Alkylamine-tethered molecules recruit FBXO22 for targeted protein degradation.

Targeted protein degradation (TPD) relies on small molecules to recruit proteins to E3 ligases to induce their ubiquitylation and degradation by the proteasome. Only a few of the approximately 600 human E3 ligases are currently amenable to this strategy. This limits the actionable target space and clinical opportunities and thus establishes the necessity to expand to additional ligases.

Discovery of a DCAF11-dependent cyanoacrylamide-containing covalent degrader of BET-proteins.

Targeted protein degradation is mediated by small molecules that induce or stabilize protein-protein interactions between targets and the ubiquitin-proteasome machinery. Currently, there remains a need to expand the repertoire of viable E3 ligases available for hijacking. Notably, covalent chemistry has been employed to engage a handful of E3 ligases, including DCAF11.

Large-scale chemoproteomics expedites ligand discovery and predicts ligand behavior in cells.

Chemical modulation of proteins enables a mechanistic understanding of biology and represents the foundation of most therapeutics. However, despite decades of research, 80% of the human proteome lacks functional ligands. Chemical proteomics has advanced fragment-based ligand discovery toward cellular systems, but throughput limitations have stymied the scalable identification of fragment-protein interactions.

BNT162b2 mRNA Vaccine-Induced Immune Response in Oral Fluids and Serum.

Objectives: The COVID-19 vaccine is currently being administered worldwide to address the ongoing pandemic. Although these vaccines have proven effective in preventing severe disease, the level of immunity required to prevent respiratory mucosal infection remains less well understood. Therefore, it is desirable to develop a noninvasive screening strategy such as oral fluid to monitor secreted antibodies longitudinally as potential surrogates of mucosal immunity.

Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T-cell lymphoma.

Leukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing severe symptoms and high mortality through chronic inflammation, tissue destruction, and serious infections. Despite numerous genomic sequencing efforts, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analyses with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL.

Dental pulp stem cells retain mesenchymal phenotype despite differentiation toward retinal neuronal fate .

Dental pulp stem cells (DPSCs) are an easily accessible, heterogenous source of mesenchymal stem cells (MSCs) that are derived from the neural crest. Evidence suggests that they have neurotrophic qualities in their undifferentiated state and can also be differentiated into neuronal and retinal cell types. There is growing interest in using DPSCs in cell-based therapies to treat glaucoma and blinding retinal diseases.

STAT5 is Expressed in CD34/CD38 Stem Cells and Serves as a Potential Molecular Target in Ph-Negative Myeloproliferative Neoplasms.

Janus kinase 2 (JAK2) and signal transducer and activator of transcription-5 (STAT5) play a key role in the pathogenesis of myeloproliferative neoplasms (MPN). In most patients, V617F or mutations are found and lead to activation of various downstream signaling cascades and molecules, including STAT5. We examined the presence and distribution of phosphorylated (p) STAT5 in neoplastic cells in patients with MPN, including polycythemia vera (PV, = 10), essential thrombocythemia (ET, = 15) and primary myelofibrosis (PMF, = 9), and in the V617F-positive cell lines HEL and SET-2.

The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease.

The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil facial tumor disease (DFTD). To unveil the molecular underpinnings of this transmissible cancer, we combined pharmacological screens with an integrated systems-biology characterization. Sensitivity to inhibitors of ERBB tyrosine kinases correlated with their overexpression.

A functional in vitro assay for screening inhibitors of STAT5B phosphorylation.

Inhibition of STAT phosphorylation is recognized as a viable therapeutic strategy for disrupting tumorigenesis. Constitutive STAT phosphorylation is found with high frequency in a number of primary tumor types, while non-cancer cells exhibit low basal activity, providing an exploitable therapeutic window. STAT activation involves phosphorylation of the SH domain by a number of tyrosine kinases followed by STAT dimerization and translocation to the nucleus.

Intranasal octenidine and universal antiseptic bathing reduce methicillin-resistant Staphylococcus aureus (MRSA) prevalence in extended care facilities.

Intranasal octenidine, an antiseptic alternative to mupirocin, can be used for methicillin-resistant Staphylococcus aureus (MRSA) decolonisation in the prevention of nosocomial transmission. A controlled before-after study was conducted in three extended-care hospitals in Singapore. All inpatients with >48 h stay were screened for MRSA colonisation in mid-2015(pre-intervention) and mid-2016(post-intervention).

Pharmacologic inhibition of STAT5 in acute myeloid leukemia.

The transcription factor STAT5 is an essential downstream mediator of many tyrosine kinases (TKs), particularly in hematopoietic cancers. STAT5 is activated by FLT3-ITD, which is a constitutively active TK driving the pathogenesis of acute myeloid leukemia (AML). Since STAT5 is a critical mediator of diverse malignant properties of AML cells, direct targeting of STAT5 is of significant clinical value.

Smooth muscle function and myosin polymerization.

Smooth muscle is able to function over a much broader length range than striated muscle. The ability to maintain contractility after a large length change is thought to be due to an adaptive process involving restructuring of the contractile apparatus to maximize overlap between the contractile filaments. The molecular mechanism for the length-adaptive behavior is largely unknown.

