Publications by authors named "Miguel Rivera"

169 Publications

Clinical Utility of Anchored Multiplex Solid Fusion Assay for Diagnosis of Bone and Soft Tissue Tumors.

Am J Surg Pathol 2021 Aug;45(8):1127-1137

James Homer Wright Pathology Laboratories.

Sarcoma diagnosis has become increasingly complex, requiring a combination of morphology, immunohistochemistry, and molecular studies to derive specific diagnoses. We evaluated the role of anchored multiplex polymerase chain reaction-based gene fusion assay in sarcoma diagnostics. Between 2015 and 2018, bone and soft tissue sarcomas with fusion assay results were compared with the histologic diagnosis. Of 143 sarcomas tested for fusions, 43 (30%) had a detectable fusion. In review, they could be classified into 2 main categories: (1) 31 tumors with concordant morphologic and fusion data; and (2) 12 tumors where the fusion panel identified an unexpected rearrangement that played a significant role in classification. The overall concordance of the fusion assay results with morphology/immunohistochemistry or alternate confirmatory molecular studies was 83%. Collectively, anchored multiplex polymerase chain reaction-based solid fusion assay represents a robust means of detecting targeted fusions with known and novel partners. The predictive value of the panel is highest in tumors that show a monomorphic cell population, round cell tumors, as well as tumors rich in inflammatory cells. However, with an increased ability to discover fusions of uncertain significance, it remains essential to emphasize that the diagnosis of bone and soft tissue neoplasms requires the integration of morphology and immunohistochemical profile with these molecular methods, for accurate diagnosis and optimal clinical management of sarcomas.
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http://dx.doi.org/10.1097/PAS.0000000000001745DOI Listing
August 2021

The deacylase SIRT5 supports melanoma viability by influencing chromatin dynamics.

J Clin Invest 2021 Jun;131(12)

Department of Biomedical Engineering and.

Cutaneous melanoma remains the most lethal skin cancer, and ranks third among all malignancies in terms of years of life lost. Despite the advent of immune checkpoint and targeted therapies, only roughly half of patients with advanced melanoma achieve a durable remission. Sirtuin 5 (SIRT5) is a member of the sirtuin family of protein deacylases that regulates metabolism and other biological processes. Germline Sirt5 deficiency is associated with mild phenotypes in mice. Here we showed that SIRT5 was required for proliferation and survival across all cutaneous melanoma genotypes tested, as well as uveal melanoma, a genetically distinct melanoma subtype that arises in the eye and is incurable once metastatic. Likewise, SIRT5 was required for efficient tumor formation by melanoma xenografts and in an autochthonous mouse Braf Pten-driven melanoma model. Via metabolite and transcriptomic analyses, we found that SIRT5 was required to maintain histone acetylation and methylation levels in melanoma cells, thereby promoting proper gene expression. SIRT5-dependent genes notably included MITF, a key lineage-specific survival oncogene in melanoma, and the c-MYC proto-oncogene. SIRT5 may represent a druggable genotype-independent addiction in melanoma.
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http://dx.doi.org/10.1172/JCI138926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203465PMC
June 2021

Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma.

Nat Med 2021 02 25;27(2):289-300. Epub 2021 Jan 25.

NanoString Technologies, Seattle, WA, USA.

Synovial sarcoma (SyS) is an aggressive neoplasm driven by the SS18-SSX fusion, and is characterized by low T cell infiltration. Here, we studied the cancer-immune interplay in SyS using an integrative approach that combines single-cell RNA sequencing (scRNA-seq), spatial profiling and genetic and pharmacological perturbations. scRNA-seq of 16,872 cells from 12 human SyS tumors uncovered a malignant subpopulation that marks immune-deprived niches in situ and is predictive of poor clinical outcomes in two independent cohorts. Functional analyses revealed that this malignant cell state is controlled by the SS18-SSX fusion, is repressed by cytokines secreted by macrophages and T cells, and can be synergistically targeted with a combination of HDAC and CDK4/CDK6 inhibitors. This drug combination enhanced malignant-cell immunogenicity in SyS models, leading to induced T cell reactivity and T cell-mediated killing. Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies.
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http://dx.doi.org/10.1038/s41591-020-01212-6DOI Listing
February 2021

Role of Conical Intersections on the Efficiency of Fluorescent Organic Molecular Crystals.

J Phys Chem A 2021 Feb 25;125(4):1012-1024. Epub 2021 Jan 25.

School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, U.K.

Organic molecular crystals are attractive materials for luminescent applications because of their promised tunability. However, the link between the chemical structure and emissive behavior is poorly understood because of the numerous interconnected factors which are at play in determining radiative and nonradiative behaviors at the solid-state level. In particular, the decay through conical intersection dominates the nonadiabatic regions of the potential energy surface, and thus, their accessibility is a telling indicator of the luminosity of the material. In this study, we investigate the radiative mechanism for five organic molecular crystals which display a solid-state emission, with a focus on the role of conical intersections in their photomechanisms. The objective is to situate the importance of the accessibility of conical intersections with regards to emissive behavior, taking into account other nonradiative decay channels, namely, vibrational decay, and exciton hopping. We begin by giving a brief overview of the structural patterns of the five systems within a larger pool of 13 crystals for a richer comparison. We observe that because of the prevalence of sheet like and herringbone packing in organic molecular crystals, the conformational diversity of crystal dimers is limited. Additionally, similarly spaced dimers have exciton coupling values of a similar order within a 50 meV interval. Next, we focus on three exemplary cases, where we disentangle the role of nonradiative decay mechanisms and show how rotational minimum energy conical intersections in vacuum lead to puckered ones in the crystal, increasing their instability upon crystallization in typical packing motifs. In contrast, molecules with puckered conical intersections in vacuum tend to conserve this trait upon crystallization, and therefore, their quantum yield of fluorescence is determined predominantly by other nonradiative decay mechanisms.
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http://dx.doi.org/10.1021/acs.jpca.0c11072DOI Listing
February 2021

LGR5 in Barrett's Esophagus and its Utility in Predicting Patients at Increased Risk of Advanced Neoplasia.

Clin Transl Gastroenterol 2020 12 22;12(1):e00272. Epub 2020 Dec 22.

Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Introduction: The expression of LGR5, a known stem cell marker, is poorly understood in Barrett's esophagus (BE) and related neoplasia. The aim of this study was to evaluate LGR5 in BE and related neoplasia and to evaluate its utility as a potential biomarker of progression to advanced neoplasia.

