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Abdominal aortic aneurysm (AAA) is a common cardiovascular disease with a strong correlation to smoking, although underlying mechanisms have been minimally explored. Electronic cigarettes (e-cigs) have gained recent broad popularity and can deliver nicotine at comparable levels to tobacco cigarettes, but effects on AAA development are unknown.We evaluated the impact of daily e-cig vaping with nicotine on AAA using two complementary murine models and found that exposure enhanced aneurysm development in both models and genders. E-cigs induced changes in key mediators of AAA development including cytokine chitinase-3-like protein 1 (CHI3L1/Chil1) and its targeting microRNA-24 (miR-24). We show that nicotine triggers inflammatory signaling and reactive oxygen species while modulating miR-24 and CHI3L1/Chil1 in vitro, and that Chil1 is crucial to e-cig-augmented aneurysm formation using a knockout model.In conclusion our work shows increased aneurysm formation along with augmented vascular inflammation in response to e-cig exposure with nicotine. Further we identify Chil1 as a key mediator in this context. Our data raise concerns regarding the potentially harmful long-term effects of e-cig nicotine vaping.Smoking is one of the most hazardous modifiable risk factors, with clear links to abdominal aortic aneurysm. E-cig vaping has displayed explosive growth in popularity. Intended for smoking cessation, it has been taken up by millions with no such clinical need, delivering nicotine addiction to new generations. The presumption that vaping is safer than tobacco overlooks the potential cardiovascular risks of nicotine. This study shows for the first time that inhaled e-cig nicotine vapor augments experimental AAA and aortic inflammation, suggests a mechanistic role for the cytokine Chil1/CHI3L1 and its regulator microRNA-24, and raises red flags regarding longitudinal e-cig safety.

List of Antibodies

Non–small cell lung cancer (NSCLC) is characterized by genomic alterations, yet a targetable mutation has not been discovered in nearly half of all patients. Recent studies have identified amplification of RICTOR, an mTORC2-specific cofactor, as a novel actionable target in NSCLC. mTORC2 is one of two distinct mTOR complexes to sense environmental cues and regulate a variety of cellular processes, including cell growth, proliferation, and metabolism, all of which promote tumorigenesis when aberrantly regulated. Interestingly, other components of mTORC2 are not coamplified with RICTOR in human lung cancer, raising the question as to whether RICTOR amplification-induced changes are dependent on mTORC2 function. To model RICTOR amplification, we overexpressed Rictor using the Cas9 Synergistic Activation Mediator system. Overexpression of Rictor increased mTORC2 integrity and signaling, but at the expense of mTORC1, suggesting that overexpressed Rictor recruits common components away from mTORC1. Additionally, Rictor overexpression increases the proliferation and growth of NSCLC 3D cultures and tumors in vivo. Conversely, knockout of RICTOR leads to decreased mTORC2 formation and activity, but increased mTORC1 function. Because Rictor has mTOR-dependent and -independent functions, we also knocked out mLST8, a shared mTOR cofactor but is specifically required for mTORC2 function. Inducible loss of mLST8 in RICTOR-amplified NSCLC cells inhibited mTORC2 integrity and signaling, tumor cell proliferation, and tumor growth. Collectively, these data identify a mechanism for Rictor-driven tumor progression and provide further rationale for the development of an mTORC2-specific inhibitor.Implications:RICTOR amplification drives NSCLC proliferation through formation of mTORC2, suggesting mTORC2-specific inhibition could be a beneficial therapeutic option.

