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1.
J Pak Med Assoc ; 74(1): 187-188, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38219200

RESUMO

Unsuspected thyroid cancer can be detected in multinodular goiter (MNG) where the risk of malignancy is 7-9%. Fine needle aspiration (FNAc) is performed in case of suspicious findings on ultrasound. With benign FNAC results there is no need for surgery unless the patient has pressure symptoms or cosmetic concerns, but the risk of overlooked malignancy is always present. We present the case of a patient with unexpected detection of papillary thyroid cancer on thyroid scan.


Assuntos
Bócio Nodular , Neoplasias da Glândula Tireoide , Humanos , Tireoidectomia , Bócio Nodular/diagnóstico por imagem , Bócio Nodular/cirurgia , Pertecnetato Tc 99m de Sódio , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/diagnóstico , Biópsia por Agulha Fina
2.
Plants (Basel) ; 12(3)2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36771731

RESUMO

Cadmium (Cd) is a non-essential and toxic metal that accumulates in plant's tissues and diminishes plant growth and productivity. In the present study, differential root transcriptomic analysis was carried out to identify Cd stress-responsive gene networks and functional annotation under Cd stress in wheat seedlings. For this purpose, the Yannong 0428 wheat cultivar was incubated with 40 µm/L of CdCl2·2.5H2O for 6 h at three different seedling growth days. After the quality screening, using the Illumina Hiseq 2000 platform, more than 2482 million clean reads were retrieved. Following this, 84.8% to 89.3% of the clean reads at three time points under normal conditions and 86.5% to 89.1% of the reads from the Cd stress condition were mapped onto the wheat reference genome. In contrast, at three separate seedling growth days, the data analysis revealed a total of 6221 differentially expressed genes (DEGs), including 1543 (24.8%) up-regulated genes and 4678 (75.8%) down-regulated genes. In total, 120 DEGs were co-expressed throughout all the growth days, whereas 1096, 1088, and 2265 DEGs were found to be selectively up-/down-regulated at 7d, 14d, and 30d, respectively. However, the clustering of DEGs, through utilizing the Kyoto Encyclopedia of Genes and Genomes (KEGG), revealed that the DEGs in the metabolic category were frequently annotated for phenylpropanoid biosynthesis. In comparison, a considerable number of DEGs were linked to protein processing in the endoplasmic reticulum under the process of genetic information processing. Similarly, in categories in organismal systems and cellular processes, DEGs were found in plant hormone signal transduction pathways, and DEGs were identified in the plant-pathogen interaction pathway, respectively. However, DEGs in "endocytosis pathways" were enriched in environmental information processing. In addition, in-depth annotations of roughly specific heavy metal stress-response genes and pathways were also mined, and the expression patterns of eight DEGs were studied using quantitative real-time PCR. The results were congruent with the findings of RNA sequencing regarding transcript abundance in the studied wheat cultivar.

3.
J Clin Lab Anal ; 37(4): e24851, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36807631

RESUMO

The burden of HPV varies by country and HIV status. The study aimed to evaluate HPV types prevalent in HIV-positive females compared with HIV-negative females in the local population of the federal capital territory in Pakistan. METHOD: The selected female population consisted of 65 already diagnosed HIV-positive females and 135 HIV-negative females. Cervical scrap was collected and analyzed for HPV and cytology. RESULTS: The prevalence of HPV in HIV-positive patients was 36.9%, higher than HIV-negative patients (4.4%). 12.30% had cervical cytology interpreted as "LSIL" and 87.69% had cytology interpreted as "NIL." The high-risk type was detected in 15.39% while 21.54% showed low-risk HPV types. Among the high-risk types, HPV18 (6.15%), HPV16 (4.62%), HPV45 (3.07%), HPV33 (1.53%), HPV58 (3.07%), and HPV68 (1.53%) were found. In patients with LSIL, high-risk HPV accounts for 62.5%. Risk factors, such as age, marital status, educational status, residence, parity, other STDs, and contraceptives, were analyzed to find the correlation with HPV infection Age ≤35 years (OR 1.21, 95% CI, 0.44-3.34), illiterate and incomplete secondary education (OR 1.08, 95% CI, 0.37-3.15), and those reported not to use contraceptives (OR: 1.90; 95% CI: 0.67-5.42) have an association for increased risk of HPV infection. CONCLUSION: HPV18, HPV16, HPV58, HPV45, HPV68, and HPV33 were identified among high-risk HPV types. High-risk HPV was detected in 62.5% of low-grade squamous intraepithelial lesions. The data is useful for health policymakers to develop a strategy for HPV screening and prophylactic vaccination to prevent cervical cancer.


