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SpaceX Mission to Carry University Pathogen Research

Salmonella

Salmonella bacteria (Centers for Disease Control and Prevention)

12 December 2014. The next launch of the SpaceX Dragon spacecraft to the International Space Station will carry a set of specially-configured petri dishes testing the effect of microgravity on the virulence of salmonella bacteria. The research is the work of microbiologists at Arizona State University and engineers at University of Colorado in Boulder.

Salmonella bacteria are a major source of food poisoning in the U.S., causing 1 million cases each year, along with 19,000 hospitalizations and 380 deaths. Studying behavior of salmonella in space has immediate benefits for the health of astronauts, but can also benefit broader knowledge of the bacterium, since tests can be conducted without the effects of earth-bound gravity that may mask some of the microbe’s biochemical properties.

The tests will infect a number of tiny Caenorhabditis elegans, or C. elegans  nematodes, a type of worm, with salmonella bacteria. C. elegans is a well-studied model organism that grows quickly, is translucent, and has a genome with half of its genes related to those of humans. The tests were designed in the lab of microbiologist Cheryl Nickerson at Arizona State in Tempe, and sponsored by NASA’s Ames Research Center in California.

The petri dishes are built into a specially-designed unit designed by BioServe Space Technologies, a lab in Colorado-Boulder’s engineering school. Earlier resupply missions to the International Space Station carried individual petri dishes, but BioServe says this mission will carry 6 petri dishes configured in a multiple-well casing that provides more uniform conditions.

The petri dishes will be monitored by automated video devices called ScanCams, also built by BioServe Space Technologies. The system will move three high-def cameras to predetermined points near the dishes to record the activity of the infected C. elegans. The video will be processed and transmitted to BioServe’s control center in Boulder, where the feeds will be shared with Nickerson’s lab in Tempe.

Earlier studies of microgravity on salmonella behavior conducted by Nickerson and Bioserve found evidence of increased virulence of the bacteria in space, but the samples were preserved in orbit and returned to Earth for later analysis. Being able to study the impact of microgravity in real time should provide a more accurate reading, by removing the delay and potential errors from reintroducing specimens to Earth’s gravity.

The new tests “will allow researchers to determine the ‘death curve’ of the infected nematodes and compare it with identical experiments being conducted on Earth,” says Bioserve’s director Louis Stodieck in a university statement.

The petri dishes and ScanCams will be loaded on a SpaceX Dragon spacecraft for launch on 19 December from Cape Canaveral in Florida. After launching the Dragon into orbit, SpaceX is expected to try landing the Falcon 9 launch vehicle’s first stage on a floating barge, about the size of a football field, in the Atlantic Ocean. If successful, the landing in the ocean will give SpaceX a reusable vehicle for future launches.

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Test Reveals, Measures Breast Cancer Recurrence Risk

Mammogram

(Centers for Disease Control and Prevention)

12 December 2014. A study by Genomic Health, a developer of diagnostics for personalized cancer treatments, shows its test of an early-stage breast cancer can predict long-term chances of recurrence. Frederick Baehner, a pathologist at University of California in San Francisco and vice-president of Genomic Health, is scheduled to present the findings with colleagues today at a symposium on breast cancer in San Antonio.

Genomic Health, in Redwood City, California, develops genomic tests for diagnosing precise characteristics of cancer to help guide physicians’ treatment decisions. Its main product, a test called Oncotype DX, is offered for people with breast, prostate, and colon cancers. The breast cancer tests are designed for early stages of the disease, including a form known as ductal carcinoma in situ, or DCIS., the most common type of non-invasive breast cancer.

With DCIS, the cancer begins inside the breast’s milk ducts and has not spread to surrounding tissue. While DCIS itself is not life-threatening, women with the condition are at higher risk of breast cancer occurring again, usually within 10 years after the first diagnosis. BreastCancer.org cites data from American Cancer Society indicating some 60,000 cases of DCIS are diagnosed each year in the U.S., accounting for 1 in 5 cases of breast cancer.

