Involvement of 5-HT2A receptor hyperfunction in the anxiety-like behavior induced by doxorubicin and cyclophosphamide combination treatment in rats

We examined whether combination treatment with doxorubicin and cyclophosphamide, a traditional chemotherapy for breast cancer, induced anxiety-like behavior in rats. Furthermore, we evaluated the role of the serotonin (5-HT)2A receptor subtype in the anxiety-like behavior induced by such chemotherapy. Rats were intraperitoneally injected with doxorubicin and cyclophosphamide once a week for 2 weeks. This caused the rats to display anxiety-like behavior during the light–dark test. In addition, we examined the rats' 5-HT2A receptor-mediated behavioral responses. Combination treatment with doxorubicin and cyclophosphamide significantly increased (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, (a 5-HT2A receptor agonist)-induced wet-dog shake activity. This anxiety-like behavior was significantly inhibited by mirtazapine, a 5-HT2A receptor antagonist/5-HT1A receptor agonist, and tandospirone, a partial 5-HT1A receptor agonist, but not by fluoxetine, a selective serotonin reuptake inhibitor. The anxiety-like behavior induced by doxorubicin and cyclophosphamide combination treatment is mediated by hyperfunctioning of the 5-HT2A receptor. Thus, 5-HT2A receptor antagonists or 5-HT1A receptor agonists might be useful for treating chemotherapy-induced anxiety disorders. Keywords: Doxorubicin, Cyclophosphamide, 5-HT2A receptor, Anxiet

Effect of Mirogabalin on Chemotherapy-Induced Peripheral Neuropathy Caused by Gemcitabine plus Nab-Paclitaxel Therapy in Pancreatic Cancer Patients: A Pilot Study

Background: Gemcitabine/nab-paclitaxel therapy (GnP) is widely used to treat pancreatic cancer (PC), but chemotherapy-induced peripheral neuropathy (CIPN) is common. The CIPN is also reported to be related by microvascular damage as the basis for toxic neuropathy. However, no sufficient treatment options are available for CIPN. Mirogabalin is a novel drug for treating peripheral neuropathy. We investigated the effects of mirogabalin on CIPN due to GnP. Methods: Patients who had received GnP for PC and had taken mirogabalin for CIPN, were included. Patients completed a questionnaire about their symptoms before and after taking mirogabalin. The outcome was the change in numbness and tingling scores on the patient-reported outcomes version of the Common Terminology Criteria for Adverse Events, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Chemotherapy-Induced Peripheral Neuropathy (EORTC-QLQ-CIPN20), numerical rating scale, and adverse events (AEs). Results: Increased numbness and tingling severity (1.84 vs. 1.76; p = 0.63) and interference (1.42 vs. 1.44; p = 0.80) were not seen in any of the 25 enrolled patients. The scores on the sensory subscale of the EORTC-QLQ-CIPN improved significantly after treatment (17.5 vs. 15.7; p = 0.02). Adverse events occurred in 22 patients (88%), but there were no serious AEs (≥grade 3). Conclusions: Mirogabalin may control the progression of CIPN caused by GnP and significantly improved sensory neuropathy. However, as the incidence of AEs is high, mirogabalin should be used with caution. (UMIN:R000044039)

Role of Peroral Cholangioscopy in the Diagnosis of Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is characterized by idiopathic biliary stricture followed by progressive cholestasis and fibrosis. When diagnosing PSC, its differentiation from other types of sclerosing cholangitis and cholangiocarcinoma is necessary. The cholangioscopic findings of PSC have not been investigated sufficiently. PSC and IgG4-related sclerosing cholangitis are difficult to distinguish by peroral cholangioscopy (POCS), but POCS is useful for excluding cholangiocarcinoma. POCS findings vary according to the condition and stage of disease. In the active phase, findings such as mucosal erythema, ulceration, fibrinous white exudate, and an irregular surface are observed and may reflect strong inflammation in the biliary epithelium. On the other hand, findings such as scarring, pseudodiverticula, and bile duct stenosis appear in the chronic phase and may reflect fibrosis and stenosis resulting from repeated inflammation. Observation of inside the bile duct by POCS might confirm the current PSC activity. Because POCS offers not only information regarding the diagnosis of PSC and PSC-associated cholangiocarcinoma but also the current statuses of biliary inflammation and stenosis, POCS could significantly contribute to the diagnosis and treatment of PSC once the characteristic findings of PSC are confirmed by future studies

Endoscopic Ultrasonography Findings of Early and Suspected Early Chronic Pancreatitis

