Loss of feedback regulation between FAM3B and androgen receptor driving prostate cancer progression.

BACKGROUND: Although the fusion of the transmembrane serine protease 2 gene (TMPRSS2) with the erythroblast transformation-specific-related gene (ERG), or TMPRSS2-ERG, occurs frequently in prostate cancer, its impact on clinical outcomes remains controversial. Roughly half of TMPRSS2-ERG fusions occur through intrachromosomal deletion of interstitial genes and the remainder via insertional chromosomal rearrangements. Because prostate cancers with deletion-derived TMPRSS2-ERG fusions are more aggressive than those with insertional fusions, we investigated the impact of interstitial gene loss on prostate cancer progression. METHODS: We conducted an unbiased analysis of transcriptome data from large collections of prostate cancer samples and employed diverse in vitro and in vivo models combined with genetic approaches to characterize the interstitial gene loss that imposes the most important impact on clinical outcome. RESULTS: This analysis identified FAM3B as the top-ranked interstitial gene whose loss is associated with a poor prognosis. The association between FAM3B loss and poor clinical outcome extended to fusion-negative prostate cancers where FAM3B downregulation occurred through epigenetic imprinting. Importantly, FAM3B loss drives disease progression in prostate cancer. FAM3B acts as an intermediator of a self-governing androgen receptor feedback loop. Specifically, androgen receptor upregulates FAM3B expression by binding to an intronic enhancer to induce an enhancer RNA and facilitate enhancer-promoter looping. FAM3B, in turn, attenuates androgen receptor signaling. CONCLUSION: Loss of FAM3B in prostate cancer, whether through the TMPRSS2-ERG translocation or epigenetic imprinting, causes an exit from this autoregulatory loop to unleash androgen receptor activity and prostate cancer progression. These findings establish FAM3B loss as a new driver of prostate cancer progression and support the utility of FAM3B loss as a biomarker to better define aggressive prostate cancer.

Safety and effectiveness of oral medium to high dose blonanserin in patients with schizophrenia: subgroup analysis from a prospective, multicenter, post-marketing surveillance study in mainland China.

BACKGROUND: Blonanserin (BNS) had been undergoing post-market surveillance (PMS) since September 2018. Using the surveillance data, we did this analysis to assess the safety and effectiveness of different doses of BNS to explore a sufficient dose range of BNS in Chinese patients with schizophrenia (SZ). METHODS: A 12-week, prospective, observational, single-arm, multicenter, open-label PMS was conducted. In this analysis, we divided the patients from PMS into low, medium to high, and high dose groups based on the dose of BNS they received, with medium to high dose group being the focus. The Brief Psychiatric Rating Scale (BPRS) scores at week 2 or 4, 6 or 8, and 12 were calculated to evaluate the effectiveness of BNS in improving psychiatric symptoms. The safety of BNS was reported as the incidence of adverse drug reactions. RESULTS: 364 patients were included in the medium to high dose group, of which 321 completed the surveillance, with a dropout rate of 11.8%. The mean daily dose was 15.1 ± 1.92 mg. The BPRS total score was 50.1 ± 11.95 at baseline and decreased to 26.6 ± 7.43 at 12 weeks (P < 0.001). When compared with other groups, the median to high dose group achieved significantly more reduction in BPRS score at week 12 (P = 0.004 versus low dose and P = 0.033 versus higher dose). Extrapyramidal symptoms [EPS (46.4%)] were the most common adverse reactions in the medium to high group. The average weight gain during the surveillance was 0.5 ± 2.56 kg and prolactin elevation occurred in 2.2% patients. Most adverse reactions were mild. CONCLUSIONS: BNS at medium to high doses (mean 15.1 mg/d) significantly improved symptoms of SZ and was well-tolerated. Most ADRs were mild, and the likelihood of causing metabolic side effects and prolactin elevations was low. Medium to high dose of BNS is a more potent treatment choice for SZ. TRIAL REGISTRATION NUMBER: ChiCTR2100048734. Date of registration: 2021/07/15 (retrospectively registered).

A Vision sensing-based automatic evaluation method for teaching effect based on deep residual network.