Methods: We evaluated total 137 patients, including 119 with BE and 18 with normal gastroesophageal mucosa for expression of LGR5 using RNA in situ hybridization; this also included 28 progressors and 30 nonprogressors. The LGR5 stain was evaluated using 1 qualitative and 2 quantitative parameters, using manual and automated platforms.

Results: Surface LGR5 expression was mainly seen in high-grade dysplasia (12/18) compared with low-grade dysplasia (1/8) and nondysplastic BE (0/17) (P < 0.0001). In contrast to nondysplastic BE, low- and high-grade dysplasia showed a higher percentage of mean number of LGR5-positive crypts per patient (P < 0.0001) and an increase in the mean number of LGR5 transcripts per cell (P < 0.0001). The mean percentage of LGR5-positive crypts per patient and the mean number of LGR5 transcripts per cell were also significantly higher in nondysplastic BE from progressor compared with nonprogressor (P < 0.0001, P = 0.014). The sensitivity and specificity of LGR5 for distinguishing progressor from nonprogressor were 50% and 87%, respectively.

Discussion: BE-related advanced neoplasia shows an expansion of the LGR5-positive cellular compartment, supporting its role as a stem cell marker in this disease. Quantitative LGR5 expression and surface epithelial reactivity are novel biomarkers of increased risk of progression to advanced neoplasia in BE.
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http://dx.doi.org/10.14309/ctg.0000000000000272DOI Listing
December 2020

The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies.

Life Sci Alliance 2021 02 23;4(2). Epub 2020 Dec 23.

Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland

Synovial sarcoma (SyS) is an aggressive mesenchymal malignancy invariably associated with the chromosomal translocation t(X:18; p11:q11), which results in the in-frame fusion of the BAF complex gene to one of three genes. Fusion of SS18 to SSX generates an aberrant transcriptional regulator, which, in permissive cells, drives tumor development by initiating major chromatin remodeling events that disrupt the balance between BAF-mediated gene activation and polycomb-dependent repression. Here, we developed SyS organoids and performed genome-wide epigenomic profiling of these models and mesenchymal precursors to define SyS-specific chromatin remodeling mechanisms and dependencies. We show that SS18-SSX induces broad BAF domains at its binding sites, which oppose polycomb repressor complex (PRC) 2 activity, while facilitating recruitment of a non-canonical (nc)PRC1 variant. Along with the uncoupling of polycomb complexes, we observed H3K27me3 eviction, H2AK119ub deposition and the establishment of de novo active regulatory elements that drive SyS identity. These alterations are completely reversible upon SS18-SSX depletion and are associated with vulnerability to USP7 loss, a core member of ncPRC1.1. Using the power of primary tumor organoids, our work helps define the mechanisms of epigenetic dysregulation on which SyS cells are dependent.
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http://dx.doi.org/10.26508/lsa.202000808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768195PMC
February 2021

Temporal and spatial heterogeneity of host response to SARS-CoV-2 pulmonary infection.

Nat Commun 2020 12 9;11(1):6319. Epub 2020 Dec 9.

Department of Pathology, Brigham and Woman's Hospital, Boston, MA, 02115, USA.

The relationship of SARS-CoV-2 pulmonary infection and severity of disease is not fully understood. Here we show analysis of autopsy specimens from 24 patients who succumbed to SARS-CoV-2 infection using a combination of different RNA and protein analytical platforms to characterize inter-patient and intra-patient heterogeneity of pulmonary virus infection. There is a spectrum of high and low virus cases associated with duration of disease. High viral cases have high activation of interferon pathway genes and a predominant M1-like macrophage infiltrate. Low viral cases are more heterogeneous likely reflecting inherent patient differences in the evolution of host response, but there is consistent indication of pulmonary epithelial cell recovery based on napsin A immunohistochemistry and RNA expression of surfactant and mucin genes. Using a digital spatial profiling platform, we find the virus corresponds to distinct spatial expression of interferon response genes demonstrating the intra-pulmonary heterogeneity of SARS-CoV-2 infection.
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http://dx.doi.org/10.1038/s41467-020-20139-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725958PMC
December 2020

Paediatric Strategy Forum for medicinal product development of epigenetic modifiers for children: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

Eur J Cancer 2020 11 26;139:135-148. Epub 2020 Sep 26.

Solving Kids' Cancer, USA.

The fifth multistakeholder Paediatric Strategy Forum focussed on epigenetic modifier therapies for children and adolescents with cancer. As most mutations in paediatric malignancies influence chromatin-associated proteins or transcription and paediatric cancers are driven by developmental gene expression programs, targeting epigenetic mechanisms is predicted to be a very important therapeutic approach in paediatric cancer. The Research to Accelerate Cures and Equity (RACE) for Children Act FDARA amendments to section 505B of the FD&C Act was implemented in August 2020, and as there are many epigenetic targets on the FDA Paediatric Molecular Targets List, clinical evaluation of epigenetic modifiers in paediatric cancers should be considered early in drug development. Companies are also required to submit to the EMA paediatric investigation plans aiming to ensure that the necessary data to support the authorisation of a medicine for children in EU are of high quality and ethically researched. The specific aims of the forum were i) to identify epigenetic targets or mechanisms of action associated with epigenetic modification relevant to paediatric cancers and ii) to define the landscape for paediatric drug development of epigenetic modifier therapies. DNA methyltransferase inhibitors/hypomethylating agents and histone deacetylase inhibitors were largely excluded from discussion as the aim was to discuss those targets for which therapeutic agents are currently in early paediatric and adult development. Epigenetics is an evolving field and could be highly relevant to many paediatric cancers; the biology is multifaceted and new targets are frequently emerging. Targeting epigenetic mechanisms in paediatric malignancy has in most circumstances yet to reach or extend beyond clinical proof of concept, as many targets do not yet have available investigational drugs developed. Eight classes of medicinal products were discussed and prioritised based on the existing level of science to support early evaluation in children: inhibitors of menin, DOT1L, EZH2, EED, BET, PRMT5 and LSD1 and a retinoic acid receptor alpha agonist. Menin inhibitors should be moved rapidly into paediatric development, in view of their biological rationale, strong preclinical activity and ability to fulfil an unmet clinical need. A combination approach is critical for successful utilisation of any epigenetic modifiers (e.g. EZH2 and EED) and exploration of the optimum combination(s) should be supported by preclinical research and, where possible, molecular biomarker validation in advance of clinical translation. A follow-up multistakeholder meeting focussing on BET inhibitors will be held to define how to prioritise the multiple compounds in clinical development that could be evaluated in children with cancer. As epigenetic modifiers are relatively early in development in paediatrics, there is a clear opportunity to shape the landscape of therapies targeting the epigenome in order that efficient and optimum plans for their evaluation in children and adolescents are developed in a timely manner.
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http://dx.doi.org/10.1016/j.ejca.2020.08.014DOI Listing
November 2020

Comparison of RNA In Situ Hybridization and Immunohistochemistry Techniques for the Detection and Localization of SARS-CoV-2 in Human Tissues.

