Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 337
Filtrar
1.
Int J Urol ; 28(1): 69-74, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33131119

RESUMO

OBJECTIVE: To evaluate the impact of cancer therapy on post-treatment ejaculation in patients with testicular cancer. METHODS: A total of 74 testicular cancer survivors provided completed International Index of Erectile Function-15 questionnaires before and after treatment between 2010 and 2017. Sexual function, particularly ejaculatory function, was evaluated before and after treatment. In this study, patients who answered "1 = almost never/never" or "2 = a few times" for questionnaire number 9 (ejaculation frequency) were defined as having "ejaculation disorder." RESULTS: Of 74 testicular cancer survivors, 50 (68%) had no ejaculation disorders before treatment. Four (44%) of nine survivors, who received chemotherapy and retroperitoneal lymph node dissection, developed ejaculation disorders after treatment. On multivariate analysis, retroperitoneal lymph node dissection was a significant predictor of post-treatment ejaculation disorder (P = 0.042). Of 60 survivors with evaluable ejaculation function after treatment, 24 (40%) did not attempt sexual intercourse, and multivariate analysis showed ejaculation disorder had a significant negative impact on having sexual intercourse (P = 0.035). Furthermore, the mean International Index of Erectile Function-15 scores in the groups with and without ejaculation disorders after treatment were 24.0 and 51.9, respectively (P < 0.001). CONCLUSION: Ejaculation disorders occur at high rate after retroperitoneal lymph node dissection. Many testicular cancer survivors reporting no sexual intercourse have ejaculation disorders, suggesting an adverse impact on sexual life. Urologists should provide proper counselling regarding the risk of ejaculation disorder and its possible impact on sexual life.

2.
Intern Med ; 60(1): 131-136, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830178

RESUMO

A 76-year-old woman with dermatomyositis was being treated with prednisolone, tacrolimus, and mycophenolate mofetil. There was a solitary lung nodule in the right middle lobe on chest computed tomography at a routine follow-up examination. A transbronchial lung biopsy was performed, and the histopathologic findings indicated diffuse large B-cell lymphoma. An immunodeficiency-associated lymphoproliferative disorder was suspected, and mycophenolate mofetil was stopped without adding any other therapy. Nine months later, the pulmonary nodule had disappeared on chest computed tomography.

3.
Int J Biol Macromol ; 170: 415-423, 2020 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-33373636

RESUMO

Alzheimer's disease (AD), a common chronic neurodegenerative disease, has become a major public health concern. Despite years of research, therapeutics for AD are limited. Overexpression of secretory glutaminyl cyclase (sQC) in AD brain leads to the formation of a highly neurotoxic pyroglutamate variant of amyloid beta, pGlu-Aß, which acts as a potential seed for the aggregation of full length Aß. Preventing the formation of pGlu-Aß through inhibition of sQC has become an attractive disease-modifying therapy in AD. In this current study, through a pharmacophore assisted high throughput virtual screening, we report a novel sQC inhibitor (Cpd-41) with a piperidine-4-carboxamide moiety (IC50 = 34 µM). Systematic molecular docking, MD simulations and X-ray crystallographic analysis provided atomistic details of the binding of Cpd-41 in the active site of sQC. The unique mode of binding and moderate toxicity of Cpd-41 make this molecule an attractive candidate for designing high affinity sQC inhibitors.

