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2.
Sci Total Environ ; 801: 149772, 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34438158

RESUMO

Seafloor methane emission is widespread on both active and passive continental margins, which may exerts significant impact on global climate change, ocean acidification, cold seep ecosystem, and global carbon cycle. However, due to the limitation of the thick water body, systematic knowledge of detection, quantification and activity of the submarine methane seepage is still unreachable, which greatly limits the assessment of the environmental impact. In 2018, a comprehensive geological survey, including multibeam mapping, seafloor observation, and seismic reflection profiling, was conducted using R/V "Haiyangdizhi 10" on the Makran continental margin. Sixty-five gas flares, which indicated seafloor methane seepage, were detected in a total survey area of 32,000 km2. The total methane flux of the surveyed area is estimated to be 4.7-5.9 × 103 Mg/yr, accounting for 0.013-0.016% of the global seafloor methane emission. In addition, three gas seeps, which were active in 2007, were inactive during our survey in 2018. It is inferred that the intermittent activity might be related to the periodic pressure release and accumulation in the system. All the flares vanish in the water column, which indicates that all the methane gas was oxidized and/or dissolved by seawater. No methane was observed entering the atmosphere in gas phase. In this study, we present new data sets of methane seeps on the Makran continental margin, which are useful to better understand the behavior of the submarine methane seepage.

3.
Cancers (Basel) ; 13(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34359755

RESUMO

Ovarian clear cell carcinoma (OCCC) is a rare subtype of epithelial ovarian cancer characterised by a high frequency of loss-of-function ARID1A mutations and a poor response to chemotherapy. Despite their generally low mutational burden, an intratumoural T cell response has been reported in a subset of OCCC, with ARID1A purported to be a biomarker for the response to the immune checkpoint blockade independent of micro-satellite instability (MSI). However, assessment of the different immune cell types and spatial distribution specifically within OCCC patients has not been described to date. Here, we characterised the immune landscape of OCCC by profiling a cohort of 33 microsatellite stable OCCCs at the genomic, gene expression and histological level using targeted sequencing, gene expression profiling using the NanoString targeted immune panel, and multiplex immunofluorescence to assess the spatial distribution and abundance of immune cell populations at the protein level. Analysis of these tumours and subsequent independent validation identified an immune-related gene expression signature associated with risk of recurrence of OCCC. Whilst histological quantification of tumour-infiltrating lymphocytes (TIL, Salgado scoring) showed no association with the risk of recurrence or ARID1A mutational status, the characterisation of TILs via multiplexed immunofluorescence identified spatial differences in immunosuppressive cell populations in OCCC. Tumour-associated macrophages (TAM) and regulatory T cells were excluded from the vicinity of tumour cells in low-risk patients, suggesting that high-risk patients have a more immunosuppressive microenvironment. We also found that TAMs and cytotoxic T cells were also excluded from the vicinity of tumour cells in ARID1A-mutated OCCCs compared to ARID1A wild-type tumours, suggesting that the exclusion of these immune effectors could determine the host response of ARID1A-mutant OCCCs to therapy. Overall, our study has provided new insights into the immune landscape and prognostic associations in OCCC and suggest that tailored immunotherapeutic approaches may be warranted for different subgroups of OCCC patients.

4.
J Ayub Med Coll Abbottabad ; 33(2): 207-212, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34137530

RESUMO

BACKGROUND: Thalassemia major is the severe form of ß thalassemia characterized by severe anaemia, hepatosplenomegaly and facioskeletal changes due to increased haemolysis of defective red blood cells. In iron overload states, high levels of iron exceed the iron-carrying capacity of transferrin within the plasma, leading to the formation of nontransferrin-bound iron form. These nontransferrin-bound iron forms can be taken up into cells, including liver, heart, and endocrine cells leading to organ damage. To prevent complications associated with hemosiderosis, iron chelation therapy remains one of the main objectives of clinical management of the patients affected by Thalassemia Major. METHODS: Thirty-seven patients were enrolled using non randomized convenience sampling technique after the written consent from patients. Patients age 2-30 years were enrolled in this study. Serum Ferritin, ALT, Serum Creatinine were checked at the start of the study, 3 months, 6months and then at the end of the study, i.e., at 9 months of the commencement of the study. They were also assessed for other side effects pertaining to oral tolerability of the drug like vomiting, nausea, GI upset, diarrhoea, urinary complaints or any other subjective complaint. RESULTS: Of the 37 patients, 20 were male (54.1%) and 17 were female (45.9%). Mean age of the patients was 10.2 years (Min. 3 years, Max 21 years). The average serum Ferritin at baseline was noted as 3440 which increased after a period of 3 months, 6 months and 9 months with average of 3359, 3677 and 4394 respectively. After the period of 9 months largest 95% confidence interval of serum Ferritin levels was observed in the range of 3420.17 to 5368.63. In our study, 17 patients required alternative chelation (46%). These patients needed IV Deferioxamine because of the rising trend of Serum Ferritin after the study. CONCLUSIONS: From the results of our study, we infer that oral Deferasirox is not an effective iron chelator. If the patients are taking oral deferasirox, their Serum Ferritin should be checked 3 monthlies. The drug is effective only in maintaining Serum Ferritin levels with levels less than 1500ng/ml. Intravenous Deferioxamine still should be preferred over oral iron chelators for effective control of iron overload and its complications.