Am J Surg Pathol 2021 01;45(1):14-24

Departments of Pathology.

Coronavirus disease-19 (COVID-19) is caused by a newly discovered coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although SARS-CoV-2 is visualized on electron microscopy, there is an increasing demand for widely applicable techniques to visualize viral components within tissue specimens. Viral protein and RNA can be detected on formalin-fixed paraffin-embedded (FFPE) tissue using immunohistochemistry (IHC) and in situ hybridization (ISH), respectively. Herein, we evaluate the staining performance of ISH for SARS-CoV-2 and an IHC directed at the SARS-CoV nucleocapsid protein and compare these results to a gold standard, tissue quantitative real-time polymerase chain reaction (qRT-PCR). We evaluated FFPE sections from 8 COVID-19 autopsies, including 19 pulmonary and 39 extrapulmonary samples including the heart, liver, kidney, small intestine, skin, adipose tissue, and bone marrow. We performed RNA-ISH for SARS-CoV-2 on all cases with IHC for SARS-CoV and SARS-CoV-2 qRT-PCR performed on selected cases. Lungs from 37 autopsies performed before the COVID-19 pandemic served as negative controls. The ISH and IHC slides were reviewed by 4 observers to record a consensus opinion. Selected ISH and IHC slides were also reviewed by 4 independent observers. Evidence of SARS-CoV-2 was identified on both the IHC and ISH platforms. Within the postmortem lung, detected viral protein and RNA were often extracellular, predominantly within hyaline membranes in patients with diffuse alveolar damage. Among individual cases, there was regional variation in the amount of detectable virus in lung samples. Intracellular viral RNA and protein was localized to pneumocytes and immune cells. Viral RNA was detected on RNA-ISH in 13 of 19 (68%) pulmonary FFPE blocks from patients with COVID-19. Viral protein was detected on IHC in 8 of 9 (88%) pulmonary FFPE blocks from patients with COVID-19, although in 5 cases the stain was interpreted as equivocal. From the control cohort, FFPE blocks from all 37 patients were negative for SARS-CoV-2 RNA-ISH, whereas 5 of 13 cases were positive on IHC. Collectively, when compared with qRT-PCR on individual tissue blocks, the sensitivity and specificity for ISH was 86.7% and 100%, respectively, while those for IHC were 85.7% and 53.3%, respectively. The interobserver variability for ISH ranged from moderate to almost perfect, whereas that for IHC ranged from slight to moderate. All extrapulmonary samples from COVID-19-positive cases were negative for SARS-CoV-2 by ISH, IHC, and qRT-PCR. SARS-CoV-2 is detectable on both RNA-ISH and nucleocapsid IHC. In the lung, viral RNA and nucleocapsid protein is predominantly extracellular and within hyaline membranes in some cases, while intracellular locations are more prominent in others. The intracellular virus is detected within pneumocytes, bronchial epithelial cells, and possibly immune cells. The ISH platform is more specific, easier to analyze and the interpretation is associated with the improved interobserver agreement. ISH, IHC, and qRT-PCR failed to detect the virus in the heart, liver, and kidney.
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http://dx.doi.org/10.1097/PAS.0000000000001563DOI Listing
January 2021

Temporal and Spatial Heterogeneity of Host Response to SARS-CoV-2 Pulmonary Infection.

medRxiv 2020 Aug 2. Epub 2020 Aug 2.

Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.

The relationship of SARS-CoV-2 lung infection and severity of pulmonary disease is not fully understood. We analyzed autopsy specimens from 24 patients who succumbed to SARS-CoV-2 infection using a combination of different RNA and protein analytical platforms to characterize inter- and intra- patient heterogeneity of pulmonary virus infection. There was a spectrum of high and low virus cases that was associated with duration of disease and activation of interferon pathway genes. Using a digital spatial profiling platform, the virus corresponded to distinct spatial expression of interferon response genes and immune checkpoint genes demonstrating the intra-pulmonary heterogeneity of SARS-CoV-2 infection.
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http://dx.doi.org/10.1101/2020.07.30.20165241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402055PMC
August 2020

hPCL3S promotes proliferation and migration of androgen-independent prostate cancer cells.

Oncotarget 2020 Mar 24;11(12):1051-1074. Epub 2020 Mar 24.

University de Lille, CNRS, Institut Pasteur de Lille, UMR 8161m M3T, Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.

Polycomb repressive complex 2 (PRC2) allows the deposition of H3K27me3. PRC2 facultative subunits modulate its activity and recruitment such as hPCL3/PHF19, a human ortholog of Drosophila Polycomb-like protein (PCL). These proteins contain a TUDOR domain binding H3K36me3, two PHD domains and a "Winged-helix" domain involved in GC-rich DNA binding. The human PCL3 locus encodes the full-length hPCL3L protein and a shorter isoform, hPCL3S containing the TUDOR and PHD1 domains only. In this study, we demonstrated by RT-qPCR analyses of 25 prostate tumors that hPCL3S is frequently up-regulated. In addition, hPCL3S is overexpressed in the androgen-independent DU145 and PC3 cells, but not in the androgen-dependent LNCaP cells. knockdown decreased the proliferation and migration of DU145 and PC3 whereas its forced expression into LNCaP increased these properties. A mutant hPCL3S unable to bind H3K36me3 (TUDOR-W50A) increased proliferation and migration of LNCaP similarly to wt hPCL3S whereas inactivation of its PHD1 domain decreased proliferation. These effects partially relied on the up-regulation of genes known to be important for the proliferation and/or migration of prostate cancer cells such as , and . Collectively, our results suggest hPCL3S as a new potential therapeutic target in castration resistant prostate cancers.
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http://dx.doi.org/10.18632/oncotarget.27511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105160PMC
March 2020

Prognostic impact of hyponatraemia and hypernatraemia at admission and discharge in heart failure patients with preserved, mid-range and reduced ejection fraction.

