A 50‐year‐old Japanese woman with advanced breast cancer presented with productive cough and dyspnea while she was receiving a sixth cycle of chemotherapy including atezolizumab. Chest computed ...tomography revealed bronchiolitis and transbronchial lung cryobiopsy revealed eosinophilic bronchiolitis. Corticosteroid therapy successfully resolved her symptoms. Eosinophilic bronchiolitis is a rare but important immune‐related adverse event; herein, we discuss its diagnosis and possible pathophysiology.
A 50‐year‐old Japanese woman with advanced breast cancer presented with productive cough and dyspnea while she was receiving chemotherapy containing atezolizumab. From chest computed tomography and transbronchial lung cryobiopsy, she was diagnosed with eosinophilic bronchiolitis, and corticosteroid therapy successfully resolved her symptoms. Eosinophilic bronchiolitis is a rare but important immune‐related adverse event; herein, we discuss its diagnosis and possible pathophysiology.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Crohn's disease is an inflammatory disease of the gut caused by a complex interplay among genetic, microbial, and environmental factors. The intestinal tract is constantly exposed to metals and other ...trace elements ingested as food. Synchrotron radiation-induced X-ray fluorescence spectroscopy and X-ray absorption fine structure analysis revealed the deposition of nickel particles within Crohn's disease tissue specimens. After nickel particle stimulation, THP-1 cells showed filopodia formation and autophagic vacuoles containing lipid bodies. Nickel particles precipitated colitis in mice bearing mutations of the IBD susceptibility protein A20/TNFAIP3. Nickel particles also exacerbated dextran sulfate sodium-induced colitis in mice harboring myeloid cell-specific Atg5 deficiency. These findings illustrate that nickel particle ingestion may worsen Crohn's disease by perturbing autophagic processes in the intestine, providing new insights into environmental factors in Crohn's disease pathogenesis.
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•Nickel particles are present in Crohn's disease tissue.•Nickel particles trigger autophagy in macrophages.•Nickel particles exacerbate DSS colitis in macrophage-specific Atg5-deficient mice.•Nickel particles exacerbate intestinal inflammation in A20/TNFAIP3-mutated mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Expression of mucin MUC2, a component of the colonic mucus layer, plays a crucial role in intestinal homeostasis. Here, we describe a new regulator of MUC2 expression, the deubiquitinase ZRANB1 ...(Trabid). A ZRANB1 mutation changing cysteine to serine in amino acid position 443, affects ubiquitination. To analyze ZRANB1 function in the intestine, we generated Zranb1 C443S mutant knock-in (Zranb1C443S/C443S) mice using the CRISPR/Cas9 system. Zranb1C443S/C443S mice exhibited decreased mRNA expression and MUC2 production. Colonic organoids from Zranb1C443S/C443S mice displayed decreased Muc2 mRNA expression following differentiation into goblet cells. Finally, we analyzed dextran sulfate sodium-induced colitis to understand ZRANB1's role in intestinal inflammation. Zranb1C443S/C443S mice with colitis exhibited significant weight loss, reduced colon length, and worsening clinical and pathological scores, indicating that ZRANB1 contributes to intestinal homeostasis. Together, these results suggest that ZRANB1 regulates MUC2 expression and intestinal inflammation, which may help elucidating the pathogenesis of inflammatory bowel disease and developing new therapeutics targeting ZRANB1.
•ZRANB1 regulates MUC2 expression and intestinal inflammation.•In the intestine, a single point mutation to ZRANB1 altered MUC2 expression.•ZRANB1 contributes to intestinal homeostasis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Astrocytes regulate synaptic transmission in the central nervous system. Astrocytes in vivo have "stems" that express glial fibrillary acidic protein (GFAP), intermediate filaments, and peripheral ...astrocyte processes (PAPs), which contain actin-rich cytoskeletal structures. At the PAPs, the perisynaptic glia contacts and enwraps synapses, and modulates glia-neuronal communication. Cultured astrocytes have been an invaluable tool for studying roles of astrocytes; however, the morphology of mammalian primary astrocytes cultured in conventional medium containing fetal bovine serum (FBS) was similar to that of fibroblasts, and many culture conditions have been developed to generate stellate astrocytes observed in vivo. Avian astrocytes have been prepared from embryonic chick forebrain and maintained at a high cell density in conventional FBS-containing medium as mammalian astrocytes, thus the morphological analysis of chicken astrocytes has not yet been performed. In the present study, we report that the morphology of astrocytes freshly harvested from the forebrain of a chicken embryo in serum-free Neurobasal medium with B-27 supplement and basic fibroblast growth factor (bFGF) is similar to that of the astrocyte morphology in vivo. We also find that astrocytes in this medium express similar levels of GFAP and two actin-binding proteins as astrocytes in conventional FBS-containing medium, although they have different morphologies. Furthermore, we confirmed that cryopreserved astrocytes differentiate faster than freshly harvested astrocytes.
