Correction: DUB3 and USP7 de-ubiquitinating enzymes control replication inhibitor Geminin: molecular characterization and associations with breast cancer.

The final sentence of the Acknowledgements should be as follows: This work was supported by grants from Instituto de Salud Carlos III (BA15/00092), Spanish Ministry of Economy and Competitiveness/EU-ERDF (SAF2016-80626-R, SAF2013-49149-R, BFU2014-51672-REDC), Fundación CajaCanarias (AP2015/008) to RF, and the Australian National Health and Medical Research (NHMRC program grant to SRL and KKK (APP1017028).

Low-dose-rate brachytherapy for prostate cancer in renal transplant recipients.

PURPOSE: Prostate cancer (PCa) is the most common malignancy among men and one of the most common neoplasms affecting renal transplant recipients (RTRs). The available treatments for localized PCa among the general population (GP), surgery and external beam radiotherapy, carry a risk of damage to the transplanted kidney, the ureters, and the bladder and therefore tend to be avoided by most groups. The objective of this study was to assess the efficacy and feasibility of low-dose-rate brachytherapy (LDR-BT) for PCa in RTRs. METHODS AND MATERIALS: We carried out a retrospective review on all RTRs diagnosed of PCa who had undergone LDR-BT at our institution between 2000 and 2015. Nine patients met these criteria, but 1 did not fulfill the followup. Hence, we analyzed 8 patients. We reviewed all clinical data for PCa and graft function in these patients and compared the results with the GP. RESULTS: Mean baseline prostate-specific antigen was 6.8 ± 1.9 ng/mL. All PCa had a Gleason score of 6 and were classified as low risk according the Europe Association of Urology guidelines. Mean followup after seed implantation was 48 ± 12.8 months. All 8 patients remain free of prostate-specific antigen failure. Five-year progression-free survival, cancer-specific survival, and overall survival rates were 100%, 100%, and 62.5%. There was no specific toxicity associated with LDR-BT, and there were no acute adverse events affecting the graft. CONCLUSIONS: LDR-BT is a feasible and acceptable treatment for localized PCa in RTRs. Oncological outcomes are similar to the GP, and there is minimal toxicity to the renal graft.

DUB3 and USP7 de-ubiquitinating enzymes control replication inhibitor Geminin: molecular characterization and associations with breast cancer.

This corrects the article DOI: 10.1038/onc.2017.21.

Deciphering Tacrolimus-Induced Toxicity in Pancreatic ß Cells.

ß Cell transcription factors such as forkhead box protein O1 (FoxO1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), pancreatic and duodenal homeobox 1, and neuronal differentiation 1, are dysfunctional in type 2 diabetes mellitus (T2DM). Posttransplant diabetes mellitus resembles T2DM and reflects interaction between pretransplant insulin resistance and immunosuppressants, mainly calcineurin inhibitors (CNIs). We evaluated the effect of tacrolimus (TAC), cyclosporine A (CsA), and metabolic stressors (glucose plus palmitate) on insulinoma ß cells in vitro and in pancreata of obese and lean Zucker rats. Cells were cultured for 5 days with 100 µM palmitate and 22 mM glucose; CsA (250 ng/mL) or TAC (15 ng/mL) were added in the last 48 h. Glucose plus palmitate increased nuclear FoxO1 and decreased nuclear MafA. TAC in addition to glucose plus palmitate magnified these changes in nuclear factors, whereas CsA did not. In addition to glucose plus palmitate, both drugs reduced insulin content, and TAC also affected insulin secretion. TAC withdrawal or conversion to CsA restored these changes. Similar results were observed in pancreata of obese animals on CNIs. TAC and CsA, in addition to glucose plus palmitate, induced comparable inhibition of calcineurin and nuclear factor of activated T cells (NFAT); therefore, TAC potentiates glucolipotoxicity in ß cells, possibly by sharing common pathways of ß cell dysfunction. TAC-induced ß cell dysfunction is potentially reversible. Inhibition of the calcineurin-NFAT pathway may contribute to the diabetogenic effect of CNIs but does not explain the stronger effect of TAC compared with CsA.

DUB3 and USP7 de-ubiquitinating enzymes control replication inhibitor Geminin: molecular characterization and associations with breast cancer.

