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Biomedical subjects

D E Cohn

Publications and source records attributed to D E Cohn.

At least 19 recordsLinked to original sources
PubMed2001

Genotypic and phenotypic progression in endometrial tumorigenesis: determining when defects in DNA mismatch repair and KRAS2 occur.

We set out to determine the relative timing of loss of DNA mismatch repair and KRAS2 mutation in endometrial tumorigenesis. We studied endometrial carcinoma (CA) and synchronous atypical endometrial hyperplasia (AEH), the premalignant precursor of endometrial cancer. Carcinoma and hyperplasia were investigated for loss of mismatch repair as evidenced by microsatellite instability (MSI) and for KRAS2 mutations. Endometrial cancers previously shown to be MSI-positive were evaluated for KRAS2 codon 12 and 13 mutations. DNA was isolated from foci of AEH concomitant with, but physically remote from, the cancers by use of tissues prepared by laser capture microdissection (LCM). The AEH DNAs were then assessed for MSI and KRAS2 mutations. Of 210 endometrial CAs investigated, 51 (26%) were MSI-positive, and among those, 21 (41%) arose concomitantly with AEH. Of 41 foci of AEH (mean, two foci per patient) investigated, 34 (83%) were MSI-positive. KRAS2 mutations were seen in 5/51 (10%) MSI-positive carcinomas. From the five patients informative for both KRAS2 mutation and MSI, 10 foci of AEH were available for investigation. All 10 AEH specimens (100%) were MSI-positive, and six (60%) had the KRAS2 mutation present in the coexisting CA. The observation that some MSI-positive AEH specimens lack the KRAS2 mutation seen in the coexisting CA supports a model in which loss of DNA mismatch repair precedes KRAS2 mutation. However, in addition to the absence of KRAS2 mutations in AEH, we discovered mutations in LCM hyperplasia and carcinoma specimens that were not present in the portion of the cancers originally investigated. These discordant genotypes suggest genetic heterogeneity in endometrial hyperplasia and concomitant cancer.

Base Pair Mismatch↗
PubMed2001

Factors predicting subcutaneous implanted central venous port function: the relationship between catheter tip location and port failure in patients with gynecologic malignancies.

OBJECTIVE: We set out to determine the factors that predict subcutaneous implanted central venous port function. Specifically, we sought to determine whether the location of the catheter tip is correlated with port failure. METHODS: A review of all gynecologic oncology patients who underwent initial port placement between 1993 and 1998 was undertaken. The initial chest radiograph following port placement was reviewed, and the venous location of the catheter tip was recorded. Patients were followed until port removal, death, or the last documentation of port function. RESULTS: Two hundred thirty-six patients underwent port placement during the study period. The majority of patients (97%) had their port placed for intravenous chemotherapy. The median time of port duration in patients with a functional port was 21.6 months. Forty of the 236 ports (17%) were removed because of device malfunction. Catheter tips were located in the central venous system in 164 (69%) cases and outside of the central venous system in 72 (31%) cases. Removal secondary to malfunction was significantly higher when the catheter tip was located outside of the central venous system (30/72 (42%) versus 10/164 (6%), P = 0.001). By life-table analysis, ports removed for malfunction with their tips located centrally had a significantly longer median duration of functional use than those whose tips were located peripherally (78 versus 44 months, P = 0.0001). CONCLUSIONS: The rate of port removal secondary to malfunction is significantly less if the catheter tip is located in the central venous system. Confirmation of the location of the catheter tip is imperative for the long-term function of a subcutaneous implanted central venous port.

Adult↗
PubMed2001

Meigs' syndrome with an elevated CA 125 from benign Brenner tumors.

BACKGROUND: Meigs' syndrome refers to solid, benign ovarian tumors, ascites, hydrothorax, and resolution of these signs after surgery. Meigs' syndrome with an elevated CA 125 secondary to benign Brenner tumors is exceedingly rare. CASE: A postmenopausal woman presented with a large pelvic mass, ascites, and a right pleural effusion. Serum CA 125 was 759 IU/mL. Ascitic fluid, pleural fluid, and fine needle aspiration of the mass were without evidence of malignancy. Exploratory laparotomy with total abdominal hysterectomy and bilateral salpingo-oophorectomy revealed benign Brenner tumors. Immunohistochemical staining for CA 125 showed immunoreactivity in the omentum only. Postoperatively, her signs and symptoms resolved completely and did not recur. CONCLUSION: Cytologic or histologic confirmation of malignancy is imperative in patients with a pelvic mass, ascites, hydrothorax, and elevated CA 125 before initiating chemotherapy.

