Full-depth epidermis tomography using a Mirau-based full-field optical coherence tomography

With a Gaussian-like broadband light source from high brightness Ce3+:YAG single-clad crystal fiber, a full-field optical coherence tomography using a home-designed Mirau objective realized high quality images of in vivo and excised skin tissues. With a 40 x silicone-oil-immersion Mirau objective, the achieved spatial resolutions in axial and lateral directions were 0.9 and 0.51 mu m, respectively. Such a high spatial resolution enables the separation of lamellar structure of the full epidermis in both the cross-sectional and en face planes. The number of layers of stratum corneum and its thickness were quantitatively measured. This label free and non-invasive optical probe could be useful for evaluating the water barrier of skin tissue in clinics. As a preliminary in vivo experiment, the blood vessel in dermis was also observed, and the flowing of the red blood cells and location of the melanocyte were traced. (C)2014 Optical Society of Americ

1,2-Ethanedithiol-Induced Erythema Multiforme-Like Contact Dermatitis

Contact dermatitis simulating erythema multiforme can be caused by many allergens. The chemical agent 1,2- ethanedithiol, which serves as a protective group in chemical synthesis, has hitherto only been implicated as an irritant. We report on a 22-year-old female chemistry student who developed widespread erythema multiforme-like lesions after local contact with 1,2-ethanedithiol. Many target lesions were observed bilaterally on her hands, forearms, arms, and on her forehead. One such lesion was histologically compatible with erythema multiforme. The patient had a positive patch test to 1,2-ethanedithiol, whereas none of 30 healthy subjects showed a positive reaction. However, eight of the 30 controls (26 .7%) developed irritant reactions to 1,2-ethanedithiol. Cautious handling of the compound is a prudent precaution

Toward Single-Mode Active Crystal Fibers for Next-Generation High-Power Fiber Devices

We report what we believe to be the first demonstration of a facile approach with controlled geometry for the production of crystal-core ceramic-clad hybrid fibers for scaling fiber devices to high average powers. The process consists of dip coating a solution of polycrystalline alumina onto a high-crystallinity 40-mu m-diameter Ti:sapphire single-crystalline core followed by thermal treatments. Comparison of the measured refractive index with high-resolution transmission electron microscopy reveals that a Ca/Si-rich intragranular layer is precipitated at grain boundaries by impurity segregation and liquid-phase formation due to the relief of misfit strain energy in the Al2O3 matrix, slightly perturbing the refractive index and hence the optical properties. Additionally, electron backscatter diffractions supply further evidence that the Ti:sapphire single-crystalline core provides the template for growth into a sacrificial polycrystalline cladding, bringing the core and cladding into a direct bond. The thus-prepared doped crystal core with the undoped crystal cladding was achieved through the abnormal grain-growth process. The presented results provide a general guideline both for controlling crystal growth and for the performance of hybrid materials and provides insights into how one might design single-mode high-power crystal fiber devices

Roles of Tumor-Associated Macrophages and Cyclooxygenase-2 in the patholgenesis of Human Basal Cell Carcinoma

