HER2 G776S mutation promotes oncogenic potential in colorectal cancer cells when accompanied by loss of APC function

Clinical cancer genome sequencing detects oncogenic variants that are potential targets for cancer treatment, but it also detects variants of unknown significance. These variants may interact with each other to influence tumor pathophysiology, however, such interactions have not been fully elucidated. Additionally, the effect of target therapy for those variants also unclarified. In this study, we investigated the biological functions of a HER2 mutation (G776S mutation) of unknown pathological significance, which was detected together with APC mutation by cancer genome sequencing of samples from a colorectal cancer (CRC) patient. Transfection of the HER2 G776S mutation alone slightly increased the kinase activity and phosphorylation of HER2 protein, but did not activate HER2 downstream signaling or alter the cell phenotype. On the other hand, the HER2 G776S mutation was shown to have strong oncogenic potential when loss of APC function was accompanied. We revealed that loss of APC function increased Wnt pathway activity but also increased RAS-GTP, which increased ERK phosphorylation triggered by HER2 G776S transfection. In addition, afatinib, a pan-HER tyrosine kinase inhibitor, suppressed tumor growth in xenografts derived from HER2 G776S-transfected CRC cells. These findings suggest that this HER2 mutation in CRC may be a potential therapeutic target

Drug retention of sarilumab, baricitinib, and tofacitinib in patients with rheumatoid arthritis: the ANSWER cohort study

Objectives: The aim of this multicenter, retrospective study was to clarify the retention rates of sarilumab (SAR), baricitinib (BAR), and tofacitinib (TOF) in patients with rheumatoid arthritis (RA). Methods: Patients treated with either SAR (n = 62), BAR (n = 166), or TOF (n = 185) (females, 80.9%; age, 61.0 years; disease duration, 11.1 years; rheumatoid factor positivity, 84.4%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate, 4.3; concomitant prednisolone dose, 5.3 mg/day [47.0%] and methotrexate dose, 8.8 mg/week [58.4%]; biologics- or Janus kinase inhibitors-switched cases 78.4%) were included. The reasons for drug discontinuation were classified into 4 major categories (lack of effectiveness, toxic adverse events, non-toxic reasons, and remission) by each attending physician. The drug retention rate was estimated at 18 months using the Kaplan–Meier method and adjusted for potential confounders by Cox proportional hazards modeling. Results: The discontinuation rates of SAR, BAR, and TOF for the corresponding reasons were as follows, respectively: lack of effectiveness (15.7%, 15.6%, and 21.5%; P = 0.84), toxic adverse events (15.8%, 12.1%, and 12.3%; P = 0.35), non-toxic reasons (10.9%, 7.7%, and 6.8%; P = 0.35), and remission (0.0%, 2.8%, and 0.0%; P = 1.0). The overall retention rates excluding non-toxic reasons and remission were as follows: 68.8% for SAR, 72.5% for BAR, and 66.7% for TOF (P = 0.54). Conclusions: After adjustment by potent confounders, SAR, BAR, and TOF showed similar discontinuation rates due to lack of effectiveness and toxic adverse events.Key Points• This is the first retrospective multicenter study that aimed to clarify the retention rates and reasons for discontinuation of SAR, BAR, and TOF in patients with RA.This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1007/s10067-021-05609-7Ebina K., Hirano T., Maeda Y., et al. Drug retention of sarilumab, baricitinib, and tofacitinib in patients with rheumatoid arthritis: the ANSWER cohort study. Clinical Rheumatology 40, 2673 (2021

Factors affecting drug retention of Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study

This multi-center, retrospective study aimed to clarify the factors affecting drug retention of the Janus kinase inhibitors (JAKi) including baricitinib (BAR) and tofacitinib (TOF) in patients with RA. Patients were as follows; females, 80.6%; age, 60.5 years; DAS28-ESR, 4.3; treated with either BAR (n = 166) or TOF (n = 185); bDMARDs- or JAKi-switched cases (76.6%). The reasons for drug discontinuation were classified into four major categories. The drug retention was evaluated at 24 months using the Kaplan–Meier method and multivariate Cox proportional hazards modelling adjusted by confounders. Discontinuation rates for the corresponding reasons were as follows; ineffectiveness (22.3%), toxic adverse events (13.3%), non-toxic reasons (7.2%) and remission (0.0%). Prior history of anti-interleukin-6 receptor antibody (aIL-6R) ineffectiveness significantly increased the risk of treatment discontinuation due to ineffectiveness (p = 0.020). Aging (≥ 75 years) (p = 0.028), usage of PSL ≥ 5 mg/day (p = 0.017) and female sex (p = 0.041) significantly increased the risk of treatment discontinuation due to toxic adverse events. Factors not associated with treatment discontinuation were: number of prior bDMARDs or JAKi, concomitant MTX usage, difference of JAKi, and prior use of TNF inhibitor, CTLA4-Ig or other JAKi.Ebina K., Hirano T., Maeda Y., et al. Factors affecting drug retention of Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study. Scientific Reports 12, 134 (2022); https://doi.org/10.1038/s41598-021-04075-0

