The objective of this study is to investigate the dose perturbations introduced by the implanted gold fiducial markers in the prostate cancer intensity modulated proton therapy (IMPT) and the impacts of different plan...The objective of this study is to investigate the dose perturbations introduced by the implanted gold fiducial markers in the prostate cancer intensity modulated proton therapy (IMPT) and the impacts of different plan designs on the pertur-bations. Five proton plans: a single lateral field 3D-modulation (3D-mod) plan, 2 fields laterally opposing 3D-mod plan, 6-, 9-, and 18-field distal edge tracking (DET) plans were designed on the CT images of a prostate patient. The dose distributions were first generated for the plans free of fiducial markers with 78 Gy prescribed to 95% of the PTV. To derive the dose perturbations of the gold fiducial markers, three cylindrical shaped gold fiducial markers (3 mm long and 1 mm in diameter) were artificially inserted into the prostate, and the dose distributions were re-computed. Monte Carlo method was used for dose computation. It was found that the gold fiducial markers perturbed the dose distribu-tions, especially along the beam paths. The markers caused a shadowing effect reducing the doses in the areas beyond the markers. Overall, due to the presence of the fiducial markers, D99% of prostate were reduced by 2.96 Gy, 4.21 Gy, 0.16 Gy, 0.34 Gy, 0.15 Gy for the plans of single field 3D-mod, 2-field parallel opposed 3D-mod, 6-, 9-, and 18-field DET respectively. Our study showed these dose perturbation effects decreased with the increase of number of beam angles. Up to 6 beam angles may be required to reduce the dose perturbations from the gold fiducial markers to a clini- cally acceptable level in IMPT.展开更多
Objective: To study the relationship between the expression of human cyclin B1 in colorectal carcinomas and the pathological characters. Methods: The Expression of cyclin B1 in 66 cases of colorectal carcinomas were d...Objective: To study the relationship between the expression of human cyclin B1 in colorectal carcinomas and the pathological characters. Methods: The Expression of cyclin B1 in 66 cases of colorectal carcinomas were detected by flow cytometry and immunohistochemistry. Then the relationship between the expression of cyclin B1 in colorectal carcinomas and pathological characters was analyzed with statistics. Results: The expression of cyclin B1 in colorectal carcinomas had associa- tivity with the cancer cell differentiation (P<0.05); However, the expression of cyclin B1 in colorectal carcinomas had no obvious associativity with cancer cell infiltrate depth and lymph nodes metastasis (P>0.05). Conclusion: In the colorectal cancers with high expression of cyclin B1, the cancer cells would present high differentiation; with low expression of cyclin B1 the cancer cells would present low differentiation. Along with the expression of cyclin B1 from high to low, the cancer cells differentiation has the tendency from high to low too.展开更多
The tumor microenvironment(TME)is a complex network composed of non-tumor cells,extracellular matrix,blood vessels,and various molecular signals that surround and profoundly influence tumor progression.As one of the k...The tumor microenvironment(TME)is a complex network composed of non-tumor cells,extracellular matrix,blood vessels,and various molecular signals that surround and profoundly influence tumor progression.As one of the key immune effector cells within the TME,mast cells(MCs)exhibit functional complexity,and their specific roles remain widely debated.Depending on the cancer type,spatial distribution,and interactions with other TME components,MCs can demonstrate dual regulatory capabilities—either promoting or inhibiting tumor growth.This characteristic has made them an important focus in current tumor immunology research.This review aims to systematically review the current understanding of MCs in the TME,with emphasis on their characteristics and functional differences across various tumor types,pathological status,and species.In recent years,advances in the understanding of MC markers,activation mechanisms,and biological functions have made targeting specific MC subsets an emerging therapeutic strategy.By comprehensively examining the origin,activation mechanisms,cellular interactions,and therapeutic regulation ofMCs,this review provides new perspectives and a basis for future directions in tumor research and treatment.展开更多
AIM:To investigate whether the inhibition of autophagy by chloroquine(CQ)sensitizes rectal tumors to radiation therapy(RT)or concurrent chemoradiation(chemoRT).METHODS:In vitro,HCT-116 and HT-29 colorectal cancer(CRC)...AIM:To investigate whether the inhibition of autophagy by chloroquine(CQ)sensitizes rectal tumors to radiation therapy(RT)or concurrent chemoradiation(chemoRT).METHODS:In vitro,HCT-116 and HT-29 colorectal cancer(CRC)cell lines were treated as following:(1)PBS;(2)CQ;(3)5-fluorouracil(5-FU);(4)RT;(5)CQ and RT;(6)5-FU and RT;(7)CQ and 5-FU;and(8)5-FU and CQ and RT.Each group was then exposed to various doses of radiation(0-8 Gy)depending on the experiment.Cell viability and proliferative capacity were measured by3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)and clonogenic assays.Clonogenic survivalcurves were constructed and compared across treatment groups.Autophagy status was determined by assessing the LC3-Ⅱto LC3-Ⅰratio on western blot analysis,autophagosome formation on electron microscopy and identification of a perinuclear punctate pattern with GFPlabeled LC3 on fluorescence microscopy.Cell cycle arrest and cell death were evaluated by FACS and AnnexinⅤanalysis.All experiments were performed in triplicate and statistical analysis was performed by the student’s t test to compare means between treatment groups.RESULTS:RT(2-8 Gy)induced autophagy in HCT-116and HT-29 CRC cell lines at 4 and 6 h post-radiation,respectively,as measured by increasing LC3-Ⅱto LC3-Ⅰratio on western blot.Additionally,electron microscopy demonstrated autophagy induction in HT-29 cells24 h following irradiation at a dose of 8 Gy.Drug treatment with 5-FU(25μmol/L)induced autophagy and the combination of 5-FU and RT demonstrated synergism in autophagy induction.CQ(10μmol/L)alone and in combination with RT effectively inhibited autophagy and sensitized both HCT-116 and HT-29 cells to treatment with radiation(8 Gy;P<0.001 and 0.00001,respectively).Significant decrease in clonogenic survival was seen only in the HT-29 cell line,when CQ was combined with RT at doses of 2 and 8 Gy(P<0.5 and P=0.05,respectively).There were no differences in cell cycle progression or Annexin V staining upon CQ addition to RT.CONCLUSION:Autophagy inhibition by CQ increases CRC cell sensitivity to concurrent treatment with 5-FU and RT in vitro,suggesting that addition of CQ to chemoRT improves CRC treatment response.展开更多