4.
Biochem J ; 2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33355669

RESUMO

Herpes simplex virus 1 (HSV-1) is a human DNA virus that causes cold sores, keratitis, meningitis, and encephalitis. Ubiquitination is a post-translational protein modification essential for regulation of cellular events, such as proteasomal degradation, signal transduction, and protein trafficking. The process is also involved in events for establishing viral infection and replication. The first step in ubiquitination involves ubiquitin (Ub) binding with Ub-activating enzyme (E1, also termed UBE1) via a thioester linkage. Our results show that HSV-1 infection alters protein ubiquitination pattern in host cells, as evidenced by MS spectra and co-immunoprecipitation assays. HSV-1 induced ubiquitination of UBE1a isoform via an isopeptide bond with Lys604. Moreover, we show that ubiquitination of K604 in UBE1a enhances UBE1a activity; that is, the activity of ubiquitin-transfer to E2 enzyme. Subsequently, we investigated the functional role of UBE1a and ubiquitination of K604 in UBE1a. We found that UBE1-knockdown increased HSV-1 DNA replication and viral production. Further, overexpression of UBE1a, but not a UBE1a K604A mutant, suppressed viral replication. Furthermore, we found that UBE1a and ubiquitination at K604 in UBE1a retarded expression of HSV-1 major capsid protein, ICP5. Our findings show that UBE1a functions as an antiviral factor that becomes activated upon ubiquitination at Lys604.

5.
Tohoku J Exp Med ; 252(4): 329-337, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33268602

RESUMO

Disasters influence various health conditions; however, little has been reported about urinary symptoms. The objective of this study is to evaluate whether night-time urinary frequency was influenced by the Great East Japan Earthquake (GEJE) in March 2011. We also evaluated seasonal variation of night-time frequency, which may affect the primary objective. A retrospective chart review was conducted on 300 evaluable patients who resided in the impacted area: 263 men with benign prostatic hyperplasia and/or overactive bladder and 37 women with overactive bladder. Data concerning night-time frequency were collected repeatedly every three months from March 2009 until March 2014, then compared yearly and seasonally among same patients. In addition, night-time frequency was analyzed for potential relations to sex, age, comorbidities, and whether residences had been destroyed. There was a significant increase of night-time frequency during 2011-2013 when compared yearly with 2009 and 2010. In seasonal comparisons of the entire period, night-time frequency was greater during autumn and winter compared with summer. In quarterly comparisons, a sudden increase was not observed after the GEJE, but night-time frequency was increased significantly in spring, summer and autumn in 2011 when compared with the corresponding seasons in 2010. While hypertension was related to exacerbation of night-time frequency during winter, we did not find any factors associated with increase after the disaster out of sex, age, comorbidities or residential situations. In conclusion, night-time urinary frequency is increased shortly after the GEJE and remains elevated for the following three years along with seasonal variation.

6.
Viruses ; 12(12)2020 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-33291814

RESUMO

Herpes simplex virus-1 (HSV-1) is the causative agent of cold sores, keratitis, meningitis, and encephalitis. HSV-1-encoded ICP5, the major capsid protein, is essential for capsid assembly during viral replication. Ubiquitination is a post-translational modification that plays a critical role in the regulation of cellular events such as proteasomal degradation, protein trafficking, and the antiviral response and viral events such as the establishment of infection and viral replication. Ub-activating enzyme (E1, also named UBE1) is involved in the first step in the ubiquitination. However, it is still unknown whether UBE1 contributes to viral infection or the cellular antiviral response. Here, we found that UBE1a suppressed HSV-1 replication and contributed to the antiviral response. The UBE1a inhibitor PYR-41 increased HSV-1 production. Immunofluorescence analysis revealed that UBE1a highly expressing cells presented low ICP5 expression, and vice versa. UBE1a inhibition by PYR-41 and shRNA increased ICP5 expression in HSV-1-infected cells. UBE1a reduced and retarded ICP5 protein expression, without affecting transcription of ICP5 mRNA or degradation of ICP5 protein. Additionally, UBE1a interacted with ICP27, and both partially co-localized at the Hsc70 foci/virus-induced chaperone-enriched (VICE) domains. PYR-41 reduced the co-localization of UBE1a and ICP27. Thus, our findings provide insights into the mechanism of UBE1a in the cellular response to viral infection.

