A Wnt/β-catenin signaling inhibitor, IMU1003, suppresses the emergence of osimertinib-resistant colonies from gefitinib-resistant non-small cell lung cancer cells.

Drug resistance has become a challenge in effective longterm molecular targeted therapy. Longterm non-small cell lung cancer (NSCLC) treatments with the first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) shorten the effective duration of the third-generation EGFR-TKI, osimertinib, via genetic or epigenetic mechanisms in addition to the gatekeeper mutation T790M. This study reproduced this persistence in vitro using gefitinib-resistant NSCLC PC-9 cells (GR cells) and revealed that pharmacological nuclear localization inhibition of β-catenin suppressed the osimertinib resistance.

Influence of the COVID-19 pandemic on regular clinic visits and medication prescriptions among people with diabetes: Retrospective cohort analysis of health care claims.

The aim of this study was to investigate the effect of the COVID-19 pandemic on regular clinic visits among people with diabetes and to elucidate the factors related to visit patterns among these patients during the pandemic. This was a longitudinal study using anonymized insurance claims data from the Joint Health Insurance Society in Tokyo from October 2017 to September 2020. First, we identified patients with diabetes who were fully enrolled in the health plan from fiscal year 2017 until September 2020 and who were regularly receiving glucose-lowering medications (every 1-3 months) from October 2017 to September 2018.

How do patients with chronic illnesses respond to a public health crisis? Evidence from diabetic patients in Japan during the COVID-19 pandemic.

How do people change their healthcare behavior when a public health crisis occurs? Within a year of its emergence, coronavirus disease 2019 (COVID-19) has gradually infiltrated our lives and altered our lifestyles, including our healthcare behaviors. In Japan, which faces China across the East China Sea and accepted 924,800 Chinese tourists in January 2020, the emergence and spread of COVID-19 provides a unique opportunity to study people's reactions and adaptations to a pandemic. Patients with chronic illnesses who require regular doctor visits are particularly affected by such crises.

Domestication of chemicals attacking metazoan embryogenesis: identification of safe natural products modifying developmental signaling pathways in human.

Soil microorganisms are rich sources of bioactive natural products. Interspecies interactions are the cues of their production and refine biological activities. These interactions in natural environments include the interplay between microorganisms and Metazoans (animals), such as nematodes, insects, and ticks.

Switching from Intravenous to Oral Tacrolimus Reduces its Blood Concentration in Paediatric Cancer Patients.

Background/aim: Tacrolimus is an essential immunosuppressant for successful allogeneic haematopoietic stem cell transplantation (Allo-HSCT). This study aimed to examine the change in the blood concentration of tacrolimus during switching from intravenous to oral administration in allo-HSCT for paediatric cancer to predict the optimal dosage.

Patients And Methods: We retrospectively examined the medical records of 63 patients who received allo-HSCT and were administered tacrolimus.

Synthesis and evaluation of azalamellarin N and its A-ring-modified analogues as non-covalent inhibitors of the EGFR T790M/L858R mutant.

Azalamellarin N, a synthetic lactam congener of the marine natural product lamellarin N, and its A-ring-modified analogues were synthesized and evaluated as potent and non-covalent inhibitors of the drug-resistant epidermal growth factor receptor T790M/L858R mutant. An in vitro tyrosine kinase assay indicated that the inhibitory activities of the synthetic azalamellarin analogues were higher than those of the corresponding lamellarins. The azalamellarin analogue bearing two 3-(dimethylamino)propoxy groups at C20- and C21-positions exhibited the highest activity and selectivity against the mutant kinase [IC (T790M/L858R) = 1.

Lamellarin 14, a derivative of marine alkaloids, inhibits the T790M/C797S mutant epidermal growth factor receptor.

The emergence of acquired resistance is a major concern associated with molecularly targeted kinase inhibitors. The C797S mutation in the epidermal growth factor receptor (EGFR) confers resistance to osimertinib, a third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI). We report that the derivatization of the marine alkaloid topoisomerase inhibitor lamellarin N provides a structurally new class of EGFR-TKIs.

IMU1003, an atrarate derivative, inhibits Wnt/β-catenin signaling.

Aberrant activation of the canonical Wnt/β-catenin signaling pathway triggers tumorigenesis in various tissues. This study identified an atrarate compound, IMU14, derived from filamentous fungi as an inhibitor of Wnt/β-catenin signaling in phenotypic chemical inhibitor screening of the zebrafish eyeless phenotype. Its derivatization resulted in synthesis of IMU1003 with enhanced Wnt inhibitory activity.

Bucillamine Prevents Afatinib-Mediated Inhibition of Epidermal Growth Factor Receptor Signaling.

Molecular targeting therapies often cause characteristic adverse effects, such as skin rash during anti-epidermal growth factor receptor (EGFR) therapies, making treatment continuation difficult. In contrast, skin symptoms induced by EGFR inhibition are strongly correlated with the overall survival of the therapies. Therefore, controlling adverse effects not only facilitates treatment continuation but also increases clinical benefits.

Clotrimazole inhibits the Wnt/β-catenin pathway by activating two eIF2α kinases: The heme-regulated translational inhibitor and the double-stranded RNA-induced protein kinase.

The Wnt/β-catenin signaling pathway controls cell proliferation and differentiation, and therefore, when this pathway is excessively activated, it causes tumorigenesis. Our chemical suppressor screening in zebrafish embryos identified antifungal azoles including clotrimazole, miconazole, and itraconazole, as Wnt/β-catenin signaling inhibitors. Here we show the mechanism underlying the Wnt/β-catenin pathway inhibition by antifungal azoles.

