Negative regulators of T-cell activation: potential targets for therapeutic intervention in cancer, autoimmune disease, and persistent infections

http://pubget.com/search?q=Immunological+Reviews%5Blatest%5D

Immunol Rev 229(1):67-87 (2009)

Tsvetelina Pentcheva-Hoang, Emily Corse and James P Allison

Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Summary: The generation of productive adaptive immune responses depends on the antigen-specific activation of T and B cells. The outcome of T-cell receptor engagement is influenced by signals from both positive and negative regulatory molecules that can either activate or inhibit T-cell function. CD28 and cytotoxic T-lymphocyte antigen-4 are the prototypical members of an immunoglobulin domain-containing protein family that play important roles in the control of T-cell responses against infection, cancer, and in autoimmune disease. Although the precise molecular details of their functions are still under active investigation, tumors and chronic pathogens seem to have exploited these pathways to achieve immune evasion. Furthermore, malfunction of the inhibitory arm of the immune response appears responsible for the development of multiple autoimmune pathologies. As a result, the negative regulators of T-cell activation have become attractive targets for therapeutic intervention in cancer, chronic infection, and autoimmune disease. The application of findings from basic research has provided insight into the manipulation of these pathways in the clinic and offers promising strategies for the treatment of disease. | PMID: 19426215

Rheumatoid Arthritis Meds Associated With Increased Shingles Risk

http://www.elements4health.com/rheumatoid-arthritis-meds-associated-with-increased-shingles-risk.html

• According to a study, use of certain medications known as monoclonal anti– tumor necrosis factor α (TNF-α) antibodies for the treatment of rheumatoid arthritis appears to be associated with an increased risk for herpes zoster (shingles), the painful infection characterized by blisters.

• Rheumatoid arthritis is an inflammatory disease that attacks the synovium lining of the joints, causing pain, swelling, stiffness, and loss of function. There is no cure for rheumatoid arthritis.

• Patients with rheumatoid arthritis are at increased risk of herpes zoster compared with the general population. Herpes zoster is one of the most common adverse events reported in clinical trials of anti–TNF-α agents.

• There has been evidence from some studies that patients treated with anti–TNF-α agents are at an increased risk of bacterial infections, but little is known about the risk of viral infections, such as herpes zoster, in patients with rheumatoid arthritis receiving these types of medications. 

• Anja Strangfeld and colleagues investigated the association of various rheumatoid arthritis treatments, including anti–TNF-α therapy, with the risk of herpes zoster. The researchers analyzed data from patients who began treatment with adalimumab or infliximab (monoclonal anti–TNF-α antibodies), etanercept (a fusion protein), the monotherapeutic agent anakinra, or when patients changed conventional disease-modifying anti-rheumatic drug (DMARD). Treatment, clinical status and adverse events were assessed by rheumatologists at fixed points during follow-up (of up to three years). A total of 5,040 patients were included in the analysis.

• There were 86 cases of herpes zoster among 82 patients. Thirty-nine occurrences could be attributed to treatment with anti–TNF-α antibodies (23 to etanercept, 24 to conventional DMARDs). The researchers found a significant association between herpes zoster and treatment with the monoclonal anti–TNF-α antibodies infliximab and adalimumab, although this risk was lower than the threshold for clinical significance. There was no significant association between herpes zoster and treatment with etanercept, or anti–TNF-α treatment as a class. 

• A significantly higher risk of developing herpes zoster was found for rheumatoid arthritis patients of older age and for treatment with glucocorticoids (steroid hormones that are widely used as anti-inflammatory medications).
  
  

Top 20 Countries in ALL FIELDS paper citation, 1998-August 31, 2008

http://sciencewatch.com/dr/cou/2008/08decALL/
Top 20 Countries in ALL FIELDS, 1998-August 31, 2008


                                 Ranked by Citations
    Rank                       Field             Papers Citations  Citations Per Paper
1 USA                        2,959,661       42,269,694               14.28
2 GERMANY                766,146         8,787,460               11.47
3 ENGLAND                 678,686        8,768,475               12.92
4 JAPAN                        796,807        7,201,664                 9.04
5 FRANCE                    548,279        5,933,187               10.82
6 CANADA                    414,248        4,837,825               11.68
7 ITALY                         394,428        4,044,512               10.25
8 NETHERLANDS        231,682        3,148,005               13.59
9 AUSTRALIA               267,134        2,784,738               10.42
10 PEOPLES R CHINA 573,486        2,646,085                 4.61
11 SPAIN                      292,146         2,602,330                 8.91
12 SWITZERLAND       168,527         2,502,210               14.85
13 SWEDEN                 174,418          2,257,641              12.94
14 BELGIUM                125,520          1,461,478              11.64
15 SCOTLAND             106,209           1,422,252             13.39
16 DENMARK                 91,670          1,262,693             13.77
17 SOUTH KOREA        218,077          1,256,724               5.76
18 ISRAEL                     109,637          1,210,807             11.04
19 RUSSIA                      276,801         1,135,496               4.10
20 INDIA                         237,364         1,088,425               4.59
SOURCE: Essential Science Indicators from Thomson Reuters.

                                          Ranked by Papers
   Rank                                 Field           PapersCitations     Citations Per Paper
1 USA                              2,959,661           42,269,694          14.28
2 JAPAN                             796,807             7,201,664            9.04
3 GERMANY                      766,146             8,787,460           11.47
4 ENGLAND                       678,686             8,768,475          12.92
5 PEOPLES R CHINA         573,486             2,646,085            4.61
6 FRANCE                           548,279             5,933,187          10.82
7 CANADA                           414,248             4,837,825          11.68
8 ITALY                                394,428             4,044,512          10.25
9 SPAIN                                292,146             2,602,330            8.91
10 RUSSIA                            276,801             1,135,496            4.10
11 AUSTRALIA                    267,134             2,784,738           10.42
12 INDIA                              237,364              1,088,425             4.59
13 NETHERLANDS             231,682               3,148,005           13.59
14 SOUTH KOREA              218,077                1,256,724             5.76
15 SWEDEN                        174,418                 2,257,641          12.94
16 SWITZERLAND              168,527                 2,502,210         14.85
17 BRAZIL                           157,860                    880,821           5.58
18 TAIWAN                          144,807                    828,751           5.72
19 POLAND                         131,646                     766,033           5.82
20 BELGIUM                       125,520                   1,461,478        11.64
SOURCE: Essential Science Indicators from Thomson Reuters.

