Towards more drug-like proteomimetics: two-faced, synthetic α-helix mimetics based on a purine scaffold.

Mimicry of two faces of an α-helix might yield more potent and more selective inhibitors of aberrant, helix-mediated protein-protein interactions (PPI). Herein, we demonstrate that a 2,6,9-tri-substituted purine is capable of disrupting the Mcl-1-Bak-BH3 PPI through effective mimicry of key residues on opposing faces of the Bak-BH3 α-helix.

Evaluation of alloreactivity in kidney transplant recipients treated with antithymocyte globulin versus IL-2 receptor blocker.

Induction therapy is used in kidney transplantation to inhibit the activation of donor-reactive T cells which are detrimental to transplant outcomes. The choice of induction therapy is decided based on perceived immunological risk rather than by direct measurement of donor T-cell reactivity. We hypothesized that immune cellular alloreactivity pretransplantation can be quantified and that blocking versus depleting therapies have differential effects on the level of donor and third-party cellular alloreactivity. We studied 31 kidney transplant recipients treated with either antithymocyte globulin (ATG) or an IL-2 receptor blocker. We tested pre- and posttransplant peripheral blood cells by flow cytometry to characterize T-cell populations and by IFN-γ ELISPOT assays to assess the level of cellular alloreactivity. CD8(+) T cells were more resistant to depletion by ATG than CD4(+) T cells. Posttransplantation, frequencies of donor-reactive T cells were markedly decreased in the ATG-treated group but not in the IL-2 receptor blocker group, whereas the frequencies of third-party alloreactivity remained nearly equivalent. In conclusion, when ATG is used, marked and prolonged donor hyporesponsiveness with minimal effects on nondonor responses is observed. In contrast, induction with the IL-2 receptor blocker is less effective at diminishing donor T-cell reactivity.

A nonlinear contextually aware prompting system (N-CAPS) to assist workers with intellectual and developmental disabilities to perform factory assembly tasks: system overview and pilot testing.

PURPOSE: This paper presents a new cognitive assistive technology, nonlinear contextually aware prompting system (N-CAPS) that uses advanced sensing and artificial intelligence to monitor and provide assistance to workers with cognitive disabilities during a factory assembly task. METHODS: The N-CAPS system was designed through the application of various computer vision and artificial intelligence algorithms that allows the system to track a user during a specific assembly task, and then provide verbal and visual prompts to the worker as needed. A pilot study was completed with the N-CAPS solution in order to investigate whether it was an appropriate intervention. Four participants completed the required assembly task five different times, using the N-CAPS system. RESULTS: The participants completed all of the trials that they attempted with 85.7% of the steps completed without assistance from the job coach. Of the 85.7% of steps completed independently, 32.5% of these were completed in response to prompts given by N-CAPS. Overall system accuracy was 83.3%, the overall sensitivity was 86.2% and the overall specificity was 82.4%. CONCLUSIONS: The results from the study were positive in that they showed that this type of technology does have merit with this population. Implications for Rehabilitation It provides a concise summary of the importance of work in the lives of people with intellectual disabilities and how technology can support this life goal. It describes the first artificially intelligent system designed to support workers with intellectually disabilities. It provides evidence that individuals with intellectual disabilities can perform a work task in response to technology.

In vivo purging of bone marrow in children with poor-risk neuroblastoma for marrow collection and autologous bone marrow transplantation.

