Repurposing Synthetic Congeners of a Natural Product Aurone Unveils a Lead Antitumor Agent Inhibiting Folded P-Loop Conformation of MET Receptor Tyrosine Kinase.

A library of 24 congeners of the natural product sulfuretin were evaluated against nine panels representing nine cancer diseases. While sulfuretin elicited very weak activities at 10 µM concentration, congener 1t was identified as a potential compound triggering growth inhibition of diverse cell lines. Mechanistic studies in HCT116 colon cancer cells revealed that congener 1t dose-dependently increased levels of cleaved-caspases 8 and 9 and cleaved-PARP, while it concentration-dependently decreased levels of CDK4, CDK6, Cdc25A, and Cyclin D and E resulting in induction of cell cycle arrest and apoptosis in colon cancer HCT116 cells. Mechanistic study also presented MET receptor tyrosine kinase as the molecular target mediating the anticancer activity of compound 1t in HCT116 cells. In silico study predicted folded p-loop conformation as the form of MET receptor tyrosine kinase responsible for binding of compound 1t. Together, the current study presents compound 1t as an interesting anticancer lead for further development.

Positional scanning of natural product hispidol's ring-B: discovery of highly selective human monoamine oxidase-B inhibitor analogues downregulating neuroinflammation for management of neurodegenerative diseases.

Multifunctional molecules might offer better treatment of complex multifactorial neurological diseases. Monoaminergic pathways dysregulation and neuroinflammation are common convergence points in diverse neurodegenerative and neuropsychiatric disorders. Aiming to target these diseases, polypharmacological agents modulating both monoaminergic pathways and neuroinflammatory were addressed. A library of analogues of the natural product hispidol was prepared and evaluated for inhibition of monoamine oxidases (MAOs) isoforms. Several molecules emerged as selective potential MAO B inhibitors. The most promising compounds were further evaluated in vitro for their impact on microglia viability, induced production of proinflammatory mediators and MAO-B inhibition mechanism. Amongst tested compounds, 1p was a safe potent competitive reversible MAO-B inhibitor and inhibitor of microglial production of neuroinflammatory mediators; NO and PGE2. In-silico study provided insights into molecular basis of the observed selective MAO B inhibition. This study presents compound 1p as a promising lead compound for management of neurodegenerative disease.

Pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs as possible candidates against neglected tropical diseases (NTDs): identification of hit compounds towards development of potential treatment of Leishmania donovani.

A rational-based process was adopted for repurposing pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs bearing variable acyl chains, different stereochemical configuration and/or positional relationships. Structural features were highly influential on activity. Amongst, enantiomer 1e having 1,2-vicinal relationship for the -CH2O- and the N-acyl moieties, a saturated palmitoyl chain and an opposite stereochemical configuration to natural sphingolipids was the most potent hit compound against promastigotes showing IC50 value of 28.32 µM. The corresponding enantiomer 1a was 2-fold less potent showing a eudismic ratio of 0.54 in promastigotes. Compounds 1a and 1e inhibited the growth of amastigotes more potently relative to promastigotes. Amongst, enantiomer 1a as the more selective and safer. In silico docking study using a homology model of Leishmania donovani inositol phosphoceramide synthase (IPCS) provided plausible reasoning for the molecular factors underlying the found activity. Collectively, this study suggests compounds 1a and 1e as potential hit compounds for further development of new antileishmanial agents.

Sex differences in the association between stroke and bone mineral density in elderly Koreans: The Korean National Health and Nutrition Examination Survey, 2008-2010.

OBJECTIVES: The aim of this study was to investigate whether osteoporosis is more prevalent in elderly Korean people who have had a stroke and whether the association differs by sex. STUDY DESIGN: A total of 3806 elderly subjects (1951 men and 1855 women) from the Korea National Health and Nutrition Examination Survey were included in this study. Stroke history was determined by self-administered questionnaire. Bone mineral density (BMD) was measured at the lumbar spine, total hip, and neck of the femur using dual-energy X-ray absorptiometry. It was categorized as normal, osteopenia, or osteoporosis. RESULTS: In men who had had a stroke, the prevalence of osteoporosis was greater than that of both osteopenia and normal BMD, and the prevalence of osteopenia was greater than that of normal BMD (p<0.001). However, there were no significant differences in BMD level among women who had had a stroke. Men who had had a stroke undertook less vigorous exercise and moderate-or-vigorous exercise than did men who had not had a stroke (p=0.002 and 0.030, respectively). After adjusting for all covariates, the mean BMD at the lumbar spine, total hip and neck of the femur was lower in men who had had a stroke than in men who had not (p=0.034, 0.002, and 0.005, respectively). There were no significant differences in mean BMD at any of the three sites between women who had and women who had not had a stroke. CONCLUSION: Men who have had a stroke have a higher prevalence of osteopenia and osteoporosis, and have lower BMD at the total hip and femur neck than men who have not had a stroke.