Aged↗
PubMed2000

Atypical clustering of gynecologic malignancies: A family study including molecular analysis of candidate genes.

OBJECTIVE: We set out to determine whether hereditary nonpolyposis colorectal cancer (HNPCC) was responsible for cancer susceptibility in a family with gynecologic malignancies in three consecutive generations. METHODS: A detailed family history study, including review of medical records, was undertaken. Tumor DNAs from affected family members were evaluated for microsatellite instability (MSI). Linkage between cancer susceptibility and the candidate DNA mismatch repair genes MLH1, MSH2, MSH3, and MSH6 (GTBP) was investigated. MLH1 and MSH2 protein expression was evaluated by immunohistochemistry and MSH2 was investigated for mutation. RESULTS: Four gynecologic malignancies in the core family were confirmed. MSI was seen in six of seven cancers studied. The only MSI-negative tumor was an ovarian cancer from the proband's maternal grandmother, which arose at the age of 92. Haplotype analysis using chromosome 2p markers implicated the MSH2 gene in this family's cancer susceptibility. MSH2 protein expression was absent in an MSI-positive colon cancer from an affected family member. CONCLUSIONS: The inability to exclude linkage of MSH2 with the disease susceptibility, the presence of the MSI phenotype in cancers from family members sharing the same region of chromosome 2p, and the lack of immunodetectable MSH2 point to MSH2-associated HNPCC as a cause for this family's cancer susceptibility. Continued efforts to increase awareness of the heritability of endometrial cancer should improve our understanding of the disease, with resultant improved surveillance strategies, recommendations for surgical and chemoprophylaxis, and identification of patients at risk for malignancy as a result of HNPCC.

Adult↗
PubMed2000

Absence of PTEN repeat tract mutation in endometrial cancers with microsatellite instability.

OBJECTIVE: PTEN, a tumor suppressor gene shown to be frequently mutated in endometrial cancers, has been suggested to be a target of microsatellite instability (MSI)-driven mutagenesis. We set out to investigate the relationship between MSI and PTEN mutation in a large series of primary endometrial carcinomas. METHODS: Thirty-nine MSI-positive endometrial cancers were evaluated by single-strand conformational variant analysis and direct sequencing to screen all nine PTEN exons for mutation. RESULTS: Fifteen specimens (38%) demonstrated 16 PTEN mutations. We observed only one alteration in the poly-adenine repeat of exon 8 that is suggested to be a target for mutation in endometrial cancers with MSI. Seven of 16 (44%) mutations in our series were deletions of >/=3 bp, a class of mutation not usually associated with tumors with defective DNA mismatch repair. To determine the significance of this high frequency of deletion, 26 additional endometrial cancers without MSI were matched with the 39 MSI-positive cancers for the prognostic factors of tumor histology, stage, grade, and patient race. The MSI-positive tumors had a significantly higher frequency of deletions involving >/=3 bp when compared with the MSI-negative group (5/11 versus 0/10, P = 0.035). CONCLUSIONS: Repeat tract mutation in PTEN is an uncommon event in MSI-positive cancers. Deletion of >/=3 bp in this gene is more common in MSI-positive cancers when compared with tumors without MSI.

DNA Mutational Analysis↗
PubMed2000

Radical hysterectomy for cervical cancer in obese women.

