Nuclear VCP drives colorectal cancer progression by promoting fatty acid oxidation.

Fatty acid oxidation (FAO) fuels many cancers. However, knowledge of pathways that drive FAO in cancer remains unclear. Here, we revealed that valosin-containing protein (VCP) upregulates FAO to promote colorectal cancer growth. Mechanistically, nuclear VCP binds to histone deacetylase 1 (HDAC1) and facilitates its degradation, thus promoting the transcription of FAO genes, including the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A). FAO is an alternative fuel for cancer cells in environments exhibiting limited glucose availability. We observed that a VCP inhibitor blocked the upregulation of FAO activity and CPT1A expression triggered by metformin in colorectal cancer (CRC) cells. Combined VCP inhibitor and metformin prove more effective than either agent alone in culture and in vivo. Our study illustrates the molecular mechanism underlying the regulation of FAO by nuclear VCP and demonstrates the potential therapeutic utility of VCP inhibitor and metformin combination treatment for colorectal cancer.

Paeoniflorin alleviates lipopolysaccharide-induced disseminated intravascular coagulation by inhibiting inflammation and coagulation activation.

Lipopolysaccharide (LPS) is a toxic component of the outer membrane of gram-negative bacteria that can activate the blood coagulation system, leading to disseminated intravascular coagulation (DIC). DIC is a syndrome characterized by thromboembolism and multiple organ failure. Herein, the beneficial effect of paeoniflorin (PF) on the alleviation of LPS-induced DIC was investigated with an experimental DIC mouse model. Briefly, mice were randomly divided into the following six groups: (1) control; (2) LPS; (3) heparin; (4) low-PF treatment; (5) medium-PF treatment; and (6) high-PF treatment. The histological morphology of the liver and kidney was observed, and the coagulation indicators (such as prothrombin time), function indicators (such as alanine transferase), and inflammatory factors (such as TNF-α) were detected. Additionally, an in vitro cell inflammation model using RAW 264.7 murine macrophages was established. Activation of the nuclear factor kappa B (NF-κB) signaling pathway and tumor necrosis factor-α (TNF-α) were determined by western blotting. Based on our findings, PF could significantly improve the histological morphology of the liver and kidney, indicating that PF protects the liver and kidney against damage induced by LPS. Additionally, PF improved the function and coagulation indicators and reduced the production of inflammatory factors. In vitro, PF inhibited the expression of TNF-α by suppressing NF-κB signaling pathway activation. Collectively, our findings support the hypothesis that PF has anti-inflammatory and anticoagulation effects for the alleviation of LPS-induced DIC. PF is thus a potential co-treatment option for DIC.

Resiniferatoxin for treatment of lifelong premature ejaculation: a preliminary study.

OBJECTIVES: To evaluate the efficacy of resiniferatoxin in the treatment of patients with lifelong premature ejaculation. METHODS: A total of 41 outpatients (mean age 26.14 ± 4 years) with premature ejaculation completed the present study. They were randomly separated into the resiniferatoxin group and the placebo group. The resiniferatoxin group included 11 patients with redundant prepuce and 10 patients without redundant prepuce, whereas the placebo group contained 10 patients with redundant prepuce and 10 patients without. For the treatment, the glans were respectively soaked in 30 mL of resiniferatoxin with a concentration of 100 nmol/L or 10% alcohol solution for 30 min before sexual intercourse. Clinical efficacy was assessed by using the Chinese Index of Sexual Function for Premature Ejaculation-5 and the intravaginal ejaculation latency time before or 4 weeks after the treatment. The side-effects were also evaluated. RESULTS: In the resiniferatoxin group, the effective rate of patients with redundant prepuce was 63.6%, and both the intravaginal ejaculation latency time and Chinese Index of Sexual Function for Premature Ejaculation-5 significantly increased (P < 0.05). However, the effective rate of patients without redundant prepuce was 20%, and there were no significant changes of their intravaginal ejaculation latency time and Chinese Index of Sexual Function for Premature Ejaculation-5 before and after the resiniferatoxin treatment (P > 0.05). The total effective rate of patients treated with resiniferatoxin was 42.9%. In the placebo group, the effective rate of patients with or without redundant prepuce was 20% and 10%, respectively. The total effective rate of patients treated with placebo was 15%, and there were no significant changes of their intravaginal ejaculation latency time and Chinese Index of Sexual Function for Premature Ejaculation-5 before and after the placebo treatment (P > 0.05). The side-effects included a slight burning sensation for the glans penis and dysuria. CONCLUSIONS: These preliminary results show that resiniferatoxin might be suitable for treating patients with lifelong premature ejaculation and particularly those with redundant prepuce.