A comparison of oxycodone and fentanyl in intravenous patient-controlled analgesia after laparoscopic hysterectomy.

BACKGROUND: We planned to compare the effect of intravenous oxycodone and fentanyl on post-operative pain after laparoscopic hysterectomy. METHODS: We examined 60 patients were randomized to postoperative pain treatment with either oxycodone (n = 30, Group O) or fentanyl (n = 30, Group F). The patients received 10 mg oxycodone/100 µg fentanyl with ketorolac 30 mg before the end of anesthesia and then continued with patient-controlled analgesia for 48 h postoperatively. RESULTS: The accumulated oxycodone consumption was less than fentanyl during 8, 24 and 48 h postoperatively. Numeric rating score of Group O showed significantly lower than that of Group F during 30 min, 2, 4, 8 and 24 h postoperatively. The incidences of adverse reactions were similar in the two groups, though the incidence of nausea was higher in the Group O during the 24 and 48 h postoperative period. CONCLUSIONS: Oxycodone IV-PCA was more advantageous than fentanyl IV-PCA for laparoscopic hysterectomy in view of accumulated oxycodone consumption, pain control and cost beneficial effect. However, patient satisfaction was not good in the group O compared to group F.

Reversible Pulmonary Arterial Hypertension Associated with Dasatinib for Chronic Myeloid Leukemia.

We describe two cases of pulmonary arterial hypertension (PAH) that occurred under dasatinib treatment and were resolved after dasatinib discontinuation. Two patients with chronic phase chronic myeloid leukemia (CML) were switched to dasatinib therapy because of hematological progress while receiving imatinib. These patients had New York Heart Association (NYHA) functional class II dyspnea with elevated right ventricular systolic pressure (RVSP), which progressed under dasatinib treatment. After dasatinib treatment was discontinued, subjective symptoms were improved to NYHA functional class I and the follow-up transthoracic Doppler echocardiography showed improved RVSP. Treatment with an alternate tyrosine kinase inhibitor was initiated and had been continued without development of dyspnea or elevation of RVSP. This report suggests that dasatinib can cause the reversible PAH, therefore, routine cardiopulmonary evaluation before and during treatment with dasatinib may be needed in CML patients with clinical manifestations.

Prognostic factors for outcomes of allogeneic stem cell transplantation in chronic phase chronic myeloid leukemia in the era of tyrosine kinase inhibitors.

The aim of this study was to estimate the prognostic factors for the outcomes of chronic myeloid leukemia (CML) patients receiving allogeneic stem cell transplantation (SCT) in chronic phase (CP) in the era of tyrosine kinase inhibitors (TKIs). Ninety-seven patients who underwent allogeneic SCT in CP were analyzed. Forty-seven were TKI-naïve at the time of transplant, and 50 received TKI(s) treatment before transplantation. After a median follow-up of 115.8 months, the 4-year overall survival and event-free survival were 80.4 and 58.8%, respectively. Multivariate analysis showed that there were no differences in survival outcomes based on prior TKI therapy. Older age was a prognostic factor for higher treatment-related mortality (TRM), and the type of graft source and younger age were associated with relapse, but prior TKI therapy and disease status at the time of transplant were not associated with either TRM or relapse. Additionally, a major molecular response at 1 month and an MR(4.5) at 3 months were important predictors of favorable long-term outcomes. This study demonstrates the prognostic factors for the outcomes of allogeneic SCT in CP CML and shows that survival outcomes were not affected by the administration of long-term multi-TKI treatment prior to transplantation.

Predictive factors for successful imatinib cessation in chronic myeloid leukemia patients treated with imatinib.