OBJECTIVE: To estimate the morbidity, adequacy of surgery, and survival of obese women undergoing radical hysterectomy and pelvic lymphadenectomy. METHODS: Patients with stage I and IIa cervical cancer and a body mass index (BMI) over 30 kg/m(2) and absolute weight greater than 85 kg explored with the intent for radical hysterectomy between 1986 and 1998 were identified. Patient characteristics, surgical, pathologic, and follow-up data were extracted and survival curves were generated. RESULTS: Forty-eight obese women were identified who were explored for radical hysterectomy and pelvic lymph node dissection. The median BMI was 36 kg/m(2), and the median weight was 95 kg. Thirty-five patients (73%) had stage Ib1 disease. Despite the obesity of the study group, none had severe comorbidity. The procedure was completed in 46 patients, and abandoned in two because of metastatic disease. For patients undergoing radical hysterectomy and pelvic lymph node dissection, median blood loss was 800 mL. No patient developed fistulas. Residual tumor was present in 26 (57%) hysterectomy specimens, and margins were without disease in 45 specimens (98%). A median of 26 pelvic lymph nodes were obtained per procedure, and six patients (13%) had positive nodes. Five-year overall and disease-free survival are 84% (95% confidence interval [CI] 70.9, 97.5) and 80% (95% CI 65.2, 93.8), respectively, at a median follow-up of 36 months. CONCLUSION: In this carefully selected obese group, we demonstrate that radical hysterectomy and pelvic lymph node dissection can be performed with adequate surgical resection, acceptable morbidity, and excellent survival.

Adult↗
PubMed2000

Gestational trophoblastic diseases: new standards for therapy.

Gestational trophoblastic disease (GTD) is a spectrum of rare neoplastic conditions that are highly curable, even in the presence of widely metastatic disease. These diseases vary from partial hydatidiform mole, which rarely metastasizes and infrequently requires treatment with chemotherapy, to choriocarcinoma, for which multi-agent chemotherapy is the standard treatment. Much has been learned regarding the epidemiology of this disease, and our understanding of the genetics underlying GTD is rapidly expanding. As technology such as ultrasonography and sensitive tests for beta-human chorionic gonadotropin have evolved, the presentation of molar pregnancy has significantly changed, although the incidence of persistent GTD has not decreased. This review highlights these recent advancements in the epidemiology, genetics, diagnosis, and treatment of gestational trophoblastic disease.

Female↗
PubMed1998

Mesothelial pelvic lymph node inclusions mimicking metastatic thyroid carcinoma.

Benign lymph node inclusions are commonly encountered during surgery for gynecologic neoplasms and are potential mimics of metastatic disease. A 52-year-old woman presented with ascites, a complex adnexal mass, and a CA-125 of 1891 units/mL. A staging laparotomy was performed, diagnosing struma ovarii. Pathologic evaluation of pelvic lymph nodes demonstrated mesothelial inclusions in nodal sinuses suspicious for metastatic disease. Immunocytochemical evaluation revealed benign mesothelial inclusions rather than metastatic thyroid carcinoma. Benign mesothelial lymph node inclusions in nodal sinuses are potential mimics of metastatic carcinoma. Their presence in pelvic lymph nodes has not previously been reported. Given the potential difficulty in determining the origin of these inclusions, immunocytochemical evaluation is useful in reaching the correct diagnosis.

Diagnosis, Differential↗
PubMed1998

Adenocarcinoma of the uterine cervix metastatic to lymph nodes.

OBJECTIVE: We set out to evaluate the prognostic factors in cervical adenocarcinoma metastatic to lymph nodes. STUDY DESIGN: We performed a retrospective review of 40 patients with cervical adenocarcinoma and lymph node metastasis from 1976 to 1996. RESULTS: Thirty-four patients had adenocarcinoma, and six had adenosquamous carcinoma. Median survival was 50 months. The median survival for patients with stage I disease was 69 months. Stage at diagnosis, treatment with radical hysterectomy, and receiving adjuvant therapy were associated with prolonged survival. A trend toward improved survival was noted with the use of concurrent radiation and chemotherapy as an adjuvant therapy. CONCLUSIONS: Adenocarcinoma metastatic to the lymph nodes does not have a uniformly poor prognosis, especially with early-stage disease. Improved survival was observed with the use of adjuvant therapy, specifically the use of combined chemotherapy and radiation after radical hysterectomy. The optimal therapy in this setting is yet to be determined.

Adenocarcinoma↗
PubMed1986

Effects of fasting on citrate transport by the brush-border membrane of rat kidney.

