Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells

Only 40% of patients with advanced ovarian cancer survive more than 5 years. We have previously shown that pitavastatin induces regression of ovarian cancer xenografts in mice. To evaluate whether the response of ovarian cancer cells to pitavastatin is potentiated by farnesyl diphosphate synthase inhibitors or geranylgeraniol transferase I inhibitors, we evaluated combinations of pitavastatin with zoledronic acid, risedronate and GGTI-2133 in a panel of ovarian cancer cells. Pitavastatin (IC50 = 0.6-14 μM), zoledronic acid (IC50 = 21-57 μM), risedronate (IC50 > 100 μM) or GGTI-2133 (IC50 > 25 μM) inhibited the growth of ovarian cancer cell cultures. Combinations of pitavastatin with zoledronic acid displayed additive or synergistic effects in cell growth assays in 10 of 11 cell lines evaluated as well as in trypan blue exclusion, cellular ATP or caspase 3/7, 8 and 9 assays. Pitavastatin reduced levels of GGT-IIβ and the membrane localization of several small GTPases and this was potentiated by zoledronic acid. siRNA to GGT-Iβ and GGT-IIβ used in combination, but not when used individually, significantly increased the sensitivity of cells to pitavastatin. These data suggest that zoledronic acid, a drug already in clinical use, may be usefully combined with pitavastatin in the treatment of ovarian cancer

Lumbar Spinal Stenosis: The Reliability, Sensitivity and Specificity of the Nerve Root Sedimentation Sign

Introduction: This study is to evaluate the reliability, sensitivity and specificity of nerve root sedimentation sign (NRS) in our populations. The NRS is a radiological sign to diagnose lumbar spinal stenosis (LSS). It is claimed to be reliable with high sensitivity and specificity. Materials and Methods: A total of 82 MRI images from 43 patients in Group A (LSS) and 39 patients in Group B (non LSS) were analysed and compared for the presence of the NRS sign. Two assessors were used to evaluate intra and inter-assessor reliability of this sign based on 56 (33 patients, Group A and 23 patients, Group B). The findings were statistically analysed using SPSS software. Results: There was a significant association between spinal claudication and leg numbness with LSS (p<0.001 and Kappa=0.857, p<0.001). The inter-assessor reliability was also good (Kappa of 0.786, p<0.001). Conclusion: The NRS sign has high sensitivity and specificity for diagnosing LSS. The sign also has good intra and inter-assessor reliability

The Morphometric Study of Degenerative Lateral Canal Stenosis at L4-L5 and L5-S1 Using Magnetic Resonance Imaging (MRI): Feasibility Analysis for Posterior Surgical Decompression

This study was to evaluate the morphological features of degenerative spinal stenosis and adequacy of lateral canal stenosis decompression via unilateral and bilateral laminectomy. Measurements of facet joint angulation (FJA), mid facet point (MFP), mid facet point distance (MFPD), the narrowest point of the lateral spinal canal (NPLC) and the narrowest point of the lateral spinal canal distance (NPLCD) were performed. At L4L5 of the right and left side, the mean distance between the lateral border of the dura and MFP was 1.0 ± 0.2 cm and 1.0 ± 0.3cm respectively. The mean NPLC was seen at 0.7 ± 0.3 and 0.7 ± 0.3 cm cm from the dura. At L5S1 of the right and left side, the mean distance between the lateral border of the dura and MFP was 1.2± 0.2 and 1.3 ± 0.2 cm respectively. The mean NPLC was seen at 0.8 ± 0.4 and 0.9 ± 0.5 cm from the dura. Unilateral laminectomy may result in incomplete decompression

Isochondodendrine and 2[prime or minute]-norcocsuline: additional alkaloids from Triclisia subcordata induce cytotoxicity and apoptosis in ovarian cancer cell lines