Copy number analysis of TCGA NSCLC samples with RICTOR amplification

Purpose: Patients with metastatic or recurrent Ewing’s sarcoma family of tumors and alveolar rhabdomyosarcoma have Experimental Design: Fifty-two patients with translocation positive, recurrent, or metastatic Ewing’s sarcoma family of tumors or alveolar rhabdomyosarcoma underwent prechemotherapy cell harvest via apheresis for potential receipt of immunotherapy. Following completion of standard multimodal therapy, 30 patients ultimately initiated immunotherapy and were sequentially assigned to three cohorts. All cohorts received autologous T cells, influenza vaccinations, and dendritic cells pulsed with peptides derived from tumor-specific translocation breakpoints and E7, a peptide known to bind HLA-A2. Cohort 1 received moderate-dose recombinant human interleukin-2 (rhIL-2), cohort 2 received low-dose rhIL-2, and cohort 3 did not receive rhIL-2.Results: All immunotherapy recipients generated influenza-specific immune responses, whereas immune responses to the translocation breakpoint peptides occurred in 39%, and only 25% of HLA-A2+ patients developed E7-specific responses. Toxicity was minimal. Intention-to-treat analysis revealed a 31% 5-year overall survival for all patients apheresed (median potential follow-up 7.3 years) with a 43% 5-year overall survival for patients initiating immunotherapy.Conclusions: Consolidative immunotherapy is a scientifically based and clinically practical approach for integrating immunotherapy into a multimodal regimen for chemoresponsive cancer. Patients receiving immunotherapy experienced minimal toxicity and favorable survival. The robust influenza immune responses observed suggest that postchemotherapy immune incompetence will not fundamentally limit this approach. Future studies will seek to increase efficacy by using more immunogenic antigens and more potent dendritic cells.

Supplementary Tables S1-S3 from A Pilot Study of Consolidative Immunotherapy in Patients with High-Risk Pediatric Sarcomas

Objective: To review the evolution of the national trends in the prescription of androgen deprivation therapy, new androgen-receptor pathway targeting agents and chemotherapy in the management of prostate cancer [PCa] in Australia. Methods: From January 2009 to December 2020, pharmaceutical benefits scheme [PBS] code were identified and extracted for Luteinising hormonereleasing hormone [LHRH] agonists and antagonists, anti-androgens, new androgen-receptor pathway targeting agents [ARTA] and chemotherapy. Dataanalysis and figure generation were performed in Excel. Formal statistical hypothesis testing was not performed as the aim was to illustrate general longitudinal prescribing patterns. Results: Overall the national prescriptions rate for PCa has increased between 2009 and 2020. All LHRH agents described in the literature are available in Australia. Goserelin was the first marketed LHRH agonists in Australia and is still being prescribed at a disproportionately high frequency compared to other agents. Despite COVID-19, no change towards long-acting LHRH agents was noted. Next, cyproterone acetate and bicalutamide were the two most dispensed anti-androgens and a mirror-image transition in prescribing pattern between those agents was observed in favour of bicalutamide. Since the introduction of Enzalutamide on the PBS, its prescriptions rate rose rapidly and has now surpassed Abiraterone. For those with metastatic prostate cancer, docetaxel was the preferred agent over cabazitaxel both in the pubic and private hospitals. Conclusions: Prostate cancer mortality-to-incidence ratio in Australia is among the lowest in the developed world. The majority of the treatments for prostate cancer as recommended by guidelines worldwide are available in Australia. Most the established therapies are also scheduled on the PBS affording accessibility to many.

BACKGROUND With growing worldwide endoscopy experience, endonasal and supraorbital removal of tuberculum sellae meningiomas (TSM) has increased. OBJECTIVE To describe anatomic factors for guiding approach selection and outcomes. METHODS Retrospective analysis of patients undergoing endonasal or supraorbital TSM resection: approach criteria, clinical outcomes, acute magnetic resonance imaging (MRI) fluid-attenuated inversion-recovery (FLAIR)/T2 changes. RESULTS From 2008 to 2020, 33 patients (mean age 55 ± 11 yr) were identified: 20 (61%) had endonasal and 13 (39%) supraorbital removal. Comparing endonasal and supraorbital approaches, mean tumor volume (3.7 ± 3.5 cm3 vs 7.7 ± 8.5 cm3, P = .07); percent tumor above planum (42% vs 65%, P = .02), and lateral tumor beyond supraclinoid internal carotid arteries (1.4 ± 2.0 mm vs 4.0 ± 3.2 mm, P = .006) were greater for supraorbital route. Sellar depth was greater for endonasal route tumors (12.2 ± 2.6 mm vs 9.3 ± 2.4 mm, P = .003). Endoscopy, used in 10/13(77%) supraorbital cases, was helpful in additional tumor removal in 4/10(40%). Gross total removal and mean volumetric tumor resection were 16/20(80%) and 97.5% by endonasal, and 5/13(39%) and 96% by supraorbital route. Vision improved in 12/17 (71%) endonasal, 6/8 (75%) supraorbital operations, and worsened in 1 (3%) supraorbital case. Endonasal approach with optic canal decompression increased over study period: 15/20 (75%) endonasal patients vs 1/13(8%) supraorbital (P

