January 30, 2017
University of Exeter
The growth of bacteria can be stimulated by antibiotics, scientists have discovered.
The growth of bacteria can be stimulated by antibiotics, scientists at the University of Exeter have discovered.
The EPSRC-funded researchers exposed E.coli bacteria to eight rounds of antibiotic treatment over four days and found the bug — which can cause severe stomach pain, diarrhea and kidney failure in humans — had increased antibiotic resistance with each treatment.
This had been expected, but researchers were surprised to find mutated E.coli reproduced faster than before encountering the drugs and formed populations that were three times larger because of the mutations.
This was only seen in bacteria exposed to antibiotics — and when researchers took the drug away, the evolutionary changes were not undone and the new-found abilities remained.
“Our research suggests there could be added benefits for E.coli bacteria when they evolve resistance to clinical levels of antibiotics,” said lead author Professor Robert Beardmore, of the University of Exeter.
“It’s often said that Darwinian evolution is slow, but nothing could be further from the truth, particularly when bacteria are exposed to antibiotics.
“Bacteria have a remarkable ability to rearrange their DNA and this can stop drugs working, sometimes in a matter of days.
“While rapid DNA change can be dangerous to a human cell, to a bacterium like E.coli it can have multiple benefits, provided they hit on the right changes.”
The researchers tested the effects of the antibiotic doxycycline on E.coli as part of a study of DNA changes brought about by antibiotics.
The E.coli “uber-bug” that subsequently evolved was safely frozen at -80C and the scientists used genetic sequencing to find out which DNA changes were responsible for its unusual evolution.
Some changes are well known and have been seen in clinical patients, like E.coli producing more antibiotic pumps that bacteria exploit to push antibiotics out of the cell.
Another change saw the loss of DNA that is known to describe a dormant virus.
“Our best guess is that losing viral DNA stops the E.coli destroying itself, so we see more bacterial cells growing once the increase in pump DNA allows them to resist the antibiotic in the first place,” said Dr Carlos Reding, who was part of the study.
“This creates an evolutionary force for change on two regions of the E.coli genome.
“Normally, self-destruction can help bacteria colonise surfaces through the production of biofilms. You see biofilms in a dirty sink when you look down the plughole.
“But our study used liquid conditions, a bit like the bloodstream, so the E.coli could give up on its biofilm lifestyle in favour of increasing cell production.”
Dr Mark Hewlett, also of the University of Exeter, added: “It is said by some that drug resistance evolution doesn’t take place at high dosages but our paper shows that it can and that bacteria can change in ways that would not be beneficial for the treatment of certain types of infection.
“This shows it’s important to use the right antibiotic on patients as soon as possible so we don’t see adaptations like these in the clinic.”
- Carlos Reding-Roman, Mark Hewlett, Sarah Duxbury, Fabio Gori, Ivana Gudelj, Robert Beardmore. The unconstrained evolution of fast and efficient antibiotic-resistant bacterial genomes. Nature Ecology & Evolution, 2017; 1: 0050 DOI: 10.1038/s41559-016-0050
Source: University of Exeter. “Antibiotics can boost bacterial reproduction.” ScienceDaily. ScienceDaily, 30 January 2017. <www.sciencedaily.com/releases/2017/01/170130110927.htm>.
Orphan Drug Development at Target Health Inc.
Target Health is very pleased that it has prepared, submitted and obtained over 20 orphan drug designations, with 3 of these products reaching the market. There were 2 additional orphan programs in which Target Health played a major role. One program was in cystic fibrosis, on behalf of our good friend and colleague, Dr. Tibor Sipos President and CEO of Digestive Care Inc, which was approved by FDA in 2012, without an ODD. The second program was for Regeneron, where Target e*CRF was used in the development program of Arcalyst, for the treatment of Cryopyrin-Associated Periodic Syndromes which was approved in 2008.
