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1.
J Cutan Pathol ; 51(8): 576-582, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38666479

RESUMO

Melanoma's rare capacity to undergo heterologous differentiation can create significant diagnostic challenges. The molecular mechanisms underlying this phenomenon are not well understood. We present an unusual case of subungual melanoma exhibiting extensive cartilaginous differentiation and provide insights into its molecular and cytogenomic features. Histopathologically, the tumor was predominantly composed of nodules of malignant cartilage in association with a smaller population of nested epithelioid to rhabdoid cells. Immunohistochemically, the tumor cells in both components were positive for S100, SOX10, and PRAME, and were negative for Melan-A and HMB-45. Molecular analysis by whole exome DNA sequence did not detect any pathogenic variants in genes commonly implicated in melanoma. Additional analysis by SNP chromosomal microarray revealed a complex genome characterized by numerous chromosomal losses and gains, including a homozygous deletion of the CDKN2A locus and a heterozygous deletion of the locus containing EXT2, a tumor suppressor implicated in hereditary multiple osteochondromas and secondary chondrosarcomas. This case underscores the importance of recognizing cartilaginous differentiation as a rare manifestation of melanoma, particularly at subungual sites, and suggests that at least some of these melanomas may be driven by non-canonical molecular pathways.


Assuntos
Melanoma , Doenças da Unha , Neoplasias Cutâneas , Humanos , Melanoma/patologia , Melanoma/genética , Melanoma/diagnóstico , Melanoma/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Doenças da Unha/patologia , Doenças da Unha/genética , Doenças da Unha/metabolismo , Diferenciação Celular , Masculino , Cartilagem/patologia , Cartilagem/metabolismo , Feminino , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo , Proteínas S100/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Antígenos de Neoplasias
2.
Ann Surg ; 280(1): 108-117, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38482665

RESUMO

OBJECTIVE: To compare the perioperative outcomes of robotic liver surgery (RLS) and laparoscopic liver surgery (LLS) in various settings. BACKGROUND: Clear advantages of RLS over LLS have rarely been demonstrated, and the associated costs of robotic surgery are generally higher than those of laparoscopic surgery. Therefore, the exact role of the robotic approach in minimally invasive liver surgery remains to be defined. METHODS: In this international retrospective cohort study, the outcomes of patients who underwent RLS and LLS for all indications between 2009 and 2021 in 34 hepatobiliary referral centers were compared. Subgroup analyses were performed to compare both approaches across several types of procedures: (1) minor resections in the anterolateral (2, 3, 4b, 5, and 6) or (2) posterosuperior segments (1, 4a, 7, 8), and (3) major resections (≥3 contiguous segments). Propensity score matching was used to mitigate the influence of selection bias. The primary outcome was textbook outcome in liver surgery (TOLS), previously defined as the absence of intraoperative incidents ≥grade 2, postoperative bile leak ≥grade B, severe morbidity, readmission, and 90-day or in-hospital mortality with the presence of an R0 resection margin in case of malignancy. The absence of a prolonged length of stay was added to define TOLS+. RESULTS: Among the 10.075 included patients, 1.507 underwent RLS and 8.568 LLS. After propensity score matching, both groups constituted 1.505 patients. RLS was associated with higher rates of TOLS (78.3% vs 71.8%, P < 0.001) and TOLS+ (55% vs 50.4%, P = 0.026), less Pringle usage (39.1% vs 47.1%, P < 0.001), blood loss (100 vs 200 milliliters, P < 0.001), transfusions (4.9% vs 7.9%, P = 0.003), conversions (2.7% vs 8.8%, P < 0.001), overall morbidity (19.3% vs 25.7%, P < 0.001), and microscopically irradical resection margins (10.1% vs. 13.8%, P = 0.015), and shorter operative times (190 vs 210 minutes, P = 0.015). In the subgroups, RLS tended to have higher TOLS rates, compared with LLS, for minor resections in the posterosuperior segments (n = 431 per group, 75.9% vs 71.2%, P = 0.184) and major resections (n = 321 per group, 72.9% vs 67.5%, P = 0.086), although these differences did not reach statistical significance. CONCLUSIONS: While both produce excellent outcomes, RLS might facilitate slightly higher TOLS rates than LLS.


