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Exploring human plasma proteomic variations in mucolipidosis type IV.

Mucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by loss of function of the lysosomal channel transient receptor potential mucolipin-1, TRPML1, and is associated with an early brain phenotype consisting of glial reactivity, hypomyelination, and lysosomal abnormalities. Although the field is approaching the first translationally relevant therapy, we currently lack a molecular signature of disease that can be used to detect therapeutic efficacy. Here, we analyzed 7,322 proteins in the plasma proteome f

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… Haploinsufficiency of cytosolic serine hydroxymethyltransferase in the Smith-Magenis syndrome. Am. J. Hum. Genet. 1995;57:1342–1350. 29. Hanzelmann S., Castelo R., Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinf. 2013;14:7. doi: 10.1186/1471-2105-14-7. 30. …

Long-term follow up of tandem autologous-allogeneic hematopoietic cell transplantation for multiple myeloma.

We previously reported initial results in 102 multiple myeloma (MM) patients treated with sequential high-dose melphalan and autologous hematopoietic cell transplantation followed by 200 cGy total body irradiation with or without fludarabine 90 mg/m2 and allogeneic hematopoietic cell transplantation. Here we present long-term clinical outcomes among the 102 initial patients and among 142 additional patients, with a median follow up of 8.3 (range 1.0-18.1) years. Donors included human leukocyte antigen identical siblings (n=179) and HLA-matched unrelated donors (n=65). A total of 209 patients (

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… Teoh PJ Chung TH Sebastian S p53 haploinsufficiency and functional abnormalities in multiple myeloma . Leukemia . 2014 ; 28 ( 10 ): 2066 – 2074 . 24625551 10.1038/leu.2014.102 23. …

A gain-of-function p53 mutant synergizes with oncogenic NRAS to promote acute myeloid leukemia in mice.

We previously demonstrated that a subset of acute myeloid leukemia (AML) patients with concurrent RAS pathway and TP53 mutations have an extremely poor prognosis and that most of these TP53 mutations are missense mutations. Here, we report that, in contrast to the mixed AML and T cell malignancy that developed in NrasG12D/+ p53-/- (NP-/-) mice, NrasG12D/+ p53R172H/+ (NPmut) mice rapidly developed inflammation-associated AML. Under the inflammatory conditions, NPmut hematopoietic stem and progenitor cells (HSPCs) displayed imbalanced myelopoiesis and lymphopoiesis and mostly normal cell prolife

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… hematopoiesis Stem Cells 2016 34 7 1859 1871 10.1002/stem.2355 26972179 PMC5358545 23 Kong G et al Loss of wild-type Kras promotes activation of all Ras isoforms in oncogenic Kras-induced leukemogenesis Leukemia 2016 30 7 1542 1551 10.1038/leu.2016.40 27055865 PMC5316475 24 Chang YI et al Dnmt3a haploinsufficiency …

R-spondin signaling as a pivotal regulator of tissue development and homeostasis.

R-spondins (Rspos) are cysteine-rich secreted glycoproteins which control a variety of cellular functions and are essential for embryonic development and tissue homeostasis. R-spondins (Rspo1 to 4) have high structural similarity and share 60% sequence homology. It has been shown that their cysteine-rich furin-like (FU) domain and the thrombospondin (TSP) type I repeat domain are essential for initiating downstream signaling cascades and therefore for their biological functions. Although numerous studies have unveiled their pivotal role as critical developmental regulators, the most important

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… Of note, my laboratory have reported that Rspo3 haploinsufficiency in mice unexpectedly leads to higher trabecular bone mass [85] . Recently, in vitro study using human adipose-derived stem cells (hASCs) also showed that Rspo3 knockdown by shRNA induced increased osteogenic potential [86] . …

Protein kinase CK2: a potential therapeutic target for diverse human diseases.

