CANCER CELL:: Proteasome inhibitor mechanism in MM.

Cancer Cell, Volume 24, Issue 3, 289-304, 9 September 2013 Copyright © 2013 Elsevier Inc. All rights reserved. 10.1016/j.ccr.2013.08.009 Authors Chungyee Leung-Hagesteijn, Natalie Erdmann, Grace Cheung, Jonathan J. Keats, A. Keith Stewart, Donna E. Reece, Kim Chan Chung, Rodger E. Tiedemann Highlights MM tumors contain Xbp1s− progenitors that survive proteasome inhibition Xbp1s absence arrests secretory maturation and ER loading, reducing ERAD dependence PI resistance mechanisms in patients differ from in vitro models These data help explain the failure to cure MM with current therapy Summary Proteasome inhibitor (PI) resistance mechanisms in multiple myeloma (MM) remain controversial. We report the existence of a progenitor organization in primary MM that recapitulates maturation stages between B cells and plasma cells and that contributes to clinical PI resistance. Xbp1s− tumor B cells and pre-plasmablasts survive therapeutic PI, preventing cure, while maturation arrest of MM before the plasmablast stage enables progressive disease on PI treatment. Mechanistically, suppression of Xbp1s in MM is shown to induce bortezomib resistance via de-commitment to plasma cell maturation and immunoglobulin production, diminishing endoplasmic reticulum (ER) front-loading and cytotoxic susceptibility to PI-induced inhibition of ER-associated degradation. These results reveal the tumor progenitor structure in MM and highlight its role in therapeutic failure.

UK: Max HOTOPF "HEALTHCARE EUROPA"

Too little, too late as the health supertankers start to turn What is to be gleaned from the latest OECD Health at a Glance 2013? The healthcare service supertankers are starting to alter course but progress remains slow and icebergs of diabetes, dementia and longer life expectancies dwarf expenditure. News French state plans activity ceilings for hospitals The French private hospital sector is enraged by the government’s latest ploy. Behind the scenes, however, we suspect that there is a deal to be done. Asklepios issues loan note - so what happens next? Asklepios has raised €350m with a promissory note. We talk to President of the company Bernard Broermann, and look at how the Helios-Rhoen deal has reshaped the German hospital sector. Hungary - healthcare reform paying off Hungarian sources say that the healthcare reforms pushed through by minister of state for health, Dr. Miklós Szócska, under the Fidesz government, has succeeded in cutting costs substantially. Meanwhile, the government has upped healthcare expenditure ahead of 2014 elections. Medical Properties plans more deals in Europe Medical Properties Trust (MPT), the US healthcare REIT specialising in hospital property, is scouring Northern and Western Europe for deals, following its purchase of the property portfolio of RHM Kliniken. We take a look at its strategy. MC bids for Slotervaart as Dutch hospital sector opens up The Netherlands is on track to pass legislation which would enable private investors to buy shares in the not-for-profit general hospital sector which provides almost all inpatient acute care in the country. Meanwhile, it looks as though Slotervaart, a privatised hospital whose shareholders have been fighting each other looks likely to be taken over by MC Groep, which is one of the first privatisation players in the country. We talk to Chris Van Den Haak, partner at BDO Netherlands, who has just written a report on the financial health of the Dutch general hospital sector. Are we about to see a tsunami of privatisation? Interview/Feature Interview: Dag Andersson, CEO, Diaverum With close to 300 dialysis centres in 19 countries, Dag Andersson claims to run “the most global healthcare service in the world”. We look at how Diaverum is starting to offer a much wider range of services. The company is majority owned by private equity house Bridgepoint, which hired JP Morgan in January 2013 to review its strategic options.