Apigenin （4＇,5,7-trihydroxyflavone） is a member of the flavone subclass of flavonoids present in fruits and vegetables. The involvement of autophagy in the apigenin-induced apoptotic death of human breast cancer ce...Apigenin （4＇,5,7-trihydroxyflavone） is a member of the flavone subclass of flavonoids present in fruits and vegetables. The involvement of autophagy in the apigenin-induced apoptotic death of human breast cancer cells was investigated. Cell proliferation and viability were assessed by 3-（4,5-dimethylthiazol- 2-yl）-2,5-diphenyltetrazolium bromide （MTT） and clonogenic assays. Flow cytometry, fluorescent staining and Western blot analysis were employed to detect apoptosis and autophagy, and the role of autophagy was assessed using autophagy inhibitors. Apigenin dose- and time-dependently repressed the proliferation and clonogenic survival of the human breast cancer T47D and MDA-MB-231 cell lines. The death of T47D and MDA-MB-231 cells was due to apoptosis associated with increased levels of Caspase3, PARP cleavage and Bax/Bcl-2 ratios. The results from flow cytometry and fluorescent staining also verified the occurrence of apoptosis. In addition, the apigenin-treated cells exhibited autophagy, as characterized by the appearance of autophagosomes under fluorescence microscopy and the accumulation of acidic vesicular organelles （AVOs） by flow cytometry. Furthermore, the results of the Western blot analysis revealed that the level of LC3-Ⅱ, the processed form of LC3-Ⅰ, was increased. Treatment with the autophagy inhibitor, 3-methyladenine （3-MA）, significantly enhanced the apoptosis induced by apigenin, which was accompanied by an increase in the level of PARP cleavage. Similar results were also confirmed by flow cytometry and fluorescence microscopy. These results indicate that apigenin has apoptosis- and autophagy-inducing effects in breast cancer cells. Autophagy plays a cyto-protective role in apigenin-induced apoptosis, and the combination of apigenin and an autophagy inhibitor may be a promising strategy for breast cancer control.展开更多
Cellular senescence is an irreversible cell cycle arrest triggered by the activation of oncogenes or mitogenic signaling as well as the enforced expression of tumor suppressors such as p53, p16INK4A and promyelocytic ...Cellular senescence is an irreversible cell cycle arrest triggered by the activation of oncogenes or mitogenic signaling as well as the enforced expression of tumor suppressors such as p53, p16INK4A and promyelocytic leukemia protein （PML） in normal cells. E2F-binding protein 1 （E2FBP1）, a transcription regulator for E2F, induces PML reduction and suppresses the formation of PML-nuclear bodies, whereas the down-regulation of E2FBP1 provokes the PML-dependent premature senescence in human normal fibroblasts. Here we report that the depletion of E2FBP1 induces the accumulation of PML through the Ras-dependent activation of MAP kinase signaling. The cellular levels of p16INK4A and p53 are elevated during premature senescence induced by depletion of E2FBP1, and the depletion of p16INK4A, but not p53 rescued senescent cells from growth arrest. Therefore, the premature senescence induced by E2FBP1 depletion is achieved through the pl6INK4A-Rb pathway. Similar to human normal fibroblasts, the growth inhibition induced by E2FBP1 depletion is also observed in human tumor cells with intact p16INK4A and Rb. These results suggest that E2FBP1 functions as a critical antagonist to the pI6INK4A-Rb tumor suppressor machinery by regulating PML stability.展开更多
AIM:To compare the efficacy of cell-free derivatives from Bone marrow derived human mesenchymal stem cells(hMSCs) in wound therapy.METHODS:hMSCs have been shown to play an important role in wound therapy.The present s...AIM:To compare the efficacy of cell-free derivatives from Bone marrow derived human mesenchymal stem cells(hMSCs) in wound therapy.METHODS:hMSCs have been shown to play an important role in wound therapy.The present study sought to compare efficacy of hMSCs and cell-free derivatives of hMSCs,which may be clinically more relevant as they are easier to prepare,formulate and transport.hMSCs were isolated from human bone marrow and cultured.Multi lineage differentiation of hMSCs was performed to confirm their identity.The ability of hMSCs to migrate was evaluated using in vitro and in vivo migration assays.Cell lysates and conditioned medium concentrate was prepared from hMSCs(see Methods for details).Wounds were induced in mice and wound areas were measure before and after cell and cell-free derivative treatment.RNA and proteins were extracted from the skin and cytokine levels were measured.RESULTS:Co-culture of hMSCs with keratinocytes resulted in increased expression of CXCL-12(SDF1) and ENA78(CXCL-5) in the conditioned media indicating that the hMSCs can respond to signals from keratinocytes.Accelerated wound closure was observed when hMSCs were injected near the site of excisional wounds in athymic as well as NOD/SCID mice.Interestingly,cell-free lysates prepared from hMSCs were also effective in inducing accelerated wound closure and increased expression of SDF1 and CXCL-5 at the wound bed.Additionally,concentrated media from hMSCs as well as an emulsion containing lysates prepared from hMSCs was also found to be more effective in rapid re-epithelialization than fibroblasts or vehicle-alone control.Use of cell-free derivatives may help replace expensive wound care approaches including use of growth factors,epidermal/dermal substitutes,synthetic membranes,cytokines,and matrix components,and most importantly avoid transmission of pathogens from human and animal products.CONCLUSION:These results encourage development of derivatives of hMSCs for wound care and re-epithelialization applications.展开更多
Dear Editor, We examined myelin formation by oligodendrocytes co-transplanted with immunosuppressive mesenchymal stem cells （MSCs）. Oligodendrocyte precursor cells （OPCs） were grafted into the mouse retina, and gr...Dear Editor, We examined myelin formation by oligodendrocytes co-transplanted with immunosuppressive mesenchymal stem cells （MSCs）. Oligodendrocyte precursor cells （OPCs） were grafted into the mouse retina, and graft survival and maturation was determined with or without adjunctive MSCs. Green fluorescent protein （GFP）-labeled MSCs were present at 2 but not 6 weeks post transplant,展开更多