PURPOSE: To evaluate the following prospectively in poor-risk neuroblastoma (NBL) patients: (1) the feasibility and efficacy of in vivo purging of bone marrow; and (2) the outcome after autologous bone marrow transplantation (ABMT) when immunologically tumor-free, unpurged autografts were used. PATIENTS AND METHODS: Twenty-three children with poor-risk NBL were evaluated during induction chemotherapy by repeat bone marrow examinations, including aspirate, biopsy, and an immunofluorescence method using the anti-GD2 monoclonal antibody 3A7. Nineteen patients completed the program with surgery with or without local irradiation followed by ABMT. RESULTS: Autologous bone marrow grafts, both immunologically and cytologically clean, were obtained and used in 19 of 23 children. The overall 4-year disease-free survival of the 19 grafted children was 53%, with a toxic death rate of 16% and a posttransplant relapse rate of 37%. According to the in vivo purging efficacy of the 18 children with initial marrow disease, the following three groups were formed: patients with (1) perfect in vivo purging (n = 5); (2) eventually successful in vivo purging (n = 8); and (3) unsuccesful in vivo purging (n = 5). The 4-year DFS was 100%, 67%, and 0%, respectively (P < 0.001). The five patients with unsuccessful in vivo purging failed because of resistant/progressive bulky disease. CONCLUSION: In patients with poor-risk NBL, in vivo purging of bone marrow by conventional chemotherapy is feasible, can be monitored, and the purging efficacy during the first 3 months after diagnosis is a strong prognostic factor reflecting tumor responsiveness to therapy. Autografting with immunologically clean, unpurged marrows gives a DFS well comparable to previous studies using ex vivo purging.

Risk of subsequent malignant neoplasms among 1,641 Hodgkin's disease patients diagnosed in childhood and adolescence: a population-based cohort study in the five Nordic countries. Association of the Nordic Cancer Registries and the Nordic Society of Pediatric Hematology and Oncology.

PURPOSE: To assess the risk of subsequent malignant neoplasms among Hodgkin's disease patients diagnosed before 20 years of age in the five Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden). PATIENTS AND METHODS: There were 1,641 Hodgkin's disease patients identified through the national cancer registries since the 1940s or 1950s. The patients were monitored for 17,000 person-years until the end of 1991. Expected figures were derived from the age-specific incidence rates in each country and standardized incidence ratios (SIR) were calculated. RESULTS: A total of 62 subsequent neoplasms were diagnosed (SIR, 7.7; 95% confidence interval [CI], 5.9 to 9.9). The overall cumulative risk of subsequent neoplasms was 1.9% at the 10-year follow-up point, 6.9% at 20 years, and 18% at 30 years. There were 26 subsequent neoplasms among males (SIR, 6.5; 95% CI, 4.3 to 9.6) and 36 among females (SIR, 8.9; 95% CI, 6.2 to 12), of which 16 were breast cancers (SIR, 17; 95% CI, 9.9 to 28). High risks were seen for thyroid cancer (SIR, 33; 95% CI, 15 to 62), for secondary leukemia (SIR, 17; 95% CI, 6.9 to 35), and for non-Hodgkin's lymphoma (SIR, 15; 95% CI, 4.9 to 35). The relative risk increased from 3.3 (95% CI, 1.2 to 7.1) for Hodgkin's disease patients diagnosed in the 1940s and 1950s to 15 (95% CI, 7.4 to 27) in the 1980s. The highest risk of secondary leukemia (SIR, 68; 95% CI, 18 to 174) was seen among those diagnosed with Hodgkin's disease in the 1980s. CONCLUSION: Patients who survive Hodgkin's disease at a young age are at very high relative risk of subsequent malignant neoplasms throughout their lives. In particular, the high relative risk of breast cancer following Hodgkin's disease in the teenage years calls for enhanced activity for early diagnosis.

Pituitary size assessed with magnetic resonance imaging as a measure of growth hormone secretion in long term survivors of childhood cancer.

