Patient-specific modeling of diffuse large B-cell lymphoma

Personalized medicine aims to tailor treatment to patients based on their individual genetic or molecular background. Especially in diseases with a large molecular heterogeneity, such as diffuse large B-cell lymphoma (DLBCL), personalized medicine has the potential to improve outcome and/or to reduce resistance towards treatment. However, integration of patient-specific information into a computational model is challenging and has not been achieved for DLBCL. Here, we developed a computational model describing signaling pathways and expression of critical germinal center markers. The model integrates the regulatory mechanism of the signaling and gene expression network and covers more than 50 components, many carrying genetic lesions common in DLBCL. Using clinical and genomic data of 164 primary DLBCL patients, we implemented mutations, structural variants and copy number alterations as perturbations in the model using the CoLoMoTo notebook. Leveraging patient-specific genotypes and simulation of the expression of marker genes in specific germinal center conditions allows us to predict the consequence of the modeled pathways for each patient. Finally, besides modeling how genetic perturbations alter physiological signaling, we also predicted for each patient model the effect of rational inhibitors, such as Ibrutinib, that are currently discussed as possible DLBCL treatments, showing patient-dependent variations in effectiveness and synergies

Confluence of geodesic paths and separating loops in large planar quadrangulations

We consider planar quadrangulations with three marked vertices and discuss the geometry of triangles made of three geodesic paths joining them. We also study the geometry of minimal separating loops, i.e. paths of minimal length among all closed paths passing by one of the three vertices and separating the two others in the quadrangulation. We concentrate on the universal scaling limit of large quadrangulations, also known as the Brownian map, where pairs of geodesic paths or minimal separating loops have common parts of non-zero macroscopic length. This is the phenomenon of confluence, which distinguishes the geometry of random quadrangulations from that of smooth surfaces. We characterize the universal probability distribution for the lengths of these common parts.Comment: 48 pages, 33 color figures. Final version, with one concluding paragraph and one reference added, and several other small correction

Success of Endoscopic Pharyngoesophageal Dilation after Head and Neck Cancer Treatment

To assess clinical success and safety of endoscopic pharyngoesophageal dilation after chemoradiation or radiation for head and neck cancer and to identify variables associated with dilation failure

Patient preference and acceptability of calcium plus vitamin D3 supplementation: a randomised, open, cross-over trial

Preference for a drug formulation is important in adherence to long-term medication for chronic illnesses such as osteoporosis. We investigated the preference for and acceptability of chewable tablet containing calcium and vitamin D (Calci Chew D3, Nycomed) compared to that of a sachet containing calcium and vitamin D3 (Cad, Will-Pharma). This open, randomised, cross-over trial was set up to compare the preference and acceptability of two calcium plus vitamin D3 formulations (both with 500 mg calcium and 400/440 IU vitamin D3), given twice a day in patients with osteoporosis. Preference and acceptability were assessed by means of questionnaires. Preference was determined by asking the question, which treatment the patient preferred, and acceptability was measured by scoring five variables, using rating scales. Of the 102 patients indicating a preference for a trial medication, 67% preferred the chewable tablet, 19% the sachet with calcium and vitamin D3, and 15% stated no preference. The significant preference for Calci Chew D3 (p < 0.0001) was associated with higher scores for all five acceptability variables. The two formulations were tolerated equally well. A significant greater number of patients considered the chewable tablet as preferable and acceptable to the sachet, containing calcium and vitamin D3. Trial registration: Current Controlled Trials ISRCTN18822358

Vitamin D and Systemic Lupus Erythematosus: Bones, Muscles, and Joints

Vitamin D3, or cholecalciferol, is the naturally occurring form of vitamin D that is converted in the skin and hydroxylated in the liver and kidney to the active form found in humans. The main role for vitamin D is calcium homeostasis, and low levels of vitamin D result in lower gastrointestinal absorption of calcium. Vitamin D is also critical for mineralization of bone tissue, muscle function, and coordination. Recent studies have found prevention of bone mass loss and reduction in falls and fractures in patients supplemented with vitamin D. A high percentage of systemic lupus erythematosus patients are reported to have insufficient or deficient levels of vitamin D. This paper reviews the biology of vitamin D, its role in calcium homeostasis, and how it contributes to the maintenance of bone, muscle, and joint function in older adults and individuals with systemic lupus erythematosus