Objective： To study the effects of apigenin on vascular endothelial growth factor （VEGF） in human breast cancer cells （MDA-MB-231. Methods： MTT assay was used to detect the cell proliferation inhibitory effect of...Objective： To study the effects of apigenin on vascular endothelial growth factor （VEGF） in human breast cancer cells （MDA-MB-231. Methods： MTT assay was used to detect the cell proliferation inhibitory effect of apigenin on MDA-MB-231 cell. ELISA was used to determine the protein level of VEGF secreted by MDA-MB-231 cells. RT-PCR was used to detect mRNA levels of VEGF in MDA-MB-231 cells. The protein levels of HIF-1α, p-AKT, p-ERK1/2, and p53 were detected by Western Blotting. Results： Apigenin did not inhibit the cell viability of MDA-MB-231 cell. Apigenin reduced the secretion and mRNA levels of VEGF in MDA-MB-231 cells. Additionally, apigenin decreased the expressions of HIF-1α, p-AKT and p-ERK1/2, but induced the expression of p53. Conclusion： Apigenin can inhibit VEGF expression in human breast cancer cells, and this may be achieved through decreasing HIF-1α.展开更多
Critical to the generation of an effective therapeutic antitumor immune response is the elicitation of effective antigen presentation coupled with overcoming tumor-immune escape mechanisms. Towards this end, we aimed ...Critical to the generation of an effective therapeutic antitumor immune response is the elicitation of effective antigen presentation coupled with overcoming tumor-immune escape mechanisms. Towards this end, we aimed to understand the therapeutic effectiveness of a polymer based vaccine approach at enhancing the anti-tumor responses in a tumor-bearing mouse model. While we and others have previously demonstrated the effectiveness of PLGA based systems in delivering antigen etc., studies scarcely focus on understanding the immunological mechanisms of polymer based therapies in tumor bearing treatment models. Considering tumors modulate the immune system and consequently the efficacy of therapies, understanding treatment mechanisms in the presence of tumor will help lead to more efficacious treatment options. We demonstrate here that a poly(lactic-co-glycolic acid) (PLGA) based delivery system encapsulating tumor antigen (OVA) and the TLR9 agonist CpG motif DNA administered into the tumor microenvironment initiates an effective type 1 mediated (IFN-γ producing) anti-tumor response in a syngeneic murine model of T cell lymphoma (E.G7-OVA). Although E.G7-OVA tumors spontaneously generate antigen specific CTLs in draining lymph nodes (LN), tumors progress rapidly. Modulation of the tumor microenvironment via local PLGA based therapy led to the generation of a systemic antigen specific Th1 response, absent in the non-polymer delivery method, subsequently associated with reduced tumor growth and prolongation of survival. These studies provide further insight into the use of a PLGA-based therapeutic approach at modulating the tumor microenvironment and highlight the need for analyzing the treatment effects in a tumor bearing model.展开更多
Objective and Impact Statement.Distinguishing tumors from normal tissues is vital in the intraoperative diagnosis and pathological examination.In this work,we propose to utilize Raman spectroscopy as a novel modality ...Objective and Impact Statement.Distinguishing tumors from normal tissues is vital in the intraoperative diagnosis and pathological examination.In this work,we propose to utilize Raman spectroscopy as a novel modality in surgery to detect colorectal cancer tissues.Introduction.Raman spectra can reflect the substance components of the target tissues.However,the feature peak is slight and hard to detect due to environmental noise.Collecting a high-quality Raman spectroscopy dataset and developing effective deep learning detection methods are possibly viable approaches.Methods.First,we collect a large Raman spectroscopy dataset from 26 colorectal cancer patients with the Raman shift ranging from 385 to 1545 cm^(−1).Second,a one-dimensional residual convolutional neural network(1D-ResNet)architecture is designed to classify the tumor tissues of colorectal cancer.Third,we visualize and interpret the fingerprint peaks found by our deep learning model.Results.Experimental results show that our deep learning method achieves 98.5%accuracy in the detection of colorectal cancer and outperforms traditional methods.Conclusion.Overall,Raman spectra are a novel modality for clinical detection of colorectal cancer.Our proposed ensemble 1D-ResNet could effectively classify the Raman spectra obtained from colorectal tumor tissues or normal tissues.展开更多
We explore the hypothesis that a potential explanation for the initiation of motor neuron disease is an unappreciated vulnerability in central nervous system defense,the direct delivery of neurotoxins into motor neuro...We explore the hypothesis that a potential explanation for the initiation of motor neuron disease is an unappreciated vulnerability in central nervous system defense,the direct delivery of neurotoxins into motor neurons via peripheral nerve retrograde transport.This further suggests a mechanism for focal initiation of neuro-degenerative diseases in general,with subsequent spread by network degeneration as suggested by the Frost-Diamond hypothesis.We propose this vulnerability may be a byproduct of vertebrate evolution in a benign aquatic environment,where external surfaces were not exposed to concentrated neurotoxins.展开更多
AIM: To detect the effect of intraoperative prostaglandin E1 (PGE1) infusion on survival of esophagectomized patients due to cancer. METHODS: In this preliminary study, a double blinded placebo based clinical trial wa...AIM: To detect the effect of intraoperative prostaglandin E1 (PGE1) infusion on survival of esophagectomized patients due to cancer. METHODS: In this preliminary study, a double blinded placebo based clinical trial was performed. Thirty patients with esophageal cancer scheduled for esophagectomy via the transthoracic approach were randomized by a block randomization method, in two equal groups: PGE1 group - infusion of PGE1 (20 ng/kg per minute) in the operating room and placebo group - saline 0.9% with the same volume and rate. The infusion began before induction of anesthesia and finished just before transfer to the intensive care unit. The patients, anesthetist, intensive care physicians, nurses and surgeons were blinded to both study groups. All the patients were anesthetized with the same method. For postoperative pain control, a thoracic epidural catheter was placed for all patients before induction of anesthesia. We followed up the patients until October 2010. Basic characteristics, duration of anesthesia, total surgery and thoracotomy time, preoperative hemoglobin, length of tumor, grade of histological differentiation, disease stage, number of lymph nodes in the resected mass, number of readmissions to hospital, total duration of readmission and survival rates were compared between the two groups. Some of the data originates from the historical data reported in our previous study. We report them for better realization of the follow up results. RESULTS: The patients’ characteristics and perioperative variables were compared between the two groups. There were no significant differences in age (P = 0.48), gender (P = 0.27), body mass index (P = 0.77), American Society of Anesthesiologists physical status more than?I?