Diallyl disulfide and diallyl trisulfide in garlic as novel therapeutic agents to overcome drug resistance in breast cancer

Breast cancer is one of the leading causes of cancer-related deaths in women worldwide. It is a cancer that originates from the mammary ducts and involves mutations in multiple genes. Recently, the treatment of breast cancer has become increasingly challenging owing to the increase in tumor heterogeneity and aggressiveness, which gives rise to therapeutic resistance. Epidemiological, population-based, and hospital-based case-control studies have demonstrated an association between high intake of certain Allium vegetables and a reduced risk in the development of breast cancer. Diallyl disulfide (DADS) and diallyl trisulfide (DATS) are the main allyl sulfur compounds present in garlic, and are known to exhibit anticancer activity as they interfere with breast cancer cell proliferation, tumor metastasis, and angiogenesis. The present review highlights multidrug resistance mechanisms and their signaling pathways in breast cancer. This review discusses the potential anticancer activities of DADS and DATS, with emphasis on drug resistance in triple-negative breast cancer (TNBC). Understanding the anticancer activities of DADS and DATS provides insights into their potential in targeting drug resistance mechanisms of TNBC, especially in clinical studies.     

脂联素对高脂饮食诱导的胰岛素抵抗子宫内膜癌裸鼠移植瘤生长的影响

目的 探讨脂联素对高脂饮食诱导裸鼠胰岛素抵抗子宫内膜癌移植瘤生长的影响。方法 40只裸鼠随机分成高脂组和普食组，每组20只，分别喂养高脂饲料（high-fat diet，HFD）和普通饲料（normal diet，ND），10周后测定裸鼠空腹血糖（fasting blood glucose，FBG）和空腹血胰岛素（fasting serum insulin，FINS）水平，计算胰岛素抵抗指数（HOMA-IR），建立胰岛素抵抗裸鼠模型。第11周接种子宫内膜癌HEC-1B细胞，待瘤体长至0.5 cm时，两组随机选取10只裸鼠腹腔注射脂联素（adiponectin，APN）分为HFD+APN组、ND+APN组；其余裸鼠分别注射0.9%氯化钠分为HFD组、ND组；14周后，测定各组血糖和血脂的代谢情况。结果 高脂组裸鼠10周后的平均体重、体长、FBG、FINS、HOMA-IR均大于普食组，糖耐量试验和胰岛素耐量试验结果显示血糖水平亦高于普食组（均P＜0.05）；接种子宫内膜癌HEC-1B细胞后均成瘤，建模成功。HFD+APN组和ND+APN组移植瘤平均重量和体积增长速度均分别低于HFD组和ND组（均P<0.05）。HFD组和HFD+APN组14周后的FINS、HOMA-IR、TC和TG均较ND组和ND+APN明显升高（均P<0.01），且HFD组明显高于HFD+APN组（均P<0.01）；HFD+APN组的血脂联素水平低于ND+APN组（P<0.01），HFD组则低于ND组（P<0.05）。结论 脂联素可改善高脂饮食导致的胰岛素抵抗，抑制子宫内膜癌移植瘤生长。     

社区获得性肺炎的中西医治疗研究进展

社区获得性肺炎(Community Acquired Pneumonia,CAP)是比较常见的院外肺部炎性疾病之一,随着细菌、支原体、衣原体等多种病原体的耐药率的上升,以及病患梯度的范围增加,CAP的发病率呈逐年上升的趋势,死亡率日益增高,导致医疗资源消耗巨大。目前临床上CAP的患者主要依靠经验性治疗。正确选择抗生素、减少病原体的耐药率,优化肺部炎症疾病的医疗方案,提高CAP临床治愈率已经成为临床医生当前面临的一项重大挑战。中药制剂具有广谱抗菌、调节免疫、不易耐药、简便价廉等特点,是解决上述难题的一个很好途径。     

FLT3 Inhibition in Acute Myeloid Leukemia

Mutations in the FLT3 receptor tyrosine kinase are the most frequently found mutations in acute myeloid leukemia (AML). Patients with FLT3 internal tandem duplication (ITD) mutations have poor prognoses. The approved FLT3 tyrosine kinase inhibitors (TKIs) midostaurin and gilteritinib improve survival in AML with FLT3 mutations. Multiple other FLT3 inhibitors are in clinical development. Patients frequently relapse after response to FLT3 inhibitors and the optimal use of FLT3 inhibitors in the upfront, relapse, and maintenance settings remain to be established. We will discuss the biology of FLT3, approved and investigational FLT3 inhibitors, resistance mechanisms, and emerging FLT3 TKI combination clinical trials.     