CK2 is a constitutively active Ser/Thr protein kinase, which phosphorylates hundreds of substrates, controls several signaling pathways, and is implicated in a plethora of human diseases. Its best documented role is in cancer, where it regulates practically all malignant hallmarks. Other well-known functions of CK2 are in human infections; in particular, several viruses exploit host cell CK2 for their life cycle. Very recently, also SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has been found to enhance CK2 activity and to induce the phosphorylation of several CK2 substrates (ei

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… The Lys198Arg mutation was identified also in an 8-year-old Japanese boy showing a phenotype resembling Kleefstra syndrome (severe intellectual disability and synophrys), a syndrome that can be caused by haploinsufficiency of EHMT1 gene, encoding a histone methyltrasferase. 242 The overlapping phenotype … A CSNK2B haploinsufficiency emerged in some patients, but the functional role of the CSNK2B variants remains still unknown. …

Preclinical efficacy of tasquinimod in myelodysplastic neoplasms: Restoring erythropoiesis and mitigating bone loss.

Myelodysplastic neoplasms (MDSs) are clonal disorders characterized by ineffective hematopoiesis, dysplasia, and a risk of transformation into acute myeloid leukemia. MDS is also associated with a higher incidence of osteoporosis, suggesting a complex interplay between hematopoiesis, the bone marrow (BM) microenvironment, and bone homeostasis. Targeting inflammation has emerged as a promising therapeutic strategy, particularly in lower risk MDS. Tasquinimod (TASQ) is a small-molecule inhibitor of the inflammatory alarmin S100A9, blocking its interaction with TLR4 and RAGE receptors. We investi

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… Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9 . Nat Med . 2016 ; 22 ( 3 ): 288 ‐ 297 . 10.1038/nm.4047 26878232 PMC4870050 25 Shi L , Zhao Y , Fei C , et al. …

The Current Landscape of Secondary Malignancies after CAR T-Cell Therapies: How Could Malignancies Be Prevented?

Chimeric antigen receptor (CAR) T-cell therapies have revolutionised the field of haematological malignancies by achieving impressive remission rates in patients with highly refractory haematological malignancies, improving overall survival. To date, six commercial anti-CD19 and anti-BCMA CAR T-cell products have been approved by the Food and Drug Administration (FDA) for the treatment of relapsed/refractory B-cell haematological malignancies and multiple myeloma. The indications for CAR T-cell therapies are gradually expanding, with these therapies being investigated in a variety of diseases,

Glucosylsphingosine (Lyso-Gb1) as a reliable biomarker in Gaucher disease: a narrative review.

BACKGROUND: Gaucher disease (GD) is a rare, inherited, autosomal recessive disorder caused by a deficiency of the lysosomal enzyme, acid β-glucosidase. Its diagnosis is achieved via measurements of acid β-glucosidase activity in either fresh peripheral blood leukocytes or dried blood spots, and confirmed by identifying characteristic mutations in the GBA1 gene. Currently, several biomarkers are available for disease monitoring. Chitotriosidase has been used over the last 20 years to assess the severity of GD, but lacks specificity in GD patients. Conversely, the deacylated form of glucosylcera

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… GBA haploinsufficiency accelerates alpha-synuclein pathology with altered lipid metabolism in a prodromal model of Parkinson's disease. Hum Mol Genet. 2019;28(11):1894–1904. doi: 10.1093/hmg/ddz030. 59. Gundner AL, Duran-Pacheco G, Zimmermann S, Ruf I, Moors T, Baumann K, et al. …

The osteogenic niche-targeted arsenic nanoparticles prevent colonization of disseminated breast tumor cells in the bone.