We investigated 37 long term survivors of childhood cancer to study the relationship among growth, GH secretion, and pituitary size. The median follow-up time after diagnosis was 13.2 yr. The pituitary gland was visualized with magnetic resonance imaging. Radiated patients (n = 25) had a reduced relative height and showed a greater reduction in relative height after diagnosis than nonradiated patients (n = 12). The patients had lower spontaneous nocturnal GH secretion than controls due to a reduced peak amplitude. Spontaneous GH secretion was lower in radiated patients than in nonradiated subjects. The patients had lower plasma insulin-like growth factor-I (IGF-I) and serum IGF-binding protein-3 (IGFBP-3) concentrations than the controls. Radiated subjects had decreased IGF-I and IGFBP-3 concentrations compared to nonradiated subjects. Half of the patients (20 of 37) evaluated with magnetic resonance imaging had a reduced pituitary size (pituitary height, < -2 SD score). Radiated subjects had smaller pituitary glands than nonradiated ones. Seventeen of 20 patients (85%) with reduced pituitary size had decreased nocturnal GH release. There was a positive correlation between nocturnal GH secretion, plasma IGF-I, and serum IGFBP-3 levels, on the one hand, and pituitary height, on the other. These results indicate that cranial radiation may result in tissue damage, leading to decreased pituitary size, reduced spontaneous GH secretion, and impaired linear growth. The finding of reduced IGF-I levels in both radiated and nonradiated patients combined with decreased IGFBP-3 concentrations in radiated patients, indicates that cytotoxic chemotherapy may induce hepatic damage resulting in decreased IGF-I synthesis.

Long-term survivors of childhood cancer have an increased risk of manifesting the metabolic syndrome.

Survivors of childhood cancer have been reported to have a severalfold increased risk of death from cardiovascular disease. A cluster of metabolic abnormalities, including obesity, insulin resistance, hyperinsulinemia, glucose intolerance, hypertension, and dyslipidemia, have been designated as forming a metabolic syndrome that is associated with increased cardiovascular mortality. We studied 50 survivors (23 males) of childhood cancer, aged 10.5-31.2 yr, an average of 12.6 yr (range, 7.9-21.3 yr) after their diagnosis and compared them with 50 age- and sex-matched controls for signs of the metabolic syndrome by examining clinical and anthropometric measures, serum lipid profile, and fasting plasma insulin and glucose concentrations. Spontaneous nocturnal GH secretion was also evaluated in the cancer survivors. The patients had increased relative weight (P = 0.03) and body fat mass (P < 0.001), decreased serum high density lipoprotein (HDL) cholesterol (P < 0.001), and a reduced ratio of HDL to total cholesterol (P = 0.01). Fasting plasma glucose and insulin levels were higher (P < 0.001 and P = 0.003, respectively) in the cancer survivors than in the controls. The patients had an increased risk [odds ratio (OR), 4.5; 95% confidence interval (CI), 1.3-15.8; P = 0.01] of obesity (relative weight, > 120%), fasting hyperinsulinemia ( > 111 pmol/L; OR, 3.0; 95% CI, 1.0-8.6; P = 0.04), and reduced HDL cholesterol ( < 1.07 mmol/L; OR, 7.9; 95% CI, 2.2 to 29.6; P < 0.001). A combination of obesity, hyperinsulinemia, and low HDL cholesterol was seen in eight cancer survivors (16%), but in none of the controls (P = 0.01). This high risk group was characterized by reduced spontaneous GH secretion (P = 0.02). Long term survivors of childhood cancer appear to have an increased risk of manifestations of the metabolic syndrome. Decreased GH secretion may contribute to these metabolic abnormalities.

An increased loading dose of ondansetron: a north european, double-blind randomised study in children, comparing 5 mg/m2 with 10 mg/m2.

A North European, randomised, double-blind study, comparing a loading-dose of ondansetron of 5 mg/m2 with 10 mg/m2, administered intravenously before highly emetogenic chemotherapy, was carried out in 187 chemotherapy-naïve children. In the first 24 h, both groups received further ondansetron intravenously at a dose of 5 mg/m2 8-hourly. Thereafter, ondansetron was given at an oral dose of 4 or 8 mg depending on the surface area of the child, three times a day and continued for at least 3 days after the last day of chemotherapy. There was no difference in the control of emesis between the two groups. Ondansetron provided good control of emesis and nausea on day 1 with 71-72% of patients experiencing two or fewer emetic episodes (complete or major responders) and 90-86% of patients reporting nausea as none or mild. There was also no difference in the efficacy of the treatment arms in the control of emesis and nausea on subsequent days of the study period. Both anti-emetic regimens were well-tolerated.

