Facebook 要上市，大领导这几天看新闻老有Facebook上市的消息，心动了，小领导是 Facebook 迷，跟我说一定要把她积攒的几千美元零用钱全部投进Facebook去，说地球人都知道 Facebook的名气，不会错。 小领导曾经在一个孩子的网站玩过虚拟股票，结果一败涂地。她玩股票永远输，从来没有赢过，人人网上市的时候，她听我说这个社会媒体可能会火，结果买了以后就大跌。后来她买百度也是在最高点。中国概念玩不转，玩其他的，也是每次一进股票，结果总是下跌。于是小领导自我安慰说，她其实可以帮助别人发财：as soon as I buy any stocks, it is time for those who hold these stocks to sell. It never fails. 一时的手气好坏赚不了钱，手气老是好或老是坏才可以，至少理论上如此，要的就是预测的 consistency 啊。不过这次她要求玩真格的了，谁叫 Mark Zuckerberg 是她的偶像呢（她的另一位偶像是不久前去世的苹果创始人 Steve Jobs） 。 我跟两位领导说，既然我们都是股票盲，那么就意思意思，定下一个数，输光为止，赢了就继续玩，输光绝不再往里面填。领导同意这个方案，说全世界的人都玩股票，我们怎么也玩一把。 昨天看文章说，因为散户没有可能第一时间购买 IPO，所以根据过去的规律，等到散户上场，股票已经冲上去了，风险太大。（以前很 naive，曾经胡说过要第一时间炒IPO，稳赚不赔 一说就破一试就灵的 发财 秘诀- （ 立委） ：这句话只对大投机家有效，他们也一直是这样发的，散户根本没有这个资格和机会啊。） 投资专家预测，如果 FACEBOOK IPO 起价定为 30 美元，保守的估计是，等到散户可以上场的时候，就已经冲到 80-90 美元，当天终场时候的交易价甚至可以冲到 100+ 美元。 但是，紧接着第二三天，应该是大幅度回落的时候，那些大户投机者和机构持股人会抛售套现，股票甚至可能会降低到 50 美元左右，也就是说，你即便第一时间按照 80 美元购得，在此后的几天里，极有可能缩水四成。当然如果你不做短期的 day trade，而是 hold 住它，股票一般会慢慢回升到 80 以上，这个过程快的话需要几周，慢的话需要半年多。回看 LinkedIn 上市以来的曲线，大体如此，LinkedIn 经过多半年的起伏跌宕，现在差不多又回到上市初期的最高点了。Google 当年的走向也类似，上市巨头的头一年股市起伏都是有大致规律可循的（难得的是，Google 后几年也基本一直强势走高；IT 业最厉害的还是苹果的二次起飞的奇迹：以 iPod 作为转机的开始，最近几年借 iPhone 和 iPad 的技术创新，其股票强势简直让人瞠目结舌，其市值已经超过Google和微软 两大巨头的总和，乖乖隆的东！至于 Facebook 的长远趋势，现在预测尚为时过早，因为究竟社会媒体里面的广告盈利模式或其他盈利模式是否还有巨大的潜力空间，还没有人敢下结论，虽然总体趋势应该是肯定和正面的）。 因此，专家建议，对于散户，最佳进场时间应该是 IPO 一周以后的某个时间，那时候的趋势已经比较明显也稳定，然后给自己定下一个心理价位，譬如说如果股价回落到最高点的 20% （或 30% or 40%）就毅然进场。然后 hold 住，直到它涨上去 50% （或 60% or 80%，or whatever 你觉得你对所赚感到满意的心理价位）即可抛售。 心理价位的两个边界事先定好，根据走势可以做微调，但是不要轻易改变， 不知进退， 贪得无厌，这才是成功对策。当然人多是善变的动物，不容易把握，实在怕把握不住，也可以把价位设定到程序中，由程序自动启动购买和抛售的时机（可是怎么用此类工具啊，还不知道）。 下列文章可以一看“Facebook IPO: Five Things To Consider Before You Buy Facebook Stock”： http://www.ibtimes.com/articles/338662/20120508/facebook-ipo-five-stock-price-date.htm
2012年4月，《Nature Reviews Drug Discovery》报道，Genentech公司研究开发的Hedgehog抑制剂vismodegib成为由美国食品和药物管理局批准的第一个治疗基底细胞癌的药物，这是对用于多个治疗方案的患者而言是一个积极的消息，也许是一个同样重要的临床里程碑，vismodegib被批准是一个重大的科学成就：该药是上市的第一个靶向于Hedgehog信号转导通路的抑制剂。 Hedgehog信号通路对细胞早期生长和发展起关键的调节作用。在包括基底细胞癌等多种类型的恶性肿瘤中都发现Hedgehog信号通路发生突变。Vismodegib是一个口服、具有高选择性的Hedgehog信号通络小分子抑制剂，用于治疗不适合采用手术治疗的晚期基底细胞癌患者。由于在该类患者中目前还没有标准治疗药物，所以FDA给予Vismodegib快速审评的地位，本品的审评决议期为2012年3月8日。 有关Hedgehog信号转导通路的抑制剂的研究进展可参考我们发表在《中国药物化学杂志》2010年20(5):414-425的综述性文章。 原文： In January, Genentech's vismodegib became the first drug to be approved by the US Food and Drug Administration for advanced basal cell carcinoma (BCC), which is positive news for these patients who have had few treatment options. Perhaps just as important as the clinical milestone, vismodegib's approval represents a significant scientific achievement: the drug is the first on the market to target the Hedgehog (HH) signalling pathway. “We are overjoyed with the news that a HH signalling inhibitor is at last on the market — we have been dreaming of this for 15 years,” says Jingwu Xie of Indiana University, Indianapolis, USA, who was part of one of the teams that in 1996 identified the mutated gene responsible for BCC. We have been dreaming of this for 15 years. Yet although vismodegib's approval for metastatic and inoperable locally advanced BCC is encouraging news for the field, an elephant in the room looms large: will HH inhibitors prove to be effective in a broader range of more common tumour types? Vismodegib and other HH inhibitors act as targeted therapies in the BCC setting (in which specific HH pathway mutations lead to aberrant pathway activity), but despite implications that HH signalling is important in other cancers there is no clear genetic basis for efficacy in these. “In BCC, HH signalling is the cause of the disease, whereas in other cancers its activation may be only one of many drivers,” explains Xie. “We probably don't understand yet how to use in these diseases,” adds Genentech's Frederic de Sauvage, who initiated biological studies of the HH pathway at the company in 1996. Vismodegib is also the first of a new broader class of anticancer agents that target embryonic signalling pathways, which also include Notch and WNT. Researchers commented, however, that because each of these operate independently — with distinct targets and biomarkers, and