Chronic pancreatitis (CP) is associated with a risk of pancreatic cancer and is characterized by irreversible morphological changes, fibrosis, calcification, and exocrine and endocrine insufficiency. CP is a progressive disease with a poor prognosis and is typically diagnosed at an advanced stage. The Japan Pancreas Society proposed criteria for early CP in 2009, and their usefulness has been reported. Recently, a mechanism definition was proposed by the International Consensus Guidelines and early CP was defined as a disease state that is not based on disease duration. CP is diagnosed by computed tomography, magnetic resonance imaging, and endoscopic cholangiopancreatography, which can detect calcification and dilation of the pancreatic ducts; however, detecting early CP with these modalities is difficult because subtle changes in early CP occur before established CP or end-stage CP. Endoscopic ultrasonography (EUS) is useful in the diagnosis of early CP because it allows high-resolution, close-up observation of the pancreas. In addition to imaging findings, EUS with elastography enables measurement of the stiffness of the pancreas, an objective diagnostic measure. Understanding the EUS findings of early CP is important because a histological diagnosis is problematic, and other modalities are not capable of detecting subtle changes in early CP

Facilitative interaction networks in experimental microbial community dynamics

Facilitative interactions between microbial species are ubiquitous in various types of ecosystems on the Earth. Therefore, inferring how entangled webs of interspecific interactions shift through time in microbial ecosystems is an essential step for understanding ecological processes driving microbiome dynamics. By compiling shotgun metagenomic sequencing data of an experimental microbial community, we examined how the architectural features of facilitative interaction networks could change through time. A metabolic modeling approach for estimating dependence between microbial genomes (species) allowed us to infer the network structure of potential facilitative interactions at 13 time points through the 110-day monitoring of experimental microbiomes. We then found that positive feedback loops, which were theoretically predicted to promote cascade breakdown of ecological communities, existed within the inferred networks of metabolic interactions prior to the drastic community-compositional shift observed in the microbiome time-series. We further applied “directed-graph” analyses to pinpoint potential keystone species located at the “upper stream” positions of such feedback loops. These analyses on facilitative interactions will help us understand key mechanisms causing catastrophic shifts in microbial community structure

Mutation Type and Intracranial Aneurysm Formation in Autosomal Dominant Polycystic Kidney Disease

Background Screening for intracranial aneurysms (IAs) in patients with risk factors of IA is recommended. However, genetic risk factors of IA in patients with autosomal dominant polycystic kidney disease (ADPKD) remain unclear, and genotype–phenotype relationships in IAs in patients with ADPKD have not been clarified. Therefore, we aimed to clarify the associations between germline mutations and IA formation in patients with ADPKD. Methods A total of 135 patients with ADPKD who were evaluated for ADPKD mutations were examined for IA formation in this single‐center observational study. Results The incidence of de novo IA formation was 1.3% per patient‐year. Age at IA diagnosis was younger in patients with frameshift (median, 36 years; P=0.003) and splicing mutations (median, 43 years; P=0.046) than in patients with substitutions (median, 63 years). Multivariable analyses showed that IA was associated with female sex (odds ratio [OR], 3.32 [95% CI, 1.10–10.01]; P=0.03), a family history of IA or subarachnoid hemorrhage (OR, 3.05 [95% CI, 1.07–8.71]; P=0.04), estimated glomerular filtration rate (OR, 0.69 [95% CI, 0.54–0.87]; P=0.002), and splicing mutations (OR, 9.30 [95% CI, 1.71–50.44]; P=0.01). Splicing mutations showed a significant association with IA formation even in subcohorts with minimal risk factors for IA, such as age <50 years (OR, 19.52 [95% CI, 3.22–118.51]; P=0.001), nonhypertension (OR, 49.28 [95% CI, 3.60–673.98]; P=0.004), and nonsmoking behavior (OR, 27.79 [95% CI, 3.49–221.21]; P=0.002). Conversely, substitutions showed significant associations with IA formation in subcohorts such as age ≥50 years (OR, 8.66; 95% CI, 1.43–52.51; P=0.02) and chronic kidney disease stages 4 and 5 (OR, 10.70 [95% CI, 1.05–108.75]; P=0.045). Conclusions Genetic analyses in patients with ADPKD could contribute to IA screening and could be useful for evaluating the prognosis, including complications. IA screening should be recommended for patients with ADPKD who have splicing and frameshift mutations and for older patients or patients with advanced ADPKD who have substitutions