Pilot study to evaluate the safety and effectiveness of etidronate treatment for arterial calcification due to deficiency of CD73 (ACDC).

BACKGROUND: Arterial calcification due to deficiency of CD73 (ACDC; OMIM 211800) is a rare genetic disease resulting in calcium deposits in arteries and small joints causing claudication, resting pain, severe joint pain, and deformities. Currently, there are no standard treatments for ACDC. Our previous work identified etidronate as a potential targeted ACDC treatment, using in vitro and in vivo disease models with patient-derived cells. In this study, we test the safety and effectiveness of etidronate in attenuating the progression of lower-extremity arterial calcification and vascular blood flow based on the computed tomography (CT) calcium score and ankle-brachial index (ABI). METHODS: Seven adult patients with a confirmed genetic diagnosis of ACDC were enrolled in an open-label, nonrandomized, single-arm pilot study for etidronate treatment. They took etidronate daily for 14 days every 3 months and were examined at the NIH Clinical Center bi-annually for 3 years. They received a baseline evaluation as well as yearly follow up after treatment. Study visits included imaging studies, exercise tolerance tests with ABIs, clinical blood and urine testing, and full dental exams. RESULTS: Etidronate treatment appeared to have slowed the progression of further vascular calcification in lower extremities as measured by CT but did not have an effect in reversing vascular and/or periarticular joint calcifications in our small ACDC cohort. CONCLUSIONS: Etidronate was found to be safe and well tolerated by our patients and, despite the small sample size, appeared to show an effect in slowing the progression of calcification in our ACDC patient cohort.(ClinicalTrials.gov Identifier NCT01585402).

Engineering a platelet-rich plasma-based multifunctional injectable hydrogel with photothermal, antibacterial, and antioxidant properties for skin regeneration.

Wound healing remains a significant challenge worldwide, necessitating the development of new wound dressings to aid in the healing process. This study presents a novel photothermally active hydrogel that contains platelet-rich plasma (PRP) for infected wound healing. The hydrogel was formed in a one pot synthesis approach by mixing alginate (Alg), gelatin (GT), polydopamine (PDA), and PRP, followed by the addition of CaCl2 as a cross-linker to prepare a multifunctional hydrogel (AGC-PRP-PDA). The hydrogel exhibited improved strength and good swelling properties. PDA nanoparticles (NPs) within the hydrogel endowed them with high photothermal properties and excellent antibacterial and antioxidant activities. Moreover, the hydrogels sustained the release of growth factors due to their ability to protect PRP. The hydrogels also exhibited good hemocompatibility and cytocompatibility, as well as high hemostatic properties. In animal experiments, the injectable hydrogels effectively filled irregular wounds and promoted infected wound healing by accelerating re-epithelialization, facilitating collagen deposition, and enhancing angiogenesis. The study also indicated that near-infrared light improved the healing process. Overall, these hydrogels with antibacterial, antioxidant, and hemostatic properties, as well as sustained growth factor release, show significant potential for skin regeneration in full-thickness, bacteria-infected wounds.

Comparison of CT and Dixon MR Abdominal Adipose Tissue Quantification Using a Unified Computer-Assisted Software Framework.

PURPOSE: Reliable and objective measures of abdominal fat distribution across imaging modalities are essential for various clinical and research scenarios, such as assessing cardiometabolic disease risk due to obesity. We aimed to compare quantitative measures of subcutaneous (SAT) and visceral (VAT) adipose tissues in the abdomen between computed tomography (CT) and Dixon-based magnetic resonance (MR) images using a unified computer-assisted software framework. MATERIALS AND METHODS: This study included 21 subjects who underwent abdominal CT and Dixon MR imaging on the same day. For each subject, two matched axial CT and fat-only MR images at the L2-L3 and the L4-L5 intervertebral levels were selected for fat quantification. For each image, an outer and an inner abdominal wall regions as well as SAT and VAT pixel masks were automatically generated by our software. The computer-generated results were then inspected and corrected by an expert reader. RESULTS: There were excellent agreements for both abdominal wall segmentation and adipose tissue quantification between matched CT and MR images. Pearson coefficients were 0.97 for both outer and inner region segmentation, 0.99 for SAT, and 0.97 for VAT quantification. Bland-Altman analyses indicated minimum biases in all comparisons. CONCLUSION: We showed that abdominal adipose tissue can be reliably quantified from both CT and Dixon MR images using a unified computer-assisted software framework. This flexible framework has a simple-to-use workflow to measure SAT and VAT from both modalities to support various clinical research applications.

