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Since chemotherapy is a main strategy to treat triple-negative breast cancer (TNBC) patients currently, identifying a biomarker to predict chemotherapeutic responses is urgently needed for patients to avoid suffering through unnecessary chemotherapeutic treatments. Here, we found that the endogenous expression of TNFSF13 in a panel of TNBC cell lines highly correlates with paclitaxel (PTX) and doxorubicin IC50 concentrations. Whereas knocking down TNFSF13 enhances PTX effectiveness in PTX-insensitive MDA-MB231 cells, recombinant TNFSF13 (recTNFSF13) desensitizes PTX-sensitive HCC1806 cells to PTX treatment. Moreover, Kaplan-Meier analysis revealed that higher TNFSF13 mRNA expression significantly predicts an increased risk for cancer recurrence in estrogen receptor (ER)-negative breast cancer patients receiving an anthracycline-based treatment. Accordingly, immunohistochemistry experiments indicated that higher levels of TNFSF13 protein are detected in TNBC patients who do not respond to an anthracycline-based treatment. The in silico analysis and Western blotting demonstrated that TNFSF13 expression inversely associates with the activity of the Akt-mTOR pathway, which acts as a negative regulator of autophagy activity. Significantly, the pharmaceutical inhibition of autophagy activity restores the therapeutic effectiveness of PTX in TNFSF13-treated HCC1806 cells. These findings suggest that TNFSF13 can serve as a predictive biomarker for TNBC patients, who can use it to decide whether to receive chemotherapy. KEY MESSAGES: TNFSF13 upregulation correlates with a poor response to chemotherapy in TNBCs. TNFSF13 promotes autophagy initiation in chemotherapeutic resistant TNBCs. Therapeutic targeting of autophagy initiation overcomes the TNFSF13-related chemoresistance. TNFSF13 could be a predictive biomarker for TNBC patients receiving chemotherapy.

