Inducement of ER Stress by PAD Inhibitor BB-Cl-Amidine to Effectively Kill AML Cells.

OBJECTIVE: Acute myeloid leukemia (AML) is a highly heterogeneous and recurrent hematological malignancy. Despite the emergence of novel chemotherapy drugs, AML patients' complete remission (CR) remains unsatisfactory. Consequently, it is imperative to discover new therapeutic targets or medications to treat AML. Such epigenetic changes like DNA methylation and histone modification play vital roles in AML. Peptidylarginine deminase (PAD) is a protein family of histone demethylases, among which the PAD2 and PAD4 expression have been demonstrated to be elevated in AML patients, thus suggesting a potential role of PADs in the development or maintenance of AML and the potential for the identification of novel therapeutic targets. METHODS: AML cells were treated in vitro with the pan-PAD inhibitor BB-Cl-Amidine (BB-Cl-A). The AML cell lines were effectively induced into apoptosis by BB-Cl-A. However, the PAD4-specific inhibitor GSK484 did not. RESULTS: PAD2 played a significant role in AML. Furthermore, we found that BB-Cl-A could activate the endoplasmic reticulum (ER) stress response, as evidenced by an increase in phosphorylated PERK (p-PERK) and eIF2α (p-eIF2α). As a result of the ER stress activation, the BB-Cl-A effectively induced apoptosis in the AML cells. CONCLUSION: Our findings indicated that PAD2 plays a role in ER homeostasis maintenance and apoptosis prevention. Therefore, targeting PAD2 with BB-Cl-A could represent a novel therapeutic strategy for treating AML.

Resveratrol: Review on its discovery, anti-leukemia effects and pharmacokinetics.

Resveratrol, found in variety of plants, is a natural stilbene structure polyphenol. It has various pharmacological effects, such as antioxidation, anti-aging, anti-inflammation, anti-cancer, antiobesity, anti-diabetes, cardioprotection, neuroprotection. Recently, anti-leukemia activities of resveratrol has been studied extensively via its effects on a variety of biological processes involving cell proliferation, apoptosis, autophagy. Current treatments of leukemia mainly rely on intensive chemotherapy or hematopoietic stem cell transplantation, however, these treatments are still with poor survival and high treatment-related mortality. Therefore, it is extremely needed to find relatively non-toxic medicines with minimal side effects but sufficient therapeutic efficacy. Resveratrol is one such potential candidate owing to its reported anti-leukemia effect. In this review, we summarized resveratrol's discovery, sources and isolation methods, administration methods, effects in different types of leukemia, pharmacokinetics and toxicities, aiming to exploit resveratrol as a potential drug candidate for anti-leukemia.

Improving tuberculosis case detection in underdeveloped multi-ethnic regions with high disease burden: a case study of integrated control program in China.

BACKGROUND: In the underdeveloped multi-ethnic regions of China, high tuberculosis (TB) burden and regional inequity in access to healthcare service increase the challenge of achieving the End TB goals. Among all the provinces, the highest TB burden is reported in Xinjiang, where ethnic minorities and older people have suffered most. However, current case-finding strategy is inadequate given the complex social determinants and suboptimal case detection rates. Thus, we developed an integrated TB control program to improve case detection and conducted a pilot in Xinjiang from 2014 to 2015. In this case study, we summarized the activities and key findings. We also shared the experiences and challenges of implementing interventions and provided recommendations to inform the TB control program in the future. CASE PRESENTATION: The pilot interventions were implemented in one selected town in Yining based on local TB control programs. By applying tailor-made educational materials, outreach TB educational activities were conducted in diverse ways. In 22 Masjids, the trained imams promoted TB education to the Muslims, covering 20,440 person-times in 88 delivered preaching sessions. In seven schools, 1944 students were educated by the teachers and contributed to educating 6929 family members. In the village communities, 13,073 residents participated in household education and screening. Among them, 12,292 people aged under 65 years were investigated for suspicious pulmonary TB symptoms, where six TB patients were diagnosed out of 89 TB suspects; 781 older people were mobilized for screening directly by chest X-ray, where 10 patients were diagnosed out of 692 participants. Supportive healthcare system, multi-sectoral cooperation and multi-channel financing mechanism were the successful experiences of implementation. The interventions were proved to be more effective than the previous performance: the number of TB suspects consulting doctors and patients detected increased by 50% and 26%, respectively. The potential challenges, implications and recommendations should been taken into account for further program improvement. CONCLUSIONS: In underdeveloped multi-ethnic regions with high TB burden, improving case detection is necessary and the interventions can be feasible and effective within a supportive system. More intensive educational and training approaches, a high index of TB suspicion and prioritization of older people in screening are recommended. To sustain and scale up the program, the impacts, cost-effectiveness, feasibility and acceptability of interventions warrant further research and evaluation in each specific context.

Synthesis of new 4-anilinoquinazoline analogues and evaluation of their EGFR inhibitor activity.

Thirteen of 4-anilinoquinazoline derivatives with imine groups at position 6 of quinazoline ring were synthesized and their antitumor activities were evaluated by MTT assay and Western blotting analysis. Among these compounds, 13a-131 were reported first time. The MTT assay was carried out on three human cancer cell lines (A549, HepG2 and SMMC7721) with EGFR highly expressed. Among the tested compounds, 13i and 13j exhibited notable inhibition potency and their IC50 values on three cell lines were equivalent to or less than those of gefitinib. Compound 14, without imine group substituted, displayed excellent inhibitor potency only on A549 cell line. Compounds 14 and 13j were chosen to perform Western blotting analysis on A549. The results showed that both of the compounds could inhibit the expression level of phosphorylated EGFR remarkably. It was concluded that the inhibitor potency of compound 14 was almost equivalent to that of gefitinib and the inhibitor potency of 13j was better than that of gefitinib.

Benign giant-cell tumor of the common bile duct: a case report.

Primary giant-cell tumors rarely arise in the common bile duct. We herein report a case of primary giant-cell tumor of the common bile duct. The patient was an 81-year-old male who was diagnosed with a well-defined 1.2-cm mass projecting into the lumen of the middle common bile duct. Excision of the gallbladder and extrahepatic bile duct and a Roux-en-Y cholangiojejunostomy were performed. Histologically, the tumor had no association with carcinomas of epithelial origin and was similar to giant-cell tumors of the bone. The tumor consisted of a mixture of mononuclear and multinucleated osteoclast-like giant cells. The mononuclear cells showed no atypical features, and their nuclei were similar to those of the multinucleated giant cells. CD68 was expressed on the mononuclear and multinucleated osteoclast-like giant cells, whereas CD163 immunoreactivity was restricted to the mononuclear cells. Six months after the operation, the patient was still alive and had no recurrence. The interest of this case lies in the rarity of this entity, the difficulty of preoperative diagnosis, and this tumor's possible confusion with other malignant tumors.