A Combined Region- and Pixel-Based Deep Learning Approach for Quantifying Abdominal Adipose Tissue in Adolescents Using Dixon Magnetic Resonance Imaging.

BACKGROUND: The development of adipose tissue during adolescence may provide valuable insights into obesity-associated diseases. We propose an automated convolutional neural network (CNN) approach using Dixon-based magnetic resonance imaging (MRI) to quantity abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in children and adolescents. METHODS: 474 abdominal Dixon MRI scans of 136 young healthy volunteers (aged 8-18) were included in this study. For each scan, an axial fat-only Dixon image located at the L2-L3 disc space and another image at the L4-L5 disc space were selected for quantification. For each image, an outer and an inner region around the abdomen wall, as well as SAT and VAT pixel masks, were generated by expert readers as reference standards. A standard U-Net CNN architecture was then used to train two models: one for region segmentation and one for fat pixel classification. The performance was evaluated using the dice similarity coefficient (DSC) with fivefold cross-validation, and by Pearson correlation and the Student's t-test against the reference standards. RESULTS: For the DSC results, means and standard deviations of the outer region, inner region, SAT, and VAT comparisons were 0.974 ± 0.026, 0.997 ± 0.003, 0.981 ± 0.025, and 0.932 ± 0.047, respectively. Pearson coefficients were 1.000 for both outer and inner regions, and 1.000 and 0.982 for SAT and VAT comparisons, respectively (all p = NS). CONCLUSION: These results show that our method not only provides excellent agreement with the reference SAT and VAT measurements, but also accurate abdominal wall region segmentation. The proposed combined region- and pixel-based CNN approach provides automated abdominal wall segmentation as well as SAT and VAT quantification with Dixon MRI and enables objective longitudinal assessment of adipose tissues in children during adolescence.

Splenic Size and Volume Measurements in Patients with Chronic Lymphocytic Leukemia.

RATIONALE AND OBJECTIVES: To determine which methods of assessment of splenic size most accurately represent the actual spleen volume in patients with Chronic Lymphocytic Leukemia (CLL). MATERIALS AND METHODS: The Abdominal Computed Tomography images of 48 patients with CLL enrolled on a phase 2 clinical trial at two time-points before and after 2-months of continuous acalabrutinib treatment were analyzed. Linear one-dimensional measurements of the spleen were taken in different planes. Two-dimensional and three-dimensional measurements were calculated from the linear measurements using mathematical formulae. The spleen volume was determined by manual segmentation as the ground truth. Data derived were analyzed using Pearson correlation and statistical significance was set at p < 0.05. RESULTS: Among the single-dimensional measurements, the strongest correlation with the segmented splenic volume was the sagittal long axis diameter (LAD) (r = 0.89, p < 0.05), followed closely by Coronal LAD (r = 0.87, p < 0.05) and cephalocaudal length (iwCLL) (r = 0.84, p < 0.05). For the two-dimensional indices, the sum of LAD and short axis diameter (SAD) of the spleen in axial plane showed good correlation with the splenic volume (r = 0.77, p < 0.05). Among the three-dimensional indices, the splenic index (0.523 x axial LAD x axial SAD x coronal height) and a formula for volume (30 + 0.58 x axial LAD x axial SAD x coronal height) had the strongest correlation (both r = 0.92, p < 0.05) with the spleen volume. CONCLUSION: The three-dimensional formulae showed the strongest correlation with volumetric reference spleen measurement. Among unidimensional measurements, the sagittal LAD had the best correlation with the actual splenic volume. The two-dimensional calculation methods were less reliable.

Injectable Antibacterial Gelatin-Based Hydrogel Incorporated with Two-Dimensional Nanosheets for Multimodal Healing of Bacteria-Infected Wounds.

