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Major depressive disorder (MDD) is a debilitating mental disorder that can be treated with a number of different antidepressant therapies, each with its own unique prescribing considerations. Complicating the selection of an appropriate antidepressant for adults with MDD is the heterogeneity of clinical profiles and depression subtypes. Additionally, patient comorbidities, preferences, and likelihood of adhering to treatment must all be considered when selecting an appropriate therapy. With the majority of prescriptions being written by primary care practitioners, it is appropriate to review the unique characteristics of all available antidepressants, including safety considerations. Prior to initiating antidepressant treatment and when patients do not respond adequately to initial therapy and/or exhibit any hypomanic or manic symptoms, bipolar disorder must be ruled out, and evaluation for psychiatric comorbidities must be considered as well. Patients with an inadequate response may then require a treatment switch to another drug with a different mechanism of action, combination, or augmentation strategy. In this narrative review, we propose that careful selection of the most appropriate antidepressant for adult patients with MDD based on their clinical profile and comorbidities is vital for initial treatment selection.Strategies must be considered for addressing partial and inadequate responses as well to help patients achieve full remission and sustained functional recovery. This review also highlights data for MDD clinical outcomes for which gaps in the literature have been identified, including the effects of antidepressants on functional outcomes, sleep disturbances, emotional and cognitive blunting, anxiety, and residual symptoms of depression.

Significance: Emerging evidence suggests that perivascular adipose tissue (PVAT) has a relevant role in the control of vascular tone in physiology and pathology. Healthy PVAT has anticontractile, anti-inflammatory, and antioxidative actions. Accumulating data from both human and experimental animal models indicate that PVAT dysfunction is conceivably coupled to cardiovascular diseases, and it is associated with vascular inflammation, oxidative stress, and arterial remodeling. Therefore, "healthy" PVAT may constitute a novel therapeutic target for the prevention and treatment of cardiovascular diseases. Recent Advances: Hydrogen sulfide (H 2 S) has been recognized as a vascular anti-contractile factor released from PVAT. The enzymes deputed to H 2 S biosynthesis are variously expressed in PVAT and strictly dependent on the vascular bed and species. Metabolic and cardiovascular diseases can alter the morphological and secretory characteristics of PVAT, influencing also the H 2 S signaling. Here, we discuss the role of PVAT-derived H 2 S in healthy conditions and its relevance in alterations occurring in vascular disorders. Critical Issues: We discuss how a better understanding may help in the prevention of vascular dysfunction related to alteration in PVAT-released H 2 S as well as the importance of the interplay between PVAT and H 2 S. Future Directions: We propose future directions to evaluate the contribution of each enzyme involved in H 2 S biosynthesis and their alteration/switch occurring in vascular disorders and the remaining challenges in investigating the role of H 2 S. Antioxid. Redox Signal . 37, 84-97.

Sarcopenia is a gradual and generalized skeletal muscle (SKM) syndrome, characterized by the impairment of muscle components and functionality. Hydrogen sulfide (H 2 S), endogenously formed within the body from the activity of cystathionine-γ-lyase (CSE), cystathionine- β-synthase (CBS), and mercaptopyruvate sulfurtransferase, is involved in SKM function. Here, in an in vitro model of sarcopenia based on damage induced by dexamethasone (DEX, 1 μM, 48 h treatment) in C2C12-derived myotubes, we investigated the protective potential of exogenous and endogenous sources of H 2 S, i.e., glucoraphanin (30 μM), L-cysteine (150 μM), and 3-mercaptopyruvate (150 μM). DEX impaired the H 2 S signalling in terms of a reduction in CBS and CSE expression and H 2 S biosynthesis. Glucoraphanin and 3-mercaptopyruvate but not L-cysteine prevented the apoptotic process induced by DEX. In parallel, the H 2 S-releasing molecules reduced the oxidative unbalance evoked by DEX, reducing catalase activity, O 2 - levels, and protein carbonylation. Glucoraphanin, 3-mercaptopyruvate, and L-cysteine avoided the changes in myotubes morphology and morphometrics after DEX treatment. In conclusion, in an in vitro model of sarcopenia, an impairment in CBS/CSE/H 2 S signalling occurs, whereas glucoraphanin, a natural H 2 S-releasing molecule, appears more effective for preventing the SKM damage. Therefore, glucoraphanin supplementation could be an innovative therapeutic approach in the management of sarcopenia.

Primary care clinicians have a vital role to play in the diagnosis and management of patients with major depressive disorder (MDD). This includes screening for MDD as well as identifying other possible psychiatric disorders including bipolar disorder and/or other comorbidities. Once MDD is confirmed, partnering with patients in the shared decision-making process while considering different treatment options and best management of MDD over the course of their illness is recommended. Vortioxetine has been approved for the treatment of adults with MDD since 2013, and subsequent US label updates indicate that vortioxetine may be particularly beneficial for specific populations of patients with MDD, including those with treatment-emergent sexual dysfunction and patients experiencing certain cognitive symptoms. Given these recent label updates, this prescribing guide for vortioxetine aims to provide clear and practical guidance for primary care clinicians on the safe and effective use of vortioxetine for the treatment of MDD, including how to identify appropriate patients for treatment., Competing Interests: C. Brendan Montano has received consulting fees from AbbVie, Acadia, Alkermes, Arbor, Eisai, Neos, Novo Nordisk, Otsuka, Sunovion, Supernus, and Takeda, and has also received payment/honoraria from AbbVie, Arbor, Eisai, Otsuka, and Takeda. W. Clay Jackson has received consulting fees and payment/honoraria from AbbVie, Alkermes, Genentech, Otsuka, and Sunovion; has received honoraria from AbbVie, Alkermes, Genentech, Otsuka, and Sunovion for attending meetings and/or travel; and has participated on a data safety monitoring board or advisory board for AbbVie, Alkermes, Genentech, Otsuka, and Sunovion. Denise Vanacore has received payments/honoraria from AbbVie. Richard Weisler has received grants or contracts from Allergan, Alkermes, Astellas, Axsome Therapeutics, Ironshore, Janssen, Lundbeck, Major League Baseball (MLB), Neos Therapeutics, Otsuka America Pharmaceuticals, Sirtsei Pharmaceuticals, Shire, Supernus Pharmaceuticals, Takeda, and Validus. The authors report no other conflicts of interest in this work., (© 2022 Montano et al.)

