The Application of Umbilical Cord Blood-derived Platelet Gel for Skin Ulcers Associated With Chronic Graft-Versus-Host Disease in Pediatrics: A Randomized Trial.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative strategy against a variety of malignant and nonmalignant disorders. However, acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) commonly complicate this approach, culminating in substantial morbidities and mortalities. The integumentary system is the preponderant organ involved in cGVHD, and its response to existing treatments, including well-versed immunosuppressants and novel targeted therapies, is not desirable. Despite the rarity, ulcers of sclerotic skin cGVHD are treatment-refractory and associated with significant morbidities and an exaggerated risk of infectious complications. Platelet-rich plasma (PRP) and its derivatives are endowed with growth factors and proangiogenic molecules and hold regenerative potential. This study aimed to assess the safety and efficacy of the application of platelet gel-containing dressing against ulcerative skin cGVHD in pediatric patients. This randomized trial is conducted at the hematopoietic stem cell transplantation unit of the Children's Medical Center Hospital in Tehran, Iran. Twenty-one pediatric patients (aged between 5 and 15 years) were initially enrolled, and 16 met the inclusion criteria. All cases (4 females) were recipients of allo-HSCT who had been complicated with symmetrically or near-symmetrically ulcerative sclerotic skin cGVHD. Fresh umbilical cord blood (UCB) was obtained from healthy donors and underwent centrifugation using a novel PRP preparation kit in a single-step process. Platelet gel was produced by adding thrombin to the isolated buffy coat layer. Two similar ulcers of each patient were randomized to receive either conventional dressing or platelet gels up to 6 times. At each time point evaluation, ulcer size and its relative reduction compared to the basal size were recorded. Included patients received a total of 80 platelet gel-containing dressings. While the mean sizes of randomized ulcers at the beginning of the study were similar, their differences became significant 15 days after the initiation of intervention (P = .019). In addition, the mean reduction in the ulcers' surface area (in comparison to their baseline values) was significantly higher for the intervention arm at all evaluation points (P = .001 for day 5 and P < .001 for subsequent time points). At the end of the trial, the number of ulcers with a more than 50% reduction in size was 14 (87.5%) in the intervention arm (including 6 completely healed ulcers) versus 1 (6.25%, which was not completely healed) in the control arm (P < .001). None of the patients exhibited any localized or systemic treatment-related adverse events. In this study, using a relatively large number of cases, we showed that UCB-derived platelet gel is a safe, feasible, and effective curative approach for skin ulcers of sclerotic skin cGVHD in pediatric patients. Designing upcoming trials on the efficacy of this therapeutic approach for ocular, mucosal, and acute skin GVHD is prudent. Retrospectively registered at the Iranian Registry of Clinical Trials (registration number IRCT20190101042197N1) on August 24, 2020.

Posterior Reversible Encephalopathy Syndrome in Pediatric Hematopoietic Stem Cell Transplantation with Beta Major Thalassemia: The Association between the PRES Occurrence and Class of Beta Major Thalassemia.

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only definitive curative option for ß-major thalassemia patients (ß-MT). Posterior reversible encephalopathy syndrome (PRES) is a pervasive neurological complication which typically occurs following HSCT. ß-MT patients are prone to a higher PRES incidence due to long-term immunosuppression; thus, it is imperative that these patients are closely monitored for PRES after HSCT. PATIENTS AND METHODS: We included 148 pediatric patients with ß-MT who underwent HSCT between March 2015 and August 2022 in Children's Medical Center. Patients in this study were divided into two groups. The association between PRES and class of ß-MT and other risk factors were assessed and the overall survival rate was determined. RESULTS: Fourteen out of 112 patients (12%) with class I and II ß-MT developed PRES. However, PRES occurred in 11 out of 36 patients (30.5%) with ß-MT-III. Our results indicated that there was a significant association between class III ß-MT and the occurrence of (P = .004). Additionally, acute graft-versus-host disease (aGVHD) occurred in 80% and 44.7% of patients in the PRES and non-PRES groups, respectively (P = .001). The results of the Kaplan-Meier analysis revealed that the 5-year overall survival (OS) was 75.6% in the PRES group versus 95% in the non-PRES group, which was statistically significant (P = .001). CONCLUSION: Based on our results, pediatric ß-MT III patients are at a higher risk of developing PRES. Additionally, pediatric ß-MT patients with a history of aGVHD, regardless of disease class, are more likely to develop PRES. Considering these results, PRES has a higher chance of being the etiology of symptoms and should be considered more often in these patients.