Decreased pituitary gland height after radiation treatment to the hypothalamic-pituitary axis evaluated by MR.

PURPOSE: To evaluate treatment-related changes in pituitary gland morphology after childhood cancer and to compare these findings with growth data. METHODS: Forty-three survivors of childhood cancer were evaluated by cranial MR imaging. Twenty-nine of the patients had received radiation therapy to the hypothalamic-pituitary axis with doses of 10 to 46 Gy. The height of the pituitary gland was measured from midline sagittal images and compared with age- and sex-matched controls. Pituitary gland heights were compared with body height standard deviation scores in patients. RESULTS: The patients who had received radiation therapy to the hypothalamic-pituitary axis had significantly smaller pituitary glands than patients in the nonirradiated group or their age- and sex-matched controls (mean, 3.5 mm versus 5.9 and 5.8 mm, respectively). They were also significantly shorter than patients in the nonirradiated group. CONCLUSION: Radiation therapy to the hypothalamic-pituitary area may lead to poor growth of the pituitary gland and short stature.

Aminoterminal propeptide of type III procollagen in cerebrospinal fluid. Variation with age and in childhood leukemia.

Analyses of the aminoterminal propeptide of type III procollagen (PIIINP) in the cerebrospinal fluid (CSF) of 55 children and five young adults without any structural central nervous system (CNS) lesion are reported. The concentration was age-dependent, in that infants and small children had quite high values, whereas the concentration remained relatively constant after the age of 1.5 years. The concentrations of PIIINP in the CSF of 44 children with acute lymphoblastic leukemia (ALL) were prospectively determined at the time of diagnosis and during treatment, since deposition of type III collagen is known to occur during fibroproliferative responses triggered by inflammation. Chemical arachnoiditis is known to be associated with intrathecal methotrexate therapy in children with leukemia. The mean concentration in these children at diagnosis (5.8 micrograms/l +/- SD 2.8 micrograms/l) did not differ from that in age-matched controls (6.7 micrograms/l +/- SD 3.2 micrograms/l). Depending on type of the disease, the children were treated according to two different protocols. PIIINP concentrations were significantly higher during the therapy phases which included intrathecally administered methotrexate (P less than 0.001) than at diagnosis of the disease. Corticosteroid treatments were always associated with a significant decrease in PIIINP concentrations (P less than 0.01 and P less than 0.001 in the two groups, respectively), irrespective of the therapy phase. The results suggest that an increase in PIIINP concentration in the CSF of children with ALL is an indicator of a fibroproliferative response in the arachnoid. Corticosteroids may repress this response and possibly also prevent the development of adhesions in the arachnoid.

Vincristine therapy for children with acute lymphoblastic leukemia impairs conduction in the entire peripheral nerve.

Somatosensory evoked potentials were measured prospectively in 38 children with acute lymphoblastic leukemia to evaluate the side effects of vincristine therapy on conduction of the peripheral nerves. Nineteen patients at standard risk received vincristine 12 mg/m2 during induction therapy and 19 patients at intermediate or high risk received 6 mg/m2 during induction therapy and an additional 6 mg/m2 during delayed intensification therapy. These latencies were compared with those of 38 age-, height-, and sex-matched controls. A prolongation in the peripheral conduction time of the posterior tibial nerve was found in the standard risk patients after induction compared with that of the controls, and a delay was found not only from the ankle to the popliteal fossa, but also from the popliteal fossa to the spinal cord (P < .01). The conduction times of the median nerve from the wrist to the plexus (P < .01) and from the wrist to the spinal cord (P < .01) were prolonged after delayed intensification therapy. There was a significant delay in the median and tibial nerve conduction between the intermediate and high risk patients and their controls after a total vincristine dose of 12 mg/m2. These delays were found along the entire length of the nerves, especially in the proximal part of the tibial nerve (P < .001).

The importance of regular dental treatment in patients with cyclic neutropenia. Follow-up of 2 cases.