Dopamine has a favorable therapeutic profile but has not been widely used to treat hypotension during microvascular breast reconstruction. The purpose of this study was to evaluate outcomes in patients who received dopamine during breast reconstruction using deep inferior epigastric perforator (DIEP) free flaps and compare them with patients who did not receive dopamine.A single-center retrospective review was performed for patients who underwent breast reconstruction with DIEP free flaps between October 2018 and March 2020. Patient demographics, comorbidities, fluid balance, hospital stay, and adverse outcomes were compared between patients who received at least 1 h of dopamine (DA) and patients who did not receive dopamine (ND). Subgroup analyses were performed for bilateral procedures and patients who received dopamine.Twenty-five patients in the DA group and 43 patients in the ND group met the inclusion criteria. There were no flap-related complications. Patients who had dopamine initiated to maintain blood pressures had a higher total volume of intravenous fluid (ND:3.81L vs. DA:5.04L, p = 0.005). However, DA patients exhibited decreased fluid requirements (ND:839 mL/h vs. DA:479 mL/h, p = 0.004) and increased urine output (ND:98.0 mL/h vs. DA:340 mL/h, p = 0.001) once dopamine was initiated. Intraoperative urine output (ND:1.37 L vs. DA:3.48 L, p 0.001) and rate (ND:1.9 ml/kg/h vs. DA:3.7 ml/kg/h, p 0.001) were increased in the DA group. The fluid balance of patients undergoing bilateral procedures was closer to neutral for patients who received dopamine (ND:+3.43 L vs. DA:+2.26 L, p = 0.03).Dopamine is safe to use in microvascular breast reconstruction. It may be beneficial for hemodynamically labile patients by stabilizing blood pressure and facilitating a neutral fluid balance.

Using matrix norm techniques, we give a unified convergence analysis of a general projection method for computing stationary density functions of Frobenius-Perron operators associated with piecewise C 2 and stretching transformations of the unit interval.

Background Multiple studies have demonstrated that ketamine, a glutamate receptor blocker, may decrease postoperative pain in abdominal and orthopedic surgeries. However, its role with spinal anesthesia and total knee arthroplasty (TKA) remains unknown. The purpose of this study is to determine the efficacy of subanesthetic dosing of ketamine during TKA on postoperative pain and narcotic consumption. Methods In this prospective, randomized, double-blinded clinical trial, we enrolled 91 patients undergoing primary TKA with spinal anesthesia in a single institution from 2017 to 2018. Patients were randomized to receive intraoperative ketamine infusion at a rate of 6 mcg/kg/min for 75 minutes or a saline placebo. All patients received spinal anesthesia and otherwise identical surgical approaches, pain management, and rehabilitation protocols. Patient-reported visual analog pain scores were calculated preoperatively, postoperative days (POD) 0-7, and 2 weeks. Narcotic consumption was evaluated on POD 0 and 1. Results There was no difference in average pain between ketamine and placebo at all time points except for at PODs 1 (45 vs 56, P = .041) and 4 (39 vs 49, P = .040). For least pain experienced, patients administered with ketamine experienced a reduction in pain only at POD 4 (22 vs 35, P = .011). There was no difference in maximum pain cohorts at all time points of the study or in-hospital morphine equivalents between the 2 cohorts. Conclusion As part of multimodal pain management protocol, intraoperative ketamine does not result in a clinically significant improvement in pain and narcotic consumption following TKA.

In the present work, for the first time, we employ Ulam's method to estimate and to predict the existence of the probability density functions of single species populations with chaotic dynamics. In particular, given a chaotic map, we show that Ulam's method generates a sequence of density functions in L 1 -space that may converge weakly to a function in L 1 -space. In such a case we show that the limiting function generates an absolutely continuous (w.r.t. the Lebesgue measure) invariant measure (w.r.t. the given chaotic map) and therefore the limiting function is the probability density function of the chaotic map. This fact can be used to determine the existence and estimate the probability density functions of chaotic biological systems.

