International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors.

BACKGROUND: Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represent a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology-based topics spanning the field. METHODS: In accordance with prior International Consensus Statement on Allergy and Rhinology documents, ICSNT assigned each topic as an Evidence-Based Review with Recommendations, Evidence-Based Review, and Literature Review based on the level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses format, and completed sections underwent a thorough and iterative consensus-building process. The final document underwent rigorous synthesis and review prior to publication. RESULTS: The ICSNT document consists of four major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology-based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention. CONCLUSION: As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses.

STAT5B mutations in myeloid neoplasms differ by disease subtypes but characterize a subset of chronic myeloid neoplasms with eosinophilia and/or basophilia.

STAT5B has been reported as a recurrent mutation in myeloid neoplasms (MNs) with eosinophilia, but the overall frequency and importance across a spectrum of MNs are largely unknown. We conducted a multicenter study on a series of 82 MNs with STAT5B mutations detected by next-generation sequencing. The estimated frequency of STAT5B mutation in MNs was low.

External validation of the first prognostic nomogram for older adults with cancer.

Background: The geriatric oncology population tends to be complex because of multimorbidity, functional and cognitive decline, malnutrition and social frailty. Prognostic indices for predicting survival of elderly cancer patients to guide treatment remain scarce. A nomogram based on all domains of the geriatric assessment was previously developed at the National Cancer Centre Singapore (NCCS) to predict overall survival (OS) in elderly cancer patients. This nomogram comprised of six variables (age, eastern cooperative oncology group performance status, disease stage, geriatric depression scale (GDS), DETERMINE nutritional index and serum albumin). Objectives: To externally validate the NCCS prognostic nomogram. Design: This is a prospective cohort study. Methods: The nomogram was developed based on a training cohort of 249 patients aged ⩾70 years who attended the NCCS outpatient geriatric oncology clinic between May 2007 and November 2010. External validation of the nomogram using the Royston and Altman approach was carried out on an independent testing cohort of 252 patients from the same clinic between July 2015 and June 2017. Model misspecification, discrimination and calibration were assessed. Results: Median OS of the testing cohort was 3.1 years, which was significantly higher than the corresponding 1.0 year for the training cohort (log-rank p < 0.001). The nomogram achieved a high level of discrimination in the testing cohort (0.7112), comparable to the training cohort (0.7108). Predicted death probabilities were generally well calibrated with the observed death probabilities, as the joint test of calibration-in-the-large estimates at year 1, 2 and 3 from zeros and calibration slope from one was insignificant with p = 0.432. There were model misspecifications in GDS and serum albumin. Conclusion: This study externally validated the prognostic nomogram in an independent cohort of geriatric oncology patients. This supports the use of this nomogram in clinical practice.

Whole-brain mapping of long-range inputs to the VIP-expressing inhibitory neurons in the primary motor cortex.

The primary motor cortex (MOp) is an important site for motor skill learning. Interestingly, neurons in MOp possess reward-related activity, presumably to facilitate reward-based motor learning. While pyramidal neurons (PNs) and different subtypes of GABAergic inhibitory interneurons (INs) in MOp all undergo cell-type specific plastic changes during motor learning, the vasoactive intestinal peptide-expressing inhibitory interneurons (VIP-INs) in MOp have been shown to preferentially respond to reward and play a critical role in the early phases of motor learning by triggering local circuit plasticity. To understand how VIP-INs might integrate various streams of information, such as sensory, pre-motor, and reward-related inputs, to regulate local plasticity in MOp, we performed monosynaptic rabies tracing experiments and employed an automated cell counting pipeline to generate a comprehensive map of brain-wide inputs to VIP-INs in MOp. We then compared this input profile to the brain-wide inputs to somatostatin-expressing inhibitory interneurons (SST-INs) and parvalbumin-expressing inhibitory interneurons (PV-INs) in MOp. We found that while all cell types received major inputs from sensory, motor, and prefrontal cortical regions, as well as from various thalamic nuclei, VIP-INs received more inputs from the orbital frontal cortex (ORB) - a region associated with reinforcement learning and value predictions. Our findings provide insight on how the brain leverages microcircuit motifs by both integrating and partitioning different streams of long-range input to modulate local circuit activity and plasticity.

