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C Cohen

Publications and source records attributed to C Cohen.

At least 127 records · Page 7Linked to original sources
PubMed1998

A conserved C-terminal assembly region in paramyosin and myosin rods.

The assembly of myosin and paramyosin into filaments in muscle has been shown to depend in part on the interactions of regular periodic patches of charge on the surface of the rod regions of these alpha-helical coiled-coil proteins. It has also been known for some time that a relatively small region near the C-terminus of both molecules is critical for both solubility and assembly. This domain appears to function as a modulator of assembly in both proteins. Recently, a specific 29-residue region in the C-terminus of human fast muscle myosin rod has been shown to be essential for filament formation, and this sequence has been shown to be present in other vertebrate and invertebrate myosins. We show here that paramyosin also displays this specific conserved domain. Moreover, we have found that this domain is part of a longer distinctive region in both paramyosin and myosin: this region lacks the periodic variation in charge found in the rest of both coiled coils, has a unique charge profile, a relatively neutral total charge, and a high proportion of large apolar residues in surface positions. These results may be useful in designing site-directed mutagenesis studies to identify the target regions on neighboring molecules which interact with this C-terminal domain and so establish the mechanism of its function.

Actin Cytoskeleton↗
PubMed1998

Preferential involvement of D3 versus D2 dopamine receptors in the effects of dopamine receptor ligands on oral ethanol self-administration in rats.

There is evidence that dopamine transmission is involved in reinforcement processes and the present study investigated the relative involvement of D3 versus D2 dopamine receptors in the effects of dopamine ligands on the reinforcing action of ethanol. Rats were trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task using a saccharin-fading procedure. When preference in responding for ethanol over water had developed the rats were tested with several dopamine agonists and antagonists. Pretreatment with the non-selective dopamine agonist, apomorphine (0.01-0.1 mg/kg), the preferential D2 agonist, bromocriptine (1-10 mg/kg) and the selective D3 agonists, 7-OH-DPAT (0.003-0.1 mg/kg), PD 128907 (0.1-3 mg/kg), (+)3PPP (0.3-3 mg/kg), quinelorane (0.0001-0.003 mg/kg) and quinpirole (0.003-0.03 mg/kg), resulted in dose-dependent decreases in responding for ethanol. The relative potencies of the dopamine agonists to decrease ethanol self-administration were highly correlated with their published potencies to produce in vitro functional D3 but not D2 responses. Active doses could be considered as those selectively stimulating receptors involved in the control of dopamine release, suggesting that reduction of dopamine transmission was associated with a decrease in ethanol-reinforced responding. This conclusion was further supported by the finding that pretreatment with the D2/D3 dopamine antagonists, haloperidol (0.1-0.4 mg/kg) and tiapride (10-60 mg/kg), decreased responding for ethanol at doses which have been shown previously to block dopamine transmission.

Alcohol Drinking↗
PubMed1998

Angiogenesis as a predictor of survival after surgical resection for stage I non-small-cell lung cancer.

OBJECTIVES: Some patients with surgically resected stage I non-small-cell lung cancer eventually have metastatic disease. A histologic marker of metastatic potential and diminished survival for stage I non-small-cell lung cancer may distinguish this patient population. This study evaluates the degree of angiogenesis as a predictor of cancer-related death after operation for stage I non-small-cell lung cancer. METHODS: Demographic, surgical, and histopathologic data, including presence of vascular invasion, were reviewed for 106 patients with stage I non-small-cell lung cancer from 1985 through 1990. Visual quantitation of microvessels immunostained with factor VIII-related antigen and CD31 in 5 microm sections from the paraffin blocks of tissue defined rumor angiogenesis. RESULTS: Follow-up was 95.1% complete, mean 5.2 +/- 3.0 years. Lung cancer-related mortality rate was 24.4% at 5 years. Mean microvessel counts were 20.7 +/- 11.2 for FVIII and 29.6 +/- 18.1 for CD31. Univariate analysis revealed an FVIII count of at least 20 (p = 0.025) and blood vessel invasion (p = 0.017) to be significant predictors of disease-related death. After adjustment for other patient and tumor characteristics, multivariate Cox regression analysis found an FVIII count of at least 20 (hazard ratio 2.9) and blood vessel invasion (hazard ratio 3.7) to be significant independent correlates of lung cancer death (p = 0.018 and p = 0.011, respectively). CD31 quantitation did not predict survival on univariate or multivariate analyses and did not correlate strongly with FVIII quantitation (Spearman's rank correlation r = 0.19). CONCLUSIONS: This analysis reveals a significant association between tumor neovascularization and cancer-related mortality rate among patients with stage I non-small-cell lung cancer. Microvessel quantitation of FVIII, as an indicator of tumor angiogenesis and metastatic potential, may define a subset of patients with stage I non-small-cell lung cancer who could benefit from adjuvant therapy after surgical resection.

