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Covalent modification by the small protein ubiquitin can target proteins for destruction by the proteasome, but the ubiquitin signal itself is recycled. Surprisingly, proteasomes contain three different deubiquitinating enzymes (DUBs). Recent work by Zhang and Zou et al. reveals how one of these enzymes, Usp14, regulates, and is regulated by, the proteasome.
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Complexo de Endopeptidases do Proteassoma , Ubiquitina , Enzimas Desubiquitinantes/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismoRESUMO
Proteasome inhibitors are widely used anticancer drugs. The three clinically approved agents are modified small peptides that preferentially target one of the proteasome's three active sites (ß5) at physiologic concentrations. In addition to these drugs, there is also an endogenous proteasome inhibitor, PI31/Fub1, that enters the proteasome's interior to simultaneously yet specifically inhibit all three active sites. Here, we have used PI31's evolutionarily optimized inhibitory mechanisms to develop a suite of potent and specific ß2 inhibitors. The lead compound strongly inhibited growth of multiple myeloma cells as a standalone agent, indicating the compound's cell permeability and establishing ß2 as a potential therapeutic target in multiple myeloma. The lead compound also showed strong synergy with the existing ß5 inhibitor bortezomib; such combination therapies might help with existing challenges of resistance and severe side effects. These results represent an effective method for rational structure-guided development of proteasome inhibitors.
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Antineoplásicos , Mieloma Múltiplo , Humanos , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/química , Bortezomib/farmacologia , Bortezomib/uso terapêuticoRESUMO
BACKGROUND: The increased prevalence of antimicrobial resistant (AMR) infections is a significant global health threat, resulting in increased morbidity, mortality, and costs. The drivers of AMR are complex and potentially impacted by socioeconomic factors. We investigated the relationships between geographic and socioeconomic factors and AMR. METHODS: We collected select patient bacterial culture results from 2015 to 2020 from electronic health records (EHR) of two expansive healthcare systems within the Dallas-Fort Worth, TX (DFW) metropolitan area. Among individuals with EHR records who resided in the four most populus counties in DFW, culture data were aggregated. Case counts for each organism studied were standardized per 1,000 persons per area population. Using residential addresses, the cultures were geocoded and linked to socioeconomic index values. Spatial autocorrelation tests identified geographic clusters of high and low AMR organism prevalence and correlations with established socioeconomic indices. RESULTS: We found significant clusters of AMR organisms in areas with high levels of deprivation, as measured by the Area Deprivation Index (ADI). We found a significant spatial autocorrelation between ADI and the prevalence of AMR organisms, particularly for AmpC and MRSA with 14% and 13%, respectively, of the variability in prevalence rates being attributable to their relationship with the ADI values of the neighboring locations. CONCLUSIONS: We found that areas with a high ADI are more likely to have higher rates of AMR organisms. Interventions that improve socioeconomic factors such as poverty, unemployment, decreased access to healthcare, crowding, and sanitation in these areas of high prevalence may reduce the spread of AMR.
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Much of cellular activity is mediated by large multisubunit complexes. However, many of these complexes are too complicated to assemble spontaneously. Instead, their biogenesis is facilitated by dedicated chaperone proteins, which are themselves excluded from the final product. This is the case for the proteasome, a ubiquitous and highly conserved cellular regulator that mediates most selective intracellular protein degradation in eukaryotes. The proteasome consists of two subcomplexes: the core particle (CP), where proteolysis occurs, and the regulatory particle (RP), which controls substrate access to the CP. Ten chaperones function in proteasome biogenesis. Here, we review the pathway of CP biogenesis, which requires five of these chaperones and proceeds through a highly ordered multistep pathway. We focus on recent advances in our understanding of CP assembly, with an emphasis on structural insights. This pathway of CP biogenesis represents one of the most dramatic examples of chaperone-mediated assembly and provides a paradigm for understanding how large multisubunit complexes can be produced.
