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Biomedical subjects

R Makuch

Publications and source records attributed to R Makuch.

At least 37 records · Page 2Linked to original sources
PubMed1993

Low-grade astrocytomas may arise from different astrocyte lineages.

The management of low-grade astrocytomas remains a challenge. Although the majority of these tumors have common histological features, they may have very different clinical manifestations and rates of proliferation. Because low-grade astrocytomas are composed of relatively well-differentiated neoplastic cells that closely resemble the astrocytic phenotype, it is possible that some of these lesions express antigens that characterize astrocyte lineages. The authors performed an immunohistochemical analysis of 20 low-grade astrocytomas with A2B5, a monoclonal antibody to a ganglioside found in early postnatal Type 2 (fibrillary) astrocytes, but absent in Type 1 (protoplasmic) astrocytes, and anti-glial fibrillary acidic protein to determine whether the expression of these antigens could be used to determine the histogenesis of these tumors. These findings were compared with the clinical and imaging features of these tumors. The percentages of cells positive for A2B5 and glial fibrillary acidic protein was strongly correlated with the location of the tumor within the cortex or white matter and with the length of preoperative symptoms. Tumors based in the cortex contained significantly fewer A2B5-positive and glial fibrillary acidic protein-positive cells than white matter tumors. In addition, lesions that caused a relatively short period of preoperative symptoms (< 1 year) had significantly more A2B5-positive and glial fibrillary acidic protein-positive cells than lesions responsible for a long preoperative history (mean, 12.9 years). These findings suggest that slow-growing, cortically based low-grade astrocytomas have a phenotype consistent with the Type 1 (protoplasmic) astrocyte lineage, while white matter low-grade astrocytomas express antigens consistent with the Type 2 (fibrillary) astrocyte lineage.

Adolescent↗
PubMed1993

A phase II trial of mitomycin C, 5-fluorouracil and radiation therapy in the treatment of unresectable non-small cell lung cancer.

We conducted a study evaluating the efficacy of simultaneous administration of 5-fluorouracil, mitomycin C, and X-irradiation in unresectable Stage III non-small cell lung cancer. Radiation was delivered in a split course to a total of 55 Gy. In the first course, radiation was administered daily in 250 cGy fractions for 12 treatments. Following a two week rest, an additional 10 treatments of 200 cGy fractions were delivered. Chemotherapy consisted of 10 mg/M2 of mitomycin C on day 1, and 1000 mg/M2 per day of 5-fluorouracil by continuous infusion on days 1 through 5 and 29 through 33. Twenty-one enrolled patients were evaluable. The overall response rate was 52% (95% confidence intervals 31-73%), with a median duration of response of 42 weeks. There were 5 complete responders (24%) and four of these patients remain disease-free with follow-up between 24-54 months. The median survival time for all patients was 59 weeks. For the complete responders the median survival time has not yet been reached, but is in excess of 42 months. Toxicity consisted of moderate stomatitis and myelosuppression. The sustained remissions obtained by 4 of 21 patients (18%) treated with concurrent mitomycin C, 5-fluorouracil and x-irradiation are encouraging and deserve further study.

Adenocarcinoma↗
PubMed1992

Lys-373 of actin is involved in binding to caldesmon.

Limited proteolysis of actin with trypsin removes its two or three C-terminal amino acid residues [Proc. Natl. Acad. Sci. USA 81 (1984) 3680-3684]. Carboxypeptidase B-treatment of G- and F-actin previously digested with trypsin revealed that in the first case preferential release of three and in the second two C-terminal amino acid residues takes place. Tryptic removal of three but not two C-terminal amino acid residues of actin causes weakening of its interaction with caldesmon and lowering of the caldesmon-induced inhibitory effect on actomyosin ATPase activity. Therefore, it is concluded that the third amino acid residue from the C terminus of actin, Lys-373, is important for the interaction with caldesmon.

Actins↗
PubMed1992

The importance of C-terminal amino acid residues of actin to the inhibition of actomyosin ATPase activity by caldesmon and troponin I.

Proteolytic elimination of three C-terminal amino acid residues from actin weakens its interaction with caldesmon and troponin I and, in consequence, lowers the inhibitory effects of both proteins on actomyosin ATPase activity. These results prove the importance of C-terminal extremity of actin to the overall interaction of this protein with caldesmon and troponin I.

Actins↗
PubMed1992

Evidence that dyslexia may represent the lower tail of a normal distribution of reading ability.

