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Erythropoiesis: insights into pathophysiology and treatments in 2017.

Erythropoiesis is a tightly-regulated and complex process originating in the bone marrow from a multipotent stem cell and terminating in a mature, enucleated erythrocyte.Altered red cell production can result from the direct impairment of medullary erythropoiesis, as seen in the thalassemia syndromes, inherited bone marrow failure as well as in the anemia of chronic disease. Alternatively, in disorders such as sickle cell disease (SCD) as well as enzymopathies and membrane defects, medullary erythropoiesis is not, or only minimally, directly impaired. Despite these differences in pathophysiolo

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… Activin Signalling Activins are soluble ligands, expressed in various tissues that belong to a large group of proteins called the transforming growth factor β (TGF-β) family. … Activin expression, particularly activin A and bone morphogenic protein (BMP) 2 and 4 have been shown to have a role in the regulation of erythropoiesis (Maguer-Satta et al. 2003 ). …

The Genetic Epidemiology of Pediatric Pulmonary Arterial Hypertension.

OBJECTIVE: To describe the prevalence of pulmonary arterial hypertension (PAH)-associated gene mutations, and other genetic characteristics in a national cohort of children with PAH from the Dutch National registry and to explore genotype-phenotype associations and outcomes. STUDY DESIGN: Children (n = 70) diagnosed with idiopathic PAH, heritable PAH, PAH associated with congenital heart disease with coincidental shunt (PAH-congenital heart disease group 3), PAH after closure of a cardiac shunt (PAH-congenital heart disease group 4), or PAH associated with other noncardiac conditions were enr

Local expressions of TGF-beta1, TGF-beta1RI, CTGF, and Smad-7 in Helicobacter pylori-associated gastritis.

OBJECTIVE: Transforming growth-factor (TGF)-beta1 and Smad-7 play important roles in Helicobacter pylori (H. pylori)-associated gastritis. Connective tissue growth factor (CTGF) can facilitate the TGF-beta/Smad signaling by switching off Smad-7. The purpose of this study was to examine the in situ expressions of these cytokines in the gastric antrum with or without H. pylori infection. MATERIAL AND METHODS: Antral specimens from 166 patients (96 M, 70 F, median age 52 years, range 26 to 76 years) were used in this study. H. pylori infection status was determined by histological examination an

Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins.

BACKGROUND: Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-beta (TGF-beta) superfamily, underlie many cases of familial and sporadic primary pulmonary hypertension (PPH). We postulated that pulmonary artery smooth muscle cells (PASMCs) from patients with PPH might demonstrate abnormal growth responses to TGF-beta superfamily members. METHODS AND RESULTS: For studies of (3)H-thymidine incorporation or cell proliferation, PASMCs (passages 4 to 8) were derived from main pulmonary arteries. In control cells, 24-hour

Endocervical cancer is associated with an increase in the ligands and receptors for transforming growth factor-beta and a contrasting decrease in p27(Kip1).

OBJECTIVE: The aim of this study was to investigate the relationship between the expression of the TGF-beta ligands and TGF-beta receptors to the expression of p27(Kip1), a TGF-beta-regulated gene, in endocervical cancer. METHODS: To examine the expression of TGF-beta and p27(Kip1) in malignant transformation of the uterine endocervix, a panel of 23 formalin-fixed and paraffin-embedded human cervical specimens, including 8 with benign endocervical glands, 8 with cervical adenocarcinoma in situ, and 7 with cervical adenocarcinomas, was used. Tissues were immunostained with polyclonal antibodie

Interaction among cells of bone, immune system, and solid tumors leads to bone metastases.

Bone metastases are a dismal consequence for different types of solid tumors, such as breast, prostate, lung, and kidney cancer. The mechanisms regulating the interactions among bone, immune system, and tumor cells have been deeply investigated, and many studies are ongoing to define the specific role of the different cells in the bone metastatic process. The affinity of some tumors to growth in bone results from the special microenvironment provided by bone. Moreover, immune system and bone have a bidirectional relationship: bone cells express surface molecules ruling the expansion of hemopoi

Cardiac Cachexia: Unaddressed Aspect in Cancer Patients.

