Analysis of SIRT1 Gene SNPs and Clinical Characteristics in Medication-Related Osteonecrosis of the Jaw.

Certain genetic factors, including single-nucleotide polymorphisms (SNPs) in the SIRT1 gene, have been linked to medication-related osteonecrosis of the jaw (MRONJ). This study examined four SNPs in the SIRT1 gene and implemented multivariate statistical analysis to analyze genetic and clinical factors in MRONJ patients. Genomic DNA was isolated from peripheral blood samples of 63 patients of European origin treated for MRONJ, and four SNP genotypes in the gene encoding the SIRT-1 protein were determined by Sanger sequencing. The allele frequencies measured in the MRONJ population were compared with allele frequencies measured in the European population in the National Center for Biotechnology Information Allele Frequency Aggregator (NCBI ALFA) database. Genetic and clinical factors were examined with multivariate statistical analysis. A C:A allele distribution ratio of 77.8:22.2 was measured in the rs932658 SNP. In the ALFA project, a C:A allele distribution ratio of 59.9:40.1 was detected in the European population, which was found to be a significant difference (p = 4.5 × 10-5). Multivariate statistical analysis revealed a positive correlation (0.275) between the genotype of SNP rs932658 and the number of stages improved during appropriate MRONJ therapy. It is concluded that allele A in SNP rs932658 in the SIRT1 gene acts as a protective factor in MRONJ.

Novel family of [RuCp(N,N)(P)]+ compounds with simultaneous anticancer and antibacterial activity: Biological evaluation and solution chemistry studies.

A family of ten novel ruthenium(II)-cyclopentadienyl organometallics of general formula [Ru(η5-C5H5)(N,N)(PPh2(C6H4COOR)][CF3SO3] (1-10) in which (N,N) = 4,4'-R'-2,2'-bipyridyl (R = -H or -CH2CH2OH; R' = -H, -CH3, -OCH3, -CH2OH, and -CH2-biotin) was prepared from [Ru(η5-C5H5)(PPh2(C6H4COOH))2Cl]. All compounds were fully characterized by means of several spectroscopic and analytical techniques, and the molecular structures of [Ru(η5-C5H5)(PPh2(C6H4COOH))2Cl], 1, 3 and 4 have been additionally studied by single-crystal X-ray diffraction. The anticancer activity of all compounds was evaluated in sensitive and multidrug-resistant counterpart cell lines from human colorectal cancer (Colo 205 and Colo 320) and non-small cell lung cancer NSCLC (A549, NCI-H460 versus NCI-H460/R) as well. Notably, compounds 6 and 7 (R CH2CH2OH and (N,N) = bipy or Me2bipy, respectively) showed antiproliferative effect against both cell lines with high intrinsic selectivity towards cancer cells. The antibacterial activity of all compounds was also evaluated against both Gram negative and Gram positive strains, and some compounds in the series showed potent antibacterial activity against Staphylococcus aureus strains, including the methicillin-resistant MRSA strains. Solution speciation studies revealed that the complexes bearing the PPh2(C6H4COO-) ligand are neutral at physiological pH (7.4) in contrast with their ethylene glycol derivatives that have a permanent positive charge. While all compounds are lipophilic, the difference in the distribution coefficient for neutral and charged complexes is around one order of magnitude. Complexes 6 and 7 exhibited excellent biological activity and were selected for further studies. Spectrofluorometric methods were used to investigate their interaction with biomolecules such as human serum albumin (HSA) and calf thymus DNA (ct-DNA). For these complexes, binding site II of HSA is a possible binding pocket through non-covalent interactions. The release of ethidium from the DNA adduct by the charged complexes proves their interaction with DNA in contrast to the neutral ones. In conclusion, Ru(II)-cyclopentadienyl complexes with 2,2'-bipyridyl-derivatives and an ethylene glycol moiety tethered to the phenylphosphane co-ligand are very promising from a therapeutic perspective, in particular complexes 6 and 7 that display remarkable antibacterial activity with a high anti-proliferative effect against colon and non-small cell lung cancers, both clinically challenging neoplasias in need of effective solutions.

Radiation Exposure Reduction by Digital Variance Angiography in Lower Limb Angiography: A Randomized Controlled Trial.