In the study, researchers led by Eileen Rakovitch of Sunnybrook Health Sciences Center in Toronto — also a presenter at the San Antonio symposium — analyzed tumor samples from some 1,200 DCIS patients collected between 1994 and 2003 in Ontario. The analysis included 571 patients who had breast-conserving surgery, such as a lumpectomy, that removed the entire tumor. Tests of the tissue with Oncotype DX returned quantified risk estimates for local recurrence in the next 10 years.

The Oncotype DX risk estimates showed more than 6 in 10 of patients (62%) providing tissue samples were at low risk of recurrence in the following 10 years, which correlates with rates of local recurrence of DCIS or more invasive forms of breast cancer. Genomic Health says those results are consistent with findings from an an earlier validation study conducted with  ECOG-ACRIN Cancer Research Group, a consortium of 650 institutions involved in cancer research, showing 70 percent of DCIS cases were at low risk of recurrence.

Identifying risk of recurrence of breast cancer is important in guiding decisions on submitting the patient to radiation therapy, considered the standard of care after surgery.

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Trial Testing Blood Filter Device for Hepatitis C Virus

Microscopic view of the hepatitis C virus (VA.gov)

Microscopic view of the hepatitis C virus (VA.gov)

11 December 2014. Aethlon Medical Inc. is beginning patient recruitment for  an early-stage safety and feasibility study of its blood filtration device with patients in kidney dialysis who also have hepatitis C. The San Diego medical device developer plans to test the Hemopurifier device at DaVita Medical Center in Houston.

Patients with kidney disease needing dialysis face a somewhat higher risk of contracting hepatitis B and C from exposure to blood of another patient with hepatitis B or C viruses. While a vaccine exists for hepatitis B, there is no such vaccine for hepatitis C. According to National Kidney Foundation, the chance of contracting hepatitis B or C from dialysis is small because of infection control measures taken by dialysis centers, but the foundation recommends hepatitis C testing for long-term dialysis patients.

Aethlon Medical’s Hemopurifier is a device that reduces viral pathogens in the blood stream, including HIV and hepatitis C, as well as other pandemic threats including Ebola. The company says previous studies, including human trials, show Hemopurifier reduces viral loads by 50 percent during a 4-hour treatment. A clinical trial in India is testing the device in combination with standard hepatitis C care for its ability to accelerate reductions in viral loads.

In the new clinical trial, Aethlon is recruiting 10 patients with end-stage renal disease and diagnosed with hepatitis C. The patients will first be checked for vital signs, blood chemistries, liver function, and adverse events during a 1-week period with 3 standard dialysis sessions. The patients will then be given Hemopurifier treatments 3 times a week in conjunction with their dialysis sessions during weeks 2 and 3.

The trial’s main objective is to test for safety of the device with this patient population, measured by the rate of adverse events occurring during the test period. The trial is also testing for clinical benefits, in this case effect on viral loads — level of virus in the blood — as well as number of viral copies or virus particles.

Aethlon says once safety of the device is determined, it expects to begin late-stage trials of the Hemopurifier as a treatment for a variety of chronic viral diseases, including pandemic and bioterror threats. The company says it also plans to petition FDA for a humanitarian exemption to use the Hemopurifier with Ebola and orphan disease cases. Aethlon says the device was tested in the lab with Ebola, dengue, and lassa hemorrhagic viruses, 2009 H1N1 influenza, reconstructed 1918 influenza, and monkeypox as a model for smallpox.

The company is also testing the Hemopurifier with exosomes — nanoscale sacs filled with fluids — associated with cancer, in collaboration with Sarcoma Oncology Center in Santa Monica, California. This research is investigating the ability of the device to remove exosomes suppressing the immune system from blood of advanced-stage cancer patients.

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Flexible Pulse Oximeter Designed for Wearable Devices

Ana Arias

Ana Arias (Univ of California, Berkeley)

11 December 2014. Engineers at University of California in Berkeley developed techniques for building inexpensive sensors to measure pulse rate and blood oxygen levels into flexible materials suitable for wearable monitors or fitness devices. The team led by UC-Berkeley electrical engineering professor Ana Arias published its results online yesterday in the journal Nature Communications (paid subscription required).