Non–small cell lung cancer (NSCLC) is characterized by genomic alterations, yet a targetable mutation has not been discovered in nearly half of all patients. Recent studies have identified amplification of RICTOR, an mTORC2-specific cofactor, as a novel actionable target in NSCLC. mTORC2 is one of two distinct mTOR complexes to sense environmental cues and regulate a variety of cellular processes, including cell growth, proliferation, and metabolism, all of which promote tumorigenesis when aberrantly regulated. Interestingly, other components of mTORC2 are not coamplified with RICTOR in human lung cancer, raising the question as to whether RICTOR amplification-induced changes are dependent on mTORC2 function. To model RICTOR amplification, we overexpressed Rictor using the Cas9 Synergistic Activation Mediator system. Overexpression of Rictor increased mTORC2 integrity and signaling, but at the expense of mTORC1, suggesting that overexpressed Rictor recruits common components away from mTORC1. Additionally, Rictor overexpression increases the proliferation and growth of NSCLC 3D cultures and tumors in vivo. Conversely, knockout of RICTOR leads to decreased mTORC2 formation and activity, but increased mTORC1 function. Because Rictor has mTOR-dependent and -independent functions, we also knocked out mLST8, a shared mTOR cofactor but is specifically required for mTORC2 function. Inducible loss of mLST8 in RICTOR-amplified NSCLC cells inhibited mTORC2 integrity and signaling, tumor cell proliferation, and tumor growth. Collectively, these data identify a mechanism for Rictor-driven tumor progression and provide further rationale for the development of an mTORC2-specific inhibitor. Implications: RICTOR amplification drives NSCLC proliferation through formation of mTORC2, suggesting mTORC2-specific inhibition could be a beneficial therapeutic option.

Prospective evidence for the clinical role and efficacy of prostate specific membrane antigen (PSMA) positron emission tomography (PET)/magnetic resonance imaging (MRI) combining MRI characterization and localization of lesions with PET avidity in comparison to conventional imaging is limited. In a prospective clinical trial, we aimed to evaluate the diagnostic yield and therapeutic impact of PSMA PET/MRI in men with biochemical recurrence (BCR) following curative therapy. A single-centre, prospective clinical trial at the Princess Alexandra Hospital recruited 30 patients with BCR. Patients underwent PSMA PET/MRI and concurrent conventional CT chest, abdomen, pelvis and whole-body bone scan. Biopsy was performed when safety possible for histological correlation of identified lesions. Clinical efficacy and impact of PSMA PET findings were evaluated. 30 patients with BCR were recruited (median PSA 0.69 ng/ml). PSMA avid lesions were present in 21 patients (70%). 23 patients were previously treated with definitive surgery, 6 patients received external beam radiotherapy and 1 patient had low dose rate brachytherapy. A total of 8 of 9 lesions biopsied were positive (88.9% histological correlation). PSMA PET/MRI detected local recurrence (p = 0.005) and pelvic lesions (p = 0.06) more accurately than conventional imaging. PSMA PET/MRI may be useful in staging men with biochemical recurrence, especially when PSA is low. Our data demonstrates a high detection rate, especially for locally recurrent disease, and highlights the role of this modality when PSA is low. This modality has the potential to significantly improve prostate cancer detection and may have implications for earlier salvage treatment, avoidance of futile local therapy and change patient management to lead to improved outcomes.

