Novel potent molecular glue degraders against broad range of hematological cancer cell lines via multiple neosubstrates degradation.

Background: Targeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness.

Methods: Phenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders.

Discovery of highly potent and selective KRAS degraders by VHL-recruiting PROTACs for the treatment of tumors with KRAS-Mutation.

Although several covalent KRAS inhibitors have made great progress in the treatment of KRAS-mutant cancer, their clinical applications are limited by adaptive resistance, motivating novel therapeutic strategies. Through drug design and structure optimization, a series of highly potent and selective KRAS Proteolysis Targeting Chimeras (PROTACs) were developed by incorporating AMG510 and VHL ligand VH032. Among them, degrader YN14 significantly inhibited KRAS-dependent cancer cells growth with nanomolar IC and DC values, and ＞ 95 % maximum degradation (D).

Application of Dynamic Enhanced Magnetic Resonance Imaging Texture Analysis Combined with ADCs in Predicting Pelvic Lymph Metastasis of Prostate Cancer.

Objective: The application value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) texture analysis combined with apparent diffusion coefficient (ADC) in predicting pelvic lymph node metastasis of prostate cancer was explored.

Methods: The clinical and imaging data of 151 patients with prostate cancer admitted to The Affiliated Tumor Hospital of Guizhou Medical University from November 2019 to November 2021 were retrospectively analysed. According to the final pathological diagnosis results, they were divided into two groups: Metastasis group (n = 63, pelvic lymph node metastasis) and non-metastasis group (n = 88, no pelvic lymph node metastasis).

Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with alterations.

Various c-mesenchymal-to-epithelial transition (c-MET) inhibitors are effective in the treatment of non-small cell lung cancer; however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras (PROTACs) namely and based on thalidomide and tepotinib.

Study on microstructure and extinction characteristics of particulate matter in diesel engine fueled with different biodiesels.

Biodiesel combustion particulate matter (PM) is different from diesel combustion PM in terms of microscopic morphology, which directly affects the optical properties of PM. To investigate the effect of the microstructure of biodiesel PM on the extinction characteristics, an experiment was performed on a high-pressure common rail diesel engine to collect PM from three kinds of biodiesel (the main raw materials were soybean oil methyl eater (SME), palm oil methyl eater (PME), and waste cooking oil methyl eater (WME), respectively). The particle size distribution, micro morphology, and extinction characteristics of biodiesel PM were analyzed.

Discovery of highly potent and selective CRBN-recruiting EGFR degraders in vivo.

Currently, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are widely used in the treatment of non-small cell lung cancer (NSCLC). However, the inevitable drug resistance and side effects are the current main obstacle, which motivating novel therapies. Proteolysis targeting chimera (PROTAC), a lately-developed technology to target proteins for degradation, has been utilized for drug development.

Intraocular lens power calculation after two different successive corneal refractive surgeries.

Purpose: To report two challenging intraocular lens power calculation cases with patients each underwent different successive corneal refractive surgeries, respectively.

Observations: Biometry data, including the Back to Front corneal radii ratio (B/F ratio), were collected by Lenstar, IOL Master, and Pentacam AXL for Case 1 (received radial keratotomy (RK) and photorefractive keratectomy (PRK)) and Case 2 (received RK and laser-assisted in situ keratomileusis (LASIK)). The IOL power calculation was determined by several methods, including Shammas, Haigis-L, and Barrett True-K, which are available in the American Society of Cataract and Refractive Surgery online calculator and Pentacam AXL.

High-Fat Diet-Induced Functional and Pathologic Changes in Lacrimal Gland.

The lacrimal gland is critical for maintaining the homeostasis of the ocular surface microenvironment through secreting aqueous tears in mammals. Many systemic diseases such as Sjögren syndrome, rheumatoid arthritis, and diabetes can alter the lacrimal gland function, eventually resulting in aqueous tear-deficient dry eye. Here, a high-fat diet (HFD) experimental mouse model was used to clarify how hyperlipidemia affects lacrimal gland function.

A Novel Tissue-Engineered Corneal Stromal Equivalent Based on Amniotic Membrane and Keratocytes.