Nano-curcumin effects on nicotine dependence, depression, anxiety and metabolic parameters in smokers: A randomized double-blind clinical study.

Background: Smoking is clearly associated with metabolic profiles/abnormalities, psychological dysfunction, and symptoms of nicotine dependence. Nano-Curcumin (Nano-CUR) is a medicinal herb with antianxiety, antioxidant antidepressant-like effects, and anti-inflammatory properties. This RCT aimed to determine the therapeutic effects of Nano-CUR in smokers on clinical symptoms and metabolic parameters. Methods: This trial was conducted on 70 participants with cigarette smoking. Smokers in two arms received soft gel capsules Nano-CUR 80 mg/daily for 3 months (n = 35) and placebo (n = 35), respectively. Primary outcomes (Nicotine dependence syndrome scale, depression, and anxiety beck score), and secondary outcomes (glycemic, lipid, stress oxidative, and inflammation profiles) were analyzed before and 3-months after the intervention in smokers. Results: Nano-CUR supplementation significantly decreased nitric oxide, malondialdehyde, and C-reactive protein levels (P < 0.05), compared to the control. Furthermore, no significant effect change was shown in nicotine dependence syndrome, depression, anxiety, and other metabolic parameters (p > 0.05). Conclusion: Nano-CUR intake may have favorable effects on C-reactive protein, malondialdehyde, and nitric oxide in subjects with cigarette smoking. More RCT are required to evaluate the effectiveness of Nano-CUR supplementations in smokers in order to reject or support these conclude.

A comprehensive comparison between TBI vs non-TBI-based conditioning regimen in pediatric patients with acute lymphoblastic leukemia: A systematic review and meta-analysis.

INTRODUCTION: We aimed to evaluate the efficacy, safety, and latent toxicity of total body irradiation (TBI)-based conditioning regimens compared to non-TBI regimens for pediatric patients (under 18 years old) with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: A systematic search was performed on MEDLINE, Scopus, WOS, and PMC. Also, a search for grey literature was performed on Google Scholar and relevant articles' references were included. Relevant articles which met the inclusion criteria were retrieved up to October 31th, 2022. CMA version 2 was used for the quantitative synthesis of the data. RESULTS: Eight studies on efficacy and safety of TBI and non-TBI as a conditioning regimen were analyzed and six comparative studies on late toxicity were investigated. The meta-analysis revealed a hazard ratio (HR) of 1.508 (95% CI 0.96-2.35) for overall survival (OS) in instances of non-TBI conditioning. Also, an HR of 1.503 (95% CI 1.006-2.25) for disease-free- survival (DFS) favoring TBI-based conditioning. Late complications were reported to be significantly higher in the TBI conditioning regimen group than in the non-TBI group. CONCLUSION: It appears that non-TBI regimens are as effective as TBI regimens in pediatrics with ALL regarding OS. Occurrence of latent toxicity is higher with TBI conditioning regimen. Conversely, TBI-based regimens are superior to non-TBI conditioning regimens regarding DFS. Considering all aspects, non-TBI conditioning regimens can be an alternative treatment option for pediatric ALL undergoing HSCT.

Dynamic roles of small RNAs and DNA methylation associated with heterosis in allotetraploid cotton (Gossypium hirsutum L.).