BACKGROUND: digital variance angiography (DVA) provides higher image quality than digital subtraction angiography (DSA). This study investigates whether the quality reserve of DVA allows for radiation dose reduction during lower limb angiography (LLA), and compares the performance of two DVA algorithms. METHODS: this prospective block-randomized controlled study enrolled 114 peripheral arterial disease patients undergoing LLA into normal dose (ND, 1.2 µGy/frame, n = 57) or low-dose (LD, 0.36 µGy/frame, n = 57) groups. DSA images were generated in both groups, DVA1 and DVA2 images were generated in the LD group. Total and DSA-related radiation dose area product (DAP) were analyzed. Image quality was assessed on a 5-grade Likert scale by six readers. RESULTS: the total and DSA-related DAP were reduced by 38% and 61% in the LD group. The overall visual evaluation scores (median (IQR)) of LD-DSA (3.50 (1.17)) were significantly lower than the ND-DSA scores (3.83 (1.00), p < 0.001). There was no difference between ND-DSA and LD-DVA1 (3.83 (1.17)), but the LD-DVA2 scores were significantly higher (4.00 (0.83), p < 0.01). The difference between LD-DVA2 and LD-DVA1 was also significant (p < 0.001). CONCLUSIONS: DVA significantly reduced the total and DSA-related radiation dose in LLA, without affecting the image quality. LD-DVA2 images outperformed LD-DVA1, therefore DVA2 might be especially beneficial in lower limb interventions.

Possible use of Digital Variance Angiography in Liver Transarterial Chemoembolization: A Retrospective Observational Study.

PURPOSE: Digital variance angiography (DVA), a recently developed image processing technology, provided higher contrast-to-noise ratio (CNR) and better image quality (IQ) during lower limb interventions than digital subtraction angiography (DSA). Our aim was to investigate whether this quality improvement can be observed also during liver transarterial chemoembolization (TACE). MATERIALS AND METHODS: We retrospectively compared the CNR and IQ parameters of DSA and DVA images from 25 patients (65% male, mean ± SD age: 67.5 ± 11.2 years) underwent TACE intervention at our institute. CNR was calculated on 50 images. IQ of every image set was evaluated by 5 experts using 4-grade Likert scales. Both single image evaluation and paired image comparison were performed in a blinded and randomized manner. The diagnostic value was evaluated based on the possibility to identify lesions and feeding arteries. RESULTS: DVA provided significantly higher CNR (mean CNRDVA/CNRDSA was 1.33). DVA images received significantly higher individual Likert score (mean ± SEM 3.34 ± 0,08 vs. 2.89 ± 0.11, Wilcoxon signed-rank p < 0.001) and proved to be superior also in paired comparisons (median comparison score 1.60 [IQR:2.40], one sample Wilcoxon p < 0.001 compared to equal quality level). DSA could not detect lesion and feeding artery in 28 and 36% of cases, and allowed clear detection only in 22% and 16%, respectively. In contrast, DVA failed only in 8 and 18% and clearly revealed lesions and feeding arteries in 32 and 26%, respectively. CONCLUSION: In our study, DVA provided higher quality images and better diagnostic insight than DSA; therefore, DVA could represent a useful tool in liver TACE interventions. LEVEL OF EVIDENCE: III Non-consecutive study.

A comparative study on the metal complexes of an anticancer estradiol-hydroxamate conjugate and salicylhydroxamic acid.

Hydroxamic acids bearing an (O,O) donor set are well-known metal-chelating compounds with diverse biological activities including anticancer activity. Since steroid conjugation with a pharmacophoric moiety may have the potential to improve this effect, a salicylhydroxamic acid-estradiol hybrid molecule (E2HA) was synthesized. Only minimal effect of the conjugation on the proton dissociation constants was observed in comparison to salicylhydroxamic acid (SHA). The complexation with essential metal ions (iron, copper) was characterized, since E2HA may exert its cytotoxicity through the binding of these ions in cells. UV-visible spectrophotometric and pH-potentiometric titrations revealed the formation of high-stability complexes, while the Fe(III) preference over Fe(II) was proved by cyclic voltammetry and spectroelectrochemical measurements. Complex formation with half-sandwich Rh(III)(η5-Cp*) and Ru(II)(η6-p-cymene) organometallic cations was also studied as it may improve the anticancer effect and the pharmacokinetic profile of the ligand. At equimolar concentration the speciation is complicated because of the presence of mononuclear and binuclear complexes. The complexes readily react with small molecules e.g. glutathione, 1-methylimidazole and nucleosides, having major effect on solution speciation, namely mixed-ligand complex formation and ligand displacement occur. These processes serve as models for the interactions with biomolecules in the body. E2HA exerted moderate anticancer activity (IC50 = 25-59 µM) in the tested three human cancer cell lines (Colo205, Colo320 and MCF-7), while being non-toxic on non-cancerous MRC-5 cells. Meanwhile, SHA was inactive in the same cells. Complexation with half-sandwich Rh(III) and Ru(II) cations had only a minor improvement on the cytotoxic effect of E2HA.