Assuntos
Infecções por HIV , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Gravidez , Humanos , Feminino , Adulto , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/epidemiologia , Prevalência , Neoplasias do Colo do Útero/patologia , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Papillomaviridae , Genótipo
4.
J Pak Med Assoc ; 72(7): 1454-1455, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36156583

RESUMO

Tc-99m Methylene Diphosphonate (MDP) bone scintigraphy has been used for the assessment of benign as well as malignant skeletal conditions. Non-osseous radiotracer uptake on bone scan is an unusual finding. It is usually performed for metastatic bone disease, and is generally not an indication in multiple myeloma, as osteolytic lesions typically show no radiotracer uptake. Despite this, substantial number of multiple myeloma patients undergo bone scintigraphy due to their presentation imitating a metastatic bone disease. We describe a case of multiple myeloma, where extra osseous uptake in lung and diffuse hepatic, has been noted on bone scan.


Assuntos
Doenças Ósseas , Mieloma Múltiplo , Osso e Ossos , Humanos , Mieloma Múltiplo/diagnóstico por imagem , Compostos Radiofarmacêuticos , Medronato de Tecnécio Tc 99m
5.
Viral Immunol ; 35(2): 142-149, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35167759

RESUMO

Human health has always been challenged by variety of viral infections, but severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has surpassed all previous viral diseases and emerged as a major health challenge around the globe. Real-time polymerase chain reaction (PCR) is the gold standard for the diagnosis of SARS-CoV-2 and serological assay provides a compliment to diagnosis after second week of infection. The aim of the study is the characterization of antibody response to SARS-CoV-2 in the blood sample of diagnosed coronavirus disease 2019 (COVID-19) patients, and its potential association with factors such as age, gender, time, and symptoms. Serum from 248 confirmed SARS-CoV-2 patients was investigated for antibodies. Elecsys anti-SARS chemiluminescent immune assay was performed for the detection of nucleocapsid-specific antibodies. Association of antibody response with gender, age, and time after onset of symptoms was analyzed. Among 248 PCR positive SARS-CoV-2 patients, 214 (86.3%) have virus-specific antibody signals. Antibodies positivity rate was higher in male patient patients as compared with female patients (90.8% vs. 79.2%, p = 0.009). Patients aged 30-40 years had the highest antibody positivity rate as compared with other groups (89.10%, p = 0.04). Patients age group >60 years had a lower positivity rate (75%, p = 0.04). The increasing trend in the antibodies detection with time was observed, maximum positive antibodies response rate observed at 8 weeks. Patients were categorized on the basis of clinical symptoms into asymptomatic, mild, and moderate; 17.7% were asymptomatic, 60.5% showed mild symptoms, and 21.8% showed moderate symptoms of the disease. Males were seen to be more asymptomatic as compared with females (i.e., 59.1% to 40.9%). The serological test for SARS-CoV-2 has a high sensitivity at >2 weeks after the positive PCR result or onset of illness. In addition, the serological response differs among patients based on gender, age, as well as time between the onset of symptoms or PCR confirmation and sample collection for the study of antibody response.


