Radiotherapy Plan Quality Assurance in NRG Oncology Trials for Brain and Head/Neck Cancers: An AI-Enhanced Knowledge-Based Approach

The quality of radiation therapy (RT) treatment plans directly affects the outcomes of clinical trials. KBP solutions have been utilized in RT plan quality assurance (QA). In this study, we evaluated the quality of RT plans for brain and head/neck cancers enrolled in multi-institutional clinical trials utilizing a KBP approach. The evaluation was conducted on 203 glioblastoma (GBM) patients enrolled in NRG-BN001 and 70 nasopharyngeal carcinoma (NPC) patients enrolled in NRG-HN001. For each trial, fifty high-quality photon plans were utilized to build a KBP photon model. A KBP proton model was generated using intensity-modulated proton therapy (IMPT) plans generated on 50 patients originally treated with photon RT. These models were then applied to generate KBP plans for the remaining patients, which were compared against the submitted plans for quality evaluation, including in terms of protocol compliance, target coverage, and organ-at-risk (OAR) doses. RT plans generated by the KBP models were demonstrated to have superior quality compared to the submitted plans. KBP IMPT plans can decrease the variation of proton plan quality and could possibly be used as a tool for developing improved plans in the future. Additionally, the KBP tool proved to be an effective instrument for RT plan QA in multi-center clinical trials

Differential effects of low-dose and high-dose beta-carotene supplementation on the signs of photoaging and type I procollagen gene expression in human skin in vivo

Background: Although the photoprotective effects of β-carotene are thought to originate from its antioxidant properties, some studies documented pro-oxidant effects of β-carotene. Objective: Our purpose was to determine the effects of 2 different doses of dietary β-carotene on wrinkles and elasticity, procollagen gene expression and ultraviolet (UV)-induced DNA damage in human skin. Methods: Thirty healthy female subjects over the age of 50 years were randomized and received 2 different doses (30 and 90 mg/day) of β-carotene for 90 days. The baseline status was used as control. At baseline and completion of the study, facial wrinkles and elasticity were measured objectively. Buttock skin was taken to determine the type I procollagen, matrix metalloproteinase-1 and fibrillin-1 mRNA levels, and UV-induced thymine dimer and 8-hydroxy-2′-deoxyguanosine formation. Results: β-Carotene improved facial wrinkles and elasticity significantly only in the low-dose group. The minimal erythema dose decreased significantly only in the high-dose group. Type I procollagen mRNA levels were significantly increased to 4.4 ± 1.6 times the baseline level only in the low-dose group, and procollagen immunostaining increased accordingly. UV-induced thymine dimer staining was reduced in the low-dose group but tended to increase in the high-dose group. 8-hydroxy-2′-deoxyguanosine staining was significantly reduced in the low-dose group. Conclusions: 30 mg/day of β-carotene supplementation is demonstrated to prevent and repair photoaging.OAIID:oai:osos.snu.ac.kr:snu2010-01/102/2008000790/5SEQ:5PERF_CD:SNU2010-01EVAL_ITEM_CD:102USER_ID:2008000790ADJUST_YN:NEMP_ID:A079501DEPT_CD:801CITE_RATE:2.714FILENAME:beta-carotene.pdfDEPT_NM:의학과SCOPUS_YN:YCONFIRM:

Topical application of 17beta-estradiol increases extracellular matrix protein synthesis by stimulating TGF-Beta signaling in aged human skin in vivo

To investigate the effects of topically applied 17beta-estradiol on the expression of extracellular matrix proteins in aged human skin, 17beta-estradiol (0.01%) and its vehicle (70% propylene glycol, 30% ethanol) were applied to aged (68-82 y, eight females and five males) human buttock skin under occlusion for 2 wk (three times per week). Topical 17beta-estradiol was found to increase the expression of type 1 procollagen mRNA and protein significantly in human aged skin in vivo. In addition, metalloproteinase (MMP-1 protein levels were reduced by topical 17beta-estradiol. The expressions of TGF-beta1, TGF-beta type II receptor, and Sma and Mad related (Smad)3 were increased by topical 17 beta-estradiol in aged human skin, and TGF-beta1 neutralizing antibody inhibited 17beta-estradiol-induced procollagen synthesis in cultured fibroblasts. We also found that the expressions of tropoelastin and fibrillin-1 mRNA and protein, and elastic fibers in aged skin were also increased by topical 17beta-estradiol. Topical 17beta-estradiol also increased keratinocyte proliferation and the epidermal thickness in aged human skin. We also observed the same effects of topical 17beta-estradiol in young skin. In conclusion, our results suggest that topical 17beta-estradiol treatment may improve the cutaneous function of aged human skin by improving the connective tissue and increasing epidermal thickness

