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Purpose: Chk1 inhibitors, such as AZD7762, are in clinical development in combination with cytotoxic agents for the treatment of solid tumors, including pancreatic cancers. To maximize the likelihood of their clinical success, it is essential to optimize drug scheduling as well as pharmacodynamic biomarkers in preclinical models.Experimental Design: We tested multiple schedules of administration of gemcitabine and AZD7762 on the survival of pancreatic cancer cells. Potential pharmacodynamic biomarkers including pChk1, pChk2, pHistone H3, and caspase-3 were evaluated in vitro, followed by assessment of promising candidate biomarkers in vivo. We then went on to determine the contributions of PP2A and DNA damage to the mechanism(s) of induction of the identified biomarker, pS345 Chk1.Results: AZD7762 given during and after or after gemcitabine administration produced maximum chemosensitization. In vivo, AZD7762 significantly inhibited the growth of pancreatic tumor xenografts in response to gemcitabine. Of the biomarkers assessed, pS345 Chk1 was most consistently increased in response to gemcitabine and AZD7762 in tumors and normal tissues (hair follicles). pS345 Chk1 induction in response to gemcitabine and AZD7762 occurred in the presence of PP2A inhibition and in association with elevated γH2AX, suggesting that DNA damage is an underlying mechanism.Conclusions: AZD7762 sensitizes pancreatic cancer cells and tumors to gemcitabine in association with induction of pS345 Chk1. Together these data support the clinical investigation of AZD7762 with gemcitabine in pancreatic cancer under a dosing schedule in which gemcitabine is administered concurrent with or before AZD7762 and in conjunction with skin biopsies to measure pS345 Chk1. Clin Cancer Res; 17(11); 3706–15. ©2011 AACR.

Supplementary Figures S1-S5; Supplementary Tables S1-S2.

Supplementary Figures 1-3, Tables 1-3 from Mechanism of Radiosensitization by the Chk1/2 Inhibitor AZD7762 Involves Abrogation of the G2 Checkpoint and Inhibition of Homologous Recombinational DNA Repair

The median survival for patients with locally advanced pancreatic cancer treated with gemcitabine and radiation is approximately 1 year. To develop improved treatment, we have combined a Chk1/2-targeted agent, AZD7762, currently in phase I clinical trials, with gemcitabine and ionizing radiation in preclinical pancreatic tumor models. We found that in vitro AZD7762 alone or in combination with gemcitabine significantly sensitized MiaPaCa-2 cells to radiation. AZD7762 inhibited Chk1 autophosphorylation (S296 Chk1), stabilized Cdc25A, and increased ATR/ATM–mediated Chk1 phosphorylation (S345 Chk1). Radiosensitization by AZD7762 was associated with abrogation of the G2 checkpoint as well as with inhibition of Rad51 focus formation, inhibition of homologous recombination repair, and persistent γ-H2AX expression. AZD7762 was also a radiation sensitizer in multiple tumor xenograft models. In both MiaPaCa-2- and patient-derived xenografts, AZD7762 significantly prolonged the median time required for tumor volume doubling in response to gemcitabine and radiation. Together, our findings suggest that G2 checkpoint abrogation and homologous recombination repair inhibition both contribute to sensitization by Chk1 inhibition. Furthermore, they support the clinical use of AZD7762 in combination with gemcitabine and radiation for patients with locally advanced pancreatic cancer. Cancer Res; 70(12); 4972–81. ©2010 AACR.

Background IBD patients have an increased risk of reporting a colorectal cancer. According to SCENIC, endoscopic resection (ER) should be preferred to biopsies for visible precancerous lesions in absence of stigmata of invasive cancer or submucosal fibrosis. However, the evidence is still lacking on specific outcomes of ER for the management of dysplastic lesions in IBD. Aim of this study was to evaluate the effectiveness and safety of ER of visible precancerous lesions in IBD patients. Methods In this retrospective study, we included consecutive IBD patients referred to an Endoscopy Unit (2016-2022) to undergo a ER, including endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD) and hybrid EMR-ESD (hESD), of visible precancerous lesions. The primary outcome was the assessment of rates of en bloc resection, R0 resection and adverse events (AEs). The secondary outcome was the rate of post-ER surgery and surgery for refractory IBD. En bloc resection was defined as excision of the targeted lesion in a single specimen. R0 resection was defined as resection with lateral and deep margins free of dysplasia/neoplasia on histopathology. Among AEs, we considered bleeding and perforation. Results A total of 67 visible lesions (64.18% non-polypoid, 53.73% left-side colon, median size 25 mm±20 mm, 65.67% neoplastic pit-pattern) in 67 patients with colonic IBD (56.72% male, median age 58 yrs±15 yrs, 68.66% ulcerative colitis, median disease duration 160 months±98 months, 58.21% active disease) were included. ESD, hESD, and EMR was performed in 20.9%, 6%, and 73.1% of cases. The final histopathological diagnoses after ER were inflammatory polyp in 32.84%, SSL in 8.96%, LGD in 40.30%, HGD in 13.42%, adenocarcinoma in 2.99%, and squamous cell carcinoma in 1.49% of cases. Excluding inflammatory polyps, en bloc resection was achieved in 14/14(100%), 3/4(75%), and 15/27(55%) lesions in case of ESD, hESD, and EMR (ESD+hESD vs EMR p Conclusion Our findings showed that ER (including ESD, hESD, and EMR) of visible precancerous lesions performed in a tertiary center might be considered feasible, safe and effective in IBD patients, despite the presence of submucosal fibrosis. These data should be confirmed in a wider IBD population referring from different specialized Endoscopy Units.

