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D Corcos

Publications and source records attributed to D Corcos.

At least 19 recordsLinked to original sources
PubMed2001

Expression of a V region-less B cell receptor confers a tolerance-like phenotype on transgenic B cells.

Neoplastic B cells from H chain disease patients express a truncated B cell receptor (BCR), comprising a membrane Ig that lacks part of its extracellular domain. It has been speculated that deletion of the Ag binding domain would confer a constitutive activity on the BCR, as it has been shown for oncogenic growth factor receptors. A V region-less BCR has constitutive activity, because in transgenic mice it causes inhibition of endogenous H chain gene rearrangements and relieves the requirement for surrogate L chain in pre-B cell development. However, it has been speculated that normal Ag receptors also display constitutive activity. Here we show that transgenic B cells expressing a membrane H chain disease protein on their surface are phenotypically and functionally similar to B cells developing in the presence of their cognate Ag and that cells with normal levels of mutant BCR are eliminated in spleen via a bcl-2 sensitive pathway while progressing toward the mature stage. In contrast, cells with lower levels of mutant receptors develop as mature B cells. These findings support the view that the truncated BCR has a constitutive activity that mimics ligand binding, in analogy to what has been shown for oncogenic growth factor receptors.

Animals↗
PubMed1997

Recombining sequence recombination in normal kappa-chain-expressing B cells.

Recombining sequence (RS) recombination is a DNA rearrangement that deletes one or two C kappa alleles in a large proportion of lambda-expressing B cells. Since its discovery, this recombination has been suggested to play a role in activating lambda gene rearrangements. A model involving a positive signal generated by RS recombination seems to be excluded, but another model that is still under consideration proposes that RS recombination removes DNA sequences within the kappa locus that would interfere with lambda gene assembly. Using PCR assays, we have found that kappa-expressing cells account for the majority of RS rearrangements in mouse spleen. RS rearrangements were also detected by Southern blot in kappa-secreting hybridomas. Quantification of rearrangements indicates that approximately 12% of kappa cells bear an RS recombination. From this finding, we infer that once a cell has performed an RS recombination on one kappa allele, it has a 3 times higher probability of rearranging functionally its other kappa allele rather than one of the lambda genes. These data call into question the role of RS recombination in the switch from kappa to lambda and suggest another function for this nonproductive rearrangement.

Alleles↗
PubMed1997

Directional control of planar human arm movement.

We examined the patterns of joint kinematics and torques in two kinds of sagittal plane reaching movements. One consisted of movements from a fixed initial position with the arm partially outstretched, to different targets, equidistant from the initial position and located according to the hours of a clock. The other series added movements from different initial positions and directions and >40-80 cm distances. Dynamic muscle torque was calculated by inverse dynamic equations with the gravitational components removed. In making movements in almost every direction, the dynamic components of the muscle torques at both the elbow and shoulder were related almost linearly to each other. Both were similarly shaped, biphasic, almost synchronous and symmetrical pulses. These findings are consistent with our previously reported observations, which we termed a linear synergy. The relative scaling of the two joint torques changes continuously and regularly with movement direction. This was confirmed by calculating a vector defined by the dynamic components of the shoulder and elbow torques. The vector rotates smoothly about an ellipse in intrinsic, joint torque space as the direction of hand motion rotates about a circle in extrinsic Cartesian space. This confirms a second implication of linear synergy that the scaling constant between the linearly related joint torques is directionally dependent. Multiple linear regression showed that the torque at each joint scales as a simple linear function of the angular displacement at both joints, in spite of the complex nonlinear dynamics of multijoint movement. The coefficients of this function are independent of the initial arm position and movement distance and are the same for all subjects. This is an unanticipated finding. We discuss these observations in terms of the hypothesis that voluntary, multiple degrees of freedom, rapid reaching movements may use rule-based, feed-forward control of dynamic joint torque. Rule-based control of joint torque with separate dynamic and static controllers is an alternative to models such as those based on the equilibrium point hypotheses that rely on a positionally based controller to produce both dynamic and static torque components. It is also an alternative to feed-forward models that directly solve the problems of inverse dynamics. Our experimental findings are not necessarily incompatible with any of the alternative models, but they describe new, additional findings for which we need to account. The rules are chosen by the nervous system according to features of the kinematic task to couple muscle contraction at the shoulder and elbow in a linear synergy. Speed and load control preserves the relative magnitudes of the dynamic torques while directional control is accomplished by modulating them in a differential manner. This control system operates in parallel with a positional control system that solves the problems of postural stability.