Intern Med J 2021 Jun;51(6):930-938

Cardiology Department, Hospital General Universitario Gregorio Marañón, CIBERCV, Madrid, Spain.

Background: Hyponatraemia is common in patients with acute heart failure (HF).

Aims: To determine the impact of sodium disturbances on mortality and readmissions in HF with reduced left ventricular ejection fraction (HFrEF), preserved ejection fraction (HFpEF) and mid-range ejection fraction (HFmrEF).

Methods: This study was a prospective multicentre consecutive registry in 20 hospitals, including patients admitted due to acute HF in cardiology departments. Sodium <135 mmol/L was considered hyponatraemia, >145 mmol/L hypernatraemia and 135-145 mmol/L normal.

Results: A total of 1309 patients was included. Mean age was 72.0 ± 11.9 years, and 810 (61.9%) were male. Mean serum sodium level was 138.6 ± 4.7 mmol/L at hospital admission and 138.1 ± 4.1 mmol/L at discharge. The evolution of sodium levels was: normal-at-admission/normal-at-discharge 941 (71.9%), abnormal-at-admission/normal-at-discharge 127 (9.7%), normal-at-admission/abnormal-at-discharge 155 (11.8%) and abnormal-at-admission/abnormal-at-discharge 86 (6.6%). Hyponatraemia at discharge was more common in HFrEF (109 (20.7%)) than in HFpEF (79 (13.9%)) and HFmrEF (27 (12%)), P = 0.003. The prevalence of hypernatraemia at discharge was similar in the three groups: HFrEF (10 (1.9%)), HFpEF (12 (2.1%)) and HFmrEF (4 (1.9%)), P = 0.96. In multivariate analysis, abnormal sodium concentrations at hospital admission (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.15-1.76, P = 0.001) and discharge (HR 1.33, 95% CI 1.08-1.64, P = 0.007) were both independently associated with increased mortality and readmissions at 12 months.

Conclusions: Hyponatraemia and hypernatraemia at admission and discharge predict a poor outcome in patients with acute HF regardless of left ventricular ejection fraction. Hyponatraemia at discharge is more frequent in HFrEF than in the other groups.
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http://dx.doi.org/10.1111/imj.14836DOI Listing
June 2021

LIN28B Underlies the Pathogenesis of a Subclass of Ewing Sarcoma LIN28B Control of EWS-FLI1 Stability.

Cell Rep 2020 03;30(13):4567-4583.e5

Experimental Pathology Service, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland. Electronic address:

Ewing sarcoma (EwS) is associated with poor prognosis despite current multimodal therapy. Targeting of EWS-FLI1, the fusion protein responsible for its pathogenesis, and its principal downstream targets has not yet produced satisfactory therapeutic options, fueling the search for alternative approaches. Here, we show that the oncofetal RNA-binding protein LIN28B regulates the stability of EWS-FLI1 mRNA in ~10% of EwSs. LIN28B depletion in these tumors leads to a decrease in the expression of EWS-FLI1 and its direct transcriptional network, abrogating EwS cell self-renewal and tumorigenicity. Moreover, pharmacological inhibition of LIN28B mimics the effect of LIN28B depletion, suggesting that LIN28B sustains the emergence of a subset of EwS in which it also serves as an effective therapeutic target.
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http://dx.doi.org/10.1016/j.celrep.2019.12.053DOI Listing
March 2020

The Association of Aquaporin-1 Gene with Marathon Running Performance Level: a Confirmatory Study Conducted in Male Hispanic Marathon Runners.

Sports Med Open 2020 Mar 20;6(1):16. Epub 2020 Mar 20.

Hospital Civil de Culiacán, Culiacán, Sinaloa, México.

Background: Replication studies are essential for identifying credible associations between alleles and phenotypes. Validation of genotype-phenotype associations in the sports and exercise field is rare. An initial genetic association study suggested that rs1049305 (C > G) in the 3' untranslated region (3'UTR) of the aquaporin-1 (AQP1) gene was associated with marathon running (MR) performance level in Hispanic males. To validate this finding, we conducted a replication analysis in an independent case-control sample of Hispanic male marathon runners (n = 1430; cases n = 713 and controls n = 717). A meta-analysis was utilized to test the extent of the association between the initial results and the present report. It also provided to test the heterogeneity (variation) between the two studies.

Results: The replication study showed a statistically significant (p ≤ 0.05) association between rs1049305 (C > G) of the AQP1 gene and MR performance level. Association test results using a fixed effect model for the combined, original study and the present report, yielded an odds ratio = 1.28, 95% confidence interval = 1.13-1.45, p = 0.0001. The extent of the measures of heterogeneity was Tau-squared = 0, H statistic = 1, I statistic = 0, and Cochran's Q test (Q = 0.29; p value 0.59), indicated the variation between studies were due to chance and not to differences in heterogeneity between the two studies. Within the limitations of the present replication, contrast of two studies and its effects on meta-analysis, the findings were robust.

Conclusion: This study successfully replicated the results of Martínez et al. (Med Sportiva 13:251-5, 2009). The meta-analysis provided further epidemiological credibility for the hypothesis of association between the DNA rs1049305 (C > G) variation in the 3'UTR of the AQP1 gene and MR running performance level in Hispanics male marathon runners. It is not precluded that a linked DNA structure in the surrounding molecular neighborhood could be of influence by been part of the overly complex phenotype of MR performance level.
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http://dx.doi.org/10.1186/s40798-020-00243-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083975PMC
March 2020

fromage: A library for the study of molecular crystal excited states at the aggregate scale.

J Comput Chem 2020 04 7;41(10):1045-1058. Epub 2020 Jan 7.

Department of Chemistry, School of Biological and Chemical Sciences, Queen Mary University of London, London, UK.

