Medical treatment does not reduce surgery rates in children with adenoid hypertrophy.

OBJECTIVE: We sought to study adenoidectomy rates in children with adenoid hypertrophy (AH) who were either treated with medical therapy or not during a 2-year follow-up period in a longitudinal population-based study. METHODS: We retrospectively identified healthy children aged 1-18 years between 2014 and 2020 with AH diagnosis from the Clalit Health Services database, the largest healthcare maintenance organization in Israel. The main outcome was adenoidectomy alone or in combination with other procedures performed within 2 years after diagnosis. The treatment group consisted of children who received medical therapy, defined as a pharmacy purchase of montelukast, nasal steroid sprays and/or antihistamines (medical therapy aimed to reduce AH) for ≥2 consecutive months, while the control group consisted of untreated children. RESULTS: We identified 68,356 unique children with AH, of them 56 % were boys, with a mean age of 4.9 ± 3.3 years. Of them, 5310 (7.7 %) received medical therapy. Overall, 6633 (9.7 %) underwent adenoidectomy within 2 years following diagnosis. There was no significant difference in surgery referral rates between the treatment and the control groups, 10 % vs. 9.7 %, respectively (p = 0.3). When adjusted for age and sex, the likelihood of undergoing adenoidectomy was similar in both groups (HR = 0.98, 95 % CI = 0.90-1.07, p = 0.6). Among operated children, the average time from diagnosis to surgery was statistically significantly longer in the treatment group than in the control group, 346 ± 180 vs 311 ± 175 days (p < 0.001). CONCLUSION: Prescribing montelukast, nasal steroids and/or oral antihistamines was not associated with a reduction in adenoidectomy rates and was associated with an average surgery delay of 35 days.

Role of Nudt2 in Anchorage-Independent Growth and Cell Migration of Human Melanoma.

Nudt2 encodes a diadenosine tetraphosphate (Ap4A) hydrolase that catalyzes the hydrolysis of Ap4A and is involved in the lysyl tRNA synthetase-Ap4A-Nudt2 (LysRS-Ap4A-Nudt2) signaling pathway. We have previously demonstrated that this pathway is active in non-small cell lung cancer. Nudt2 was shown to be involved in cell proliferation in breast cancer, making it an important target in cancer therapy. Currently, the function of Nudt2 in malignant melanoma has not been demonstrated. Therefore, we investigated the role played by Nudt2 in the growth of human melanoma. Our study showed that Nudt2 knockdown suppressed anchorage-independent growth of human melanoma cells in vitro. The in vivo effect of Nudt2 was determined by investigating the role played by Nudt2 knockdown on the ability of the cells to form tumors in a mice xenograft model. Nudt2 knockdown significantly suppressed tumor growth in this model. Moreover, overexpression of Nudt2 resulted in an increase in anchorage-independent growth of these cells, whereas Nudt2 knockdown decreased their migration. In addition, Nudt2 knockdown reduced vimentin expression. Vimentin is one of the mesenchymal markers that are involved in the epithelial mesenchymal transition (EMT) process. Thus, Nudt2 plays an important role in promoting anchorage-independent growth and cell migration in melanoma.