Introduction: We aimed to report the oncological outcomes of ESRD patients with histories of urological malignancies who were subsequently submitted to kidney transplantation (KT)., Material and Method: Retrospective study lead in the Puigvert Foundation (Barcelona) registry of 1,200 KT performed from 1988 to 2018. Eighty-five urological malignancies that were treated before KT in 81 patients were identified: 15 (18%) prostate cancers, 49 (58%) RCC, 19 (22%) urothelial carcinomas and 2 (2%) testicular cancers. Baseline characteristics, cancer staging, treatment and follow-up were registered as well as the chronology of the start of dialysis, inscription on the waiting list and kidney transplantation. Endpoints included were cancer recurrence, metastatic progression, cancer-specific death and overall survival., Results: In a median follow-up of 13.1 years (2.2-32), 16/85 (19%) cancer recurrences were reported, with 3 (4%) who progressed to metastasis and died of cancer. Median overall survival after cancer treatment was 25.3 years and cancer-specific survival was 95% at 25 years. Median time from cancer treatment to kidney transplantation was 4.8 years: 3.7 years in prostate cancer, 3.9 years in RCC and 8.8 years in bladder cancer. The median time from start of dialysis to kidney transplantation was 1.8 years in patients with histories of urological malignancy versus 0.5 year in the total cohort of 1,200 renal transplanted over the same period., Conclusions: Well-selected patients with histories of urological malignancies greatly benefit from kidney transplantation with infrequent and late cancer recurrence. Waiting time could be optimized in low-risk prostate cancer and RCC, but more robust data are needed., (Copyright © 2021 AEU. Published by Elsevier España, S.L.U. All rights reserved.)

Objectives: To compare the detection rate of Bacillus Calmette-Guérin (BCG) refractory tumors between white light cystoscopy (WL-C) and Photodynamic Diagnosis cystoscopy (PDD-C). Materials and Methods: We performed a monocentric retrospective study that included all consecutive patients with high-risk nonmuscle-invasive bladder cancer (NMIBC) diagnosed from January 2017 to January 2021. All patients had an initial transurethral resection of bladder tumor (TURBT) with photodynamic diagnosis ± restaging TURBT if needed, followed by full-dose BCG induction. Within 8 weeks following BCG induction, all patients had both WL-C and PDD-C under general anesthesia ± TURBT in case of suspicious lesion. The primary end point was the detection of bladder cancer (BC) at post-BCG cystoscopy. Results: A total of 136 consecutive patients met inclusion criteria. Initial BC characteristics were: 35.6% of T1 tumor, 92.6% high grade, and 48.6% associated CIS. BC was diagnosed in 33/136 cases (24%) at early PDD-C after BCG induction: 77% Ta, 23% T1, 56% associated CIS, 68% high grade, and 6% muscle-invasive bladder cancer. Sensibility and Specificity of WL-C and PDD-C: 41% vs 91% ( p  < 0.001) and 86% vs 75% ( p  = 0.001). PDD-C detected 16 additional tumors: 81.3% Ta, 18.7% T1, 75% associated CIS, and 75% high grade. Conclusions: Systematic use of PDD after BCG induction increased the detection of BCG-refractory tumors and led to significant modification in the treatment of high-risk NMIBC. Future studies are needed to evaluate long-term oncologic benefit of early PDD reevaluation and its cost-effectiveness.

Introduction: Appropriate risk stratification and complete tumor ablation are the key factors to optimize the oncologic outcomes of patients undertaking endoscopic management for upper urinary tract urothelial carcinoma (UTUC). We aimed to identify risk factors associated to tumor recurrence and progression in a contemporary cohort of patients diagnosed and treated with the latest endourologic technologies. Patients and Methods: Forty-seven patients were selected between January-2015 and March-2019 for an endoscopic management of UTUC. Last generation of digital ureteroscopes with image-enhancing technologies were used for the detection of the lesions. The retrograde approach was the most frequent access ( n  = 45/47). The confocal laser endomicroscopy and multiple biopsy devices were variably used according to site and tumor presentation for their characterization. Holmium and Thulium lasers were variably used, with their combination being the preferred approach in case of larger lesions. Primary endpoints included the identification of factors associated with UTUC recurrence and progression, and bladder tumor recurrence. Results: Median follow-up (FU) was 24 months (interquartile range 17-44). On multivariate analysis, bladder cancer (BC) recurrence was associated to previous contralateral UTUC (hazard ratios: 5.08 confidence interval [95% CI: 1.35-18.94], p  < 0.05) and tumor size (hazard ratios: 1.07 [95% CI: 1.00-1.14], p  < 0.05). UTUC recurrence was associated to incomplete clearance after primary treatment (hazard ratios: 4.99 [95% CI: 1.15-21.62], p  < 0.05), while UTUC progression was significantly related to the number of UTUC recurrences (hazard ratios: 3.10 [95% CI: 1.27-7.53], p  < 0.05). No significant survival differences in BC/UTUC recurrence, as well as in UTUC progression, were detected between risk groups. No Clavien-Dindo grade >2 were detected; one patient developed ureteric stricture at 7-month FU. Limitations involve retrospective nature of the study and relatively small number of patients. Conclusions: The appropriate use of latest technology may enhance the oncologic outcomes of the endoscopic management of UTUC without compromising the safety of the approach. Among the prognostic factors identified in our series, UTUC recurrence seems to be associated to disease progression.

