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Background: For prostate cancer, accurate prediction of the pathological stage before surgery is very important. Therefore, the aim of the present study was establishing the prostate-specific antigen (PSA) threshold nomogram to predict pathologically advanced prostate cancer using the novel method of area under the receiver operating characteristic curve boosting (AUCBoost)., Methods: The medical records of patients with clinically localized prostate cancer who underwent robot-assisted radical prostatectomy were retrospectively reviewed. Multivariate logistic regression analysis was performed to identify clinical covariates significantly associated with pathological tumor stage ≥3a. The best combination of the variables was determined by validated values of the area under the curve (AUC). The optimal individualized PSA threshold values were developed using AUCBoost., Results: In the multivariate logistic regression analysis, PSA, prostate volume, clinical tumor stage, Gleason Grade Group, the number of positive cores, and the percentage of positive cores were independent predictive factors for pathological tumor stage ≥3a. A combination model comprising PSA, prostate volume, clinical tumor stage, percent positive core, and Gleason Grade Group produced the highest AUC for predicting pathological tumor stage ≥3a (AUC = 0.777). The PSA threshold values for detecting pathological tumor stage ≥3a were calculated and a table of individualized PSA threshold nomogram was developed using AUCBoost., Conclusions: We developed a nomogram of the PSA threshold values for predicting adverse pathological tumor stages of prostate cancer using a novel statistical method. Further validation is necessary; however, the individualized PSA threshold nomogram may be useful in determining treatment strategies before surgery., Competing Interests: Conflicts of interest and Financial disclosures The authors have no conflicts of interest directly relevant to the content of this article. The corresponding author (T.H.) was supported by JSPS KAKENHI Grant Number 18K09209. The second author (O.K.) was supported by JSPS KAKENHI Grant Number 18K11190., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Neutropenia is a major adverse event of docetaxel-based chemotherapy. The present study was undertaken to evaluate the incidence of neutropenia and to develop a nomogram for predicting Grade 4 neutropenia during the first cycle of docetaxel-based chemotherapy in patients with castration-resistant prostate cancer (CRPC)., Patients and Methods: This study included 112 patients with CRPC treated with docetaxel-based systemic chemotherapy. We evaluated the incidence and risk factors for Grade 4 neutropenia in the first cycle of chemotherapy., Results: Sixty-two of 112 patients (55.4%) developed Grade 4 neutropenia in the first cycle of docetaxel-based chemotherapy. There were significant differences in age, baseline white blood cell count, and baseline neutrophil count between patients with non-Grade 4 neutropenia and those with Grade 4 neutropenia in univariate analyses. The serum prostate-specific antigen level, hemoglobin level, creatinine, albumin, Eastern Cooperative Oncology Group performance status, metastatic sites, extent of disease, and history of external beam radiotherapy to the prostate were not significantly different between the 2 groups. Multivariate logistic regression analysis showed that age (odds ratio [OR], 1.08; P = .019) and baseline neutrophil counts (OR, 0.79; P = .045) were significant independent risk factors for severe neutropenia. A nomogram and a calibration plot on the basis of these results were developed from a multivariate logistic regression analysis to predict the probability of Grade 4 neutropenia., Conclusion: Age and baseline neutrophil counts were significant independent risk factors for Grade 4 neutropenia. The nomogram to predict it provides useful information for the management of patients with CRPC treated with docetaxel chemotherapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to investigate the effect of positive surgical margin (PSM) without extraprostatic extension after robot-assisted radical prostatectomy (RARP)., Materials and Methods: We retrospectively reviewed 837 patients who underwent RARP for clinically localized prostate cancer without neoadjuvant endocrine therapy. The pT2+category lesions were defined according to World Health Organization classification. The actuarial probabilities of biochemical recurrence-free survival (BCR-FS) were determined using Kaplan-Meier analysis. Univariate and multivariate Cox proportional hazards regression analyses were also used to identify independent predictors for BCR., Results: Of the 837 patients, 102 (12.2%) experienced BCR during the follow-up period. The BCR-FS rate was significantly higher in patients with pT2+category tumors than in those with pT3a category tumors, and significantly lower in patients with pT2+category tumors than that in those with pT2 category tumors without PSM. The BCR-FS rate of patients with pT2+category tumors was significantly higher than that with pT3a category tumors with PSM but not significantly different from that with pT3a category tumors without PSM. In a multivariate analysis, the pathological T category considering pT2+category was one of independent predictive factors for BCR., Conclusions: This study support the hypothesis that the pT2+category disease is associated with a significantly increased risk of BCR in patients with organ-confined prostate cancer after RARP. As PSM can be avoided in some cases, urologists should continually seek to improve their operative skills and to reduce the rate of PSM, especially in patients with organ-confined prostate cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We present a case of a 67-year-old man with intussusception of the right ureter associated with a fibroepithelial polyp. The concentric sign and line sign are characteristic radiological findings in intussusception, and these findings could be seen in the present case. Although this entity is rare, its radiological findings are specific. Multidetector row computed tomography and its multiplanar reconstruction make the diagnosis feasible, although the qualitative diagnosis of the tumor was difficult., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The recently discovered enzyme hydroxycinnamoyl CoA: shikimate hydroxycinnamoyl transferase (HCT) catalyzes the reactions both immediately preceding and following the insertion of the 3-hydroxyl group into monolignol precursors. A number of independent transgenic lines of alfalfa (Medicago sativa L.) were generated in which the levels of HCT were reduced through antisense HCT expression under control of the bean PAL2 promoter which is preferentially expressed in vascular tissue. Reduction of enzyme activity in these lines was from at least 15-50%. The most severely down-regulated lines exhibited significant stunting, reduction of biomass and delayed flowering. HCT down-regulation resulted in strongly reduced lignin content and striking changes in lignin monomer composition, with predominant deposition of 4-hydroxyphenyl units in the lignin. Vascular structure was impaired in the most strongly down-regulated lines. Analysis of forage quality parameters showed strong reductions of neutral- and acid-detergent fiber in the down-regulated lines, in parallel with large increases (up to 20%) in dry matter forage digestibility. Although manipulation of lignin biosynthesis can greatly improve forage digestibility, accompanying effects on plant development need to be better understood.