The design and development of multifunctional injectable hydrogels with high photothermal antibacterial activity and shape adaptability to accelerate bacteria-infected wound healing is of critical importance in clinical applications. In this study, a hybrid hydrogel composed of gelatin, iron, and MnO2 nanosheets was prepared by multiple interactions, including coordinative and hydrogen bonding as well as electrostatic attraction. The introduced MnO2 and Fe components made the hydrogels photothermally and chemodynamically active, thereby endowing them with potent antibacterial capabilities against both Gram-negative and Gram-positive bacteria. Because of the Fenton activity of the hydrogels, they could produce abandoned oxygen, which is highly crucial in the healing process of wounds. They also showed good cytocompatibility and hemocompatibility as well as high hemostatic properties. Moreover, the injectable hydrogels could fill irregular wounds and significantly accelerate bacteria-infected wound healing through decreasing the inflammatory response and increasing blood vessels. These features indicated the promising potential of the multifunctional hydrogel for healing infected full-thickness wounds.

Family clustering of SARS-CoV-2 in Qazvin, Northwest of Iran.

Background: Human infection affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been recognized as a global health concern. We report the epidemiological and clinical characteristics of patients with a familial cluster of SARS-CoV-2 from Qazvin province (located in the northwest of Iran). Methods: In this cross-sectional study, we enrolled 332 hospitalized patients that were confirmed SARS-CoV-2 diseases with laboratory-based (PT-PCR) test in Qazvin province, Iran. Having family infection transmission and subsequently, family clustering of SARS-COV-2 disease was assessed with the Generalized Estimating Equation model in patients. Results: Crude odds ratio estimates of creating family clustering of SARS-CoV-2 infection was 0.47 times [95% CI: 0.23, 0.98, p=0.045] less for female compared to the males; 2.26 [95% CI: 1.11, 4.58, p=0.024] and 2.69 [95% CI: 1.47, 4.93, p=0.001] for SARS-CoV-2 patients that had digestive and muscle pain in comparison with those did not this mentioned symptoms, respectively. 1.52 [95% CI: 1.05, 2.23, p=0.024] for patients with a longer hospitalization compared with patients that had shorter duration of hospitalization and adjusted odds ratio estimates were 2.13 [95% CI: 1.12, 4.03, p=0.020] for patients who receive public health services in comparison those did not receive public health services. Conclusion: Our findings confirm the person-to-person transmission of this novel coronavirus in family settings and hospitals, and the reports of infected travelers in other geographical regions. Major gaps in our knowledge about the potential factors in creating family clustering of SARS-CoV-2 infection, epidemiology, duration of human transmission and etc. need fulfillment by future studies.

Vertebral Bone Mineral Density, Vertebral Strength, and Syndesmophyte Growth in Ankylosing Spondylitis: The Importance of Bridging.

OBJECTIVE: To examine the relationship between vertebral trabecular bone mineral density (tBMD), vertebral strength, and syndesmophytes in patients with ankylosing spondylitis (AS) using quantitative computed tomography (QCT). METHODS: We performed QCT of the spine to measure syndesmophytes and tBMD in 5 vertebrae (T11-L3) in 61 patients with AS. Finite element analysis was performed to measure vertebral strength in compressive overload, including in trabecular and cortical compartments. In cross-sectional analyses, we examined associations of syndesmophyte height with tBMD and vertebral strength in each vertebra. In 33 patients followed up for 2 years, we investigated whether baseline tBMD and vertebral strength predicted syndesmophyte growth in the same vertebra, and vice versa. RESULTS: In the cross-sectional analyses, 126 vertebrae had bridging, 77 vertebrae had nonbridging syndesmophytes, and 83 vertebrae had no syndesmophytes. There were strong inverse associations between syndesmophyte height and tBMD, total strength, and trabecular strength only among bridged vertebrae. In the longitudinal analysis, nonbridged vertebrae with low tBMD (adjusted ß = -0.01 [95% confidence interval (95% CI) -0.019, -0.0012]) and low strength (adjusted ß = -0.0003 [95% CI -0.0004, -0.0002]) had more syndesmophyte growth over time. Similar associations were absent among bridged vertebrae. Conversely, vertebrae with bridging at baseline had a significant loss in percent tBMD over time (adjusted ß = -0.001 [95% CI -0.0017, -0.0004]). CONCLUSION: Associations between syndesmophytes and vertebral density and strength in AS differ between bridged and nonbridged vertebrae. Among nonbridged vertebrae, low tBMD and strength are associated with syndesmophyte growth. Bridging is associated with large subsequent losses in tBMD, possibly due to mechanical offloading.

