Toll and Toll-like receptor signalling in development

The membrane receptor Toll and the related Toll-like receptors (TLRs) are best known for their universal function in innate immunity. However, Toll/TLRs were initially discovered in a developmental context, and recent studies have revealed that Toll/TLRs carry out previously unanticipated functions in development, regulating cell fate, cell number, neural circuit connectivity and synaptogenesis. Furthermore, knowledge of their molecular mechanisms of action is expanding and has highlighted that Toll/TLRs function beyond the canonical NF-kappa B pathway to regulate cell-to-cell communication and signalling at the synapse. Here, we provide an overview of Toll/TLR signalling and discuss how this signalling pathway regulates various aspects of development across species

Mathematical Model of the Transmission Dynamics of Genital Elephantiasis (Lymphatic Filariasis)

This thesis presents a deterministic compartmental model, developed and analyzed to investigate the dynamics of lymphatic filariasis disease, through mosquito-borne infection. The model is in eight compartments: five for the human population and three for the mosquito population based on the microfilariae and antibody levels. The existence of the invariant region where the model is epidemiologically feasible and the positivity of the solution were established. The existence of Disease-free equilibrium (DFE) and the Endemic equilibrium (EE) were determined. Stability analysis of the disease-free equilibrium was investigated via the threshold parameter (reproduction number Ro) obtained using the next generation matrix technique. The model was found to be locally asymptotically stable when the basic reproduction number is less than unity for both special and non special case. It was also revealed that the disease is endemic when Ro > 1. It was proved through Lyapunov method that the DFE and EE are globally asymptotically stable. Simulation analysis was also carried out and it was shown that even when all lymphatic filariasis cases displaying elephantiasis symptoms are put on treatment it will not be able to eradicate the disease. This result suggests that effective control of lymphatic filariasis may lie in treatment for those displaying symptoms. It was also shown that if on the long run as the biting rate of the Mosquitoes increases, the infected population increases. Then as biting rate decreases, then the chronic infected individuals are completely eradicated from the population while the highly infected humans are reduced.  The simulation also showed the impact of the effectiveness of treatment on the chronic infected humans, where we see that the population reduces rigorously until we get to a period of 70 days and then begins to increase again. This shows that the treatment strategies are not effective or perfect. Hence there are chances of fail in treatment. Furthermore our analysis shows that on a long run the trend continues indefinitely. Key words: Genital Elephantiasis, Mathematical Modeling, Lymphatic filariasis, Endemic Equilibrium (EE

Pancreaticobiliary Malignancies in the Emergency Room: Management of Acute Complications and Oncological Emergencies

Background Management of pancreaticobiliary (PB) malignancies remains a clinical challenge. In this review, we focus on the management of oncological emergencies in PB malignancies and the potential complication of associated therapeutic interventions. Methods Biobliographic review of current evidence on the management of oncological emergencies, their potential complications, as well as synthesis of recommendations was performed. The pathogenesis, frequency, related symptoms as well as appropriate investigations are presented. Results The oncologic emergencies in PB patients were summarised in six categories: (1) hematological (including febrile neutropaenia, thrombocytopenia, coagulopathies), (2) gastrointestinal (gastric outlet and biliary obstruction, gastrointestinal bleeding), (3) thromboembolic events, (4) ascites, (5) metabolic disorders and (6) neurologic complications. The pathogenesis, frequency, related symptoms as well as appropriate investigations are also presented. Conclusion Patients with PB malignancies are at increased risk of a wide variation of medical emergencies. Clinical knowledge, early recognition and collaboration with the relevant specialties are critical to manage these complications effectively, tailoring overall management around the actual prognosis and individuals’ expectations

Silencing of caveolin-1 in fibroblasts as opposed to epithelial tumor cells results in increased tumor growth rate and chemoresistance in a human pancreatic cancer model

