Kinase-inactivated CDK6 preserves the long-term functionality of adult hematopoietic stem cells.

Hematopoietic stem cells (HSCs) are characterized by the ability to self-renew and to replenish the hematopoietic system. The cell-cycle kinase cyclin-dependent kinase 6 (CDK6) regulates transcription, whereby it has both kinase-dependent and kinase-independent functions. Herein, we describe the complex role of CDK6, balancing quiescence, proliferation, self-renewal, and differentiation in activated HSCs.

Impact of refresher training on the outcomes of trachomatous trichiasis surgery.

Background/aims: Trachomatous trichiasis (TT) is a severe consequence of chronic inflammation/conjunctival scarring resulting from trachoma, the leading infectious cause of blindness worldwide. Our prospective cohort study evaluated the effectiveness of refresher training (RT) for experienced surgeons (1-22 years) on the outcomes of upper lid (UL) TT surgery in rural Ethiopia.

Methods: Patients undergoing UL TT surgery in at least one eye by a participating surgeon were included.

The impact of incorporating surgical simulation into trichiasis surgery training on operative aspects of initial live-training surgeries.

Background: While surgical simulation is regularly used in surgical training in high-income country settings, it is uncommon in low- and middle-income countries, particularly for surgical training that primarily occurs in rural areas. We designed and evaluated a novel surgical simulator for improving trachomatous trichiasis (TT) surgery training, given that trichiasis is mostly found among the poorest individuals in rural areas.

Methodology/principal Findings: TT surgery programs were invited to incorporate surgical simulation with a new, high fidelity, low-cost simulator into their training.

The nature inspired peptide [T20K]-kalata B1 induces anti-tumor effects in anaplastic large cell lymphoma.

Ribosomally synthesized and post-translationally modified peptides, such as plant cyclotides, are a diverse group of natural products well known as templates in drug discovery and therapeutic lead development. The cyclotide kalata B1 (kB1) has previously been discovered as immunosuppressive agent on T-lymphocytes, and a synthetic version of this peptide, [T20K]kB1 (T20K), has been effective in reducing clinical symptoms, such as inflammation and demyelination, in a mouse model of multiple sclerosis. Based on its T-cell modulatory impact we studied the effects of T20K and several analogs on the proliferation of anaplastic large cell lymphoma (ALCL), a heterogeneous group of clinically aggressive diseases associated with poor prognosis.

Cyclin-dependent kinase inhibitors in malignant hematopoiesis.

The cell-cycle is a tightly orchestrated process where sequential steps guarantee cellular growth linked to a correct DNA replication. The entire cell division is controlled by cyclin-dependent kinases (CDKs). CDK activation is balanced by the activating cyclins and CDK inhibitors whose correct expression, accumulation and degradation schedule the time-flow through the cell cycle phases.

CDK6 Degradation Is Counteracted by p16 and p18 in AML.

Cyclin-dependent kinase 6 (CDK6) represents a novel therapeutic target for the treatment of certain subtypes of acute myeloid leukaemia (AML). CDK4/6 kinase inhibitors have been widely studied in many cancer types and their effects may be limited by primary and secondary resistance mechanisms. CDK4/6 degraders, which eliminate kinase-dependent and kinase-independent effects, have been suggested as an alternative therapeutic option.

Investigations on Transfer of Pathogens between Foster Cows and Calves during the Suckling Period.

To date, there have been few studies on the health effects of foster cow systems, including the transmission of mastitis-associated pathogens during suckling. The present study aimed to compare the pathogens detected in the mammary glands of the foster cow with those in the oral cavities of the associated foster calves and to evaluate the resulting consequences for udder health, calf health and internal biosecurity. Quarter milk sampling of 99 foster cows from an organic dairy farm was conducted twice during the foster period.

A STAT5B-CD9 axis determines self-renewal in hematopoietic and leukemic stem cells.

The transcription factors signal transducer and activator of transcription 5A (STAT5A) and STAT5B are critical in hematopoiesis and leukemia. They are widely believed to have redundant functions, but we describe a unique role for STAT5B in driving the self-renewal of hematopoietic and leukemic stem cells (HSCs/LSCs). We find STAT5B to be specifically activated in HSCs and LSCs, where it induces many genes associated with quiescence and self-renewal, including the surface marker CD9.

Precision Medicine in Hematology 2021: Definitions, Tools, Perspectives, and Open Questions.

