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1.
Mymensingh Med J ; 22(1): 15-9, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23416802

ABSTRACT

Geographical and socio-economic factors such as climate, culture, ethnic origin, diet and life style such as smoking have been noted to influence the occurrence of bronchial carcinoma. We conducted this study to document the frequency of various histological types of bronchial carcinoma and correlated it with their demographic characteristics. This descriptive study was carried out among admitted patient with the suspicion of Bronchial carcinoma from January 2010 to January 2011 in medicine units of Mymensingh Medical College Hospital, Mymensingh. Among those only 30 consecutive histopathologically &/or cytological confirmed cases of Bronchial carcinoma were included in the study. No age, gender, environmental or occupational limits were applied for the selection of patients. Patients already diagnosed by some other hospital presenting to our unit with complications were not included in the study. Age rang were 26-70 years. Majority of patients i.e. 63.33% (n=19) were found to be in their fourth and sixth decade of life. Males were 86.66% (n=26) as compared to females 13.44% (n=4) and male to female ratio were 6.5:1. The majority of the patients were belonged to urban areas 63.34% (n=19), while 36.66% (n=11) came from the Rural population. In this study smokers were 86.66% (n=26) and nonsmokers were 13.33% (n=4). In Occupational distribution farmers were 33.33% (n=10), service holders were 20% (n=6), businessman were 16.66% (n=5), all the female were house wife 13.33% (n=4). Specimens for histopathological study were collected by trans-thoracic needle aspiration under CT or ultrasono-guided. The results of cell types in histopathologically proven 30 Bronchial carcinoma patients were; 10(33.36%) adenocarcinoma, 7(23.33%) squamous cell carcinoma, 6(20%) small cell carcinoma, 4(13.33%) large cell carcinoma and 3(10%) non-small cell carcinoma.


Subject(s)
Carcinoma, Bronchogenic/epidemiology , Lung Neoplasms/epidemiology , Adenocarcinoma/epidemiology , Adult , Age Distribution , Aged , Bangladesh/epidemiology , Carcinoma, Large Cell/epidemiology , Carcinoma, Large Cell/pathology , Carcinoma, Non-Small-Cell Lung/epidemiology , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/epidemiology , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Occupations/statistics & numerical data , Prospective Studies , Rural Population/statistics & numerical data , Sex Distribution , Small Cell Lung Carcinoma/epidemiology , Smoking/epidemiology , Tertiary Care Centers , Urban Population/statistics & numerical data
2.
Br J Dermatol ; 153(1): 11-7, 2005 Jul.
Article in English | MEDLINE | ID: mdl-16029320

ABSTRACT

Germline heterozygous loss-of-function mutations of fumarate hydratase (FH) predispose to the autosomal dominant syndrome of multiple cutaneous and uterine leiomyomatosis (MCUL). Forty-five distinct FH mutations have been identified in 76 of 89 (85%) reported probands with skin leiomyomas. This suggests that MCUL is a genetically homogeneous condition and that most patients presenting with skin leiomyomas will have underlying FH mutations. FH mutations identified include 26/45 (58%) missense; 12/45 (27%) frameshift, 4/45 (9%) nonsense changes and 3/45 (7%) different whole gene deletions. In MCUL kindreds, the majority of females with FH mutations have both skin and uterine leiomyomas. A proportion of individuals with FH mutations have associated renal cancer, a variant known as hereditary leiomyomatosis and renal cell cancer (HLRCC). If selection bias is removed, the prevalence of renal cancer in MCUL lies between one of 46 (2%) families who were not radiologically screened, and two of 32 (6%) families who were radiologically screened. Truncating, particularly frameshift, mutations appear to be significantly associated with renal cancer (P = 0.003), suggesting a possible basis for selective screening. There may also be a significantly increased rate of renal cancer in females (P = 0.004), suggesting a possible role for hormonal factors. Review of the literature suggests that, unlike most individuals presenting with skin leiomyomas, the majority of patients presenting with uterine leiomyomas or renal cancer will not have underlying FH mutations.