Assuntos
COVID-19 , SARS-CoV-2 , Adulto , Anticorpos Antivirais , Formação de Anticorpos , COVID-19/diagnóstico , Feminino , Humanos , Imunoglobulina G , Masculino , Pessoa de Meia-Idade
6.
Drug Discov Today ; 27(2): 529-537, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34592448

RESUMO

Traditionally, in vitro and in vivo methods are useful for estimating human pharmacokinetics (PK) parameters; however, it is impractical to perform these complex and expensive experiments on a large number of compounds. The integration of publicly available chemical, or medical Big Data and artificial intelligence (AI)-based approaches led to qualitative and quantitative prediction of human PK of a candidate drug. However, predicting drug response with these approaches is challenging, partially because of the adaptation of algorithmic and limitations related to experimental data. In this report, we provide an overview of machine learning (ML)-based quantitative structure-activity relationship (QSAR) models used in the assessment or prediction of PK values as well as databases available for obtaining such data.


Assuntos
Inteligência Artificial , Descoberta de Drogas , Big Data , Humanos , Aprendizado de Máquina , Farmacocinética , Relação Quantitativa Estrutura-Atividade
7.
JCO Glob Oncol ; 7: 1647-1658, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34898246

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is the commonest non-Hodgkin lymphoma encountered by hematopathologists and oncologists. Management guidelines for DLBCL are developed and published by countries with high income and do not cater for practical challenges faced in resource-constrained settings. This report by a multidisciplinary panel of experts from Pakistan is on behalf of three major national cancer societies: Society of Medical Oncology Pakistan, Pakistan Society of Hematology, and Pakistan Society of Clinical Oncology. The aim is to develop a practical and standardized guideline for managing DLBCL in Pakistan, keeping in view local challenges, which are similar across most of the low- and middle-income countries across the globe. Modified Delphi methodology was used to develop consensus guidelines. Guidelines questions were drafted, and meetings were convened by a steering committee to develop initial recommendations on the basis of local challenges and review of the literature. A consensus panel reviewed the initial draft recommendations and rated the guidelines on a five-point Likert scale; recommendations achieving more than 75% consensus were accepted. Resource grouping initially suggested by Breast Health Global Initiative was applied for resource stratification into basic, limited, and enhanced resource settings. The panel generated consensus ratings for 35 questions of interest and concluded that diagnosis and treatment recommendations in resource-constrained settings need to be based on available resources and management expertise.


Assuntos
Hematologia , Linfoma Difuso de Grandes Células B , Consenso , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/terapia , Oncologia , Paquistão/epidemiologia
8.
Int J Radiat Oncol Biol Phys ; 111(5): 1227-1236, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34418466

RESUMO

PURPOSE: Most new nasopharyngeal cancer cases occur in low-income and middle-income countries, and these patients experience poorer overall survival than that of new nasopharyngeal cancer cases in high-income countries. The goal of this research project is to determine whether the introduction of a radiation therapy quality assurance program can ultimately improve outcomes for nasopharyngeal cancer patients in lower-income and middle-income countries. This study reports the results of the first phase of the International Atomic Energy Agency Coordinated Research Project (325-E3-TM-47712). METHODS AND MATERIALS: This prospective study has 2 phases. Phase 1 is a survey of radiation therapy resources, patient characteristics and treatment, and results of radiation therapy quality assurance performed by the expert panel. An educational workshop reviewing phase 1 results for each center was completed before accrual of patients for phase 2. The ultimate aim of the study is to compare the first and second cohort of patients to see if quality assurance can result in fewer major protocol deviations and a 15% improvement in patients' 3-year progression-free survival. RESULTS: Of 14 participating centers, 13 (93%) had computed tomography simulators and linear accelerators (LINAC) with intensity modulated radiation therapy (IMRT) capacity, median 3 LINAC (range, 1-13), and median 10 radiation oncologists (range, 5-51). The annual number of nasopharyngeal cancer cases irradiated was median 54 (range, 10-627). Five of 14 centers (36%) had no local radiation therapy quality assurance. For the current phase 1 study, 134 patients were evaluated, 82.1% had MRI staging, 99.3% had metastatic workup, 65.6% undifferentiated histology, 51% stage 3 and 49% stage 4. Radiation therapy quality assurance revealed 81 (60.4%) of 134 patients had major protocol violations in gross tumor volume and high dose planning target volume contours and/or dosimetry, 28.4% patients had borderline plans, 15 (11.2%) acceptable, and only 6 (4.2%) had inevitable compromise due to tumor extent. CONCLUSIONS: This is the first International Atomic Energy Agency study to address the fundamental issue of treatment quality rather than altered treatment regimens. The high rate of unacceptable radiation therapy plans is a major concern, and we hope phase 2 will show a significant reduction and improved patient outcomes.