Up to 70% of patients with late-stage breast cancer have bone metastasis. Current treatment regimens for breast cancer bone metastasis are palliative with no therapeutic cure. Disseminated tumor cells (DTCs) colonize inside the osteogenic niches in the early stage of bone metastasis. Drug delivery into osteogenic niches to inhibit DTC colonization can prevent bone metastasis from entering its late stage and therefore cure bone metastasis. Here, we constructed a 50% DSS6 peptide conjugated nanoparticle to target the osteogenic niche. The osteogenic niche was always located at the endosteum with

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… Haploinsufficiency of Runx2 results in bone formation decrease and different BSP expression pattern changes in two transgenic mouse models J Cell Physiol 217 2008 40 47 18459139 10.1002/jcp.21472 PMC2818140 28 Boskey A.L. Spevak L. Paschalis E. Doty S.B. McKee M.D. …

Bone marrow microenvironment in myelodysplastic neoplasms: insights into pathogenesis, biomarkers, and therapeutic targets.

Myelodysplastic neoplasms (MDS) represent a heterogeneous group of malignant hematopoietic stem and progenitor cell (HSPC) disorders characterized by cytopenia, ineffective hematopoiesis, as well as the potential to progress to acute myeloid leukemia (AML). The pathogenesis of MDS is influenced by intrinsic factors, such as genetic insults, and extrinsic factors, including altered bone marrow microenvironment (BMM) composition and architecture. BMM is reprogrammed in MDS, initially to prevent the development of the disease but eventually to provide a survival advantage to dysplastic cells. Rec

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… RPS14 deletion (mouse model 1) causes erythroid differentiation defects, anemia, and megakaryocyte dysplasia, while combined haploinsufficiency of Rps14, Csnk1a1, and miR-145/146a (mouse model 2) results in anemia and macrophage activation, disrupting the BMM. …

Biological and clinical aspects of HPV-related cancers.

Cancer-related diseases represent the second overall cause of death worldwide. Human papilloma virus (HPV) is an infectious agent which is mainly sexually transmitted and may lead to HPV-associated cancers in both men and women. Almost all cervical cancers are HPV-associated, however, an increasing number of head and neck cancers (HNCs), especially oropharyngeal cancer, can be linked to HPV infection. Moreover, anogenital cancers, including vaginal, vulvar, penial, and anal cancers, represent a subset of HPV-related cancers. Whereas testing and prevention of cervical cancer have significantly

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… BRCA1 Haploinsufficiency is masked by RNF168-mediated chromatin ubiquitylation. Mol Cell. 2019;73(6):1267–81.e7. doi: 10.1016/j.molcel.2018.12.010. 65. Schipler A, Iliakis G. …

Consensus recommendations from the 2024 International Follicular Lymphoma Scientific Workshop.

AbstractFollicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. Although patients with FL have high response rates to therapy, most develop increasingly resistant disease. In addition, transformation into an aggressive lymphoma is associated with unfavorable outcomes. Many novel agents are under investigation, and early clinical data are encouraging. Aligning treatment with the underlying tumor biology and sequencing of therapies remain key clinical challenges. At the Lymphoma Research Foundation's biannual 2024 Follicular Lymphoma Scientific Workshop, experts convened to di

Notch signaling deregulation in multiple myeloma: A rational molecular target.

Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and non-tumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple

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… NOTCH SIGNALING PATHWAY A strain of Drosophila characterized by wings with irregular, “notched” margins was discovered in 1919 and lately associated to haploinsufficiency in the Notch gene [ 28 ]. …

Оптический анализ функционального воздействия демиелинации и ремиэлизации Cuprizone на межсферную нервную коммуникацию в антериорной кортекс через Corpus Callosum.

Cuprizone (CPZ) — широко используемый токсин, который вызывает демиелинизирующие заболевания в моделях животных, производя множественный склероз (MS), похожий на патологию в грызунах. CPZ является одним из немногих токсинов, которые вызывают демиелинацию и последующее воспоминание после прекращения ее применения. В этом исследовании рассматриваются функциональные последствия демиэлизации, вызванной КПЗ, и последующее восстановление нейронной связи в передней коре сингула (АКК) с уделением особого внимания соединению между полушариями через корпус каллосум (CC). Используя широкополосную высокос

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… J Integr Neurosci 22:160. 10.31083/j.jin2206160 Ojima D, Tominaga Y, Kubota T, Tada A, Takahashi H, Kishimoto Y, Tominaga T, Yamamoto T (2024) Impaired hippocampal long-term potentiation and memory deficits upon haploinsufficiency of MDGA1 can be rescued by acute administration of D-cycloserine. …

Targeting BTK in B Cell Malignancies: From Mode of Action to Resistance Mechanisms.

