Cryoprobe is a novel transbronchial biopsy (TBB) tool that yields larger tissue samples than forceps. Pathological diagnosis and biomarker analysis, such as genetic alterations and programmed death‐ligand 1 (PD‐L1) expression, are paramount for precision medicine against lung cancer. We evaluated the safety and usefulness of cryoprobe TBB for lung cancer diagnosis and biomarker analysis. In this single‐center, prospective single‐arm study, patients suspected of having or diagnosed with primary lung cancer underwent cryoprobe TBB using flexible bronchoscopy after conventional forceps TBB from the same lesion. Cryoprobe TBB was performed in 121 patients. The incidence rate of severe bleeding and serious adverse events (4% [90% confidence interval: 2%‐9%]) was significantly lower than the expected rate (20% with 30% threshold, P < 0.01). Combining both central and peripheral lesions, the diagnostic yield rate of cryoprobe samples was 76% and that of forceps samples was 84%. Compared with forceps TBB samples, cryoprobe TBB samples were larger (cryoprobe 15 mm2 vs forceps 2 mm2) and resulted in a larger proportion of definite histomorphological diagnosis (cryoprobe 86% vs forceps 74%, P < 0.01), larger amounts of DNA extracted from samples (median: cryoprobe, 1.60 µg vs forceps, 0.58 µg, P = 0.02) and RNA (median: cryoprobe, 0.62 µg vs forceps, 0.17 µg, P < 0.01) extracted from samples, and tended to yield greater rates of PD‐L1 expression >1% (51% vs 42%). In conclusion, cryoprobe is a safe and useful tool for obtaining lung cancer tissue samples of adequate size and quality, which allow morphological diagnosis and biomarker analysis for precision medicine against lung cancer. 相似文献
State‐dependent modulation of sensory systems has been studied in many organisms and is possibly mediated through neuromodulators such as monoamine neurotransmitters. Among these, dopamine is involved in many aspects of animal behaviour, including movement control, attention, motivation and cognition. However, the precise neural mechanism underlying dopaminergic modulation of behaviour induced by sensory stimuli remains poorly understood. Here, we used Drosophila melanogaster to show that dopamine can modulate the optomotor response to moving visual stimuli including noise. The optomotor response is the head‐turning response to moving objects, which is observed in most sight‐reliant animals including mammals and insects. First, the effects of the dopamine system on the optomotor response were investigated in mutant flies deficient in dopamine receptors D1R1 or D1R2, which are involved in the modulation of sleep‐arousal in flies. We examined the optomotor response in D1R1 knockout (D1R1 KO) and D1R2 knockout (D1R2 KO) flies and found that it was not affected in D1R1 KO flies; however, it was significantly reduced in D1R2 KO flies compared with the wild type. Using cell‐type‐specific expression of an RNA interference construct of D1R2, we identified the fan‐shaped body, a part of the central complex, responsible for dopamine‐mediated modulation of the optomotor response. In particular, pontine cells in the fan‐shaped body seemed important in the modulation of the optomotor response, and their neural activity was required for the optomotor response. These results suggest a novel role of the central complex in the modulation of a behaviour based on the processing of sensory stimulations. 相似文献
Coffin-Siris syndrome (CSS) is a congenital anomaly syndrome characterized by developmental delay, coarse facial features, and hypoplasia of the fifth digit's nail or phalanges. Herein, we report a case of the 8-year-old female patient who showed developmental delay associated with dysplasia in the macular and large toe area. Comprehensive genomic analysis showed no possible candidate variants, but the subsequent genomic copy number analysis revealed a novel exonic deletion in the coding region of AT-rich interactive domain-containing protein 1B (ARID1B), a gene responsible for CSS. Genomic copy number analysis can aid in diagnosing CSS by confirming undiagnosed exonic deletions in ARID1B. Furthermore, this is the first report of CSS associated with bilateral macular dysplasia. 相似文献