Assuntos
Deferasirox/uso terapêutico , Quelantes de Ferro/uso terapêutico , Talassemia beta/tratamento farmacológico , Administração Intravenosa , Adolescente , Adulto , Benzoatos/efeitos adversos , Criança , Pré-Escolar , Deferasirox/administração & dosagem , Deferasirox/efeitos adversos , Contagem de Eritrócitos , Feminino , Hepatomegalia , Humanos , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/efeitos adversos , Masculino , Triazóis/efeitos adversos , Adulto Jovem
5.
Nat Commun ; 12(1): 3636, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140467

RESUMO

To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining, without targeting Non-Homologous End Joining. In addition, ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a PARP inhibitor. Genetic perturbation screening revealed that defects in the 53BP1/Shieldin complex, which cause PARP inhibitor resistance, result in in vitro and in vivo sensitivity to small molecule Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells whilst the inhibition of DNA nucleases that promote end-resection reversed these effects, implicating these in the synthetic lethal mechanism-of-action. Taken together, these observations describe a drug class that elicits BRCA-gene synthetic lethality and PARP inhibitor synergy, as well as targeting a biomarker-defined mechanism of PARPi-resistance.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Reparo do DNA/efeitos dos fármacos , DNA Polimerase Dirigida por DNA/genética , Inibidores da Síntese de Ácido Nucleico/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Mutações Sintéticas Letais/efeitos dos fármacos , Regulação Alostérica , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , DNA Polimerase Dirigida por DNA/metabolismo , Desoxirribonucleases/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Recombinação Homóloga/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Organoides/efeitos dos fármacos , Neoplasias Ovarianas/genética , Ratos , Mutações Sintéticas Letais/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/deficiência , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
6.
Malar J ; 20(1): 254, 2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103036

RESUMO

BACKGROUND: Malaria is a life-threatening, multisystem disease caused by the plasmodial parasite with a global incidence of approximately 229 million annually. The parasites are known to have unique and crucial interactions with various body tissues during its life cycle, notably the liver, spleen, and recent work has shown the bone marrow to be a reservoir of infection. METHODS: This study is a case series of patients in whom examination of bone marrow revealed malarial parasites. A retrospective record review of 35 parasite-positive bone marrow specimens examined at Aga Khan University Hospital (AKUH), Karachi, Pakistan, over the years 2007 to 2015 was conducted. Bone marrow aspirates were collected as per International Council for Standardization in Haematology (ICSH) guidelines. RESULTS: The median age of patients was 22 years (range 1-75), and 60 % (n = 21) were male. 22 patients had evidence of Plasmodium falciparum, 12 had evidence of Plasmodium vivax and 1 patient had a mixed infection. Gametocytes and trophozoites were the most common stages identified on both peripheral blood and bone marrow examinations. Indications for bone marrow examination included fever of unknown origin and the workup of cytopenias and malignancies. CONCLUSIONS: The incidental finding of Plasmodium in samples of bone marrow suggests the reticuloendothelial system may be regularly harbour these parasites, be the infection acute or chronic in character.