                              Citations Per Paper( 10,000 papers)
           Rank                           Field            Papers Citations   CitationsPer Paper
1 SWITZERLAND              168,527                       2,502,210              14.85
2 USA                               2,959,661                    42,269,694              14.28
3 DENMARK                         91,670                      1,262,693              13.77
4 NETHERLANDS               231,682                     3,148,005              13.59
5 SCOTLAND                       106,209                     1,422,252              13.39
6 SWEDEN                           174,418                     2,257,641              12.94
7 ENGLAND                         678,686                     8,768,475              12.92
8 FINLAND                             85,567                     1,038,721              12.14
9 CANADA                            414,248                     4,837,825              11.68
10 BELGIUM                         125,520                     1,461,478              11.64
11 GERMANY                        766,146                     8,787,460              11.47
12 AUSTRIA                             87,953                        974,554              11.08
13 ISRAEL                              109,637                     1,210,807              11.04
14 NORWAY                             63,017                         691,881             10.98
15 FRANCE                             548,279                     5,933,187             10.82
16 WALES                                  35,318                        374,996            10.62
17 AUSTRALIA                         267,134                     2,784,738            10.42
18 ITALY                                   394,428                     4,044,512            10.25
19 IRELAND                               37,396                         377,181           10.09
20 NORTH IRELAND                 17,376                         174,069           10.02
SOURCE: Essential Science Indicators from Thomson Reuters.

Environmental factors--what role in autoimmune diseases?

http://www.aarda.org/infocus_article.php?ID=33

From InFocus Newsletter, September 2006 

•  Fundamentally, all autoimmune diseases are a consequence of impaired immune function that results from interactions of genetic and environmental factors. Despite important progress, much remains to be learned about these factors and their interactions. Advances in this area are providing a foundation for more effective therapies and prevention strategies.

• Approximately one-third of the risk of developing an autoimmune disease can be attributed to heritable factors; the remainder is thought to be associated with non-inherited events.
• Some of these events arise from the randomness that characterizes human exposures; and others, from the diversity of the immune system itself--a diversity that enables the immune system to recognize a broad range of bacteria and viruses.

• These environmental factors account for the occurrence of autoimmune disease in only one member of a pair of genetically identical animals or identical twins.

• Certain environmental agents play a clear role in instigating autoimmune processes. For example, drugs such as procainamide and hydrolyzine can induce a lupus-like syndrome in genetically-susceptible individuals that remits when the drug is discontinued. Other drug-induced autoimmune diseases have been described, including some of the hemolytic anemias, thrombocytopenias, and the leukopenias.
   
• The possible role of exposure to various metals in autoimmune disease has been explored, primarily through laboratory and animal studies.

• Generally, metals inhibit immune cell proliferation and activation, with notable exceptions. Mercury, gold, and silver, for example, can induce lymphocyte proliferation and subsequent autoimmunity.

• Genetically-susceptible mice develop a lupus-like condition when dosed with mercury, silver, or gold. It is likely, however, that the autoimmune disorders that result from exposure to various metals occur through distinct mechanisms.
   
• Abnormal immune responses may also be due to a deficiency of a specific substance. For example, selenium deficiency has been linked with autoimmune thyroiditis and cardiomyopathy in humans; some people with these disorders improve when given selenium supplements. As with studies of the role of metals, the mechanism of action remains unclear. 

• Other environmental exposures have been studied, but associating such exposures with specific disorders is difficult.
• Some epidemiologic information suggests an association between dietary iodine and iodine-thyroiditis, and between silica and both scleroderma and lupus in certain industrial settings.
• Additional research has explored possible relationships between autoimmune disease and exposures to organic compounds, principally the halogenated hydrocarbon trichloroethylene (TCE) and polychlorinated biphenyls (PCBs). TCE metabolites have been associated with systemic lupus erythematosus, systemic sclerosis, and other autoimmune disorders. The evidence for PCB effects is sparse.
• Similarly, a few epidemiologic studies have examined occupational exposures to dioxins; however, firm epidemiologic evidence of a cause and effect association has yet to be shown. Similarly, investigations of exposure to pesticides and estrogenic compounds are areas of considerable research interest, but they require additional exploration.
   
• Ultraviolet radiation from sun exposure can exacerbate disease in patients with systemic lupus erythematosus.
• Other epidemiologic studies suggest that ultraviolet exposure may be protective in multiple sclerosis and rheumatoid arthritis; however, conflicting animal studies indicate that ultraviolet exposure may increase autoimmune disease risk in genetically-predisposed individuals.
   
• Infectious agents are the most often cited environmental factors implicated as triggers of autoimmune diseases. A classic example is the central role of the Group A beta-hemolytic streptococcus in the development of rheumatic heart disease. Acute Guillain-Barr? syndrome has been associated with a number of bacterial and viral infections, and reactive arthritis has been linked to a variety of intestinal infections.

• Indirect evidence has implicated a number of infections in type 1 diabetes and multiple sclerosis, and it has focused renewed attention on the possible role of Epstein-Barr virus (EBV) in lupus and rheumatoid arthritis.
   
• Despite these leads, the exact mechanisms by which infection induces a particular autoimmune disease are unknown. In the case of streptococcus, it is believed than an antigen of the microorganism resembles an antigen present in the heart and that a cross-reactive immune response to the infecting microorganism causes immune-mediated damage to the heart. The phenomenon is referred to as molecular mimicry. In other instances, microorganisms or local inflammation may alter antigens of the host so that the immune system sees them as foreign. Infections may also increase immune cell expression of co-stimulatory molecules and thus promote autoimmune responses.
  
  --Source: Progress in Autoimmune Diseases Research, NIH Autoimmune Diseases Coordinating Committee "Report to Congress," March 2005
  
  

Science in: India, 2002-06

http://sciencewatch.com/dr/sci/08/may4-08_1/
Science in: India, 2002-06

• India's world share of science and social-science papers over a recent five-year period, expressed as a percentage of papers in each of 21 fields in the Thomson Reuters database. Also, India's relative citation impact compared to the world average in each field, in percentage terms.