Assuntos
Hepatectomia , Laparoscopia , Pontuação de Propensão , Procedimentos Cirúrgicos Robóticos , Humanos , Hepatectomia/métodos , Feminino , Masculino , Laparoscopia/métodos , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Complicações Pós-Operatórias/epidemiologia , Resultado do Tratamento , Hepatopatias/cirurgia
4.
BJPsych Bull ; 48(2): 100-109, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37288666

RESUMO

AIMS AND METHOD: This narrative review updates the evidence base for cancer-related post-traumatic stress disorder (PTSD). Databases were searched in December 2021, and included EMBASE, Medline, PsycINFO and PubMed. Adults diagnosed with cancer who had symptoms of PTSD were included. RESULTS: The initial search identified 182 records, and 11 studies were included in the final review. Psychological interventions were varied, and cognitive-behavioural therapy and eye movement desensitisation and reprocessing were perceived to be most efficacious. The studies were also independently rated for methodological quality, which was found to be hugely variable. CLINICAL IMPLICATIONS: There remains a lack of high-quality intervention studies for PTSD in cancer, and there is a wide range of approaches to managing these conditions, with a large heterogeneity in the cancer populations examined and methodologies used. Specific studies designed with patient and public engagement and that tailor the PTSD intervention to particular cancer populations under investigation are required.

5.
Int J Surg Pathol ; : 10668969231201411, 2023 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-37855103

RESUMO

Pineal parenchymal tumors are rare central nervous system tumors that pose diagnostic challenges for surgical pathologists. Due to their paucity, their clinicopathologic features are still being defined. We report an 86-year-old woman with a remote history of breast lobular carcinoma who presented with a 2-month neurologic history that included gait instability, blurry vision, and headaches. Magnetic resonance imaging revealed a lobular, heterogeneously enhancing pineal region mass compressing the aqueduct of Sylvius. A biopsy performed concomitant with endoscopic third ventriculostomy consisted of small sheets of cells with eosinophilic to clear cytoplasm, multipolar processes, and ovoid nuclei with stippled chromatin. Whole exome sequencing revealed a small in-frame insertion (duplication) in exon 4 of KBTBD4 (c.931_939dup, p.P311_R313dup/ p.R313_M314insPRR), which has very recently been reported in 2 pineal parenchymal tumors of intermediate differentiation (PPTID). Additionally, variants of uncertain significance in CEBPA (c.863G > C, p.R288P) and MYC (c.655T > C, p.S219P) were identified. Although PPTID is considered a disease of young adulthood, review of 2 institutional cohorts of patients with pineal region tumors revealed that 25% of individuals with PPTID were over 65 years of age. In conclusion, PPTID should be considered in the differential diagnosis of pineal region tumors in older adults.

6.
Curr Oncol ; 30(9): 8575-8585, 2023 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-37754537

RESUMO

A cancer diagnosis and its subsequent treatments are life-changing events, impacting the patient and their family. Treatment options available for cancer care are developing at pace, with more patients now able to achieve a cancer cure. This is achieved through the development of novel cancer treatments, surgery, and modern imaging, but also as a result of better understanding treatment/surgical trauma, rescue after complications, perioperative care, and innovative interventions like pre-habilitation, enhanced recovery, and enhanced post-operative care. With more patients living with and beyond cancer, the role of survivorship and quality of life after cancer treatment is gaining importance. The impact cancer treatments can have on patients vary, and the "scars" treatments leave are not always visible. To adequately support patients through their cancer journeys, we need to look past the short-term interactions they have with medical professionals and encourage them to consider their lives after cancer, which often is not a reflection of life before a cancer diagnosis.