Structure-Activity Relationship Studies of Isomeric 2,4-Diaminoquinazolines on β-Amyloid Aggregation Kinetics.

A library of isomeric 2,4-diaminoquinazoline (DAQ) derivatives were synthesized and evaluated for antiaggregation potential toward Aβ40/42. Structure-activity relationship data identified compound 3k (N (4)-(4-bromobenzyl)quinazoline-2,4-diamine) with a 4-bromobenzyl substituent as the most potent inhibitor (Aβ40 IC50 = 80 nM) and was almost 18-fold more potent compared to the reference agent curcumin (Aβ40 IC50 = 1.5 μM).

Curcumin Binding to Beta Amyloid: A Computational Study.

Curcumin, a chemical constituent present in the spice turmeric, is known to prevent the aggregation of amyloid peptide implicated in the pathophysiology of Alzheimer's disease. While curcumin is known to bind directly to various amyloid aggregates, no systematic investigations have been carried out to understand its ability to bind to the amyloid aggregates including oligomers and fibrils. In this study, we constructed computational models of (i) Aβ hexapeptide (16) KLVFFA(21) octamer steric-zipper β-sheet assembly and (ii) full-length Aβ fibril β-sheet assembly.

Osteochondroma of the mandibular condyle: Report of two surgical approaches.

Osteochondromas are common tumors of the long bones, but are rare in the craniofacial region. We detailed two different management of osteochondroma of the mandibular condyle treated utilizing three-dimensional (3D) imaging and computer-assisted planning. Simultaneous open temporomandibular joint and orthognathic surgeries were done to treat both the pathology and secondary facial asymmetry.

Selective inhibition of human acetylcholinesterase by xanthine derivatives: in vitro inhibition and molecular modeling investigations.

The commonly used beverage and psychostimulant caffeine is known to inhibit human acetylcholinesterase enzyme. This pharmacological activity of caffeine is partly responsible for its cognition enhancing properties. However, the exact mechanisms of its binding to human cholinesterases (acetyl and butyrylcholinesterase; hAChE and hBuChE) are not well known.

A randomized controlled trial to compare steroid with cyclosporine for the topical treatment of oral lichen planus.

Objective: To compare the effectiveness of cyclosporine solution versus triamcinolone acetonide in orabase in the treatment of oral lichen planus (OLP) in reducing signs and symptoms.

Study Design: One hundred thirty-nine biopsy-proven OLP patients were randomly assigned to cyclosporine (68) or steroid (71) applied onto the target lesion and affected areas. Assessments were at weeks 0, 2, 4, 8 by clinical scoring and grid measurement of the target lesion (reticulation, erythema, ulceration).

Biodistribution of phospholipid vesicles in mice bearing Lewis lung carcinoma and granuloma.

Murine biodistributions of vesicle-encapsulated [111In]NTA were obtained under a number of conditions. These included normal animals, those bearing s.c.

Liposomal blockade of the reticuloendothelial system: improved tumor imaging with small unilamellar vesicles.

The reticuloendothelial system of mice bearing EMT6 tumors was effectively blocked by intravenous injections of small unilamellar vesicles that incorporated a 6-aminomannose derivative of cholesterol in the lipid bilayer. Neutral liposomes loaded with indium-111-nitrilotriacetic acid were then injected. Fifty percent more radioactivity was deposited in tumors of the animals with blocked reticuloendothelial systems than in controls.

Stability of erythrocyte ghosts: a gamma-ray perturbed angular correlation study.

The structural integrity of erythrocyte ghosts made by the preswell and slow-dialysis techniques has been studied in vitro by use of gamma-ray perturbed angular correlation (PAC) techniques and also by standard in vitro leakage methods employing sequestered labeled markers. Complexes of 111In3+ and nitrilotriacetate were encapsulated in ghosts made from human, rabbit, rat, and mouse erythrocytes, and their leakage was monitored by both methods. In addition, 125I-labeled bovine serum albumin was encapsulated, and ghost integrity was monitored by conventional leakage measurements.

Tumor-imaging potential of liposomes loaded with In-111-NTA: biodistribution in mice.

EMT6 tumors in BALB/c mice have been successfully imaged with small (less than 0.1 mu), unilamellar lipid vesicles (SUVs) loaded with In-111 nitrilotriacetic acid (In-111 NTA). Neutral SUVs prepared from distearoyl phosphatidylcholine (DSPC) and cholesterol (CH) (ratio 2:1) delivered sufficient radioactivity to allow tumor visualization 24 hr after i.

Stability of carbohydrate-modified vesicles in vivo: comparative effects of ceramide and cholesterol glycoconjugates.

The stability and tissue distribution of lipid vesicles modified at the surface by the incorporation of either a galactosyl ceramide (GalCer) or a galactosyl cholesterol (GalChol) glycoconjugate have been studied in mice by measuring the release of vesicle-entrapped 111In. Although the tissue distributions of both vesicle types were similar, the GalCer-containing vesicles were markedly less stable than those prepared with GalChol, whether administered orally or by intraperitoneal injection. Physical characterization of the vesicles in vitro suggests that the increased disruption rate for GalCer vesicles in vivo is related to structural instabilities induced by the cerebroside, which can then result in either an increased rate of vesicle uptake by tissues or a greater susceptibility to lysis.