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Background: Although liver transplant (LT) recipients are considered a population at risk of severe features of coronavirus disease 2019 (COVID-19), data in this regard are scarce and controversial. In this study, we reported the outcome of 24 cases of LT recipients who were hospitalized due to COVID-19 and investigated the role-playing factors in the severity of the disease., Methods: In this single-center, analytic case-series study, eligible patients were among LT recipients who were hospitalized due to the diagnosis of COVID-19 based on positive results of polymerase chain reaction. Participants were categorized as severe COVID-19 if they were admitted to the intensive care unit, experienced respiratory failure demanding mechanical ventilation, or eventually died. Demographic and clinical data, COVID-19 symptoms and specific treatments, laboratory biomarkers, and immunosuppressive regimens and their alteration during the admission were recorded. Analysis was done using SPSS software., Results: Twenty-four hospitalized LT patients were included, of which nine had severe and fifteen had non-severe COVID-19. Out of 9 patients with severe COVID-19, four sadly died. The analysis and comparison between the two groups revealed longer hospital stays (P = 0.02), lower lymphocyte counts (P = 0.002), and higher levels of C-reactive protein (CRP) (P = 0.006) in patients with severe COVID-19. Patients with non-severe COVID-19 had higher doses of tacrolimus and mycophenolate in their baseline immunosuppressive regimen (both P = 0.02)., Conclusion: Lymphopenia and high CRP levels are associated with more severe forms of COVID-19 in LT patients. Mycophenolate may have protective properties against severe COVID-19. The role of severity indicators in LT patients with COVID-19 needs to be systematically recognized., (© 2024. The Author(s).)

Objective: Cardiovascular diseases (CVDs) are the leading cause of death worldwide, with atherosclerosis serving as a primary factor in their development. Platelets, leukocytes, and their interactions play a crucial role in initiating and amplifying atherosclerosis. This study aims to evaluate the levels of platelet-monocyte aggregates (PMA) and specific integrins involved in leukocyte recruitment, including macrophage-1 antigen (Mac-1) and lymphocyte functionassociated antigen-1 (Lfa-1), in patients with acute coronary syndrome (ACS)., Materials and Methods: In this case-control study, thirty-two subjects with ACS and 30 healthy individuals participated. It aimed to evaluate PMA expression and the median fluorescence intensity (MFI) of Mac-1 and Lfa-1 using flow cytometry. Dot plots and Pearson correlation coefficient were employed to examine the relationship between PMA, Mac-1, and Lfa-1. Multilevel model analysis was used to explore the effects and relationships of various parameters, including Mac-1 and Lfa-1, on PMA. Finally, receiver operating characteristic (ROC) curves were utilized to assess the diagnostic accuracy of PMA, Mac-1, and Lfa-1 markers., Results: It was observed that patients had higher PMA levels compared to the control group (58.99 ± 16.27 vs. 29.99 ± 4.19 in controls, P<0.001), which correlated with PLT (ρ=0.512, P=0.035). Additionally, CD18 and CD11b expression on monocytes were significantly elevated in patients (P<0.001) and were positively associated with PMA (β=19.09, P<0.001; β=6.90, P=0.022), but no significant relationship between CD11a and PMA was observed (β=5.06, P=0.315). PMA and Mac-1 were identified as better markers for differentiating patients from healthy individuals. (respectively, AUC=0.94, Sensitivity= 0.84, specificity=0.98; AUC=0.84, Sensitivity= 0.93, specificity=0.70)., Conclusion: The study results indicated an increase in both Mac-1 and PMA levels in patients with ACS. Additionally, the significant association observed between Mac-1 and PMA in the patient group suggests a potential relationship between these markers and ACS.

Objective: Premature ovary failure (POF) is a severe health condition with multiple negative outcomes, which deteriorate a patient's life. The current study aimed to evaluate the therapeutic effect of mesenchymal stem cells (MSCs) derived from peripheral blood in the treatment of women with the POF background., Methods: The current study was a pilot study carried-out on women younger than 40 with premature ovarian failure. Study participants underwent 4-months cell therapy using Mesenchymal stem cells extracted from peripheral bloods. Serum level of Follicle-stimulating hormone (FSH), Estradiol (E2), Anti-mullerian hormone (AMH), and Antral follicle count (AFC) were the main investigated outcomes that were assessed at baseline, month two and month four of the very small stem cell intervention., Results: Average serum level of FSH was 45.0 (12.1) mIU/mL at baseline and continually decreased during the study and reached 33.2 (12.4) mIU/mL in the fourth month. The average AMH level was 0.10 ng/mL prior to the intervention and increased to 0.13 ng/mL in the 2nd month and 0.15 ng/mL in the fourth month. The level E2 was 85.7 (23.6) pg/ml on average at baseline, while the average E2 reduced to 77.2 (25.6) pg/ml in the fourth month. Average number of AFC was 2.0 (0.8) at baseline. We observed a gradual increase in the second month (Mean AFC=2.2) and after four months it increased to 3.1 (1.8) as the highest menstrual restoration and pregnancy was observed in 10% of our study participants., Conclusions: MSCs could significantly improve hormone secretion in women with POF. Implantation of MSCs in women with POF background was associated with an increase in AMH and AFC, while it downed the serum level of E2 and FSH. MSCs could also lead to menstrual restoration and pregnancy in women with POF.

Aberrant epigenetic modifications, particularly DNA methylation, play a critical role in the pathogenesis and progression of human diseases. The current review aims to reveal the role of aberrant DNA methylation in the pathogenesis and progression of diseases and to discuss the original data obtained from international research laboratories on this topic. In the review, we mainly summarize the studies exploring the role of aberrant DNA methylation as diagnostic and prognostic biomarkers in a broad range of human diseases, including monogenic epigenetics, autoimmunity, metabolic disorders, hematologic neoplasms, and solid tumors. The last section provides a general overview of the possibility of the DNA methylation machinery from the perspective of pharmaceutic approaches. In conclusion, the study of DNA methylation machinery is a phenomenal intersection that each of its ways can reveal the mysteries of various diseases, introduce new diagnostic and prognostic biomarkers, and propose a new patient-tailored therapeutic approach for diseases., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Significance: Label-free quantitative phase imaging can potentially measure cellular dynamics with minimal perturbation, motivating efforts to develop faster and more sensitive instrumentation. We characterize fast, single-shot quantitative phase gradient microscopy (ss-QPGM) that simultaneously acquires multiple polarization components required to reconstruct phase images. We integrate a computationally efficient least squares algorithm to provide real-time, video-rate imaging (up to 75   frames / s ). The developed instrument was used to observe changes in cellular morphology and correlate these to molecular measures commonly obtained by staining., Aim: We aim to characterize a fast approach to ss-QPGM and record morphological changes in single-cell phase images. We also correlate these with biochemical changes indicating cell death using concurrently acquired fluorescence images., Approach: Here, we examine nutrient deprivation and anticancer drug-induced cell death in two different breast cell lines, viz. , M2 and MCF7. Our approach involves in-line measurements of ss-QPGM and fluorescence imaging of the cells biochemically labeled for viability., Results: We validate the accuracy of the phase measurement using a USAF1951 pattern phase target. The ss-QPGM system resolves 912.3    lp / mm , and our analysis scheme accurately retrieves the phase with a high correlation coefficient ( ∼ 0.99 ), as measured by calibrated sample thicknesses. Analyzing the contrast in phase, we estimate the spatial resolution achievable to be 0.55    μ m for this microscope. ss-QPGM time-lapse live-cell imaging reveals multiple intracellular and morphological changes during biochemically induced cell death. Inferences from co-registered images of quantitative phase and fluorescence suggest the possibility of necrosis, which agrees with previous findings., Conclusions: Label-free ss-QPGM with high-temporal resolution and high spatial fidelity is demonstrated. Its application for monitoring dynamic changes in live cells offers promising prospects., (© 2024 The Authors.)