7.
Int J Mol Sci ; 21(23)2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33266352

RESUMO

Nuclear factor-κB (NF-κB) is an important transcription factor involved in various biological functions, including tumorigenesis. Hence, NF-κB has attracted attention as a target factor for cancer treatment, leading to the development of several inhibitors. However, existing NF-κB inhibitors do not discriminate between its subunits, namely, RelA, RelB, cRel, p50, and p52. Conventional methods used to evaluate interactions between transcription factors and DNA, such as electrophoretic mobility shift assay and luciferase assays, are unsuitable for high-throughput screening (HTS) and cannot distinguish NF-κB subunits. We developed a HTS method named DNA strand exchange fluorescence resonance energy transfer (DSE-FRET). This assay is suitable for HTS and can discriminate a NF-κB subunit. Using DSE-FRET, we searched for RelA-specific inhibitors and verified RelA inhibition for 32,955 compounds. The compound A55 (2-(3-carbamoyl-6-hydroxy-4-methyl-2-oxopyridin-1(2H)-yl) acetic acid) selectively inhibited RelA-DNA binding. We propose that A55 is a seed compound for RelA-specific inhibition and could be used in clinical applications.

8.
Int J Urol ; 2020 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-33314387

RESUMO

OBJECTIVES: To compare overall survival between patients with metastatic renal cell carcinoma treated by cytoreductive nephrectomy and those not treated by cytoreductive nephrectomy. METHODS: We retrospectively evaluated 278 patients with metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitors between January 2008 and November 2019. Patients were divided into two groups: a cytoreductive nephrectomy group (immediate or deferred cytoreductive nephrectomy) and a group who received systemic tyrosine kinase inhibitor therapies alone without cytoreductive nephrectomy (control group). Overall survival comparisons were made in all patients in the control versus the cytoreductive nephrectomy group, the control versus the immediate cytoreductive nephrectomy group, the control versus the deferred cytoreductive nephrectomy group, and the deferred cytoreductive nephrectomy versus the immediate cytoreductive nephrectomy group. Analyses were weighted using the propensity score-based inverse probability of treatment weighting method to adjust for group imbalances. RESULTS: The median (range) age of the patients was 65 (59-73) years. Of the 278 patients, 132 and 146 were in the control group and the cytoreductive nephrectomy (immediate, n = 107 and deferred, n = 39) group, respectively. A significant difference was noted between the control and cytoreductive nephrectomy groups in age, clinical stage, International Metastatic Renal Cell Carcinoma Database Consortium risk factors, and the number of metastatic sites. Inverse probability of treatment weighting-adjusted Cox regression analysis showed a significant difference in overall survival between the control and the cytoreductive nephrectomy groups and between the control and the immediate or deferred cytoreductive nephrectomy groups. However, there was no significant difference in overall survival between the immediate and the deferred cytoreductive nephrectomy groups. CONCLUSIONS: Our findings suggest that metastatic renal cell carcinoma patients undergoing cytoreductive nephrectomy are more likely to have longer overall survival than those who receive tyrosine kinase inhibitor therapy only.

9.
Int J Infect Dis ; 103: 42-47, 2020 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-33176204

RESUMO

OBJECTIVES: The aim of this study was to evaluate the diagnostic utility of a novel test kit that could theoretically detect all serogroups of Legionella pneumophila for diagnosing Legionella pneumonia, in comparison with existing kits. METHODS: This study was conducted in 16 hospitals in Japan from April 2016 to December 2018. Three urinary antigen test kits were used: the novel kit (LAC-116), BinaxNOW Legionella (Binax), and Q-line Kyokutou Legionella (Q-line). In addition, sputum culture and nucleic acid detection tests and serum antibody tests were performed where possible. The diagnostic accuracy and correlations of the novel kit with the two existing kits were analyzed. RESULTS: In total, 56 patients were diagnosed with Legionella pneumonia. The sensitivities of LAC-116, Binax, and Q-line were 79%, 84%, and 71%, respectively. The overall match rate between LAC-116 and Binax was 96.8% and between LAC-116 and Q-line was 96.4%. One patient had L. pneumophila serogroup 2, and only LAC-116 showed a positive result, whereas Binax and Q-line did not. CONCLUSIONS: The novel Legionella urinary antigen test kit was useful for diagnosing Legionella pneumonia. In addition, it could detect Legionella pneumonia caused by non-L. pneumophila serogroup 1.