BACKGROUND: Heterosis is a complex phenomenon wherein the hybrids outperform their parents. Understanding the underlying molecular mechanism by which hybridization leads to higher yields in allopolyploid cotton is critical for effective breeding programs. Here, we integrated DNA methylation, transcriptomes, and small RNA profiles to comprehend the genetic and molecular basis of heterosis in allopolyploid cotton at three developmental stages. RESULTS: Transcriptome analysis revealed that numerous DEGs responsive to phytohormones (auxin and salicylic acid) were drastically altered in F1 hybrid compared to the parental lines. DEGs involved in energy metabolism and plant growth were upregulated, whereas DEGs related to basal defense were downregulated. Differences in homoeologous gene expression in F1 hybrid were greatly reduced after hybridization, suggesting that higher levels of parental expression have a vital role in heterosis. Small RNAome and methylome studies showed that the degree of DNA methylation in hybrid is higher when compared to the parents. A substantial number of allele-specific expression genes were found to be strongly regulated by CG allele-specific methylation levels. The hybrid exhibited higher 24-nt-small RNA (siRNA) expression levels than the parents. The regions in the genome with increased levels of 24-nt-siRNA were chiefly related to genes and their flanking regulatory regions, demonstrating a possible effect of these molecules on gene expression. The transposable elements correlated with siRNA clusters in the F1 hybrid had higher methylation levels but lower expression levels, which suggest that these non-additively expressed siRNA clusters, reduced the activity of transposable elements through DNA methylation in the hybrid. CONCLUSIONS: These multi-omics data provide insights into how changes in epigenetic mechanisms and gene expression patterns can lead to heterosis in allopolyploid cotton. This makes heterosis a viable tool in cotton breeding.

Evaluation of safety and efficacy of allogeneic adipose tissue-derived mesenchymal stem cells in pediatric bronchiolitis obliterans syndrome (BoS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

BACKGROUND: Allo-HSCT is a definite approach for the management of a wide variety of lethal and debilitating malignant and non-malignant disorders. However, its two main complications, acute and chronic graft-versus-host disease (GVHD), exert significant morbidities and mortalities. BoS, as a manifestation of chronic lung GVHD, is a gruesome complication of allo-HSCT, and for those with steroid-refractory disease, no approved second-line therapies exist. Mesenchymal stem cells (MSCs) exert anti-inflammatory and growth-promoting effects, and their administration against a wide range of inflammatory and neurologic disorders, as well as GVHD, has been associated with promising outcomes. However, literature on the safety and effectiveness of MSC therapy for BoS and pediatric cGVHD is scarce. METHODS: We designed a single-arm trial to administer adipose tissue (AT)-derived MSCs to pediatric patients with refractory BoS after allo-HSCT. AT-MSCs from obese, otherwise healthy donors were cultured in an ISO class 1 clean room and injected into the antecubital vein of eligible patients with a dose of 1 × 106/kg. The primary endpoints included a complete or partial response to therapy [in terms of increased forced expiratory volume in one second (FEV1) values and steroid dose reduction] and its safety profile. RESULTS: Four eligible patients with a median age of 6.5 years were enrolled in the study. Steroid-induced osteoporosis and myopathy were present in three cases. A partial response was evident in three cases after a single injection of AT-MSCs. The treatment was safe and tolerable, and no treatment-related adverse events were noted. Two patients developed manageable COVID-19 infections one and 4 months after AT-MSC injection. After a median follow-up duration of 19 months, all cases are still alive and have had no indications for lung transplantation. CONCLUSIONS: AT-MSCs could be safely administered to our pediatric cases with BoS post-allo-HSCT. Considering their advanced stage of disease, their sub-optimal functional capacity due to steroid-induced complications, and COVID-19 infection post-treatment, we believe that AT-MSC therapy can have possible efficacy in the management of pediatric BoS. The conduction of further studies with larger sample sizes and more frequent injections is prudent for further optimization of AT-MSC therapy against BoS. Trial registration Iranian Registry of Clinical Trials (IRCT), IRCT20201202049568N2. Registered 22 February 2021, https://en.irct.ir/trial/53143 .

