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Human carnosinases (CNs) are dimeric dipeptidases in the metallopeptidase M20 family. Two isoforms of carnosinases (Zn2+‐containing carnosinase 1 (CN1) found in serum and Mn2+‐carnosinase 2 (CN2) in tissue) were identified. Both CNs cleave histidine‐containing (Xaa‐His) dipeptides such as carnosine where CN2 was found to accept a broader spectrum of substrates. A loss of CN function, resulting in a high carnosine concentration, reduces risk for diabetes and neurological disorders. Although several studies on CN activities and its Michaelis complex were conducted, all shed the light on CN1 activity where the CN2 data is limited. Also, the molecular details on CN1 and CN2 similarity and dissimilarity in structure and function remain unclear. Thus, in this work, molecular dynamics (MD) simulations were employed to study structure and dynamics of human CN1 and CN2 in comparison. The results show that the different catalytic ability of both CNs is due to their pocket size and environment. CN2 can accept a wider range of substrate due to the wider mouth of a binding pocket. The L1 loop seems to play a role in gating activity. Comparing to CN2, CN1 provides more electronegative entrance, more wettability, and higher stability of catalytic metal ion‐pair in the active site which allow more efficient water‐mediated catalysis. The microscopic understanding obtained here can serve as a basis for CN inhibition strategies resulting in higher carnosine levels and consequently mitigating complications associated with diseases such as diabetes and neurological disorder. [ABSTRACT FROM AUTHOR]

ObjectivesLymph node metastases (LNMs) could be stratified into clinical N1 (cN1) and microscopic pN1 (pathological N1), which bear different biological behavior and prognosis. Our study aimed to investigate the associations between LNMs and primary tumor’s US (ultrasound) and CEUS (contrast-enhanced ultrasound) characteristics based on the stratification of LNMs into cN1 and microscopic pN1 in papillary thyroid carcinoma (PTC).MethodsFrom August 2019 to May 2020, 444 consecutive PTC patients who underwent preoperative neck US and CEUS evaluation were included. According to regional lymph node status, the patients were classified into cN1 group versus cN0 (clinical N0) group and microscopic pN1 group versus pN0 (pathological N0) group. For multiple PTCs, the largest one was selected for the evaluation of US, CEUS and clinical features. Univariate and multivariate analyses were performed to determine independent predictors of cN1 and microscopic pN1.Results85 cN1 versus 359 cN0 patients and 117 microscopic pN1 versus 242 pN0 patients were analyzed. Multivariate logistic regression analysis showed that

Objectives: Lymph node metastases (LNMs) could be stratified into clinical N1 (cN1) and microscopic pN1 (pathological N1), which bear different biological behavior and prognosis. Our study aimed to investigate the associations between LNMs and primary tumor's US (ultrasound) and CEUS (contrast-enhanced ultrasound) characteristics based on the stratification of LNMs into cN1 and microscopic pN1 in papillary thyroid carcinoma (PTC). Methods: From August 2019 to May 2020, 444 consecutive PTC patients who underwent preoperative neck US and CEUS evaluation were included. According to regional lymph node status, the patients were classified into cN1 group versus cN0 (clinical N0) group and microscopic pN1 group versus pN0 (pathological N0) group. For multiple PTCs, the largest one was selected for the evaluation of US, CEUS and clinical features. Univariate and multivariate analyses were performed to determine independent predictors of cN1 and microscopic pN1. Results: 85 cN1 versus 359 cN0 patients and 117 microscopic pN1 versus 242 pN0 patients were analyzed. Multivariate logistic regression analysis showed that <55-years-old (OR: 2.56 (1.08–6.04), male [OR: 2.18 (1.22–3.91)], large size [OR: 2.59 (1.71–3.92)], calcification [OR: 3.88 (1.58–9.51)], and hyper-enhancement [OR: 2.78 (1.22–6.30)] were independent risk factors of cN1, while <55-years-old [OR: 1.91 (1.04–3.51)], large size [OR: 1.56 (1.003–2.42)], multifocality [OR: 1.67 (1.04–2.66)] were independent risk factors of microscopic pN1. Conclusions: For patients with PTC, young age, male, large size, calcification, and hyper-enhancement were independent predictors of cN1, while young age, large size and multifocality were independent predictors of microscopic pN1. [ABSTRACT FROM AUTHOR]

