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Erythropoiesis is a tightly regulated process. Development of red blood cells occurs through differentiation of hematopoietic stem cells (HSCs) into more committed progenitors and finally into erythrocytes. Binding of erythropoietin (Epo) to its receptor (EpoR) is required for erythropoiesis as it promotes survival and late maturation of erythroid progenitors. In vivo and in vitro studies have highlighted the requirement of EpoR signaling through Janus kinase 2 (Jak2) tyrosine kinase and Stat5a/b as a central pathway. Here, we demonstrate that phospholipase C gamma 1 (Plcγ1) is activated downstream of EpoR-Jak2 independently of Stat5. Plcγ1-deficient pro-erythroblasts and erythroid progenitors exhibited strong impairment in differentiation and colony-forming potential. In vivo, suppression of Plcγ1 in immunophenotypically defined HSCs (Lin−Sca1+KIT+CD48−CD150+) severely reduced erythroid development. To identify Plcγ1 effector molecules involved in regulation of erythroid differentiation, we assessed changes occurring at the global transcriptional and DNA methylation level after inactivation of Plcγ1. The top common downstream effector was H2afy2, which encodes for the histone variant macroH2A2 (mH2A2). Inactivation of mH2A2 expression recapitulated the effects of Plcγ1 depletion on erythroid maturation. Taken together, our findings identify Plcγ1 and its downstream target mH2A2, as a 'non-canonical' Epo signaling pathway essential for erythroid differentiation. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs), fundamental constituents of the tumor microenvironment (TME), significantly influence cancer development, primarily by promoting epithelial-mesenchymal transition (EMT). EMT endows cancer cells with increased motility, invasiveness, and resistance to therapies, marking a pivotal juncture in cancer progression. The review begins with a detailed exposition on the origins of TAMs and their functional heterogeneity, providing a foundational understanding of TAM characteristics. Next, it delves into the specific molecular mechanisms through which TAMs induce EMT, including cytokines, chemokines and stromal cross-talking. Following this, the review explores TAM-induced EMT features in select cancer types with notable EMT characteristics, highlighting recent insights and the impact of TAMs on cancer progression. Finally, the review concludes with a discussion of potential therapeutic targets and strategies aimed at mitigating TAM infiltration and disrupting the EMT signaling network, thereby underscoring the potential of emerging treatments to combat TAM-mediated EMT in cancer. This comprehensive analysis reaffirms the necessity for continued exploration into TAMs' regulatory roles within cancer biology to refine therapeutic approaches and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Hutchinson‐Gilford Progeria syndrome (HGPS) is a lethal premature aging disorder caused by a de novo heterozygous mutation that leads to the accumulation of a splicing isoform of Lamin A termed progerin. Progerin expression deregulates the organization of the nuclear lamina and the epigenetic landscape. Progerin has also been observed to accumulate at low levels during normal aging in cardiovascular cells of adults that do not carry genetic mutations linked with HGPS. Therefore, the molecular mechanisms that lead to vascular dysfunction in HGPS may also play a role in vascular aging‐associated diseases, such as myocardial infarction and stroke. Here, we show that HGPS patient‐derived vascular smooth muscle cells (VSMCs) recapitulate HGPS molecular hallmarks. Transcriptional profiling revealed cardiovascular disease remodeling and reactive oxidative stress response activation in HGPS VSMCs. Proteomic analyses identified abnormal acetylation programs in HGPS VSMC replication fork complexes, resulting in reduced H4K16 acetylation. Analysis of acetylation kinetics revealed both upregulation of K16 deacetylation and downregulation of K16 acetylation. This correlates with abnormal accumulation of error‐prone nonhomologous end joining (NHEJ) repair proteins on newly replicated chromatin. The knockdown of the histone acetyltransferase MOF recapitulates preferential engagement of NHEJ repair activity in control VSMCs. Additionally, we find that primary donor‐derived coronary artery vascular smooth muscle cells from aged individuals show similar defects to HGPS VSMCs, including loss of H4K16 acetylation. Altogether, we provide insight into the molecular mechanisms underlying vascular complications associated with HGPS patients and normative aging. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) infection is a major global health issue and ranks among the top causes of liver cirrhosis and hepatocellular carcinoma. Although current antiviral medications, including nucleot(s)ide analogs and interferons, could inhibit the replication of HBV and alleviate the disease, HBV cannot be fully eradicated. The development of cellular and animal models for HBV infection plays an important role in exploring effective anti-HBV medicine. During the past decades, advancements in several cell culture systems, such as HepG2.2.15, HepAD38, HepaRG, hepatocyte-like cells, and primary human hepatocytes, have propelled the research in inhibiting HBV replication and expression and thus enriched our comprehension of the viral life cycle and enhancing antiviral drug evaluation efficacy. Mouse models, in particular, have emerged as the most extensively studied HBV animal models. Additionally, the present landscape of HBV therapeutics research now encompasses a comprehensive assessment of the virus's life cycle, targeting numerous facets and employing a variety of immunomodulatory approaches, including entry inhibitors, strategies aimed at cccDNA, RNA interference technologies, toll-like receptor agonists, and, notably, traditional Chinese medicine (TCM). This review describes the attributes and limitations of existing HBV model systems and surveys novel advancements in HBV treatment modalities, which will offer deeper insights toward discovering potentially efficacious pharmaceutical interventions. [ABSTRACT FROM AUTHOR]