Caveolin‑1 (Cav‑1) expression has been shown to be associated with tumor growth and resistance to chemotherapy in pancreatic cancer. The primary aim of this study was to explore the significance of Cav‑1 expression in pancreatic cancer cells as compared to fibroblasts in relation to cancer cell proliferation and chemoresistance, both in vitro and in vivo, in an immunodeficient mouse model. We also aimed to evaluate the immunohistochemical expression of Cav‑1 in the epithelial and stromal component of pancreatic cancer tissue specimens. The immunohistochemical staining of poorly differentiated tissue sections revealed a strong and weak Cav‑1 expression in the epithelial tumor cells and stromal fibroblasts, respectively. Conversely, the well‑differentiated areas were characterized by a weak epithelial Cav‑1 expression. Cav‑1 downregulation in cancer cells resulted in an increased proliferation in vitro; however, it had no effect on chemoresistance and growth gain in vivo. By contrast, the decreased expression of Cav‑1 in fibroblasts resulted in a growth advantage and the chemoresistance of cancer cells when they were co‑injected into immunodeficient mice to develop mixed fibroblast/cancer cell xenografts. On the whole, the findings of this study suggest that the downregulation of Cav‑1 in fibroblasts is associated with an increased tumor proliferation rate in vivo and chemoresistance. Further studies are warranted to explore whether the targeting of Cav‑1 in the stroma may represent a novel therapeutic approach in pancreatic cancer

Multicentre phase II pharmacokinetic and pharmacodynamic study of OSI-7904L in previously untreated patients with advanced gastric or gastroesophageal junction adenocarcinoma

A two-stage Simon design was used to evaluate the response rate of OSI-7904L, a liposome encapsulated thymidylate synthase inhibitor, in advanced gastric and/or gastroesophageal adenocarcinoma (A-G/GEJA), administered intravenously at 12 mg m−2 over 30 min every 21 days. Fifty patients were treated. Median age was 64 years (range 35–82), 62% were male and 89% had ECOG PS of 0/1. A total of 252 cycles were administered; median of 4 per patient (range 1–21). Twelve patients required dose reductions, mainly for skin toxicity. Investigator assessed response rate was 17.4% (95% CI 7.8–31.4) with one complete and seven partial responses in 46 evaluable patients. Twenty-one patients (42%) had stable disease. Median time to progression and survival were 12.4 and 36.9 weeks, respectively. NCI CTCAE Grade 3/4 neutropenia (14%) and thrombocytopenia (4%) were uncommon. The main G3/4 nonhaematological toxicities were skin-related 22%, stomatitis 14%, fatigue/lethargy 10%, and diarrhea 8%. Pharmacokinetic data showed high interpatient variability. Patients with higher AUC were more likely to experience G3/4 toxicity during cycle 1 while baseline homocysteine did not predict toxicity. Response did not correlate with AUC. Elevations in 2′-dU were observed indicating target inhibition. Analysis of TS genotype, TS protein and expression did not reveal any correlation with outcome. OSI-7904L has activity in A-G/GEJA similar to other active agents and an acceptable safety profile

Phase I study of TP300 in patients with advanced solid tumors with pharmacokinetic, pharmacogenetic and pharmacodynamic analyses

Background: A Phase I dose escalation first in man study assessed maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended Phase II dose of TP300, a water soluble prodrug of the Topo-1 inhibitor TP3076, and active metabolite, TP3011. <p/>Methods: Eligible patients with refractory advanced solid tumors, adequate performance status, haematologic, renal, and hepatic function. TP300 was given as a 1-hour i.v. infusion 3-weekly and pharmacokinetic (PK) profiles of TP300, TP3076 and TP3011 were analysed. Polymorphisms in CYP2D6, AOX1 and UGT1A1 were studied and DNA strand-breaks measured in peripheral blood mononuclear cells (PBMCs). <p/>Results: 32 patients received TP300 at 1, 2, 4, 6, 8, 10, 12 mg/m2. MTD was 10 mg/m2; DLTs at 12 (2/4 patients) and 10 mg/m2 (3/12) included thrombocytopenia and febrile neutropenia; diarrhea was uncommon. Six patients (five had received irinotecan), had stable disease for 1.5-5 months. TP3076 showed dose proportionality in AUC and Cmax from 1--10 mg/m2. Genetic polymorphisms had no apparent influence on exposure. DNA strand-breaks were detected after TP300 infusion. <p/>Conclusions: TP300 had predictable hematologic toxicity, and diarrhea was uncommon. AUC at MTD is substantially greater than for SN38. TP3076 and TP3011 are equi-potent with SN38, suggesting a PK advantage

Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC): A phase I dose escalating safety study and randomised dose expansion of AZD8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophagogastric adenocarcinoma

Background: AZD8931 has equipotent activity against epidermal growth factor receptor, erbB2, and erbB3. Primary objectives were to determine the recommended phase II dose (RP2D) of AZD8931 + chemotherapy, and subsequently assess safety/preliminary clinical activity in patients with operable oesophagogastric cancer (OGC). Methods: AZD8931 (20 mg, 40 mg or 60 mg bd) was given with Xelox (oxaliplatin + capecitabine) for eight 21-day cycles, continuously or with intermittent schedule (4 days on/3 off every week; 14 days on/7 off, per cycle) in a rolling-six design. Subsequently, patients with OGC were randomised 2:1 to AZD8931 + Xelox at RP2D or Xelox only for two cycles, followed by radical oesophagogastric surgery. Secondary outcomes were safety, complete resection (R0) rate, six-month progression-free survival (PFS) and overall survival. Results: During escalation, four dose-limiting toxicities were observed among 24 patients: skin rash (1) and failure to deliver 100% of Xelox because of treatment-associated grade III-IV adverse events (AEs) (3: diarrhoea and vomiting; vomiting; fatigue). Serious adverse events (SAE) occurred in 15 of 24 (63%) patients. RP2D was 20-mg bd with the 4/3 schedule. In the expansion phase, 2 of 20 (10%) patients in the Xelox + AZD8931 group and 5/10 (50%) patients in the Xelox group had grade III–IV AEs. Six-month PFS was 85% (90% CI: 66%–94%) in Xelox + AZD8931 and 100% in Xelox alone. Seven deaths (35%) occurred with Xelox + AZD8931 and one (10%) with Xelox. R0 rate was 45% (9/20) with Xelox + AZD8931 and 90% (9/10) with Xelox-alone (P = 0.024). Conclusion: Xelox + AZD8931 (20 mg bd 4/3 days) has an acceptable safety profile administered as neoadjuvant therapy in operable patients with OGC. (Trial registration: EudraCT 2011-003169-13, ISRCTN-68093791)

A Phase I/II Trial of Oral SRA737 (a Chk1 Inhibitor) Given in Combination with Low-Dose Gemcitabine in Patients with Advanced Cancer.

PURPOSE: This was a Phase I/II trial of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737 given in combination with gemcitabine. Its objectives were to establish the safety profile, recommended Phase 2 dose (RP2D), pharmacokinetics profile, and clinical activity of SRA737. PATIENTS AND METHODS: Patients with advanced solid tumors were enrolled into dose-escalation cohorts and treated in 28-day cycles with oral SRA737 on days 2, 3, 9, 10, 16, and 17, and intravenous gemcitabine on days 1, 8, and 15. Treatment was continued until progression. Each expansion cohort included up to 20 patients with specific genetically defined tumors. RESULTS: The RP2D was determined to be 500 mg SRA737 combined with low-dose (250 mg/m2) gemcitabine. Of 143 enrolled patients, 77 were treated at doses of at least 500 mg SRA737 combined with 250 mg/m2 gemcitabine. Common toxicities of nausea, vomiting, fatigue, and diarrhea were primarily mild to moderate, and rarely led to treatment discontinuation. Anemia, neutropenia, and thrombocytopenia were grade ≥3 in 11.7%, 16.7%, and 10% of patients treated at the RP2D, respectively. The objective response rate (ORR) was 10.8% overall and notably the ORR in anogenital cancer was 25%. Partial tumor responses were observed in anogenital cancer, cervical cancer, high-grade serous ovarian cancer, rectal cancer, and small cell lung cancer. CONCLUSIONS: SRA737 in combination with low-dose gemcitabine was well tolerated with lower myelotoxicity than has been seen at standard doses of gemcitabine or with other combinations of Chk1 inhibitors with gemcitabine. Tumor responses were observed in anogenital and other solid tumors