Monitoring pulse rate and oxygen saturation levels in the blood today are done with pulse oximeters, devices clipped to fingertips or earlobes. Pulse oximeters have silicon chips configured with light emitting diodes, or LEDs, to send out visible red and infrared light, and read the amount of light delivered through the tissue. The system then calculates saturation of oxygen in the blood by translating the difference in recorded light into oxygen levels, as well as measuring pulse rate.

While today’s pulse oximeters are useful devices, their electronics are expensive, and thus found largely in hospitals and clinics, and used by trained staff. Since one pulse oximeter will be attached to multiple patients, the devices must be disinfected between each use.

Arias and colleagues developed techniques for building pulse oximeter functions into flexible carbon-based materials, rather than rigid chips fabricated with silicon. Their process uses similar measurement methods, with organic LEDs emitting visible red and green light. Organic LEDs are thin carbon-based films between conductors that emit light when a current is applied, a technology found in flat-screen televisions and smartphone displays.

The researchers applied the organic LEDs to flexible plastic with printing techniques and spin coating that uses centrifugal force to deposit a solution with the material in a thin, uniform film. Their device also has an organic photodiode that converts the light received through the tissue into a current, and can be configured as well into flexible forms.

In the paper, the Berkeley team tested a prototype of their flexible pulse oximeter device, measuring pulse rate and blood oxygenation compared to a commercial device. The results show the prototype device returned readings within 1 to 2 percent of a commercial pulse oximeter.

The researchers believe the technology can be applied to inexpensive, even disposable, flexible home monitors and fitness trackers. “Because organic electronics are flexible, they can easily conform to the body,” says Arias in a university statement. She adds that sensors based on “organic electronics are cheap enough that they are disposable like a Band-Aid after use.”

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Chikungunya Virus Antibody Isolated, Tested

Mosquito (Germán Meyer)

(Germán Meyer/Flickr)

10 December 2014. Researchers from biotechnology company Integral Molecular and Blood Systems Research Institute identified and tested with lab animals a human antibody that limits viral activity causing chikungunya, a mosquito-borne disease spreading in the Western hemisphere. The team led by Integral Molecular CEO Benjamin Doranz published its findings in this month’s issue of Journal of Virology (paid subscription required).

Chikungunya is a disease caused by viruses carried by mosquitoes that results in symptoms similar to arthritis, such joint pain and swelling, but also fever, headache, muscle pain, and rash that can persist for months or years. Before 2013, chikungunya occurred in Africa, Asia, Europe and islands in the Pacific and Indian oceans. Beginning in 2013, however, cases of the disease were reported in the Caribbean, and has since spread to countries in South and North America, including the U.S. There are no treatments or vaccines to prevent getting chikungunya.

Integral Molecular, in Philadelphia, develops engineered antibodies that target proteins on membranes of cells that act as receptors of signals and move molecules into and out of cells. While cell membranes have similar basic functions, the proteins expressed can vary widely. The company’s technology, licensed from University of Pennsylvania, identifies antibodies that address specialized native cell membrane proteins, and engineer more capabilities into the antibodies if needed.

In the collaboration with Blood Systems Research Institute, Doranz and colleagues used a phage display, a device that screens interactions among proteins and DNA. The device was primed with virus-like particles developed by the company, that isolated 7 highly-specific human antibodies from patients with chikungunya.

One of the antibodies showed a greater ability than others to protect against chikungunya viruses. Tests with lab animals, conducted at Blood Systems Research Institute, showed this one antibody was able to provide protection from infection for 24 hours after exposure to the virus. Mapping of epitopes — sites on antigens that trigger T and B cell responses from the immune system — further clarified molecular binding sites on the virus surface that Integral Molecular says will help in the design of therapies or vaccines.

The antibody isolated and tested in the paper, code-named IM-CKV063 by Integral Molecular is, according to the company, one of the most potent antibodies against chikungunya discovered. “Given the rapid spread of this virus and the lack of specific treatment options,” says Doranz in a company statement, “we are committed to developing this fully human antibody into a first-in-class therapeutic.”

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Organic Farming Narrows Yield Gap With Conventional Methods

Nuna beans (Agricultural Research Service, USDA)

Nuna beans, a type of legume (Agricultural Research Service, USDA)

10 December 2014. An analysis of research studies comparing organic to conventional farming shows conventional techniques have greater yields, but by a smaller margin than previously thought. The team led by environmental scientist Claire Kremen at University of California in Berkeley published its findings in today’s issue of the journal Proceedings of the Royal Society B (paid subscription required).