Brief Report: High Levels of CD47 Expression in Thymic Epithelial Tumors.

Introduction: CD47 is a tumor antigen that inhibits phagocytosis leading to immune evasion. Anti-CD47 therapy is a promising new immunotherapy across numerous tumor types, but it has not been tested in thymic epithelial tumors (TETs): thymomas and thymic carcinomas. TETs are rare tumors that are difficult to treat, especially with programmed cell death protein 1/programmed death-ligand 1 checkpoint inhibitors, owing to the excessive rates of immune-related adverse events. This study investigated the levels of CD47 expression in TETs to explore the possibility of anti-CD47 therapy. Methods: A total of 67 thymic tumors (63 thymomas and 4 thymic carcinomas) and 14 benign thymus controls and their clinical data were included. Samples were stained for CD47 expression (rabbit monoclonal antibody SP279, Abcam, Waltham, MA) and scored for both intensity and H-score (intensity multiplied by the percentage of tumor involved). Intensity was defined as follows: 0 = none, 1 = weak, 2 = moderate, and 3 = strong. H-scores ranged from 0 to 300. Samples with an intensity score below 2 or an H-score below 150 were considered CD47low, whereas the rest were CD47high. Results: Compared with normal thymic tissues, TETs were more frequently CD47 positive and had significantly higher levels of CD47 expression. CD47 was positive in 79.1% of TETs compared with 57.1% of normal thymus. The level of CD47 expression was 16-fold higher in TETs (mean H-score 75.0 versus 4.6, p = 0.003). Multivariate analysis adjusted for age, sex, stage, resection status, and performance status revealed that CD47-high tumors were highly correlated with WHO histology type (p = 0.028). The most frequent CD47high tumors, in contrast to CD47low tumors, were types A (28.6% versus 7.5%) and AB (57.1% versus 13.2%), and the least frequent were B1 (7.1% versus 24.5%), B2 (0% versus 35.8%), B3 (7.1% versus 11.3%), and C (0% versus 7.5%). Conclusions: In contrast to normal thymus, TETs had significantly higher levels of CD47 expression. Tumor samples with high CD47 expression were mostly WHO types A and AB. This is the first study to explore CD47 expression in thymic cancers and lends support for ongoing investigation of anti-CD47 macrophage checkpoint inhibitor therapy in these tumors.

COVID-19 Vaccination Uptake Among Individuals With Immune-mediated Inflammatory Diseases in Ontario, Canada, Between December 2020 and October 2021: A Population-based Analysis.

OBJECTIVE: We assessed coronavirus disease 2019 (COVID-19) vaccine uptake among individuals with immune-mediated inflammatory diseases (IMIDs) and the Ontario general population. METHODS: We studied all residents aged ≥ 16 years who were alive and enrolled in the Ontario Health Insurance Plan as of December 14, 2020, when vaccination commenced (n = 12,435,914). Individuals with rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), psoriasis (PsO), and inflammatory bowel disease (IBD) were identified using established disease-specific case definitions applied to health administrative data. Vaccination status was extracted from the provincial COVaxON registry. Weekly cumulative proportions of first and second doses up until October 3, 2021, were expressed as the vaccinated percentage of each disease group, compared to the general Ontario population, and stratified by age. RESULTS: By October 3, 2021, the cumulative percentage with at least 1 dose was 82.1% for the general population, 88.9% for those with RA, 87.4% for AS, 90.6% for PsA, 87.3% for PsO, and 87.0% for IBD. There was also a higher total cumulative percentage with 2 doses among IMIDs (83.8-88.2%) vs the general population (77.9%). The difference was also evident when stratifying by age. Individuals with IMIDs in the youngest age group initially had earlier uptake than the general population but remain the lowest age group with 2 doses (70.6% in the general population vs. 73.7-79.2% across IMID groups). CONCLUSION: While implementation of COVID-19 vaccination programs has differed globally, these Canadian estimates are the first to reassuringly show higher COVID-19 vaccine uptake among individuals with IMIDs.