Tumor-derived cachectic factors such as proinflammatory cytokines and neuromodulators not only affect skeletal muscle but also affect other organs, including the heart, in the form of cardiac muscle atrophy, fibrosis, and eventual cardiac dysfunction, resulting in poor quality of life and reduced survival. This article reviews the holistic approaches of existing diagnostic, pathophysiological, and multimodal therapeutic interventions targeting the molecular mechanisms that are responsible for cancer-induced cardiac cachexia. The major drivers of cardiac muscle wasting in cancer patients are au

Global first-in-class drugs approved in 2023-2024: Breakthroughs and insights.

First-in-class (FIC) drugs are considered the main drivers of new drug discovery and have novel targets and mechanisms. The proportion of FIC drugs among new drugs provides fundamental guidance for both academic and pharmaceutical research. From a global perspective, 81 FIC drugs were approved in 2023 and 2024. Among them, small-molecule drugs account for a greater percentage (51.9%), illustrating the discovery of new chemical entities. Macromolecule drugs (48.1%), which mainly consist of antibody analogs, represent a growing trend as new biotechnology techniques have emerged. In terms of FIC

Myeloma bone disease: pathogenesis and management in the era of new anti-myeloma agents.

IntroductionMultiple myeloma (MM) is a malignancy of plasma cells with characteristic bone disease. Despite recent great strides achieved in MM treatment owing to the implementation of new anti-MM agents, MM is still incurable and bone destruction remains a serious unmet issue in patients with MM.ApproachIn this review, we will summarize and discuss the mechanisms of the formation of bone disease in MM and the available preclinical and clinical evidence on the treatment for MM bone disease.ConclusionsMM cells produce a variety of cytokines to stimulate receptor activator of nuclear factor-κB l

Hereditary hemorrhagic telangiectasia: diagnosis and management from the hematologist's perspective.

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant disorder that causes abnormal blood vessel formation. The diagnosis of hereditary hemorrhagic telangiectasia is clinical, based on the Curaçao criteria. Genetic mutations that have been identified include ENG, ACVRL1/ALK1, and MADH4/SMAD4, among others. Patients with HHT may have telangiectasias and arteriovenous malformations in various organs and suffer from many complications including bleeding, anemia, iron deficiency, and high-output heart failure. Families with the same mutatio

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… In the healthy patient, ligands in the extracellular space such as TGF-β, activins and BMPs bind to type I and type II serine/threonine receptors of the cell membrane. … Expression of vascular endothelial growth factor is coordinately regulated by the activin-like kinase receptors 1 and 5 in endothelial cells. Blood. 2009;114(10):2197–2206. 35. Han C, Choe S-W, Kim YH, et al. …

Preventing and Repairing Myeloma Bone Disease by Combining Conventional Antiresorptive Treatment With a Bone Anabolic Agent in Murine Models.

Multiple myeloma is a plasma cell malignancy, which develops in the bone marrow and frequently leads to severe bone destruction. Current antiresorptive therapies to treat the bone disease do little to repair damaged bone; therefore, new treatment strategies incorporating bone anabolic therapies are urgently required. We hypothesized that combination therapy using the standard of care antiresorptive zoledronic acid (Zol) with a bone anabolic (anti-TGFβ/1D11) would be more effective at treating myeloma-induced bone disease than Zol therapy alone. JJN3 myeloma-bearing mice (n = 8/group) treated w

Genetic testing and blood biomarkers in paediatric pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.

Childhood-onset pulmonary arterial hypertension (PAH) is considered complex and multifactorial, with relatively poor estimates of the natural history of the disease. Strategies allowing earlier detection, establishment of disease aetiology together with more accurate and sensitive biomarkers could enable better estimates of prognosis and individualise therapeutic strategies. Evidence is accumulating that genetic defects play an important role in the pathogenesis of idiopathic and hereditary forms of PAH. Altogether nine genes have been reported so far to be associated with childhood onset PAH

Transforming growth factor beta1 (TGFbeta1) expression in head and neck squamous cell carcinoma patients as related to prognosis.

OBJECTIVE: To systematically review the evidence of effectiveness of surgical vs. non-surgical therapy for the treatment of chronic periodontal disease. METHODS: A search was conducted for randomized controlled trials of at least 12 months duration comparing surgical with non-surgical treatment of chronic periodontal disease. Data sources included the National Library of Medicine computerised bibliographic database MEDLINE, and the Cochrane Oral Health Group (COHG) Specialist Trials Register. Screening, data abstraction and quality assessment were conducted independently by multiple reviewers

TGF-β: an active participant in the immune and metabolic microenvironment of multiple myeloma : TGF-β in the microenvironment of multiple myeloma.

