Identification of a Self-Assembling Small-Molecule Cancer Vaccine Adjuvant with an Improved Toxicity Profile.

Protein or peptide cancer vaccines usually include immune potentiators, so-called adjuvants. However, it remains challenging to identify structurally simple, chemically accessible synthetic molecules that are effective and safe as vaccine adjuvant. Here, we present cholicamideβ (), a self-assembling small-molecule vaccine adjuvant with an improved toxicity profile and proven efficacy .

Discovery of a phase-separating small molecule that selectively sequesters tubulin in cells.

Phase-separated membraneless organelles or biomolecular condensates play diverse functions in cells, however recapturing their characteristics using small organic molecules has been a challenge. In the present study, cell-lysate-based screening of 843 self-assembling small molecules led to the discovery of a simple organic molecule, named huezole, that forms liquid droplets to selectively sequester tubulin. Remarkably, this small molecule enters cultured human cells and prevents cell mitosis by forming tubulin-concentrating condensates in cells.

Combination immunotherapy of nivolumab plus ipilimumab in a lung cancer patient with Werner syndrome; a case report.

Werner syndrome (WS) is a rare progressive disorder that is characterized by premature aging of all organs. Malignancy is a frequent complication of WS, however, lung cancer patients with WS are much rare. In patients with WS, the treatment for malignancy is often limited due to other complications of severe skin ulcer, diabetes mellitus and cardiovascular disease.

Pleural empyema with gas formation caused by mixed infection of with .

is an anaerobic, gram-negative rod bacterium associated with freshwater and marine life. Human infections are rare, and most infections in humans cause gastroenteritis. Extraintestinal infections of such as pleural empyema are particularly rare.

Glucose as a Protein-Condensing Cellular Solute.

The present study reports a surprising protein-condensing effect of glucose, prompted by our accidental observation during chemical library screening under a high-glucose condition. We noticed "glucosing-out" of certain compounds, in which physiological concentrations of glucose induced compound aggregation. Adapting the "glucosing-out" concept to proteins, our proteomic analysis identified three cellular proteins (calmodulin, rho guanine nucleotide exchange factor 40, and polyubiquitin-C) that displayed robust glucose-dependent precipitation.

Discovery of Non-Cysteine-Targeting Covalent Inhibitors by Activity-Based Proteomic Screening with a Cysteine-Reactive Probe.

Covalent inhibitors of enzymes are increasingly appreciated as pharmaceutical seeds, yet discovering non-cysteine-targeting inhibitors remains challenging. Herein, we report an intriguing experience during our activity-based proteomic screening of 1601 reactive small molecules, in which we monitored the ability of library molecules to compete with a cysteine-reactive iodoacetamide probe. One epoxide molecule, F8, exhibited unexpected enhancement of the probe reactivity for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a rate-limiting glycolysis enzyme.

Gold(I)-Catalyzed Cyclization-3-Aza-Cope-Mannich Cascade and Its Application to the Synthesis of Cephalotaxine.

The discovery of a new gold(I)-catalyzed cascade reaction involving cyclization onto a vinylammonium, 3-aza-Cope rearrangement, and Mannich cyclization is reported. A variety of fused nitrogen heterocycles were prepared from simple cyclic tertiary amines using 1-5 mol % of a AuCl(PPh)/Ag[C(CN)] cocatalyst system. The developed reaction was used in a study aimed at synthesizing cephalotaxine.

Non-genetic cell-surface modification with a self-assembling molecular glue.

This report describes the development of a non-genetic cell-surface modification method, in which a self-assembling small molecule is combined with Halo-tag proteins. Cell-surface functionalization with cancer-linked extracellular proteins led to enhanced cell motility, angiogenesis, and immune shielding of the cells, paving the way for translational opportunities for cell therapy.

Comfort and safety of bronchoscopy performed under sedation and local anesthesia in elderly patients.

Although sedation for bronchoscopy improves patient comfort, there is a risk of oversedation in elderly patients. Only a few studies have evaluated the efficacy and safety of sedation for bronchoscopy in elderly patients.This study retrospectively analyzed records of 210 patients who underwent transbronchial brushing and/or biopsy under midazolam sedation at National Hospital Organization Omuta National Hospital between June 2017 and October 2019.

Discovery of Self-Assembling Small Molecules as Vaccine Adjuvants.

Immune potentiators, termed adjuvants, trigger early innate immune responses to ensure the generation of robust and long-lasting adaptive immune responses of vaccines. Presented here is a study that takes advantage of a self-assembling small-molecule library for the development of a novel vaccine adjuvant. Cell-based screening of the library and subsequent structural optimization led to the discovery of a simple, chemically tractable deoxycholate derivative (molecule 6, also named cholicamide) whose well-defined nanoassembly potently elicits innate immune responses in macrophages and dendritic cells.

Ion-Pair Extraction of Quaternary Ammoniums Using Tetracyanocyclopentadienides and Synthetic Application for Complex Ammoniums.

A simple isolation method for quaternary ammonium cations via ion-pair extraction using tetracyanocyclopentadienide (TCCP) was established. Separation of tetraethylammonium and carbachol cations was achieved by the selective extraction of tetraethylammonium with ethoxycarbonyl TCCP, which was moderately lipophilic. The ion-pair extraction with TCCPs was applied to the synthesis of complex quaternary ammonium salts, including a spiro vinylammonium that is a precursor of the novel 3-aza-Cope-Mannich cascade.