The purpose of this study was to characterize the effects of two new adenosine A2 agonists, 2-(p-(2-carboxyethyl)phenethyl amino)-5'-N-ethylcarboxamidoadenosine (CGS-21680) and N6-(2(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)-adenosine (DPMA), on erythropoietin (EPO) production in vivo and in vitro. Intravenous injections of CGS-21680 (100 to 500 nmol/kg mouse/day) and DPMA (50 to 500 nmol/kg mouse/day) for 4 days produced significant increases in serum levels of EPO in exhypoxic polycythemic mice. CGS-21680 (10(-7) to 10(-6) mol/L) and DPMA (10(-8) to 10(-5) mol/L) also produced significant increases in medium levels of EPO in a cloned EPO-producing Hep3B hepatocellular carcinoma cell line after 18 hours of incubation in 1% O2. Both compounds also increased cellular cAMP levels significantly in a dose-dependent manner after 1 hour of incubation. A2 receptor binding assays with tritiated CGS-21680 revealed a single type of adenosine receptor binding site on Hep3B cell membranes with a dissociation constant of 132.9 nmol/L and a binding capacity of 270.6 fmol/mg protein. The Ki competition binding values versus tritiated CGS-21680 were 217 nmol/L for CGS-21680 and 86.8 nmol/L for DPMA. These results indicate that adenosine A2 receptor activation amplifies EPO production in response to hypoxia, both in vivo and in vitro.