Arm↗
PubMed1996

Coordinating movement at two joints: a principle of linear covariance.

1. Six subjects performed fast, "single-joint" flexions at either the elbow or shoulder over three angular distances in a sagittal plane. Movement endpoints were located to require flexion of only a single, "focal" joint, without any external, mechanical constraint on the other, "nonfocal" joint. Three subjects performed another series of movements between two targets while moving along different paths and in which both joints were flexed. 2. We compared the torque patterns that were produced at the two joints. For single-joint movements, they were both biphasic pulses that accelerated and then decelerated the limb. 3. The torque at the nonfocal joint of a single joint movement was very close to linearly proportional to that at the focal joint throughout the movement. Elbow and shoulder torques differed by a linear scaling constant and went through extrema and zero crossings almost simultaneously. 4. In contrast, during movements in which subjects were explicitly instructed to use a hand path they would not naturally, use the linear interjoint torque scaling rule did not apply. This demonstrated that when we wish to move along a path between two targets that is not produced by linear torque covariation, we are able to modify that rule at will. 5. We speculate that linear, dynamic covariation of the torque patterns across two joints may be an important principle for reducing the number of degrees of freedom that the nervous system must independently control in performing unconstrained limb movements over naturally chosen paths.

Analysis of Variance↗
PubMed1995

Pre-B-cell development in the absence of lambda 5 in transgenic mice expressing a heavy-chain disease protein.

BACKGROUND: Heavy-chain diseases (HCDs) are human lymphoproliferative neoplasias that are characterized by the secretion of truncated immunoglobulin heavy chains devoid of light chains. We have previously proposed--by analogy to the process by which mutated growth factor receptors can be oncogenic--that because the genetic defects in HCDs result in the production of abnormal membrane-associated heavy chains lacking an antigen-binding domain, these abnormal B-cell antigen receptors might engage in ligand-independent signalling. Normal pre-B-cell development requires the presence of the pre-B-cell receptor, formed by the association of mu heavy chains with two polypeptides--so-called surrogate light chains, Vpre-B and lambda 5--that are homologous to the variable and constant portions of immunoglobulin light chains, respectively. To assess whether amino-terminal truncation of membrane-associated heavy chains results in their constitutive activation, we have examined the ability of a HCD-associated mu protein to promote pre-B-cell development in transgenic mice. RESULTS: When the mu HCD transgene is introduced into SCID mice, CD43- pre-B cells develop normally. To determine whether this pre-B-cell development requires surrogate light chains, we backcrossed mice expressing full-length or truncated mu transgenes with lambda 5-deficient mice. Our results show that the truncated heavy chain, but not the normal chain, is able to promote pre-B-cell development in the absence of lambda 5. We also show that truncated mu chains spontaneously aggregate at the surface of bone marrow cells. CONCLUSIONS: Expression of the truncated mu heavy chain overrides a tightly controlled step of pre-B-cell development, which strongly suggests that a constitutive signal is delivered by the truncated mu chain disease protein. The self-aggregation of mu chain disease proteins might account for this constitutive activation. We conclude that amino-terminal truncation of heavy chains could play a role in the genesis of HCD neoplasia if it occurs at an appropriate stage of B-cell differentiation, namely in a mature B cell.

Animals↗
PubMed1995

Organizing principles for voluntary movement: extending single-joint rules.

