The genetic differences between types 1 and 2 in von Hippel-Lindau syndrome: comprehensive meta-analysis.

BACKGROUND: Patients with von Hippel-Lindau (VHL) disease are at risk of developing tumors in the eye, brain, kidney, adrenal gland, and other organs based on their gene mutations. The VHL tumor suppressor gene contains pathogenic variants responsible for these events. This meta-analysis aims to investigate the genetic differences among the various types of VHL syndrome and their correlation with the location of mutations (exons and domains) in the VHL gene. METHOD: Papers eligible for publication until September 2023 were identified using the electronic databases of PubMed, Google Scholar, Scopus, and EMBASE. The Random Effect model was utilized to evaluate the genetic differences between type 1 and type 2 VHL syndromes. RESULTS: The prevalence of missense mutations (MSs) was found to be 58.9% in type 1, while it was 88.1% in type 2. Interestingly, the probability of observing MSs in type 1 was 0.42 times lower compared to type 2. The mutation hotspots of the VHL gene were R167Q/W, Y98H, R238W, and S65L, respectively. Although type 2 had a high presentation of Y98H and R238W, it did not have a higher S65L than type 1. The analysis demonstrated a statistically significant higher prevalence of truncated mutations (PTMs) in type 1. Among type 1, large/complete deletions (L/C DELs) were found in 16.9% of cases, whereas in type 2 only 3.7%. This difference was statistically significant with a p-value < 0.001. Overall, the probability of identifying mutations in domain 2 compared to domain 1 was found to be 2.13 times higher in type 1 (p-value < 0.001). Furthermore, the probability of detecting exon 1 in comparison with observing exon 2 in type 1 was 2.11 times higher than type 2 and revealed a statistically significant result (p-value < 0.001). The detection of exon 2 was 2.18 times higher in type 1 (p-value < 0.001). In addition, the likelihood of discovering exon 2 compared with others was significantly lower in type 1 compared with type 2 VHL (OR = 0.63, p-value = 0.015). CONCLUSIONS: We have revealed a comprehensive genetic difference between types 1 and 2 of VHL syndrome. The significant differences in MS, PTMs, L/C DELs, and the location of the mutations between type 1 and type 2 VHL patients in the Asian, European, and American populations emphasize the genetic heterogeneity of the syndrome. These findings may pave the way for the diagnosis, treatment, and further investigation of the mechanisms behind this complex genetic disorder.

The Effect of Group Counselling based on Constructive Couple Communication on Perceived Spousal Support in Uterine and Cervical Cancer Survivors: A Randomized Control Trial.

Background: Uterine and Cervical cancer survivors face challenges like the disruption of emotional and sexual relationships, struggle to maintain sexual life and intimacy, and the possibility of divorce. The study aimed to determine the effect of group counseling based on couples' constructive communication on perceived spousal support in uterine and cervical cancer survivors. Methods: A randomized controlled trial on 40 women who survived uterine and cervical cancer were recruited using convenience sampling and then randomly allocated to a couple-based constructive communication intervention group and a routine cancer center care control group from June 2019 to March 2020 in Motahhari and Imam Khomeini hospitals in Urmia. The intervention group was involved in a group counseling session weekly for 5 weeks, regarding constructive couple communication skills. Perceived spouse support was assessed using the sources of social support scale which has 4 subscales informational, instrumental, emotional, and negative support before and one week after the end of the intervention in both groups. Data analysis was performed using SPSS version 24 through Independent and paired t-tests, Mann-Whitney U test, Wilcoxon, chi-square, and ANCOVA. P value<0.05 was considered statistically significant. Results: The effect of the intervention was statistically significant in reducing negative support in the intervention group (2.70±0.80) in comparison with the control group (3.40±1.04) (P=0.03). It was also statistically significant in increasing informational support (3.45±0.71 vs. 2.15±0.80, P<0.001), instrumental support (3.15±0.58 vs. 2.85±0.74, P<0.001), and emotional support (19.40±1.60 vs. 16.10±2.10, P<0.001). Conclusion: Group counseling based on couple constructive communication increased perceived spousal support in uterine and cervical cancer survivors. Trial Registration Number: IRCT20150125020778N22.