Total body irradiation-free haploidentical peripheral blood stem cell transplantation compared to related and unrelated donor transplantation in pediatrics with acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer under the age of 15 years. Despite the recent advances in therapeutic regimens, relapse occurs in 15%-20% of pediatric patients after chemotherapy, and hematopoietic stem cell transplantation (HSCT) is the best treatment option. However, donor availability is one of the major challenges. Over the last decade, haploidentical donor (HID) transplantation has evolved as an alternative option. Herein, we aimed to compare the transplant outcomes in pediatric patients receiving total body irradiation (TBI)-free myeloablative regimens, between non-HID and HID transplant. PATIENTS AND METHODS: The study included 60 pediatric ALL patients who had undergone HSCT from October 2016 until September 2020. Forty-three patients received non-HID HSCT, while 17 patients received HID. The sources of stem cells (SC) were peripheral blood stem cells (PBSC) for all the patients. The conditioning regimen was based on busulfan and cyclophosphamide. For graft-versus-host disease (GvHD) prophylaxis, patients received cyclosporine and methotrexate in the setting of non-HID transplantation, where HIDs received post-transplant cyclosporine and cyclophosphamide. RESULTS: The cumulative incidences of 3-year overall survival (OS) were 73.1%, 66.6%, and 69.5%, for matched sibling donor-matched related donor (MSD-MRD), matched unrelated donor-mismatched unrelated donor (MUD-MMUD), and HID groups, respectively (p = .85). The cumulative incidences of grade II-IV acute GvHD for the MRD, MUD-MMUD, and HID groups were 29%, 41%, and 49%, respectively (p = .47). Furthermore, the 3-year cumulative incidence of chronic GvHD was MSD-MRD: 70% versus MUD-MMUD: 42% versus HID: 45% (p = .64). The 3-year cumulative incidence of relapse post transplantation was 45%, 18%, and 45%, respectively, for the MSD-MRD, MUD-MMUD, and HID groups, and the differences were not statistically significant (p = .55). There was a higher risk for cytomegalovirus (CMV) infection in patients receiving HID transplants compared to those of non-HIDs (p < .01). CONCLUSION: Our results indicate that PBSC-HID transplant outcomes in the setting of non-TBI conditioning are comparable to those of non-HIDs in pediatric ALL patients.

Impacts of climate change on water footprint components of rainfed and irrigated wheat in a semi-arid environment.

Climate change is one of the biggest environmental challenges that significantly impact water resources and the quantity and quality of agricultural products. Assessment of these impacts during the historical period and under future climate is essential for achieving a sustainable agricultural system in the face of climate change threats and water scarcity. In this research, we evaluated the yield and water footprint of rainfed and irrigated wheat during the historical period (1986-2015) and two future periods (2016 to 2055) in a semi-arid environment in Fars province, Iran. The future climate data was selected from the CanESM2 model outputs (bias-corrected and downscaled using the SDSM model) under the RCP4.5 scenario, and the yield projection was made using the AquaCrop model. Our result showed that for both irrigated and rainfed wheat, the yield significantly increases in southern parts of the study area in future climates, primarily because of an increase in effective precipitation. Other regions will experience a marginal yield decrease or no yield changes (in the case of irrigated wheat). Our assessments of the water footprint of wheat production showed a significant reduction in green and blue water footprints in the southern regions. In other regions, various patterns emerged for irrigated and rainfed wheat, but an overall increase was observed. The southern regions of the study area will be more suitable for wheat production owing to the higher yield and lower water footprint.

