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1.
Pharmacol Res ; 182: 106354, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35842184

RESUMO

Perivascular adipose tissue (PVAT) resides at the outermost boundary of the vascular wall, surrounding most conduit blood vessels, except for the cerebral vessels, in humans. A growing body of evidence suggests that inflammation localized within PVAT may contribute to the pathogenesis of cardiovascular disease (CVD). Patients with autoimmune rheumatic diseases (ARDs), e.g., systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), psoriasis, etc., exhibit heightened systemic inflammation and are at increased risk for CVD. Data from clinical studies in patients with ARDs support a linkage between dysfunctional adipose tissue, and PVAT in particular, in disease pathogenesis. Here, we review the data linking PVAT to the pathogenesis of CVD in patients with ARDs, focusing on the role of novel PVAT imaging techniques in defining disease risk and responses to biological therapies.


Assuntos
Doenças Autoimunes , Doenças Cardiovasculares , Síndrome do Desconforto Respiratório , Doenças Reumáticas , Tecido Adiposo/fisiologia , Doenças Autoimunes/complicações , Doenças Cardiovasculares/patologia , Humanos , Inflamação
2.
PLoS One ; 17(7): e0270018, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35834547

RESUMO

IMPORTANCE: Extracellular matrix proteins and enzymes involved in degradation have been found to be associated with tissue fibrosis and ureteropelvic junction obstruction (UPJO). In this study we developed a promising urinary biomarker model which can identify reduced renal function in UPJ obstruction patients. This can potentially serve as a non-invasive way to enhance surgical decision making for patients and urologists. OBJECTIVE: We sought to develop a predictive model to identify UPJO patients at risk for reduced renal function. DESIGN: Prospective cohort study. SETTING: Pre-operative urine samples were collected in a prospectively enrolled UPJO biomarker registry at our institution. Urinary MMP-2, MMP-7, TIMP-2, and NGAL were measured as well as clinical characteristics including hydronephrosis grade, differential renal function, t1/2, and UPJO etiology. PARTICIPANTS: Children who underwent pyeloplasty for UPJO. MAIN OUTCOME MEASUREMENT: Primary outcome was reduced renal function defined as MAG3 function <40%. Multivariable logistic regression was applied to identify the independent predictive biomarkers in the original Training cohort. Model validation and generalizability were evaluated in a new UPJO Testing cohort. RESULTS: We included 71 patients with UPJO in the original training cohort and 39 in the validation cohort. Median age was 3.3 years (70% male). By univariate analysis, reduced renal function was associated with higher MMP-2 (p = 0.064), MMP-7 (p = 0.047), NGAL (p = 0.001), and lower TIMP-2 (p = 0.033). Combining MMP-7 with TIMP-2, the multivariable logistic regression model predicted reduced renal function with good performance (AUC = 0.830; 95% CI: 0.722-0.938). The independent testing dataset validated the results with good predictive performance (AUC = 0.738). CONCLUSIONS AND RELEVANCE: Combination of urinary MMP-7 and TIMP-2 can identify reduced renal function in UPJO patients. With the high sensitivity cutoffs, patients can be categorized into high risk (aggressive management) versus lower risk (observation).


Assuntos
Hidronefrose , Metaloproteinase 7 da Matriz , Inibidor Tecidual de Metaloproteinase-2 , Obstrução Ureteral , Biomarcadores/urina , Criança , Pré-Escolar , Feminino , Humanos , Hidronefrose/etiologia , Hidronefrose/urina , Rim/fisiopatologia , Pelve Renal/fisiopatologia , Lipocalina-2/urina , Masculino , Metaloproteinase 2 da Matriz/urina , Metaloproteinase 7 da Matriz/urina , Estudos Prospectivos , Inibidor Tecidual de Metaloproteinase-2/urina , Obstrução Ureteral/complicações , Obstrução Ureteral/cirurgia , Obstrução Ureteral/urina
3.
Hepatol Commun ; 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35833455