The present studies were undertaken using a cloned erythropoietin (Ep) producing hepatocellular carcinoma cell line (Hep3B) to attempt to correlate the receptor binding properties and biological activities of 5'-N-ethylcarboxamideadenosine (NECA), N6-cyclohexyladenosine (CHA) and N6-cyclopentyldenosine (CPA). Ep and cAMP levels in cultures of Hep3B cells in response to these adenosine analogues were measured by radioimmunoassay. Receptor binding affinities of the adenosine analogues were determined by measuring inhibition of binding of [3H] NECA to Hep3B cell membranes. Scatchard analysis of [3H]NECA to Hep3B cell membranes. Scatchard analysis of [3H]NECA binding to Hep3B cell membranes indicates a single class of binding sites with a dissociation constant of 431 nM and a binding capacity of 573 fmol/mg protein. The adenosine analogues tested produced a significant increase in Ep secretion and cAMP accumulation (ED50 for cAMP accumulation, NECA = 3.3 x 10(-7) M, CHA = 4.2 x 10(-6) M, CPA = 2.2 x 10(-6) M). In addition, NECA showed a higher binding affinity (Ki, 3.8 x 10(-7) M) for Hep3B cell membranes in comparison with CHA (Ki, 6.3 x 10(-6) M) and CPA (Ki, 3.9 x 10(-6) M). These results indicate that the rank order for potency for NECA, CHA and CPA in their binding to Hep3B cell membrane receptors correlates very well with their biological effects on Ep secretion and cAMP accumulation in Hep3B cells.

The present studies were undertaken to assess the effects of 5'-N-ethylcarboxamideadenosine (NECA), an adenosine analogue, on erythropoietin (Epo) production. NECA (0.05 and 0.1 mumol/kg i.v.) produced significant increases in serum Epo levels (368.8 +/- 56.1 and 384.6 +/- 45.9 mU/ml, respectively) in exhypoxic polycythemic mice after a four hour exposure to hypoxia when compared with hypoxia controls (133.2 +/- 18.2 mU/ml). The hypoxic kidney Epo levels were 46.4 +/- 13.4 mU/kg kidney which were significantly higher than normoxic kidney Ep levels (< 1.24 mU/kg kidney). Theophylline (20 mg/kg i.p.), an adenosine receptor antagonist, significantly inhibited the stimulatory effects of NECA on serum Epo levels. In vitro cultures of an Epo producing hepatocellular carcinoma (Hep3B) cell line with NECA (> or = 10(-6) M) for 20 hours under hypoxic conditions (1% O2) produced significant increases in medium levels of Epo when compared with hypoxia controls. Hepatocellular carcinoma cells treated with NECA at a concentration range of 10(-7) M to 5 x 10(-5) M for one hour in a hypoxic atmosphere also had significantly higher cAMP levels than that of hypoxia controls. Scatchard analyses of [3H]NECA binding to membrane preparations of hepatocellular carcinoma cells showed low affinity binding sites with a dissociation-constant (Kd) of 0.44 microM and a binding capacity of 863 fmol/mg protein. These findings suggest that the increase in Epo production in response to NECA under hypoxic conditions can be attributed, at least in part, to stimulation of adenosine A2 receptors which is coupled to adenylyl cyclase activation.

Changes in O2 tension such as those associated with hypoxic ischemia or hyperoxia may potentially modulate purine nucleotide turnover and production of associated catabolites. We used an isolated perfused rat lung preparation to evaluate the effect of O2 tension on pulmonary uric acid production. Three O2 concentrations (21%, normoxia; 95%, hyperoxia; 0%, hypoxia) were utilized for both pulmonary ventilation and equilibration of recirculating perfusate. All gas mixtures contained 5% CO2 and were balanced with N2. We used Certified Virus Free Sprague-Dawley male rats weighting 250-300 g, four to five rats in each exposure regimen. After a 10-min equilibration period, we measured uric acid levels at 0 and 60 min in lung perfusate and at 60 min in lung tissue. After 60 min of ventilation/perfusion, we observed significant uric acid accumulation in both lung tissue (25-60%) and perfusate (8- to 10-fold) for all three O2 regimens. However, hypoxia produced substantially greater net uric acid concentrations (net = the difference between zero and 60 min) than either normoxia or hyperoxia (1.5-fold in lung tissue, and 2-fold in perfusate, respectively). The data suggest that pulmonary hypoxia results in greater purine catabolism leading to increased uric acid production. Vascular space uric acid, as measured in the recirculating perfusate, was proportional to lung weight changes (r = 0.99) with hypoxia exhibiting the greatest values, possibly reflecting a linkage between tissue perturbation and uric acid release. Thus, measurement of uric acid may serve as a useful marker of adenine nucleotide turnover and lung injury.