Epigenetic regulation has been thoroughly investigated in recent years and has emerged as an important aspect of chronic lymphocytic leukemia (CLL) biology. Characteristic aberrant features such as methylation patterns and global DNA hypomethylation were the early findings of the research during the last decades. The investigation in this field led to the identification of a large number of genes where methylation features correlated with important clinical and laboratory parameters. Gene-specific analyses investigated methylation in the gene body enhancer regions as well as promoter regions. The findings included genes and proteins involved in key pathways that play central roles in the pathophysiology of the disease. Τhe application of these findings beyond the theoretical understanding can not only lead to the creation of prognostic and predictive models and scores but also to the design of novel therapeutic agents. The following is a review focusing on the present knowledge about single gene/gene promoter methylation or mRNA expression in CLL cases as well as records of older data that have been published in past papers. [ABSTRACT FROM AUTHOR]

Skin cancer is a significant health concern worldwide, and early and accurate diagnosis plays a crucial role in improving patient outcomes. In recent years, deep learning models have shown remarkable success in various computer vision tasks, including image classification. In this research study, we introduce an approach for skin cancer classification using vision transformer, a state-of-the-art deep learning architecture that has demonstrated exceptional performance in diverse image analysis tasks. The study utilizes the HAM10000 dataset; a publicly available dataset comprising 10,015 skin lesion images classified into two categories: benign (6705 images) and malignant (3310 images). This dataset consists of high-resolution images captured using dermatoscopes and carefully annotated by expert dermatologists. Preprocessing techniques, such as normalization and augmentation, are applied to enhance the robustness and generalization of the model. The vision transformer architecture is adapted to the skin cancer classification task. The model leverages the self-attention mechanism to capture intricate spatial dependencies and long-range dependencies within the images, enabling it to effectively learn relevant features for accurate classification. Segment Anything Model (SAM) is employed to segment the cancerous areas from the images; achieving an IOU of 96.01% and Dice coefficient of 98.14% and then various pretrained models are used for classification using vision transformer architecture. Extensive experiments and evaluations are conducted to assess the performance of our approach. The results demonstrate the superiority of the vision transformer model over traditional deep learning architectures in skin cancer classification in general with some exceptions. Upon experimenting on six different models, ViT-Google, ViT-MAE, ViT-ResNet50, ViT-VAN, ViT-BEiT, and ViT-DiT, we found out that the ML approach achieves 96.15% accuracy using Google's ViT patch-32 model with a low false negative ratio on the test dataset, showcasing its potential as an effective tool for aiding dermatologists in the diagnosis of skin cancer. [ABSTRACT FROM AUTHOR]

The high plasticity of lung epithelial cells, has for many years, confounded the correct identification of the cell-of-origin of lung adenocarcinoma (LUAD), one of the deadliest malignancies worldwide. Here, we employ lineage-tracing mouse models to investigate the cell of origin of Eml4-Alk LUAD, and show that Club and Alveolar type 2 (AT2) cells give rise to tumours. We focus on Club cell originated tumours and find that Club cells experience an epigenetic switch by which they lose their lineage fidelity and gain an AT2-like phenotype after oncogenic transformation. Single-cell transcriptomic analyses identified two trajectories of Club cell evolution which are similar to the ones used during lung regeneration, suggesting that lung epithelial cells leverage on their plasticity and intrinsic regeneration mechanisms to give rise to a tumour. Together, this study highlights the role of Club cells in LUAD initiation, identifies the mechanism of Club cell lineage infidelity, confirms the presence of these features in human tumours, and unveils key mechanisms conferring LUAD heterogeneity., (© 2022. The Author(s).)

Transposable elements (TEs) have emerged as important factors in establishing the cell type-specific gene regulatory networks and evolutionary novelty of embryonic and placental development. Recently, studies on the role of TEs and their dysregulation in cancers have shed light on the transcriptional, transpositional, and regulatory activity of TEs, revealing that the activation of developmental transcriptional programs by TEs may have a role in the dedifferentiation of cancer cells to the progenitor-like cell states. This essay reviews the recent evidence of the cis-regulatory TEs (henceforth crTE) in normal development and malignancy as well as the key transcription factors and regulatory pathways that are implicated in both cell states, and presents existing gaps remaining to be studied, limitations of current technologies, and therapeutic possibilities., (© 2024 The Author(s). BioEssays published by Wiley Periodicals LLC.)

Aged hematopoietic stem cells (HSCs) show reduced reconstitution potential, limiting their use in transplantation settings in the clinic. We demonstrate here that exposure of aged HSCs ex vivo to a pH of 6.9 instead of the commonly used pH of 7.4 results in enhanced HSCs potential that is consistent with rejuvenation, including attenuation of the myeloid bias of aged HSC and restoration of a youthful frequency of epigenetic polarity. Rejuvenation of aged HSCs by pH 6.9 is, at least in part, due to alterations in the polyamine/methionine pathway within pH 6.9 HSCs, and consequently, attenuation of the production of spermidine also attenuated aging of HSCs. Exposure of aged HSCs to pH 6.9, or pharmacological targeting of the polyamine pathway, might thus extend the use of HSCs from aged donors for therapeutic applications., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Cell culture has long been essential for preclinical modeling of human development and disease. However, conventional two-dimensional (2D) cell culture fails to faithfully model the complexity found in vivo, and novel drug candidates that show promising results in 2D models often do not translate to the clinic. More recently, three-dimensional (3D) cell culture models have gained popularity owing to their greater physiological relevance to in vivo biology. In particular, 3D spheroid models are becoming widely used due to their ability to mimic solid tumors, both in architecture and gradation of nutrients distributed from the outer, proliferative layers into the inner, quiescent layers of cells. Similar to in vivo tumors, cell lines grown in 3D spheroid models tend to be more resistant to antitumor drug treatments than their 2D cultured counterparts, though distinct signaling pathways and gene targets conferring this resistance have yet to be fully explored. RNA interference (RNAi) is an effective tool to elucidate gene function and discover novel druggable targets in 2D models; however, only a few studies have successfully performed RNAi in complex 3D models to date. Here, we demonstrate efficient RNAi-mediated knockdown using "transfection-free" Dharmacon Accell siRNAs in three spheroid culture models, in the presence or absence of the extracellular matrix. This methodology has the potential to be scaled up for complex arrayed screening experiments, which may aid in the identification of novel druggable targets with greater clinical relevance than those identified in 2D experiments. © 2024 Dharmacon, Inc. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Generation of 3D spheroids in matrix-free ULA plates Alternate Protocol 1: Generation of Matrigel matrix-embedded 3D spheroids Alternate Protocol 2: Generation of GrowDex hydrogel-embedded 3D spheroids Basic Protocol 2: Delivery of siRNA and collection of matrix-free 3D spheroids Alternate Protocol 3: Delivery of siRNA and collection of matrix-embedded spheroids Basic Protocol 3: RNA and protein extraction from spheroids for characterization of gene knockdown., (© 2024 Dharmacon, Inc. Current Protocols published by Wiley Periodicals LLC.)