Half-Sandwich Rhodium Complexes with Releasable N-Donor Monodentate Ligands: Solution Chemical Properties and the Possibility for Acidosis Activation.

Cancer chemotherapeutics usually have serious side effects. Targeting the special properties of cancer and activation of the anticancer drug in the tumor microenvironment in situ may decrease the intensity of the side effects and improve the efficacy of therapy. In this study, half-sandwich Rh complexes are introduced, which may be activated at the acidic, extracellular pH of the tumor tissue. The synthesis and aqueous stability of mixed-ligand complexes with a general formula of [Rh(η5-Cp*)(N,N/O)(N)]2+/+ are reported, where (N,N/O) indicates bidentate 8-quinolate, ethylenediamine and 1,10-phenanthroline and (N) represents the releasable monodentate ligand with a nitrogen donor atom. UV-visible spectrophotometry, 1H NMR, and pH-potentiometry were used to determine the protonation constants of the monodentate ligands, the proton dissociation constants of the coordinated water molecules in the aqua complexes, and the formation constants of the mixed-ligand complexes. The obtained data were compared to those of the analogous Ru(η6-p-cymene) complexes. The developed mixed-ligand complexes were tested in drug-sensitive and resistant colon cancer cell lines (Colo205 and Colo320, respectively) and in four bacterial strains (Gram-positive and Gram-negative, drug-sensitive, and resistant) at different pH values (5-8). The mixed-ligand complexes with 1-methylimidazole displayed sufficient stability at pH 7.4, and their activation was found in cancer cells with decreasing pH; moreover, the mixed-ligand complexes demonstrated antimicrobial activity in Gram-positive and Gram-negative bacteria, including the resistant MRSA strain. This study proved the viability of incorporating releasable monodentate ligands into mixed-ligand half-sandwich complexes, which is supported by the biological assays.

Initial Experience Using Digital Variance Angiography in Context of Prostatic Artery Embolization in Comparison with Digital Subtraction Angiography.

RATIONALE AND OBJECTIVES: In previous clinical studies digital variance angiography (DVA) provided higher contrast-to-noise ratio (CNR) and better image quality in lower extremity angiography than digital subtraction angiography (DSA). Our aim was to investigate whether DVA has similar quality reserve in prostatic artery embolization (PAE). The secondary aim was to explore the potential advantages of the color-coded DVA (ccDVA) technology in PAE. MATERIAL AND METHODS: This retrospective study evaluated 108 angiographic acquisitions from 30 patients (mean ± SD age 68.0 ± 8.9, range 41-87) undergoing PAE between May and October 2020. DSA and DVA images were generated from the same unsubtracted acquisition, and their CNR was calculated. Visual evaluation of DVA and DSA image quality was performed by four experienced interventional radiologists in a randomized, blinded manner. The diagnostic value of DSA and ccDVA images was also evaluated using clinically relevant criteria (visibility of small [< 2.5 mm] and large arteries [> 2.5 mm], feeding arteries and tissue blush) in a paired comparison. Data were analysed by the Wilcoxon signed rank test or the binomial test, the interrater agreement was determined by the Kendall W or Fleiss Kappa analysis. RESULTS: DVA provided 4.11 times higher median CNR than DSA (IQR: 1.72). The visual score of DVA images (4.40 ± 0.05) was significantly higher than that of DSA (3.39 ± 0.07, p < 0.001). The Kendall W analysis showed moderate but significant agreement (WDVA = 0.38, WDSA = 0.53). The preference of ccDVA images was significantly higher in all criteria (63-89%) with an interrater agreement of 58-79%. The Fleiss Kappa range was 0.02-0.18, significant in all criteria except large vessels. CONCLUSION: Our data show that DVA provides higher CNR and better image quality in PAE. This quality reserve might be used for dose management (reduction of radiation dose and contrast agent volume), and ccDVA technology has also a high potential to assist PAE interventions in the future.