Multifunctionalization of Cells with a Self-Assembling Molecule to Enhance Cell Engraftment.

Cell-based therapy is a promising approach to restoring lost functions to compromised organs. However, the issue of inefficient cell engraftment remains to be resolved. Herein, we take a chemical approach to facilitate cell engraftment by using self-assembling molecules which modify two cellular traits: cell survival and invasiveness.

Prognostic factors in patients with miliary tuberculosis.

Background And Purpose: Acute respiratory distress syndrome (ARDS) complication has long been considered a factor associated with poor prognosis in patients with miliary tuberculosis. However, few reports exist on the prognostic factors of miliary tuberculosis including those complicating ARDS.

Subjects And Methods: We retrospectively examined prognoses and other clinical information obtained from medical records of a total of 68 patients diagnosed with miliary tuberculosis.

Prevalence of Airflow Limitation Defined by Pre- and Post-Bronchodilator Spirometry in a Community-Based Health Checkup: The Hisayama Study.

Spirometry in health checkup may contribute to early diagnosis of chronic obstructive pulmonary disease (COPD) and asthma. Although post-bronchodilator airflow limitation is essential for definite diagnosis of COPD and post-bronchodilator normalization of airflow is suggestive of asthma, this test has not been prevailed in health checkup. The objective of this study was to estimate the prevalence of airflow limitation defined by pre- and post-bronchodilator spirometry in health checkup.

Prevalence of asthma with airflow limitation, COPD, and COPD with variable airflow limitation in older subjects in a general Japanese population: the Hisayama Study.

Background: Elucidating the prevalence of asthma and chronic obstructive pulmonary disease (COPD) is important for designing a public health strategy. Recent studies have discriminated a phenotype of COPD with variable airflow limitation (COPD-VAL) associated with asthma-COPD overlap syndrome. Its prevalence remains uncertain.

Cigarette smoke impairs phagocytosis of apoptotic neutrophils by alveolar macrophages via inhibition of the histone deacetylase/Rac/CD9 pathways.

Efferocytosis, which is the homeostatic phagocytosis of apoptotic cells, prevents the release of toxic intracellular contents and subsequent tissue damage. Impairment of efferocytosis was reported in alveolar macrophages (AMs) of patients with chronic obstructive pulmonary disease (COPD), a common disease caused by smoking. In COPD, histone deacetylase (HDAC) activity is reduced in AMs.

IL-6 induced by double-stranded RNA augments allergic inflammation via suppression of Foxp3+ T-cell/IL-10 axis.

Activation of innate immunity against viruses in the respiratory tracts affects the development of asthma. Most respiratory viruses generate double-stranded (ds)RNA during their replication. We recently showed that a low-dose administration of polyinosinic polycytidylic acid (poly IC), a mimetic of viral dsRNA, during allergen sensitization augments airway eosinophilia and hyperresponsiveness in mice via enhanced production of IL-13 from T cells.

Preparation of allosamidin and demethylallosamidin photoaffinity probes and analysis of allosamidin-binding proteins in asthmatic mice.

Allosamidins, metabolites of Streptomyces with strong inhibitory activities toward family 18 chitinases, show a variety of biological activities in various organisms. We prepared photoaffinity and biotinylated probes of allosamidin and demethylallosamidin, the N-demethyl derivative that shows much stronger anti-asthmatic activity than allosamidin. Mild acid hydrolysis of allosamidins afforded mono-amine derivatives, which were amidated to prepare probes with a photoactivatable aryl azide and/or biotin moieties.

A zinc chelator TPEN attenuates airway hyperresponsiveness and airway inflammation in mice in vivo.

Background: Zinc is an essential element required for the cell metabolism, including gene transcription, signal transduction, immunity, and apoptosis. The pathophysiological role of zinc in asthma, however, is not entirely clear. Mast cells have been implicated in atopic asthma, and zinc deprivation has been reported to reduce mast cell activation.

IL-13 suppresses double-stranded RNA-induced IFN-λ production in lung cells.

Acute asthma exacerbations are frequently associated with respiratory viral infections. Although impaired production of type III IFNs (IFN-λs) is related to the severity of asthma exacerbation, the mechanisms underlying deficient IFN-λ production in asthma are poorly understood. Airway epithelial cells were stimulated in vitro with a synthetic mimetic of viral double-stranded RNA (dsRNA).

Single orifice vein reconstruction in left liver plus caudate lobe graft.

Background/aims: We describe the innovative techniques with single orifice vein reconstruction for the complete venous drainage in the left liver plus caudate lobe graft.

Methodology: Eight left liver plus caudate lobe grafts used for living donor adult liver transplantation were reviewed. A wide and single venous orifice was created by gathering the left, middle or its tributaries, and/or short hepatic vein using a patch vein graft or a conduit vein graft.

Primary tuberculosis of the appendix in a young male patient: report of a case.

A 23-year-old man without a history of tuberculosis presented with right lower abdominal pain and a fever. An increased inflammatory response was found, and abdominal computed tomography showed a diffuse enlargement and wall thickening in the appendix. An ileocecal abscess and perforating appendicitis were suspected.