論文中文摘要 人類基底細胞癌(human basal cell carcinoma; BCC)是最常見的人類癌症。全世界每年有幾百萬例新發生的基底細胞癌。雖然說基底細胞癌幾乎不會轉移，但是局部侵犯與組織破壞相當的常見。第二型環氧酵素 (cyclooxyngease-2; COX-2)與腫瘤相關巨噬細胞(tumor-associated macrophages; TAM)已經知道會促進許多人類癌症的腫瘤新生(tumorigenesis)、血管新生(angiogenesis)、以及轉移(metastasis)。但是，COX-2與腫瘤相關巨噬細胞在人類基底細胞癌中扮演的角色仍然不清楚。我們利用免疫組織染色的方法發現人類基底細胞癌細胞本身表現COX-2的強度與其中浸潤的腫瘤相關巨噬細胞的數目，與基底細胞癌侵襲的深度與微細血管的密度(microvessel density; MVD)有關。再利用多變項線性迴歸分析控制其他可能影響到基底細胞癌侵襲與血管新生的因素，結果發現基底細胞癌本身COX-2表現強度與腫瘤相關巨噬細胞的數量是影響基底細胞癌侵襲深度與血管新生的獨立預測因子。這代表由臨床研究發現COX-2與腫瘤相關巨噬細胞與基底細胞癌的進展有重要的關聯性。 論文的第一部分，我們著重在研究基底細胞癌細胞本身過度表現COX-2對於基底細胞癌的影響。我們建立穩定轉殖並過度表現COX-2的人類基底細胞癌細胞株。COX-2過度表現的基底細胞癌細胞株中對抗細胞凋亡的Mcl-1與Bcl-2蛋白質的表現量顯著的上升，同時產生的對於紫外線B光照射誘發細胞凋亡的抗性。COX-2過度表現也會增加基底細胞癌細胞分泌血管內皮生長因子(vascular endothelial growth factor-A; VEGF-A)與鹼性纖維母細胞生長因子(basic fibroblast growth factor; bFGF)，因而促進基底細胞癌在活體內與活體外的血管新生。如果使用COX-2專一性的siRNA減少COX-2的表現量或是用COX-2的抑制劑NS-398抑制COX-2的功能，將會減少VEGF-A與bFGF的分泌量。當COX-2過度表現的基底細胞癌細胞打入SCID老鼠體內的時候，會產生比控制組更大的異種腫瘤(xenograft)。在COX-2過度表現的異種腫瘤中發現其新生血管也比控制組的異種腫瘤中的新生血管來的多。因此，我們證實了COX-2在人類基底細胞癌細胞過度表現的確會促進基底細胞癌細胞產生對細胞凋亡的抗性、增加其血管新生與腫瘤新生的能力，因而促進基底細胞癌細胞的進展。 運用臨床上手術切除下來基底細胞癌的檢體做免疫組織染色的結果發現，在COX-2過度表現的基底細胞癌細胞團塊附近有相當多的腫瘤相關巨噬細胞聚集。免疫組織染色結果的統計上也發現，基底細胞癌當中腫瘤相關巨噬細胞的數量與基底細胞癌細胞本身COX-2的表現量成顯著的正相關。加上我們已經發現COX-2在基底細胞癌細胞內過度表現可以促進基底細胞癌的腫瘤新生與血管新生。因此，我們第二部分研究的假設是腫瘤相關巨噬細胞經過活化基底細胞癌細胞的COX-2來達到促進基底細胞癌細胞侵襲與血管新生的作用。 腫瘤相關巨噬細胞是一種M2巨噬細胞。M2巨噬細胞是由Th2細胞激素活化的巨噬細胞會促進腫瘤的生長。人類THP-1細胞株在經由phorbol myristate acetat (PMA)處理過後會變成巨噬細胞，在以往的研究中常常用來作為腫瘤相關巨噬細胞的模型。我們證明了PMA-treated THP-1巨噬細胞是一種M2巨噬細胞，它們會表現M2的表現標記(CD204與CD206)，同時表現M2的cytokine profile。基底細胞癌細胞在與PMA-treated THP-1巨噬細胞共同培養之後，會增加基底細胞癌細胞COX-2的表現、與其侵襲性及活體外血管新生的能力。但是如果將基底細胞癌細胞內的COX-2表現用COX-2專一性的siRNA或是COX-2專一性抑制劑celecoxib阻斷的話，與PMA-treated THP-1巨噬細胞共同培養誘發基底細胞癌細胞的侵襲與血管新生就會顯著的減少。與巨噬細胞共同培養會經由活化基底細胞癌中p38 MAPK/ NF-κB訊息傳遞路徑活化基底細胞癌的COX-2表現。與巨噬細胞共同培養誘發基底細胞癌侵襲性的增加，是經由活化基底細胞癌中p38 MAPK/ NF-κB/ COX-2訊息傳遞路徑活化MMP-9的分泌與活性造成基底細胞癌侵襲增加。與巨噬細胞共同培養誘發基底細胞癌血管新生的增加，也是經由活化基底細胞癌中p38 MAPK/ NF-κB/ COX-2訊息傳遞路徑活化VEGF-A與bFGF的分泌而造成基底細胞癌血管新生的增加。為了讓我們的研究結果更加一般化，我們用人類週邊血液單核球(monocytes)細胞，將之分化為巨噬細胞後加入IL-4/IL-13，使其變為M2巨噬細胞。將單核球演變而來的M2巨噬細胞與基底細胞癌細胞共同培養，結果也會促進基底細胞癌細胞產生COX-2依賴的侵襲與血管新生，同時也會增加基底細胞癌細胞分泌MMP-9、VEGF-A、與bFGF。總結來說，腫瘤相關巨噬細胞會經由COX-2依賴的路徑來促進基底細胞癌細胞的侵襲性與血管新生。 本論文研究的結果指出COX-2與腫瘤相關巨噬細胞在人類基底細胞癌細胞的致癌機轉與其進展中的重要角色。COX-2與腫瘤相關巨噬細胞可以做為未來開發新的非手術性治療人類基底細胞癌新療法的標的。Human basal cell carcinoma (BCC) is the most common human cancer. BCC affects millions of people worldwide annually. Although BCC never metastasis, but local invasion and destruction are very common. Cyclooxygenase-2 (COX-2) and tumor-associated macrophages (TAM) are known to increase tumorigenesis, angiogenesis, and metastasis in many human cancers. However, the role of COX-2 and TAM remain elusive in human basal cell carcinoma. We found that both COX-2 expression in BCC epithelial cells and number of TAM associate with increased invasion depth and microvessel density (MVD) by immunohistochemistry (IHC). Multivariate linear regression analysis showed that both grades of COX-2 expression in BCC epithelial cells as well as number of TAM are independent predictors for depth of invasion and MVD in human BCC. In the first part of the study, we focused first on the effects of COX-2 expression in human BCC cells. Overexpression of COX-2 in human BCC cell line conferred cells resistance to ultraviolet B (UVB) induced apoptosis by up-regulation of anti-apoptotic proteins Mcl-1 and Bcl-2. COX-2 overexpression also increased secretion of vascular endothelial growth factor-A (VEGF-A) and basic fibroblast growth factor (bFGF) and increased in vitro and in vivo angiogenesis. Blocking COX-2 fuction by COX-2 specific RNA interference (siRNA) or specific inhibitor NS-398 abrogated increased VEGF-A and bFGF secretion by BCC cells. When COX-2 overexpressing BCC cells were inoculated into SCID subcutaneously, they developed xenograft larger than vector control counterparts. Significant increased neovascularization was observed in COX-2 overexpressing xenograft. We confirmed COX-2 promote BCC progression by enhancing anti-apoptotic ability, angiogenesis and tumorigenesis. Prominent TAM aggregated adjacent to COX-2 overexpressing tumor nests in BCC. In addition, increased number of TAM significantly correlated grading of COX-2 expression in BCC cancer cells. Taken the special adjacency and statistics together, we hypothesized that TAM might induce COX-2 expression in BCC cells and subsequently increase invasion and angiogenesis in BCC. TAM is a kind of M2 macrophages, which is activated by Th2 cytokines. Human THP-1 cell line differentiated to macrophages after treatment with phorbol myristate acetate (PMA). We demonstrated PMA-treated THP-1 macrophages were a kind of M2 macrophages because they express M2 surface markers (i.e. CD204 & CD206) and a M2 cytokine profile. Non-contact coculture with PMA-treated THP-1 macrophages induced COX-2 expression, incrased invasiveness, and in vitro angiogenesis in human BCC cells. Once COX-2 activity was abrogated by COX-2 specific siRNA or specific inhibitor celecoxib, the increased invasiveness and angiogenesis induced by coculture were attenuated. Coculture with macrophages induced COX-2 expression in BCC by activating the p38 MAPK/NF-κB signaling pathway. Coculture with macrophages induced MMP-9 activation by p38 MAPK/ NF-κB /COX-2 cascades and increased invasion of BCC cells. Increased angiogenesis induced by coculture resulted from increased secretion of VEGF-A and bFGF by p38 MAPK/ NF-κB /COX-2 cascades. To verify our findings, we generate another kind of M2 macrophages from human peripheral monocytes. Coculture with monocyte-derived M2 macrophages also induced COX-2 dependent invasion and angiogenesis, as well as increased expression of MMP-9, VEGF-A and bFGF. We conclude that TAM might induce BCC invasion and angiogenesis via a COX-2 dependent manner in BCC cells. Our study highlights the importance of COX-2 and TAM in the pathogenesis and progression of human BCC. COX-2 and TAM might be used as therapeutic targets for the non-surgical treatments of human basal cell carcinoma in the near future.目 錄試委員會審定書………………………………………………v謝………………………………………………………………vi文摘要……………………………………………………vii-ix文摘要……………………………………………………x-xii士論文內容一章 緒論 (Introduction)……………1-22二章 研究方法與方法……………………23-34三章 結果…………………………………35-48四章 討論…………………………………49-70五章 展望…………………………………71-81六章 論文英文簡述 (Summary)…………82-92七章 參考文獻……………………………93-125八章 圖表…………………………………126-167九章 附錄…………………………………16