Systemic inflammatory markers in elderly patients undergoing transcatheter aortic valve replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) provokes an early injury response, partially represented by dynamic changes in inflammatory markers. TAVR greatly benefits the elderly and we aimed to determine whether increased inflammatory markers post-TAVR in octagenerians were different than their younger counterparts and whether it was associated with adverse clinical outcomes. METHODS: Patients with severe symptomatic aortic stenosis who underwent transfemoral TAVR from January 2010 to December 2021 were enrolled. Total white blood cells (WBC) count and subpopulation dynamics were evaluated. RESULTS: Five-hundred and seven patients were finally included in the study, 65% of these patients were 80 or more years old (54% female, median age 84 [82-87]) years, with severe symptomatic aortic stenosis. In patients aged above 80 years (patients ≥ 80), we noticed significant kinetic changes in the WBC and their differential cellular subpopulations (P < 0.0001) between admission and early days post-procedure. This was evident by a significant increase in total WBC (median 7.1 to 9.4) and absolute neutrophil count (median 4.7 to 7.4), neutrophil-lymphocyte (NL) ratio (median 2.82 to 7.21), and a meaningful decrease in absolute lymphocyte count (median 1.5 to 1.0). Implantation of self-expandable valves (SEVs) was associated with a more pronounced inflammatory response than balloon-expandable valves (BEVs). Higher WBC and neutrophil counts were associated with higher mortality and major vascular complications at 30 days, in addition, higher neutrophil counts and NL ratios were found to be correlated to arrhythmia at 30 days with P values of 0.04 and 0.028, respectively. CONCLUSION: This is the first description of a differential age-related inflammatory response in patients after TAVR, which shows an association between inflammatory markers post procedure and clinical outcome. Nevertheless, survival rates were similar in the elderly population and in younger patients, despite the presence of comorbid conditions.

Circulating Soluble TREM2 and Cardiovascular Outcome in Cohort Study of Coronary Atherosclerosis Patients.

Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) is a membrane receptor in myeloid cells that mediates cellular phagocytosis and inflammation. TREM2 and its soluble extracellular domain are clearly implicated in neuroinflammation and neurodegeneration. sTREM2 is also expressed in atherosclerotic macrophages. We hypothesized that sTREM2 would predict cardiovascular mortality in patients with established coronary atherosclerosis (CAD). Consecutive patients undergoing coronary angiography with the establishment of the diagnosis of CAD (n = 230) and without CAD (n = 53) were tested for their baseline serum sTREM2 levels. All patients were followed up for 84 months or until death occurred. sTREM2 correlated with age; however, no association was found between sTREM2 and the number of atherosclerotic vessels involved (p = 0.642). After 84 months of follow-up, 68 out of the 230 CAD patients had died. After adjusting for age and other risk factors, the adjusted hazard ratio for the highest quartile of sTREM2 was 2.37 (95% confidence interval 1.17-4.83) for death. In patients with established CAD, serum sTREM2 appears to predict cardiovascular death as a potential surrogate for plaque rupture. TREM2 and its soluble extracellular form might be implicated in the fate of the atherosclerotic plaque, but corroboration within larger studies is needed.

Dual Targeting of Soluble Oligomeric and Aggregated Transthyretin with a Monoclonal Antibody Ameliorates Experimental Neuropathy.

ATTR amyloidosis comprises a spectrum of multiple clinical presentations, including, predominantly, neuropathy and cardiomyopathy. The common triggering pathogenic protein is misfolded transthyretin, a carrier protein that destabilizes misfolds and assembles into mature amyloid fibrils. The current management of ATTR amyloidosis includes the use of agents that stabilize TTR or attenuate its liver inducible production. Herein, we tested the hypothesis that a monoclonal antibody targeting the soluble oligomeric as well as the aggregated TTR would influence experimental neuropathy. We have shown that Ab-A, our previously described humanized IgG monoclonal antibody, dose-dependently ameliorates the toxicity to neurons triggered by misfolded TTR oligomers. Furthermore, the antibody that exhibits wide misTTR epitope recognition that includes the oligomeric and aggregated forms of the protein dose-dependently enhances the uptake of misfolded TTR to microglia, the resident predominant cells of the innate immune system within the CNS. These in vitro mechanistic properties of the antibody were corroborated by experimental in vivo data showing that the antibody rapidly clears human TTR amyloid extracts infiltrated to the sciatic nerves of rats. Thus, the monoclonal antibody targeting soluble and aggregated TTR is effective in experimental neuropathy, likely due its ability to act as a neuroprotective agent, as well its misTTR-mediated clearance via microglia.

Seasonal Variation of Testosterone Levels in a Large Cohort of Men.