Simple Summary Aberrant activation of the Wnt/β-catenin pathway due to APC (adenomatous polyposis coli) loss and Kirsten ras (KRAS) mutation is highly associated with malignant evolution, e.g., metastasis, of colorectal cancer (CRC). Ral guanine nucleotide dissociation stimulator-like (RGL) proteins, such as RGL2, regulate RAS activity via controlling the exchange between GTP and GDP. Although the cross-talk between β-catenin and KRAS has been reported to promote cancer metastasis, the functional role of RGL2 remains largely unknown. Here we show that RGL2 is significantly upregulated in primary tumors compared to normal tissues and serves as a poor prognostic marker in CRC patients. Cell-based and animal experiments further demonstrate that RGL2 acts as a driver to promote the metastatic progression of CRC, most likely via preventing the protein degradation of β-catenin and KRAS. Our findings not only unveil the oncogenic function of RGL2 but also provide a new strategy to combat metastatic CRC by targeting RGL2 activity. Abstract Colorectal cancer (CRC) is one of the most common cancers and results in high mortality worldwide, owing to cancer progression, i.e., metastasis. However, the molecular mechanism underlying the metastatic evolution of CRC remains largely unknown. Here, we find that the upregulation of Ral Guanine Nucleotide Dissociation Stimulator Like 2 (RGL2) is commonly detected in primary tumors compared normal tissues and is significantly associated with a poorer prognosis in CRC patients. Moreover, RGL2 expression appeared to positively correlate with the metastatic potentials of CRC cells. Whereas RGL2 knockdown dramatically suppresses the metastatic potentials of CRC cells in vitro and in vivo, RGL2 overexpression in the poorly metastatic CRC cells and reconstitution in the RGL2-silenced CRC cells enhanced and rescued the cellular metastatic ability, respectively. Computational simulation using Gene Set Enrichment Analysis program and cell-based assays demonstrated that RGL2 expression causally associated with the activity of Wnt/β-catenin signaling axis and Kirsten ras (KRAS)S, as well as the progression of epithelial-mesenchymal transition (EMT) in the detected CRC cells. Importantly, RGL2 upregulation was capable of preventing the protein degradation of β-catenin and KRAS in CRC cells. These findings suggest that RGL2 acts as a driver to promote the metastatic progression of CRC and also serves as a poor prognostic biomarker in CRC patients.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor and has a poor prognosis and is poorly sensitive to radiotherapy or temozolomide (TMZ) chemotherapy. Therefore, identifying new biomarkers to predict therapeutic responses of GBM is urgently needed. By using The Cancer Genome Atlas (TCGA) database, we found that the upregulation of histone 2A family member J (H2AFJ), but not other H2AFs, is extensively detected in the therapeutic-insensitive mesenchymal, IDH wildtype, MGMT unmethylated, or non-G-CIMP GBM and is associated with poor TMZ responsiveness independent of radiation. Similar views were also found in GBM cell lines. Whereas H2AFJ knockdown diminished TMZ resistance, H2AFJ overexpression promoted TMZ resistance in a panel of GBM cell lines. Gene set enrichment analysis (GSEA) revealed that H2AFJ upregulation accompanied by the activation of TNF-α/NF-κB and IL-6/STAT3-related pathways is highly predicted. Luciferase-based promoter activity assay further validated that the activities of NF-κB and STAT3 are causally affected by H2AFJ expression in GBM cells. Moreover, we found that therapeutic targeting HADC3 by tacedinaline or NF-κB by ML029 is likely able to overcome the TMZ resistance in GBM cells with H2AFJ upregulation. Significantly, the GBM cohorts harboring a high-level H2AFJ transcript combined with high-level expression of TNF-α/NF-κB geneset, IL-6/STAT3 geneset or HADC3 were associated with a shorter time to tumor repopulation after initial treatment with TMZ. These findings not only provide H2AFJ as a biomarker to predict TMZ therapeutic effectiveness but also suggest a new strategy to combat TMZ-insensitive GBM by targeting the interaction network constructed by TNF-α/NF-κB, IL-6/STAT3, HDAC3, and H2AFJ.

Background: Although mTOR inhibitors have been approved as a first-line therapy for treating metastatic clear cell renal cell carcinoma (ccRCC), the lack of useful markers reduces their therapeutic effectiveness. We investigated whether IMPA2 downregulation predicts a favorable outcome in metastatic ccRCC receiving mTOR inhibitor treatment. Methods: An in silico Gene Set Enrichment Analysis (GSEA) was used to estimate correlation between the transcriptional profile of IMPA2 and mTORC1 gene set in ccRCC patients. Kaplan-Meier analysis was used to estimate the prognostic significance of the signature that combines low-level IMPA2 and high-level mTORC1 gene set expression ccRCC patients. The cellular migration and lung colony-forming assays were performed to evaluate therapeutic effectiveness of mTOR inhibition on the metastatic ccRCC cells with IMPA2 downregulation. Findings: The signature that combines low-level IMPA2 and high-level mTORC1 gene set expression correlated with a poorer prognosis in ccRCC patients. Whereas the enforced expression of exogenous IMPA2 inhibited the phosphorylation of Akt/mTORC1, artificially silencing IMPA2 led to increased phosphorylation of Akt/mTORC1 in ccRCC cells. The pharmaceutical inhibition of mTORC1 activity by rapamycin reinforced the autophagy initiation but suppressed the cellular migration and lung metastatic abilities of IMPA2-silenced ccRCC cells. In contrast, blocking autophagosome formation with 3-methyladenine rescued the mitigated metastatic potential in vitro and in vivo in IMPA2-overexpressing ccRCC cells. Interpretation: Our findings revealed that IMPA2 downregulation negatively activates mTORC1 activity and could be a biomarker for guiding the use of mTOR inhibitors or autophagy inducers to combat metastatic ccRCC in the clinic. Funding Statement: This study was supported by the Ministry of Science and Technology, Taiwan (MOST 108-2320-B-038-017-MY3) to Yuan-Feng Lin and Chia-Hao Kuei (MOST 108-2314-B-567-001) Cardinal Tien Hospital, Xindian District, New Taipei City, Taiwan (CTH108A-2A01) to Chia-Hao Kuei. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: All animal procedures were approved by the Institutional Animal Care and Use Committee at Taipei Medical University.