Background: Acute myeloid leukemia (AML) has been the most prevalent form of acute leukemia among adults, and it has been associated with poor survival rates over the last four decades. Understanding the processes involved in leukemogenesis, particularly autophagy and signaling pathways, can provide critical insights into their roles in disease development, risk assessment, and potential therapeutic interventions. This study investigated gene expression changes, focusing on MAP1LC3B and BECN1, related to autophagy, as well as PI3KCA and AKT1 in the PI3K-AKT pathway, and INPP4B, which regulates this signaling cascade., Methods: We collected blood samples from 21 AML patients and 9 healthy volunteers. Gene expression was analyzed through qPCR following RNA extraction and cDNA synthesis. Statistical analysis encompassed t-tests, ANOVA, and correlation coefficients., Results: AML patients exhibited significantly increased MAP1LC3B gene expression (****P < 0.0001; fold change = 11.9) and significantly reduced levels of INPP4B (****P < 0.0001; fold change = 0.026), AKT1 (*P < 0.05; fold change = 0.59), and PI3KCA (****P < 0.0001; fold change = 0.16) compared to healthy controls. However, BECN1 gene expression did not significantly differ between the two groups. Additionally, noteworthy correlations were observed between INPP4B and BECN1 (r = 0.57; P = 0.006) and BECN1 and PI3KCA (r = 0.61; P = 0.003) in AML patients., Conclusions: This study highlights variations in leukemogenesis pathways, exemplified by increased MAP1LC3B expression and diminished expression of regulatory genes in specific AML cases. These findings contribute to our comprehension of the molecular mechanisms underlying AML and may inform future diagnostic and therapeutic approaches., Competing Interests: Declarations of Competing Interest There are no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier Masson SAS.)

Acute myeloid leukemia (AML) is a lethal hematologic malignancy with a variable prognosis that is highly dependent on the bone marrow microenvironment. Consequently, a better understanding of the AML microenvironment is crucial for early diagnosis, risk stratification, and personalized therapy. In recent years, the role of bioinformatics as a powerful tool in clarifying the complexities of cancer has become more prominent. Gene expression profile and clinical data of 173 AML patients were downloaded from the TCGA database, and the xCell algorithm was applied to calculate the microenvironment score (MS). Then, the correlation of MS with FAB classification, and CALGB cytogenetic risk category was investigated. Differentially expressed genes (DEGs) were identified, and the correlation analysis of DEGs with patient survival was done using univariate cox. The prognostic value of candidate prognostic DEGs was confirmed based on the GEO database. In the last step, real-time PCR was used to compare the expression of the top three prognostic genes between patients and the control group. During TCGA data analysis, 716 DEGs were identified, and survival analysis results showed that 152 DEGs had survival-related changes. In addition, the prognostic value of 31 candidate prognostic genes was confirmed by GEO data analysis. Finally, the expression analysis of FLVCR2, SMO, and CREB5 genes, the most related genes to patients' survival, was significantly different between patients and control groups. In summary, we identified key microenvironment-related genes that influence the survival of AML patients and may serve as prognostic and therapeutic targets., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chimeric antigen receptors (CARs) offer a promising new approach for targeting B cell malignancies through the immune system. Despite the proven effectiveness of CAR T cells targeting CD19 and CD22 in hematological malignancies, it is imperative to note that their production remains a highly complex process. Unlike T cells, NK cells eliminate targets in a non-antigen-specific manner while avoiding graft vs. host disease (GvHD). CAR-NK cells are considered safer than CAR-T cells because they have a shorter lifespan and produce less toxic cytokines. Due to their unlimited ability to proliferate in vitro, NK-92 cells can be used as a source for CAR-engineered NK cells. We found that CARs created from the m971 anti-CD22 mAb, which specifically targets a proximal CD22 epitope, were more effective at anti-leukemic activity compared to those made with other binding domains. To further enhance the anti-leukemic capacity of NK cells, we used lentiviral transduction to generate the m971-CD28-CD3ζ NK-92. CD22 is highly expressed in B cell lymphoma. To evaluate the potential of targeting CD22, Raji cells were selected as CD22-positive cells. Our study aimed to investigate CD22 as a potential target for CAR-NK-92 therapy in the treatment of B cell lymphoma. We first generated m971-CD28-CD3ζ NK-92 that expressed a CAR for binding CD22 in vitro. Flow cytometric analysis was used to evaluate the expression of CAR. The 7AAD determined the cytotoxicity of the m971-CD28-CD3ζ NK-92 towards target lymphoma cell lines by flow cytometry assay. The ELISA assay evaluated cytokine production in CAR NK-92 cells in response to target cells. The m971-CD28-CD3ζ NK-92 cells have successfully expressed the CD22-specific CAR. m971-CD28-CD3ζ NK-92 cells efficiently lysed CD22-expressing lymphoma cell lines and produced large amounts of cytokines such as IFN-γ and GM-CSF but a lower level of IL-6 after coculturing with target cells. Based on our results, it is evident that transferring m971-CD28-CD3ζ NK-92 cells could be a promising immunotherapy for B cell lymphoma., (© 2024. The Society for In Vitro Biology.)

