Assessing CD36 and CD47 expression levels in solid tumor indications to stratify patients for VT1021 treatment.

Despite the development of cancer biomarkers and targeted therapies, most cancer patients do not have a specific biomarker directly associated with effective treatment options. We have developed VT1021 that induces the expression of thrombospondin-1 (TSP-1) in myeloid-derived suppressor cells (MDSCs) recruited to the tumor microenvironment (TME). Our studies identified CD36 and CD47 as dual biomarkers that can be used as patient stratifying tools and prognostic biomarkers for VT1021 treatment.

Phase 1 dose expansion and biomarker study assessing first-in-class tumor microenvironment modulator VT1021 in patients with advanced solid tumors.

Background: Preclinical studies have demonstrated that VT1021, a first-in-class therapeutic agent, inhibits tumor growth via stimulation of thrombospondin-1 (TSP-1) and reprograms the tumor microenvironment. We recently reported data from the dose escalation part of a phase I study of VT1021 in solid tumors. Here, we report findings from the dose expansion phase of the same study.

Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Warhead.

There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by an increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (M, 3CL) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof toward human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CL inhibitor, , bearing an unprecedented trifluoromethoxymethyl ketone warhead.

First-in-human phase I dose escalation trial of the first-in-class tumor microenvironment modulator VT1021 in advanced solid tumors.

Background: VT1021 is a cyclic peptide that induces the expression of thrombospondin-1 (TSP-1) in myeloid-derived suppressor cells (MDSCs) recruited to the tumor microenvironment (TME). TSP-1 reprograms the TME via binding to CD36 and CD47 to induce tumor and endothelial cell apoptosis as well as immune modulation in the TME.

Methods: Study VT1021-01 (ClinicalTrials.

A covalent inhibitor of the YAP-TEAD transcriptional complex identified by high-throughput screening.

Yes-associated protein (YAP), the master transcriptional effector downstream of the Hippo pathway, regulates essential cell growth and regenerative processes in animals. However, the activation of YAP observed in cancers drives cellular proliferation, metastasis, chemoresistance, and immune suppression, making it of key interest in developing precision therapeutics for oncology. As such, pharmacological inhibition of YAP by targeting its essential co-regulators, TEA domain transcription factors (TEADs) would likely promote tumor clearance in sensitive tumor types.

Pharmacological YAP activation promotes regenerative repair of cutaneous wounds.

Chronic cutaneous wounds remain a persistent unmet medical need that decreases life expectancy and quality of life. Here, we report that topical application of PY-60, a small-molecule activator of the transcriptional coactivator Yes-associated protein (YAP), promotes regenerative repair of cutaneous wounds in pig and human models. Pharmacological YAP activation enacts a reversible pro-proliferative transcriptional program in keratinocytes and dermal cells that results in accelerated re-epithelization and regranulation of the wound bed.

Targeting the Mitotic Kinesin KIF18A in Chromosomally Unstable Cancers: Hit Optimization Toward an In Vivo Chemical Probe.

Chromosomal instability (CIN) is a hallmark of cancer that results from errors in chromosome segregation during mitosis. Targeting of CIN-associated vulnerabilities is an emerging therapeutic strategy in drug development. KIF18A, a mitotic kinesin, has been shown to play a role in maintaining bipolar spindle integrity and promotes viability of CIN cancer cells.

Discovery of a Covalent Inhibitor of KRAS (AMG 510) for the Treatment of Solid Tumors.

KRAS has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRAS to identify inhibitors suitable for clinical development.

Discovery of TRPM8 Antagonist ( S)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic Acid (AMG 333), a Clinical Candidate for the Treatment of Migraine.

Transient-receptor-potential melastatin 8 (TRPM8), the predominant mammalian cold-temperature thermosensor, is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system, including nerve circuitry implicated in migraine pathogenesis: the trigeminal and pterygopalatine ganglia. Genomewide association studies have identified an association between TRPM8 and reduced risk of migraine. This disclosure focuses on medicinal-chemistry efforts to improve the druglike properties of initial leads, particularly removal of CYP3A4-induction liability and improvement of pharmacokinetic properties.

[Analysis of the efficacy and compliance of conventional immunotherapy and rush immunotherapy in patients with allergic rhinitis].

To analyze the efficacy and compliance of conventional immunotherapy(CIT)and rush immunotherapy(RIT)in patients with allergic rhinitis.This trial was a prospective study involved 404 patients with persistent AR who were allergic to house dust mite.328 patients were assigned to the conventional immunotherapy reaching the maintenance dose within 14 weeks,and 76 patients were assigned to the rush immunotherapy reaching the maintenance dose within 1 week.

Severe hydrocephalus complicated with benign paroxysmal positional vertigo: one case report.