The study of photoexcitations in molecular aggregates faces the twofold problem of the increased computational cost associated with excited states and the complexity of the interactions among the constituent monomers. A mechanistic investigation of these processes requires the analysis of the intermolecular interactions, the effect of the environment, and 3D arrangements or crystal packing on the excited states. A considerable number of techniques have been tailored to navigate these obstacles; however, they are usually restricted to in-house codes and thus require a disproportionate effort to adopt by researchers approaching the field. Herein, we present the FRamewOrk for Molecular AGgregate Excitations (fromage), which implements a collection of such techniques in a Python library complemented with ready-to-use scripts. The program structure is presented and the principal features available to the user are described: geometrical analysis, exciton characterization, and a variety of ONIOM schemes. Each is illustrated by examples of diverse organic molecules in condensed phase settings. The program is available at https://github.com/Crespo-Otero-group/fromage.
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http://dx.doi.org/10.1002/jcc.26144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079081PMC
April 2020

XPO1 Gene Therapy Attenuates Cardiac Dysfunction in Rats with Chronic Induced Myocardial Infarction.

J Cardiovasc Transl Res 2020 08 25;13(4):593-600. Epub 2019 Nov 25.

Myocardial Dysfunction and Cardiac Transplantation Unit, Health Research Institute Hospital La Fe (IIS La Fe), Avd. Fernando Abril Martorell, 106, 46026, Valencia, Spain.

Transcriptomic signature of XPO1 was highly expressed and inversely related to left ventricular function in ischemic cardiomyopathy patients. We hypothesized that treatment with AAV9-shXPO1 attenuates left ventricular dysfunction and remodeling in a myocardial infarction rat model. We induced myocardial infarction by coronary ligation in Sprague-Dawley rats (n = 10), which received AAV9-shXPO1 (n = 5) or placebo AAV9-scramble (n = 5) treatment. Serial echocardiographic assessment was performed throughout the study. After myocardial infarction, AAV9-shXPO1-treated rats showed partial recovery of left ventricular fractional shortening (16.8 ± 2.8 vs 24.6 ± 4.1%, P < 0.05) and a maintained left ventricular dimension (6.17 ± 0.95 vs 4.70 ± 0.93 mm, P < 0.05), which was not observed in non-treated rats. Furthermore, lower levels of EXP-1 (P < 0.05) and lower collagen fibers and fibrosis in cardiac tissue were observed. However, no differences were found in the IL-6 or TNFR1 plasma levels of the myocardium of AAV9-shXPO1 rats. AAV9-shXPO1 administration attenuates cardiac dysfunction and remodeling in rats after myocardial infarction, producing the gene silencing of XPO1.
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http://dx.doi.org/10.1007/s12265-019-09932-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423868PMC
August 2020

Association Between aquaporin-1 and Endurance Performance: A Systematic Review.

Sports Med Open 2019 Sep 5;5(1):40. Epub 2019 Sep 5.

Department of Kinesiology, California State University, Chico, 95929-0330, CA, USA.

Background: There is abundant and mounting information related to the molecular and biological structure and function of the Aquaporin-1 (AQP1) gene and the AQP1-Aquaporin channel. Regulation of water flow across cell membranes is essential for supporting inter- and intracellular fluid balance, which is critical for health and exercise performance. The transmembrane water channel AQP1 is important for cardiorespiratory endurance (CE) because it influences fluid transfers in erythrocytes, endothelial, and pulmonary cells and is vital for transport of ammonium, bicarbonate, carbon dioxide, glycerol, nitric oxide, potassium ion, water, and trans-epithelial and renal water. Very recent publications suggest the association between a DNA sequence variant, rs1049305 (C > G), in the 3'-untranslated region of the AQP1 gene and CE performance. Other reports indicate further significant associations between AQP1 channel and CE phenotypes. The purposes of this systematic review were to examine the extent of the associations between the AQP1 rs1049305 genotype and CE exercise performance and body fluid loss in long-distance runners and AQP1 channel associations with other CE phenotypes.

Methods: Data sources: A comprehensive review was conducted using PubMed, EMBASE, CINAHL, and Cochrane electronic databases. The search ranged from January 1, 1988, to December 31, 2018. Studies reported in English, French, and Spanish were considered. Eligibility criteria: The criteria for inclusion in the review were (a) case-control study; (b) unequivocal definition of cases and controls; (c) CE was defined as performance in endurance events, laboratory tests, and/or maximal oxygen consumption; (d) exclusion criteria of known causes; (e) genotyping performed by PCR or sequencing; (f) genotype frequencies reported; and (g) no deviation of genotype frequencies from Hardy-Weinberg equilibrium in the control group. Study appraisal: The systematic review included studies examining the AQP1 gene and AQP1 channel structure and function, associations between the AQP1 gene sequence variant rs1049305 (C > G)  and CE performance, body fluid loss in long-distance runners, and other studies reporting on the AQP1 gene and channel CE phenotype associations. Synthesis methods: For each selected study, the following data were extracted: authors, year of publication, sample size and number of cases and controls, CE definition, exclusion criteria, inclusion criteria for cases and controls, methods used for genotyping, genotype, allele frequencies and HWE for genotype frequencies in cases and control groups, and method of AQP1 gene and AQP1 channel analysis.

Results: The initial databases search found 172 pertinent studies. Of those, 46 studies were utilized in the final synthesis of the systematic review. The most relevant findings were (a) the identification of an independent replication of the association between AQP1 gene sequence variant rs1049305 (C > G) and CE performance; (b) the association of the rs1049305 C-allele with faster CE running performance; (c) in knockout model, using a linear regression analysis of distance run as a function of Aqp1 status (Aqp1-null vs. wild-type mice) and conditions of hypoxia (ambient [O] = 16%), normoxia (21%), and hyperoxia (40%) indicated that the Aqp1 knockout ran less distance than the wild-type mice (p < 0.001); (d) in vitro, a reduced AQP1 expression was associated with the presence of the rs1049305 G-allele; (e) AQP1 null humans led normal lives and were entirely unaware of any physical limitations. However, they could not support fluid homeostasis when exposed to chronic fluid overload. The limited number of studies with "adequate sample sizes" in various racial and ethnic groups precluding to perform proper in-depth statistical analysis.

Conclusions: The AQP1 gene and AQP1 channel seems to support homeostatic mechanisms, yet to be totally understood, that are auxiliary in achieving an advantage during endurance exercise. AQP1 functions are vital during exercise and have a profound influence on endurance running performance. AQP1s are underappreciated structures that play vital roles in cellular homeostasis at rest and during CE endurance running exercise. The outcome of the present systematic review provide support to the statement of hypotheses and further research endeavors on the likely influence of AQP1 gene and AQP1 channel on CE performance. Registration: The protocol is not registered.
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http://dx.doi.org/10.1186/s40798-019-0213-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728102PMC
September 2019

Novel and established EWSR1 gene fusions and associations identified by next-generation sequencing and fluorescence in-situ hybridization.

