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The αvβ3 integrin, expressed on the surface of various normal and cancer cells, is involved in numerous physiologic processes such as angiogenesis, apoptosis, and bone resorption. Because this integrin plays a key role in angiogenesis and metastasis of human tumors, αvβ3 integrin ligands are of great interest to advances in targeted therapy and cancer imaging. In this report, one-bead one-compound (OBOC) combinatorial libraries containing the arginine-glycine-aspartic acid (RGD) motif were designed and screened against K562 myeloid leukemia cells that had been transfected with the human αvβ3 integrin gene. Cyclic peptide LXW7 was identified as a leading ligand with a built-in handle that binds specifically to αvβ3 and showed comparable binding affinity (IC50 = 0.68 ± 0.08 μmol/L) to some of the well-known RGD “head-to-tail” cyclic pentapeptide ligands reported in the literature. The biotinylated form of LXW7 ligand showed similar binding strength as LXW7 against αvβ3 integrin, whereas biotinylated RGD cyclopentapeptide ligands revealed a 2- to 8-fold weaker binding affinity than their free forms. LXW7 was able to bind to both U-87MG glioblastoma and A375M melanoma cell lines, both of which express high levels of αvβ3 integrin. In vivo and ex vivo optical imaging studies with the biotinylated ligand/streptavidin-Cy5.5 complex in nude mice bearing U-87MG or A375M xenografts revealed preferential uptake of biotinylated LXW7 in tumor. When compared with biotinylated RGD cyclopentapeptide ligands, biotinylated LXW7 showed higher tumor uptake but lower liver uptake. Mol Cancer Ther; 9(10); 2714–23. ©2010 AACR.

Supplementary Data from The Use of One-Bead One-Compound Combinatorial Library Technology to Discover High-Affinity αvβ3 Integrin and Cancer Targeting Arginine-Glycine-Aspartic Acid Ligands with a Built-in Handle

Background We report the case of a patient with syphilitic testicular gumma and vasculitis with adrenal failure due to chronic steroid use. Case presentation A 63-year-old male presented with hard right eye swelling and very firm bilateral testes on palpation, which he had for 2 years. Testicular tumor markers were negative; syphilis test was positive. Radiological examination suggested aortitis and bilateral testicular malignancy. The patient received ampicillin for the infection and prednisolone for vasculitis. Left orchidectomy was performed to confirm the presence of testicular tumor; histological examinations revealed granulomatous orchitis. The prednisolone doses were adjusted because of relapses and adverse effects of steroid use. Unfortunately, the patient died in the intensive care unit because of uncontrolled blood pressure and pneumonia. Conclusions This is a rare case of syphilis with testicular involvement and vasculitis. This report shows the importance of broadening the differential diagnoses of testicular firmness.

Background Cardio-facio-cutaneous (CFC) syndrome is a human multiple congenital anomaly syndrome that is caused by activating heterozygous mutations in either BRAF, MEK1, or MEK2, three protein kinases of the Ras/mitogen-activated protein kinase (MAPK) pathway. CFC belongs to a group of syndromes known as RASopathies. Skeletal muscle hypotonia is a ubiquitous phenotype of RASopathies, especially in CFC syndrome. To better understand the underlying mechanisms for the skeletal myopathy in CFC, a mouse model with an activating BrafL597V allele was utilized. Results The activating BrafL597V allele resulted in phenotypic alterations in skeletal muscle characterized by a reduction in fiber size which leads to a reduction in muscle size which are functionally weaker. MAPK pathway activation caused inhibition of myofiber differentiation during embryonic myogenesis and global transcriptional dysregulation of developmental pathways. Inhibition in differentiation can be rescued by MEK inhibition. Conclusions A skeletal myopathy was identified in the CFC BrafL597V mouse validating the use of models to study the effect of Ras/MAPK dysregulation on skeletal myogenesis. RASopathies present a novel opportunity to identify new paradigms of myogenesis and further our understanding of Ras in development. Rescue of the phenotype by inhibitors may help advance the development of therapeutic options for RASopathy patients.

By solving the nonlinear Poisson-Boltzmann (PB) equation with a finite element method (FEM), three-dimensional (3D) spatial distributions of the electric potential (ψ, scaled) in electrolyte solutions having two charged parallel finite plates (including cubes and prismatic rods) are determined for various separations (d, scaled by the Debye length, κ-1), surface potentials (ψs), and plate dimensions (length × width × thickness, each scaled by κ-1). The total interaction force between two plates, F, is the sum of the electrostatic double-layer (EDL) repulsion (the osmotic pressure, Fosm) and the Maxwell electrostatic stress (Fes). The EDL repulsion is estimated using the distribution of ψ not only between the facing surfaces of two parallel plates but also around the other extremities of the plates. The Maxwell stress (Fes) is localized near the extremities to act as a repulsive force on the midplane between the two plates. The ratio Fes/F is 0.07-0.5, depending on d, ψs, and dimensions. It is found that, with increasing dimensions, the total F values per unit area calculated for finite plates, F, decreasingly approach the exact ones for parallel infinite plates, Finf; for example, at d = 1 and ψs = 5, the ratio F/Finf is 2.83 for plates with dimensions of 1 × 1 × 1 and 1.18 for plates of 10 × 10 × 1. The repulsions arising from the extremities cannot be neglected for plates with dimensions