Assuntos
Neoplasias Nasofaríngeas , Energia Nuclear , Radioterapia de Intensidade Modulada , Países em Desenvolvimento , Humanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/radioterapia , Estudos Prospectivos , Garantia da Qualidade dos Cuidados de Saúde , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador
9.
Artigo em Inglês | MEDLINE | ID: mdl-33820762

RESUMO

Nonsynonymous mutations are well documented in TEM ß-lactamases. The resulting amino acid changes often alter the conferred phenotype from broad spectrum (2b) conferred by TEM-1 to extended spectrum (2be), inhibitor resistant (2br), or both extended spectrum and inhibitor resistant (2ber). The encoding blaTEM genes also deviate in numerous synonymous mutations, which are not well understood. blaTEM-3 (2be), blaTEM-33 (2br), and blaTEM-109 (2ber) were studied in comparison to blaTEM-1blaTEM-33 was chosen for more detailed studies because it deviates from blaTEM-1 by a single nonsynonymous mutation and three additional synonymous mutations. Genes encoding the enzymes with only nonsynonymous or all (including synonymous) mutations plus all permutations between blaTEM-1 and blaTEM-33 were expressed in Escherichia coli cells. In disc diffusion assays, genes encoding TEM-3, TEM-33, and TEM-109 with all synonymous mutations resulted in higher resistance levels than genes without synonymous mutations. Disc diffusion assays with the 16 genes carrying all possible nucleotide change combinations between blaTEM-1 and blaTEM-33 indicated different susceptibilities for different variants. Nucleotide BLAST searches did not identify genes without synonymous mutations but did identify some without nonsynonymous mutations. Energies of possible secondary mRNA structures calculated with mfold are generally higher with synonymous mutations, suggesting that their role could be to destabilize the mRNA and facilitate its unfolding for efficient translation. In summary, our data indicate that transition from blaTEM-1 to other variant genes by simply acquiring the nonsynonymous mutations is not favored. Instead, synonymous mutations seem to support the transition to other variant genes with nonsynonymous mutations leading to different phenotypes.


Assuntos
Infecções por Escherichia coli , beta-Lactamases , Escherichia coli/genética , Humanos , Testes de Sensibilidade Microbiana , Mutação Silenciosa/genética , beta-Lactamases/genética
11.
Viral Immunol ; 33(7): 507-513, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32429831

RESUMO

Pakistan is ranked second highest after Egypt in hepatitis C virus (HCV) infection. Accurate typing is mandatory to be compliant with the World Health Organization strategy to eliminate HCV infection in 2030. We characterized the HCV genotypes using Abbott real-time polymerase chain reaction assay and indeterminate samples were sequenced. We also investigated the distribution of HCV genotype among different age groups and gender in chronic HCV patients. One thousand thirteen samples were tested for HCV genotyping using Abbott real-time HCV genotyping assay. RNA extraction from plasma was done using the m2000sp platform. The amplification and detection of genotypes was done on m2000rt instrument. The lower limit of detection assay is 500 IU/mL. The indeterminate genotypes were analyzed by sequencing of the NS5B region. We found genotype 1 in 1.68%, genotype 1b in 0.89%, genotype 1a in 0.79%, genotype 2 in 0.6, genotype 3 in 94.37%, genotype 4 in 0.4%, genotype 5 in 0.09%, and indeterminate genotype result were found in 1.18%. Abbott assay could not identify 12 samples of genotype 3 (1.18%) and gave the indeterminate result. It also fails to assign some of the samples of genotype 1 into 1a and 1b. The indeterminate genotypes were resolved by sequencing followed by phylogenetic analysis. Genotype 3 is the predominant genotype and significantly higher in females as compared with males. Genotype 1a is more common in males than in females. Indeterminate HCV genotypes on sequencing analysis identify as genotype 3a and likewise subtype of genotype1 as 1a.