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Chaperonas Moleculares , Complexo de Endopeptidases do Proteassoma , Eucariotos/metabolismo , Chaperonas Moleculares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , ProteóliseRESUMO
PURPOSE OF REVIEW: This review examines the current state and future prospects of machine learning (ML) in infection prevention and control (IPC) and antimicrobial stewardship (ASP), highlighting its potential to transform healthcare practices by enhancing the precision, efficiency, and effectiveness of interventions against infections and antimicrobial resistance. RECENT FINDINGS: ML has shown promise in improving surveillance and detection of infections, predicting infection risk, and optimizing antimicrobial use through the development of predictive analytics, natural language processing, and personalized medicine approaches. However, challenges remain, including issues related to data quality, model interpretability, ethical considerations, and integration into clinical workflows. SUMMARY: Despite these challenges, the future of ML in IPC and ASP is promising, with interdisciplinary collaboration identified as a key factor in overcoming existing barriers. ML's role in advancing personalized medicine, real-time disease monitoring, and effective IPC and ASP strategies signifies a pivotal shift towards safer, more efficient healthcare environments and improved patient care in the face of global antimicrobial resistance challenges.
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Gestão de Antimicrobianos , Aprendizado de Máquina , Humanos , Gestão de Antimicrobianos/métodos , Controle de Infecções/métodos , Medicina de Precisão/métodos , Antibacterianos/uso terapêuticoRESUMO
PURPOSE: To compare complication rates, reoperation rates, and subjective outcomes after arthroscopic and open irrigation and debridement for treatment of native knee septic arthritis. METHODS: Following The Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a systematic review of the Embase, Cochrane, and PubMed databases was performed. Comparative studies reporting clinical outcomes after arthroscopic versus open treatment for septic arthritis of the native knee in human adults were included. Excluded were case series with <10 patients, inclusion of patients <18 years old, studies on non-native joints, abstract-only publications, and studies without stratification of the involved joint. Two reviewers in duplicate independently performed search and data extraction. The quality of the included studies was assessed with the Methodological Index for Non-Randomized Studies instrument. The mean score among the included studies was 18.2 (range 16-23). RESULTS: Eleven studies were included, comprising 2,343 knees treated arthroscopically, and 1,595 treated with arthrotomy. Studies reported no differences in erythrocyte sedimentation rate, C-reactive protein, peripheral white blood cells, or symptom chronicity between groups. Nine studies (81.8%) attempted to control for potentially confounding variables in their analyses, and 4 studies (36.4%) reported significant differences in patient characteristics. Reoperation rates ranged from 0% to 50% for arthroscopy and 6% to 71% for arthrotomy. Complication rates ranged from 0% to 39.4% arthroscopically and 0% to 49% for arthrotomy. Superior patient-reported outcomes were achieved after arthroscopy in 2 studies that analyzed subjective outcomes. CONCLUSIONS: Arthroscopic management of native knee septic arthritis is a safe and effective alternative to open treatment and is associated with comparable complication rates, reoperation rates, hospitalization lengths, readmission rates, and superior patient-reported outcomes compared with open irrigation and debridement. LEVEL OF EVIDENCE: Level IV, systematic review of Level I, III, and IV studies.
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Artrite Infecciosa , Articulação do Joelho , Adolescente , Adulto , Humanos , Artrite Infecciosa/diagnóstico , Artroscopia/efeitos adversos , Desbridamento/efeitos adversos , Articulação do Joelho/cirurgia , Reoperação , Estudos RetrospectivosRESUMO
Elbow fractures are among the most common fractures sustained in pediatric patients. A specific set of pediatric elbow fractures (olecranon, radial neck, and lateral condyle fractures) comprises the ones that occur most often. It is important to review commonly accepted principles in the evaluation and treatment of these injuries as well as highlight some debates that exist within the literature regarding the optimal management of these injuries. Although management of pediatric olecranon, radial neck, and lateral condyle fractures has been well described, controversy persists among orthopaedic surgeons regarding the surgical indications and preferred fixation techniques for these injuries.