Metal Coordination and Biological Screening of a Schiff Base Derived from 8-Hydroxyquinoline and Benzothiazole.

Designing new metallodrugs for anticancer therapy is a driving force in the scientific community. Aiming to contribute to this field, we hereby report the development of a Schiff base (H2L) derived from the condensation of 2-carbaldehyde-8-hydroxyquinoline with 2-hydrazinobenzothiazole and its complexation with transition metal ions. All compounds were characterised by analytical and spectroscopic techniques, which disclosed their structure: [Cu(HL)Cl], [Cu(HL)2], [Ni(HL)(acetate)], [Ni(HL)2], [Ru(HL)Cl(DMSO)], [VO(HL)2] and [Fe(HL)2Cl(H2O)]. Different binding modes were proposed, showing the ligand's coordination versatility. The ligand proton dissociation constants were determined, and the tested compounds showed high lipophilicity and light sensitivity. The stability of all complexes in aqueous media and their ability to bind to albumin were screened. Based on an antiproliferative in vitro screening, [Ni(HL)(acetate)] and [Ru(HL)Cl(DMSO)] were selected for further studies aiming to investigate their mechanisms of action and therapeutic potential towards colon cancer. The complexes displayed IC50 < 21 µM towards murine (CT-26) and human (HCT-116) colon cancer cell lines. Importantly, both complexes exhibited superior antiproliferative properties compared to the clinically approved 5-fluorouracil. [Ni(HL)(acetate)] induced cell cycle arrest in S phase in CT-26 cells. For [Ru(HL)Cl(DMSO)] this effect was observed in both colon cancer cell lines. Additionally, both compounds significantly inhibited cell migration particularly in the human colon cancer cell line, HCT-116. Overall, the therapeutic potential of both metal complexes was demonstrated.

Digital Variance Angiography in Selective Lower Limb Interventions.

PURPOSE: To evaluate the potential benefits of digital variance angiography (DVA) in selective lower limb angiography and to compare the performance of 2 DVA algorithms (conventional DVA1 and the recently developed DVA2) to that of digital subtraction angiography (DSA). MATERIALS AND METHODS: From November 2019 to May 2020, 112 iodinated contrast media (ICM) and 40 carbon dioxide (CO2) angiograms were collected from 15 and 13 peripheral artery disease patients, respectively. The DVA files were retrospectively generated from the same unsubtracted source file as DSA. The objectively calculated contrast-to-noise ratio (CNR) and the subjective visual image quality of DSA, DVA1, and DVA2 images were statistically compared using the Wilcoxon signed-rank test. The images were evaluated by 6 radiologists (R.P.T., S.V., A.M.K., S.S.A., O.E., and J.S.) from 2 centers using a 5-grade Likert scale. RESULTS: Both DVA algorithms produced similar increase (at least 2-fold) in CNR values (P < .001) and significantly higher image quality scores than DSA, independent of the contrast agent used. The overall scores with ICM were 3.61 ± 0.05 for DSA, 4.30 ± 0.04 for DVA1, and 4.33 ± 0.04 for DVA2 (each P < .001 vs DSA). The scores for CO2 were 3.10 ± 0.14 for DSA, 3.63 ± 0.13 for DVA1 (P < .001 vs DSA), and 3.38 ± 0.13 for DVA2 (P < .05 vs DSA). CONCLUSIONS: DVA provides higher CNR and significantly better image quality in selective lower limb interventions irrespective of the contrast agent used. Between DVA algorithms, DVA1 is preferred because of its identical or better image quality than DVA2. DVA can potentially help the interventional decision process and its quality reserve might allow dose management (radiation/ICM reduction) in the future.

Digital variance angiography allows about 70% decrease of DSA-related radiation exposure in lower limb X-ray angiography.