SWISS MEDICINE: BLOOD-BRAIN BARRIER

Breaking and building the wall: The biology of the blood-brain barrier in health and disease 21/11/2013 Blood-brain-barrier The blood-brain barrier (BBB) is a complex feature of brain endothelial cells that restricts the passage of blood-borne molecules into the brain parenchyma, while ensuring the delivery of essential nutrients and selected biomolecules. Brain vasculature is anatomically distinct from that of other organs and comprises endothelial cells, pericytes and astrocytes, which collectively form the neurovascular unit (NVU). This review provides a brief overview of the cellular components of the NVU and BBB characteristics. In addition, the regulation of brain vasculature by peripheral factors such as diet and systemic disease is discussed. Abstract Proper functioning of the brain vasculature is critical for the maintenance of optimal brain function. Brain ­parenchyma is separated from blood within the cerebral vasculature by the blood-brain barrier (BBB). The BBB is a collective term for brain-specific, endothelial cell characteristics that restrict the passage into the brain of blood-borne molecules that ensure delivery of essential nutrients and selected biomolecules. The principal ­features of the vertebrate BBB are closed cell-cell junctions, a low rate of transcytosis, the expression of various solute carriers and ATP-binding cassette transporters. In addition, blood vessels in the brain are anatomically distinct. The capillary bed of brain vasculature has full longitudinal coverage by pericyte processes. Furthermore, brain vasculature is covered by glial processes, the so-called astrocyte end-feet. The term neuro­vascular unit (NVU) is often used to describe brain blood vessels in order to underline the intimate physical and functional connection between the brain tissue and blood vessels. Another special feature of brain vessels is that they are immunologically quiescent. Specifically, the expression of leucocyte-adhesion molecules is low and few peripheral leucocytes enter into the brain parenchyma. The development and maturation of the BBB and NVU is directed by signals from the surrounding neural tissue and cells forming the NVU. The formation of BBB ­specific cell-cell junctions and expression of trans­porters for glucose and biomolecules on endothelial cells is induced by the neuroepithelium, whereas pericytes regulate the low transcytosis rate of brain ­endothelium. Astrocytes have merged as regulators of BBB immune quiescence and brain water transport. Endothelial cell-cell junctions, the most intensively studied component of the BBB, are composed of adherens and tight junctions, which are established by transmembrane proteins mediating homophilic extracellular interaction. The brain endothelium is equipped with a transport system that provides a selective route for nutrients, ions and bioactive macromolecules, and ensures elimination of toxic molecules. These transporters are expressed in a polarised manner that allows the effective exchange of molecules and ions between blood and the brain parenchyma. The list of CNS pathologies (e.g. leucoencephalopathies, arteriopathies, brain calcifications) caused by the ­dysfunction of cellular and acellular components of the NVU is long. In addition, BBB breakdown is associated with common neurodegenerative diseases such as ­Alzheimer’s and Parkinson’s diseases). Pathological changes in the BBB also occur in the setting of peripheral ­diseases, e.g., acute liver failure and hypoxic conditions such as cardiac arrest. A detailed mechanistic understanding of BBB alterations in these conditions is lacking. Even less well understood is how the BBB is maintained and regulated in the healthy organism. The molecular development and regulation of the BBB is currently under intense investigation. Clearly, a collective effort from research groups working in different fields (vascular biologists, physiologists, neurobiologists etc.) is needed to better understand the development and homeostasis of complex structures such as the BBB and NVU. Although the brain vascular development and deregulation during pathological conditions is better understood at the molecular and cellular level, the majority of specific questions remain unanswered. This is a summary of an open access article on www.smw.ch. Must be cited as: Keller A. Breaking and building the wall: the biology of the blood-brain barrier in health and disease. Swiss Med Wkly. 2013,143:w13892. - See more at: http://blog.smw.ch/breaking-and-building-the-wall-the-biology-of-the-blood-brain-barrier-in-health-and-disease/#sthash.Y8ejfNBj.dpuf

EUROPEAN MULTIPLE MYELOMA ACADEMY: FREE CONFERENCE VIDEOS 2013

http://emma.medroom.at/#WSLIST

LANCET: INFECTIOUS DISEASES COMMISSION on ANTIBIOTIC RESISTANCE

http://www.reactgroup.org/uploads/news/Comments-on-The-Lancet-Infectious-Diseases-Commission-on-Antibiotic-Resistance-Nov2013.pdf

ProMED: FREE ebook by GIDEON on Infectious Diseasesof the Philippines.

A ProMED-mail post ProMED-mail is a program of the International Society for Infectious Diseases Date: Sat 16 Nov 2013 From: Uri Blackman [edited] A massive effort is underway to supply medical assistance to the Philippines. ProMED has arranged to supply a free copy of Infectious Diseases of the Philippines, 2013, to all subscribers. This e-book (411 pages, 88 graphs, 1869 references) is the only comprehensive source for background information on the status of every individual infectious disease in the Philippines. To obtain Infectious Diseases of the Philippines, 2013: 1. click on the following link: 2. click on "add to cart" 3. click on "add a coupon" and enter ProMED 4. click on "update" 5. fill in identification and mailing information where indicated You will receive a link for the e-book by e-mail, which you can open on your computer or mobile device. Infectious Diseases of the Philippines, 2013, is one in a series of 419 e-books (105 000 pages), with one title dedicated to every disease and every country in the world. All books are updated yearly. The publisher has agreed to offer a 50 percent discount on all titles to ProMED subscribers. To obtain any of these books at a discount: 1. click on the desired title(s) listed at and 2. follow instructions as for Infectious Diseases of the Philippines, 2013 3. at the stage of "add a coupon" enter 50promed13 -- Uri Blackman [We expect that the conditions in the typhoon-affected areas of the Philippines may well result in emerging disease outbreaks and increases in endemic diseases. ProMED appreciates this offer from our friends at GIDEON. - Mod.LM]