A Flow Cytometry Panel for Differential Diagnosis of Mantle Cell Lymphoma from Atypical B-Chronic Lymphocytic Leukaemia

Background: Differential diagnosis of chronic lymphoproliferative disorders (CLDs) has remained challenging due to the highly variable morphology features and immunophenotyping. Currently, the development of multiple-marker panel analyses by flow cytometry has opened a broad way for diagnosis of CLDs. Methods: We analyzed the peripheral blood and bone marrow samples of 131 patients with B-cell CLDs (including 91 chronic lymphocytic leukemia (CLL), 15 atypical CLL, 14 mantle cell lymphoma (MCL), and 11 CD5-/CD10-lymphoma patients) from April 2018 to April 2019, using a panel of specific markers by flow cytometry. Results: Our results indicated that the expression pattern of CD22, CD23, FMC-7, and CD5 allowed us to accurately and differentially diagnose the B-CLL, MCL, and CD5-/CD10- lymphoma, while it was not capable of differentiating MCL from atypical CLL. We, however, found that the expression patterns of CD38 and immunoglobulin light chain differed significantly between atypical B-CLL and MCL. CD38 and lambda light chain were remarkably expressed in MCL patients (92.8% and 85%, respectively) compared to the atypical CLL (1.1% and 0% respectively), with the p value less than 0.001 for both markers. In contrast to MCL patients, all the patients with atypical CLL, expressed kappa light chain. The immunohistochemistry method used for cyclin D1 confirmed that the flow cytometry detection of kappa and lambda light chains could provide a new approach with high sensitivity (91%) and moderate specificity (50%) to distinguish MCL patients from atypical B-CLL. Conclusion: Expression of CD5, CD20 (bright), CD22, FMC-7, CD38, and lambda light chain with no expression of CD23 can accurately detect MCL and differentiate it from atypical B-CLL

Effect of Early Bacillus Calmette-Guerin Vaccination of Pediatric Severe Combined Immunodeficiency Patients on the Outcome of Hematopoietic Stem Cell Transplantation Using a Reduced-Intensity Conditioning Regimen.

The eminence of Bacillus Calmette-Guerin (BCG) vaccine in newborn vaccination programs has been conspicuous throughout the years, especially in low-income developing countries where tuberculosis is prevalent; however, application of the BCG vaccine is not without constraints, especially in patients afflicted with immunodeficiency diseases, such as severe combined immunodeficiency (SCID). The present study aimed to evaluate whether the administration of BCG vaccine at birth could improve the outcomes of hematopoietic stem cell transplantation (HSCT) in pediatric patients with SCID. In this study, 30 SCID patients who underwent HSCT using a reduced-intensity conditioning regimen (RIC) were followed-up for 2 years post-HSCT. The outcomes of HSCT were evaluated in both non-BCG-vaccinated patients (n = 12) and BCG-vaccinated patients (n = 18). Our results show a higher incidence of acute graft-versus-host disease (aGVHD), but not of chronic GVHD, in the BCG-vaccinated patients, and a similar overall survival (OS) rate in the 2 groups. We speculate that the similar OS rate in the 2 groups, despite the risk of BGC vaccination, was because this group received an RIC conditioning regimen. There was no other difference between the 2 groups. Considering the effect of the BCG vaccine on HSCT outcome, we suggest that the administration of BCG vaccine be deferred until age 3 months so that APT testing without the interference of maternal antibodies can be performed. However, this study could benefit from a larger cohort to further validate our findings, as the possible reason for some factors not being statistically significant was our small sample size.

Women empowerment and access to maternity and reproductive healthcare in Pakistan: cross-validation of a Survey-based Index in Afghanistan (SWEI-A).

