Stoke Therapeutics, a preclinical biotech developing RNA-targeted therapies for rare genetic diseases, raised $142 million by offering 7.9 million shares at $18, above the range of $14 to $16. The company had previously filed to offer 6.7 million shares.
Stoke Therapeutics plans to list on the Nasdaq under the symbol STOK. J.P. Morgan, Cowen and Credit Suisse acted as joint book-running managers on the deal.
China will block pork imports from a third Canadian firm after a shipment was found to contain the banned feed additive ractopamine, the customs agency said on Tuesday, deepening a trade and diplomatic dispute with Canada.
The firm in question is Frigo Royal Inc, the agency said on its Wechat account. Ractopamine is used in some countries to make leaner pigs but China does not allow its use or tolerate residues in imported meat.
China will also strengthen inspections for the residue in all pork imports from Canada, the notice from the General Administration of Customs said. Quebec-based Frigo Royal did not immediately respond to a request for comment.
China halted pork imports from two other Canadian producers, Olymel LP and Drummond Export, in April because of labelling problems. It has also blocked imports of canola.
“It’s definitely not good news,” Canadian Agriculture Minister Marie-Claude Bibeau told reporters, saying food inspectors were investigating the matter.
“My message to the exporters and the industry is to be very vigilant to make sure they respect all the rules of our export agreement with China,” she added.
Relations between China and Canada nosedived last December after Vancouver police detained Meng Wanzhou, the chief financial officer of Huawei Technologies Co, on a U.S. arrest warrant. Beijing is demanding her return.
Canadian officials said this month they had been warned by China that it would step up inspections of meat imports after “recent cases of non-compliance” in pork shipments.
The Chinese customs notice said authorities in the port of Nanjing had detected ractopamine residue in a batch of Frigo Royal pork on June 3.
China had previously warned Canada that it would open all containers of Canadian meat and, in some cases, inspect 100% of the contents.
Many Canadian farmers started raising pigs without ractopamine in 2013 to boost exports to China. Pork exporters, feed manufacturers and hog farms enrol in a government program that certifies pork was produced without ractopamine, said Gary Stordy of the Canadian Pork Council farmer group.
Elanco Animal Health Inc, the manufacturer of Paylean, the commercial name for a ractopamine feed ingredient, does not sell the product in Canada, although there are other ractopamine manufacturers, spokeswoman Keri McGrath said.
In the first four months of 2019, China was Canada’s third-biggest pork export market, taking in C$310 million (£184.5 million) of pork, according to Statistics Canada.
Researchers at the University of North Carolina at Chapel Hill Gillings School of Global Public Health and their colleagues at the University of Texas at Austin and the National Institutes of Health Vaccine Research Center have discovered an antibody that broadly inhibits multiple strains of pandemic norovirus, a major step forward in the development of an effective vaccine for the dreaded stomach virus.
The study, published in the June 18 issue of Immunity, describes for the first time the structure of the binding interaction between the virus and a human antibody that may work against many strains of the pandemic ‘stomach bug.’
Research specialist Lisa Lindesmith and professor Ralph Baric, both of The Gillings School’s department of epidemiology, are co-authors on the study.
Human noroviruses are the leading cause of acute gastroenteritis, inflammation of the stomach and intestines. It accounts for nearly one in five cases of diarrhea and vomiting, and is responsible for an estimated 200,000 deaths per year, mostly in infants, children and the elderly, according to the Centers for Disease Control and Prevention. Though there are more than 30 known genotypes of human norovirus, nearly 60% of outbreaks are caused by GII.4 genotype strains that have caused periodic human pandemics since 1996 through today, the authors wrote.
“In order to design an effective vaccine for norovirus, scientists needed to identify a neutralizing antibody that could work against many strains of the virus, as well as strains that will circulate in the future,” said Baric. “This information can now be used to build better human vaccines.”
The most important discovery of this study is a human antibody that can bind to a highly conserved region of the virus common among different strains of norovirus, potentially neutralizing all GII.4 strains of norovirus that exist in nature.
Highly conserved regions are parts of the virus that do not change. A human antibody that can target these highly conserved areas will provide broad protection for a prolonged period of time. With this knowledge, vaccine developers will have a better understanding of how, and how often, to reformulate the vaccine over time.
The technology, developed by co-author George Georgiou, was used to discover the key antibody in the study and the approach is applicable to a variety of highly variable bacteria and viruses.
“This study addresses a fundamental problem in norovirus disease development that could have wide-ranging impact on global health,” says Lindesmith. “We’ve established an understanding of the virus and how it changes, how the body’s immune response targets it and how we can use that information to make a better vaccine.”
More information: Lisa C. Lindesmith et al, Sera Antibody Repertoire Analyses Reveal Mechanisms of Broad and Pandemic Strain Neutralizing Responses after Human Norovirus Vaccination, Immunity (2019). DOI: 10.1016/j.immuni.2019.05.007
An anti-inflammatory drug called ketorolac, given before surgery, can promote long-term survival in animal models of cancer metastasis, a team of scientists has found. Furthermore, so-called “pro-resolution” therapies can also trigger the immune system to eliminate metastatic cells. The research also suggests that flanking chemotherapy with anti-inflammatory drugs can unleash anti-tumor immunity.