Purpose: SLC4A10 encodes a plasma membrane-bound transporter, which mediates Na + -dependent HCO 3 - import, thus mediating net acid extrusion. Slc4a10 knockout mice show collapsed brain ventricles, an increased seizure threshold, mild behavioral abnormalities, impaired vision, and deafness., Methods: Utilizing exome/genome sequencing in families with undiagnosed neurodevelopmental disorders and international data sharing, 11 patients from 6 independent families with biallelic variants in SLC4A10 were identified. Clinico-radiological and dysmorphology assessments were conducted. A minigene assay, localization studies, intracellular pH recordings, and protein modeling were performed to study the possible functional consequences of the variant alleles., Results: The families harbor 8 segregating ultra-rare biallelic SLC4A10 variants (7 missense and 1 splicing). Phenotypically, patients present with global developmental delay/intellectual disability and central hypotonia, accompanied by variable speech delay, microcephaly, cerebellar ataxia, facial dysmorphism, and infrequently, epilepsy. Neuroimaging features range from some non-specific to distinct neuroradiological findings, including slit ventricles and a peculiar form of bilateral curvilinear nodular heterotopia. In silico analyses showed 6 of 7 missense variants affect evolutionarily conserved residues. Functional analyses supported the pathogenicity of 4 of 7 missense variants., Conclusion: We provide evidence that pathogenic biallelic SLC4A10 variants can lead to neurodevelopmental disorders characterized by variable abnormalities of the central nervous system, including altered brain ventricles, thus resembling several features observed in knockout mice., Competing Interests: Conflict of Interest James R. Lupski owns stock in 23andMe and is a paid consultant for Genome International. Rhonda E. Schnur is an employee of GeneDx, LLC. The other authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Relapse following hematopoietic stem cell transplantation (HSCT) occurs relatively frequently and is a significant risk factor for mortality in patients with acute myeloid leukemia (AML). Early diagnosis is, therefore, of utmost importance and can provide valuable guidance for appropriate and timely intervention. Here, the diagnostic value of two molecular markers, Wilms tumor 1 (WT1) and tumor suppressor protein p53 (TP53), were studied., Methods and Results: Twenty AML patients undergoing HSCT participated in this investigation. Some had relapsed following HSCT, while others were in remission. Peripheral blood (PB) and bone marrow (BM) samples were collected following relapse and remission. WT1 and TP53 messenger RNA (mRNA) expression was evaluated using reverse transcription-quantitative polymerase chain reaction (RT‒qPCR). The diagnostic value of genes was evaluated by utilizing receiver-operating characteristic (ROC) curve analysis. ROC analysis showed WT1 and TP53 as diagnostic markers for relapse after HSCT in AML patients. The mRNA expression level of WT1 was elevated in individuals who experienced relapse compared to those in a state of remission (p value < 0.01). Conversely, the expression level of TP53 mRNA was lower in individuals who had relapsed compared to those in remission (p value < 0.01)., Conclusions: WT1 and TP53 possess the potential to serve as invaluable biomarkers in the identification of molecular relapse after HSCT in patients with AML. Further studies for a definitive conclusion are recommended., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Acute myeloid leukemia (AML) is a type of blood cancer involving numerous aberrant genes and microRNAs. MiRNAs are non-coding sequences that have been proven to be players in the biological processes of various cancers. The present study is designed to illustrate the relationship between miR-155, KRAS, and CREB., Methods: This case-control study was conducted on 21 patients with AML and 9 healthy individuals. The expressions of miR-155, KRAS, and CREB were measured using RT-PCR. Demographic data were extracted from the documents of individuals. SPSS and GraphPad Prism software were used to analyze the data., Results: The expression of miR-155 in patients with AML was 35 times higher than in the control group (p < 0.0001). Also, CREB fold change increased by 1.92-fold in patients compared to the controls (p = 0.034), but no difference in KRAS was observed between the control and AML groups (p > 0.05). There was no change in miR-155, CREB, and KRAS expression based on gender, age, and blast percentage (p > 0.5). Nevertheless, there was a direct correlation between CREB and KRAS expressions (p = 0.0002). Our result showed that overexpression of CREB and KRAS would cause an increase in white blood cells (WBCs) (p = 0.001, 0.045 respectively), but there was no correlation between miR-155 with WBCs (p > 0.5)., Conclusions: Our study revealed that miR-155 and CREB had overexpression compared to the control group.

Background: Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship., Methods: Using an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity., Results: A cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and complicating phenotypic understanding. We also uncovered extreme clinical heterogeneity and high allele frequencies, occasionally incompatible with a fully penetrant recessive disorder. Human cDNA of previously described and new variants were tested in an ogdhl zebrafish knockout model, adding functional evidence for variant reclassification. We disclosed evidence of hypomorphic alleles as well as a loss-of-function variant without deleterious effects in zebrafish variant testing also showing discordant familial segregation, challenging the relationship of OGDHL as a conventional Mendelian gene. Going further, we uncovered evidence for a complex compensatory relationship among OGDH, OGDHL, and DHTKD1 isoenzymes that are associated with neurodevelopmental disorders and exhibit complex transcriptional compensation patterns with partial functional redundancy., Conclusions: Based on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous phenotype such as "OGDHL-related disorders"., (© 2023. The Author(s).)

The light absorption process is a key factor in improving the performance of perovskite solar cells (PSCs). Using arrays of metal nanostructures on semiconductors such as perovskite (CH 3 NH 3 PbI 3 ), the amount of light absorption in these layers is significantly increased. Metal nanostructures have been considered for their ability to excite plasmons (collective oscillations of free electrons). Noble metal nanoparticles placed inside solar cells, by increasing the scattering of the incident light, effectively increase the optical absorption inside PSCs; this in turn increases the electric current generated in the photovoltaic device. In this work, by calculating the cross-sectional area of dispersion and absorption on gold (Au) nanoparticles, the effects of the position of nanoparticles in the active layer (AL) and their morphology on the increase of absorption within the PSC are investigated. The optimal position of the plasmonic nanoparticle was obtained in the middle of the AL using a three-dimensional simulation method. Then, three different morphologies of nano-sphere, nano-star and nano-cubes were investigated, where the short-circuit currents (J sc ) for these three nanostructures were obtained equal to 19.01, 18.66 and 20.03 mA/cm 2 , respectively. In our study, the best morphology of the nanostructure according to the J sc value was related to the nano-cube, in which the device power conversion efficiency was equal to 16.20%, which is about 15% better than the PSC with the planar architecture., (© 2023. The Author(s).)

One of the barriers to further commercialization of the proton exchange membrane fuel cell (PEMFC) is hydrogen storage. Conventional methods are based on pressurizing the hydrogen up to 700 bar. The focus of this study is to characterize the hydrogen storage capacity of hydrogen tanks filled with MOF-5 at low pressures. Thus, Computational Fluid Dynamic (CFD) was used in a transient condition to analyze the hydrogen storage. Benefiting from the CFD model, three input parameters of the MOF-5, namely, density, specific heat, and conductivity, were utilized to develop an artificial neural network (ANN) model to find the highest mass of adsorption at the lowest required pressure. The optimum possible MOF among 729220 different possibilities, which enables the adsorption of 0.0099 kg at 139 bar, was found using a newly defined parameter called Pressure Adsorption Parameter (PAP)., (© 2023. Springer Nature Limited.)

So far, remarkable achievements have been obtained by optimizing the device architecture and modeling of solar cells is a precious and very effective way to comprehend a better description of the physical mechanisms in solar cells. As a result, this study has inspected two-dimensional simulation of perovskite solar cells (PSCs) to achieve a precise model. The solution which has been employed is based on the finite element method (FEM). First, the periodically light trapping (LT) structure has been replaced with a planar structure. Due to that, the power conversion efficiency (PCE) of PSC was obtained at 14.85%. Then, the effect of adding an SiO 2 layer to the LT structure as an anti-reflector layer was investigated. Moreover, increasing the PCE of these types of solar cells, a new structure including a layer of CH 3 NH 3 SnI 3 as an absorber layer was added to the structure of PSCs in this study, which resulted in 25.63 mA/cm 2 short circuit current (J sc ), 0.96 V open circuit voltage (V oc ), and 20.48% PCE., (© 2023. Springer Nature Limited.)