Cabozantinib plus Nivolumab Phase I Expansion Study in Patients with Metastatic Urothelial Carcinoma Refractory to Immune Checkpoint Inhibitor Therapy.

PURPOSE: This study investigated the efficacy and tolerability of cabozantinib plus nivolumab (CaboNivo) in patients with metastatic urothelial carcinoma (mUC) that progressed on checkpoint inhibition (CPI). PATIENTS AND METHODS: A phase I expansion cohort of patients with mUC who received prior CPI was treated with cabozantinib 40 mg/day and nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary goal was objective response rate (ORR) per RECIST v.1.1. Secondary objectives included progression-free survival (PFS), duration of response (DoR), overall survival (OS), safety, and tolerability. RESULTS: Twenty-nine out of 30 patients enrolled were evaluable for efficacy. Median follow-up was 22.2 months. Most patients (86.7%) received prior chemotherapy and all patients received prior CPI (median seven cycles). ORR was 16.0%, with one complete response and three partial responses (PR). Among 4 responders, 2 were primary refractory, 1 had a PR, and 1 had stable disease on prior CPI. Median DoR was 33.5 months [95% confidence interval (CI), 3.7-33.5], median PFS was 3.6 months (95% CI, 2.1-5.5), and median OS was 10.4 months (95% CI, 5.8-19.5). CaboNivo decreased immunosuppressive subsets such as regulatory T cells (Tregs) and increased potential antitumor immune subsets such as nonclassical monocytes and effector T cells. A lower percentage of monocytic myeloid-derived suppressor cells (M-MDSC) and polymorphonuclear MDSCs, lower CTLA-4 and TIM-3 expression on Tregs, and higher effector CD4+ T cells at baseline were associated with better PFS and/or OS. CONCLUSIONS: CaboNivo was clinically active, well tolerated, and favorably modulated peripheral blood immune subsets in patients with mUC refractory to CPI.

Tumor Doubling Time Using CT Volumetric Segmentation in Metastatic Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is a rare malignancy with an overall unfavorable prognosis. Clinicians treating patients with ACC have noted accelerated growth in metastatic liver lesions that requires rapid intervention compared to other metastatic locations. This study measured and compared the growth rates of metastatic ACC lesions in the lungs, liver, and lymph nodes using volumetric segmentation. A total of 12 patients with metastatic ACC (six male; six female) were selected based on their medical history. Computer tomography (CT) exams were retrospectively reviewed and a sampling of ≤5 metastatic lesions per organ were selected for evaluation. Lesions in the liver, lung, and lymph nodes were measured and evaluated by volumetric segmentation. Statistical analyses were performed to compare the volumetric growth rates of the lesions in each organ system. In this cohort, 5/12 had liver lesions, 7/12 had lung lesions, and 5/12 had lymph node lesions. A total of 92 lesions were evaluated and segmented for lesion volumetry. The volume doubling time per organ system was 27 days in the liver, 90 days in the lungs, and 95 days in the lymph nodes. In this series of 12 patients with metastatic ACC, liver lesions showed a faster growth rate than lung or lymph node lesions.

Beta-cell failure rather than insulin resistance is the major cause of abnormal glucose tolerance in Africans: insight from the Africans in America study.