The B cell receptor (BCR) signaling pathway plays a crucial role in B cell development and contributes to the pathogenesis of B cell neoplasms. In B cell malignancies, the BCR is constitutively active through both ligand-dependent and ligand-independent mechanisms, resulting in continuous Bruton tyrosine kinase (BTK) signaling activation, which provides a survival and proliferation advantage to the neoplastic clone. Among B cell malignancies, those in which the most significant results were obtained by treatment with BTK inhibitors (BTKi) include chronic lymphocytic leukemia, mantle cell lymph

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… This genetic aberration leads to haploinsufficiency of the TRAIL receptor (TRAIL-R), which causes leukemic cells to become resistant to TRAIL-induced apoptosis, independent of the mutational status of BTK and/or PLCG2 . …

Генетическая основа болезни.

Генетика в той или иной степени играет определенную роль во всех заболеваниях. Изменения в нашей ДНК и различия в том, как эта ДНК функционирует (одиночка или комбинация), наряду с окружающей средой (которая включает образ жизни), способствуют болезнетворным процессам. В рамках этого обзора изучается генетическая основа человеческих заболеваний, включая однородные генетические расстройства, хромосомные диспропорции, эпигенетические, раковые и сложные расстройства, и рассматривается вопрос о том, каким образом наше понимание и технологические достижения могут быть использованы для обеспечения н

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… With loss of this region of the X chromosome, SHOX is expressed from the other allele, therefore at only half the usual levels and this is not sufficient (haploinsufficiency) to fully achieve its required growth-related function. … Note that autosomal dominant disorders can also be caused by loss-of-function alleles, if 50% of normal gene expression from the normal allele is not sufficient, a phenomenon termed haploinsufficiency. …

Резюме докладов 53rd Конференция Европейского общества генетики человека: интерактивные электронные постеры.

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The Applications of Machine Learning in the Management of Patients Undergoing Stem Cell Transplantation: Are We Ready?

Hematopoietic stem cell transplantation (HSCT) is a life-saving therapy for hematologic malignancies, such as leukemia and lymphoma and other severe conditions but is associated with significant risks, including graft versus host disease (GVHD), relapse, and treatment-related mortality. The increasing complexity of clinical, genomic, and biomarker data has spurred interest in machine learning (ML), which has emerged as a transformative tool to enhance decision-making and optimize outcomes in HSCT. This review examines the applications of ML in HSCT, focusing on donor selection, conditioning re

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… Successful hematopoietic stem cell transplantation for complete CTLA-4 haploinsufficiency due to a de novo monoallelic 2q33.2-2q33.3 deletion. Clin. Immunol. 2020;220:108589. doi: 10.1016/j.clim.2020.108589. 4. Hawley R.G., Ramezani A., Hawley T.S. Hematopoietic stem cells. …

Pathophysiology and treatment of osteoporosis: challenges for clinical practice in older people.

Osteoporosis, a common chronic metabolic bone disease is associated with considerable morbidity and mortality. As the prevalence of osteoporosis increases with age, a paralleled elevation in the rate of incident fragility fractures will be observed. This narrative review explores the origins of bone and considers physiological mechanisms involved in bone homeostasis relevant to management and treatment. Secondary causes of osteoporosis, as well as osteosarcopenia are discussed followed by an overview of the commonly used pharmacological treatments for osteoporosis in older people.

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… Patients with haploinsufficiency of IGF-1 receptor have been found to have undesirable changes to bone architecture in accordance with this hypothesis [ 30 , 31 ]. …

Резюме докладов 51st Конференция Европейского общества генетики человека: плакаты

Аннотация не предоставлена источником. Откройте карточку для перехода к публикации.