Assuntos
Medula Óssea/parasitologia , Malária Falciparum/diagnóstico , Malária Vivax/diagnóstico , Plasmodium falciparum/isolamento & purificação , Plasmodium vivax/isolamento & purificação , Adolescente , Adulto , Idoso , Sangue/parasitologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Malária Falciparum/parasitologia , Malária Vivax/parasitologia , Masculino , Pessoa de Meia-Idade , Paquistão , Estudos Retrospectivos , Adulto Jovem
7.
Nat Commun ; 12(1): 3516, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112782

RESUMO

Profiling studies have revealed considerable phenotypic heterogeneity in cancer-associated fibroblasts (CAFs) present within the tumour microenvironment, however, functional characterisation of different CAF subsets is hampered by the lack of specific markers defining these populations. Here we show that genetic deletion of the Endo180 (MRC2) receptor, predominantly expressed by a population of matrix-remodelling CAFs, profoundly limits tumour growth and metastasis; effects that can be recapitulated in 3D co-culture assays. This impairment results from a CAF-intrinsic contractility defect and reduced CAF viability, which coupled with the lack of phenotype in the normal mouse, demonstrates that upregulated Endo180 expression by a specific, potentially targetable CAF subset is required to generate a supportive tumour microenvironment. Further, characterisation of a tumour subline selected via serial in vivo passage for its ability to overcome these stromal defects provides important insight into, how tumour cells adapt to a non-activated stroma in the early stages of metastatic colonisation.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores de Superfície Celular/metabolismo , Esferoides Celulares/metabolismo , Células Estromais/metabolismo , Microambiente Tumoral/genética , Animais , Neoplasias da Mama/patologia , Neoplasias da Mama/secundário , Fibroblastos Associados a Câncer/citologia , Proliferação de Células/genética , Sobrevivência Celular/genética , Células Cultivadas , Técnicas de Cocultura , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Feminino , Humanos , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células NIH 3T3 , Metástase Neoplásica , Receptores de Superfície Celular/genética , Ensaio Tumoral de Célula-Tronco
8.
J Pak Med Assoc ; 71(5): 1479-1482, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34091639

RESUMO

A descriptive, cross-sectional study was conducted from July 2018 to September 2018 to assess the level of awareness among healthcare workers regarding rotavirus infection and its vaccination in Rawalpindi and Islamabad. The study site was conducted at tertiary care hospitals of Rawalpindi and Islamabad. Ethical approval was obtained from the Institutional Review Board of Army Medical College, Rawalpindi. Closed and open ended questionnaires were distributed via non-probability convenient sampling. The sample size was 257. Among the study participants, 247 (96.1%) of the participants had good level of awareness regarding rotavirus, whereas 212 (82.5%) had awareness regarding the vaccine. The mean awareness score was 16.16 ± 4.097 out of a maximum score of 22. Both male and female participants had almost equal awareness regarding the rotavirus infection (Males = 96, 93.2%, Females = 151, 98%) and vaccination (Males = 87, 84%, Females = 125, 81.1%). The mean awareness was directly related with the level of education of the participants, i.e. MBBS/FCPS/MCPS = 221(85.9%), MBBS = 209(81.5%), B.Sc. Nursing = 206(80%), and Basic Education = 220(85.7%) knew about the vaccine.


Assuntos
Infecções por Rotavirus , Rotavirus , Vacinas , Estudos Transversais , Feminino , Pessoal de Saúde , Humanos , Masculino , Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/prevenção & controle , Atenção Terciária à Saúde
9.
Br J Cancer ; 125(3): 413-421, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33972745

RESUMO

BACKGROUND: This study was undertaken to develop and validate a gene expression signature that characterises oral potentially malignant disorders (OPMD) with a high risk of undergoing malignant transformation. METHODS: Patients with oral epithelial dysplasia at one hospital were selected as the 'training set' (n = 56) whilst those at another hospital were selected for the 'test set' (n = 66). RNA was extracted from formalin-fixed paraffin-embedded (FFPE) diagnostic biopsies and analysed using the NanoString nCounter platform. A targeted panel of 42 genes selected on their association with oral carcinogenesis was used to develop a prognostic gene signature. Following data normalisation, uni- and multivariable analysis, as well as prognostic modelling, were employed to develop and validate the gene signature. RESULTS: A prognostic classifier composed of 11 genes was developed using the training set. The multivariable prognostic model was used to predict patient risk scores in the test set. The prognostic gene signature was an independent predictor of malignant transformation when assessed in the test set, with the high-risk group showing worse prognosis [Hazard ratio = 12.65, p = 0.0003]. CONCLUSIONS: This study demonstrates proof of principle that RNA extracted from FFPE diagnostic biopsies of OPMD, when analysed on the NanoString nCounter platform, can be used to generate a molecular classifier that stratifies the risk of malignant transformation with promising clinical utility.