Purpose: To investigate a novel strategy in constructing tissue-engineered corneal stromal equivalent based on amniotic membrane and keratocytes.

Methods: The ultrathin amniotic membrane (UAM) was laminated, with corneal stromal cells (CSCs) distributed between the space of the layered UAMs. Calcein AM staining was used to evaluate cellular viability, morphology, and arrangement.

Public data mining plus domestic experimental study defined involvement of the old-yet-uncharacterized gene matrix-remodeling associated 7 (MXRA7) in physiopathology of the eye.

Matrix-remodeling associated 7 (MXRA7) gene was first reported in 2002 and named so for its co-expression with several genes known to relate with matrix-remodeling. However, not any studies had been intentionally performed to characterize this gene. We started defining the functions of MXRA7 by integrating bioinformatics analysis and experimental study.

Descemet's Membrane Supports Corneal Endothelial Cell Regeneration in Rabbits.

Descemet's membrane (DM) helps maintain phenotype and function of corneal endothelial cells under physiological conditions, while little is known about the function of DM in corneal endothelial wound healing process. In the current study, we performed in vivo rabbit corneal endothelial cell (CEC) injury via CEC scraping, in which DM remained intact after CECs removal, or via DM stripping, in which DM was removed together with CECs. We found rabbit corneas in the CEC scraping group healed with transparency restoration, while there was posterior fibrosis tissue formation in the corneas after DM stripping on day 14.

Dry Eye Management: Targeting the Ocular Surface Microenvironment.

Dry eye can damage the ocular surface and result in mild corneal epithelial defect to blinding corneal pannus formation and squamous metaplasia. Significant progress in the treatment of dry eye has been made in the last two decades; progressing from lubricating and hydrating the ocular surface with artificial tear to stimulating tear secretion; anti-inflammation and immune regulation. With the increase in knowledge regarding the pathophysiology of dry eye, we propose in this review the concept of ocular surface microenvironment.

ROS-mediated Different Homeostasis of Murine Corneal Epithelial Progenitor Cell Line under Oxidative Stress.

The role of ROS in stem cell biology has not been fully illustrated and understood. Here we compared the different responses and investigated the mechanism underlying oxidative stress induced by hydrogen peroxide (HO) between murine corneal epithelial progenitor cell line (TKE2) and mature murine corneal epithelial cells (MCE). TKE2 showed a different homeostasis and strong resistance to HO.

An Ultra-thin Amniotic Membrane as Carrier in Corneal Epithelium Tissue-Engineering.

Amniotic membranes (AMs) are widely used as a corneal epithelial tissue carrier in reconstruction surgery. However, the engineered tissue transparency is low due to the translucent thick underlying AM stroma. To overcome this drawback, we developed an ultra-thin AM (UAM) by using collagenase IV to strip away from the epithelial denuded AM (DAM) some of the stroma.

Serum amyloid A and pairing formyl peptide receptor 2 are expressed in corneas and involved in inflammation-mediated neovascularization.

Aim: To solidify the involvement of Saa-related pathway in corneal neovascularization (CorNV). The pathogenesis of inflammatory CorNV is not fully understood yet, and our previous study implicated that serum amyloid A (Saa) 1 (Saa1) and Saa3 were among the genes up-regulated upon CorNV induction in mice.

Methods: Microarray data obtained during our profiling project on CorNV were analyzed for the genes encoding the four SAA family members (Saa1-4), six reported SAA receptors (formyl peptide receptor 2, Tlr2, Tlr4, Cd36, Scarb1, P2rx7) and seven matrix metallopeptidases (Mmp) 1a, 1b, 2, 3, 9, 10, 13 reportedly to be expressed upon SAA pathway activation.

IL-17 plays a central role in initiating experimental Candida albicans infection in mouse corneas.

The pathogenesis of fungal infection in the cornea remains largely unclear. To understand how the immune system influences the progression of fungal infection in corneas, we inoculated immunocompetent BALB/c mice, neutrophil- or CD4⁺ T-cell-depleted BALB/c mice, and nude mice with Candida albicans. We found that only immunocompetent BALB/c mice developed typical Candida keratitis (CaK), while the other mouse strains lacked obvious clinical manifestations.