Data on two patients with cyclic neutropenia are presented. They demonstrate that regular tooth care and professional dental treatment can prevent progressive periodontal breakdown but that neglecting oral hygiene soon leads to periodontal pathology. Regular, monthly professional removal of dental plaque and calculus, and rinsing with 0.2% chlorhexidine gluconate during neutropenia help maintain periodontal attachment level. The caries susceptibility and the apical periodontitis in the intact anterior tooth of the female patient indicate the possibility of cyclic neutropenia playing a role in caries and pulpal pathology.

Prevalence and location of enamel opacities in children after anti-neoplastic therapy.

The prevalence and location of enamel opacities was recorded in 37 subjects from low-fluoride areas who had received anti-neoplastic therapy and was compared with an equal number of healthy controls. All the patients had received combination chemotherapy for a malignant disease for at least 2 yr early on in their lives. These cases, and especially those with leukemia, had more opacities than the controls, although these opacities were mild in form. The results show that childhood cancer and/or the therapy provided for this can affect the developing dentition, involving all teeth in leukemia cases and the permanent teeth of the mixed dentition period in other cancer diseases.

Second malignant neoplasms after cancer in childhood or adolescence. Nordic Society of Paediatric Haematology and Oncology Association of the Nordic Cancer Registries.

OBJECTIVE: To assess the relative risk of developing a second malignant neoplasm in people with a diagnosis of cancer in childhood and adolescence. DESIGN: Register based follow up study. SETTING: Populations of Nordic countries. SUBJECTS: 30,880 people under the age of 20 with a first malignant neoplasm diagnosed during the period 1943-87. MAIN OUTCOME MEASURES: Relative and attributable risks of second malignant neoplasms by type of first cancer, age at first diagnosis, calendar period, sex, and country. Expected figures were based on the appropriate national incidence rates for cancer. RESULTS: 247 cases of second malignant neoplasms were observed in 238 patients, yielding a relative risk for cancer of 3.6 (95% confidence interval 3.1 to 4.1). The risk changed significantly from 2.6 in people first diagnosed during the 1940s and 1950s to 6.9 among cohort members included in the late 1970s and 1980s. Increases were observed for most types of cancer. Highest levels of the relative risk were seen during the 10 years immediately after first malignant diagnosis. The incidence of second malignant neoplasms attributable to the first cancer and associated treatments, however, showed a consistent rise throughout the 45 years of follow up. CONCLUSION: The estimated risks for a second malignant neoplasm were significantly lower than those found in most large hospital based studies but compatible with the results from a similar population based study in the United Kingdom. Extent of risk and cancer pattern were similar among the Nordic countries and are believed to be representative for a large part of the European population.

[Second cancer. Risk of a second malignant neoplasm in persons with cancer in childhood and adolescence]. / Sekundaer cancer. Risiko for sekundoer malign neoplasi hos personer med cancer i barne- og ungdomsår.

Cancer treatments in early life have in previous studies been associated in with high risks of developing a second malignant neoplasm. This study reports on the relative and attributable risks of second malignant neoplasms among 30,880 people under the age of 20, who had been identified in the files of any of the five Nordic cancer registers, 1943-1987. Overall, 247 cases of second malignant neoplasms were observed in 238 patients, yielding a relative risk for cancer of 3.6 (95% confidence interval 3.1-4.1). The risk changed significantly from 2.6 in people first diagnosed during the 1940s and 1950s to 6.9 among cohort members included in the late 1970s and 1980s. Highest levels of the relative risk were seen during the ten years immediately after first malignant diagnosis. The incidence of second malignant neoplasms attributable to the first cancer and associated treatments, however, showed a consistent rise throughout the 45 years of follow up. It was concluded that the estimated risks for second malignant neoplasms were significantly lower than those found in most large hospital based studies but compatible with the results from a similar population based study in the United Kingdom. Extent of risk and cancer pattern were similar among the Nordic countries and are believed to be representative for a large part of the European population.