Assuntos
Técnicas de Genotipagem/métodos , Hepacivirus/classificação , Hepatite C/epidemiologia , Proteínas não Estruturais Virais/genética , Adulto , Idoso , Sequência de Bases , Feminino , Genótipo , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Paquistão/epidemiologia , Filogenia , RNA Viral , Kit de Reagentes para Diagnóstico , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Adulto Jovem
12.
Biomolecules ; 9(11)2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31718049

RESUMO

(1) Background: Metallo-ß-lactamases (MBLs) have raised concerns due to their ability to inactivate carbapenems and newer generation cephalosporins and the absence of clinically available MBL inhibitors. Their genes are often transferred horizontally, and the number of MBL variants has grown exponentially, with many newer variants showing enhanced enzyme activity or stability. In this study, we investigated a closely related group of variants from the IMP family that all contain the combination of mutations S115T and S119G relative to IMP-1. (2) Methods: The effects of each individual mutation and their combination in the IMP-1 sequence background in comparison to IMP-1 were investigated. Their ability to confer resistance and their in-cell expression levels were determined. All enzymes were purified, and their secondary structure and thermal stability were determined with circular dichroism. Their Zn(II) content and kinetic constants with a panel of ß-lactam antibiotics were determined. (3) Results: All four enzymes were viable and conferred resistance to all antibiotics tested except aztreonam. However, the single-mutant enzymes were slightly deficient, IMP-1S115T due to decreased enzyme activity and IMP-1-S119G due to decreased thermal stability and expression, while the double mutant did not show these defects. (4) Conclusions: These observations suggest that S119G was acquired due to its increased enzyme activity and S115T to suppress the thermal stability and expression defect introduced by S119G.


Assuntos
Antibacterianos/química , Relação Estrutura-Atividade , beta-Lactamases/genética , Substituição de Aminoácidos/genética , Antibacterianos/efeitos adversos , Regulação Enzimológica da Expressão Gênica , Humanos , Inosina Monofosfato/química , Cinética , Testes de Sensibilidade Microbiana , Mutação/genética , Estrutura Secundária de Proteína , Resistência beta-Lactâmica/genética , beta-Lactamases/química
13.
Microb Pathog ; 132: 150-155, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31059757

RESUMO

Tuberculosis is an airborne infectious disease caused by Mycobacterium tuberculosis which threatens the globe. Aminoglycosides {Amikacin (AK) & Kanamycin (KM)} are WHO recommended second-line anti-TB drugs used against the treatment of drug-resistant tuberculosis. Aminoglycosides target the steps of protein translation machinery of M.tuberculosis. Several mechanisms have been put forward to elucidate the phenomena of aminoglycosides resistance but our knowledge is still insufficient. The aim of the study was to understand the involvement of Mycobacterium tuberculosis universal stress protein (Rv2005c) in aminoglycosides resistance and virulence. To establish the relationship of universal stress protein Rv2005c with AK & KM resistance, Rv2005c was cloned, expressed in E.coli BL21 using pQE2 expression vector and antimicrobial drug susceptibility testing (DST) was carried out. STRING-10 was also used to predict the interacting protein partners of Rv2005c. DST showed that the minimum inhibitory concentration of induced recombinant cells (Rv2005c) were five and four folds shifted with AK and KM E-strips, respectively. STRING-10 showed the interacting protein partners of Rv2005c. Overexpression of Rv2005c leads to shifting in MIC which might be signifying its involvement in the survival/resistance of Mycobacteria by inhibiting/modulating the effects of AK and KM released from the E-strips. Interactome also suggests that Rv2005c and its interacting protein partners are cumulatively involved in M.tuberculosis resistance, stresses, and latency.


