Central obesity and atherogenic dyslipidemia in metabolic syndrome are associated with increased risk for colorectal adenoma in a Chinese population

<p>Abstract</p> <p>Background</p> <p>Metabolic syndrome (MetS) is composed of cardiovascular risk factors including insulin resistance, obesity, dyslipidemia, and hypertension. Most of the components of MetS have been linked to the development of neoplasm. The purpose of this study was to evaluate the relationship between individual components of MetS and colorectal adenoma.</p> <p>Methods</p> <p>The study subjects were recruited from a pool of 4872 individuals who underwent a health check-up examination during the period January 2006 to May 2008. Each participant fulfilled a structured questionnaire. MetS was defined based on the America Heart Association and National Heart Lung Blood Institute criteria. Subjects with history of colon cancer, colon polyps, colitis, or prior colonic surgery were excluded.</p> <p>Results</p> <p>A total of 4122 subjects were included for final analysis (2367 men and 1755 women; mean age, 49.6 ± 11.7 years). Of them, MetS was diagnosed in 708 men (29.9%) and in 367 women (20.9%). Among the patients with MetS, 34.6% had adenoma, 31.7% had hyperplastic polyps and 23.3% were polyp-free (p < 0.0001, Chi-square test). The adjusted OR for colorectal adenoma was significantly higher in the subjects with MetS (OR, 1.31, CI: 1.09-1.57). A stronger association between MetS and colorectal adenoma was found in men (OR:1.44, CI:1.16-1.80) than in women (OR:1.04, CI:0.74-1.46). The adjusted OR for adenoma increased as the number of MetS components increased (p for trend = 0.0001 ). When the individual components of MetS were analyzed separately, only central obesity (OR:1.36, CI:1.14-1.63), low HDL cholesterol levels (OR:1.30, CI:1.10-1.54) and high triglyceride levels (OR:1.26, CI:1.04-1.53) were independently associated with colorectal adenoma.</p> <p>Conclusions</p> <p>Of the components of MetS analyzed in this study, central obesity and dyslipidemia are independent risk factors for colorectal adenoma. With regard to the prevention of colorectal neoplasm, life-style modification such as weight reduction is worthwhile.</p

Elimination of head and neck cancer initiating cells through targeting glucose regulated protein78 signaling

<p>Abstract</p> <p>Background</p> <p>Head and neck squamous cell carcinoma (HNSCC) is a highly lethal cancer that contains cellular and functional heterogeneity. Previously, we enriched a subpopulation of highly tumorigenic head and neck cancer initiating cells (HN-CICs) from HNSCC. However, the molecular mechanisms by which to govern the characteristics of HN-CICs remain unclear. GRP78, a stress-inducible endoplasmic reticulum chaperone, has been reported to play a crucial role in the maintenance of embryonic stem cells, but the role of GRP78 in CICs has not been elucidated.</p> <p>Results</p> <p>Initially, we recognized GRP78 as a putative candidate on mediating the stemness and tumorigenic properties of HN-CICs by differential systemic analyses. Subsequently, cells with GRP78 anchored at the plasma membrane (^memGRP78⁺) exerted cancer stemness properties of self-renewal, differentiation and radioresistance. Of note, xenotransplantation assay indicated merely 100 ^memGRP78⁺HNSCCs resulted in tumor growth. Moreover, knockdown of GRP78 significantly reduced the self-renewal ability, side population cells and expression of stemness genes, but inversely promoted cell differentiation and apoptosis in HN-CICs. Targeting GRP78 also lessened tumorigenicity of HN-CICs both <it>in vitro </it>and <it>in vivo</it>. Clinically, co-expression of GRP78 and Nanog predicted the worse survival prognosis of HNSCC patients by immunohistochemical analyses. Finally, depletion of GRP78 in HN-CICs induced the expression of Bax, Caspase 3, and PTEN.</p> <p>Conclusions</p> <p>In summary, ^memGRP78 should be a novel surface marker for isolation of HN-CICs, and targeting GRP78 signaling might be a potential therapeutic strategy for HNSCC through eliminating HN-CICs.</p

Inflammatory myofibroblastic tumor of the lung- a case report

A 45-year-old man presented with a six-month history of progressive dyspnea with productive cough and wheezing. The patient was a heavy smoker and had a history of tongue cancer, hypertension, and asthma. Chest X-ray and computed tomography showed a mass lesion in the left hilar region and total collapse of the upper left lobe of the lung. Bronchoscopy revealed a whitish solid tumor obstructing the left upper lobe bronchus. Positron emission tomography showed increased tracer uptake in the lesion. A thoracoscopic lobectomy of the left upper lobe of the lung was performed. The final pathologic diagnosis was inflammatory myofibroblastic tumor

Focused ultrasound-mediated blood–brain barrier opening is safe and feasible with moderately hypofractionated radiotherapy for brainstem diffuse midline glioma

Background Diffuse midline glioma (DMG) is a pediatric tumor with dismal prognosis. Systemic strategies have been unsuccessful and radiotherapy (RT) remains the standard-of-care. A central impediment to treatment is the blood–brain barrier (BBB), which precludes drug delivery to the central nervous system (CNS). Focused ultrasound (FUS) with microbubbles can transiently and non-invasively disrupt the BBB to enhance drug delivery. This study aimed to determine the feasibility of brainstem FUS in combination with clinical doses of RT. We hypothesized that FUS-mediated BBB-opening (BBBO) is safe and feasible with 39 Gy RT. Methods To establish a safety timeline, we administered FUS to the brainstem of non-tumor bearing mice concurrent with or adjuvant to RT; our findings were validated in a syngeneic brainstem murine model of DMG receiving repeated sonication concurrent with RT. The brainstems of male B6 (Cg)-Tyrc-2J/J albino mice were intracranially injected with mouse DMG cells (PDGFB+, H3.3K27M, p53−/−). A clinical RT dose of 39 Gy in 13 fractions (39 Gy/13fx) was delivered using the Small Animal Radiation Research Platform (SARRP) or XRAD-320 irradiator. FUS was administered via a 0.5 MHz transducer, with BBBO and tumor volume monitored by magnetic resonance imaging (MRI). Results FUS-mediated BBBO did not affect cardiorespiratory rate, motor function, or tissue integrity in non-tumor bearing mice receiving RT. Tumor-bearing mice tolerated repeated brainstem BBBO concurrent with RT. 39 Gy/13fx offered local control, though disease progression occurred 3–4 weeks post-RT. Conclusion Repeated FUS-mediated BBBO is safe and feasible concurrent with RT. In our syngeneic DMG murine model, progression occurs, serving as an ideal model for future combination testing with RT and FUS-mediated drug delivery

Neurological manifestations of COVID-19 in adults and children

Different neurological manifestations of coronavirus disease 2019 (COVID-19) in adults and children and their impact have not been well characterized. We aimed to determine the prevalence of neurological manifestations and in-hospital complications among hospitalized COVID-19 patients and ascertain differences between adults and children. We conducted a prospective multicentre observational study using the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) cohort across 1507 sites worldwide from 30 January 2020 to 25 May 2021. Analyses of neurological manifestations and neurological complications considered unadjusted prevalence estimates for predefined patient subgroups, and adjusted estimates as a function of patient age and time of hospitalization using generalized linear models. Overall, 161 239 patients (158 267 adults; 2972 children) hospitalized with COVID-19 and assessed for neurological manifestations and complications were included. In adults and children, the most frequent neurological manifestations at admission were fatigue (adults: 37.4%; children: 20.4%), altered consciousness (20.9%; 6.8%), myalgia (16.9%; 7.6%), dysgeusia (7.4%; 1.9%), anosmia (6.0%; 2.2%) and seizure (1.1%; 5.2%). In adults, the most frequent in-hospital neurological complications were stroke (1.5%), seizure (1%) and CNS infection (0.2%). Each occurred more frequently in intensive care unit (ICU) than in non-ICU patients. In children, seizure was the only neurological complication to occur more frequently in ICU versus non-ICU (7.1% versus 2.3%, P &lt; 0.001). Stroke prevalence increased with increasing age, while CNS infection and seizure steadily decreased with age. There was a dramatic decrease in stroke over time during the pandemic. Hypertension, chronic neurological disease and the use of extracorporeal membrane oxygenation were associated with increased risk of stroke. Altered consciousness was associated with CNS infection, seizure and stroke. All in-hospital neurological complications were associated with increased odds of death. The likelihood of death rose with increasing age, especially after 25 years of age. In conclusion, adults and children have different neurological manifestations and in-hospital complications associated with COVID-19. Stroke risk increased with increasing age, while CNS infection and seizure risk decreased with age

Predictors of Response to Autologous Dendritic Cell Therapy in Glioblastoma Multiforme

BackgroundGlioblastoma (GBM) is the most common and lethal primary malignant glioma in adults. Dendritic cell (DC) vaccines have demonstrated promising results in GBM clinical trials. However, some patients do not respond well to DC therapy, with survival rates similar to those of conventional therapy. We retrospectively analyzed clinical and laboratory data to evaluate the factors affecting vaccine treatment.MethodsForty-seven patients with de novo GBM were enrolled at China Medical University Hospital between 2005 and 2010 and divided into two subgroups. One subgroup of 27 patients received postsurgical adjuvant immunotherapy with autologous dendritic cell/tumor antigen vaccine (ADCTA) in conjunction with conventional treatment of concomitant chemoradiotherapy (CCRT) with temozolomide. The other 20 patients received only postsurgical conventional treatment without immunotherapy. Immunohistochemistry for CD45, CD4, CD8, programed death ligand 1 (PD-L1), and programed death 1 (PD-1) was performed on sections of surgical tumor specimens and peripheral blood mononuclear cells (PBMCs). Pearson’s correlation, Cox proportional hazard model, and Kaplan–Meier analyses were performed to examine the correlations between the prognostic factors and survival rates.ResultsYounger age (&lt;57 years), gross total resection, and CCRT and PD-1+ lymphocyte counts were significant prognostic factors of overall survival (OS) and progression-free survival (PFS) in the ADCTA group. Sex, CD45+ lymphocyte count, CD4+ or CD8+ lymphocyte count, tumor PD-L1 expression, isocitrate dehydrogenase 1 mutation, and O6 methylguanine-DNA methyltransferase promoter methylation status were not significant factors in both groups. In the ADCTA group, patients with tumor-infiltrating lymphocytes (TILs) with a lower PD-1+/CD8+ ratio (≤0.21) had longer OS and PFS (median OS 60.97 months, P &lt; 0.001 and PFS 11.2 months, P &lt; 0.008) compared to those with higher PD-1+/CD8+ ratio (&gt;0.21) (median OS 20.07 months, P &lt; 0.001 and PFS 4.43 months, P &lt; 0.008). Similar results were observed in patients’ PBMCs; lymphocyte counts with lower PD-1+/CD8+ ratio (≤0.197) had longer OS and PFS. There was a significant correlation of PD-1+/CD8+ ratio between TILs and PBMCs (Pearson’s correlation R2 = 0.6002, P &lt; 0.001). By contrast, CD4−, CD8−, but PD-1+, CD45+ tumor-infiltrating lymphocytes have no impact on OS and PFS (P = 0.073 and P = 0.249, respectively).ConclusionFor patients receiving DC vaccine adjuvant therapy, better outcomes are predicted in patients with younger age, with TILs or PBMCs with lower PD-1+/CD8+ ratio, with gross tumor resection, and receiving CCRT

Abstract B104: Tid1 as a novel target for HSP-directed therapy in NSCLC.

Abstract Molecular chaperones, commonly known as heat shock proteins (HSPs), are essential for mammalian cells to maintain homeostasis. HSPs may interact with diverse co-chaperones and induce an ATPase-coupled structural change in client proteins and regulate critical signaling networks. More than 200 client proteins have been identified which may serve as important therapeutic targets in human diseases. The human tumorous imaginal disc 1 (Tid1) protein, a member of the DnaJ domain protein family, is a tumor suppressor and is known to promote ubiquitin-mediated degradation of oncogenic kinases. The Tid1 is a heat shock protein and function as molecular chaperone. In this work, we investigated the role of Tid1 in the tumorigenesis of non-small-cell lung cancer (NSCLC). The expression of two alternatively spliced isoforms of Tid1 (Tid1L and Tid1S) as well as EGFR was examined with RT-PCR and immunohistochemistry (IHC) in tumors from NSCLC patients. The expression of Tid1 was reduced in the majority of NSCLCs and an inverse correlation was observed for the expression of Tid1 and EGFR. Furthermore, we demonstrated that Tid1L, EGFR, HSP70, and HSP90 interacted with each other, and this interaction is dependent on functional DnaJ domain of the Tid1L. Overexpression of the Tid1L in lung cancer cells in vitro inhibited cell proliferation, anchorage-independent growth, and induced apoptosis. We further showed that overexpression of the Tid1L in lung cancer cells attenuated EGFR signaling activity and inhibited the activation of AKT, ERK and STAT3. In contrast, knockdown of Tid1 in EGFR-transfected lung cancer cells markedly increased the stability of EGFR. Taken together, our results support that Tid1L may play a critical role in regulating EGFR signaling in NSCLC; raising the possibility that Tid1 may be a novel target for HSP directed therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B104.</jats:p

Band-Selection of a Portal LED-Induced Autofluorescence Multispectral Imager to Improve Oral Cancer Detection

This aim of this study was to find effective spectral bands for the early detection of oral cancer. The spectral images in different bands were acquired using a self-made portable light-emitting diode (LED)-induced autofluorescence multispectral imager equipped with 365 and 405 nm excitation LEDs, emission filters with center wavelengths of 470, 505, 525, 532, 550, 595, 632, 635, and 695 nm, and a color image sensor. The spectral images of 218 healthy points in 62 healthy participants and 218 tumor points in 62 patients were collected in the ex vivo trials at China Medical University Hospital. These ex vivo trials were similar to in vivo because the spectral images of anatomical specimens were immediately acquired after the on-site tumor resection. The spectral images associated with red, blue, and green filters correlated with and without nine emission filters were quantized by four computing method, including summated intensity, the highest number of the intensity level, entropy, and fractional dimension. The combination of four computing methods, two excitation light sources with two intensities, and 30 spectral bands in three experiments formed 264 classifiers. The quantized data in each classifier was divided into two groups: one was the training group optimizing the threshold of the quantized data, and the other was validating group tested under this optimized threshold. The sensitivity, specificity, and accuracy of each classifier were derived from these tests. To identify the influential spectral bands based on the area under the region and the testing results, a single-layer network learning process was used. This was compared to conventional rules-based approaches to show its superior and faster performance. Consequently, four emission filters with the center wavelengths of 470, 505, 532, and 550 nm were selected by an AI-based method and verified using a rule-based approach. The sensitivities of six classifiers using these emission filters were more significant than 90%. The average sensitivity of these was about 96.15%, the average specificity was approximately 69.55%, and the average accuracy was about 82.85%

Band-Selection of a Portal LED-Induced Autofluorescence Multispectral Imager to Improve Oral Cancer Detection

This aim of this study was to find effective spectral bands for the early detection of oral cancer. The spectral images in different bands were acquired using a self-made portable light-emitting diode (LED)-induced autofluorescence multispectral imager equipped with 365 and 405 nm excitation LEDs, emission filters with center wavelengths of 470, 505, 525, 532, 550, 595, 632, 635, and 695 nm, and a color image sensor. The spectral images of 218 healthy points in 62 healthy participants and 218 tumor points in 62 patients were collected in the ex vivo trials at China Medical University Hospital. These ex vivo trials were similar to in vivo because the spectral images of anatomical specimens were immediately acquired after the on-site tumor resection. The spectral images associated with red, blue, and green filters correlated with and without nine emission filters were quantized by four computing method, including summated intensity, the highest number of the intensity level, entropy, and fractional dimension. The combination of four computing methods, two excitation light sources with two intensities, and 30 spectral bands in three experiments formed 264 classifiers. The quantized data in each classifier was divided into two groups: one was the training group optimizing the threshold of the quantized data, and the other was validating group tested under this optimized threshold. The sensitivity, specificity, and accuracy of each classifier were derived from these tests. To identify the influential spectral bands based on the area under the region and the testing results, a single-layer network learning process was used. This was compared to conventional rules-based approaches to show its superior and faster performance. Consequently, four emission filters with the center wavelengths of 470, 505, 532, and 550 nm were selected by an AI-based method and verified using a rule-based approach. The sensitivities of six classifiers using these emission filters were more significant than 90%. The average sensitivity of these was about 96.15%, the average specificity was approximately 69.55%, and the average accuracy was about 82.85%.</jats:p