Assuntos
Neoplasias , Sobrevivência , Humanos , Qualidade de Vida , Sobrevida , Neoplasias/cirurgia , Cuidados Pós-Operatórios
8.
Cancers (Basel) ; 15(10)2023 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-37345188

RESUMO

BACKGROUND: Laparoscopic right hemihepatectomy (L-RHH) is still considered a technically complex procedure, which should only be performed by experienced surgeons in specialized centers. Future liver remnant modulation (FLRM) strategies, including portal vein embolization (PVE), and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), might increase the surgical difficulty of L-RHH, due to the distortion of hepatic anatomy, periportal inflammation, and fibrosis. Therefore, this study aims to evaluate the safety and feasibility of L-RHH after FLRM, when compared with ex novo L-RHH. METHODS: All consecutive right hemihepatectomies performed by a single surgeon in the period between October 2007 and March 2023 were retrospectively analyzed. The patient characteristics and perioperative outcomes of L-RHH after FLRM and ex novo L-RHH were compared. RESULTS: A total of 59 patients were included in the analysis, of whom 33 underwent FLRM. Patients undergoing FLRM prior to L-RHH were most often male (93.9% vs. 42.3%, p < 0.001), had an ASA-score >2 (45.5% vs. 9.5%, p = 0.006), and underwent a two-stage hepatectomy (45.5% vs. 3.8% p < 0.001). L-RHH after FLRM was associated with longer operative time (median 360 vs. 300 min, p = 0.008) and Pringle duration (31 vs. 24 min, p = 0.011). Intraoperative blood loss, unfavorable intraoperative incidents, and conversion rates were similar in both groups. There were no significant differences in length of hospital stay and 30-day overall and severe morbidity rates. Radical resection margin (R0) and textbook outcome rates were equal. One patient who underwent an extended RHH in the FLRM group deceased within 90 days of surgery, due to post-hepatectomy liver failure. CONCLUSION: L-RHH after FLRM is more technically complex than L-RHH ex novo, as objectified by longer operative time and Pringle duration. Nevertheless, this procedure appears safe and feasible in experienced hands.

9.
Curr Protoc ; 2(11): e606, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36426882

RESUMO

Human pluripotent stem cells (hPSCs) can be grown in culture indefinitely, making them a valuable tool for use in basic biology, disease modeling, and regenerative medicine. However, over prolonged periods in culture, hPSCs tend to acquire genomic aberrations that confer growth advantages, similar to those seen in some cancers. Monitoring the genomic stability of cultured hPSCs is critical to ensuring their efficacy and safety as a therapeutic tool. Most commonly employed methods for monitoring of hPSC genomes are cytogenetic methods, such as G-banding. Nonetheless, such methods have limited resolution and sensitivity for detecting mosaicism. Single nucleotide polymorphism (SNP) array platforms are a potential alternative that could improve detection of abnormalities. Here, we outline protocols for SNP array whole-genome screening of hPSCs. Moreover, we detail the procedure for assessing the SNP array's sensitivity in detecting low-level mosaic copy-number changes. We show that mosaicism can be confidently identified in samples only once they contain 20% variants, although samples containing 10% variants typically display enough variation to warrant further investigation and confirmation, for example by using a more sensitive targeted method. Finally, we highlight the advantages and limitations of SNP arrays, including a cost comparison of SNP arrays versus other commonly employed methods for detection of genetic changes in hPSC cultures. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: DNA sample preparation for SNP arrays Basic Protocol 2: SNP array hybridization, washing, and scanning Basic Protocol 3: SNP array data analysis Support Protocol: Assessment of SNP array sensitivity for detection of mosaicism.


Assuntos
Células-Tronco Pluripotentes , Polimorfismo de Nucleotídeo Único , Humanos , Polimorfismo de Nucleotídeo Único/genética , Análise Citogenética , Mosaicismo , Hibridização de Ácido Nucleico
10.
Cytopathology ; 33(2): 222-229, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34551176

