Flow cytometry of DNMT1 as a biomarker of hypomethylating therapies.

The 5-azacytidine (AZA) and decitabine (DEC) are noncytotoxic, differentiation-inducing therapies approved for treatment of myelodysplastic syndrome, acute myeloid leukemias (AML), and under evaluation as maintenance therapy for AML postallogeneic hematopoietic stem cell transplant and to treat hemoglobinapathies. Malignant cell cytoreduction is thought to occur by S-phase specific depletion of the key epigenetic regulator, DNA methyltransferase 1 (DNMT1) that, in the case of cancers, thereby releases terminal-differentiation programs. DNMT1-targeting can also elevate expression of immune function genes (HLA-DR, MICA, MICB) to stimulate graft versus leukemia effects.

Mesenchymal stem cells enhance targeted bone growth from injectable hydrogels with BMP-2 peptides.

Osteoporosis is the most common chronic metabolic bone disease, and the prevalence of osteoporotic fractures is rapidly increasing with the aging population. While bisphosphonates can reduce bone loss and risk of fracture, these drugs are systemic, rely on long-term use, and patient compliance is low. Recombinant human bone morphogenetic protein-2 (BMP-2) is an FDA-approved protein that can offer a more targeted therapeutic than systemic treatments.

Structural variants involving MLLT10 fusion are associated with adverse outcomes in pediatric acute myeloid leukemia.

MLLT10 gene rearrangements with KMT2A occur in pediatric acute myeloid leukemia (AML) and confer poor prognosis, but the prognostic impact of MLLT10 in partnership with other genes is unknown. We conducted a retrospective study with 2080 children and young adults with AML registered on the Children's Oncology Group AAML0531 (NCT00372593) and AAML1031 trials (NCT01371981). Transcriptome profiling and/or karyotyping were performed to identify leukemia-associated fusions associated with prognosis.

Efficacy and Safety of DaxibotulinumtoxinA for Injection in Cervical Dystonia: ASPEN-1 Phase 3 Randomized Controlled Trial.

Background And Objectives: ASPEN-1 was a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, duration of response, and safety of 2 doses of DaxibotulinumtoxinA for Injection (DAXI), a novel botulinum toxin type A formulation in participants with cervical dystonia (CD).

Methods: Adults (aged 18-80 years) with moderate-to-severe CD (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] total score ≥20) were enrolled at 60 sites across 9 countries in Europe and North America. Participants were randomized (3:3:1) to single-dose intramuscular DAXI 125U, 250U, or placebo and followed for up to 36 weeks after injection.

The serum small non-coding RNA (SncRNA) landscape as a molecular biomarker of age associated muscle dysregulation and insulin resistance in older adults.

Small noncoding RNAs (sncRNAs) are implicated in age-associated pathologies, including sarcopenia and insulin resistance (IR). As potential circulating biomarkers, most studies have focussed on microRNAs (miRNAs), one class of sncRNA. This study characterized the wider circulating sncRNA transcriptome of older individuals and associations with sarcopenia and IR.

Bone turnover and mineralisation kinetics control trabecular BMDD and apparent bone density: insights from a discrete statistical bone remodelling model.

The mechanical quality of trabecular bone is influenced by its mineral content and spatial distribution, which is controlled by bone remodelling and mineralisation. Mineralisation kinetics occur in two phases: a fast primary mineralisation and a secondary mineralisation that can last from several months to years. Variations in bone turnover and mineralisation kinetics can be observed in the bone mineral density distribution (BMDD).

Immunomodulatory therapy in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS, MIS-C; RECOVERY): a randomised, controlled, open-label, platform trial.

Background: Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS), also known as multisystem inflammatory syndrome in children (MIS-C) emerged in April, 2020. The paediatric comparisons within the RECOVERY trial aimed to assess the effect of intravenous immunoglobulin or corticosteroids compared with usual care on duration of hospital stay for children with PIMS-TS and to compare tocilizumab (anti-IL-6 receptor monoclonal antibody) or anakinra (anti-IL-1 receptor antagonist) with usual care for those with inflammation refractory to initial treatment.