Ongoing clinical development programs treating orphan diseases include Dravet syndrome, Fabry disease, Growth Hormone, and Huntington’s disease.
The following is the list of orphan diseases for which Target Health obtained ODD on behalf of its clients:
Alagille syndrome; Aplastic anemia; Behcet’s disease; Burn progression in hospitalized patients; Caries prevention, head and neck cancer; Cushing’s syndrome secondary to ectopic ACTH secretion; Debridement in hospitalized patients with 3rd degree burns (EMA Approved 2012); Edema-related effects in hospitalized patients with 3rd degree burns; Fibrolamellar carcinoma (FLC); Fungal Infections; Gaucher Disease (NDA Approved 2012); Growth Hormone (Licensed to Big Pharma); Hereditary angioedema (NDA Approved 2011); Hodgkins Lymphoma; Intradialytic Hypotension (symptomatic hypotension in the immediate post-dialytic period); Invasive aspergillus infections; Multiple myeloma; Osteonecrosis of the jaw; Ovarian cancer; Rabies; Scleroderma.
For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.
Joyce Hays, Founder and Editor in Chief of On Target
Jules Mitchel, Editor
Carbamates (insecticides) Can Upset Circadian Rhythms (upsetting sleep patterns) and Increasing Diabetes Risk
This computer-generated image demonstrates how melatonin (in yellow)
and carbaryl, (in light turquoise), a commonly used insecticide, bind directly
to the same binding region on the human melatonin receptor.
Credit: Raj Rajnarayanan, UB
Synthetic chemicals commonly found in insecticides and garden products bind to the receptors that govern our biological 1) ___, University at Buffalo researchers have found. The research suggests that exposure to these insecticides could adversely affect melatonin receptor signaling, creating a higher risk for metabolic diseases such as diabetes. Published online on Dec. 27, 2016, in Chemical Research in Toxicology, the research combined a big data approach, using computer modeling on millions of chemicals, with standard wet-laboratory experiments. It was funded by a grant from the National Institute of Environmental Health Sciences, part of the N I of H, 2) ___ ___ __ ___.
Disruptions in human circadian rhythms are known to put people at higher risk for 3) ___ and other metabolic diseases but the mechanism involved is not well-understood. This is the first report demonstrating how environmental chemicals found in household products interact with human melatonin 4) ___, said Margarita L. Dubocovich, PhD, senior author on the paper and SUNY Distinguished Professor in the Department of Pharmacology and Toxicology and senior associate dean for diversity and inclusion in the Jacobs School of Medicine and Biomedical Sciences at UB. No one was thinking that the melatonin system was affected by these compounds, but that’s what our research shows, she said. The current research focuses on two 5) ___, carbaryl, the third most widely used insecticide in the U.S. but which is illegal in several countries, and carbofuran, the most toxic carbamate insecticide, which has been banned for applications on food crops for human consumption since 2009. It is still used in many countries, including Mexico and traces persist in food, plants and wildlife. We found that both 6) ___ are structurally similar to melatonin and that both showed affinity for the melatonin, MT2 receptors, that can potentially affect glucose homeostasis and insulin secretion, said Marina Popevska-Gorevski, co-author, now a scientist with Boehringer Ingelheim Pharmaceuticals, who worked in Dubocovich’s lab while earning her master’s degree at UB. That means that exposure to them could put people at higher risk for diabetes and also affect 7) ___ patterns. The results suggest that there is a need to assess environmental chemicals for their ability to disrupt circadian activity, something which is not currently being considered by federal 8) ___. The UB researchers are developing a rapid bioassay that might be able to assess environmental chemicals for this kind of activity.