Anopheles mosquitoes are the vectors of Plasmodium species, the causative agent of malaria, and a major cause of death in tropical Africa. The distribution of Anopheles species in time and space is a function of ecological factors in a given habitat. This study investigated the distribution of anopheles mosquitoes in the early wet season of 2017, in Keffi Area, Nasarawa State, Nigeria. Mosquito’s collection was carried out in four locations in the study area using two methods: Pyrethrum Spray Catch (PSC) and Centre for Disease Control (CDC) light traps. Indoor and outdoor mosquitoes were collected. All mosquitoes collected were morphologically identified using standard procedures. A total of 973 mosquitoes were collected and identified. This comprised culicines 742 (76%) and anophelines 231 (23%). There was a progressive increase in number of anophelines from April 93 (40.3%) to May 138 (59.2%). Four species of Anopheles mosquitoes were identified in the study area: An.gambiae 221 (95.7%). An.coustani 7 (3.0%), An.squamosus 2(0.9%) and An.pharoensis 1(0.4%).More Anopheles mosquitoes collected showed a statistical significant difference between the 2 months and between indoors and outdoors collection (P

Livestock and their products are the major source of animal protein. They also play a crucial role in the economy of most nations including Nigeria. However, parasitism presents a major constraint limiting livestock production in most developing countries. Therefore, this study is aimed at determining the prevalence of gastrointestinal parasites of commercial sheep and goats in Minna Abattoir, Niger Sate, Nigeria. A total of one hundred and sixty-eight (168) faecal samples were collected and analyzed for the presence of gastrointestinal parasites using saturated sodium chloride floatation techniques. An overall prevalence rate of 117 (69.64%) was recorded. Among the selected ruminants used, a prevalence rate of 48 (63.16%) and 69 (75.0%) was obtained for sheep and goats respectively. Seven (7) gastrointestinal parasites were detected; these were Strongyloides spp, Trichuris spp, Haemonchus spp., Eimeria spp., Taenia spp., Moniezia spp. and Fasciola spp. Among the parasite detected, Haemonchus spp. had the highest rate of infection 30 (25.6%) followed by Strongyloides spp. 23 (19.65%) while the least prevalence rate was recorded in Moniezia spp. 8 (6.8%). Overall, male ruminants were also more infected (Sheep: 64.44% and goats:77.78% than their females counterparts (sheep: 61.29% and goats: 71.05%). The older ruminants were more infected (sheep: 69.49% and goats: 73.91%). Chi–square analysis showed that there was no significant difference (p>0.05) on the infection rate in relation to gender and age. The results of this study suggest high prevalence of gastrointestinal parasitic infection among ruminants; therefore, effective control measures should be put in place to combat the despicable effects of gastrointestinal parasites on ruminants.

Background Advanced endoscopic technologies led to significant progress in the definition of endoscopic remission of ulcerative colitis (UC), and correlate better with histological changes, compared to standard endoscopy. However, whilst studies have assessed the diagnostic accuracy of endoscope technologies individually, there is current limited data comparing between technologies. As such, we aimed to compare the correlations between endoscopy and histology disease activity scores across endoscope technologies Methods We searched PubMed and Embase in January 2021 for eligible studies reporting the correlation between endoscopy and histology activity scores in UC. Studies were grouped by endoscope technology as standard-definition white light (SD-WLE), high-definition white light (HD-WLE), or electronic virtual chromoendoscopy (VCE), and comparisons made between these groups Results A total of N=27 studies were identified, of which N=12 were included in a meta-analysis of correlations between endoscopic and histological activity scores. Combining these returned a pooled correlation coefficient (rho) for the SD-WLE group of 0.61, which did not differ significantly from HD-WLE (rho: 0.79, p=0.140) or VCE (rho: 0.70, p=0.471) [Fig 1a]. In addition, N=4 studies reported the accuracy of endoscopic activity scores on WLE and VCE to diagnose histological remission. Pooling these found significantly higher accuracy for VCE, compared to WLE (risk ratio: 1.13, 95% CI: 1.07–1.19, p Conclusion Activity scores assessed using endoscopy are strongly correlated with activity on histology. VCE appears to have better accuracy for the diagnosis of histological remission in UC, compared to WLE.