ARTEMISININ RESISTANT MALARIA

MALARIA, ARTEMISININ RESISTANCE - SOUTHEAST ASIA ************************************************ A ProMED-mail post ProMED-mail is a program of the International Society for Infectious Diseases Date: Tue 12 Nov 2013 Source: Firstpost [edited] Rise of drug-resistant malaria in Southeast Asia ------------------------------------------------ US experts are raising the alarm over the spread of drug-resistant malaria in several Southeast Asian countries, endangering major global gains in fighting the mosquito-borne disease that kills more than 600 000 people annually. While the communicable disease wreaks its heaviest toll in Africa, it's in nations along the Mekong River where the most serious threat to treating it has emerged. The availability of therapies using the drug artemisinin has helped cut global malaria deaths by a quarter in the past decade. But resistance to it emerged on the Thai-Cambodia border in 2003, and has since been confirmed in Viet Nam and Myanmar too. It has also been detected in southwest China and suspected as far away as Guyana and Suriname, according to a new report by the Center for Strategic and International Studies think tank. The report warns that could be a health catastrophe in the making, as no alternative anti-malarial drug is on the horizon. The UN World Health Organization, or WHO, is warning that what seems to be a localized threat could easily get out of control and have serious implications for global health. "Absent elimination of the malaria parasite in the Mekong, it is only a matter of time before artemisinin resistance becomes the global norm, reversing the recent gains," writes Dr Christopher Daniel, former commander of the US Naval Medical Research Center, in the report for a conference at the Washington think tank Tuesday [12 Nov 2013]. Mosquitoes have developed resistance [it is the malaria parasite which develops resistance, not the mosquito. - Mod.EP] to antimalarial drugs before. The same happened with the drug chloroquine, which helped eliminate malaria from Europe, North America, the Caribbean, and parts of Asia and South-Central America during the 1950s. Resistance first began appearing on the Thai-Cambodia border, and by the early 1990s it was virtually useless as an antimalarial in much of the world. Nowhere are the challenges in countering the threat to drug-resistance greater than in Myanmar, also known as Burma. Some 70 percent of its 55 million people live in malaria-endemic areas, and as a nation, it accounts for about three-quarters of malaria infections and deaths in the Mekong region, the report says. Myanmar's public health system is ill-equipped to cope, as government spending on health dwindled to the equivalent of just 60 US cents per person under military rule, although it has been increased significantly under the quasi-civilian administration that took power in 2011. In a third of townships, there been virtually no public health presence for years. It's an issue of regional concern as Myanmar has large transient populations in its border regions, including ethnic minorities displaced by fighting and migrant workers who cross borders. "It is clear that this country with its chronically under-resourced health system needs urgent additional attention," Daniel said. Resistance to artemisinin can be driven by various factors: delays in giving treatment, use of counterfeit or substandard drugs, and prescribing artemisinin on its own rather than in combination with another longer-acting drug to ensure that all malaria-carrying parasites in a patient's bloodstream are killed off. Cambodia and Laos have banned the use of such monotherapies, and Myanmar's military, which manufactures pharmaceuticals, announced in June [2013] it would cease production of them by early 2014. That comports with the global push by the UN for proper testing, treating, and tracking of malaria cases to prevent the disease spreading. The Center for Strategic and International Studies is advocating greater US involvement and aid for health and fighting malaria in the Mekong region, particularly in Myanmar, where Washington has been in the vanguard of ramping up international aid, as sanctions have been eased to reward it for democratic reforms. The centrist think tank argues that it can increase America's profile in Southeast Asia in a way that will benefit needy people and not be viewed as threatening to strategic rival, China. But securing more funds won't be easy at a time when Washington is cutting back on programs for its own poor. The US is already a major contributor to international anti-malaria efforts, and in Myanmar, is promising USD 20 million per year in health assistance under its recently resumed bilateral aid program. -- Communicated by: ProMED-mail from HealthMap Alerts [The emergence of artemisinin resistance in Myanmar (Burma) and Cambodia and indeed in the rest of Southeast Asia is a matter of grave concern. This is also where resistance to chloroquine (as pointed out in the message), sulfadoxine/pyrimethamine [Fansidar(R)], and mefloquine [Lariam(R)] first developed. The main driver is probably substandard dosing where purchase of single tablets is possible and counterfeit drugs containing substandard doses are common. We have previously argued that the development of resistance is best contained by providing the population with free malaria drugs ensuring a full course of treatment with drugs which contain the active compounds in the required doses (Schlagenhauf P, Petersen E: Antimalaria drug resistance: the mono-combi-counterfeit triangle. Expert Rev Anti Infect Ther. 2009; 7(9): 1039-42). Free drugs are provided to patients with HIV and tuberculosis and should be provided to malaria patients as well to remove the market for counterfeit and substandard drugs. - Mod.EP