BACKGROUND: Dyslexia is now widely believed to be a biologically based disorder that is distinct from other, less specific reading problems. According to this view, reading ability is considered to follow a bimodal distribution, with dyslexia as the lower mode. We hypothesized that, instead, reading ability follows a normal distribution, with dyslexia at the lower end of the continuum. METHODS AND RESULTS: We used data from the Connecticut Longitudinal Study, a sample survey of 414 Connecticut children who entered kindergarten in 1983 and were followed as a longitudinal cohort. Dyslexia was defined in terms of a discrepancy score, which represents the difference between actual reading achievement and achievement predicted on the basis of measures of intelligence. Data were available from intelligence tests administered in grades 1, 3, and 5 and achievement tests administered yearly in grades 1 through 6. For each child there were 108 possible discrepancy scores ([3 x 3 years] x [2 x 6 years]) based on combinations of the ability scores (full-scale, verbal, and performance IQ) in each of three years and two achievement scores (reading and mathematics) in each of six years. We demonstrated that each of the discrepancy scores followed a univariate normal distribution and that the interrelation of two different discrepancy scores followed a bivariate normal distribution. At most, only 9 of 108 discrepancy scores (8.3 percent) and 171 of 3402 pairs of discrepancy scores (5.0 percent) were significantly different (at the 5 percent level) from the expected scores--well within the expected values for data with univariate and bivariate normal distributions, respectively. We also examined the stability of dyslexia over time. The normal-distribution model predicted (and the data indicated) that only 7 of the 25 children (28 percent) classified as having dyslexia in grade 1 would also be classified as having dyslexia in grade 3. CONCLUSIONS: Reading difficulties, including dyslexia, occur as part of a continuum that also includes normal reading ability. Dyslexia is not an all-or-none phenomenon, but like hypertension, occurs in degrees. The variability inherent in the diagnosis of dyslexia can be both quantified and predicted with use of the normal-distribution model.

Child↗
PubMed1992

A model-based prediction for transvaginal ultrasonographic identification of early intrauterine pregnancy.

OBJECTIVE: Our objective was to develop a mathematic model for the prediction of transvaginal ultrasonographic identification of intrauterine gestation as a function of human chorionic gonadotropin titer or gestational age. STUDY DESIGN: In this prospective, descriptive study normal intrauterine pregnancies of 31 patients from the Yale in vitro fertilization and embryo transfer program and infertility clinic were studied. Logistic regression analysis was used to develop a probability curve of transvaginal ultrasonographic detection of intrauterine pregnancy as a function of human chorionic gonadotropin titer or gestational age with a 5 MHz vaginal transducer. RESULTS: A model-based prediction was constructed. It revealed that nearly all intrauterine sacs should be identified by a human chorionic gonadotropin titer of 3000 mIU/ml (first international reference preparation) or by a gestational age of 37 days on the basis of the 5 MHz vaginal transducer. CONCLUSIONS: A model-based prediction for transvaginal ultrasonographic identification of early intrauterine pregnancy is presented that can be readily adapted by individual institutions using their own ultrasonographic equipment and human chorionic gonadotropin assay.

Chorionic Gonadotropin↗
PubMed1991

Functional interrelationship between calponin and caldesmon.

Calponin and caldesmon, constituents of smooth-muscle thin filaments, are considered to be potential modulators of smooth-muscle contraction. Both of them interact with actin and inhibit ATPase activity of smooth- and skeletal-muscle actomyosin. Here we show that calponin and caldesmon could bind simultaneously to F-actin when used in subsaturating amounts, whereas each one used in excess caused displacement of the other from the complex with F-actin. Calponin was more effective than caldesmon in this competition: when F-actin was saturated with calponin the binding of caldesmon was eliminated almost completely, whereas even at high molar excess of caldesmon one-third of calponin (relative to the saturation level) always remained bound to actin. The inhibitory effects of low concentrations of calponin and caldesmon on skeletal-muscle actomyosin ATPase were additive, whereas the maximum inhibition of the ATPase attained at high concentration of each of them was practically unaffected by the other one. These data suggest that calponin and caldesmon cannot operate on the same thin filaments. CA(2+)-calmodulin competed with actin for calponin binding, and at high molar excess dissociated the calponin-actin complex and reversed the calponin-induced inhibition of actomyosin ATPase activity.

Actins↗
PubMed1991

High-dose cisplatin plus dacarbazine in the treatment of metastatic melanoma.

The combination of cisplatin plus dacarbazine (DTIC) is active in metastatic melanoma with response rates reported between 10% and 55%. To optimize this regimen, a Phase II study was conducted employing a dose intensity of cisplatin higher than previously reported. Twenty-two patients were treated. Eight patients received cisplatin 100 mg/m2 on days 1 and 8 combined with DTIC 300 mg/m2 on days 1, 2, 8 and 9 (regimen A). Because of excessive toxicity, the protocol was modified so that cisplatin was given at 50 mg/m2 per day and DTIC 350 mg/m2 per day on days 1 through 3 (regimen B). The overall response rate was 32% and consisted of four partial and three complete responses (CR). The median duration of response was 6 months. Two of the CR remain in sustained, unmaintained remission in excess of 1.5 years. All seven patients that responded were treated on regimen B. High-dose cisplatin plus DTIC on a 3-day schedule represents an effective, well-tolerated therapy for metastatic melanoma.