Triclisia subcordata Oliv (Menispermeaceae) is used in herbal medicine for the treatment of cancer and other diseases in Africa. This study aims to isolate minor alkaloids present in this plant and assay their cytotoxic activities. Isochondodendrine and 2[prime or minute]-norcocsuline as two minor alkaloids together with the abundant cycleanine were isolated and identified by mass spectrometry and NMR spectroscopy. Both isochondodendrine and 2[prime or minute]-norcocsuline exhibited in vitro cytotoxicity in four ovarian cancer cell lines (A2780, IGROV-1, OVCAR-8, and OVCAR-4) with IC50 ranges of 3.5-17 [small mu ]M and 0.8-6.2 [small mu ]M respectively. These alkaloids showed mostly slightly weaker potencies when tested using normal human ovarian epithelial cells, IC50 = 10.5 +/- 1.2 [small mu ]M and 8.0 +/- 0.2 [small mu ]M for isochondodendrine and 2[prime or minute]-norcocsuline, respectively. The alkaloids induced apoptosis in ovarian cancer cells because they activated caspases 3/7, induced cleavage of PARP, increased the subG1 population in cell cycle analysis and increased Annexin V/propidium iodide staining. These observations suggest that isochondodendrine and 2[prime or minute]-norcocsuline contributing to the cytotoxic activity of T. subcordata may be suitable starting points for the future development of novel therapeutics to treat ovarian cancer

Hesitant Fuzzy Linguistic Analytic Hierarchical Process With Prioritization, Consistency Checking, and Inconsistency Repairing

Analytic hierarchy process (AHP), as one of the most important methods to tackle multiple criteria decision-making problems, has achieved much success over the past several decades. Given that linguistic expressions are much closer than numerical values or single linguistic terms to a human way of thinking and cognition, this paper investigates the AHP with comparative linguistic expressions. After providing the snapshot of classical AHP and its fuzzy extensions, we propose the framework of hesitant fuzzy linguistic AHP, which shows how to yield a decision for qualitative decision-making problems with complex linguistic expressions. First, the comparative linguistic expressions over criteria or alternatives are transformed into hesitant fuzzy linguistic elements and then the hesitant fuzzy linguistic preference relations (HFLPRs) are constructed. Considering that HFLPRs may be inconsistent, we conduct consistency checking and improving processes after obtaining priorities from the HFLPRs based on a linear programming method. Regarding the consistency-improving process, we develop a new way to establish a perfectly consistent HFLPR. The procedure of the hesitant fuzzy linguistic AHP is given in stepwise. Finally, a numerical example concerning the used-car management in a lemon market is given to illustrate the ef ciency of the proposed hesitant fuzzy linguistic AHP method.This work was supported in part by the National Natural Science Foundation of China under Grant 71771156, in part by the 2019 Sichuan Planning Project of Social Science under Grant SC18A007, in part by the 2019 Soft Science Project of Sichuan Science and Technology Department under Grant 2019JDR0141, and in part by the Project of Innovation at Sichuan University under Grant 2018hhs-43

Hospitality brand management by a score-based q-rung ortho pair fuzzy V.I.K.O.R. method integrated with the best worst method

Hospitality brand management is a primary concern in the hotel industry and the evaluation of brands can be considered as a decision-making problem with multiple criteria. The evaluation information of brands may be uncertain sometimes. The q-rung orthopair fuzzy set (q-R.O.F.S.), which represents the preference degree of a person from the positive and negative aspects, has turned out to be an efficient tool in depicting uncertainty and vagueness in the decision-making process. This article dedicates to presenting an integrated multiple criteria decision-making method with q-R.O.F.S.. Firstly, a score function of the q-R.O.F.S. is proposed to solve the deficiencies of two existing score functions. Then, a weight-determining method based on the additive consistency of the preference relation is developed. A decision-making method integrating the score function, the best worst method and the VIsekriterijumska optimizacija I KOmpromisno Resenje (V.I.K.O.R.) which means multiple criteria compromise optimisation in English) method is further proposed. Finally, a case study regarding the hospitality brand management is provided to show the applicability and validity of the proposed method

The poor design of clinical trials of statins in oncology may explain their failure – lessons for drug repurposing

Statins are widely used to treat hypercholesterolaemia. However, by inhibiting the production of mevalonate, they also reduce the production of several isoprenoids that are necessary for the function of small GTPase oncogenes such as Ras. As such, statins offer an attractive way to inhibit an “undruggable” target, suggesting that they may be usefully repurposed to treat cancer. However, despite numerous studies, there is still no consensus whether statins are useful in the oncology arena. Numerous preclinical studies have provided evidence justifying the evaluation of statins in cancer patients. Some retrospective studies of patients taking statins to control cholesterol have identified a reduced risk of cancer mortality. However, prospective clinical studies have mostly not been successful. We believe that this has occurred because many of the prospective clinical trials have been poorly designed. Many of these trials have failed to take into account some or all of the factors identified in preclinical studies that are likely to be necessary for statins to be efficacious. We suggest an improved trial design which takes these factors into account. Importantly, we suggest that the design of clinical trials of drugs which are being considered for repurposing should not assume it is appropriate to use them in the same way as they are used in their original indication. Rather, such trials deserve to be informed by preclinical studies that are comparable to those for any novel drug

Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer

Pre-clinical and retrospective studies of patients using statins to reduce plasma cholesterol have suggested that statins may be useful to treat cancer. However, prospective clinical trials have yet to demonstrate significant efficacy. We have previously shown that this is in part because a hydrophobic statin with a long half-life is necessary. Pitavastatin, the only statin with this profile, has not undergone clinical evaluation in oncology. The target of pitavastatin, hydroxymethylglutarate coenzyme-A reductase (HMGCR), was found to be over-expressed in all ovarian cancer cell lines examined and upregulated by mutated TP53, a gene commonly altered in ovarian cancer. Pitavastatin-induced apoptosis was blocked by geranylgeraniol and mevalonate, products of the HMGCR pathway, confirming that pitavastatin causes cell death through inhibition of HMGCR. Solvent extracts of human and mouse food were also able to block pitavastatin-induced apoptosis, suggesting diet might influence the outcome of clinical trials. When nude mice were maintained on a diet lacking geranylgeraniol, oral pitavastatin caused regression of Ovcar-4 tumour xenografts. However, when the animal diet was supplemented with geranylgeraniol, pitavastatin failed to prevent tumour growth. This suggests that a diet containing geranylgeraniol can limit the anti-tumour activity of pitavastatin and diet should be controlled in clinical trials of statins

Dilated Cardiomyopathy in a 2 Month-Old Infant: A Severe Form of Hypocalcemia With Vitamin D Deficient Rickets

Dilated cardiomyopathy, which mostly has an idiopathic etiology or is caused by genetic inheritance or infection, can cause irreversible congestive heart failure. Hypocalcemia is a rare etiology of reversible dilated cardiomyopathy. Here we report the case of a two-month-old girl with congestive heart failure who was diagnosed as having dilated cardiomyopathy secondary to hypocalcemia. After calcium and vitamin D replacement therapy, the patient showed a rapid reduction in hypocalcemic tetany and a rapid recovery of left ventricular function. The cause of the hypocalcemia was vitamin D deficient rickets. She was exclusively breast-fed as an infant, and her mother had a vitamin D deficiency and was diagnosed with osteomalacia

The usefulness of rapid diagnostic tests in the new context of low malaria transmission in zanzibar.

BACKGROUND\ud \ud We assessed if histidine-rich-protein-2 (HRP2) based rapid diagnostic test (RDT) remains an efficient tool for Plasmodium falciparum case detection among fever patients in Zanzibar and if primary health care workers continue to adhere to RDT results in the new epidemiological context of low malaria transmission. Further, we evaluated the performance of RDT within the newly adopted integrated management of childhood illness (IMCI) algorithm in Zanzibar.\ud \ud METHODS AND FINDINGS\ud \ud We enrolled 3890 patients aged ≥2 months with uncomplicated febrile illness in this health facility based observational study conducted in 12 primary health care facilities in Zanzibar, between May-July 2010. One patient had an inconclusive RDT result. Overall 121/3889 (3.1%) patients were RDT positive. The highest RDT positivity rate, 32/528 (6.1%), was found in children aged 5-14 years. RDT sensitivity and specificity against PCR was 76.5% (95% CI 69.0-83.9%) and 99.9% (95% CI 99.7-100%), and against blood smear microscopy 78.6% (95% CI 70.8-85.1%) and 99.7% (95% CI 99.6-99.9%), respectively. All RDT positive, but only 3/3768 RDT negative patients received anti-malarial treatment. Adherence to RDT results was thus 3887/3889 (99.9%). RDT performed well in the IMCI algorithm with equally high adherence among children <5 years as compared with other age groups.\ud \ud CONCLUSIONS\ud \ud The sensitivity of HRP-2 based RDT in the hands of health care workers compared with both PCR and microscopy for P. falciparum case detection was relatively low, whereas adherence to test results with anti-malarial treatment was excellent. Moreover, the results provide evidence that RDT can be reliably integrated in IMCI as a tool for improved childhood fever management. However, the relatively low RDT sensitivity highlights the need for improved quality control of RDT use in primary health care facilities, but also for more sensitive point-of-care malaria diagnostic tools in the new epidemiological context of low malaria transmission in Zanzibar.\ud \ud TRIAL REGISTRATION\ud \ud ClinicalTrials.gov NCT01002066