Hematopoietic stem cells (HSC) maintain blood production throughout life. Nevertheless, HSC functionality deteriorates upon physiological aging leading to the increased prevalence of haematological diseases and hematopoietic malignancies in the elderly. Deubiquitinating enzymes (DUBs) by reverting protein ubiquitination ensure proper proteostasis, a key process in HSC maintenance and fitness., (© 2024 The Author(s). FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy that is often associated with relapse and drug resistance after standard chemotherapy or targeted therapy, particularly in older patients. Hematopoietic stem cell transplants are looked upon as the ultimate salvage option with curative intent. Adoptive cell therapy using chimeric antigen receptors (CAR) has shown promise in B cell malignancies and is now being investigated in AML. Initial clinical trials have been disappointing in AML, and we review current strategies to improve efficacy for CAR approaches. The extensive number of clinical trials targeting different antigens likely reflects the genetic heterogeneity of AML. The limited number of patients reported in multiple early clinical studies makes it difficult to draw conclusions about CAR safety, but it does suggest that the efficacy of this approach in AML lags behind the success observed in B cell malignancies. There is a clear need not only to improve CAR design but also to identify targets in AML that show limited expression in normal myeloid lineage cells. [ABSTRACT FROM AUTHOR]

no abstract [ABSTRACT FROM AUTHOR]

Cockayne syndrome (CS) and UV‐sensitive syndrome (UVSS) are rare genetic disorders caused by mutation of the DNA repair and multifunctional CSA or CSB protein, but only CS patients display a progeroid and neurodegenerative phenotype, providing a unique conceptual and experimental paradigm. As DNA methylation (DNAm) remodelling is a major ageing marker, we performed genome‐wide analysis of DNAm of fibroblasts from healthy, UVSS and CS individuals. Differential analysis highlighted a CS‐specific epigenomic signature (progeroid‐related; not present in UVSS) enriched in three categories: developmental transcription factors, ion/neurotransmitter membrane transporters and synaptic neuro‐developmental genes. A large fraction of CS‐specific DNAm changes were associated with expression changes in CS samples, including in previously reported post‐mortem cerebella. The progeroid phenotype of CS was further supported by epigenomic hallmarks of ageing: the prediction of DNAm of repetitive elements suggested an hypomethylation of Alu sequences in CS, and the epigenetic clock returned a marked increase in CS biological age respect to healthy and UVSS cells. The epigenomic remodelling of accelerated ageing in CS displayed both commonalities and differences with other progeroid diseases and regular ageing. CS shared DNAm changes with normal ageing more than other progeroid diseases do, and included genes functionally validated for regular ageing. Collectively, our results support the existence of an epigenomic basis of accelerated ageing in CS and unveil new genes and pathways that are potentially associated with the progeroid/degenerative phenotype. [ABSTRACT FROM AUTHOR]

Leukemia invades the bone marrow progressively and, through unknown mechanisms, outcompetes healthy hematopoiesis. Protein arginine methyltransferases 1 (PRMT1) are found in prokaryotes and eukaryotes cells. They are necessary for a number of biological processes and have been linked to several human diseases, including cancer. Small compounds that target PRMT1 have a significant impact on both functional research and clinical disease treatment. In fact, numerous PRMT1 inhibitors targeting the S-adenosyl-L-methionine binding region have been studied. Through topographical descriptors, quantitative structure-activity relationships (QSAR) were developed in order to identify the most effective PRMT1 inhibitors among 17 compounds. The model built using linear discriminant analysis allows us to accurately classify over 90% of the investigated active substances. Antileukemic activity is predicted using a multilinear regression analysis, and it can account for more than 56% of the variation. Both analyses are validated using an internal "leave some out" test. The developed model could be utilized in future preclinical experiments with novel drugs. [ABSTRACT FROM AUTHOR]