The UC-Berkeley team reviewed 115 studies with more than 1,000 observations comparing practices of organic and conventional growers, a number 3 times higher than previously published reviews of this kind, say the authors. “With global food needs predicted to greatly increase in the next 50 years” says Kremen in a university statement, “it’s critical to look more closely at organic farming, because aside from the environmental impacts of industrial agriculture, the ability of synthetic fertilizers to increase crop yields has been declining.”

The researchers used a new analytical framework, which they say better accounts for variability and structure of the data. With this change in approach, the team found conventional methods still had higher yields overall compared to organic techniques, but the 19 percent difference is smaller than reported in previous work.

In some cases the difference in yields between conventional and organic techniques were too small be statistically reliable. One example is leguminous crops, such as beans, peas, and lentils. The researchers also found some organic crop methods more successful than others in competing with conventional techniques, specifically crop rotation that reduced the difference in yields to 8 percent, and growing several crops together on the same field that closed the yield gap to 9 percent.

The authors argue that in food production, organic farming can be a competitive alternative to industrial agriculture. Kremen notes as well that “increasing the proportion of agriculture that uses sustainable, organic methods of farming is not a choice, it’s a necessity. We simply can’t continue to produce food far into the future without taking care of our soils, water, and biodiversity.”

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Fewer Americans on Pain Meds, But in Risky Combinations

Back pain (FDA)

(U.S. Food and Drug Administration)

9 December 2014. A review of insurance claims from 2009 to 2013 shows fewer Americans taking opioid pain medications, but for longer periods than originally prescribed and in potentially dangerous combinations. Results of the review were released today in a report by the pharmacy-benefit management company Express Scripts in St. Louis, and authored by Lynne Nowak, the company’s medical director.

Opioids are medications that act by reducing the intensity of pain signals to areas of the brain controlling emotion, thus diminishing effects of the pain stimulus. Popular opioid drugs include hydrocodone (example: Vicodin), oxycodone (OxyContin and Percocet), morphine, and codeine, which can also be taken for colds and coughs. The company notes that the U.S. has about 5 percent of the world’s population, but consumes some 80 percent of the world’s opioid supply.

Nowak and colleagues reviewed 36 million anonymized Express Scripts pharmacy insurance claims made by 6.8 million people in the U.S. between 2009 and 2013, who filled at least one prescription for an opioid pain reliever to treat either acute (short-term) or longer-term pain. Short-term users were defined as people who were prescribed opioid pain medications for 30 days or less in a 1-year period, while longer-term or chronic users are people receiving pain medication supplies of more than 30 days in a 1-year period.

The findings show the number of people in the U.S. filling pain prescriptions dropped 9 percent between 2009 and 2013, particularly short-term pain drug users that declined 11 percent over that 5-year period. Short-term opioid users represent about 8 in 10 of people filling pain prescriptions.

Nonetheless, the number of opioid pain prescriptions and number of days taking the medications rose by 8 percent from 2009 to 2013. The percentage of longer term pain medication users stayed stable over the 5-year study period. The authors estimate the number of number of people with health insurance in the U.S. taking opioids for more than 30 days in a year to number 9.4 million.

In addition, about half of long-term opioid pain medication users continued to use the medications for 3 years or more. Moreover, nearly half (47%) of the people taking pain medications for longer periods, were using drugs normally prescribed for short-term, not long-term use. As a result, note the authors, these patients were at a higher risk of addiction. Chronic pain medication users filled on average 56 short-acting opioids over 3 years, almost 19 prescriptions per year.

The researchers found nearly 6 in 10 (59%) using pain opioids are taking these medications in potentially dangerous combinations. Among these mixtures, nearly 3 in 10 (29%) of longer-term users have concurrent prescriptions for anti-anxiety drugs known as benzodiazepines as well as opioids. Nearly the same proportion (28%) are taking muscle relaxants, and 8 percent are taking all 3 kinds of medications.