Field	Percentage of papers from India	Relative impact compared to world
Materials Science	5.12	-25
Agricultural Sciences	5.06	-57
Chemistry	4.81	-34
Physics	3.71	-20
Plant & Animal Sciences	3.44	-65
Pharmacology	3.21	-45
Engineering	2.93	-28
Geosciences	2.72	-51
India's overall percent share, all fields: 2.63
Ecology/Environmental	2.55	-51
Space Science	2.52	-47
Microbiology	2.18	-50
Biology & Biochemistry	2.06	-56
Mathematics	1.72	-43
Computer Science	1.57	-29
Immunology	1.19	-65
Clinical Medicine	1.18	-56
Molec. Biol. & Genetics	1.17	-62
Economics & Business	0.75	-52
Social Sciences	0.73	-44
Neurosciences & Behavior	0.55	-51
Psychology/Psychiatry	0.30	-38

• Between 2002 and 2006, Thomson Reuters indexed 106,958 papers that listed at least one author address in India. Of those papers, the highest percentage appeared in journals classified in the field of materials science. As the right-hand column indicates, India's cites-per-paper average in materials science for the five-year period was at 75% of the world mark (or 25% below: 1.99 cites per paper for India versus the world score of 2.64 cites). Although research in India has yet to attain the world average in any of the main fields shown here, the nation's relative-impact performance was comparatively strong not only in materials science but in physics, engineering, and computer science..

• SOURCE: National Science Indicators, 1981-2006 (containing listings of output and citation statistics for more than 170 countries; available in standard and deluxe versions from the Research Services Group).

A Genetic Clue to Why Autism Affects Boys More

http://www.time.com/time/health/article/0,8599,1899756,00.html

• The newly discovered autism-risk gene, identified by authors as CACNA1G, is more common in boys than in girls (why that's so is still not clear), and the authors suggest it plays a role in boys' increased risk of the developmental disorder.
• CACNA1G, which sits on chromosome 17, amid other genes that have been previously linked to autism, is responsible for regulating the flow of calcium into and out of cells.
• Nerve cells in the brain rely on calcium to become activated, and research suggests that imbalances in the mineral can result in the overstimulation of neural connections and create developmental problems, such as autism and even epilepsy, which is also a common feature of autism.
• "Our current theories about autism suggest that the disorder is related to overexcitability at nerve endings," says Geri Dawson, chief science officer of Autism Speaks, an advocacy group that provided the genetic data used by the study's authors. "It's interesting to see that the gene they identified appears to modulate excitability of neurons."
• For the new study, researchers at the University of California, Los Angeles (UCLA), combed the genetic database of the Autism Genetic Resource Exchange (AGRE), a resource of DNA from 2,000 families with at least one autistic child.
• The scientists focused on the more than 1,000 genetic samples of families in which at least one son was affected by the disorder, prompted by the results of an earlier study using the same database, which identified a rich autism-related genetic region on chromosome 17 that contained genetic variants more common in boys than in girls.
• While nearly 40% of the general population has the most common form of CACNA1G, one variant of the gene was more prevalent in autistic boys, researchers found. "There is a strong genetic signal in this region," says Dr. Daniel Geschwind, director of UCLA's Center for Autism Research and Treatment and one of the study's co-authors. "But this gene doesn't explain all of that signal or even half of it. What that means is that there are many more genes in this region contributing to autism."

Digital Disease Detection — Harnessing the Web for Public Health Surveillance

http://content.nejm.org/cgi/content/full/360/21/2153?query=TOC
John S. Brownstein, Ph.D., Clark C. Freifeld, B.S., and Lawrence C. Madoff, M.D.

• The Internet has become a critical medium for clinicians, public health practitioners, and laypeople seeking health information. Data about diseases and outbreaks are disseminated not only through online announcements by government agencies but also through informal channels, ranging from press reports to blogs to chat rooms to analyses of Web searches (see Digital Resources for Disease Detection). Collectively, these sources provide a view of global health that is fundamentally different from that yielded by the disease reporting of the traditional public health infrastructure.¹

• Over the past 15 years, Internet technology has become integral to public health surveillance. Systems using informal electronic information have been credited with reducing the time to recognition of an outbreak, preventing governments from suppressing outbreak information, and facilitating public health responses to outbreaks and emerging diseases. Because Web-based sources frequently contain data not captured through traditional government communication channels, they are useful to public health agencies, including the Global Outbreak Alert and Response Network of the World Health Organization (WHO), which relies on such sources for daily surveillance activities.

• Early efforts in this area were made by the International Society for Infectious Diseases' Program for Monitoring Emerging Diseases, or ProMED-mail, which was founded in 1994 and has grown into a large, publicly available reporting system, with more than 45,000 subscribers in 188 countries.²
  
• ProMED uses the Internet to disseminate information on outbreaks by e-mailing and posting case reports, including many gleaned from readers, along with expert commentary.
  
• In 1997, the Public Health Agency of Canada, in collaboration with the WHO, created the Global Public Health Intelligence Network (GPHIN), whose software retrieves relevant articles from news aggregators every 15 minutes, using extensive search queries.
  
• ProMED and GPHIN played critical roles in informing public health officials of the outbreak of SARS, or severe acute respiratory syndrome, in Guangdong, China, as early as November 2002, by identifying informal reports on the Web through news media and chat-room discussions.

• More recently, the advent of openly available news aggregators and visualization tools has spawned a new generation of disease-surveillance "mashups" (Web application hybrids) that can mine, categorize, filter, and visualize online intelligence about epidemics in real time.
• For instance, HealthMap is an openly available public health intelligence system that uses data from disparate sources to produce a global view of ongoing infectious disease threats. It has between 1000 and 150,000 users per day, including public health officials, clinicians, and international travelers.
  
• Other similar systems include MediSys, Argus, EpiSPIDER, BioCaster, and the Wildlife Disease Information Node. Automated analysis of online video materials and radio broadcasts will soon provide additional sources for early detection.

• The ease of use of blogs, mailing lists, RSS (Really Simple Syndication) feeds, and freely available mapping technology has meant that even an individual expert can create an important global resource. For instance, Declan Butler, a reporter at Nature, took aggregated data from various sources to provide a view of the spread of H5N1 avian influenza on a Google Earth interface. Similarly, Claudinne Roe of the Office of the Director of National Intelligence produces the Avian Influenza Daily Digest and blog, a collection of unclassified information about confirmed and suspected human and animal cases of H5N1 influenza.

