Objectives: Although Aurora kinase A (AURKA) expression has been investigated in many cancer types, studies focusing on its role in hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) are limited. In this study, we examined the activity of AURKA and its substrates (PLK1, P53, and BRCA1) in HBV-HCC and cryptogenic hepatocellular carcinoma (Cr-HCC) cases. Methods: The study groups consisted of HBV-HCC, Cr-HCC, and healthy liver tissue cases. AURKA copy number variation (CNV) was analyzed using molecular methods. AURKA expression was evaluated by molecular and immunohistochemical (IHC) methods. AURKA substrates P53Ser315, PLK1Thr210, and BRCA1 were also analyzed by IHC. Results: There was no increase in AURKA gene copy number among the groups (2−∆∆Ct < 2). AURKA level was significantly increased in both test groups (p < 0.001). At the protein level, AURKA was significantly higher in both cancer groups compared to the control group (p < 0.001). Phospho-P53Ser315 levels were significantly higher in both HBV-HCC and Cr-HCC groups compared to the control group (p = 0.002 and p < 0.001, respectively). Cr-HCC cases also showed significantly higher levels compared to HBV-HCC (p = 0.025). For phospho-PLK1Thr210, Cr-HCC cases showed statistically higher expression compared to both the control group and HBV-HCC cases (p = 0.001).

A series of 1-alkyl-3-(1-methylbenzotriazolyl)benzimidazole palladium(II) complexes (3a-f) has been synthesized and fully characterized by spectroscopic methods and single-crystal X-ray diffraction analysis. Structural studies indicate that N-alkyl substitution significantly affects the coordination geometry of the complexes. For the first time, Pd(II)-carbene complexes based on a benzimidazole-benzotriazole hybrid framework have been explored as catalysts for C-N bond formation via the N-alkylation of amines with alcohol derivatives. All complexes exhibited high catalytic efficiency in the alkylation of aniline derivatives with aryl alcohols under solvent-free conditions, affording excellent conversions within 24 h at a low catalyst loading (2.5 mol%). These findings highlight an efficient and sustainable protocol for C-N bond construction.In addition to their catalytic properties, the complexes were evaluated for antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and the fungal strains Candida albicans and Candida glabrata. Among them, compound 2e showed the most pronounced antimicrobial effect. Cytotoxicity studies further revealed that complex 3f exhibits higher activity than cisplatin across the tested cell lines. Overall, these results demonstrate that the synthesized Pd(II) complexes represent a versatile platform combining efficient catalytic performance with relevant biological activity. Structure-activity relationships emphasize the critical role of N-alkyl substitution in modulating both catalytic and biological properties.

Background: This study introduces an experimental model of a large, full-thickness skin defect and evaluates how adipose-derived stem cells characterized by high self-renewal and differentiation capacity affect both wound healing and the wound microenvironment when delivered using two different local application methods. Materials and Methods: In this preclinical study, we established an excisional full-thickness skin defect model involving approximately 30% of the total body surface area (TBSA). Five experimental groups were formed, each containing equal numbers of male and female rats: (1) subdermal ADSC injection (ADSC-I) (n = 8), (2) application of an acellular dermal matrix (ADM) seeded with ADSCs (n = 8) (ADSC-ADM), (3) ADM alone (n = 8), (4) subdermal saline injection (n = 8) (SS-I), and (5) an untreated skin-defect sham group (n = 8). Wound healing and wound microenvironment parameters were assessed at regular intervals using macroscopic and microscopic evaluations, as well as various quantitative measurements. The study was terminated when complete wound closure was achieved in all animals of at least one experimental group. Results: The most favorable healing outcomes were observed in the two ADSC-treated groups. More favorable microenvironmental conditions in the stem cell groups were detected from day 14 onward. Complete closure of the dermal defects occurred by day 32 in the ADSC-I group, whereas none of the other groups achieved full wound closure within the study period. Conclusions: Local application of adipose-derived stem cells may accelerate wound healing by favorably modulating the wound microenvironment.

