2011年8月15日 星期一

癌症防治新方法 – 生物神經法

楊維邦 博士 2011/8

我們必須先介紹兩位生物神經法的主角,即細胞核轉錄因子(Nuclear Factor - Kappa B,簡稱
NF-KB),及腫瘤抑制蛋白(Protein 53,簡稱P53)。NF-KB 是造成身體發炎的主要調節物質,而P53則是抑制腫瘤產生的主要物質。這兩種物質相互影響而造成身體發炎的一連串事件,也是癌症形成的重要因素。

先來說說NF-KB,它是一蛋白的複合體,在很多動物(包括人類)的細胞裏都存在著。平常都
很安靜地躲在細胞質裏,但當其被激發而被喚醒後(如何被激發喚醒,後有詳細說明),會立刻跑到細胞核及粒腺體裏面。細胞核及粒腺體裏面有著生物的整個基因體,因此NF-KB 便會使得個別基因體產生免疫效果的基因表現出來,同時那些會保護細胞不致於死亡的基因也會表現出來,更甚者那些使細胞增殖的基因亦被表現出來。這原本是件好事,是我們身體為了對抗受傷或是被外界入侵的一種自我保護措施。這種NF-KB 所造成身體局部的反應便是所謂發炎的現象。但問題是:如果NF-KB 這些動作一直被激發著,則細胞都將變成快速增殖及抗拒死亡,這就是細胞癌化及癌症進行的模式。所以,NF-KB 長期被激發就會造成慢性發炎現象;也就會形成了癌症。此種進行模式目前已普遍被醫界所接受。

再來看看P53,它是一53 千道頓的蛋白質分子,它被稱為基因體的守護神,也被稱為天使基
因。因為它守護著基因體,使其保持穩定,不被破壞。當細胞要分裂複製時,P53 會先把基因體巡視一遍,如果發覺基因體有被破壞時,則會請基因修補分子對基因體進行修補動作。如果基因體被破壞過大或該細胞已夠老化(分裂50~60 次),則P53 便會啟動另一程序,使細胞自行死亡,即所謂細胞凋零。所以如果我們身體的P53 都沒有被抑制或被破壞時,則細胞便不能抗拒死亡,所以癌症也就不會產生了。但問題是:NF-KB 和P53 之活化都需要同一種叫做P21 的伙伴。這個P21 伙伴若被NF-KB 搶走,則NF-KB 就被活化,但P53 便因沒有伙伴而會被抑制。反過來如果P53 搶走了P21 伙伴,則P53 會活化而NF-KB 則被抑制。

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2011年8月9日 星期二

NFkB/p53 crosstalk - a promising new therapeutic target

Gunter Schneider, Oliver H. Kramer

Abstract

The transcription factors p53 and NFkB determine cellular fate and are involved in the pathogenesis of most-if not all-cancers. The crosstalk between these transcription factors becomes increasingly appreciated as an important mechanism operative during all stages of tumorigenesis, metastasis, and immunological surveillance. In this review, we summarize molecular mechanisms resulating cross-signaling between p53 and NFkB proteins and how dysregulated interactions between p53 and NFkB family members contribute to oncogenesis. We furthermore analyze how such signaling modules represent targets for the design of novel intervention strategies using established compounds and powerful combination therapies.


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2011年8月8日 星期一

The Developing Brain and Cancer

The GW Institute for Neuroscience hosts annual symposium.

By Anna Miller
April 28, 2011

Just a few decades ago, the connection between neurobiology and cancer biology was suspected but unspoken.

“Today, it represents one of the most robust interfaces between basic neuroscience and clinical medicine,” said Anthony-Samuel LaMantia, professor of pharmacology and physiology in the GW School of Medicine and Health Sciences (SMHS) and founding director of the GW Institute for Neuroscience (GWIN), at the first annual Neuroscience Symposium on Wednesday.

The symposium featured four leading researchers who highlighted the latest advances in the field of neuroscience that contribute to the understanding of how the brain develops and how cancer can compromise the developing brain.

Held at the Marvin Center, the daylong event brought together close to 80 researchers, graduate students and scientists and was sponsored by SMHS, the Office of the Vice President for Research and the Columbian College of Arts and Sciences — the three entities that support GWIN.

Sally Moody, professor of anatomy and regenerative biology in SMHS, delivered the first keynote address, which highlighted the earliest stages of nervous system development.

“In all vertebrates, we have several steps that take you from the initiation of embryonic cells becoming neural to when you get actual, independent, specified kinds of neurons,” she said.

