Small molecule protein assembly modulators with pan-cancer therapeutic efficacy.

Two structurally unrelated small molecule chemotypes, represented by compounds PAV-617 and PAV-951, with antiviral activity in cell culture against Mpox virus (formerly known as monkeypox virus) and human immunodeficiency virus (HIV) respectively, were studied for anti-cancer efficacy. Each exhibited apparent pan-cancer cytotoxicity with reasonable pharmacokinetics. Non-toxicity is demonstrated in a non-cancer cell line and in mice at doses achieving drug exposure at active concentrations.

Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes.

Reactive changes of glial cells during neuroinflammation impact brain disorders and disease progression. Elucidating the mechanisms that control reactive gliosis may help us to understand brain pathophysiology and improve outcomes. Here, we report that adult ablation of autism spectrum disorder (ASD)-associated CHD8 in astrocytes attenuates reactive gliosis via remodeling chromatin accessibility, changing gene expression.

Identity and nature of neural stem cells in the adult human subventricular zone.

The existence of neural stem cells (NSCs) in adult human brain neurogenic regions remains unresolved. To address this, we created a cell atlas of the adult human subventricular zone (SVZ) derived from fresh neurosurgical samples using single-cell transcriptomics. We discovered 2 adult radial glia (RG)-like populations, aRG1 and aRG2.

Localization of Hand and Wrist Anatomic Structures Among Physical Medicine and Rehabilitation Residents: Implication of Ultrasonography in Palpation Skill Verification.

Objective: The objective of this cross-sectional study is to evaluate the accuracy of physical medicine and rehabilitation (PM&R) resident palpation skills of hand and wrist joint and soft tissue structures using ultrasonography (US) verification.

Methods: PM&R residents palpated hand and wrist anatomic structures in an outpatient musculoskeletal (MSK) clinic. Once the presumed structures were localized, residents marked a one centimeter size circle on the overlying skin with an ink marker.

Invasive growth associated with cold-inducible RNA-binding protein expression drives recurrence of surgically resected brain metastases.

Background: Sixty percent of surgically resected brain metastases (BrM) recur within 1 year. These recurrences have long been thought to result from the dispersion of cancer cells during surgery. We tested the alternative hypothesis that invasion of cancer cells into the adjacent brain plays a significant role in local recurrence and shortened overall survival.

Author Correction: Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy.

Cancer stem cells are critical for cancer initiation, development, and treatment resistance. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To overcome these limitations, we performed single-cell RNA sequencing on 53586 adult glioblastoma cells and 22637 normal human fetal brain cells, and compared the lineage hierarchy of the developing human brain to the transcriptome of cancer cells.

Evaluation of Resident Palpation Skills in Foot and Ankle Anatomic Structures Using Bedside Ultrasound.

Objective: The objective is to determine the accuracy of foot and ankle joint and soft tissue structure palpation in Physical Medicine and Rehabilitation (PM&R) residents using ultrasonography (US) verification.

Methods: PM&R residents were tested in an outpatient musculoskeletal (MSK) clinic on palpated foot and ankle anatomic structures in a human model. Once the presumed structures were localized, residents marked a 1 cm size circle on the overlying skin with a ink marker.

Inhibition of glioblastoma cell proliferation, invasion, and mechanism of action of a novel hydroxamic acid hybrid molecule.

Glioblastoma multiforme is one of the most aggressive brain tumors and current therapies with temozolomide or suberoylanilide hydroxamic acid (SAHA, vorinostat) show considerable limitations. SAHA is a histone deacetylase (HDAC) inhibitor that can cause undesirable side effects due to the lack of selectivity. We show here properties of a novel hybrid molecule, sahaquine, which selectively inhibits cytoplasmic HDAC6 at nanomolar concentrations without markedly suppressing class I HDACs.

Spirulina maxima peptides suppress mast cell degranulation via inactivating Akt and MAPKs phosphorylation in RBL-2H3 cells.