Adult↗
PubMed1991

A phase II trial of cyclosporin A in the treatment of refractory metastatic colorectal cancer.

Cyclosporin A (CSA) is an immunosuppressive agent that in experimental models has antiproliferative activity against colon cancer and other human neoplasms. A phase II trial was conducted to evaluate CSA in refractory colorectal malignancies. CSA was administered at a starting dose of 7.0 mg/kg twice daily (total dose, 14 mg/kg/day) and escalated to tolerance. Of 18 patients with measurable disease, 17 were evaluable. All had been treated with one fluorouracil-containing regimen. The European Cooperative Oncology Group (ECOG) performance status was 0 or 1 in 17 of the 18 patients. No objective responses were seen. Four patients maintained stable disease lasting from 10 to 75+ weeks. Significant toxicity occurred in 9 of 17 (53%) patients. Dose reduction was necessary in 10 of 17 (59%). Sustained escalation beyond the initial dose was possible in only two cases. Toxicities included nausea and vomiting (71%), nephrotoxicity (41%), fatigue (35%), flu-like symptoms (29%), and neurotoxicity (18%). In the dose and schedule employed in this trial, CSA is ineffective in refractory colorectal cancer and produces significant toxicity.

Bone Neoplasms↗
PubMed1990

Efficacy of adjuvant chemotherapy for patients with resectable head and neck cancer: a subset analysis of the Head and Neck Contracts Program.

To evaluate the efficacy of adjuvant chemotherapy for patients with advanced head and neck squamous cancer, the Head and Neck Contracts Program conducted a three-arm study comparing standard surgery and radiation, induction chemotherapy (cisplatin and bleomycin) plus standard therapy, and induction chemotherapy plus standard therapy followed by maintenance cisplatin for 6 months. As previously reported, this trial of 462 patients demonstrated no significant difference in disease-free survival or survival, but a significantly lower metastatic rate in the maintenance arm. To determine whether particular subgroups may have benefited from adjuvant therapy, we evaluated results based on primary site, and tumor (T) and node (N) stage. Of the 192 patients with oral cavity cancer, those on the maintenance arm had a significantly improved 3-year disease-free survival (67%) compared with the standard arm (49%) or induction arm (44%) (overall P = .05). For hypopharyngeal and laryngeal cancers there was no marked overall benefit. For the 106 patients with T1 plus T2 disease, there was marginal improvement in disease-free survival for the maintenance group (72%) compared with the standard group (47%) or induction group (43%) (overall P = .09). There was no advantage for patients with T3 and T4 disease. There was superior disease-free survival for patients with N1 disease on the maintenance arm (70%) compared with the standard arm (42%) (P = .024). The same was true for disease-free survival in 109 patients with N2 disease: standard (52%), induction (30%), maintenance (84%) (overall P less than .001). There was no benefit for N3 disease. A significant survival advantage with maintenance chemotherapy was only seen for N2 disease (overall P = .04). Since head and neck cancer patients are a heterogeneous group, there may be particular sites and stages for which adjuvant chemotherapy would be advantageous, and subset analysis can help indicate directions for new trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Location of the calmodulin- and actin-binding domains at the C-terminus of caldesmon.

Digestion of caldesmon with carboxypeptidase Y is accompanied by loss of its ability to inhibit actomyosin ATPase activity and to bind actin and calmodulin. Similarly, carboxypeptidase Y digestion of a terminal 40 kDa chymotryptic fragment of caldesmon abolishes its inhibition of the actomyosin ATPase and binding to actin and calmodulin. This represents the first direct demonstration that these functional domains of caldesmon are located close to the carboxy-terminus of the molecule.

Actins↗
PubMed1989

Issues in planning and interpreting active control equivalence studies.

Active control equivalence studies, with the goal of demonstrating therapeutic equivalence between a new and an active control treatment, are becoming more widespread due to current therapies that reflect previous successes in the development of new treatments. Because ethical requirements preclude the use of a placebo or no-treatment control for internal study validation, certain methodologic issues arise in active control equivalence trials that require special attention. We emphasize a special feature of this alternative study design, namely, its reliance on an implicit "historical control assumption". To conclude that a new drug is efficacious on the basis of an active control equivalence study (ACES) requires a fundamental assumption that the active control drug would have performed better than a placebo, had a placebo been used in the trial. In designing an ACES, one needs some assurance that historical estimates of the active control drug's efficacy relative to placebo are applicable to the new experimental setting. Steps that can be taken to compile such evidence and to justify the use of an active control equivalence design are described. These issues are illustrated in the context of a planned study to evaluate the efficacy of a new drug for the prevention of stroke, using aspirin as an active control.