Red Ginseng Root Extract Mixed with Torilus Fructus and Corni Fructus Improves Facial Wrinkles and Increases Type I Procollagen Synthesis in Human Skin: A Randomized, Double-Blind, Placebo-Controlled Study

Red ginseng contains many bioactive constituents, including various ginsenosides that are believed to have antioxidant, immunostimulatory, and anti-aging activities. Yet, no controlled human study has explored its effects on photoaged skin. This study determined whether long-term intake of a red ginseng extract-containing Torilus fructus and Corni fructus mixture reduces facial wrinkles and increases collagen synthesis in human skin. Healthy female volunteers over 40 years of age were randomized in a double-blind fashion to receive either red ginseng extract-containing herbal mixture at 3 g/day or placebo for 24 weeks. Facial wrinkles, elasticity, epidermal water content, erythema, and pigmentation were measured objectively. Facial skin samples were taken before and after treatment, and real-time polymerase chain reaction and immunohistochemical analyses were undertaken for expression of type I procollagen, matrix metalloproteinase (MMP)-9, and fibrillin-1, which are wrinkle-related biochemical markers. A total of 82 subjects completed the study. Facial wrinkles were significantly improved, type I procollagen gene and protein expression was increased, MMP-9 gene induction was prevented, and fibrillin-1 fiber length was elongated only in the treatment group. No changes were seen in the facial elasticity, epidermal water content, facial erythema and pigmentation, and epidermal thickness in either group. Thus a red ginseng extract-containing Torilus fructus and Corni fructus mixture improves facial wrinkles, a clinical sign of photoaging, and this improvement is associated with biochemical and histological evidence of increased collagen synthesis in the dermis. These results substantiate the alleged beneficial effects of red ginseng on photoaging and support its use as an effective ``beauty food.``This study was supported in part by a grant to J.H.C. from the Korea Tobacco and Ginseng Corporation.Lau CH, 2008, PHYTOTHER RES, V22, P1384, DOI 10.1002/ptr.2513Lee J, 2007, J ETHNOPHARMACOL, V109, P29, DOI 10.1016/j.jep.2006.06.008Kimura Y, 2006, BRIT J PHARMACOL, V148, P860, DOI 10.1038/sj.bjp.0706794Lee PS, 2006, INT J PHARM, V316, P29, DOI 10.1016/j.ijpharm.2006.02.035Jung SH, 2006, INT J CANCER, V118, P490Han KL, 2006, BIOL PHARM BULL, V29, P110Son ED, 2005, J INVEST DERMATOL, V124, P1149, DOI 10.1111/j.0022-202X.2005.23736.xKim S, 2004, BIOCHEM BIOPH RES CO, V316, P348, DOI 10.1016/j.bbrc.2004.02.046Yokozawa T, 2004, J PHARM PHARMACOL, V56, P107, DOI 10.1211/0022357022449Chung JH, 2003, J AM ACAD DERMATOL, V49, P690, DOI 10.1067/S0190-9622(03)02127-3Lee EH, 2003, J INVEST DERMATOL, V121, P607, DOI 10.1046/j.1523-1747.2003.12425.xChung JH, 2003, PHOTODERMATOL PHOTO, V19, P109Choo MK, 2003, PLANTA MED, V69, P518, DOI 10.1055/s-2003-40653Inomata S, 2003, J INVEST DERMATOL, V120, P128Fisher GJ, 2002, ARCH DERMATOL, V138, P1462Brenneisen P, 2002, ANN NY ACAD SCI, V973, P31Attele AS, 1999, BIOCHEM PHARMACOL, V58, P1685, DOI 10.1016/S0006-2952(99)00212-9Voces J, 1999, COMP BIOCHEM PHYS C, V123, P175Lee BH, 1998, PLANTA MED, V64, P500Fisher GJ, 1998, J CLIN INVEST, V101, P1432Kim KH, 1998, PLANTA MED, V64, P110Fisher GJ, 1997, NEW ENGL J MED, V337, P1419Hasegawa H, 1997, PLANTA MED, V63, P436Gillis CN, 1997, BIOCHEM PHARMACOL, V54, P1Lee YS, 1997, ANTICANCER RES, V17, P323Hasegawa H, 1996, PLANTA MED, V62, P453Fisher GJ, 1996, NATURE, V379, P335Zhang DX, 1996, FREE RADICAL BIO MED, V20, P145BLUMENTHAL M, 1996, GERMAN COMMISSION ELEE FC, 1992, FACTS GINSENG ELIXIRKARIKURA M, 1991, CHEM PHARM BULL, V39, P2357EMONARD H, 1990, CELL MOL BIOL, V36, P131GILCHREST BA, 1989, J AM ACAD DERMATOL, V21, P610SIEGEL RK, 1979, JAMA-J AM MED ASSOC, V241, P1614PALMER BV, 1978, BRIT MED J, V1, P1284SOBEL H, 1970, STEROIDS, V16, P1BREKHMAN II, 1969, ANNU REV PHARMACOLOG, V9, P419