Insulinoma with symptoms of suspected transient ischemic attack : A case report

We report the case of a６７-year-old woman who had symptoms suggestive of a transient ischemic attack（TIA）, such as lightheadedness and transient visual changes before meals for ４ months. She experienced altered consciousness before lunch and was taken to the emergency room２weeks ago. She had repeated hypoglycemia with a blood glucose level of ３１ mg/dL. Insulin secretion was not suppressed, with an immunoreactive insulin level of １４．０ μU/mL and connecting peptide immunoreactivity of １．８３ ng/mL for occasional blood glucose levels of ４９ mg/dL. Dynamic CT revealed a １７‐mm mass enhanced during the arterial phase in the pancreatic uncinate process, suggestive of a pancreatic neuroendocrine tumor. A selective arterial secretagogue（calcium）injection test revealed the localization of insulinoma in the head of the pancreas. Therefore, pancreatoduodenectomy was performed. Hyperglycemia occurred after the surgery, and it was judged that the insulinoma was resected. This case showed TIA-like symptoms without signs of sympathetic overdrive associated with hypoglycemia. Thus, the diagnosis was delayed. Insulinoma may present with symptoms of neuroglycopenia but not autonomic activity due to hypoglycemia. Insulinoma should be distinguished in patients with unknown neurological symptoms since neuroglycopenia caused by insulinoma is diverse

Conversion of glycerol into allyl alcohol over potassium-supported zirconia-iron oxide catalyst

The catalytic conversion of glycerol was performed with iron oxide-based catalysts for production of allyl alcohol using a fixed-bed flow reactor at 623 K under atmospheric pressure. The glycerol dehydration proceeds on acid sites of catalysts while the allyl alcohol production is assumed to be catalyzed by non-acidic sites of catalysts through a hydrogen transfer mechanism. Different alkali metals, including Na, K, Rb, and Cs were supported on ZrO2-FeOx and all of them gave impressively higher allyl alcohol yield and suppressed glycerol dehydration due to the reduced catalyst acidic property. K-supported ZrO2-FeOx (K/ZrO2-FeOx) was chosen for further studies, and allyl alcohol yield remarkably increased up to 27 mol% C at the K content of 3-5 mol%. Since no external hydrogen gas is supplied to the system, the hydrogen transfer mechanism should take place between the reaction of glycerol and either hydrogen atoms derived from formic acid forming during the reaction, or active hydrogen species produced from the decomposition of H2O by ZrO2. Addition of Al2O3 to K/ZrO2-FeOx (K/Al2O3-ZrO2-FeOx) was examined in order to improve structure stability during the glycerol conversion. Al2O3 addition to the catalyst was effective to achieve higher structure stability, leading to high glycerol conversion with stable allyl alcohol yield of above 25 mol% C. Moreover, K/Al2O3-ZrO2-FeOx can be applicable to the conversion of crude glycerol which is the waste solution obtained from biodiesel production. (C) 2013 Elsevier B.V. All rights reserved

Left ventricular global longitudinal strain calculated from manually traced endocardial border lengths utilizing the images for routine ejection fraction measurement by biplane method of disks

Purpose The purpose of this study was to test whether the fractional change in the endocardial border length between end-diastole and end-systole as manually traced in left ventricular ejection fraction (LVEF) measurement using the biplane method of disks (MOD) was consistent with the global longitudinal strain derived from speckle-tracking echocardiography. Methods For 105 patients who underwent echocardiography, two- and four-chamber images with manually traced endocardial lines for LVEF measurement by MOD were stored. LV endocardial lengths at end-diastole and at end-systole were measured on both images to calculate the fractional length changes, which were averaged (GLS(MOD)). Speckle-tracking analysis was performed to measure global longitudinal strains in the apical two- and four-chamber and long-axis images, and the three values were averaged (GLS(STE)) according to the ASE and EACVI guidelines. Results There was no significant difference between GLS(MOD) and GLS(STE). GLS(MOD) correlated well with GLS(STE) (r = 0.81, p < 0.001), and there was no fixed bias in the Bland-Altman analysis. The intraclass correlations for the intra- and inter-observer comparisons for GLS(STE) were excellent, and those for GLS(MOD) were adequate. Conclusion The fractional LV endocardial border length change, GLS(MOD), showed sufficient agreement with GLS(STE) to justify its use as a substitute for the STE-derived global longitudinal strain