Adult↗
PubMed1988

A prospective randomized trial of HLA-matched versus mismatched single-donor platelet transfusions in cancer patients.

The use of histocompatability antigen (HLA)-matched platelets has been advocated for the support of thrombocytopenic cancer patients. We randomized 78 newly diagnosed cancer patients prospectively (before thrombocytopenia) to receive either HLA-matched or mismatched single-donor platelet transfusions. Three hundred forty-one platelet transfusions were given for 80 separate episodes of therapy-induced thrombocytopenia in 33 patients. Forty-five patients receiving intensive chemotherapy did not develop significant (less than 20,000 platelets/mm3) thrombocytopenia and did not receive a platelet transfusion. No marked difference was observed between the matched and mismatched groups in regard to number of total platelet transfusions per patient (median, 3 vs. 5, respectively; P = 0.076), number of platelet transfusions per episode (median, 3.0 vs. 3.5, respectively; P = 0.28), or days between transfusions (median, 2 vs. 2, respectively, P greater than 0.4). Bleeding episodes, although rare, tended to be of increased severity in the mismatched group. Febrile patients receiving mismatched platelets tended to have a lower posttransfusion increment increase than their nonfebrile counterparts (P = 0.068), although a similar trend could not be demonstrated between febrile and nonfebrile patients who received matched platelets (P = 0.22). Patients treated as outpatients had significantly higher posttransfusion increments than when transfused as inpatients when they were given mismatched platelets (P less than 0.0005). Development of antiplatelet antibody did not appear to affect response to platelet transfusions. Only one patient developed sustained high-level antibody titers. In patients where thrombocytopenia was significant, the transfusion of HLA-matched platelets did not appear to offer a significant advantage. However, HLA-matched platelet transfusions tended to be associated with higher posttransfusion increments in febrile patients and a trend toward fewer severe bleeding episodes. A multi-institution trial containing a large number of patients is needed to evaluate trends observed in this study.

Adolescent↗
PubMed1987

Evaluation of circulating malignant cells provides prognostic information in cutaneous T cell lymphoma.

Peripheral blood lymphocyte morphology was evaluated prospectively by light microscopy of blood smears and E rosette preparations in 160 patients with cutaneous T cell lymphoma (CTCL). Blood involvement was related to the type of cutaneous T-stage, being present in 90% of patients with erythroderma (T4), 27% of those with cutaneous tumors (T3), 9% of those with generalized (T2), and 0% of those with limited skin plaques (T1). Untreated patients with blood involvement (38 of 105) had a higher frequency of CTCL in lymph nodes and viscera and survival inferior to that of patients with normal or nondiagnostic lymphocyte morphology (P less than .001). Multivariate analysis showed skin stage and age to be the most important pretreatment risk factors for survival. Although blood involvement was not an independent risk factor for the entire group, it appeared to have some adverse influence in the T2/T3 subsets (P = .051). Both lymphocytosis and size distribution of the circulating CTCL cells at initial diagnosis influenced survival. Patients with "mixed cell" cytology (greater than 20% large [greater than 11 microns] CTCL cells), had a worse survival than those with predominantly small circulating CTCL cells (P = .009). The former were more likely to have aggressive features, including lymph node effacement by tumor (P less than .001) and visceral disease (P = .074), than were "small cell" patients. Our data indicate that detailed review of the blood lymphocyte morphology in patients with diagnosed or suspected CTCL is helpful in predicting extent of disease and prognosis.

Age Factors↗
PubMed1985

Histopathologic grading of squamous cell carcinoma of the uterine cervix. An evaluation of 70 stage Ib patients.

Multiple histopathologic parameters were evaluated to determine which were of prognostic value in predicting patient outcome. Seventy patients with clinical stage Ib squamous cell carcinoma constituted the study population. The patients were primarily treated by surgery, with actuarial survival rates of 76%, 68%, and 57% at 5-, 10-, and 15-year intervals. Eight of 57 patients (14%) with lymph node material available for review had pelvic lymph node metastases and a decreased survival rate (P less than 0.001). Thirty-six patients had 5 mm or less depth of tumor invasion in their hysterectomy specimen and a 5-year survival rate of 94%. Thirty patients had greater than 5 mm of invasion in resected uteri and a 5-year survival rate of 58% (P = 0.007). None of the patients with less than 5 mm of invasion died of their disease. Evaluation of nine histologic parameters in the initial biopsy specimens demonstrated that only vascular invasion (lymphatic and/or capillary) predicted a poor outcome (P = 0.046). Cell size, inflammatory response, degree of keratinization, or any of the other histologic parameters tested failed to demonstrate significant prognostic value in this study.

Adult↗