Subject(s)
Fumarate Hydratase/genetics , Leiomyoma/genetics , Mutation , Neoplastic Syndromes, Hereditary/genetics , Skin Neoplasms/genetics , Female , Genetic Predisposition to Disease , Humans , Kidney Neoplasms/genetics , Uterine Neoplasms/genetics
3.
Hum Mol Genet ; 14(15): 2231-9, 2005 Aug 01.
Article in English | MEDLINE | ID: mdl-15987702

ABSTRACT

The nuclear-encoded Krebs cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDHB, -C and -D), act as tumour suppressors. Germline mutations in FH predispose individuals to leiomyomas and renal cell cancer (HLRCC), whereas mutations in SDH cause paragangliomas and phaeochromocytomas (HPGL). In this study, we have shown that FH-deficient cells and tumours accumulate fumarate and, to a lesser extent, succinate. SDH-deficient tumours principally accumulate succinate. In situ analyses showed that these tumours also have over-expression of hypoxia-inducible factor 1alpha (HIF1alpha), activation of HIF1alphatargets (such as vascular endothelial growth factor) and high microvessel density. We found no evidence of increased reactive oxygen species in our cells. Our data provide in vivo evidence to support the hypothesis that increased succinate and/or fumarate causes stabilization of HIF1alpha a plausible mechanism, inhibition of HIF prolyl hydroxylases, has previously been suggested by in vitro studies. The basic mechanism of tumorigenesis in HPGL and HLRCC is likely to be pseudo-hypoxic drive, just as it is in von Hippel-Lindau syndrome.


Subject(s)
Fumarate Hydratase/genetics , Germ-Line Mutation , Succinate Dehydrogenase/genetics , Succinate Dehydrogenase/metabolism , Carcinoma, Renal Cell/metabolism , Citric Acid Cycle/physiology , Female , Fumarate Hydratase/metabolism , Humans , Leiomyoma/genetics , Leiomyoma/metabolism , Neoplasms/genetics , Neoplasms/metabolism , Paraganglioma/genetics , Paraganglioma/metabolism , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A/metabolism
4.
Cancer Genet Cytogenet ; 147(2): 121-7, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14623461

ABSTRACT

Exonuclease 1 (EXO1) is a candidate gene for colorectal tumor susceptibility because it is believed to play a role in mismatch repair. There have been several studies investigating the role of EXO1 in mismatch repair but few investigating its role in causing clinical disease. In one recent study, germline variants of EXO1 were reported to be associated with predisposition to colorectal cancer in families with phenotypes similar to hereditary nonpolyposis colon cancer (HNPCC). We recently identified nine individuals from two British families with multiple cutaneous and uterine leiomyomatosis with independently arising heterozygous germline deletions of 1q42.3 approximately q43 encompassing not only FH, the multiple leiomyomatosis-associated gene, but also several flanking genes, including EXO1. We investigated these families for any indication of predisposition to colorectal cancer or other HNPCC spectrum cancers by means of detailed questionnaires, interviews, and examination of EXO1-null skin leiomyomata for microsatellite instability (MSI). No individual in these families had developed colorectal cancer or known colorectal adenomas, and none had any symptoms warranting gastrointestinal or other investigation. EXO1-null tumors showed no evidence of MSI. This study questions the functional significance of previously reported variants of EXO1 reported in HNPCC-like families and suggests that in humans there may be other as yet undiscovered proteins that have exonuclease function overlapping with that of EXO1 in DNA mismatch repair. Also of interest is the absence of phenotypic abnormality apart from multiple leiomyomatosis in any deletion carrier even though the adjacent genes RGS7, KMO, CHML, and OPN3 were also deleted.


Subject(s)
Colorectal Neoplasms/genetics , Exodeoxyribonucleases/genetics , Genomic Instability , Microsatellite Repeats , Sequence Deletion , Adult , Aged , Colorectal Neoplasms/etiology , DNA Repair Enzymes , Female , Genotype , Haplotypes , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Pedigree
5.
Hum Mol Genet ; 12(11): 1241-52, 2003 Jun 01.
Article in English | MEDLINE | ID: mdl-12761039