Evaluating the impact of mesenchymal stem cell therapy on visual acuity and retinal nerve fiber layer thickness in optic neuropathy patients: a comprehensive systematic review and meta-analysis.

BACKGROUND: Stem cell therapy has emerged as a potential therapeutic avenue for optic neuropathy patients. To assess its safety and efficacy, we conducted a systematic review and meta-analysis, focusing on the latest evidence pertaining to the improvement of visual acuity (VA) through stem cell therapy. METHODS: We analyzed Each database from its inception until June 2024. PubMed, Scopus, and Google Scholar were systematically searched to identify the included studies. Data were extracted regarding the year of publication, the name of the first author, sample size, VA (Log Mar), and Retinal Nerve Fiber Layer (RNFL) thickness. PRISMA protocol was used as a guide to perform this meta-analysis. STATA 16 was used for statistical analysis. RESULTS: A total of 66 eyes were examined in seven papers. Based on the meta-analysis, the mean VA (Log MAR) of patients with optic neuropathy improved from 0.90 to 0.65 following stem cell therapy intervention (p-value = 0.001). The thickness of the RNFLs did not demonstrate a significant change (p-value was 0.174). CONCLUSION: According to this systematic review and meta-analysis, stem cell therapy may improve the visual acuity of patients with optic neuropathy. Aside from the traditional therapy that can be provided to patients with optic neuropathy, stem cell therapy may also be beneficial.

Investigation of germline VHL variants in Iranian patients with retinal capillary hemangioblastoma and genotype-phenotype analysis.

BACKGROUND: Retinal capillary hemangioblastoma (RCH), while sporadic in some cases, is the most common and earliest manifestation of von Hippel-Lindau disease (VHL). This is the first report on different types of VHL variants and genotype-phenotype correlations in Iranian families with RCH. MATERIALS AND METHODS: In this prospective observational case series study, 17 families with RCH were included. PCR was performed to amplify 3 exons of VHL gene. Afterward, Sanger sequencing was performed on all PCR products. For the detection of VHL copy number variations, MLPA was used. RESULTS: Our study identified 10 different types of VHL variants. Missense mutations were the most common variants found and affected the structure of α domain of the VHL protein (pVHL). The majority of mutations (72.7%) in the patients with RCH and central nervous system hemangioblastoma (CNS-HB) were located on α domain. CONCLUSION: α domain of VHL may play a potential role in the pathogenesis of RCH. Our findings suggest that genotype-phenotype characteristics in those variants in α- domain may predispose patients to RCH with CNS-HB.

Spotlight on Targeted Chemotherapy in Retinoblastoma: Safety, Efficacy, and Patient Outcomes.

As the most common primary intraocular malignancy of childhood, retinoblastoma (RB) has had a complex journey in its management, following a course from enucleation as the first life-saving treatment to numerous globe-salvaging therapies during the last century. Currently, this potentially lethal disease has achieved high survival rates owing to multidisciplinary management and the introduction of neoadjuvant and multimodal chemotherapy. Therefore, the goal of treatment is shifting toward conserving the globe and vision as much as possible. Up until recently, many advanced cases of RB were enucleated primarily; however, targeted chemotherapy via the ophthalmic artery and management of intraocular seeding by local administration of chemotherapeutic agents have revolutionized the globe-conserving therapies. The added benefit of avoiding systemic complications of cytotoxic drugs resulted in these methods gaining popularity, and they are becoming a main part of care in many referral centers. Initially, there were some safety concerns regarding these approaches; however, increasing experience has shown that these modalities are relatively safe procedures and many complications can be averted by changing the choice of the drug and using some prophylactic measures. It is hoped that, in the near future, with advances in early diagnosis and patient-targeted molecular therapies, as well as gene-editing techniques, the patient's vision can be saved even in advanced RB.