Assuntos
Aminoglicosídeos/farmacologia , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , DNA Bacteriano/isolamento & purificação , Farmacorresistência Bacteriana Múltipla/genética , Amicacina/farmacologia , Antígenos de Bactérias/metabolismo , Antituberculosos/farmacologia , Proteínas de Bactérias/metabolismo , Clonagem Molecular , DNA Bacteriano/genética , Regulação Bacteriana da Expressão Gênica , Canamicina/farmacologia , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/metabolismo , Mapas de Interação de Proteínas , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
14.
Drug Discov Today ; 24(1): 179-188, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30031878

RESUMO

Polycomb repressive complex 2 (PRC2) plays a significant part in histone methylation - trimethylating K27 at H3, an epigenetic hallmark of gene silencing. Inhibition of PRC2 has been reported as a promising strategy for the treatment of various cancers. Significant efforts have been made toward the development of PRC2 inhibitors and some of them have progressed to clinical trials. The binding mode of these inhibitors is well understood. Here, we summarize the advances in drug discovery and development for PRC2 component inhibitors by focusing on their chemotypes, activity, selectivity and binding modes. We believe that such analysis will provide new avenues for the design and development of next-generation PRC2 inhibitors through establishment of a structure-based drug design platform.


Assuntos
Complexo Repressor Polycomb 2/antagonistas & inibidores , Animais , Epigênese Genética , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Complexo Repressor Polycomb 2/química , Complexo Repressor Polycomb 2/metabolismo
15.
Fam Cancer ; 18(2): 261-265, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30478739

RESUMO

Precise genetic counseling and prenatal diagnosis are often hindered by incomplete penetrance of risk variance and complex patterns of inheritance. Here, we performed a clinical and genetic study of a five-generation Pakistani family with a history of multiple cases of childhood brain tumors. Six affected individuals died of brain tumors at very early ages and three were confirmed as having a homozygous mutation in exon 6 of the PMS2 gene (c.543delT). Fifteen members of the family were identified as heterozygous carriers of this mutation with a lack of cancer incidence. Both clinical manifestations and genetic test results of brain tumor patients in the family support the diagnosis of constitutional mismatch repair deficiency (CMMRD) syndrome, a condition in which individuals carry homozygous germline mutations in mismatch repair machinery genes with an early onset of malignancies such as glioma. This information was used to guide prenatal diagnosis with genetic testing on chorionic villus samples for the family. This is the first report of prenatal genetic diagnosis of hereditary brain tumor.


Assuntos
Neoplasias Encefálicas/diagnóstico , Amostra da Vilosidade Coriônica , Neoplasias Colorretais/diagnóstico , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Síndromes Neoplásicas Hereditárias/diagnóstico , Fatores Etários , Idade de Início , Neoplasias Encefálicas/genética , Criança , Pré-Escolar , Neoplasias Colorretais/genética , Consanguinidade , Éxons/genética , Feminino , Aconselhamento Genético , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Heterozigoto , Homozigoto , Humanos , Lactente , Masculino , Síndromes Neoplásicas Hereditárias/genética , Paquistão , Linhagem , Gravidez
16.
J Chem Inf Model ; 58(9): 1902-1914, 2018 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-30107123

