PROBING THE IMPACT OF GAMMA-IRRADIATION ON THE METABOLIC STATE OF NEURAL STEM AND PRECURSOR CELLS USING DUAL-WAVELENGTH INTRINSIC SIGNAL TWO-PHOTON EXCITED FLUORESCENCE

Two-photon excitedfluorescence(TPEF)spectroscopy and imaging were used to investigate the effects of gamma-irradiation on neural stem and precursor cells(NSPCs).While the observed signal from reduced nicotinamide adenine dinucleotide(NADH)was localized to the mitochondria,the signal typically associated with oxidizedflavoproteins(Fp)was distributed diffusely throughout the cell.The measured TPEF emission and excitation spectra were similar to the established spectra of NAD(P)H and Fp.Fpfluorescence intensity was markedly increased by addition of the electron transport chain(ETC)modulator menadione to the medium,along with a concomitant decrease in the NAD(P)H signal.Three-dimensional(3D)neurospheres were imaged to obtain the cellular metabolic index(CMI),calculated as the ratio of Fp to NAD(P)Hfluorescence intensity.Radiation effects were found to differ between low-dose(
50 cGy)and high-dose(50 cGy)exposures.Low-dose irradiation caused a marked drop in CMI values accompanied by increased cellular proliferation.At higher doses,both NAD(P)H and Fp signals increased,leading to an overall elevation in CMI values.Thesefindings underscore the complex relationship between radiation dose,metabolic state,and proliferation status in NSPCs and highlight the ability of TPEF spectroscopy and imaging to characterize metabolism in 3D spheroids.

Higher radiation dose with a shorter treatment duration improves outcome for locally advanced carcinoma of anal canal

AIM: To assess whether radiation dose and duration of treatment influence local control and survival of patients with locally advanced anal cancer treated with definitive chemoradiation. METHODS: Twenty-eight consecutive patients who were treated with definitive radiation therapy for bulky anal cancers (> 5 cm in size) were reviewed. Nineteen patients had T3 lesions, 8 patients had T4 lesions, and 15 patients had lymph node involvement. The median tumor size was 7.5 cm. All but one patient received concurrent chemoradiation. The median radiation dose was 54 Gy. The median duration of treatment was 58 d. RESULTS: With a median follow-up of 2.5 years in all patients and 7.8 years in living patients, the 2-year local recurrence-free probability was 57% and overall survival rate was 67%. Neither radiation dose nor duration of treatment alone was predictive of either time to local failure or overall survival. However, longer treatment breaks can potentially mask an advantage over higher radiation doses. Therefore, we examined those patients who received ≥ 54 Gy within 60 d, comparing them to the rest of the patients. Of patients who received ≥ 54 Gy within 60 d, local progression-free probability was 89% versus 42% for the rest of the group (P = 0.01). CONCLUSION: Local failure is a significant problem in locally advanced carcinomas of the anal canal. Higher radiation doses with limited treatment breaks may offer an increase in local control and survival.

Specific bone region localization of osteolytic versus osteoblastic lesions in a patient-derived xenograft model of bone metastatic prostate cancer

Objective:Bone metastasis occurs in up to 90%of men with advanced prostate cancer and leads to fractures,severe pain and therapy-resistance.Bone metastases induce a spectrum of types of bone lesions which can respond differently to therapy even within individual prostate cancer patients.Thus,the special environment of the bone makes the disease more complicated and incurable.A model in which bone lesions are reproducibly induced that mirrors the complexity seen in patients would be invaluable for pre-clinical testing of novel treatments.The microstructural changes in the femurs of mice implanted with PCSD1,a new patient-derived xenograft from a surgical prostate cancer bone metastasis specimen,were determined.Methods:Quantitative micro-computed tomography(micro-CT)and histological analyses were performed to evaluate the effects of direct injection of PCSD1 cells or media alone(Control)into the right femurs of Rag2
/
gc
/
male mice.Results:Bone lesions formed only in femurs of mice injected with PCSD1 cells.Bone volume(BV)was significantly decreased at the proximal and distal ends of the femurs(p<0.01)whereas BV(p<0.05)and bone shaft diameter(p<0.01)were significantly increased along the femur shaft.Conclusion:PCSD1 cells reproducibly induced bone loss leading to osteolytic lesions at the ends of the femur,and,in contrast,induced aberrant bone formation leading to osteoblastic lesions along the femur shaft.Therefore,the interaction of PCSD1 cells with different bone region-specific microenvironments specified the type of bone lesion.Our approach can be used to determine if different bone regions support more therapy resistant tumor growth,thus,requiring novel treatments.