Review: New horizons in retinoblastoma treatment: an updated review article.

Retinoblastoma (Rb) is a rare childhood intraocular malignancy with an incidence rate of approximately 9000 children per year worldwide. The management of Rb is inherently complex and depends on several factors. The orders of priorities in the treatment of Rb are saving life, globe salvage and vision salvage. Rarity and the young age at diagnosis impede conducting randomized clinical trials (RCTs) for new therapeutic options, and therefore pre-RCTs studies are needed. This review provides an overview of advances in Rb treatment options, focusing on the emergence of new small molecules to treat Rb. Articles related to the management and treatments of Rb were searched in different databases. Several studies and animal models discussing recent advances in the treatment of Rb were included to have a better grasp of the biological mechanisms of Rb. Over the years, the principles of management and treatment of Rb have changed significantly. Innovations in targeted therapies and molecular biology have led to improved patient and ocular survival. However, there is still a need for further evaluation of the long-term effects of these new treatments.

Transfer of the Long Head Biceps Tendon to Conjoined Tendon in Proximal Humerus Fractures with Cleavage or Comminution at the Bicipital Groove.

Objective: To evaluate the clinical and radiographic findings of long head biceps tendon (LHBT) transfer in traumatic proximal humeral fractures with the biceps groove breakage or comminution. Methods: In this interventional study, subjects surveyed in terms of shoulder function, clinical signs of LHBT tendinitis, radiographic signs of transferred biceps as a possible depressor of the shoulder, and mechanical changes of the scapula. Data were analyzed in SPSS version 21. Results: Fifteen patients were included in the case group (tendon transfer to the conjoined tendon), and 10 patients were evaluated in the control group (non-transfer or non-manipulation of the exposed tendon in the fracture callus of biceps groove). The mean age of the study population was 46.56±14.31 years, and the majority of patients (14.56%) were men. The differences between two groups were not significant in terms of the American Society of Shoulder and Elbow Surgeons (ASES) score, University of California at Los Angeles (UCLA) score, and constant shoulder score (CSS) (p=0.535, p=0.419, and p=0.266, respectively). Also, there was no significant differences between the case and control groups regarding the biceps muscle involvement (Popeye sign: p=1.00; tenderness: p=0.477; pain: p=1.00; speed test: p=1.00; Yergason's test: p=1.00). Conclusion: LHBT transfer to the conjoined tendon in proximal humerus fractures with cleavage or comminution at the bicipital groove showed no advantages.

A meta-analysis of different von Hippel Lindau mutations: are they related to retinal capillary hemangioblastoma?

Retinal capillary hemangioblastomas (RCH) is a benign tumor that represents the initial manifestation in roughly half of Von Hippel Lindau (VHL) patients. They may also occur sporadically without systemic involvement. A first meta-analysis study was investigated to estimate the prevalence of Retinal capillary hemangioblastoma (RCH) in Von Hippel Lindau (VHL) syndrome, and its relation to type and location of mutations in VHL gene. The electronic databases of PubMed, Scopus, Embase, and Google Scholar were utilized to find eligible papers published up to May 2020. Lastly, after the different prevalence of RCH in Europe compared to other continents was noted, we decided to consider European and non-European patients separately. The Random effect model was used to evaluate the relation between developing RCH and types of mutations. The overall prevalence of RCH among VHL patients is about 47%. The prevalence of RCH was significantly higher in Europe in comparison with non-Europeans (p value < 0.001). Overall, the differences between the prevalence of RCH among different mutation types were not statistically significant. However, in Europe, the prevalence of RCH was significantly higher in patients with truncation mutation (p value = 0.007). In Europe, the RCH in VHL patients who had a mutation in exon 2 was significantly lower in comparison with exon 1 (p value = 0.001); but in non-Europeans, the prevalence of RCH in VHL patients that involved exon 2 was significantly higher in comparison with VHL patients with a mutation in exon1 (p value = 0.012). The highest risk of developing RCH was reported among Europeans. Overall, this study showed that the prevalence of RCH in VHL syndrome is not related to type or location of mutations and difference of RCH prevalence is probably depends on other genetic or environmental factor that should be considered in subsequent studies.