Lung metastasis (LM) is commonly found in triple-negative breast cancer (TNBC); however, the molecular mechanism underlying TNBC metastasis to lungs remains largely unknown. We thus aimed to uncover a possible mechanism for the LM of TNBC. Here we show that the phosphorylation of Akt and mTORC1 was positively but the autophagy activity was negatively correlated with endogenous Gαh levels and cell invasion ability in TNBC cell lines. Whereas the knockdown of Gαh, as well as blocking its binding with PLC-δ1 by a synthetic peptide inhibitor, in the highly invasive MDA-MB231 cells dramatically suppressed Akt/mTORC1 phosphorylation and blocked autophagosome degradation, the overexpression of Gαh in the poorly invasive HCC1806 cells enhanced Akt/mTORC1 phosphorylation but promoted autophagosome degradation. The pharmaceutical inhibition of autophagy initiation by 3-methyladenine was found to rescue the cell invasion ability and LM potential of Gαh-silenced MDA-MB231 cells. In contrast, the inhibition of mTORC1 activity by rapamycin suppressed autophagosome degradation but mitigated the cell invasion ability and LM potential of Gαh-overexpressing HCC1806 cells. These findings demonstrate that the induction of autophagy activity or the inhibition of Akt-mTORC1 axis provides a useful strategy to combat the Gαh/PLC-δ1-driven LM of TNBC.

Urinoma, defined as the urine leakage beyond the urinary tract, is commonly induced by blunt trauma or urinary tract obstruction by stone, intra-abdominal malignancy, or retroperitoneal fibrosis. Spontaneous urinoma is rare and parenchymal pathologic change is rarely mentioned when urinoma is found. We present a case of a 28-year-old woman with bilateral flank pain induced by spontaneous urinoma. The lady received chronic analgesics because of migraine. After intravenous ketorolac injection, bilateral perirenal urinoma developed. Renal biopsy showed acute interstitial nephritis associated with nonsteroid anti-inflammatory drug (NSAID). After discontinuing the medication, urinoma subsided, and the patient was discharged with normal serum creatinine. This was the first case of urinoma induced by NSAID-related interstitial nephritis, and pathophysiology and management of spontaneous urinoma are discussed.

Radiotherapy is commonly used to treat patients with oral squamous cell carcinoma (OSCC), but a subpopulation of OSCC patients shows a poor response to irradiation treatment. Therefore, identifying a biomarker to predict the effectiveness of radiotherapy in OSCC patients is urgently needed. In silico analysis of public databases revealed that upregulation of CHRNA5, the gene encoding nicotinic acetylcholine receptor subunit alpha-5, is extensively detected in primary tumors compared to normal tissues and predicts poor prognosis in OSCC patients. Moreover, CHRNA5 transcript level was causally associated with the effective dose of irradiation in a panel of OSCC cell lines. Artificial silencing of CHRNA5 expression enhanced, but nicotine reduced, the radiosensitivity of OSCC cells. Gene set enrichment analysis demonstrated that the E2F signaling pathway is highly activated in OSCC tissues with high levels of CHRNA5 and in those derived from patients with cancer recurrence after radiotherapy. CHRNA5 knockdown predominantly suppressed E2F activity and decreased the phosphorylation of the Rb protein, however, nicotine treatment dramatically promoted E2F activity and increased Rb phosphorylation, which was mitigated after CHRNA5 knockdown in OSCC cells. Notably, the signature combining increased mRNA levels of CHRNA5 and the E2F signaling gene set was associated with worse recurrence-free survival probability in OSCC patients recorded to be receiving radiotherapy. Our findings suggest that CHRNA5 is not only a useful biomarker for predicting the effectiveness of radiotherapy but also a druggable target to enhance the cancericidal effect of irradiation on OSCC.