Although substantial quantities of potent therapies for multiple myeloma (MM) have been established, MM remains an incurable disease. In recent years, our understanding of the initiation, development, and metastasis of cancers has made a qualitative leap. Cancers attain the abilities to maintain proliferation signals, escape growth inhibitors, resist cell death, induce angiogenesis, and more importantly, escape anti-tumor immunity and reprogram metabolism, which are the hallmarks of cancers. Besides, different cancers have different tumor microenvironments (TME), thus, we pay more attention to

Therapeutic strategies against cancer cachexia.

Cancer cachexia has two main components: anorexia and metabolic alterations. The main changes associated with the development of this multi-organic syndrome are glucose intolerance, fat depletion and muscle protein hypercatabolism. The aim of this paper is to review the more recent therapeutic approaches designed to counteract the wasting suffered by the cancer patient with cachexia. Among the most promising approaches we can include the use of ghrelin agonists, beta-blockers, beta-adrenergic agonists, androgen receptor agonists and anti-myostatin peptides. The multi-targeted approach seems es

Pericytes as targets in hereditary hemorrhagic telangiectasia.

Defective paracrine Transforming Growth Factor-β (TGF-β) signaling between endothelial cells and the neighboring mural cells have been thought to lead to the development of vascular lesions that are characteristic of Hereditary Hemorrhagic Telangiectasia (HHT). This review highlights recent progress in our understanding of TGF-β signaling in mural cell recruitment and vessel stabilization and how perturbed TGF-β signaling might contribute to defective endothelial-mural cell interaction affecting vessel functionalities. Our recent findings have provided exciting insights into the role of thalid

Muscle and Bone Defects in Metastatic Disease.

PURPOSE OF REVIEW: The present review addresses most recently identified mechanisms implicated in metastasis-induced bone resorption and muscle-wasting syndrome, known as cachexia. RECENT FINDINGS: Metastatic disease in bone and soft tissues is often associated with skeletal muscle defects. Recent studies have identified a number of secreted molecules and extracellular vesicles that contribute to cancer cell growth and metastasis leading to bone destruction and muscle atrophy. In addition, alterations in muscle microenvironment including dysfunctions in hepatic and mitochondrial metabolism ha

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… Specifically, activin type 2 receptor (ActRIIB) or its ligands such as myostatin, GDF11, and activins are attractive therapeutic targets considering their important role in the regulation of muscle growth. … Endogenous antagonist follistatin-like 3 (FSTL3) binds to activins, GDF8, and GDF11 [ 77 ], without affecting other ligands of the TGF-β family. …

Therapeutic effects of the novel subtype-selective histone deacetylase inhibitor chidamide on myeloma-associated bone disease.

Histone deacetylases are promising therapeutic targets in hematological malignancies. In the work herein, we investigated the effect of chidamide, a new subtype-selective histone deacetylase inhibitor that was independently produced in China, on multiple myeloma and its associated bone diseases using different models. The cytotoxicity of chidamide toward myeloma is due to its induction of cell apoptosis and cell cycle arrest by increasing the levels of caspase family proteins p21 and p27, among others. Furthermore, chidamide exhibited significant cytotoxicity against myeloma cells co-cultured

TGF-β in hematologic malignancies: molecular functions and clinical applications.

Transforming growth factor-β (TGF-β) represents a family of multifunctional cytokines, primarily secreted by megakaryocytes, monocytes, T lymphocytes, bone marrow stromal cells, and other cell types. TGF-β plays an essential role in various physiological processes, including the regulation of cell proliferation, differentiation, apoptosis, and immune homeostasis. As a key immunoregulatory cytokine, TGF-β contributes to an immunosuppressive network within the microenvironment of hematologic malignancies by modulating the functions of both adaptive and innate immune cells. Current studies have s

Diagnosis and treatment of bone disease in multiple myeloma: spotlight on spinal involvement.

Bone disease is observed in almost 80% of newly diagnosed symptomatic multiple myeloma patients, and spine is the bone site that is more frequently affected by myeloma-induced osteoporosis, osteolyses, or compression fractures. In almost 20% of the cases, spinal cord compression may occur; diagnosis and treatment must be carried out rapidly in order to avoid a permanent sensitive or motor defect. Although whole body skeletal X-ray is considered mandatory for multiple myeloma staging, magnetic resonance imaging is presently considered the most appropriate diagnostic technique for the evaluation