Chronic scrotal pain caused by Mild Epididymitis:Report of a series of 44 cases.

OBJECTIVES: Patients with idiopathic chronic scrotal pain are challenging to both the general practioner and urologist. In this study, we tried to recognize mild epididymitis as an underrecogniczed cause of idiopathic chronic scrotal pain. Methods : We described a consecutive series of 44 patients with idiopathic chronic scrotal pain characterized by mild scrotal pain, mild to moderate tenderness of epididymis without abnormal swelling of epididymis. We obtained a detailed history and physical examination along with routine urinalysis and Doppler ultrasound to identify the characteristics of this new clinical entity. Results : A consecutive series of 44 patients who were primarily diagnosed as "idiopathic chronic scrotal pain" came to our hospital. All had the sign of mild to moderate tenderness on the affected epididymis without epididymis enlargement. Doppler ultrasound showed the affected epididymis with normal size and no abnormal change. We treated them with antibiotics orally along with cessation of strenuous activity and all fully recovered from scrotal pain. CONCLUSION: In this study, we recognized mild epididymitis as an underrecogniczed cause of idiopathic chronic scrotal pain. It was characterized by mild scrotal pain, mild to moderate tenderness of epididymis without abnormal enlargement of epididymis.

Erratum: [Corrigendum] miR­216a­5p acts as an oncogene in renal cell carcinoma.

[This corrects the article DOI: 10.3892/etm.2018.5881.].

[Retracted] Oncogenic miR-23a-5p is associated with cellular function in RCC.

Following the publication of this article, a concerned reader drew to the Editor's attention that, for the invasion and migration assay data shown in Fig. 4 on p. 2314, three pairs of data panels were overlapping, such that data which were intended to show the results from differently performed experiments were obtained from a smaller number of original sources. Moreover, after having conducted an internal investigation, the Editorial Office also observed that some of the flow cytometric data shown in Fig. 6 were duplicated in Fig. 7. Considering the number of overlapping data panels that have been identified in this published paper, the Editor of Molecular Medicine Reports has concluded that the article should be retracted from the publication on account of a lack of confidence in the integrity of the data. Upon contacting the authors about this matter, they accepted the decision to retract this paper. The Editor apologizes to the readership for any inconvenience caused, and thanks the interested reader for drawing this matter to our attention. [Molecular Medicine Reports 16: 2309-2317, 2017; DOI: 10.3892/mmr.2017.6829].

[Corrigendum] Identification of lncRNA EGOT as a tumor suppressor in renal cell carcinoma.

Subsequently to the publication of the above paper, an interested reader drew to the authors' attention that, concerrning the Transwell cell migration and invasion assay data shown in Fig. 6A and B for the 786­O cell line on p. 7206, the pcDNA3.1­EGOT 'Migration' and 'Invasion' (a­1 and b­1) data panels appeared to contain overlapping sections of data, such that they were potentially derived from the same original source, where these panels were intended to show the results from differently performed experiments. The authors have re­examined their original data, and realize that the 'Invasion' (b­1) panel in Fig. 6B was inadvertently chosen incorrectly. The revised version of Fig. 6, now featuring the correct data for the 'Invasion' experiment (B1 in the replacement figure) in Fig. 6B, is shown on the next page. Note that this error did not adversely affect either the results or the overall conclusions reported in this study. All the authors agree with the publication of this corrigendum, and are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this. They also wish to apologize to the readership of the Journal for any inconvenience caused.[Molecular Medicine Reports 16: 7072­7079, 2017; DOI: 10.3892/mmr.2017.7470].