Objectives: The aim of the study was to evaluate in a large cohort of males with a wide range of age, metabolic status, and coexistent morbidities whether month of blood test performance was associated with total and bioavailable testosterone levels independent of age, body mass index (BMI), existing cardiovascular disease (CVD), and CVD risk factors. Methods: Cross-sectional study includes data from computerized medical records of 27,328 men aged 20-70, treated by the largest healthcare organization in Israel, who had undergone testosterone measurement. In 7,940 subjects with available sex-hormone-binding globulin levels, bioavailable testosterone was calculated. Results: Total and bioavailable testosterone levels gradually decreased with age and BMI (P < 0.001) and were significantly lower in men with diabetes, hypertension, hyperlipidemia, and known CVD, but were higher in current smokers compared with nonsmokers (P < 0.001). Hormone levels were highest in August-October declined after and lowest in March. Overall, both total and bioavailable testosterone levels were significantly lower in March compared to August-October (P < 0.001). In a linear regression analysis, age, BMI, current smoking, and month of testing were independently associated with total (P < 0.001) and bioavailable testosterone levels (P=0.002), and diabetes was associated with total testosterone (P < 0.001). Conclusion: In a large cohort of men with a wide range of age, BMI, and comorbidities, month of testing was independently associated with total and bioavailable testosterone levels. These data provide strong evidence that seasonal variation has to be considered in clinical practice.

The Incidence of Myocarditis and Pericarditis in Post COVID-19 Unvaccinated Patients-A Large Population-Based Study.

Myocarditis and pericarditis are potential post-acute cardiac sequelae of COVID-19 infection, arising from adaptive immune responses. We aimed to study the incidence of post-acute COVID-19 myocarditis and pericarditis. Retrospective cohort study of 196,992 adults after COVID-19 infection in Clalit Health Services members in Israel between March 2020 and January 2021. Inpatient myocarditis and pericarditis diagnoses were retrieved from day 10 after positive PCR. Follow-up was censored on 28 February 2021, with minimum observation of 18 days. The control cohort of 590,976 adults with at least one negative PCR and no positive PCR were age- and sex-matched. Since the Israeli vaccination program was initiated on 20 December 2020, the time-period matching of the control cohort was calculated backward from 15 December 2020. Nine post-COVID-19 patients developed myocarditis (0.0046%), and eleven patients were diagnosed with pericarditis (0.0056%). In the control cohort, 27 patients had myocarditis (0.0046%) and 52 had pericarditis (0.0088%). Age (adjusted hazard ratio [aHR] 0.96, 95% confidence interval [CI]; 0.93 to 1.00) and male sex (aHR 4.42; 95% CI, 1.64 to 11.96) were associated with myocarditis. Male sex (aHR 1.93; 95% CI 1.09 to 3.41) and peripheral vascular disease (aHR 4.20; 95% CI 1.50 to 11.72) were associated with pericarditis. Post COVID-19 infection was not associated with either myocarditis (aHR 1.08; 95% CI 0.45 to 2.56) or pericarditis (aHR 0.53; 95% CI 0.25 to 1.13). We did not observe an increased incidence of neither pericarditis nor myocarditis in adult patients recovering from COVID-19 infection.

Transthyretin Cardiac Amyloidosis Scintigraphy Using Planar D-SPECT on Dedicated Cardiac CZT Camera.

BACKGROUND: Bone scintigraphy is a main diagnostic tool in suspected ATTR patients. Almost all literature is based on conventional whole body gamma cameras, and there is very sparse data evaluating the use of dedicated cardiac CZT cameras. The aim of this study was to evaluate the utility of bone scintigraphy in suspected transthyretin cardiac amyloidosis (ATTR-CA) patients on a dedicated cardiac CZT camera. METHODS: Seventy-three patients with suspected ATTR-CA underwent planar and SPECT Tc-99 m pyrophosphate scintigraphy using dedicated cardiac CZT camera between May and August 2019. RESULTS: Planar D-SPECT image quality was mostly good. Six patients were identified as ATTR-CA positive. Inter-observer agreement based on both Perugini score and on planar D-SPECT H/CL ratio was excellent. CONCLUSIONS: ATTR-CA scintigraphy using dedicated cardiac CZT camera was feasible, and yielded planar D-SPECT images with excellent inter-observer agreement.