Costello syndrome (CS) is a congenital disorder caused by heterozygous activating germline HRAS mutations in the canonical Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. CS is one of the RASopathies, a large group of syndromes caused by mutations within various components of the Ras/MAPK pathway. An important part of the phenotype that greatly impacts quality of life is hypotonia. To gain a better understanding of the mechanisms underlying hypotonia in CS, a mouse model with an activating HrasG12V allele was utilized. We identified a skeletal myopathy that was due, in part, to inhibition of embryonic myogenesis and myofiber formation, resulting in a reduction in myofiber size and number that led to reduced muscle mass and strength. In addition to hyperactivation of the Ras/MAPK and PI3K/AKT pathways, there was a significant reduction in p38 signaling, as well as global transcriptional alterations consistent with the myopathic phenotype. Inhibition of Ras/MAPK pathway signaling using a MEK inhibitor rescued the HrasG12V myopathy phenotype both in vitro and in vivo, demonstrating that increased MAPK signaling is the main cause of the muscle phenotype in CS., Summary: A Costello syndrome (CS) mouse model carrying a heterozygous Hras p.G12V mutation was utilized to investigate Ras pathway dysregulation, revealing that increased MAPK signaling is the main cause of the muscle phenotype in CS.

Segmental testicular infarction is a rare condition. Patients present with clinical features similar to torsion and testicular tumors, with most undergoing surgery. A 55-year-old male patient presented with left scrotal pain. We did a Doppler ultrasonogram and magnetic resonance imaging to diagnose his condition and rule out testicular torsion and tumor. We decided not to operate and asked the patient for follow-up. There was no pain in the left testis, and magnetic resonance imaging showed a reduction in the left testicular lesion after 4 months.

Formulas for interaction forces F(s) and the free energy G(s) between two parallel charged prismatic rods of various scaled values of d, ψs, and L in skewed configurations are obtained, where s is the lengthwise positional difference between the front-end faces of the respective rods, and d is the minimal distance between the opposing faces of the rods, ψs is the electric surface potential, L is the length of the rods. To obtain the free-energy function G(s), (i) 3D spatial distributions of the electric potential ψ around two rods were determined by numerically solving the nonlinear Poisson-Boltzmann equation with a finite element method, (ii) with the ψ distributions so determined, the lengthwise interaction electrostatic Maxwell stress tangential to the midplane between the rods was calculated to obtain the (discrete) s dependence of the stress, and (iii) by introducing two different fitting functions, the discrete s dependence was transformed into a continuous force function, F(s), which was then lengthwise integrated to derive G(s). It was found that the curves of G(s) linearly decreased with increasing s between 1 and L + 1 due to a localization of the stress. Although natural, it is of interest that the values of G(0) calculated for rods of various values of d, ψs, and L were in good agreement with those of the interaction free energy obtained in our preceding work by the widthwise integration of repulsive electrostatic forces normal to the midplane between the parallel rods in nonskewed configurations.

We present a case of lung adenocarcinoma metastasizing to the right clear cell renal cell carcinoma diagnosed by computed tomography (CT)-guided renal biopsy and immunohistochemistry. A 72-year-old male patient had right lower abdominal pain for 3 days, followed by right loin pain for 10 days. On CT scan, renal cell cancer was suspected with multiple metastases. Renal cell cancer with metastatic lung adenocarcinoma was diagnosed on CT-guided renal biopsy with positive immunohistochemical markers. The patient, unfortunately, expired after few days of diagnosis. Tumor-to-tumor metastasis is an unusual disease, and its tumors are aggressive. A definite diagnosis of tumor-to-tumor metastasis is a clinical challenge. Immunohistochemistry helped us in the diagnosis without the primary lesion biopsy.

Cardio-facio-cutaneous (CFC) syndrome is a human multiple congenital anomaly syndrome that is caused by activating heterozygous mutations in either BRAF, MEK1, or MEK2, three protein kinases of the Ras/mitogen-activated protein kinase (MAPK) pathway. CFC belongs to a group of syndromes known as RASopathies. Skeletal muscle hypotonia is a ubiquitous phenotype of RASopathies, especially in CFC syndrome. To better understand the underlying mechanisms for the skeletal myopathy in CFC, a mouse model with an activating BrafThe activating BrafA skeletal myopathy was identified in the CFC Braf