[Retracted] miR­660­5p is associated with cell migration, invasion, proliferation and apoptosis in renal cell carcinoma.

Following the publication of the above article, the authors contacted the Editorial Office to explain that a couple of errors concerning data handling/labelling had been made, firstly during the preparation of the representative images in Fig. 3B, resulting in the wrong image being selected for the data panel showing the ACHN cells treated with 'Inhibitor NC' at 0 h experiment, and secondly in Fig. 5A, resulting in the wrong image being selected for the data panel showing the ACHN cells treated with 'Inhibitor NC' experiment. The authors requested that a corrigendum be published to take account of the errors that were made during the preparation of this figure. Subsequently, an independent investigation of the published data was undertaken by the Editorial Office, which revealed that the 'Inhibitor' data panel in Fig. 6A and the 'Mimic NC' data panel in Fig. 6B were also overlapping, such that these data were likely to have been derived from the same original source, even though these data panels were intended to have shown the results from differently performed experiments. The Editor of Molecular Medicine Reports has considered the authors' request to publish a corrigendum, but given the number of overlapping data panels that have been identified and the number of figures that would be in need of correction, the Editor has decided to decline the authors' request to publish a corrigendum on account of an overall lack of confidence in the presented data, and instead has determined that the paper should be retracted. Upon receiving this news from the Editor, the authors accepted the Editor's decision. The Editor apologizes to the readership of the Journal for any inconvenience caused. [Molecular Medicine Reports 17: 2051­2060, 2018; DOI: 10.3892/mmr.2017.8052].

[Corrigendum] MicroRNA­222­3p promotes tumor cell migration and invasion and inhibits apoptosis, and is correlated with an unfavorable prognosis of patients with renal cell carcinoma.

Following the publication of the above article, an interested reader drew to the attention of the Editorial Office that, in Fig. 3A on p. 530, two pairs of data panels were overlapping, such that certain of the panels appeared to have been derived from the same original sources where the results from differently performed experiments were intended to have been portrayed. The authors have examined their original data, and realize that errors associated with data handling/labelling during the preparation of the representative images in Fig. 3A had occurred. The revised version of Fig. 3, showing the correct data for the 'NC/ACHN/Invasion and Migration' data panels, the 'Inhibitor NC/786­O' panel and the 'Inhibitor NC/ACHN/Invasion' panel, is shown on the next page. The authors can confirm that the errors associated with this figure did not have any significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of International Journal of Molecular Medicine for giving them the opportunity to publish this Corrigendum; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 43: 525­534, 2019; DOI: 10.3892/ijmm.2018.3931].

Prostatic Schistosoma japonicum with atypical immunophenotyping of individual glandular tubes: a case report and review of the literature.

There are few cases of prostatic schistosomiasis. Here we report a case of Schistosoma japonicum of the prostate, in which the immunophenotyping of individual glandular tubes was atypical. Whether the S. japonicum infection contributed to the lesion or not is unknown. We suspect the lesion was a sign of early precancerous hyperplasia. Follow-up of this patient may give clues about the relationship between schistosomiasis and prostate cancer. This is the first case report of prostatic S. japonicum in the English literatures. A review of the literature is carried out.

GLIDR promotes the aggressiveness progression of prostate cancer cells by sponging miR-128-3p.