The automatic evaluation of the teaching effect has been a technical problem for many years. Because only video frames are available for it, and the information extraction from such dynamic scenes still remains challenging. In recent years, the progress of deep learning has boosted the application of computer vision in many areas, which can provide much insight into the above issue. As a consequence, this paper proposes a vision sensing-based automatic evaluation method for teaching effects based on deep residual network (DRN). The DRN is utilized to construct a backbone network for sensing from visual features such as attending status, taking notes, playing phones, looking outside, etc. The extracted visual features are further selected as the basis for the evaluation of the teaching effect. We have also collected some realistic course images to establish a real-world dataset for the performance assessment of the proposal. The proposed method is implemented on collected datasets via computer programming-based simulation experiments, so as to obtain accuracy assessment results as measurement. The obtained results show that the proposal can well perceive typical visual features from video frames of courses and realize automatic evaluation of the teaching effect.

The role of ß-catenin in cardiac diseases.

The Wnt/ß-catenin signaling pathway is a classical Wnt pathway that regulates the stability and nuclear localization of ß-catenin and plays an important role in adult heart development and cardiac tissue homeostasis. In recent years, an increasing number of researchers have implicated the dysregulation of this signaling pathway in a variety of cardiac diseases, such as myocardial infarction, arrhythmias, arrhythmogenic cardiomyopathy, diabetic cardiomyopathies, and myocardial hypertrophy. The morbidity and mortality of cardiac diseases are increasing, which brings great challenges to clinical treatment and seriously affects patient health. Thus, understanding the biological roles of the Wnt/ß-catenin pathway in these diseases may be essential for cardiac disease treatment and diagnosis to improve patient quality of life. In this review, we summarize current research on the roles of ß-catenin in human cardiac diseases and potential inhibitors of Wnt/ß-catenin, which may provide new strategies for cardiac disease therapies.

Effectiveness and safety of blonanserin in young and middle-aged female patients with schizophrenia: data from a post-marketing surveillance.

BACKGROUND: A post-marketing surveillance of blonanserin has been ongoing since September 2018. The aim of this study was to assess the effectiveness and safety of oral blonanserin in Chinese young and middle-aged female patients with schizophrenia in real clinical settings, using the data from the post-marketing surveillance. METHODS: A 12-week, prospective, multi-center, open-label, post-marketing surveillance was conducted. Female patients aged 18-40 years were included in this analysis. The Brief Psychiatric Rating Scale (BPRS) was used to evaluate the effectiveness of blonanserin in improving psychiatric symptoms. The incidence of adverse drug reactions (ADRs) such as of extrapyramidal symptoms (EPS), prolactin elevation and the weight gain were used to evaluate the safety profile of blonanserin. RESULTS: A total of 392 patients were included both in the safety and full analysis sets, 311 patients completed the surveillance protocol. The BPRS total score was 48.8 ± 14.11 at the baseline, decreasing to 25.5 ± 7.56 at 12 weeks (P < 0.001, compared with baseline). EPS (20.2%) including akathisia, tremor, dystonia, and parkinsonism were found as the most frequent ADRs. The mean weight gain was 0.27 ± 2.5 kg at 12 weeks from the baseline. Four cases (1%) of prolactin elevation were observed during the period of surveillance. CONCLUSION: Blonanserin significantly improved the symptoms of schizophrenia in female patients aged 18-40 years; the drug was well tolerated and had a low tendency to cause metabolic side effects, including prolactin elevation in these patients. Blonanserin might be a reasonable drug for the treatment of schizophrenia in young and middle-aged female patients.

Breast cancer cells survive chemotherapy by activating targetable immune-modulatory programs characterized by PD-L1 or CD80.