10.
Tohoku J Exp Med ; 252(3): 219-224, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33148936

RESUMO

Testicular cancer occurs in the testes of the male reproductive system and is the most common cancer in adolescent and young adult (AYA) men. However, recently, there have been more cases of testicular cancer in men older than 40 years. Therefore, trends of testicular cancer during the past 40 years were retrospectively examined, focusing on age and histology. Patients who were diagnosed with testicular cancer at our institution between 1980 and 2019 were enrolled in this study. The patients were divided into groups by the year of diagnosis (1980s, 1990s, 2000s, and 2010s), age at diagnosis (14, 15 to 39, and older than 40 years), and histological type (seminoma and non-seminoma). A total of 563 patients were diagnosed with testicular cancer over the 40-year period. The median age at diagnosis increased continuously, from 28 years to 31 years, 34 years, and 38 years in each period, respectively (p < 0.001). Moreover, most testicular cancer patients were of the AYA generation, whereas the ratio of patients older than 40 years increased significantly since 2000 (p < 0.001). The relative proportion of seminoma also increased more than 50% since 2000. In the seminoma group, median age increased from 31 years to 41 years during the 40-year period (p < 0.001). In conclusion, the age at diagnosis is rising for testicular cancer patients. Clinicians should recognize that testicular cancer affects not only the AYA generation, but there has been a shift to older than 40 years, especially in seminoma.

11.
Int J Urol ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33174259

RESUMO

OBJECTIVE: To validate the Japanese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 in Japanese-speaking testicular cancer survivors. METHODS: A total of 200 testicular cancer survivors were recruited at eight high-volume institutions in Japan. The participants completed the Japanese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 and the International Index of Erectile Function 15 questionnaires. A total of 40 participants completed a retest of the questionnaires 2 weeks after the first response. The psychometric properties of the Japanese version including test-retest reliability, internal consistency and concurrent validity were evaluated. RESULTS: The mean age at response was 43 years (range 22-74 years), and the mean period after treatment was 77 months (range 0-416 months). The response rate for each item, except sexual function, was high, and the percentage of missing values was less than 3.5%. For test-retest reliability, seven of 12 scales met the criteria (intraclass correlation 0.70-0.86). For internal consistency, four of seven scales met the criteria (Cronbach's alpha 0.62-0.91). For concurrent validity, treatment side effects of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 were related to some domains of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. The sex-related subscales of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 were moderately correlated with some International Index of Erectile Function 15 domains. CONCLUSIONS: The psychometric properties of the Japanese version are equivalent to the properties of the original European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26. The Japanese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 questionnaire is a useful tool to assess the health-related quality of life of testicular cancer patients.

12.
Sci Rep ; 10(1): 20551, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239745

RESUMO

Percutaneous endoscopic gastrostomy (PEG), which is frequently used for nutrition management in patients having difficulty with oral intake, is considered a safe procedure. However, serious complications may occur depending on site of the puncture. This study aimed to clarify whether push method PEG construction at the posterior wall (PW) of the greater curvature (GC) had a higher risk of complications. We retrospectively investigated the relationship between puncture site at the PW of the GC and early acute complications in 540 patients receiving PEG. Early acute complications were defined as bleeding or perforation within 30 days after the PEG procedure. PEG-related complications were observed in 80 patients in total, with early acute complications detected in 42 patients. PEG construction at the PW of the GC in 12 cases exhibited a significantly higher occurrence of early acute complications versus PEG at other sites (41.7% vs. 7.0%, p = 0.001). Further, multivariate analysis revealed PW at the GC to be independently associated with early acute complications (OR 9.59, 95% CI 2.82-32.61; p = 0.0003). It may be desirable to avoid PEG at the PW of the GC. If performed, clinicians should pay careful attention to early acute complications.