ABSTRACT

Germline mutations of the fumarate hydratase (FH, fumarase) gene are found in the recessive FH deficiency syndrome and in dominantly inherited susceptibility to multiple cutaneous and uterine leiomyomatosis (MCUL). We have previously reported a number of germline FH mutations from MCUL patients. In this study, we report additional FH mutations in MCUL and FH deficiency patients. Mutations can readily be found in about 75% of MCUL cases and most cases of FH deficiency. Some of the more common FH mutations are probably derived from founding individuals. Protein-truncating FH mutations are functionally null alleles. Disease-associated missense FH changes map to highly conserved residues, mostly in or around the enzyme's active site or activation site; we predict that these mutations severely compromise enzyme function. The mutation spectra in FH deficiency and MCUL are similar, although in the latter mutations tend to occur earlier in the gene and, perhaps, are more likely to result in a truncated or absent protein. We have found that not all mutation-carrier parents of FH deficiency children have a strong predisposition to leiomyomata. We have confirmed that renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome, and have shown that these cancers may have either type II papillary or collecting duct morphology. We have found no association between the type or site of FH mutation and any aspect of the MCUL phenotype. Biochemical assay for reduced FH functional activity in the germline of MCUL patients can indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. We conclude that MCUL is probably a genetically homogeneous tumour predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity, with currently unknown functional consequences for the smooth muscle or kidney cell.


Subject(s)
Fumarate Hydratase/genetics , Kidney Neoplasms/genetics , Leiomyomatosis/genetics , Mutation , Skin Neoplasms/genetics , Uterine Neoplasms/genetics , Amino Acid Metabolism, Inborn Errors/genetics , Amino Acid Sequence , Enzyme Stability , Female , Fumarate Hydratase/chemistry , Fumarate Hydratase/deficiency , Fumarate Hydratase/metabolism , Genetic Predisposition to Disease , Germ-Line Mutation , Humans , Kidney Neoplasms/secondary , Leiomyomatosis/pathology , Molecular Sequence Data , Protein Conformation , RNA Stability , RNA, Messenger/metabolism , Sequence Homology, Amino Acid , Skin Neoplasms/pathology , Uterine Neoplasms/pathology
6.
Am J Hum Genet ; 68(5): 1264-9, 2001 May.
Article in English | MEDLINE | ID: mdl-11283798

ABSTRACT

Dominant transmission of multiple uterine and cutaneous smooth-muscle tumors is seen in the disorder multiple leiomyomatosis (ML). We undertook a genomewide screen of 11 families segregating ML and found evidence for linkage to chromosome 1q42.3-q43 (maximum multipoint LOD score 5.40). Haplotype construction and analysis of recombinations permitted the minimal interval containing the locus, which we have designated "MCUL1," to be refined to an approximately 14-cM region flanked by markers D1S517 and D1S2842. Allelic-loss studies of tumors indicated that MCUL1 may act as a tumor suppressor. Identification of MCUL1 should have wide interest, since this gene may harbor low-penetrance variants predisposing to the common form of uterine fibroids and/or may undergo somatic mutation in sporadic leiomyomata.


Subject(s)
Chromosomes, Human, Pair 1/genetics , Leiomyomatosis/genetics , Uterine Neoplasms/genetics , Chromosome Mapping , Female , Genes, Tumor Suppressor/genetics , Genetic Markers/genetics , Genetic Predisposition to Disease/genetics , Haplotypes/genetics , Humans , Lod Score , Loss of Heterozygosity/genetics , Male , Mutation/genetics , Pedigree , Penetrance , Recombination, Genetic/genetics , Software
7.
J Clin Endocrinol Metab ; 58(1): 206-11, 1984 Jan.
Article in English | MEDLINE | ID: mdl-6315760

ABSTRACT

Receptor-mediated uptake of low density lipoproteins (LDL) provides an important source of cholesterol for corticosteroid synthesis by human adrenocortical cells grown in tissue culture. Recent studies have indicated an impaired adrenocortical response to prolonged ACTH stimulation in patients with abetalipoproteinemia (who lack plasma LDL) and in patients with homozygous familial hypercholesterolemia (FH), who have a virtual absence of high affinity LDL receptors. In the present study we examined parameters of adrenocortical function in four women with well characterized heterozygous FH to assess whether a 50% reduction in the number of LDL receptors measured in vitro influenced the response of the adrenal cortex to prolonged stimulation with ACTH. Biochemical studies of the binding, internalization, and degradation of [125I]LDL were undertaken in cultured skin fibroblasts from each patient, and all patients had reduced LDL receptor activity. The adrenocortical response to a 36-h iv infusion of alpha ACTH-(1-24) (Cortrosyn) was evaluated in the four patients with heterozygous FH and in five normal women. Stimulation with iv ACTH resulted in rapid increases in the serum concentrations of cortisol in both groups and plateau concentrations of 55-60 micrograms/dl. The rates of increase and the plateau concentrations were similar in the control and FH patients. Similarly, rates of excretion of 17-hydroxycorticosteroids and cortisol were similar in the normal subjects and FH patients. These results indicate that a 50% reduction in the number of high affinity LDL receptors due to the presence of one abnormal gene at the LDL receptor locus does not result in any impairment in the delivery of cholesterol to the adrenal cortex during conditions of maximal corticosteroid production.