Background and Purpose: l-cysteine or hydrogen sulfide (H 2 S) donors induce a biphasic effect on precontracted isolated vessels. The contractile effect occurs within a concentration range of 10 nM to 3 μM followed by vasodilatation at 30-100 μM. Here, we have investigated the signalling involved in the H 2 S-induced contraction., Experimental Approach: Vascular response to NaHS or l-cysteine is evaluated on isolated precontracted with phenylephrine vessel rings harvested from wild type, cystathionine γ-lyase (CSE -/- ), soluble guanylyl cyclase (sGC α1 -/- ) and endothelial nitric oxide synthase (eNOS -/- ) knock-out mice. The cAMP, cGMP and inosine 3',5'-cyclic monophosphate (cIMP) levels are simultaneously quantified using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. The involvement of sGC, phosphodiesterase (PDE) 4A and PDE5 are also evaluated., Key Results: CSE-derived H 2 S-induced contraction requires an intact eNOS/NO/sGC pathway and involves cIMP as a second messenger. H 2 S contractile effect involves a transient increase of cGMP and cAMP metabolism caused by PDE5 and PDE4A, thus unmasking cIMP contracting action. The stable cell-permeable analogue of cIMP elicits concentration-dependent contraction on a stable background tone induced by phenylephrine. The lack of cIMP, coupled to the hypocontractility displayed by vessels harvested from CSE -/- mice, confirms that H 2 S-induced contraction involves cIMP., Conclusion and Implications: The endothelium dynamically regulates vessel homeostasis by modulating contractile tone. This also involves CSE-derived H 2 S that is mediated by cIMP., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objective: To evaluate the long-term oncological and functional results of the ablative treatment of T1a kidney malignancies by percutaneous radiofrequency (RF)., Materials and Methods: Monocentric retrospective study including all patients treated for renal cell carcinoma (RCC) T1a by radiofrequency, in our center, from 2005 to 2009. All patients had a tumor biopsy before treatment. The primary endpoint was local recurrence. A total of 44 RCCs in 41 consecutive patients were treated (1 patient had 3 synchronous tumors and 1 patient had 2 tumors). There were 26 clear cell RCCs, 13 papillary RCCs and 5 chromophobe RCCs. The median age at diagnosis was 70 years [48-82]. The median American Society of Anesthesiologists (ASA) score was 2 [1-3] and the median glomerular filtration rate (GFR) was 64mL/min [26-109]. Furhman grade was defined for 39 tumors (Clear cell RCC and papillary RCC), of which 82% were grade 1-2. The median tumor size was 20mm [11-40], and the median RENAL score was 4 [4-6]. Complications were assessed according to the Clavien-Dindo classification. Overall survival, recurrence-free survival and metastasis-free survival were calculated using the Kaplan-Meier method., Results: Median follow-up was 90.5 months [17.8-145.3]. Three (7%) local recurrences were reported within a median of 26 months [12-93]. All were treated by a 2nd RF. The overall 10-year survival was 70% (95% CI [56-85]). The 10-year recurrence-free survival was 72% (95% CI [57-88]). The 10-year metastasis-free survival was 87% (95% CI [74-97]). The median GFR on the date of the last news was 51mL/min [16-98] (P=0.05). Post-RFA complications consisted in 5 (11.3%) Clavien-Dindo 1-2 complications. No high grade (Clavien ≥3)., Conclusion: Percutaneous radiofrequency for RCC T1a is an alternative. It appears to be safe with low morbidity, satisfaying long-term oncological and functional results, but a risk of reprocessing of 7%., Level of Evidence: 3., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The emergence of pan-resistant strains in nosocomial settings underscores the urgent need of novel therapies targeting vital bacterial functions. Bacterial iron metabolism is a fascinating target for new antimicrobials. Iron mimetic metal Ga(III) has been repurposed as an antimicrobial drug, in pre-clinical studies and recent clinical studies have raised the possibility of using Ga(III) for the treatment of P. aeruginosa pulmonary infection. Ga(III) has been approved by FDA for the treatment of cancer, autoimmune and bone resorption disorders. However, some critical issues affect the therapeutic schedule of Ga(III), principally the intra-venous (i.v.) administration, and the nephrotoxicity caused by prolonged administration. Ga(III) aerosolization could represent a viable alternative for treatment of lung infections, since delivery of antimicrobial agents to the airways maximizes drug concentration at the site of infection, improves the therapeutic efficacy, and alleviates systemic toxic effects. We demonstrate the advantage of inhaled vs i.v. administered Ga(III), in terms of bio-distribution and lung acute toxicity, by using a rat model. In vivo results support the use of Ga(III) for inhalation since intra-tracheal Ga(III) delivery improved its persistence in the lung, while the i.v. administration caused rapid clearance and did not allow to attain a significant Ga(III) concentration in this organ. Moreover, local and systemic acute toxicity following intra-tracheal administration was not observed, since no significant signs of inflammation were found. At this stage of evidence, the direct administration of Ga(III) to the lung appears feasible and safe, boosting the development of Ga(III)-based drugs for inhalation therapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To assess the efficacy of the combination of Tadalafil 5 mg and nutritional supplements composed by Panax ginseng, Moringa Oleifera and Rutin on erectile function in men with mild and moderate vasculogenic ED., Methods: we prospectively enrolled 86 patients divided into two groups A (45), B (33) in this multicenter randomized, doubleblind, placebo-controlled trial . Drop out was 8 patients (3 patients in group A and 5 in Group B). At screening visit patients underwent clinical examination, blood test (hormonal and metabolic profile) and filled out the IIEF-5 questionnaire and the SEP-2, SEP-3. Patients were randomized by a computergenerated list to receive either Tadalafil 5 mg once daily plus nutritional supplement once daily (group A) or Tadalafil 5 mg plus placebo with the same administration schedule (group B) for 3 months. Blood samples, IIEF-5, SEP-2 and SEP-3 have been collected again after 3 months. cGMP was measured in platelets of 38 patients at baseline and after one months., Results: Mean age was 59.98 ± 6.90 (range 38-69), mean IIEF-5 score at baseline was 13.59 ± 3.90. After three months of treatment, IIEF-5 score significantly improved in both groups compared to baseline (13.18 ± 3.75 vs 20.48 ± 2.24, p < 0.0001; 14.15 ± 4.09 vs 19.06 ± 4.36, p < 0.0001, in group A and group B respectively). Patients treated with Tadalafil plus nutritional supplement showed a significantly higher increase in IIEF-5 score compared to those who received placebo (7.27 ± 2.20 and 4.9 ± 2.79, respectively; p < 0.0001;). No hormonal differences and metabolic effects were found. According cGMP result, nutritional supplements ameliorates and extends the activity of the chronic treatment., Conclusions: IIEF-5 significant increase in group B, can be ascribed to the nutritional supplement properties and antioxidant effects of moringa oleifera, ginseng and rutin and this can enhance the endothelial NO and cGMP production.

Introduction: We aimed to report the oncological outcomes of ESRD patients with histories of urological malignancies who were subsequently submitted to kidney transplantation (KT)., Material and Method: Retrospective study lead in the Puigvert Foundation (Barcelona) registry of 1,200 KT performed from 1988 to 2018. Eighty-five urological malignancies that were treated before KT in 81 patients were identified: 15 (18%) prostate cancers, 49 (58%) RCC, 19 (22%) urothelial carcinomas and 2 (2%) testicular cancers. Baseline characteristics, cancer staging, treatment and follow-up were registered as well as the chronology of the start of dialysis, inscription on the waiting list and kidney transplantation. Endpoints included were cancer recurrence, metastatic progression, cancer-specific death and overall survival., Results: In a median follow-up of 13.1 years (2.2-32), 16/85 (19%) cancer recurrences were reported, with 3 (4%) who progressed to metastasis and died of cancer. Median overall survival after cancer treatment was 25.3 years and cancer-specific survival was 95% at 25 years. Median time from cancer treatment to kidney transplantation was 4.8 years: 3.7 years in prostate cancer, 3.9 years in RCC and 8.8 years in bladder cancer. The median time from start of dialysis to kidney transplantation was 1.8 years in patients with histories of urological malignancy versus 0.5 year in the total cohort of 1,200 renal transplanted over the same period., Conclusions: Well-selected patients with histories of urological malignancies greatly benefit from kidney transplantation with infrequent and late cancer recurrence. Waiting time could be optimized in low-risk prostate cancer and RCC, but more robust data are needed., (Copyright © 2021 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.)