Objective Docetaxel remains a main treatment for metastatic castration-resistant prostate cancer (mCRPC); however, the development of docetaxel resistance has been found in some mCRPC patients. The aim of this work is to identify an effective biomarker for predicting therapeutic effectiveness of docetaxel in mCRPC patients. Methods We examined DNA polymerase theta (POLQ) expression in The Cancer Genome Atlas (TCGA) database and Tissue microarray. Kaplan-Meier analyses were performed to estimate the prognostic significance of POLQ. A series of functional analyses were conducted in cell lines and xenograft models. Regulated pathways were predicted by Geneset Enrichment Analysis (GSEA) software and further investigated by luciferase reporter and RT-PCR assays. Results We found that POLQ mRNA levels in CRPC tissues was significantly higher than that of other DNA polymerases in non-CRPC prostate tissues. POLQ upregulation was extensively detected in mCRPC and strongly predicted a poor prognosis. POLQ knockdown enhanced docetaxel sensitivity in a cell-based cytotoxicity assay and promoted the therapeutic effect on the tumor growth of metastatic PC-3M cells in xenograft models. The computational simulation by GSEA software significantly predicted the association between POLQ upregulation and the activation of E2F/G2M checkpoint-related pathways. Moreover, luciferase reporter and RT-PCR assays demonstrated that POLQ knockdown downregulated the transcriptional regulatory activity of E2F and repressed E2F/G2M checkpoint-regulated CDK1 in mCRPC cells. Conclusion Our results suggest that POLQ serves as a predictive factor for poor docetaxel response and provide a novel strategy to enhance the anticancer effects of docetaxel therapy by targeting POLQ in mCRPC patients.

A series of bidentate ligands were examined to improve the catalytic activity of l -lactide (LA) polymerization by using n-butyl lithium and BnOH. For LA polymerization, n-butyl lithium with tetraisopropyl methylenebis(phosphonate) (L8 ) showed the greatest catalytic activity but with poor controllability of the polymer molecular weight. The polydispersity indices (PDIs) could be improved without BnOH addition, but Mn GPC was much different from the Mn Cal . 1H NMR spectra confirmed that the cyclized PLA was obtained, thus implying that active chain-end mechanisms were operative in LA polymerization.

Objective: To evaluate the impact of intravesical prostatic protrusion (IPP) and prostatic calcification on medical treatment for male lower urinary tract symptoms (LUTS). Materials and methods: Men over the age of 40 years with total International Prostate Symptom Score (IPSS) ≥ 8 were recruited from January to August 2013. The maximal flow rate, postvoiding residual (PVR) urine volume, total prostate volume (TPV), transitional zone volume (TZV), transitional zone index (TZI), and grades of IPP and prostate calcification were recorded. All patients received α-blocker monotherapy, and Global Response Assessment (GRA) was used to determine treatment response 1 month after the treatment. The primary end point was to compare the treatment results in patients with and without significant IPP or prostate calcification. Univariate and multivariate logistic regression analyses were performed to determine whether IPP and prostatic calcification are predictors of improved outcome (GRA ≥ 1). Results: We enrolled 112 men with a mean age of 65.5 (range, 42–89) years. IPP was significantly positively correlated with TPV, TZV, TZI, and PVR. Prostatic calcification was significantly negatively correlated with total IPSS, IPSS Voiding, and IPSS Storage. After 1-month treatment with α-blockers, the average total IPSS decreased from 18.2 ± 7.4 to 13.1 ± 4.5. Sixty-nine patients (61.6%) reported improved outcomes. Patients with large prostate volumes (TPV ≥ 40 mL) and small prostate volumes (TPV