Haematopoiesis within the bone marrow (BM) represents a complex and dynamic process intricately regulated by neural signaling pathways. This delicate orchestration is susceptible to disruption by factors such as aging, diabetes, and obesity, which can impair the BM niche and consequently affect haematopoiesis. Genetic mutations in Tet2, Dnmt3a, Asxl1, and Jak2 are known to give rise to clonal haematopoiesis of intermediate potential (CHIP), a condition linked to age-related haematological malignancies. Despite these insights, the exact roles of circadian rhythms, sphingosine-1-phosphate (S1P), stromal cell-derived factor-1 (SDF-1), sterile inflammation, and the complement cascade on various BM niche cells remain inadequately understood. Further research is needed to elucidate how BM niche cells contribute to these malignancies through neural regulation and their potential in the development of gene-corrected stem cells. This literature review describes the updated functional aspects of BM niche cells in haematopoiesis within the context of haematological malignancies, with a particular focus on neural signaling and the potential of radiomitigators in acute radiation syndrome. Additionally, it underscores the pressing need for technological advancements in stem cell-based therapies to alleviate the impacts of immunological stressors. Recent studies have illuminated the microheterogeneity and temporal stochasticity of niche cells within the BM during haematopoiesis, emphasizing the updated roles of neural signaling and immunosurveillance. The development of gene-corrected stem cells capable of producing blood, immune cells, and tissue-resident progeny is essential for combating age-related haematological malignancies and overcoming immunological challenges. This review aims to provide a comprehensive overview of these evolving insights and their implications for future therapeutic strategies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Despite increased sophistication in DNA methylation (DNAm) measurement and methods, conducting studies in specific populations such as the hematopoietic stem cell transplant (HCT) population, presents unique challenges and study design considerations. In this article, we explain the motivation for investigating DNAm in the HCT population, highlighting important study design features and key findings in a longitudinal prospective pilot study of DNAm in 32 patients undergoing autologous HCT in Central Virginia, USA. We also discuss limitations and challenges to generating robust results. We observed that HCT does not prevent high-quality DNA from being extracted from whole blood for DNAm research and that longitudinal prospective studies that span pre- and 2-months post-HCT are feasible. Critically, we did not observe significant impacts of cancer diagnosis, time since transplant, age, or chromosomal sex on overall DNAm data dimensionality. These observations demonstrate that while extreme care is required to ensure generalizable, accurate, and interpretable results, researchers should not avoid HCT-DNAm research simply for fear that the transplant procedure or presence of a cancer diagnosis will prevent meaningful conclusions from being drawn. DNAm is an attractive biomarker that is understudied in patients undergoing HCT and needs to expand to improve precise prediction of HCT outcomes. [ABSTRACT FROM AUTHOR]

Periosteal stem and progenitor cells (PSPCs) are major contributors to bone maintenance and repair. Deciphering the molecular mechanisms that regulate their function is crucial for the successful generation and application of future therapeutics. Here, we pinpoint Hox transcription factors as necessary and sufficient for periosteal stem cell function. Hox genes are transcriptionally enriched in periosteal stem cells and their overexpression in more committed progenitors drives reprogramming to a naïve, self-renewing stem celllike state. Crucially, individual Hox family members are expressed in a location-specific manner and their stem cell-promoting activity is only observed when the Hox gene is matched to the anatomical origin of the PSPC, demonstrating a role for the embryonic Hox code in adult stem cells. Finally, we demonstrate that Hoxa10 overexpression partially restores the age-related decline in fracture repair. Together, our data highlight the importance of Hox genes as key regulators of PSPC identity in skeletal homeostasis and repair. [ABSTRACT FROM AUTHOR]

Advances in molecular biology and genetic testing have greatly improved our understanding of the genetic basis of hematologic malignancies and have enabled the identification of new cancer predisposition syndromes. Recognizing a germline mutation in a patient affected by a hematologic malignancy allows for a tailored treatment approach to minimize toxicities. It informs the donor selection, the timing, and the conditioning strategy for hematopoietic stem cell transplantation, as well as the comorbidities evaluation and surveillance strategies. This review provides an overview of germline mutations that predispose to hematologic malignancies, focusing on those most common during childhood and adolescence, based on the new International Consensus Classification of Myeloid and Lymphoid Neoplasms. [ABSTRACT FROM AUTHOR]

Epigenetic alterations are implicated in tumour immune evasion and immune checkpoint blockade (ICB) resistance. SET domain bifurcated histone methyltransferase 1 (SETDB1) is a histone lysine methyltransferase that catalyses histone H3K9 di- and tri-methylation on euchromatin, and growing evidence indicates that SETDB1 amplification and abnormal activation are significantly correlated with the unfavourable prognosis of multiple malignant tumours and contribute to tumourigenesis and progression, immune evasion and ICB resistance. The main underlying mechanism is H3K9me3 deposition by SETDB1 on tumour-suppressive genes, retrotransposons, and immune genes. SETDB1 targeting is a promising approach to cancer therapy, particularly immunotherapy, because of its regulatory effects on endogenous retroviruses. However, SETDB1- targeted therapy remains challenging due to potential side effects and the lack of antagonists with high selectivity and potency. Here, we review the role of SETDB1 in tumourigenesis and immune regulation and present the current challenges and future perspectives of SETDB1 targeted therapy. [ABSTRACT FROM AUTHOR]

Acute myeloid leukaemia (AML) is the most prevalent type of acute leukaemia in adults, with a heterogenous cytogenetics landscapes. NPM1 mutated AML was designated as a provisional entity in 2008 World Health Organisation (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues. In 2017, fourth edition was revised and AML was recognised as a distinct entity with distinctive cytological, molecular and clinicopathological features. For example, AML with NPM1 mutation is strongly associated with acute myelomonocytic and acute monocytic leukemia. In recent studies, AML with both NPM1 and FLT3- ITD mutations, had been associated of blasts with cup-like nuclei. We described this characteristical morphology in a 68-year-old female who was diagnosed with AML alongside NPM1 and FLT3-ITD mutation. She presented with a short history of fever and laboratory findings of hyperleukocytosis, mild anemia and thrombocytopenia. A diagnosis of AML was proposed from the cytological and flow cytometry examinations. The full blood picture and bone marrow aspirate showed some of the blasts with cup-like nuclei and the flow cytometry examination showed characteristical feature which was suggestive of AML with NPM1 mutation. Polymerase chain reaction (PCR) detected mutation in FLT3-internal tandem duplication (ITD) and NPM1. This patient was treated with AML protocol but succumbed due to sepsis. This case highlighted the importance of recognising this clinicopathological presentations to provide rapid diagnosis and guide for the appropriate molecular testing. In this study, new treatment modalities available for this type of AML and literature review of previous studies were also discussed. [ABSTRACT FROM AUTHOR]