Adenocarcinoma↗
PubMed1998

Sex and androgenic steroid receptor expression in hepatic adenomas.

Sex hormones and anabolic-androgenic steroids are implicated in the development and progression of hepatic adenomas (HA). We studied the expression of their receptors in HA and adjacent liver. Archival tissue sections of 27 HA (16 resections, four needle biopsies, seven aspirations) from 18 patients, and the adjacent liver, were immunostained with monoclonal antibody to estrogen receptor (ER, 1/80) (Dako, Carpinteria, CA), progesterone receptor (PR, 1/50) (BioGenex, San Ramon, CA), and androgen receptor (AR, 1/80) (BioGenex). An avidin-biotin complex technique was used with microwave antigen retrieval. Nuclear expression was assessed as 1+ to 3+ intensity, with semiquantitation of the percentage of nuclei immunopositive. Five percent or more nuclei immunopositive was regarded as positive. The 18 patients included 16 females of 34 years mean age (range, 16 to 49) with an available history of oral contraceptives in five; the two men were 24 and 30 years, with no history of androgenic steroids. ER, PR, and AR were present in seven (26%) (1+/-2+ intensity, 5% to 10% of nuclei) of HA, seven (26%) (1+/-2+ intensity, 5% to 30% of nuclei) and nine (33%) (1+/-3+ intensity, 5% to 80% of nuclei), respectively. In the adjacent liver in 11 cases, there were one (9%) ER, (2+ intensity, 5% of nuclei), four (36%) PR (1+/-2+ intensity, 5% to 20% of nuclei), and two (18%) AR (2+/-3+ intensity, 10% of nuclei). Receptors are present and may mediate the action of sex hormones or androgenic steroids on HA and adjacent liver, but in less than one third of patients. This may have therapeutic implications.

Adenoma↗
PubMed1998

Life circumstances and personal resources as predictors of the ten-year course of depression.

A 10-year naturalistic study of 313 patients who entered treatment for unipolar depression and a community comparison group of 284 nondepressed adults was conducted. We compared life stressors, social resources, personal resources, and coping among patients who were remitted (N = 76), partially remitted (N = 146), or nonremitted (N = 91). Compared with the controls and the remitted patients, the partially remitted and nonremitted patients consistently experienced more life stressors and fewer social resources, were less easygoing, and relied more on avoidance coping. A less easygoing disposition, fewer close relationships, and more reliance on avoidance coping were associated with higher odds of experiencing a course of partial remission or nonremission. In addition, more depressive symptoms and medical conditions predicted nonremission.

Adaptation, Psychological↗
PubMed1998

Ki67 expression in lichen sclerosus of vulva in patients with and without associated squamous cell carcinoma.