Subject(s)
Adrenal Cortex/metabolism , Adrenocorticotropic Hormone/pharmacology , Hyperlipoproteinemia Type II/metabolism , 17-Hydroxycorticosteroids/urine , Adolescent , Adrenal Cortex/drug effects , Adult , Cells, Cultured , Cosyntropin/pharmacology , Female , Fibroblasts/metabolism , Humans , Hydrocortisone/metabolism , Receptors, Cell Surface/metabolism , Receptors, LDL , Skin/metabolism
8.
Atherosclerosis ; 49(3): 295-305, 1983 Dec.
Article in English | MEDLINE | ID: mdl-6318779

ABSTRACT

Despite a complete lack of apoprotein B-containing lipoproteins from the plasma of patients with abetalipoproteinemia, rates of cholesterol synthesis measured in vivo or in freshly isolated cells in vitro are not markedly elevated. These observations suggest that other lipoprotein particles present in the plasma of patients with abetalipoproteinemia may regulate cellular cholesterol synthesis in this disorder. In the present report we have studied the effects of lipoprotein fractions from plasma of normal subjects, patients with abetalipoproteinemia, and a patient with Type III hyperlipoproteinemia on cholesterol synthesis in cultured human fibroblasts. LDL from normal subjects or the HDL2 fraction from the plasma of patients with abetalipoproteinemia were effective inhibitors of cholesterol synthesis (greater than 75% inhibition at 20 micrograms protein/ml) whereas HDL3 from normal or abetalipoproteinemia plasma stimulated cholesterol synthesis. Rates of cholesterol synthesis in fibroblasts from a patient with receptor-negative homozygous familial hypercholesterolemia were only minimally reduced by prior incubation in media containing either normal LDL or HDL2 from the plasma of a patient with abetalipoproteinemia. We conclude that lipoproteins present in the HDL2 fraction of plasma from patients with abetalipoproteinemia (which are relatively rich in apoprotein E) are effective regulators of cholesterol synthesis in normal human fibroblasts and that this regulation is mediated by an interaction of these lipoproteins with the LDL (B, E) receptor. These in vitro findings may explain why rates of cholesterol synthesis are not markedly elevated in patients with abetalipoproteinemia studied in vivo.


Subject(s)
Abetalipoproteinemia/blood , Cholesterol/biosynthesis , Lipoproteins/blood , Adult , Apolipoproteins/blood , Apolipoproteins E , Fibroblasts , Humans , Hyperlipoproteinemia Type III/blood , Lipoproteins, HDL/blood , Lipoproteins, LDL/blood , Receptors, Cell Surface/blood , Receptors, Lipoprotein
9.
Metabolism ; 32(9): 869-73, 1983 Sep.
Article in English | MEDLINE | ID: mdl-6888269

ABSTRACT

The purpose of this study was to examine whether an absence of triglyceride-rich lipoproteins (chylomicrons and very-low-density lipoproteins) in plasma is associated with any changes in the enzyme activity of lipoprotein lipase or hepatic lipase after heparin administration. To study this, the activities of hepatic lipase and lipoprotein lipase were determined in control subjects, in two patients with heterozygous hypobetalipoproteinemia, and in three patients with phenotypic abetalipoproteinemia after administration of heparin. Both enzymes showed normal activity in the patients with hypobetalipoproteinemia, but showed consistently reduced activity in the patients with abetalipoproteinemia. Hepatic lipase activity in plasma samples from these three patients obtained 15 minutes after intravenous injection of heparin was 55%, 87%, and 46% of that of the controls, whereas corresponding values in plasma samples obtained 30 minutes after heparin were 47%, 70%, and 57%, respectively. Lipoprotein lipase activity in the three patients with abetalipoproteinemia was 46%, 29%, and 34% of that of the controls in the samples obtained 15 minutes after heparin injection, whereas the values obtained after 30 minutes were 53%, 64%, and 47% of that of the controls. We conclude that an inherent absence of triglyceride-rich lipoproteins, as occurs in abetalipoproteinemia, is associated with reduced enzyme activity of both hepatic lipase and lipoprotein lipase in plasma after heparin administration.