During the past few years, our understanding of molecular mechanisms and cellular interactions relevant to malignant blood cell disorders has improved substantially. New insights include a detailed knowledge about disease-initiating exogenous factors, endogenous (genetic, somatic, epigenetic) elicitors or facilitators of disease evolution, and drug actions and interactions that underlie efficacy and adverse event profiles in defined cohorts of patients. As a result, precision medicine and personalized medicine are rapidly growing new disciplines that support the clinician in making the correct diagnosis, in predicting outcomes, and in optimally selecting patients for interventional therapies.

A robust approach for the generation of functional hematopoietic progenitor cell lines to model leukemic transformation.

Studies of molecular mechanisms of hematopoiesis and leukemogenesis are hampered by the unavailability of progenitor cell lines that accurately mimic the situation in vivo. We now report a robust method to generate and maintain LSK (Lin-, Sca-1+, c-Kit+) cells, which closely resemble MPP1 cells. HPCLSKs reconstitute hematopoiesis in lethally irradiated recipient mice over >8 months.

CDK4/6 and MAPK-Crosstalk as Opportunity for Cancer Treatment.

Despite the development of targeted therapies and novel inhibitors, cancer remains an undefeated disease. Resistance mechanisms arise quickly and alternative treatment options are urgently required, which may be partially met by drug combinations. Protein kinases as signaling switchboards are frequently deregulated in cancer and signify vulnerable nodes and potential therapeutic targets.

The Effect of CDK6 Expression on DNA Methylation and DNMT3B Regulation.

CDK6 is frequently overexpressed in various cancer types and functions as a positive regulator of the cell cycle and as a coregulator of gene transcription. We provide evidence that CDK6 is involved in the process of DNA methylation, at least in ALL. We observe a positive correlation of CDK6 and DNMT expression in a large number of ALL samples.

Distinct Modes of Balancing Glomerular Cell Proteostasis in Mucolipidosis Type II and III Prevent Proteinuria.

Background: The mechanisms balancing proteostasis in glomerular cells are unknown. Mucolipidosis (ML) II and III are rare lysosomal storage disorders associated with mutations of the Golgi-resident GlcNAc-1-phosphotransferase, which generates mannose 6-phosphate residues on lysosomal enzymes. Without this modification, lysosomal enzymes are missorted to the extracellular space, which results in lysosomal dysfunction of many cell types.

The role of CDK6 in cancer.

The regulation and function of cyclin-dependent kinase 6 (CDK6)- and cyclin-dependent kinase 4 (CDK4)-cyclin complexes are commonly altered with enhanced kinase activity found in hematopoietic malignancies, breast cancer and melanoma making CDK4 and CDK6 attractive targets for therapeutic interference. Although dual CDK4/6 inhibitors have revolutionized treatment of breast cancer patients and reveal promising results in several solid tumors and hematological malignancies, there is a need for novel compounds targeting the versatile kinase-independent functions of CDK6 to improve cancer treatment. The following review summarizes the latest findings on CDK6 in cancer development and discusses novel therapeutic approaches to selectively inhibit CDK6s function as a transcriptional regulator.

CDK6 Inhibition: A Novel Approach in AML Management.

Acute myeloid leukemia (AML) is a complex disease with an aggressive clinical course and high mortality rate. The standard of care for patients has only changed minimally over the past 40 years. However, potentially useful agents have moved from bench to bedside with the potential to revolutionize therapeutic strategies.

Acute cutaneous botryomycosis of the hands.

Botryomycosis is a rare bacterial infection which is most commonly caused by . It usually affects the skin but can also involve the viscera. The cutaneous form typically presents as ulcerated plaques or nodules that evolve over months to years to form discharging sinuses.

The interplay of CDK4 and CDK6 in melanoma.

The cyclin-dependent kinases CDK4 and CDK6 promote progression through the cell cycle, where their functions are considered to be redundant. Recent studies have identified an additional role for CDK6 in the transcriptional regulation of cancer-relevant genes such as VEGF-A and EGR1 in hematopoietic malignancies. We show that the CDK4/6 inhibitor PD0332991 causes a significant decrease in tumor growth in a xenotransplantation mouse model of human melanoma.

CDK6 coordinates mutant MPN via NF-κB and apoptotic networks.

Over 80% of patients with myeloproliferative neoplasms (MPNs) harbor the acquired somatic mutation. JAK inhibition is not curative and fails to induce a persistent response in most patients, illustrating the need for the development of novel therapeutic approaches. We describe a critical role for CDK6 in MPN evolution.

Estrogen Regulates Bone Turnover by Targeting RANKL Expression in Bone Lining Cells.

Estrogen is critical for skeletal homeostasis and regulates bone remodeling, in part, by modulating the expression of receptor activator of NF-κB ligand (RANKL), an essential cytokine for bone resorption by osteoclasts. RANKL can be produced by a variety of hematopoietic (e.g.