AIMS: To investigate the malignant potential of lichen sclerosus, a study using the cell proliferation marker Ki67 comparing lichen sclerosus with and without associated squamous cell carcinoma was performed. METHODS AND RESULTS: Formalin-fixed, paraffin-embedded slides of 13 cases of lichen sclerosus with associated carcinoma, and 31 cases without associated carcinoma, including 16 random cases, seven with epidermal thickening and eight with epidermal thinning, were examined by the immunoperoxidase technique for Ki67, a cell proliferation marker. Ki67 reactivity was mostly seen in the basal and parabasal cells in both groups of lichen sclerosus and this pattern was similar to normal skin, squamous cell hyperplasia and analogous to that of one form of squamous cell carcinoma. There was a mean of 50 Ki67 positive cells per 100 basal cells in lichen sclerosus with associated squamous cell carcinoma; however, in squamous cell hyperplasia adjacent to carcinoma this rose to 90 Ki67 positive cells per 100 basal cells. In lichen sclerosus without associated carcinoma, the random cases had a count of 53 per 100 basal cells, those with epidermal thickening 53 and those with thinning 42. Non-genital normal skin had a count of 71 per 100 basal cells. CONCLUSION: The lack of qualitative differences of Ki67 expression in normal skin, in lichen sclerosus with and without carcinoma, in squamous cell hyperplasia and in one form of squamous cell carcinoma indicates that these conditions share a common localized pattern of cell proliferation and does not support or deny the malignant potential of lichen sclerosus. The higher Ki67 count in squamous cell hyperplasia adjacent to carcinoma could indicate premalignancy or a reaction to the carcinoma. In patients without carcinoma, the higher Ki67 count in thickened lichen sclerosus compared to thinned suggests that some or all of the cases of thickened lichen sclerosus were lichen sclerosus with squamous cell hyperplasia or that lichen simplex chronicus superimposed on lichen sclerosus has a higher Ki67 expression or that the distinction between squamous cell hyperplasia and lichen simplex chronicus is only one of terminology.

Basal Cell Carcinoma↗
PubMed1998

Image cytometric measurement of nuclear proliferation markers (MIB-1, PCNA) in astrocytomas. Prognostic significance.

Proliferative activity in astrocytomas, measured by image cytometry, was related to prognosis. Fifty-eight astrocytic neoplasms (grade 1 or 2, 11; grade 3, 31; glioblastoma multiforme, 16) were immunostained for Ki-67 (MIB-1; 1:50) and proliferating cell nuclear antigen (PCNA; prediluted). Proliferative activity (nuclear immunostain) was measured as the percentage positive nuclear area by image cytometry. With a median of 12.0% and 24.0% for MIB-1 and PCNA, respectively, for all astrocytomas, the mean percentage positive nuclear area for MIB-1 and PCNA was, respectively, 3.06% and 13.11% in low-grade (1 or 2) astrocytomas, 14.34% and 29.68% in high-grade (3) astrocytomas, and 18.77% and 44.11% in glioblastoma multiforme (grade 4). One-way analysis of variance showed a significant correlation between the histologic grade and MIB-1 and between the histologic grade and PCNA. The Cox Proportional Hazards Regression Model showed a statistically significant correlation between survival and MIB-1 and between survival and PCNA. Increasing proliferation correlated with shortened survival. Proliferation in astrocytomas, measured as MIB-1 and PCNA by image cytometry, correlates significantly with histologic grade and patient survival, providing useful additional information for determining the diagnosis and prognosis.

Adolescent↗
PubMed1998

Use of the umbilicus in reconstruction of the vulva and vagina with a rectus abdominis musculocutaneous flap.

Flap reconstruction of the vulva and vagina following gynecological ablative procedures has become an integral part of the management of gynecological oncology patients. The benefits of flap reconstruction, including early primary healing, improved cosmesis over skin grafting, and prolonged secondary wound healing, have been well accepted. Additionally, the creation of a neovagina or neovulva often restores the sexual function and positive body image of the patient lost to radical procedures. The gracilis musculocutaneous flap has been used extensively in flap reconstruction but reports of partial flap necrosis and the need for extensive dissection of both thighs have led to alternative flap choices. The rectus musculocutaneous flap, with its hardier cutaneous blood supply, is often too bulky and difficult to inset delicately around the preserved urethral and vaginal cuff. The umbilicus has the required soft tissue, and its conically contoured depression allows for delicate insetting of the rectus abdominis musculocutaneous flap around the urethral cuff. We present 2 patients who underwent vertical rectus musculocutaneous flaps with umbilical soft tissue to restore urinary function and to create a cosmetic nonfunctional vagina.

Abdominal Muscles↗
PubMed1998

A preceptorship program in an Israeli bone marrow transplantation unit.