Methods: We did this randomised, controlled, open-label, platform trial in 51 hospitals in the UK.

"Only fixation" in cases with failed decompression for lumbar canal stenosis - Analysis of outcome in 14 cases.

Aim: The rationale of "only fixation" of affected spinal segments without any form of bone or soft-tissue decompression in cases with failed decompressive laminectomy for lumbar canal stenosis is discussed on the basis of an experience with 14 cases.

Materials And Methods: During the period between 2010 and 2022, 14 patients who symptomatically worsened or did not improve following a long-segment "wide" decompressive laminectomy for multisegmental lumbar canal stenosis were identified. All patients were treated by segmental spinal stabilization aimed at arthrodesis by facetal distraction by Goel's facetal spacers (6 cases) or Camille's transarticular facetal fixation (8 cases).

Opportunistically identifiable vertebral fractures on routine radiological imaging predict mortality: observational cohort study.

Unlabelled: In men and women with opportunistically identifiable vertebral fractures (VFs) on routine CT scans including the chest and/or abdomen, the risk of death is 51% higher than in those with no VF on the CT scan, and 325% higher than an age- and sex-matched general population cohort.

Purpose: There is little knowledge about the risk of death in patients with VFs present on routine radiological imaging. We evaluated the risk of death in men and women aged 50 years or older with opportunistically identifiable VFs on routine CT scans and not treated with osteoporosis medications.

Management of Atopy with Dupilumab and Omalizumab in CADINS Disease.

The caspase activation and recruitment domain 11 (CARD11) gene encodes a scaffold protein required for lymphocyte antigen receptor signaling. Dominant-negative, loss-of-function (LOF) pathogenic variants in CARD11 result in CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease. Patients with CADINS suffer with severe atopic manifestations including atopic dermatitis, food allergy, and chronic spontaneous urticaria in addition to recurrent infections and autoimmunity.

Fully Automated Analysis of the Anatomic and Mechanical Axes From Pediatric Standing Lower Limb Radiographs Using Convolutional Neural Networks.

Background: Lower limb alignment is the quantification of a set of parameters that are commonly measured radiographically to test for and track a wide range of skeletal pathologies. Determining limb alignment is a commonly performed yet laborious task in the pediatric orthopaedic setting and is therefore an interesting goal for automation.

Methods: We employ a machine learning approach using convolutional neural networks (CNNs) to segment pediatric weight-bearing lower limb radiographs.

Thyroiditis After Parathyroidectomy.

Various clinical manifestations of thyroiditis after parathyroidectomy have been reported in the literature, ranging from mild symptoms to tachyarrhythmias and myocardial infarction. We report 2 cases of post-parathyroidectomy thyroiditis. Both patients had primary hyperparathyroidism and underwent parathyroidectomy for a solitary parathyroid adenoma.

Poly-ε-Caprolactone 3D-Printed Porous Scaffold in a Femoral Condyle Defect Model Induces Early Osteo-Regeneration.

Large bone reconstruction following trauma poses significant challenges for reconstructive surgeons, leading to a healthcare burden for health systems, long-term pain for patients, and complex disorders such as infections that are difficult to resolve. The use of bone substitutes is suboptimal for substantial bone loss, as they induce localized atrophy and are generally weak, and unable to support load. A combination of strong polycaprolactone (PCL)-based scaffolds, with an average channel size of 330 µm, enriched with 20% / of hydroxyapatite (HA), β-tricalcium phosphate (TCP), or Bioglass 45S5 (Bioglass), has been developed and tested for bone regeneration in a critical-size ovine femoral condyle defect model.

MC180295 is a highly potent and selective CDK9 inhibitor with preclinical in vitro and in vivo efficacy in cancer.

Background: Inhibition of cyclin-dependent kinase 9 (CDK9), a novel epigenetic target in cancer, can reactivate epigenetically silenced genes in cancer by dephosphorylating the SWI/SNF chromatin remodeler BRG1. Here, we characterized the anti-tumor efficacy of MC180295, a newly developed CDK9 inhibitor.

Methods: In this study, we explored the pharmacokinetics of MC180295 in mice and rats, and tested the anti-tumor efficacy of MC180295, and its enantiomers, in multiple cancer cell lines and mouse models.