(P = 0.71), and smoking (P = 0.65). The PGE1 and placebo group were comparable in the following variables: duration of anesthesia (277 ± 50 vs 270 ± 67, P = 0.86), duration of thoracotomy (89 ± 35 vs 96 ± 19, P = 0.46), duration of operation (234 ± 37 vs 240 ± 66, P = 0.75), volume of blood loss during operation (520 ± 130 vs 630 ± 330, P = 0.34), and preoperative hemoglobin (14.4 ± 2 vs 14.7 ± 1.9, P = 0.62), respectively. No hemodynamic complications requiring an infusion of dopamine or cessation of the PGE1 infusion were encountered. Cancer variables were compared between the PGE1 and placebo group. Length of tumor (11.9 ± 3 vs 12.3 ± 3, P = 0.83), poor/undifferentiated grade of histological differentiation [3 (20%) vs 3 (20%), P = 0.78], disease stage III [5 (33.3%), 4 (26.7%), P = 0.72] and more than 3 lymph nodes in the resected mass [3 (20%) vs 2 (13.3%), P = 0.79] were similar in both groups. All the patients were discharged from hospital except one patient in the control group who died because of a post operative myocardial infarction. No life threatening postoperative complication occurred in any patient. The results of outcome and survival were the same in PGE1 and placebo group: number of readmissions (2.1 ± 1 vs 1.9 ± 1, P = 0.61), total duration of readmission (27 ± 12 vs 29 ± 12, P = 0.67), survival rate (10.1 ± 3.8 vs 9.6 ± 3.4, P = 0.71), overall survival rate after one year [8 (53.3%) vs 7 (47%), P = 0.72], overall survival rate after two years [3 (20%) vs 3 (20%), P = 0.99], and overall survival rate after three years [0 vs 1 (6.7%), P = 0.99], respectively. CONCLUSION: In conclusion, PGE1 did not shorten or lengthen the survival of patients with esophageal cancer. Larger studies are suggested.展开更多
A technique for multiple deep-inspiration breath-hold (DIBH) volumetric modulated arc therapy (VMAT) for a lung tumor has been proposed with 10 MV flattening-filter-free beams and an image sensor measuring a distance ...A technique for multiple deep-inspiration breath-hold (DIBH) volumetric modulated arc therapy (VMAT) for a lung tumor has been proposed with 10 MV flattening-filter-free beams and an image sensor measuring a distance map to thorax surface. Planning CT images were acquired under a DIBH condition and a clinical target volume (CTV) was contoured. This procedure was repeated five times and an internal target volume (ITV) among the multiple DIBHs was created by integrating the five CTVs. A planning target volume (PTV) was defined by adding an isotropic margin of 5 mm to the ITV. Immediately before treatment, a 30-second half-arc cone-beam computer tomography (CBCT) imaging was performed under another DIBH condition, and the couch was repositioned so that tumor may be located inside the PTV contours. An infrared distance measurement device having laser diodes and an image sensor was attached to the couch, and a distance map to the patient thorax surface was recorded as a reference during still another DIBH condition. A half-arc segmented VMAT beams with two beam interrupts were delivered to the patient under multiple DIBHs, where the delivery time of each of the three segmented beams was 30 seconds. During the beam delivery, the distance map was monitored in real time to confirm that the distance to the thorax surface remained unchanged. In-treatment CBCT images suggested that the tumor position at the time of tumor registration was accurately reproduced during the DIBH VMAT delivery.展开更多
The Natural Killer Cell (NKC) is the cell-mediated cornerstone of innate immunity. The purpose of this reviewis to give a historical perspective of the discovery of the Natural Killer Cell (NKC)and to apply the use of...The Natural Killer Cell (NKC) is the cell-mediated cornerstone of innate immunity. The purpose of this reviewis to give a historical perspective of the discovery of the Natural Killer Cell (NKC)and to apply the use of supplements in the enhancement of NKC in human cancers for the developmentof human health and well-being.Since the discovery of the NKC, as observed by Nomarski optics, scanning (SEM)/transmission electron microscopy (TEM) with cellular numeration and enrichment using bovine serum albumin (BSA) continuous gradients, there have been significant research and clinical studies to increase the effectiveness of NKC in the destruction of cancer cells. Based on significant research and clinical studies, at least 16 components have been identified that enhance or may enhance, based on their immune modulator activity, the NKC. These supplements include Alpha LipoicAcid, Arabinoxylin, Curcumin, Garlic, Genistein, Ginseng, Lentinan, Mistletoe, N-Acetylcysteine, Resveratrol, Selenium, Vitamin B, Vitamin C, Vitamin D3, Vitamin E and zinc.展开更多
Sixty seven cases with special types of early gastric cancer collected from 119 early gastric cancer specimens surgically resected in the Cancer Institute of CMU from 1964 to 1987 are reported. The pathological and bi...Sixty seven cases with special types of early gastric cancer collected from 119 early gastric cancer specimens surgically resected in the Cancer Institute of CMU from 1964 to 1987 are reported. The pathological and biological characteristics of superficial spreading focal penetrating types, microcarcinoma and small carcinoma, "Pin-point cancer", multiple early cancer and gastric stump cancer were analysed. The authors believe that understanding these special types of early gastric cancer is of great importance not only in the study of histogenesis but also in clinical treatment and prevention of gastric cancer.展开更多
The intestinal barrier is crucial for homeostasis.This study aimed to investigate the protective effects of earthworm protein hydrolysates(EWPH)on the intestinal mucosal barrier and elucidate the underlying mechanisms...The intestinal barrier is crucial for homeostasis.This study aimed to investigate the protective effects of earthworm protein hydrolysates(EWPH)on the intestinal mucosal barrier and elucidate the underlying mechanisms.We first hydrolyzed earthworm protein using alcalase and identified the primary peptide components of EWPH through Nano LC-MS/MS analysis.Network pharmacology and bioinformatics approaches were employed to predict potential targets associated with the intestinal mucosal barrier.Experimentally,we demonstrated that EWPH effectively protects against dextran sulfate sodium(DSS)-induced intestinal barrier damage in mice.The protective mechanisms involve not only the inhibition of the Toll-like receptor 4(TLR4)-nuclear factor-kB(NF-kB)/mitogen-activated protein kinases(MAPK)signaling pathway in the intestinal epithelium but also the suppression of other key molecules implicated in intestinal mucosal barrier damage,including phosphorylated-SRC proto-oncogene(p-SRC),phosphorylated-signal transducer and activator of transcription 3(p-STAT3),Caspase-3,and matrix metalloproteinase-9(MMP9),thereby mitigating intestinal inflammation and mucosal barrier injury.This study provides evidence that EWPH have the potential to safeguard the intestinal barrier hemostasis.展开更多