quite often in different tumour types — there are few lessons from HH development that can be extrapolated. Homing in on Hedgehog The HH pathway was first identified in 1980 in the fruitfly, when researchers identified mutations in a gene that caused the insects to develop abnormally; the flies looked spiky, and so scientists named the gene and pathway 'Hedgehog'. A related pathway in humans similarly has a crucial role in development, modulating cell growth and differentiation at the cellular level, with a particular importance within the neural tube and skeleton. In most adult tissues it is silenced. In 1996, direct evidence of a cancer link came to light when different teams of researchers identified the mutated gene responsible for Gorlin syndrome: a rare, inherited condition that predisposes patients to BCC. This gene, patched 1 (PTCH1), encodes a transmembrane receptor for several HH protein ligands. Soon after the link to hereditary BCC was elucidated, researchers independently implicated abnormal HH signalling in over 90% of cases of sporadic BCCs. In animal models, activation of the pathway was shown to be sufficient to drive BCC tumour formation. The first HH pathway inhibitor was discovered long before the pathway. After finding that sheep that ate the poisonous plant Veratrum californicum gave birth to one-eyed lambs, a phenotype called cyclopia, researchers set out to understand the cause. In 1968 they identified the culprit, a compound they named cyclopamine. Nearly three decades later, cyclopamine was found to block HH activity by binding the Smoothened receptor (SMO), a transmembrane protein whose function is normally inhibited by PTCH1 in the absence of HH ligand. When HH ligand binds to PTCH1, SMO is released to signal downstream, especially via the downstream GLI transcription factors. Vismodegib is also a SMO inhibitor, but with greater potency and more favourable pharmaceutical properties than cyclopamine. So far, all of the other HH inhibitors in clinical development are also SMO inhibitors ( Table 1 ), although they are structurally distinct from one another. Many researchers would like to be able to block GLI activity, to overcome resistance to SMO inhibition through SMO mutation (which can happen in BCC), and for cases in which GLI is activated through independent oncogenic signalling pathways, but have so far only had preliminary preclinical success. Table 1 | Selected Hedgehog inhibitors in the pipeline Drug name Lead company Lead indications (secondary indications) Status Erivedge Roche/Genentech BCC Approved LDE225 Novartis BCC (brain cancer, CML, pancreatic cancer) Phase II Saridegib Infinity Pharmaceuticals Bone cancer, myelofibrosis (HNSCC, BCC) Phase II BMS-833923 Bristol-Myers Squibb Cancer Phase I/II LEQ506 Novartis Cancer Phase I PF-04449913 Pfizer Cancer Phase I TAK-441 Millennium/Takeda Cancer Phase I BCC, basal cell carcinoma; CML, chronic myeloid leukaemia; HNSCC, head and neck squamous cell carcinoma. Clinical questions remain In the 104-patient single-arm Phase II study of vismodegib that enabled approval, the drug resulted in a 43% response rate in patients with locally advanced disease, and a 30% response rate in patients with metastatic disease. Median progression-free survival for both groups was 9.5 months, but overall survival data are not yet available. Historically, median overall survival has been reported to be about 8 months for metastatic BCC. In other indications, however, the clinical data to date have not been promising. Development of vismodegib in metastatic colorectal cancer and in advanced recurrent ovarian cancer was suspended in 2010 after Phase II trials failed to show sufficient efficacy. Infinity's saridegib, one of the other leading HH inhibitors, failed earlier this year to show an overall survival benefit in metastatic pancreatic cancer. These failures stem largely from an incomplete understanding of how HH signalling may contribute to disease in these cancers. Whereas mutations in PTCH1 and SMO lead to aberrant HH pathway activation in BCC (and in some rare childhood medulloblastomas), they are not routinely