Proton Beam Ocular Treatment in Eyes with Intraocular Silicone Oil: Effects on Physical Beam Parameters and Clinical Relevance of Silicone Oil in EYEPLAN Dose-Volume Histograms

Proton beam therapy (PBRT) is an essential tool in the treatment of certain ocular tumors due to its characteristic fall-off and sharp beam parameters at critical structures. Review of clinical cases in our ocular PBRT program identified patients with silicone oil used as an intraocular tamponade following pars plana vitrectomy for repair of retinal detachment. Patient’s eye may be filled with silicone oil prior to PBRT for an ocular tumor. The objective of this study was to extend our knowledge of the physical characteristics of proton beams in silicone oil by measuring dose within a silicone tank itself, hence better representing the surgical eye, as well as applying the range changes to EYEPLAN software to estimate clinical impact. The relevant proton beam physical parameters in silicone oil were studied using a 67.5 MeV un-modulated proton beam. The beam parameters being defined included: 1) residual range;2) peak/plateau ratio;3) full width at half maximum (FWHM) of the Bragg peak;and 4) distal penumbra. Initially, the dose uniformity of the proton beam was confirmed at 10 mm and 28 mm depth, corresponding to plateau and peak region of the Bragg peak using Gefchromic film. Once the beam was established as expected, three sets of measurements of the beam parameters were taken in: a) water (control);b) silicone-1000 oil and water;and c) silicone-1000 oil only. Central-axis depth-ionization measurements were performed in a tank (“main tank”) with a 0.1cc ionization chamber (Model IC-18, Far west) having walls made of Shonka A150 plastic. The tank was 92 mm (length) × 40 mm (height) × 40 mm (depth). The tank had a 0.13 mm thick kapton entrance window through which the proton beam was incident. The ionization chamber was always positioned in the center of the circular field of diameter 30 mm with the phantom surface at isocenter. The ionization chamber measurements were taken at defined depths in increments of 2 mm, from 0 to 35 mm. To define the effect of silicone oil on the physical characteristics of proton beam, the above-defined three sets of measurements were made. In the first run (a), the Bragg-peak measurements were made in the main tank filled with water. In the second run (b), a second smaller tank filled with 10 mm depth silicone oil was placed in front of the water tank and the measurements were repeated in water. In the third run (c), the water in the main tank was replaced with silicone oil and the measurements were repeated in silicone directly (no second tank in runs “a” and “c”). Finally, the effects of change in range on dose distribution based on the EYEPLAN&reg;treatment planning software of patients with lesions in close proximity to the disc/macula as well as ciliary body tumors were studied. The uniformity of the radiation across the treatment volume shows that the radiation field was uniform within ± 3% at 10 mm depth and within ±4% at 28 mm depth. Parameters evaluated for the three runs (a, b, c) included: 1) residual range;2) peak/plateau ratio;3) FWHM of the Bragg curve;and 4) distal penumbra. The measured data revealed that the un-modulated Bragg peak had a penetration at the isocenter of: a) 30 mm in water;b) 31.5 mm in silicone and water;and c) 32 mm range in silicone oil. The peak/plateau ratio of the depth dose curve is 3.1:1 in all three set-ups. The FWHM is: a) 9 mm in water;b) 10 mm in silicone and water;and c) 11 mm in silicone oil. The distal penumbra (from 90% to 20%) was: a) 1.1 mm;b) 1.4 mm;and c) 2 mm. Clinical relevance of the extended distal range in silicone was studied for impact in EYEPLAN treatment software, including cases in which tumors were in close proximity to the optic disc/nerve and macula as well as cases in which anterior ciliary body tumors were treated. The potential change of range by 2 mm in silicone would impact the dose-volume histograms (DVH) importantly for the posterior structures. In ciliary body/anterior tumors, an increase in distal range in silicone could result in optic disc/macula dose and length of optic nerve treated, compared with original EYEPLAN model DVHs. The use of silicone oil as a surgical tamponade in the treatment of retinal detachments has important implications for PBRT treatment planning. In patients with intraocular silicone oil, the physical parameters of the beam should be closely examined and DVHs for posterior structures should be analyzed for potential increased doses to the macula, disc, and length of optic nerve in the field. The change in beam parameters due to silicone oil is essential to consider in treatment planning and DVH interpretation for ocular patients with posterior as well as anterior ocular tumors.