文摘The objective of this study is to investigate the dose perturbations introduced by the implanted gold fiducial markers in the prostate cancer intensity modulated proton therapy (IMPT) and the impacts of different plan designs on the pertur-bations. Five proton plans: a single lateral field 3D-modulation (3D-mod) plan, 2 fields laterally opposing 3D-mod plan, 6-, 9-, and 18-field distal edge tracking (DET) plans were designed on the CT images of a prostate patient. The dose distributions were first generated for the plans free of fiducial markers with 78 Gy prescribed to 95% of the PTV. To derive the dose perturbations of the gold fiducial markers, three cylindrical shaped gold fiducial markers (3 mm long and 1 mm in diameter) were artificially inserted into the prostate, and the dose distributions were re-computed. Monte Carlo method was used for dose computation. It was found that the gold fiducial markers perturbed the dose distribu-tions, especially along the beam paths. The markers caused a shadowing effect reducing the doses in the areas beyond the markers. Overall, due to the presence of the fiducial markers, D99% of prostate were reduced by 2.96 Gy, 4.21 Gy, 0.16 Gy, 0.34 Gy, 0.15 Gy for the plans of single field 3D-mod, 2-field parallel opposed 3D-mod, 6-, 9-, and 18-field DET respectively. Our study showed these dose perturbation effects decreased with the increase of number of beam angles. Up to 6 beam angles may be required to reduce the dose perturbations from the gold fiducial markers to a clini- cally acceptable level in IMPT.
基金Supported by grants from the State Key Basic Research Development Program of China (973 program, No. 2004CB518705) and the Science Foundation Ministry of Health, China (Cell cycle diagnosis and analysis of clinic tumor III).
文摘Objective: To study the relationship between the expression of human cyclin B1 in colorectal carcinomas and the pathological characters. Methods: The Expression of cyclin B1 in 66 cases of colorectal carcinomas were detected by flow cytometry and immunohistochemistry. Then the relationship between the expression of cyclin B1 in colorectal carcinomas and pathological characters was analyzed with statistics. Results: The expression of cyclin B1 in colorectal carcinomas had associa- tivity with the cancer cell differentiation (P<0.05); However, the expression of cyclin B1 in colorectal carcinomas had no obvious associativity with cancer cell infiltrate depth and lymph nodes metastasis (P>0.05). Conclusion: In the colorectal cancers with high expression of cyclin B1, the cancer cells would present high differentiation; with low expression of cyclin B1 the cancer cells would present low differentiation. Along with the expression of cyclin B1 from high to low, the cancer cells differentiation has the tendency from high to low too.
基金supported by the Guangdong Basic and Applied Basic Research Foundation(2022A1515220184,Lewei Zhu)Hebei Natural Science Foundation(H2024105019).
文摘The tumor microenvironment(TME)is a complex network composed of non-tumor cells,extracellular matrix,blood vessels,and various molecular signals that surround and profoundly influence tumor progression.As one of the key immune effector cells within the TME,mast cells(MCs)exhibit functional complexity,and their specific roles remain widely debated.Depending on the cancer type,spatial distribution,and interactions with other TME components,MCs can demonstrate dual regulatory capabilities—either promoting or inhibiting tumor growth.This characteristic has made them an important focus in current tumor immunology research.This review aims to systematically review the current understanding of MCs in the TME,with emphasis on their characteristics and functional differences across various tumor types,pathological status,and species.In recent years,advances in the understanding of MC markers,activation mechanisms,and biological functions have made targeting specific MC subsets an emerging therapeutic strategy.By comprehensively examining the origin,activation mechanisms,cellular interactions,and therapeutic regulation ofMCs,this review provides new perspectives and a basis for future directions in tumor research and treatment.
文摘AIM:To investigate whether the inhibition of autophagy by chloroquine(CQ)sensitizes rectal tumors to radiation therapy(RT)or concurrent chemoradiation(chemoRT).METHODS:In vitro,HCT-116 and HT-29 colorectal cancer(CRC)cell lines were treated as following:(1)PBS;(2)CQ;(3)5-fluorouracil(5-FU);(4)RT;(5)CQ and RT;(6)5-FU and RT;(7)CQ and 5-FU;and(8)5-FU and CQ and RT.Each group was then exposed to various doses of radiation(0-8 Gy)depending on the experiment.Cell viability and proliferative capacity were measured by3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)and clonogenic assays.Clonogenic survivalcurves were constructed and compared across treatment groups.Autophagy status was determined by assessing the LC3-Ⅱto LC3-Ⅰratio on western blot analysis,autophagosome formation on electron microscopy and identification of a perinuclear punctate pattern with GFPlabeled LC3 on fluorescence microscopy.Cell cycle arrest and cell death were evaluated by FACS and AnnexinⅤanalysis.All experiments were performed in triplicate and statistical analysis was performed by the student’s t test to compare means between treatment groups.RESULTS:RT(2-8 Gy)induced autophagy in HCT-116and HT-29 CRC cell lines at 4 and 6 h post-radiation,respectively,as measured by increasing LC3-Ⅱto LC3-Ⅰratio on western blot.Additionally,electron microscopy demonstrated autophagy induction in HT-29 cells24 h following irradiation at a dose of 8 Gy.Drug treatment with 5-FU(25μmol/L)induced autophagy and the combination of 5-FU and RT demonstrated synergism in autophagy induction.CQ(10μmol/L)alone and in combination with RT effectively inhibited autophagy and sensitized both HCT-116 and HT-29 cells to treatment with radiation(8 Gy;P<0.001 and 0.00001,respectively).Significant decrease in clonogenic survival was seen only in the HT-29 cell line,when CQ was combined with RT at doses of 2 and 8 Gy(P<0.5 and P=0.05,respectively).There were no differences in cell cycle progression or Annexin V staining upon CQ addition to RT.CONCLUSION:Autophagy inhibition by CQ increases CRC cell sensitivity to concurrent treatment with 5-FU and RT in vitro,suggesting that addition of CQ to chemoRT improves CRC treatment response.