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Fraturas do Cotovelo , Lesões no Cotovelo , Articulação do Cotovelo , Fraturas Ósseas , Criança , Humanos , Cotovelo , Articulação do Cotovelo/diagnóstico por imagem , Articulação do Cotovelo/cirurgia , Fixação Interna de Fraturas , Resultado do TratamentoRESUMO
The active sites of the proteasome are housed within its central core particle (CP), a barrel-shaped chamber of four stacked heptameric rings, and access of substrates to the CP interior is mediated by gates at either axial end. These gates are constitutively closed and may be opened by the regulatory particle (RP), which binds the CP and facilitates substrate degradation. We recently showed that the heterodimeric CP assembly chaperones Pba1/2 also mediate gate opening through an unexpected structural arrangement that facilitates the insertion of the N terminus of Pba1 into the CP interior; however, the full mechanism of Pba1/2-mediated gate opening is unclear. Here, we report a detailed analysis of CP gate modulation by Pba1/2. The clustering of key residues at the interface between neighboring α-subunits is a critical feature of RP-mediated gate opening, and we find that Pba1/2 recapitulate this strategy. Unlike RP, which inserts at six α-subunit interfaces, Pba1/2 insert at only two α-subunit interfaces. Nevertheless, Pba1/2 are able to regulate six of the seven interfacial clusters, largely through direct interactions. The N terminus of Pba1 also physically interacts with the center of the gate, disrupting the intersubunit contacts that maintain the closed state. This novel mechanism of gate modulation appears to be unique to Pba1/2 and therefore likely occurs only during proteasome assembly. Our data suggest that release of Pba1/2 at the conclusion of assembly is what allows the nascent CP to assume its mature gate conformation, which is primarily closed, until activated by RP.
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Complexo de Endopeptidases do Proteassoma , Proteínas de Saccharomyces cerevisiae , Citoplasma/metabolismo , Chaperonas Moleculares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMO
Armillaria species show considerable variation in ecological roles and virulence, from mycorrhizae and saprophytes to important root pathogens of trees and horticultural crops. We studied two Armillaria species that can be found in coniferous forests of northwestern USA and southwestern Canada. Armillaria altimontana not only is considered as a weak, opportunistic pathogen of coniferous trees, but it also appears to exhibit in situ biological control against A. solidipes, formerly North American A. ostoyae, which is considered a virulent pathogen of coniferous trees. Here, we describe their genome assemblies and present a functional annotation of the predicted genes and proteins for the two Armillaria species that exhibit contrasting ecological roles. In addition, the soil microbial communities were examined in association with the two Armillaria species within a 45-year-old plantation of western white pine (Pinus monticola) in northern Idaho, USA, where A. altimontana was associated with improved tree growth and survival, while A. solidipes was associated with reduced growth and survival. The results from this study reveal a high similarity between the genomes of the beneficial/non-pathogenic A. altimontana and pathogenic A. solidipes; however, many relatively small differences in gene content were identified that could contribute to differences in ecological lifestyles and interactions with woody hosts and soil microbial communities.
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Armillaria , Pinus , Traqueófitas , Armillaria/genética , Solo , Árvores , Florestas , GenômicaRESUMO
Deep penetrating nevi (DPN) are uncommon but distinctive melanocytic neoplasms that show an epithelioid to spindle cell morphology, prominent pigmentation with melanophages, and a plexiform growth pattern. Molecularly, most DPN are thought to be characterized by dual activation of the mitogen-activated protein kinase and the wingless-related integration site (Wnt) pathways, the latter being most commonly driven by activating ß-catenin mutations. DPN-like melanomas are very rare but can be recognized through their overlapping morphologic and architectural features with DPN. Familial adenomatous polyposis (FAP) is a hereditary cancer predisposition syndrome associated with multiple tumor types including colorectal carcinoma and desmoid fibromatosis. Like DPN, FAP is also driven by activation of the Wnt pathway, most commonly through loss of function mutations in APC, which is a major negative regulator of ß-catenin. Here we report two cases of DPN-like melanoma arising in FAP patients. While the small number of cases precludes definitive establishment of an etiologic link between these entities, the shared molecular pathogenesis of DPN-like lesions and FAP suggests that FAP patients may be at increased risk for this rare subtype of melanoma.
