Integrated analysis of mismatch repair system in malignant astrocytomas

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.Malignant astrocytomas are the most aggressive primary brain tumors with a poor prognosis despite optimal treatment. Dysfunction of mismatch repair (MMR) system accelerates the accumulation of mutations throughout the genome causing uncontrolled cell growth. The aim of this study was to characterize the MMR system defects that could be involved in malignant astrocytoma pathogenesis. We analyzed protein expression and promoter methylation of MLH1, MSH2 and MSH6 as well as microsatellite instability (MSI) and MMR gene mutations in a set of 96 low- and high-grade astrocytomas. Forty-one astrocytomas failed to express at least one MMR protein. Loss of MSH2 expression was more frequent in low-grade astrocytomas. Loss of MLH1 expression was associated with MLH1 promoter hypermethylation and MLH1 -93G>A promoter polymorphism. However, MSI was not related with MMR protein expression and only 5% of tumors were MSI-High. Furthermore, the incidence of tumors carrying germline mutations in MMR genes was low and only one glioblastoma was associated with Lynch syndrome. Interestingly, survival analysis identified that tumors lacking MSH6 expression presented longer overall survival in high-grade astrocytoma patients treated only with radiotherapy while MSH6 expression did not modify the prognosis of those patients treated with both radiotherapy and chemotherapy. Our findings suggest that MMR system alterations are a frequent event in malignant astrocytomas and might help to define a subgroup of patients with different outcome.This work was supported by Fondo de Investigación Sanitaria (FIS PI 10/00219), Instituto de Estudios de Ciencias de la Salud de Castilla y León IECSCYL and Junta de Castilla y León y Fondo Social Europeo (Orden EDU/330/2008).Peer Reviewe

Patterns of incidental perineural invasion and prognosis in cutaneous squamous cell carcinoma: A multicenter, retrospective cohort study

To the Editor: Perineural invasion (PNI) is rare and usually incidental in cutaneous squamous cell carcinoma (SCC), with an incidence of 2.5% to 14%.1 Incidental PNI is associated with poor prognosis in cutaneous SCC,2 and some evidence suggests its outcome differs, depending on the PNI pattern. We evaluated patterns of incidental PNI, using a multicenter retrospective cohort of 140 cutaneous SCCs with incidental PNI to determine the influence of nerve involvement on cutaneous SCC prognosis.Dr Canueto is partially supported ~ by grants PI18/000587 (Instituto de Salud Carlos III, cofinanced by Fondo Europeo de Desarrollo Regional) and GRS 1835/A/18 (Gerencia Regional de Salud de Castilla y Leon)

Axillary silicone lymphadenopathy presenting with a lump and altered sensation in the breast: a case report

<p>Abstract</p> <p>Introduction</p> <p>Silicone lymphadenopathy is a rare but recognised complication of procedures involving the use of silicone. It has a poorly understood mechanism but is thought to occur following the transportation of silicone particles from silicone-containing prostheses to lymph nodes by macrophages.</p> <p>Case presentation</p> <p>We report of a case involving a 35-year-old woman who presented to the breast clinic with a breast lump and altered sensation below her left nipple 5 years after bilateral cosmetic breast augmentations. A small lump was detected inferior to the nipple but clinical examination and initial ultrasound investigation showed both implants to be intact. However, mammography and magnetic resonance imaging of both breasts revealed both intracapsular and extracapsular rupture of the left breast prosthesis. The patient went on to develop a flu-like illness and tender lumps in the left axilla and right mastoid regions. An excision biopsy of the left axillary lesion and replacement of the ruptured implant was performed. Subsequent histological analysis showed that the axillary lump was a lymph node containing large amounts of silicone.</p> <p>Conclusion</p> <p>The exclusion of malignancy remains the priority when dealing with lumps in the breast or axilla. Silicone lymphadenopathy should however be considered as a differential diagnosis in patients in whom silicone prostheses are present.</p

Effect of resource spatial correlation and Hunter-Fisher-Gatherer mobility on social cooperation in Tierra del Fuego

This article presents an agent-based model designed to explore the development of cooperation in hunter-fisher-gatherer societies that face a dilemma of sharing an unpredictable resource that is randomly distributed in space. The model is a stylised abstraction of the Yamana society, which inhabited the channels and islands of the southernmost part of Tierra del Fuego (Argentina-Chile). According to ethnographic sources, the Yamana developed cooperative behaviour supported by an indirect reciprocity mechanism: whenever someone found an extraordinary confluence of resources, such as a beached whale, they would use smoke signals to announce their find, bringing people together to share food and exchange different types of social capital. The model provides insight on how the spatial concentration of beachings and agents’ movements in the space can influence cooperation. We conclude that the emergence of informal and dynamic communities that operate as a vigilance network preserves cooperation and makes defection very costly.MICINN http://www.idi.mineco.gob.es/ CSD2010-00034 (SimulPast CONSOLIDER-INGENIO 2010) and HAR2009-06996; the government of Castilla y Leónhttp://www.jcyl.es/ GREX251-2009; the Argentine CONICET http://www.conicet.gov.ar/PIP-0706; and the Wenner-Gren Foundation for Anthropological Researchhttp://www.wennergren.org/ "Social Aggregation: A Yamana Society's Short Term Episode to Analyse Social Interaction, Tierra del Fuego, Argentina". The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip

MicroRNA signature from extracellular vesicles of HCV/HIV co-infected individuals differs from HCV mono-infected

Hepatitis C virus (HCV) coinfection with human immunodeficiency virus (HIV) has a detrimental impact on disease progression. Increasing evidence points to extracellular vesicles (EVs) as important players of the host-viral cross-talk. The microRNAs (miRNAs), as essential components of EVs cargo, are key regulators of normal cellular processes and also promote viral replication, viral pathogenesis, and disease progression. We aimed to characterize the plasma-derived EVs miRNA signature of chronic HCV infected and HIV coinfected patients to unravel the molecular mechanisms of coinfection. EVs were purified and characterized from 50 plasma samples (21 HCV mono- and 29 HCV/HIV co-infected). EV-derived small RNAs were isolated and analyzed by massive sequencing. Known and de novo miRNAs were identified with miRDeep2. Significant differentially expressed (SDE) miRNA identification was performed with generalized linear models and their putative dysregulated biological pathways were evaluated. Study groups were similar for most clinical and epidemiological characteristics. No differences were observed in EVs size or concentration between groups. Therefore, HCV/HIV co-infection condition did not affect the concentration or size of EVs but produced a disturbance in plasma-derived EVs miRNA cargo. Thus, a total of 149 miRNAs were identified (143 known and 6 de novo) leading to 37 SDE miRNAs of which 15 were upregulated and 22 downregulated in HCV/HIV co-infected patients. SDE miRNAs regulate genes involved in inflammation, fibrosis, and cancer, modulating different biological pathways related to HCV and HIV pathogenesis. These findings may help to develop new generation biomarkers and treatment strategies, in addition to elucidate the mechanisms underlying virus-host interaction. KEY MESSAGES: HCV and HCV/HIV displayed similar plasma-EV size and concentration. EVs- derived miRNA profile was characterized by NGS. 37 SDE miRNAs between HCV and HCV/HIV were observed. SDE miRNAs regulate genes involved in inflammation, fibrosis and cancer.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work has been supported by grants from (1) Institute of Health Carlos III, Spain [PI18CIII/00020/ to AFR], (2) PID2021–126781OB-I00 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”, (3) The SPANISH AIDS Research Network RD16CIII/0002/0002 - ISCIII – FEDER, (4) Centro de Investigación en Red en Enfermedades Infecciosas (CIBERINFEC) CB21/13/00044, (5) the National Agency for Scientific and Technology Promotion (ANPCyT) (PICT 2017 Nº713), and (6) the National Research Council (CONICET, PIP 2021-2023). V.C. received funding form the Asociación Universitaria Iberoamericana de Postgrado (AUIP) for the Academic Mobility Scholarship Program. P.V., E.D.M., and M.V.P. are members of the CONICET-Research Career Program. V.C. is a fellow from ANPCyT. The funder’s had no role in the study design, data collection and analysis, decision to publish, or the preparation of the manuscript.S

Synthetic Conjugates of Ursodeoxycholic Acid Inhibit Cystogenesis in Experimental Models of Polycystic Liver Disease

Altres ajuts: Suported by IKERBASQUE, Basque foundation for Science (M.J. Perugorria and J.M. Banales), Spain; "Junta de Castilla y Leon" (J.J.G. Marin: SA06P17); "Diputación Foral Gipuzkoa" (J.M. Banales: DFG15/010, DFG16/004; M.J. Perugorria: DFG18/114, DFG19/081), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD to J.M. Banales), Department of Health of the Basque Country (J.M. Banales: 2017111010; M.J. Perugorria: 2019111024), and Euskadi RIS3 (J.M. Banales: 2016222001, 2017222014, and 2018222029; 2019222054); La Caixa Scientific Foundation (J.M. Banales: HR17-00601); "Fundación Científica de la Asociación Española Contra el Cáncer" (AECC Scientific Foundation, to J.M. Banales and J.J.G. Marin); and "Centro Internacional sobre el Envejecimiento", Spain (J.J.G. Marin: OLD-HEPAMARKER, 0348-CIE-6-E). A. Santos-Laso by the Basque Government (PRE_2018_2_0195), and Pui Y. Lee-Law by the European Association for the Study of the Liver (EASL; Sheila Sherlock Award). Basque Government (F.P. Cossío: IT-324-07). I. Rivilla had a postdoctoral contract from the Donostia International Physics Center.Background and Aims: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. Approach and Results: Here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters. Conclusions: These UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs

Primary myoepithelial carcinoma of the lung: a rare entity treated with parenchymal sparing resection