Bone marrow transplantation (BMT) departments are unique in character. This is due largely to the following factors: the diseases treated, long-term hospitalization, strong family involvement in the care of patients, and the use of experimental treatment. Because of these factors, clinical experiences in a BMT unit may be a threatening experience for both nursing students and nurses. The BMT unit at Hadassah Hospital has, therefore, developed and implemented a preceptorship program for nursing students and nurses involved in advanced courses. The program includes three aspects: (a) a comprehensive medical knowledge base, (b) instruction in special nursing skills aimed at meeting both the physical and psychologic needs of BMT patients and their families, and (c) supervised involvement in patient and family education and counseling. Our goal is to enable students to care for patients throughout the BMT experience, from admission to post-BMT follow-up. Feedback elicited from students who have undergone the program was positive. They said that the program helped them overcome their fears and encouraged them to apply for nursing jobs in the unit.

Bone Marrow Transplantation↗
PubMed1997

Structures of four Ca2+-bound troponin C at 2.0 A resolution: further insights into the Ca2+-switch in the calmodulin superfamily.

BACKGROUND: In contrast to Ca2+4-bound calmodulin (CaM), which has evolved to bind to many target sequences and thus regulate the function of a variety of enzymes, troponin C (TnC) is a bistable switch which controls contraction in striated muscles. The specific target of TnC is troponin I (TnI), the inhibitory subunit of the troponin complex on the thin filaments of muscle. To date, only the crystal structure of Ca2+2-bound TnC (i.e. in the 'off' state) had been determined, which together with the structure of Ca2+4-bound CaM formed the basis for the so-called 'HMJ' model of the conformational changes in TnC upon Ca2+ binding. NMR spectroscopic studies of Ca2+4-bound TnC (i.e. in the 'on' state) have recently been carried out, but the detailed conformational changes that take place upon switching from the off to the on state have not yet been described. RESULTS: We have determined the crystal structures of two forms of expressed rabbit Ca2+4-bound TnC to 2.0 A resolution. The structures show that the conformation of the N-terminal lobe (N lobe) is similar to that predicted by the HMJ model. Our results also reveal, in detail, the residues involved in binding of Ca2+ in the regulatory N lobe of the molecule. We show that the central helix, which links the N and C lobes of TnC, is better stabilized in the Ca2+2-bound than in the Ca2+4-bound state of the molecule. Comparison of the crystal structures of the off and on states of TnC reveals the specific linkages in the molecule that change in the transition from off to on state upon Ca2+-binding. Small sequence differences are also shown to account for large functional differences between CaM and TnC. CONCLUSIONS: The two lobes of TnC are designed to respond to Ca2+-binding quite differently, although the structures with bound Ca2+ are very similar. A small number of differences in the sequences of these two lobes accounts for the fact that the C lobe is stabilized only in the open (Ca2+-bound) state, whereas the N lobe can switch between two stable states. This difference accounts for the Ca2+-dependent and Ca2+-independent interactions of the N and C lobe. The C lobe of TnC is always linked to TnI, whereas the N lobe can maintain its regulatory role - binding strongly to TnI at critical levels of Ca2+ - and in contrast, forming a stable closed conformation in the absence of Ca2+.

Animals↗
PubMed1997

Cooperative effects of INK4a and ras in melanoma susceptibility in vivo.

The familial melanoma gene (INK4a/MTS1/CDKN2) encodes potent tumor suppressor activity. Although mice null for the ink4a homolog develop a cancer-prone condition, a pathogenetic link to melanoma susceptibility has yet to be established. Here we report that mice with melanocyte-specific expression of activated H-rasG12V on an ink4a-deficient background develop spontaneous cutaneous melanomas after a short latency and with high penetrance. Consistent loss of the wild-type ink4a allele was observed in tumors arising in ink4a heterozygous transgenic mice. No homozygous deletion of the neighboring ink4b gene was detected. Moreover, as in human melanomas, the p53 gene remained in a wild-type configuration with no observed mutation or allelic loss. These results show that loss of ink4a and activation of Ras can cooperate to accelerate the development of melanoma and provide the first in vivo experimental evidence for a causal relationship between ink4a deficiency and the pathogenesis of melanoma. In addition, this mouse model affords a system in which to identify and analyze pathways involved in tumor progression against the backdrop of genetic alterations encountered in human melanomas.