基金supported by the National Natural Science Foundation of China (Grant no. 81001186)the Tianjin Municipal Natural Science Foundation (Grant no. 10JCYBJ C14100,11JCZDJC28000,13JCYBJC21800)
文摘Apigenin （4＇,5,7-trihydroxyflavone） is a member of the flavone subclass of flavonoids present in fruits and vegetables. The involvement of autophagy in the apigenin-induced apoptotic death of human breast cancer cells was investigated. Cell proliferation and viability were assessed by 3-（4,5-dimethylthiazol- 2-yl）-2,5-diphenyltetrazolium bromide （MTT） and clonogenic assays. Flow cytometry, fluorescent staining and Western blot analysis were employed to detect apoptosis and autophagy, and the role of autophagy was assessed using autophagy inhibitors. Apigenin dose- and time-dependently repressed the proliferation and clonogenic survival of the human breast cancer T47D and MDA-MB-231 cell lines. The death of T47D and MDA-MB-231 cells was due to apoptosis associated with increased levels of Caspase3, PARP cleavage and Bax/Bcl-2 ratios. The results from flow cytometry and fluorescent staining also verified the occurrence of apoptosis. In addition, the apigenin-treated cells exhibited autophagy, as characterized by the appearance of autophagosomes under fluorescence microscopy and the accumulation of acidic vesicular organelles （AVOs） by flow cytometry. Furthermore, the results of the Western blot analysis revealed that the level of LC3-Ⅱ, the processed form of LC3-Ⅰ, was increased. Treatment with the autophagy inhibitor, 3-methyladenine （3-MA）, significantly enhanced the apoptosis induced by apigenin, which was accompanied by an increase in the level of PARP cleavage. Similar results were also confirmed by flow cytometry and fluorescence microscopy. These results indicate that apigenin has apoptosis- and autophagy-inducing effects in breast cancer cells. Autophagy plays a cyto-protective role in apigenin-induced apoptosis, and the combination of apigenin and an autophagy inhibitor may be a promising strategy for breast cancer control.
基金supported by a Grant-in Aid for Scientific Research from the Japan Society for the Promotion of Science
文摘Cellular senescence is an irreversible cell cycle arrest triggered by the activation of oncogenes or mitogenic signaling as well as the enforced expression of tumor suppressors such as p53, p16INK4A and promyelocytic leukemia protein （PML） in normal cells. E2F-binding protein 1 （E2FBP1）, a transcription regulator for E2F, induces PML reduction and suppresses the formation of PML-nuclear bodies, whereas the down-regulation of E2FBP1 provokes the PML-dependent premature senescence in human normal fibroblasts. Here we report that the depletion of E2FBP1 induces the accumulation of PML through the Ras-dependent activation of MAP kinase signaling. The cellular levels of p16INK4A and p53 are elevated during premature senescence induced by depletion of E2FBP1, and the depletion of p16INK4A, but not p53 rescued senescent cells from growth arrest. Therefore, the premature senescence induced by E2FBP1 depletion is achieved through the pl6INK4A-Rb pathway. Similar to human normal fibroblasts, the growth inhibition induced by E2FBP1 depletion is also observed in human tumor cells with intact p16INK4A and Rb. These results suggest that E2FBP1 functions as a critical antagonist to the pI6INK4A-Rb tumor suppressor machinery by regulating PML stability.
基金Supported by (in part) a Grant from Office of Patents and Licensing,UMDNJ
文摘AIM:To compare the efficacy of cell-free derivatives from Bone marrow derived human mesenchymal stem cells(hMSCs) in wound therapy.METHODS:hMSCs have been shown to play an important role in wound therapy.The present study sought to compare efficacy of hMSCs and cell-free derivatives of hMSCs,which may be clinically more relevant as they are easier to prepare,formulate and transport.hMSCs were isolated from human bone marrow and cultured.Multi lineage differentiation of hMSCs was performed to confirm their identity.The ability of hMSCs to migrate was evaluated using in vitro and in vivo migration assays.Cell lysates and conditioned medium concentrate was prepared from hMSCs(see Methods for details).Wounds were induced in mice and wound areas were measure before and after cell and cell-free derivative treatment.RNA and proteins were extracted from the skin and cytokine levels were measured.RESULTS:Co-culture of hMSCs with keratinocytes resulted in increased expression of CXCL-12(SDF1) and ENA78(CXCL-5) in the conditioned media indicating that the hMSCs can respond to signals from keratinocytes.Accelerated wound closure was observed when hMSCs were injected near the site of excisional wounds in athymic as well as NOD/SCID mice.Interestingly,cell-free lysates prepared from hMSCs were also effective in inducing accelerated wound closure and increased expression of SDF1 and CXCL-5 at the wound bed.Additionally,concentrated media from hMSCs as well as an emulsion containing lysates prepared from hMSCs was also found to be more effective in rapid re-epithelialization than fibroblasts or vehicle-alone control.Use of cell-free derivatives may help replace expensive wound care approaches including use of growth factors,epidermal/dermal substitutes,synthetic membranes,cytokines,and matrix components,and most importantly avoid transmission of pathogens from human and animal products.CONCLUSION:These results encourage development of derivatives of hMSCs for wound care and re-epithelialization applications.