Artificial intelligence for dermatopathology: Current trends and the road ahead.

Artificial intelligence (AI), including deep learning methods that leverage neural network-based algorithms, hold significant promise for dermatopathology and other areas of diagnostic pathology in research and clinical practice. There has been significant progress over past several years in applying AI to analyzing digital histopathology images for diagnosis. While much work in AI analysis of histopathology data remains investigational, recent regulatory agency approval in Europe and United States of AI-assisted tools for clinical use in histopathologic diagnosis of prostate and breast cancer herald broader movement of AI into the clinical diagnostic realm of anatomic pathology, including dermatopathology. However, significant challenges remain in translating AI from research into clinical practice, including algorithmic real-world performance, robustness to variation in data sets and practice settings, effective integration into clinical workflows, and cost effectiveness. This review introduces core concepts and terminology in AI, and assesses current progress and challenges in applying AI to dermatopathology.

Artificial intelligence for prediction of donor liver allograft steatosis and early post-transplantation graft failure.

BACKGROUND: Donor livers undergo subjective pathologist review of steatosis before transplantation to mitigate the risk for early allograft dysfunction (EAD). We developed an objective, computer vision artificial intelligence (CVAI) platform to score donor liver steatosis and compared its capability for predicting EAD against pathologist steatosis scores. METHODS: Two pathologists scored digitized donor liver biopsy slides from 2014 to 2019. We trained four CVAI platforms with 1:99 training:prediction split. Mean intersection-over-union (IU) characterized CVAI model accuracy. We defined EAD using liver function tests within 1 week of transplantation. We calculated separate EAD logistic regression models with CVAI and pathologist steatosis and compared the models' discrimination and internal calibration. RESULTS: From 90 liver biopsies, 25,494 images trained CVAI models yielding peak mean IU = 0.80. CVAI steatosis scores were lower than pathologist scores (median 3% vs 20%, P < 0.001). Among 41 transplanted grafts, 46% developed EAD. The median CVAI steatosis score was higher for those with EAD (2.9% vs 1.9%, P = 0.02). CVAI steatosis was independently associated with EAD after adjusting for donor age, donor diabetes, and MELD score (aOR = 1.34, 95%CI = 1.03-1.75, P = 0.03). CONCLUSION: The CVAI steatosis EAD model demonstrated slightly better calibration than pathologist steatosis, meriting further investigation into which modality most accurately and reliably predicts post-transplantation outcomes.

Maternal Schizophrenia, Skin-to-Skin Contact, and Infant Feeding Initiation.

BACKGROUND: The World Health Organization recommends mothers and infants be in direct skin-to-skin contact immediately after birth and initiate breastfeeding as soon as possible. Little is known in women with schizophrenia. METHODS: We conducted a population-based cohort study using administrative health data from Ontario, Canada (2012-2014), comparing women with (n = 471) and without schizophrenia (n = 218 435), and their infants, on the primary outcomes of any skin-to-skin contact and opportunity to initiate breastfeeding within the first 2 h after birth. For dyads with available data, secondary outcomes of intention to breastfeed, breastfeeding support, any breastmilk, and exclusive breastmilk at discharge were assessed. Modified Poisson regression was used to generate relative risks (aRR) and 95% confidence intervals (CI), adjusted for maternal age, parity, neighbourhood income, region of residence, smoking in pregnancy, and maternal medical and non-psychotic psychiatric comorbidity for all outcomes. RESULTS: Maternal schizophrenia was associated with lower likelihood of skin-to-skin contact (65.2% vs 78.1%; aRR 0.88, 95% CI: 0.82-0.94), and breastfeeding initiation post-delivery (38.9% vs 52.6% aRR 0.80, CI: 0.71-0.90) compared to dyads unexposed to maternal schizophrenia. Secondary outcomes followed a similar pattern. The magnitude of the effect was slightly less when restricting the cohort to full-term, vaginal deliveries, not admitted to NICU, and infant not discharged to social services. CONCLUSIONS: Reduced maternal-infant skin-to-skin contact and breastfeeding initiation immediately after birth may significantly impact maternal-child bonding and the establishment breastfeeding in this population. Mothers with schizophrenia may require individualized support to promote these WHO recommended hospital practices in the early post-natal period.