Our aim was to investigate whether the previously observed higher contrast-to-noise ratio (CNR) and better image quality of Digital Variance Angiography (DVA) - compared to Digital Subtraction Angiography (DSA) - can be used to reduce radiation exposure in lower limb X-ray angiography. This prospective study enrolled 30 peripheral artery disease patients (mean ± SD age 70 ± 8 years) undergoing diagnostic angiography. In all patients, both normal (1.2 µGy/frame; 100%) and low-dose (0.36 µGy/frame; 30%) protocols were used for the acquisition of images in three anatomical regions (abdominal, femoral, crural). The CNR of DSA and DVA images were calculated, and the visual quality was evaluated by seven specialists using a 5-grade Likert scale. For investigating non-inferiority, the difference of low-dose DVA and normal dose DSA scores (DVA30-DSA100) was analyzed. DVA produced two- to three-fold CNR and significantly higher visual score than DSA. DVA30 proved to be superior to DSA100 in the crural region (difference 0.25 ± 0.07, p < 0.001), and there was no significant difference in the femoral (- 0.08 ± 0.06, p = 0.435) and abdominal (- 0.10 ± 0.09, p = 0.350) regions. Our data show that DVA allows about 70% reduction of DSA-related radiation exposure in lower limb X-ray angiography, providing a potential new radiation protection tool for the patients and the medical staff.

8-Hydroxyquinoline-Amino Acid Hybrids and Their Half-Sandwich Rh and Ru Complexes: Synthesis, Anticancer Activities, Solution Chemistry and Interaction with Biomolecules.

Solution chemical properties of two novel 8-hydroxyquinoline-D-proline and homo-proline hybrids were investigated along with their complex formation with [Rh(η5-C5Me5)(H2O)3]2+ and [Ru(η6-p-cymene)(H2O)3]2+ ions by pH-potentiometry, UV-visible spectrophotometry and 1H NMR spectroscopy. Due to the zwitterionic structure of the ligands, they possess excellent water solubility as well as their complexes. The complexes exhibit high solution stability in a wide pH range; no significant dissociation occurs at physiological pH. The hybrids and their Rh(η5-C5Me5) complexes displayed enhanced cytotoxicity in human colon adenocarcinoma cell lines and exhibited multidrug resistance selectivity. In addition, the Rh(η5-C5Me5) complexes showed increased selectivity to the chemosensitive cancer cells over the normal cells; meanwhile, the Ru(η6-p-cymene) complexes were inactive, most likely due to arene loss. Interaction of the complexes with human serum albumin (HSA) and calf-thymus DNA (ct-DNA) was investigated by capillary electrophoresis, fluorometry and circular dichroism. The complexes are able to bind strongly to HSA and ct-DNA, but DNA cleavage was not observed. Changing the five-membered proline ring to the six-membered homoproline resulted in increased lipophilicity and cytotoxicity of the Rh(η5-C5Me5) complexes while changing the configuration (L vs. D) rather has an impact on HSA or ct-DNA binding.

Critical factors affecting the albumin binding of half-sandwich Ru(ii) and Rh(iii) complexes of 8-hydroxyquinolines and oligopyridines.

There is significant interest today in the interaction of half-sandwich anticancer organometallic complexes with proteins. It is considered as a crucial factor in the transport and mode of action of these compounds; thus it can affect their overall pharmacological and toxicological profiles. Albumin binding of high stability Ru(ii)(η6-p-cymene) and Rh(iii)(η5-C5Me5) complexes formed with 8-hydroxyquinoline, its 5-chloro-7-((proline-1-yl)methyl) substituted derivative, 2,2'-bipyridine and 1,10-phenanthroline is discussed herein. The interaction with human serum albumin in terms of kinetic aspects, binding strength and possible binding sites was studied in detail by means of various methods such as 1H NMR spectroscopy, UV-visible spectrophotometry, steady-state and time-resolved fluorometry, ultrafiltration and capillary zone electrophoresis. Ru(ii)(η6-p-cymene)(2,2'-bipyridine) and Ru(ii)(η6-p-cymene)(1,10-phenanthroline) complexes do not bind to the protein measurably, most probably due to kinetic reasons. However, other complexes bind significantly to albumin with fairly different kinetics to albumin. The binding affinity towards hydrophobic binding pockets shows correlation with lipophilicity along with the actual charge of the respective complexes. The studied complexes preserve their original structure upon interaction with albumin. Formation constants computed for the binding of these metal complexes to histidine-containing model oligopeptides demonstrated significant ternary complex formation, pointing out the importance of histidine coordination in the binding of these types of complexes.