Context: Patients with clinically lymph node-positive (cN1) prostate cancer (PCa) are traditionally regarded to have metastatic disease, and the role of local therapy (LT) in their treatment remains unclear., Objective: To evaluate the outcomes of cN1 PCa patients treated with LT, and secondarily to compare between different modalities of LT, including radiotherapy (RT) and radical prostatectomy (RP)., Evidence Acquisition: A bibliographic search was performed using Medline, Embase, and the Cochrane Library to identify studies comparing the survival outcomes of cN1 PCa patients treated with LT (RT or RP) with those who did not receive any form of LT (observation or androgen deprivation therapy alone). The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) recommendations were followed. Survival outcomes of the addition of LT were assessed using a random-effect model., Evidence Synthesis: A total of 8522 patients across eight studies were included. LT significantly improved overall survival (OS) across all time points from 2 to 10 yr compared with patients without LT, most notably providing a durable benefit in 10-yr OS (odds ratio [OR]: 1.49, 95% confidence interval [CI] 1.06-2.10). Both RT and RP were associated with benefits to both OS and recurrence-free survival, with no significant difference in OS between both modalities in medium-term follow-up (4-yr OR: 0.76, 95% CI 0.41-1.40, p = 0.19)., Conclusions: Regardless of modality, the use of LT in cN1 patients improved OS. Future studies should aim to identify patients who could benefit from LT and include more comprehensive survival data including biochemical recurrence., Patient Summary: In this study, we evaluated the outcomes of clinically lymph node-positive (cN1) prostate cancer (PCa) patients treated with local therapy (LT) and compared between different modalities of LT, including radiotherapy (RT) and radical prostatectomy (RP). We found that the addition of LT for cN1 PCa patients leads to a significant improvement in survival outcomes, most notably for overall survival, with no significant difference between RT and RP., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Patients diagnosed with clinically node-positive prostate cancer represent a population that has historically been thought to harbor systemic disease. Increasing evidence supports the role of local therapies in advanced disease, but few studies have focused on this particular population. In this review we discuss the limited role for conventional cross sectional imaging for accurate nodal staging and how molecular imaging, although early results are promising, is still far from widespread clinical utilization. To date, evidence regarding the role of radical prostatectomy and pelvic lymph node dissection in clinically node-positive disease comes from retrospective studies; overall surgery appears to be a reasonable option in selected patients, with improved oncological outcomes that could be attributed to both to its potential curative role in disease localized to the pelvis and to the improved staging to help guide subsequent multimodal treatment. The role of surgery in clinically node-positive disease needs higher-level evidence but meanwhile, radical prostatectomy with extended pelvic lymph-node dissection can be offered as a part of a multimodality approach with the patient.

Patients diagnosed with clinically node-positive prostate cancer represent a population that has historically been thought to harbor systemic disease. Increasing evidence supports the role of local therapies in advanced disease, but few studies have focused on this particular population. In this review we discuss the limited role for conventional cross sectional imaging for accurate nodal staging and how molecular imaging, although early results are promising, is still far from widespread clinical utilization. To date, evidence regarding the role of radical prostatectomy and pelvic lymph node dissection in clinically node-positive disease comes from retrospective studies; overall surgery appears to be a reasonable option in selected patients, with improved oncological outcomes that could be attributed to both to its potential curative role in disease localized to the pelvis and to the improved staging to help guide subsequent multimodal treatment. The role of surgery in clinically node-positive disease needs higher-level evidence but meanwhile, radical prostatectomy with extended pelvic lymph-node dissection can be offered as a part of a multimodality approach with the patient. [ABSTRACT FROM AUTHOR]

In humans, low serum carnosinase (CN1) activity protects patients with type 2 diabetes from diabetic nephropathy. We now characterized the interaction of thiol-containing compounds with CN1 cysteine residue at position 102, which is important for CN1 activity. Reduced glutathione (GSH), N-acetylcysteine and cysteine (3.2 ± 0.4, 2.0 ± 0.3, 1.6 ± 0.2 µmol/mg/h/mM; p

