Immune checkpoint inhibitor-induced inflammatory arthritis: identification and management

ABSTRACT

Introduction

Immune checkpoint inhibitors (ICIs) have proved to be groundbreaking in the field of oncology. However, immune system overactivation from ICIs has introduced a novel medical entity known as immune-related adverse events (irAEs), that can affect any organ or tissue. ICI-induced inflammatory arthritis (ICI-IIA) is the most common musculoskeletal irAE and can lead to significant morbidity and limitation in anti-cancer therapy.     

盆底肌锻炼联合度洛西汀治疗女性压力性尿失禁对照观察

目的：探讨盆底肌锻炼联合度洛西汀治疗女性压力性尿失禁的临床疗效和安全性。方法将80例女性压力性尿失禁患者随机分为两组,每组40例,均予以盆底肌锻炼治疗,研究组在此基础上联合度洛西汀治疗,观察8周。采用尿垫试验和尿失禁自我等级评价评定临床疗效。结果治疗8周末,研究组治愈率为86．8％、总有效率为100％,对照组分别为54．1％、70．3％,研究组显著高于对照组（ P＜0．01）;两组尿失禁量及尿失禁自我等级评价评分均较治疗前显著下降（P＜0．01）,研究组较对照组下降更显著（P＜0．01）。研究组偶见轻度头晕、头痛、口干等,且患者可耐受。结论盆底肌锻炼联合度洛西汀治疗女性压力性尿失禁疗效显著,优于单用盆底肌锻炼治疗,值得临床推广应用。     

Effects of ICI204,448, naloxone methiodide and levocetirizine on the scratching behavior induced by a κ-opioid antagonist,nor-BNI,in ICR mice

Objective: In this study, we aimed to study the effects of ICI204,448, naloxone methiodide and levocetirizine on the scratching behavior induced by intradermal injection of a ?-opioid antagonist, nor-binaltorphimine (nor-BNI), into the rostral back of ICR mice were investigated.

Materials and methods: Male ICR mice weighing 30?35 g were used. The number of scratching episodes were counted for 60 min after i.d. injection of nor-BNI.

Results: nor-BNI dose dependently increased in the number of scratching episodes in ICR mice. nor-BNI-induced scratching behavior was inhibited by not only nalfurafine but also ICI204,448, a peripherally selective ?-opioid agonist. Naloxone and naloxone methiodide, a peripherally restricted ?-opioid antagonist, also inhibited nor-BNI-induced scratching behavior. Scratching behavior induced by nor-BNI was inhibited by chlorpheniramine as well as levocetirizine, a third-generation H₁ antagonist that does not cross into the CNS.

Conclusion: These results suggest that scratching behavior induced by this ?-opioid antagonist, nor-BNI, is related to not only central but also peripheral opioid and H₁ receptors.     

Inhibitory effects of glycopyrronium,formoterol, and budesonide on coronavirus HCoV-229E replication and cytokine production by primary cultures of human nasal and tracheal epithelial cells

BackgroundCoronavirus 229E (HCoV-229E), one of the causes of the common cold, exacerbates chronic obstructive pulmonary disease (COPD) and bronchial asthma. Long-acting muscarinic antagonists and β₂-agonists and inhaled corticosteroids inhibit the exacerbation of COPD and bronchial asthma caused by infection with viruses, including HCoV-229E. However, the effects of these drugs on HCoV-229E replication and infection-induced inflammation in the human airway are unknown.MethodsPrimary human nasal (HNE) and tracheal (HTE) epithelial cell cultures were infected with HCoV-229E.ResultsPretreatment of HNE and HTE cells with glycopyrronium or formoterol decreased viral RNA levels and/or titers, the expression of the HCoV-229E receptor CD13, the number and fluorescence intensity of acidic endosomes where HCoV-229E RNA enters the cytoplasm, and the infection-induced production of cytokines, including IL-6, IL-8, and IFN-β. Treatment of the cells with the CD13 inhibitor 2′2′-dipyridyl decreased viral titers. Pretreatment of the cells with a combination of three drugs (glycopyrronium, formoterol, and budesonide) exerted additive inhibitory effects on viral titers and cytokine production. Pretreatment of HNE cells with glycopyrronium or formoterol reduced the susceptibility to infection, and pretreatment with the three drugs inhibited activation of nuclear factor-kappa B p50 and p65 proteins. Pretreatment with formoterol increased cAMP levels and treatment with cAMP decreased viral titers, CD13 expression, and the fluorescence intensity of acidic endosomes.ConclusionsThese findings suggest that glycopyrronium, formoterol, and a combination of glycopyrronium, formoterol, and budesonide inhibit HCoV-229E replication partly by inhibiting receptor expression and/or endosomal function and that these drugs modulate infection-induced inflammation in the airway.     