Although recent studies have suggested that cessation of imatinib (IM) in chronic myeloid leukemia patients can be associated with sustained response, further validation is needed to explore predictive factors. In a prospective, multicenter study, chronic phase patients were eligible for cessation of IM therapy after more than 3 years if they had no detectable BCR-ABL1 transcript for at least 2 years. A total of 48 patients with a median age of 47 years (19-74 years) were enrolled. Twenty patients received IM for post-transplant relapse. After a median follow-up of 15.8 months (1.4-28.2 months) after IM discontinuation, nine of the non-transplant group lost undetectable molecular residual disease (UMRD) and major molecular response (MMR), whereas none of the 20 patients in the transplant group experienced UMRD loss. Probabilities for sustained MMR and UMRD were 64.4% and 66.3% in the non-transplant group, respectively. Of nine patients re-treated with IM, eight patients re-achieved MMR at a median of 1.7 months (0.9-2.8 months). Seven of these patients re-achieved UMRD at a median of 5.6 months (2.8-12.1 months). Previous transplantation, IM duration, and UMRD duration were significantly associated with sustained molecular responses. Our data strongly suggest that immunological control contributes to sustained suppression of residual leukemia cell expansion and that IM can be safely discontinued in patients with post-transplant relapse.

The long-term clinical implications of clonal chromosomal abnormalities in newly diagnosed chronic phase chronic myeloid leukemia patients treated with imatinib mesylate.

The aim of this study was to evaluate the long-term clinical significance of an additional chromosomal abnormality (ACA), variant Philadelphia chromosome (vPh) at diagnosis, and newly developed other chromosomal abnormalities (OCA) in patients with chronic myeloid leukemia (CML) on imatinib (IM) therapy. Sequential cytogenetic data from 281 consecutive new chronic phase CML patients were analyzed. With a median follow-up of 78.6 months, the 22 patients with vPh (P = 0.034) or ACA (P = 0.034) at diagnosis had more events of IM failure than did the patients with a standard Ph. The 5-year overall survival (OS), event-free survival (EFS), and failure-free survival (FFS) rates for patients with vPh at diagnosis were 77.8%, 75.0%, and 53.3%, respectively; for patients with ACA at diagnosis, 100%, 66.3%, and 52.1%, respectively; and for patients with a standard Ph, 96.0%, 91.3%, and 83.7%, respectively. During IM therapy, eight patients developed an OCA, which had no impact on outcomes as a time-dependent covariate in our Cox proportional hazards regression models. This study showed that vPh was associated with poor OS and FFS and that ACA had adverse effects on EFS and FFS. In addition, no OCA, except monosomy 7, had any prognostic impact, suggesting that the development of OCA may not require a change in treatment strategy.

A comparison of sufentanil and fentanyl for patient-controlled epidural analgesia in arthroplasty.

BACKGROUND: The use of lipid soluble opioids such as fentanyl, alfentanil and sufentanil are recently on the increase for patient-controlled epidural analgesia (PCEA). In this study, the effects and adequate dose of sufentanil in arthroplasty were investigated. METHODS: Eighty patients scheduled for arthroplasty were enrolled for the study. Seventy-one patients (ASA physical status I-III) were randomly allocated into four groups. All groups received 0.1% ropivacaine through PCEA and each group received either fentanyl (group F: fentanyl 4 µg/ml) or sufentanil (group S1: sufentanil 0.5 µg/ml, group S2: sufentanil 0.75 µg/ml, and group S3: sufentanil 1.0 µg/ml). Postoperative pain scores were evaluated using VAS (visual analog scale, 0-10) and side effects such as hypotension, nausea/vomiting, pruritus and the degree of satisfaction were evaluated at 1, 6, 12, 24, 48 hours after surgery. RESULTS: Postoperative pain score (VAS) decreased gradually and the highest VAS score was recorded at 1 hour postoperative for all four groups. There were no differences in the degree of satisfaction and postoperative pain score between all groups. The incidence of pruritus was significantly lower in group S1 than in groups S2 and S3. CONCLUSIONS: The incidence of side effects were significantly lower in group S1 (0.1% ropivacaine plus sufentanil 0.5 µg/ml). Therefore, 0.5 µg/ml of sufentanil through PCEA is the recommended dose for postoperative pain control in arthroplasty.