RESUMO

BACKGROUND: Solitary fibrous tumour (SFT) is a unique mesenchymal neoplasm with classic features on histology and is characterised by the NAB2-STAT6 gene fusion. There are rare reports of SFTs with pancreatic involvement and only two cases in the literature reporting its features by preoperative fine needle aspiration (FNA). Herein, we characterise the cytomorphological features of four SFTs involving the pancreas by FNA to establish a preoperative diagnostic approach. METHODS: The anatomic pathology archives of two academic medical centres were searched to identify patients with a pancreatic FNA cytology specimen and a confirmed diagnosis of SFT by surgical resection. The clinical history, pathological diagnosis, cytomorphological findings, and results of immunohistochemistry (IHC) were reviewed. RESULTS: Four SFTs were identified from four patients with a median age of 59 years. The morphological features were variable but most frequently showed a bland spindled-to-epithelioid proliferation in fragments and single cells with small, oval, elongated, and hypochromatic nuclei in a haphazard arrangement with or without dense collagen. One tumour presented with a concurrent metastasis and showed a pure epithelioid component with necrosis and enlarged, hyperchromatic nuclei with conspicuous nucleoli and scattered mitoses. IHC was necessary for all diagnoses which were confirmed by surgical resection. CONCLUSIONS: SFTs with pancreatic involvement are rare, and non-specific features and tumour heterogeneity can pose a diagnostic challenge on FNA; however, IHC can be used to make a definitive diagnosis. As a result, FNA is a simple, safe, cost-effective, and accurate approach that can be used to diagnose SFT in the pancreas.


Assuntos
Tumores Fibrosos Solitários , Biópsia por Agulha Fina/métodos , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Pâncreas/patologia , Tumores Fibrosos Solitários/diagnóstico , Tumores Fibrosos Solitários/patologia
11.
Nat Commun ; 12(1): 7204, 2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-34893606

RESUMO

The H3K27me2/me3 histone demethylase KDM6B is essential to neuroblastoma cell survival. However, the mechanism of KDM6B action remains poorly defined. We demonstrate that inhibition of KDM6B activity 1) reduces the chromatin accessibility of E2F target genes and MYCN, 2) selectively leads to an increase of H3K27me3 but a decrease of the enhancer mark H3K4me1 at the CTCF and BORIS binding sites, which may, consequently, disrupt the long-range chromatin interaction of MYCN and E2F target genes, and 3) phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout confers neuroblastoma cell resistance to both palbociclib and the KDM6 inhibitor GSK-J4. These data indicate that KDM6B promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma.


Assuntos
Quinase 4 Dependente de Ciclina/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo , Oncogenes/genética , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/genética , Epigenômica , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Proteína Proto-Oncogênica N-Myc/genética , Fatores de Transcrição
12.
Front Microbiol ; 12: 743126, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34777289

RESUMO

Characterizing Mycobacterium abscessus complex (MABSC) biofilms under host-relevant conditions is essential to the design of informed therapeutic strategies targeted to this persistent, drug-tolerant, population of extracellular bacilli. Using synthetic cystic fibrosis medium (SCFM) which we previously reported to closely mimic the conditions encountered by MABSC in actual cystic fibrosis (CF) sputum and a new model of biofilm formation, we show that MABSC biofilms formed under these conditions are substantially different from previously reported biofilms grown in standard laboratory media in terms of their composition, gene expression profile and stress response. Extracellular DNA (eDNA), mannose-and glucose-containing glycans and phospholipids, rather than proteins and mycolic acids, were revealed as key extracellular matrix (ECM) constituents holding clusters of bacilli together. None of the environmental cues previously reported to impact biofilm development had any significant effect on SCFM-grown biofilms, most likely reflecting the fact that SCFM is a nutrient-rich environment in which MABSC finds a variety of ways of coping with stresses. Finally, molecular determinants were identified that may represent attractive new targets for the development of adjunct therapeutics targeting MABSC biofilms in persons with CF.

13.
Adv Healthc Mater ; 10(13): e2001368, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34050609

RESUMO

Advanced stage ovarian cancer is challenging to treat due to widespread seeding of tumor spheroids throughout the mesothelial lining of the peritoneal cavity. In this work, a therapeutic strategy using graphene nanoribbons (GNR) functionalized with 4-arm polyethylene glycol (PEG) and chlorin e6 (Ce6), a sonosensitizer, to target metastatic ovarian cancer spheroids is reported. GNR-PEG-Ce6 adsorbs onto the spheroids and disrupts their adhesion to extracellular matrix proteins or LP-9 mesothelial cells. Furthermore, for spheroids that do adhere, GNR-PEG-Ce6 delays spheroid disaggregation and spreading as well as mesothelial clearance, key metastatic processes following adhesion. Owing to the sonodynamic effects of Ce6 and its localized delivery via the biomaterial, GNR-PEG-Ce6 can kill ovarian cancer spheroids adhered to LP-9 cell monolayers when combined with mild ultrasound irradiation. The interaction with GNR-PEG-Ce6 also loosens cell-cell adhesions within the spheroids, rendering them more susceptible to treatment with the chemotherapeutic agents cisplatin and paclitaxel, which typically have difficulty in penetrating ovarian cancer spheroids. Thus, this material can facilitate effective chemotherapeutic and sonodynamic combination therapies. Finally, the adhesion inhibiting and sonodynamic effects of GNR-PEG-Ce6 are also validated with tumor spheroids derived from the ascites fluid of ovarian cancer patients, providing evidence of the translational potential of this biomaterial approach.


