Conventional chemotherapy: millions of cures, unresolved therapeutic index.

In recent decades, millions of patients with cancer have been cured by chemotherapy alone. By 'cure', we mean that patients with cancers that would be fatal if left untreated receive a time-limited course of chemotherapy and their cancer disappears, never to return. In an era when hundreds of thousands of cancer genomes have been sequenced, a remarkable fact persists: in most patients who have been cured, we still do not fully understand the mechanisms underlying the therapeutic index by which the tumour cells are killed, but normal cells are somehow spared.

Creg1 Regulates Erythroid Development via TGF-β/Smad2-Klf1 Axis in Zebrafish.

Understanding the regulation of normal erythroid development will help to develop new potential therapeutic strategies for disorders of the erythroid lineage. Cellular repressor of E1A-stimulated genes 1 (CREG1) is a glycoprotein that has been implicated in the regulation of tissue homeostasis. However, its role in erythropoiesis remains largely undefined.

History of Developing Acute Promyelocytic Leukemia Treatment and Role of Promyelocytic Leukemia Bodies.

The story of acute promyelocytic leukemia (APL) discovery, physiopathology, and treatment is a unique journey, transforming the most aggressive form of leukemia to the most curable. It followed an empirical route fueled by clinical breakthroughs driving major advances in biochemistry and cell biology, including the discovery of PML nuclear bodies (PML NBs) and their central role in APL physiopathology. Beyond APL, PML NBs have emerged as key players in a wide variety of biological functions, including tumor-suppression and SUMO-initiated protein degradation, underscoring their broad importance.

Acute Promyelocytic Leukemia, Retinoic Acid, and Arsenic: A Tale of Dualities.

Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)/retinoic acid receptor α (RARA) fusion oncoprotein. Over the years, it has emerged as a model system to understand how this simple (and sometimes sole) genetic alteration can transform hematopoietic progenitors through the acquisition of dominant-negative properties toward both transcriptional control by nuclear receptors and PML-mediated senescence. The fortuitous identification of two drugs, arsenic trioxide (ATO) and all--retinoic acid (ATRA), that respectively bind PML and RARA to initiate PML/RARA degradation, has allowed an unprecedented dissection of the cellular and molecular mechanisms involved in patients' cure by the ATO/ATRA combination.

Znf687 recruits Brd4-Smrt complex to regulate gfi1aa during neutrophil development.

Neutrophils are key component of the innate immune system in vertebrates. Diverse transcription factors and cofactors act in a well-coordinated manner to ensure proper neutrophil development. Dysregulation of the transcriptional program triggering neutrophil differentiation is associated with various human hematologic disorders such as neutropenia, neutrophilia, and leukemia.

Hypereosinophilic vasculitis with Raynaud phenomenon presentation: a case report.

Background: Previous case series have reported idiopathic eosinophilic vasculitis as a potential manifestation of hypereosinophilic syndrome (HES). This condition is characterized by digital necrotizing, systemic vasculitis that affects varying-sized blood vessels. This report presents our experience in treating a patient with eosinophilic vasculitis.

Characteristics of brain magnetic resonance imaging in acute methanol intoxication: Report of 3 cases.

Acute methanol intoxication is uncommon. Methanol is mildly toxic, but its metabolites are formic acid and formaldehyde, causing total metabolism, visual disturbances, and central nervous system disturbances, leading to coma and death. Magnetic resonance imaging (MRI) is very important for the diagnosis and prognosis of methanol intoxication.

Conservative versus Invasive Strategy in Elderly Patients with Non-ST-Elevation Myocardial Infarction: Insights from the International POPular Age Registry.

This registry assessed the impact of conservative and invasive strategies on major adverse clinical events (MACE) in elderly patients with non-ST-elevation myocardial infarction (NSTEMI). Patients aged ≥75 years with NSTEMI were prospectively registered from European centers and followed up for one year. Outcomes were compared between conservative and invasive groups in the overall population and a propensity score-matched (PSM) cohort.

Structural Basis of PML-RARA Oncoprotein Targeting by Arsenic Unravels a Cysteine Rheostat Controlling PML Body Assembly and Function.

Unlabelled: PML nuclear bodies (NB) are disrupted in PML-RARA-driven acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) cures 70% of patients with APL, driving PML-RARA degradation and NB reformation. In non-APL cells, arsenic binding onto PML also amplifies NB formation.

Laser Controlled Manipulation of Microbubbles on a Surface with Silica-Coated Gold Nanoparticle Array.

Microbubble generation and manipulation play critical roles in diverse applications such as microfluidic mixing, pumping, and microrobot propulsion. However, existing methods are typically limited to lateral movements on customized substrates or rely on specific liquids with particular properties or designed concentration gradients, thereby hindering their practical applications. To address this challenge, this paper presents a method that enables robust vertical manipulation of microbubbles.

The PML hub: An emerging actor of leukemia therapies.

PML assembles into nuclear domains that have attracted considerable attention from cell and cancer biologists. Upon stress, PML nuclear bodies modulate sumoylation and other post-translational modifications, providing an integrated molecular framework for the multiple roles of PML in apoptosis, senescence, or metabolism. PML is both a sensor and an effector of oxidative stress.

Modeling the significance of dynamic capability on the performance of microfinance institutions.

According to strategic management theory, dynamic capability plays a significant role in enhancing organizational performance. Using a cross-sectional research design, the current study quantitatively assesses the mediating effect of dynamic capability on the relationships of total quality management, customer intellectual capital, and human resource management practice with the performance of microfinance institutions. An online survey involving 120 members of Induk Koperasi Kredit, a credit union association in West Kalimantan, Indonesia, is conducted.

Ypel5 regulates liver development and function in zebrafish.

YPEL5 is a member of the Yippee-like (YPEL) gene family that is evolutionarily conserved in eukaryotic species. To date, the physiological function of YPEL5 has not been assessed due to a paucity of genetic animal models. Here, using CRISPR/Cas9-mediated genome editing, we generated a stable ypel5-/- mutant zebrafish line.

Zbtb14 regulates monocyte and macrophage development through inhibiting expression in zebrafish.

Macrophages and their precursor cells, monocytes, are the first line of defense of the body against foreign pathogens and tissue damage. Although the origins of macrophages are diverse, some common transcription factors (such as PU.1) are required to ensure proper development of monocytes/macrophages.

Exploration of nuclear body-enhanced sumoylation reveals that PML represses 2-cell features of embryonic stem cells.

Membrane-less organelles are condensates formed by phase separation whose functions often remain enigmatic. Upon oxidative stress, PML scaffolds Nuclear Bodies (NBs) to regulate senescence or metabolic adaptation. PML NBs recruit many partner proteins, but the actual biochemical mechanism underlying their pleiotropic functions remains elusive.

Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia.

By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures.

Sumoylation in Physiology, Pathology and Therapy.

Sumoylation is an essential post-translational modification that has evolved to regulate intricate networks within emerging complexities of eukaryotic cells. Thousands of target substrates are modified by SUMO peptides, leading to changes in protein function, stability or localization, often by modulating interactions. At the cellular level, sumoylation functions as a key regulator of transcription, nuclear integrity, proliferation, senescence, lineage commitment and stemness.