The work is part of a larger effort by Dubocovich and her colleagues at UB to develop their Chem2Risk pipeline, combining UB’s expertise in computational biology and melatonin receptor pharmacology.Our approach seamlessly integrates the screening of environmental chemicals through computer simulation, in vitro and in vivo techniques to gauge the risk these chemicals present for various disease end points, explained Raj Rajnarayanan, PhD, lead author and assistant professor of pharmacology and toxicology at UB. The UB database contains about four million chemicals reported to have some level of toxicity. From those, we identified hundreds of thousands of compounds that had readily available chemical structures so that we could study them, Rajnarayanan explained. After grouping the chemicals in clusters according to their similarity, they found several with functional groups similar to melatonin. Using predictive computational modeling and in vitro experiments with cells that express human melatonin receptors, they found that carbamates selectively interact with a melatonin receptor. That interaction can disrupt melatonin signaling and alter important regulatory processes in the body. By directly interacting with melatonin receptors in the 9) ___ and peripheral tissues, environmental chemicals, such as carbaryl, may disrupt key physiological processes leading to misaligned circadian rhythms, sleep patterns, and altered metabolic functions increasing the risk for chronic diseases such as diabetes and metabolic disorders, said Dubocovich. For example, she explained, there is a fine balance between the release of insulin and glucose from the 10) ___pancreas at very specific times of day, but if that balance becomes disrupted over a long period of time, there is a higher risk of developing diabetes.
Editor’s note: If insecticides are as harmful to humans, as the above research finds, imagine how destructive, pesticides have been to the honey bee population, around the world. Due to colony collapse disorder, honey bees have been disappearing for over ten years or more. Now there is concrete evidence that answers the mystery of why honey bees have been disappearing by the millions.
Source: University at Buffalo; Journal Reference: Marina Popovska-Gorevski, Margarita L. Dubocovich, Rajendram V. Rajnarayanan. Carbamate Insecticides Target Human Melatonin Receptors. Chemical Research in Toxicology, 2017; ScienceDaily.com
ANSWERS: 1) clocks; 2) National Institutes of Health; 3) diabetes; 4) receptors; 5) chemicals; 6) insecticides; 7) sleeping; 8) regulators; 9) brain; 10) pancreas
Thrilling Rescue Revealed, of U.S. Medics & Nurses, During WW 2 in Albania
U.S. Medics at work during WW2; Source: Public Domain, Wikipedia Commons
Harold Hayes was a member of a band of airborne American medics and nurses who crash-landed in Nazi-occupied Albania in 1943 and trekked 600 miles to their rescue. All of these brave heroes were military trained army lieutenants. Harold Hayes, was the last surviving member of a band of airborne American medics and nurses who crashed-landed in Nazi-occupied Albania in 1943 and survived German attacks, blizzards and horrific privations on a 600-mile trek to their rescue on the Adriatic coast. He died last Sunday in Medford, Ore. He was 94. His death, at a hospital, followed an operation to remove a blood clot from his leg, his daughter Margaret Bleakley said.
The survival of the 30 noncombatants was a long-held secret of World War II: the story of 13 female nurses, 13 male medics and the four-man crew of a medical evacuation plane who were stranded behind enemy lines for nine weeks, hiding in villages and caves in wintry mountains, afflicted with lice and dysentery, often near starvation and hunted by German patrols. Their odyssey was classified during the war and for years afterward to protect partisan fighters, Allied agents and villagers who gave them food, shelter and guidance. Some were shot by the Germans for their acts of kindness, and after the war, as rumors became death sentences, those even suspected of helping the Americans were executed by Albania’s Communist dictator, Enver Hoxha, whose rule ended with his death in 1985.
For many years, I didn’t say anything about what happened in Albania, Mr. Hayes said in a 2015 telephone interview with The New York Times from his assisted-living home in Medford. After the war was over, Hoxha was ruthless. If he discovered the names of anyone who had helped us, he had them and their families executed. Mr. Hayes had no special role in the group’s survival, but by outliving all his wartime comrades, he became a last conduit for their story, which was related in a 1999 memoir by one of the nurses, and more recently in several books, notably The Secret Rescue (2013), by Cate Lineberry, whose account relied heavily on Mr. Hayes’s recollections.