Gender Differences in the Outcomes of Drug-Coated Balloon Treatment in Symptomatic Femoropopliteal Arterial Disease.

OBJECTIVES: To assess 24-month outcome differences based on sex in symptomatic femoro-popliteal arterial disease of patients treated with drug-coated balloon (DCB). BACKGROUND: Peripheral artery disease affects over 12 million people in the United States. Drug-coated balloons have shown to be effective in treating patients with symptomatic femoropopliteal arterial occlusive disease. Debate remains regarding its safety and efficacy in female gender. We investigated the differential treatment effect between genders. METHODS: Patients (93 females and 102 males) with symptomatic femoropopliteal arterial disease treated with DCB from November 2014 to November 2015 were included in this retrospective study. We compared the resting ankle-brachial indices (ABIs) and peak systolic velocities (PSVs) by arterial duplex between the male and female patients at 6, 12, and 24 months postintervention. RESULTS: Females had significantly smaller vessels (4.70 ± 0.9, P = .02) and higher body mass index (BMI; 30.0 ± 3.7, P = .002) than males. Females had significantly decreased ABI and PSV at the 6-month (ABI: 0.90 ± 0.15, P = .05 and PSV: 188.30 ± 103.1, P = .02), 12-month (ABI: 0.86 ± 0.15, P < .0001 and PSV: 219.10 ± 100.10, P = .001), and at 24-month (ABI: 0.84 ± 0.2, P = .0001 and PSV: 251.0 ± 135.9, P < .0001) intervals when compared to males. Females had increased clinically driven target lesion revascularization (TLR) at 6 months (females = 8 vs males = 4, P = .22), 12 months (females = 12 vs males = 4, P = .02), and 24 months (females = 14 vs males = 6, P = .03). In simple logistic regression analysis, BMI, age, reference vessel diameter (RVD), and gender were strongly associated with target lesion restenosis. The final model included the above and it produced the following odds ratios (ORs): BMI (OR = 1.07, 95% confidence interval [CI]: 0.98-1.2), age (OR: 1.0, CI: 0.96-1.03), RVD (OR: 1.6, CI: 1.02-2.4), and gender (OR: 3.5, CI: 1.6-7.8). CONCLUSION: Females treated with DCBs have significantly decreased ABI, PSVs, and an increased rate of TLR than their male counterparts.

Impact of a deep learning assistant on the histopathologic classification of liver cancer.

Artificial intelligence (AI) algorithms continue to rival human performance on a variety of clinical tasks, while their actual impact on human diagnosticians, when incorporated into clinical workflows, remains relatively unexplored. In this study, we developed a deep learning-based assistant to help pathologists differentiate between two subtypes of primary liver cancer, hepatocellular carcinoma and cholangiocarcinoma, on hematoxylin and eosin-stained whole-slide images (WSI), and evaluated its effect on the diagnostic performance of 11 pathologists with varying levels of expertise. Our model achieved accuracies of 0.885 on a validation set of 26 WSI, and 0.842 on an independent test set of 80 WSI. Although use of the assistant did not change the mean accuracy of the 11 pathologists (p = 0.184, OR = 1.281), it significantly improved the accuracy (p = 0.045, OR = 1.499) of a subset of nine pathologists who fell within well-defined experience levels (GI subspecialists, non-GI subspecialists, and trainees). In the assisted state, model accuracy significantly impacted the diagnostic decisions of all 11 pathologists. As expected, when the model's prediction was correct, assistance significantly improved accuracy (p = 0.000, OR = 4.289), whereas when the model's prediction was incorrect, assistance significantly decreased accuracy (p = 0.000, OR = 0.253), with both effects holding across all pathologist experience levels and case difficulty levels. Our results highlight the challenges of translating AI models into the clinical setting, and emphasize the importance of taking into account potential unintended negative consequences of model assistance when designing and testing medical AI-assistance tools.

