The Reach-Avoid Problem for Constant-Rate Multi-Mode Systems

A constant-rate multi-mode system is a hybrid system that can switch freely among a finite set of modes, and whose dynamics is specified by a finite number of real-valued variables with mode-dependent constant rates. Alur, Wojtczak, and Trivedi have shown that reachability problems for constant-rate multi-mode systems for open and convex safety sets can be solved in polynomial time. In this paper, we study the reachability problem for non-convex state spaces and show that this problem is in general undecidable. We recover decidability by making certain assumptions about the safety set. We present a new algorithm to solve this problem and compare its performance with the popular sampling based algorithm rapidly-exploring random tree (RRT) as implemented in the Open Motion Planning Library (OMPL).Comment: 26 page

Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity

MDM2–MDMX complexes bind the p53 tumor-suppressor protein, inhibiting p53's transcriptional activity and targeting p53 for proteasomal degradation. Inhibitors that disrupt binding between p53 and MDM2 efficiently activate a p53 response, but their use in the treatment of cancers that retain wild-type p53 may be limited by on-target toxicities due to p53 activation in normal tissue. Guided by a novel crystal structure of the MDM2–MDMX–E2(UbcH5B)–ubiquitin complex, we designed MDM2 mutants that prevent E2–ubiquitin binding without altering the RING-domain structure. These mutants lack MDM2's E3 activity but retain the ability to limit p53′s transcriptional activity and allow cell proliferation. Cells expressing these mutants respond more quickly to cellular stress than cells expressing wild-type MDM2, but basal p53 control is maintained. Targeting the MDM2 E3-ligase activity could therefore widen the therapeutic window of p53 activation in tumors

Phase I trial of oxaliplatin with fluorouracil, folinic acid and concurrent radiotherapy for oesophageal cancer

This dose escalation study was designed to determine the maximum tolerated dose (MTD) and recommended doses (RDs) of 5-fluorouracil (5FU), folinic acid and oxaliplatin (FOLFOX) with concomitant radiotherapy in inoperable/metastatic oesophageal squamous cell carcinoma or adenocarcinoma. Patients received three courses of LV5FU2 regimen (folinic acid 200 mg m−2, bolus 5FU 300–400 mg/m2, continuous infusion 5FU 400–600 mg m−2 on days 1 and 2) and escalating doses of oxaliplatin 50 to 100 mg m−2 on day 1 (FOLFOX). This regimen was repeated every 2 weeks, concomitant to a 50-gray radiotherapy per 5 weeks. Three more cycles were delivered after completion of radiation therapy. Three to six patients were allocated to each of the five dose levels until MTD was reached. Thirty-three patients were enroled and 21 had metastatic disease. Maximum tolerated dose was oxaliplatin 100 mg m−2, and continuous infusion 5FU was 600 mg m−2 day− (level 5). The most common toxicities were neutropenia, dysphagia and oesophagitis. The RDs were those of FOLFOX-4 regimen (oxaliplatin 85 mg m−2 and full doses of LV5FU2). The overall response was 48.5%, including 12% complete response. Response rate on primary tumour was 62.9%. This FOLFOX-4 regimen was reasonably well tolerated and effective in inoperable/metastatic oesophageal carcinoma and warrants additional investigation

Combined modality chemoradiation in elderly oesophageal cancer patients

We present a single institution experience with 5-FU, mitomycin-C based chemoradiation for the primary treatment of elderly patients with oesophageal cancer. Twenty-five patients with a median age of 77 years (range 66–88) with a diagnosis of stage II–III squamous cell or adenocarcinoma of the oesophagus were treated at Memorial Sloan Kettering from 1996 to 2001 with two cycles of concurrent 5-FU, mitomycin-C and 50.4 Gy. Owing to age and comorbidity, these patients were not considered surgical candidates. The Charlson comorbidity score was used to evaluate patient comorbidity. Nine patients (36%) experienced grade 3–4 haematologic toxicity. Of the 23 patients evaluable for response, 17 patients (68%) had a negative post-treatment endoscopy and CT scan without evidence of progressive disease. Eleven patients (44%) are alive and 10 (40%) remain without evidence of recurrent or progressive oesophageal cancer at a median follow-up of 35 months. The median overall survival was 35 months and 2-year survival 64%. There was no significant difference in overall survival between Charlson score ⩽2 and those with a score ⩾2 (P=0.10). Similar survival was observed for patients with adenocarcinoma or squamous carcinoma. Primary chemoradiation with two cycles of 5-FU, mitomycin-C, and 50.4 Gy in elderly patients is an active regimen with moderate toxicity, despite the advanced age and heavy comorbidity burden of this cohort. Patients with local/regional oesophageal cancer with adequate functional status should not be excluded from potentially curative treatment based on age alone