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose: The aim of this study was to evaluate whether the prevalence of celiac among attention-deficit/hyperactivity disorder (ADHD) patients is higher than among the normal population., Methods: The present study was a prospective one investigating ADHD children referred to the Neurology Clinic and Pediatric Ward at Amir Al-Momenin Hospital of Zabol (Sistan and Baluchestan, Iran) in 2019 after their parents' signing of a consent form. All patients underwent Biocard™ Celiac and serology tests. Data were analyzed with SPSS version 21 software., Results: Of all 76 ADHD children undergoing a serum IgA antibodies concentration test, 58 (76%) were male and 18 (23.7%) were female. The mean age of the children was 6.9 ± 2.4, ranging from 2 years to 12 years. The diagnosis of IgA immunodeficiency was rejected for all children based on total serum IgA antibody results. The overall mean anti-tissue transglutaminase (TTG) level was 6.8 ± 5.3 U/ml, ranging from 0.2 to 37 U/ml. There was no significant difference regarding TTG levels between boys and girls (5.1 vs. 6.0) U/ml. Based on the anti-TTG level results, no celiac case was found among the ADHD patients., Conclusions: There is as yet no evidence suggesting a link between celiac disease and ADHD. Thus, routine celiac disease screening when evaluating for ADHD (and is not recommended). However, the possibility of untreated celiac disease predisposing an individual to ADHD-like behaviors should be considered. Hence, physicians are recommended to evaluate a broad range of physical symptoms, in addition to typical neuropsychiatric symptoms, when evaluating ADHD patients., Competing Interests: Absent., (© 2023 Institute of Psychiatry and Neurology. Production and hosting by Termedia sp. z o.o.)

The hippocampal formation plays a central role in the development of temporal lobe epilepsy (TLE), a disease characterized by recurrent, unprovoked epileptic discharges. TLE is a neurologic disorder characterized by acute long-lasting seizures (i.e., abnormal electrical activity in the brain) or seizures that occur in close proximity without recovery, typically after a brain injury or status epilepticus. After status epilepticus, epileptogenic hyperexcitability develops gradually over the following months to years, resulting in the emergence of chronic, recurrent seizures. Acting as a filter or gate, the hippocampal dentate gyrus (DG) normally prevents excessive excitation from propagating through the hippocampus, and is considered a critical region in the progression of epileptogenesis in pathological conditions. Importantly, lipid-derived endogenous cannabinoids (endocannabinoids), which are produced on demand as retrograde messengers, are central regulators of neuronal activity in the DG circuit. In this review, we summarize recent findings concerning the role of the DG in controlling hyperexcitability and propose how DG regulation by cannabinoids (CBs) could provide avenues for therapeutic interventions. We also highlight possible pathways and manipulations that could be relevant for the control of hyperexcitation. The use of CB compounds to treat epilepsies is controversial, as anecdotal evidence is not always validated by clinical trials. Recent publications shed light on the importance of the DG as a region regulating incoming hippocampal excitability during epileptogenesis. We review recent findings concerning the modulation of the hippocampal DG circuitry by CBs and discuss putative underlying pathways. A better understanding of the mechanisms by which CBs exert their action during seizures may be useful to improve therapies., (© 2023 International League Against Epilepsy.)

The growing use of aptamers as target recognition elements in label-free biosensing necessitates corresponding transducers that can be used in relevant environments. While popular in many fields, capacitive sensors have seen relatively little, but growing use in conjunction with aptamers for sensing diverse targets. Few reports have shown physiologically relevant sensitivity in laboratory conditions and a cohesive picture on how target capture modifies the measured capacitance has been lacking. In this review, we assess the current state of the field in three areas: small molecule, protein, and cell sensing. We critically analyze the proposed hypotheses on how aptamer-target capture modifies the capacitance, as many mechanistic postulations appear to conflict between published works. As the field matures, we encourage future works to investigate individual aptamer-target interactions and to interrogate the physical mechanisms leading to measured changes in capacitance. To this point, we provide recommendations on best practices for developing aptasensors with a particular focus on considerations for biosensing in clinical settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Relapse is a frequent occurrence in autologous hematopoietic stem cell transplantation (AHSCT), and early relapse after AHSCT results in poor survival and low quality of life. Predictive marker determination for AHSCT outcomes could be helpful in the prevention of relapse through personalized medicine. Here the predictive value of circulatory microRNAs (miRs) expression for AHSCT outcomes was studied., Methods: 50 MM and lymphoma candidates for AHSCT participated in this study. Two plasma samples were obtained before AHSCT from each candidate; one before mobilization and the other after conditioning. Extracellular vesicles (EVs) were isolated by ultracentrifugation. miR-125b, miR-126, miR-150, and miR-155 expression were analyzed in both plasma and EVs using real time polymerase chain reaction analysis. Other data related to AHSCT and its outcomes were also collected. The predictive value of miRs and other factors for outcomes was assessed by multi-variant analysis., Results: By 90 weeks follow up after AHSCT, multi-variant and ROC analysis showed miR-125b as a predictive marker for relapse, high lactate dehydrogenase (LDH), and high erythrocyte sedimentation rate (ESR). The cumulative incidence of relapse, high LDH, and high ESR increased with an increase in circulatory miR-125b expression., Conclusion: miR-125b could be applicable in prognosis evaluation and also create a possible new targeted therapy opportunity for enhanced outcomes and survival after AHSCT., Trial Registration: The study was retrospectively registered. Ethic code No: IR.UMSHA.REC.1400.541., (© 2023. The Author(s).)

Objectives: Microvesicles (MVs) are small membrane-bound particles that act as a vehicle to transfer their contents, such as proteins, RNAs, and miRNAs, to the target cells, making them undergo several changes. Depending on the origin and the target cell, MVs may cause cell survival or apoptosis. This study investigated the effects of MVs released from the leukemic K562 cell line on the human bone marrow mesenchymal stem cells (hBM-MSCs) to evaluate changes in the survival or apoptosis of the cells in an in vitro system., Materials and Methods: In this experimental study, we added the isolated MVs from the K562 cell line to hBM-MSCs, and after three and then seven days, subsequently cell count, cell viability, transmission electron microscopy, tracing MVs by carboxyfluorescein diacetate, succinimidyl ester (CFSE) solution, flow cytometry analysis for Annexin-V/PI staining and qPCR for the evaluation of BCL- 2, KI67 , and BAX expression were carried out. On the 10 th day of the culture, hBM-MSCs were examined by Oil red O and Alizarin Red staining to evaluate their differentiation into adipocytes and osteoblasts., Results: There was a significant decrease in cell viability and KI67 and BCL-2 expression; however, BAX was significantly upregulated in the hBM-MSCs compared to control groups. Annexin-V/PI staining results also showed the apoptotic effects of K562-MVs on hBM-MSCs. Moreover, the differentiation of hBM-MSCs into adipocytes and osteoblasts was not observed., Conclusion: MVs from the leukemic cell line could affect the viability of normal hBM-MSCs and induce cell apoptosis., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article.

