responsibility payment imposed by the ACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the "individual mandate." On December 14, 2018, a U.S. District Court Judge in the Northern District of Texas, or the Texas District Court Judge, ruled that the individual mandate is a critical and inseverable feature of the Affordable Care Act, and therefore, because it was repealed as part of the TCJA, the remaining provisions of the Affordable Care Act are invalid as well. While the Trump Administration and CMS have both stated that the ruling will have no immediate effect, and on December 30, 2018 the Texas District Court Judge issued an order staying the judgment pending appeal, it is unclear how this decision, subsequent appeals and other efforts to repeal and replace the Affordable Care Act will impact the Affordable Care Act and our business. Adoption of government controls and measures, and tightening of restrictive policies in jurisdictions with existing controls and measures, could limit payments for pharmaceuticals.

lease component as a single component. The Company is still evaluating the full impact this standard will have on its consolidated financial statements and related disclosures but expects to recognize substantially all of its leases on the balance sheet by recording a right-to-use asset and a corresponding lease liability. The Company has formalized processes and controls to identify, classify and measure new leases in accordance with ASU 2016-02.

For both MRP and DCP, if a concerned member state objects to the grant of a marketing authorization on the grounds of a potential serious risk to public health, it may raise a reasoned objection with the reference member state. The points of disagreement are in the first instance referred to the Co-ordination Group on MRP and DCP to reach an agreement within 60 days of the communication of the points of disagreement. If member states fail to reach an agreement, then the matter is referred to the EMA and CHMP for arbitration. The CHMP is required to deliver a reasoned opinion within 60 days of the date on which the matter is referred. The scientific opinion adopted by the CHMP forms the basis for a binding European Commission decision.

There’s a chemical contamination story in the generic drug industry that just isn’t going away. Late last summer, some lots of valsartan were recalled due to detection of N-nitrosodimethylamine (NDMA), and the problem has just continued since then. We’ll get into the chemistry of this problem in a minute, but first off, looking at this situation in detail tells you a lot about the generic drug business. A key point is that there are often just a few sources of actual API (active pharmaceutical ingredient). Other companies buy this material and formulate it into capsules, tablets, etc., and then still more companies repackage these. The patented drug world, by contrast, is a lot easier to follow, since while a drug is under patent there’s only one company that’s authorized to market it. They may well have several suppliers for different starting materials or for different steps of their synthesis, but it’s at least one defined route managed by one company.

Trapani, J. A. & Smyth, M. J. Functional significance of the perforin/granzyme cell death pathway. Nat. Rev. Immunol. 2, 735–747 (2002).

Studler, J. M., Glowinski, J. & Levi-Strauss, M. An abundant mRNA of the embryonic brain persists at a high level in cerebellum, hippocampus and olfactory bulb during adulthood. The European journal of neuroscience. 5, 614–623 (1993).

On September 22, 2016, we entered into an investigator initiated clinical trial agreement, or the UCSD Agreement, with the Regents of the University of California on behalf of its San Diego campus, or UCSD, to conduct a Phase 1/2A study, or the ARTISAN Study, entitled: “A Phase I-IIa Study to Assess Safety, Tolerability, Efficacy, and Pharmacokinetics of Aramchol in a NAFLD Juvenile Population”, or the Protocol. The ARTISAN Study (ARamchol Trial to Improve Steatosis in Adolescent NAFLD) will be led by Jeffrey Schwimmer, MD, professor of pediatrics, UC San Diego School of Medicine and Director, Fatty Liver Clinic, Rady Children’s Hospital, San Diego. We expect patient enrolment of the ARTISAN Study to commence during 2019.

        General and administrative expenses increased by $4.7 million to $14.5 million for the year ended December 31, 2018, from $9.8 million for the year ended December 31, 2017. This was primarily attributable to $1.7 million increase in compensation, benefits and other employee-related expenses due to 2018 salary increases and higher average headcount to support our increased activities; a $1.1 million

TNF-α expression of BMSCs on blank, PE, PAr and PArN at day 3 is measured by real time PCR, relative to the GAPDH expression and normalized to the TNF-α expression on blank, (**, p < 0.01) denote statistical significance compared to the blank group.

If we encounter difficulties enrolling patients in our clinical trials, our clinical development activities could be delayed or otherwise adversely affected.

        Net loss increased by approximately $10.5 million to $64.9 million for the year ended December 31, 2018, from $54.4 million for the year ended December 31, 2017. The increase in net loss was primarily due to the increases in research and development and general and administrative expenses discussed above, partially offset by the increases in collaboration revenue and interest income discussed above.

Similar to the findings observed with CD38 and TRPM2 in NK cells, perforin was scattered inside the NK cells mostly inside cytolytic granules and co-localizing with TRPM2 even before stimulation with tumor cells (Fig. 6c, upper panel). Like CD38, perforin co-migrated with TRPM2 to the immunological synapse upon stimulation with B16F10 cells (Fig. 6c, middle panel). Such tumor cell-induced perforin migration was not detected in TRPM2−/− NK cells (Fig. 6c, lower panel), suggesting that TRPM2 was essential for perforin migration towards the immunological synapse. The finding that perforin migration towards the synapse requires CD38 as well (Fig. 2b) suggests that both CD38 and TRPM2 are absolutely essential for the migration of perforin (or possibly cytolytic granules as well) toward the immunological synapse when NK cells encounter tumor cells.