Animals↗
PubMed1997

Effects of dihydropyridine Ca2+ channel blockers on the discriminative stimulus and the motor impairing effects of (+/-)-Bay K 8644.

Functional interactions between the dihydropyridine Ca2+ channel activator, (+/-)-Bay K 8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethyphenyl )-pyridine-5-carboxylate), and several dihydropyridine L-type Ca2+ channel blockers were investigated on rotarod performance in mice and in rats trained to discriminate between (+/-)Bay K 8644 and saline. When administered alone, (+/-)-Bay K 8644 produced dose-dependent impairments of rotarod activity with an ED50 of 1.3 mg/kg. Pretreatment with nifedipine (10-30 mg/kg) produced dose-dependent rightward shifts of the (+/-)-Bay K 8644 dose-response curve. In contrast, pretreatment with several other dihydropyridine L-type Ca2+ channel blockers, including nicardipine, nimodipine, isradipine and nitrendipine, did not modify the (+/-)-Bay K 8644 dose-effect function. Rats learned to discriminate between (+/-)-Bay K 8644 (0.5 mg/kg) and saline in an average of 65 training sessions. In substitution tests, the Ca2+ channel activator engendered dose-related increases in the percentage of rats selecting the drug-associated lever with an ED50 of 0.19 mg/kg. Pretreatment with nifedipine (10 mg/kg) produced a rightward shift of the (+/-)-Bay K 8644 dose-response function. Pretreatment with nicardipine (2.5 mg/kg) only partially antagonised the training dose of (+/-)-Bay K 8644 whereas nimodipine (0.6-10 mg/kg) did not affect the (+/-)-Bay K 8644 discriminative stimulus. The results of the present study show that the behavioural effects of the dihydropyridine Ca2+ channel activator are differentially modified by dihydropyridine L-type Ca2+ channel blockers. These results may suggest that dihydropyridine blockers possess different intrinsic activities or act at different binding sites.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1997

A 29 residue region of the sarcomeric myosin rod is necessary for filament formation.

Myosin is a motor protein whose functional unit in the sarcomere is the thick filament. The myosin molecule is capable of self-assembly into thick filaments through its alpha-helical coiled-coil rod domain. To define more precisely the sequence requirements for this assembly, segments of the human fast IId skeletal myosin rod were expressed in Escherichia coli and examined differential solubility and the formation of ordered paracrystals. We show that both properties appear to require a 29 residue sequence (residues 1874 to 1902) near the C terminus of the rod region. To test further the role of this region in assembly, a protein was constructed which consisted of this assembly competence domain (ACD) fused to the carboxy terminus of an assembly-incompetent myosin rod fragment. This chimeric fragment exhibited myosin's characteristic solubility properties and formed ordered paracrystals. To complement these in vitro experiments, both a full-length myosin heavy chain (MYH) and one from which the 29 residues were deleted were transfected into cultured mammalian cells. While the full-length construct formed the spindle-shaped structures characteristic of arrays of thick filaments, the deleted MYH showed only diffuse staining throughout the cytoplasm by light microscopy. Thus, there appears to be a specific sequence in the C-terminal region of the myosin heavy chain rod which is necessary for ordered paracrystal formation and is sufficient to confer assembly properties to an assembly-incompetent rod fragment.

Amino Acid Sequence↗
PubMed1997

Enhanced radiosensitization with interferon-alpha-2b and cisplatin in the treatment of locally advanced cervical carcinoma.