Genome-wide Association Study Identified Chromosome 8 Locus Associated with Medication-Related Osteonecrosis of the Jaw.

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious drug-related adverse event. To identify pharmacogenomic markers of MRONJ associated with bisphosphonate therapy, we conducted a genomewide association study (GWAS) meta-analysis followed by functional analysis of 5,008 individuals of European ancestry treated with bisphosphonates, which includes the largest number of MRONJ cases to date (444 cases and 4,564 controls). Discovery GWAS was performed in randomly selected 70% of the patients with cancer and replication GWAS was performed in the remaining 30% of the patients with cancer treated with intravenous bisphosphonates followed by meta-analysis of all 3,639 patients with cancer. GWAS was also performed in 1,369 patients with osteoporosis treated with oral bisphosphonates. The lead single-nucleotide polymorphism (SNP), rs2736308 on chromosome 8, was associated with an increased risk of MRONJ with an odds ratio (OR) of 2.71 and 95% confidence interval (CI) of 1.90-3.86 (P = 3.57*10-8 ) in the meta-analysis of patients with cancer. This SNP was validated in the MRONJ GWAS in patients with osteoporosis (OR: 2.82, 95% CI: 1.55-4.09, P = 6.84*10-4 ). The meta-analysis combining patients with cancer and patients with osteoporosis yielded the same lead SNP rs2736308 on chromosome 8 as the top SNP (OR: 2.74, 95% CI: 2.09-3.39, P = 9.65*10-11 ). This locus is associated with regulation of the BLK, CTSB, and FDFT1 genes, which had been associated with bone mineral density. FDFT1 encodes a membrane-associated enzyme, which is implicated in the bisphosphonate pathway. This study provides insights into the potential mechanism of MRONJ.

Half-sandwich organometallic Ru and Rh complexes of (N,N) donor compounds: effect of ligand methylation on solution speciation and anticancer activity.

A series of half-sandwich polypyridyl complexes was synthesized and compared focusing on structural, cytotoxic and aqueous solution behaviour. The formula of the synthesized complexes is [M(arene)(N,N)Cl]Cl, where M: Ru or Rh, arene: p-cymene, toluene or C5Me5-, (N,N): 2,2'-bipyridine (bpy), 4,4'-dimethyl-2,2'-bipyridine (dmb), 1,10-phenanthroline (phen) or 2,9-dimethyl-1,10-phenanthroline (neo). The structures of five half-sandwich complexes were determined by X-ray crystallography. It was found that introducing methyl groups next to the coordinating nitrogen atoms of the bidentate ligand causes steric congestion around the metal centre which changes the angle between ligand planes. The ligands and the Rh complexes showed significant cytotoxicity in A2780 and MES-SA cancer cell lines (IC50 = 0.1-56 µM) and in the cisplatin-resistant A2780cis cells. Paradoxically, phen and dmb as well as their half-sandwich Rh complexes showed increased toxicity against multidrug resistant MES-SA/Dx5 cells. In contrast, coordination to Ru caused loss of toxicity. Solution equilibrium constants showed that the studied metal complexes have high stability, and no dissociation was found for Ru and Rh complexes even at micromolar concentrations in a wide pH range. However, in the case of Ru complexes a slow and irreversible decomposition, namely arene loss, was also observed, which was more pronounced in light exposure in aqueous solution. In the case of neo, the methyl groups next to the nitrogen atoms significantly decrease the stability of complexes. For Rh complexes, the order of the stability constants corrected with ligand basicity (log K*): 9.78 (phen) > 9.01 (dmb) > 8.89 (bpy) > 3.93 (neo). The coordinated neo resulted in an enormous decrease in the chloride ion affinity of Ru compounds. Based on the results, a universal model was introduced for the prediction of chloride ion capability of half-sandwich Rh and Ru complexes. It combines the effects of the bidentate ligand and the M(arene) part using only two terms, performing multilinear regression procedure.

SIRT1 Gene SNP rs932658 Is Associated With Medication-Related Osteonecrosis of the Jaw.