Profiling of genes associated with the murine model of oxygen-induced retinopathy.

Purpose: To compare the clinical features and gene expression patterns of the physiologic development of retinal vessels and oxygen-induced retinopathy (OIR) in a mouse model, with the aim of identifying differential regulators of physiologic and pathological angiogenesis in the retina.

Methods: C57BL/6J mice were used. Seven-day-old pups were subjected to OIR induction following the standard protocols of entering a hyperoxic chamber on day 7 (P7) and returning to a normoxic condition (relative hypoxia) on day 12 (P12).

Low concentration of S100A8/9 promotes angiogenesis-related activity of vascular endothelial cells: bridges among inflammation, angiogenesis, and tumorigenesis?

Previous studies showed that several members of the S100A family are involved in neovascularization and tumor development. This study checked whether low concentrations of S100A8 or S100A9 has any effect on the behaviour of vascular endothelial cells. A human umbilical vascular endothelial cell (HUVEC) line was used to measure vascular endothelial cell bioactivity related to angiogenesis, such as cell proliferation, migration, and vessel formation.

αA-crystallin in the pathogenesis and intervention of experimental murine corneal neovascularization.

This study was to determine the potential roles of lens crystallins in the pathogenesis of corneal neovascularization (CorNV) and implications in therapy of CorNV-related diseases. Suture- or chemical burn-induced CorNV in different strains of mice were used. Changes of gene expression patterns were analyzed by microarray, and the results of interesting genes were confirmed by real-time quantitative PCR and Western blot.

Comparison of genome-wide gene expression in suture- and alkali burn-induced murine corneal neovascularization.

Purpose: Suture placement and alkali burn to the cornea are often used to induce inflammatory corneal neovascularization (CorNV) models in animals. This study compares the changes in genome-wide gene expression under these two CorNV conditions in mice.

Methods: CorNV were induced in Balb/c mice by three interrupted 10-0 sutures placed at sites about 1 mm from the corneal apex, or by alkali burns that were 2 mm in size in the central area of the cornea.

Specific inhibition of Candida albicans growth in vitro by antibodies from experimental Candida keratitis mice.

To investigate the role of humoral immunity in the response to experimental keratitis, Balb/c mice were primed by one of three protocols: i) intranasal inhalation of live Candida spores; ii) subcutaneous injection of heat-inactivated spores; or iii) induction and healing of primary CaK. Experimental murine CaK was then induced in the three groups of primed mice and one group of unprimed mice by intrastromal injection of live Candida albicans spores. Totally 30 mice were included in each group.

Physiological expression of lens α-, β-, and γ-crystallins in murine and human corneas.

Purpose: How corneal transparency is formed/maintained remains largely unclear. A group of enzymes which are referred to as enzymatic crystallins were proposed to contribute to corneal transparency in various animals. This study investigated whether the three classical lens crystallins, namely α-, β-, and γ-crystallins, exist in mouse and human corneas.

Selection of housekeeping genes for use in quantitative reverse transcription PCR assays on the murine cornea.

Purpose: To evaluate the suitability of common housekeeping genes (HKGs) for use in quantitative reverse transcription PCR (qRT-PCR) assays of the cornea in various murine disease models.

Methods: CORNEAL DISEASE MODELS STUDIED WERE: 1) corneal neovascularization (CorNV) induced by suture or chemical burn, 2) corneal infection with Candida albicans or Aspergillus fumigatus by intrastromal injection of live spores, and 3) perforating corneal injury (PCI) in Balb/c mice or C57BL/6 mice. Expression of 8 HKGs (glyceraldehyde-3-phosphate dehydrogenase [GAPDH], beta-actin [ACTB], lactate dehydrogenase A [LDHA], ribosomal protein L5 [RPL5], ubiquitin C [UBC], peptidylprolyl isomerase A [PPIA], TATA-box binding protein [TBP1], and hypoxanthine guanine phosphoribosyl transferase [HPRT1]) in the cornea were measured at various time points by microarray hybridization or qRT-PCR and the data analyzed using geNorm and NormFinder.