In this study, the suppressive effects of peptides P1 (LDAVNR) and P2 (MMLDF) from enzymatic hydrolysate of Spirulina maxima on mast cell degranulation was elucidated. It was revealed that P1 and P2 exhibited significant inhibition on cell degranulation via decreasing β-hexosaminidase release at concentration of 200 μM. Moreover, the inhibitory effects of P1 and P2 on expression and production of interleukin (IL)-13 were evidenced.

Antibody-Antisense Oligonucleotide Conjugate Downregulates a Key Gene in Glioblastoma Stem Cells.

Glioblastoma stem cells (GSCs) are invasive, treatment-resistant brain cancer cells that express downregulated in renal cell carcinoma (DRR), also called FAM107A, a genetic driver of GSC invasion. We developed antibody-antisense oligonucleotide (AON) conjugates to target and reduce DRR/FAM107A expression. Specifically, we used antibodies against antigens expressed on the GSCs, such as CD44 and EphA2, conjugated to chemically modified AONs against DRR/FAM107A, which were designed as chimeras of DNA and 2'-deoxy-2'-fluoro-beta-D-arabinonucleic acid (FANA) for increased nuclease stability and mRNA affinity.

The Role of Pelvic Floor Muscle Training in the Conservative and Surgical Management of Female Stress Urinary Incontinence: Does the Strength of the Pelvic Floor Muscles Matter?

The purpose of this review is to provide an in-depth overview of the role of pelvic floor muscle (PFM) training in the management of stress urinary incontinence (SUI). The definition, epidemiology, and pathogenesis of SUI are described. We review the anatomy of the PFM and the importance of PFM strength in maintaining urinary continence and establishing normal voiding function.

Pelvic Pain: An Overview.

Although the cause of chronic pelvic pain (CPP) is multifactorial, a substantial number of cases have musculoskeletal and neuromuscular causes. Multiple stakeholders, including physicians with varying degrees of pain training ranging from primary care physicians, obstetricians, gynecologists, urologists, neurologists, gastroenterologists, psychologists, physical therapists, and physiatrists, are involved in the care of these patients. Physiatrists play a pivotal role in the treatment of patients with CPP because their training focuses on improving quality of life through a holistic approach to patient management and on the musculoskeletal and neuromuscular systems.

Inhibition of carbonic anhydrase IX in glioblastoma multiforme.

Carbonic anhydrase IX (CAIX) is a transmembrane enzyme upregulated in several types of tumors including glioblastoma multiforme (GBM). GBM is among the most aggressive tumors among gliomas. Temozolomide (TMZ) therapy combined with surgical or radiation approaches is the standard treatment but not effective in long term.

Is Genicular Nerve Radiofrequency Ablation Safe? A Literature Review and Anatomical Study.

Genicular nerve radiofrequency ablation (RFA) has recently gained popularity as an intervention for chronic knee pain in patients who have failed other conservative or surgical treatments. Long-term efficacy and adverse events are still largely unknown. Under fluoroscopic guidance, thermal RFA targets the lateral superior, medial superior, and medial inferior genicular nerves, which run in close proximity to the genicular arteries that play a crucial role in supplying the distal femur, knee joint, meniscus, and patella.

Arabinonucleic acids: 2'-stereoisomeric modulators of siRNA activity.

We have investigated, for the first time, short interfering duplexes containing arabinonucleotides (ANA; the 2'-stereoisomer of RNA), as well as combinations of ANA with RNA, and their 2'-fluorinated derivatives 2F-ANA and/or 2'F-RNA. The results show that ANA is especially well accommodated in the sense strand of small interfering RNA (siRNA) duplexes, which can be extensively modified with little effect on potency. Furthermore, combining ANA with RNA and 2'F-ANA in siRNA passenger strands, particularly in patterns that bias duplex thermal stability, produces duplexes with similar (and sometimes enhanced) potency compared with native siRNA.

Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine.