• Although news media represent an important adjunct to the public health infrastructure, the information they report pales in comparison to the potential collective intelligence that can be garnered from the public. An estimated 37 to 52% of Americans seek health-related information on the Internet each year, generally using search engines to find advice on conditions, symptoms, and treatments.
• Logs of users' chosen keywords and location information encoded in their computers' IP (Internet Protocol) addresses can be analyzed to provide a low-cost data stream yielding important insights into current disease trends.³
  
• The power of these data has been demonstrated by studies of search engines provided by Google⁴ and Yahoo,⁵ in which data on searches using influenza-related keywords were used to generate an epidemic curve that closely matched that generated by traditional surveillance for influenza-related illness, deaths, and laboratory results.
• Google Flu Trends now provides a prospective view of current influenza search patterns throughout the United States.

• An example of the power of search-term surveillance can be found in an examination of the recent peanut-butter–associated outbreak of Salmonella enterica serotype Typhimurium.

• Using Google Insights for Search, a search-volume reporting tool from Google:-
  

1. we compared the epidemic curve of onset dates for confirmed infections with trends in the volume of Internet searches on related terms in the United States.

2. Search terms included "diarrhea," "peanut butter," "food poisoning," "recall," and "salmonella," and search volumes were compared with the corresponding volumes from the previous year.
   

• Though mining the Web is a valuable new direction these sources cannot replace the efforts of public health practitioners and clinicians. The Internet is also providing new opportunities for connecting experts who identify and report outbreaks.
• Information technologies such as wikis, social networks, and Web-based portals can facilitate communication and collaboration to accelerate the dissemination of reports of infectious diseases and aid in mobilizing a response.
• Some scientific societies are now leveraging technologies for distributed data exchange, analysis, and visualization.
  

1. For instance, the International Society for Disease Surveillance has created the Distributed Surveillance Taskforce for Real-Time Influenza Burden Tracking and Evaluation (DiSTRIBuTE), a group of state and local health departments that use the Web to share, integrate, and analyze health data across large regions.
2. And the International Society of Travel Medicine, in collaboration with the Centers for Disease Control and Prevention (CDC), has created the GeoSentinel project, which brings together travel and tropical-medicine clinics in an electronic network for surveillance of travel-related illnesses. S
3. imilarly, the Emerging Infections Network, administered by the Infectious Diseases Society of America in collaboration with the CDC, is a Web-based network of more than 1000 infectious disease specialists that is geared toward finding cases during outbreaks and detecting new or unusual clinical events.

• Eventually, mobile-phone technology, enabled by global positioning systems and coupled with short-message-service messaging (texting) and "microblogging" (with Twitter), might also come into play. For instance, an organization called Innovative Support to Emergencies, Diseases, and Disasters (InSTEDD) has developed open-source technology to permit seamless cross-border communication between mobile devices for early warning and response in resource-constrained settings.

• Information overload, false reports, lack of specificity of signals, and sensitivity to external forces such as media interest may limit the realization of their potential for public health practice and clinical decision making. Sources such as analyses of search-term use and news media may also face difficulties with verification and follow-up. Though they hold promise, these new technologies require careful evaluation. Ultimately, the Internet provides a powerful communications channel, but it is health care professionals and the public who will best determine how to use this channel for surveillance, prevention, and control of emerging diseases.

Digital Resources for Disease Detection.

Sample Web-based data sources

ProMED-mail, www.promedmail.org

Global Public Health Intelligence Network (GPHIN), www.phac-aspc.gc.ca/media/nr-rp/2004/2004_gphin-rmispbk-eng.php

HealthMap, www.healthmap.org

MediSys, http://medusa.jrc.it

EpiSPIDER, www.epispider.org

BioCaster, http://biocaster.nii.ac.jp

Wildlife Disease Information Node, http://wildlifedisease.nbii.gov

H5N1 Google Earth mashup, www.nature.com/avianflu/google-earth

Avian Influenza Daily Digest and blog, www.aidailydigest.blogspot.com

Google Flu Trends, www.google.org/flutrends

Google Insights for Search, www.google.com/insights/search

DiSTRIBuTE, www.syndromic.org/projects/DiSTRIBuTE.htm

GeoSentinel, www.istm.org/geosentinel/main.html

Emerging Infections Network, http://ein.idsociety.org

Argus, http://biodefense.georgetown.edu

Sample health-related social-networking sites

Physicians, www.sermo.com

Patients, www.patientslikeme.com

Everyone, www.healthysocial.org

Healing the Heart with Bone-Marrow Cells

http://www.technologyreview.com/biomedicine/22676/?nlid=2042
A new treatment may help angina sufferers who are resistant to surgery and medication.

• Injecting the hearts of angina sufferers with cells extracted from their own bone marrow can reverse the condition and relieve its symptoms, a new study suggests.

• The Dutch cardiologists behind the placebo-controlled study say that the results may lead to radical new treatments for patients for whom surgery and medication bring little or no relief from this painful and debilitating condition, which results from narrowed arteries that cannot supply enough blood to the heart during exercise. All 50 subjects involved in the study were resistant to existing treatments.

• Three months after being given the injections, patients' hearts were less starved of blood, and they were able to exercise more, researchers report in the latest issue of the Journal of the American Medical Association.

• Lead researcher Douwe Atsma, a cardiologist at Leiden University Medical Center, in the Netherlands, hopes that follow-up studies, which are currently in progress, will also reveal lower death rates among those who received the treatment.
  

• Atsma's team first fed catheters through patients' femoral veins, up into the aorta, and then into the heart's left ventricle--the chamber that pumps oxygen-rich blood back in the circulation. By touching an electro-sensitive tip around the chamber's surface, the researchers were able to locate areas of low electrical activity, where diminished blood supply had caused cells to die. They built up a "map" of the left ventricular surface of all 50 patients.

• The researchers then took bone marrow from participants' hips and extracted the mass of mononuclear cells--an ill-defined mix of stem cells and progenitor cells.