1. Four subjects performed fast flexions of the elbow or shoulder over three different distances. Elbow flexions were performed both in a horizontal, single-degree-of-freedom manipulandum and in a sagittal plane with the limb unconstrained. Shoulder flexions were only performed in the sagittal plane by the unconstrained limb. We simultaneously recorded kinematic and electromyographic (EMG) patterns at the "focal" joint, that which the subject intentionally flexed, and at the other, "nonfocal" joint that the subject had been instructed to not flex. 2. Comparisons of the elbow EMG patterns across tasks show that agonist and antagonist muscles were similar in pattern but not size, reflecting the net muscle torque patterns. Comparisons at the shoulder also revealed similar EMG patterns across tasks that reflected net muscle torques. 3. Comparisons of EMG patterns across joints show that elbow and shoulder flexors behaved similarly. This was not true of the extensors. The triceps EMG burst was delayed for longer distances but the posterior deltoid had an early, distance-invariant onset. 4. Similarities in EMG reflect torque demands required at the focal joint to produce flexion and at the nonfocal joint to reduce extension induced by dynamic interactions with the focal, flexing joint. These similarities appear despite very different kinematic intentions and outcomes. This argues against a strong role for length-sensitive reflexes in their generation. 5. These results support the hypothesis that movements are controlled by muscle activation patterns that are planned for the expected torque requirements of the task. This general rule is true whether we are performing single-joint or multiple-joint movements, with or without external constraints. The similarities between single-joint and multijoint movement control may be a consequence of ontogenetic development of multijoint movement strategies that prove useful and are therefore also expressed under the constrained conditions of specialized tasks such as those performed in single-joint manipulanda.

Adult↗
PubMed1991

Allelic exclusion in transgenic mice expressing a heavy chain disease-like human mu protein.

Heavy chain diseases (HCD) are neoplastic proliferations of B cells which secrete truncated immunoglobulin heavy chains without associated light chains. These proteins are encoded by mutated genes which may also give rise to truncated membrane immunoglobulins. The neoplastic cells proliferate in vivo although they cannot bind any antigen, due to deletions in the variable domain of their antigen receptors. The reason for the clonal proliferation of HCD cells and the biological effects of the truncated membrane-bound chains are presently unknown. We wanted to determine whether the expression of HCD proteins would interfere with B cell development. To this end we made transgenic mice with a human mu gene, lacking the VDJ exon, that encodes a protein similar to that produced in two cases of HCD. Transgenic mice were also produced with a similar construct but encoding only the membrane-bound form of the truncated mu chain. Transgene encoded C mu proteins are expressed on the cell surface without associated light chains and are responsible for allelic exclusion of murine heavy chains.

Animals↗
PubMed1991

Stimulation of methotrexate resistance and dihydrofolate reductase gene amplification by c-myc.

We have hypothesized that the c-myc oncogene might promote DNA amplification. Resistance to methotrexate (MTX), a widely used cancer chemotherapeutic agent, often results from amplification of the gene coding for the target enzyme, dihydrofolate reductase (DHFR). We report here that gratuitously induced expression of c-myc in rat fibroblasts grown in the presence of MTX greatly increases the number of colonies resistant to the drug. This effect is not related to an alteration of cell growth, and it can also be observed to a lesser extent when c-myc is induced prior to selection in MTX. The DHFR gene is amplified in nearly half of the colonies cultured under selection conditions. Given the likely role of the c-myc product in DNA replication, these results strongly suggest that expression of c-myc plays a role in methotrexate resistance by promoting DNA amplification.

Animals↗
PubMed1989

Intrathecal baclofen for severe spinal spasticity.

We studied the effect of the intrathecal infusion of baclofen, an agonist of gamma-aminobutyric acid, on abnormal muscle tone and spasms associated with spinal spasticity, in a randomized double-blind crossover study. Twenty patients with spinal spasticity caused by multiple sclerosis or spinal-cord injury who had had no response to treatment with oral baclofen received an intrathecal infusion of baclofen or saline for three days. The infusions were administered by means of a programmable pump implanted in the lumbar subarachnoid space. Muscle tone decreased in all 20 patients (mean [+/- SD] Ashworth score for rigidity, from 4.0 +/- 1.0 to 1.2 +/- 0.4; P less than 0.0001), and spasms were decreased in 18 of the 19 patients who had spasms (mean [+/- SD] score for spasm frequency, from 3.3 +/- 1.2 to 0.4 +/- 0.8; P less than 0.0005). Tests for motor function, neurologic examination, and assessments by the patients correctly indicated when baclofen was being infused in all cases. All patients were then entered in an open long-term trial of continuous infusion of intrathecal baclofen. During a mean follow-up period of 19.2 months (range, 10 to 33), muscle tone has been maintained within the normal range (mean Ashworth score, 1.0 +/- 0.1) and spasms have been reduced to a level that does not interfere with activities of daily living (mean spasm score, 0.3 +/- 0.6). No drowsiness or confusion occurred, one pump failed, and two catheters became dislodged and had to be replaced. No infections were observed. Our observations suggest that intrathecal baclofen is an effective long-term treatment for spinal spasticity that has not responded to oral baclofen.