It is well-known that the physiological uterine peristalsis, related to several phases of reproductive functions, plays a pivotal role in fertility and female reproductive health. Here, we have addressed the role of hydrogen sulfide (H 2 S) signaling in changes of uterine contractions driven by diabetes in non-obese diabetic (NOD) mice, a murine model of type-1 diabetes mellitus. The isolated uterus of NOD mice showed a significant reduction in spontaneous motility coupled to a generalized hypo-contractility to uterotonic agents. The levels of cyclic nucleotides, cAMP and cGMP, notoriously involved in the regulation of uterus homeostasis, were significantly elevated in NOD mouse uteri. This increase was well-correlated with the higher levels of H 2 S, a non-specific endogenous inhibitor of phosphodiesterases. The exposure of isolated uterus to L-cysteine (L-Cys), but not to sodium hydrogen sulfide, the exogenous source of H 2 S, showed a weak tocolytic effect in the uterus of NOD mice. Western blot analysis revealed a reorganization of the enzymatic expression with an upregulation of 3-mercaptopyruvate-sulfurtransferase (3-MST) coupled to a reduction in both cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) expression. In conclusion, the increased levels of cyclic nucleotides dysregulate the uterus peristalsis and contractility in diabetic mice through an increase in basal H 2 S synthesis suggesting a role of 3-MST.

Background: Recently, robot-assisted kidney transplantation (RAKT) was recently introduced as renal replacement mini-invasive surgery., Objective: To report surgical technique, including tips and tricks, and the learning curve for RAKT., Design, Setting, and Participants: All consecutive RAKTs performed in the five highest-volume centers of the European Robotic Urological Society RAKT group were reviewed, and a step-by-step description of the technique was compiled., Surgical Procedure: Surgeries were performed with Da Vinci Si/Xi. The patient was placed in the lithotomy position. The Trendelenburg position was set at 20-30° and the robot was docked between the legs., Measurements: Shewhart control charts and cumulative summation (CUSUM) graphs and trifecta were generated to assess the learning curve according to rewarming time (RWT), intra/postoperative complications, and renal graft function (glomerular filtration rate) on days 7 and 30, and at 1 yr. Linear regressions were performed to compare the learning curves of each surgeon., Results and Limitations: Arterial anastomosis time was below the alarm/alert line in 93.3%/88.9% of RAKTs, while venous anastomosis time was below the alarm/alert line in 88.9%/73.9%. The nonanastomotic RWT exceeded +3 standard deviation (SD) in 24.7% of procedures and +2SD in 37.1%. In only 46% cases, the RWT was below the alert line. The ureteroneocystostomy time was below +2SD and +3SD in 87.9% and 90.2% of cases, respectively. CUSUM showed that the learning curve for arterial anastomosis required up to 35 (mean = 16) cases. Complications and delayed graft function rates decreased significantly and reached a plateau after the first 20 cases. Trifecta was achieved in 75% (24/32) of the cases after the first 34 RAKTs in each center., Conclusions: A minimum of 35 cases are necessary to reach reproducibility in terms of RWT, complications, and functional results., Patient Summary: Robot-assisted kidney transplantation requires a learning curve of 35 cases to achieve reproducibility in terms of timing, complications, and functional results. Synergy between the surgeon and the assistant is crucial to reduce rewarming time. High-grade complications and delayed graft function are rare after ten surgeries. Hands-on training and proctorship are highly recommended., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: To compare oncological, functional and post-operative outcomes of hemi (HC) vs. whole gland (WGC) cryoablation as first line treatment of localized prostate cancer., Material and Method: Sixty-six consecutive patients undertaking whole-gland cryoablation (WGC=40) or hemi-cryoablation (HC=26) in a tertiary referral centre between 2010 and 2018 were included. All patients had a low-intermediate risk prostate cancer according to D'Amico risk classification. Hemi-ablation was proposed in case of biopsy and prostate MRI proven unilateral prostate cancer. Primary endpoint was Cryotherapy Failure for which 3 definitions were considered and compared: 1) biochemical failure (> PSA nadir+≥ 2 ng/mL), 2) positive prostate re-biopsy with Gleason score ≥ 7, 3) initiation of further prostate cancer treatment., Results: Median patients age at treatment was 74 [42-81] vs. 76 [71-80] years in WGC vs. HC group, respectively (p=.08). Low and intermediate D'Amico risk group were 15% and 85% vs. 23% and 77% (p=.75), respectively. Median follow- up time was 41 [1.5-99.0] vs. 27 [0.9-93] months (p=.03). Four-years cryotherapy failure free survival in WGC vs. HC were 69% vs. 53% with definition 1 (p=.24), 82% vs. 80% with definition 2 (p=.95), 83% vs. 77% with definition 3 (p=.73). Early and 1-year urinary continence were 60% and 83% in WGC vs. 72% and 83% in HC (p=.26). De novo impotency after cryotherapy was 75% vs. 46% (p=.33) in WGC vs. HC., Conclusions: In our cohort of highly selected patients with unilateral low/intermediate risk PCa, hemi-cryoablation may provide similar oncological outcomes and less early complications compared to whole-gland cryoablation., (Copyright © 2019 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: The Graduate Nurse Education (GNE) Demonstration seeks to increase the number of advanced practice registered nurses (APRNs) in clinical practice. With the overall increase in APRN programs and, particularly, enrollment in nurse practitioner (NP) programs, there is growing competition among students to secure quality clinical precepting experiences., Purpose: This study describes NPs' and physicians' experiences with precepting APRN students within the Greater Philadelphia GNE Consortium., Methods: This was a cross-sectional descriptive survey of 1,021 NP and physician preceptors who provided clinical practicum experiences for at least one of the nine Greater Philadelphia GNE Consortium schools., Results: Differences between NP and physician precepting experiences regarding the importance of various factors in their decisions to precept were explored. Both NP and physician preceptors provide clinical practicum experiences to APRN students because they enjoy doing so. However, they differ regarding what they find important in their decisions to precept such as having protected time to precept and educational opportunities., Implications for Practice: As universities work to recruit quality preceptors, they should consider tailoring their approach based on the preceptor's clinical role. In addition, schools located within the same region should consider streamlining administrative processes to form sustaining and productive clinical partnerships.

Primary penile cancer is a rare malignant disease. In most cases, it presents as a clinically obvious lesion leading to early diagnosis in most patients. However, even in developed Countries, it carries a significant social stigma leading to diagnosis at locally advanced stages in a non-negligible proportion of patients. Yet, bulky penile lesions are becoming extremely rare in current clinical practice. We present a case of a patient with a giant primary penile cancer managed with radical penectomy, bilateral inguinal lymphadenectomy and perineal urethrostomy, who experienced disease recurrence six months after surgery and died with metastatic disease after denial of further treatment. The management of our case was challenging due to the extremely late diagnosis, the huge dimensions and the infiltrative nature of the tumor; however, from a histopathological perspective, the cancer itself did not display any microscopic peculiarity. Our case highlights that such bulky penile tumors can still occur in current urologic practice and require complex salvage surgical interventions in the context of a multidisciplinary setting.