Evaluation of the Therapeutic Effect of the Traditional Herbal Medicine Atrifil and Oshagh Gum on Testosterone-Induced Benign Prostatic Hyperplasia in Wistar Rats.

Benign prostatic hyperplasia (BPH) is a common disease that affects elderly men with various complications. This study evaluates the effects of an Iranian traditional herbal medicine "Atrifil and Oshagh gum" on BPH in male Wistar rats. Atrifil is a combination of three medicinal plants: Emblica officinalis Gaertn, Terminalia chebula Retz, and Terminalia bellerica Retz" extracts, and Oshagh gum is Dorema ammoniacum D. Dono gum. In this study, 30 male Wistar rats were divided into five groups: normal control, disease, finasteride, and extract with 300 and 600 mg/kg groups. The extract is a combination of hydroalcoholic Atrifil extract and Oshagh gum. All groups received intramuscular testosterone enanthate to induce BPH except the normal control group. On the twenty-eighth day, prostate glands were separated. Histopathological changes were observed. Furthermore, the prostate-specific antigen (PSA) and prostate weights were measured. The binding propensities of finasteride, equol, and flavonoids present in this extract such as quercetin, rutin, and kaempferol for 5α-reductase, estrogen receptor alpha and beta, and estrogen-related receptor gamma were assessed using in silico docking approach. Histopathological evaluation, biochemical parameter, and PSA level results indicated significant inhibition of accruing and progression of BPH in groups treated with 600 mg/kg extract (p < 0.01). Furthermore, molecular docking showed that rutin had a high affinity to bind the receptors 5α-reductase, estrogen receptor beta, and estrogen-related receptor gamma even more than finasteride, and on average, quercetin had a higher affinity to all these receptors. In the end, it can be concluded that Atrifil and Oshagh gum is effective in preventing BPH.

Global Incidence and Trend of Uveal Melanoma from 1943-2015: A Meta-Analysis.

BACKGROUND: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults arising from uveal tissue melanocytes. Considering limited population based studies, we performed a meta-analysis of uveal melanoma incidence rate in worldwide. METHODS: For this meta-analysis, the electronic database of PubMed, Scopus, Embase and Google Scholar were utilized. Qualified Cohort studies and registry system databases were included in the study. Trend analysis and the estimation of incidences were reported. Thereafter subgroup analysis on gender and diagnostic tests were performed. Analyses were done using random effect models. RESULTS: A total of 22 publications were eligible to include in the meta-analysis. The incidence rates of uveal melanoma were 5.74 (95%CI: 4.37-7.11) and 7.30 (95%CI: 6.36-8.24) in North America and Europe respectively. The analysis showed a significant decreasing trend in North America. It was expected that the risk of UM decreased approximately 0.09 (SE=0.04) per million persons per year. No significant trend was detected in Europe. There was not any significant difference between the incidence rate in male and female (6.58, 95%CI: 5.42-7.75 vs. 5.44, 95%CI: 4.40-6.48). In addition, the reported incidence rates in different diagnostic approaches were similar (6.61, 95%CI: 5.63-7.58 in clinical vs. 6.67, 95%CI: 5.83-7.42 in histological). CONCLUSION: This analysis confirmed in recent decades, there has been a steady decline in the incidence in North America. However, in European countries where they still have the highest incidence worldwide, the trend was stable. It seems that international melanoma registration collaboration can conduct a unified, multicentral study to estimate the worldwide incidence of UM and impact of different factors on its rate.