Tumor-Associated Macrophage-Induced Invasion and Angiogenesis of Human Basal Cell Carcinoma Cells by Cyclooxygenase-2 Induction

Tumor-associated macrophages (TAMs) and cyclooxygenase-2 ( COX-2) are associated with invasion, angiogenesis, and poor prognosis in many human cancers. However, the role of TAMs in human basal cell carcinoma (BCC) remains elusive. We found that the number of TAMs infiltrating the tumor is correlated with the depth of invasion, microvessel density, and COX-2 expression in human BCC cells. TAMs also aggregate near COX-2 expressing BCC tumor nests. We hypothesize that TAMs might activate COX-2 in BCC cells and subsequently increase their invasion and angiogenesis. TAMs are a kind of M2 macrophage derived from macrophages exposed to Th2 cytokines. M2-polarized macrophages derived from peripheral blood monocytes were cocultured with BCC cells without direct contact. Coculture with the M2 macrophages induced COX-2-dependent invasion and angiogenesis of BCC cells . Human THP-1 cell line cells, after treated with phorbol myristate acetate (PMA), differentiated to macrophages with M2 functional profiles. Coculture with PMA-treated THP-1 macrophages induced COX-2-dependent release of matrix metalloproteinase-9 and subsequent increased invasion of BCC cells. Macrophages also induced COX-2-dependent secretion of basic fibroblast growth factor and vascular endothelial growth factor-A, and increased angiogenesis in BCC cells