Breast cancer cells must avoid intrinsic and extrinsic cell death to relapse following chemotherapy. Entering senescence enables survival from mitotic catastrophe, apoptosis and nutrient deprivation, but mechanisms of immune evasion are poorly understood. Here we show that breast tumors surviving chemotherapy activate complex programs of immune modulation. Characterization of residual disease revealed distinct tumor cell populations. The first population was characterized by interferon response genes, typified by Cd274, whose expression required chemotherapy to enhance chromatin accessibility, enabling recruitment of IRF1 transcription factor. A second population was characterized by p53 signaling, typified by CD80 expression. Treating mammary tumors with chemotherapy followed by targeting the PD-L1 and/or CD80 axes resulted in marked accumulation of T cells and improved response; however, even combination strategies failed to fully eradicate tumors in the majority of cases. Our findings reveal the challenge of eliminating residual disease populated by senescent cells expressing redundant immune inhibitory pathways and highlight the need for rational immune targeting strategies.

The mechanism of the anti-inflammatory effect of Oldenlandia diffusa on arthritis model rats: a quantitative proteomic and network pharmacologic study.

Background: In China, Oldenlandia diffusa (OD) has been prescribed as a therapeutic herb for rheumatoid arthritis (RA). We previously conducted a preliminary study of the anti-inflammatory effect of OD, and the purpose of this study is to further investigate its mechanism. Methods: We performed a quantitative proteomic analysis of synovium, identified the differentially expressed proteins, and performed bioinformatics analyses. With the help of network pharmacology, we aimed to find the key synovial proteins which OD or its key compound might influence. To verify the result, liquid chromatography-mass spectrometry (LC-MS) was applied to quantify and qualify the absorbable potential compounds of OD. The anti-inflammatory effect was evaluated by morphological, histopathological, and cytokine analyses. Target proteins were observed by immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). Results: MMP3 and CAV1 were identified as 2 of the differentially expressed proteins in RA synovium, and might be influenced by quercetin, the active compound of OD. MMP3 might be altered through atherosclerosis signaling, while CAV1 might be altered through caveolar-mediated endocytosis signaling. According to our verification, quercetin was identified as the absorbed and effective compound of OD, and it could exert an anti-inflammatory effect on the collagen-induced arthritis (CIA) model, including serum cytokine expression, synovial hyperplasia and lymphocyte infiltration, articular cartilage lesion. Quercetin could also down-regulate the synovial expression of MMP3 and CAV1, and could exert better effects at a high dose. Conclusions: Quercetin was the main active compound of OD in the treatment of RA. OD might alleviate inflammatory responses in CIA rats by suppressing the expression of MMP3 and CAV1 through quercetin, and at a high dose, quercetin could exert a better anti-inflammatory effect.

Down-regulation of NOTCH1 and PKM2 can inhibit the growth and metastasis of colorectal cancer cells.

BACKGROUND: Previous studies have revealed the overexpression of Notch receptor 1 (NOTCH1) and pyruvate kinase M2 (PKM2) in colorectal cancer (CRC) tissue and their relationship to disease development. However, whether there is synergy between PKM2 and NOTCH1 needs to be verified. This study aims to analyze the mechanism and relationship between NOTCH1 and PKM2 in CRC. METHODS: Immunohistochemistry was used to measure the expression of NOTCH1 and PKM2 in colorectal cancer, and the correlation between them was analyzed by Pearson test. The protein and mRNA expressions in CRC cell lines were determined by western blot (WB) and real-time quantitative reverse transcription PCR (qRT-PCR). Compound 3K and tangeretin (TGN) were used to inhibit the expressions of PKM2 and NOTCH1, respectively. The wound healing assay and CCK-8 assay were applied to measure the migration and proliferation of cancer cells. RESULTS: Immunohistochemical analysis showed that NOTCH1 and PKM2 were overexpressed in patients with colorectal cancer, and patients with overexpression showed a higher number of lymph node metastases and high tumor stage (III+IV) (P<0.05). In addition, Pearson test showed that the level of NOTCH1 was positively correlated with the level of PKM2 (P<0.05). WB and qRT-PCR showed that the protein and mRNA levels of NOTCH1 and PKM2 in colorectal cancer cells were significantly up-regulated (P<0.05). The inhibition of PKM2 and NOTCH1 had a synergistic effect on reducing the invasion and proliferation of CRC cells. CONCLUSION: NOTCH1 and PKM2 are highly expressed in CRC patients. Inhibiting the expression of NOTCH1 and PKM2 can inhibit the growth and metastasis of CRC cells, providing therapeutic targets for the treatment of CRC.