• In 25 of the patients, the researchers injected around 100,000 cells into angina-affected areas on the ventricular surface, using a modified form of the same catheter. The remaining 25 patients received a placebo injection of saline.

• Three months after the treatment, more catheter tests showed that the average number of diseased grid areas in the hearts of treated patients had fallen from 4.2 to 1.8, or 57 percent. In patients given the placebo, the number fell from 3.8 to 3.1--a significantly smaller 18 percent reduction.

• Bone-marrow recipients were also able to expend more energy on an exercise bike after three months: 114 kilocalories, compared with 107--a small but significant change. Placebo patients experienced an improvement of just 101 kilocalories compared with 99.

• Earlier trials in which researchers sought to treat heart-attack victims with their own bone-marrow cells produced mixed results. Some studies found moderate improvements in a few measures of heart function, but none showed a clear health benefit.

Sending Genes into the Brain

http://www.technologyreview.com/biomedicine/22675/?nlid=2042
More-invasive therapies show promise for treating Parkinson's.

• The brain has long presented a special challenge to drug developers: tightly enclosed by the blood brain barrier, it remains locked to many therapies delivered orally or intravenously.

• However, thanks to more-precise methods of targeting the brain, advances in brain imaging, and the growing popularity of implanted stimulators for treating neurological diseases, the brain is no longer off limits. This is highlighted by a number of new clinical trials involving Parkinson's patients, in which a therapeutic gene or another treatment is delivered directly to a specific part of the brain.

• Drugs that replace the chemical messenger dopamine have been very effective in treating Parkinson's disease, but the benefits of these medications frequently decline over time. About a third of the more than half a million Parkinson's patients in the United States are in the later stages of the disease and resistant to medication. One option for these patients is deep brain stimulation (DBS)--a surgical procedure in which an electrode is implanted directly into the brain. While the exact mechanism underlying the benefits of DBS is unknown, scientists believe that the electrical pulses sent to the damaged part of the brain override the abnormal neural signaling that triggers tremors, rigidity, and other symptoms of Parkinson's.

• More than 40,000 people worldwide have undergone the procedure--a figure that reflects its relative safety and efficacy, as well as a growing acceptance of more-invasive treatments for neurological disease. Many academic researchers and some startup companies are now searching for new alternatives that also directly target the brain, but which involve shorter surgical time and a better prognosis. While DBS is effective in reducing the symptoms of Parkinson's disease, it does not cure it.

• One approach is to correct abnormal activity with gene therapy rather than with electricity. Neurologix, a biotechnology company based in Fort Lee, NJ, has developed a novel gene-therapy treatment that is now being tested in clinical trials.
  
• The therapeutic gene involved, called GAD, codes for an enzyme that catalyzes production of the chemical messenger GABA. (Dopamine is a chemical precursor to GABA, and the cells that produce it are lost in Parkinson's.) "By delivering the gene, you can bypass the area affected by cell death," said John Mordock, the company's chief executive officer, at the Neurotechnology Industry conference in San Francisco last week. "It's taken up into the cells, allowing them to express GABA, restoring balance to the circuit."

• As with DBS, surgeons first drill a small hole in the skull, then insert an electrode to search for a small brain area called the subthalamic nucleus, which emits a characteristic pattern of electrical activity. But the electrode is then removed, and a small catheter is inserted, and a small pump infuses the genetic material into the brain. The specialized drug-delivery device was developed by Medtronic, a medical-device company that also markets DBS systems. Mordock says that Neurologix plans to market the device and the gene-therapy treatment together.

• A second approach is to use gene therapy to slow or prevent cell death in the brain area ravaged by Parkinson's. Federoff is overseeing an academic consortium planning human tests of a gene therapy that codes for a protein called GDNF (glia-derived neurotropic factor), which enhances neuronal survival. The therapy is also delivered via a catheter in the brain, but the infusion is driven by a small pressure gradient, a technique known as convection-enhanced delivery. Federoff, who is also the founder of Canadian startup MedGenesis Therapeutix, which is commercializing the technology, says that this allows for more-targeted delivery.

• Scientists can add a labeled marker to the gene-therapy solution, which can then be seen on CT or MRI scans and used to visualize the diffusion of the molecules in the brain. Researchers have already used this technique to deliver therapies to patients with brain cancer.
  

Detecting Aircraft Pathogens Before It's Too Late

http://www.technologyreview.com/computing/22667/?nlid=2037
A new study suggests that single particle detectors should be used to help control pandemics.

• Each year, an estimated 600 million passengers fly in the United States, and of those, roughly 350,000 are international travelers, according to the Bureau of Transportation Statistics. This leaves commercial airliners vulnerable to biological contamination and makes the spread of disease a real threat.

• Now researchers at the MITRE Corporation have conducted a study that, for the first time, looks at the particle distribution of exhaled breath to better understand how airborne pathogens spread in aircraft cabins, and how best to detect the particles that could contain viruses.

• "The most important point is that if you want to detect infectious viruses from exhaled breath, you need a biosensor with single particle detection," says Grace Hwang, principal investigator of the study and a lead biosensors scientist at MITRE. "Most commercially available biosensors need 10 million viruses before they can inform the user that a virus of concern has been caught, and usually diagnosis takes three to four hours." This is problematic, adds Hwang, since most viruses are found in low concentrations when expelled from an infected person, and many flights do not last more than 90 minutes.

• In addition, the researchers determined that most particles stayed suspended in the aisle, so when booking a trip, take a window seat, says Michael Harkin, a member of the MITRE team, who presented the research at the 2009 IEEE Conference on Technologies for Homeland Security. Particles also did not travel far outside the contaminated row, and if they did, it was across the row. Previously, it was thought that contaminants would travel front to back, or back to front. "There was minimal exposure to the row in front of, and to the window passengers in, [the contaminated row]," says Harkin. Thus, the researchers concluded that biosensors should be placed at the ceiling of the aircraft cabin, about every four rows.

• "Our goal is to capture the infected cases coming into the U.S. before people are symptomatic," says Hwang. "That will buy time to defend against a pandemic spread, and the economic benefits would be enormous."