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse drug reaction. Our previous whole-exome sequencing study found SIRT1 intronic region single-nucleotide polymorphism (SNP) rs7896005 to be associated with MRONJ in cancer patients treated with intravenous (iv) bisphosphonates (BPs). This study aimed to identify causal variants for this association. In silico analyses identified three SNPs (rs3758391, rs932658, and rs2394443) in the SIRT1 promoter region that are in high linkage disequilibrium (r2 > 0.8) with rs7896005. To validate the association between these SNPs and MRONJ, we genotyped these three SNPs on the germline DNA from 104 cancer patients of European ancestry treated with iv BPs (46 cases and 58 controls). Multivariable logistic regression analysis showed the minor alleles of these three SNPs were associated with lower odds for MRONJ. The odds ratios (95% confidence interval) and p values were 0.351 (0.164-0.751; p = 0.007) for rs3758391, 0.351 (0.164-0.751; p = 0.007) for rs932658, and 0.331 (0.157-0.697; p = 0.0036) for rs2394443, respectively. In the reporter gene assays, constructs containing rs932658 with variant allele A had higher luciferase activity than the reference allele, whereas constructs containing SNP rs3758391 and/or rs2394443 did not significantly affect activity. These results indicate that the promoter SNP rs932658 regulates the expression of SIRT1 and presumably lowers the risk of MRONJ by increasing SIRT1 expression. © 2020 American Society for Bone and Mineral Research (ASBMR).

Initial evidence of a 50% reduction of contrast media using digital variance angiography in endovascular carotid interventions.

PURPOSE: In previous clinical studies Digital Variance Angiography (DVA) provided higher signal-to-noise ratio (SNR) and better image quality than Digital Subtraction Angiography (DSA). Our aim was to investigate whether this quality reserve of DVA provides an opportunity for the reduction of iodinated contrast media (ICM) in carotid X-ray angiography (CXA). METHOD: Our prospective study enrolled 26 patients (67.0 ±â€¯8.1 years) undergoing carotid percutaneous transluminal angioplasty. The SNR of DSA and DVA image pairs obtained by a standard (100 %, 6 mL ICM) or a low-dose (50 %, 3 mL ICM) protocol were compared. Visual evaluation of all images was performed by five specialists using a 5-grade rating scale. The quality of DSA100 and DVA50 videos was also compared. RESULTS: DVA provided more than two-fold SNR, the median SNRDVA/SNRDSA ratio was 2.06 (100 %) and 2.25 (50 %). In the visual evaluation, the DVA100 score (3.73 ±â€¯0.06) was significantly higher than the DSA100 score (3.52 ±â€¯0.07, Wilcoxon p < 0.001), and the DVA50 score (3.64 ±â€¯0.13) was also significantly higher than the DSA50 score (3.01 ±â€¯0.17, Wilcoxon p < 0.001). While the low-dose protocol significantly decreased the DSA score (Mann-Whitney p < 0.01, DSA100 vs DSA50), it had no effect on the DVA score (DVA100 vs DVA50). There was no statistical difference between the DSA100 and DVA50 scores. Evaluators preferred the diagnostic value of DVA50 to DSA100 videos in 61% of comparisons, the interrater agreement was 69 % (Fleiss' kappa 0.35, p < 0.001). CONCLUSIONS: Our data show that DVA allows a substantial (50 %) ICM reduction in CXA without affecting the quality and diagnostic value of angiograms.

BET 1: The role of remdesivir in COVID-19 infection.

A short-cut review of the available medical literature was carried out to establish whether remdesivir was an effective treatment for patients with confirmed COVID-19 infection. After abstract review, five papers were found to answer this clinical question using the detailed search strategy. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. It is concluded that despite some recent promising studies, further well-designed and larger trials are needed to answer this specific question.

Genetic variants of VDR and CYP2R1 affect BMI independently of serum vitamin D concentrations.

BACKGROUND: Vitamin D metabolism and obesity have been linked by several studies, however the reason for this association is unclear. Our objective was to investigate potential correlations between genetic variants in key enzymes of vitamin D metabolism and the body mass index on a representative and random sample of Hungarian adults. METHODS: Altogether 462 severely vitamin D deficient individuals were studied at the end of winter in order to decrease environmental and maximize any relevant genetic effect. Furthermore, participants with lifestyle factors known to affect vitamin D homeostasis were also excluded. We selected 23 target SNPs in five genes that encode key proteins of vitamin D metabolism (NADSYN1, GC, CYP24A1, CYP2R1, VDR). RESULTS: Variants in 2 genetic polymorphisms; rs2853564 (VDR) and rs11023374 (CYP2R1) showed a significant association with participants' BMI. These associations survived further adjustment for total-, free-, or bioactive-25(OH) vitamin D levels, although the variance explained by these 2 SNPS in BMI heterogeneity was only 3.2%. CONCLUSION: Our results show two novel examples of the relationship between genetics of vitamin D and BMI, highlighting the potential role of vitamin D hormone in the physiology of obesity.