Quality of life, long-term survivors and long-term outcome from the ABC-02 study.

Background The ABC-02 (Advanced Biliary Tract Cancer) study established cisplatin and gemcitabine (CisGem) as the standard first-line chemotherapy for patients with locally advanced or metastatic biliary tract cancer (BTC). We examine quality of life (QoL), describe the long-term survivors and provide a long-term outcome.Methods A total of 410 BTC patients were randomised to receive either CisGem or gemcitabine alone (Gem); 324 patients consented to complete EORTC QLQ-C30 and EORTC QLQ-PAN26 QoL questionnaires; 268 (83%) patients returned at least one QoL questionnaire (134 in each arm). Long-term survivors were defined as those surviving over 2 years and we performed a final analysis of the primary outcome; overall survival (OS).Results Most QoL scales showed a trend favouring the combined CisGem arm, including functional and symptomatic scales, although the differences were not statistically significant. Forty-five (11%)) patients survived at least 2 years (34 received CisGem and 11 Gem) and 21 (5%) 3 years or more (14 received CisGem and 7 Gem). After a median follow-up of 9.2 months and 398 deaths, the median OS was 11.7 months for CisGem and 8.1 months for Gem (hazard ratio (HR)=0.65, 95% CI: 0.53-0.79, P<0.001).Conclusions The survival advantage of CisGem compared to Gem was not associated with an improvement or deterioration of QoL. Long-term survivors were more likely to have received CisGem and the long-term OS is identical to that previously described

The Journal of Nutrition Nutrition and Disease Tart Cherry Juice Decreases Oxidative Stress in Healthy Older Men and Women 1-3

Abstract Compared with young adults, older adults have significantly impaired capacities to resist oxidative damage when faced with acute stress such as ischemia/reperfusion. This impairment likely contributes to increased morbidity and mortality in older adults in response to acute trauma, infections, and the susceptibility to diseases such as atherosclerosis, cancer, diabetes, and Alzheimer&apos;s disease. Consumption of foods high in polyphenols, particularly anthocyanins, have been associated with improved health, but the mechanisms contributing to these salutary effects remain to be fully established. This study tested the hypothesis that consumption of tart cherry juice containing high levels of anthocyanins improves the capacity of older adults to resist oxidative damage during acute oxidative stress. In a double-blind, placebo-controlled, crossover design, 12 volunteers [6 men and 6 women; age 69 6 4 y (61-75 y)] consumed in random order either tart cherry juice or placebo (240 mL twice daily for 14 d) separated by a 4-wk washout period. The capacity to resist oxidative damage was measured as the changes in plasma F 2 -isoprostane levels in response to forearm ischemia-reperfusion (I/R) before and after each treatment. The tart cherry juice intervention reduced the I/R-induced F 2 -isoprostane response (P , 0.05), whereas placebo had no significant effect. The tart cherry juice intervention also reduced basal urinary excretion of oxidized nucleic acids (8-hydroxy-29-deoxyguanosine, 8-hydroxyguanosine) (P , 0.05) but not urinary excretion of isoprostanes. These data suggest that consumption of tart cherry juice improves antioxidant defenses in vivo in older adults as shown by an increased capacity to constrain an oxidative challenge and reduced oxidative damage to nucleic acids