RESUMO

In nonalcoholic fatty liver disease (NAFLD) the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 variant is a contributor. In mice, the Pnpla3 148M variant accumulates on lipid droplets and probably leads to sequestration of a lipase cofactor leading to impaired mobilization of triglycerides. To advance our understanding of the localization and abundance of PNPLA3 protein in humans, we used liver biopsies from patients with NAFLD to investigate the link to NAFLD and the PNPLA3 148M genotype. We experimentally qualified an antibody against human PNPLA3. Hepatic PNPLA3 protein fractional area and localization were determined by immunohistochemistry in biopsies from a well-characterized NAFLD cohort of 67 patients. Potential differences in hepatic PNPLA3 protein levels among patients related to degree of steatosis, lobular inflammation, ballooning, and fibrosis, and PNPLA3 I148M gene variants were assessed. Immunohistochemistry staining in biopsies from patients with NAFLD showed that hepatic PNPLA3 protein was predominantly localized to the membranes of small and large lipid droplets in hepatocytes. PNPLA3 protein levels correlated strongly with steatosis grade (p = 0.000027) and were also significantly higher in patients with lobular inflammation (p = 0.009), ballooning (p = 0.022), and significant fibrosis (stage 2-4, p = 0.014). In addition, PNPLA3 levels were higher in PNPLA3 rs738409 148M (CG, GG) risk allele carriers compared to 148I (CC) nonrisk allele carriers (p = 0.0029). Conclusion: PNPLA3 protein levels were associated with increased hepatic lipid content and disease severity in patients with NAFLD and were higher in PNPLA3 rs738409 (148M) risk allele carriers. Our hypothesis that increased hepatic levels of PNPLA3 may be part of the pathophysiological mechanism of NAFLD is supported.

4.
5.
Circulation ; 146(5): 412-426, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35862076

RESUMO

BACKGROUND: The human heart has limited capacity to generate new cardiomyocytes and this capacity declines with age. Because loss of cardiomyocytes may contribute to heart failure, it is crucial to explore stimuli of endogenous cardiac regeneration to favorably shift the balance between loss of cardiomyocytes and the birth of new cardiomyocytes in the aged heart. We have previously shown that cardiomyogenesis can be activated by exercise in the young adult mouse heart. Whether exercise also induces cardiomyogenesis in aged hearts, however, is still unknown. Here, we aim to investigate the effect of exercise on the generation of new cardiomyocytes in the aged heart. METHODS: Aged (20-month-old) mice were subjected to an 8-week voluntary running protocol, and age-matched sedentary animals served as controls. Cardiomyogenesis in aged hearts was assessed on the basis of 15N-thymidine incorporation and multi-isotope imaging mass spectrometry. We analyzed 1793 cardiomyocytes from 5 aged sedentary mice and compared these with 2002 cardiomyocytes from 5 aged exercised mice, followed by advanced histology and imaging to account for ploidy and nucleation status of the cell. RNA sequencing and subsequent bioinformatic analyses were performed to investigate transcriptional changes induced by exercise specifically in aged hearts in comparison with young hearts. RESULTS: Cardiomyogenesis was observed at a significantly higher frequency in exercised compared with sedentary aged hearts on the basis of the detection of mononucleated/diploid 15N-thymidine-labeled cardiomyocytes. No mononucleated/diploid 15N-thymidine-labeled cardiomyocyte was detected in sedentary aged mice. The annual rate of mononucleated/diploid 15N-thymidine-labeled cardiomyocytes in aged exercised mice was 2.3% per year. This compares with our previously reported annual rate of 7.5% in young exercised mice and 1.63% in young sedentary mice. Transcriptional profiling of young and aged exercised murine hearts and their sedentary controls revealed that exercise induces pathways related to circadian rhythm, irrespective of age. One known oscillating transcript, however, that was exclusively upregulated in aged exercised hearts, was isoform 1.4 of regulator of calcineurin, whose regulation and functional role were explored further. CONCLUSIONS: Our data demonstrate that voluntary running in part restores cardiomyogenesis in aged mice and suggest that pathways associated with circadian rhythm may play a role in physiologically stimulated cardiomyogenesis.