Correct control of DNA replication is crucial to maintain genomic stability in dividing cells. Inappropriate re-licensing of replicated origins is associated with chromosomal instability (CIN), a hallmark of cancer progression that at the same time provides potential opportunities for therapeutic intervention. Geminin is a critical inhibitor of the DNA replication licensing factor Cdt1. To properly achieve its functions, Geminin levels are tightly regulated through the cell cycle by ubiquitin-dependent proteasomal degradation, but the de-ubiquitinating enzymes (DUBs) involved had not been identified. Here we report that DUB3 and USP7 control human Geminin. Overexpression of either DUB3 or USP7 increases Geminin levels through reduced ubiquitination. Conversely, depletion of DUB3 or USP7 reduces Geminin levels, and DUB3 knockdown increases re-replication events, analogous to the effect of Geminin depletion. In exploring potential clinical implications, we found that USP7 and Geminin are strongly correlated in a cohort of invasive breast cancers (P<1.01E-08). As expected, Geminin expression is highly prognostic. Interestingly, we found a non-monotonic relationship between USP7 and breast cancer-specific survival, with both very low or high levels of USP7 associated with poor outcome, independent of estrogen receptor status. Altogether, our data identify DUB3 and USP7 as factors that regulate DNA replication by controlling Geminin protein stability, and suggest that USP7 may be involved in Geminin dysregulation during breast cancer progression.

Prediction of the energy required for extracorporeal shock wave lithotripsy of certain stones composition using simple radiology and computerized axial tomography.

OBJECTIVE: To demonstrate that urinary lithiasis have a specific susceptibility to fracture through extracorporeal shock wave lithotripsy (ESWL), which is common for all calculi with the same composition and which can be estimated before treatment using CT or plain x-ray. MATERIAL AND METHOD: We present an in vitro, prospective, randomized, blind and multi-centre study involving 308 urinary calculi. 193 of these met the inclusion criteria: whole calculi composed purely of calcium oxalate monohydrate (COM), uric acid (UA) or carbonate apatite (CA), or a mix of oxalate (COMix) and of a size greater than 0.5 cm. The samples were broken using lithotripsy until reaching a pre-established level of comminution. The variables employed were energy dose (Edose) per cm(3) of lithiasis and Edose adjusted to lithiasic surface (EdAJ) per cm(3). RESULTS: COM was the hardest, requiring an Edose of 119,624 mJ/cm(3) and an EdAJ of 36,983 mJ/cm(3), followed by COMix (75,501/36,983), CA (22,734/21,186) and UA (22,580/6,837) (P < .05). Gmax y Gmda were correlated with Edose (r = 0.434/r = 0.420) and EdAJ (r = 0.599/r = 0.545) (P < .01). UH were correlated, in bone window and soft tissue window, with Edose/cm(3) (r = 0.478/r = 0.539) y EdAJ/cm(3) (r = 0.745/r = 0.758) (P < .01). CONCLUSIONS: In our in vitro research lithiasis require, due to the specific nature of their composition, a given amount of energy in order to be broken by ESWL, which is inherent to all those sharing the same composition, and can be predicted using CT or plain x-ray.

Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization.

BACKGROUND AND PURPOSE: The sigma-1 (σ(1) ) receptor is a ligand-regulated molecular chaperone that has been involved in pain, but there is limited understanding of the actions associated with its pharmacological modulation. Indeed, the selectivity and pharmacological properties of σ(1) receptor ligands used as pharmacological tools are unclear and the demonstration that σ(1) receptor antagonists have efficacy in reversing central sensitization-related pain sensitivity is still missing. EXPERIMENTAL APPROACH: The pharmacological properties of a novel σ(1) receptor antagonist (S1RA) were first characterized. S1RA was then used to investigate the effect of pharmacological antagonism of σ(1) receptors on in vivo nociception in sensitizing conditions and on in vitro spinal cord sensitization in mice. Drug levels and autoradiographic, ex vivo binding for σ(1) receptor occupancy were measured to substantiate behavioural data. KEY RESULTS: Formalin-induced nociception (both phases), capsaicin-induced mechanical hypersensitivity and sciatic nerve injury-induced mechanical and thermal hypersensitivity were dose-dependently inhibited by systemic administration of S1RA. Occupancy of σ(1) receptors in the CNS was significantly correlated with the antinociceptive effects. No pharmacodynamic tolerance to the antiallodynic and antihyperalgesic effect developed following repeated administration of S1RA to nerve-injured mice. As a mechanistic correlate, electrophysiological recordings demonstrated that pharmacological antagonism of σ(1) receptors attenuated the wind-up responses in spinal cords sensitized by repetitive nociceptive stimulation. CONCLUSIONS AND IMPLICATIONS: These findings contribute to evidence identifying the σ(1) receptor as a modulator of activity-induced spinal sensitization and pain hypersensitivity, and suggest σ(1) receptor antagonists as potential novel treatments for neuropathic pain.