10.
J Exp Clin Cancer Res ; 40(1): 161, 2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-33964942

RESUMO

BACKGROUND: Improvement of radiotherapy efficacy requires better insight in the dynamic responses that occur during irradiation. Here, we aimed to identify the molecular responses that are triggered during clinically applied fractionated irradiation. METHODS: Gene expression analysis was performed by RNAseq or microarray analysis of cancer cells or xenograft tumors, respectively, subjected to 3-5 weeks of 5 × 2 Gy/week. Validation of altered gene expression was performed by qPCR and/or ELISA in multiple cancer cell lines as well as in pre- and on-treatment biopsies from esophageal cancer patients ( NCT02072720 ). Targeted protein inhibition and CRISPR/Cas-induced gene knockout was used to analyze the role of type I interferons and cGAS/STING signaling pathway in the molecular and cellular response to fractionated irradiation. RESULTS: Gene expression analysis identified type I interferon signaling as the most significantly enriched biological process induced during fractionated irradiation. The commonality of this response was confirmed in all irradiated cell lines, the xenograft tumors and in biopsies from esophageal cancer patients. Time-course analyses demonstrated a peak in interferon-stimulated gene (ISG) expression within 2-3 weeks of treatment. The response was accompanied by a variable induction of predominantly interferon-beta and/or -lambda, but blocking these interferons did not affect ISG expression induction. The same was true for targeted inhibition of the upstream regulatory STING protein while knockout of STING expression only delayed the ISG expression induction. CONCLUSIONS: Collectively, the presented data show that clinically applied fractionated low-dose irradiation can induce a delayed type I interferon response that occurs independently of interferon expression or STING signaling. These findings have implications for current efforts that aim to target the type I interferon response for cancer treatment.

11.
Nat Protoc ; 16(4): 2257-2285, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33837305

RESUMO

The ability to identify regulatory interactions that mediate gene expression changes through distal elements, such as risk loci, is transforming our understanding of how genomes are spatially organized and regulated. Capture Hi-C (CHi-C) is a powerful tool to delineate such regulatory interactions. However, primary analysis and downstream interpretation of CHi-C profiles remains challenging and relies on disparate tools with ad-hoc input/output formats and specific assumptions for statistical modeling. Here we present a data processing and interaction calling toolkit (CHiCANE), specialized for the analysis and meaningful interpretation of CHi-C assays. In this protocol, we demonstrate applications of CHiCANE to region capture Hi-C (rCHi-C) and promoter capture Hi-C (pCHi-C) libraries, followed by quality assessment of interaction peaks, as well as downstream analysis specific to rCHi-C and pCHi-C to aid functional interpretation. For a typical rCHi-C/pCHi-C dataset this protocol takes up to 3 d for users with a moderate understanding of R programming and statistical concepts, although this is dependent on dataset size and compute power available. CHiCANE is freely available at https://cran.r-project.org/web/packages/chicane .


Assuntos
Genômica/métodos , Sequências Reguladoras de Ácido Nucleico/genética , Elementos Facilitadores Genéticos/genética , Epigenoma , Genoma , Código das Histonas , Modelos Genéticos , Anotação de Sequência Molecular , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas , Locos de Características Quantitativas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estatística como Assunto
12.
Langmuir ; 37(10): 3214-3222, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33657802

RESUMO

2,4,6-Trichlorophenol (2,4,6 TCP) is one of the hazardous toxicants, which has severe impacts on the environment and human health. This study is designed to develop a highly sensitive and selective electrochemical sensor based on CuO nanostructures for the detection of 2,4,6 TCP. The CuO nanostructures were synthesized through an aqueous chemical growth method and characterized by versatile analytical techniques, for example, Fourier transform infrared spectroscopy, field emission scanning electron microscopy, atomic force microscopy, energy-dispersive spectrometry, and X-ray diffraction. The characterization tools revealed a high crystalline nature, exceptional phase purity, nanoball morphology with an average size of around 18.7 nm for the CuO nanostructures. The synthesized material was used to modify a glassy carbon electrode (GCE) with the help of Nafion as a binder to improve its efficiency and sensitivity. The CuO/Nafion/GCE was proven to be a potential sensor for the determination of 2,4,6 TCP under optimized conditions at a scan rate of 70 mV/s, potential range of 0.1-1.0 V, and phosphate buffer of neutral pH as the supporting electrolyte. The linear range for 2,4,6 TCP was set from (1 to 120 µM) with a low limit of detection value calculated to be 0.046 µM. The developed sensor was effectively applied for water samples with acceptable recovery values from 95.9 to 100.6%.