INTRODUCTION: Uncertainties exist on whether the main determinant of abnormal glucose tolerance (Abnl-GT) in Africans is ß-cell failure or insulin resistance (IR). Therefore, we determined the prevalence, phenotype and characteristics of Abnl-GT due to ß-cell failure versus IR in 486 African-born blacks (male: 64%, age: 38±10 years (mean±SD)) living in America. RESEARCH DESIGN AND METHODS: Oral glucose tolerance test were performed. Abnl-GT is a term which includes both diabetes and prediabetes and was defined as fasting plasma glucose (FPG) ≥5.6 mmol/L and/or 2-hour glucose ≥7.8 mmol/L. IR was defined by the lowest quartile of the Matsuda Index (≤2.98) and retested using the upper quartile of homeostatic model assessment of insulin resistance (HOMA-IR) (≥2.07). Abnl-GT-IR required both Abnl-GT and IR. Abnl-GT-ß-cell failure was defined as Abnl-GT without IR. Beta-cell compensation was assessed by the Disposition Index (DI). Fasting lipids were measured. Visceral adipose tissue (VAT) volume was obtained with abdominal CT scan. RESULTS: The prevalence of Abnl-GT was 37% (182/486). For participants with Abnl-GT, IR occurred in 38% (69/182) and ß-cell failure in 62% (113/182). Compared with Africans with Abnl-GT-IR, Africans with Abnl-GT-ß-cell failure had lower body mass index (BMI) (30.8±4.3 vs 27.4±4.0 kg/m2), a lower prevalence of obesity (52% vs 19%), less VAT (163±72 vs 107±63 cm2), lower triglyceride (1.21±0.60 vs 0.85±0.42 mmol/L) and lower FPG (5.9±1.4 vs 5.3±0.6 mmol/L) and 2-hour glucose concentrations (10.0±3.1 vs 9.0±1.9 mmol/L) (all p<0.001) and higher DI, high-density lipoprotein (HDL), low-density lipoprotein particle size and HDL particle size (all p<0.01). Analyses with Matsuda Index and HOMA-IR yielded similar results. Potential confounders such as income, education, alcohol and fiber intake did not differ by group. CONCLUSIONS: Beta-cell failure occurred in two-thirds of participants with Abnl-GT and may be a more frequent determinant of Abnl-GT in Africans than IR. As BMI category, degree of glycemia and lipid profile appeared more favorable when Abnl-GT was due to ß-cell failure rather than IR, the clinical course and optimal interventions may differ. TRIAL REGISTRATION NUMBER: NCT00001853.

Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma.

Background: We assessed whether serial ctDNA monitoring of plasma and saliva predicts response and resistance to osimertinib in EGFR-mutant lung adenocarcinoma. Three ctDNA technologies-blood-based droplet-digital PCR (ddPCR), next-generation sequencing (NGS), and saliva-based EFIRM liquid biopsy (eLB)-were employed to investigate their complementary roles. Methods: Plasma and saliva samples were collected from patients enrolled in a prospective clinical trial of osimertinib and local ablative therapy upon progression (NCT02759835). Plasma was analyzed by ddPCR and NGS. Saliva was analyzed by eLB. Results: A total of 25 patients were included. We analyzed 534 samples by ddPCR (n = 25), 256 samples by NGS (n = 24) and 371 samples by eLB (n = 22). Among 20 patients who progressed, ctDNA progression predated RECIST 1.1 progression by a median of 118 days (range: 61-272 days) in 11 (55%) patients. Of nine patients without ctDNA progression by ddPCR, two patients had an increase in mutant EGFR by eLB and two patients were found to have ctDNA progression by NGS. Levels of ctDNA measured by ddPCR and NGS at early time points, but not volumetric tumor burden, were associated with PFS. EGFR/ERBB2/MET/KRAS amplifications, EGFR C797S, PIK3CA E545K, PTEN V9del, and CTNNB1 S45P were key resistance mechanisms identified by NGS. Conclusion: Serial assessment of ctDNA in plasma and saliva predicts response and resistance to osimertinib, with each assay having supplementary roles.

Phase I Clinical Trial of an Autologous Dendritic Cell Vaccine Against HER2 Shows Safety and Preliminary Clinical Efficacy.