Augmentation of the therapeutic efficacy of WEE1 kinase inhibitor AZD1775 by inhibiting the YAP-E2F1-DNA damage response pathway axis.

The main reasons for failure of cancer chemotherapy are intrinsic and acquired drug resistance. The Hippo pathway effector Yes-associated protein (YAP) is associated with resistance to both cytotoxic and molecular targeted drugs. Several lines of evidence indicate that YAP activates transcriptional programmes to promote cell cycle progression and DNA damage responses.

Sensitisation of Cancer Cells to MLN8237, an Aurora-A Inhibitor, by YAP/TAZ Inactivation.

Background: Transcriptional co-activators YES-associated protein (YAP) and transcriptional coactivator with PDZ-motif (TAZ) stimulate the expression of cell cycle-related genes to permit for tumour cell growth. MLN8237 is a potent aurora-A kinase inhibitor; however, patients responding to MLN8237 are limited. Therefore, rational combination therapy could enhance their response.

Design, synthesis, and evaluation of A-ring-modified lamellarin N analogues as noncovalent inhibitors of the EGFR T790M/L858R mutant.

A series of A-ring-modified lamellarin N analogues were designed, synthesized, and evaluated as potential noncovalent inhibitors of the EGFR T790M/L858R mutant, a causal factor in the drug-resistant non-small cell lung cancer. Several water-soluble ammonium- or guanidinium-tethered analogues exhibited good kinase inhibitory activities. The most promising analogue, 14f, displayed an excellent inhibitory profile against the T790M/L858R mutant [IC (WT) = 31.

Dynamic Phenotypic Transition of Breast Cancer Cells Revealed by Self-floating Cell Culture.

Background: Breast tumor heterogeneity leads to phenotypic diversity, such as tumor-initiating and metastatic properties and drug sensitivity.

Materials And Methods: We found that a self-floating cell (SFC) culture enriches a drug-resistant subpopulation in a HER2-positive breast cancer cell line. SFCs were analyzed for cancer stem cell markers, gene expression profiles, and sensitivity for anticancer drugs.

[Screening for Chemical Suppressors of the Wnt/β-catenin Signaling Pathway].

Aberrant activation of Wnt/β-catenin canonical signaling is observed in multiple malignant tumors, and is recognized as an attractive therapeutic target for molecular targeted drugs. This signaling pathway is also involved in maintaining pluripotency in adult stem cells. Therefore, lowering potential stem cell toxicity is a key factor for the development of a Wnt/β-catenin signaling inhibitor.

JAK3 inhibitor VI is a mutant specific inhibitor for epidermal growth factor receptor with the gatekeeper mutation T790M.

Aim: To identify non-quinazoline kinase inhibitors effective against drug resistant mutants of epidermal growth factor receptor (EGFR).

Methods: A kinase inhibitor library was subjected to screening for specific inhibition pertaining to the in vitro kinase activation of EGFR with the gatekeeper mutation T790M, which is resistant to small molecular weight tyrosine kinase inhibitors (TKIs) for EGFR in non-small cell lung cancers (NSCLCs). This inhibitory effect was confirmed by measuring autophosphorylation of EGFR T790M/L858R in NCI-H1975 cells, an NSCLC cell line harboring the gatekeeper mutation.

A zebrafish chemical suppressor screening identifies small molecule inhibitors of the Wnt/β-catenin pathway.

Genetic screening for suppressor mutants has been successfully used to identify important signaling regulators. Using an analogy to genetic suppressor screening, we developed a chemical suppressor screening method to identify inhibitors of the Wnt/β-catenin signaling pathway. We used zebrafish embryos in which chemically induced β-catenin accumulation led to an "eyeless" phenotype and conducted a pilot screening for compounds that restored eye development.

p38MAPK and Rho-dependent kinase are involved in anoikis induced by anicequol or 25-hydroxycholesterol in DLD-1 colon cancer cells.

Anchorage-independent growth is evidence of the malignant transformation of cells. We previously reported the characterization of anicequol, a novel inhibitor of the anchorage-independent growth of tumor cells, and here we show that the effects of 25-hydroxycholesterol (25-HC) on colon cancer cells were very similar to those of anicequol. By analyzing the effects of inhibitors and performing RNA interference experiments, we found that p38 mitogen-activated protein kinase (p38MAPK) was involved in anicequol- and 25-HC-induced anoikis in DLD-1 cells.

Involvement of heparan sulfate 3-O-sulfotransferase isoform-1 in the insulin secretion pathway.

Unlabelled: Aims/Introduction:  Heparan sulfate (HS) mediates a variety of molecular recognition events that are essential for differentiation, morphogenesis and homeostasis through various HS forms that result from differential sulfate modification. Recently, we found that HS is localized exclusively around βß-cells in islets of adult mice and is required for insulin secretion. The aim of this study was to examine the contribution of HS sulfate groups to insulin secretion.

Identification of LY83583 as a specific inhibitor of Candida albicans MPS1 protein kinase.

Candida albicans is the most common and virulent fungus causing candidiasis in various parts of the body and can be lethal to immunocompromised patients. All currently known antifungal therapies are drugs which cause serious side effects in the host. An inhibitor specific for fungus survival is an ideal therapeutic.

Production of hydrogen sulfide by two enzymes associated with biosynthesis of homocysteine and lanthionine in Fusobacterium nucleatum subsp. nucleatum ATCC 25586.

Fusobacterium nucleatum produces a large amount of the toxic metabolite hydrogen sulfide in the oral cavity. Here, we report the molecular basis of F. nucleatum H(2)S production, which is associated with two different enzymes: the previously reported Cdl (Fn1220) and the newly identified Lcd (Fn0625).