BACKGROUND:Small RNAs play a pivotal role in gene regulation, mediating RNAinduced transcriptional activation and post-transcriptional gene silencing. Their high specificity and versatility make them indispensable tools for investigating gene function, elucidating disease mechanisms, and developing targeted therapeutic strategies. METHODS:We developed an AuNP-based RNA delivery system to enhance stability and uptake of therapeutic RNAs targeting TP53 and KRAS pathways. AuNPs were synthesized via citrate reduction and conjugated with siRNA.923 (KRAS-targeting siRNA) and dsP53-285 (p53-stimulating saRNA). A549 and HCT116 cells were transfected with conjugates. Gene expression was analyzed by RT-qPCR and Western blotting. Functional assays, including flow cytometry for cell cycle and apoptosis, MTT and colony formation assays for proliferation, and transwell assays for migration and invasion, were conducted. RESULTS:Individual transfection of AuNP-conjugated siRNA.923 effectively downregulated KRAS expression, whereas AuNP-dsP53-285 upregulated TP53 expression in both A549 and HCT116 cell lines. Co-transfection with AuNP-siRNA.923/dsP53-285 resulted in a significantly greater increase in TP53 mRNA and protein levels, without affecting KRAS mRNA or protein levels, in both cell lines compared with individual transfections. Functionally, the AuNP-based dual small RNA delivery system induced cell cycle arrest at the G0/G1 phase, significantly enhanced apoptosis, and markedly reduced cell proliferation, colony formation, migration, and invasion relative to individual RNA transfections. CONCLUSION:These findings demonstrate that AuNP-mediated co-delivery of siRNA and saRNA effectively modulates the KRAS-p53 signaling axis and enhances therapeutic potential in KRASmutant, TP53-wild-type cancers. Further studies, including in vivo investigations, are warranted to evaluate the translational feasibility and clinical relevance of this combinatorial approach.

In this study new N-alkylbenzimidazole derivatives 1a-e and their related tris(benzimidazole)(nitrato)silver(I) complexes 2a-e were prepared and characterized by FT-IR, 1H,13C{1H} NMR spectroscopy, and elemental analysis, which support the proposed structures. Further confirmations of structural details were provided by a single-crystal X-ray. A single crystal of tris(N-alkylbenzimidazole)(nitrato)silver(I) 2e shows that the coordination geometry around Ag slightly distorted tetrahedral geometry. Further, the synthesized compounds were evaluated for their antimicrobial activities against bacteria Escherichia coli, P. aeruginosa, S. aureus, and the fungal strains C. albicans and C. glabrata. The results indicated that the activity shown by the tested compounds, especially against Gram-negative bacteria, is valuable for the development of new treatment options against these microorganisms. Especially, the drug development potential of N-alkyl-5,6-dimethylbenzimdazole 1b and complexes 2b, 2c, and 2e showing the highest antimicrobial activity. Also, the alkylbenzimidazole substituent 1b and 1e and the Tris(1-alkylbenzimidazole)silver(I) 2c showed remarkable activity against fungi strains. Complexes 2a, 2b, 2c, 2d, and 2e also showed high cytotoxicity. The synthesized complexes demonstrated higher cytotoxicity relative to Cisplatin across all tested cell lines. Furthemore, a mild catalytic protocol for benzaldehyde, amine, and phenylacetylene coupling (A3-coupling) allows for the selective synthesis of propargyl amines using N-alkylbenzimidazole silver(I) nitrate catalysts with conversion of 100 %. The present approach is environmentally benign and water is generated as the sole by product.

We report herein the efficient synthesis of new benzimidazolium salts (A1-A6) and their corresponding selenium-NHC complexes (B1-B6), along with the evaluation of their cytotoxicity profiles against two cancer cell lines (HCT116 and SH-SY5Y) and one normal cell line (BEAS-2B). The findings revealed that the benzimidazolium salts (A1-A6) exhibited significantly higher cytotoxicity toward all tested cell lines compared to their selenium derivatives (B1-B6). Among them, compounds A3, A4, and A5 showed the most potent cytotoxic effects, with IC50 values ranging from 3.09 to 26.12 µM, approximately ten times lower than that of cisplatin. However, these compounds also exhibited relatively low IC50 values in normal BEAS-2B cells, although still higher than those observed in the cancer cell lines, indicating a preferential cytotoxicity toward cancer cells. Structure-activity relationship analysis revealed that the benzimidazolium core acts as the pharmacophore of these compounds, while substitution on the aromatic ring-particularly with bulky groups-enhances cytotoxicity. Conversely, incorporation of the selenium atom was found to markedly reduce or even eliminate cytotoxicity up to concentrations of 800 µM. Further in silico studies were conducted to gain a deeper understanding of the molecular structures and chemical reactivity of these compounds. In addition, molecular docking studies against PARP-1 and tubulin highlighted the strong inhibitory potential of the most active compounds (A3, A4, and A5) toward both targets, suggesting their potential involvement in the observed cytotoxic effects. Overall, these investigations propose benzimidazolium salts A3, A4, and A5 as promising anticancer agents and highlight the selenium derivatives as non-toxic selenium-based NHC complexes. Further studies should be undertaken to optimize the biological activity of these compounds and to enhance their selectivity toward cancer cells.