Association of RB1 rs9568036 and CDKN1A rs1801270 Polymorphisms with Retinoblastoma Susceptibility.

Purpose: To investigate the association of polymorphisms (rs9568036 and rs1801270) in the RB1 and P21 genes with susceptibility to retinoblastoma (RB). Methods: This case-control study was designed with 50 patients with RB and 50 controls. Polymerase chain reaction was performed to amplify the intron 17 of RB1 rs9568036 and exon 2 of P21 rs1801270. Then, all the amplified fragments were subjected to directional sequencing, and finally, the association between genotypes and the development of RB risk and invasion was studied. Results: A statistically significant difference in genotypic or allele frequencies of single-nucleotide polymorphisms (SNPs) (rs1801270 and rs9568036) was found between Iranian RB patients and the controls (P > 0.05). However, the frequency of genotype RB1 rs9568036 observed a statically significant difference in the RB patients compared to the control group, and the nonwild-type allele A increased the chance of susceptibility to developing RB by 2.92 times. Conclusion: The rs9568036 SNP in the RB1 gene may increase susceptibility to the development of RB in the affected patients. In spite of that, this polymorphism does not influence RB patient's invasion. Further investigation with a large enough sample size is recommended to validate this hypothesis.

Fe(II)-phthalocyanine supported on chitosan aerogel as a catalyst for oxidation of alcohols and alkyl arenes.

Manipulation of materials is considered as one of the eminent strategies to create desirable catalysts. In this regard, increasing surface area and decreasing dimensions of catalysts have been widely employed on account of effectiveness of these methods. Herein, aerogel form of chitosan as a sustainable, and high aspect ratio compound is employed as a green support for the catalytic purposes. Chitosan aerogel was modified with Fe(II)-phthalocyanine to produce a heterogeneous catalyst for oxidation reactions. The synthesized catalyst promoted the oxidation reactions of alcohols and alkyl arenes to the corresponding aldehydes and ketones using H2O2 as an oxidant in 24 h. The reactions for aliphatic and aromatic alcohols gave turnover numbers of 106-109 at 80 °C and 106-117 at room temperature, respectively. The oxidations of alkyl arenes were carried out with turnover numbers laying in the range of 106-117 at 100 °C. The low toxicity, inexpensive nature, and recycling possibility of the catalyst accompanied by the reaction mild conditions, clean oxidant, and excellent yields offer chitosan aerogel modified with Fe(II)-phthalocyanine as a promising catalyst for oxidation reactions.

Young Breast Cancer: Novel Gene Methylation in WBC.

INTRODUCTION: Breast cancer is a highly diverse disease, and epigenomic alterations, as principle changes in the pathogenesis of breast cancer, have recently been noticed in epimarker research on peripheral blood. METHODS: In this study, DNA samples isolated from the white blood cells of 30 breast cancer patients were compared to 30 healthy controls using methylated DNA immunoprecipitation microarray (MeDIP-chip) to determine differentially methylated region as a potential epimarker in cancer and control cases. RESULTS: A total of 1799 differentially methylated regions were identified, including ZNF154, BCL9, and HOXD9, in which significant methylation differences were confirmed in breast cancer patients through a quantitative real-time polymerase chain reaction. Differential methylation of the mentioned genes has been reported in different cancer tissues and cell-free DNA, including breast cancer. Methylation of those genes listed in the white blood cells of our young patients not only relates to their importance in the pathogenesis of breast cancer but may also highlight their potential as primary epimarkers that can warrant further evaluation in large cohort studies. It is important to note that methylation alteration in WBC, as well as genetic mutation, can be identified years before cancer development, which emphasizes this issue as a potential screening marker.

Chitosan-selenium nanoparticles (Cs-Se NPs) modulate the photosynthesis parameters, antioxidant enzymes activities and essential oils in Dracocephalum moldavica L. under cadmium toxicity stress.