Background: Based on the potential involvement of Toll-like receptor (TLR) signalling in the pathogenesis of neonatal lupus (NL), it was hypothesised that fetal exposure to hydroxychloroquine (HCQ), a TLR inhibitor, might reduce the risk of anti-SSA/Ro/SSB/La antibody-associated cardiac manifestations of NL (cardiac-NL).

Methods: Cardiac-NL children (N=50) and controls (N=151) were drawn from the following overlapping pregnancy studies: Research Registry for NL; PR Interval and Dexamethasone Evaluation in Cardiac-NL; and Predictors of Pregnancy Outcomes: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus (SLE). Pregnancies met the following inclusion criteria: documentation of maternal anti-SSA/Ro/SSB/La antibodies at pregnancy, confirmation of medication use and child's outcome, a diagnosis of SLE before pregnancy and birth by 31 December 2007.

Escherichia coli expression and refolding of E/K-coil-tagged EGF generates fully bioactive EGF for diverse applications.

Heterodimerizing peptides, such as the de novo designed E5/K5 peptide pair, have several applications including as tags for protein purification or immobilization. Recently, we demonstrated that E5-tagged epidermal growth factor (EGF), when bound to a K4 expressing adenovirus, promotes retargeting of the adenovirus to EGFR expressing target cells. In this study, we present the Escherichia coli expression, refolding and purification of human EGF fused with the E5-coil (E5-coil-EGF) or with the K5-coil (K5-coil-EGF).

Raft-dependent endocytosis of autocrine motility factor is phosphatidylinositol 3-kinase-dependent in breast carcinoma cells.

Autocrine motility factor (AMF) is internalized via a receptor-mediated, dynamin-dependent, cholesterol-sensitive raft pathway to the smooth endoplasmic reticulum that is negatively regulated by caveolin-1. Expression of AMF and its receptor (AMFR) is associated with tumor progression and malignancy; however, the extent to which the raft-dependent uptake of AMF is tumor cell-specific has yet to be addressed. By Western blot and cell surface fluorescence-activated cell sorter (FACS) analysis, AMFR expression is increased in tumorigenic MCF7 and metastatic MDA-231 and MDA-435 breast cancer cell lines relative to dysplastic MCF10A mammary epithelial cells.

The gene product of the gp78/AMFR ubiquitin E3 ligase cDNA is selectively recognized by the 3F3A antibody within a subdomain of the endoplasmic reticulum.

The receptor for the autocrine motility factor/phosphoglucose isomerase cytokine (gp78 or AMFR) has been extensively characterized using the 3F3A monoclonal antibody. Cloning of AMFR identified a seven-transmembrane domain G-protein-coupled receptor ubiquitin E3 ligase whose identity as AMFR was based on prior expression cloning with the 3F3A mAb that generated a truncated sequence. We show here that the gp78/AMFR gene product is indeed recognized by the 3F3A mAb.

Ganglioside GM1 levels are a determinant of the extent of caveolae/raft-dependent endocytosis of cholera toxin to the Golgi apparatus.

Cholera toxin is associated with caveolae and raft domains in various cell types and previous studies have shown that cholera toxin can be internalized by caveolae/raft-dependent endocytosis as well as by other pathways. We undertook the study of cholera toxin endocytosis in CaCo-2 and HeLa cells. CaCo-2 cells do not express detectable levels of caveolin and, relative to HeLa cells, also present significantly reduced expression of ganglioside GM1, the cholera toxin receptor, that remains Triton X-100 insoluble.

Caveolae/raft-dependent endocytosis.

Although caveolae are well-characterized subdomains of glycolipid rafts, their distinctive morphology and association with caveolins has led to their internalization being considered different from that of rafts. In this review, we propose that caveolae and rafts are internalized via a common pathway, caveolae/raft-dependent endocytosis, defined by its clathrin independence, dynamin dependence, and sensitivity to cholesterol depletion. The regulatory role of caveolin-1 and ligand sorting in this complex endocytic pathway are specifically addressed.