Using her work with frog embryos as a guide, Dr. Moody hypothesized that the expression of FoxD4/5, one of the earliest genes in the network, plays a key role in neural stem cell fate, particularly through its activation of a group of genes called Sox.

The second keynote speaker was Michael Dyer, a member of St. Jude Children’s Research Hospital in the Department of Developmental Neurobiology and co-leader of the Developmental Therapeutics for Solid Malignancies Program. Dr. Dyer discussed how his work studying retinoblastoma, a childhood cancer of the eye, has helped bridge the gap between developmental neurobiology and cancer genetics.

Among many influential discoveries, Dr. Dyer explained how his lab’s approach to studying tumor cells led to the unpredictable finding that adult neurons can divide without losing their distinctive features.

“What we’ve shown is that everybody was right over the years: These tumors have properties of different cell types. It’s just that nobody considered the possibility that they were all the same cell,” Dr. Dyer said.

Vittorio Gallo, professor of neuroscience at SMHS, director and Wolf-Pack Chair in Neuroscience at Children’s National Medical Center’s Center for Neuroscience Research, presented the third keynote address.

Dr. Gallo discussed how certain signaling pathways help to maintain the balance between specific types of neurons developed in the brain that are critical under both normal conditions and after injury. These pathways contribute to the growth and development of neural progenitor cells, one of the groups of neurons. Because neural progenitor cells and these pathways may influence the formation of brain tumors, they are important to understand for potential clinical applications, Dr. Gallo said.

Scott Loren Pomeroy, Bronson Crothers Professor of Neurology at Harvard Medical School and
Neurologist-in-Chief at Children's Hospital Boston, delivered the final keynote address about medulloblastoma, the most common type of malignant brain tumor in children.

Dr. Pomeroy explained how the reclassification of medulloblastoma into various subtypes is leading to the creation of better targeted therapies. These therapies, he said, may not only improve survival, but they may also help to mitigate the harsh side effects seen with current therapies that treat all medulloblastomas as equals.

“We hope to find common pathways that we will be able to block with a reasonable small number of drugs that don’t have horrible side effects and fundamentally change how we treat the tumors,” said Dr. Pomeroy. “I would say we are much closer to that today than we were 10 years ago.”

Paaqua Grant, Amanda Mathews, Mathew Raymond and Carrie House, graduate students from SMHS’s Institute of Biomedical Sciences, also delivered presentations on their research projects.

The day concluded with a panel hosted by the GW Cancer Institute and moderated by its executive director, Steven Patierno, professor of pharmacology and physiology at SMHS. Panelists included Drs. LaMantia, Dyer and Pomeroy; Javad Nazarian, assistant professor of integrative systems biology at SMHS; Norman Lee, professor in the Department of Pharmacology and Physiology at SMHS; and Weiqun Peng, associate professor of physics in the Columbian College of Arts and Sciences.

The panelists discussed the future challenges and possibilities in the realm of neuroscience research. Dr. Nazarian spoke about the promise of using cerebrospinal fluid as a way to detect and target tumors that cannot be isolated. Other panelists addressed the possibility of the existence of cancer stem cells and raised concerns about computational barriers.

“I still feel like there’s a lot hidden in our data,” said Dr. Dyer. “And I don’t know where it’s going to come from, but I feel there’s going to be a really smart person out there that’s going to figure out a totally out-ofthe-box way to look at this, and it’s going to revolutionize the way we look at all this data.”

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2011年8月2日 星期二

Why Cancer and Inflammation?

Seth Rakoff-Nahoum

Abstract

Central to the development of cancer are genetic changes that endow these “cancer cells” with many of the hallmarks of cancer, such as self-sufficient growth and resistance to antigrowth and pro-death signals. However, while the genetic changes that occur within cancer cells  themselves, such as activated oncogenes or dysfunctional tumor suppressors, are responsible for many aspects of cancer development, they are not sufficient. Tumor promotion and  progression are dependent on ancillary processes provided by cells of the tumor environment
but that are not necessarily cancerous themselves. Inflammation has long been associated with the development of cancer. This review will discuss the reflexive relationship between cancer and inflammation with particular focus on how considering the role of inflammation in physiologic processes such as the maintenance of tissue homeostasis and repair may provide a logical framework for understanding the connection between the inflammatory response and cancer.