Paclitaxel (PTX) is a common regimen used to treat patients with ovarian cancer. Although approximately 60% of ovarian cancer patients exhibit a pathologic complete response (pCR), approximately 40% of patients appear to be insensitive to PTX adjuvant therapy. Thus, identifying a useful biomarker to predict pCR would be of great help to ovarian cancer patients who decide to receive PTX treatment. We found that FBXL7 was downregulated in OVSAHO (PTX-sensitive) but upregulated in KURAMOCHI (PTX-resistant) cells after PTX treatment at cytotoxic concentrations. Moreover, our data showed that the fold change of FBXL7 expression post-treatment with PTX was causally correlated with the 50% inhibitory concentrations (IC50) of PTX in a panel of ovarian cancer cell lines. In assessments of progression-free survival probability, high levels of FBXL7 transcript strongly predicted a poor prognosis and unfavorable response to PTX-based chemotherapy in patients with ovarian cancer. The knockdown of FBXL7 predominantly enhanced the cytotoxic effectiveness of PTX on the PTX-resistant KURAMOCHI cells. FBXL7 may be a useful biomarker for predicting complete pathologic response in ovarian cancer patients who decide to receive post-operative PTX therapy.

Mirabegron, the first β3-adrenoceptor agonist introduced for use in clinical practice, differs from antimuscarinic agents in terms of mechanism of action. This review discusses various perspectives on mirabegron in terms of efficacy, mechanism of action, pharmacokinetics, safety, and tolerability for overactive bladder syndrome in studies conducted thus far. Mirabegron administered at daily doses of 25 mg, 50 mg, and 100 mg demonstrated significant improvements in micturition frequency, urgency incontinence, and mean volume voided/micturition as early as the first assessment, and these were maintained throughout the treatment course. Mirabegron seemed well tolerated. The most common adverse events observed with mirabegron in clinical trials were hypertension, nasopharyngitis, and urinary tract infection. The incidence of dry mouth was similar to that with placebo, between 3- and 5-fold lower than with 4 mg tolterodine extended release. Considering that dry mouth is the most bothersome adverse event associated with antimuscarinic drugs and often a reason for treatment discontinuation, mirabegron may be a valuable treatment option for these patients. The benefit of mirabegron (at doses of 50 mg and 100 mg) was also evident in elderly patients and in both treatment-naive patients and those who previously discontinued antimuscarinic therapy. Mirabegron can also be used in combination with antimuscarinics or in addition to alpha blockers. Mirabegron may quickly become a standard treatment of overactive bladder syndrome.

Cerebral vascular disease is the sudden onset brain tissue damage and subsequent loss of brain function due to ischemia (white infarct) or hemorrhage (red infarct). Voiding dysfunction is a common sequela after a cerebrovascular accident (CVA). Urinary incontinence occurs in 43.5% of CVA patients within 3 months of the event.1 Incontinence is not life-threatening, and the degree of morbidity often declines over time. Twelve months after CVA, 37.7% of patients continue to have symptoms of urge incontinence.1 The severity and trend of incontinence are dependent on the severity of the stroke and the patient’s age.1 Lower urinary tract symptoms (LUTSs), especially storage symptoms such as frequency and urgency with or without urge incontinence, are commonly present in the 3 months following a CVA.2e4 Pathophysiological conditions other than CVA can cause LUTSs in old age, such as bladder outlet obstruction (BOO), and might lead to confusion in diagnosing and treating voiding dysfunction in older men with a history of CVA.5,6 Foley catheter insertion is the most common method of addressing this problem. Involuntary detrusor muscle contractions are the most common urodynamic finding in patients after a CVA; however, patients with chronic CVA may have both detrusor overactivity (DO) during the storage phase and loss of coordination of urethral sphincter relaxation during voiding that causes urinary incontinence or difficult urination.7,8 Detrusor underactivity (DU) and detrusor hyperreflexia with impaired contractility (DHIC) are other problematic issues that can occur in elderly patients with multiple CVAs or in the acute