Objective: Acute myeloid leukemia (AML) is a heterogeneous clonal disorder resulting from a complex interplay between leukemic cells and supporting factors from their microenvironment. In this context, extracellular vesicles (EVs) have been shown to play an essential role in forming a tumor-protective microenvironment. In this study, we examined the influence of AML-derived EVs on cellular and molecular characterization of bone marrow mesenchymal stromal cells (BM-MSCs), particularly alteration in the expression of genes (IL-6, Gas-6, and Galectin-3) relating to relapse and chemoresistance., Methods: MSCs were co-cultured with different concentrations of AML-EVs. Our data has been achieved by MTT assay, ROS assay, proliferation assay and apoptosis assay. RT-qPCR was also performed for gene expression analysis., Results: Our results demonstrated that AML-EVs impact the MSCs characterization in a concentration-dependent manner. We revealed higher viability, increased Ki-67 and BCL-2, and lower ROS levels in MSCs treated with a 40 µg/mL dose of EVs. On the other hand, the rate of MSCs apoptosis and BAX expression exposed to a 60 µg/mL dose of EVs were increased compared with the control group. In addition, RT-qPCR results showed that the expression of IL-6, Gas-6, and Galectin-3 was significantly up-regulated in treated MSCs with a 40 µg/mL dose of EVs., Conclusion: Because the overexpression of IL-6, Gas-6, and Galectin-3 has contributed to chemoresistance and relapse, our findings suggest that AML-EVs propel MSCs to express these genes, which in turn could guard leukemic cells from chemotherapy-inflicted damages and eventually lead to relapse., Competing Interests: Conflicts of Interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

COVID-19 disease manifests itself in a wide range of signs and symptoms, beginning with mild symptoms, such as fever, cough, and dyspnea, progressing to acute respiratory distress syndrome (ARDS) and death in some cases. The cytokine storm, or an excess of cytokines released locally, is assumed to be the primary cause of ARDS and mortality in COVID-19 patients. To enhance the survival rate of COVID-19 patients, early management of the cytokine storm with immunomodulators is crucial. Although the effectiveness of some immunosuppressants, such as corticosteroids and tocilizumab, has been studied in clinical trials, the administration of these drugs should be exercised cautiously. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid from Cannabis sativa extracts with anti-inflammatory properties. This review is intended to discuss the possible utility of CBD for the management of COVID-19 patients, particularly those with ARDS., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: Non-constant current stimulation (NCCS) is a neuromodulatory method in which weak alternating, pulsed or random currents are delivered to the human head via scalp or earlobe electrodes. This approach is widely used in basic and translational studies. However, the underlying mechanisms of NCCS, which lead to biological and behavioral effects in the brain, remain largely unknown. In this review, we characterize NCCS techniques currently being utilized in neuroscience investigations, including transcranial alternating current stimulation (tACS), transcranial pulsed current stimulation (tPCS), transcranial random noise stimulation (tRNS), and cranial electrotherapy stimulation (CES). Method: We unsystematically searched all relevant conference papers, journal articles, chapters, and textbooks on the biological mechanisms of NCCS techniques. Results: The fundamental idea of NCCS is that these low-level currents can interact with neuronal activity, modulate neuroplasticity and entrain cortical networks, thus, modifying cognition and behavior. We elucidate the mechanisms of action for each NCCS technique. These techniques may cause microscopic effects (such as affecting ion channels and neurotransmission systems) and macroscopic effects (such as affecting brain oscillations and functional connectivity) on the brain through different mechanisms of action (such as neural entrainment and stochastic resonance). Conclusion: The appeal of NCCS is its potential to modulate neuroplasticity noninvasively, along with the ease of use and good tolerability. Promising and interesting evidence has been reported for the capacity of NCCS to affect neural circuits and the behaviors under their control. Today, the challenge is to utilize this advancement optimally. Continuing methodological advancements with NCCS approaches will enable researchers to better understand how NCCS can be utilized for the modulation of nervous system activity and subsequent behaviors, with possible applications to non-clinical and clinical practices., Competing Interests: None., (Copyright © 2023 Tehran University of Medical Sciences.)

Background: Resistance exercise induces thrombocytosis and increases platelet activation and function. These changes might be related to exercise variables including exercise intensity and type., Objective: We compared the effects of traditional resistance exercise (TRE) and circuit resistance exercise (CRE) on cellular markers of platelet activation and function., Methods: In this crossover study ten healthy male (mean±SD: age, 25.6±2.4 years) subjects performed TRE encompassed 3 sets of 10 repetitions at 100% of 10-RM (10 repetition maximum) for 6 exercises, and CRE protocols included 3 sets of 10 repetitions at 100% of 10-RM for all 6 exercises consecutively, in two separate weeks. To measure platelet indices, PAC1, CD41a, CD42b and CD62P three blood samples were taken before, immediately after exercise, and after 30 min recovery., Results: Lactate concentration, blood pressure, platelet count (PLT), and mean platelet volume (MPV) were significantly (p < 0.05) increased following both resistance exercise trials. Significant increases in PAC1, and CD62P; and significant reductions for CD42b and CD41a were detected following both REs (p < 0.05). However, changes in PAC1 and CD62P were significantly different between the two protocols (p < 0.05), with higher increases detected following CRE., Conclusions: Acute RE increases platelet indices and platelet activation; and that CRE results in higher platelet activation than TRE, probably due to exercise-induced increases in shear stress.

Recently, the impressive achievements accomplished in multijunction (tandem) perovskite solar cells have triggered a huge research effort to boost their performance. Here, using a three-dimensional (3D) finite element method (FEM) technique, we propose and investigate a parallel tandem PSCs consisting of two absorbing layers of MoTe 2 and CH 3 NH 3 PbI 3 with cascaded bandgaps to more efficiently use the near-infrared (NIR) solar spectrum. Endowed with a bandgap of about 1 eV, the MoTe 2 layer in conjunction with a CH 3 NH 3 PbI 3 layer is able to broaden the light absorption range of structure beyond the wavelength of 800 nm, up to 1200 nm. In addition to this, the MoTe 2 material can not only appreciably harvest light even with a thickness as low as 20 nm due to their high absorption coefficient, but also make a perfect band alignment with the CH 3 NH 3 PbI 3 layer. As a result, the proposed multijunction PCS yields a high power conversion efficiency (PCE) of 18.52% with a V OC of 0.83 V, J sc of 26.25 mA/cm 2 , and FF of 0.84, which is considerably greater than its corresponding single-junction PSCs with PCE, V OC , J sc , and FF of, 14.01%, 1.14 V, 15.20 mA/cm 2 , and 0.81, respectively. Furthermore, to mitigate the V OC loss caused by the low bandgap of MoTe 2 , we demonstrate an increase in V OC from 0.84 to 0.928 V and in PCE from 18.52% to 20.32%, when we replace a reduced graphene oxide (rGO) layer with Spiro-OMeTAD layer as a hole transport layer (HTL)., (© 2022. The Author(s).)

Despite current efforts in organ-on-chip engineering to construct miniature cardiac models, they often lack some physiological aspects of the heart, including fiber orientation. This motivates the development of bioartificial left ventricle models that mimic the myofiber orientation of the native ventricle. Herein, an approach relying on microfabricated elastomers that enables hierarchical assembly of 2D aligned cell sheets into a functional conical cardiac ventricle is described. Soft lithography and injection molding techniques are used to fabricate micro-grooves on an elastomeric polymer scaffold with three different orientations ranging from -60° to +60°, each on a separate trapezoidal construct. The width of the micro-grooves is optimized to direct the majority of cells along the groove direction and while periodic breaks are used to promote cell-cell contact. The scaffold is wrapped around a central mandrel to obtain a conical-shaped left ventricle model inspired by the size of a human left ventricle 19 weeks post-gestation. Rectangular micro-scale holes are incorporated to alleviate oxygen diffusional limitations within the 3D scaffold. Cardiomyocytes within the 3D left ventricle constructs showed high viability in all layers after 7 days of cultivation. The hierarchically assembled left ventricle also provided functional readouts such as calcium transients and ejection fraction., (© 2022 Wiley-VCH GmbH.)