Early effectiveness of BNT162b2 Covid-19 vaccine in preventing SARS-CoV-2 infection in healthcare personnel in six Israeli hospitals (CoVEHPI).

BACKGROUND: Methodologically rigorous studies on Covid-19 vaccine effectiveness (VE) in preventing SARS-CoV-2 infection are critically needed to inform national and global policy on Covid-19 vaccine use. In Israel, healthcare personnel (HCP) were initially prioritized for Covid-19 vaccination, creating an ideal setting to evaluate early real-world VE in a closely monitored population. METHODS: We conducted a prospective study among HCP in 6 hospitals to estimate the effectiveness of the BNT162b2 mRNA Covid-19 vaccine in preventing SARS-CoV-2 infection. Participants filled out weekly symptom questionnaires, provided weekly nasal specimens, and three serology samples - at enrollment, 30 days and 90 days. We estimated VE against PCR-confirmed SARS-CoV-2 infection using the Cox Proportional Hazards model and against a combined PCR/serology endpoint using Fisher's exact test. RESULTS: Of the 1567 HCP enrolled between December 27, 2020 and February 15, 2021, 1250 previously uninfected participants were included in the primary analysis; 998 (79.8%) were vaccinated with their first dose prior to or at enrollment, all with Pfizer BNT162b2 mRNA vaccine. There were four PCR-positive events among vaccinated participants, and nine among unvaccinated participants. Adjusted two-dose VE against any PCR-confirmed infection was 94.5% (95% CI: 82.6%-98.2%); adjusted two-dose VE against a combined endpoint of PCR and seroconversion for a 60-day follow-up period was 94.5% (95% CI: 63.0%-99.0%). Five PCR-positive samples from study participants were sequenced; all were alpha variant. CONCLUSIONS: Our prospective VE study of HCP in Israel with rigorous weekly surveillance found very high VE for two doses of Pfizer BNT162b2 mRNA vaccine against SARS-CoV-2 infection in recently vaccinated HCP during a period of predominant alpha variant circulation. FUNDING: Clalit Health Services.

The Role Played by Transcription Factor E3 in Modulating Cardiac Hypertrophy.

Transcription factor E3 (TFE3), which is a key regulator of cellular adaptation, is expressed in most tissues, including the heart, and is reportedly overexpressed during cardiac hypertrophy. In this study, TFE3's role in cardiac hypertrophy was investigated. To understand TFE3's physiological importance in cardiac hypertrophy, pressure-overload cardiac hypertrophy was induced through transverse aortic constriction (TAC) in both wild-type (WT) and TFE3 knockout mice (TFE3-/-). Eleven weeks after TAC induction, cardiac hypertrophy was observed in both WT and TFE3-/- mice. However, significant reductions in ejection fraction and fractional shortening were observed in WT mice compared to TFE3-/- mice. To understand the mechanism, we found that myosin heavy chain (Myh7), which increases during hemodynamic overload, was lower in TFE3-/- TAC mice than in WT TAC mice, whereas extracellular signal-regulated protein kinases (ERK) phosphorylation, which confers cardioprotection, was lower in the left ventricles of WT mice than in TFE3-/- mice. We also found high expressions of TFE3, histone, and MYH7 and low expression of pERK in the normal human heart compared to the hypertensive heart. In the H9c2 cell line, we found that ERK inhibition caused TFE3 nuclear localization. In addition, we found that MYH7 was associated with TFE3, and during TFE3 knockdown, MYH7 and histone were downregulated. Therefore, we showed that TFE3 expression was increased in the mouse model of cardiac hypertrophy and tissues from human hypertensive hearts, whereas pERK was decreased reversibly, which suggested that TFE3 is involved in cardiac hypertrophy through TFE3-histone-MYH7-pERK signaling.