Assuntos
Grafite , Nanotubos de Carbono , Neoplasias Ovarianas , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Ovarianas/terapia , Esferoides Celulares
14.
J Clin Pathol ; 74(1): 43-47, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32467321

RESUMO

AIMS: Osimertinib is a third-generation EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor that is effective in non-small cell lung cancer (NSCLC) harbouring the EGFR T790M mutation. The Idylla EGFR Mutation Test is a rapid cartridge-based method for detecting T790M and other EGFR mutations. However, false negative T790M results have been reported, and the sensitivity of the assay for this mutation is uncertain. METHODS: Eighty NSCLC samples were tested by both Idylla and a next-generation sequencing (NGS) assay; 46 were from patients at disease progression, and 24 of these had known T790M mutations. Droplet digital PCR (ddPCR) was used to confirm NGS findings in samples with the T790M mutation. RESULTS: Of 19 samples with T790M variant allele frequencies (VAF) higher than the stated 5% limit of detection, 14 were detected by Idylla (sensitivity 74%, 95% CI 49% to 90%). Where sufficient sample remained, ddPCR was consistent with NGS findings in all samples. False negative T790M results were associated with higher EGFR control Cq values (median 22.8 vs 19.8), presence of the EGFR Q787Q polymorphism in cis (80% vs 44%) and presence of an invalid T790M amplification curve. An EGFR exon 19 indel with VAF >5% was also not detected by the Idylla assay in two samples. CONCLUSIONS: The Idylla EGFR Mutation Test has reduced sensitivity for the T790M mutation compared with NGS and ddPCR methods. The presence of an invalid T790M amplification curve may indicate a possible false negative result that warrants further testing by an orthogonal method.


Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/farmacologia , Alelos , Substituição de Aminoácidos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Variação Genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Sensibilidade e Especificidade , Análise de Sequência de DNA
15.
ACS Infect Dis ; 6(8): 2143-2154, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32551551

RESUMO

Understanding the physiological processes underlying the ability of Mycobacterium abscessus to become a chronic pathogen of the cystic fibrosis (CF) lung is important to the development of prophylactic and therapeutic strategies to better control and treat pulmonary infections caused by these bacteria. Gene expression profiling of a diversity of M. abscessus complex isolates points to amino acids being significant sources of carbon and energy for M. abscessus in both CF sputum and synthetic CF medium and to the bacterium undergoing an important metabolic reprogramming in order to adapt to this particular nutritional environment. Cell envelope analyses conducted on the same representative isolates further revealed unexpected structural alterations in major cell surface glycolipids known as the glycopeptidolipids (GPLs). Besides showing an increase in triglycosylated forms of these lipids, CF sputum- and synthetic CF medium-grown isolates presented as yet unknown forms of GPLs representing as much as 10% to 20% of the total GPL content of the cells, in which the classical amino alcohol located at the carboxy terminal of the peptide, alaninol, is replaced with the branched-chain amino alcohol leucinol. Importantly, both these lipid changes were exacerbated by the presence of mucin in the culture medium. Collectively, our results reveal potential new drug targets against M. abscessus in the CF airway and point to mucin as an important host signal modulating the cell surface composition of this pathogen.