Background: This study was performed to investigate lead levels in neonates born to the mothers suffering from opiate use disorder (OUD) and the association of lead levels with the Apgar score., Methods: The present cross-sectional study included 56 neonates who were referred to the neonatal ward of Amir-Al Momenin Hospital, Zabol. The neonates were divided into two groups: the neonates whose mothers suffered OUD and the control group. Data were collected using a researcher-prepared questionnaire, and blood lead level was determined using the atomic absorption method. Data were statistically analyzed., Results: In all, 56 neonates (28 from OUD mothers and 28 from the control mothers) were included in this study. Among the women with OUD, 16 (57%) used inhaled opium, while 12 (43%) consumed opium orally. There was a significant difference regarding Apgar score (9.76 ± 2.11 versus. 7.11 ± 4.21; p = 0.02) and the neonate's blood lead level (2.33 ± 1.3 µg/dl versus 7.33 ± 5.9 µg/dl) between the control and OUD groups (p < 0.001). The odds ratio of abnormally elevated blood lead level rose with increasing duration of maternal opiate disorder for opiate usage durations of 3 to 5 years (adjusted odds ratio [OR] 42.82, 95% confidence interval [CI] 3.27-561, p = 0.004) and > 5 years (adjusted OR 45.5, 95% CI 2.97-698, p = 0.006)., Conclusion: The results of this study suggested a significant relationship between maternal opium consumption during pregnancy and neonatal serum lead levels, as well as decreased neonatal Apgar score., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, ein Teil von Springer Nature.)

Objective: Intracellular signaling networks rely on proper membrane organization to control an array of cellular processes such as metabolism, proliferation, apoptosis, and macroautophagy in eukaryotic cells and organisms. Phosphatidylinositol 4-phosphate (PI4P) emerged as an essential regulatory lipid within organelle membranes that defines their lipid composition and signaling properties. PI4P is generated by four distinct phosphatidylinositol 4-kinases (PI4K) in mammalian cells: PI4KA, PI4KB, PI4K2A, PI4K2B. Animal models and human genetic studies suggest vital roles of PI4K enzymes in development and function of various organs, including the nervous system. Bi-allelic variants in PI4KA were recently associated with neurodevelopmental disorders (NDD), brain malformations, leukodystrophy, primary immunodeficiency, and inflammatory bowel disease. Here, we describe patients from two unrelated consanguineous families with PI4K2A deficiency and functionally explored the pathogenic mechanism., Methods: Two patients with PI4K2A deficiency were identified by exome sequencing, presenting with developmental and epileptic-dyskinetic encephalopathy. Neuroimaging showed corpus callosum dysgenesis, diffuse white matter volume loss, and hypoplastic vermis. In addition to NDD, we observed recurrent infections and death at toddler age. We further explored identified variants with cellular assays., Results: This clinical presentation overlaps with what was previously reported in two affected siblings with homozygous nonsense PI4K2A variant. Cellular studies analyzing these human variants confirmed their deleterious effect on PI4K2A activity and, together with the central role of PI4K2A in Rab7-associated vesicular trafficking, establish a link between late endosome-lysosome defects and NDD., Interpretation: Our study establishes the genotype-phenotype spectrum of PI4K-associated NDD and highlights several commonalities with other innate errors of intracellular trafficking., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Hereby, we aimed to investigate the expression of prostaglandin-endoperoxide synthase 2 (PTGS2) and Vascular Endothelial Factor-C (VEGF-C) besides the methylation of PTGS2 in AML patients. VEGF-C and PTGS2 expression analysis were evaluated in newly diagnosed AML patients and healthy controls by quantitative Reverse Transcriptase PCR method. Also, PTGS2 methylation status was evaluated by Methylation-Sensitive High-Resolution Melting Curve Analysis (MS-HRM). While 34% of patients were female, the mean age of the patients was 43.41 ± 17.60 years suffering mostly from M4 (48.21%) type of AML. Although methylation level between patients and controls was not significantly different, none of the normal controls showed methylation in the PTGS2 promoter. PTGS2 and VEGF-C levels were elevated in AML cases and correlated with WBC, Platelet, and Hemoglobin levels. The survival of patients with overexpressed VEGF-C and PTGS2 was poorer than others. It can be concluded that PTGS2 and especially VEGF-C expression but not PTGS2 methylation can be considered as diagnostic biomarkers for AML., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Pathogenic variants in PEX-genes can affect peroxisome assembly and function and cause Zellweger spectrum disorders (ZSDs), characterized by variable phenotypes in terms of disease severity, age of onset and clinical presentations. So far, defects in at least 15 PEX-genes have been implicated in Mendelian diseases, but in some of the ultra-rare ZSD subtypes genotype-phenotype correlations and disease mechanisms remain elusive., Methods: We report five families carrying biallelic variants in PEX13. The identified variants were initially evaluated by using a combination of computational approaches. Immunofluorescence and complementation studies on patient-derived fibroblasts were performed in two patients to investigate the cellular impact of the identified mutations., Results: Three out of five families carried a recurrent p.Arg294Trp non-synonymous variant. Individuals affected with PEX13-related ZSD presented heterogeneous clinical features, including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy. Computational predictions highlighted the involvement of the Arg294 residue in PEX13 homodimerization, and the analysis of blind docking predicted that the p.Arg294Trp variant alters the formation of dimers, impairing the stability of the PEX13/PEX14 translocation module. Studies on muscle tissues and patient-derived fibroblasts revealed biochemical alterations of mitochondrial function and identified mislocalized mitochondria and a reduced number of peroxisomes with abnormal PEX13 concentration., Conclusions: This study expands the phenotypic and mutational spectrum of PEX13-related ZSDs and also highlight a variety of disease mechanisms contributing to PEX13-related clinical phenotypes, including the emerging contribution of secondary mitochondrial dysfunction to the pathophysiology of ZSDs., (© 2022. The Author(s).)

Despite capturing the imagination of scientists for decades, the goal of creating an artificial heart for transplantation proved to be significantly more challenging than initially anticipated. Toward this goal, recent ground-breaking studies demonstrate the development of functional left ventricular (LV) models. LV models are artificially constructed 3D chambers that are capable of containing liquid within the engineered cavity and exhibit the functionality of native LV including contraction, ejection of fluid, and electrical impulse propagation. Various hydrogels and polymers have been used in manufacturing of LV models, relying on techniques such as electrospinning, bioprinting, casting, and molding. Most studies scaled down the models based on the dimensions of the human or rat ventricle. Initially, neonatal rat cardiomyocytes were the cell type of choice for construction the LV models. Yet, as the stem cell biology field advanced, recent studies focused on the use of cardiomyocytes derived from human induced pluripotent stem cells. In this review, we first describe the physiological characteristics of the human heart, to establish the parameter space for modeling. We then elaborate on current advances in the field and compare recently developed LV models among themselves and with the native human left ventricle. Fabrication methods, cell types, biomaterials, functional properties, and disease modeling capability are some of the major parameters that have distinguished these models. We also highlight some of the current challenges in this field, such as vascularization, cell composition and fidelity, and discuss potential solutions to overcome them.