Photoprotective and anti-skin-aging effects of eicosapentaenoic acid in human skin in vivo

Skin aging can be attributed to photoaging (extrinsic) and chronological (intrinsic) aging. Photoaging and intrinsic aging are induced by damage to human skin attributable to repeated exposure to ultraviolet (UV) irradiation and to the passage of time, respectively. In our previous report, eicosapentaenoic acid (EPA) was found to inhibit UV-induced matrix metalloproteinase-1 (MMP-1) expression in human dermal fibroblasts. Therefore, we investigated the effects of EPA on UV-induced skin damage and intrinsic aging by applying EPA topically to young and aged human skin, respectively. By immunohistochemical analysis and Western blotting, we found that topical application of EPA reduced UV-induced epidermal thickening and inhibited collagen decrease induced by UV light. It was also found that EPA attenuated UV-induced MMP-1 and MMP-9 expression by inhibiting UV-induced c-Jun phosphorylation, which is closely related to UV-induced activator protein-1 activation, and by inhibiting JNK and p38 activation. EPA also inhibited UV-induced cyclooxygenase-2 (COX-2) expression without altering COX-1 expression. Moreover, it was found that EPA increased collagen and elastic fibers (tropoelastin and fibrillin-1) expression by increasing transformin growth factor-beta expression in aged human skin. Together, these results demonstrate that topical EPA has potential as an anti-skin-aging agent

Phosphatidylserine prevents UV-induced decrease of type I procollagen and increase of MMP-1 in dermal fibroblasts and human skin in vivo

In an effort to find topical agents that prevent or retard cutaneous aging, seven functional lipids were screened for their procollagen-upregulating and matrix metalloproteinase (MMP)-1-downregulating activities in human dermal fibroblasts by Western blotting. The preventive effect on ultraviolet (UV)-induced decrease of procollagen was demonstrated in phosphatidylserine (PS), lysophosphatidylserine (LPS), lysophosphatidic acid (LPA), N-acetyl phytosphingosine (NAPS), and tetraacetyl phytosphingosine (TAPS). Furthermore, PS, LPS, and LPA upregulated procollagen expression in unirradiated basal conditions. The inhibitory effect on UV-induced MMP-1 expression was seen in NAPS, TAPS, LPA, PS, lysophosphatidylglycerol, and LPS. PS was chosen as the most suitable candidate anti-aging chemical for the subsequent in vivo studies. We investigated the effects of PS on acute UV response and chronologic skin aging by topically applying it to young skin before UV irradiation and to aged human skin, respectively. Real-time PCR and Western blot revealed that in the young skin, PS treatment prevented UV-induced reduction in procollagen expression and inhibited UV-induced MMP-1 expression. PS also blocked UV-induced IL-6 and COX-2 gene expression in cultured fibroblasts dose-dependently. In the aged skin, PS caused increased procollagen transcription and procollagen immunostaining in the upper dermis, and a significant decrease in MMP-1 expression at both mRNA and protein levels. These results indicate that topical PS has anti-skin-aging properties and point to the potential use of PS as a therapeutic agent in the prevention and treatment of cutaneous aging