Relationship Between pH Shifts and Rate of Healing in Chronic Nonhealing Venous Stasis Lower-Extremity Wounds.

Venous stasis ulcers represent the majority of lower-extremity ulcers and place a considerable financial burden on the American health care system. Current standard of care therapies remain sub-optimal with 50% of venous stasis ulcers remaining unhealed after 4 months. Sixteen consecutive wounds were enrolled across 8 participants at a single center and underwent pH-driven therapy in addition to standard care as dictated by physicians. Following wound debridement, the pH of the wound bed was measured using pH strips. If acidic, normal saline was used to rinse the wound at every dressing change. If alkaline, nonsterile gauze was soaked in 0.25% acetic acid and applied to the wound for a minimum of 30 seconds. Participants were followed for 4 weeks with research staff observing compliance throughout. All 16 wounds had an alkaline pH at baseline, with an average pH of 8.25 ± 0.55 (range 7.5 to 9). Average area of the wound at the time of enrollment was (mean ± standard deviation) 285.48 ± 43.68 mm2, and average age of the wound was 37.5 ± 20.3 months (range 3 to 72). A simple linear regression model found a moderate relationship between pH and the rate of healing of chronic nonhealing venous stasis lower-extremity wounds (correlation coefficient  = 0.61). For every 1-unit change in pH, we can expect to see a change in wound size of 116.05 mm2. This is the first US-based, open-label, prospective study that examined the effect of pH on the rate of healing in chronic nonhealing venous stasis ulcer lowerextremity wounds.

BRANCH RETINAL VEIN OCCLUSION SECONDARY TO A RETINAL ARTERIOLAR MACROANEURYSM: A NOVEL MECHANISM SUPPORTED BY MULTIMODAL IMAGING.

BACKGROUND/PURPOSE: To report a case of a branch retinal vein occlusion secondary to a retinal arteriolar macroaneurysm (RAM). METHODS: Retrospective case report describing examination findings, treatment outcome and unique multimodal imaging features demonstrated on fluorescein angiography, optical coherence tomography, optical coherence tomography angiography and adaptive optics photography of the retinal vessels and RAM. RESULTS: A 61-year-old man presented with 20/200 vision in the right eye because of a branch retinal vein occlusion secondary to a RAM. After sector panretinal photocoagulation and a course of 24 intravitreal antivascular endothelial growth factor injections over 4 years, visual acuity improved to 20/25. Fluorescein angiography showed filling of the RAM even after 4 years. Optical coherence tomography angiography demonstrated venous collateral vessels in both the superficial and deep capillary plexuses, and adaptive optics imaging revealed a gap between the RAM wall and occluded vein. CONCLUSION: Multimodal imaging of this unusual presentation illustrated a novel mechanism of branch retinal vein occlusion in which a primary RAM adjacent to the junction of two retinal veins led to obstruction of venous flow without evidence of direct compression. This supports the theory that perianeurysmal microenvironment changes may be of importance in the pathogenesis of venous occlusion.

Detection and Surveillance of Bladder Cancer Using Urine Tumor DNA.

Current regimens for the detection and surveillance of bladder cancer are invasive and have suboptimal sensitivity. Here, we present a novel high-throughput sequencing (HTS) method for detection of urine tumor DNA (utDNA) called utDNA CAPP-Seq (uCAPP-Seq) and apply it to 67 healthy adults and 118 patients with early-stage bladder cancer who had urine collected either prior to treatment or during surveillance. Using this targeted sequencing approach, we detected a median of 6 mutations per patient with bladder cancer and observed surprisingly frequent mutations of the PLEKHS1 promoter (46%), suggesting these mutations represent a useful biomarker for detection of bladder cancer. We detected utDNA pretreatment in 93% of cases using a tumor mutation-informed approach and in 84% when blinded to tumor mutation status, with 96% to 100% specificity. In the surveillance setting, we detected utDNA in 91% of patients who ultimately recurred, with utDNA detection preceding clinical progression in 92% of cases. uCAPP-Seq outperformed a commonly used ancillary test (UroVysion, P = 0.02) and cytology and cystoscopy combined (P ≤ 0.006), detecting 100% of bladder cancer cases detected by cytology and 82% that cytology missed. Our results indicate that uCAPP-Seq is a promising approach for early detection and surveillance of bladder cancer. SIGNIFICANCE: This study shows that utDNA can be detected using HTS with high sensitivity and specificity in patients with early-stage bladder cancer and during post-treatment surveillance, significantly outperforming standard diagnostic modalities and facilitating noninvasive detection, genotyping, and monitoring.This article is highlighted in the In This Issue feature, p. 453.