In humans, low serum carnosinase (CN1) activity protects patients with type 2 diabetes from diabetic nephropathy. We now characterized the interaction of thiol-containing compounds with CN1 cysteine residue at position 102, which is important for CN1 activity. Reduced glutathione (GSH), N-acetylcysteine and cysteine (3.2 ± 0.4, 2.0 ± 0.3, 1.6 ± 0.2 µmol/mg/h/mM;p < .05) lowered dose-dependently recombinant CN1 (rCN1) efficiency (5.2 ± 0.2 µmol/mg/h/mM) and normalized increased CN1 activity renal tissue samples of diabetic mice. Inhibition was allosteric. Substitution of rCN1 cysteine residues at position 102 (Mut1C102S) and 229 (Mut2C229S) revealed that only cysteine-102 is influenced by cysteinylation. Molecular dynamic simulation confirmed a conformational rearrangement of negatively charged residues surrounding the zinc ions causing a partial shift of the carnosine ammonium head and resulting in a less effective pose of the substrate within the catalytic cavity and decreased activity. Cysteine-compounds influence the dynamic behaviour of CN1 and therefore present a promising option for the treatment of diabetes. [ABSTRACT FROM PUBLISHER]

Résumé Le programme hospitalier de recherche clinique (PHRC) Oligopelvis 2 est basé sur l’hypothèse que la radiothérapie pelvienne de rattrapage pourrait prolonger l’intervalle entre une première et une deuxième séquence d’hormonothérapie intermittente chez des patients atteints d’oligométastases ganglionnaires pelviennes d’un cancer de la prostate. Il s’agit étude de phase 3 qui comparera une hormonothérapie intermittente (bras standard) et la même hormonothérapie avec une radiothérapie pelvienne extensive de rattrapage (bras expérimental). The Oligopelvis 2 studies is based on the assumption that salvage pelvic radiotherapy may prolong the interval between the first and the second intermittent hormone therapy sequence in pelvic lymph node oligometastatic prostate cancer. This phase 3 study will compare intermittent hormone therapy (standard arm) alone or combined with salvage pelvic radiotherapy (experimental arm). [ABSTRACT FROM AUTHOR]

Abstract: Background: We reported an association of a particular allele of the carnosinase (CNDP1 Mannheim) gene with reduced serum carnosinase (CN1) activity and absence of nephropathy in diabetic patients. Carnosine protects against the adverse effects of high glucose levels but serum carnosine concentration was generally low. Methods: We measured the concentration of two further histidine dipeptides, anserine and homocarnosine, via HPLC. CN1 activity was measured fluorometically and for concentration we developed a capture ELISA. Results: We found an association between the CNDP1 Mannheim allele and reduced serum CN1 activity for all three dipeptides but no correlation to serum concentrations although anserine and homocarnosine inhibited carnosinase activity. Patients with liver cirrhosis have low CN1 activity (0.24±0.17μmol/ml/h, n =7 males; normal range: 3.2±1.1, n =104; p <0.05) and CN1 concentrations (2.3±1.5μg/ml; normal range: 24.9±8.9, p <0.05) but surprisingly, histidine dipeptide concentrations in serum are not increased compared to controls. Conclusions: Serum histidine dipeptide concentrations are not correlated to CN1 activity. The protective effect of low CN1 activity might be related either to turnover of CN1 substrates or a protective function of dipeptides might be localized in other tissues. [Copyright &y& Elsevier]

Activity of carnosinase (CN1), the only dipeptidase with substrate specificity for carnosine or homocarnosine, varies greatly between individuals but increases clearly and significantly with age. Surprisingly, the lower CN1 activity in children is not reflected by differences in CN1 protein concentrations. CN1 is present in different allosteric conformations in children and adults since all sera obtained from children but not from adults were positive in ELISA and addition of DTT to the latter sera increased OD450 values. There was no quantitative difference in the amount of monomeric CN1 between children and adults. Further, CN1 activity was dose dependently inhibited by homocarnosine. Addition of 80 μM homocarnosine lowered Vmax for carnosine from 440 to 356 pmol/min/μg and increased Km from 175 to 210 μM. The estimated Ki for homocarnosine was higher (240 μM). Homocarnosine inhibits carnosine degradation and high homocarnosine concentrations in cerebrospinal fluid (CSF) may explain the lower carnosine degradation in CSF compared to serum. Because CN1 is implicated in the susceptibility for diabetic nephropathy (DN), our findings may have clinical implications for the treatment of diabetic patients with a high risk to develop DN. Homocarnosine treatment can be expected to reduce CN1 activity toward carnosine, resulting in higher carnosine levels. [ABSTRACT FROM AUTHOR]