The findings, published in Journal of Clinical Investigation, also provide a mechanistic explanation for the anti-metastatic effects of ketorolac, previously observed in human breast cancer surgery.
Vikas P. Sukhatme, MD, ScD, dean of Emory University School of Medicine, is senior author of the paper. He was previously at Beth Israel Deaconess Medical Center and Harvard Medical School, with lead authors Dipak Panigrahy, MD and Allison Gartung, PhD.
“Collectively, our findings suggest a potential paradigm shift in our approach to resectable cancers,” says Sukhatme. “Clinical trials are now urgently needed to validate these animal studies.”
Most cancer-related deaths come from metastases, the spread of cancer cells from a primary tumor to surrounding tissues or distant organs. The cells that seed metastases are often in microscopic clusters – a surgeon can’t see them. Chemotherapy, typically given after or prior to surgery is aimed at eradicating these cancer cells in the hopes of preventing cancer recurrence. However, chemotherapy can sometimes stir up inflammation, promoting metastasis.
Credit: Emory University
“Cancer therapy is a double-edged sword,” says Panigrahy. “Surgery and chemotherapy can induce an inflammatory or immunosuppressive injury response that promotes dormant metastatic cells to start proliferating, leading to tumor recurrence.”
Ketorolac is an inexpensive NSAID (nonsteroidal anti-inflammatory drug). Because of concern over side effects, it is only approved by the FDA for short-term pain management “at the opioid level.” It differs from other NSAIDs in that it preferentially inhibits the enzyme COX-1, more than COX-2. Other studies of prevention of cancer recurrence have focused on COX-2 inhibitors.
In the paper, the researchers show that preoperative, but not postoperative, ketorolac administration (as it typically is currently used), can eradicate cancer metastasis in mouse models and extend survival of animals. The effects appear to depend on COX-1 inhibition, because other NSAIDS did not display the same survival benefits. A further increase in the percentage of animals that survived following resection of the primary tumor was noted when ketorolac was combined with low dose aspirin and omega 3 fatty acids. Of note, resolvins, metabolic products of omega 3 fatty acids that accelerate the resolution of inflammation, also gave similar effects.
The researchers gained insight into how these approaches could be combined with other anti-cancer therapies. Ketorolac and the resolvins appear to indirectly stimulate T cells, part of the immune system, augmenting the action of immunotherapies such as checkpoint inhibitors, but conflicting with chemotherapy.
The authors conclude: “…we and others are showing that it may be possible to eradicate micrometastatic disease and dormant tumor cells without chemotherapy. Here, we demonstrate that unleashing T cell immunity by preoperative suppression of systemic inflammation or stimulation of inflammation resolution exhibits potent antitumor activity, even curing mice of micrometastases” which are largely responsible for cancer recurrence following surgery.
More information: Dipak Panigrahy et al. Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases, Journal of Clinical Investigation (2019). DOI: 10.1172/JCI127282
Inflammation in a sound-processing region of the brain mediates ringing in the ears in mice that have noise-induced hearing loss, according to a study publishing June 18 in the open-access journal PLOS Biology by Shaowen Bao of the University of Arizona, and colleagues.
Hearing loss is a widespread condition that affects approximately 500 million individuals, and is a major risk factor for tinnitus—the perception of noise or ringing in the ears. Recent studies indicate that hearing loss causes inflammation—the immune system‘s response to injury and infection—in the auditory pathway. But its contribution to hearing loss-related conditions such as tinnitus is still poorly understood. To address this gap in knowledge, Bao and his colleagues examined neuroinflammation—inflammation that affects the nervous system—in the auditory cortex of the brain following noise-induced hearing loss, and its role in tinnitus, in rodent models.
The results indicate that noise-induced hearing loss is associated with elevated levels of molecules called proinflammatory cytokines and the activation of non-neuronal cells called microglia—two defining features of neuroinflammatory responses—in the primary auditory cortex. Experiments in mice that incur noise-induced hearing loss showed that a cell-signaling molecule called tumor necrosis factor alpha (TNF-α) mediates neuroinflammation, tinnitus, and synaptic imbalance—an altered pattern of signaling between neurons. Moreover, the researchers found that pharmacological blockade of TNF-α or depletion of microglia prevented tinnitus in mice with noise-induced hearing loss. According to the authors, the findings suggest that neuroinflammation may be a therapeutic target for treating tinnitus and other hearing loss-related disorders.
Trial demonstrated linaclotide improved overall abdominal symptoms of bloating, pain and discomfort in adult irritable bowl syndrome with constipation.
Also met secondary endpoints.
Linaclotide was well-tolerated in this Phase IIIb study, with the most commonly reported adverse event being diarrhea.