The complex X-ray spectrum of NGC 4507

XMM-Newton and Chandra/HETG spectra of the Compton-thin (NH 4x10^{23} cm^{-2}) Seyfert 2 galaxy, NGC 4507, are analyzed and discussed. The main results are: a) the soft X-ray emission is rich in emission lines; an (at least) two--zone photoionization region is required to explain the large range of ionization states. b) The 6.4 keV iron line is likely emitted from Compton-thick matter, implying the presence of two circumnuclear cold regions, one Compton-thick (the emitter), one Compton-thin (the cold absorber). c) Evidence of an Fe xxv absorption line is found in the Chandra/HETG spectrum. The column density of the ionized absorber is estimated to be a few x10^{22} cm^{-2}.Comment: accepted for publication in A&

Mucinous histology predicts for poor response rate and overall survival of patients with colorectal cancer and treated with first-line oxaliplatin- and/or irinotecan-based chemotherapy

The objective of this study was to investigate the efficacy of first-line chemotherapy containing irinotecan and/or oxaliplatin in patients with advanced mucinous colorectal cancer. Prognostic factors associated with response rate and survival were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. The population included 255 patients, of whom 49 (19%) had mucinous and 206 (81%) had non-mucinous colorectal cancer. The overall response rates for mucinous and non-mucinous tumours were 18.4 (95% CI, 7.5–29.2%) and 49% (95% CI, 42.2–55.8%), respectively (P=0.0002). After a median follow-up of 45 months, median overall survival for the mucinous patients was 14.0 months compared with 23.4 months for the non-mucinous group (hazard ratio (HR), 1.74; CI 95%, 1.27–3.31; P=0.0034). After adjustment for significant features by multivariate Cox regression analysis, mucinous histology was associated with poor overall survival (HR, 1.593, 95% CI, 1.05–2.40; P=0.0267), together with performance status ECOG 2, number of metastatic sites ⩾2, and peritoneal metastases. This retrospective analysis shows that patients with mucinous colorectal cancer have poor responsiveness to oxaliplatin/irinotecan-based first-line combination chemotherapy and an unfavourable prognosis compared with non-mucinous colorectal cancer patients

Electron Tomography of Fusiform Vesicles and Their Organization in Urothelial Cells

The formation of fusiform vesicles (FVs) is one of the most distinctive features in the urothelium of the urinary bladder. FVs represent compartments for intracellular transport of urothelial plaques, which modulate the surface area of the superficial urothelial (umbrella) cells during the distension-contraction cycle. We have analysed the three-dimensional (3D) structure of FVs and their organization in umbrella cells of mouse urinary bladders. Compared to chemical fixation, high pressure freezing gave a new insight into the ultrastructure of urothelial cells. Electron tomography on serial sections revealed that mature FVs had a shape of flattened discs, with a diameter of up to 1.2 µm. The lumen between the two opposing asymmetrically thickened membranes was very narrow, ranging from 5 nm to 10 nm. Freeze-fracturing and immunolabelling confirmed that FVs contain two opposing urothelial plaques connected by a hinge region that made an omega shaped curvature. In the central cytoplasm, 4–15 FVs were often organized into stacks. In the subapical cytoplasm, FVs were mainly organized as individual vesicles. Distension-contraction cycles did not affect the shape of mature FVs; however, their orientation changed from parallel in distended to perpendicular in contracted bladder with respect to the apical plasma membrane. In the intermediate cells, shorter and more dilated immature FVs were present. The salient outcome from this research is the first comprehensive, high resolution 3D view of the ultrastructure of FVs and how they are organized differently depending on their location in the cytoplasm of umbrella cells. The shape of mature FVs and their organization into tightly packed stacks makes them a perfect storage compartment, which transports large amounts of urothelial plaques while occupying a small volume of umbrella cell cytoplasm

Intensified concurrent chemoradiotherapy with 5-fluorouracil and irinotecan as neoadjuvant treatment in patients with locally advanced rectal cancer