Two novel pyrazole-based ligands, namely 4-chloro-N-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)aniline (L1, bidentate) and 4-chloro-N,N-bis((3,5-dimethyl-1H-pyrazol-1-yl)methyl)aniline (L2, tridentate), were synthesized via a Mannich-type condensation of 1-(hydroxymethyl)− 3,5-dimethylpyrazole with 4-chloroaniline in acetonitrile, yielding 97

In this research, we present the successful synthesis of benzimidazolium salts (2a-e) and their corresponding selenium-NHC adducts (3a-e), achieved with satisfactory yields ranging from 75% to 88%, and characterized using spectroscopic techniques, including NMR, FTIR, and mass spectrometry analysis. This work is the first to evaluate the antimicrobial activities and molecular docking studies of these novel compounds, shedding light on the limited enhancement provided by selenium incorporation and providing valuable insights into their enzyme inhibition mechanisms. The antimicrobial and antifungal activities of these compounds were evaluated against various bacterial and yeast strains using disk diffusion and minimum inhibitory concentration (MIC) methods. Benzimidazolium salts, particularly 2d and 2e, demonstrated superior antimicrobial efficacy against Staphylococcus aureus with inhibition zones of 26.73 mm and 18.10 mm and MIC values of 1.56 μg/mL, and against Candida albicans with inhibition zones of 18.10 mm and MIC values of 25 μg/mL and 12.5 μg/mL respectively, significantly outperforming the reference agents Ampicillin (15.33 mm inhibition zone; MIC: 25 μg/mL for S. aureus) and Caspofungin (14.30 mm inhibition zone; MIC: 25 μg/mL for C. albicans). Additionally, compounds 2d and 2e exhibited better activity against Escherichia coli with MIC values of 12.5 μg/mL compared to Ampicillin (25 μg/mL). Conversely, selenium-NHC compounds exhibited moderate to weak activity, with inhibition zones ranging from 8.35 to 11.93 mm and MIC values ranging from 100 to 800 μg/mL, and did not outperform the reference agents. To elucidate the potential mechanism of action, molecular docking studies were performed on compound 2d and its derivative 3d against three key bacterial enzymesDNA gyrase, dihydrofolate reductase (DHFR), and tyrosyl-tRNA synthetase (TyrRS)in addition to the fungal sterol 14-α-demethylase (CYP51) to assess possible antifungal interactions. The results revealed strong binding affinities for both bacterial and fungal enzymes. The compounds interact with crucial amino acids in the enzyme active sites, mirroring the interactions of native ligands. However, the presence of selenium in complex 3d did not enhance its inhibitory activity significantly compared to the salt 2d. The findings highlight the potential of benzimidazolium salts, particularly 2d and 2e, as promising therapeutic agents for microbial infections, with selenium incorporation offering limited enhancement in activity.

