Schwarz, E. C., Qu, B. & Hoth, M. Calcium, cancer and killing: the role of calcium in killing cancer cells by cytotoxic T lymphocytes and natural killer cells. Biochim. Biophys. Acta. 1833, 1603–1611 (2013).

Our foreign currency exposures give rise to market risk associated with exchange rate movements of the Euro and NIS mainly against the U.S. dollar because a large portion of our expenses are denominated in Euros and NIS. Our Euro expenses consist principally of payments made to sub-contractors and consultants for pre-clinical studies, clinical trials and other research and development activities. Our NIS expenses consist principally of payments made to employees, subcontractors and consultants for pre-clinical studies, clinical trials, professional services, other research and development activities and general and administrative activities. We anticipate that a large portion of our expenses will continue to be denominated in currencies other than the U.S. dollar. Our financial position, results of operations and cash flow are subject to fluctuations due to changes in foreign currency exchange rates. Our results of operations and cash flow are, therefore, subject to fluctuations due to changes in foreign currency exchange rates and may be adversely affected in the future due to changes in foreign exchange rates. Approximately 31% of our expected expenses are denominated in NIS. Changes of 5% and 10% in the U.S. dollar to NIS exchange rate will increase/decrease our operation expenses by 1.55% and 3.1%, respectively. Approximately 20% of our expected expenses are denominated in Euros. Changes of 5% and 10% in the U.S. dollar to Euro exchange rate will increase/decrease our operation expenses by 1.0% and 2.0%, respectively. To date, fluctuations in the exchange rates have not materially affected our results of operations or financial condition for the periods under review.

        The FDA, the EMA and other regulatory authorities may also impose requirements for costly post-marketing studies or clinical trials and surveillance to monitor the safety or efficacy of a product. The FDA and other agencies, including the Department of Justice, closely regulate and monitor the post-approval marketing and promotion of products to ensure that they are manufactured, marketed and distributed only for the approved indications and in accordance with the provisions of the approved labeling. The FDA imposes stringent restrictions on manufacturers’ communications regarding off-label use and if we, or any future collaborators, do not market any of our product candidates for which we, or they, receive marketing approval for only their approved indications, we, or they, may be subject to warnings or enforcement action for off-label marketing. Violation of the FDCA and other statutes relating to the promotion and advertising of prescription drugs may lead to investigations or allegations of violations of federal and state health care fraud and abuse laws and state consumer protection laws, including the False Claims Act.

        We post our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, and any amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, on the investor relations section of our public website (www.rapharma.com), free of charge, as soon as reasonably practicable after we electronically file such material with, or furnish it to, the SEC. In addition, you can read our SEC filings over the Internet at the SEC’s website at https://www.sec.gov/. The contents of these websites are not incorporated into this Annual Report on Form 10-K. Further, our references to the URLs for these websites are intended to be inactive textual references only.

Observation of the mRNA expression levels of the osteogenic markers helps to distinguish the stages of differentiation and maturation of BMSCs into osteoblasts. Previous studies48,49 have shown that ALP is secreted during the early stage of osteogenic differentiation, whereas OCN, a marker of a mature osteoblast differentiation, is a necessary factor for bone calcification and mineralization. BSP is one of the major non-collagenous glycosylated phosphoproteins of the extracellular matrix in bone. It is a mineralized tissue-specific protein that is expressed in differentiated osteoblasts and appears to function in the initial mineralization of bone. In this study, expression of bone-related genes, including Runx-2, ALP, OCN and BSP, is observed to be upregulated in the PArN-BMSCs cultures after 3 days but in the PAr-BMSCs, all the gene expressions are not significantly changed compared to the blank (Fig. 4c). By monitoring the Runx-2 and OCN protein levels, the BMSCs are collected from PE, Par, and PArN at day 7. It is the matrix maturation stage of osteogenic differentiation and the ECM and stem cell functions are kept in balance. Our results (Fig. 4d) confirm that the charged surface (PArN) with tertiary amines increase bone-related protein products. By considering cell calcification, gene expression, and protein production, the positively-charged tertiary amines on PArN have significant effects on signaling BMSCs to differentiate via the osteogenic pathway, while the C-C and C = C groups on PAr are less effective in osteogenesis despite excellent cell attachment and proliferation. It is consistent with chitosan12,50 and polypeptide51 with amino groups.

These issues would not have come up in a customer review of changes to the manufacturing process, either. So if the resulting problems reflect a failure of change management, it occurred at a fundamental level.

I have not figured out the reason that different studies come to different conclusions, but here is what they agree on:  

        If a product with orphan status receives the first FDA approval for the disease or condition for which it has such designation or for a select indication or use within the rare disease or condition for which it was designated, the product generally will be receiving orphan product exclusivity. Orphan product exclusivity means that the FDA may not approve any other applications for the same product for the same indication for seven years, except in certain limited circumstances. Competitors may receive approval of different products for the indication for which the orphan product has exclusivity and may obtain approval for the same product but for a different indication. If a drug or drug product designated as an orphan product ultimately receives marketing approval for an indication broader than what was designated in its orphan product application, it may not be entitled to exclusivity.

Alexion Pharmaceuticals, Inc . (NasdaqGM: ALXN ) Alexion Pharmaceuticals, Inc. is a biopharmaceutical company working to develop and deliver life-changing drug therapies for patients with serious and life-threatening medical conditions. Alexion is engaged in the discovery, development and commercialization of therapeutic products aimed at treating patients with a wide array of severe disease states, including hematologic diseases, cancer, and autoimmune disorders.

The Company was incorporated in Israel on July 31, 2013 and commenced operations on February 2, 2014.

Du, J., Xie, J. & Yue, L. Intracellular calcium activates TRPM2 and its alternative spliced isoforms. Proc. Natl. Acad. Sci. U.S.A. 106, 7239–7244 (2009).

Japan and Russia are keen to move ahead with their island (known as the “Northern Territories” to the Japanese and “Southern Kurils” to the Russians) dispute. At the end of WWII in 1945, the Soviet Union occupied those islands and ejected 17,000 Japanese residents. Since then, Japan has been trying to get the islands back. The most concerted attempts were made during Abe’s meeting with Putin at their bilateral meeting in St Petersburg. This time round, Abe made the same proposal for joint development of the islands while Putin promised to make it easier for Japanese to visit the islands. The islands are one of the issues that have prevented the two countries from signing a formal peace treaty after the end of WWII. While skirting around the issue of the islands’ sovereignty, the armed forces of Japan and Russia agreed to have exchanges. This may help contribute to confidence building measures in the region. They also signed 11 bilateral agreements related to trade and commerce.