Business Model of Cosmetic Center in Public Hospital--- Illustrated by a Medical Center

醫學美容產業最近十年來在台灣蓬勃的發展。主要原因是(1)非侵襲性醫學美容科技(如雷射光療、注射美容)的進步；(2)另外因為健保給付偏低，醫院需開發自費收益；(3)政府政策引導醫療服務產業化，例如自由經濟示範區、推動國際醫療、觀光醫療等政策。雖然醫學美容有產業化的趨勢，不過醫美服務目前被認定是醫療行為(非單純商業交易)，因此受到醫療相關法規的嚴格管控。許多公私立醫院均設立醫學美容中心，加上專門醫美診所不斷設立，市場漸趨飽和，競爭也日趨激烈。彼得‧杜拉克曾說：『二十一世紀的競爭是商業模式的競爭。』公立醫療院所因為受限於法令規定的限制，其應變速度與靈活度相較於私立院所來的小。如何在激烈的兢爭中生存，有賴於商業模式設計。本研究先從文獻探討著手，了解企業轉型的利基策略，分析各種利潤模式與利潤區。進一步在對於商業模式做分拆解析，並探討Johnson等人提出的商業模式在創新理論。本研究將運用個案研究法，深入剖析商業模式再創新的四個連動要素：(1)顧客價值主張；(2)利潤公式；(3)關鍵資源；(4)關鍵流程。基於本研究的結果，希望可以提供公立醫療院所在競爭激烈的美容市場中佔住利基市場，穩定與持續的成長，發揮商業模式的整體綜效。Medical cosmetics are booming in Taiwan in the past decade. The main reasons includes: (1) Development of new non-invasive technology (i.e. lasers and injectables); (2) Poor insurance reimbursement prompts hospitals to generate new revenue stream; (3) Healthcare industrialization policy: Free economics pilot zones promotes international healthcare and bundled with tourism. However, medical cosmetics are still regarded as a medical practice and under strict regulations. Numerous public or private hospitals have increased their exposures to medical cosmetics, along with specialized cosmetic clinics, the market becomes increasingly crowded and intensive competitive. Peter F. Drucker once said: “Business model competition is the major management challenge in 21st century.” Restrained by regulations, public hospital are less agile in maneuver. To survive in this keen competition, rely on business model design. Started from literature review, current trends of value migration and profit zones shifts are illustrated. How to reinvent profitable business models are thoroughly discussed. The four components of successful business model, i.e. customer value proposition, profit formula, key resources, and key process, are demonstrated in our case study. The proposed model is also applicable to other public hospital to ensure a sustainable growth in medical cosmetic field.口試委員審定書…………………………………………………i 誌謝………………………………………………………………ii 中文摘要…………………………………………………………iii 英文摘要…………………………………………………………iv 目 錄 …………………………………………………………v 圖目錄 …………………………………………………………viii 表目錄 …………………………………………………………ix 第一章 緒論 ………………………………………………1 第一節 研究背景與動機………………………………………1 第二節 研究目的………………………………………………4 第三節 研究方法與設計………………………………………5 第四節 論文架構………………………………………………6 第二章 文獻探討……………………………………………7 第一節 商業設計與企業價值轉移……………………………7 第二節 利潤區與利潤模式...………………………………11 第三節 商業模式建立……………………………………….17 第四節 商業模式再創新理論……………………………….20 第三章 產業分析……………………………………………23 第一節 全球醫學美容產業現況與趨勢……………………23 第二節 台灣美容醫學服務市場之法令規範………………32 第三節 台灣美容醫學產業環境概況分析…………………36 第四節 五力分析……………………………………………41 第四章 個案研究分析與討論……………………………44 第一節 個案醫學美容中心及其經營策略…………………45 第二節 商業模式關鍵成功因素：顧客價值主張…………56 第三節 商業模式關鍵成功因素：利潤公式………………62 第四節 商業模式關鍵成功因素：關鍵資產………………68 第五節 商業模式關鍵成功因素：關鍵流程………………74 第六節 個案『美容中心』經營困境與因應策略…………78 第五章 結論與建議………………………………………80 第一節 研究結論……………………………………………80 第二節 研究貢獻……………………………………………81 第三節 實務研究建議………………………………………82 第四節 後續相關研究建議…………………………………83 參考文獻……………………………………………………85. 一、中文文獻…………………………………………………85 二、英文文獻…………………………………………………87 三、參考網站…………………………………………………87 附錄……………………………………………………………8