This study reports the effects of cyclic adenosine 3'-5' monophosphate (cAMP) and hypoxia on erythropoietin biosynthesis in an erythropoietin-producing hepatocellular carcinoma cell line (Hep3B). Erythropoietin levels in the medium and cell extracts of low-density Hep3B cells after 20-hour incubation under hypoxic conditions (1% O2) were 25.33 +/- 1.50 mU/ml/10(7) cells and 3.60 +/- 0.50 mU/10(7) cells, respectively. These levels were significantly higher than in the respective normoxic controls (medium, 2.51 +/- 0.31 mU/ml/10(7) cells; cell extracts, undetectable [less than 0.31 mU/10(7) cells]). Cobalt also produced a significant increase in medium and cell erythropoietin levels. However, hypoxia and cobalt alone failed to produce an increase in cAMP accumulation in the cell cultures. Erythropoietin levels in the medium and cell extracts from cells exposed to 8-bromo cAMP (1 x 10(-4) mol/L) and forskolin (4 x 10(-6) mol/L) in a hypoxic atmosphere were significantly (p less than 0.05) higher than in the respective hypoxic controls. In addition, forskolin produced a significant (p less than 0.05) increase in cAMP accumulation (180 +/- 11.5 pmol/10(6) cells) under hypoxic conditions compared with the hypoxic controls (cAMP, 2.27 +/- 0.33 pmol/10(6) cells). These results suggest that cAMP elevation is not required in vitro in Hep3B cells for the increase in medium and cell levels of erythropoietin after hypoxia, but may be involved indirectly in erythropoietin biosynthesis, secretion, or both in vivo through some synergistic action with hypoxia.

Oxidant-mediated epithelial injury and repair processes may promote the development of pulmonary fibrosis. The authors examined this hypothesis by inducing oxidant injury in hamsters with intratracheally instilled mixtures of glucose, glucose oxidase (GO) and lactoperoxidase at weekly intervals. Solutions containing denatured GO (DE) served as a control treatment. One and six days after each treatment, anesthetized animals were sacrificed and lavaged, and their lungs and plasma were preserved for further study. Although DE-treatment consistently evoked a transient, neutrophil-rich inflammatory response, no significant biochemical or morphologic changes were detected at the ensuing 6-day time points. In contrast, repeated GO treatments prolonged inflammation and injured the alveolar epithelium, evidenced by significantly greater levels of neutrophils and macrophages in bronchoalveolar lavage fluid (BALF) and increased BALF levels of protein, beta-glucuronidase and lactic dehydrogenase activities. Active GO also altered BALF lymphocytes and monocytes, but no discernable pattern emerged. Fibrotic, consolidated parenchyma appeared after the second and third GO exposures, coinciding with increased levels of total collagen, prolyl hydroxylase activity, and anti-oxidant enzyme activities. Although alveolitis and type II cell hyperplasia were observed after the initial treatment, polyplike nodules covered by hyperplastic, undifferentiated epithelium were evident after the third treatment. After each exposure, GO-treated animals had larger volumes of parenchymal lesion than DE-treated hamsters. These data indicate that normal alveolar epithelial repair processes were greatly disrupted by repeated oxidant injury and suggest that repeated and/or continued epithelial injury may contribute to the development of pulmonary fibrosis.