13.
NPJ Breast Cancer ; 7(1): 24, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674617

RESUMO

In breast cancer (BC), detecting low volumes of axillary lymph node (ALN) metastasis pre-operatively is difficult and novel biomarkers are needed. We recently showed that patient-derived ALNs can be sustained ex-vivo using normothermic perfusion. We now compare reactive (tumour-free; n = 5) and macrometastatic (containing tumour deposits >2 mm; n = 4) ALNs by combining whole section multiplex immunofluorescence with TMT-labelled LC-MS/MS of the circulating perfusate. Macrometastases contained significantly fewer B cells and T cells (CD4+/CD8+/regulatory) than reactive nodes (p = 0.02). Similarly, pathway analysis of the perfusate proteome (119/1453 proteins significantly differentially expressed) showed that immune function was diminished in macrometastases in favour of 'extracellular matrix degradation'; only 'neutrophil degranulation' was preserved. Qualitative comparison of the perfusate proteome to that of node-positive pancreatic and prostatic adenocarcinoma also highlighted 'neutrophil degranulation' as a contributing factor to nodal metastasis. Thus, metastasis-induced changes in the REPLICANT perfusate proteome are detectable, and could facilitate biomarker discovery.

14.
J Pak Med Assoc ; 71(Suppl 1)(1): S103-S105, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33582733

RESUMO

There is a need of a new model of education and training to be implemented in the Bachelors of Dental Surgery curriculum in the relevant Pakistani institutions. The current review article was planned to suggest such a model in the light of literature aimed at building the capacity of dental graduates in a competency-driven approach with the objective of offering safe, efficient and comprehensive care to dental patients. The outcome of the reforms suggested shall prepare dental graduates suitably geared towards providing community-oriented family dental care right from their formative years. Moreover, the suggested internship model can also help to address the issue of inefficiency related to patient-care.


Assuntos
Assistência Odontológica Integral , Internato e Residência , Currículo , Educação em Odontologia , Humanos , Faculdades de Odontologia , Ensino
15.
Allergol Immunopathol (Madr) ; 49(1): 159-164, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33528945

RESUMO

Coronavirus disease 2019 (COVID-19) is a disease caused by a new strain of coronavirus named as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Globally, since the outbreak, more than seven million confirmed cases of COVID-19 have been reported. The rapid spread and increase in the number of new cases is due to person-to-person transmission. To further control its transmission, early laboratory diagnosis of both asymptomatic and symptomatic patients is crucial. Presently, the COVID-19 diagnosis of infected individuals is dependent on computed tomography scanning and real-time polymerase chain reaction (PCR). The latter is considered more sensitive and efficient for early diagnosis. In this review, general comparisons are made (cases, fatality rate, incubation period, clinical features, and reservoirs) and diagnostic laboratory procedures (specimens, extraction methods, and positive rates by real-time PCR) are compared between SARS, Middle East Respiratory Syndrome, and SARS-2. In total, 8982 SARS-2 suspected patients specimen data were retrieved, in which 40.9% (n = 3678) were detected as positive by real-time PCR. The specimen-wise high detection rate was observed from bronchoalveolar lavage, followed by saliva, nasal swabs, and sputum. As the COVID-19 cases are persistently increasing, the selection of appropriate specimens and laboratory assay would help in rapid and timely diagnosis.