Background: Many patients undergo unwanted prostate biopsy due to unreliability of prostate-specific antigen (PSA). PSA density (PSAD), free PSA, free-to-total PSA ratio, prebiopsy MRI are used to diagnose prostate cancer (PCa). Since 1863, correlations between inflammation and cancer have been identified and explored; thus, the role of various blood parameters in detecting cancer has been studied, especially neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Here, we evaluated whether these parameters before prostate biopsy can diagnose prostate cancer in our hospital.Methods: We conducted a retrospective study from January 2014 to January 2018. Prostate cancer patients were divided into significant cancer (Gleason Score ≥ 7) and insignificant cancer (Gleason Score < 7). NLR, PLR, and other clinical parameters were taken before the prostate biopsy. We then analyzed the associations of NLR and PLR alone or with PSA, with significant prostate cancer. Results: We included 463 patients, of whom 60.3% (279) had prostate cancer and 75.6 % (211) had a Gleason score (GS) of ≥ 7. PSA and PSAD in the clinically significant prostate cancer patient group were around two times more than those in the insignificant prostate cancer group. PV, NLR, PLR, and combined markers were more in the GS ≥ 7 population group. PSA combined with PLR (PPLR) and PSA with NLR (PNLR) had better area under a curve (AUC) (0.732 and 0.730, resp.), with statistical significance, than PSA, NLR, and PLR alone (0.723, 0.585, and 0.590). In the multivariate analysis using separate models with PSA and NLR or PLR compared to age, DRE-positive lesions, PV, PSAD; PNLR, and PPLR were statistically significant in finding aggressive prostate cancer. When combined markers were used together, despite the high correlations, PSA and NLR were nearly significant (p = 0.062) in detecting the GS ≥ 7 population.Conclusion: The combined use of PSA with PLR and PSA with NLR helps detect the differences between clinically significant and insignificant prostate cancer.

Cardio-facio-cutaneous syndrome (CFC) is one of the RASopathies and is caused by germline mutations that activate the Ras/mitogen-activated protein kinase (MAPK) pathway. CFC is due to heterozygous germline mutations in protein kinases BRAF, MEK1, or MEK2 and rarely in KRAS, a small GTPase. CFC is a multiple congenital anomaly disorder in which individuals may have craniofacial dysmorphia, heart issues, skin and hair anomalies, and delayed development. Pathogenic variants for CFC syndrome are usually considered de novo because vertical transmission has only been reported with MEK2 and KRAS. The index case was a 3-year-old male with features consistent with the clinical diagnosis of CFC. Sequencing revealed a previously reported heterozygous likely pathogenic variant BRAF p.G464R. Upon detailed family history, the index case's pregnant mother was noted to have similar features to her son. Targeted familial testing of the BRAF pathogenic variant was performed on the mother, confirming her diagnosis. Prenatal genetic testing for the fetus was declined, but postnatal molecular testing of the index case's sister was positive for the familial BRAF p.G464R variant. Functional analysis of the variant demonstrated increased kinase activity. We report the first identified vertically transmitted functional BRAF pathogenic variant. Our findings emphasize the importance of obtaining a comprehensive evaluation of family members and that activating pathogenic variants within the canonical MAPK cascade mediated by BRAF are compatible with human reproduction.

OBJECTIVE: This study aimed to assess the relationship of the prostate cancer and Gleason scores (GSs) or ISUP Grade system with prostate volume (PV) as assessed by magnetic resonance imaging (MRI) cognitive biopsy and standard biopsy. MATERIAL AND METHODS: Data were collected from 659 patients who underwent MRI cognitive biopsy and standard biopsy from January 2014 to January 2018. The biopsies were performed because of increased prostate-specific antigen (PSA) levels (>4 ng/mL) and/or abnormal digital rectal examination findings. Transrectal ultrasound was used to measure PV. RESULTS: Prostate cancer detection rates in patients with increased PVs of ≤40 cc and >40 cc were 68.8% and 51.6% (p40 cc were 68% and 73%, and 22.3% and 37.8%, respectively, for those with ISUP Grade group ≥4 (Gleason score ≥8) (p=0.003). Among the patients with PV>40 cc, univariate logistic regression showed a significant relationship between ISUP Grade group ≥2 and PSA, free/total PSA, PSA density, and MRI (p40 cc. CONCLUSION: Although the detection rates of prostate cancer decreased as PV increased, the detection of prostate cancer aggressiveness increased as PV increased. This increase in high ISUP Grade lesions with the rise in PV is due to the use of MRI during prostate biopsy with standard biopsy.