Silybin is a flavonolignan extracted from Silybum marianum (milk thistle) with hepatoprotective, antioxidant, and anti-inflammatory activity. Several studies have shown that silybin is highly effective to prevent and treat different types of cancer and that its antitumor mechanisms involve the arrest of the cell cycle and/or apoptosis. An MTT assay was performed to study cell viability, lipid peroxidation, extracellular NO production, and scavenger enzyme activity were studied by Thiobarbituric Acid-Reactive Species (TBARS) assay, NO assay, and MnSOD assay, respectively. Cell cycle and apoptosis analysis were performed by FACS. miRNA profiling were evaluated by real time PCR. In this study, we demonstrated that Silybin induced growth inhibition blocking the Hepg2 cells in G1 phase of cell cycle and activating the process of programmed cell death. Moreover, the antiproliferative effects of silybin were paralleled by a strong increase of the number of ceramides involved in the modulation of miRNA secretion. In particular, after treatment with silybin, miR223-3p and miR16-5p were upregulated, while miR-92-3p was downregulated ( p < 0.05). In conclusion, our results suggest that silybin-Induced apoptosis occurs in parallel to the increase of ceramides synthesis and miRNAs secretion in HepG2 cells.

Cystic nephroma is a benign kidney tumor, which presents as a unilateral cystic mass without solid elements. We presented the first case of cystic nephroma treated with robotic nephron-sparing surgery in a pediatric patient. The procedure adopted was the robot-assisted simple enucleation of the lesion, without arterial clamping., Competing Interests: The authors declare no conflict of interest., (Copyright 2019, Mary Ann Liebert, Inc., publishers.)

Under physiological conditions, the small intestine represents a barrier against harmful antigens and pathogens. Maintaining of the intestinal barrier depends largely on cell⁻cell interactions (adherent-junctions) and cell⁻matrix interactions (tight-junctions). Inflammatory bowel disease is characterized by chronic inflammation, which induces a destructuring of the architecture junctional epithelial proteins with consequent rupture of the intestinal barrier. Recently, a peptide identified by Bubalus bubalis milk-derived products (MBCP) has been able to reduce oxidative stress in intestinal epithelial cells and erythrocytes. Our aim was to evaluate the therapeutic potential of MBCP in inflammatory bowel disease (IBD). We studied the effect of MBCP on (i) inflamed human intestinal Caco2 cells and (ii) dinitrobenzene sulfonic acid (DNBS) mice model of colitis. We have shown that MBCP, at non-cytotoxic concentrations, both in vitro and in vivo induced the adherent epithelial junctions organization, modulated the nuclear factor (NF)-κB pathway and reduced the intestinal permeability. Furthermore, the MBCP reverted the atropine and tubocurarine injury effects on adherent-junctions. The data obtained showed that MBCP possesses anti-inflammatory effects both in vitro and in vivo . These results could have an important impact on the therapeutic potential of MBCP in helping to restore the intestinal epithelium integrity damaged by inflammation.

Bisphenol A (BPA) and silybin are considered xenoestrogens and could interfere with the action of endogenous hormones. It was demonstrated a higher level of BPA in plasma of nonalcoholic steatohepatitis (NASH) patients, compared to those with steatosis (NAFL). We investigated the effect of BPA and silybin, alone or in combination, on proliferation, oxidative stress and steroid metabolism in HepG2 grown in high glucose concentration medium (H-HepG2). Cell viability was assessed by adding 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). TBARS were quantified by spectrophotometry. The effect of BPA, silybin and their combination on the expression of phosphorilized extracellular signal-regulated kinase (ERK), ERK and Caspase 3 was determined by Western blot analysis. The identifications of lipids and steroid hormones was performed by mass spectrometry. BPA elicited in H-HepG2 oxidative stress and steroid hormones oxidation leading to the formation of metabolite with estrogenic and genotoxic potentials. Silybin ameliorates the harmful BPA-induced effect decreasing glucose uptake and lipid peroxidation. Moreover silybin activates the synthesis of vitamin D3 metabolites and prevent the steroid hormones oxidation. BPA could be considered as an important risk factor in worsening and progression of NAFLD. At the same time silybin could be a valid support to counteract these effects in NASH patients.

Background: The aim of this paper is to report the first preliminary experience with intraoperative indocyanine green (ICG) fluorescence videography (IFV) to assess graft and ureteral reperfusion during robot-assisted kidney transplantation (RAKT)., Methods: We prospectively collected data from consecutive patients undergoing RAKT and IFV from living-donors at our Institution between January 2017 and April 2018. RAKT was performed following the principles of the Vattikuti-Medanta technique. ICG was injected intravenously after vascular anastomoses to quantitate graft and ureteral fluorescence signal. The signal intensity within selected intraoperative snapshots was evaluated for renal parenchyma, ureter and vascular anastomoses. A systematic review of the English-language literature about the topic was performed according to the PRISMA statement recommendations., Results: Six patients were included. Neither conversions to open surgery nor major intra- or postoperative complications were recorded. At a median follow-up of 12 months (IQR 8-13), median estimated glomerular filtration rate was 64.2 mL/min/1.73 m2 (IQR 45.3-98.4). Intraoperative quantitative assessment of ICG fluorescence was successful in all patients. Of the five studies selected by our review, mostly prospective studies, all including open KT series. Yet, most studies were limited by lack of quantitative measures of IFV fluorescence., Conclusions: IFV during RAKT is feasible and safe and provides a reliable assessment of graft reperfusion. Larger studies are needed to standardize the technique and to evaluate the association between fluorescence signal, ultrasound parameters and postoperative kidney function.

This study was conceived to evaluate the effects of three different diets on body composition, metabolic parameters, and serum oxidative status. We enrolled three groups of healthy men (omnivores, vegetarians, and vegans) with similar age, weight and BMI, and we observed a significant decrease in muscle mass index and lean body mass in vegan compared to vegetarian and omnivore groups, and higher serum homocysteine levels in vegetarians and vegans compared to omnivores. We studied whether serum from omnivore, vegetarian, and vegan subjects affected oxidative stress, growth and differentiation of both cardiomyoblast cell line H9c2 and H-H9c2 (H9c2 treated with H 2 O 2 to induce oxidative damage). We demonstrated that vegan sera treatment of both H9c2 and H-H9c2 cells induced an increase of TBARS values and cell death and a decrease of free NO 2- compared to vegetarian and omnivorous sera. Afterwards, we investigated the protective effects of vegan, vegetarian, and omnivore sera on the morphological changes induced by H 2 O 2 in H9c2 cell line. We showed that the omnivorous sera had major antioxidant and differentiation properties compared to vegetarian and vegan sera. Finally, we evaluated the influence of the three different groups of sera on MAPKs pathway and our data suggested that ERK expression increased in H-H9c2 cells treated with vegetarian and vegan sera and could promote cell death. The results obtained in this study demonstrated that restrictive vegan diet could not prevent the onset of metabolic and cardiovascular diseases nor protect by oxidative damage., (© 2018 Wiley Periodicals, Inc.)