• The need for such sensors was evident in the 2003 outbreak of Severe Acute Respiratory Syndrome (SARS), which originated in an Air China flight from Hong Kong to Beijing, spread through 18 countries, and resulted in 774 fatalities. Asian economies suffered $11 billion in damages. "If you have an appropriate device to detect pathogens on aircraft, which is a huge challenge, then you are prepared for a deadly outbreak," says Byron Jones, associate dean for research and graduate programs at Kansas State University, and director of its engineering experiment station.
• "We have seen how the swine flu spreads, and while it has turned out to be a mild disease, if it were something deadly and contagious like typhoid fever, it could be a different story." Jones is also part of a team of experts at the Air Transportation Center for Excellence currently looking into the healthfulness of aircrafts.
• To conduct the study, MITRE researchers used a computational fluid dynamics model to investigate the extreme coughing and sneezing situations of seven passengers known as "super spreaders." (Super spreaders cough and sneeze at a rate of 50 times per hour.) The software modeled the aircraft ventilation of a Boeing 767 airliner cabin, as many prior studies have done to determine the optimal sensor placement. But that does not tell you anything about the number of particles exhaled, says Hwang.
  
• The researchers found the fluid volume in saliva and divided it by the number of particles from a sneeze and a cough to get a distribution of particles. This, coupled with the data from the computational fluid dynamics model, allowed the researchers to compute the number of collectable bioparticles, says Hwang.
• The researchers found that contamination traveled farther in sneezing than in coughing cases, and that particles from the two window-seat passengers entered the outlet vents quickly and were the least circulated in the cabin. In contrast, particles from the three passengers in the center row lingered and were not transported as effectively as particles exhaled from passengers in the two aisle seats of the aircraft's two outside rows.

• For the purposes of the study, the researchers assumed that they had approximately 90 minutes to detect a virus. That's about the length of time that it takes to fly from Vancouver to San Francisco--a flight that often carries passengers who have just arrived from Asia.

• Gendreau cautions that while the study did use sophisticated modeling techniques, the researchers did make assumptions about the super spreaders: "We don't have a good idea of super spreaders' characteristics." However, the Center for Disease Control is putting a lot of money into addressing such knowledge gaps, and MITRE's study is a nice start, says Gendreau.

• The MITRE researchers also determined that to detect the presence of viruses, ultrasensitive biosensors are necessary. "The particles are small and dispersed, so you need detection down to the single particle level," says Harkin. Currently, there are no commercial biosensors that can do that. Hwang and researchers at the University of California, San Diego, are building a novel surface plasmon polariton biosensor that has performed single molecule resolution in the laboratory.
  
• The sensor uses a plasmonic substrate with a gold surface that is perforated with nanometer-wide holes. A glycoprotein is attached to the gold surface inside each hole, and the researchers monitor the resonance of the photons that get transmitted through the gold nanohole. When a pathogen like H1N1 or H1N5 binds to the glycoprotein, the resonance changes. The work was featured in Nature earlier this year.

A Laptop Cooled with Ionic Wind

http://www.technologyreview.com/computing/22668/?nlid=2037
Anyone who uses a laptop will be familiar with the whir that the fan makes as it kicks in when the processor's temperature reaches around 100 °F. As laptops and other electronics have gotten smaller and thinner, researchers have begun searching for alternative cooling methods, which add less bulk and are quieter.

• One novel idea is to cool a system by using ions to push air molecules across a hot microprocessor, thereby creating a cooling breeze. So-called ionic-cooling systems have been demonstrated in research labs before, but now Tessera, an international chip-packaging company based in San Jose, CA, has demonstrated an ionic-cooling system integrated into a working laptop.

• Researchers from Tessera and the University of Washington presented details of the ionic-cooling system at the IEEE Semi-Therm Symposium in March. The system can extract roughly 30 percent more heat from a laptop than a conventional fan can, and lab tests show that it could potentially consume only half as much power, the company says.

• The ionic-cooler is based on work originally done in 2006 by Alexander Mamishev, a professor of electrical engineering at the University of Washington, and his colleagues. Last year, Tessera licensed the technology, and the company has since modified it to fit into a laptop. In addition to removing heat more efficiently than a fan, "it has silent operation--no moving parts," Mamishev says. "This is a big milestone."

• Tessera's ionic cooler sits near a vent inside the laptop. Heat pipes, which transfer heat using the evaporation and condensation of a fluid, draw heat away from the computer's processing units and toward the ionic-cooling system.
• Inside the ionic-cooling device are two electrodes: one that ionizes air molecules such as nitrogen, and another that acts as a receiver for those molecules. When a voltage is applied between the two electrodes, the ions flow from the emitter electrode to the collector. As they move, their momentum pushes neutral air molecules across a hot spot, cooling it down.

• One of the main challenges of integrating an ionic-cooling system into a laptop was designing a sufficiently compact voltage converter capable of converting the laptop battery's 12 volts DC into the approximately 3,000 volts required to operate the cooler. Using a power supply from a cold cathode fluorescent lamp, engineers at the company were able to construct a supply that is only three centimeters square.

• Tessera isn't the only company looking at ionic breeze as a means to cool consumer electronics. Researchers at Garimella's own lab at Purdue have demonstrated a similar technology, which is being developed commercially by an early-stage Silicon Valley startup called Ventiva.

• Neither technology is quite ready for the next generation of laptops, though. A major challenge will be ensuring the reliability of the electrodes. Laptops are built to operate for at least 30,000 hours, and in early tests of the ionic-cooling system, certain electrode materials corroded too quickly. Without giving specifics, due to pending patents, Honer says that engineers at the company have identified better materials and are focusing on optimizing their lifetime.

• Another hurdle for the technology is the accumulation of dust. Honer says that his engineers are trying to make sure that the ionic cooler is "as insensitive to dust as a fan." He adds that one way to protect the cooler from potentially damaging particles is to use a prefilter.

Gain of function of mutant p53: The mutant p53/NF-Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation

Cancer Cell, Volume 10, Issue 3, 1 September 2006, Pages 191-202
Silvia Di Agostino, Sabrina Strano, Velia Emiliozzi, Valentina Zerbini, Marcella Mottolese, Ada Sacchi, Giovanni Blandino and Giulia Piaggio

Summary

• This article investigates the mechanistic aspects of mutant p53 gain of function in response to DNA damage. We show that mutant forms of p53 protein interact with NF-Y.
  