Background: The AR-V7 splice variant is a cause of castration-resistant prostate cancer (CRPC). However, testing for the presence of AR-V7 by real-time polymerase chain reaction (RT-PCR) shows AR-V7 positivity in healthy individuals. We hypothesized that the positivity reflects contamination by hematopoietic cells. We tried a novel circulating tumor cell (CTC) enrichment instrument, using Celsee, to clear hematopoietic cells. Methods: We tested whole blood or Celsee-enriched samples for AR-V7 by RT-PCR, and included samples from 41 CRPC patients undergoing sequential therapy. We evaluated the associations between AR-V7 status and clinical factors. We evaluated factors affecting AR-V7 positivity. Results: AR-V7 positivity was lower in Celsee-enriched than in whole blood specimens. AR-V7 and clinical factors did not predict the therapy effectiveness. We found no significant differences in the effectiveness of enzalutamide/abiraterone (Enz/Abi) upon AR-V7 evaluation. All AR-V7 positive patients had resistance to Enz/Abi. Docetaxel (DTX), cabazitaxel (CBZ), and Radium223 treatment showed no significant difference in the treatment effectiveness, regardless of AR-V7 presence. AR-V7 was more frequently positive than Extent of disease (EOD) 2 in cases with bone metastases. Conclusion: Celsee CTC enrichment suppresses AR-V7 false positivity. All AR-V7 positive patients presented resistance to Enz/Abi. DTX, CBZ, and Radium223 were effective and remain treatment options. AR-V7 positivity should progressively appear in patients with advanced bone metastases.

Background: The AR-V7 splice variant is a cause of castration-resistant prostate cancer (CRPC). However, testing for the presence of AR-V7 by RT-PCR shows AR-V7 positivity in healthy individuals. We hypothesized that the positivity reflected contamination by hematopoietic cells. We tried a novel CTC enrichment instrument using Celsee® to clear hematopoietic cells. Methods: We tested whole blood or Celsee-enriched samples for AR-V7 by RT-PCR and included samples from 41 CRPC patients undergoing sequential therapy. We evaluated the associations between AR-V7 status and clinical factors. We evaluated factors affecting AR-V7 positivity. Results: AR-V7 positivity was lower in Celsee-enriched than in whole blood specimens. AR-V7 and clinical factors did not predict the therapy effectiveness. We found no significant differences in the effectiveness of Enz/Abi upon AR-V7 evaluation. All AR-V7 positive patients had resistance to Enz/Abi. DTX, CBZ, and Radium223 treatment showed no significant difference in the treatment effectiveness, regardless of AR-V7 presence. AR-V7 was more frequently positive than EOD2 in cases with bone metastases. Conclusion: Celsee® CTC enrichment suppresses the AR-V7 false positivity. All AR-V7 positive patients presented resistance to Enz/Abi. DTX, CBZ, and Radium223 were effective and remained treatment options. AR-V7 positivity should progressively appear in patients with advanced bone metastases.

Objectives To assess the effect of cernitin pollen extract on serum prostate-specific antigen level prostate biopsy candidates, and to develop an ideal protocol to avoid an unnecessary biopsy procedure. Methods A total of 61 patients were administrated cernitin pollen extract tablets (two tablets t.i.d.) for 30 days, and then underwent a prostate biopsy with ≥12 systematic and targeted biopsy cores obtained. Serum prostate-specific antigen levels were examined before and after administration of the pollen extract, and the change in serum prostate-specific antigen and the rate of change were analyzed in relation to negative and positive biopsy results for cancer. Results The mean change in serum prostate-specific antigen and rate of change after administration of cernitin pollen extract in all patients were -0.6 ± 1.4 ng/mL and -7.6 ± 16.1%, respectively, which were significantly different from the baseline values (P = 0.0003 and P = 0.0005, respectively). When prostate-specific antigen change values and rates were compared between patients negative and positive for cancer, a significant difference between those groups was observed (P = 0.04 and P = 0.03, respectively). Conclusions The present study is the first to show that an ideal protocol using cernitin pollen extract has the potential to avoid an unnecessary prostate biopsy procedure in patients with elevated prostate-specific antigen, possibly caused by inflammation. Additional studies with greater numbers of participants are required to confirm our findings and develop an ideal protocol.