PURPOSE: To evaluate the efficacy and toxicity of interferon-alpha-2b (IFN-alpha) and cisplatin given concomitantly with radiation therapy (RT) in the treatment of locally advanced cervical carcinoma. MATERIALS AND METHODS: Twenty-one patients with stage bulky Ib-IIIb (Ib, 2; IIa, 2; IIb, 8; IIIb, 9) cervical carcinoma were treated with combined IFN-alpha (5 million IU) subcutaneously three times per week and cisplatin (25 mg/m2) i.v. infusion over 2 h weekly for 7 weeks, given concomitantly with RT (4500 cGy of external beam plus 2 brachytherapy procedures). Total radiation doses delivered ranged from 7500 to 9960 cGy (median, 9300 cGy). Follow-up ranged from 16 to 33 months (median, 25 months). RESULTS: The 2-year local control rate was 100%. The only sites of disease recurrence were distant. Freedom from distant metastases, disease-free survival, and overall survival at 2 years was 76%. Late complication rates were high. Grade 4 rectosigmoid, bladder, and small bowel complication rates were 49, 18, and 23% at 2 years. Late toxicity was seen earlier than expected with rectosigmoid complications observed 5 to 11.5 months (median, 8 months) after completion of treatment. CONCLUSION: Combination IFN-alpha and cisplatin produced a marked effect of enhanced radiosensitization as evidenced by 100% local tumor control and high late normal tissue complication rates. Due to the unacceptable late toxicity, its routine clinical use cannot be recommended. Further investigation is needed to determine whether a therapeutic window exists such that the use of lower doses of IFN-alpha, cisplatin, or RT can increase tumor control with more acceptable normal tissue toxicity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Equivalence of nasal spray and subcutaneous formulations of salmon calcitonin.

The aim of this study was to assess the efficacy and safety of nasal spray and subcutaneous formulations of salmon calcitonin. Two-hundred-four patients, 27 males and 177 females, aged 72 years on average, with a recent, painful, vertebral crush fracture were given either 50 IU/day of subcutaneous salmon calcitonin (SCSCT, 102 patients) or 200 IU/day of intranasal salmon calcitonin (INSCT, 102 patients) for 30 consecutive days, according to a double-blind, double-placebo design. The two-sided 95% confidence interval of the difference between the two formulations for the pain on D30 assessed by Huskisson's Visual Analogue Scale (VAS) [-5.3 mm, 7.9 mm] was included in the [-10 mm, 10 mm] reference interval. Equivalence of the two formulations, was demonstrated. At the end of the study, the 95% confidence intervals of VAS of both treatment groups were included in the [0 mm, 30 mm] interval, which is considered to be clinically pertinent. Relief was obtained in less than 10 days for more than 50% of patients. The urinary hydroxyproline/creatinine and calcium/creatinine ratios remained constant between D1 and D30 with both formulations. General safety was comparable between the two formulations. Local safety of INSCT was similar to that of its placebo.

Administration, Intranasal↗
PubMed1997

Tumor angiogenesis as a prognostic factor in laryngeal cancer.

BACKGROUND: Lymph node metastasis is the single greatest predictor of recurrence in laryngeal cancer. Prognostic factors are needed to target patients who may benefit from adjuvant therapy. Tumor angiogenesis correlates with metastasis in breast, bladder, and oral cavity cancer and may have prognostic value in other tumors. METHODS: In order to examine the relationship of tumor angiogenesis to recurrence, 51 patients with squamous cell carcinoma of the larynx were reviewed. In a blinded design, previously sectioned slides were chosen for advanced tumor and highest vessel concentration. Samples were cut and immunocytochemically stained for CD-31 (an endothelial marker). A computer image analyzer quantitated the percent area of staining. Variables were statistically examined against recurrence. RESULTS: Patients were stratified by percent tumor staining. Nodal involvement was seen in 9 (36%) patients with tumor staining < or = 20% and in 20 (77%) with tumor staining > 20% (P = 0.003). Patients with < or = 20% staining and without metastasis had a 13% rate of recurrence whereas patients with > 20% staining and without metastasis had a 67% rate of recurrence (P = 0.025). CONCLUSIONS: Though nodal status was suggestive of predictability, only angiogenesis is a statistically significant predictor of recurrence in node negative patients (P = 0.025). Angiogenesis shows strong correlation with regional recurrence and may be used as an independent prognostic indicator to determine clinically node negative patients who may be at higher risk for metastasis and require adjuvant therapy.

Carcinoma, Squamous Cell↗