A case of TAFRO syndrome maintained in remission for 5 years after discontinuation of tocilizumab.

TAFRO syndrome is a subtype of idiopathic multicentric Castleman's disease (iMCD) that is characterised by thrombocytopenia, generalised oedema, fever, bone marrow fibrosis, renal failure, and organ enlargement and has a poor prognosis. The prognosis of TAFRO syndrome is worse than that of iMCD-not otherwise specified, with a high mortality rate. There are only a few long-term follow-up reports after remission of TAFRO syndrome with tocilizumab (TCZ) treatment in a patient in whom all drugs were discontinued after attaining sustained remission. Here, we report a case in which interleukin-6 negativity was confirmed and remission was maintained without relapse for 5 years after all drug treatments, including TCZ, were discontinued.

Design and biological evaluation of imidazo[1,2-a]pyridines as novel and potent ASK1 inhibitors.

Imidazo[1,2-a]pyridine derivatives were designed, synthesized, and evaluated as inhibitors of the apoptosis signal-regulating kinase 1 (ASK1). These were based on a benzothiazole derivative that was discovered from high-throughput screening of our compound library. As a result, we identified potent, selective, and orally bioavailable ASK1 inhibitors for wide range of therapeutic targets.

Exacerbation of Ulcerative Colitis with Tocilizumab: A Report of Two Cases, One with Takayasu Arteritis and the Other with Relapsing Polychondritis.

Tocilizumab (TCZ), a biologic that blocks the signal transduction of interleukin-6, has been used for the treatment of various autoimmune diseases. Many of these cases are sometimes complicated by ulcerative colitis (UC). However, the effect of TCZ on UC is unclear. We experienced two cases with concomitant UC that were treated with TCZ, one for Takayasu arteritis (TAK) and the other for relapsing polychondritis (RP). TCZ did not improve UC in either of these cases. TCZ might have adverse effects on the intestinal tract, since interleukin-6 signaling plays an important role in intestinal epithelium maintenance. Treatment with TCZ should therefore be carefully provided in patients complicated with UC.

Recent Outpatient Services in General Internal Medicine: 6.4% of Symptomatic Patients Were Post-Acute COVID-19.

PURPOSE: It is important to understand how COVID-19 is affecting general outpatient services, since hospitals see a wide variety of patients. This study aimed to evaluate the incidence and clinical picture of COVID-19 in general outpatient services. Currently, the diagnosis of COVID-19 depends strongly on the results of polymerase chain reaction (PCR) assays. However, since the sensitivity of PCR tests for SARS-CoV-2 is not high enough to assure confidence. On the other hand, the SARS-CoV-2 antibody (Ab) test is highly sensitive after 2 weeks of symptom onset, and might complement the PCR test. Therefore, we measured Ab in addition to PCR to obtain a more accurate clinical profile of COVID-19, which might be helpful in building future practice strategies. PATIENTS: The study patients were those who visited our department for the first time between November 2020 and March 2021 and fulfilled the enrolment criteria. METHODS: All patients underwent total SARS-CoV-2 Ab testing, and PCR tests were performed in only some of them; patients were classified according to the performance of PCR tests for comparisons. RESULTS: Ninety-four patients who underwent Ab testing during the study period were eligible for study enrolment, and the PCR test was performed in 40 of them. Only one patient was diagnosed with acute stage COVID-19 based on a positive PCR test. Antibodies were positive in six (6.4%) of the 94 patients. Five of the six Ab-positive patients were negative for PCR, and the test was not performed in the sixth patient. All the six patients had prior symptoms suggestive of infection, and respiratory symptoms were more noticeable than fever. The Ab positivity rate was significantly higher than published data. CONCLUSION: COVID-19 is not rare in general outpatient services and can be missed based on PCR tests alone. The diagnosis should be made from a comprehensive perspective.

Nucleus accumbens pathways control cell-specific gene expression in the medial prefrontal cortex.

The medial prefrontal cortex (mPFC) is a critical component of a cortico-basal ganglia-thalamo-cortical loop regulating limbic and cognitive functions. Within this circuit, two distinct nucleus accumbens (NAc) output neuron types, dopamine D1 or D2 receptor-expressing neurons, dynamically control the flow of information through basal ganglia nuclei that eventually project back to the mPFC to complete the loop. Thus, chronic dysfunction of the NAc may result in mPFC transcriptomal changes, which in turn contribute to disease conditions associated with the mPFC and basal ganglia. Here, we used RNA sequencing to analyse differentially expressed genes (DEGs) in the mPFC following a reversible neurotransmission blocking technique in D1 or D2 receptor-expressing NAc neurons, respectively (D1-RNB, or D2-RNB). Gene Set Enrichment Analysis revealed that gene sets of layer 5b and 6 pyramidal neurons were enriched in DEGs of the mPFC downregulated in both NAc D1- and D2-RNB mice. In contrast, gene sets of layer 5a pyramidal neurons were enriched in upregulated DEGs of the mPFC in D1-RNB mice, and downregulated DEGs of the mPFC in D2-RNB mice. These findings reveal for the first time that NAc output pathways play an important role in controlling mPFC gene expression.

Acute and chronic effects of exercise on mRNA expression in the skeletal muscle of two mouse models of peripheral artery disease.

Endurance exercise improves walking performance in patients with peripheral artery disease (PAD), which is characterized by skeletal muscle dysfunction caused by lower extremity ischemia. Although transcriptional analyses of exercise-induced changes in normal animals and healthy volunteers have been reported, no detailed study has explored exercise-induced alterations in gene expression in PAD animal models. Here, we determined the acute and chronic effects of exercise on mRNA expression in the skeletal muscles of two mouse models of PAD. Three particular gene categories were investigated: known exercise-responsive genes (Pgc1a, Il6, Nr4a1, Nr4a2, and Nr4a3); myogenic and muscle regeneration-related genes (Myf5, Myogenin, Myomaker, and Myh3); and Gpr56 and its ligand Col3a1. PAD was induced by bilateral femoral artery ligation in normal C57BL/6 and diabetic KK-Ay mice. From 1 week after surgery, repetitive twice-weekly 30-min treadmill endurance exercise sessions were applied. Altered mRNA expression in the soleus muscles was measured in both the acute and chronic phases. In the acute phase, transcript levels of exercise-inducible genes showed significant increases in both C57BL/6 and diabetic KK-Ay PAD mice; levels of regeneration-related genes showed little alteration, and those of Gpr56 increased immediately and significantly after exercise in both models. In the chronic phase, transcript levels of Pgc1a, Myf5, Myogenin, Myomaker, Myh3, Gpr56, and Col3a1 were upregulated significantly in sedentary C57BL/6 PAD mice compared with that in sham-operated mice. Exercise training inhibited the upregulation of Col3a1, Myf5, and Myogenin significantly. In KK-Ay PAD mice, only Gpr56 mRNA levels increased significantly compared with those in sham-operated mice. RNA sequence analysis revealed 33 and 166 differentially upregulated, and 363 and 99 downregulated, genes after exercise training in C57BL/6 PAD and KK-Ay PAD mice, respectively. In summary, we detected significant alterations of skeletal muscle genes after exercise in PAD mouse models and characterized their expression patterns.

Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. 1. Exploration of [5,6]-fused bicyclic scaffolds.

To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.