Oral squamous cell carcinoma (OSCC) is one of the most aggressive and deadliest tumors worldwide. The aryl hydrocarbon receptor (AHR) is a nuclear transcription factor known as a dioxin receptor and mediates the toxic effects of industrial contaminants. In addition, AHR has been implicated in multiple cellular processes and its expression has been shown to play a critical role in tumorigenesis, including human oral cancer cell lines. In the present study, we evaluated the expression of AHR/HSP-90 in 25 formalin‑fixed, paraffin-embedded human oral cancer specimens by IHC analysis. CYP1A1 expression was regarded as an AHR reporter gene. The data indicated a complete correlation between AHR expression and cancer grade enabling us to propose AHR as a prognostic marker of oral cancer. Moreover, in OSCC cell line CAL27, we observed the modulatory effect of polydatin, a widespread natural substance and direct precursor of resveratrol, on AHR expression. A computational approach was performed to predict the site of interaction of polydatin on the AHR surface. Our studies confirm the involvement of AHR signaling in the clinicopathological specimens of oral cancer and suggest the use of polydatin for oral cancer prevention.

Objective: To describe our step-by-step technique for robotic intracorporeal neobladder configuration, including the stages of conception, development and exploration of this surgical innovation, according to the Idea, Development, Exploration, Assessment, Long-term follow-up (IDEAL) Collaboration guidelines., Patients and Methods: The Florence robotic intracorporeal neobladder (FloRIN) was performed employing the following main surgical steps: isolation of 50 cm of ileum; bowel anastomosis; urethro-ileal anastomosis creating an asymmetrical 'U'-shape (30 cm distally and 20 cm proximally to anastomosis), ileum detubularisation; posterior wall reconfiguration as an 'L'; bladder neck reconstruction; anterior folding of the posterior plate to reach the 12 o'clock position; uretero-enteral 'orthotopic' bilateral anastomosis. The conception and development of the FloRIN followed the IDEAL guidelines recommended stages: Phase 1 (simulation) involved the neobladder robotic configuration using silicone models. Phase 2a (development) aimed to reproduce the configuration in an open fashion in one patient, and then in the first three robotic procedures. Phase 2b (exploration) consisted of the technique standardisation in 15 consecutive robotic approaches. Phase 2a and 2b included urodynamics and imaging assessment of the patients treated., Results: From February 2016 to September 2017 FloRIN was performed in 18 patients. Comparing the first three (Phase 2a) with the subsequent 15 patients (Phase 2b), the median (interquartile range [IQR]) reconstruction operating time was 260 (220-340) vs 160 (150-210) min, respectively. Postoperative surgical complications occurred in four of the 18 patients (22.1%), including one surgical Clavien-Dindo Grade III and three Grade I, postoperative medical Clavien-Dindo Grade II complications occurred in three (16.7%) patients. On urodynamic examination (available in nine [50%] patients) the median (IQR) reservoir cystometric capacity, compliance, and post-void residual were 240 (220-267) mL, 18 (12.5-19.8) mL/cmH 2 O, and 0 (0-50) mL, respectively. Ultrasonography showed no Grade ≥2 vesico-ureteric reflux., Conclusion: We describe the FloRIN configuration, showing its technical feasibility with acceptable time efficiency. The first cases studied had good reservoir capacity, low pressure with no reflux, and complete voiding., (© 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.)

[This corrects the article DOI: 10.18632/oncotarget.16725.].

Testicular cancer (TC) is one of the most common neoplasms that occurs in male and includes germ cell tumors (GCT), sex cord-gonadal stromal tumors and secondary testicular tumors. Diagnosis of TC involves the evaluation of serum tumor markers alpha-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase, but clinically several types of immunohistochemical markers are more useful and more sensitive in GCT, but not in teratoma. These new biomarkers are genes expressed in primordial germ cells/gonocytes and embryonic pluripotency-related cells but not in normal adult germ cells and they include PLAP, OCT3/4 (POU5F1), NANOG, SOX2, REX1, AP-2γ (TFAP2C) and LIN28. Gene expression in GCT is regulated, at least in part, by DNA and histone modifications, and the epigenetic profile of these tumours is characterised by genome-wide demethylation. There are different epigenetic modifications in TG-subtypes that reflect the normal developmental switch in primordial germ cells from an under- to normally methylated genome. The main purpose of this review is to illustrate the findings of recent investigations in the classification of male genital organs, the discoveries in the use of prognostic and diagnostic markers and the epigenetic aberrations mainly affecting the patterns of DNA methylation/histone modifications of genes (especially tumor suppressors) and microRNAs (miRNAs)., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Prostate cancer is the second highest cause of cancer mortality after lung tumours. In USA it affects about 2.8 million men and the incidence increases with age in many countries. Therefore, early diagnosis is a very important step for patient clinical evaluation and for a selective and efficient therapy. The study of miRNAs' functions and molecular mechanisms has brought new knowledge in biological processes of cancer. In prostate cancer there is a deregulation of several miRNAs that may function as tumour suppressors or oncogenes. The aim of this review is to analyze the progress made to our understanding of the role of miRNA dysregulation in prostate cancer tumourigenesis.

Sorafenib is an antitumor drug for treatment of advanced hepatocellular carcinoma (HCC). It acts as a multikinase inhibitor suppressing cell proliferation and angiogenesis. Human microRNA-125a-5p (miR-125a) is endowed with similar activities and is frequently downregulated in HCC. Looking for a potential microRNA-based mechanism of action of the drug, we found that sorafenib increases cellular expression of miR-125a in cultured HuH-7 and HepG2 HCC cells. Upregulation of the microRNA inhibited cell proliferation by suppression of sirtuin-7, a NAD(+)-dependent deacetylase, and p21/p27-dependent cell cycle arrest in G1. Later, recruitment of miR-125a in the antiproliferative activity of sorafenib was inquired by modulating its expression in combination with the drug treatment. This analysis showed that intracellular delivery of miR-125a had no additive effect on the antiproliferative activity of sorafenib, whereas a miR-125a inhibitor could counteract it. Finally, evaluation of other oncogenic targets of miR-125a revealed its ability to interfere with the expression of matrix metalloproteinase-11, Zbtb7a proto-oncogene, and c-Raf, possibly contributing to the antiproliferative activity of the drug. J. Cell. Physiol. 232: 1907-1913, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Prostate cancer is a main urological disease associated with significant morbidity and mortality. Radical prostatectomy and radiotherapy are potentially curative for localized prostate cancer, while androgen deprivation therapy is the initial systemic therapy for metastatic prostate disease. However, despite temporary response, most patients relapse and evolve into castration resistant cancer.Epithelial-mesenchymal transition (EMT) is a complex gradual process that occurs during embryonic development and/or tumor progression. During this process, cells lose their epithelial characteristics and acquire mesenchymal features. Increasing evidences indicate that EMT promotes prostate cancer metastatic progression and it is closely correlated with increased stemness and drug resistance.In this review, we discuss the main molecular events that directly or indirectly govern the EMT program in prostate cancer, in order to better define the role and the mechanisms underlying this process in prostate cancer progression and therapeutic resistance.