Assuntos
Fibrose Cística , Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Glicolipídeos , Humanos , Mycobacterium abscessus/genética , Escarro
16.
Pathology ; 52(4): 410-420, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32359774

RESUMO

We sought to review the prevalence of EGFR T790M and other EGFR mutations associated with either proven or probable tyrosine kinase inhibitor (TKI) resistance in the Australasian lung cancer population and to perform histopathological correlation in a subset of cases. Retrospective statistical analysis was performed on a set of targeted lung cancer gene mutation tests (FIND IT gene panel) performed at Sonic Healthcare during 2018 and early 2019. A total of 1833 lung adenocarcinoma tumour samples underwent somatic mutation testing. EGFR mutations were found in 28% (n=514) of patients, in whom 9.3% (n=48) T790M mutations were present (always combined with other EGFR mutations) and 4.8% (n=25) exon 20 insertions were found. We also compared the prevalence of EGFR mutations identified in our population with that of the four largest publicly available lung cancer cohorts (total n=576 samples). Finally, a subset of 38 samples of primary/and or metastatic lung adenocarcinomas from 23 patients, including five with serial biopsies, underwent detailed morphological analysis. No reproducible morphological correlates were found to be associated with T790M, exon 20 resistance mutations or rarer co-occurring EGFR mutations. Although this may be subject to referral bias towards patients with resistant disease, the incidence of EGFR and T790M mutations is higher in this series from an Australasian population than in other similar publicly available lung adenocarcinoma cohorts. We conclude that histopathological features cannot be used to predict the acquisition of EGFR resistance.


Assuntos
Adenocarcinoma de Pulmão/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Receptores ErbB/genética , Feminino , Genes erbB-1 , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Prevalência , Estudos Retrospectivos
17.
Psychopharmacology (Berl) ; 237(1): 11-19, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31792645

RESUMO

BACKGROUND: People with schizophrenia frequently have cognitive dysfunction, which does not respond to pharmacological interventions. Varenicline has been identified as a potential treatment option for nicotinic receptor dysfunction with a potential to treat cognitive impairment in schizophrenia. METHODS: We conducted a systematic review of Pubmed, Embase, Psycinfo, CINAHL and the Cochrane Schizophrenia Trial Registry for randomised controlled trials of varenicline in people with schizophrenia for cognitive dysfunction. We excluded trials among people with dementia. We then undertook a meta-analysis with the primary outcome of difference in change of cognitive measures between varenicline and placebo as well as secondary outcomes of difference in rates of adverse events. We conducted a sensitivity analysis on smoking status and study duration. RESULTS: We included four papers in the meta-analysis (n = 339). Varenicline was not superior to placebo for overall cognition (SMD = -0.022, 95% CI -0.154-0.110; Z = -0.333; p = 0.739), attention (SMD = -0.047, 95% CI -0.199-0.104; Z = -0.613; p = 0.540), executive function (SMD = -0.060, 95% CI -0.469-0.348; Z =- 0.290; p = 0.772) or processing speed (SMD = 0.038, 95% CI -0.232-0.308; Z = 0.279; p = 0.780). There was no difference in psychotic symptoms, but varenicline was associated with higher rates of nausea. Sensitivity analyses for smoking status and study duration did not alter the results. CONCLUSION: Within the present literature, varenicline does not appear to be a useful target compound for improving cognitive impairment in schizophrenia. Based on these results, a trial would need over 2500 participants to be powered to show statistically significant findings.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Agonistas Nicotínicos/uso terapêutico , Esquizofrenia/complicações , Vareniclina/uso terapêutico , Humanos , Esquizofrenia/tratamento farmacológico
18.
Oncogene ; 39(8): 1619-1633, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31723239

RESUMO

Tumor cells must alter their antioxidant capacity for maximal metastatic potential. Yet the antioxidant adaptations required for ovarian cancer transcoelomic metastasis, which is the passive dissemination of cells in the peritoneal cavity, remain largely unexplored. Somewhat contradicting the need for oxidant scavenging are previous observations that expression of SIRT3, a nutrient stress sensor and regulator of mitochondrial antioxidant defenses, is often suppressed in many primary tumors. We have discovered that this mitochondrial deacetylase is specifically upregulated in a context-dependent manner in cancer cells. SIRT3 activity and expression transiently increased following ovarian cancer cell detachment and in tumor cells derived from malignant ascites of high-grade serous adenocarcinoma patients. Mechanistically, SIRT3 prevents mitochondrial superoxide surges in detached cells by regulating the manganese superoxide dismutase (SOD2). This mitochondrial stress response is under dual regulation by SIRT3. SIRT3 rapidly increases SOD2 activity as an early adaptation to cellular detachment, which is followed by SIRT3-dependent increases in SOD2 mRNA during sustained anchorage-independence. In addition, SIRT3 inhibits glycolytic capacity in anchorage-independent cells thereby contributing to metabolic changes in response to detachment. While manipulation of SIRT3 expression has few deleterious effects on cancer cells in attached conditions, SIRT3 upregulation and SIRT3-mediated oxidant scavenging are required for anoikis resistance in vitro following matrix detachment, and both SIRT3 and SOD2 are necessary for colonization of the peritoneal cavity in vivo. Our results highlight the novel context-specific, pro-metastatic role of SIRT3 in ovarian cancer.