Adult↗
PubMed1989

Functional outcome after delivery of intrathecal baclofen.

Patients with multiple sclerosis or spinal cord injury often have severe, disabling spasticity. This is frequently treated with oral medications or with destructive neurosurgical procedures. We report on a group of patients with spasticity not relieved by these methods. These patients were subsequently treated with intrathecal baclofen delivered by an implanted programmable drug pump. Twenty-one patients have received this form of treatment, and the functional status of eight has been tracked by the Patient Evaluation Conference System (PECS) for at least six months. In most cases, spasticity, performance of bowel and bladder programs, and performance of ADL improved after delivery of intrathecal baclofen. The improvements appear to be due to the decrease in hypertonicity and the increased ease of movement (passive or active) in affected extremities. Intrathecal baclofen should be considered as a treatment method in patients with severe spasticity of spinal origin.

Activities of Daily Living↗
PubMed1988

Increased expression of the N-myc gene during normal and neoplastic rat liver growth.

The activation of N-myc and c-myc genes has been implicated in the genesis of a variety of cancers. In order to determine whether this activation is related to the process of cell growth, we examined N-myc and c-myc expression in rat hepatocytes when growth was stimulated by partial hepatectomy and in rat liver during neoplastic growth induced by diethylnitrosamine. The levels of N-myc and c-myc mRNAs, which are very low in hepatocytes from normal rats, were increased at least 20-fold within 3 h after partial hepatectomy and decreased rapidly by 6 h. A second transient peak of c-myc and N-myc mRNAs occurred around 9 and 48 h, respectively. N-myc and c-myc expressions were also induced in carcinoma nodules by diethylnitrosamine. A high level of N-myc transcript was observed in hepatocytes as early as 1 month after the carcinogen administration, whereas c-myc transcript was detected at a high level only several months later in carcinoma nodules. Our results suggest that the transient expression of N-myc and c-myc oncogenes during the prereplicative stage of liver regeneration may be associated with the entry of hepatocytes into the cell cycle, and that N-myc expression is not limited to tumors of neural characteristics as has been previously shown but is also observed in cancer from epithelial origin.

Animals↗
PubMed1987

Expression of c-myc is under dietary control in rat liver.

Expression of c-myc has often been related to the control of growth and differentiation of a variety of cell types. However, in some cases, such a relation has not been found. The rate of cell division is very low in liver, but c-myc expression is yet easily detected. We show here that a short-time physiological fasting results in a dramatic decrease of c-myc expression in rat liver. This effect does not seem to be dependent on glucagon, since administration of glucagon leads to an increase in c-myc mRNA. This is to our knowledge, the first evidence of a physiological variation of proto-oncogene expression linked to food intake, and we suggest that this variation could play a role in liver cell growth control.

Animals↗
PubMed1986

Isolation and characterization of complementary DNA clones for genes overexpressed in chemically induced rat hepatomas.