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Polipose Adenomatosa do Colo , Melanoma , Nevo , Humanos , beta Catenina/metabolismo , Polipose Adenomatosa do Colo/complicações , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Melanoma/patologia , Proteína da Polipose Adenomatosa do Colo/genética , MutaçãoRESUMO
In addition to melanoma, a large and diverse family of tumors shows melanocytic differentiation. The best characterized member of this family is clear cell sarcoma, which is characterized by EWSR1::ATF1 and EWSR1::CREB1 fusions. These fusions drive the transcription of MITF, the master regulator of melanocytic differentiation. Clear cell tumor with melanocytic differentiation and MITF::CREM translocation is a recently described tumor with some similarities to clear cell sarcoma. However, only a single case has been reported. Here, we describe a second molecularly proven case that arose on the scalp of a newborn baby. In contrast to the prior reported case, the current case showed predominantly high-grade cytomorphologic features with only focal clear cell areas. Similar to the prior case, the tumor showed immunohistochemical evidence of neural crest origin/differentiation with prominent melanocytic differentiation. The fusion breakpoints were also similar and preserved the transcriptional activation domain of CREM, suggesting that CREM hyperactivity is a major feature of this tumor type. The current tumor showed a short-interval recurrence. These results expand the clinical and pathologic spectrum of this potentially new entity.
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Melanoma , Sarcoma de Células Claras , Recém-Nascido , Humanos , Sarcoma de Células Claras/genética , Translocação Genética , Diferenciação Celular , Proteínas de Fusão Oncogênica/genética , Fator de Transcrição Associado à Microftalmia , Modulador de Elemento de Resposta do AMP Cíclico/genéticaRESUMO
ABSTRACT: Epithelioid fibrous histiocytoma (EFH) is a distinctive benign cutaneous neoplasm composed of uniform epithelioid cells, often with binucleated cells. EFH are characterized by the presence of anaplastic lymphoma kinase ( ALK ) gene rearrangements with a variety of binding partners. These rearrangements result in the overexpression of ALK , which can be detected using immunohistochemistry. Cytoplasmic ALK expression is by far the most common pattern encountered. Here, we describe a case of EFH with a distinctive intranuclear dot-like ALK expression pattern. Subsequent next-generation DNA sequencing revealed a novel SP100::ALK gene fusion. Speckled protein-100 (SP100) is a constituent of nuclear dots, also known as promyelocytic leukemia bodies, which are still poorly understood membraneless subnuclear structures. Thus, this novel ALK fusion partner seems to explain this distinctive pattern of ALK localization. We examined ALK expression patterns in 11 other cases of EFH, but all showed typical cytoplasmic localization. This study expands the morphologic and molecular spectrum of EFH, provides a dramatic illustration of the ability of fusion partners to control protein localization, and implies that tumorigenic ALK signaling may occur at a variety of subcellular locations.
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Histiocitoma Fibroso Benigno , Neoplasias Cutâneas , Humanos , Quinase do Linfoma Anaplásico/genética , Histiocitoma Fibroso Benigno/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fusão Gênica , Rearranjo GênicoRESUMO
SMARCA4-deficient undifferentiated malignant neoplasms (SD-UMN) comprise a group of aggressive tumors with epithelioid morphology that are characterized by loss of function of SMARCA4, a component of the SWI/SNF chromatin remodeling complex. SD-UMN was first recognized in the thoracic cavity but is now appreciated to occur at multiple anatomic sites. A notable exception has been skin. Here we report the first two cases of primary cutaneous SD-UMN and compare their features to a cohort of eight visceral cases arising in lung, gastrointestinal tract, and gallbladder. Evidence for a bona fide cutaneous origin included extensive clinical, radiologic, and serologic analyses that failed to identify a metastatic source as well as the molecular identification of a UV-associated mutational pattern. The cutaneous cases showed strikingly similar morphologic, immunohistochemical, and molecular features to the visceral cases, strongly suggesting that they belong to this family of tumors. In addition to biallelic inactivation of SMARCA4, both cutaneous tumors also showed biallelic inactivation of TP53 and CDKN2A, findings which also appear common in visceral cases. One patient died of disease at 18 months after diagnosis, consistent with the aggressive nature of this tumor. Our results expand the anatomic spectrum of SD-UMN, adding this entity to an already challenging differential diagnosis that includes melanoma, squamous cell carcinoma, Merkel cell carcinoma, epithelioid sarcoma, and others. Given the potentially aggressive nature of SD-UMN, the timely and accurate diagnosis of this entity may have implications for prognosis and therapy.