Abstract Introduction Hemoglobinopathies are among the most common inherited diseases worldwide. Countries with a high prevalence of carriers have implemented population-based premarital screening to prevent the disease. In Turkey, a national hemoglobinopathy control program (NHCP) was officially launched in 2003. This program includes carrier screening, which is preceded by genetic counseling, public education, and prenatal diagnosis (PND). However, a study conducted among registered patients in the National Hemoglobinopathy Registry (NHR) of the Turkish Hematology Association between 2011 and 2015 (Turk J Hematol 2018;35:12-18) did not show a consistent decline in the number of affected births over time in Turkey. Since those times, Turkey has experienced a significant influx of over 3 million Syrian migrants. Furthermore, a substantial number of patients of all ages have been added to the NHR over the last decade. This study examines the changing trends in the births of affected children in Turkey, utilizing data from the recent NHR database. Methods The demographics of patients included in the NHR were evaluated. We collected data on patients born in each year from 2000 onward, noting that those born since 2005 represent the affected births following the implementation of NHCP. Patients of other nationalities were evaluated separately, as it remains unclear whether they were born in Turkey. All births with hemoglobinopathies over 25 years, between 2000 and 2024, were evaluated by dividing the time into 5-year periods, with the first 5 years representing the period before the establishment of the NHCP. The latter data was projected for the following five-year periods between 2005 and 2024 and then compared to the actual data from the same period. The information regarding premarital screening, genetic counseling, and PND was collected from the parents. Results The NHR includes a total of 5,075 patients, comprising 4,255 with thalassemia and 820 with sickle cell disorders. Among these patients, 372 are immigrants. Notably, 38% of the registered Turkish citizen patients (n = 1,784) were born between 2005 and 2024, and 1,629 of those had thalassemia. Between 2000 and 2004, a total of 718 births were recorded. The average number of births each year was 144 ± 6 (median 146). Over the following five-year periods, a gradual decline in the average number of births was observed as; 2005-2009, 133 ± 12 (median 142), 2010-2014, 113 ± 6 (median 114), 2015-2019, 85 ± 7 (median 88), and 2020-2024, 26 ± 11 (median 28). The significant decline in the final five-year period requires caution, as not all pediatric centers have updated their registries between 2020 and 2024. In contrast, out of 372 patients from other nationalities, 308 were born between 2005 and 2024, with a gradual increase in births at five-year intervals, peaking with the highest number (n = 114) during the period from 2015 to 2019. Only 32% of parents of patients born after 2004 underwent premarital screening. The screening rate was much lower among migrant couples, at just 5%. Of those who were screened, 60% received information about being at-risk couples to have affected children. However, only 30.5% of these couples opted for prenatal diagnosis (PND), yet went on to have their babies, even though the law permitted the termination of pregnancies involving affected babies. Additionally, 21% of parents reported receiving inaccurate results for their carrier status, while 19% did not receive any information about the screening at all. ConclusionsAn analysis of the registry reveals that the NHCP has achieved a 37% reduction in the number of births with hemoglobinopathies over the past 20 years, demonstrating a consistent and gradual decline since its inception. However, it is essential to address the program's shortcomings that may hinder even greater success. Additionally, an urgent strategy is needed for the migrated population of reproductive age, taking into account the societal values of that community.

Necrotizing enterocolitis (NEC) is a severe and often catastrophic gastrointestinal emergency that predominantly affects neonates, especially those born prematurely, and is associated with high rates of morbidity and mortality. Despite its significant clinical impact, the precise etiology and molecular pathogenesis of NEC remain incompletely understood. In this study, we conducted global transcriptomic profiling using high-throughput RNA sequencing in 11 premature neonates diagnosed with NEC, following rigorous inclusion and exclusion criteria. Compared to healthy controls, we identified 1,204 differentially expressed genes (DEGs), including 636 upregulated and 568 downregulated transcripts. Notably, genes involved in hypoxia-induced apoptosis (e.g., HIF1 AAS3, HIF1 AAS1), the caspase cascade (BCL2, BCL6, CASP5, CASP7), and inflammation (IL1RAP, IL6ST, TNFAIP3, TNFRSF10 A, TLR6, TLR10) were significantly upregulated. In contrast, IL18, a key modulator of inflammatory responses, was downregulated. Interestingly, several genes encoding selenoproteins (GPX1, GPX4, SELENON, SELENOM, SELENOF, SELENOW, SELENOT) were also downregulated, suggesting molecular evidence of selenium deficiency. Gene ontology and pathway enrichment analyses revealed widespread dysregulation in pathways related to hypoxia response, systemic inflammation, coagulation, antimicrobial defense, mitochondrial function, autophagy, selenium metabolism, and apoptosis. Collectively, our findings provide novel insights into the molecular underpinnings of NEC in premature infants and suggest that systemic hypoxia, oxidative stress, selenium deficiency, and programmed cell death contribute significantly to its pathogenesis.