Skin cancer has shown a sharp increase in prevalence over the past few decades and currently accounts for one-third of all cancers diagnosed. The most lethal form of skin cancer is melanoma, which develops in 4% of individuals. The rising prevalence and increased number of fatalities of skin cancer put a significant burden on healthcare resources and the economy. However, early detection and treatment greatly improve survival rates for patients with skin cancer. Since the rising rates of both the incidence and mortality have been particularly noticeable with melanoma, significant resources have been allocated to research aimed at earlier diagnosis and a deeper knowledge of the disease. Dermoscopy, reflectance confocal microscopy, optical coherence tomography, multiphoton-excited fluorescence imaging, and dermatofluorescence are only a few of the optical modalities reviewed here that have been employed to enhance noninvasive diagnosis of skin cancer in recent years. This review article discusses the methodology behind newly emerging noninvasive optical diagnostic technologies, their clinical applications, and advantages and disadvantages of these techniques, as well as the potential for their further advancement in the future. [ABSTRACT FROM AUTHOR]

Juvenile myelomonocytic leukemia (JMML) is a rare hematopoietic malignancy in children, with an incidence of 1.2 per million children per year. At this moment, we present a case report and a brief literature review of JMML in a child, primarily focused on its applicability in low-middle income countries. A 3.5-year-old male was referred to our tertiary center due to pallor, enlarging abdomen and neck mass, recurrent fever, and chronic diarrhea. Initial laboratory workup showed hemoglobin of 6.4 g/dl, white blood cell of 315.62 × 103/μL, and platelet of 17 × 103/μL. Blood smears showed 10% suspected blasts, 17% myelocytes, and 17% metamyelocytes with thrombocytopenic crisis. The HbF level was 5.8%. BCR-ABL gene tested negative. The patient was diagnosed with juvenile myelomonocytic leukemia. Considering that HSCT could not be done in our center and lack other financial possibilities to seek treatment abroad, the family agreed to do the palliative treatment. The patient was treated with oral 6-mercaptopurine and subcutaneous cytarabine. Four weeks after receiving 6-mercaptopurine, the white blood cell count decreased to 10.6 × 103/μL and the spleen size was half of the original size. The patient continued chemotherapy until week 15, chemotherapy was stopped, but 16 weeks after the diagnosis of JMML, he developed severe thrombocytopenia, endophthalmitis, and sepsis and passed away. As a conclusion, in JMML cases in developing countries without HSCT, palliative chemotherapy is acceptable, and palliative care is an important aspect. [ABSTRACT FROM AUTHOR]

Background. Melanomas, the most common human malignancy, are primarily diagnosed visually, beginning with an initial clinical screening and followed potentially by dermoscopic analysis, a biopsy, and histopathological examination. We aimed to systematically review the performance and quality of machine learning-based methods in distinguishing melanoma and benign nevus in the relevant literature. Method. Four databases (Web of Science, PubMed, Embase, and the Cochrane library) were searched to retrieve the relevant studies published until March 26, 2022. The Predictive model Deviation Risk Assessment tool (PROBAST) was used to assess the deviation risk of opposing law. Result. This systematic review included thirty researches with 114007 subjects and 71 machine learning models. The convolutional neural network was the main machine learning method. The pooled sensitivity was 85% (95% CI 82–87%), the specificity was 86% (82–88%), and the C -index was 0.87 (0.84–0.90). Conclusion. The findings of our study showed that ML algorithms had high sensitivity and specificity for distinguishing between melanoma and benign nevi. This suggests that state-of-the-art ML-based algorithms for distinguishing melanoma from benign nevi may be ready for clinical use. However, a large proportion of the earlier published studies had methodological flaws, such as lack of external validation and lack of clinician comparisons. The results of these studies should be interpreted with caution. [ABSTRACT FROM AUTHOR]