Harold Hayes and the other medics and nurses were part of a Medical Air Evacuation Transport Squadron. The United States medical air evacuation program was an innovative new medical military program within the Army Air Forces that transported wounded and sick from hospitals near the frontlines to better-equipped facilities for additional care. It was started in 1942, and during the war transported more than one million troops, with only forty-six dying in flight. In 1945, General of the Army Dwight Eisenhower deemed air evacuation as important as other WWII medical innovations, including penicillin and sulfa drugs. At the time the air evacuation program was developed in 1942, most Americans had never been on an airplane before. In fact, on January 14, 1943, FDR became the first U.S. president to fly on official business while on his way to the Casablanca Conference. The perilous adventure began two months after Italy surrendered and Allied forces invaded Italy to begin pushing the Germans back across Europe. On Nov. 8, 1943, the nurses, medics and fliers of the Army Air Force’s 807th Medical Air Evacuation Transport Squadron took off from Catania, Sicily, bound for Bari, on Italy’s east coast, where hundreds of wounded troops awaited air evacuation. Their twin-engine cargo plane carried no weapons, but the pilot, First Lt. Charles Thrasher, 22, anticipated no fighting. With him were a co-pilot, radio operator and crew chief. The nurses, all second lieutenants, were 22 to 32 years old. The medics, including Mr. Hayes, 21, from Indianola, Iowa, were all equivalent to staff sergeants and ranged in age from 21 to 36.
There wasn’t a cloud in the sky when we left the airfield, but the closer we got to Bari, the more clouds appeared. We were soon caught in a violent storm and lost all communication with the station at Bari. The plane’s compass and communications failed. In addition, the plane was low on gas. The pilots ascended above the clouds, but when the plane got up to about 8,000 feet, the wings started icing up, so we had to dive down through the clouds. Blown 100 miles off course, our plane crossed over into Albania. We could see a coastline; the pilots thought we might have flown across Italy and were near Italy’s western coast. They didn’t realize we’d crossed the Adriatic. The pilots tried to land on what looked like an abandoned airfield, and that’s when someone started shooting at us. The pilots immediately headed for the clouds. That was probably the scariest part?flying through a valley where the tops of the mountains were higher than the clouds. When we emerged from the clouds, our plane was very close to a German fighter plane and then to another, which attacked with antiaircraft guns. The pilots continued trying to dodge the enemy planes and eventually found a place near a lake where we crash-landed, 25 miles inland. When they started landing, medic, Harold Hayes thought the pilots wouldn’t be able to stop in time and that they would end up in the water. The pilots braked hard, and the landing gear sank in the mud. Just before the plane would have hit the water, it came to a violent stop. The force embedded the plane’s nose in the marshy ground, and the fuselage hovered upright for a few seconds before falling to the ground in a belly flop. The crew chief in the back of the plane was the only one not strapped in, and he went flying forward. Willis Shumway, 23, the crew chief, was the only casualty, with a knee injury that left him unable to walk. The disoriented Americans had no idea where they were. Fearing a fuel explosion, they scrambled out of the plane and encountered their first bit of luck. Striding out of a woods was a band of rugged-looking men with rifles and daggers. One spoke a little English. He was Hasan Gina, an anti-German partisan leader. He told the Americans they were in Albania. Two resistance groups were essentially fighting to see who would control Albania after the war ended. The partisans who met the Americans were one group, and the Balli Kombetar, or BK, was the second group. The BK was a right-wing nationalist group, opposed to the communist-led National Liberation Movement. The two groups had formed when the Italians occupied Albania. Italy had surrendered to the Allies in September 1943, two months before the Germans took control of the country. When the partisans led the Americans through the countryside they had to avoid not only the Germans but also the BK. Later, they would learn that they were 150 miles east of Bari, on the wrong side of the Adriatic, surrounded by German forces that had occupied Albania for months, and were caught in a civil war between rival partisan groups. With only a general plan to reach the west coast and somehow cross the Adriatic to Italy, the group began walking in the wrong direction.
