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1.
J Cancer ; 9(23): 4341-4345, 2018.
Article in English | MEDLINE | ID: mdl-30519338

ABSTRACT

The most frequently reported genetic aberration among polycythemia vera (PV) patients is a gain of function mutation V617F in exon 14 of Janus kinase 2 (JAK2) gene. However in many investigations, V617F negative PV patients have been reported to harbor mutations in JAK 2 exon 12. We investigated 24 patients with PV (diagnosed following 2016 WHO guidelines) to detect V617F mutation through allele specific PCR. The frequency of which was found to be 19/24 (79.2 %). Later on JAK2 exon 12 and 14 was amplified by conventional PCR in V617F negative patients and subjected to sequence analysis. A total of 03 mutated sites in exon 12 were detected in only two V617F-negative patients 2/5 (40%). All three substitutions were heterozygous i.e. F537F/I found in both patients and R528R/T, which is a novel mutation. In addition, one patient 1/5 (10%) manifested amino acid substitution V617A in JAK2 exon 14. Hematological parameters of individuals harboring mutations do not vary significantly than rest of the PV patients. Previous history and 2.3 years of follow-up studies reveal 15-year survival of V617F positive patients (n=19) to be 76%, while it is 94% for wild type V617 patients (n=05). Mean TLC of the patient cohort was 17.6± 9.1 x 109/L, mean platelet count was 552± 253 x 109/L, mean hemoglobin was 16.9± 3.2 g/dl, mean corpuscular volume (MCV) was 77.2± 13.0 fl and mean corpuscular hemoglobin (MCH) was 25.6± 3.9 pg. This is the very first attempt from Pakistan to screen JAK2-exon 12 mutations in PV patients. We further aim to investigate Jak2 exon 12 mutations in larger number of PV patients to assess their clinical relevance and role in disease onset, progression and transformation.

2.
PLoS One ; 8(2): e55717, 2013.
Article in English | MEDLINE | ID: mdl-23409026

ABSTRACT

BACKGROUND: BCR-ABL kinase domain mutations are infrequently detected in newly diagnosed chronic-phase chronic myeloid leukemia (CML) patients. Recent studies indicate the presence of pre-existing BCR-ABL mutations in a higher percentage of CML patients when CD34+ stem/progenitor cells are investigated using sensitive techniques, and these mutations are associated with imatinib resistance and disease progression. However, such studies were limited to smaller number of patients. METHODS: We investigated BCR-ABL kinase domain mutations in CD34+ cells from 100 chronic-phase CML patients by multiplex allele-specific PCR and sequencing at diagnosis. Mutations were re-investigated upon manifestation of imatinib resistance using allele-specific PCR and direct sequencing of BCR-ABL kinase domain. RESULTS: Pre-existing BCR-ABL mutations were detected in 32/100 patients and included F311L, M351T, and T315I. After a median follow-up of 30 months (range 8-48), all patients with pre-existing BCR-ABL mutations exhibited imatinib resistance. Of the 68 patients without pre-existing BCR-ABL mutations, 24 developed imatinib resistance; allele-specific PCR and BCR-ABL kinase domain sequencing detected mutations in 22 of these patients. All 32 patients with pre-existing BCR-ABL mutations had the same mutations after manifestation of imatinib-resistance. In imatinib-resistant patients without pre-existing BCR-ABL mutations, we detected F311L, M351T, Y253F, and T315I mutations. All imatinib-resistant patients except T315I and Y253F mutations responded to imatinib dose escalation. CONCLUSION: Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. Thus, mutation testing using CD34+ cells may facilitate improved, patient-tailored treatment.


Subject(s)
Benzamides/therapeutic use , Fusion Proteins, bcr-abl/genetics , Leukemia, Myeloid, Chronic-Phase/drug therapy , Leukemia, Myeloid, Chronic-Phase/genetics , Mutation , Piperazines/therapeutic use , Protein Interaction Domains and Motifs/genetics , Pyrimidines/therapeutic use , Adolescent , Adult , Aged , Antigens, CD34/metabolism , Antineoplastic Agents/therapeutic use , Base Sequence , Child , Drug Resistance, Neoplasm/genetics , Female , Fusion Proteins, bcr-abl/chemistry , Hematopoietic Stem Cells/metabolism , Humans , Imatinib Mesylate , Leukemia, Myeloid, Chronic-Phase/metabolism , Male , Middle Aged , Protein Kinase Inhibitors/therapeutic use , Young Adult
3.
Asian Pac J Cancer Prev ; 13(11): 5469-75, 2012.
Article in English | MEDLINE | ID: mdl-23317202

