerbated ROS accumulation and enhanced ferroptosis in the GBM cells. Administration of S670 (50 mg·kg-1·d-1, i.g.) for 12 days in a U87 mouse xenograft model significantly inhibited tumor growth with reduced Ki67 expression and increased LC3 and LAMP2 expression in the tumor tissues. Taken together, S670 induces ferroptosis by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome in GBM cells. S670 could serve as a drug candidate for the treatment of GBM.

Apolipoprotein C1 promotes glioblastoma tumorigenesis by reducing KEAP1/NRF2 and CBS-regulated ferroptosis.

Glioblastoma (GBM), a malignant brain tumor, is a world-wide health problem because of its poor prognosis and high rates of recurrence and mortality. Apolipoprotein C1 (APOC1) is the smallest of apolipoproteins, implicated in many diseases. Recent studies have shown that APOC1 promotes tumorigenesis and development of several types of cancer. In this study we investigated the role of APOC1 in GBM tumorigenesis. Using in silico assays we showed that APOC1 was highly expressed in GBM tissues and its expression was closely related to GBM progression. We showed that APOC1 protein expression was markedly increased in four GBM cell lines (U251, U138, A172 and U87) compared to the normal brain glia cell lines (HEB, HA1800). In U251 cells, overexpression of APOC1 promoted cell proliferation, migration, invasion and colony information, which was reversed by APOC1 knockdown. APOC1 knockdown also markedly inhibited the growth of GBM xenografts in the ventricle of nude mice. We further demonstrated that APOC1 reduced ferroptosis by inhibiting KEAP1, promoting nuclear translocation of NRF2 and increasing expression of HO-1 and NQO1 in GBM cells. APOC1 also induced ferroptosis resistance by increasing cystathionine beta-synthase (CBS) expression, which promoted trans-sulfuration and increased GSH synthesis, ultimately leading to an increase in glutathione peroxidase-4 (GPX4). Thus, APOC1 plays a key role in GBM tumorigenesis, conferring resistance to ferroptosis, and may be a promising therapeutic target for GBM.

ADH1C inhibits progression of colorectal cancer through the ADH1C/PHGDH /PSAT1/serine metabolic pathway.

Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women worldwide. CRC is the second leading cause of cancer-related deaths. Although some progress in the treatment of CRC has been achieved, the molecular mechanism of CRC is still unclear. In this study, alcohol dehydrogenase 1C(ADH1C) was first identified as a target gene closely associated with the development of CRC by the comprehensive application of transcriptomics, proteomics, metabonomics and in silico analysis. The ADH1C mRNA and protein expression in CRC cell lines and tumor tissues was lower than that in normal intestinal epithelial cell lines and healthy tissues. Overexpression of ADH1C inhibited the growth, migration, invasion and colony formation of CRC cell lines and prevented the growth of xenograft tumors in nude mice. The inhibitory effects of ADH1C on CRC cells in vitro were exerted by reducing the expression of PHGDH/PSAT1 and the serine level. This inhibition could be partially reversed by adding serine to the culture medium. These results showed that ADH1C is a potential drug target in CRC.

Clinical Course and Outcome Patterns of Acute-on-chronic Liver Failure: A Multicenter Retrospective Cohort Study.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is acute decompensation of liver function in the setting of chronic liver disease, and characterized by high short-term mortality. In this study, we sought to investigate the clinical course of patients at specific time points, and to propose dynamic prognostic criteria. METHODS: We assessed the clinical course of 453 patients with ACLF during a 12-week follow-up period in this retrospective multicenter study. The clinical course of patients was defined as disease recovery, improvement, worsening or steady patterns based on the variation tendency in prothrombin activity (PTA) and total bilirubin (TB) at different time points. RESULTS: Resolution of PTA was observed in 231 patients (51%) at 12 weeks after the diagnosis of ACLF. Among the remaining patients, 66 (14.6%) showed improvement and 156 (34.4%) showed a steady or worsening course. In patients with resolved PTA, the clinical course of TB exhibited resolved pattern in 95.2%, improved in 3.9%, and steady or worse in 0.8%. Correspondingly, in patients with improved PTA, these values for TB were 28.8%, 27.3%, and 43.9%, respectively. In patients with steady or worsening PTA, these values for TB were 5.7%, 32.3%, and 65.6%, respectively. Dynamic prognostic criteria were developed by combining the clinical course of PTA/TB and the clinical outcomes at 4 and 12 weeks after diagnosis in ACLF patients. CONCLUSIONS: We propose the following dynamic prognostic criteria: rapid progression, slow progression, rapid recovery, slow recovery, and slow persistence, which lay the foundation for precise prediction of prognosis and the improvement of ACLF therapy.

Skin and soft tissue infection caused by Cysteiniphilum litorale in an immunocompetent patient: A case report.