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Carcinoma de Células Escamosas , Neuroblastoma , Sarcoma , Humanos , Imuno-Histoquímica , Biomarcadores Tumorais/genética , Sarcoma/patologia , Prognóstico , DNA Helicases/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genéticaRESUMO
AIMS: Blue naevi are benign melanocytic lesions that typically occur in the dermis. Melanoma arising in blue naevus is rare, and shows a molecular profile distinct from conventional forms of cutaneous melanoma and more similar to uveal melanoma and central nervous system (CNS) melanocytomas. In contrast to conventional cutaneous melanoma, these tumour types typically show activating driver mutations in GNAQ or GNA11, a low mutational burden without evidence of a UV signature and a reproducible pattern of chromosomal copy number changes. Blue naevi can also occur at extracutaneous sites. Here we report two cases of melanoma arising in extracutaneous blue naevus and compare their molecular features to cohorts of melanoma arising in cutaneous blue naevus (five patients) and uveal melanoma (six patients). METHODS AND RESULTS: We describe the clinical, histomorphological, immunohistochemical and molecular findings in these two cases of melanoma arising in extracutaneous blue naevus. We compare their molecular profiles to melanomas arising in cutaneous blue naevus and uveal melanoma using a targeted next-generation DNA sequencing platform and find striking similarities between all three groups. CONCLUSIONS: The close relationship between blue naevus-associated melanomas, regardless of their anatomical site, supports and validates the concept of melanoma arising in extracutaneous blue naevus and suggests that the two groups share common pathogenic mechanisms. The similarity of both groups to uveal melanoma in turn supports the close relationship between blue naevus-associated melanoma, uveal melanoma and CNS melanocytoma, and their distinction from conventional UV-associated melanoma. These findings have important implications for prognosis and therapy.
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Melanoma , Nevo Azul , Neoplasias Cutâneas , Neoplasias Uveais , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Humanos , Melanoma/patologia , Mutação , Nevo Azul/genética , Nevo Azul/patologia , Neoplasias Cutâneas/patologia , Neoplasias Uveais/genética , Melanoma Maligno CutâneoRESUMO
Methylammonium (MA+) lead halide perovskites (MAPbX3) have been widely investigated for photovoltaic applications, with the addition of Cs improving structural and thermal stability. This study reports the complete A site miscibility of Cs+ and MA+ cations in the lead chloride and lead bromide perovskites with nominal stoichiometric formulae (CsxMA1-x)Pb(Cl/Br)3 (x = 0, 0.13, 0.25, 0.37, 0.50, 0.63, 0.75, 0.87, 1). These suites of materials were synthesized mechanochemically as a simple, cost-effective synthesis technique to produce highly ordered, single phase particles. In contrast to previous studies using conventional synthetic routes that have reported significant solubility gaps, this solvent-free approach induces complete miscibility within the dual cation Cs+/MA+ system, with the resultant structures exhibiting high short-range and long-range atomic ordering across the entire compositional range that are devoid of solvent inclusions and disorder. The subtle structural evolution from cubic to orthorhombic symmetry reflecting PbX6 octahedral tilting was studied using complementary high resolution TEM, powder XRD, multinuclear 133Cs/207Pb/1H MAS NMR, DSC, XPS and UV/vis approaches. The phase purity and exceptional structural order were reflected in the very high resolution HRTEM images presented from particles with crystallite sizes in the â¼80-170 nm range, and the stability and long lifetimes of the Br series (10-20 min) and the Cl series (â¼30 s-1 min) under the 200 kV/146 µA e- beam. Rietveld refinements associated with the room temperature PXRD study demonstrated that each system converged towards single phase compositions that were very close to the intended target stoichiometries, thus indicating the complete miscibility within these dual cation Cs+/MA+ solid solution systems. The multinuclear MAS NMR data showed a distinct sensitivity to the changing solid solution compositions across the MAPbX3-CsPbX3 partition. In particular, the 133Cs shifts demonstrated a sensitivity to the cubic-orthorhombic phase transition while the 133Cs T1s exhibited a pronounced sensitivity to the variable Cs+ cation mobility across the compositional range. Variable temperature PXRD studies facilitated the production of phase diagrams mapping the Cs+/MA+ compositional space for the (CsxMA1-x)PbCl3 and (CsxMA1-x)PbBr3 solid solution series, while Tauc plots of the UV/vis data exhibited reducing bandgaps with increasing MA+ incorporation through ranges of cubic phases where octahedral tilting was absent.