RESUMO

The global rise of metallo-ß-lactamases (MBLs) is problematic due to their ability to inactivate most ß-lactam antibiotics. MBL inhibitors that could be coadministered with and restore the efficacy of ß-lactams are highly sought after. In this study, we employ virtual screening of candidate MBL inhibitors without thiols or carboxylates to avoid off-target effects using the Avalanche software package, followed by experimental validation of the selected compounds. As target enzymes, we chose the clinically relevant B1 MBLs NDM-1, IMP-1, and VIM-2. Among 32 compounds selected from an approximately 1.5 million compound library, 6 exhibited IC50 values less than 40 µM against NDM-1 and/or IMP-1. The most potent inhibitors of NDM-1, IMP-1, and VIM-2 had IC50 values of 19 ± 2, 14 ± 1, and 50 ± 20 µM, respectively. While chemically diverse, the most potent inhibitors all contain combinations of hydroxyl, ketone, ester, amide, or sulfonyl groups. Docking studies suggest that these electron-dense moieties are involved in Zn(II) coordination and interaction with protein residues. These novel scaffolds could serve as the basis for further development of MBL inhibitors. A procedure for renaming NDM-1 residues to conform to the class B ß-lactamase (BBL) numbering scheme is also included.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/classificação , beta-Lactamases/metabolismo , Antibacterianos/química , Antibacterianos/farmacologia , Dicroísmo Circular , Simulação por Computador , Escherichia coli/genética , Escherichia coli/metabolismo , Regulação Enzimológica da Expressão Gênica , Espectrometria de Massas , Modelos Químicos , Estrutura Molecular , Software
17.
Pak J Med Sci ; 34(2): 235-239, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29805386

RESUMO

BACKGROUND & OBJECTIVE: Everolimus-eluting stents, compared with bare metal stents, reduced the risk of restenosis in clinical trials with strict inclusion and exclusion criteria. The objective of this study was to determine the three months clinical outcomes of Everolimus Eluting Stents in patients with stable angina pectoris in Pakistani population. METHODS: It was a descriptive cross-sectional study and the data was collected from Catheterization Laboratory Cardiology Department Lady Readings Hospital Peshawar. Our study included all the patients with stable coronary artery disease who had received Everolimus eluting stents from August, 2013, to April, 2014. Total study duration was 09 months. The primary end points were the rate of target vessel revascularization, myocardial infarction at three months. All those patients who received Everolimus coronary stents were recalled after three months from the index procedure and enquired about target vessel revascularization (TVR), myocardial infarction and hospitalization over the last three months. Data analysis was done using SPSS version 16. RESULTS: Our study included 378 patients with stable ischemic heart disease who underwent revascularization with Everolimus eluting stent. These patients were followed up for a period of 3 months for target vessel revascularization(TVR) and myocardial infarction(MI). Mean age was 57.04±9.307, males were (72%). Left Anterior Descending (LAD) and Left circumflex (LCx) were the predominant vessels vascularized. Mean length of Everolimus eluting stent was 21.91± 4.6 while mean diameter of stent was 2.90±0.248. Thirteen (3.4%) patients had TVR and 14 (3.7%) patients had MI during three months follow up after PCI. TVR and MI were prevalent in patients who received longer Everolimus stents as compared to those who received shorter stents at three months, and the difference between the two was statistically significant. CONCLUSION: Short-term results from this study suggest that real-world outcomes among 378 patients are comparable to those reported in other registries and trials, and safety outcomes as measured by rates of TVR, MI were low. The long-term safety of Everolimus-eluting stents needs to be ascertained in large, randomized trials.