After five days, they rested at a partisan-controlled town called Berat, but their respite was brief. German forces entered the town and three nurses were separated. They hid in Berat for four months while the group continued.
Over the ensuing weeks, they trekked through mountains and valleys, battling starvation, parasites and diarrhea. Sometimes they had to cut back or travel in circles to avoid German patrols. Lt. Gavan Duffy, a British secret agent, found the group in eastern Albania and began leading them westward, intending to reach the coast. At Gjirokaster, German troops blocked the way, and the Americans were too sick and exhausted to go on. He radioed for an American air rescue. Two C-47 cargo planes flew in with fighter escorts. But the Germans disrupted the landing. On Jan. 9, after a 63-day ordeal, they finally boarded a British launch and crossed to Italy.
The Americans knew almost nothing of Albania, a small, mostly Muslim country that had changed little in centuries. The mountainous terrain was dotted with impoverished villages. There were no railroads and few roads. Mules and horses were the main transportation. There was little running water or electricity. Winters were brutal, food was scarce, and blood feuds were common among the ferociously proud peoples. With only a general plan to reach the west coast and somehow cross the Adriatic to Italy, the Americans began walking in the wrong direction. Over the ensuing weeks, guided by the partisans, they trekked through mountains and valleys, sometimes cutting back or traveling in circles to avoid German patrols, living in the open or sheltering in villages and sharing cornbread with peasants. The Americans were soon listed as missing in action, and War Department telegrams, beginning regret to inform you, were sent to their families back home.
The survivors, meantime, carried Sergeant Shumway on a stretcher made of seats from the plane; they later found pack animals for him. After five days, they rested at a partisan-controlled town called Berat, where they were cheered, mistaken for the vanguard of an Allied invasion to liberate Albania. They also met other partisan leaders, and learned of a British agent who had recently parachuted into the country. Their respite lasted only a few days. Then, they awoke to gunfire and the explosion of artillery shells as German forces entered the town. In the ensuing confusion, German planes strafed a truck carrying some of the escaping Americans. Three nurses were separated from the main group and left behind in Berat; they took refuge in a farmhouse, and remained in hiding in the area for four months. The main group of Americans climbed on foot to a mountain village and were caught in a crossfire between partisan groups. It was the first time the Americans had heard of the rival group, and they were beginning to realize they were in as much danger from the country’s internal battle as they were from the Germans, Ms. Lineberry wrote in The Secret Rescue. They encountered other perils. Some of the blankets offered to them to ward off the cold night air were infested with fleas and lice, the author wrote. Since they’d crashed, most of them had been unable to bathe, aside from splashing some water on their faces and arms from mountain streams or an occasional basin, and they were all filthy and now battling fleas, lice and the GIs, Army slang for diarrhea. The Americans were often unable to find food. Facing starvation, they made tea by boiling straw and ate berries that worsened their diarrhea. Sharing with peasants was sometimes a culture shock. Mr. Hayes and another medic saw a sheep’s head roasted over coals, then split in half with an ax. The Americans watched wide-eyed as two women each took one-half of the head and ate everything, including the eyeballs, Ms. Lineberry wrote. Nothing was wasted.