Objectives: Ureteropyeloscopy has recently become an essential technique in the diagnosis of upper urinary tract tumors. However, no consensus has been reached regarding its indications. In addition, it is accompanied by several limitations and potential adverse events such as dissemination of malignant cells, adhesion of the ureter to the surrounding tissue, ureteral stricture, and ureteral perforation. In order to determine when and what circumstances dictate the need for ureteropyeloscopy to detect upper urinary tract tumors, we investigated the indications for ureteropyeloscopy based on voided urine cytology and preoperative radiographic findings. Patients and Methods: In this retrospective study, we evaluated 92 patients (62 men and 30 women) with a mean age of 66.4 years (range, 15–87 years) who had undergone diagnostic ureteropyeloscopy at our institution for the past 10 years. All patients were divided into six subgroups based on voided urine cytology and preoperative radiographic findings: subgroups A1 (n = 18) and A2 (n = 2), positive cytology (positive catheter urine cytology/negative catheter urine cytology) and positive images; Subgroup B (n = 19), positive cytology and negative images; Subgroups C1 (n = 30) and C2 (n = 10), negative cytology and positive images (upper urinary tract carcinomas/other abnormal findings); Subgroup D (n = 13), negative cytology and negative images. Ureteropyeloscopic findings including histology were compared with urine cytology and radiographic findings. Results: Voided urine cytology exhibited 60.4% sensitivity and 77.3% specificity, while preoperative radiographic findings exhibited 70.8% sensitivity and 63.6% specificity. Carcinomas were detected in all patients in Subgroups A1 and A2. Carcinomas were also detected in 9 patients (47.4%) in Subgroup B, of whom 5 showed a history of bladder tumors. The remaining 10 patients all had a history of bladder cancer. In Subgroups C1, C2, and D, carcinomas were detected in 14 patients (46.7%), 1 patient (10%), and 4 patients (30.8%), respectively. These results suggested that ureteropyeloscopy should be recommended for patients with negative cytology. Three complications (pyelonephritis, renal failure, and urinary retention) were noted, but none of these was severe and all were cured within a few days. No malignant findings were obtained in any of the patients during follow-up after negative findings in ureteropyeloscopy. Conclusions: Ureteropyeloscopy is essential for detecting upper urinary tract carcinoma in patients with negative voided urine cytology and positive radiographic findings. In addition, ureteropyeloscopy seems to be used commonly among patients with positive urine cytology and negative radiographic findings, or those with bleeding from the ureteral orifice. However, unless conservative nephron-sparing treatment is considered, ureteropyeloscopy may be unnecessary for patients with positive urine cytology and positive radiographic findings.

Objectives: Prostatic abscesses are rare. The incidence of prostatic abscess has declined markedly with the widespread use of antibiotics. Obtaining improvement is difficult in many cases of prostate abscess. Today, there are no guidelines or algorithms for the treatment of prostatic abscess. In this study, the shape and size of the abscess, in addition to patient background characteristics and the clinical course, were evaluated, and the treatment strategy for prostatic abscess was examined. Methods and Material: All patients with a diagnosis of prostatic abscess in Showa University Hospital between 2003 and 2017 were retrospectively reviewed. Regarding the treatment options, the patients were divided into two groups, the conservative therapy group and the drainage group. In each group, background characteristics, culture reports, shape/size of abscess, and the presence of recurrence were evaluated. Results: All 18 patients with a diagnosis of prostatic abscess between 2003 and 2017 were retrospectively reviewed; 13 patients improved with conservative treatment alone, but drainage was performed in five patients with poor response to antibiotic therapy. All five cases requiring transurethral drainage were multifocal abscesses. Conclusions: In making a decision about the approach for drainage, it is important to assess the size and shape of the abscess using transrectal ultrasonography (TRUS), computed tomography (CT) and magnetic resonance imaging (MRI). If the abscess is the multifocal type, drainage should be considered. Based on the present study, whether the abscess is focal type or multifocal type, transurethral drainage should be considered if the abscess size exceeds 30 mm.

Objectives To assess the outcomes of the tissue fixation system midurethral sling for the treatment of intrinsic sphincter deficiency. Methods We retrospectively studied a total of 96 intrinsic sphincter deficiency patients treated with the tissue fixation system midurethral sling at Yokohama Motomachi Women's Clinic from 2006 to 2015. We evaluated intraoperative and 1-year postoperative results. Regarding the cure rate, we divided patients into three groups: (i) patients with maximum urethral closure pressure

Identifying "druggable" targets and their corresponding therapeutic agents are two fundamental challenges in drug discovery research. The one-bead-one-compound (OBOC) combinatorial library method has been developed to discover peptides or small molecules that bind to a specific target protein or elicit a specific cellular response. The phage display cDNA expression proteome library method has been employed to identify target proteins that interact with specific compounds. Here, we combined these two high-throughput approaches, efficiently interrogated approximately 10(13) possible molecular interactions, and identified 91 small molecule compound beads that interacted strongly with the phage library. Of 19 compounds resynthesized, 4 were cytotoxic against cancer cells; one of these compounds was found to interact with EIF5B and inhibit protein translation. As more binding pairs are confirmed and evaluated, the "library-against-library" screening approach and the resulting small molecule-protein domain interaction database may serve as a valuable tool for basic research and drug development.

Excessive ammonia is harmful to the body. It is mostly hepatic in origin. Hyperammonemia due to urinary tract infection (UTI) is rare. We report a case of hyperammonemia with UTI and urinary retention. A 94-year-old female arrived at our hospital with impaired consciousness that lasted for a day. On arrival, her Glasgow Coma Scale was E1V1M5, blood ammonia was 272 ng/dl, and urinalysis revealed a large number of white and red blood cells. Abdominal computed tomography scan revealed a distended bladder and wall thickness with no hydronephrosis. Urine cultures were positive for urease-producing Corynebacterium, Escherichia coli, and Staphylococcus aureus. The patient was diagnosed with hyperammonemia with UTI and urinary retention. After urinary catheterization, blood ammonia levels normalized, and consciousness improved. We need to consider ammonia toxicity in UTI patients with urine retention presenting with altered consciousness.