Safety and Effectiveness of Blonanserin in Chinese Patients with Schizophrenia: An Interim Analysis of a 12-Week Open-Label Prospective Multi-Center Post-marketing Surveillance.

Schizophrenia is an unexplained, complex and serious mental illness. Blonanserin (BNS) is a new antipsychotic drug widely used in the treatment of schizophrenia. However, large-scale clinical studies have not been conducted in China. A multi-center, prospective, open-label, 12-week surveillance was carried out to evaluate the safety and effectiveness of BNS in patients with schizophrenia in China. Safety assessments included adverse drug reactions (ADRs), extrapyramidal symptoms (EPS), akathisia, concomitant medications for EPS by the end of treatment, and the changes in body weight from baseline by the end of treatment. The effectiveness was evaluated by the Brief Psychiatric Rating Scale (BPRS). From September 2018 to May 2020, of the 1,060 patients enrolled, 1,018 were included in the full analysis set (FAS) and safety set (SS), respectively. ADRs were developed in 205 patients among the included, the incidence being 20.1%. ADRs of EPS occurred in 169 patients, the incidence being 16.6%, ADRs of akathisia occurred in 90 patients, the incidence being 8.8%; concomitant therapeutic and prophylactic agents for EPS accounts for 19.2%; 4.0% of patients had a ≥7% increase in body weight from baseline at 12 weeks after initiating treatment. Using the last-observation-carried-forward (LOCF) method, the changes in total BPRS scores were -11.2 ± 10.17 (N = 1,018), -16.8 ± 12.69 (N = 1,018) and -20.6 ± 13.99 (N = 1,018) after 2/4, 6/8, or 12 weeks, respectively. 53.5% (545/1,018) patients showed response to blonanserin treatment in week 12. The post-marketing surveillance results of BNS demonstrates safety profile and effectiveness of the drug.

Mouse model and human patient data reveal critical roles for Pten and p53 in suppressing POLE mutant tumor development.

Mutations in the exonuclease domain of POLE are associated with tumors harboring very high mutation burdens. The mechanisms linking this significant mutation accumulation and tumor development remain poorly understood. Pole +/P286R;Trp53 +/- mice showed accelerated cancer mortality compared to Pole +/P286R;Trp53 +/+ mice. Cells from Pole +/P286R mice showed increased p53 activation, and subsequent loss of p53 permitted rapid growth, implicating canonical p53 loss of heterozygosity in POLE mutant tumor growth. However, p53 status had no effect on tumor mutation burden or single base substitution signatures in POLE mutant tumors from mice or humans. Pten has important roles in maintaining genome stability. We find that PTEN mutations are highly enriched in human POLE mutant tumors, including many in POLE signature contexts. One such signature mutation, PTEN-F341V, was previously shown in a mouse model to specifically decrease nuclear Pten and lead to increased DNA damage. We found tumors in Pole +/P286R mice that spontaneously acquired PtenF341V mutations and were associated with significantly reduced nuclear Pten and elevated DNA damage. Re-analysis of human TCGA (The Cancer Genome Atlas) data showed that all PTEN-F341V mutations occurred in tumors with mutations in POLE. Taken together with recent published work, our results support the idea that development of POLE mutant tumors may involve disabling surveillance of nuclear DNA damage in addition to POLE-mediated hypermutagenesis.

The roles of galectins in hepatic diseases.

Hepatic diseases include all diseases that occur in the liver, including hepatitis, cirrhosis, hepatocellular carcinoma, etc. Hepatic diseases worldwide are characterized by high incidences of digestive system diseases, which present with subtle symptoms, are difficult to treat and have high mortality. Galectins are ß-galactoside-binding proteins that have been found to be aberrantly expressed during hepatic disease progression. An increasing number of studies have shown that abnormal expression of galectins is extensively involved in hepatic diseases, such as hepatocellular carcinoma (HCC), liver cirrhosis, hepatitis and liver fibrosis. Galectins function as intracellular and extracellular hepatic disease regulators mainly through the binding of their carbohydrate recognition domain to glycoconjugates expressed in hepatocytes. In this review, we summarize current research on the various roles of galectins in cirrhosis, hepatitis, liver fibrosis and HCC, which may provide a preliminary theoretical basis for the exploration of new targets for the treatment of hepatic diseases.