Subject(s)
Abetalipoproteinemia/enzymology , Heparin/pharmacology , Hypobetalipoproteinemias/enzymology , Hypolipoproteinemias/enzymology , Lipase/metabolism , Lipoprotein Lipase/blood , Liver/enzymology , Abetalipoproteinemia/blood , Adolescent , Adult , Child , Female , Humans , Hypobetalipoproteinemias/blood , Male
10.
Proc Natl Acad Sci U S A ; 80(11): 3475-9, 1983 Jun.
Article in English | MEDLINE | ID: mdl-6304711

ABSTRACT

Despite an absence of low density lipoproteins (LDLs) and chylomicron remnants from plasma, the rates of cholesterol synthesis or the number of LDL receptors expressed on freshly isolated cells from patients with abetalipoproteinemia are not markedly increased. These observations suggest that other lipoprotein particles present in the plasma of patients with abetalipoproteinemia may regulate LDL receptor activity and the rates of cellular cholesterol synthesis in this disorder. In the present report we have studied the effects of lipoprotein fractions from the plasma of normal subjects, patients with abetalipoproteinemia, and a patient with dysbetalipoproteinemia on the binding, internalization, and degradation of 125I-labeled LDL (125I-LDL) by cultured human fibroblasts. LDL from normal subjects or the high density lipoprotein fraction HDL2 from the plasma of patients with abetalipoproteinemia effectively down-regulated LDL receptor activity (greater than 50% inhibition at 20 micrograms of protein per ml). HDL2 from the plasma of patients with abetalipoproteinemia also effectively reduced the binding, internalization, and degradation of 125I-LDL by cultured human fibroblasts. 125I-HDL2 from the plasma of patients with abetalipoproteinemia was bound, internalized, and degraded by cultured human fibroblasts; this process was competitively inhibited by unlabeled normal LDL or HDL2 from abetalipoproteinemic plasma and was 1/6th to 1/8th times as high when 125I-HDL2 was incubated with fibroblasts from a patient with receptor-negative homozygous familial hypercholesterolemia. We conclude that lipoproteins present in the HDL2 fraction of plasma from patients with abetalipoproteinemia (which are relatively rich in apoprotein E) are effective regulators of LDL receptor activity in normal human fibroblasts. These in vitro findings may explain why the in vivo rates of cholesterol synthesis and the number of LDL receptors expressed on freshly isolated cells from patients with abetalipoproteinemia are not markedly increased.


Subject(s)
Abetalipoproteinemia/blood , Lipoproteins, LDL/metabolism , Lipoproteins/blood , Receptors, Cell Surface/metabolism , Cells, Cultured , Fibroblasts/metabolism , Humans , Kinetics , Lipoproteins, HDL/blood , Receptors, LDL , Skin/metabolism
11.
Endocrinology ; 98(4): 859-63, 1976 Apr.
Article in English | MEDLINE | ID: mdl-1278095

ABSTRACT

Prostaglandin, dehydrogenase activity was determined in deciduomal and myometrial tissues during growth and regression of the deciduoma during pseudopregnancy. The hormonal control of prostaglandin dehydrogenase activity in these tissues was determined in experiments with ovariectomized pseudopregnant rats. Prostaglandin dehydrogenase activity for both prostaglandin E1 (PGE1) and prostaglandin F2alpha (PGF2alpha) in deciduomal and myometrial tissues increased during the growth of the deciduoma and decreased during the regression phase. No prostaglandin dehydrogenase activity was detected in non-decidualized pseudopregnant rat uteri. In ovarictomized pseudopregnant rats, progesterone and estrogen increased prostaglandin dehydrogenase activity for PGE1 in the deciduoma and myometrium; no synergistic action of the hormones was observed. Progesterone increased prostaglandin dehydrogenase activity for PGF2alpha in the deciduoma, but had no effect in the myometrium. The increases during decidualization in dehydrogenase activity for PGE1 and PGF2alpha, and the enhanced inactivation of these luteolytic substances would provide an explantation for the prolonged pseudopregnancy which results from decidualization of the uterus.


Subject(s)
Alcohol Oxidoreductases/metabolism , Decidua/growth & development , Estrogens/metabolism , Hydroxyprostaglandin Dehydrogenases/metabolism , Myometrium/enzymology , Progesterone/metabolism , Uterus/enzymology , Animals , Decidua/enzymology , Female , Prostaglandins E/metabolism , Prostaglandins F/metabolism , Pseudopregnancy , Rats , Time Factors , Uterus/metabolism
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