As autumn waned, blizzards enveloped the Americans. Their clothing was too thin. Their shoes were worn out. Though all their feet soon felt like blocks of ice and their bodies shivered, they knew they had to keep going, Ms. Lineberry wrote. The snow was coming down so fast they could barely see the person in front of them, but they had to stay together to avoid losing one another in the blinding white storm. On Nov. 27, British intelligence in Albania learned from partisans that the American plane had crashed and that the nurses, medics and crew were alive, trying to reach the coast. Gen. Dwight D. Eisenhower, the Allied commander in Europe, and President Franklin D. Roosevelt and the families of the missing were told. In December, an American rescue plan was developed, led by an Army captain, Lloyd G. Smith, 24, who was assigned to the Office of Strategic Services, precursor of the Central Intelligence Agency. Under cover of darkness, he slipped onto the heavily guarded Albanian coast by boat and set up a base camp in a cave in the cliffs overlooking the Adriatic. Others joined him, and they moved inland to find the Americans. The British, meantime, organized a second rescue effort under Lt. Gavan Duffy, a secret agent who with a small team had reached Albania months earlier by parachute and on foot. Through partisan contacts, he found the Americans in eastern Albania and began leading them westward, intending to reach the coast. But halfway there, at Gjirokaster, German troops blocked the way, and the Americans were too sick and exhausted to go on. He radioed for an American air rescue. Two C-47 cargo planes flew in with fighter escorts. But the Germans disrupted the landing, and Lieutenant Duffy called it off. The Americans, after the euphoria of nearly being rescued, were crushed. But they resumed their journey, and with American and British help reached the coast. On Jan. 9, after a 63-day ordeal, 27 Americans – 10 nurses and 17 medics and fliers – boarded a British launch and crossed to Italy. Three nurses remained behind in German-occupied Berat. Captain Lloyd Smith brought them to safety in March 1944. They rode pack mules most of the way to the coast and were met by a torpedo boat, which took them across the Adriatic.
Kostaq Stefa was the main Albanian partisan leader, who led the Americans for several weeks. Sadly, when Kostaq returned from helping the Americans, he was tortured for several days by the BK. After the war, communist dictator Enver Hoxha had Stefa executed in 1948. He left behind a widow and five children.
After the war, Mr. Hayes returned to civilian life, attended Iowa State College and became an aeronautical engineer for North American Aviation, designing military planes and conducting studies for the Air Force and the National Aeronautics and Space Administration until he retired in 1984. He married the former Betty Allen in 1944. She and their daughter survive him, as does another daughter, Victoria Sprott; two brothers, Karl and James; a sister, Virginia McCall; two grandsons; and a great-granddaughter. Harold Lyle Hayes was born in Pekin, Iowa, on April 11, 1922, to Ralph and Jenella Van Gorp Hayes. He graduated from high school in Indianola in 1940. After Japan attacked Pearl Harbor on Dec. 7, 1941, he was drafted, volunteered as a medic and by 1943 was in Sicily, flying evacuation missions. When he first returned to Allied lines, he had nightmares of being chased, Ms. Lineberry wrote of Mr. Hayes. Those faded with time, but as was true of many in the group, he rarely talked about his ordeal over the years. Source: The New York Times, by Robert D. McFadden
Trends and Patterns of Disparities in Cancer Mortality Among US Counties, 1980-2014
Cancer is a leading cause of morbidity and mortality in the United States which results in a high economic burden. As a result, a study published in the Journal of the American Medical Association (2017;317(4):388-406), was performed to estimate age-standardized mortality rates by US county from 29 cancers.
For the study, deidentified death records from the National Center for Health Statistics (NCHS) and population counts from the Census Bureau, the NCHS, and the Human Mortality Database from 1980 to 2014 were used. Validated small area estimation models were also used to estimate county-level mortality rates from 29 cancers including: lip and oral cavity; nasopharynx; other pharynx; esophageal; stomach; colon and rectum; liver; gallbladder and biliary; pancreatic; larynx; tracheal, bronchus, and lung; malignant skin melanoma; nonmelanoma skin cancer; breast; cervical; uterine; ovarian; prostate; testicular; kidney; bladder; brain and nervous system; thyroid; mesothelioma; Hodgkin lymphoma; non-Hodgkin lymphoma; multiple myeloma; leukemia; and all other cancers combined.