Initial Operating Room Experience with Digital Variance Angiography in Carbon Dioxide-Assisted Lower Limb Interventions: A Pilot Study.

PURPOSE: In retrospective clinical studies digital variance angiography (DVA) provided higher contrast-to-noise ratio and better image quality than digital subtraction angiography (DSA). Our aim was to verify the clinical usefulness and benefits of DVA in carbon dioxide (CO2)-assisted lower limb interventions. MATERIALS AND METHODS: A workstation running the DVA software was integrated into a Siemens Artis Zee with Pure angiography system, and this new image processing technology was used in four patients (3 male, 1 female, age: 76.2 ± 4.2 years) with peripheral artery disease (PAD, Rutherford 2-3) and impaired renal function (average eGFR 25.5 ± 11.2 ml/min/1.73 m2). The DSA and DVA images of 46 CO2-assisted runs were visually evaluated by five experts in single-image evaluation using a 5-grade Likert scale and in paired comparisons. RESULTS: DVA images received significantly higher score (3.84 ± 0.10) than DSA images (3.31 ± 0.10, p < 0.001). Raters preferred DVA images in terms of diagnostic value and usefulness for therapeutic decisions in 85.2% and 83.9% of all comparisons, respectively. These benefits were achieved at lower frame rates (1-3 FPS) than usually recommended for CO2 angiography (4-6 FPS). No adverse events were recorded during or after the procedures. CONCLUSIONS: Our initial experience shows that DVA might facilitate the correct diagnostic and therapeutic decisions, and potentially help to reduce radiation exposure in lower limb CO2 angiography. Although the dose management capabilities of DVA have to be validated in further clinical studies, this technology might be a useful new tool in the operating room and contributes to the safety and efficacy of CO2-enhanced endovascular interventions. LEVEL OF EVIDENCE: Level IV.

An 8-hydroxyquinoline-proline hybrid with multidrug resistance reversal activity and the solution chemistry of its half-sandwich organometallic Ru and Rh complexes.

Herein the design and synthesis of a new 8-hydroxyquinoline derivative, (S)-5-chloro-7-((proline-1-yl)methyl)8-hydroxyquinoline (HQCl-Pro), with good water solubility and multidrug resistance reversal activity are reported. In this work the proton dissociation processes of HQCl-Pro and its complex formation with [Rh(η5-C5Me5)(H2O)3]2+, [Ru(η6-p-cymene)(H2O)3]2+ and [Ru(η6-toluene)(H2O)3]2+ were investigated by the combined use of pH-potentiometry, UV-visible spectrometry and 1H NMR spectroscopy. Our results revealed the prominent solution stability of the complexes in all cases. The lipophilicity of the complexes increased with the chloride ion concentration, and the complexes showed moderate log D values (-0.8 to +0.4) at pH 7.4 at all tested Cl- concentrations. The formation of mixed hydroxido complexes from the aqua complexes was characterized by relatively high pKa values (8.45-9.62 in chloride-free medium). Complexation processes are much slower with the Ru(η6-arene) triaqua cations than with [Rh(η5-C5Me5)(H2O)3]2+. Both the pKa values and H2O/Cl- exchange constants of the Ru-complexes are lower by 0.5-1.0 orders of magnitude than those of the Rh analogue. Arene loss (p-cymene and toluene) and oxidation were found in the case of Ru-complexes when an excess of HQCl-Pro and aromatic (N,N) bidentate ligands was added. The cytotoxicity and antiproliferative effect of HQCl-Pro and its complexes were assayed in vitro. In contrast to the structurally familiar 8-hydroxyquinoline, HQCl-Pro and its Rh(η5-C5Me5) complex were somewhat more effective against drug resistant Colo 320 adenocarcinoma human cells compared to the drug sensitive Colo 205 cells. The Ru- and Rh-complexes showed a similar metal uptake level after 4 h, while a longer incubation time resulted in higher cellular Rh concentration.