The prognosis of patients with solid tumours has remarkably improved with the development of molecular-targeted drugs and immune checkpoint inhibitors. However, the improvements in the prognosis of ...pancreatic cancer and biliary tract cancer is delayed compared to other carcinomas, and the 5-year survival rates of distal-stage disease are approximately 10 and 20%, respectively. However, a comprehensive analysis of tumour cells using The Cancer Genome Atlas (TCGA) project has led to the identification of various driver mutations. Evidently, few mutations exist across organs, and basket trials targeting driver mutations regardless of the primary organ are being actively conducted. Such basket trials not only focus on the gate keeper-type oncogene mutations, such as HER2 and BRAF, but also focus on the caretaker-type tumour suppressor genes, such as BRCA1/2, mismatch repair-related genes, which cause hereditary cancer syndrome. As oncogene panel testing is a vital approach in routine practice, clinicians should devise a strategy for improved understanding of the cancer genome. Here, the gene mutation profiles of pancreatic cancer and biliary tract cancer have been outlined and the current status of tumour-agnostic therapy in these cancers has been reported.
NTRK fusion-positive tumors are known to be highly sensitive to TRK inhibitors, such as larotrectinib and entrectinib. Therefore, identification of patients who can potentially benefit from these ...inhibitors is important; however, the frequency of NTRK fusions in Japanese patients with colorectal cancer (CRC) is unknown. We performed pan-TRK staining using TMA-based immunohistochemistry (IHC) on samples from 971 consecutive Japanese CRC cases from a single institution. Positive cases were further analyzed using NanoString and subsequent targeted RNA sequencing. We found three positive cases using TRK-IHC. Furthermore, the Nanostring assay supported the presence of NTRK fusion in these cases. Subsequent targeted RNA-sequencing and RT-PCR revealed two cases with TPM3-NTRK1 and one with TPR-NTRK1. The TNM stages of these cases were stage I, stage IIA, and stage IIIB, and two showed microsatellite instability-high status. Next-generation sequencing analysis using Cancer hotspot panel revealed TP53 and SMAD4 mutations in separate cases. IHC of β-catenin did not show nuclear accumulation. We found three cases (0.31%) of CRC with NTRK1 fusion among 971 consecutive Japanese CRC cases. No potential driver alterations other than NTRK fusion were identified in these three patients.
There is a close relationship between the gut microbiota and metabolic disorders. In this study, acute administration of the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide to mice ...increased the cecal levels of caseinolytic protease B, a component of Escherichia coli, and of norepinephrine. Chemical sympathectomy blocked these events. Norepinephrine was found to pass into the intestinal lumen in vitro. c-Fos staining of the intermediolateral nucleus was identified as indirect evidence of sympathetic nervous system activation of the intestinal tract by GLP-1RA. Under normal conditions, the increase in E. coli did not affect the host. However, in mice with colitis, bacterial translocation was observed with attenuation of tight junction gene expression. This is the first study to investigate the unique underlying mechanisms related the effects of GLP-1RA on changes in the gut bacterium.
Li‐Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome, and the majority of patients with LFS have been identified with germline variants in the p53 tumor suppressor (TP53) gene. ...In the past three decades, considerable case reports of TP53 germline variants have been published in Japan. To the best of our knowledge, there have been no large‐scale studies of Japanese patients with LFS. In this study, we aimed to identify Japanese patients with TP53 germline variants and to reveal the characteristics of LFS in Japan. We collected reported cases by reviewing the medical literature and cases diagnosed at the institutions of the authors. We identified 68 individuals from 48 families with TP53 germline pathogenic or likely pathogenic variants. Of the 48 families, 35 (72.9%) had missense variants, most of which were located within the DNA‐binding loop. A total of 128 tumors were identified in the 68 affected individuals. The 128 tumor sites were as follows: breast, 25; bones, 16; brain, 12; hematological, 11; soft tissues, 10; stomach, 10; lung, 10; colorectum, 10; adrenal gland, 9; liver, 4; and others, 11. Unique phenotype patterns of LFS were shown in Japan in comparison with those in a large national LFS cohort study in France. Above all, a higher frequency of patients with stomach cancer was observed in Japanese TP53 germline variant carriers. These results may provide useful information for the clinical management of LFS in Japan.
Comparing this study in Japan with a large national Li‐Fraumeni syndrome cohort study in France, the unique phenotype patterns of Li‐Fraumeni syndrome was shown in Japan. Especially, the higher frequency of patients with stomach cancer in Japanese TP53 germline variants carriers was shown.