Creating safe and effective anticancer pharmaceuticals with an imidazolidine heterocyclic ring was the goal of this project. Starting with 1-(2-hydroxypropyl)imidazoline and N, N-dimethylformamide dimethyl acetal, substituted-imidazolidine derivatives (3a-h) have been generated. The anti-tumor potential of the imidazolidine derivatives (3a-h) was further investigated using the human colon cancer cell line HCT116 and the human neuroblastoma cell line SH-SY5Y. All of the synthesized compounds, except for All synthesized compounds, except for the salt 3f (1-(2-hydroxypropyl)-3-(3,4,5-trimethoxybenzyl) imidazolinium chloride) which was not active against the HCT116 cancer cell line, were active against the two cell lines. According to the results of biological tests, the inhibitory concentration (IC50) values ranged from 45.44 mu M to 663.73 mu M. The salt 3 g showed the highest anticancer effect, particularly against the HCT116 cancer cell line, with a selectivity index reaching 2.75. Also, optimized molecules were analyzed by molecular docking methods against crystal structures of Vascular Endothelial Growth Factor Receptors (VEGFR2) and Cytochrome P450 17A1, and their binding affinities, interaction details and inhibition constants were determined. The molecules were additionally evaluated for possible drug-likeness and bioavailability scores which include absorption, distribution, metabolism, excretion and toxicity aspects.

In this study, a series of novel pyrazolyl-pyrazolone derivatives was synthesized via a Knoevenagel condensation reaction using trisodium citrate as a catalyst, highlighting an environmentally sustainable and cost-effective approach. The synthesized compounds were characterized through comprehensive analytical techniques, including NMR spectroscopy, HRMS, and melting point determination. Biological evaluations demonstrated diverse and promising activities: compound 6i exhibited exceptional antioxidant activity across DPPH, ABTS, and Ferric-phenanthroline assays, outperforming standard antioxidants like BHT and BHA. In parallel, anticancer assays against SH-SY5Y and HCT116 cell lines revealed compounds 6e, 6j, and 6k as potent cytotoxic agents, with IC50 values significantly lower than cisplatin, the reference drug. Notably, compound 6j showed remarkable selectivity towards cancer cells with reduced cytotoxicity on non-cancerous BEAS-2B cells. Molecular docking studies confirmed strong binding interactions of the active compounds with key cancer-related protein targets, shedding light on their mechanisms of action. These findings not only highlight the therapeutic potential of pyrazolyl-pyrazolone derivatives as dual antioxidant and anticancer agents but also emphasize the value of sustainable chemical processes in drug development.

This study aimed to synthesize a novel series of N-heterocyclic compounds and evaluate their integrated pharmacological potential by coupling in vitro selective cytotoxicity on tumor and normal cell lines with predictive in silico ADME-Tox profiling. This research highlights the anti-cancer potential of twelve synthesized compounds, five of which are new chemical entities never before described in the literature. Their detailed structural characterization (NMR 1H, 13C, IR), combined with in silico predictions (ADME-Tox), confirmed their ability to cross essential biological barriers, in particular the intestinal membrane and, for certain derivatives, the BBB. Biological evaluations conducted on SH-SY5Y (neuroblastoma) and HCT116 (colorectal carcinoma) cell lines revealed several compounds with IC50 values lower than those of cisplatin while exhibiting reduced cytotoxicity towards the normal human epithelial BEAS-2B cell line. In particular, the compound (1H-imidazol-1-yl)methanol (designated as Compound 6) stands out with IC50 values of 6.97 ± 0.06µM on SH-SY5Y and 10.70 ± 0.33µM on HCT116, significantly lower than those of cisplatin under the same experimental conditions. This profile, combined with virtually no toxicity on normal BEAS-2B cells (IC50 > 800µM), highlights its remarkable selectivity. These results highlight optimized pharmacological properties and suggest the potential for developing selective therapeutic agents against different types of cancer, particularly neuronal and colorectal tumors. Future research will focus on in-depth mechanistic studies and in vivo validation to optimize the efficacy, pharmacokinetics, and safety of these promising molecules.