Previous studies have shown that bleomycin-induced pulmonary fibrosis is accompanied by elevated levels of calcium and calmodulin, which are important in the regulation of many biologic processes. The authors have further extended these observations and assessed the effect of a calmodulin inhibitor, trifluoperazine, on bleomycin-induced lung damage with biochemical, morphometric, and bronchoalveolar lavage techniques. The cumulative mortality due to bleomycin was not significantly reduced in animals receiving trifluoperazine. Trifluoperazine had no apparent effect on lung levels of collagen and DNA elevated by bleomycin. However, morphometric studies showed that the volume density of the lesion, the volume of amorphous material and interstitial inflammation, and the number of monocytes within lesions were less in the lungs of bleomycin-treated hamsters receiving trifluoperazine daily. When compared with hamsters treated with bleomycin alone, animals treated with both bleomycin and trifluoperazine had significantly fewer lymphocytes in their bronchoalveolar lavage fluid. The data suggest that trifluoperazine reduced the acute inflammation which accompanies bleomycin pneumotoxicity but did not affect the subsequent development of pulmonary fibrosis. It has been postulated that the observed antiinflammatory action of trifluoperazine may be due to inhibition of calmodulin-dependent leukocyte functions.

In the present study, the effects of intratracheal administration of bleomycin have been examined on daily food intake and on plasma levels of glucose, cortisol, and insulin, and on lung levels of calmodulin, calcium, and collagen in hamsters. Since bleomycin treatment caused nutritional deficiency leading to loss of body weight, we have included pair-fed and control-fed as control groups in order to rule out the nutritional deficiency-related effects on these measurements. Bleomycin-treated animals showed a dramatic decrease in daily food intake and body weight as compared to control-fed animals. Bleomycin-treated animals were hyperglycemic when compared to nutritionally comparable pair-fed animals and had plasma glucose levels similar to those of control-fed animals. Plasma cortisol levels in bleomycin-treated and pair-fed animals showed a time-dependent increasing trend, whereas plasma insulin levels in both groups tended to decrease. The lung levels of calmodulin and calcium in bleomycin-treated animals were significantly increased when compared with the pair-fed or control-fed group. Bleomycin-treated animals had significantly higher levels of lung collagen than pair-fed or control-fed at 7 and 13 days after treatment. The lung collagen content in pair-fed animals was significantly less than that of control-fed at 13 days. It was concluded that a disturbance in carbohydrate metabolism and increased lung levels of calmodulin and calcium might be somehow involved in fibroproliferative changes of the lung in bleomycin-treated animals.

Reactive oxygen species (ROS) have been closely associated with a number of pathological disorders, including interstitial pulmonary fibrosis. While models of ROS-induced fibrosis offer advantages over chemically-induced fibrosis, the biochemical and morphological features of ROS-induced fibrosis have yet to be extensively documented. In this study, we evaluated the effect of initial ROS dose on lung injury and repair. Male hamsters received a single dose of glucose, glucose oxidase and lactoperoxidase via the intratracheal route. From 3 to 14 days post-treatment, a significant dose-related body weight loss was observed. There was a trend towards greater mortality with increasing dose. After 2 weeks, we noted significant, dose-related increases in lung levels of collagen, lipid peroxidation products, nucleic acids, and protein. Similarly, total lung catalase, lactic dehydrogenase and glutathione reductase activities were also elevated significantly above control values in a dose-related fashion. A concurrent, dose-dependent thickening of alveolar septa in ROS-treated lungs was composed of epithelial hyperplasia, hyperemia, edema and accumulations of interstitial fibers and macrophages. Interstitial and alveolar macrophages in ROS-induced lesions were enlarged and contained numerous primary and secondary lysosomes. These results demonstrate that, in the hamster lung, injury induced by enzyme-generated ROS can initiate dose-dependent fibroproliferative changes which eventuate into interstitial fibrosis.

To characterize mouth to anus transit of intestinal contents, polyethylene glycol (PEG) was given as an intestinal marker to 11 healthy infants, and daily fecal collections were analyzed for PEG concentration per unit of dry stool weight for 9-15 d. Fecal PEG excretion followed first-order kinetics. Thus, half-life (t1/2) and volume of distribution (Vd) of PEG in the gut could be computed for each of seven infants who received continuous daily PEG doses and t1/2 only for four infants who received a single PEG dose. t1/2 of PEG in the gut was 0.99 +/- 0.48 d (means +/- SD). Vd for PEG in the gut was 18.74 +/- 15.38 g of fecal dry weight. We propose that whole-gut transit be expressed in terms of t1/2 and Vd of intestinal contents because these may better characterize the changes in intestinal transit that occur with disease or dietary modifications.