Assuntos
Miócitos Cardíacos , Condicionamento Físico Animal , Animais , Calcineurina/metabolismo , Humanos , Lactente , Camundongos , Miócitos Cardíacos/citologia , Timidina/metabolismo
6.
Data Brief ; 42: 108306, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35664657

RESUMO

This metabolite dataset was collected from transgenic murine retinal ganglion cells (RGC) expressing bacterial channelrhodopsin labeled with fluorescent protein. Mice were subjected to optic nerve crush (ONC) with subsequent RGC stimulation of channelrhodopsin with blue light (promoting regeneration) or non-stimulation (control). ONC induces retinal ganglion cell degeneration over time with progressive loss of axons. In transgenic bacterial channelrhodopsin expressing RGC cells, light stimulation promotes regeneration of ONC axons. Genetically matched wild-type uninjured optic nerves were analyzed as controls for comparison. Metabolites were carefully extracted from finely minced optic nerve tissue using a solvent system (initial separation using 1:1 methanol and H2O and second extraction using 8:1:1 of acetonitrile:acetone:methanol). Untargeted liquid chromatography-mass spectrometry profiling was performed using fractionation on a Vanquish Horizon Binary UHPLC. Subsequent analyses were performed on an inline coupled Q-Exactive Orbitrap instrument. Metabolites were identified using Compound DiscovererTM software. Statistical analysis was performed using MetaboAnalyst 5.0. This data is available on Metabolomics Workbench, Study ID ST002111.

7.
Nat Commun ; 13(1): 3165, 2022 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-35672367

RESUMO

Detailed knowledge on how bacteria evade antibiotics and eventually develop resistance could open avenues for novel therapeutics and diagnostics. It is thereby key to develop a comprehensive genome-wide understanding of how bacteria process antibiotic stress, and how modulation of the involved processes affects their ability to overcome said stress. Here we undertake a comprehensive genetic analysis of how the human pathogen Streptococcus pneumoniae responds to 20 antibiotics. We build a genome-wide atlas of drug susceptibility determinants and generated a genetic interaction network that connects cellular processes and genes of unknown function, which we show can be used as therapeutic targets. Pathway analysis reveals a genome-wide atlas of cellular processes that can make a bacterium less susceptible, and often tolerant, in an antibiotic specific manner. Importantly, modulation of these processes confers fitness benefits during active infections under antibiotic selection. Moreover, screening of sequenced clinical isolates demonstrates that mutations in genes that decrease antibiotic sensitivity and increase tolerance readily evolve and are frequently associated with resistant strains, indicating such mutations could be harbingers for the emergence of antibiotic resistance.


Assuntos
Antibacterianos , Streptococcus pneumoniae , Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos , Tolerância a Medicamentos , Humanos , Testes de Sensibilidade Microbiana
8.
Data Brief ; 42: 108304, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35677457

RESUMO

This labeled quantitative proteomics dataset was collected from a transgenic channel rhodopsin mouse model (Chr2) subjected to light stimulation after traumatic optic nerve crush (ONC). Protein extraction was performed by careful mincing of the tissue in extraction buffer (TEAB, NaCl and SDS). Protein amounts were normalized across samples using dot blot densitometry and ImageJ software. Samples were labeled for quantification using a modified TMTpro™ 16plex Label Reagent Set (Thermo Scientific™) after performing an overnight trypsin digestion. Untargeted liquid chromatography-mass spectrometry was performed on an Easy-nLC 1000 liquid chromatograph coupled to a Q Exactive mass spectrometer (LC-MS/MS). Data analysis was performed using Proteome Discoverer™ 2.5 (Thermo Scientific™). This data has been deposited to the ProteomeXchange (PX) and is available through PRIDE with the identifier PXD032788.