Background No previous population-based study has evaluated the natural course of Crohn’s disease (CD) over three decades in non-Caucasians. We previously reported a 30-year trend in the epidemiology of inflammatory bowel disease (IBD) in the Songpa-Kangdong (SK) District of Seoul, Korea between 1986 and 2015 (1). In this study, we aimed to analyse the long-term natural course of Korean patients with CD in the SK-IBD population-based cohort. Methods All patients newly diagnosed with CD between 1986 and 2015 were enrolled in this study. To assess the temporal trends in treatment paradigms and in the prognosis of CD, patients were divided into two cohorts according to the year of CD diagnosis: cohort 1, 1986–2003 and cohort 2, 2004–2015 (the anti-tumour necrosis factor [anti-TNF] era). Disease characteristics at diagnosis, outcomes and their predictors were evaluated. Results A total of 418 patients were enrolled. There were 318 males (76.1%) and median age at CD diagnosis was 22 years (interquartile range [IQR], 18–29). Disease location at CD diagnosis was ileal in 104 patients (24.9%), colonic in 39 (9.3%), and ileocolonic in 275 (65.8%). Disease behaviour at CD diagnosis was inflammatory in 339 patients (81.1%), stricturing in 34 (8.1%), and penetrating in 45 (10.8%). Perianal fistula/abscess was present in 43.3% (n = 181) before or at CD diagnosis. During the median follow-up of 108.1 months, the overall use of systemic corticosteroids, thiopurines, and anti-TNF agents was 57.4%, 80.9%, and 34.2%, respectively. Compared with the cohort 1, the cumulative probability of commencing corticosteroids decreased (p = 0.001), whereas that of commencing thiopurines and anti-TNF agents increased (both p < 0.001) in the cohort 2. A total of 113 patients (27.0%) underwent intestinal resection, demonstrating cumulative risks of intestinal resection at 1, 5, 10, 20, and 25 years after diagnosis of 12.5%, 16.5%, 25.6%, 49.7%, and 55.5%, respectively. Multivariate Cox regression analysis revealed that stricturing behaviour at diagnosis (hazard ratio [HR] 2.393, 95% confidence interval [CI] 1.234–4.641), penetrating behaviour at diagnosis (HR 4.514, 95% CI 1.752–11.629), and the cohort 2 (HR 0.530, 95% CI 0.297–0.945) were independent predictors of intestinal resection. The standardised mortality ratio was 1.867 (95% confidence interval, 0.502–4.780). Conclusion Korean patients showed a similar clinical course and intestinal resection rate compared with Western patients. The risk of intestinal resection has decreased in the anti-TNF era. Reference

In [6] we have shown that the Frobenius-Perron operators associated with a one parameter family of piecewise linear chaotic maps have a common invariant (fixed) density map. In this paper we show the uniqueness of the common invariant density map and analyze the corresponding fixed point algorithm.

This paper extracts the factors determining the implied volatility skew movements of KOSPI200 index options by applying PCA (Principal Component Analysis). In particular, we analyze the movement of skew depending on the changes of the underlying asset price. As a result, it turned out that two factors can explain 94.6%~99.8% of the whole movement of implied volatility. The factor1 could be interpreted as ‘parallel shift’, and factor2 as the movement of ‘tilt or slope’. We also find some significant structural changes in the movement of skew after the Financial Crisis. The explanatory power of factor1 becomes more important on the movement of skew in both call and put options after the financial crisis. On the other hand, the influences of the factor2 is less. In general, after financial crisis, the volatility skew has the strong tendency to move in parallel. This implies that the changes in the option price or implied volatility due to the some shocks becomes more independent of the strike prices.

The maximum entropy method for the Hausdorff moment problem suffers from ill conditioning as it uses monomial basis {1,x,x2,...,xn}. The maximum entropy method for the Chebyshev moment probelm was studied to overcome this drawback in. In this paper we review and modify the maximum entropy method for the Hausdorff and Chebyshev moment problems studied in and present the maximum entropy method for the Legendre moment problem. We also give the algorithms of converting the Hausdorff moments into the Chebyshev and Lengendre moments, respectively, and utilizing the corresponding maximum entropy method.

Significant advances over the last 2 decades in imaging technology, instrumentation, anatomical knowledge, and reconstructive techniques have resulted in the endonasal endoscopic approach becoming an integral part of modern skull base surgery. With growing use and greater experience, surgical outcomes continue to incrementally improve across many skull base pathologies, including those tumors that impact vision and ocular motility. The importance of the learning curve and use of a multi-disciplinary approach is critical to maximizing success, minimizing complications, and enhancing quality of life in these patients. Realizing the limits of the endonasal route and reasonable use of transcranial approaches such as the supraorbital eyebrow craniotomy, it may br appropriate to consider nonsurgical therapy including various forms of radiotherapy [corrected] and medical treatment options.