Salmonella enterica serovar Gallinarum biovar Gallinarum (S. Gallinarum) is a host-specific pathogen causing systemic infection in poultry, which leads to significant economic losses due to high ...mortality. However, little is known about the dynamic process of systemic infection and pathogenic characteristics of S. Gallinarum in chickens. In the present study, we developed an oral infection model that reproduces the pathology of S. Gallinarum and clarified the host immune response of the infected chickens. Chickens at 20 days of age orally inoculated at a dose of 108 colony forming unit (CFU) showed typical clinical signs of fowl typhoid and died between 6 and 10 days post infection. The inoculated S. Gallinarum rapidly disseminated to multple organs and the bacterial counts increased in the liver and spleen at 3 days post infection. Pathological changes associated wirh inflammation in the liver and spleen became apparent at 4 days post infection, and increased expression of interferon (IFN)-γ and interleuikin (IL)-12 in the liver and spleen did not observed until 3 days post infection. These results indicate that S. Gallinarum rapidly spread to entire body through intestine, and the low-level of inflammatory responses in the liver during the early stage of infection may contribute to rapid, systemic dissemination of the bacteria. Our infection model and findings will contribute to the better understanding of the pathogenic mechanism of S. Gallinarum, and provide new insights into the prevention and control of fowl typhoid.
Mutations in neurofilament genes have been linked to several neuromuscular disorders. The neurofilament heavy (NEFH) gene was identified as the causative gene of Charcot-Marie-Tooth disease type 2CC ...(CMT2CC) in 2016, with a toxic gain of function mechanism caused by the translation and aggregation of cryptic amyloidogenic element (CAE) in the 3' untranslated region (UTR). But the NEFH-related clinical and genetic spectrums are still unclear in Japan.
We analyzed all variants in the NEFH gene from our in-house whole-exome sequencing data, established from Japanese nationwide patients with neuromuscular disorders, including Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy (SMA).
We identified a c.3017dup (p.Pro1007Alafs*56) variant in NEFH from three families clinically diagnosed with CMT, and one family with SMA. In addition to the patients presented with typical peripheral neuropathies, pyramidal signs were observed from one CMT patient. Whereas the SMA patients showed severe characteristic weakness of triceps brachii and quadriceps femoris. All of these four families reside in Kagoshima Prefecture of Japan, and a following haplotype analysis strongly suggests a founder effect.
This is the original report referring to a founder mutation in NEFH. The clinical diversity in our study, comprising CMT, with or without pyramidal signs, and SMA, suggest an extensive involvement of peripheral nerve, anterior horn cells, or both. Our findings broaden the phenotypic spectrum of NEFH-related disorders.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective The coronavirus disease 2019 (COVID-19) pandemic has changed the inpatient treatment practice for bacterial pneumonia. Upon hospitalization, isolation is required while waiting for the ...polymerase chain reaction (PCR) test result, which may lead to limited access to medical resources and fewer room visits by medical staff. However, little is known about the relationship between isolation and the clinical outcomes of bacterial pneumonia. We hypothesized that isolation of suspected COVID-19 patients who are eventually diagnosed with bacterial pneumonia is associated with a prolonged length of hospitalization as compared with non-isolation. Patients This is a single-center, retrospective observational study of hospitalized adult patients diagnosed with bacterial pneumonia from January 2018 to September 2021. The patients were divided into a non-isolated (patients hospitalized between January 2018 and December 2019, who were not isolated at all) and an isolated group (patients hospitalized between January 2020 and September 2021, who were initially isolated because COVID-19 was suspected). The primary outcome was a prolonged length of hospitalization (≥14 days), and its relationship with isolation was analyzed using logistic regression analysis adjusted for age, sex, CURB-65, and the Charlson Comorbidity Index. Results Among 917 eligible patients, 214 (23%) underwent isolation. In the logistic regression analysis, the isolated group independently had a prolonged length of hospitalization as compared with the non-isolated group (odds ratio 1.49; 95% confidence interval 1.08-2.07, p=0.015). There was no significant difference in antibiotic use duration between the groups. Conclusion The isolation of bacterial pneumonia patients suspected of COVID-19 was associated with prolonged length of hospitalization.
Although dabrafenib plus trametinib has been approved for BRAF V600E mutation positive advanced non‐small cell lung cancer (NSCLC), data on its efficacy against uncommon BRAF mutations are still ...limited due to their rare frequency. We report a case of 70‐year‐old woman with BRAF V600_W604 deletion–insertion R‐positive stage IVA lung adenocarcinoma, who was successfully treated with dabrafenib plus trametinib. Herein, we discuss the oncogenic role of uncommon BRAF mutations and highlight the importance of performing comprehensive genomic profiling on patients without any targetable gene alterations in companion diagnostics.
A 70‐year‐old woman with stage IVA lung adenocarcinoma underwent comprehensive genomic profiling (CGP) after failure of second‐line therapy, which revealed BRAF V600_W604 deletion–insertion. She was successfully treated with dabrafenib 300 mg/day plus trametinib 2 mg/day. CGP should be considered when initial companion diagnostics do not detect druggable oncogene alterations.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
We encountered a patient with severe coronavirus disease 2019 (COVID‐19)‐related pneumonia, who died of progressive respiratory acidosis after 2 months of treatment with mechanical ventilation. The ...autopsy revealed diffuse alveolar damage (DAD) without any active signs of fungal or bacterial infections, suggesting prolonged and over‐activated immune responses against COVID‐19 infection. When COVID‐19 patients develop acute respiratory distress syndrome, it is essential to remember that the infection can progress to DAD a few months after the disease onset.
We experienced a fatal case of coronavirus disease‐2019 (COVID‐19) pneumonia, who died of progressive respiratory acidosis after 2 months of treatment with mechanical ventilation. The autopsy revealed diffuse alveolar damage (DAD) without any active signs of fungal or bacterial infections, suggesting prolonged and over‐activated immune responses against COVID‐19 infection. When COVID‐19 patients develop acute respiratory distress syndrome, it is essential to remember that the infection can progress to DAD a few months after the disease onset.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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