9.
Curr Issues Mol Biol ; 44(5): 2015-2028, 2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35678665

RESUMO

Gut microbiome balance plays a key role in human health and maintains gut barrier integrity. Dysbiosis, referring to impaired gut microbiome, is linked to a variety of diseases, including cancers, through modulation of the inflammatory process. Most studies concentrated on adenocarcinoma of different sites with very limited information on gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In this study, we have analyzed the gut microbiome (both fungal and bacterial communities) in patients with metastatic GEP-NENs. Fecal samples were collected and compared with matched healthy control samples using logistic regression distances utilizing R package MatchIt (version 4.2.0, Daniel E. Ho, Stanford, CA, USA). We examined differences in microbiome profiles between GEP-NENs and control samples using small subunit (SSU) rRNA (16S), ITS1, ITS4 genomic regions for their ability to accurately characterize bacterial and fungal communities. We correlated the results with different behavioral and dietary habits, and tumor features including differentiation, grade, primary site, and therapeutic response. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant. Gut samples of 34 patients (12 males, 22 females, median age 64 years) with metastatic GEP-NENs (22 small bowel, 10 pancreatic, 1 gall bladder, and 1 unknown primary) were analyzed. Twenty-nine patients had well differentiated GEP-neuroendocrine tumors (GEP-NETs), (G1 = 14, G2 = 12, G3 = 3) and five patients had poorly differentiated GEP-neuroendocrine carcinomas (GEP-NECs). Patients with GEP-NENs had significantly decreased bacterial species and increased fungi (notably Candida species, Ascomycota, and species belonging to saccharomycetes) compared to controls. Patients with GEP-NECs had significantly enriched populations of specific bacteria and fungi (such as Enterobacter hormaechei, Bacteroides fragilis and Trichosporon asahii) compared to those with GEP-NETs (p = 0.048, 0.0022 and 0.034, respectively). In addition, higher grade GEP-NETs were associated with significantly higher Bacteroides fragilis (p = 0.022), and Eggerthella lenta (p = 0.00018) species compared to lower grade tumors. There were substantial differences associated with dietary habits and therapeutic responses. This is the first study to analyze the role of the microbiome environment in patients with GEP-NENs. There were significant differences between GEP-NETs and GEP-NECs, supporting the role of the gut microbiome in the pathogenesis of these two distinct entities.

10.
Advers Resil Sci ; : 1-13, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35692379

RESUMO

Little is known about how Asian American families, as well as other racially marginalized families, communicate about ethnic and racial group histories, particularly regarding historical trauma. Unlike personal trauma, historical trauma refers to distressing or life-threatening events which members of a group with a shared social identity experience together and pass on to their descendants. It has been studied in a variety of groups and contexts, notably in Holocaust survivors and their families and in Native American communities. The concept has seen limited application to Asian American groups, despite its relevance to their unique and shared lived experiences. For instance, the majority of Asian Americans have immigrated from countries across Asia that have been profoundly affected by war and political upheaval in the past century. Research on historical trauma among Asian Americans has focused primarily on refugees who fled the US wars in Southeast Asia, with some research on Japanese Americans who were incarcerated during World War II. Historical trauma related to other major events, such as the India/Pakistan Partition, the Chinese Civil War and Cultural Revolution, the Korean War, and the Sri Lankan Civil War, have not been examined among Asian Americans. A lack of recognition of these historical traumas within families and communities, as well as in the psychological literature, may mask important pre-migration history effects on Asian American families across generations. In this paper, we consider how historical trauma impacts Asian American individuals, families, and communities. We also examine the role of intergenerational communication in historical trauma and in Asian American families and communities. Finally, we discuss historical trauma among Asian Americans within the framework of radical healing, particularly how intergenerational communication about historical trauma can raise critical consciousness, facilitate ethnic-racial identity development, and reinforce ethnic-racial socialization.

11.
Int J Cancer ; 2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35762443

RESUMO

High-grade neuroendocrine tumors (NETs) of the lung consist of small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNEC). Both exhibit aggressive malignancy with poor prognosis. The transformation of lung adenocarcinoma (ADC) to SCLC or LCNEC also contributes to acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Despite initially being responsive to chemotherapy, high-grade NET patients inevitably develop drug resistance; thus, novel therapeutic targets are urgently needed for these patients. Our study reported that VGF (nerve growth factor inducible), a factor mainly expressed in neurons during neural development, is highly expressed in SCLC and LCNEC as well as in a subset of ADCs, whereas targeting VGF attenuates cancer cell growth and tumor formation. High VGF expression was associated with advanced stage SCLC and predicted poor prognosis in lung ADC. In addition, EGFR-TKI selection enriched VGF expression in TKI-resistant ADC under epigenetic control. The VGF locus possessed the HDAC1 binding site, and treatment of ADC cells with the HDAC1 inhibitor induced VGF expression. High VGF expression was associated with chemoresistance, and silencing VGF induced BMF and BCL2L11 expression and rendered lung cancer cells sensitive to chemotherapy drugs. These findings suggested the potential of VGF as a prognostic factor and therapeutic target in lung cancers with neuroendocrine feature.