This study aimed to evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy intensified with irinotecan in patients with locally advanced rectal cancer. Eligible patients had nonmetastatic disease at a locally advanced stage that made R0 resection and sphincter preservation uncertain. They received preoperative radiation over 6 weeks to 45 Gy and boost of 5.4 Gy and concurrent continuous infusion 5-fluorouracil 250 mg m−2 day−1 and weekly irinotecan 40 mg m−2. In all, 37 patients entered the study. T stage at baseline as determined by ultrasound was T2/T3/T4 in 2/19/16 patients; 31 patients had lymph node involvement. The predominant toxicity was diarrhoea (grade 3/4 in 10/2 patients). Haematologic toxicity and surgical complications were moderate. Among 36 patients undergoing surgery, 32 (89%) had R0 resection and 23 (64%) sphincter preservation. Pathologic complete response (pCR) was achieved in eight (22%) of 36 patients, and 10 patients (28%) had only microscopic residual disease. At 4 years, overall survival was 66%, disease-free survival 73%, local relapse rate 7%, and distant failure rate 24%. Extent of resection and postoperative nodal status were significant predictors of overall and disease-free survival. Intensified neoadjuvant chemoradiotherapy with irinotecan can be safely administered and results in a high pCR rate

Depression symptomatology and diagnosis: discordance between patients and physicians in primary care settings

<p>Abstract</p> <p>Background</p> <p>To examine the agreement between depression symptoms using an assessment tool (PHQ-9), and physician documentation of the same symptoms during a clinic visit, and then to examine how the presence of these symptoms affects depression diagnosis in primary care settings.</p> <p>Methods</p> <p>Interviewer administered surveys and medical record reviews. A total of 304 participants were recruited from 2321 participants screened for depression at two large urban primary care community settings.</p> <p>Results</p> <p>Of the 2321 participants screened for depression 304 were positive for depression and of these 75.3% (n = 229) were significantly depressed (PHQ-9 score ≥ 10). Of these, 31.0% were diagnosed by a physician with a depressive disorder. A total of 57.6% (n = 175) of study participants had both significant depression symptoms and functional impairment. Of these 37.7% were diagnosed by physicians as depressed. Cohen's Kappa analysis, used to determine the agreement between depression symptoms elicited using the PHQ-9 and physician documentation of these symptoms showed only slight agreement (0.001–0.101) for all depression symptoms using standard agreement rating scales. Further analysis showed that only suicidal ideation and hypersomnia or insomnia were associated with an increased likelihood of physician depression diagnosis (OR 5.41 P sig < .01 and (OR 2.02 P sig < .05 respectively). Other depression symptoms and chronic medical conditions had no affect on physician depression diagnosis.</p> <p>Conclusion</p> <p>Two-thirds of individuals with depression are undiagnosed in primary care settings. While functional impairment increases the rate of physician diagnosis of depression, the agreement between a structured assessment and physician elicited and or documented symptoms during a clinical encounter is very low. Suicidality, hypersomnia and insomnia are associated with an increase in the rate of depression diagnosis even when physician and self report of the symptom differ. Interventions that emphasize the use of routine structured screening of primary care patients might also improve the rate of diagnosis of depression in these settings. Further studies are needed to explore depression symptom assessment during physician patient encounter in primary care settings.</p

Berberine Radiosensitizes Human Esophageal Cancer Cells by Downregulating Homologous Recombination Repair Protein RAD51

Esophageal squamous cell carcinomas (ESCC) have poor prognosis. While combined modality of chemotherapy and radiotherapy increases survival, most patients die within five years. Development of agents that confer cancer cell-specific chemo- and radiosensitivity may improve the therapy of ESCC. We here reported the discovery of berberine as a potent radiosensitizing agent on ESCC cells. by RNA interference similarly radiosensitized the cancer cells, and, conversely, introduction of exogenous RAD51 was able to significantly counteract the radiosensitizing effect of berberine, thus establishing RAD51 as a key determinant in radiation sensitivity. We also observed that RAD51 was commonly overexpressed in human ESCC tissues, suggesting that it is necessary to downregulate RAD51 to achieve high radio- or chemotherapeutic efficacy of ESCC in clinic, because overexpression of RAD51 is known to confer radio- and chemoresistance.Berberine can effectively downregulate RAD51 in conferring radiosensitivity on esophageal cancer cells. Its clinical application as an adjuvant in chemotherapy and radiotherapy of esophageal cancers should be explored