In order to characterize the genes overexpressed in an hepatoma cell line, the HTC cells, and in diethylnitrosamine induced solid hepatomas, we constructed a complementary DNA library from HTC cells and performed differential screening with probes from HTC cells, from malignant nodules obtained 70 weeks after the carcinogen treatment, and from hepatocytes from normal rat liver. Eight clones corresponding to messenger RNAs (mRNAs) much more expressed in hepatomas than in hepatocytes from normal liver were isolated. Three, clones pHT 71, pHT 13, and pHT 26, were further analyzed by the study of their corresponding transcripts in hepatocytes from regenerating liver and in the hepatocytes from the nontumorous parts of the liver. Clone pHT 71 corresponds to a single 2.3-kilobase mRNA which is present in high levels in carcinoma nodules in hepatoma cell lines, in the nontumorous parts of the liver, and in hepatocytes isolated from regenerating liver 30 h after partial hepatectomy. Clone pHT 13 hybridizes with three distinct transcripts 3.8, 2.6, and 1.6 kilobases long. High levels of the 3.8- and 1.6-kilobase mRNAs are present in carcinoma nodules, in hepatoma cell lines, and in the nontumorous parts of the liver. However, the levels of these RNAs are similar in hepatocytes from regenerating liver and in hepatocytes obtained from normal rat liver. Clone pHT 26 corresponds to a 0.6-kilobase mRNA which exists at a high level only in cancer nodules and in hepatoma cell lines. We were unable to observe any cross-hybridization between these clones and the oncogenes which have been found to be expressed in hepatomas (c-fos, c-Ha-ras, c-Ki-ras, N-ras, and c-myc). The mRNAs corresponding to the three clones have not been detected in various tissues from normal adult rats. Our study shows that a high level of these mRNAs might be associated with rat liver carcinogenesis.

Animals↗
PubMed1985

Expression of c-fos oncogene during hepatocarcinogenesis, liver regeneration and in synchronized HTC cells.

We have studied the expression of c-fos gene in rat hepatoma induced by DENA. An increase of c-fos mRNA concentration was observed after 8 days, but the maximal 5- to 6-fold increase was observed after 70 weeks. This increase was found in perinodular hepatocytes as well as in cancer nodules. c-fos expression was also enhanced during liver regeneration at a period corresponding to cell proliferation. In HTC cells the arrest of the cell cycle at early G1 phase by addition of sodium butyrate was accompanied by a strong increase of c-fos gene expression. However the c-fos mRNA rapidly decreased after removal of sodium butyrate during the progression of the cells in the cell cycle and increased transiently when the cells entered again in G1 phase.

Animals↗
PubMed1984

Correlated increase of the expression of the c-ras genes in chemically induced hepatocarcinomas.

The expression of the c-Ha-ras, the c-Ki-ras and the N-ras genes was measured by the dot blot technique in rat liver tumors induced by a short diethylnitrosamine (DENA) treatment and in the surrounding liver cells. A 2 to 25 times higher level of transcript was found as well in the surrounding cells, as in the tumor cells, as compared to the level in hepatocytes. In addition the increase of expression was parallel for the three ras genes. We conclude that this enhanced expression can be attributed to an epigenetic mechanism and it can, in certain cases, be dissociated from cell proliferation.

Animals↗
PubMed1984

Systematic search for 1 alpha,25-dihydroxy-vitamin D3 receptors in human breast carcinomas.

We looked systematically for the presence of receptor like binding sites for 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) in the cytosol from 22 breast cancers. Cytosols were centrifuged on 5-20% sucrose gradients after labeling with tritiated 1,25 (OH)2D3 (3H-1,25(OH)2D3 or 25-hydroxyvitamin D3 (25(OH)D3 alone or in the presence of a large excess of these unlabeled sterols. Binding sites for 1,25 (OH)2D3 migrating in the 3.5-3.7 S region were found in 7 out of 22 cancers, while 5.5-6.5 binding sites for 25 (OH)D3 were found in all cytosols. In a patient in whom cytosol containing a 3.5-3.7 S binding site was in sufficient amount, quantification of 1,25 (OH)2D3 binding indicated a KD of 0.28 nM and a maximal binding capacity of 0.15 pmol/mg prot. No relation was found between the presence or the absence of 1,25 (OH)2D3 binding sites and the histological type, the extension of the cancer, the presence of radiological or histological calcifications, the amount of estrogen or progesterone receptors, the plasma calcium or phosphate concentration and the emergence of metastases after 1 year. The significance of the presence of receptor-like binding sites for 1,25-(OH)2D3 in one third of breast cancers remains therefore unknown at the present time.

Breast Neoplasms↗