Hum Pathol 2019 11 17;93:65-73. Epub 2019 Aug 17.

Massachusetts General Hospital, Department of Pathology, and Harvard Medical School, Boston, MA, 02114, USA. Electronic address:

EWSR1 is a 'promiscuous' gene that can fuse with many different partner genes in phenotypically identical tumors or partner with the same genes in morphologically and behaviorally different neoplasms. Our study set out to examine the EWSR1 fusions identified at our institution over a 3-year period, using various methods, their association with specific entities and possible detection of novel partners and associations. Sixty-three consecutive cases investigated for EWSR1 gene fusions between 2015 and 2018 at our institution were included in this study. Fusions were identified by either break-apart fluorescence in-situ hybridization (FISH), our clinical RNA-based assay for fusion transcript detection or both. Twenty-eight cases were concurrently tested by FISH and NGS, 24 were tested by FISH alone and 11 by NGS alone. Of the 28 cases with dual testing, 24 were positive by both assays for an EWSR1 gene fusion, 3 cases were discordant with a positive FISH assay and a negative NGS assay, and 1 case was discordant with a negative FISH assay but a positive NGS assay. Three novel fusions were identified: a complex rearrangement involving three genes (EWSR1/RBFOX2/ERG) in Ewing sarcoma, a EWSR1/TCF7L2 fusion in a colon adenocarcinoma, and a EWSR1/TFEB fusion in a translocation-associated renal cell carcinoma. Both colonic adenocarcinoma and renal cell carcinoma had not been previously associated with EWSR1 rearrangements to our knowledge. In a subset of cases, detection of a specific partner had an impact on the histological diagnosis and patient management. In our experience, the use of a targeted NGS-based fusion assay is superior to EWSR1 break-apart FISH for the detection of known and novel EWSR1 rearrangements and fusion partners, particularly given the emerging understanding that distinct fusion partners result in different diseases with distinct prognostic and therapeutic implications.
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http://dx.doi.org/10.1016/j.humpath.2019.08.006DOI Listing
November 2019

Resolving medulloblastoma cellular architecture by single-cell genomics.

Nature 2019 08 24;572(7767):74-79. Epub 2019 Jul 24.

Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Research Discovery Institute, La Jolla, CA, USA.

Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.
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http://dx.doi.org/10.1038/s41586-019-1434-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754173PMC
August 2019

Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer.

Cell 2019 06 30;178(1):160-175.e27. Epub 2019 May 30.

Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.

Single-cell technologies have described heterogeneity across tissues, but the spatial distribution and forces that drive single-cell phenotypes have not been well defined. Combining single-cell RNA and protein analytics in studying the role of stromal cancer-associated fibroblasts (CAFs) in modulating heterogeneity in pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) model systems, we have identified significant single-cell population shifts toward invasive epithelial-to-mesenchymal transition (EMT) and proliferative (PRO) phenotypes linked with mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling. Using high-content digital imaging of RNA in situ hybridization in 195 PDAC tumors, we quantified these EMT and PRO subpopulations in 319,626 individual cancer cells that can be classified within the context of distinct tumor gland "units." Tumor gland typing provided an additional layer of intratumoral heterogeneity that was associated with differences in stromal abundance and clinical outcomes. This demonstrates the impact of the stroma in shaping tumor architecture by altering inherent patterns of tumor glands in human PDAC.
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http://dx.doi.org/10.1016/j.cell.2019.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697165PMC
June 2019

The altered expression of autophagy-related genes participates in heart failure: NRBP2 and CALCOCO2 are associated with left ventricular dysfunction parameters in human dilated cardiomyopathy.

PLoS One 2019 22;14(4):e0215818. Epub 2019 Apr 22.

Cardiocirculatory Unit, Health Research Institute of La Fe University Hospital (IIS La Fe), Valencia, Spain.

This study aimed to analyze changes in the expression of autophagy- and phagocytosis-related genes in patients with dilated cardiomyopathy (DCM), especially in relation to left ventricular (LV) dysfunction. Furthermore, transmission electron microscopy of the diseased tissue was carried out to investigate if the gene expression changes are translated into ultrastructural alterations. LV tissue samples from patients with DCM (n = 13) and from controls (CNT; n = 10) were analyzed by RNA-sequencing, whereupon the altered expression (P < 0.05) of 13 autophagy- and 3 phagocytosis-related genes was observed. The expression changes of the autophagy-related genes NRBP2 and CALCOCO2 were associated with cardiac dysfunction and remodeling (P < 0.05). The affected patients had a higher activity of these degradation processes, as evidenced by the greater number of autophagic structures in the DCM tissue (P < 0.001). Differences in the ultrastructural distribution were also found between the DCM and CNT tissues. These results show that in patients with DCM, the altered expression of NRBP2 and CALCOCO2 is related to LV dysfunction and remodeling. Clarification of the molecular mechanisms of cardiac autophagy would help in the future development of therapies to improve LV performance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215818PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476534PMC
January 2020

Giant Cell Lesions of the Maxillofacial Skeleton Express RANKL by RNA In Situ Hybridization Regardless of Histologic Pattern.

Am J Surg Pathol 2019 06;43(6):819-826

Departments of Pathology.

Maxillofacial central giant cell lesions (CGCLs) are often locally aggressive tumors in young patients that may be histologically very similar to or quite distinct when compared with giant cell tumors (GCTs) of long bones. It has been well established that GCTs express high levels of receptor activator of nuclear factor-kappa B ligand (RANKL) and are amenable to treatment with denosumab. To assess the predictive value of morphology, we evaluated CGCLs with GCT-like or non-GCT-like histology for RANKL expression by RNA in situ hybridization. Tumors were classified by clinical and radiographic criteria as aggressive or nonaggressive and histopathologically as resembling GCT or non-GCT-like. RNA in situ hybridization for RANKL mRNA was performed and scored semiquantitatively based on the magnification at which the signal was first detected. There were 17 patients (M:F=8:9) with a median age of 15 years. Nine patients were children under 18 years of age. In 10 patients, tumors were characterized as GCT-like and in 7, non-GCT-like; 6 occurred in the setting of a known associated syndrome. Of the sporadic tumors, 9/11 (82%) were classified as aggressive. Fifteen of 17 (88%) tumors strongly expressed RANKL (8/9 aggressive, 2/2 nonaggressive; 10/10 GCT-like and 5/7 non-GCT-like). Two patients with clinically aggressive CGCL, GCT-like histology and high tumor RANKL expression were identified as candidates for a trial of denosumab with notable clinical response. CGCLs demonstrate strong and diffuse RANKL mRNA expression in mononuclear stromal cells, regardless of histology or presence of an associated syndrome. Denosumab may be clinically beneficial in aggressive CGCLs.
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http://dx.doi.org/10.1097/PAS.0000000000001257DOI Listing
June 2019

Discharge treatment with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker after a heart failure hospitalisation is associated with a better prognosis irrespective of left ventricular ejection fraction.