Opioids, muscle relaxants and benzodiazepines all act as sedatives, and can slow down the respiratory system. The authors note that the combination of benzodiazepines and opioids is the most common cause of overdose deaths involving multiple drugs. Women account for about two-thirds of people taking these potentially hazardous combinations.

“There could be instances when prescribing these combinations of drugs is appropriate, but not at this scale,” says Nowak in a company statement. “The fact that the majority of these patients are being treated by multiple physicians and pharmacies signals a communication breakdown that leads to dangerous use.”

Use of opioids depends to some extent on the age of the patient. The highest proportion of opioid users are people age 65 and over; some 9 percent of that group in 2013 took pain medications. However, adults age 20 to 44 filled more opioid prescriptions — 10, on average — than people in other age categories. The number of days of medication per prescription also rose 10 percent between 2009 and 2013 for this age group. While women are more likely than men to take opioids for pain, men are more likely to fill more prescriptions and take higher doses.

Of the 25 cities with the greatest number of longer-term opioid users, 24 of those cities have populations of 100,000 or fewer. In addition, the researchers found the vast majority of these cities were located in Kentucky, Alabama, Georgia, and Arkansas. These states claim 41 of the 50 cities with the highest prevalence of opioid use in the country.

States with most opioid use

(Express Scripts)

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Technique Devised for 3-D Immunotherapy Injections

Mesoporous silica rods

Mesoporous silica rods or MSRs that assemble into a porous 3-D matrix (Wyss Institute, Harvard University)

9 December 2014. Biomedical engineers at Harvard University designed a biomaterial that in lab animals assembles into a three-dimensional framework for delivery of therapies triggering an immune response to treat cancer and infectious diseases. The team from the lab of David Mooney at Harvard’s Wyss Institute for Biologically Inspired Engineering published its findings yesterday in the journal Nature Biotechnology (paid subscription required).

Mooney and colleagues — including researchers from Harvard, affiliated research centers, and Sungkyunkwan University in Korea — were seeking an alternative to surgical transplants of cells cultured in the lab for therapies that harness the immune system to fight diseases, such as immunotherapy for cancer. The alternative in this case uses biodegradable silica rods that can be injected under the skin and form into a scaffold or matrix. The micro-scale silica rods are built with even smaller nanoscale pores that can be filled with agents, such as cytokines and other proteins, genetic material, or antigens that generate a therapeutic response from the immune system.

After injection, the silica rods spontaneously collect together under the skin at the injection site, much like a a pile of straws or matchsticks; see image at top. While not forming into a predetermined structure, the silica rods develop into enough of a matrix with micro-sized openings that allow for millions of dendritic cells — the kind that look for and capture antigens to trigger an immune response — to collect in those gaps.

After dendritic cells collect in the scaffold, the agents loaded in the porous slica rods are released that initiate the immune response. Once activated, the dendritic cells travel from the scaffold to the lymph nodes where T-cells in the immune system are directed to fight invading cancer cells or infectious microbes. The biodegradable silica rods at the injection site then begin to dissolve and are naturally removed.

The researchers tested the technique in lab mice injected with silica rods carrying a vaccine formulation. The team observed the matrix of silica rods collected dendritic cells that traveled to lymph nodes, and found the mice had higher T-cell levels after the injections indicating an immune response.

Graduate student and co-lead author Aileen Li says in a university statement that altering the surface properties and pore size of the mesoporous silica rods or MSRs makes it possible to program and control the release of therapeutic agents, thus making the technique applicable to a number of diseases. “Although right now we are focusing on developing a cancer vaccine,” notes Li, “in the future we could be able to manipulate which type of dendritic cells or other types of immune cells are recruited to the 3-D scaffold by using different kinds of cytokines released from the MSRs.”

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Pfizer, Biotech Partner on Hemophilia B Gene Therapy

Adeno-associated virus

Adeno-associated virus (LBL.gov)

8 December 2014. Spark Therapeutics, a biotechnology firm in Philadelphia, is collaborating with the pharmaceutical company Pfizer to commercialize Spark’s gene therapy technology as a treatment for hemophilia B. Spark Therapeutics can gain as much as $280 million in the deal that involves sharing worldwide rights to Spark’s technology for hemophilia B with Pfizer.