Assuntos
Neoplasias Ovarianas/patologia , Sirtuína 3/metabolismo , Sobrevivência Celular , Ativação Enzimática , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glicólise , Humanos , Mitocôndrias/metabolismo , Metástase Neoplásica , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 3/deficiência , Sirtuína 3/genética , Superóxido Dismutase/metabolismo
19.
Am Surg ; 84(6): 783-788, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29981602

RESUMO

To promote residency preparedness, the Association of American Medical Colleges defined 13 core entrustable professional activities for entering residency (CEPAERs), which represent tasks that students should be able to perform on day one of residency. At the authors' institution, a four-week surgery boot camp course is offered to senior medical students, which may provide an effective mechanism for teaching the CEPAERs. Nine senior students participating in a surgery boot camp course were subjected to pre- and post-course surveys. Student expectations were closely aligned with the CEPAERs. Competence was demonstrated in all CEPAERs; however, four students did require remediation with Advanced Cardiovascular Life Support before achieving competence. In the "death on the wards module," we found a significant increase in student confidence (19.78, SD 1.47, P > 0.05 vs 31.56, SD 1.49, P < 0.01) and knowledge (16.11, SD 1.32, P > 0.05 vs 31.33, SD 2.04, P < 0.01). In a one-year follow-up survey, all participants agreed that the boot camp course was useful and positively impacted their intern year. Surgical boot camp courses provide an effective and reproducible means for teaching the CEPAERs and was found useful in preparing medical students for residency.


Assuntos
Currículo , Educação de Graduação em Medicina , Cirurgia Geral/educação , Internato e Residência , Competência Clínica , Humanos
20.
Childs Nerv Syst ; 34(8): 1557-1562, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29594462

RESUMO

PURPOSE: Rotation of the lipoma-neural placode has been noted in transitional lumbosacral lipomas. The purpose of this study was to confirm this rotation; that this rotation occurs with a preference to the left, and correlates with clinical symptoms. In addition, this study tests the hypothesis that this rotation occurs through local mechanical forces rather than intrinsic congenital malformation. METHODS: Lipomas were classified as per the Chapman classification. Degree of rotation of the placode from the coronal plane was recorded along with the presence of herniation outside of the vertebral canal. Abnormalities on urodynamic testing were recorded, along with neuro-orthopaedic signs picked up on formal neuro-physiotherapy assessment. RESULTS: Placode rotation occurs more frequently in the transitional group. Regardless of lipoma classification, rotation was much more common to the left. Furthermore, when lateralisation of symptoms was present, this strongly correlated with the direct of rotation. There was no difference in rotation of the placode whether it was within (lipomyelocoele) or without the vertebral canal (lipomyelomeningocoele). CONCLUSIONS: Placode rotation is a feature of transitional lumbosacral lipomas and may account for the increase in symptoms amongst this subgroup. Herniation of the placode outside the vertebral canal does not increase the risk of rotation suggesting a congenital cause for this finding rather than a purely mechanical explanation.


Assuntos
Lipoma/diagnóstico por imagem , Rotação , Neoplasias da Medula Espinal/diagnóstico por imagem , Raízes Nervosas Espinhais/diagnóstico por imagem , Humanos , Lipoma/fisiopatologia , Região Lombossacral/diagnóstico por imagem , Região Lombossacral/fisiopatologia , Estudos Retrospectivos , Neoplasias da Medula Espinal/fisiopatologia
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