BACKGROUND: Despite recent advances, there is an urgent need for agents targeting HER2-expressing cancers other than breast cancer. We report a phase I study (NCT01730118) of a dendritic cell (DC) vaccine targeting HER2 in patients with metastatic cancer or bladder cancer at high risk of relapse. PATIENTS AND METHODS: Part 1 of the study enrolled patients with HER2-expressing metastatic cancer that had progressed after at least standard treatment and patients who underwent definitive treatment for invasive bladder cancer with no evidence of disease at the time of enrollment. Part 2 enrolled patients with HER2-expressing metastatic cancer who had progressed after anti-HER2 therapy. The DC vaccines were prepared from autologous monocytes and transduced with an adenoviral vector expressing the extracellular and transmembrane domains of HER2 (AdHER2). A total of five doses were planned, and adverse events were recorded in patients who received at least one dose. Objective response was evaluated by unidimensional immune-related response criteria every 8 weeks in patients who received at least two doses. Humoral and cellular immunogenicity were assessed in patients who received more than three doses. RESULTS: A total of 33 patients were enrolled at four dose levels (5 × 106, 10 × 106, 20 × 106, and 40 × 106 DCs). Median follow-up duration was 36 weeks (4-124); 10 patients completed five doses. The main reason for going off-study was disease progression. The main adverse events attributable to the vaccine were injection-site reactions. No cardiac toxicity was noted. Seven of 21 evaluable patients (33.3%) demonstrated clinical benefit (1 complete response, 1 partial response, and 5 stable disease). After ≥3 doses, an antibody response was detected in 3 of 13 patients (23.1%), including patients with complete and partial responses. Lymphocytes from 10 of 11 patients (90.9%) showed induction of anti-HER2 responses measured by the production of at least one of interferon-gamma, granzyme B, or tumor necrosis factor-alpha, and there were multifunctional responses in 8 of 11 patients (72.7%). CONCLUSIONS: The AdHER2 DC vaccine showed evidence of immunogenicity and preliminary clinical benefit in patients with HER2-expressing cancers, along with an excellent safety profile. It shows promise for further clinical applications, especially in combination regimens.

Forecasting the monthly incidence rate of brucellosis in west of Iran using time series and data mining from 2010 to 2019.

BACKGROUND: The identification of statistical models for the accurate forecast and timely determination of the outbreak of infectious diseases is very important for the healthcare system. Thus, this study was conducted to assess and compare the performance of four machine-learning methods in modeling and forecasting brucellosis time series data based on climatic parameters. METHODS: In this cohort study, human brucellosis cases and climatic parameters were analyzed on a monthly basis for the Qazvin province-located in northwestern Iran- over a period of 9 years (2010-2018). The data were classified into two subsets of education (80%) and testing (20%). Artificial neural network methods (radial basis function and multilayer perceptron), support vector machine and random forest were fitted to each set. Performance analysis of the models were done using the Root Mean Square Error (RMSE), Mean Absolute Error (MAE), Mean Absolute Root Error (MARE), and R2 criteria. RESULTS: The incidence rate of the brucellosis in Qazvin province was 27.43 per 100,000 during 2010-2019. Based on our results, the values of the RMSE (0.22), MAE (0.175), MARE (0.007) criteria were smaller for the multilayer perceptron neural network than their values in the other three models. Moreover, the R2 (0.99) value was bigger in this model. Therefore, the multilayer perceptron neural network exhibited better performance in forecasting the studied data. The average wind speed and mean temperature were the most effective climatic parameters in the incidence of this disease. CONCLUSIONS: The multilayer perceptron neural network can be used as an effective method in detecting the behavioral trend of brucellosis over time. Nevertheless, further studies focusing on the application and comparison of these methods are needed to detect the most appropriate forecast method for this disease.

TFPI2 and NDRG4 gene promoter methylation analysis in peripheral blood mononuclear cells are novel epigenetic noninvasive biomarkers for colorectal cancer diagnosis.