Transthyretin cardiac amyloidosis in patients after TAVR: clinical and echocardiographic findings and long term survival.

AIMS: The aim of this study was to examine the prevalence of amyloid transthyretin (ATTR) cardiac amyloidosis in patients 1-2 years after trans-catheter aortic valve replacement (TAVR) and to assess their clinical and echocardiographic outcome and long-term survival. METHODS AND RESULTS: We enrolled 88 patients, mean age 81 years, 534 (390-711) days after TAVR. Patients underwent a Tc99m-PYP scintigraphy for the diagnosis of ATTR cardiac amyloidosis. Eleven (12.5%) participants were diagnosed with ATTR cardiac amyloidosis. Eighty eight per cent of patients without amyloidosis were in New York Heart Association Classes 1-2 after TAVR, compared with 64% patients with ATTR cardiac amyloidosis (P = 0.022). There were no differences in left ventricular (LV) ejection fraction (P = 0.69) between patients with and without ATTR cardiac amyloidosis at enrolment. The LV mass index and pulmonary artery pressure were significantly higher in patients with ATTR cardiac amyloidosis (P = 0.046 and P = 0.002, respectively). Global longitudinal strain and myocardial work efficiency were significantly lower in patients with ATTR cardiac amyloidosis (P = 0.031 and P = 0.048, respectively). We assessed changes in echocardiographic data, from the time of TAVR to enrolment, and as expected, there was a significant decrease in aortic valve gradient in both groups. There was a significant reduction in LV mass and LV mass index and improvement in basal segment LV strain in the ATTR cardiac amyloidosis negative group (P = 0.045, P = 0.046 and 0.023, respectively). However, in the ATTR cardiac amyloidosis group the change in LV mass and LV mass index and LV basal strain values was not significant (P = 0.24, P = 0.13 and P = 0.35, respectively). The were no significant changes in other echocardiographic parameters in both groups. The patients were followed for 1150 (1086-1221) days after enrolment. Twenty seven patients had at least one cardiac hospitalization during of follow up, of them seven were with ATTR cardiac amyloidosis and 20 patients without amyloidosis (P = 0.017). Eighteen patients (20%) died during follow up; 12 (14%) patients died due to cardiac causes. There was no difference in all-cause and cardiac mortality between patients with and without ATTR cardiac amyloidosis (P = 0.6 and P = 0.53, respectively). CONCLUSIONS: The long-term survival after TAVR is not significantly affected by the presence of ATTR cardiac amyloidosis. However, the clinical course of these patients and the LV hemodynamic improvement is less favourable. This hypothesis-generating study suggests screening for ATTR cardiac amyloidosis in patients who underwent TAVR and have limited clinical or echocardiographic improvement, because they may potentially improve with new therapies for ATTR cardiac amyolidosis.

Skin exposure to UVB light induces a skin-brain-gonad axis and sexual behavior.

Ultraviolet (UV) light affects endocrinological and behavioral aspects of sexuality via an unknown mechanism. Here we discover that ultraviolet B (UVB) exposure enhances the levels of sex-steroid hormones and sexual behavior, which are mediated by the skin. In female mice, UVB exposure increases hypothalamus-pituitary-gonadal axis hormone levels, resulting in larger ovaries; extends estrus days; and increases anti-Mullerian hormone (AMH) expression. UVB exposure also enhances the sexual responsiveness and attractiveness of females and male-female interactions. Conditional knockout of p53 specifically in skin keratinocytes abolishes the effects of UVB. Thus, UVB triggers a skin-brain-gonadal axis through skin p53 activation. In humans, solar exposure enhances romantic passion in both genders and aggressiveness in men, as seen in analysis of individual questionaries, and positively correlates with testosterone level. Our findings suggest opportunities for treatment of sex-steroid-related dysfunctions.