BACKGROUND: Despite the obvious violation of women's rights in Pakistan and the vital necessity for women empowerment, a unified country-specific index measuring women empowerment is not yet available. This study cross-validated a survey-based women empowerment index from Afghanistan to be used in Pakistan. METHODS: The data for married Pakistani women aged 15-49 in the 2017-18 Pakistan demographic health survey was used to construct the final model using the explanatory and confirmatory factor analyses. The Cronbach's alpha test examined the internal consistency of the developed index. To assess the convergence validity of the index, the association of each emerged domain with indicators of access to reproductive and maternity care was assessed by Poisson regression analysis adjusting for wealth index. RESULTS: The final index had six domains; namely, labor force participation, attitude toward violence, decision-making, access to healthcare, literacy, age at critical life events predicting women empowerment of married Pakistani women with decent reliability (Cronbach's α = 0.70), and validity (SRSEA&SRMR < 0.05, CFI&TLI > 0.92). The emerged domains were significantly associated with at least one of four indicators for access to reproductive and maternity care; indicative of a favorable convergence validity. CONCLUSION: Pakistan and Afghanistan are associated as brother countries with shared religious and ethnocultural identities in which women are perceived inferior to men and in critical need of empowering efforts. The results of this study reflect upon this resemblance in sociocultural structure by yielding similar domains for women's empowerment in Pakistan building upon an index previously developed for Afghan women. The developed index could inform the design of future policies, interventions, and research recognizing the important indicators of women empowerment in Pakistan and could enhance the comparability of the results across future studies.

Therapeutic approaches for relapsed/refractory adult acute lymphoblastic leukemia (ALL), a review on monoclonal antibodies and targeted therapies.

Acute lymphoblastic leukemia (ALL) is the malignant transformation of lymphoid progenitors that affects both children and adults. Although the outcome of pediatric patients has been improved dramatically, there are still many challenges in the treatment of adults. Patients with primary resistant or relapsed disease have the worst outcome and despite the administration of intensified multi-agents chemotherapies, the outcome of this group remains very poor. Accordingly, the development of novel therapeutic options is considered necessary. Having a comprehensive insight into the pathophysiology of ALL and aberrant signaling pathways is crucial for introducing effective targeted therapies. Combination therapies with new drugs and innovative targeted therapies with the aim of affecting the main aberrant signaling pathways in the disease are considered as new approaches. Here we tried to have a comprehensive review on the potential molecular targets in the treatment of refractory/relapsed ALL and the current therapeutic agents.

Temporal and regional shifts of crop species diversity in rainfed and irrigated cropland in Iran.

Concerns about the negative effects of declining agricultural biodiversity due to modern agricultural practices and climatic constraints in various parts of the world, including Iran, on the sustainability of agricultural ecosystems are increasingly growing. However, the historical knowledge of temporal and spatial biodiversity is lacking. To determine the value and trend of crop diversity in Iran, we used biodiversity indices based on the area under rainfed and irrigated crops and total cropland area from 1991 to 2018. There were large fluctuations in the amount of cultivated area in the past 30 years, peaking around 2005 to 2007 with about 13.1 million cultivated hectares. However, no general trend in increase or decrease of total cultivated land was shown. The crop species diversity of irrigated cropland was higher than the rainfed and total cropland. The Shannon diversity index showed a constant trend with a negligible slope, but species richness was increased, which was related to the rise in the area of some crop species in recent years. The area of wheat and barley had a significant impact on crop diversity, so Shannon diversity index reduced with their dominance. Overall, this study revealed that the Iranian agricultural system relies on wheat and barley. We warn that by increasing the area of these crops and the prevalence of monoculture, the probability of damage from external factors such as sudden weather changes or the spread of diseases will increase, leading to instability and production risks in the future.

Apoptosis Effects of Oxalis corniculata L. Extract on Human MCF-7 Breast Cancer Cell Line:.