中文摘要:
癌症之發生主要源自於基因之改變,這些改變是癌症細胞擁有好幾個特徵,即自主生長,能抗拒抑制生長和摧毀凋零之訊息。雖然,引起癌化之基因改變是發生在細胞裡面;諸如癌化基因之啟動或抑制癌化基因之因子失去功能,這些都能引起癌症,但是只有這些是不夠的。腫瘤之進展需要一些由周邊正常細胞所提供之輔助環境條件。發炎很早便被認定與癌症發展有關。本論文會討論癌症和發炎的反射反應關係,特別從發炎之生理過程及其維持生理系統平衡和修補來了解發炎及癌症之因果關係。


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Inflammation and cancer: How hot is the link?

Bharat B. Aggarwal , Shishir Shishodia , Santosh K. Sandur , Manoj K. Pandey , Gautam Sethi

Abstract

Although inflammation has long been known as a localized protective reaction of tissue to irritation, injury, or infection, characterized by pain, redness, swelling, and sometimes loss of function, there has been a new realization about its role in a wide variety of diseases, including cancer. While acute inflammation is a part of the defense response, chronic inflammation can lead to cancer, diabetes, cardiovascular, pulmonary, and neurological diseases. Several pro-inflammatory gene products have been identified that mediate a critical role in suppression of apoptosis, proliferation, angiogenesis, invasion, and metastasis. Among these gene products are TNF and members of its superfamily, IL-1a, IL-1b, IL-6, IL-8, IL-18, chemokines, MMP-9, VEGF, COX-2, and 5-LOX. The expression of all these genes are mainly regulated by the transcription factor NF-kB, which is constitutively active in most tumors and is induced by carcinogens (such as cigarette smoke), tumor promoters, carcinogenic viral proteins (HIV-tat, HIV-nef, HIV-vpr, KHSV, EBV-LMP1, HTLV1-tax, HPV, HCV, and HBV), chemotherapeutic agents, and g-irradiation. These observations imply that antiinflammatory agents that suppress NF-kB or NF-kB-regulated products should have a potential in both the prevention and treatment of cancer. The current review describes in detail the critical link between inflammation and cancer.

中文摘要:
雖然,我們很早便知道發炎是一個為保護受傷、感染、刺激而產生之局部地區之過程,跟而引起之疼痛、紅腫及一些身體之功能消失;現在我們更清楚,發炎其實在很多疾病上扮演著很多種功能,包括癌症。急性發炎是自衛免疫的一部分,但慢性發炎卻會英氣癌症、糖尿病、心血管疾病、肺病及神經性疾病。有數個發炎基因所產生之化學分子已被認出,它們會在抵抗凋零、擴散、血管增生、侵犯、轉移的過程中,扮演主要的角色。這些基因化學分子便是TNF,及一個超級家庭中之IL-1α,IL-1β,IL-6,IL-8,IL-18,化學激素如MMP-9,VEGF,COX-2及5-LOX都在其中。這些基因之表現,是由一個叫NF-Kβ錄制因子所調控,而該錄制因子在腫瘤中非常活躍,且是有致癌物質(如抽煙)、腫瘤催化劑、致癌病毒蛋白質(如HIV-tat、HIV-vpr、HIV-nef、KHSV、EBV-LMP1、HTLV1-tax、HPV、HOV與HBV),化學治療之藥物,及γ-輻射所啟動。這些事實表示抗發炎因素可以經過壓制NF-Kβ或是NF-Kβ之產生化學物來進行癌症之預防及治療。

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2011年8月1日 星期一

Y. 未分類

Y1 神經免疫控制
Neural Control of Immunity【資料來源:Bio-Inspired Technology (2011)】

Y2 NFkB/p53 crosstalk - 一種新的治療指標
NFkB/p53 crosstalk - a promising new therapeutic target【資料來源:Biochimica et Biophysica Acta (2011)】

Neural Control of Immunity

The immune system protects against invasive pathogens through the production of pro-inflammatorycytokines, which initiates a cascade of events to promote tissue repair. However, excessive or unrestrained release of pro-inflammatory cytokines can result in a range of chronic inflammatory conditions and disease states.

The vagus nerve plays a key role in regulating the inflammatory response. The vagus nerve is
composed of approximately 90% afferent (i.e., fibres that carry information from the organs to the brain) and 10% efferent fibres (i.e., fibres that carry information from the brain to the organs). It has a key role in conveying sensory information about the state of the viscera to the central nervous system. The vagus nerve innervates numerous visceral regions including the heart, oesophagus, gastrointestinal tract, liver and pancreas.

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