Cysteiniphilum litorale is a Gram-negative coccobacillus first isolated from the seawater of Wailingding Island near the estuary of Pearl River in southern China. This organism was previously not considered to cause disease in animals or humans. We report a case of a 19-year-old female patient infected with abscess caused by C. litorale in the middle digit of her right hand after minor trauma during the handling of estuarine shrimps at home. C. litorale was cultured from the wound exudate of the patient and identified by 16S rRNA gene sequencing. Whether C. litorale may be transmitted to humans via other channels requires further exploration.

Neuron-specific deletion of presenilin enhancer2 causes progressive astrogliosis and age-related neurodegeneration in the cortex independent of the Notch signaling.

INTRODUCTION: Presenilin enhancer2 (Pen-2) is an essential subunit of γ-secretase, which is a key protease responsible for the cleavage of amyloid precursor protein (APP) and Notch. Mutations on Pen-2 cause familial Alzheimer disease (AD). However, it remains unknown whether Pen-2 regulates neuronal survival and neuroinflammation in the adult brain. METHODS: Forebrain neuron-specific Pen-2 conditional knockout (Pen-2 cKO) mice were generated for this study. Pen-2 cKO mice expressing Notch1 intracellular domain (NICD) conditionally in cortical neurons were also generated. RESULTS: Loss of Pen-2 causes astrogliosis followed by age-dependent cortical atrophy and neuronal loss. Loss of Pen-2 results in microgliosis and enhanced inflammatory responses in the cortex. Expression of NICD in Pen-2 cKO cortices ameliorates neither neurodegeneration nor neuroinflammation. CONCLUSIONS: Pen-2 is required for neuronal survival in the adult cerebral cortex. The Notch signaling may not be involved in neurodegeneration caused by loss of Pen-2.

Epigenome-Wide Tobacco-Related Methylation Signature Identification and Their Multilevel Regulatory Network Inference for Lung Adenocarcinoma.

Tobacco exposure is one of the major risks for the initiation and progress of lung cancer. The exact corresponding mechanisms, however, are mainly unknown. Recently, a growing body of evidence has been collected supporting the involvement of DNA methylation in the regulation of gene expression in cancer cells. The identification of tobacco-related signature methylation probes and the analysis of their regulatory networks at different molecular levels may be of a great help for understanding tobacco-related tumorigenesis. Three independent lung adenocarcinoma (LUAD) datasets were used to train and validate the tobacco exposure pattern classification model. A deep selecting method was proposed and used to identify methylation signature probes from hundreds of thousands of the whole epigenome probes. Then, BIMC (biweight midcorrelation coefficient) algorithm, SRC (Spearman's rank correlation) analysis, and shortest path tracing method were explored to identify associated genes at gene regulation level and protein-protein interaction level, respectively. Afterwards, the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis and GO (Gene Ontology) enrichment analysis were used to analyze their molecular functions and associated pathways. 105 probes were identified as tobacco-related DNA methylation signatures. They belong to 95 genes which are involved in hsa04512, hsa04151, and other important pathways. At gene regulation level, 33 genes are uncovered to be highly related to signature probes by both BIMC and SRC methods. Among them, FARSB and other eight genes were uncovered as Hub genes in the gene regulatory network. Meanwhile, the PPI network about these 33 genes showed that MAGOH, FYN, and other five genes were the most connected core genes among them. These analysis results may provide clues for a clear biological interpretation in the molecular mechanism of tumorigenesis. Moreover, the identified signature probes may serve as potential drug targets for the precision medicine of LUAD.

A multiple genomic data fused SF2 prediction model, signature identification, and gene regulatory network inference for personalized radiotherapy.

Radiotherapy is one of the most important cancer treatments, but its response varies greatly among individual patients. Therefore, the prediction of radiosensitivity, identification of potential signature genes, and inference of their regulatory networks are important for clinical and oncological reasons. Here, we proposed a novel multiple genomic fused partial least squares deep regression method to simultaneously analyze multi-genomic data. Using 60 National Cancer Institute cell lines as examples, we aimed to identify signature genes by optimizing the radiosensitivity prediction model and uncovering regulatory relationships. A total of 113 signature genes were selected from more than 20,000 genes. The root mean square error of the model was only 0.0025, which was much lower than previously published results, suggesting that our method can predict radiosensitivity with the highest accuracy. Additionally, our regulatory network analysis identified 24 highly important 'hub' genes. The data analysis workflow we propose provides a unified and computational framework to harness the full potential of large-scale integrated cancer genomic data for integrative signature discovery. Furthermore, the regression model, signature genes, and their regulatory network should provide a reliable quantitative reference for optimizing personalized treatment options, and may aid our understanding of cancer progress mechanisms.

Patients beliefs and attitudes towards deprescribing: Can deprescribing success be predicted?