A 67-year-old man with type 1 diabetes, Cronkhite-Canada syndrome, and membranous nephropathy who received insulin therapy was admitted to our hospital with right hemiplegia and dysarthria. Brain ...magnetic resonance imaging revealed a lesion with a high diffusion-weighted imaging signal and low apparent diffusion coefficient signal in the posterior limb of the left internal capsule. He was hypoglycemic with a blood glucose level of 56 mg/dL (3.1 mmol/L). Following glucose administration, the patient’s symptoms resolved within several hours. The patient experienced similar transient hypoglycemic hemiplegia at midnight, three times within 10 days. In a literature review of 170 cases of hypoglycemic hemiplegia, 26 cases of recurrent hemiplegia were investigated. Recurrent hypoglycemic hemiplegia occurs more frequently on the right side than on the left side, and most recurrences occur within approximately a week, almost exclusively at midnight and in the early morning. We speculate that hypoglycemia-associated autonomic failure may be involved in the nocturnal recurrence of episodes. In our patient, depleted endogenous insulin secretion and lipodystrophy at the injection site, may have acted as additional factors, leading to severe hypoglycemia despite the absence of apparent autonomic neuropathy. Clinically, it is important to recognize hypoglycemia as a cause of hemiplegia to avoid unnecessary intervention and to maintain an appropriate blood glucose level at midnight and early in the morning to prevent recurrent hypoglycemic hemiplegia.
A whole-cell biohybrid catalyst where a (pentamethylcyclopentadienyl)rhodium(III) (Cp*Rh(III)) complex was covalently incorporated into the cavity of nitrobindin (NB), a β-barrel protein, was ...prepared on an E. coli cell surface to produce isoquinolines via C(sp2)–H bond activation. In this whole-cell biohybrid system, the Cp*Rh(III)-dithiophosphate complex with latent catalytic activity was utilized as a precursor of the metal cofactor. Strong chelation of the dithiophosphate ligands protects the rhodium complex from being deactivated by abundant nucleophiles in cellular environments during conjugation of the cofactor with the protein scaffold. The whole-cell biohybrid catalyst was then activated upon addition of Ag+ ion to dissociate the dithiophosphate ligands and promoted cycloaddition of acetophenone oxime with diphenylacetylene. Furthermore, the activity of the Cp*Rh(III)-linked whole-cell biohybrid catalyst was enhanced 2.1-fold by introducing glutamate residues at positions adjacent to the Cp*Rh(III) cofactor. These results indicate that the use of the Cp*Rh(III)-dithiophosphate complex with switchable activity from a “latent” form to an “active” form provides a new strategy for generating whole-cell biohybrid catalysts.
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•A dithiophosphate-coordinated rhodium complex was prepared for a biohybrid catalyst.•The rhodium complex was conjugated to nitrobindin scaffold displayed on cell surface.•Addition of Ag+ ion activates the catalyst for a C–H bond functionalization reaction.•The whole-cell biohybrid catalyst promotes cycloaddition of oxime with alkyne.•Site-directed mutagenesis enhances the activity of the whole-cell biohybrid catalyst.
Atomic hydrogen on the surface of a metal with high hydrogen solubility is of particular interest for the hydrogenation of carbon dioxide. In a mixture of hydrogen and carbon dioxide, methane was ...markedly formed on the metal hydride ZrCoHx in the course of the hydrogen desorption and not on the pristine intermetallic. The surface analysis was performed by means of time‐of‐flight secondary ion mass spectroscopy and near‐ambient pressure X‐ray photoelectron spectroscopy, for the in situ analysis. The aim was to elucidate the origin of the catalytic activity of the metal hydride. Since at the initial stage the dissociation of impinging hydrogen molecules is hindered by a high activation barrier of the oxidised surface, the atomic hydrogen flux from the metal hydride is crucial for the reduction of carbon dioxide and surface oxides at interfacial sites.
Tracking hydrogen: A mixture of hydrogen and carbon dioxide generates methane on the metal hydride ZrCoHx and not on the pristine intermetallic. The atomic hydrogen flux from the metal hydride is crucial for CO2 reduction.