Glioblastoma downregulated RNA (GLIDR) is a newly discovered long non-coding RNA (lncRNA) that its increased expression indicates a poor prognosis of prostate cancer (PCa). However, the effect of GLIDR on PCa cells is not clear. Our study investigated the role and molecular mechanism of GLIDR in PCa cells. The results showed that GLIDR expression levels were higher in PCa samples and cells than in control. GLIDR could regulate the invasive potential, epithelial-to-mesenchymal transition (EMT) and proliferation in PC-3 and LnCaP cells. Besides, GLIDR could weaken the inhibitory effects of miR-128-3p on invasion, EMT and proliferation in PCa cells. Western blotting proved that miR-128-3p affected the expression of EMT markers, such as E-cadherin, Snail and N-cadherin, and GLIDR could reversed the effects of miR-128-3p on the expression levels of EMT markers in PCa cells. In addition, knockdown of miR-128-3p stimulated the invasion, EMT, and proliferation in PCa cells, whereas these effects were reversed when GLIDR expression was knocked down. GLIDR knockdown inhibited the invasion, EMT, and proliferation in PCa cells, and GLIDR was shown to sponge miR-128-3p. Together, these results highlight GLIDR as a potential therapeutic target for the PCa treatment.

Targeting VCP potentiates immune checkpoint therapy for colorectal cancer.

Immune checkpoint blockade therapies are still ineffective for most patients with colorectal cancer (CRC). Immunogenic cell death (ICD) enables the release of key immunostimulatory signals to drive efficient anti-tumor immunity, which could be used to potentiate the effects of immune checkpoint inhibitors. Here, we showed that inhibition of valosin-containing protein (VCP) elicits ICD in CRC. Meanwhile, VCP inhibitor upregulates PD-L1 expression and compromises anti-tumor immunity in vivo. Mechanistically, VCP transcriptionally regulates PD-L1 expression in a JAK1-dependent manner. Combining VCP inhibitor with anti-PD1 remodels tumor immune microenvironment and reduces tumor growth in mouse models of CRC. Addition of oncolytic virus further augments the therapeutic activity of the combination regimen. Our study shows the molecular mechanism for regulating PD-L1 expression by VCP and suggests that inhibition of VCP has the potential to increase the efficacy of immunotherapy in CRC.

IDH1 mutation impairs antiviral response and potentiates oncolytic virotherapy in glioma.

IDH1 mutations frequently occur early in human glioma. While IDH1 mutation has been shown to promote gliomagenesis via DNA and histone methylation, little is known regarding its regulation in antiviral immunity. Here, we discover that IDH1 mutation inhibits virus-induced interferon (IFN) antiviral responses in glioma cells. Mechanistically, D2HG produced by mutant IDH1 enhances the binding of DNMT1 to IRF3/7 promoters such that IRF3/7 are downregulated, leading to impaired type I IFN response in glioma cells, which enhances the susceptibility of gliomas to viral infection. Furthermore, we identify DNMT1 as a potential biomarker predicting which IDH1mut gliomas are most likely to respond to oncolytic virus. Finally, both D2HG and ectopic mutant IDH1 can potentiate the replication and oncolytic efficacy of VSVΔ51 in female mouse models. These findings reveal a pivotal role for IDH1 mutation in regulating antiviral response and demonstrate that IDH1 mutation confers sensitivity to oncolytic virotherapy.

Ketamine-associated urinary tract dysfunction: an underrecognized clinical entity.

INTRODUCTION: The use of ketamine as a recreational drug is on the increase among young adults attending clubs and parties. Recreational ketamine users have anecdotally reported increased lower urinary tract symptoms while using the substance. METHODS: We describe the severe lower urinary tract symptoms experienced in 6 patients with chronic recreational ketamine use. We obtained a detailed history and physical examination along with further investigation to identify a relationship between recreational ketamine use and these symptoms. RESULTS: The urine cultures were sterile in all cases. Intravenous urography was performed in 3 patients and demonstrated bilateral upper ureteric narrow, mild bilateral hydronephrosis and contracted bladder urodynamic studies showed detrusor instability with urinary leakage when the bladder was filled to a capacity of 30- 50 ml. Cystoscopy revealed a small capacity bladder with erythematous lesions throughout the bladder. Bladder biopsies were performed in 3 patients and showed up as chronic cystitis. Ketamine cessation along with intravesical sodium hyaluronate solution appeared to provide some symptomatic relief. CONCLUSION: Ketamine-associated urinary tract dysfunction appears to be a relatively new clinical phenomenon. The pathological mechanism of ketamine-associated urinary tract dysfunction is unknown and current management strategies are ketamine cessation along with intravesical sodium hyaluronate solution.