Résumé Les cancers de prostate avec métastases ganglionnaires pelviennes inaugurales représentent une proportion faible de l’ensemble des cancers de prostate pour lesquels peu de données prospectives sont disponibles. Néanmoins, la plupart des données rétrospectives ou de cohorte sont nettement en faveur d’une place pour l’association de radiothérapie et d’hormonothérapie dans cette situation clinique. Seules des études prospectives randomisées permettraient de mieux préciser les modalités d’administration de la radiothérapie (dose totale ? fractionnement ? volume ?) et de l’hormonothérapie (place des hormonothérapies de nouvelle génération ? durée ?). Node-positive prostate cancer patients represent a small proportion of all prostate cancers for whom limited prospective information is available. Most retrospective or cohort data strongly suggest however that radiotherapy combined with androgen-depriving therapies is the preferable treatment in this setting. Only randomized clinical trials would be able to better define both radiotherapy (dose? volume? fractionation?) and androgen-depriving therapies (duration? role of novel androgen-depriving therapy?) modalities. [ABSTRACT FROM AUTHOR]

Carnosinase 1 (CN1) is encoded by the Cndp1 gene and degrades carnosine and anserine, two natural histidine-containing dipeptides. In vitro and in vivo studies suggest carnosine- and anserine-mediated protection against long-term sequelae of reactive metabolites accumulating, e.g., in diabetes mellitus. We have characterized the metabolic impact of CN1 in 11- and 55-week-old Cndp1-knockout (Cndp1-KO) mice and litter-matched wildtypes (WT). In Cndp1-KO mice, renal carnosine and anserine concentrations were gender-specifically increased 2- to 9-fold, respectively in the kidney and both most abundant in the renal cortex, but remained unchanged in all other organs and in serum. Renal oxidized/reduced glutathione concentrations, renal morphology and function were unaltered. In Cndp1-KO mice at week 11, renal asparagine, serine and glutamine levels and at week 55, renal arginine concentration were reduced. Renal heat-shock-protein 70 (Hspa1a/b) mRNA declined with age in WT but not in Cndp1-KO mice, transcription factor heat-shock-factor 1 was higher in 55-week-old KO mice. Fasting blood glucose concentrations decreased with age in WT mice, but were unchanged in Cndp1-KO mice. Blood glucose response to intraperitoneal insulin was gender- but not genotype-dependent, the response to intraperitoneal glucose injection was similar in all groups. A global Cndp1-KO selectively, age- and gender-specifically, increases renal carnosine and anserine concentrations, alters renal amino acid- and HSP70 profile and modifies systemic glucose homeostasis. Increase of the natural occurring carnosine and anserine levels in the kidney by modulation of CN1 represents a promising therapeutic approach to mitigate or prevent chronic kidney diseases such as diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Node-positive prostate cancer patients represent a small proportion of all prostate cancers for whom limited prospective information is available. Most retrospective or cohort data strongly suggest however that radiotherapy combined with androgen-depriving therapies is the preferable treatment in this setting. Only randomized clinical trials would be able to better define both radiotherapy (dose? volume? fractionation?) and androgen-depriving therapies (duration? role of novel androgen-depriving therapy?) modalities., (Copyright © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Objective: The aim of this study was to analyze clinicopathological backgrounds and prognosis of clinical N1 non-small cell lung cancer and clarify the difference between bulky and non-bulky cN1 diseases., Methods: We reviewed 110 patients with completely resected cN1 non-small cell lung cancer and examined the prognostic impact of lymph node size. We classified the swollen lymph nodes into two groups based on their size on chest computed tomography: short-axis diameter ≥20 mm (=bulky group) or <20 mm (=non-bulky group)., Results: The bulky group consisted of 10 patients, and the non-bulky group comprised 100 patients. There was no significant difference in the upstaging rate to pathological N2 between the bulky and non-bulky groups (31% vs. 30%; P = 0.63). The 5-year recurrence-free survival rate and 5-year overall survival rate of both groups did not differ significantly (P = 0.36, P = 0.30, respectively). Our results suggested the possibility that the size of the swollen lymph nodes had no impact on the prognosis in cN1 non-small cell lung cancer patients. In comparison of surgical procedure, pneumonectomy was performed in the bulky group more frequently than the non-bulky group (70% vs. 19%; P < 0.01)., Conclusions: Bulky cN1 disease was not different from non-bulky disease in the prognosis and the upstaging rate to pN2. Curative resection should be indicated to resectable bulky cN1 disease as with non-bulky disease, with careful pre-operative evaluation and preparation considering the possibility of pneumonectomy., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)