Assuntos
Teste de Ácido Nucleico para COVID-19 , COVID-19/diagnóstico , Reação em Cadeia da Polimerase em Tempo Real , SARS-CoV-2/isolamento & purificação , Lavagem Broncoalveolar , COVID-19/fisiopatologia , COVID-19/virologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Humanos , Nasofaringe/virologia , SARS-CoV-2/genética , Saliva/virologia , Síndrome Respiratória Aguda Grave/diagnóstico , Síndrome Respiratória Aguda Grave/virologia , Escarro/virologia
16.
Allergol. immunopatol ; 49(1): 159-164, ene.-feb. 2021. tab
Artigo em Inglês | IBECS | ID: ibc-197113

RESUMO

Coronavirus disease 2019 (COVID-19) is a disease caused by a new strain of coronavirus named as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Globally, since the outbreak, more than seven million confirmed cases of COVID-19 have been reported. The rapid spread and increase in the number of new cases is due to person-to-person transmission. To further control its transmission, early laboratory diagnosis of both asymptomatic and symptomatic patients is crucial. Presently, the COVID-19 diagnosis of infected individuals is dependent on computed tomography scanning and real-time polymerase chain reaction (PCR). The latter is considered more sensitive and efficient for early diagnosis. In this review, general comparisons are made (cases, fatality rate, incubation period, clinical features, and reservoirs) and diagnostic laboratory procedures (specimens, extraction methods, and positive rates by real-time PCR) are compared between SARS, Middle East Respiratory Syndrome, and SARS-2. In total, 8982 SARS-2 suspected patients specimen data were retrieved, in which 40.9% (n = 3678) were detected as positive by real-time PCR. The specimen-wise high detection rate was observed from bronchoalveolar lavage, followed by saliva, nasal swabs, and sputum. As the COVID-19 cases are persistently increasing, the selection of appropriate specimens and laboratory assay would help in rapid and timely diagnosis


No disponible


Assuntos
Humanos , Infecções por Coronavirus/diagnóstico , Pneumonia Viral/diagnóstico , Pandemias , Betacoronavirus , Reação em Cadeia da Polimerase em Tempo Real/métodos
17.
Cancer Res ; 81(4): 847-859, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33509944

RESUMO

Triple-negative breast cancers (TNBC) are resistant to standard-of-care chemotherapy and lack known targetable driver gene alterations. Identification of novel drivers could aid the discovery of new treatment strategies for this hard-to-treat patient population, yet studies using high-throughput and accurate models to define the functions of driver genes in TNBC to date have been limited. Here, we employed unbiased functional genomics screening of the 200 most frequently mutated genes in breast cancer, using spheroid cultures to model in vivo-like conditions, and identified the histone acetyltransferase CREBBP as a novel tumor suppressor in TNBC. CREBBP protein expression in patient tumor samples was absent in 8% of TNBCs and at a high frequency in other tumors, including squamous lung cancer, where CREBBP-inactivating mutations are common. In TNBC, CREBBP alterations were associated with higher genomic heterogeneity and poorer patient survival and resulted in upregulation and dependency on a FOXM1 proliferative program. Targeting FOXM1-driven proliferation indirectly with clinical CDK4/6 inhibitors (CDK4/6i) selectively impaired growth in spheroids, cell line xenografts, and patient-derived models from multiple tumor types with CREBBP mutations or loss of protein expression. In conclusion, we have identified CREBBP as a novel driver in aggressive TNBC and identified an associated genetic vulnerability in tumor cells with alterations in CREBBP and provide a preclinical rationale for assessing CREBBP alterations as a biomarker of CDK4/6i response in a new patient population. SIGNIFICANCE: This study demonstrates that CREBBP genomic alterations drive aggressive TNBC, lung cancer, and lymphomas and may be selectively treated with clinical CDK4/6 inhibitors.


Assuntos
Proteína de Ligação a CREB/fisiologia , Carcinogênese/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Animais , Proteína de Ligação a CREB/genética , Proliferação de Células/genética , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Genômica/métodos , Células HCT116 , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Terapia de Alvo Molecular , Mutação , Invasividade Neoplásica , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Transplant Proc ; 53(1): 119-123, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32690312

RESUMO

PURPOSE: We examined the role of obesity and intraoperative red blood cell (RBC) and platelet transfusion in early allograft dysfunction (EAD) following liver transplantation (LT). METHODS: This is a retrospective analysis of 239 adult deceased-donor LT recipients over a 10-year period. EAD was defined by Olthoff's criteria. Data collection included donor (D) and recipient (R) age, body mass index (BMI) ≥ 35 kg/m2, diabetes mellitus, allograft macrosteatosis, and intraoperative (RBC) and platelet administration. We employed logistic regression to evaluate associations of these factors with EAD. Results are presented as odds ratios (OR) and 95% confidence intervals (CI) with corresponding P values. A P ≤ .05 was considered statistically significant. RESULTS: EAD occurred in 85 recipients (36%). Macrosteatosis data were available for 199 donors. In the multivariate analyses, BMI-D ≥ 35 kg/m2 increased the odds of developing EAD by 156% in the entire cohort (OR 2.56, 95% CI 1.09-6.01) and by 187% in recipients with macrosteatosis data (n = 199, OR 2.87, 95% CI 1.15-7.15). Each unit of RBCs increased the odds for EAD by 8% (OR 1.08, 95% CI 1.02-1.14) and, for the subgroup of 238 recipients with macrosteatosis data, by 9% (OR 1.09, 95% CI 1.02-1.16). CONCLUSION: We found a significant independent association of donor obesity and intraoperative RBC transfusion with EAD but no such association for platelet administration, MELD score, age, recipient obesity, and diabetes.