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INTRODUCTION: During the emergence of the SARS-CoV-2 (COVID-19) pandemic, there were substantial changes in United States (U.S.) emergency department (ED) volumes and acuity of patient presentation compared to more recent years. Thus, the purpose of this study was to characterize the incidence of specific upper extremity (UE) injuries presenting to U.S. EDs during the COVID-19 pandemic and analyze trends across age groups and rates of hospital admission compared to years prior. METHODS: The National Electronic Injury Surveillance System (NEISS) database was queried to identify patients who presented to U.S. EDs for an UE orthopaedic injury between 2016 and 2020. Chi-square analysis and logistic regression were used to assess for differences in ED presentation volume and hospital admissions between pre-pandemic (2016 through 2019) and during-pandemic (2020) times. RESULTS: These queries returned 285,583 cases, representing a total estimate of 10,452,166 injuries presenting to EDs across the U.S. The mean incidence of UE orthopaedic injuries was 640.2 (95% CI, 638.2-642.3) injuries per 100,000 person-years, with the greatest year to year decrease in incidence occurring between 2019 and 2020 (20.1%). The largest number of estimated admissions occurred in 2020, with a total 135,018 admissions (95% CI, 131,518-138,517), a 41.6% increase from the average number of admissions between 2016 and 2019. CONCLUSION: There was a 20.1% decrease in the incidence of UE orthopaedic injuries presenting to EDs after the start of the COVID-19 pandemic with a concomitant 41.2% increase in the number of hospital admissions from the ED in 2020 compared to recent pre-pandemic years. We speculate that at least some elective, semi-elective or urgent ambulatory surgeries were canceled or delayed due to the pandemic and were subsequently directed to the ED for admission. Regardless of the cause of increased UE orthopaedic admissions, policy planners and administrators should be aware of the additional stresses placed on already burdened ED and inpatient services. LEVEL OF EVIDENCE: Level III - Retrospective Cohort Study.
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Traumatismos do Braço , COVID-19 , Traumatismos do Braço/epidemiologia , COVID-19/epidemiologia , Serviço Hospitalar de Emergência , Humanos , Pandemias , Estudos Retrospectivos , SARS-CoV-2 , Estados Unidos/epidemiologia , Extremidade SuperiorRESUMO
ABSTRACT: Hidradenoma is a benign cutaneous adnexal neoplasm that occurs across a wide age range and at a variety of anatomic sites. Its most characteristic morphologic feature is the presence of diverse cell types including squamoid, clear, plasmacytoid, and mucinous cells. Hidradenoma is morphologically and molecularly similar to mucoepidermoid carcinoma, and both tumors are characterized by recurrent CRTC1-MAML2 cytogenetic translocations. Previous studies have suggested that approximately half of hidradenomas possess this translocation. This finding raised the question of whether translocation-negative hidradenomas might have an alternate molecular basis. Here, we sought to reevaluate the frequency of MAML2 translocation in hidradenoma in a series of 20 cases. We find that 90% show evidence of MAML2 translocation, suggesting that this genetic event is a nearly invariant feature of hidradenoma. These results inform our molecular understanding of this tumor and may be useful in challenging cases to distinguish hidradenoma from its histologic mimics.