18.
Int J Infect Dis ; 66: 83-89, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29138009

RESUMO

BACKGROUND: Globally, cervical cancer is the fourth most common cancer in women and the seventh most common cancer overall, accounting for an estimated 300 000 annual deaths. Human papillomavirus (HPV) is the second most common cause of cervical cancer worldwide. HPV screening is not a common practice in Pakistan. The aim of this study was to determine the prevalence of HPV and HPV types in women with a normal cytology of the cervix living in the upper and lower regions of Punjab, Pakistan, and to analyze the risk factors for HPV in this region. METHODS: PCR analysis was performed for 1011 female patients with a normal cytology of the cervix from various districts of Punjab Province, Pakistan. Risk factors for the acquisition of HPV were studied. High-risk HPV types (HPV16 and HPV18) were detected using the Abbott Real Time HR HPV test. To determine the genotype, partial L1 region sequences of HPV-positive samples were subjected to sequencing using MY/09/MY11 primers, and a phylogenetic tree was constructed using CLC software. RESULTS: The study found a 4.74% prevalence of HPV, with the most frequent HPV type found being the low-risk HPV6 (in 25% of infected individuals), followed by HPV55 (22.9%), HPV11 (20.8%), and high-risk types HPV45 (12.5%), HPV33 (8.33%), HPV18 (6.25%), and HPV16 (4.16%). Phylogenetic analysis of all HPV types in this study showed 80-99% nucleotide identity with types related to the same species. The sequences were clustered with China, India, Mexico, Iran, Slovenia, and Germany, showing the diversity in origin of the various genotypes prevalent in Pakistan. CONCLUSIONS: In this population with a normal cervical cytology, the prevalence of high-risk HPV types was very low. The major prevalent HPV genotype in Punjab Province of Pakistan was the low-risk HPV type 6, followed by HPV type 55. Sequencing of the partial L1 region suggested that the region was highly conserved in all reported sequences. This study highlights the need to conduct robust epidemiological studies in the region and to develop regular HPV screening so that the situation does not reach an alarming stage resulting in cervical cancer.


Assuntos
Colo do Útero/virologia , Papillomaviridae/genética , Infecções por Papillomavirus/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Colo do Útero/anatomia & histologia , Feminino , Genótipo , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Irã (Geográfico) , Programas de Rastreamento , Pessoa de Meia-Idade , Paquistão/epidemiologia , Papillomaviridae/classificação , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/patologia , Filogenia , Prevalência , Fatores de Risco , Adulto Jovem
19.
J Coll Physicians Surg Pak ; 27(12): 775-777, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29185406

RESUMO

The authors are reporting an anaesthetic management of patient presenting with left parietal lobe space occupying lesion and scheduled for Awake-craniotomy. Awake-throughout approach using scalp block was planned. Among techniques reported for keeping patient awake during the surgery, this one is really underutilized. The successful conduct requires thorough preoperative assessment and psychological preparation. We used powerpoint presentation as a preoperative teaching tool. The anatomical landmark technique was used to institute scalp block, where individual nerves were targeted bilaterally. Patient remained stable throughout and participated actively in intraoperative neurological monitoring. Postoperative period showed remarkable recovery, better pain control, and shorter length of stay in hospital.


Assuntos
Anestesia Local/métodos , Anestésicos/administração & dosagem , Sedação Consciente/métodos , Craniotomia/métodos , Neoplasias Encefálicas/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória , Duração da Cirurgia , Medição da Dor , Cuidados Pré-Operatórios , Neoplasias Supratentoriais/cirurgia , Resultado do Tratamento , Vigília
20.
J Coll Physicians Surg Pak ; 27(9): 579-581, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29017678

RESUMO

Mammary analogue secretory carcinoma (MASC) is a rare salivary gland malignancy that exhibits resemblance with secretory carcinoma of the breast (SC) due to the presence of ETV6-NTRK3 gene fusion, formerly classified as acinic cell carcinoma. It is a slowly growing painless tumor that exhibits wide range of clinical behavior. This tumor typically affects middle aged people. Less than 100 such cases have been reported in the literature so far with only 8 case reports of patients less than 19 years of age. Very little is known about the clinical management of such cases. We hereby report a case of 15-year boy who had been managed for MASC of left parotid gland with exision.


Assuntos
Neoplasias da Mama/patologia , Carcinoma/patologia , Carcinoma Secretor Análogo ao Mamário/patologia , Glândula Parótida/diagnóstico por imagem , Neoplasias das Glândulas Salivares/patologia , Adolescente , Biópsia por Agulha Fina , Humanos , Masculino , Glândula Parótida/cirurgia , Resultado do Tratamento
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