• The expression of cyclin A, cyclin B1, cdk1, and cdc25C, as well as the cdk1-associated kinase activities, is upregulated after DNA damage, provoking a mutant p53/NF-Y-dependent increase in DNA synthesis.
  
• Mutant p53 binds NF-Y target promoters and, upon DNA damage, recruits p300, leading to histone acetylation. The recruitment of mutant p53 to the CCAAT sites is severely impaired upon abrogation of NF-YA expression.
  
• Endogenous NF-Y, mutant p53, and p300 proteins form a triple complex upon DNA damage. We demonstrate that aberrant transcriptional regulation underlies the ability of mutant p53 proteins to act as oncogenic factors.

• NF-Y is an ubiquitous heteromeric CCAAT-binding protein composed of three subunits, NF-YA, NF-YB, NF-YC, all necessary for DNA-binding.

• NF-Y sequences are available from several species: the NF-YA gene is cloned from man, rat, mouse, S. pombe, Brassica napus, Schistosoma mansoni and sea urchin (38-41); NF-YB from Kluyveromyces lactis, Aspergillus nidulans, Zea mais, lamprey, Xenopus, and chicken.

• Each of the three subunits displays highly conserved domains in all species. The NF-YA homology domain can be sharply divided into subunit-association and DNA-contacting subdomains. NF-YB and NF-YC tight association is a prerequisite for NF-YA binding and sequence-specific DNA interactions.

• Both NF-YB and NF-YC conserved domains contain putative histone fold motifs. This motif, common to all core histones, is composed of three a-helices separated by short loops/strand regions. NF-YA and NF-YC contain activation domains rich in Glutamines and hydrophobic residues.

Cdk1-Dependent Regulation of the Mitotic Inhibitor Wee1

Cell, Volume 122, Issue 3, 12 August 2005, Pages 407-420

Stacy L. Harvey, Alyson Charlet, Wilhelm Haas, Steven P. Gygi and Douglas R. Kellogg

Summary

• The Wee1 kinase phosphorylates and inhibits cyclin-dependent kinase 1 (Cdk1), thereby delaying entry into mitosis until appropriate conditions have been met.
  
• An understanding of the mechanisms that regulate Wee1 should provide new insight into how cells make the decision to enter mitosis. We report here that Swe1, the budding-yeast homolog of Wee1, is directly regulated by Cdk1.
• Phosphorylation of Swe1 by Cdk1 activates Swe1 and is required for formation of a stable Swe1-Cdk1 complex that maintains Cdk1 in the inhibited state. Dephosphorylation of Cdk1 leads to further phosphorylation of Swe1 and release of Cdk1. Thus, Cdk1 both positively and negatively regulates its own inhibitor. Regulation of the Swe1-Cdk1 complex is likely to play a critical role in controlling the transition into mitosis.

Disease-Associated Prion Protein Oligomers Inhibit the 26S Proteasome

• The mechanism of cell death in prion disease is unknown but is associated with the production of a misfolded conformer of the prion protein.
• We report that disease-associated prion protein specifically inhibits the proteolytic subunits of the 26S proteasome.
  
• Using reporter substrates, fluorogenic peptides, and an activity probe for the subunits, this inhibitory effect was demonstrated in pure 26S proteasome and three different cell lines.
• By challenge with recombinant prion and other amyloidogenic proteins, we demonstrate that only the prion protein in a nonnative sheet conformation inhibits the 26S proteasome at stoichiometric concentrations.
  
• Preincubation with an antibody specific for aggregation intermediates abrogates this inhibition, consistent with an oligomeric species mediating this effect. We also present evidence for a direct relationship between prion neuropathology and impairment of the ubiquitin-proteasome system (UPS) in prion-infected UPS-reporter mice.
  
• Together, these data suggest a mechanism for intracellular neurotoxicity mediated by oligomers of misfolded prion protein. new proteins. that recognize polyubiquitin tags attached to protein substrates and initiate the degradation process. The overall system of ubiquitination and proteasomal degradation is known as the

• Proteasomes are large protein complexes inside all eukaryotes and archaea, as well as in some bacteria.

1. In eukaryotes, they are located in the nucleus and the cytoplasm.^[1] The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that carry out such reactions are called proteases.
   
2. Proteasomes are part of a major mechanism by which cells regulate the concentration of particular proteins and degrade misfolded proteins. The degradation process yields peptides of about seven to eight amino acids long, which can then be further degraded into amino acids and used in synthesizing^[2]
3. Proteins are tagged for degradation by a small protein called ubiquitin. The tagging reaction is catalyzed by enzymes called ubiquitin ligases. Once a protein is tagged with a single ubiquitin molecule, this is a signal to other ligases to attach additional ubiquitin molecules. The result is a polyubiquitin chain that is bound by the proteasome, allowing it to degrade the tagged protein.^[2]
4. In structure, the proteasome is a large barrel-like complex containing a "core" of four stacked rings around a central pore.
   
5. Each ring is composed of seven individual proteins. The inner two rings are made of seven β subunits that contain the six protease active sites. These sites are located on the interior surface of the rings, so that the target protein must enter the central pore before it is degraded.
   
6. The outer two rings each contain seven α subunits whose function is to maintain a "gate" through which proteins enter the barrel. These α subunits are controlled by binding to "cap" structures or regulatory particlesubiquitin-proteasome system.
7. The proteasomal degradation pathway is essential for many cellular processes, including the cell cycle, the regulation of gene expression, and responses to oxidative stress.
   
8. The importance of proteolytic degradation inside cells and the role of ubiquitin in proteolytic pathways was acknowledged in the award of the 2004 Nobel Prize in Chemistry to Aaron Ciechanover, Avram Hershko and Irwin Rose.^[3]

• amyloidogenic proteins:-The various protein deposits of brain amyloidosis share common ultrastructural, biophysical, and histological properties. These amyloidogenic deposits can be composed of distinct proteins, which are conceptually associated with different diseases.
  

1. Amyloidogenic proteins are typically soluble monomeric precursors, which undergo remarkable conformation changes associated with the polymerization into 8- to 10-nm wide fibrils, which culminate in the formation of amyloid aggregates.
2. Some amyloidogenic inclusions are extracellular, such as senile plaques of Alzheimer’s disease, which are composed of amyloid beta (Abeta) peptides.
3. Intracytoplasmic amyloid aggregates, such as neurofibrillary tangles in Alzheimer’s disease and Lewy bodies in Parkinson’s disease, are composed of the proteins tau and alpha-synuclein, respectively. These proteins are directly linked to the etiology of spectrum of neurodegenerative diseases, coining the terms "tauopathies" and "synucleinopathies."