In view of damaging impacts of cadmium (Cd) toxicity on various vital processes of plants and strategies for alleviating these effects, selenium (Se) application has been recently achieved great attention. In addition, chitosan (CS) and its nano-form, besides many positive effects on plants, could be considered as an excellent adsorption matrix and a carrier for a wide range of materials like Se with various applications in agricultural sector. For that point, the combination nano-form of Se and CS (CS-Se NPs), using CS as a carrier and control releaser for Se, could enhance Se efficiency particularly at lower doses under stress conditions. Therefore, Se (10 mg L-1), CS (0.1%) and CS-Se NPs (in two concentrations; 5 and 10 mg L-1) were applied on Moldavian balm plant under 0, 2.5 and 5 mg kg-1 Cd-stress conditions. The results demonstrated that mostly Se and CS-Se NPs treatments could lessen negative effects of Cd-stress conditions through enhancing agronomic traits, photosynthetic pigments, chlorophyll fluorescence parameters and SPAD, proline, phenols, antioxidant enzymes activities and some dominant constituents of essential oils and decreasing MDA and H2O2. These encouraging impacts were more significant at lower dose of CS-Se NPs (5 mg L-1) introducing it as the best treatment to ameliorate Moldavian balm performance under Cd-stress conditions. In conclusion, CS-Se NPs could be considered as a supportive approach in plant production mainly under different heavy metal stressful conditions and probably a potential plant growth promoting and stress protecting agent with new outlooks for applying in agricultural sector.

RETRACTED: Clinical significance of ITPA rs67002563 polymorphism in patients with acute lymphoblastic leukemia treated with 6-mercaptopurine.

This article has been retracted at the request of the Authors as it was published without the knowledge of the full research group, using data that had already been published by the same research group in another study in Leukemia Research (http://dx.doi.org/10.1016/j.leukres.2015.06.016).

Frequency of ITPA gene polymorphisms in Iranian patients with acute lymphoblastic leukemia and prediction of its myelosuppressive effects.

6-Mercaptopurine (6-MP) plays an important role in treatment of childhood acute lymphoblastic leukemia (ALL). Inosine triphosphate pyrophosphohydrolase (ITPA) is an enzyme involved in 6-MP metabolic pathway that convert the inosine triphosphate (ITP) to inosine monophosphate (IMP) and prevents the accumulation of the toxic metabolite ITP. Our objective was to evaluate the ITPA 94C>A, IVS2+21A>C polymorphisms in patients with ALL treated with 6-MP and prediction of its clinical outcomes. Our study population consisted of 70 patients diagnosed with ALL in the Division of Hematology-Oncology of Tehran Mofid Hospital. PCR was carried out to amplify exon 2, exon 3, intron 2, and intron 3 of ITPA gene then, all the amplified fragments were subjected to directional sequencing and then association between genotype and 6-MP toxicity was studied. In this study two exonic variants including 94C>A and 138G>A showed a prevalence of 8.5% and 36.4%, respectively. Two intronic variants, IVS2+21A>C and IVS3+101G>A were found in 13.5% and 7% of the samples, respectively. The rate of myelosuppression in the presence of mutant homozygote and heterozygous alleles (94C>A, 138G>A, IVS2+21A>C and IVS3+101G>A) was higher than that of wild type alleles during the use of 6-MP. Hepatotoxicity in patients with mutant homozygous and heterozygous 94C>A and IVS3+101G>A during the treatment 6-MP was higher than before treatment with 6-MP. Our results showed that patients with aberrant ITPase genotype (mutant homozygous or heterozygous), more likely to be myelosuppressed and show liver toxicity after treatment with 6-MP. Our results suggest that pre-therapeutic screening of patients for ITPA 94C>A, IVS2+21A>C and IVS3+101G>A can help in minimizing the adverse effects of 6-MP in ALL patients.