BACKGROUND: The ability of questionnaires such as the Patients' Attitudes Towards Deprescribing (PATD) or the Beliefs about Medicines Questionnaire (Specific section) (BMQ-Specific) to successfully identify patients who will deprescribe remains unknown. OBJECTIVE: To determine if screening questionnaires assessing patients' attitudes and beliefs towards medications and deprescribing can predict deprescribing outcomes. METHODS: This is a post-hoc secondary analysis of the D-PRESCRIBE trial. 489 community-dwelling adults (≥65 years) who were chronic users (≥3 months) of a potentially inappropriate medication were randomized to a pharmacist-led educational intervention or usual care. Association between baseline responses to PATD and BMQ-Specific items and successful deprescribing was calculated. To determine predictive ability of questionnaire items, receiver operating characteristic curves (ROC) were constructed and area under the curve was calculated. RESULTS: At baseline, 86% of participants (95% confidence interval [CI] 83-89%) indicated a willingness to deprescribe, yet only 41% (95%CI 37-46%) successfully deprescribed. Six items were associated with deprescribing success, however, no PATD or BMQ-Specific item - either independently or in combination - meaningfully distinguished which participants succeeded or failed deprescribing attempts at 6-months (AUC < 0.7). CONCLUSION: Current tools to assess patient's attitudes and beliefs towards medication use and/or deprescribing have low predictive validity for successful deprescribing.

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High temperature stress occurs frequently in rice due to global warming. High-temperature hazard during the booting-flowering and grain-filling stages is one of the major factors limiting rice yield and quality. Here, we summarized the occurrence characteristics (identification, classification, region, and time) of high-temperature hazards, and the effects of high temperature on rice growth and development, including physiology, grain yield, and grain quality. Furthermore, we reviewed molecular biology aspects including quantitative trait locus mapping, transcriptome analysis, proteome analysis, and the monitoring, early warning, risk assessment of high-temperature hazards in rice. The defensive measures against high temperature in rice including selecting heat-resistant varieties, improving field management practices and spraying exogenous substances were intensively described. Finally, future research work on high-temperature hazards in rice was prospected to provide the scientific support for rice high-temperature defense, agricultural disaster reduction, and agricultural efficiency improvement.

Dissecting basilar artery aneurysm manifesting as sudden sensorineural hearing loss: a case report and literature review.

Highlights • Dissecting basilar artery aneurysm (DBAA) is relatively rare. • We report the first case of a DBAA manifesting as sudden sensorineural hearing loss. • This case report adds to the symptom spectrum of DBAA.

Does a Consumer-Targeted Deprescribing Intervention Compromise Patient-Healthcare Provider Trust?

One in four community-dwelling older adults is prescribed an inappropriate medication. Educational interventions aimed at patients to reduce inappropriate medications may cause patients to question their prescriber’s judgment. The objective of this study was to determine whether a patient-focused deprescribing intervention compromised trust between older adults and their healthcare providers. An educational brochure was distributed to community-dwelling older adults by community pharmacists in order to trigger deprescribing conversations. At baseline and 6-months post-intervention, participants completed the Primary Care Assessment Survey, which measures patient trust in doctors and pharmacists. Changes in trust were ascertained post-intervention. Proportions with 95% confidence intervals (CI), and logistic regression were used to determine a shift in trust and associated predictors. 352 participants responded to the questionnaire at both time points. The majority of participants had no change or gained trust in their doctors for items related to the choice of medical care (78.5%, 95% CI = 74.2–82.8), communication transparency (75.4%, 95% CI = 70.7–79.8), and overall trust (81.9%, 95% CI = 77.9–86.0). Similar results were obtained for participants’ perceptions of their pharmacists, with trust remaining intact for items related to the choice of medical care (79.4%, 95% CI = 75.3–83.9), transparency in communicating (82.0%, 95% CI = 78.0–86.1), and overall trust (81.6%, 95% CI = 77.5–85.7). Neither age, sex nor the medication class targeted for deprescribing was associated with a loss of trust. Overall, the results indicate that patient-focused deprescribing interventions do not shift patients’ trust in their healthcare providers in a negative direction.

[Efficacy of Bortezomib for Maintenance therapy of Patients with Multiple Myeloma].