Antibiotic prescription policy for acute otitis media: do we follow the guidelines?

BACKGROUND: Acute otitis media (AOM) is a common cause for antibiotic prescription. Most guidelines endorse abstaining from immediate antibiotic treatment ('watchful waiting', WW) in mild-moderate episodes. We studied adherence rates to the latest AOM guidelines (2013), in terms of antibiotic type and prescription options. METHODS: In this population-based study, AOM episodes were identified in Clalit Health Services-insured children aged 0-10 years between 2011 and 2018, using a data-sharing platform. After identifying the index, prescription and issuing dates for antibiotics for each AOM episode, treatment was categorized as immediate (≤2 days after diagnosis) or WW (antibiotic not prescribed/issued; prescribed ≤2 days after diagnosis but issued on Days 2-7; or prescribed/issued on Days 2-7). Guideline adherence was measured according to age. RESULTS: Of the 491 106 episodes, 361 518 (73.6%) were treated with antibiotics. Following the 2013 guidelines, the ratio of episodes in children aged ≤6 months that were adherent (immediate treatment) was higher (OR = 1.22; 95% CI 1.15-1.29; P < 0.001), whereas the adherent episode ratio for children aged 6-24 months and 2-10 years (WW) was lower (OR = 0.87; 95% CI 0.85-0.88 and OR = 0.94; 95% CI 0.92-0.96, respectively; P < 0.001). Antibiotic prescription rates after 2013 for children aged ≤6 months were not different (OR = 1.03; 95% CI 0.96-1.1; P = 0.4), but were higher in children aged 6-24 months and 2-10 years (OR = 1.07; 95% CI 1.05-1.09; P < 0.001 and OR = 1.02; 95% CI 1.01-1.04; P = 0.015, respectively). Amoxicillin was the most common antibiotic, administered in 75.6% of episodes. Azithromycin was most commonly associated with treatment failure (6.6%). CONCLUSIONS: Improved adherence to the 2013 guidelines was observed only in children aged ≤6 months and over-treatment with antibiotics was still high.

Wild-type TTR amyloidosis among patients with unexplained heart failure and systolic LV dysfunction.

AIM: Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of heart failure (HF) with preserved left ventricular ejection fraction (LVEF), typically presenting as restrictive cardiomyopathy. The potential co-existence of ATTR-CA with systolic heart failure has not been studied. The aim of this study is to describe the prevalence of ATTR-CA and its clinical characteristics in HF patients with reduced LVEF. METHODS: Patients with an unexplained cause of LV systolic dysfunction were screened for ATTR-CA by a 99mTc-PYP planar scintigraphy. Patients in whom presence of ≥ 2 uptake was confirmed by SPECT imaging were included. Their clinical, laboratory and echocardiographic data were collected. RESULTS: Out of 75 patients (mean age 65±12 years, LVEF 35.8±7.9%) included in this study, 7 (9.3%) patients (mean age 75±6 years, LVEF 32.0±8.3%) had ATTR-CA. Patients with ATTR-CA were more symptomatic at diagnosis (NYHA FC 3-4 (86% vs 35% (p = 0.03)) and had a more severe clinical course evident by recurrent hospitalizations for HF, and a need for intravenous diuretic treatment (p = 0.04 and p<0.01, respectively) at follow-up, compared with patients with no ATTR-CA. Patients with ATTR-CA had similar LVEF but a clear trend for larger LV mass index (157.1±60.6 g/m2 vs. 121.0±39.5 g/m2, p = 0.07) and a larger proportions of ATTR-CA patients had IVS thickness >13 mm (57.1% vs 13.1%, p = 0.02) as compared to HF patients with no ATTR-CA. CONCLUSION: In our study, a meaningful percentage of patients with unexplained LV dysfunction had a co-existing ATTR-CA indicating that the clinical heterogeneity of ATTR-CA is much broader than previously thought.

Pneumococcal Conjugated Vaccines Decreased Acute Otitis Media Burden: A Population-Based Study in Israel.