Fasting in rats decreases plasma citrate levels and reduces urinary citrate excretion by the kidney. After 72 h of fasting, the endogenous renal citrate clearance was decreased and the fractional citrate excretion was 0.026 +/- 0.008 compared with 0.218 +/- 0.030 in control fed rats. To determine whether these findings result from an adaptation in citrate transport across the plasma membrane of the renal tubular cell, Na+ gradient-dependent [14C]citrate uptake was examined in brush-border membrane vesicles (BBMW) prepared from kidneys of fed and 72-h fasted rats. The initial rate (10 s) of Na+ gradient-stimulated uptake of 100 microM citrate was significantly increased in BBMW from kidneys of fasted rats (380 +/- 24.9 pmol/mg prot) compared with fed rats (255 +/- 24.9 pmol/mg prot). Arterial acid-base parameters from conscious animals were similar between the two groups. There was no significant difference in Na+-independent citrate uptake or in L-glutamine uptake measured at 20 s in BBMV from the kidneys of fasted compared with fed rats. An adaptation occurs in the brush-border membrane of the renal tubular cell of fasting rats, unrelated to systemic acidosis, that may result in increased reabsorption of citrate.

Acid-Base Equilibrium↗
PubMed1984

Glutamine transport in renal basolateral vesicles from dogs with metabolic acidosis.

To determine whether the increased ammonia production per nephron in chronic metabolic acidosis is accompanied by augmented L-glutamine transport across the basolateral membrane of the renal cortical cell and consequent increased availability of this ammoniagenic amino acid, we measured L-[3H]glutamine transport in basolateral membrane vesicles (BLMV) isolated from kidneys of normal and acidotic dogs. Na+ -dependent electrogenic transport of L-[3H]glutamine was demonstrated in BLMV from kidneys of normal dogs that exhibited saturability over the concentration range of 25 microM to 2 mM L-glutamine. The apparent Km was 416 +/- 114 microM and Vmax was 536 +/- 129 pmol X mg protein-1 X 15 s-1. The initial rate of Na+ -dependent L-[3H]glutamine transport was increased in BLMV from kidneys of acidotic dogs, as reflected by an increased apparent Vmax. We conclude that an adaptation resulting in greater uptake of L-glutamine across the basolateral membrane of the renal cortical cell may underlie, in part, the increased rate of ammonia production per nephron seen in chronic metabolic acidosis.

Acidosis↗
PubMed1983

Effect of parathyroid hormone on Na+-dependent phosphate transport and cAMP-dependent 32P phosphorylation in brush border vesicles from isolated perfused canine kidneys.

Concentrative uptake of 32Pi induced by the dissipation of a Na+ gradient (overshoot) was demonstrated in brush border membrane vesicles obtained from isolated perfused canine kidneys. Na+-dependent 32Pi transport was decreased in brush border vesicles from isolated kidneys perfused with parathyroid hormone (PTH) for 2 h compared to uptake measured in vesicles from kidneys perfused without PTH. Cyclic AMP-dependent 32P phosphorylation of a 62,000 Mr protein band was demonstrable on autoradiograms of sodium dodecyl sulfate-polyacrylamide gels of membrane suspensions from kidneys perfused +/- PTH. Evidence that perfusion with PTH resulted in cAMP-dependent phosphorylation in isolated kidneys from parathyroidectomized dogs (decreased cAMP-dependent 32P phosphorylation of the 62,000-Mr band in brush border vesicles) was obtained after 2-h perfusion with PTH. Decreased 32P phosphorylation was not observed if membranes were allowed to dephosphorylate prior to 32P phosphorylation in vitro. We conclude that brush border vesicles from isolated perfused canine kidneys can be used to study the action of PTH on Na+-Pi cotransport in brush border membranes and on cAMP-dependent phosphorylation of the membrane. It is strongly suggested that PTH effects changes in Na+-dependent 32Pi transport in isolated brush border vesicles and changes in 32P phosphorylation of vesicles via a direct action on the renal cortical cell rather than as a consequence of extrarenal actions of the hormone.

Animals↗
PubMed1983

Metabolic acidosis and parathyroidectomy increase Na+-H+ exchange in brush border vesicles.

Na+-H+ exchange across the brush border membrane of the renal proximal tubular cell is a mechanism for Na+ reabsorption and H+ secretion. An electroneutral Na+-H+ exchange activity has been identified in isolated renal brush border membrane vesicles from rat and dog kidney, and increased Na+-H+ exchange has been measured in brush border membrane vesicles from remnant kidneys of dogs with chronic renal failure. To ascertain whether changes in H+ secretion by the kidney observed in chronic metabolic acidosis and in states of altered parathyroid function might result from altered Na+-H+ exchange across the renal cortical cellular brush border membrane, we measured Na+-H+ exchange in brush border membrane vesicles from kidneys of dogs with chronic metabolic acidosis and from kidneys of thyroparathyroidectomized dogs. Increased amiloride-sensitive Na+-H+ exchange was demonstrated in brush border membrane vesicles from kidneys of both groups of dogs, suggesting that adaptations in H+ excretion in chronic metabolic acidosis and hypoparathyroidism might be explained by increased activity of a renal brush border membrane Na+-H+ exchanger.