文摘Dear Editor, We examined myelin formation by oligodendrocytes co-transplanted with immunosuppressive mesenchymal stem cells （MSCs）. Oligodendrocyte precursor cells （OPCs） were grafted into the mouse retina, and graft survival and maturation was determined with or without adjunctive MSCs. Green fluorescent protein （GFP）-labeled MSCs were present at 2 but not 6 weeks post transplant,
文摘Objective： To study the effects of apigenin on vascular endothelial growth factor （VEGF） in human breast cancer cells （MDA-MB-231. Methods： MTT assay was used to detect the cell proliferation inhibitory effect of apigenin on MDA-MB-231 cell. ELISA was used to determine the protein level of VEGF secreted by MDA-MB-231 cells. RT-PCR was used to detect mRNA levels of VEGF in MDA-MB-231 cells. The protein levels of HIF-1α, p-AKT, p-ERK1/2, and p53 were detected by Western Blotting. Results： Apigenin did not inhibit the cell viability of MDA-MB-231 cell. Apigenin reduced the secretion and mRNA levels of VEGF in MDA-MB-231 cells. Additionally, apigenin decreased the expressions of HIF-1α, p-AKT and p-ERK1/2, but induced the expression of p53. Conclusion： Apigenin can inhibit VEGF expression in human breast cancer cells, and this may be achieved through decreasing HIF-1α.
文摘Critical to the generation of an effective therapeutic antitumor immune response is the elicitation of effective antigen presentation coupled with overcoming tumor-immune escape mechanisms. Towards this end, we aimed to understand the therapeutic effectiveness of a polymer based vaccine approach at enhancing the anti-tumor responses in a tumor-bearing mouse model. While we and others have previously demonstrated the effectiveness of PLGA based systems in delivering antigen etc., studies scarcely focus on understanding the immunological mechanisms of polymer based therapies in tumor bearing treatment models. Considering tumors modulate the immune system and consequently the efficacy of therapies, understanding treatment mechanisms in the presence of tumor will help lead to more efficacious treatment options. We demonstrate here that a poly(lactic-co-glycolic acid) (PLGA) based delivery system encapsulating tumor antigen (OVA) and the TLR9 agonist CpG motif DNA administered into the tumor microenvironment initiates an effective type 1 mediated (IFN-γ producing) anti-tumor response in a syngeneic murine model of T cell lymphoma (E.G7-OVA). Although E.G7-OVA tumors spontaneously generate antigen specific CTLs in draining lymph nodes (LN), tumors progress rapidly. Modulation of the tumor microenvironment via local PLGA based therapy led to the generation of a systemic antigen specific Th1 response, absent in the non-polymer delivery method, subsequently associated with reduced tumor growth and prolongation of survival. These studies provide further insight into the use of a PLGA-based therapeutic approach at modulating the tumor microenvironment and highlight the need for analyzing the treatment effects in a tumor bearing model.
基金supported by the National Research and Development Program of China under grant No.2019YFB1404802the Zhejiang University Education Foundation under grants No.K18-511120-004,No.K17-511120-017,and No.K17-518051-02+3 种基金the Zhejiang Public Welfare Technology Research Project under grant No.LGF20F020013the Medical and Health Research Project of Zhejiang Province of China (No.2019KY667)the Key Laboratory of Medical Neurobiology of Zhejiang Provincesupported in part by NSF Grant CCF-1617735.
文摘Objective and Impact Statement.Distinguishing tumors from normal tissues is vital in the intraoperative diagnosis and pathological examination.In this work,we propose to utilize Raman spectroscopy as a novel modality in surgery to detect colorectal cancer tissues.Introduction.Raman spectra can reflect the substance components of the target tissues.However,the feature peak is slight and hard to detect due to environmental noise.Collecting a high-quality Raman spectroscopy dataset and developing effective deep learning detection methods are possibly viable approaches.Methods.First,we collect a large Raman spectroscopy dataset from 26 colorectal cancer patients with the Raman shift ranging from 385 to 1545 cm^(−1).Second,a one-dimensional residual convolutional neural network(1D-ResNet)architecture is designed to classify the tumor tissues of colorectal cancer.Third,we visualize and interpret the fingerprint peaks found by our deep learning model.Results.Experimental results show that our deep learning method achieves 98.5%accuracy in the detection of colorectal cancer and outperforms traditional methods.Conclusion.Overall,Raman spectra are a novel modality for clinical detection of colorectal cancer.Our proposed ensemble 1D-ResNet could effectively classify the Raman spectra obtained from colorectal tumor tissues or normal tissues.
基金supported by grants from the New Jersey Commission on Spinal Cord Research (05-304711-015)
文摘We explore the hypothesis that a potential explanation for the initiation of motor neuron disease is an unappreciated vulnerability in central nervous system defense,the direct delivery of neurotoxins into motor neurons via peripheral nerve retrograde transport.This further suggests a mechanism for focal initiation of neuro-degenerative diseases in general,with subsequent spread by network degeneration as suggested by the Frost-Diamond hypothesis.We propose this vulnerability may be a byproduct of vertebrate evolution in a benign aquatic environment,where external surfaces were not exposed to concentrated neurotoxins.