OBJECTIVE: To study time trends in all-cause acute otitis media (AOM) burden by calculating incidence rates of AOM episodes and recurrent acute otitis media (rAOM) cases in highly immunized pediatric population during the pre- and post-pneumococcal conjugated vaccine (PCV) years. STUDY DESIGN: In this population-based study, AOM episodes and rAOM cases were identified in Clalit Health Services-insured Israeli children aged 0-10 years between 2005 and 2018 by using a data-sharing platform. Because a near-sequential implementation of PCV-7/PCV-13 occurred within a 1-year period (2009/2010), we compared AOM visits before (2005-July 2009) and after (August 2009-2018) the introduction of PCVs. We focused on children younger than 2 years of age, who are the target population of PCVs and are at AOM peak age. RESULTS: We identified 805 389 AOM episodes contributed by 270 137 children. The median number of AOM episodes was 2 (IQR 1-4). A downward trend of incidence rates of AOM episodes was observed during the post-PCV years in children younger than age 9 years (P < .001). The largest decrease (21%) was observed in children younger than 1 year, from 807/1000 children during the pre-PCV years to 640/1000 during the post-PCV years (P < .001). An average annual decrease of ∼14/1000 AOM episodes was calculated in children younger than 1 year old (ß = -13.39, 95% CI -16.25 to -10.53, P < .001). Of rAOM cases, documented in 84 237 (31.2%) children, 74% were in children younger than 2 years, and 55% were in boys. The risk to develop rAOM significantly decreased during the post-PCV years in children younger than 2 years (hazard ratio 0.893, 95% CI 0.878-0.908; P < .001). CONCLUSIONS: AOM burden significantly decreased following PCVs introduction in highly immunized children.

A novel monoclonal antibody targeting aggregated transthyretin facilitates its removal and functional recovery in an experimental model.

AIMS: Cardiac amyloidosis typically manifests as heart failure with preserved left ventricular function due to extracellular plaques comprising aggregated TTR. Despite recent success in halting disease progression with a TTR stabilizer and encouraging preliminary findings with TTR silencers, these agents are not targeting preexisting plaques. Herein, we report the development of a novel monoclonal antibody capable of attenuating experimental cardiac amyloidosis. METHODS AND RESULTS: We generated an IgG1 monoclonal antibody against aggregated TTR that immunoprecipitated the protein in the sera of patients with wild-type ATTR (wtATTR) and robustly stained cardiac plaques from patients. The antibody was shown to facilitate aggregated-TTR uptake by various myeloid cells and to protect cardiomyocytes from TTR-inducible toxicity. In a novel in vivo model of wtATTR amyloidosis, the antibody enhanced the disappearance of the pyrophosphate signals attesting for a rapid amyloid deposit removal and degradation and also exhibited improved echocardiographic measures of cardiac performance. Importantly, a capture ELISA developed based on the antibody exhibited higher levels of aggregated TTR in the sera of wtATTR amyloidosis patients as compared to control patients with heart failure suggesting a potential applicability in diagnosis and pharmacodynamic guidance of dosing. CONCLUSION: We developed a proprietary antibody targeting aggregated TTR that exhibits beneficial effects in a novel experimental wtATTR model and also possesses a potential diagnostic utility. The antibody could potentially be tested as a disease modifying agent in ATTR amyloidosis.

Correction: Serine 207 phosphorylated lysyl-tRNA synthetase predicts disease-free survival of non-small-cell lung carcinoma.

[This corrects the article DOI: 10.18632/oncotarget.18053.].

Serine 207 phosphorylated lysyl-tRNA synthetase predicts disease-free survival of non-small-cell lung carcinoma.