Assuntos
Diabetes Mellitus , Transfusão de Eritrócitos/efeitos adversos , Transplante de Fígado/efeitos adversos , Obesidade/complicações , Disfunção Primária do Enxerto/etiologia , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
19.
Br J Cancer ; 124(2): 494-505, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33028955

RESUMO

BACKGROUND: Glutamine (Gln) is an abundant nutrient used by cancer cells. Breast cancers cells and particularly triple-receptor negative breast cancer (TNBC) are reported to be dependent on Gln to produce the energy required for survival and proliferation. Despite intense research on the role of the intracellular Gln pathway, few reports have focussed on Gln transporters in breast cancer and TNBC. METHODS: The role and localisation of the Gln transporter SLC38A2/SNAT2 in response to Gln deprivation or pharmacological stresses was examined in a panel of breast cancer cell lines. Subsequently, the effect of SLC38A2 knockdown in Gln-sensitive cell lines was analysed. The prognostic value of SLC38A2 in a cohort of breast cancer was determined by immunohistochemistry. RESULTS: SLC38A2 was identified as a strongly expressed amino acid transporter in six breast cancer cell lines. We confirmed an autophagic route of degradation for SLC38A2. SLC38A2 knockdown decreased Gln consumption, inhibited cell growth, induced autophagy and led to ROS production in a subgroup of Gln-sensitive cell lines. High expression of SLC38A2 protein was associated with poor breast cancer specific survival in a large cohort of patients (p = 0.004), particularly in TNBC (p = 0.02). CONCLUSIONS: These results position SLC38A2 as a selective target for inhibiting growth of Gln-dependent breast cancer cell lines.


Assuntos
Sistema A de Transporte de Aminoácidos/metabolismo , Glutamina/metabolismo , Estresse Oxidativo/fisiologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Linhagem Celular Tumoral , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico
20.
Cardiovasc Revasc Med ; 22: 36-41, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32739125

RESUMO

BACKGROUND/PURPOSE: Calcified coronary artery stenosis remains a challenge for Percutaneous Coronary Intervention (PCI). Calcium modification is facilitated by rotablation and is used in 1-3% of cases. Data on rotablation in patients ≥80 years is limited and perceived to be high risk. We compared PCI with rotablation and outcomes between patients ≥80 years and those <80 years. METHODS/MATERIALS: Retrospective analysis was performed of consecutive patients who underwent rotablation and PCI from 3 United Kingdom (UK) PCI Centres (2014-2017). In-hospital outcomes (composite of stroke, myocardial infarction, death, emergency coronary artery bypass graft surgery, vascular damage, coronary perforation, advanced AV-block, bleeding and renal impairment) and 30 day mortality risk score was compared between groups. RESULTS: 213 patients were included. 33.3% (n = 71) were ≥80 years. Baseline and angiographic characteristics were similar in the two groups. Older patients were more likely to present with acute coronary syndrome (ACS) (≥80 years 53.5% vs. 33.8% in <80 years, p = 0.006) and had increased hospital stay (≥80 years 2.8 days (±6.0) vs. 1.3 days (±1.9) <80 years, p = 0.009). Majority of PCI were performed through radial access (≥80 years 91.5% vs. 88.0% <80 years, p = 0.43). In-hospital composite outcomes were similar between the groups (≥80 years 5.6% vs. 4.9% <80 years, p = 1.0). The 30-day mortality risk score demonstrated a higher average risk of 2.5% in ≥80 years versus under 1% risk in <80 years (p < 0.001). CONCLUSION: This study demonstrates that outcomes after rotablation in the very elderly are similar to younger patients despite being high risk and presenting with ACS.

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