Upper urinary tract neuroendocrine carcinoma (UUT-NEC) is extremely rare and has a poor prognosis. Although a few cases of successful treatment have been reported, no treatment has shown established efficacy.We analyzed 70 UUT-NEC patients, including 68 with small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC) reported between 1985 and 2017 and 2 treated at our hospital.Median patient age was 66 years, 58.6% were men, and 60% were of Asian descent. Most UUT-NECs were SCNEC (68; 95.7%), whereas LCNEC was very rare (2; 2.9%). More than half of the patients had accompanying other histological components, the most common being urothelial carcinoma (51.5%), whereas 41.4% had NEC alone. Of the 70 patients, 27 underwent additional therapy (e.g., chemotherapy and radiotherapy) along with surgery. Median survival was 15 months. In univariate analysis, stages T1-2 disease showed better prognosis than stages T3-4 (P 0.001). Additional treatment (e.g., chemotherapy and radiotherapy) significantly improved prognosis (P = 0.014). Moreover, platinum-based chemotherapy also was associated with improved prognosis (P = 0.017). For platinum-based chemotherapy, multicollinearity with additional treatments was strong, and, thus, these data were not included in the analysis. Multivariate analysis revealed pathological stage (T1-2 vs. T3-4; P = 0.003) and additional treatment (P = 0.028) to be independent predictors of improved prognosis.Although UUT-NEC has a poor prognosis, additional treatment along with surgery and therapeutic intervention and stage T1-2 disease are independent factors to improve prognosis.

Background and objectives The pathophysiologic aspects of parasympathetic nerve (PN) function during sleep in patients with obstructive sleep apnea (OSA) studied by classical power spectrum analysis on heart rate variability (HRV) are highly controversial. The controversy is attributed to methodologic concerns, such as poor time resolution involved in power spectrum analysis. We aimed to establish the appropriate method for the investigation of PN function in OSA patients with apneas and hypopneas using instantaneous time–frequency analysis with complex demodulation (CD) and sufficient time resolution. Methods A total of 30 patients with PSG-confirmed mild to severe OSA were recruited for the analysis of frequency spectra contained in R-R intervals (RRI) of overnight electrocardiograph (ECG) tracings. High-frequency (HF) domains ranging between 0.15 and 0.40 Hz were selected for analysis. Among these domains, the HF domain with the maximum instantaneous amplitude was defined as the main HF peak and was used as the surrogate marker of PN discharge. Based on density spectrum array (DSA) map for main HF peak constructed with a time scale of 1 s and a frequency resolution of 0.002 Hz (HF-DSA map), the shift in central frequency (CF) of main HF peak over time was continuously monitored. When the main HF peak with the same CF lasted for more than 20 s or 5 min on HF-DSA map, the PN function was considered to be stable or very stable. The measurements were then repeated after continuous positive airway pressure (CPAP) treatment. Results The extent of PN-evoked modulation of RRI was enhanced in nonrapid eye movement (NREM) sleep, though the stability was reduced in both NREM and rapid eye movement (REM) sleep. These peculiar behaviors of PN function were reversed by CPAP treatment. Conclusion We found that instantaneous time–frequency analysis allowed estimation of transitional changes in PN function during sleep in OSA patients.

Introduction To evaluate the clinical effectiveness and quality of life (QOL) of outpatient mid-urethral tissue fixation system sling (TFS) procedures for urodynamic stress urinary incontinence (SUI) at 3-year follow-up. Methods We analyzed 50 mid-urethral TFS sling operations between 2007 and 2012 at Yokohama Motomachi Women’s Clinic LUNA. The primary outcome was success defined as a negative 24-h pad test, negative cough and Valsalva stress test, and no re-treatment for SUI. Secondary outcome was improvement in quality of life, which was assessed using the Incontinence Questionnaire-Short Form (ICIQ-SF) and the Incontinence Impact Questionnaire Short Form (IIQ-7). The 3-year postoperative scores were compared with baseline scores using the Wilcoxon signed rank test. A 5% two-sided significance level was used for all statistical testing. Results All operations were carried out on an outpatient basis with no intraoperative complications. The primary cure rate result at 3-year follow-up was 90%. Median total ICIQ-SF score changed from 12 (6–20) to 0 (0–14) and median total IIQ-7 score changed from 156 (0–300) to 0 (0.00–16.7) at 3-year follow-up. Conclusions Results show that the TFS mid-urethral sling operation is a simple, safe, effective procedure that may be done without difficulty at a freestanding clinic on an outpatient basis and favorably improves subjective QOL of the patient.

Polyorchidism is a rare congenital condition associated with various anomalies; triorchidism is the most common form of this condition. A 21-year-old patient visited our hospital with pain in the right testis. He was diagnosed with right-sided polyorchidism with torsion and underwent manual detorsion followed by orchidopexy. We preserved the extra testis but did not perform histology, as radiological examination revealed no malignant features.