BACKGROUND: As a result of the growing prevalence of colorectal cancer (CRC), new screening and early detection methods are required. Among the novel biomarkers, DNA methylation has emerged as a high-potential diagnosis/screening molecular marker. The present study aimed to assess non-invasive early diagnosis of CRC by examining promoter methylation of TFPI2 and NDRG4 genes in peripheral blood mononuclear cells (PBMCs). METHODS: Fifty CRC patients and 50 normal controls were recruited to the present study. Quantitative methylation of the promoter region of the TFPI2 and NDRG4 genes was analyzed in DNA extracted from PBMCs of all cases and control subjects using a methylation-quantification endonuclease-resistant DNA (MethyQESD) method. RESULTS: The sensitivity and specificity of the TFPI2 gene for the diagnosis of CRC was 88% and 92%, respectively, and, for the NDRG4 gene, it was 86% and 92%, respectively. The methylation range for the TFPI2 gene was 43.93% and 11.56% in patients and controls, respectively, and, for the NDRG4 gene, it was 38.8% in CRC patients and 12.23% in healthy controls (p < 0.001). In addition, we observed that a higher percentage of methylation was correlated with the higher stage of CRC. CONCLUSIONS: The results of the present study reveal that PBMCs are reliable sources of methylation analysis for CRC screening. Furthermore, the TFPI2 and NDRG4 genes provide sufficiently high sensitivity and specificity to be nominated for use in a novel noninvasive CRC screening method in PBMCs.

The Epidemiology of Aggression and Associated Factors among Iranian Adult Population: A National Survey.

BACKGROUND: This survey was conducted to determine the level of aggression among the Iranian adult population and underlying predisposing factors. STUDY DESIGN: A cross-sectional study. METHODS: This cross-sectional study included 10,957 participants, involving 23 out of the 31 provinces of Iran in 2019. The outcome of interest was aggression, evaluated by the Buss & Perry aggression questionnaire. The association between aggression and 34 demographic, behavioral, social, and cultural characteristics was assessed using simple and multiple linear regression. RESULTS: The overall mean (SD) score of aggression was 77.10 (22.53). Based on the severity of aggression, the participants were categorized into four groups as follows: 2,464 (23.1%) nonaggressive, 4,692 (43.9%) mild, 3,071 (28.8%) moderate, and 454 (4.2%) severe aggressive. Aggression was more likely to occur in people with the following characteristics: younger ages, having several siblings, lower ranks of birth, having an intimate friend of the opposite sex, having an aggressive father/mother, history of parental divorce, interest in watching action/porn movies, listening to music, history of escape from home/school, using neuropsychiatric drugs, using illicit drugs, history of suicidal thoughts/attempt, and family conflict and hostility. Aggression was less likely to occur with the following characteristics: reading, regular physical exercise, the ability to control anger, regular prayer, adherence to avoid lying, respect to other people's rights, sexual satisfaction, and attachment to parents. CONCLUSION: A majority of the population has some degree of aggression. Aggression is a multifactorial behavior corresponding with several demographical, social, cultural, and religious factors, some of which back to early childhood events.

Single nucleotide polymorphism rs10889677 in miRNAs Let-7e and Let-7f binding site of IL23R gene is a strong colorectal cancer determinant: Report and meta-analysis.

Single nucleotide polymorphisms (SNPs) in the recognition sites of microRNAs (miRNAs), located at 3' untranslated region (UTR) of mRNAs, interfere with posttranslational gene regulation. Deregulation of genes may contribute to some disease susceptibility including colorectal cancer (CRC). In the present study, in a case-control setup, 167 CRC patients and 161 control subjects were studied for allele and genotype frequency of rs10889677 polymorphism in miRNAs Let-7e and Let-7f binding sites at 3' UTR of IL23R gene using PCR-RFLP assay. Also, related articles were retrieved from MEDLINE, Cochrane review, Google Scholar and Scopus databases for meta-analysis study. According to our results, AA genotype of SNP rs10889677 was significantly correlated with increased risk of CRC (OR = 3.10; 95% CI [1.86-5.18]; P: < 0.001). In a meta-analysis on 10 risk estimates for the CC versus AA genotype, we found an inverse association between CC SNPs and risk of all cancer (OR = 0.59; 95% CI [0.49-0.71]; P < 0.001). In conclusion, our results demonstrate that rs10889677 polymorphism is significantly associated with CRC risk.

Epidemiological Features of Human Brucellosis in Iran (2011-2018) and Prediction of Brucellosis with Data-Mining Models.