Background: Hyperbilirubinemia is a common problem in neonates. The aim of this study was to evaluate the effect of synbiotic in addition to routine phototherapy on the treatment of neonatal jaundice., Method: This double-blind clinical trial, was performed on 194, 3-14 days old neonates. Neonates were divided into intervention and placebo groups. The intervention group received 5 drops of oral synbiotic daily along with phototherapy and the placebo group underwent phototherapy plus a placebo. Gestational age, age, weight, sex, initial and daily bilirubin level, frequency of defecation, mode of delivery, and length of hospitalization were assessed., Results: The rate of bilirubin reduction on the first day of admission was significantly higher in the intervention group (2.9±1.81 vs. 2.06±1.93, p = 0.002). The mean level of bilirubin on the second (9.8±1.92 vs. 10.88±2.26) and third days (8.06±1.54 vs. 9.86±1.7) was lower in the intervention group (p = 0.001). The proportion of discharged patients in the third and fourth days was higher in the intervention group compared to the control (65% vs. 41%, 99% vs. 86.5%, respectively, p = 0.001). However, the duration of hospitalization was shorter in the intervention group compared to the control (2.36±0.5 vs. 2.74±0.74, p = 0.001)., Conclusion: Based on our results, daily treatment with 5 drops of synbiotic along with phototherapy can be a safe and effective modality in faster bilirubin reduction, decreasing the hospitalization period and phototherapy. Therefore, it seems that it can be used as an adjunct therapy for neonates with jaundice.

In spite of successful initial remission, chemo-resistance and relapse are still concerning points in acute myeloid leukemia (AML) treatment strategies. Multidrug resistance (MDR) appears to be the major contributor of chemo-resistance, arising in some sub-clones of cancers and could be developed in others. The aim of this study was to investigate the role of extracellular vesicles (EVs) derived from AML patients on the transmission of chemo-resistance phenotype. Ultracentrifugation was employed to isolate EVs from healthy controls, new cases, and relapsed AML patients. The EVs size, morphology, and immunophenotype were determined by dynamic light scattering, TEM, and flow cytometry respectively. Bradford assay was performed to measure the protein content of EVs. MTT assay and flow cytometry analysis were also used to determine the viability index, induction of apoptosis, and ROS generation in U937 cells. The expression level of two efflux pumps was assessed using qRT-PCR analysis. Findings of TEM, DLS, and flow cytometry confirmed that EVs had a desirable shape, size, and surface markers. EVs derived from both new cases and relapsed AML patients significantly reduced idarubicin-induced apoptosis in the U937 cells. The analysis of drug efflux pumps gens revealed that EVs over-express MRD1 and MRP1 in the target cells. These findings suggested a novel role of EVs in mediating the acquired chemo-resistance in AML patients by inducing the expression of the drug efflux pumps; however, further investigations will be required to elucidate other underlying mechanisms of resistance that are mediated by EVs.

Epigenetic alterations could cause leukemia through the activation of normally silent loci or silencing of normally active loci. We herein aimed to compare the expression patterns of a histone modifiers panel consisted of SUV39H1, PRDM16, UHRF2, KDM2B, and KDM3C between acute myeloid leukemia(AML) cells and normal cells and to assess the correlation of these genes with the expression of vital tumor suppressor genes, including p16 INK4A and p53. Bone marrow or peripheral blood samples of 50 AML patients at diagnosis and also 18 subjects with a normal hematopoietic system as a control group were obtained after informed consent. Then, qRT-PCR was performed to determine the expression levels of the aforementioned genes. We found a broad alteration in the expression signature of five out of seven studied genes in AML patients as compared with the control group. UHRF2 and p53 were remarkably downregulated in AML patients (P<0.001), while SUV39H1, PRDM16, and KDM3C were significantly overexpressed (P<0.01). Based on the Spearman rank correlation, SUV39H1 and KDM2B negatively regulated both p16 INK4A and p53 expression. Taken together, our findings provided preliminary evidence regarding the pervasive mRNA perturbation of histone modifiers and their plausible influences on critical tumor suppressor genes. Future studies in this area would be required to assist in establishing these results in the clinical practice of AML patients., Competing Interests: Declaration of Competing Interest Vahid Amiri, Mohammad Hossein Mohammadi, Mohammad Rafiee, Behrooz Ghezelbash and Sina Salari and Mehdi Allahbakhshian Farsani have no conflicts of interest., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest There is no conflict of interest., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Britannin, a Sesquiterpene Lactone isolated from Inula aucheriana, has recently gained attraction in the therapeutic fields due to its anti-tumor properties. This study was designed to evaluate the effect of this agent on Acute Lymphoblastic Leukemia (ALL) cell lines, either as a monotherapy or in combination with Vincristine (VCR)., Methods and Results: To determine the anti-leukemic effects of Britannin on ALL-derived cell lines and suggest a mechanism of action for the agent, we used MTT assay, Annexin-V/PI staining, ROS assay, and real-time PCR analysis. Moreover, by using a combination index (CI), we evaluated the synergistic effect of Britannin on Vincristine. We found that unlike normal Peripheral Blood Mononuclear Cells (PBMCs) and L929 cells, Britannin reduced the viability of NALM-6, REH, and JURKAT cells. Among tested cells, NALM-6 cells had the highest sensitivity to Britannin, and this agent was able to induce p21/p27-mediated G1 cell cycle arrest and Reactive Oxygen Specious (ROS)-mediated apoptotic cell death in this cell line. When NALM-6 cells were treated with Nacetyl-L-Cysteine (NAC), a scavenger of ROS, Britannin could induce neither apoptosis nor reduce the survival of the cells suggesting that the cytotoxic effect of Britannin is induced through ROS-dependent manner. Moreover, we found that a low dose of Britannin enhanced the effect of Vincristine in NALM-6 cells by inducing apoptotic cell death via altering the expression of apoptotic-related genes., Conclusions: Overall, our results proposed a mechanism for the cytotoxic effect of Britannin, either as a single agent or in combination with Vincristine, in NALM-6 cells., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

The early death, which is more common in acute promyelocytic leukemia (APL) patients rather than other types of acute myelocytic leukemia (AML) highlights the importance of appropriate diagnostic method for early detection of this disease. The low sensitivity of the conventional methods, low tumor burden in some patients, and the need for bone marrow sampling are some of the diagnostic challenges on the way of proper detection of APL. Given these, we aimed to compare the efficacy of extracellular vesicles (EVs), as a diagnostic tool, with the existing methods. RT-PCR, qPCR, and flow cytometry were applied on EVs and their corresponding associated cellular component collected from 18 APL new cases, 23 patients with minimal residual disease (MRD), and NB4 cell line. RT-PCR results were positive in both cellular and vesicular components of all new cases, NB4 cells, and EVs in contrary to MRD cases. Normalized copy numbers (NCN) of PML-RARα were 5100 and 3950 for cell and EVs, respectively (p < 0.05). There was a significant difference in the NCN of PML-RARα between cells and EVs in BM samples. Investigating the effect of storage at room temperature revealed that PML-RARα level was retained near to the baseline level in EVs, but there was a significant reduction in its copy number in the cellular component during 7 days. Taken together, given to the acceptable stability, EVs could be introduced as a non-invasive liquid biopsy that alongside existing methods could remarkably change the paradigm of APL diagnostic approaches., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The involvement of microRNAs in the regulation of hematopoietic stem cells paves the way for their use in the management of autologous HSC transplantation (AHSCT). We aimed to evaluate the predictive value of circulatory microRNAs in extracellular vesicles (EVs) and plasma in platelet and neutrophil engraftment. Circulatory miR-125b, mir-126, miR-150, and miR-155 expression was assessed in isolated EVs and plasma in samples collected from AHSCT candidates. Multivariate analysis, COX models, and ROC assessment were performed to evaluate the predictive values of these microRNAs in platelet and neutrophil engraftment. miR-155 expression following conditioning with other clinical factors such as chemotherapy courses after diagnosis was the most significant predictors of platelet/neutrophil engraftment. A CD34 + cell count ≥ 3.5 × 10 6 /kg combined with miR-155 could be used as an engraftment predictor; however, in cases where the CD34 + cell count was < 3.5 × 10 6 /kg, this parameter lost its predictive value for engraftment and could be replaced by miR-155. The correlation between miR-155 and platelet/neutrophil engraftment even with lower numbers of CD34 + cells suggests the importance of this microRNA in the prediction of AHSCT outcome. Moreover, miR-155 could be utilized in therapeutic approaches to provide a better outcome for patients undergoing AHSCT., (© 2021. Japanese Society of Hematology.)