A multicenter study of posttransplantation low-dose inotuzumab ozogamicin to prevent relapse of acute lymphoblastic leukemia.

The curative potential of allogeneic hematopoietic transplantation (allo-HCT) in patients with acute lymphoblastic leukemia (ALL) is hampered by relapse. Inotuzumab ozogamicin (INO) is an anti-CD22 monoclonal antibody bound to calicheamicin, which has significant activity against ALL. We hypothesized that low-dose INO would be safe and feasible after allo-HCT.

Cellular behavior and extracellular matrix turnover in bovine annulus fibrosus cells under hydrostatic pressure and deviatoric strain.

Intervertebral disc herniation is a common spinal disorder that is often treated with discectomy when conservative measures fail. To devise therapeutic strategies for tears in the annulus fibrosus (AF), the regenerative capability of AF cells under spinal loading needs to be addressed. We hypothesized that the compressive loading associated with deformation in AF cells reduces synthetic and degradative activities in extracellular matrix and cell proliferation.

Clinical, Radiographic, and Patient-Reported Outcomes of First Metatarsophalangeal Interposition Arthrodesis Using Porous Titanium Wedges.

Background: First metatarsophalangeal (MTP) arthrodesis is a common surgical procedure for addressing hallux MTP pathology. In the setting of revision procedures with significant bone loss, porous titanium wedges may provide an alternative to structural bone autograft or allograft.

Objective: The purpose of this study is to report the clinical and radiographic outcomes achieved in first MTP interposition arthrodesis using porous titanium wedges.

Comparing age- and bone-related differences in collagen fiber orientation: A case study of bats and laboratory mice using quantitative polarized light microscopy.

As bones age in most mammals, they typically become more fragile. This state of bone fragility is often associated with more homogenous collagen fiber orientations (CFO). Unlike most mammals, bats maintain mechanically competent bone throughout their lifespans, but little is known of positional and age-related changes in CFO within wing bones.

Comparative Osteogenesis of Three Clinical Bone Graft Materials: An In Vivo Study.

Purpose: To investigate bone regeneration among three different bone graft materials in a rat calvarum model.

Materials And Methods: A total of 24 rats had two 5-mm defects placed per calvarial. Rats were divided into four groups: bovine xenograft (XG), demineralized bone matrix (DBM), mineralized bone graft (MBG), and collagen membrane control (CC).

Expansion of human hematopoietic stem cells by inhibiting translation.

Hematopoietic stem cell (HSC) transplantation using umbilical cord blood (UCB) is a potentially life-saving treatment for leukemia and bone marrow failure but is limited by the low number of HSCs in UCB. The loss of HSCs after ex vivo manipulation is also a major obstacle to gene editing for inherited blood disorders. HSCs require a low rate of translation to maintain their capacity for self-renewal, but hematopoietic cytokines used to expand HSCs stimulate protein synthesis and impair long-term self-renewal.

Cranial anatomy of Libognathus sheddi Small, 1997 (Parareptilia, Procolophonidae) from the Upper Triassic Dockum Group of West Texas, USA.

Libognathus sheddi, a leptopleuronine procolophonid from the Upper Triassic Cooper Canyon Formation, Dockum Group, West Texas, was based on an isolated left dentary and partial coronoid. New material referable to Libognathus sheddi, from the Cooper Canyon Formation, provides new information on the cranial anatomy. This new cranial material includes the antorbital portion of a skull, a left maxilla and premaxilla, quadratojugals, and dentaries, including intact tooth rows in the upper and lower jaws.

Glucagon-like peptide-1 receptor signaling modifies the extent of diabetic kidney disease through dampening the receptor for advanced glycation end products-induced inflammation.

Glucagon like peptide-1 (GLP-1) is a hormone produced and released by cells of the gastrointestinal tract following meal ingestion. GLP-1 receptor agonists (GLP-1RA) exhibit kidney-protective actions through poorly understood mechanisms. Here we interrogated whether the receptor for advanced glycation end products (RAGE) plays a role in mediating the actions of GLP-1 on inflammation and diabetic kidney disease.