Decidual granulomatous reaction in a placenta from a preeclamptic pregnancy: a case report and review of the literature.

We report a case of decidual perivascular non-necrotizing granulomas in a placenta from a pregnancy complicated by severe preeclampsia with no evidence of infection. The mother was a 20-year-old primigravida with severe preeclampsia diagnosed in the third trimester with subsequent delivery of a healthy baby boy at 37 weeks 5 days gestation. Pathologic examination of the placenta showed scattered non-necrotizing granulomas in decidua, often adjacent to remodeled decidual arteries without fibrinoid necrosis. These were well-formed, non-necrotizing granulomas with scant lymphoid cuffs. Polarization microscopy did not show foreign material. There were no histopathologic or clinical findings suggestive of maternal-fetal infection or systemic vasculitis at the time of delivery, and the mother had no other reported conditions associated with granulomatous inflammation. Our case demonstrates that granulomatous reaction may be seen in the placenta from a pregnancy complicated by severe preeclampsia, although work-up for infection may be indicated.

Melatonin as a promising agent of regulating stem cell biology and its application in disease therapy.

Stem cells have emerged as an important approach to repair and regenerate damaged tissues or organs and show great therapeutic potential in a variety of diseases. However, the low survival of engrafted stem cells still remains a major challenge for stem cell therapy. As a major hormone from the pineal gland, melatonin has been shown to play an important role in regulating the physiological and pathological functions of stem cells, such as promoting proliferation, migration and differentiation. Thus, melatonin combined with stem cell transplantation displayed promising application potential in neurodegenerative diseases, liver cirrhosis, wound healing, myocardial infarction, kidney ischemia injury, osteoporosis, etc. It exerts its physiological and pathological functions through its anti-oxidant, anti-inflammatory, anti-apoptosis and anti-ageing properties. Here, we summarize recent advances on exploring the biological role of melatonin in stem cells, and discuss its potential applications in stem cell-based therapy.

Astragalus Polysaccharide Attenuated Iron Overload-Induced Dysfunction of Mesenchymal Stem Cells via Suppressing Mitochondrial ROS.

BACKGROUND/AIMS: Bone marrow-derived mesenchymal stem cells (BMSCs) have the ability to differentiate into multilineage cells such as osteoblasts, chondrocytes, and cardiomyocytes. Dysfunction of BMSCs in response to pathological stimuli participates in the development of diseases such as osteoporosis. Astragalus polysaccharide (APS) is a major active ingredient of Astragalus membranaceus, a commonly used anti-aging herb in traditional Chinese medicine. The aim of this study was to investigate whether APS protects against iron overload-induced dysfunction of BMSCs and its underlying mechanisms. METHODS: BMSCs were exposed to ferric ammonium citrate (FAC) with or without different concentrations of APS. The viability and proliferation of BMSCs were assessed by CCK-8 assay and EdU staining. Cell apoptosis, senescence and pluripotency were examined utilizing TUNEL staining, ß-galactosidase staining and qRT-PCR respectively. The reactive oxygen species (ROS) level was assessed in BMSCs with a DCFH-DA probe and MitoSOX Red staining. RESULTS: Firstly, we found that iron overload induced by FAC markedly reduced the viability and proliferation of BMSCs, but treatment with APS at 10, 30 and 100 µg/mL was able to counter the reduction of cell proliferation. Furthermore, exposure to FAC led to apoptosis and senescence in BMSCs, which were partially attenuated by APS. The pluripotent genes Nanog, Sox2 and Oct4 were shown to be downregulated in BMSCs after FAC treatment, however APS inhibited the reduction of Nanog, Sox2 and Oct4 expression. Further study uncovered that APS treatment abrogated the increase of intracellular and mitochondrial ROS level in FAC-treated BMSCs. CONCLUSION: Treatment of BMSCs with APS to impede mitochondrial ROS accumulation can remarkably inhibit apoptosis, senescence, and the reduction of proliferation and pluripotency of BMSCs caused by FAC-induced iron overload.

Characterization of Eicosanoids Produced by Adipocyte Lipolysis: IMPLICATION OF CYCLOOXYGENASE-2 IN ADIPOSE INFLAMMATION.

Excessive adipocyte lipolysis generates lipid mediators and triggers inflammation in adipose tissue. However, the specific roles of lipolysis-generated mediators in adipose inflammation remain to be elucidated. In the present study, cultured 3T3-L1 adipocytes were treated with isoproterenol to activate lipolysis and the fatty acyl lipidome of released lipids was determined by using LC-MS/MS. We observed that ß-adrenergic activation elevated levels of approximately fifty lipid species, including metabolites of cyclooxygenases, lipoxygenases, epoxygenases, and other sources. Moreover, we found that ß-adrenergic activation induced cyclooxygenase 2 (COX-2), not COX-1, expression in a manner that depended on activation of hormone-sensitive lipase (HSL) in cultured adipocytes and in the epididymal white adipose tissue (EWAT) of C57BL/6 mice. We found that lipolysis activates the JNK/NFκB signaling pathway and inhibition of the JNK/NFκB axis abrogated the lipolysis-stimulated COX-2 expression. In addition, pharmacological inhibition of COX-2 activity diminished levels of COX-2 metabolites during lipolytic activation. Inhibition of COX-2 abrogated the induction of CCL2/MCP-1 expression by ß-adrenergic activation and prevented recruitment of macrophage/monocyte to adipose tissue. Collectively, our data indicate that excessive adipocyte lipolysis activates the JNK/NFκB pathway leading to the up-regulation of COX-2 expression and recruitment of inflammatory macrophages.

Does the method of radiologic surveillance affect survival after resection of stage I non-small cell lung cancer?

OBJECTIVES: Controversy persists regarding appropriate radiographic surveillance strategies after lung cancer resection. We compared the impact of surveillance computed tomography scan versus chest radiography in patients who underwent resection for stage I lung cancer. METHODS: A retrospective analysis was performed of all patients undergoing resection for pathologic stage I lung cancer from January 2000 to April 2013. After resection, follow-up included routine history and physical examination in conjunction with chest radiography or computed tomography at the discretion of the treating physician. Identification of successive lung malignancy (ie, recurrence at any new site or new primary) and survival were recorded. RESULTS: There were 554 evaluable patients, with 232 receiving routine postoperative computed tomography and 322 receiving routine chest radiography. Postoperative 5-year survival was 67.8% in the computed tomography group versus 74.8% in the chest radiography group (P = .603). Successive lung malignancy was found in 27% (63/232) of patients receiving computed tomography versus 22% (72/322) receiving chest radiography (P = .19). The mean time from surgery to diagnosis of successive malignancy was 1.93 years for computed tomography versus 2.56 years for chest radiography (P = .046). For the computed tomography group, 41% (26/63) of successive malignancies were treated with curative intent versus 40% (29/72) in the chest radiography group (P = .639). Cox proportional hazard analysis indicated imaging modality (computed tomography vs chest radiography) was not associated with survival (P = .958). CONCLUSIONS: Surveillance computed tomography may result in earlier diagnosis of successive malignancy versus chest radiography in stage I lung cancer, although no difference in survival was demonstrated. A randomized trial would help determine the impact of postoperative surveillance strategies on survival.