Adrenocortical carcinoma, an unusual extracolonic tumor associated with Lynch II syndrome.

Lynch syndrome (LS) is an autosomal dominant condition that predisposes to colorectal cancer and specific other tumors. Extracolonic tumors occur mainly in the endometrium, stomach, ovary, small intestine and urinary tract. The presence of rare tumors in patients belonging to families who have Lynch syndrome is always interesting, because the question arises whether these tumors should be considered as a coincidence or are related with the syndrome. In this last case, they are also the result of the defect in the mismatch repair system, opening the possibility of extending the tumor spectrum associated with the syndrome. Here we describe a patient from a Lynch syndrome family with a germline mutation c.2063T>G (p.M688R) in the MSH2 gene, who developed an adrenal cortical carcinoma, a tumor not usually associated with LS. We analyzed the adrenocortical tumour for microsatellite instability (MSI), LOH and the presence of the germline c.2063T>G (M688R) mutation. The adrenal cortical carcinoma showed the MSH2 mutation, loss of heterozygosity of the normal allele in the MSH2 gene and loss of immunohistochemical expression for MSH2 protein, but no microsatellite instability. Additionally, the adrenal cortical carcinoma did not harbour a TP53 mutation. The molecular study indicates that this adrenal cortical cancer is probably due to the mismatch repair defect.

Epidemiology of systemic lupus erythematosus in Asia.

In this paper we aim to review the prevalence, incidence and disease presentation of lupus patients in Asian populations. The database of the National Library of Medicine (MEDLINE) through PUBMED up to September 2009 was searched for relevant articles using the search terms 'systemic lupus erythematosus', 'epidemiology', and 'Asia'. Articles on lupus prevalence, incidence, and clinical manifestations were retrieved and their bibliographies further screened for relevant articles. Proceedings of national, regional, and international rheumatology and SLE conferences were likewise searched for relevant abstracts. Retrieval rate of relevant articles was approximately 80%. Prevalence and incidence figures are expressed per 100,000 populations. Among the articles reviewed, epidemiologic information was usually obtained through population surveys or hospital cohorts. Prevalence data are available from 24 countries, and generally fall within 30-50/100,000 population. However, one survey showed a higher prevalence of 70 (Shanghai), while three others showed a lower prevalence of 3.2-19.3 (India, Japan, Saudi Arabia). Only three countries have recorded incidence rates and these varied from 0.9 to 3.1 per annum. Thirty articles from 21 countries describe lupus disease presentation. Common manifestations include mucocutaneous lesions (seen in 52-98% of patients) and arthritis/musculoskeletal complaints (36-95%). Antinuclear antibodies were generally positive in 89-100% of patients, except for two studies. Renal involvement ranged from 18% to 100% with most articles reporting this in >50% of their patients. Discoid lesions, serositis, and neurologic involvement were the least frequently seen symptoms. There is varying epidemiologic information regarding systemic lupus erythematosus among countries in Asia. Prevalence rates usually fall within 30-50/100,000 population. Incidence rates, as reported from three countries, varied from 0.9/100,000 to 3.1% per annum. It is difficult to make generalizations about how the epidemiologic character of the disease varies from country to country. However, similarities in disease manifestations can be observed. .

Localization and gestation-dependent pattern of corticotrophin-releasing factor receptor subtypes in ovine fetal distal colon.