HOXA1 promotes proliferation and metastasis of bladder cancer by enhancing SMAD3 transcription.

BACKGROUND: Recent studies showed that HOXA1 can promote or suppress the transcription of target genes via binding to their promoter region, therefore regulating the development and progression of various cancers. However, the biological function of HOXA1 in bladder cancer (Bca) remains unknown. METHODS: qRT-PCR and Western blot assay was performed to measure the mRNA protein level of HOXA1 in Bca cells. CCK-8 and cell colony formation assay were carried out to detect cell proliferation ability. Wound healing assay was applied to detect cell migration ability, while transwell assay was applied to detect cell invasion ability. Chromatin Immunoprecipitation (ChIP) and dual-luciferase reporter assay were used to investigate the molecular mechanisms underlying HOXA1. RESULTS: In this study, we discovered that HOXA1 mRNA and protein was dramatically increased in Bca tissues and cells compared to matched normal tissues and normal bladder epithelial cell. Enhanced HOXA1 expression was positively correlated with bigger tumor size and lymphatic metastasis, causing shorter overall survival to Bca patients. Knockdown of HOXA1 obviously impaired cell proliferation and metastasis ability. Further experiments proved that HOXA1 could strength the transcription of SMAD3 via binding to the promoter region of SMAD3. CONCLUSION: In conclusion, our study suggested that HOXA1 contributed to the growth and metastasis of Bca and it might serve as a tumor biomarker for Bca treatment and prognosis monitoring.

Engineered CRISPR/Cas13d Sensing hTERT Selectively Inhibits the Progression of Bladder Cancer In Vitro.

Aptazyme and CRISPR/Cas gene editing system were widely used for regulating gene expression in various diseases, including cancer. This work aimed to reconstruct CRISPR/Cas13d tool for sensing hTERT exclusively based on the new device OFF-switch hTERT aptazyme that was inserted into the 3' UTR of the Cas13d. In bladder cancer cells, hTERT ligand bound to aptamer in OFF-switch hTERT aptazyme to inhibit the degradation of Cas13d. Results showed that engineered CRISPR/Cas13d sensing hTERT suppressed cell proliferation, migration, invasion and induced cell apoptosis in bladder cancer 5637 and T24 cells without affecting normal HFF cells. In short, we constructed engineered CRISPR/Cas13d sensing hTERT selectively inhibited the progression of bladder cancer cells significantly. It may serve as a promising specifically effective therapy for bladder cancer cells.

FAM64A is an androgen receptor-regulated feedback tumor promoter in prostate cancer.

Endocrine therapy for prostate cancer (PCa) mainly inhibits androgen receptor (AR) signaling, due to increased androgen synthesis and AR changes, PCa evolved into castration-resistant prostate cancer (CRPC). The function of Family With Sequence Similarity 64 Member A (FAM64A) and its association with prostate cancer has not been reported. In our research, we first reported that FAM64A is up-regulated and positively associated with poor prognosis of patients with prostate cancer (PCa) by TCGA database and immunohistochemistry staining. Moreover, knockdown of FAM64A significantly suppressed the proliferation, migration, invasion, and cell cycle of PCa cells in vitro. Mechanistically, FAM64A expression was increased by dihydrotestosterone (DHT) through direct binding of AR to FAM64A promoter, and notably promoted the proliferation, migration, invasion, and cell cycle of androgen-dependent cell line of PCa. In addition, abnormal expression of FAM64A affects the immune and interferon signaling pathway of PCa cells. In conclusion, FAM64A was up-regulated by AR through directly binding to its specific promoter region to promote the development of PCa, and was associated with the immune mechanism and interferon signaling pathway, which provided a better understanding and a new potential for treating PCa.