12.
JCI Insight ; 7(13)2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35653195

RESUMO

Apolipoprotein C-III (apoC-III) is a critical regulator of triglyceride metabolism and correlates positively with hypertriglyceridemia and cardiovascular disease (CVD). It remains unclear if therapeutic apoC-III lowering reduces CVD risk and if the CVD correlation depends on the lipid-lowering or antiinflammatory properties. We determined the impact of interventional apoC-III lowering on atherogenesis using an apoC-III antisense oligonucleotide (ASO) in 2 hypertriglyceridemic mouse models where the intervention lowers plasma triglycerides and in a third lipid-refractory model. On a high-cholesterol Western diet apoC-III ASO treatment did not alter atherosclerotic lesion size but did attenuate advanced and unstable plaque development in the triglyceride-responsive mouse models. No lesion size or composition improvement was observed with apoC-III ASO in the lipid-refractory mice. To circumvent confounding effects of continuous high-cholesterol feeding, we tested the impact of interventional apoC-III lowering when switching to a cholesterol-poor diet after 12 weeks of Western diet. In this diet switch regimen, apoC-III ASO treatment significantly reduced plasma triglycerides, atherosclerotic lesion progression, and necrotic core area and increased fibrous cap thickness in lipid-responsive mice. Again, apoC-III ASO treatment did not alter triglyceride levels, lesion development, and lesion composition in lipid-refractory mice after the diet switch. Our findings suggest that interventional apoC-III lowering might be an effective strategy to reduce atherosclerosis lesion size and improve plaque stability when lipid lowering is achieved.


Assuntos
Aterosclerose , Hiperlipidemias , Placa Aterosclerótica , Animais , Apolipoproteína C-III , Proteínas de Transporte , Colesterol , Camundongos , Oligonucleotídeos , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Triglicerídeos/metabolismo
15.
Artigo em Inglês | MEDLINE | ID: mdl-35754346

RESUMO

SIGNIFICANCE: Thioredoxin interacting protein (TXNIP) is a member of the arrestin foldsuperfamily with important cellular functions, including cellular transport, mitochondrial energy generation and protein cycling. It is the only arrestin-domain protein known to covalently bind to thioredoxin and plays roles in glucose metabolism, inflammation, apoptosis, and cancer. RECENT ADVANCES: The crystal structure of the TXNIP-thioredoxin complex provided details about this fascinating interaction. Recent studies showed that TXNIP is induced by endoplasmic reticulum stress, activates NLR family pyrin domain containing 3 (NLRP3) inflammasomes, and can regulate glucose transport into cells. The tumor suppressor role of TXNIP in various cancer types and the role of TXNIP in fructose absorption are now described. CRITICAL ISSUES: The influence of TXNIP on redox state is more complex than its interaction with thioredoxin. FUTURE DIRECTIONS: It is incompletely understood which functions of TXNIP are thioredoxin-dependent. It is also unclear whether TXNIP binding can inhibit glucose transporters without endocytosis. TXNIP-regulated control of endoplasmic reticulum stress should also be investigated further.

16.
Artigo em Inglês | MEDLINE | ID: mdl-35543419

RESUMO

Nucleic acid biomarkers hold great potential as key indicators for the diagnosis and monitoring of diseases. Herein we design and implement bifunctional chimeric biomolecules composed of a solid-binding peptide (SBP) domain that specifically adsorbs onto solid sensor surfaces and a peptide nucleic acid (PNA) moiety that facilitates anchoring of antisense oligonucleotide (ASO) probes for the detection of nucleic acid targets. A gold-binding peptide, AuBP1, previously selected by directed evolution to specifically bind to gold, served as the basis for immobilizing nucleic acid probes onto gold substrates. Using surface plasmon resonance (SPR) spectroscopy and quartz crystal microbalance (QCM) analyses, we demonstrate the sequential biomolecular assembly of the heterofunctional solid-binding peptide-antisense oligomer (SBP-ASO) construct onto a sensor surface and the subsequent detection of DNA in an aqueous environment. The effect of steric hindrance on optimal probe assembly is observed, establishing that less packing density results in greater target capture efficacy. In addition, an adsorbed layer of chimeric solid-binding peptide-peptide nucleic acid (SBP-PNA) undergoes viscoelastic changes at the solid-liquid interface upon probe immobilization and DNA target capture, whereby the rigid biofunctional layer becomes more flexible. The dual nature of the chimeric construct is highly amenable to a variety of platforms allowing for both specific recognition and probe immobilization on the sensor surface, while the modular design of the solid-binding peptide-antisense oligonucleotide provides facile functionalization of a wide diversity of solid substrates.