Increased expression of 14-3-3varepsilon protein in intrinsically aged and photoaged human skin in vivo

Skin aging is a complicated process associated with the passage of time and environmental exposure, especially to UV light. This aging phenomenon is related to alterations in various cellular mechanisms, such as changes in apoptosis, perturbations to cellular signaling, and an increased genetic instability. In this study, we investigated changes of proteins involved in intrinsic aging by the proteomic analysis of human sun-protected (upper inner arm) young and aged dermis. One of the proteins upregulated in aged dermis was identified as 14-3-3epsilon. This protein is an isoform of 14-3-3 protein, which is involved in cellular processes like signal transduction, cell cycle arrest, and apoptosis. 14-3-3epsilon is consistently found to be upregulated in the sun-protected dermis of aged skin, by Western blotting and immunohistochemical staining. In addition, we demonstrate that the expression of 14-3-3epsilon is further upregulated in the sun-exposed (photodamaged) dermis, and that the UV irradiation of young skin significantly upregulates 14-3-3epsilon in vivo. Our results suggest the possibility that the cellular processes related to 14-3-3epsilon protein play an important role in the photoaging and intrinsic aging of human skin

Quantification of nanoscale nuclear refractive index changes during the cell cycle

Intrigued by our recent finding that the nuclear refractive index is significantly increased in malignant cells and histologically normal cells in clinical histology specimens derived from cancer patients, we sought to identify potential biological mechanisms underlying the observed phenomena. The cell cycle is an ordered series of events that describes the intervals of cell growth, DNA replication, and mitosis that precede cell division. Since abnormal cell cycles and increased proliferation are characteristic of many human cancer cells, we hypothesized that the observed increase in nuclear refractive index could be related to an abundance or accumulation of cells derived from cancer patients at a specific point or phase(s) of the cell cycle. Here we show that changes in nuclear refractive index of fixed cells are seen as synchronized populations of cells that proceed through the cell cycle, and that increased nuclear refractive index is strongly correlated with increased DNA content. We therefore propose that an abundance of cells undergoing DNA replication and mitosis may explain the increase in nuclear refractive index observed in both malignant and histologically normal cells from cancer patients. Our findings suggest that nuclear refractive index may be a novel physical parameter for early cancer detection and risk stratification

The palladacycle complex AJ-5 induces apoptotic cell death while reducing autophagic flux in rhabdomyosarcoma cells

Abstract Rhabdomyosarcoma (RMS) forms in skeletal muscle and is the most common soft tissue sarcoma in children and adolescents. Current treatment is associated with debilitating side effects and treatment outcomes for patients with metastatic disease are dismal. Recently, a novel binuclear palladacycle, AJ-5, was shown to exert potent cytotoxicity in melanoma and breast cancer and to present with negligible adverse effects in mice. This study investigates the anti-cancer activity of AJ-5 in alveolar and embryonal RMS. IC50 values of ≤ 0.2 µM were determined for AJ-5 and it displayed a favourable selectivity index of >2. Clonogenic and migration assays showed that AJ-5 inhibited the ability of RMS cells to survive and migrate, respectively. Western blotting revealed that AJ-5 induced levels of key DNA damage response proteins (γH2AX, p-ATM and p-Chk2) and the p38/MAPK stress pathway. This correlated with an upregulation of p21 and a G1 cell cycle arrest. Annexin V-FITC/propidium iodide staining revealed that AJ-5 induced apoptosis and necrosis. Apoptosis was confirmed by the detection of cleaved PARP and increased levels and activity of cleaved caspases-3, -7, -8 and -9. Furthermore, AJ-5 reduced autophagic flux as shown by reduced LC3II accumulation in the presence of bafilomycin A1 and a significant reduction in autophagosome flux J. Finally, pharmacokinetic studies in mice show that AJ-5 has a promising half-life and that its volume of distribution is high, its clearance low and its intraperitoneal absorption is good. Together these findings suggest that AJ-5 may be an effective chemotherapeutic with a desirable mechanism of action for treating drug-resistant and advanced sarcomas