Intern Med J 2019 12;49(12):1505-1513

Cardiology Department, Hospital General Universitario Gregorio Marañón, CIBERCV, Madrid, Spain.

Background: Medical therapy could improve the prognosis of real-life patients discharged after a heart failure (HF) hospitalisation.

Aim: To determine the impact of discharge HF treatment on mortality and readmissions in different left ventricular ejection fraction (LVEF) groups.

Methods: Multicentre prospective registry in 20 Spanish hospitals. Patients were enrolled after a HF hospitalisation.

Results: A total of 1831 patients was included (583 (31.8%) HF with reduced ejection fraction (HFrEF); 227 (12.4%) HF with midrange ejection fraction (HFmrEF); 610 (33.3%) HF with preserved ejection fraction (HFpEF), and 411 (22.4%) with unknown LVEF). Angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARB) at discharge were independently associated with a reduction in: (i) all-cause mortality: hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.41-0.74, P < 0.001, with a similar effect in the four groups; (ii) mortality due to refractory HF HR 0.45, 95% CI 0.29-0.64, P < 0.001, with a similar effect in the three groups with known LVEF; (iii) mortality/HF admissions (HR 0.61; 95% CI: 0.50-0.74), more evident in HFrEF (HR 0.54; 95% CI: 0.38-0.78) compared with HRmEF (HR 0.64; 95% CI 0.40-1.02), or HFpEF (HR 0.70; 95% CI 0.53-0.92). In patients with HFrEF triple therapy (ACE inhibitor/ARB + beta blocker + mineralocorticoid receptor antagonist) was associated with the lowest mortality risk (HR 0.21; 95% CI: 0.08-0.57, P = 0.002) compared with patients that received none of these drugs.

Conclusions: Discharge treatment with ACE inhibitor/ARB after a HF hospitalisation is associated with a reduction in all-cause and refractory HF mortality, irrespective of LVEF.
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http://dx.doi.org/10.1111/imj.14289DOI Listing
December 2019

ONIOM(QM:QM') Electrostatic Embedding Schemes for Photochemistry in Molecular Crystals.

J Chem Theory Comput 2019 Apr 21;15(4):2504-2516. Epub 2019 Mar 21.

School of Biological and Chemical Sciences , Queen Mary University of London , Mile End Road , London E1 4NS , U.K.

Understanding photoinduced processes in molecular crystals is central to the design of highly emissive materials such as organic lasers and organic light-emitting diodes. The modeling of such processes is, however, hindered by the lack of excited state methodologies tailored for these systems. Embedding approaches based on the Ewald sum can be used in conjunction with excited state electronic structure methods to model the localized excitations which characterize these materials. In this article, we describe the implementation of a two-level ONIOM(QM:QM') point charge embedding approach based on the Ewald method, the ONIOM Ewald embedded cluster (OEEC) model. An alternative self-consistent method is also considered to simulate the response of the environment to the excitation. Two molecular crystals with opposing photochemical behavior were used to benchmark the results with single reference and multireference methods. We observed that the inclusion of an explicit ground state cluster surrounding the QM region was imperative for the exploration of the excited state potential energy surfaces. Using OEEC, accurate absorption and emission energies as well as S-S conical intersections were obtained for both crystals. We discuss the implications of the use of these embedding schemes considering the degree of localization of the excitation. The methods discussed herein are implemented in an open source platform (fromage, https://github.com/Crespo-Otero-group/fromage ) which acts as an interface between popular electronic structure codes (Gaussian, Turbomole, and Molcas).
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http://dx.doi.org/10.1021/acs.jctc.8b01180DOI Listing
April 2019

COX-2 mediates tumor-stromal prolactin signaling to initiate tumorigenesis.

Proc Natl Acad Sci U S A 2019 03 28;116(12):5223-5232. Epub 2019 Feb 28.

Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129;

Tumor-stromal communication within the microenvironment contributes to initiation of metastasis and may present a therapeutic opportunity. Using serial single-cell RNA sequencing in an orthotopic mouse prostate cancer model, we find up-regulation of prolactin receptor as cancer cells that have disseminated to the lungs expand into micrometastases. Secretion of the ligand prolactin by adjacent lung stromal cells is induced by tumor cell production of the COX-2 synthetic product prostaglandin E2 (PGE2). PGE2 treatment of fibroblasts activates the orphan nuclear receptor NR4A (Nur77), with prolactin as a major transcriptional target for the NR4A-retinoid X receptor (RXR) heterodimer. Ectopic expression of prolactin receptor in mouse cancer cells enhances micrometastasis, while treatment with the COX-2 inhibitor celecoxib abrogates prolactin secretion by fibroblasts and reduces tumor initiation. Across multiple human cancers, COX-2, prolactin, and prolactin receptor show consistent differential expression in tumor and stromal compartments. Such paracrine cross-talk may thus contribute to the documented efficacy of COX-2 inhibitors in cancer suppression.
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http://dx.doi.org/10.1073/pnas.1819303116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431196PMC
March 2019

KCNA4 Gene Variant is Auxiliary in Endurance Running Performance Level.

Int J Sports Med 2019 May 27;40(5):354-358. Epub 2019 Feb 27.

Department Physical Medicine, Rehabilitation & Sports Medicine, University of Puerto Rico School of Medicine, San Juan, Puerto Rico.