ERK-MAPK signaling opposes Rho-kinase to promote endothelial cell survival and sprouting during angiogenesis

Cancer Cell, Volume 9, Issue 1, 1 January 2006, Pages 33-44
Georgia Mavria, Yvonne Vercoulen, Maggie Yeo, Hugh Paterson, Maria Karasarides, Richard Marais, Demelza Bird and Christopher J. Marshall

Summary

Inhibition of ERK-MAPK signaling by expression of dominant-negative MEK1 in the tumor vasculature suppresses angiogenesis and tumor growth. In an organotypic tissue culture angiogenesis assay, ERK-MAPK inhibition during the migratory phase results in loss of bipolarity, detachment, and cell death of isolated endothelial cells and retraction of sprouting tubules. These effects are the consequence of upregulated Rho-kinase signaling. Transient inhibition of Rho-kinase rescues the effects of ERK-MAPK inhibition in vitro and in vivo, promotes sprouting, and increases vessel length in tumors. We propose a regulatory role of Rho-kinase by ERK-MAPK during angiogenesis that acts through the control of actomyosin contractility. Our data delineate a mechanism by which ERK-MAPK promotes endothelial cell survival and sprouting by downregulating Rho-kinase signaling.

Further Evidence for BRCA1 Communication with the Inactive X Chromosome

Cell, Volume 128, Issue 5, 9 March 2007, Pages 991-1002
Daniel P. Silver, Stoil D. Dimitrov, Jean Feunteun, Rebecca Gelman, Ronny Drapkin, Shihua D. Lu, Elena Shestakova, Soundarapandian Velmurugan, Nicholas DeNunzio, Serban Dragomir, Jessica Mar, Xiaoling Liu, Sven Rottenberg, Jos Jonkers, Shridar Ganesan and David M. Livingston

Summary

, a breast and ovarian cancer-suppressor gene, exerts tumor-suppressing functions that appear to be associated, at least in part, with its DNA repair, checkpoint, and mitotic regulatory activities. Earlier work from our laboratory also suggested an ability of BRCA1 to communicate with the inactive X chromosome (Xi) in female somatic cells (). (this issue of ) have challenged this conclusion. Here we discuss recently published data from our laboratory and others and present new results that, together, provide further support for a role of BRCA1 in the regulation of XIST concentration on Xi in somatic cells.

Mutations in the ERGolgi Intermediate Compartment Protein ERGIC-53 Cause Combined Deficiency of Coagulation Factors V and VIII

Cell, Volume 93, Issue 1, 3 April 1998, Pages 61-70
William C Nichols, Uri Seligsohn, Ariella Zivelin, Valeri H Terry, Colette E Hertel, Matthew A Wheatley, Micheline J Moussalli, Hans-Peter Hauri, Nicola Ciavarella, Randal J Kaufman and David Ginsburg

Summary

Combined deficiency of factors V and VIII is an autosomal recessive bleeding disorder resulting from alterations in an unknown gene on chromosome 18q, distinct from the factor V and factor VIII genes. ERGIC-53, a component of the ERGolgi intermediate compartment, was mapped to a YAC and BAC contig containing the critical region for the combined factors V and VIII deficiency gene. DNA sequence analysis identified two different mutations, accounting for all affected individuals in nine families studied. Immunofluorescence and Western analysis of immortalized lymphocytes from patients homozygous for either of the two mutations demonstrate complete lack of expression of the mutated gene in these cells. These findings suggest that ERGIC-53 may function as a molecular chaperone for the transport from ER to Golgi of a specific subset of secreted proteins, including coagulation factors V and VIII.

p8/TTD-A as a Repair-Specific TFIIH Subunit

Molecular Cell, Volume 21, Issue 2, 20 January 2006, Pages 215-226
Frédéric Coin, Luca Proietti De Santis, Tiziana Nardo, Olga Zlobinskaya, Miria Stefanini and Jean-Marc Egly

Summary

How subunits of the transcription/repair factor TFIIH cooperate to allow for the removal of DNA lesions or for the transcription of genes is crucial to understand the functioning of this complex. Here, we reveal that p8/TTD-A, the tenth subunit of TFIIH, has a critical role in DNA repair where it triggers DNA opening by stimulating XPB ATPase activity together with the damage recognition factor XPC-hHR23B. Fluorescent antibody labeling shows that such opening is needed for the recruitment of XPA to the site of the damage. By contrast, p8 is dispensable for RNA synthesis and doesn't interfere with the transcriptional function of CAK, although both interact with the XPD subunit. Interestingly, p8 overexpression in TTD-XPD cells counteracts the detrimental effect of XPD mutations by restoring the cellular TFIIH concentration. These findings resolve the primary functions of p8 and unveil how TFIIH components specifically direct the complex toward repair or transcription.

Nucleotide Excision Repair Driven by the Dissociation of CAK from TFIIH

Molecular Cell, Volume 31, Issue 1, 11 July 2008, Pages 9-20
Frédéric Coin, Valentyn Oksenych, Vincent Mocquet, Stefanie Groh, Christine Blattner and Jean Marc Egly

Summary

The transcription/DNA repair factor TFIIH is organized into a core that associates with the CDK-activating kinase (CAK) complex. Using chromatin immunoprecipitation, we have followed the composition of TFIIH over time after UV irradiation of repair-proficient or -deficient human cells. We show that TFIIH changes subunit composition in response to DNA damage. The CAK is released from the core during nucleotide excision repair (NER). Using reconstituted in vitro NER assay, we show that XPA catalyzes the detachment of the CAK from the core, together with the arrival of the other NER-specific factors. The release of the CAK from the core TFIIH promotes the incision/excision of the damaged oligonucleotide and thereby the repair of the DNA. Following repair, the CAK reappears with the core TFIIH on the chromatin, together with the resumption of transcription. Our findings demonstrate that the composition of TFIIH is dynamic to adapt its engagement in distinct cellular processes.