Extended experience with a non-cytotoxic DNMT1-targeting regimen of decitabine to treat myeloid malignancies

The nucleoside analogue decitabine can deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1), an effect that occurs, and is saturated at, low concentrations/doses. A reason to pursue this molecular-targeted effect instead of the DNA damage/cytotoxicity produced with high concentrations/doses, is that non-cytotoxic DNMT1-depletion can cytoreduce even p53-null myeloid malignancies while sparing normal haematopoiesis. We thus identified minimum doses of decitabine (0·1–0·2 mg/kg) that deplete DNMT1 without off-target anti-metabolite effects/cytotoxicity, and then administered these well-tolerated doses frequently 1–2X/week to increase S-phase dependent DNMT1-depletion, and used a Myeloid Malignancy Registry to evaluate long-term outcomes in 69 patients treated this way. Consistent with the scientific rationale, treatment was well-tolerated and durable responses were produced (~40%) in genetically heterogeneous disease and the very elderly.     

Large granular lymphocytic leukaemia after solid organ and haematopoietic stem cell transplantation

T-cell large granular lymphocytic leukaemia (T-LGLL) is a chronic clonal lymphoproliferative disorder of cytotoxic T lymphocytes which commonly occurs in older patients and is often associated with autoimmune diseases. Among 246 patients with T-LGLL seen at our institution over the last 10 years, we encountered 15 cases following solid organ or haematopoietic stem cell transplantation. Here, we studied the clinical characterization of these cases and compared them to de novo T-LGLL. This experience represented a clear picture of the intricate nature of the disease manifestation and the complexities of several immune mechanisms triggering the clonal expansion.     

Aesthetic Finger Prosthesis

Complete or partial fingers are the most commonly encountered forms of partial hand losses. Though finger amputations are commonly due to traumatic injuries, digit loss may also be attributed to congenital malformations and disease. Irrespective of the etiology, the loss of a finger has a considerable functional and psychological impact on an individual. In order to alleviate these problems, partial or complete finger prosthesis may be fabricated. This clinical report portrays a method to fabricate silicone rubber prosthesis for a patient who has a partial finger loss caused due to trauma.     

Ins and outs of Helicobacter pylori association with autoimmune rheumatic diseases

Helicobacter pylori (H. pylori) infection is widely prevalent throughout worldwide. H. pylori manage a long-term survival in hostile environment of human stomach leading to peptic ulcer diseases and gastric cancer. But mostly infected person remains asymptomatic. Its chronic interaction with immune system makes H. pylori as an attractive candidate for the researchers to study its association with autoimmune diseases. This article presents a review of the literature on the association of H. pylori infection in selective autoimmune rheumatic diseases (RD). The authors used MeSH terms “Helicobacter pylori” with “rheumatoid arthritis,”“systemic lupus erythematosus,” or “fibromyalgia” to search PubMed database. All relevant studies identified were included. Despite extensive medical advancement many questions on role of H. pylori infection in autoimmune RD still remain unanswered. Further studies are therefore needed to address the role of H. pylori in pathogenesis of RD.     

A novel allosteric modulator of the cannabinoid CB1 receptor ameliorates hyperdopaminergia endophenotypes in rodent models

The endocannabinoid system (eCBs) encompasses the endocannabinoids, their synthetic and degradative enzymes, and cannabinoid (CB) receptors. The eCBs mediates inhibition of neurotransmitter release and acts as a major homeostatic system. Many aspects of the eCBs are altered in a number of psychiatric disorders including schizophrenia, which is characterized by dysregulation of dopaminergic signaling. The GluN1-Knockdown (GluN1KD) and Dopamine Transporter Knockout (DATKO) mice are models of hyperdopaminergia, which display abnormal psychosis-related behaviors, including hyperlocomotion and changes in pre-pulse inhibition (PPI). Here, we investigate the ability of a novel CB₁ receptor (CB₁R) allosteric modulator, ABM300, to ameliorate these dysregulated behaviors. ABM300 was characterized in vitro (receptor binding, β-arrestin2 recruitment, ERK1/2 phosphorylation, cAMP inhibition) and in vivo (anxiety-like behaviors, cannabimimetic effects, novel environment exploratory behavior, pre-pulse inhibition, conditioned avoidance response) to assess the effects of the compound in dysregulated behaviors within the transgenic models. In vitro, ABM300 increased CB₁R agonist binding but acted as an inhibitor of CB₁R agonist induced signaling, including β-arrestin2 translocation, ERK phosphorylation and cAMP inhibition. In vivo, ABM300 did not elicit anxiogenic-like or cannabimimetic effects, but it decreased novelty-induced hyperactivity, exaggerated stereotypy, and vertical exploration in both transgenic models of hyperdopaminergia, as well as normalizing PPI in DATKO mice. The data demonstrate for the first time that a CB₁R allosteric modulator ameliorates the behavioral deficits in two models of increased dopamine, warranting further investigation as a potential therapeutic target in psychiatry.Subject terms: Pharmacology, Sensorimotor processing     

MeCP2 mutation causes distinguishable phases of acute and chronic defects in synaptogenesis and maintenance, respectively

Over 200 mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2) are known to cause Rett syndrome (RTT), a multiphasic neurodevelopmental disorder that results in motor and cognitive impairments; however, little is known about the neurobiology of RTT. Here, we employ the MeCP2^308/y mouse model of RTT to investigate the course of the neuronal defects imparted by MeCP2 mutation. Using the olfactory system as a neurodevelopmental model, we describe an acute but transient defect in olfactory sensory neuron maturation during synaptogenesis and elaboration of the glomerular neuropil. This defect is overcome through compensatory responses that restore homeostasis. However, a chronic problem in glomerular organization emerges, which eventually leads to increased neuronal apoptosis. This multiphasic course comprising acute developmental and chronic defects in synaptogenesis and maintenance may represent the neurobiological correlates of clinical RTT, and suggests that different therapeutic strategies may be appropriate at different clinical stages of this disease.     

Intermediate band solar cell materials through the doping of group-VA elements (N,P, As and Sb) in Cu2ZnSiSe4

The electronic structure and optical properties of group-VA (N, P, As, and Sb)-doped Cu₂ZnSiSe₄ alloys have been studied using a hybrid functional through density functional theory calculations. The minor lattice distortion and small formation energy indicate that synthesis of these alloys is highly possible in experiment. For each doped alloy, an isolated and partially filled intermediate band (IB) appears in its band structure. The doping-induced IB is mainly contributed by the s states of the doped group-VA atom and the p states of four neighboring Se atoms, and slightly by the d states of eight Cu atoms. The existence of an IB obviously enhances the absorption coefficient with two additional absorption peaks in the visible light range. For P, As and Sb-doped Cu₂ZnSiSe₄ alloys, not only the bandgap between the valence band maximum and the conduction band minimum but also the sub bandgap between the valence band maximum and the IB are very close to the optimal values for visible light absorption. Therefore, these alloys are recommended as good candidates for IB solar cell materials.

The doping of group-VA elements in Cu₂ZnSiSe₄ induces an intermediate band and enhances the absorption coefficient with two additional peaks.