基金Supported by The Cancer Research Center of the Cancer Institute in Iran
文摘AIM: To detect the effect of intraoperative prostaglandin E1 (PGE1) infusion on survival of esophagectomized patients due to cancer. METHODS: In this preliminary study, a double blinded placebo based clinical trial was performed. Thirty patients with esophageal cancer scheduled for esophagectomy via the transthoracic approach were randomized by a block randomization method, in two equal groups: PGE1 group - infusion of PGE1 (20 ng/kg per minute) in the operating room and placebo group - saline 0.9% with the same volume and rate. The infusion began before induction of anesthesia and finished just before transfer to the intensive care unit. The patients, anesthetist, intensive care physicians, nurses and surgeons were blinded to both study groups. All the patients were anesthetized with the same method. For postoperative pain control, a thoracic epidural catheter was placed for all patients before induction of anesthesia. We followed up the patients until October 2010. Basic characteristics, duration of anesthesia, total surgery and thoracotomy time, preoperative hemoglobin, length of tumor, grade of histological differentiation, disease stage, number of lymph nodes in the resected mass, number of readmissions to hospital, total duration of readmission and survival rates were compared between the two groups. Some of the data originates from the historical data reported in our previous study. We report them for better realization of the follow up results. RESULTS: The patients’ characteristics and perioperative variables were compared between the two groups. There were no significant differences in age (P = 0.48), gender (P = 0.27), body mass index (P = 0.77), American Society of Anesthesiologists physical status more than?I?(P = 0.71), and smoking (P = 0.65). The PGE1 and placebo group were comparable in the following variables: duration of anesthesia (277 ± 50 vs 270 ± 67, P = 0.86), duration of thoracotomy (89 ± 35 vs 96 ± 19, P = 0.46), duration of operation (234 ± 37 vs 240 ± 66, P = 0.75), volume of blood loss during operation (520 ± 130 vs 630 ± 330, P = 0.34), and preoperative hemoglobin (14.4 ± 2 vs 14.7 ± 1.9, P = 0.62), respectively. No hemodynamic complications requiring an infusion of dopamine or cessation of the PGE1 infusion were encountered. Cancer variables were compared between the PGE1 and placebo group. Length of tumor (11.9 ± 3 vs 12.3 ± 3, P = 0.83), poor/undifferentiated grade of histological differentiation [3 (20%) vs 3 (20%), P = 0.78], disease stage III [5 (33.3%), 4 (26.7%), P = 0.72] and more than 3 lymph nodes in the resected mass [3 (20%) vs 2 (13.3%), P = 0.79] were similar in both groups. All the patients were discharged from hospital except one patient in the control group who died because of a post operative myocardial infarction. No life threatening postoperative complication occurred in any patient. The results of outcome and survival were the same in PGE1 and placebo group: number of readmissions (2.1 ± 1 vs 1.9 ± 1, P = 0.61), total duration of readmission (27 ± 12 vs 29 ± 12, P = 0.67), survival rate (10.1 ± 3.8 vs 9.6 ± 3.4, P = 0.71), overall survival rate after one year [8 (53.3%) vs 7 (47%), P = 0.72], overall survival rate after two years [3 (20%) vs 3 (20%), P = 0.99], and overall survival rate after three years [0 vs 1 (6.7%), P = 0.99], respectively. CONCLUSION: In conclusion, PGE1 did not shorten or lengthen the survival of patients with esophageal cancer. Larger studies are suggested.
文摘A technique for multiple deep-inspiration breath-hold (DIBH) volumetric modulated arc therapy (VMAT) for a lung tumor has been proposed with 10 MV flattening-filter-free beams and an image sensor measuring a distance map to thorax surface. Planning CT images were acquired under a DIBH condition and a clinical target volume (CTV) was contoured. This procedure was repeated five times and an internal target volume (ITV) among the multiple DIBHs was created by integrating the five CTVs. A planning target volume (PTV) was defined by adding an isotropic margin of 5 mm to the ITV. Immediately before treatment, a 30-second half-arc cone-beam computer tomography (CBCT) imaging was performed under another DIBH condition, and the couch was repositioned so that tumor may be located inside the PTV contours. An infrared distance measurement device having laser diodes and an image sensor was attached to the couch, and a distance map to the patient thorax surface was recorded as a reference during still another DIBH condition. A half-arc segmented VMAT beams with two beam interrupts were delivered to the patient under multiple DIBHs, where the delivery time of each of the three segmented beams was 30 seconds. During the beam delivery, the distance map was monitored in real time to confirm that the distance to the thorax surface remained unchanged. In-treatment CBCT images suggested that the tumor position at the time of tumor registration was accurately reproduced during the DIBH VMAT delivery.
文摘The Natural Killer Cell (NKC) is the cell-mediated cornerstone of innate immunity. The purpose of this reviewis to give a historical perspective of the discovery of the Natural Killer Cell (NKC)and to apply the use of supplements in the enhancement of NKC in human cancers for the developmentof human health and well-being.Since the discovery of the NKC, as observed by Nomarski optics, scanning (SEM)/transmission electron microscopy (TEM) with cellular numeration and enrichment using bovine serum albumin (BSA) continuous gradients, there have been significant research and clinical studies to increase the effectiveness of NKC in the destruction of cancer cells. Based on significant research and clinical studies, at least 16 components have been identified that enhance or may enhance, based on their immune modulator activity, the NKC. These supplements include Alpha LipoicAcid, Arabinoxylin, Curcumin, Garlic, Genistein, Ginseng, Lentinan, Mistletoe, N-Acetylcysteine, Resveratrol, Selenium, Vitamin B, Vitamin C, Vitamin D3, Vitamin E and zinc.
文摘Sixty seven cases with special types of early gastric cancer collected from 119 early gastric cancer specimens surgically resected in the Cancer Institute of CMU from 1964 to 1987 are reported. The pathological and biological characteristics of superficial spreading focal penetrating types, microcarcinoma and small carcinoma, "Pin-point cancer", multiple early cancer and gastric stump cancer were analysed. The authors believe that understanding these special types of early gastric cancer is of great importance not only in the study of histogenesis but also in clinical treatment and prevention of gastric cancer.
文摘The intestinal barrier is crucial for homeostasis.This study aimed to investigate the protective effects of earthworm protein hydrolysates(EWPH)on the intestinal mucosal barrier and elucidate the underlying mechanisms.We first hydrolyzed earthworm protein using alcalase and identified the primary peptide components of EWPH through Nano LC-MS/MS analysis.Network pharmacology and bioinformatics approaches were employed to predict potential targets associated with the intestinal mucosal barrier.Experimentally,we demonstrated that EWPH effectively protects against dextran sulfate sodium(DSS)-induced intestinal barrier damage in mice.The protective mechanisms involve not only the inhibition of the Toll-like receptor 4(TLR4)-nuclear factor-kB(NF-kB)/mitogen-activated protein kinases(MAPK)signaling pathway in the intestinal epithelium but also the suppression of other key molecules implicated in intestinal mucosal barrier damage,including phosphorylated-SRC proto-oncogene(p-SRC),phosphorylated-signal transducer and activator of transcription 3(p-STAT3),Caspase-3,and matrix metalloproteinase-9(MMP9),thereby mitigating intestinal inflammation and mucosal barrier injury.This study provides evidence that EWPH have the potential to safeguard the intestinal barrier hemostasis.