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Objective: This study aimed to identify specific dysregulated genes with potential diagnostic and predictive values for JAK2V617F+ myelofibrosis. Methods: Two gene expression datasets of CD34+ hematopoietic stem and progenitor cells (HSPCs) from patients with JAK2V617F+ myeloproliferative neoplasm (MPN) [n = 66, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)] and healthy controls (HC) (n = 30) were acquired from the GEO (Gene Expression Omnibus) database. The differentially expressed genes (DEGs) were screened between each JAK2V617F+ MPN entity and HC. Subsequently, functional enrichment analyses, including Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and Gene Set Enrichment Analysis (GSEA), were conducted to decipher the important biological effects of DEGs. Protein-protein interaction (PPI) networks of the DEGs were constructed to identify hub genes and significant modules. Another two gene expression profiles of patients with JAK2V617F+ MPN [n = 23, including PV, ET, secondary myelofibrosis (SMF), and PMF] and HC (n = 6) from GEO were used as external validation datasets to prove the reliability of the identified signatures. Results: KEGG analysis revealed the upregulated genes in three JAK2V617F+ MPN entities compared with HC were essentially enriched in inflammatory pathways and immune response signaling pathways, and the number of these pathways enriched in PMF was obviously more than that in PV and ET. Following the PPI analysis, 10 genes primarily related to inflammation and immune response were found upregulated in different JAK2V617F+ MPN entities. In addition, Reactome enrichment analysis indicated that interferon signaling pathways were enriched specifically in PMF but not in PV or ET. Furthermore, several interferon (IFN)-stimulated genes were identified to be uniquely upregulated in JAK2V617F+ PMF. The external datasets validated the upregulation of four interferon-related genes (OAS1, IFITM3, GBP1, and GBP2) in JAK2V617F+ myelofibrosis. The receiver operating characteristic (ROC) curves indicate that the four genes have high area under the ROC curve (AUC) values when distinguishing JAK2V617F+ myelofibrosis from PV or ET. Conclusion: Four interferon-stimulated genes (OAS1, IFITM3, GBP1, and GBP2) exclusively upregulated in JAK2V617F+ myelofibrosis might have the potential to be the auxiliary molecular diagnostic and predictive indicators of myelofibrosis. [ABSTRACT FROM AUTHOR]

The benefit of molecularly-informed therapies in cancer of unknown primary (CUP) is unclear. Here, we use comprehensive molecular characterization by whole genome/exome, transcriptome and methylome analysis in 70 CUP patients to reveal substantial mutational heterogeneity with TP53, MUC16, KRAS, LRP1B and CSMD3 being the most frequently mutated known cancer-related genes. The most common fusion partner is FGFR2, the most common focal homozygous deletion affects CDKN2A. 56/70 (80%) patients receive genomics-based treatment recommendations which are applied in 20/56 (36%) cases. Transcriptome and methylome data provide evidence for the underlying entity in 62/70 (89%) cases. Germline analysis reveals five (likely) pathogenic mutations in five patients. Recommended off-label therapies translate into a mean PFS ratio of 3.6 with a median PFS1 of 2.9 months (17 patients) and a median PFS2 of 7.8 months (20 patients). Our data emphasize the clinical value of molecular analysis and underline the need for innovative, mechanism-based clinical trials. The identification of molecular biomarkers in cancer of unknown primary site (CUP) cases may enable the improvement of prognosis in these patients. Here, the authors integrate whole genome/exome, transcriptome and methylome data in 70 CUP patients, recommend therapies based on their analysis and report clinical outcome data. [ABSTRACT FROM AUTHOR]

Since the identification of NM23 (now called NME1) as the first metastasis suppressor gene (MSG), a small number of other gene products and non-coding RNAs have been identified that suppress specific parameters of the metastatic cascade, yet which have little or no ability to regulate primary tumor initiation or maintenance. MSG can regulate various pathways or cell biological functions such as those controlling mitogen-activated protein kinase pathway mediators, cell-cell and cell-extracellular matrix protein adhesion, cytoskeletal architecture, G-protein-coupled receptors, apoptosis, and transcriptional complexes. One defining facet of this gene class is that their expression is typically downregulated, not mutated, in metastasis, such that any effective therapeutic intervention would involve their re-expression. This review will address the therapeutic targeting of MSG, once thought to be a daunting task only facilitated by ectopically re-expressing MSG in metastatic cells in vivo. Examples will be cited of attempts to identify actionable oncogenic pathways that might suppress the formation or progression of metastases through the re-expression of specific metastasis suppressors., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Janus kinase (JAK) is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2. The JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer conditions. Targeting the JAK family kinases with small-molecule inhibitors has proved to be effective in the treatment of different types of diseases. In the current review, eleven of the JAK inhibitors that received approval for clinical use have been discussed. These drugs are abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib. The aim of the current review was to provide an integrated overview of the chemical and pharmacological data of the globally approved JAK inhibitors. The synthetic routes of the eleven drugs were described. In addition, their inhibitory activities against different kinases and their pharmacological uses have also been explained. Moreover, their crystal structures with different kinases were summarized, with a primary focus on their binding modes and interactions. The proposed metabolic pathways and metabolites of these drugs were also illustrated. To sum up, the data in the current review could help in the design of new JAK inhibitors with potential therapeutic benefits in inflammatory and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Skin cancer is one of the most common diseases that can be initially detected by visual observation and further with the help of dermoscopic analysis and other tests. As at an initial stage, visual observation gives the opportunity of utilizing artificial intelligence to intercept the different skin images, so several skin lesion classification methods using deep learning based on convolution neural network (CNN) and annotated skin photos exhibit improved results. In this respect, the paper presents a reliable approach for diagnosing skin cancer utilizing dermoscopy images in order to improve health care professionals' visual perception and diagnostic abilities to discriminate benign from malignant lesions. The swarm intelligence (SI) algorithms were used for skin lesion region of interest (RoI) segmentation from dermoscopy images, and the speeded-up robust features (SURF) was used for feature extraction of the RoI marked as the best segmentation result obtained using the Grasshopper Optimization Algorithm (GOA). The skin lesions are classified into two groups using CNN against three data sets, namely, ISIC-2017, ISIC-2018, and PH-2 data sets. The proposed segmentation and classification techniques' results are assessed in terms of classification accuracy, sensitivity, specificity, F-measure, precision, MCC, dice coefficient, and Jaccard index, with an average classification accuracy of 98.42 percent, precision of 97.73 percent, and MCC of 0.9704 percent. In every performance measure, our suggested strategy exceeds previous work. [ABSTRACT FROM AUTHOR]