YES1 activation induces acquired resistance to neratinib in HER2‐amplified breast and lung cancers

Molecular‐targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan‐HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2‐positive breast cancer. However, acquired resistance of various cancers to molecular‐targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib‐resistant cell lines from HER2‐amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib‐resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1‐amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2‐targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.     

Buckling Resistance of Various Nickel-Titanium Glide Path Preparation Instruments in Dynamic or Static Mode

IntroductionThe aim of this study was to compare the buckling resistance of nickel-titanium (NiTi) instruments for glide path preparation depending on the test mode (static vs dynamic).MethodsThe conventional PathFile (PF; Dentsply Sirona, Ballaigues, Switzerland) and heat-treated ProGlider (PG, Dentsply Sirona) and WaveOne Gold Glider (WG, Dentsply Sirona) were evaluated. The instrument tips were placed in a small dimple prepared in an aluminum cube in a customized device. The file was then pushed in the axial direction at a 1.0-mm/s crosshead speed with rotation (dynamic mode) or without rotation (static mode). The dynamic mode of WG used its dedicated reciprocating rotation, whereas the others were rotated continuously at 300 rpm. The axial load and lateral buckling displacement were simultaneously measured. Data were analyzed statistically using 2-way analysis of variance (P = .05).ResultsThe buckling resistance in the dynamic mode was higher than in the static mode for PG and WG (P < .05), whereas PF was not influenced by test modes (P > .05). In the dynamic mode, the PG required the highest buckling load followed by PF and WG (P < .05). In the static mode, the WG showed the lowest load (P < .05). The dynamic mode showed significantly more upper level lateral buckling displacement than in the static mode (P < .05).ConclusionsWhen the glide path preparation instruments moved in the dynamic mode as in clinical situations, the buckling resistance of the heat-treated NiTi glide path instruments was higher than in the static condition. The heat-treated instruments may have better buckling resistance than the conventional NiTi instrument in clinical situations.     

Assessment of heavy metals by ICP-OES and their impact on insulin stimulating hormone and carbohydrate metabolizing enzymes

Arsenic (As) and cadmium (Cd) have recently emerged as major health concerns owing to their strong association with diabetes mellitus (DM). We aimed to investigate the heavy metals exposure towards incidence of DM at various enzymatic and hormonal levels. Additionally, association of As and Cd with Zinc (Zn, essential metal) was also evaluated. Spot urine samples were collected to assess As, Cd and Zn through ICP-OES. Serum was analyzed by assay method for fasting blood glucose, liver and renal function biomarkers. ELISA was performed to investigate the impact of heavy metals on HbA1c, α-amylase, DPP-IV, IGF-1, leptin, GSH, MDA, SOD, HDL, FFA, TG and interleukin (IL)-6. Association of heavy metals with DM was measured by odds ratio (OR) and level of significance was assessed by Chi-squared test. Unpaired student's t-test was used to compare DM-associated risk factors in heavy metals-exposed and unexposed participants. As and Cd were detectable in 75.4% and 83% participants with mean concentration of 75.5 ppb and 54.5 ppb, respectively. For As exposure, OR in the third quartile was maximum ie 1.34 (95% CI, 0.80 to 2.23), however the result was not statistically significant (P > .05). For Cd exposure, OR in the fourth quartile was considerably high, 1.62 (95% CI, 1.00 to 2.61), with a significant probability value (P < .05). Urinary Cd was negatively associated with Zn. As and Cd exposure increases the incidence of DM in the general population. Impaired hormonal and enzymatic levels in diabetic and non-diabetic exposed participants reflect the multiple organ damage by heavy metal exposure.