Meconium passage is frequently observed in association with feto-maternal stress factors such as hypoxia and infection, but the triggering mechanism is unknown. We hypothesize that differential regulation of corticotrophin-releasing factor (CRF) receptors during gestation play an important role in determining the susceptibilities of the fetus to stress-induced in utero meconium passage at term. We examined the innervation patterns of CRF-receptor type 1 (CRF-R1), a stimulator of gastrointestinal motility and CRF-receptor type II (CRF-R2), an inhibitor of gastrointestinal motility in ovine fetal distal colonic segments from very preterm to term gestation. Both CRF-R1 and CRF-R2 receptors were present in muscularis mucosa as well as in longitudinal and circular smooth muscle layers in fetal distal colonic segments at all gestational ages. Quantitative image analysis indicated a 42% increase in CRF-R1 receptor immunoreactivity in muscularis mucosa and a 30% in longitudinal smooth muscle layers from very preterm to term. In contrast, CRF-R2 receptor immunoreactivity in muscularis mucosa as well as in longitudinal and circular smooth muscle layers decreased by 38%, 55% and 51%, respectively, at term. The percentage of enteric ganglia and the number of enteric neurons expressing CRF-R1 receptors were high at term. Western blot analysis identified 235 and 50 kDa molecular species of CRF-R1 receptors and 37 and 28 kDa molecular species of CRF-R2 receptors. In summary, we speculate that downregulation of CRF-R2 receptor abundance with concurrent increases in CRF-R1 receptor levels in myenteric-smooth muscle unit with advancing gestation sensitizes the colonic motility responses to stressors.

Changes in the epidemiology of meticillin-resistant Staphylococcus aureus associated with the emergence of EMRSA-16 at a university hospital.

This study investigated the molecular epidemiology of meticillin-resistant Staphylococcus aureus (MRSA) in the University Hospital of the Canary Islands (HUC) in order to evaluate epidemiological changes over a six-year period. Clinical and epidemiological data were collected between May 2000 and December 2003, and isolates were subjected to pulsed-field gel electrophoresis (PFGE), multi-locus sequence typing (MLST), SCCmec typing and spa typing. Since 2000, the rate of MRSA infections has increased at the HUC, coinciding with the emergence and spread of the EMRSA-16 clone (ST36-MRSA-II) and replacement of the Iberian clone (ST247-MRSA-I). Genotypic changes were associated with changes in the epidemiological profile. The mean age and proportion of patients over 60 years old (P=0.01) and the proportion of respiratory infections (P=0.001) increased significantly. Gentamicin and tetracycline susceptibility of MRSA isolates increased (P<0.001) following the emergence of EMRSA-16. Combining PFGE, SCCmec and MLST has been instrumental in understanding these changes and defining the clones circulating in the HUC patient population.

Presentation and role of transplantation in adult patients with type 1 primary hyperoxaluria and the I244T AGXT mutation: Single-center experience.

Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by allelic and clinical heterogeneity. We aim to describe the presentation and full single-center experience of the management of PH1 patients bearing the mutation described in our community (I244T mutation+polymorphism P11L). Since 1983, 12 patients with recurrent renal lithiasis have been diagnosed with PH1 and renal failure in the Canary Islands, Spain. Diagnostic confirmation was based on the presence of oxalosis in undecalcified bone or kidney allograft biopsy, reduced alanine:glyoxylate aminotransferase activity in liver biopsy, and blood DNA analysis. Patients underwent different treatment modalities depending on individual clinical circumstances and therapeutic possibilities at the time of diagnosis: hemodialysis, isolated kidney, simultaneous liver-kidney, or pre-emptive liver transplantation. In all cases, the presentation of advanced renal disease was relatively late (>13 years) and no cases were reported during lactancy or childhood. The eight patients treated with hemodialysis or isolated kidney transplantation showed unfavorable evolution leading to death over a variable period of time. In contrast, the four patients undergoing liver transplantation (three liver+kidney and one pre-emptive liver alone) showed favorable long-term allograft and patient survival (up to 12 years follow-up). In conclusion, in this PH1 population, all bearing the I244T mutation, the development of end-stage renal disease was distinctive during late adolescence or adulthood. Our long-term results support pre-emptive liver transplantation at early stages of renal failure, and kidney-liver transplantation for those with advanced renal disease.

[Renal oncocytoma. Review of our 22 patients]. / Oncocitoma renal. Revisión de nuestra serie de 22 pacientes.