13.
Dig Endosc ; 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33107134

RESUMO

OBJECTIVES: There are few reports on the long-term prognosis of papillary tumors after endoscopic papillectomy. Here, we report a retrospective study of the therapeutic effects, long-term prognosis, and affecting factors. METHODS: The inclusion criteria were papillary adenoma with/without an adenocarcinoma component on biopsy results and ≤10 mm intraductal extension, and the exclusion criteria were moderate to poorly differentiated adenocarcinoma on biopsy results. If no residual lesion was confirmed ≥6 months after the last endoscopic treatment, remission was defined. Subsequently, follow-up endoscopy was scheduled once a year. Surgery was required in the case of adenocarcinoma recurrence or intraductal lesions >10 mm. The rates of adverse events, remission, recurrence, and need for surgery were examined. The affecting factors were calculated. RESULTS: There were a total of 253 subjects, including 65 with adenocarcinoma. Pancreatitis (7.5%), bleeding (9.1%) and perforation (2.8%) were observed as adverse events. Among 221 subjects with ≥6 months of follow-up, 212 (95.9%) were in remission. The cumulative recurrence rate using the Kaplan-Meier analysis at 5 years was 16.9% (22 cases), with the need for surgery in 5.9% (5 cases). Intraductal extension on preoperative diagnosis was the only significant risk factor for both recurrence (P<0.001) and the need for surgery (P=0.005). The presence of adenocarcinoma had no significant effect. CONCLUSION: Although remission was achieved in more than 95% of our patients, we observed a high rate of recurrence at the long-term follow-up, which was significantly associated with intraductal extension but not with the presence of adenocarcinoma.

14.
J Endourol ; 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33107332

RESUMO

Introduction: To improve the outcomes and extend the adaptation of salvage surgery for intractable urinary tract problems, this study retrospectively investigated indications and outcomes of retroperitoneal surgery based on retroperitoneal laparoscopic ureterolysis (RLU), in which the ureter is dissected with or without nephrolysis. Patients and Methods: Twenty-three salvage surgeries based on RLU were performed on 22 patients at our hospital between November 2002 and July 2017. Intractable urinary tract problems included lower urinary tract dysfunctions, refractory urinary fistulas, middle or lower ureter troubles, ureteroileal anastomotic strictures, and stomal stricture of cutaneous ureterostomy. After RLU, various urinary tract reconstructions were performed through minimal laparotomy under a retroperitoneal approach. Results: In all patients, RLU secured a sufficient length of ureter for subsequent urinary tract reconstructions, irrespective of intra-abdominal adhesions. Twelve cutaneous ureterostomies, one reconstruction of cutaneous ureterostomy, two ureteroileal reanastomoses, and five ureterovesicostomies were effectively performed after unilateral RLU. Three retroperitoneoscopic transureteroureterostomies with cutaneous ureterostomy were reconstructed after bilateral RLU. Over a median follow-up of 8 months (interquartile range, 2-80 months), two patients (8.7%) required additional procedures. Conclusions: Retroperitoneal salvage surgery based on RLU appears useful to salvage intractable urinary tract problems, avoiding intra-abdominal adhesions and securing a sufficient ureteral length for subsequent urinary tract reconstructions. This surgical procedure is minimally invasive and contributes to improving patient quality of life.