17.
G3 (Bethesda) ; 12(7)2022 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35567477

RESUMO

Somatic missense mutations in histone genes turn these essential proteins into oncohistones, which can drive oncogenesis. Understanding how missense mutations alter histone function is challenging in mammals as mutations occur in a single histone gene. For example, described oncohistone mutations predominantly occur in the histone H3.3 gene, despite the human genome encoding 15 H3 genes. To understand how oncogenic histone missense mutations alter histone function, we leveraged the budding yeast model, which contains only 2 H3 genes, to explore the functional consequences of oncohistones H3K36M, H3G34W, H3G34L, H3G34R, and H3G34V. Analysis of cells that express each of these variants as the sole copy of H3 reveals that H3K36 mutants show different drug sensitivities compared to H3G34 mutants. This finding suggests that changes to proximal amino acids in the H3 N-terminal tail alter distinct biological pathways. We exploited the caffeine-sensitive growth of H3K36-mutant cells to perform a high copy suppressor screen. This screen identified genes linked to histone function and transcriptional regulation, including Esa1, a histone H4/H2A acetyltransferase; Tos4, a forkhead-associated domain-containing gene expression regulator; Pho92, an N6-methyladenosine RNA-binding protein; and Sgv1/Bur1, a cyclin-dependent kinase. We show that the Esa1 lysine acetyltransferase activity is critical for suppression of the caffeine-sensitive growth of H3K36R-mutant cells while the previously characterized binding interactions of Tos4 and Pho92 are not required for suppression. This screen identifies pathways that could be altered by oncohistone mutations and highlights the value of yeast genetics to identify pathways altered by such mutations.


Assuntos
Histonas , Proteínas de Saccharomyces cerevisiae , Animais , Cafeína , Carcinogênese/genética , Histona Acetiltransferases/metabolismo , Histonas/metabolismo , Humanos , Mamíferos , Mutação , Mutação de Sentido Incorreto , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo
18.
J Pediatr Surg ; 57(8): 1687-1693, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35525806

RESUMO

BACKGROUND: Vaginal reconstruction with autologous buccal mucosa graft offers a promising alternative to the use of skin grafts and vascularized intestinal segments. Given the novelty of this procedure, the optimal approach to postoperative wound management remains unclear with current practices often requiring many months of vaginal stents/molds. This study aims to evaluate a newly developed negative pressure intravaginal wound vacuum placed at the conclusion of the vaginoplasty with the goals of facilitating graft take and healing. METHODS: A retrospective review of patients (age 12-21 years) who underwent eight primary and secondary vaginoplasty procedures using autologous buccal mucosa coupled with intravaginal wound vacuum placement was performed. RESULTS: Vaginal reconstruction with fenestrated full-thickness buccal mucosa graft and intravaginal wound vacuum placement was successfully performed eight times in seven patients at a median age of 15.6 years. Four patients underwent robotic vaginal pull-through with buccal mucosa serving as an interposition graft, and four patients underwent vaginoplasty with buccal graft alone. All cases had excellent engraftment at time of wound vacuum removal on postoperative day seven and had healthy-appearing buccal mucosa at a mean follow-up of 148 days. Postoperatively, one patient developed a stricture at the anastomosis between native vagina and buccal mucosa graft, requiring a second buccal mucosa graft six months after the first operation. CONCLUSIONS: The use of autologous buccal mucosa graft for primary and secondary vaginal reconstruction coupled with intravaginal wound vacuum therapy offers a promising new approach. Negative pressure wound vacuum therapy may provide a more optimal wound healing environment for improved outcomes. TYPE OF STUDY: Retrospective Study LEVELS OF EVIDENCE: Level IV.