It has been reported that polyomaviruses are the microbes which can be a cause of several human pathological conditions including cancers, nephropathy, progressive multifocal leukoencephalopathy and gynaecological disease. Although investigators proposed some mechanisms used by the viruses to induce the disorders, the roles played by chemokines in the pathogenesis of polyomaviruses infections are yet to be clarified. This review article investigated recent studies regarding the roles played by chemokines in the pathogenesis of the polyomaviruses infections. The research in the literature revealed that CXC chemokines, including CXCL1, CXCL5, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12 and CXCL16, significantly participate in the pathogenesis of polyomaviruses. CC chemokines, such as CCL2, CCL5 and CCL20 also participate in the induction of the pathological conditions. Therefore, it appears that CXC chemokines may be considered as the strategic factors involved in the pathogenesis of polyomaviruses.

Multiple factors, including growth factors, are shown to be culprits of cancer outset and persistence. Among growth factors, insulin-like growth factors (IGFs) family are of more importance in the prognosis of blood malignancies. After binding to their corresponding receptor, IGFs initiate PI3K/AKT signaling pathway and increase the translation of intracellular proteins, such as cell division-related proteins. They also stimulate the transcription of cell division-related genes using the Ras-GTP pathway. In addition to organs such as the liver, IGFs are secreted by tumor cells and can cause growth and proliferation of self or tumor cells via autocrine and paracrine methods. Current studies indicate that decreasing the effects of IGF by blocking them, their receptors, or PI3K/AKT pathway using various drugs could help to suppress the division of tumor cells. Here, we delineate the role of the IGF family in hematologic malignancies and their potential mechanisms., (© 2020 Wiley Periodicals LLC.)

Background and Aims: As a curative procedure, hematopoietic stemcell transplantation (HSCT) is an approved treatment for many malignant orbenign hematologic and non-hematologic diseases. There are different outcomes of HSCT, as well as several parameters influencing these outcomes., Methods: We had searched scientific sources like Web ofScience and PubMed with a combination of keywords such as HSCT, engraftment,survival, outcomes, etc. Totally, 80 articles were included., Results: Here we have reviewed the effective factors onmain outcomes of HSCT including engraftment, survival, graft versus hostdisease, and Mobilization. Also, the prediction of hematological reconstitutionand some novel suggestions leading to better outcomes are reviewed., Conclusion: The study will be applicable for improvedmanagement of autologous and allogeneic HSCT process to increase the procedureefficiency., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

LKB1 is a significant tumor suppressor and epigenetic regulator playing a vital role in different types of cancers. SHMT1 and GLDC are two critical genes of the epigenetic pathway influenced by LKB1. As epigenetic is the major cause of AML pathogenesis, this study aimed at investigating LKB1, SHMT1, and GLDC gene expression levels in acute myeloid leukemia patients. The present study was conducted on LKB1, SHMT1, and GLDC gene expression levels in 60 de novo AML samples and 30 normal controls using real-time RT-PCR. The results showed that LKB1 and SHMT1 have respectively a significantly lower ( P  < 0.05) and higher ( P  < 0.05) expression level than that of normal controls. Furthermore, the correlation between LKB1 with SHMT1 and GLDC was significant and positive ( P value: 0.015, r: 0.299). Positive findings confirm that metabolic pathways alongside the LKB1 association drive the epigenetic axis and its substrate production. Therefore, it can be concluded that the newly-discovered pathway in the pathogenesis of this disease provides new insights into the design of therapeutic targets., Competing Interests: Conflict of interestThe authors declare that they have no competing interests., (© Indian Society of Hematology and Blood Transfusion 2020.)

Background: Effective treatment of acute myeloid leukemia (AML) is still controversial, therefore; a comprehensive understanding regarding the impaired cellular signaling pathways in AML can be useful in designing new therapeutic approaches. Among signaling pathways involved in AML, the mammalian target of rapamycin (mTOR) signaling pathway is of particular importance. While dysregulation of mTOR signaling has been reported in a wide range of patients with AML, but most studies have focused on mTOR downstream targets, and mTOR upstream targets have been overlooked., Objective: In this study, expression of mTOR genes and three upstream targets (5' adenosine monophosphate-activated protein kinase (AMPK, adiponectin, and sestrin 2) involved in mTOR signaling was investigated., Materials and Methods: In this study, expression of mTOR, AMPK, sestrin 2, and adiponectin genes in 60 patients with AML were evaluated compared to those of 30 healthy individuals as controls using the Real-Time polymerase chain reaction (Real-Time RT-PCR) method., Results: According to the results, there was a significant difference in the expression of all the studied genes in patients in comparison to the normal control group (P <0.05). Expression of the mTOR gene was increased, while expression of AMPK, sestrin 2, and adiponectin genes was decreased in the patients with AML. Mean expression of the genes (2-ΔCt) (AMPK, sestrin 2, adiponectin, and mTOR) was equal to 7.9, 3.2, 3.74, and 1.49 for controls and 6, 2.1, 2.83, and 2.64 for patients with AML, respectively., Conclusions: Given the decreased expression levels of sestrin 2, adiponectin, and AMPK genes as tumor inhibitors and the increased expression level of the mTOR gene as an oncogene in the patients with AML in our study, it is thought that disruption of this pathway may be involved in leukemogenesis and can be considered as an effective factor in the progression of cancer., (Copyright: © 2021 The Author(s); Published by Iranian Journal of Biotechnology.)

Recent advances have driven the development of stem cell-derived, self-organizing, three-dimensional miniature organs, termed organoids, which mimic different eye tissues including the retina, cornea, and lens. Organoids and engineered microfluidic organ-on-chips (organ chips) are transformative technologies that show promise in simulating the architectural and functional complexity of native organs. Accordingly, they enable exploration of facets of human disease and development not accurately recapitulated by animal models. Together, these technologies will increase our understanding of the basic physiology of different eye structures, enable us to interrogate unknown aspects of ophthalmic disease pathogenesis, and serve as clinically-relevant surrogates for the evaluation of ocular therapeutics. Both the burden and prevalence of monogenic and multifactorial ophthalmic diseases, which can cause visual impairment or blindness, in the human population warrants a paradigm shift towards organoids and organ chips that can provide sensitive, quantitative, and scalable phenotypic assays. In this article, we review the current situation of organoids and organ chips in ophthalmology and discuss how they can be leveraged for translational applications., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)