OBJECTIVE: To observe the efficacy of chemotherapy consisted of bortezomib as main druy in maintenance therapy for recurrence of newly diagnosed MM patients. METHODS: The clinical data and outcome of 37 MM patients during 2008-2013 were analyzed retrospectively, the 37 MM patients were divided into 2 group: 19 cases including 13 cases of newly diagnosed MM with symptoms and 6 cases of relapsed refractory MM were enrolled in group A; 17 cases of newly diagnosed MM with symptoms were enrolled in group B. The patients of group A received maintenance therapy consisted of bortezomib plus dexamethasone (VD group), while the patient group B received maintenance therapy consisted of melphalan plus prednisone(MP group), then the therapeutic efficacy of 2 group was compared. RESULTS: The overall response rate(ORR) in VD groupe was 84.2%(16/19), out of which CR rate reached 42%(8/19), PR rate reached 31.6%(6/19), MR rate reached 10.5%(3/19). During median follow-up for 21.8(5-51) months, death occurred, while the ORR in MP group was 52(9/17), out of which CR rate was 23.5%(4/17), PR rate reached 23.5%(4/17), MR rate reached 5.9%(1/17). Druing median follow-up for 16.4(4-39) months, the worteity reaced 64.7%(11/17). The differencr between 2 groups was significant(P<0.05). The median OS time of patients in VD group was 21.6 months, that in MP group was 17.9 months(P<0.05). The median PFS in VD group and MP group were 13.4 and 9.4 months respectively(P<0.001). CONCLUSION: The ORR and CR rates of bortezomib maintenance therapy for newly diagnosed and relapsed / refractory MM patients are very high, and its toxicity can be controlled, therefore, the patients need maintenance therapy after remission.

Surface expression of anti-CD3scfv stimulates locoregional immunotherapy against hepatocellular carcinoma depending on the E1A-engineered human umbilical cord mesenchymal stem cells.

Tumor antigens is at the core of cancer immunotherapy, however, the ideal antigen selection is difficult especially in poorly immunogenic tumors. In this study, we designed a strategy to modify hepatocellular carcinoma (HCC) cells by surface expressing anti-CD3scfv within the tumor site strictly, which depended on the E1A-engineered human umbilical cord mesenchymal stem cells (HUMSC.E1A) delivery system. Subsequently, membrane-bound anti-CD3scfv actived the lymphocytes which lysed HCC cells bypassing the expression of antigens or MHC restriction. First, we constructed the anti-CD3scfv gene driven by human α-fetoprotein (AFP) promoter into an adenoviral vector and the E1A gene into the lentiviral vector. Our results showed that anti-CD3scfv could specifically express on the surface of HCC cells and activate the lymphocytes to kill target cells effectively in vitro. HUMSC infected by AdCD3scfv followed by LentiR.E1A could support the adenoviral replication and packaging in vitro 36 h after LentiR.E1A infection. Using a subcutaneous HepG2 xenograft model, we confirmed that AdCD3scfv and LentiR.E1A co-transfected HUMSC could migrate selectively to the tumor site and produce considerable adenoviruses. The new generated AdCD3scfv infected and modified tumor cells successfully. Mice injected with the MSC.E1A.AdCD3scfv and lymphocytes significantly inhibited the tumor growth compared with control groups. Furthermore, 5-fluorouracil (5-FU) could sensitize adenovirus infection at low MOI resulting in improved lymphocytes cytotoxicity in vitro and in vivo. In summary, this study provides a promising strategy for solid tumor immunotherapy.

[Associations of HLA gene with leukemia in 1186 cases].

The purpose of this study was to evaluate the potential associations between HLA-A, B, DRB1 gene and leukemia. A total of 1186 leukemic patients, including 326 patients with acute lymphoblastic leukemia (ALL), 545 patients with acute myeloid leukemia (AML), 315 patients with chronic myeloid leukemia (CML), and 1234 healthy unrelated donors were typed and were compared in a single centre by using same technique, then the Bonferroni correction method was used to correct the Type I error. The results indicated that as compared with the control,the frequency of HLA-DRB1(*)09 in ALL group significantly decreased (10.87% versus 16.08%; Pc = 0.014, OR = 0.637, 95% CI = 0.487-0.834), while in comparison with control, the frequency of HLA-B(*)18 in CML group was significantly higher (1.28% vs 0.20%; Pc = 0.039, OR = 6.336, 95% CI = 2.066-19.434). The positive and negative relation may exist between certain HLA molecules and leukemia. The negative relation between HLA-DRB1(*)09 and ALL indicated that DRB1*09 might play an important role by a restricted T-cell immune response in the early leukemogenic events, whereas the positive relation between HLA-B(*)18 and CML suggests that the B(*)18 molecules may not actively present leukemia-specific antigens resulting in immune escape. It is concluded that these findings can contribute to developing more appropriate method in leukemic immunotherapy.

Premature sebaceous hyperplasia in an adolescent boy.

Sebaceous hyperplasia is a common, benign condition of the sebaceous glands in adults of middle age or older, occurring primarily on the face and neck. In adolescent or young adult patients, it is a rare entity called premature sebaceous hyperplasia (PSH). Previous reports indicate that the onset of PSH occurs during or shortly after puberty, with an average age-at-onset of 19 years. Here we present an extremely rare prepubescent case of PSH that developed on the right side of a boy's neck when he was 8 years old.