POLE Mutation Spectra Are Shaped by the Mutant Allele Identity, Its Abundance, and Mismatch Repair Status.

Human tumors with exonuclease domain mutations in the gene encoding DNA polymerase ε (POLE) have incredibly high mutation burdens. These errors arise in four unique mutation signatures occurring in different relative amounts, the etiologies of which remain poorly understood. We used CRISPR-Cas9 to engineer human cell lines expressing POLE tumor variants, with and without mismatch repair (MMR). Whole-exome sequencing of these cells after defined numbers of population doublings permitted analysis of nascent mutation accumulation. Unlike an exonuclease active site mutant that we previously characterized, POLE cancer mutants readily drive signature mutagenesis in the presence of functional MMR. Comparison of cell line and human patient data suggests that the relative abundance of mutation signatures partitions POLE tumors into distinct subgroups dependent on the nature of the POLE allele, its expression level, and MMR status. These results suggest that different POLE mutants have previously unappreciated differences in replication fidelity and mutagenesis.

Characterization of a PLDζ2 Homology Gene from Developing Castor Bean Endosperm.

Castor oil contains approximately 90% ricinoleic acid (RA) which is stored mainly in the form of tri-ricinoleic acid containing triacylglycerols (TAG). Ricinoleate is synthesized from oleate (18:1n-9) esterified to the sn-2 position of phosphatidylcholine (PtdCho) catalyzed by oleoyl-12-hydroxylase. PtdCho-derived diacylglycerol (DAG) is an important substrate pool for TAG synthesis, and the interconversion between PtdCho and DAG has been shown to play a critical role in channeling hydroxy fatty acids (HFA) to TAG. Although phospholipase D (PLD) has been reported to catalyze the hydrolysis of PtdCho to produce phosphatidic acid which can then be converted to DAG, its potential functions in the channeling of RA from PtdCho to DAG and the assembly of RA on TAG is largely unknown. In the present study, 11 PLD genes were identified from the Castor Bean Genome Database. Gene expression analysis indicated that RcPLD9 is expressed at relatively high levels in developing seeds compared to other plant tissues. Sequence and phylogenetic analyses revealed that RcPLD9 is a homolog of Arabidopsis PLDζ2. Overexpression of RcPLD9 in the Arabidopsis CL7 line producing C18-HFA resulted in RA content reductions in the polar lipid fraction (mainly PtdCho) and mono-HFA-TAG, but increased RA content in di-HFA-TAG. Since part of RA in di-HFA-TAG is derived from HFA-DAG, the results indicated that RcPLD9 facilitates the channeling of RA from PtdCho to DAG for its assembly on TAG in developing seeds.

Multi-plasmon resonances enhanced two-photon coherent anti-Stokes Raman scattering by nanorods.

The development of new structures allows two-photon coherent anti-Stokes Raman scattering (TPCARS) to be strongly enhanced by multiple surface plasmon resonances (MSPRs). In this paper, plasmonic structure consisting of two Ag nanorods is designed and the enhancement of TPCARS is investigated. By properly selecting designing structure parameters, strong MSPRs peaks at 1020 nm and 505 nm are obtained, which can enhance the TPCARS signal based on the frequency match of the fundamental frequency and frequency doubling. The enhancement factor of TPCARS can reach as high as 3.66 × 1028 with significant electric field enhancements under appropriate selection of system parameters. Furthermore, the two-photon process can be controlled at different optical frequencies by changing the geometric parameters of Ag nanorods. The new scheme advanced in this work can help to achieve single molecule level of CARS, and may have a potential to increase the intensity and resolution of nonlinear optical imaging.

Anti-Inflammatory Effects of p-Coumaric Acid, a Natural Compound of Oldenlandia diffusa, on Arthritis Model Rats.