15.
Am J Cancer Res ; 10(8): 2523-2534, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32905529

RESUMO

The efficacy of cisplatin-based chemotherapy in patients with bladder cancer is often limited due to the development of therapeutic resistance. Our recent findings in bladder cancer suggested that activation of prostaglandin receptors (e.g. EP2, EP4) or cyclooxygenase (COX)-2 induced cisplatin resistance. Meanwhile, emerging evidence indicates the involvement of estrogen receptor-ß (ERß) signals in urothelial cancer progression. In this study, we aimed to investigate whether ERß activity was associated with cisplatin sensitivity in bladder cancer. Immunohistochemistry in muscle-invasive bladder cancer specimens from 55 patients who had subsequently received at least 3 cycles of cisplatin + gemcitabine neoadjuvant chemotherapy showed that ERß was positive in 38% of responders vs. 71% of non-responders (P = 0.016), including 42% of male responders vs. 65% of male non-responders (P = 0.142) and 20% of female responders vs. 100% of female non-responders (P = 0.048). Then, cisplatin cytotoxicity was compared in human bladder cancer cell lines. Control sublines endogenously expressing ERß were significantly more resistant to cisplatin treatment at its pharmacological concentrations, compared with ERß knockdown sublines via short hairpin RNA virus infection. An ER modulator tamoxifen increased sensitivity to cisplatin in ERα-negative/ERß-positive cell lines, while, in an estrogen-depleted condition, 17ß-estradiol reduced it. Additionally, western blot showed considerable elevation in ERß expression in cisplatin-resistant bladder cancer sublines, compared with respective controls. Moreover, treatment with tamoxifen or a COX-2 inhibitor celecoxib increased cisplatin sensitivity even in resistant cells, while COX-2/EP2/EP4 inhibitor treatment resulted in reduced expression of ERß. The expression and activity of ß-catenin known to involve cisplatin resistance was also up-regulated in cisplatin-resistant cells, which was further induced by 17ß-estradiol treatment. The present results suggest that estrogen-mediated ERß signaling plays an important role in modulating cisplatin sensitivity in bladder cancer cells. Targeting ERß during chemotherapy may thus be a useful strategy to overcome cisplatin resistance especially in female patients with ERß-positive bladder cancer.

16.
J Surg Case Rep ; 2020(8): rjaa150, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32855787

RESUMO

Urinary incontinence is one of the common complications after radical prostatectomy along with inguinal hernia. Artificial urethral sphincter implantation is widely accepted as a treatment option. We report two surgical cases of inguinal hernia after artificial urethral sphincter implantation for urinary incontinence following radical prostatectomy. In Case 1, since the device went through the inguinal canal, adhesion around the pubis was extremely hard. In Case 2, the device was placed on the ventral side of the rectus abdominis muscle, so it was operable almost as normal. In each case, the surgical procedure was considered carefully after confirming the location of the device by preoperative computed tomography and ultrasonography. Hernia repair was successfully performed using the Lichtenstein method. There are few reports regarding surgical repair of inguinal hernia following artificial urinary sphincter implantation. Preoperative image and appropriate choice of approach could facilitate safe and secure surgery.

17.
Front Cell Dev Biol ; 8: 670, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32850804

RESUMO

DDHD1 and DDHD2 are both intracellular phospholipases A1 and hydrolyze phosphatidic acid in vitro. Given that phosphatidic acid participates in neurite outgrowth, we examined whether DDHD1 and DDHD2 regulate neurite outgrowth. Depletion of DDHD1 from SH-SY5Y and PC12 cells caused elongation of neurites, whereas DDHD2 depletion prevented neurite elongation. Rescue experiments demonstrated that the enzymatic activity of DDHD1 is necessary for the prevention of neurite elongation. Depletion of DDHD1 caused enlargement of early endosomes and stimulated tubulation of recycling endosomes positive for phosphatidic acid-binding proteins syndapin2 and MICAL-L1. Knockout of DDHD1 enhanced transferrin recycling from recycling endosomes to the cell surface. Our results suggest that DDHD1 negatively controls the formation of a local phosphatidic acid-rich domain in recycling endosomes that serves as a membrane source for neurite outgrowth.