This review summarizes the main pathophysiological basis of the relationship between metabolic syndrome, endocrine disruptor exposure and prostate cancer that is the most common cancer among men in industrialized countries. Metabolic syndrome is a cluster of metabolic and hormonal factors having a central role in the initiation and recurrence of many western chronic diseases including hormonal-related cancers and it is considered as the world's leading health problem in the coming years. Many biological factors correlate metabolic syndrome to prostate cancer and this review is aimed to focus, principally, on growth factors, cytokines, adipokines, central obesity, endocrine abnormalities and exposure to specific endocrine disruptors, a cluster of chemicals, to which we are daily exposed, with a hormone-like structure influencing oncogenes, tumor suppressors and proteins with a key role in metabolism, cell survival and chemo-resistance of prostate cancer cells. Finally, this review will analyze, from a molecular point of view, how specific foods could reduce the relative risk of incidence and recurrence of prostate cancer or inhibit the biological effects of endocrine disruptors on prostate cancer cells. On the basis of these considerations, prostate cancer remains a great health problem in terms of incidence and prevalence and interventional studies based on the treatment of metabolic syndrome in cancer patients, minimizing exposure to endocrine disruptors, could be a key point in the overall management of this disease.

The gold standard for the detection of urothelial carcinoma is represented by urethro-cystoscopy and biopsy. Both procedures are invasive and expensive and therefore cytology is often used as first approach to investigate on a possible neoplasia, being a safe and cost-effective diagnostic modality of evaluation. Because cytology alone is not highly sensitive for detection of low grade urothelial carcinoma and recurrence of the disease, several adjunct markers and urine based tests for urothelial carcinoma have been developed, which can help in the final diagnosis. In particular, ProEx C is an immunohistochemical cocktail containing antibodies direct against topoisomerase IIα (TOP2A) and minichromosome maintenance 2 (MCM2) proteins. It proved to be a valid biomarker especially in detecting squamous intraepithelial lesions in cervical liquid-based samples and in discerning these lesions from their mimickers, as well as in ovarian, endometrial, vulvar, primary and metastatic melanomas, breast, pancreatic and renal cell carcinomas. This brief review covers the effective utility of ProEx C as adjunct tool in assessing the urothelial lesions in urine cytology, also providing prognostic and therapeutic information to help in clinical decisions., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Objective: To compare fosfomycin trometamol (FT) and ciprofloxacin (CIP) for antibiotic prophylaxis in transrectal prostate biopsy (TR-PB)., Patients and Methods: Data for 1109 patients (mean age 66.7 ± 8.45) who underwent TR-PB between March to September 2015 in seven Italian urological institutions were retrospectively reviewed, of which 632 received FT (Group 1) and 477 received CIP (Group 2) for prophylaxis. We reviewed all urine culture results obtained after the procedure, all adverse drug reactions (ADRs) related to the drug and all febrile and/or symptomatic urinary tract infections (UTIs) occurring within 1 month after TR-PB. The rate of symptomatic UTIs and the rate of ADRs were considered the main outcome measures., Results: In the total study population, 72/1109 (6.5 %) patients experienced symptomatic UTIs and among these 11 (0.9 % of total) had urosepsis. Out of 72, 53 (73.6 %) symptomatic UTIs were caused by fluoroquinolone-resistant strains. Out of 632, 10 (1.6 %) patients in Group 1 and 62/477 (12.9 %) patients in Group 2 had symptomatic UTIs (p < 0.001); in particular, 2/632 (0.3 %) patients in Group 1 and 9/477 (1.8 %) patients in Group 2 had urosepsis (p < 0.001). No differences were reported in terms of adverse events (0.6 vs 0.4 %; p = 0.70). A Charlson comorbidity index ≤1 and type of antimicrobial prophylaxis (FT) were found to be associated with a lower probability of symptomatic UTIs in the multivariate model., Conclusions: Antibiotic prophylaxis with FT for TR-PB had a lower rate of adverse events and a lower rate of symptomatic UTIs as compared with CIP. Fosfomycin trometamol appears as an attractive alternative prophylactic regimen in prostate biopsies.

Notwithstanding the peculiar sensitivity to cisplatin-based treatment, resulting in a very high percentage of cures even in advanced stages of the disease, still we do not know the biological mechanisms that make Testicular Germ Cell Tumor (TGCT) "unique" in the oncology scene. p53 and MDM2 seem to play a pivotal role, according to several in vitro observations, but no correlation has been found between their mutational or expression status in tissue samples and patients clinical outcome. Furthermore, other players seem to be on stage: DNA Damage Repair Machinery (DDR) , especially Homologous Recombination (HR) proteins, above all Ataxia Telangiectasia Mutated (ATM), cooperates with p53 in response to DNA damage, activating apoptotic cascade and contributing to cell "fate". Homologous Recombination deficiency has been assumed to be a Germ Cell Tumor characteristic underlying platinum-sensitivity, whereby Poly(ADP-ribose) polymerase (PARP), an enzyme involved in HR DNA repair, is an intriguing target: PARP inhibitors have already entered in clinical practice of other malignancies and trials are recruiting TGCT patients in order to validate their role in this disease. This paper aims to summarize evidence, trying to outline an overview of DDR implications not only in TGCT curability, but also in resistance to chemotherapy.

Oxidative stress plays a major role in ethanol-induced liver damage, and agents with antioxidant properties are promising as therapeutic opportunities in alcoholic liver disease. In the present work, we investigated the effect of S-adenosylmethionine (AdoMet), Tyrosol (Tyr), and their combination on HepG2 cells exposed to ethanol exploring the potential molecular mechanisms. We exposed HepG2 cells to 1 M ethanol for 4 and 48 h; thereafter, we recorded a decreased cell viability, increase of intracellular reactive oxygen species (ROS) and lipid accumulation, and the release into culture medium of markers of liver disease such as triacylglycerol, cholesterol, transaminases, albumin, ferritin, and homocysteine. On the other hand, AdoMet and Tyrosol were able to attenuate or antagonize these adverse changes induced by acute exposure to ethanol. The protective effects were paralleled by increased Sirtuin 1 protein expression and nuclear translocation and increased ERK1/2 phosphorylation that were both responsible for the protection of cells from apoptosis. Moreover, AdoMet increased p53 and p21 expression, while Tyrosol reduced p21 expression and enhanced the expression of uncleaved caspase 3 and 9, suggesting that its protective effect may be related to the inhibition of the apoptotic machinery. Altogether, our data show that AdoMet and Tyrosol exert beneficial effects in ethanol-induced oxidative stress in HepG2 cells and provide a rationale for their potential use in combination in the prevention of ethanol-induced liver damage.