ABSTRACT

BACKGROUND AND OBJECTIVES: Acute lymphoblastic leukemia (ALL) is a complex genetic disease involving many fusion oncogenes (FO) having prognostic significance. The frequency of various FO can vary in different ethnic groups, with important implications for prognosis, drug selection and treatment outcome. METHOD: We studied fusion oncogenes in 101 pediatric ALL patients using interphase FISH and RT-PCR, and their associations with clinical features and treatment outcome. RESULTS: Five most common fusion genes i.e. BCR-ABL t (22; 9), TCF3-PBX1 (t 1; 19), ETV6-RUNX1 (t 12; 21), MLL-AF4 (t 4; 11) and SIL-TAL1 (del 1p32) were found in 89/101 (88.1%) patients. Frequency of BCR-ABL was 44.5% (45/101). BCR-ABL positive patients had a significantly lower survival (43.7±4.24 weeks) and higher white cell count as compared to others, except patients with MLL-AF4. The highest relapse-free survival was documented with ETV6-RUNX1 (14.2 months) followed closely by those cases in which no gene was detected (13.100). RFS with BCR-ABL, MLL-AF4, TCF3-PBX1 and SIL-TAL1 was less than 10 months (8.0, 3.6, 5.5 and 8.1 months, respectively). CONCLUSIONS: This is the first study from Pakistan correlating molecular markers with disease biology and treatment outcome in pediatric ALL. It revealed the highest reported frequency of BCR-ABL FO in pediatric ALL, associated with poor overall survival. Our data indicate an immediate need for incorporation of tyrosine kinase inhibitors in the treatment of BCR-ABL+ pediatric ALL in this population and the development of facilities for stem cell transplantation.


Subject(s)
Core Binding Factor Alpha 2 Subunit/genetics , Fusion Proteins, bcr-abl/genetics , Myeloid-Lymphoid Leukemia Protein/genetics , Oncogene Proteins, Fusion/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Child , Child, Preschool , Female , Humans , Male , Pakistan , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Survival Rate , Treatment Outcome
4.
Int J Biol Markers ; 26(2): 75-81, 2011.
Article in English | MEDLINE | ID: mdl-21623584

ABSTRACT

The touchstone to evaluate accurately the aggressiveness and invasiveness of prostate cancer is something of a holy grail in the facet of urologic oncology. Gene expression and sequencing studies have improved our interpretations of the genetic determinants of the disease but are unsuccessful in the establishment of any unified classification to improve the molecular stratification. These questions addressing failure in rational drug design are difficult to answer in the multifaceted and heterogeneous pathogenesis of prostate cancer. In this review, we have developed a roadmap of the "recalcitrant prostate cancer proteome" to recognize the aspects of prostate cancer that may be helpful in effectively translating these findings to the clinic.


Subject(s)
Cell Transformation, Neoplastic/genetics , MicroRNAs/genetics , Prostatic Neoplasms/genetics , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Disease Progression , Humans , Male , Neoplastic Stem Cells/metabolism , Prostatic Neoplasms/pathology , Proteome/genetics , Receptor, Fibroblast Growth Factor, Type 1/genetics , Signal Transduction
5.
J Hazard Mater ; 156(1-3): 64-73, 2008 Aug 15.
Article in English | MEDLINE | ID: mdl-18242826

ABSTRACT

The present study reports the use of locally available fish (Labeo rohita) scales for Pb(II) removal from aqueous solutions under different experimental conditions. Maximum Pb(II) adsorption (196.8 mg g(-1)) occurred at pH 3.5. Pb(II) sorption was found to be pH, dose, initial metal concentration, contact time and shaking speed dependent while particle size and temperature independent. Experimental data of Pb(II) biosorption onto fish scales fitted well to Freundlich isotherm model in comparison to the model of Langmuir. The fast adsorption process in first 30 min followed by subsequent slow adsorption rate was suitably described by pseudo-second order model. In addition, this study was designed to evaluate the effect of physical and chemical pretreatments on surface properties of fish scales by the application of Fourier Transform Infrared (FTIR) Spectroscopic analysis. Physical pretreatments resulted in partial degradation of some functional groups. Alkaline pretreatments of fish scales did not have any significant influence on the nature of functional groups responsible for Pb(II) uptake, while acidic pretreatments resulted in degeneration of the most of functional groups on biosorbent cell wall. FTIR analysis confirmed the involvement of amino, carboxylic, phosphate and carbonyl groups in Pb(II) biosorption by fish scales.


Subject(s)
Fishes/metabolism , Lead/metabolism , Spectroscopy, Fourier Transform Infrared/methods , Animals , Lead/chemistry
6.
Protein Pept Lett ; 13(7): 665-71, 2006.
Article in English | MEDLINE | ID: mdl-17018008

ABSTRACT

Purified glucoamylase from Arachniotus citrinus was immobilized on polyacrylamide gel with 70% yield of immobilization. The immobilization improved the pH optima, temperature optima, values of K(m), V(max), and activation energy. Irreversible thermal denaturation studies of soluble and immobilized glucoamylase indicated that immobilization decreased the entropy and enthalpy of deactivation by magnitudes and made the immobilized glucoamylase thermodynamically more stable.


Subject(s)
Ascomycota/enzymology , Enzymes, Immobilized , Glucan 1,4-alpha-Glucosidase/physiology , Kinetics , Thermodynamics
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