Primary lung myoepithelial carcinomas are rare neoplasms arising from the salivary glands of the respiratory epithelium. Given the rare occurrences and reports of these tumors, appropriate recommendations for resection are difficult to formulate. Although classified as low-grade neoplasms, these tumors have a significant rate of recurrence and distant metastasis

Synthetic conjugates of ursodeoxycholic acid inhibit cystogenesis in experimental models of polycystic liver disease

Background and aims: polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. Approach and results: here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters. Conclusions: these UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs

Synthetic Conjugates of Ursodeoxycholic Acid Inhibit Cystogenesis in Experimental Models of Polycystic Liver Disease

Background and Aims Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. Approach and Results Here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters. Conclusions These UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs.Supported by the Spanish Carlos III Health Institute (ISCIII; J.M. Banales: FIS PI15/01132, PI18/01075 and Miguel Servet Program CON14/00129; M.J. Perugorria: PI14/00399, PI17/00022; J.J.G. Marin: FIS PI16/00598) cofinanced by "Fondo Europeo de Desarrollo Regional" (FEDER); CIBERehd (ISCIII): J.M. Banales, M.J. Perugorria, L. Bujanda, and J.J.G. Marin; Spanish Ministry of Economy and Competitiveness (M. J. Perugorria: Ramon y Cajal Program RYC-2015-17755); IKERBASQUE, Basque foundation for Science (M.J. Perugorria and J.M. Banales), Spain; "Junta de Castilla y Leon" (J.J.G. Marin: SA06P17); " Diputacion Foral Gipuzkoa" (J.M. Banales: DFG15/010, DFG16/004; M.J. Perugorria: DFG18/114, DFG19/081), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD to J.M. Banales), Department of Health of the Basque Country (J.M. Banales: 2017111010; M.J. Perugorria: 2019111024), and Euskadi RIS3 (J.M. Banales: 2016222001, 2017222014, and 2018222029; 2019222054); La Caixa Scientific Foundation (J.M. Banales: HR17-00601); "Fundacion Cientifica de la Asociacion Espanola Contra el Cancer" (AECC Scientific Foundation, to J.M. Banales and J.J.G. Marin); and "Centro Internacional sobre el Envejecimiento", Spain (J.J.G. Marin: OLD-HEPAMARKER, 0348-CIE-6-E). F.J. Caballero-Camino was funded by the Spanish Ministry of Science and Innovation (BES-2014-069148), A. Santos-Laso by the Basque Government (PRE_2018_2_0195), and Pui Y. Lee-Law by the European Association for the Study of the Liver (EASL; Sheila Sherlock Award). The Spanish Ministry of Science and Innovation supported F. P. Cossio: (CTQ2016-80375-P and CTQ2014-51912-REDC) as well as the Basque Government (F.P. Cossio: IT-324-07). I. Rivilla had a postdoctoral contract from the Donostia International Physics Center

Different HCV Exposure Drives Specific miRNA Profile in PBMCs of HIV Patients

Micro RNAs (miRNAs) are essential players in HIV and HCV infections, as both viruses modulate cellular miRNAs and interact with the miRNA-mediated host response. We aim to analyze the miRNA profile of HIV patients with different exposure to HCV to explore specific signatures in the miRNA profile of PBMCs for each type of infection. We massively sequenced small RNAs of PBMCs from 117 HIV+ infected patients: 45 HIV+ patients chronically infected with HCV (HIV/HCV+), 36 HIV+ that spontaneously clarified HCV after acute infection (HIV/HCV-) and 36 HIV+ patients without previous HCV infection (HIV). Thirty-two healthy patients were used as healthy controls (HC). Differential expression analysis showed significantly differentially expressed (SDE) miRNAs in HIV/HCV+ (n = 153), HIV/HCV- (n = 169) and HIV (n = 153) patients. We found putative dysregulated pathways, such as infectious-related and PI3K signaling pathways, common in all contrasts. Specifically, putatively targeted genes involved in antifolate resistance (HIV/HV+), cancer-related pathways (HIV/HCV-) and HIF-signaling (HIV) were identified, among others. Our findings revealed that HCV strongly influences the expression profile of PBMCs from HIV patients through the disruption of its miRNome. Thus, different HCV exposure can be identified by specific miRNA signatures in PBMCs.This work has been supported by grants from Institute of Health Carlos III, [PI15CIII/00031 and PI18CIII/00020/ to AFR and VB] and the Foundation Universidad Alfonso X el Sabio-Santander [grant number 1.010.932 to AFR] and the Spanish AIDS Research Network (RD16CIII/0002/0002), and Centro de Investigación Biomédica en Red (CIBER) en Enfermedades Infecciosas (CB21/13/00044). AFR is supported by the Miguel Servet programme from Fondo de Investigación Sanitaria (ISCIII) [CP14/CIII/00010 and CPII20CIII/0001].info:eu-repo/semantics/publishedVersio