Pyoderma gangrenosum (PG) is an extra-intestinal skin lesion in inflammatory bowel disease (IBD) as is erythema nodosum. Vedolizumab (VED) is a monoclonal antibody that targets α4β7 integrin and has an intestinal selective mechanism. Despite good therapeutic effects on colitis, the effect on extra-intestinal manifestations (EIMs) remains unclear. Here we report a case of ulcerative colitis complicated by PG during treatment with VED, which was successfully treated with prednisolone in combination with adsorptive granulocyte and monocyte apheresis (GMA). The patient was a 50-year-old woman with a past medical history of extensive ulcerative colitis managed by golimumab (GLM). She developed flare symptoms due to loss of response to GLM, and treatment was switched to VED. Her gastrointestinal symptoms were improved with VED treatment with less frequent bowel movements. However, infiltrative erythema with pain appeared on the right lower leg and right knee, and expanded and gradually ulcerated. Her skin lesions were treated with corticosteroid, but showed poor improvement. Therefore, granulocyte and monocyte apheresis (GMA) treatment was administered in combination with prednisolone. After 3 months, the ulcer gradually improved, and at the time of this writing, the eruptions were nearly replaced by epithelial tissue. This case study showed that patients with UC and EIMS may respond well to combination therapy of VED and GMA. GMA has a very favorable safety profile. On the other hand, the causal connection between VED and PG is still unclear. We believe that a combination therapy involving VED and GMA in IBD patients with EIMs warrants consideration. 相似文献
Solar urticaria has unique spectra, such as inhibition and augmentation. The clinical significance of these spectra, especially augmentation, is not well understood. Reported cases of solar urticaria with augmentation spectra are extremely rare in the published English-language work. The purposes of this study were to evaluate the clinical features of solar urticaria with augmentation spectra and to elucidate the mechanisms and clinical importance of the spectra. We experienced 11 cases (five females, six males; mean age, 40.1 years; range, 1–74) of solar urticaria with augmentation spectra from April 2007 to July 2019. Augmentation spectra were UV-B in three cases, UV-A in two, visible light in four, UV-A and UV-B in one, and UV-A and visible light in one. Augmentation spectra were observed before action spectra in four cases, after in six, and before and after in one. Injection of sera irradiated with action spectra and augmentation spectra in vitro induced stronger immediate reactions than those of only action spectrum-irradiated sera in four of five cases. The results of injection tests suggested that augmentation spectra enhance the production of urticaria-forming factor. Clinically, we observed severe urticarial reactions in four cases, including anaphylaxis in three and moderate urticarial reactions in three. These results suggest that augmentation spectra are not as rare as previously thought and that they are associated with the severity of solar urticaria. Therefore, phototesting for both augmentation and action spectra should be performed to provide appropriate guidance for patients with solar urticaria. 相似文献
In this study, total body clearance (CLt), volume of distribution at steady state (Vss) and plasma concentration–time profiles in humans of model compounds were predicted using chimeric mice with humanized livers.
On the basis of assumption that unbound intrinsic clearance (CLUint) per liver weight in chimeric mice was equal to those in humans, CLt were predicted by substituting human liver blood flow and liver weights in well-stirred model. Vss were predicted by Rodgers equation using scaling factors of tissue-plasma concentration ratios (SFKp) in chimeric mice estimated from a difference between the observed and predicted Vss. These physiological approaches showed high prediction accuracy for CLt and Vss values in humans.
We compared the predictability of CLt and Vss determined by the physiologically based predictive approach using chimeric mice with those from predictive methods reported by Pharmaceutical Research Manufacturers of America. The physiological approach using chimeric mice indicated the best prediction accuracy in each predictive method.
Simulation of human plasma concentration–time profiles were generally successful with physiologically based pharmacokinetic (PBPK) model incorporating CLUint and SFKp obtained from chimeric mice.
Combined application of chimeric mice and PBPK modeling is effective for prediction of human PK in various compounds.