Introduction and hypothesis In 2005, a new minimally invasive procedure, the tissue fixation system (TFS) was reported. Like TVT (tension-free vaginal tape), the TFS works by creating a foreign body collagenous tissue reaction that reinforces a weakened pelvic ligament. The objective was to assess the effectiveness and perioperative safety of TFS in a day surgery clinic for the treatment of pelvic organ prolapse (POP). Methods The TFS tape was applied in a tunnel adjacent to natural ligaments to repair the anterior cervical ring and cardinal ligament, paravaginal tissues and uterosacral ligaments under local anesthesia/sedation. We prospectively studied 60 patients, mean age 67, between October 2008 and February 2010 at Women’s Clinic LUNA. Levels of POP were grade 2 (n = 20; 7 %), grade 3 (n = 30; 55 %), and grade 4 (n = 4; 7 %) according to the ICS POPQ classification. Fifty-four patients (90 %) who underwent a total of 162 POP operations presented for review. Follow-up was performed at 12 months. We defined surgical failure according to the ICS POPQ classification. We used prolapse quality of life (P-QOL) questions for QOL measurement. Results Ninety-eight percent of patients were discharged on the day of surgery. Of the162 TFS operations reviewed, 157 were successful and 5 failed. The 5 failed operations comprised 4 cystoceles and 1 rectocele. Two patients developed cervical protrusions at the introitus at 6 months with no prolapse of the uterine body. We found 5 cases of erosion in 162 tape insertions. The total number of patients who had no complications, no surgical failures, no erosions, no sensation of bulging, and no cervical protrusions was 47 (87 %). Conclusions The TFS uses the same surgical principle for repair as the TVT; this principle vastly minimizes the volume of mesh used, erosions, and other complications.

Objective: The aim of the present study was to assess the effects of onabotulinumtoxinA injection for refractory non-neurogenic overactive bladder (OAB) for 12 months. Methods: For patients with persistent urgency urinary incontinence (UUI) more than once a week despite taking anti-cholinergic agents or incapability to continue the agents because of adverse effects, 100 units of onabotulinumtoxinA was injected at 30 sites in the sub-epithelial bladder wall. Efficacy was assessed every month up to 12 months after injection, using a three-day frequency-volume chart (FVC) and postvoid residual urine (PVR), three questionnaires, and a simple score of Global Response Assessment (GRA). Failure was defined as when GRA was negative and additional treatment was administered. Results: Nine men and eight women aged 67 ± 12 years were included. On FVC, frequencies of urgency, UUI and daytime urination significantly decreased up to the 11th month. PVR significantly increased at the first and second months but no patient required catheterization. The total scores of Overactive Bladder Symptom Score and International Consultation on Incontinence Questionnaire Short Form were significantly decreased for 10 and eight months, respectively. The score of GRA was significantly improved for eight months. The median time to failure was 11.0 months. Conclusion: This study suggests that onabotulinumtoxinA submucosal injection is promising for refractory non-neurogenic OAB. It is anticipated that the treatment is effective for eight to nine months and approximately 40% of the patients do not require anticholinergics at the 12th month postoperatively.

There is a need to develop novel targeted imaging and therapeutic agents that can aid in early diagnosis, detection of metastasis and treatment of melanoma. Alpha-3 integrin is overexpressed in 82% of metastatic melanomas in humans and may be a potential target for peptide ligands carrying therapeutic agents. Five melanoma cell lines were generated from canine primary oral and metastatic canine tumors, grown in mice, and validated with melanoma markers Melan A, S-100, Micropthalmia transcription factor (MITF), Tyrosinase, and MART-1. The melanoma cell lines were tested for binding affinity to previously published alpha-3 integrin-binding peptides containing the cdGXGXXc motif. Fluorescent conjugates of the alpha-3 integrin binding OA02 peptide were used to quantify receptor affinity in the cell lines, a specimen of canine primary oral melanoma, and melanoma xenografts. Alpha-3 integrin was expressed by all 5 canine melanoma cell lines. Four of the 5 lines as well as the primary canine tumor showed affinity to alpha-3 integrin binding peptides with the cdGXGXXc motif. Optical imaging of canine melanoma xenografts in nude mice indicates rapid, strong uptake of the optical tracer in the tumor with an average persistence of approximately 48 hours. Ex vivo images showed high tumor-to-background ratio, with tumor signals more than twice that of the kidney and other vital organs. We propose that integrin alpha-3 integrin binding ligands could potentially become useful probes for imaging and delivery of cytotoxic agents for the treatment of melanoma.