BACKGROUND: Brucellosis is known as the major zoonotic disease. We aimed to compare the performance of some data-mining models in predicting the monthly brucellosis cases in Iran. STUDY DESIGN: Population-based cohort study. METHODS: Three data mining techniques including the Support Vector Machine (SVM), Multivariate Adaptive Regression Splines (MARS), and Random Forest (RF) besides to one classic model including Auto-Regressive Integrated Moving Average (ARIMA) was used to predict the monthly incidence of brucellosis in Iran during 2011-2018. We used several criteria (root mean square error (RMSE), mean absolute error (MAE), coefficient of determination (R2) and intra-class correlation coefficient (ICC) for appraising the accuracy of prediction and performance of our models. All analysis was done using free statistical software of R3.4.0 RESULTS: Overall 118867 cases (with a mean age of 34.01±1.65 yr) of brucellosis were observed and seven-year incidence rate of brucellosis in Iran was 21.78 (95% CI: 21.66, 21.91). The majority of patients (58.84%) were male and 25-29 yr old. The first three provinces with the highest incidence rate of brucellosis included the following; Kurdistan (71.39 per 100000), Lorestan (68.09 per 100000) and Hamadan (56.24 per 100000). CONCLUSION: Brucellosis was more common in males, 25-29 aged yr, western provinces and spring months. The disease had a decreasing trend in the last years. MARS model was more appropriate rather than data mining models for prediction of monthly incidence rate of brucellosis.

Evaluation of miR-21 Inhibition and its Impact on Cancer Susceptibility Candidate 2 Long Noncoding RNA in Colorectal Cancer Cell Line.

BACKGROUND: Both microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) have been shown to have a critical role in the regulation of cellular processes such as cell growth and apoptosis, as well as cancer progression and metastasis. lncRNAs are aberrantly expressed in many diseases including cancer. Although it is well known that miRNAs can target a large number of protein-coding genes, little is known whether miRNAs can also target lncRNAs. In the present study, we determine whether miR-21 can regulate lncRNA cancer susceptibility candidate 2 (CASC2) in colorectal cancer. MATERIALS AND METHODS: LS174T cells were transfected with locked nucleic acid (LNA)-anti-miR-21 and scrambled LNA for 24, 48 and 72 h. The expression of miR-21 and lncCASC2 was evaluated by quantitative reverse transcriptase polymerase chain reaction. RESULTS: However, contrary to what we expected and reported by others, lncCASC2 quantity was significantly reduced in LNA treated LS174T cells compared to the scrambled treated and normal untreated cells (P < 0.05). CONCLUSION: The interaction of miRNA and lncRNA are not as simple as suggested by other reports. Moreover, it could be complex molecular mechanisms underlying the communication of various noncoding RNA elements.

Magnetic resonance imaging to determine the incidence of brain ischaemia in patients with beta-thalassaemia intermedia.

UNLABELLED: One complication in patients with beta-thalassaemia who had prolonged survival is chronic hypercoagulable state, which results in thromboembolic events involving major organs including the brain. We determined the prevalence of microthrombosis in the brain in an asymptomatic subgroup of patients with b-thalassaemia intermedia (TI) who had undergone splenectomy. This retrospective review included 200 patients with TI diagnosed on the basis of blood count, haemoglobin (Hb) electrophoresis and clinical data. Their ages ranged from 18 to 34 years, 19 (63.3%) were women and 11 (36.7%) were men. We selected 30 patients at random who fulfilled the inclusion criteria: Hb concentration >7 g/dl), splenectomy and platelet count >500,000/ml. Their mean Hb concentration was 8.4 g/dl and their mean ferritin concentration was 519 ng/ml. Magnetic resonance imaging (MRI) was done in every patient, and the findings were interpreted by an expert neuroradiologist. Imaging studies showed pathological findings in 28% of the patients. Six had changes in the white matter suggestive of ischaemia and two had evidence of small infarctions. CONCLUSION: 1) In this small subset of patients diagnostic magnetic resonance imaging to monitor early asymptomatic or subclinical vascular damage in the brain can be considered when they reach the age of 20 years, and repeated every 3-5 years. 2) Treatment with antiplatelet aggregants is suggested in patients with documented asymptomatic brain ischaemia. 3) These results require confirmation in a larger group of similar patients with other types of thalassaemia who are multitransfused or have an intact spleen.