It has been shown that various tRNA synthetases exhibit non-canonical activities unrelated to their original role in translation. We have previously described a signal transduction pathway in which serine 207 phosphorylated lysyl-tRNA synthetase (P-s207 LysRS) is released from the cytoplasmic multi-tRNA synthetase complex (MSC) into the nucleus, where it activates the transcription factor MITF in stimulated cultured mast cells and cardiomyocytes. Here we describe a similar transformation of LysRS due to EGFR signaling activation in human lung cancer. Our data shows that activation of the EGFR results in phosphorylation of LysRS at position serine 207, its release from the MSC and translocation to the nucleus. We then generated a P-s207 LysRS rabbit polyclonalantibody and tested 242 tissue micro-array samples derived from non-small-cell lung cancer patients. Highly positive nuclear staining for P-s207 LysRS was noted in patients with EGFR mutations as compared to WT EGFR patients and was associated with improved mean disease-free survival (DFS). In addition, patients with mutated EGFR and negative lymph node metastases had better DFS when P-s207 LysRS was present in the nucleus. The data presented strongly suggests functional and prognostic significance of P-s207 LysRS in non-small-cell lung cancer.

Diagnostic Computed Tomography Coregistration With In-111-DTPA-Octreotide Single Photon Emission Tomography/Low-Dose Computed Tomography.

OBJECTIVES: In-111-DTPA-octreotide (OctreoScan) is still pivotal for neuroendocrine tumor imaging, despite the introduction of Ga-68-octreotide tracers. Low-dose computed tomography (LDCT) assists in the localization of SPECT findings but often results in uncertain interpretation. This retrospective study evaluates the impact of coregistration of In-111-DTPA-octreotide SPECT/LDCT with diagnostic CT on interpretation. METHODS: Thirty-five consecutive studies, in which coregistration was performed because of uncertain interpretation, were evaluated. Presence of somatostatin receptors was categorized retrospectively as definitely positive, probably positive, probably negative, or definitely negative with and without rigid registration with diagnostic CT, and possible added value of coregistration was evaluated. RESULTS: Coregistration was performed in 35 studies. However, on subsequent reading, 4 SPECT/CTs yielded definite results and were omitted. Coregistration was helpful in 30 of the remaining 31 cases, changing reading to definitely positive (7) or to definitely negative (23). In 13 of the 23 cases, diagnosis changed from probably positive to definitely negative. Coregistration contributed in 42 of 48 sites, with greatest benefit in the liver (13/14), pancreas (10/10), and lymph nodes (6/6). CONCLUSIONS: Coregistration is becoming increasingly easier and may be utilized when SPECT/LDCT is inconclusive.

Pyruvate dehydrogenase has a major role in mast cell function, and its activity is regulated by mitochondrial microphthalmia transcription factor.

BACKGROUND: We have recently observed that oxidative phosphorylation-mediated ATP production is essential for mast cell function. Pyruvate dehydrogenase (PDH) is the main regulator of the Krebs cycle and is located upstream of the electron transport chain. However, the role of PDH in mast cell function has not been described. Microphthalmia transcription factor (MITF) regulates the development, number, and function of mast cells. Localization of MITF to the mitochondria and its interaction with mitochondrial proteins has not been explored. OBJECTIVE: We sought to explore the role played by PDH in mast cell exocytosis and to determine whether MITF is localized in the mitochondria and involved in regulation of PDH activity. METHODS: Experiments were performed in vitro by using human and mouse mast cells, as well as rat basophil leukemia cells, and in vivo in mice. The effect of PDH inhibition on mast cell function was examined. PDH interaction with MITF was measured before and after immunologic activation. Furthermore, mitochondrial localization of MITF and its effect on PDH activity were determined. RESULTS: PDH is essential for immunologically mediated degranulation of mast cells. After activation, PDH is serine dephosphorylated. In addition, for the first time, we show that MITF is partially located in the mitochondria and interacts with PDH. This interaction is dependent on the phosphorylation state of PDH. Furthermore, mitochondrial MITF regulates PDH activity. CONCLUSION: The association of mitochondrial MITF with PDH emerges as an important regulator of mast cell function. Our findings indicate that PDH could arise as a new target for the manipulation of allergic diseases.