Accumulations of hypertrophic, intensely glial fibrillary acidic protein-positive (GFAP+) astroglia, which also express immunoreactive nestin and vimentin, are prominent features of multiple sclerosis lesions. The issues of the cellular origin of hypertrophic GFAP+/vimentin+/nestin+“reactive” astroglia and also the plasticities and lineage relationships among three macroglial progenitor populations—oligodendrocyte progenitor cells (OPCs), astrocytes and ependymal cells—during multiple sclerosis and other CNS diseases remain controversial. We used genetic fate-mappings with a battery of inducible Cre drivers (Olig2-Cre-ERT2, GFAP-Cre-ERT2, FoxJ1-Cre-ERT2and Nestin-Cre-ERT2) to explore these issues in adult mice with myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis (EAE). The proliferative rate of spinal cord OPCs rose fivefold above control levels during EAE, and numbers of oligodendroglia increased as well, but astrogenesis from OPCs was rare. Spinal cord ependymal cells, previously reported to be multipotent, did not augment their low proliferative rate, nor give rise to astroglia or OPCs. Instead, the hypertrophic, vimentin+/nestin+, reactive astroglia that accumulated in spinal cord in this multiple sclerosis model were derived by proliferation and phenotypic transformation of fibrous astroglia in white matter, and solely by phenotypic transformation of protoplasmic astroglia in gray matter. This comprehensive analysis of macroglial plasticity in EAE helps to clarify the origins of astrogliosis in CNS inflammatory demyelinative disorders.

We prepared monodisperse colloidal β-FeOOH (square prismatic crystalline) nanorods. Self-assembled dry thin films of the rods were formed on quartz substrates by evaporating drops of repulsive-rod suspensions. Using spectroscopic ellipsometry, the complex refractive index spectra of the β-FeOOH nanorod films were deduced, which are further corrected on the basis of absorption spectra measured for β-FeOOH nanorod suspensions, with aid of the Kramers-Kronig relation and an optical two-phase mixing model. Simultaneously, in this correction process, the rod volume fraction in the films and the complex mean refractive index spectra of purely the rod were extracted together. The real part of the refractive index spectra of the β-FeOOH rod, n'(c)(λ), shows a maximal value of 2.365 (aver.) at 410 nm (λ(m)) (hence a normal dispersion at λ > λ(m) and an anomalous dispersion at λ < λ(m)). At λ = 589.3 nm (λ(D) for "sodium light"), the n'(c)(λ) value is consistent with refractive indices predicted by Gladstone-Dale's and Anderson's refractivity formulas with the density of the β-FeOOH rod, 3.638 ± 0.104 g/cm(3), measured in this work.

The αvβ3 integrin, expressed on the surface of various normal and cancer cells, is involved in numerous physiologic processes such as angiogenesis, apoptosis, and bone resorption. Because this integrin plays a key role in angiogenesis and metastasis of human tumors, αvβ3 integrin ligands are of great interest to advances in targeted therapy and cancer imaging. In this report, one-bead one-compound (OBOC) combinatorial libraries containing the arginine-glycine-aspartic acid (RGD) motif were designed and screened against K562 myeloid leukemia cells that had been transfected with the human αvβ3 integrin gene. Cyclic peptide LXW7 was identified as a leading ligand with a built-in handle that binds specifically to αvβ3 and showed comparable binding affinity (IC50 = 0.68 ± 0.08 μmol/L) to some of the well-known RGD “head-to-tail” cyclic pentapeptide ligands reported in the literature. The biotinylated form of LXW7 ligand showed similar binding strength as LXW7 against αvβ3 integrin, whereas biotinylated RGD cyclopentapeptide ligands revealed a 2- to 8-fold weaker binding affinity than their free forms. LXW7 was able to bind to both U-87MG glioblastoma and A375M melanoma cell lines, both of which express high levels of αvβ3 integrin. In vivo and ex vivo optical imaging studies with the biotinylated ligand/streptavidin-Cy5.5 complex in nude mice bearing U-87MG or A375M xenografts revealed preferential uptake of biotinylated LXW7 in tumor. When compared with biotinylated RGD cyclopentapeptide ligands, biotinylated LXW7 showed higher tumor uptake but lower liver uptake. Mol Cancer Ther; 9(10); 2714–23. ©2010 AACR.

Previous studies have shown that oligodendroglial progenitor cells (OPCs) can give rise to neuronsin vitroand in perinatal cerebral cortexin vivo. We now report that OPCs in adult murine piriform cortex express low levels of doublecortin, a marker for migratory and immature neurons. Additionally, these OPCs express Sox2, a neural stem cell marker, and Pax6, a transcription factor characteristic of progenitors for cortical glutamatergic neurons. Genetic fate-mapping by means of an inducible Cre–LoxP recombination system proved that these OPCs differentiate into pyramidal glutamatergic neurons in piriform cortex. Several lines of evidence indicated that these newly formed neurons became functionally integrated into the cortical neuronal network. Our data suggest that NG2+/PDGFRα+proteolipid protein promoter-expressing progenitors generate pyramidal glutamatergic neurons within normal adult piriform cortex.