UNLABELLED: Renal oncocytoma (OR) is a benign tumor. It may represent up to 3-7% of solid kidney masses, and shows specifics cellular and evolutive characteristics. Metacronicity, multifocality and bilateralism has been reported. MATERIALS AND METHODS: Between 1986 and 2005, 478 kidney tumors have been surgically treated at our institution. We report the frequency and characteristics of OR in our patients, compared with renal cell carcinomas (RCC). We try to find out the rate of multifocality, bilateralism and other tumor association, and the number of neoplasms originally diagnosed as OR before surgery. Mean and median follow up: 36.86 and 13 months (1-193). Specific survival rate 100%. RESULTS: We found 24 OR in 10 men and 12 women with a mean age of 59 years (34-84). 12 in the left kidney and 12 in the right one, one patient presenting oncocytomatosis. Tumor mean size was 4.64 cm (1-12.5 cm). Tumors were discovered incidentally in 17 cases. Presentation symptoms in the rest of patients were gross hematuria. CONCLUSIONS: The rate of OR found in our sample population of renal tumors undergoing surgery matches other series already published. Two synchronic OR, but not metacronous, bilateral or metastatic tumors were found. All cases presented a benign evolution.

[Complex vesicoureteral reflux. Our experience]. / Reflujo vesicoureteral complejo. Revisión de nuestra serie.

OBJECTIVE: To analize the proportion of complex reflux in the whole amount of patients treated endoscopically of vesicoureteral reflux in our hospital. To determine the endoscopic treatment success in complex reflux, and the influence of reflux grade in it. MATERIAL AND METHODS: We present our experience between 1992 and 2003 with three kinds of substances (polytetrafluoroethylene, polydimethylsiloxane and dextranomer-hyaluronic acid copolymer). We treated complex reflux in 74 patients with endoscopic injection. All patients were scheduled to have voiding cystourethrogram 3 and 9 moths after injection. A positive response was defined as grade 0 or I reflux. RESULTS: Reflux was solved using the endoscopic procedure in 86.25% after first injection, 93.75% after second and 96.25% after third. The corresponding results for reflux grade II, III and IV were 88.9%, 83.3% and 100%. CONCLUSIONS: We conclude that subureteral injection of different sustances (Teflon, Macroplastique or Deflux) is a useful treatment for most cases of vesicoureteral reflux. We propose it as first step of treatment.

[Xanthogranulomatous pyelonephritis in childhood. A case report]. / Pielonefritis xantogranulomatosa en la infancia. A propósito de un caso.

Xanthogranulomatous pyelonephritis is an uncommon chronic inflammatory renal disorder. Most cases have been described in middle aged women and it is extremely rare in children. We report a case of a 4 year old girl who suffered from recurrent urinary tract infection and antibiotic therapy resistance. She had low growth-rate and palpable left renal mass on examination and was confirmed by radiological findings. We performed left kidney partial resection and then histological examination showed focal xanthogranulomatous pyelonephritis. The focal form of the disease may respond to antibiotic treatment although usually an enucleation or partial resection must be performed. In conclusion xanthogranulomatous pyelonephritis should be considered in the differential diagnosis of a renal mass and recurrent urinary tract infection in childhood.

[Cystic ureteritis in a kidney transplantation candidate]. / Ureteritis quística en paciente candidata a trasplante renal.

Cystic ureteritis is a very uncommon pathology, whose pathogenesis is not well established. It is usually asociated with chronic infectious factors. It presents unspecific symptoms but characteristic radiologic findings. There is not an especific treatment for this disease. Kidney transplant is the final pathway for patients with chronic renal failure. We report a case of cystic ureteritis diagnosed during pre-transplant study.

[Retroperitoneal malignant fibrous histiocytoma]. / Histiocitoma maligno fibroso retroperitoneal.

We report a new case of retroperitoneal tumor: a malignant fibrous histiocytoma, in its less aggressive histologic type, the mixoid variety. This is a recently isolated histologic presentation from other sarcomas, with a low incidence, non-specific clinic findings and poor prognosis due to its tendency to reappear and to produce metastasis.

[Retroperitoneal neurilemmona]. / Neurilemoma retroperitoneal.

Schwannoma is an uncommon tumor arising from neural sheath of peripheral nerves. Histological findings showing Antoni A and B zones are the main diagnostic features. We report a new case of a retroperitoneal located one, which is not its most usual place to appear, in a 60 year old male, presenting left flank pain. He received surgical treatment, having a satisfactory evolution.