Diagnosis and treatment of a rare tumor-bladder paraganglioma.

Bladder paragangliomas are very rare tumors that are often misdiagnosed. The present study retrospectively analyzed the clinical data and follow-up results of patients with bladder paraganglioma that were treated surgically in Peking University Shenzhen Hospital between 2012 and 2018, and reviewed the relevant literature. A total of 4 patients with bladder paraganglioma were treated surgically from 2012 to 2018. All patients were female with ages ranging from 28 to 54 years old (average, 47.25). A total of one patient exhibited micturition attacks and palpitations, and one other exhibited gross hematuria. A total of two patients exhibited while no obvious symptoms. One patient exhibited elevated plasma catecholamine, was well prepared with medicine and underwent partial cystectomy, and 3 patients were not successfully diagnosed with paraganglioma before surgery. These patients received transurethral resection and 2 had distinct blood pressure elevation during operation. After surgery, the patients were followed-up for 5-69 months, during which all had normal blood pressure and none experienced recurrence. Bladder paragangliomas exhibit a variety of clinical presentations, which can be nonspecific for the non-functional ones, therefore may easily lead to misdiagnosis. Surgeons must fully consider the possibility of this disease when dealing with non-epithelial bladder tumors. Surgical resection is an effective treatment. For cases successfully diagnosed before surgery, partial cystectomy should be a treatment priority.

CLC-3 and SOX2 regulate the cell cycle in DU145 cells.

Sex determining region Y-box 2 (SOX2) is a transcription factor that serves a role in numerous different types of malignant cancer. Altered expression of chloride channel proteins has been described in a variety of malignancies. However, the association between SOX2 and chloride channel proteins is not yet fully understood. The present study investigated the association between SOX2 and chloride voltage-gated channel 3 (CLC-3) in prostate cancer. Flow cytometry demonstrated that the inactivation of CLC-3 or SOX2 arrested cell cycle progression in the G0/G1 phase. Furthermore, CLC-3 was observed to bind to SOX2, and vice versa, by co-immunoprecipitation. SOX2 appears to initiate and maintain prostate cancer tumorigenesis, in part, by modulating the cell cycle. These findings indicate the potential of SOX2 and CLC-3 as targets for the development of multi-targeted therapeutics.

Tetrahydropalmatine has a therapeutic effect in a lipopolysaccharide-induced disseminated intravascular coagulation model.

OBJECTIVES: The aim of this study was to determine the therapeutic effects of tetrahydropalmatine (Tet) on disseminated intravascular coagulation (DIC) by exploring the role of Tet using a lipopolysaccharide (LPS)-induced DIC model. Methods/Materials: We established a mouse DIC model by injecting LPS. Hematoxylin-eosin (HE) staining was performed to detect liver and kidney damage. Blood samples were obtained to determine liver and kidney injury indexes, coagulation indexes, and inflammatory cytokines. An in vitro cell inflammation model was also established. Tumor necrosis factor-α (TNF-α) levels and nuclear factor kappa B (NF-κB) signaling pathway activation were determined by western blot. RESULT: Tet ameliorated the damage to organ tissues, improved coagulation indexes, and reduced the inflammatory cytokine production in LPS-induced mouse DIC. Tet also inhibited TNF-α expression by suppressing NF-κB signaling pathway activation in an in vitro LPS model using RAW 264.7 macrophages. CONCLUSIONS: Tet has a mitigating and therapeutic effect on the LPS-induced DIC model via anticoagulant and anti-inflammatory effects, showing its potential as an adjunct to DIC treatment.