Efficacy of different doses and time intervals of oral vitamin D supplementation with or without calcium in elderly nursing home residents

Summary: The effect of equivalent oral doses of vitamin D3 600 IU/day, 4200 IU/week and 18,000 IU/month on vitamin D status was compared in a randomized clinical trial in nursing home residents. A daily dose was more effective than a weekly dose, and a monthly dose was the least effective. Introduction: It is assumed that equivalent daily, weekly or monthly doses of vitamin D3 equally influence vitamin D status. This was investigated in a randomized clinical trial in nursing home residents. Methods: The study was performed in ten nursing homes including 338 subjects (76 male and 262 female), with a mean age of 84 (± SD 6.3 years). They received oral vitamin D3 either 600 IU/day, or 4200 IU/week, or 18,000 IU/month or placebo. After 4 months, calcium was added during 2 weeks, 320 mg/day or 640 mg/day or placebo. Outcome: serum levels of 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH) and bone turnover markers. Statistical approach: linear multilevel analysis. Results: At baseline, mean serum 25(OH)D was 25.0 nmol/L (SD 10.9), and in 98%, it was lower than 50 nmol/L. After 4 months, mean serum 25(OH)D levels increased to 62.5 nmol/L (after daily vitamin D3 69.9 nmol/L, weekly 67.2 nmol/L and monthly 53.1 nmol/L, P<0.001 between groups). Median serum PTH levels decreased by 23% (p<0.001). Bone turnover markers did not decrease. Calcium supplementation had no effect on serum PTH and bone turnover. Conclusion: Daily vitamin D was more effective than weekly, and monthly administration was the least effective. © 2007 International Osteoporosis Foundation and National Osteoporosis Foundation

An Asian viewpoint on the use of vitamin D and calcium in osteoporosis treatment: Physician and patient attitudes and beliefs

<p>Abstract</p> <p>Background</p> <p>Osteoporosis treatment guidelines recommend calcium and vitamin D supplementation for both prevention as well as treatment, however, compliance with these guidelines is often unsatisfactory. This study investigated the opinion of Asian physicians and Asian patients regarding vitamin D and calcium and patients' use of both.</p> <p>Methods</p> <p>Physicians selected from Malaysia, Taiwan, Philippines, Korea and Singapore were asked to grade the significance of vitamin D and calcium in the treatment of osteoporosis and their patients' use of these supplements. In addition, physicians recruited seven eligible osteoporotic women to answer a questionnaire to determine their use of vitamin D and calcium, and their attitudes and beliefs regarding these supplements.</p> <p>Results</p> <p>In total, 237 physicians and 1463 osteoporosis patients completed the questionnaire. The results revealed that 22% of physicians in Malaysia, 12% in Taiwan, 72% in the Philippines, 50% in Korea and 24% in Singapore rated the importance of vitamin D supplementation as being extremely important. For calcium, 27% of physicians in Malaysia, 30% in Taiwan, 80% in the Philippines, 50% in Korea and 38% in Singapore rated the importance as being extremely important. Forty-three percent of patients in Malaysia, 38% in Taiwan, 73% in the Philippines, 35% in Korea and 39% in Singapore rated the importance of vitamin D as being extremely important. For calcium, 69% of patients in Malaysia, 58% in Taiwan, 90% in the Philippines, 70% in Korea and 55% in Singapore rated the importance as being extremely important. In addition, results of the patient questionnaire revealed that only a very small number regularly took both supplements. In addition, the results indicated that, with the exception of patients from the Philippines, the majority of patients had no or infrequent discussion with their physician about vitamin D and calcium.</p> <p>Conclusions</p> <p>There is generally suboptimal appreciation by both physicians and patients of the importance of vitamin D and calcium for maintenance of bone health as reflected in the low number of patients who reported regularly taking these supplements. Recognition of this problem should translate to appropriate action to improve education for both physicians and patients, with a goal to increase use of these supplements among Asian patients with osteoporosis.</p