In this study, a new series of 1-(2-ethylhexyl)-3-(alkyl)-5,6-dimethylbenzimidazol-2-ylidene]silver(I) complexes has been synthesized and investigated their in vitro antibacterial, antifungal and anticancer properties. All molecules were characterized by 1H NMR, 13C NMR, and IR spectroscopy techniques. In vitro antimicrobial activity of the synthesized compounds investigated in this work was tested against the reference strains: Escherichia coli (ATCC 25922), Staphylococcus aureus (ATCC 29213) and Pseudomonas aeruginosa (ATCC 27853), Candida albicans (ATCC MYA-2876) and Candida glabrata (ATCC 2001). Anticancer properties of samples were evaluated against A549, HCT116 and BEAS-2B cells lines. All silver-NHC complexes showed antibacterial activity against the tested bacterial and fungal strains.

N-heterocyclic derivatives frameworks are a promising axis for antimicrobial discovery, yet aligning cellular efficacy with developability remains challenging. We examined 14 derivatives to derive qualitative structure-activity trends while integrating in-silico filters. Compounds were prepared and assayed by a standardized disc-diffusion test (800 µg/disc) against Candida albicans, C. glabrata, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus, enabling comparison within a matched series. Measurable inhibition zones were observed; for example, compound 5 ((1 H-1,2,4-triazol-1-yl)methanol) gave ≈ 15.2 ± 0.5 mm (C. albicans) and ≈ 19.8 ± 0.6 mm (C. glabrata), while compound 6 ((1 H-imidazol-1-yl)methanol) showed ≈ 12.8 ± 0.4 mm and ≈ 15.3 ± 0.5 mm, respectively. Bacterial effects reached > 26 mm on E. coli (compound 5) and up to 32 mm on S. aureus (compound 6), compared with ampicillin discs (≈ 14–15 mm). In parallel, molecular docking (AutoDock Vina) at mechanistically relevant targets AmpC (1KE4) and CYP51 (5TL8) yielded plausible binding poses with representative affinities in the ≈ − 6 to − 7.8 kcal mol−1 range for several analogues, interpreted qualitatively as mechanistic context rather than rank-order predictors. Overall, this integrated approach provides mechanistic insight and hypothesis-generating SAR, guiding risk-aware prioritization for subsequent quantitative susceptibility testing and focused optimization.

A series of N-alkylbenzimidazole silver(I) complexes were synthesized and fully characterized by FT-IR, Mass, 1H, 13C{1H} NMR spectroscopy, and elemental analysis. Synthesized N-alkylbenzimidazole silver(I) complexes were investigated for their antimicrobial activities against bacteria Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and the fungal strains Candida albicans and Candida glabrata. All the complexes (2a-f) showed higher antimicrobial activity against bacteria than fungi strains. In particular, complexes 2b and 2e showed comparable activity to Ampicillin against Escherichia coli. Also, all complexes showed better activity than Ampicillin against Pseudomonas aeruginosa. The complex 2e showed remarkable activity against Candida albicans (12.5 mu g/mL) and Candida glabrata (25 mu g/mL). The molecules that were first optimized by DFT-based calculation methods were also analyzed by molecular docking methods against DNA gyrase of E. Coli, CYP51 from Candida glabrata, and Penicillin Binding Protein-3.

Objectives:We describe the clinical pictures of an index case with dystonia and his family resulting from VPS16 and MEFV genetic variations based on previously published data and discuss the mechanisms that may have brought out the clinical findings. Methods:A 17-year-old male had generalized dystonia that started at age 6 years, non-febrile abdominal pain attacks and was diagnosed with type 1 diabetes at age 14 years. Meanwhile, his 13-year-old sister had the same clinical presentation. His father was diabetic and his mother was asymptomatic. There was no consanguinity between the parents. Genetic variations were detected with whole exome sequencing. Results:VPS16 c.1513C>T/p.Arg505* (likely pathogenic), MEFV c.2080A>G p.Met694val (pathogenic) and MEFV c.1772T>C p.Ile591Thr (unknown significance) heterozygous variants were detected in his siblings. The father had VPS16 c.1513C>T/p.Arg505* and MEFV c.2080A>G p Met694val variations and the mother had MEFV c.1772T>C p.Ile591Thr variations. Conclusions:The occurrence of these diseases in siblings but their absence in the parents suggests the idea that the coexistence of two separate variations in the VPS16 and MEFV genes determines the phenotype. In addition, the increase in MEFV variation load in this family and the fact that DM occurs at an earlier age suggest that inflammation may cause an early diabetic clinical presentation.