The synthesis of a series of highly functionalized DNTQ-based derivatives is described. In vitro, most of the compounds exerted a cytotoxic effect against several tumour cell lines comparable to or greater than that of doxorubicin. Here we demonstrate that compound 14, the less cardiotoxic compound of this series, induced cell differentiation and was distributed mainly in the cytoplasm in the human glioblastoma LN229 cell line. Moreover, compound 14 reduced both cellular glucose uptake and serine/threonine kinase AKT expression, and triggered cell apoptosis. These findings suggest that highly functionalized DTNQ-based derivatives are promising pharmacological tools for the study of human solid tumours., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Hepatocellular carcinoma (HCC) is the third cause of cancer-related deaths worldwide. Sorafenib is the only approved drug for patients with advanced HCC but has shown limited activity. microRNAs (miRs) have been involved in several neoplasms including HCC suggesting their use or targeting as good tools for HCC treatment. The purpose of this study was to identify novel approaches to sensitize HCC cells to sorafenib through miRs. miR-423-5p was validated as positive regulator of autophagy in HCC cell lines by transient transfection of miR and anti-miR molecules. miR-423-5p expression level was evaluated by real-time polymerase chain reaction (PCR) in sera collected from 39 HCC patients before and after treatment with sorafenib. HCC cells were cotreated with sorafenib and miR-423-5p and the effects on cell cycle, apoptosis, and autophagy were evaluated. Secretory miR-423-5p was upregulated both in vitro and in vivo by sorafenib treatment and its increase was correlated with response to therapy since 75% of patients in which an increase of secretory miR423-5p was found were in partial remission or stable disease after 6 moths from the beginning of therapy. HCC cells transfected with miR-423-5p showed an increase of cell percentage in S-phase of cell cycle paralleled by a similar increase of autophagic cells evaluated at both fluorescence activated cell sorter (FACS) and transmission electron microscopy. Our results suggest the miR423-5p can be used as a useful tool to predict response to sorafenib in HCC patients and is involved in autophagy regulation in HCC cells.

Fluoropyrimidines are key agents for the treatment of gastrointestinal tract adenocarcinomas. The possible cardiotoxic effects in patients and occupationally exposed workers are multifactorial and remain a puzzle to solve for investigators. In the present study, we study what cell death pathways and what doses can determine direct cardiotoxic effects of 5-fluorouracil (5-FU) and doxorubicin (DOXO) on rat cardiocytes (H9c2) and a human colon adenocarcinoma (HT-29) cell line, already reported to be sensitive to 5-FU. We have found that 5-FU induced 50% growth inhibition (IC:50) at 72 h with concentrations of 400 μM and 4 μM on H9c2 and HT-29, respectively. Moreover, we have found that the addition of Levofolinic Acid (LF) to 5-FU potentiated the growth inhibition induced by 5-FU. The growth inhibition induced by 5-FU alone or in combination with LF in cardiocytes was paralleled by an increase of thiobarbituric acid-reactive species (Tbars) and end products of nitric oxide (NO) suggesting the increase of the oxidative stress status in cardiocytes. Interestingly, these effects were strongly potentiated by the addition of LF, a biochemical modulator of 5-FU activity. Our data suggest that agents such as 5-FU different from anthracyclines, conventionally related to the induction of cardiotoxic effects, can also induce cardiocyte damage paralleled by oxidative stress. The strategies based upon the use of scavengers could be used in order to prevent this effect., (Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

The resistance of growing human colon cancer cells to chemotherapy agents has been correlated to endogenous overexpression of stress proteins including the family of heat shock proteins (HSPs). Previously, we have demonstrated that a quinone-based mimetic dipeptide, named DTNQ-Pro, induced differentiation of growing Caco-2 cells through inhibition of HSP70 and HSP90. In addition, our product induced a HSP27 and vimentin intracellular redistribution. In the present study, we have evaluated whether a decrease of stress proteins induced by DTNQ-Pro in Caco-2 cells could sensitize these cells to treatment with 5-fluorouracil (5-FU) cytotoxicity. The pretreatment of Caco-2 with 500 nM of DTNQ-Pro increases lipid peroxidation and decreases expression of p38 mitogen-activated protein kinase (MAPK) and FOXO3a. At the same experimental conditions, an increase of the 5-FU-induced growth inhibition of Caco-2 cells was recorded. These effects could be due to enhanced DTNQ-Pro-induced membrane lipid peroxidation that, in turn, causes the sensitization of cancer cells to the cytotoxicity mediated by 5-FU.

Background and Purpose: The resistance of human colon adenocarcinoma cells to antineoplastic agents may be related to the high endogenous expression of stress proteins, including the family of heat shock proteins (HSPs). Recently, a quinone-based pentacyclic derivative, DTNQ-Pro, showed high cytotoxic activity in human colon carcinoma cell lines. The aim of the present study was to determine the precise cellular mechanisms of this cytotoxic action of DTNQ-Pro., Experimental Approach: Using human colorectal carcinoma-derived Caco-2 cells as a model, we studied the effects of DTNQ-Pro on cellular viability and oxidative stress; HSP70 and HSP27 accumulation; and cell cycle, differentiation and apoptosis., Key Results: Incubation of Caco-2 cells with DTNQ-Pro reduced cell growth and increased the levels of reactive oxygen species in mitochondria. After 48 h of treatment, cells surviving showed an increased expression of Mn-superoxide dismutase (SOD), nitric oxide production and membrane lipid peroxidation. Treatment with DTNQ-Pro decreased HSP70 expression, and redistributed HSP27 and vimentin within the cell. DTNQ-Pro down-regulated the expression of A and B cyclins with arrest of the cell cycle in S phase and increased cellular differentiation. A second treatment of Caco-2 cells with DTNQ-Pro induced cellular death by activation of the apoptotic pathway., Conclusions and Implications: DTNQ-Pro causes Caco-2 cell death by induction of apoptosis via inhibition of HSP70 accumulation and the intracellular redistribution of HSP27. These findings suggest the potential use of DTNQ-Pro in combination chemotherapy for colon cancer.

Bioactive peptides are present in a latent state, encrypted within the amino acid sequence of milk proteins, requiring enzymatic proteolysis for their release. They can be produced by gastrointestinal digestion or food processing, thus they can be present in fermented milks, cheese and also in the by-products of dairy industry such as waste whey. The spectrum of biological activity covered by milk-derived peptides is extremely wide, including antibacterial, immunostimulating, antihypertensive, antithrombotic and opioid actions. However, the characterisation of milk-derived peptides with classical analytical methodologies is severely challenged by the complexity of the milk protein fraction and by the wide dynamic range of relative peptide abundance in both dairy products and by-products. Here we report the characterisation of the peptide fraction released in the whey during the different production stages of Mozzarella di Bufala Campana cheese. The peptide extracts were separated by RP HPLC and analysed by MS in order to identify the peptides produced and to trace the pathway of formation of potential bioactive peptides. The antioxidant properties and the modulatory effect on the cell cycle exerted by the peptide extracts were also studied in CaCo2 cell line. We found that a significant antiproliferative effect on CaCo2 was exerted by Mozzarella di Bufala waste whey peptides.