An Overview of the Control System for Dose Delivery at the UCSF Dedicated Ocular Proton Beam

Since 1978, the University of California San Francisco (UCSF) Ocular Tumor Program has been using particle therapy for treating ocular patients with malignant as well as benign eye disease. Helium ion beams were used initially and were produced by two synchrotron-based systems: first by the 184-inch synchro-cyclotron and later by the Bevalac, at the Lawrence Berkeley National Laboratory (LBNL). Since 1994, protons, produced by a cyclotron-based system at the Crocker Nuclear Laboratory (CNL) Eye Treatment Facility (ETF), have been used for this purpose. The CNL cyclotron produces a 67.5 MeV beam, allowing for a uniquely homogeneous beam for eye treatment, without degradation of the beam or manipulation of the beam line. This paper describes, in detail, the control system for beam delivery, as implemented for measuring and delivering the radiation to ocular tumors at CNL. The control system allows for optimal delivery and rapid termination of the irradiation after the desired dose is achieved. In addition, several safeguard systems are discussed, as these are essential for such a system in the event of failure of software, electronics, or other hardware. The QA analysis shows that the total range of the proton beam is 30.7 ± 1.0 mm in water at iso-center. The beam distal penumbra (80% - 20%) is 1.1 mm for a range-modulated beam at a collimator to iso-center distance of 50 mm. Daily QA checks confirm that the range and modulation is within 0.1 mm. The beam flatness and symmetry in a 25 mm diameter beam are ±1% - 2%. Variation in the daily dosimetry system, as compared to standard dosimetry, is within ±3.5%, with a mean variation of 0.72(±1.9)% and 0.85(±2.3)% for segmented transmission ionization chambers IC1 (upstream) and IC2 (downstream), respectively. From May 1994 to the end of 2015, UCSF has treated 1838 proton ocular patients at the Davis ETF. During this period, no treatments were missed due to any cyclotron or control system failures. The overall performance, maintenance, and quality assurance of the cyclotron and the ocular control system have been excellent.

A Biomechanical Model of Human Lung Deformation Utilizing Patient-Specific Elastic Property

A biomechanical model is developed and validated for breathing-induced deformation of human lung. Specifically, a subject-specific poro-elastic lung model is used to predict the displacement over the breathing cycle and compared with displacement derived from high resolution image registration. The lung geometry is derived from four-dimensional computed tomography (4DCT) scan dataset of two human subjects. The heterogeneous Young’s modulus is estimated using inverse analysis method. The numerical simulation uses fluid-structure interaction technique to solve the coupled airflow equations and structural dynamics of the lung tissue. The modelled displacement is validated by comparison with the 4DCT registration results.

Does burning fat make tumor immune hot? Discovery of cD47 overexpression by radiation induced fatty acid oxidation

Although extensively studied,it is unknown what is the major cellular energy driving tumor metastasis after anti-cancer radiotherapy.Metabolic reprogramming is one of the fundamental hallmarks in carcinogenesis and tumor progression featured with the increased glycolysis in solid tumors.However,accumulating evidence indicates that in addition to the rudimentary glycolytic pathway,tumor cells are capable of reactivating mitochondrial OxPHOS under genotoxic stress condition to meet the increasing cellular fuel demand for repairing and surviving anti-cancer radiation.Such dynamic metabolic rewiring may play a key role in cancer therapy resistance and metastasis.Interestingly,data from our group and others have demonstrated that cancer cells can re-activate mitochondrial oxidative respiration to boost an annexing energy to meet the increasing cellular fuel demand for tumor cells surviving genotoxic anti-cancer therapy with metastatic potential.