Hemophilia B is an inherited disorder that results from the absence of a clotting protein in blood known as factor IX or FIX. People with hemophilia B bleed longer than people with FIX, with some 60 percent of cases considered severe, meaning people with the condition experience bleeding after an injury, including spontaneous bleeding into muscles and joints. Spark Therapeutics cites data from the 2012 World Federation of Hemophilia Annual Global Survey, indicating some 26,000 males worldwide suffer from hemophilia B.

Spark Therapeutics develops gene therapies for inherited diseases based on research conducted at Children’s Hospital of Philadelphia, a teaching hospital of University of Pennsylvania. The company’s technology uses engineered adeno-associated viruses, benign microbes designed to deliver genetic material into the cells of patients with defective genes. The company began in October 2013, founded by four scientists from Children’s Hospital, including hemotologist Katherine High, who now serves as Spark’s president and chief scientist.

One of Spark’s therapies, code-named Spk-FIX, is designed to deliver genetic material with an adeno-associated virus to the liver, where coagulation factors including FIX are produced. The company says proof-of-concept and early-stage clinical trials show Spk-FIX expresses a therapeutic gene in the liver that stimulates FIX at sufficient levels for patients to discontinue preventive or replacement treatments for some periods of time.

Under the deal with Pfizer, Spark Therapeutics will continue early and intermediate-stage clinical trials of Spk-FIX, while Pfizer will be responsible for subsequent late-stage trials, regulatory approvals, and worldwide commercialization of the product. Spark is receiving an initial $20 million payment from Pfizer, and will be eligible for for up to $260 million in further milestone payments for multiple hemophilia B treatment candidates. Spark can also receive royalties on sales of products developed in the partnership.

Pfizer is developing other drugs for hemophilia, including BeneFIX, an engineered replacement FIX treatment. In July, Pfizer reported a late-stage clinical trial showing BeneFIX taken once a week reduced annual bleeding rates of people with hemophilia B compared to a placebo.

Pfizer also announced today the appointment of Michael Linden, a virology professor at King’s College London, to a 2-year assignment leading the company’s gene therapy program in rare deseases. Linden’s research includes studies of the biochemistry and structure of adeno-associated virus proteins.

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Merck Buys Antibiotic Maker in $9.5 Billion Deal

New York Stock Exchange entrance (A. Kotok)

(A. Kotok)

8 December 2014. The pharmaceutical company Merck agreed today to acquire Cubist Pharmaceuticals, a developer of antibiotics, in a deal valued at $9.5 billion. Under the agreement Merck will pay Cubist stockholders $102 a share in cash — the stock closed at about $74 a share on Friday — equaling $8.4 billion, as well as covering some $1.1 billion in Cubist net debt, for a total value of $9.5 billion.

Cubist Pharmaceuticals, in Lexington, Massachusetts, specializes in development of new antibiotics, particularly treatments for infections from bacteria resistant to conventional antibiotics, including those found in health care settings. Cubist’s currently approved drugs include Cubicin for treating Methicillin-resistant Staphylococcus aureus (MRSA), as well as treatments for Clostridium difficile, skin and skin structure infections, and aid in recovery fom gastrointestinal surgery.

The company has several new drugs and added applications for current therapies awaiting FDA approval or in intermediate or late-stage clinical trials, focusing on hospital-acquired infections. Pipeline drugs include treatments for urinary tract infections, hospital-acquired and ventilator-associated bacterial pneumonia, Clostridium difficile, and opioid-induced constipation. Cubist also has a beta-lactamase inhibitor, a new class of antibiotic for the company, in early-stage trials designed to prevent beta-lactamase enzymes associated with antibiotic resistance from deactivating antibiotics.

Merck says the Cubist acquisition will help bolster its portfolio of drugs designed for hospitals and acute care facilities. The company notes hospitals now represent about a quarter of all health care spending, and have favorable regulatory and reimbursement trends in the industry. Merck has several new antibiotics in clinical trials, including treatments for Clostridium difficile and a beta-lactamase inhibitor for severe bacterial infections.

Merck expects the Cubist acquisition to add some $1 billion to its revenues in 2015. In 2013, Merck had total annual revenues of about $44 billion, down from $47.3 billion in 2012.

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