Assuntos
Tratamento de Ferimentos com Pressão Negativa , Procedimentos Cirúrgicos Reconstrutivos , Adolescente , Adulto , Criança , Feminino , Procedimentos Cirúrgicos em Ginecologia/métodos , Humanos , Mucosa Bucal/transplante , Procedimentos Cirúrgicos Reconstrutivos/métodos , Estudos Retrospectivos , Vagina/cirurgia , Adulto Jovem
19.
Curr Oncol ; 29(5): 3637-3646, 2022 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35621682

RESUMO

BACKGROUND: To determine the risk of mortality and factors associated with survival amongst patients diagnosed with primary hepatic angiosarcoma (PHA). METHODS: All patients diagnosed with hepatocellular carcinoma (HCC) or PHA from 2004 to 2014 were identified from the National Cancer Database (NCDB). Further analysis was performed within the cohort of patients with PHA to assess the impact of surgery, chemotherapy, radiation, and facility type on overall survival (OS). A multivariable analysis using the Cox proportional methods and a survival analysis using the Kaplan-Meier method were used. RESULTS: A total of 117,633 patients with HCC were identified, out of whom 346 patients had PHA. Patients with PHA had a mean age of 62.9 years (SD 13.7), the majority were men (64.7%), white (85.8%), and had a Charlson comorbidity index (CCI) of zero (66.2%). A third of the patients with PHA (35.7%) received chemotherapy, and 14.6% underwent a surgical resection. The median survival was 1.9 months (1.8-2.4 months) compared to patients with HCC (10.4 months, 10.2-10.5) (aHR-2.41, 95% CI: 2.10-2.77, p < 0.0001). Surgical resection was associated with a higher median survival (7.7 versus 1.8 months, aHR-0.23, 95% CI: 0.15-0.37, p < 0.0001). A receipt of chemotherapy was associated with a higher median survival than no chemotherapy (5.1 versus 1.2 months, aHR-0.44, 95% CI: 0.32-0.60, p < 0.0001), although the survival benefit did not persist long term. CONCLUSION: PHA is associated with poor outcomes. A surgical resection and chemotherapy are associated with improved survival outcomes; however, the long-term benefits of chemotherapy are limited.


Assuntos
Carcinoma Hepatocelular , Hemangiossarcoma , Neoplasias Hepáticas , Carcinoma Hepatocelular/terapia , Feminino , Hemangiossarcoma/terapia , Humanos , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
20.
Front Genet ; 13: 888025, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35571054

RESUMO

There is considerable variability in the susceptibility and progression for COVID-19 and it appears to be strongly correlated with age, gender, ethnicity and pre-existing health conditions. However, to our knowledge, cohort studies of COVID-19 in clinically vulnerable groups are lacking. Host genetics has also emerged as a major risk factor for COVID-19, and variation in the ACE2 receptor, which facilitates entry of the SARS-CoV-2 virus into the cell, has become a major focus of attention. Thus, we interrogated an ethnically diverse cohort of National Health Service (NHS) patients in the United Kingdom (United Kingdom) to assess the association between variants in the ACE2 locus and COVID-19 risk. We analysed whole-genome sequencing (WGS) data of 1,837 cases who were tested positive for SARS-CoV-2, and 37,207 controls who were not tested, from the UK's 100,000 Genomes Project (100KGP) for the presence of ACE2 coding variants and extract expression quantitative trait loci (eQTLs). We identified a splice site variant (rs2285666) associated with increased ACE2 expression with an overrepresentation in SARS-CoV-2 positive patients relative to 100KGP controls (p = 0.015), and in hospitalised European patients relative to outpatients in intra-ethnic comparisons (p = 0.029). We also compared the prevalence of 288 eQTLs, of which 23 were enriched in SARS-CoV-2 positive patients. The eQTL rs12006793 had the largest effect size (d = 0.91), which decreases ACE2 expression and is more prevalent in controls, thus potentially reducing the risk of COVID-19. We identified three novel nonsynonymous variants predicted to alter ACE2 function, and showed that three variants (p.K26R, p. H378R, p. Y515N) alter receptor affinity for the viral Spike (S) protein. Variant p. N720D, more prevalent in the European population (p < 0.001), potentially increases viral entry by affecting the ACE2-TMPRSS2 complex. The spectrum of genetic variants in ACE2 may inform risk stratification of COVID-19 patients and could partially explain the differences in disease susceptibility and severity among different ethnic groups.

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