Background: The emergence of molecular targeted therapies (MTTs) has altered the treatment landscape for hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2−) metastatic ...breast cancer (MBC). The objective of this study was to describe treatment patterns, clinical outcomes, and safety profiles for patients with HR+/HER2− MBC treated with palbociclib, abemaciclib, or everolimus in clinical practice. Methods: Forty-five patients with HR+/HER2− MBC were enrolled; 40 received MTT as the third line or later and 5 received MTT as the first/second line. The results were compared with those of clinical trials. Results: Median overall progression-free survival (PFS) was 5.3 months (95% confidence interval CI 2.8-8.4), and PFS was similar for patients receiving first/second line (5.5 months, 95% CI 1.8-) and third line or later (5.1 months, 95% CI 2.8-9.4) treatments. Eleven patients continued with the same regimen for >1 year; treatment is ongoing for 15 patients. In 23 patients (51%), everolimus was administered before cyclin-dependent kinase (CDK) 4/6 inhibitors. The most frequent grade 3 or worse adverse event (AE) with CDK4/6 inhibitors was neutropenia, whereas grade 3 or worse AEs with everolimus were Pneumocystis pneumonia, sepsis, and stomatitis. Conclusions: MTT was mostly used in third or later lines, and PFS was similar for patients receiving first/second line and third or later line treatments. However, this study included heavily treated patients and a small number of cases. Treatment options should consider maximal patient benefit, as indicated by the results of clinical trials.
The crosstalk between sodium-glucose cotransporter 2 (SGLT2) inhibition and a membrane-associated endocytic receptor megalin function involved in renal proximal tubular protein overload in ...progressive diabetic nephropathy (DN) is uncertain. Here, we determined whether SGLT2 inhibition affects megalin endocytic function through suppressing its O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) and protects the diabetic kidney from protein overload.
We treated 8-week-old male non-obese and hypoinsulinemic KK/Ta-Ins2Akita (KK/Ta-Akita) mice which develop progressive DN with an SGLT2 inhibitor ipragliflozin or insulin for 6 weeks, and investigated the endocytic function (proximal tubular protein reabsorption), renal expression and O-GlcNAcylation of megalin along with their effects on renal phenotypes including histology and biochemical markers.
The treatment with ipragliflozin, but not insulin, suppressed megalin O-GlcNAcylation and accelerated its internalization, resulting in reduction in proximal tubular reabsorption of the highly filtered plasma proteins such as albumin and neutrophil gelatinase-associated lipocalin. These alterations following the ipragliflozin treatment contributed to amelioration of proximal tubular protein overload, mitochondrial morphological abnormality, and renal oxidative stress and tubulointerstitial fibrosis.
The present study provides a novel crosstalk mechanism between SGLT2 inhibition and megalin underlying the potential renal benefits of SGLT2 inhibition in DN.
•SGLT2 inhibition suppresses renal proximal tubule megalin O-GlcNAcylation.•Diminished O-GlcNAcylation promotes proximal tubule megalin internalization.•Proximal tubule megalin internalization reduces its endocytic function.•Reduced megalin endocytic function ameliorates renal protein overload in diabetes.•Amelioration of protein overload attenuates proximal tubule mitochondrial injury.
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Prenatal nicotine exposure (PNE) causes behavioral abnormalities in offspring, such as an enhancement of impulsivity and decrease in attention at adolescence. Here we examined the ...effects of galantamine (GAL) on the behavioral and electrophysiological changes induced by PNE in mice. Pregnant C57BL/6J mice were exposed to nicotine (0.2 mg/mL) dissolved in sweetened (2% saccharin) drinking water during gestational day 14 and perinatal day 0 (P0). At the ages of postnatal days 42–49 (P42-P49), female offspring displayed impulsivity in the cliff avoidance test and impairment of visual attention in the object-based attention test. Decrease of long-term potentiation (LTP) and extracellular glutamate levels were observed in the prefrontal cortex of PNE mice. Systemic treatment with GAL (1 mg/kg, s.c.), an allosteric potentiating ligand for the nicotinic acetylcholine receptor (nAChR) and a weak cholinesterase inhibitor, attenuated the enhancement of impulsivity and impairment of attention induced by PNE in mice. Further, GAL reversed the impairment of LTP induced by PNE in the prefrontal cortex of mice, although it failed to attenuate the decrease of extracellular glutamate levels. The effects of GAL were blocked by an α 7 nAChR antagonist, methyllycaconitine (1 mg/kg, i.p.). These results suggest that PNE during cortex development affects nicotinic cholinergic-dependent plasticity and formation of impulsivity and attention. Furthermore, GAL could be a useful drug for cognitive impairments-related to attention deficit hyperactivity disorder.
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