The present is an observational study following a genetic epidemiology model using a case-control design. We tested the hypothesis of an association between the prevalence of the genotypic and allelic frequencies distribution of the potassium voltage-gated channel of the shaker related subfamily member 4 gene (KCNA4) rs1323860 (C/T transition) and endurance performance level in Hispanic male marathon runners (MR). The subjects (n=1876) were adult Hispanic male MR. Fast-MR (cases; n=938) were finishers in the top 3 percentile. Slow MR (controls; n=938) were finishers in the lowest 3 percentile of their respective age. Genomic DNA was purified from a whole blood sample. Polymerase chain reaction was used to amplify a KCNA4 SNP which consists of a C/T (rs1323860) transition. The observed genotype frequencies, in both Cases and Controls, met Hardy-Weinberg equilibrium (X, P≥0.05). Genotype and allele frequencies were statistically different (P<0.01) between cases and controls. Odds ratio revealed that the C allele was 1.33 times more likely prevalent in the cases than in the controls (95% CI; 1.17, 1.51; P<0.001). The magnitude of the statistical power for the present study was 0.86. In conclusion, the findings strongly suggest that KCNA4 gene rs1323860 (C/T transition) is auxiliary in the complex phenotype of endurance running performance level in Hispanic male marathon runners.
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http://dx.doi.org/10.1055/a-0824-5394DOI Listing
May 2019

Adherence to Exercise Programs in Older Adults: Informative Report.

Gerontol Geriatr Med 2019 Jan-Dec;5:2333721418823604. Epub 2019 Jan 22.

University of Puerto Rico, San Juan, Puerto Rico.

This informative report focuses on filling information gaps regarding adherence to physical activity and exercise in the health care spectrum of older adults (OA) and an overview of the benefits of physical activity for OA. Healthy People 2000, 2010, and 2020 are public health programs from the U.S. Department of Health and Human Services that set national goals and objectives for promoting health and preventing disease. The programs include 10 leading health indicators that reflect major health problems, which concern OA. Exercise and physical activity are among the most important factors affecting health and longevity, but exercise adherence is a significant hindrance in achieving health goals in the OA. Exercise adherence in OA is a multifactorial problem encompassing many biopsychosocial factors. Factors affecting adherence in the OA include socioeconomic status, education level, living arrangements, health status, pacemakers, physical fitness, and depression. Improving adherence could have a significant impact on longevity, quality of life, and health care costs.
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http://dx.doi.org/10.1177/2333721418823604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343518PMC
January 2019

MDM2 RNA In Situ Hybridization for the Diagnosis of Atypical Lipomatous Tumor: A Study Evaluating DNA, RNA, and Protein Expression.

Am J Surg Pathol 2019 04;43(4):446-454

Departments of Pathology.

The distinction of atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) from its benign counterpart, lipoma, may represent a challenge. MDM2 DNA amplification is used as the gold standard as MDM2 immunohistochemistry lacks specificity and sensitivity. Herein, we investigate the diagnostic utility of MDM2 RNA in situ hybridization (RNA-ISH) and compare the test with MDM2 immunohistochemistry and MDM2 DNA fluorescence in situ hybridization (FISH) in benign and malignant lipomatous neoplasms. We evaluated 109 neoplasms including 27 lipomas, 25 spindle cell lipomas, 32 ALTs/WDLs, and 25 dedifferentiated liposarcomas (DDL). The validation cohort included 14 lipoma-like neoplasms that lacked unequivocal features of ALT/WDL and in which MDM2 immunohistochemistry was either equivocal, negative or falsely positive. Immunohistochemistry, automated RNA-ISH and DNA-FISH for MDM2 were performed. Tumors with diffuse nuclear staining or >50 dots per cell on RNA-ISH were considered positive. All lipomas and lipoma variants were negative for RNA-ISH while all ALTs/WDLs and DDLs were positive. Eighty percent (24/30) and 92% (22/24) of ALTs/WDLs and DDLs were positive for MDM2 immunohistochemistry. Lipomas and its variants were negative for MDM2 amplification; 92% and 100% of ALTs/WDLs and DDLs showed MDM2 DNA amplification. The mean percentage of ALT/WDL tumor cells showing MDM2 RNA-ISH positivity was 73% compared with 24% on MDM2 immunohistochemistry. RNA-ISH correctly classified all 10 ALTs/WDLs and all 4 lipomas in the validation cohort. The performance of MDM2 RNA-ISH and MDM2 DNA-FISH are equivalent. MDM2 RNA-ISH can be of diagnostic value in histologically challenging lipomatous neoplasms. The automated MDM2 RNA-ISH assay should allow for more widespread use of MDM2 testing and for a more sensitive and specific diagnosis of ALT/WDL.
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http://dx.doi.org/10.1097/PAS.0000000000001199DOI Listing
April 2019

The histological diagnosis of IgG4-related disease on small biopsies: challenges and pitfalls.

Histopathology 2019 Apr 10;74(5):688-698. Epub 2019 Mar 10.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Aims: The pathological diagnosis of IgG4-related disease (IgG4-RD) relies on histology, IgG4-positive cells, and an increased IgG4/IgG ratio. Small biopsies from patients with a presumptive diagnosis of IgG4-RD often fail to meet consensus histological criteria. The aims of this study were to evaluate consecutive small biopsies from patients with a presumptive diagnosis of IgG4-RD, and to assess the significance of the pathological findings.

Methods And Results: We evaluated 55 small biopsies from patients with a presumptive diagnosis of IgG4-RD. The retrospective cohort comprised 71 patients with IgG4-RD and 57 mimics. We performed immunohistochemistry (IHC) and in-situ hybridisation (ISH) for IgG4 and IgG. Twenty-six patients from the prospective cohort met the histological criteria for IgG4-RD (definite); 29 patients lacked one or more pathological features (borderline). Twenty biopsies (36%) lacked both storiform fibrosis and obliterative phlebitis, and nine (16%) lacked an increase in the number of IgG4-positive plasma cells. Ninety-three per cent of patients showed an IgG4/total IgG ratio of >40% (>30% by ISH). There were no differences in the incidence of multiorgan disease (P = 0.9), serum IgG4 levels (P = 0.6) and response to therapy between the definite and borderline groups. A strong correlation (Pearson 0.77) between the IHC and ISH platforms was noted with regard to the IgG4/total IgG ratio.

Conclusion: Patients with a presumptive diagnosis of IgG4-RD but lacking the characteristic pathological features of this disease appear to be clinically similar to those who meet the current pathological criteria. An elevated IgG4/total IgG ratio is the most sensitive pathological feature, and ISH provides a robust quantification platform. We recommend evaluating tumefactive lymphoplasmacytic infiltrates with an increased IgG4/IgG ratio, regardless of histological features, for IgG4-RD.
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http://dx.doi.org/10.1111/his.13787DOI Listing
April 2019
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