Background: Recently, the non-toxic properties of natural plant products have gained more focus as anticancer agents. Therefore, this study aimed to assess the apoptosis effects of the ethanolic extract of Oxalis corniculata on the MCF-7 breast cancer cell line.Materials and Methods: In this experimental study, aerial parts of O. corniculata were collected in Lahijan city (Iran), and after confirmation, they were dried and extracted with ethanol for 24 h. Then, the total phenolic and flavonoid contents of the extract were measured. The 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay was used to measure the antioxidant properties of the extract. Selected cell lines (MCF-7 and human dermal fibroblast) were cultured in 6-wells dishes (1×106 cells/well). After 72 h of treating the extract, cytotoxicity was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The expression of apoptotic genes (such as p53, bcl-2, bax, and CD95) was studied by real-time polymerase chain reaction (PCR). Results: The extract's total phenolic content was 31.30±02 µg of gallic acid equivalents/mg of dry extract, and the total flavonoid content was 49.61±04 µg of quercetin as equivalents/mg of extract. The antioxidant activity ofO. corniculata was measured at the dose of 619.2 µg/µl, indicating that it decreases cancer cell viability and enhances apoptosis. Within the half maximal inhibitory concentrations, real-time PCR revealed substantial increases in p53 (P<0.001), CD95 (P<0.05), and bcl-2 expression (P<0.05) in MCF-7 cells treated with O. corniculata. Conclusion: This study suggests that O. corniculata may cause apoptosis by oxidative stress in cancer cells.[GMJ.2022;11:e2484].

Identifying Key Lysosome-Related Genes Associated with Drug-Resistant Breast Cancer Using Computational and Systems Biology Approach.

Background: Drug resistance in breast cancer is an unsolved problem in treating patients. It has been recently discussed that lysosomes contribute to the invasion and angiogenesis of cancer cells. There is evidence that lysosomes can also cause multi-drug resistance. We analyzed this emerging concept in breast cancer through computational and systems biology approaches. Objectives: We aimed to identify the key lysosome-related genes associated with drug-resistant breast cancer. Methods: All genes contributing to the structure and function of lysosomes were inquired through the Human Lysosome Gene Database. The prioritized top 51 genes from the provided lists of Endeavour, ToppGene, and GPSy as prioritization tools were selected. All lysosomal genes and 12 breast cancer-related genes aligned to identify the most similar genes to breast cancer-related genes. Different centralities were applied to score each human protein to calculate the most central lysosomal genes in the human protein-protein interaction (PPI) network. Common genes were extracted from the results of the mentioned methods as a selected gene set. For Gene Ontology enrichment, the selected gene set was analyzed by WebGestalt, DAVID, and KOBAS. The PPI network was constructed via the STRING database. The PPI network was analyzed utilizing Cytoscape for topology network interaction and CytoHubba to extract hub genes. Results: Based on biological studies, literature reviews, and comparing all mentioned analyzing methods, six genes were introduced as essential in breast cancer. This computational approach to all lysosome-related genes suggested that candidate genes include PRF1, TLR9, CLTC, GJA1, AP3B1, and RPTOR. The analyses of these six genes suggest that they may have a crucial role in breast cancer development, which has rarely been evaluated. These genes have a potential therapeutic implication for new drug discovery for chemo-resistant breast cancer. Conclusions: The present work focused on all the functional and structural lysosome-related genes associated with breast cancer. It revealed the top six lysosome hub genes that might serve as therapeutic targets in drug-resistant breast cancer. Since these genes play a pivotal role in the structure and function of lysosomes, targeting them can effectively overcome drug resistance.

Drug Repurposing Against Angiotensin-Converting Enzyme-Related Carboxypeptidase (ACE2) Through Computational Approach.

Ongoing novel coronavirus (COVID-19) with high mortality is an infectious disease in the world which epidemic in 2019 with human-human transmission. According to the literature, S-protein is one of the main proteins of COVID-19 that bind to the human cell receptor angiotensin-converting enzyme 2 (ACE2). In this study, it was attempted to identify the main effective drugs approved that may be repurposed to the binding site of ACE2. High throughput virtual screening based on the docking study was performed to know which one of the small-molecules had a potential interaction with ACE2 structure. Forasmuch as investigating and identifying the best ACE2 inhibitors among more than 3,500 small-molecules is time-consuming, supercomputer was utilized to apply docking-based virtual screening. Outputs of the proposed computational model revealed that vincristine, vinbelastin and bisoctrizole can significantly bind to ACE2 and may interface with its normal activity.