In this study, we reported one female patient diagnosed with severe hydrocephalus who presented with benign paroxysmal positional vertigo (BPPV). She presented with progressive headache and dizziness prior to hospitalization as chief complaints. She received Diagnostic Dix-Hallpike and Roll tests to make a definite diagnosis.

Indoor Allergen Levels and Household Distributions in Nine Cities Across China.

Objective: Chinese allergic subjects have high levels of sensitization to house dust mite (HDM) and other indoor allergens. This study quantifies common indoor allergen levels in Chinese households.

Methods: Dust samples were collected from nine cities.

Family Smoking, Exposure to Secondhand Smoke at Home and Family Unhappiness in Children.

Tobacco use adversely affects many aspects of well-being and is disliked by non-smokers. However, its association with family happiness is unknown. We investigated the associations of family unhappiness with smoking in family members and secondhand smoke (SHS) exposure at home in Hong Kong children.

Reactions to Thirdhand Smoke are Associated with Openness to Smoking in Young Never Smoking Children.

To investigate the associations between reactions to thirdhand smoke (THS) and openness to smoking in young children. In a school-based survey in Hong Kong, 4762 Chinese primary school students reported their reactions to THS (one or more of 'pleasant/happy', 'nausea', 'excited', 'heart beat faster', 'relaxed', 'dislike the smell', 'like the smell', 'dizzy', 'coughing/choking', 'eye uncomfortable' and 'none of the above'), smoking status and openness to smoking (lack of a firm intention not to smoke). Factor structure of reactions to THS was investigated with factor scores calculated and categorised.

Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors.

In nonsmall cell lung cancer (NSCLC), the threonine(790)-methionine(790) (T790M) point mutation of EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Herein, we describe the optimization of a series of 7-oxopyrido[2,3-d]pyrimidinyl-derived irreversible inhibitors of EGFR kinase. This led to the discovery of compound 24 which potently inhibits gefitinib-resistant EGFR(L858R,T790M) with 100-fold selectivity over wild-type EGFR.

Has‑miR‑125a and 125b are induced by treatment with cisplatin in nasopharyngeal carcinoma and inhibit apoptosis in a p53‑dependent manner by targeting p53 mRNA.

MicroRNA (miRNA) is a class of non‑coding RNA, which targets mRNAs of interest and suppresses its expression by degradation or translational inhibition. miRNA (miR)‑125a and miR‑125b were previously demonstrated to translationally and transcriptionally inhibit the expression of p53. The observed downregulation of the protein level of p53 in cisplatin‑treated patients with nasopharyngeal carcinoma (NPC) indicates the association between cisplatin resistance, miR‑125a and miR‑125b.

An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities.

BACE1 inhibition to prevent Aβ peptide formation is considered to be a potential route to a disease-modifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure- and property-based approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain Aβ levels in both rats and nonhuman primates.

Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer's disease.

The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer's disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Aβ levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model.

Femoral fractures in infants: a comparison of Bryant traction and modified Pavlik harness.

Bryant traction is a commonly used method for femoral shaft fractures in children, but many disadvantages have been reported. Pavlik harness with exact clinical effect and fewer complications has gained increasing popularity in resent years. The objective of this study was to evaluate and compare modified Pavlik harness with Bryant traction for infant with a femoral shaft fracture.

Discovery of 2-methylpyridine-based biaryl amides as γ-secretase modulators for the treatment of Alzheimer's disease.

γ-Secretase modulators (GSMs) are potentially disease-modifying treatments for Alzheimer's disease. They selectively lower pathogenic Aβ42 levels by shifting the enzyme cleavage sites without inhibiting γ-secretase activity, possibly avoiding known adverse effects observed with complete inhibition of the enzyme complex. A cell-based HTS effort identified the sulfonamide 1 as a GSM lead.

Incidence of non-tunnelled central venous catheter-related infections in oncologic patients receiving chemotherapy in an outpatient setting.

Introduction: Central venous catheters (CVCs) are becoming more popular for delivery of outpatient courses of intravenous therapy such as chemotherapy and long-term antibiotics. The incidence of non-tunnelled type CVC-related infections in patients with solid tumours receiving chemotherapy in an ambulatory setting has not been well studied. We aimed to determine the baseline data on CVC-related infections in this retrospective study conducted from January 2005 to December 2007.

Discovery of dehydro-oxopiperazine acetamides as novel bradykinin B1 receptor antagonists with enhanced in vitro potency.

In a series of bradykinin B1 antagonists, we discovered that replacement of oxopiperazine acetamides with dehydro-oxopiperazine acetamides provided compounds with enhanced activity against the B1 receptor. The synthesis and SAR leading to potent analogs with reduced molecular weight will be discussed.