18.
Anesth Pain Med ; 10(2): e97758, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32754428

RESUMO

Background: Several behavioral tests have been devised to assess pain in rodent models, one of which is the Chronic constriction injury (CCI) model of the sciatic nerve, including the sensitivity of the paw evaluated through reflex reactions to heat or mechanical stimuli. However, because of their high restless activity and responsiveness to humans, it is tough to give the moving animals consistent stimuli to get consistent and reliable reactions. Methods: Experiments were performed on male C57BL/6J mice (aged eight weeks) and prairie voles (aged eight weeks). Sham animals (five mice and six prairie voles) and CCI animals (six mice and seven prairie voles) were tested before surgery, four days after, and seven days after surgery. Each animal was rated using a modified rating scale for the scoring of nociceptive behavior. The mechanical threshold test was administered by applying arterial clips to the base of toes under isoflurane-induced sedation. Results: The right hind paw of the CCI administered side showed significant increases in the scores of nociceptive behavior on day 4 and day 7. The right hind paw of the CCI-administered side showed significant reductions in the mechanical threshold test on day 4 and day 7. Conclusions: The results of the mechanical threshold test were consistent with those of the scoring of nociceptive behavior in CCI model animals, and the method of using arterial clips under sedation was useful for the mechanical threshold test.

19.
Bioorg Med Chem Lett ; 30(19): 127458, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32755678

RESUMO

Sirtuin proteins are a highly conserved class of nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacylases. The pleiotropic human isoform 2 of Sirtuins (SIRT2) has been engaged in the pathogenesis of cancer in a plethora of reports around the globe. Thus, SIRT2 modulation is deemed as a promising approach for pharmaceutical intervention. Previously, we reported S-Trityl-l-Cysteine (STLC)-ornamented dimethylaminopyridine chemical entity named STC4 with a significant SIRT2 inhibitory capacity; this was separate from the conventional application of STLC scaffold as a kinesin-5 inhibitor. An interactive molecular docking study of SIRT2 and STC4 showed interaction between Asn168 of SIRT2 and the methyl ester of STC4, that appears to hinder STC4 to reach the selective pocket of the protein unlike strong SIRT2 inhibitor SirReal2. To improve its activity, herein, we utilized S-trityl cysteamine pharmacophore lacking the methyl ester. Nine compounds were synthesized and assayed affording three biopertinent SIRT2 inhibitors, and two of them, STCY1 and STCY6 showed higher inhibitory activity than STC4. These compounds have pronounced anti-proliferative activities against different cancer cell lines. A molecular docking study was executed to shed light on the supposed binding mode of the lead compound, STCY1, into the selective pocket of SIRT2 by interaction of the nitrogen of pyridine ring of the compound and Ala135 of the protein. The outcome of the study exposes that the active compounds are effective intermediates to construct more potent biological agents.

20.
Tohoku J Exp Med ; 252(1): 1-8, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32814720

RESUMO

Carbohydrate antigens are associated with carcinogenesis, cancer invasion, and metastasis and their expression reflect biological activities of various cancers. We previously reported that expression of disialosyl globopentaosyl ceramide (DSGb5), one of carbohydrate antigens, in radical prostatectomy specimens independently predicted biochemical recurrence (i.e., elevating serum prostate specific antigen without recurrent lesions in the image) after radical prostatectomy. However, it is important to evaluate the prognosis at the diagnosis. In this study we investigated DSGb5 expression in prostate biopsy specimens to develop a novel biomarker for providing appropriate management. Between 2005 and 2011, patients who underwent both prostate biopsy and radical prostatectomy in our institution were included. The median follow-up period was 88 months. DSGb5 expression was assessed by immunohistochemical staining and defined 116 patients as high DSGb5 expression (42 patients) or low DSGb5 expression (74 patients). High DSGb5 expression was significantly associated with lymphovascular invasion in radical prostatectomy specimens on both univariate and multivariable analyses (p = 0.028, 0.027). On multivariable analysis, Gleason Score in prostatectomy specimen, positive resection margin, and DSGb5 expression in the biopsy specimen were independently associated with biochemical recurrence-free survival following radical prostatectomy (p = 0.004, 0.008, 0.024). When targeting only patients with negative resection margin, DSGb5 expression was significantly associated with biochemical recurrence-free survival on both univariate and multivariable analyses (p = 0.006, 0.007). DSGb5 expression in prostate biopsy specimens is predictive of lymphovascular invasion and biochemical recurrence-free survival following radical prostatectomy. DSGb5 is a potential biomarker for preoperatively predicting oncological outcomes of prostate cancer.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA