A vascular mechanism to explain thermally mediated variations in deep-body cooling rates during the immersion of profoundly hyperthermic individuals.
Exp Physiol. 2018 Jan 18;:
Authors: Caldwell JN, van den Heuvel AMJ, Kerry P, Clark MJ, Peoples GE, Taylor NAS
Physiologically trivial time differences for cooling the intrathoracic viscera of hyperthermic individuals have been reported between cold- and temperate-water immersion treatments. One explanation for that observation is reduced convective heat delivery to the skin during cold immersion, and this experiment was designed to test both the validity of that observation, and its underlying hypothesis. Eight healthy males participated in four head-out, water immersions: two when normothermic, and two following exercise-induced, moderate-profound hyperthermia. Two water temperatures were used within each thermal state: temperate (26°C) and cold (14°C). Tissue temperatures were measured at three deep-body sites (oesophagus, auditory canal, rectum) and eight skin surfaces, with cutaneous vascular responses simultaneously evaluated from both forearms (laser-Doppler flowmetry and venous-occlusion plethysmography). During the cold immersion of normothermic individuals, oesophageal temperature decreased relative to baseline (-0.31°C over 20 min; P < 0.05), whilst rectal temperature increased (0.20°C; P < 0.05). When rendered hyperthermic, oesophageal (-0.75°C) and rectal temperatures decreased (-0.05°C) during the transition period (< 8.5 min, mostly in air at 22°C), with the former dropping to 37.5°C just 54 s faster when immersed in cold, than in temperate water (P < 0.05). Minimal cutaneous vasoconstriction occurred during either normothermic immersion, whereas pronounced constriction was evident during both immersions when subjects were hyperthermic, with the colder water eliciting a greater vascular response (P < 0.05). It was concluded that the rapid intrathoracic cooling of asymptomatic, hyperthermic individuals in temperate water was a reproducible phenomenon, with slower than expected cooling in cold water brought about by stronger cutaneous vasoconstriction reducing convective heat delivery to the periphery. This article is protected by copyright. All rights reserved.
PMID: 29345019 [PubMed - as supplied by publisher]
pH-Responsible fluorescent carbon nanoparticles for tumor selective theranostics via pH-turn on/off fluorescence and photothermal effect in vivo and in vitro.
Nanoscale. 2018 Jan 18;:
Authors: Kang EB, Lee JE, Mazrad ZAI, In I, Jeong JH, Park SY
We developed nanoparticles comprising a photothermal dye (IR825)-loaded carbonized zwitterionic polymer [FNP-I] as "switch-on" pH-responsive fluorescence probes to sense intracellular cancer cells and for near-infrared (NIR) controllable photothermal therapy (PTT) in vivo and in vitro. The fluorescent "off" of FNP-I was activated after reaching the cancer cell environment, where the zwitterionic compartment of FNP lost its hydrophobicity to induce PTT-mediated heat release of IR825 under NIR irradiation in the tumor. Approximately 100% of the IR825 was released from the FNP core to generate high thermal conversion to completely kill the cancer cells. Furthermore, after intravenous treatment of FNP-I into MDAMB-231-cell bearing mice, pH-responsive photothermal therapy was observed, achieving marked ablation of tumor cells with release of IR825 under tumor environment conditions. In addition, fluorescent signals were clearly found at the tumor site after 3 h, decreasing at the 6 h time point. The in vitro and in vivo detection system demonstrated good cellular uptake and biocompatibility as a potential imaging-guided photothermal therapy nanotool for cancer treatment. Interestingly, the synergism of the biosensor and PTT in single FNP-I platform led to more effective cancer cell killing than either monotherapy, providing a new approach for cancer treatment.
PMID: 29344592 [PubMed - as supplied by publisher]
Combining radiation with hyperthermia: a multiscale model informed by in vitro experiments.
J R Soc Interface. 2018 Jan;15(138):
Authors: Brüningk S, Powathil G, Ziegenhein P, Ijaz J, Rivens I, Nill S, Chaplain M, Oelfke U, Ter Haar G
Combined radiotherapy and hyperthermia offer great potential for the successful treatment of radio-resistant tumours through thermo-radiosensitization. Tumour response heterogeneity, due to intrinsic, or micro-environmentally induced factors, may greatly influence treatment outcome, but is difficult to account for using traditional treatment planning approaches. Systems oncology simulation, using mathematical models designed to predict tumour growth and treatment response, provides a powerful tool for analysis and optimization of combined treatments. We present a framework that simulates such combination treatments on a cellular level. This multiscale hybrid cellular automaton simulates large cell populations (up to 107 cells) in vitro, while allowing individual cell-cycle progression, and treatment response by modelling radiation-induced mitotic cell death, and immediate cell kill in response to heating. Based on a calibration using a number of experimental growth, cell cycle and survival datasets for HCT116 cells, model predictions agreed well (R2 > 0.95) with experimental data within the range of (thermal and radiation) doses tested (0-40 CEM43, 0-5 Gy). The proposed framework offers flexibility for modelling multimodality treatment combinations in different scenarios. It may therefore provide an important step towards the modelling of personalized therapies using a virtual patient tumour.
PMID: 29343635 [PubMed - in process]
A heterogeneous tissue model for treatment planning for magnetic resonance-guided laser interstitial thermal therapy.
Int J Hyperthermia. 2018 Jan 17;:1-35
Authors: Mitchell D, Fahrenholtz S, MacLellan C, Bastos D, Rao G, Prabhu S, Weinberg J, Hazle J, Stafford J, Fuentes D
We evaluated a physics-based model for planning for magnetic resonance-guided laser interstitial thermal therapy for focal brain lesions. Linear superposition of analytical point source solutions to the steady-state Pennes bioheat transfer equation simulates laser-induced heating in brain tissue. The line integral of the photon attenuation from the laser source enables computation of the laser interaction with heterogeneous tissue. Magnetic resonance thermometry data sets (n = 31) were used to calibrate and retrospectively validate the model's thermal ablation prediction accuracy, which was quantified by the Dice similarity coefficient (DSC) between model-predicted and measured ablation regions (T > 57°C). A Gaussian mixture model was used to identify independent tissue labels on pretreatment anatomical magnetic resonance images. The tissue-dependent optical attenuation coefficients within these labels were calibrated using an interior point method that maximizes DSC agreement with thermometry. The distribution of calibrated tissue properties formed a population model for our patient cohort. Model prediction accuracy was cross-validated using the population mean of the calibrated tissue properties. A homogeneous tissue model was used as a reference control. The median DSC values in cross-validation were 0.829 for the homogeneous model and 0.840 for the heterogeneous model. In cross-validation, the heterogeneous model produced a DSC higher than that produced by the homogeneous model in 23 of the 31 brain lesion ablations. Results of a paired, two-tailed Wilcoxon signed-rank test indicated that the performance improvement of the heterogeneous model over that of the homogeneous model was statistically significant (p < 0.01).
PMID: 29343140 [PubMed - as supplied by publisher]
Primary SWL Is an Efficient and Cost-Effective Treatment for Lower Pole Renal Stones Between 10 and 20 mm in Size: A Large Single Center Study.
J Endourol. 2017 May;31(5):510-516
Authors: Chan LH, Good DW, Laing K, Phipps S, Thomas BG, Keanie JY, Tolley DA, Cutress ML
INTRODUCTION: To assess the clinical features, outcomes, complications, and cost-effectiveness of shockwave lithotripsy (SWL), flexible ureterorenoscopy (FURS), and percutaneous nephrolithotomy (PCNL) in the treatment of lower pole (LP) stones (10-20 mm) in a large tertiary referral center.
PATIENTS AND METHODS: Consecutive patients treated for solitary LP stones (10-20 mm) between 2008 and 2013 were identified from a prospective database. SWL was used as primary treatment in all cases (following a stone multidisciplinary team assessment), with FURS and PCNL reserved for SWL contraindications, failure, or patient choice. "Success" was defined as stone free and/or clinically insignificant stone fragments (≤3 mm) at 1 and 3 months follow-up. Effect of anatomy on SWL success was determined from using CT images and regression analysis. Average cost per treatment modality (including additional second-line treatments) was calculated for each group using the National Health Service England 2014/15 National Tariff Healthcare Resource Group codes.
RESULTS: Two hundred twenty-five patients were included (mean age 54.9; median stone size 12 mm). One hundred ninety-eight (88%), 21 (9.3%), and 6 (2.7%) patients underwent SWL, FURS, and PCNL as primary treatments, respectively, for median stone sizes of 12, 12, and 20 mm. Overall success rates were 82.8%, 76.1%, and 66.7%, respectively (p < 0.05). Sixty-three percent of patients undergoing primary SWL were effectively treated after one session. Anatomical analysis determined infundibulopelvic angle and infundibular length to be significantly different in patients effectively treated with SWL (p = 0.04). The average cost per treatment modality was also significantly lower for SWL (£750) than for FURS (£1261) or PCNL (£2658) (p < 0.01).
CONCLUSION: SWL is both an efficacious and cost-effective primary treatment for patients with solitary LP stones (10-20 mm). The majority of patients can be effectively treated with primary SWL in a dedicated stone center, with the benefits of a short length of stay, low complication, and auxiliary treatment rates. The referral of such patients to high-volume lithotripsy centers with demonstrable outcomes should be given due consideration.
PMID: 28355100 [PubMed - indexed for MEDLINE]
SIRT1 protects the heart from ER stress-induced cell death through eIF2α deacetylation.
Cell Death Differ. 2017 02;24(2):343-356
Authors: Prola A, Pires Da Silva J, Guilbert A, Lecru L, Piquereau J, Ribeiro M, Mateo P, Gressette M, Fortin D, Boursier C, Gallerne C, Caillard A, Samuel JL, François H, Sinclair DA, Eid P, Ventura-Clapier R, Garnier A, Lemaire C
Over the past decade, endoplasmic reticulum (ER) stress has emerged as an important mechanism involved in the pathogenesis of cardiovascular diseases including heart failure. Cardiac therapy based on ER stress modulation is viewed as a promising avenue toward effective therapies for the diseased heart. Here, we tested whether sirtuin-1 (SIRT1), a NAD+-dependent deacetylase, participates in modulating ER stress response in the heart. Using cardiomyocytes and adult-inducible SIRT1 knockout mice, we demonstrate that SIRT1 inhibition or deficiency increases ER stress-induced cardiac injury, whereas activation of SIRT1 by the SIRT1-activating compound STAC-3 is protective. Analysis of the expression of markers of the three main branches of the unfolded protein response (i.e., PERK/eIF2α, ATF6 and IRE1) showed that SIRT1 protects cardiomyocytes from ER stress-induced apoptosis by attenuating PERK/eIF2α pathway activation. We also present evidence that SIRT1 physically interacts with and deacetylates eIF2α. Mass spectrometry analysis identified lysines K141 and K143 as the acetylation sites on eIF2α targeted by SIRT1. Furthermore, mutation of K143 to arginine to mimic eIF2α deacetylation confers protection against ER stress-induced apoptosis. Collectively, our findings indicate that eIF2α deacetylation on lysine K143 by SIRT1 is a novel regulatory mechanism for protecting cardiac cells from ER stress and suggest that activation of SIRT1 has potential as a therapeutic approach to protect the heart against ER stress-induced injury.
PMID: 27911441 [PubMed - indexed for MEDLINE]
Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells.
Cell Death Differ. 2017 Feb;24(2):300-316
Authors: Kramer D, Stark N, Schulz-Heddergott R, Erytch N, Edmunds S, Roßmann L, Bastians H, Concin N, Moll UM, Dobbelstein M
All current regimens for treating ovarian cancer center around carboplatin as standard first line. The HSP90 inhibitor ganetespib is currently being assessed in advanced clinical oncology trials. Thus, we tested the combined effects of ganetespib and carboplatin on a panel of 15 human ovarian cancer lines. Strikingly, the two drugs strongly synergized in cytotoxicity in tumor cells lacking wild-type p53. Mechanistically, ganetespib and carboplatin in combination, but not individually, induced persistent DNA damage causing massive global chromosome fragmentation. Live-cell microscopy revealed chromosome fragmentation occurring to a dramatic degree when cells condensed their chromatin in preparation for mitosis, followed by cell death in mitosis or upon aberrant exit from mitosis. HSP90 inhibition caused the rapid decay of key components of the Fanconi anemia pathway required for repair of carboplatin-induced interstrand crosslinks (ICLs), as well as of cell cycle checkpoint mediators. Overexpressing FancA rescued the DNA damage induced by the drug combination, indicating that FancA is indeed a key client of Hsp90 that enables cancer cell survival in the presence of ICLs. Conversely, depletion of nuclease DNA2 prevented chromosomal fragmentation, pointing to an imbalance of defective repair in the face of uncontrolled nuclease activity as mechanistic basis for the observed premitotic DNA fragmentation. Importantly, the drug combination induced robust antitumor activity in xenograft models, again accompanied with depletion of FancA. In sum, our findings indicate that ganetespib strongly potentiates the antitumor efficacy of carboplatin by causing combined inhibition of DNA repair and cell cycle control mechanisms, thus triggering global chromosome disruption, aberrant mitosis and cell death.
PMID: 27834954 [PubMed - indexed for MEDLINE]
Targeting the fungal calcium-calcineurin signaling network in overcoming drug resistance.
Future Med Chem. 2016 08;8(12):1379-81
Authors: Li X, Sun S
PMID: 27463738 [PubMed - indexed for MEDLINE]
Digital Glissonectomy: A Safe Perihepatic Peritonectomy.
Ann Surg Oncol. 2016 Nov;23(12):3978-3985
Authors: Passot G, Kim BJ, Vaudoyer D, Kepenekian V, Bonnefoy I, Bakrin N, Cotte E, Glehen O
BACKGROUND: Complete cytoreductive surgery (CRS), combining organ resection and peritonectomy, is the only treatment that could offer cure for patients with peritoneal carcinomatosis. Initially, when the Glisson's capsule was involved without deep liver parenchyma invasion, either electroevaporation or Glisson's capsule resection was proposed. The objective of this study is to present and evaluate the safety of this standardized digital glissonectomy.
METHODS: Since 2009, the peritonectomy of the Glisson's capsule, or digital glissonectomy, has been standardized at our institution.
RESULTS: Among 655 patients who underwent a complete CRS between 2009 and 2014, 91 (14 %) glissonectomies were performed. Pseudomyxoma peritonei was the primary indication, and a glissonectomy was more frequently performed for patients with high peritoneal cancer index. The morbidity and mortality of CRS were not increased after glissonectomy (p = 0.069 and 0.949, respectively).
CONCLUSIONS: Digital glissonectomy is feasible and safe, when proposed for superficial deposits on Glisson's capsule.
PMID: 27342827 [PubMed - indexed for MEDLINE]
CRS-HIPEC Prolongs Survival but is Not Curative for Patients with Peritoneal Carcinomatosis of Gastric Cancer.
Ann Surg Oncol. 2016 Nov;23(12):3972-3977
Authors: Boerner T, Graichen A, Jeiter T, Zemann F, Renner P, März L, Soeder Y, Schlitt HJ, Piso P, Dahlke MH
PURPOSE: Peritoneal carcinomatosis (PC) is a dismal feature of gastric cancer that most often is treated by systemic palliative chemotherapy. In this retrospective matched pairs-analysis, we sought to establish whether specific patient subgroups alternatively should be offered a multimodal therapy concept, including cytoreductive surgery (CRS) and intraoperative hyperthermic chemotherapy (HIPEC).
METHODS: Clinical outcomes of 38 consecutive patients treated with gastrectomy, CRS and HIPEC for advanced gastric cancer with PC were compared to patients treated by palliative management (with and without gastrectomy) and to patients with advanced gastric cancer with no evidence of PC. Kaplan-Meier survival curves and multivariate Cox regression models were applied.
RESULTS: Median survival time after gastrectomy was similar between patients receiving CRS-HIPEC and matched control patients operated for advanced gastric cancer without PC [18.1 months, confidence interval (CI) 10.1-26.0 vs. 21.8 months, CI 8.0-35.5 months], resulting in comparable 5-year survival (11.9 vs. 12.1 %). The median survival time after first diagnosis of PC for gastric cancer was 17.2 months (CI 10.1-24.2 months) in the CRS-HIPEC group compared with 11.0 months (CI 7.4-14.6 months) for those treated by gastrectomy and chemotherapy alone, resulting in a twofold increase of 2-year survival (35.8 vs. 16.9 %).
CONCLUSIONS: We provide retrospective evidence that multimodal treatment with gastrectomy, CRS, and HIPEC is associated with improved survival for patients with PC of advanced gastric cancer compared with gastrectomy and palliative chemotherapy alone. We also show that patients treated with CRS-HIPEC have comparable survival to matched control patients without PC. However, regardless of treatment scheme, all patients subsequently recur and die of disease.
PMID: 27313067 [PubMed - indexed for MEDLINE]