OBJECTIVES: In China, Oldenlandia diffusa (OD) is a natural herb that is widely used and has been proven to be effective in the treatment of rheumatoid arthritis (RA). This study aimed to preliminarily reveal the mechanism by which OD exerts its beneficial effect. METHODS: Ultra-performance liquid chromatography photodiode array was applied to identify the absorbable compounds in the plasma of collagen-induced arthritis (CIA) model rats. After 2 weeks, an OD decoction or the identified absorbable compound was administered to CIA rats. Morphology, X-ray images of the joints, pathological images, arthritis index, and cytokine (TNF-α and IL-6) levels were evaluated. RESULTS: p-Coumaric acid (p-CA) was identified as the absorbed compound in plasma. After administration of p-CA solution or the OD decoction, symptoms in the treated rats were alleviated as compared to the untreated model rats, and inflammatory cell infiltration was suppressed. The arthritis index and serum levels of TNF-α and IL-6 were decreased as compared to the control group. CONCLUSIONS: OD may exert its anti-inflammatory effect on RA via its active ingredient, p-CA. This information sheds light on the mechanism by which OD exerts its anti-inflammatory effort in RA and forms the basis for further development of therapeutic agents for RA.

Development and Validation of a Sensitive and Specific LC-MS-MS Method for the Determination of Acotiamide in Rat Plasma.

Acotiamide is a new prokinetic drug that is used to treat functional dyspepsia (FD). A sensitive and specific LC-MS-MS method has been developed and validated for the analysis of acotiamide in rat plasma. The assay involved a simple protein precipitation (PPT) step with methanol-acetonitrile (50:50, v/v) and a gradient elution using a mobile phase consisting of water containing 0.1% formic acid and methanol containing 0.1% formic acid. The analytes were chromatographed on a reverse-phase Agilent Zorbax XDB C18 column (2.1 mm × 50 mm, 3.5 µm) with a flow rate of 0.50 mL/min. The analytes were monitored by tandem-mass spectrometry with positive electrospray ionization. The precursor-product transitions (m/z) in the positive ion mode were 451.4 → 271.3 and 386.2 → 122.2 for acotiamide and buspirone (internal standard, IS), respectively. The assay was shown to be linear over the range of 0.10-200 ng/mL, with a lower limit of quantification of 0.10 ng/mL. The method was shown to be reproducible and reliable with the inter- and intra-batch accuracy and precision were within ±15%. The assay has been successfully used for pharmacokinetic evaluation of acotiamide after intravenous and oral administration of 10 mg/kg acotiamide in rats. The oral absolute bioavailability (F) of acotiamide in rats was estimated to be 38.4 ± 13.5% with an elimination half-life (t1/2) value of 9.11 ± 0.40 h.

[Analysis of astaxanthin in Phaffia rhodozyma using laser tweezers raman spectroscopy].

In the present paper, a method was established based on laser tweezer Raman spectroscopy for rapid quantification of astaxanthin in Phaffia rhodozyma cells. First, the Raman spectra of astaxanthin standard solution with different concentrations were determined and the standard curve for astaxanthin with the peak intensity at 1 520 cm- was plotted; And then the Phaffia yeast cells cultivated in different nitrogen source and carbon source medium were divided into two parts, one for the detection of Raman spectra, and the other for the determination of ultraviolet visible spectrophotometry; Finally the relationship between the two methods was analyzed. The correlation coefficient of standard curve for astaxanthin is 0.998 3. Comparing laser tweezers Raman spectroscopy method with traditional ultraviolet visible spectrophotometry in analyzing the content of astaxanthin in unit mass Phaffia rhodozyma and the yield of astaxanthin in unit volume fermentation broth of Phaffia rhodozyma, the authors found that the data obtained have good linear relationship. And the correlation coefficients are 0.917 7 and 0.905 4, respectively. Therefore, both methods have almost the same effect of measuement. But laser tweezers Raman spectroscopy method is more efficient in the quantitative analysis of astaxanthin in Phaffia rhodozyma cells.