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Acrospiroma , Adenoma de Glândula Sudorípara , Carcinoma Mucoepidermoide , Neoplasias das Glândulas Sudoríparas , Acrospiroma/genética , Proteínas de Ligação a DNA/genética , Rearranjo Gênico , Humanos , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias das Glândulas Sudoríparas/genética , Transativadores/genética , Fatores de Transcrição/genética , Translocação GenéticaRESUMO
ABSTRACT: Trichilemmoma is a benign cutaneous neoplasm that recapitulates the outer root sheath of the hair follicle. Trichilemmomas may occur sporadically or in association with Cowden syndrome, which is characterized by germline mutations in the lipid phosphatase PTEN (phosphatase and tensin homolog on chromosome 10). Interestingly, most sporadic trichilemmomas do not show PTEN aberrations, but rather activating mutations in HRAS. Despite these important advances, a comprehensive genetic analysis of trichilemmoma has not been reported. Here, we used a next-generation DNA sequencing platform to study 9 sporadic trichilemmoma cases. Seven cases (7/9; 78%) harbored activating mutations in HRAS, consistent with previous findings. Unexpectedly, we identified recurrent mutations in the tyrosine phosphatase PTPN14 (protein tyrosine phosphatase nonreceptor type 14) in 4 cases (4/9; 44%). Three of these cases also harbored HRAS mutations, whereas one case occurred in the absence of a HRAS mutation and showed evidence of biallelic inactivation of PTPN14. Finally, one case (1/9; 11%) showed biallelic inactivation of PTEN in the absence of a HRAS (or PTPN14) mutation. These data suggest at least 3 distinct pathways of molecular pathogenesis in sporadic trichilemmoma and identify PTPN14 as a potentially important contributor to trichilemmoma biology.
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Doenças do Cabelo , Síndrome do Hamartoma Múltiplo , Proteínas Tirosina Fosfatases não Receptoras , Neoplasias Cutâneas , Doenças do Cabelo/genética , Doenças do Cabelo/patologia , Folículo Piloso/patologia , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/patologia , Humanos , Mutação , PTEN Fosfo-Hidrolase/genética , Proteínas Tirosina Fosfatases não Receptoras/genética , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologiaRESUMO
Prospective serial sampling of 70 patients revealed clinically relevant cycle thresholds (Ct) occurring 9, 26, and 36 days after symptom onset. Race, gender, and corticosteroids apparently did not influence RNA positivity. In a retrospective analysis of 180 patients, initial Ct did not correlate with requirements for admission or intensive care.
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COVID-19 , SARS-CoV-2 , Hospitalização , Humanos , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Struvite-K (MgKPO4·6H2O) is a magnesium potassium phosphate mineral with naturally cementitious properties, which is finding increasing usage as an inorganic cement for niche applications including nuclear waste management and rapid road repair. Struvite-K is also of interest in sustainable phosphate recovery from wastewater and, as such, a detailed knowledge of the crystal chemistry and high-temperature behavior is required to support further laboratory investigations and industrial applications. In this study, the local chemical environments of synthetic struvite-K were investigated using high-field solid-state 25Mg and 39K MAS NMR techniques, alongside 31P MAS NMR and thermal analysis. A single resonance was present in each of the 25Mg and 39K MAS NMR spectra, reported here for the first time alongside the experimental and calculated isotropic chemical shifts, which were comparable to the available data for isostructural struvite (MgNH4PO4·6H2O). An in situ high-temperature XRD analysis of struvite-K revealed the presence of a crystalline-amorphous-crystalline transition that occurred between 30 and 350 °C, following the single dehydration step of struvite-K. Between 50 and 300 °C, struvite-K dehydration yielded a transient disordered (amorphous) phase identified here for the first time, denoted δ-MgKPO4. At 350 °C, recrystallization was observed, yielding ß-MgKPO4, commensurate with an endothermic DTA event. A subsequent phase transition to γ-MgKPO4 was observed on further heating, which reversed on cooling, resulting in the α-MgKPO4 structure stabilized at room temperature. This behavior was dissimilar from that of struvite exposed to high temperature, where NH4 liberation occurs at temperatures >50 °C, indicating that struvite-K could potentially withstand high temperatures via a transition to MgKPO4.