found in other tumour types such as colorectal cancer, ovarian cancer and pancreatic cancer. HH ligand overexpression, via an unspecific mechanism, is instead thought by some researchers to sometimes lead to aberrant pathway activity. “HH has been implicated in many tumours, but the jury is still out on whether there is a role for HH inhibitors in cancers where the pathway is not mutated,” says de Sauvage. In addition, it is unclear whether HH signalling acts oncogenically on cell proliferation, survival and/or metastasis, and whether it acts via paracrine or autocrine mechanisms in different tumour types. “If we don't know the real mechanism, it is hard to target the pathway,” says Xie. Clinical trial data have as yet provided little insight into these questions, but William Matsui of Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, hopes they will soon. Xie, meanwhile, argues for more careful preclinical studies using orthotopic rather than subcutaneous mouse models. Another key possibility for the HH pathway is that, along with the WNT and Notch pathways, it is important for the regulation of the 'cancer stem cells' (CSCs), a small subset of tumour cells that are believed to be the cause of resistance to many cancer therapies and lead to disease recurrence. HH–GLI1 signalling may have a crucial role in promoting CSC self-renewal and progenitor expansion across many tumour types, says Ariel Ruiz i Altaba, of the University of Geneva, Switzerland, who led a team that linked sporadic BCC and HH–GLI1 signalling in the 1990s. However, the primary data supporting this theory come from only a small set of tumour types, and there are extremely limited data from humans to back it up. “There are more claims from limited experiments than evidence to support the theory that HH works through regulating CSCs,” says Xie. Further studies, including plans to measure the numbers of CSCs before and after treatment in US National Cancer Institute trials of vismodegib, are underway to provide further clarity. Another issue is that the field currently only understands the skeleton of the pathway, says Ruiz i Altaba. “To know which tumours may respond, we need to better understand the details.” To know which tumours may respond, we need to better understand the details. There is also confusion about how common HH signalling activation is in different cancers. This may be due to a lack of samples analysed of a certain tumour type, because HH signalling may only be active in the hard-to-detect CSCs, or because different researchers have used different standards to define pathway activation. “There was a group that showed that almost 100% of breast cancers had HH pathway activation, whereas another showed almost none had this,” says Xie. Many researchers, therefore, are hunting for biomarkers that can robustly show pathway activation, such as expression levels of HH ligand, SMO and GLI1, to predict patient response. If paracrine signalling is involved, downstream stromal biomarkers such as WNT, insulin-like growth factor and vascular endothelial growth factor may be important, adds de Sauvage. As yet, however, no robust biomarkers — or evidence of benefit in subgroup populations — have been reported from clinical trials. Through whichever mechanisms HH signalling may be working, researchers generally do not believe that — even if it is a driver pathway — it is likely to be the only one. Understanding the crosstalk between it and other tumour-promoting pathways is therefore crucial to uncovering potential benefit from combination therapies. Vismodegib's approval may spur combination testing, given that “once a drug gets approved, companies are more comfortable testing it in combination with other drugs”, says Glen Weiss at TGen in Phoenix, Arizona, USA. Possible combination candidates include inhibitors of well-known oncogenic pathways, such as RAS, which may cause GLI1 activation in a SMO-independent manner, or WNT or Notch inhibitors, in cases where these are co-activated. “We don't know yet where HH inhibitors will be most effective — the field is wide open,” concludes Matsui.
标签: 上市