基于非均匀有理B样条的女性盆腔三维数字化模型的构建

目的建立基于中国数字化可视人体的非均匀有理B样条(Non-Uniform Rational B-Spline,NURBS)三维盆腔模型。方法选取中国可视化人体数据集的盆腔部分,应用Photoshop分割出各盆腔结构后并获取各结构的轮廓线,基于盆腔结构的表面轮廓线应用Isosurf软件生成三角化表面网格,然后将其输入犀牛(Rhinoceros)软件,进行控制参数设定与NURBS曲面重建。结果对盆腔中膀胱、直肠、子宫、卵巢、血管、阴道、输尿管、股骨、尿道等主要结构进行了分割,并构建了NURBS女性盆腔三维数字化模型,所建立的模型几何外型逼真,整体清晰,实体感强。结论本研究实现了对女性盆腔主要结构的NURBS曲面建模,所获取的数字化模型可为解剖教学、手术仿真以及运动医学等提供科研教学平台。

Evaluating different routes of extracellular vesicle administration for cranial therapies

Aim:Human stem cell-derived extracellular vesicles(EV)provide many advantages over cell-based therapies for the treatment of functionally compromised tissue beds and organ sites.Here we aimed to highlight multiple administration routes for the potential treatment of various forms of brain injury.Methods:Human neural stem cell-derived EV were isolated from conditioned media and administered via three distinct routes:intrahippocampal transplantation,retro-orbital vein injection,and intranasal.EV were administered after which brains were evaluated to determine the capability of EV to translocate into normal tissue.Results:Data showed no significant differences in the amount of EV able to translocate across the brain,indicating the functional equivalence of each administration route to effectively deliver EV to the brain parenchyma.Conclusion:Findings show that both systemic administration routes(retro-orbital vein or intranasal delivery)afforded effective penetrance and perfusion of EV throughout the brain in a minimally invasive manner,and point to a translationally tractable option for treating certain neurological disorders including those resulting from cranial irradiation procedures.

Artificial intelligence in radiotherapy:a technological review

Radiation therapy(RT)is widely used to treat cancer.Technological advances in RT have occurred in the past 30 years.These advances,such as three-dimensional image guidance,intensity modulation,and robotics,created challenges and opportunities for the next breakthrough,in which artificial intelligence(AI)will possibly play important roles.AI will replace certain repetitive and labor-intensive tasks and improve the accuracy and consistency of others,particularly those with increased complexity because of technological advances.The improvement in efficiency and consistency is important to manage the increasing cancer patient burden to the society.Furthermore,AI may provide new functionalities that facilitate satisfactory RT.The functionalities include superior images for real-time intervention and adaptive and personalized RT.AI may effectively synthesize and analyze big data for such purposes.This review describes the RT workflow and identifies areas,including imaging,treatment planning,quality assurance,and outcome prediction,that benefit from AI.This review primarily focuses on deep-learning techniques,although conventional machine-learning techniques are also mentioned.

Nuclear TIGAR mediates an epigenetic and metabolic autoregulatory loop via NRF2 in cancer therapeutic resistance

Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance.However,their interplays are poorly understood.We report here that elevated TIGAR(TP53-induced glycolysis and apoptosis regulator),an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2(nuclear receptor binding SET domain protein 2),is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark.Mechanistically,TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2,H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new(NSD2)and established(NQO1/2,PRDX1 and GSTM4)targets of NRF2,independent of its enzymatic activity.Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis.In addition,nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival.These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.

前列腺癌术后早期补救治疗与辅助治疗的比较

ARTISTIC合作进行的前瞻性适应性meta分析表明,与早期补救性放疗相比,根治性前列腺切除术后的辅助放疗不能改善无事件生存率。从减少过度治疗和相关副作用方面看,早期补救性放疗优于辅助放疗。对于局限性前列腺癌患者,根治性前列腺切除术的目标是清除整个原发肿瘤。在某些患者中可以达到此目标,但在其他患者中术后可能会有残余的癌组织。为防止高危患者局部复发,通常在根治性前列腺切除术后对前列腺床进行放疗。