Aging of the blood system is characterized by increased hematopoietic stem cells (HSCs) and myeloid‐biased differentiation leading to higher propensity for hematological malignancies. Unraveling cell‐intrinsic mechanisms regulating HSC aging could aid reversal or slowing of aging. Asrij/OCIAD1 is an evolutionarily conserved regulator of hematopoiesis and governs mitochondrial, endosomal, and proteasomal function in mammalian stem cells. Asrij deletion in mice causes loss of HSC quiescence, myeloid skewing, reduced p53 and increased DNA damage, features attributed to aged HSCs. Mechanistically, Asrij controls p53 ubiquitination and degradation and AKT/STAT5 activation. Asrij localizes to endosomes and mitochondria. As decline in organelle structure and function are common hallmarks of aging, we asked whether Asrij regulates organelle function in aged HSCs. We find that chronologically aged wild‐type (WT) HSCs had reduced Asrij levels. Expectedly, young asrij KO mice had reduced AcH4K16 levels; however, transcriptome analysis of KO HSCs showed a modest overlap of gene expression with aged WT HSCs. Further, analysis of organelle structure and function in asrij KO mice revealed significant changes, namely damaged mitochondria, elevated ROS; impaired endosomal trafficking seen by increased cleaved Notch1, reduced Rab5; and reduced 26S proteasome activity. Pharmacological correction of mitochondrial and proteasome activity in asrij KO mice restored HSC and myeloid cell frequencies. Furthermore, lysophosphatidic acid‐induced Asrij upregulation in aged WT mice rescued mitochondrial and proteasome activity and restored HSC frequency. Our results highlight a new role for Asrij in preventing HSC aging by regulating organelle homeostasis and will help decipher organelle dynamics in HSC longevity. [ABSTRACT FROM AUTHOR]

During the acute phase of Chagas disease, Trypanosoma cruzi circulation through the bloodstream leads to high tissue parasitism in the host. In primary lymphoid organs, progenitor cell reduction paralleled transient immunosuppression. Herein we showed that acute oral infection in mice promotes diffuse parasitism in bone marrow cells at 14 and 21 days post-infection (dpi), with perivascular regions, intravascular regions, and regions near the bone being target sites of parasite replication. Phenotypic analysis of hematopoietic differentiation in the bone marrow of infected mice showed that the cell number in the tissue is decreased (lineage-negative and lineage-positive cells). Interestingly, analysis of hematopoietic branching points showed that hematopoietic stem and progenitor cells (HSPCs) were significantly increased at 14 dpi. In addition, the pool of progenitors with stem plasticity (HSC-MPP3), as well as multipotent progenitors (MPPs) such as MPP4, also showed this pattern of increase. In contrast, subsequent progenitors that arise from MPPs, such as common lymphoid progenitors (CLPs), lymphoid-primed MPPs (LMPPs), and myeloid progenitors, were not enhanced; conversely, all presented numeric decline. Annexin V staining revealed that cell death increase in the initial hematopoietic branching point probably is not linked to CLPs and that myeloid progenitors decreased at 14 and 21 dpi. In parallel, our investigation provided clues that myeloid progenitor decrease could be associated with an atypical expression of Sca-1 in this population leading to a remarkable increase on LSK-like cells at 14 dpi within the HSPC compartment. Finally, these results led us to investigate HSPC presence in the spleen as a phenomenon triggered during emergency hematopoiesis due to mobilization or expansion of these cells in extramedullary sites. Splenocyte analysis showed a progressive increase in HSPCs between 14 and 21 dpi. Altogether, our study shows that the bone marrow is a target tissue in T. cruzi orally infected mice, leading to a hematopoietic disturbance with LSK-like cell bias accounting on HSPCs possibly affecting myeloid progenitor numbers. The LMPP and CLP reduction converges with defective thymocyte development. Lastly, it is tempting to speculate that the extramedullary hematopoiesis seen in the spleen is a mechanism involved in the hematological maintenance reported during the acute phase of oral T. cruzi infection. [ABSTRACT FROM AUTHOR]

Melanoma detection, prognosis, and treatment represent challenging and complex areas of cutaneous oncology with considerable impact on patient outcomes and healthcare economics. Artificial intelligence (AI) applications in these tasks are rapidly developing. Neural networks with increasing levels of sophistication are being implemented in clinical image, dermoscopic image, and histopathologic specimen classification of pigmented lesions. These efforts hold promise of earlier and highly accurate melanoma detection, as well as reliable prognostication and prediction of therapeutic response. Herein, we provide a brief introduction to AI, discuss contemporary investigational applications of AI in melanoma, and summarize challenges encountered with AI. [ABSTRACT FROM AUTHOR]

In order to solve the problems of low accuracy and low efficiency of answer prediction in machine reading comprehension, a multitext English reading comprehension model based on the deep belief neural network is proposed. Firstly, the paragraph selector in the multitext reading comprehension model is constructed. Secondly, the text reader is designed, and the deep belief neural network is introduced to predict the question answering probability. Finally, the popular English dataset of SQuAD is used for test analysis. The final results show that, after the comparative analysis of different learning methods, it is found that the English multitext reading comprehension model has a strong reading comprehension ability. In addition, two evaluation methods are used to score the overall performance of the model, which shows that the overall score of the English multitext reading comprehension model based on the deep confidence neural network is more than 90, and the efficiency will not be reduced because of the change of the number of documents in the dataset. The above results show that the use of the deep belief neural network to improve the probability generation performance of the model can well solve the task of English multitext reading comprehension, effectively reduce the difficulty of machine reading comprehension in multitask reading, and has a good guiding significance for promoting human convenient Internet knowledge acquisition. [ABSTRACT FROM AUTHOR]