Acidosis↗
PubMed1982

Increased Na+-H+ exchange in brush border vesicles from dogs with renal failure.

In the remnant kidney model of chronic renal failure, absolute reabsorption of Na+ in the proximal tubule of the remaining nephrons is increased over normal. Absolute proximal tubular reabsorption of bicarbonate and proximal tubular H+ excretion per nephron have also been shown to be increased over normal in his model of renal disease. Na+ uptake in membrane vesicles isolated from the brush border membrane of remnant kidneys of dogs with chronic renal failure is increased over uptake in membrane vesicles isolated from kidneys of normal dogs. In the present studies an amiloride-sensitive, electroneutral Na+-H+ exchanger was identified in canine renal brush border membrane vesicles. Na+ uptake in membrane vesicles in the presence of an initial H+ gradient (intravesicular pH less than extravesicular pH) was increased in membrane vesicles isolated from the remnant kidneys of dogs with chronic renal failure over that in membrane vesicles from kidneys of normal dogs. This increase was abolished by amiloride. It is possible that the alterations in Na+ and bicarbonate reabsorption and H+ excretion in the remnant kidney model of chronic renal failure can be explained on the basis of increased activity of the Na+-H+ exchanger in the renal brush border membrane.

Animals↗
PubMed1981

Effect of the proton electrochemical gradient on maleimide inactivation of active transport in Escherichia coli membrane vesicles.

Many active transport systems present in Escherichia coli membrane vesicles are inhibited by maleimides and other sulfhydryl reagents. These reagents do not interfere with the oxidation of reduced phenazine methosulfate or with the electrochemical proton gradient (delta muH+). The rate of inactivation is increased in the presence of reduced phenazine methosulfate, and it is shown that the electrochemical proton gradient is responsible for the effect. Furthermore, similar effects observed with the proline and melibiose transport systems. Thus, it appears that either the reactivity or accessibility of a sulfhydryl group(s) in each of these carriers is altered by the presence of a transmembrane delta muH+. The findings are consistent with the notion that delta muH+, in addition to acting as the immediate driving force the active transport, may bring about structural or conformational changes in certain membrane proteins that catalyze active transport.

Biological Transport, Active↗
PubMed1981

Relationship between the Na+/H+ antiporter and Na+/substrate symport in Bacillus alcalophilus.

The Na+/H+ antiporter of the obligate alkalophile Bacillus alcalophilus facilitates growth at alkaline pH and precludes growth below pH 8.5. Thus, nonalkalophilic mutant strains do not exhibit Na+/H+ antiport activity and, interestingly, such strains concomitantly lose the ability to catalyze Na+-dependent accumulation of alpha-aminoisobutyrate [Krulwich, T. A., Mandel, D. G. Bornstein, R. F. & Guffanti, A. A. (1979) Biochem. Biophys. Res. Commun. 91, 58-62]. Several other Na+-dependent transport systems are now documented in vesicles from the wild-type strain, and it is demonstrated that these systems are defective in vesicles from the nonalkalophilic mutant KM23. Surprisingly, the defect seems to result not from the loss of Na+/H+ antiport activity per se but from a pleiotropic defect in the Na+/substrate symporters themselves. Monensin, an ionophore that catalyzes Na+/H+ exchange, does not restore respiration-driven Na+/substrate symport in KM23 vesicles. Moreover, with KM23 vesicles, efflux of alpha-aminoisobutyrate, L-malate, and L-aspartate down their respective concentration gradients is not stimulated by Na+, in contrast to the observations with wild-type vesicles. Because monensin should ameliorate a simple defect in Na+/H+ antiport activity and the antiporter should not be required for Na+/substrate symport down a concentration gradient, the results suggest that there may be a direct relationship between the antiporter and various Na+/substrate symporters. One possibility is that the systems share a Na+-translocating subunit.

Aminoisobutyric Acids↗