Drug repositioning based on gene expression data for human HER2-positive breast cancer.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer represents approximately 15-30% of all invasive breast cancers. Despite the recent advances in therapeutic practices of HER2 subtype, drug resistance and tumor recurrence still have remained as major problems. Drug discovery is a long and difficult process, so the aim of this study is to find potential new application for existing therapeutic agents. Gene expression data for breast invasive carcinoma were retrieved from The Cancer Genome Atlas (TCGA) database. The normal and tumor samples were analyzed using Linear Models for Microarray Data (LIMMA) R package in order to find the differentially expressed genes (DEGs). These genes were used as entry for the library of integrated network-based cellular signatures (LINCS) L1000CDS2 software and suggested 24 repurposed drugs. According to the obtained results, some of these drugs including vorinostat, mocetinostat, alvocidib, CGP-60474, BMS-387032, AT-7519, and curcumin have significant functional similarity and structural correlation with FDA-approved breast cancer drugs. Based on the drug-target network, which consisted of the repurposed drugs and their target genes, the aforementioned drugs had the highest degrees. Moreover, the experimental approach verified curcumin as an effective therapeutic agent for HER2 positive breast cancer. Hence, our work suggested that some repurposed drugs based on gene expression data can be noticed as potential drugs for the treatment of HER2-positive breast cancer.

Extracellular Vesicles in Acute Leukemia: A Mesmerizing Journey With a Focus on Transferred microRNAs.

Despite their small size, the membrane-bound particles named extracellular vesicles (EVs) seem to play an enormous role in the pathogenesis of acute leukemia. From oncogenic hematopoietic stem cells (HSCs) to become leukemic cells to alter the architecture of bone marrow (BM) microenvironment, EVs are critical components of leukemia development. As a carrier of essential molecules, especially a group of small non-coding RNAs known as miRNA, recently, EVs have attracted tremendous attention as a prognostic factor. Given the importance of miRNAs in the early stages of leukemogenesis and also their critical parts in the development of drug-resistant phenotype, it seems that the importance of EVs in the development of leukemia is more than what is expected. To be familiar with the clinical value of leukemia-derived EVs, this review aimed to briefly shed light on the biology of EVs and to discuss the role of EV-derived miRNAs in the development of acute myeloid leukemia and acute lymphoblastic leukemia. By elaborating the advances and challenges concerning the isolation of EVs, we discuss whether EVs could have a prognostic value in the clinical setting for leukemia.

IFNG-AS1 and MAF4 long non-coding RNAs are upregulated in acute leukemia patients who underwent bone marrow transplantation.

PURPOSE OF THE STUDY: Acute graft versus host disease (aGVHD) is an immune-mediated reaction that results in impaired immune and body function after allogeneic hematopoietic stem cell transplantation (allo-HSCT). lncRNAs have been discovered as particular T cell regulators, and alloreactive T cells have been known as a critical factor in aGVHD. As a result, we investigated the importance of lnc-MAF4 and IFNG-AS1 expression levels in aGVHD patients versus non-aGVHD patients. MATERIAL AND METHODS: This research included 38 patients with hematological disorders who were undergoing primary allo-HSCT. Human identical siblings or unrelated donors were used to collect stem cell. Samples were taken within days 0, 7, 14, 28, and 52±8 after transplantation. The expression of lncRNA levels was measured using the QRT-PCR technique. And the data were analyzed using GraphPad Prism 6 RESULTS: Our data revealed that LncRNA MAF4 and INFG-AS1 expression levels in aGVHD were not significantly different compared to the non-GVHD group immediately after transplantation, nor at day 7 or 14. However, the aGVHD group showed an overt up-regulation of the two lncRNAs on samples taken at day 28 and 52±8 compared to non-GVHD patients. DISCUSSION: Since the intracellular pathway of these lncRNAs shows a direct relationship with the IFNγ cytokine production resulting in differentiation to TH1 cells and inhibition of differentiation to TH2 cells, they can be, therefore, considered as suitable molecular candidates for the prediction of aGVHD in patients receiving HSCT.