Background: DNA methylation affects the development, progression, and prognosis of various cancers. This study aimed to identify DNA methylated-differentially expressed genes (DEGs) and develop a methylation-driven gene model to evaluate the prognosis of ovarian cancer (OC). Methods: DNA methylation and mRNA expression profiles of OC patients were downloaded from The Cancer Genome Atlas, Genotype-Tissue Expression, and Gene Expression Omnibus databases. We used the R package MethylMix to identify DNA methylation-regulated DEGs and built a prognostic signature using LASSO Cox regression. A quantitative nomogram was then drawn based on the risk score and clinicopathological features. Results: We identified 56 methylation-related DEGs and constructed a prognostic risk signature with four genes according to the LASSO Cox regression algorithm. A higher risk score not only predicted poor prognosis, but also was an independent poor prognostic indicator, which was validated by receiver operating characteristic (ROC) curves and the validation cohort. A nomogram consisting of the risk score, age, FIGO stage, and tumor status was generated to predict 3- and 5-year overall survival (OS) in the training cohort. The joint survival analysis of DNA methylation and mRNA expression demonstrated that the two genes may serve as independent prognostic biomarkers for OS in OC. Conclusion: The established qualitative risk score model was found to be robust for evaluating individualized prognosis of OC and in guiding therapy. [ABSTRACT FROM AUTHOR]

Chronic Myeloid Leukemia (CML) is a hematological disorder characterized by the clonal expansion of a hematopoietic stem cell carrying the Philadelphia chromosome that juxtaposes the BCR and ABL1 genes. The ensuing BCR-ABL1 chimeric oncogene is characterized by a breakpoint region that generally involves exons 1, 13 or 14 in BCR and exon 2 in ABL1. Additional breakpoint regions, generating uncommon BCR-ABL1 fusion transcripts, have been detected in various CML patients. However, to date, the impact of these infrequent transcripts on BCR-ABL1 -dependent leukemogenesis and sensitivity to tyrosine kinase inhibitors (TKIs) remain unclear. We analyzed the transforming potential and TKIs responsiveness of three atypical BCR-ABL1 fusions identified in CML patients, and of two additional BCR-ABL1 constructs with lab-engineered breakpoints. We observed that modifications in the DC2 domain of BCR and SH3 region of ABL1 affect BCR-ABL1 catalytic efficiency and leukemogenic ability. Moreover, employing immortalized cell lines and primary CD34-positive progenitors, we demonstrate that these modifications lead to reduced BCR-ABL1 sensitivity to imatinib, dasatinib and ponatinib but not nilotinib. We conclude that BCR-ABL1 oncoproteins displaying uncommon breakpoints involving the DC2 and SH3 domains are successfully inhibited by nilotinib treatment. [ABSTRACT FROM AUTHOR]

Transposable elements form a major fraction of the genome in various eukaryotic species. Although deleterious effects of transpositions within the genome have been reported, recent findings suggest that transposable elements can function as novel regulatory elements to fine‐tune gene expression. Transposable elements can impact the chromatin state through processes such as heterochromatin formation, enhancer–promoter interactions, and chromatin boundary formation, mainly because of the functions of chromatin‐based pathways that regulate the expression of transposable elements via DNA methylation and repressive histone modification. Therefore, transposable elements can rewire the chromatin state and gene expression depending on their insertions. Here, we review the findings that reveal the role of transposable elements as modifiers of the chromatin state and gene expression as well as the molecular mechanisms capable of inducing these changes. [ABSTRACT FROM AUTHOR]

Genetic variability, epigenetic variability, and gene expression variability (noise) are generally considered independently in their relationship with phenotypic variation. However, they appear to be intrinsically interconnected and influence it in combination. The study of the interplay between genetic and epigenetic variability has the longest history. This article rather considers the introduction of gene expression variability in its relationships with the two others and reviews for the first time experimental evidences over the four relationships connected to gene expression noise. They show how introducing this third source of variability complicates the way of thinking evolvability and the emergence of biological novelty. Finally, cancer cells are proposed to be an ideal model to decipher the dynamic interplay between genetic, epigenetic, and gene expression variability when one of them is either experimentally increased or therapeutically targeted. This interplay is also discussed in an evolutionary perspective in the context of cancer cell drug resistance. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) represents a most common cancer among women worldwide. The outcomes of this disease remain dismal due to frequent recurrence and metastasis. Inositol‐1,4,5‐trisphosphate‐3‐kinase‐A (ITPKA) plays an important role in regulating calcium signaling and actin dynamics. The dysregulation of ITPKA has been observed in several human cancers. The present study aimed to assess ITPKA expression and its prognostic value in BC. Methods: ITPKA expression was examined via quantitative real‐time polymerase chain reaction (qRT‐PCR) and immunohistochemistry (IHC) methods. In addition, Kaplan–Meier survival analysis and Cox regression analysis were performed to evaluate prognostic value of ITPKA in BC. Results: Upregulated ITPKA expression was found in BC samples, according to both qRT‐PCR and IHC analyses (all p <.05). ITPKA expression was positively correlated with lymph node metastasis (p =.021) and TNM stage (p =.009). Moreover, BC patients with high expression of ITPKA had poor overall survival compared with those with low expression (log‐rank p <.05). Cox analysis verified that ITPKA expression was an independent prognostic factor for BC patients (HR = 4.239, 95%CI = 2.221–8.093 and p =.000). Conclusion: BC cases show increased expression of ITPKA. ITPKA may act as an independent prognostic biomarker in BC. [ABSTRACT FROM AUTHOR]