Combination of immunotherapy and radiotherapy in the treatment of brain metastases from non-small cell lung cancer

It was commonly assumed in the past that blood-brain barrier could efficiently prohibit penetration of large peptide molecules, such as monoclonal antibodies, including programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors. This belief has been recently revised by studies that demonstrate the presence of functional lymphatic vessels lining the dural sinuses. Furthermore, the activated circulating T cells have been shown to cross the blood-brain barrier. Such observations created strong rationale for attempts of immunotherapy for patients with brain metastases, used either alone or in combination with radiotherapy. The expected benefit from immunotherapy particularly refers to patients without targetable “driver” mutations who are not considered as candidates for novel targeted therapies. Current inference on efficacy and safety of combination of immunotherapy and radiotherapy in the treatment of brain metastases from non-small cell lung cancer (NSCLC) origins, in most, from the retrospective studies. The existing data suggest that use of immune checkpoint inhibitors (ICIs) with brain radiotherapy improves patients outcome, compared to brain radiotherapy alone. The available data also suggest that concurrent use of ICI and stereotactic radiation therapy (SRT) for brain metastases from NSCLC is tolerable and appears more effective than sequential combination of radiotherapy and ICI. Use of steroids appeared detrimental. Since a dependence between the risk of adverse events and type of ICI therapy as well as tumor pathology was found, further studies are required to establish optimal dosage, selection of drugs and sequence of ICI and brain radiotherapy in patients with brain metastases from NSCLC.     

Myositis as an adverse event of immune checkpoint blockade for cancer therapy

Objectives

Immune checkpoint inhibitors (ICIs) can successfully treat cancer, but their use can be hindered by serious immune-related adverse events. We report six patients receiving ICIs who presented with de novo myositis.

Bisphenol a regulates the estrogen receptor alpha signaling in developing hippocampus of male rats through estrogen receptor

Bisphenol A (BPA), one of the most common environmental endocrine disruptors, has been recognized to have wide adverse effects on the brain development and behavior. These adversities are related to its ability to bind estrogen receptor (ER) with subsequent alteration of its expression in the target areas. However, very little is known about whether BPA exposure also affects ER phosphorylation and its translocation to nucleus during postnatal development, two critical steps for its function. Here, we found that during development from postnatal day 7 (P7) to P21, the alpha subtype of ER (ERα) in the hippocampus of male rats experienced remarkable alterations in terms of its expression, phosphorylation and translocation to nucleus. Exposure to low level of BPA had bidirectional, development‐dependent effects on the expression of ERα mRNA and protein, but decreased ERα phosphorylation and impaired its translocation to nucleus throughout the period investigated. Treatment with low dose of ICI 182,780 (ICI), an ER antagonist to block the binding of ER with BPA, reversed the altered ERα following BPA exposure, highlighting critical involvement of ER. Moreover, ICI treatment rescued the hippocampus‐dependent behavioral deficits in the adult rats experiencing early‐life BPA exposure. Overall, our results indicate that BPA interferes with the ERα signaling in the developing hippocampus in an ER‐dependent manner, which may underlie its adverse behavioral and cognitive outcomes in adult animals. © 2014 Wiley Periodicals, Inc.     

One-hertz subthreshold rTMS increases the threshold for evoking inhibition in the human motor cortex

Despite indisputable evidence that repetitive transcranial magnetic stimulation (rTMS) modulates motor cortical excitability, the effects of subthreshold low-frequency rTMS on intracortical inhibition (ICI) are controversial. In this paper we investigated whether increasing the level of baseline ICI increases the sensitivity of ICI for disclosing the after-effects of rTMS on cortical excitability. In experiment 1, we studied changes in ICI, tested at two different baseline levels, after a train of 900 subthreshold rTMS pulses delivered at 1 Hz. In experiment 2, we studied whether the same conditioning rTMS train changed the ICI threshold, and in experiment 3 whether it changed the facilitatory I-wave interaction. Conditioning rTMS reduced ICI tested at a baseline level of 75% but left ICI tested at a baseline level of 50% unchanged. It also increased the ICI threshold but left the facilitatory I-wave interaction unchanged. These findings suggest that conditioning rTMS selectively reduced ICI tested at a baseline level of 75% by increasing the threshold for evoking inhibition in the motor cortex. The inhibitory system mediating ICI may therefore be more efficient than other motor cortical systems in reducing high cortical excitability after external intervention. Hence studies investigating the after-effects of rTMS should standardize ICI levels at baseline.