The main outcome measures were age-standardized cancer mortality rates by county, year, gender, and cancer type. A total of 19,511,910 cancer deaths were recorded in the United States between 1980 and 2014, including 5,656,423 due to tracheal, bronchus, and lung cancer; 2,484,476 due to colon and rectum cancer; 1,573,593 due to breast cancer; 1,077,030 due to prostate cancer; 1,157,878 due to pancreatic cancer; 209,314 due to uterine cancer; 421,628 due to kidney cancer; 487,518 due to liver cancer; 13,927 due to testicular cancer; and 829,396 due to non-Hodgkin lymphoma.
Results showed that cancer mortality decreased by 20.1% between 1980 and 2014, from 240.2 to 192.0 deaths per 100,000 population. However, there were large differences in the mortality rate among counties throughout the period: in 1980, cancer mortality ranged from 130.6/100,000 in Summit County, Colorado, to 386.9/100,000 in North Slope Borough, Alaska, and in 2014 from 70.7 in Summit County, Colorado, to 503.1 in Union County, Florida. For many cancers, there were distinct clusters of counties with especially high mortality. The location of these clusters varied by type of cancer and were spread in different regions of the United States. Clusters of breast cancer were present in the southern belt and along the Mississippi River, while liver cancer was high along the Texas-Mexico border, and clusters of kidney cancer were observed in North and South Dakota and counties in West Virginia, Ohio, Indiana, Louisiana, Oklahoma, Texas, Alaska, and Illinois.
According to the authors, while mortality declined overall in the United States between 1980 and 2014, over this same period, there were important changes in trends, patterns, and differences in cancer mortality among US counties. The authors added that these patterns may inform further research into improving prevention and treatment.
The Cancer Genome Atlas (TCGA) Research Network Study Identifies Genomic Features of Cervical Cancer
Cervical cancer accounts for more than 500,000 new cases of cancer and more than 250,000 deaths each year worldwide. According to NIH, the vast majority of cases of cervical cancer are caused by persistent infection with oncogenic types of HPV, and that effective preventive vaccines against the most oncogenic forms of HPV have been available for a number of years, with vaccination having the long-term potential to reduce the number of cases of cervical cancer.
According to an article published in Nature (23 January 2017), The Cancer Genome Atlas (TCGA) Research Network has identified novel genomic and molecular characteristics of cervical cancer that will aid in the subclassification of the disease and may help target therapies that are most appropriate for each patient. The new study, a comprehensive analysis of the genomes of 178 primary cervical cancers, found that over 70% of the tumors had genomic alterations in either one or both of two important cell signaling pathways. The authors also found, unexpectedly, that a subset of tumors did not show evidence of human papillomavirus (HPV) infection.
According to the authors, unfortunately most women who will develop cervical cancer in the next couple of decades are already beyond the recommended age for vaccination and will not be protected by the vaccine. Therefore, cervical cancer is still a disease in need of effective therapies, and this latest TCGA analysis could help advance efforts to find drugs that target important elements of cervical cancer genomes in addition to the HPV genes.
An aspect of the study that is of particular interest was the identification of a unique set of eight cervical cancers that showed molecular similarities to endometrial cancers. These endometrial-like cancers were mainly HPV-negative, and they all had high frequencies of mutations in the KRAS, ARID1A, and PTEN genes. According to the authors, the identification of HPV-negative endometrial-like tumors confirms that not all cervical cancers are related to HPV infection and that a small percentage of cervical tumors may be due to strictly genetic or other factors.
Because immunotherapies are becoming increasingly important for cancer therapy, the authors examined genes that code for known immune targets to see if any were amplified, which may predict responsiveness to immunotherapy. They found amplification of several such genes, specifically CD274 (which encodes the PD-L1 immune checkpoint protein) and PDCD1LG2 (which encodes the PD-L2 immune checkpoint protein). Several checkpoint inhibitors have been shown to be effective immunotherapeutic agents. In addition, the TCGA analysis identified several novel mutated genes in cervical cancer, including MED1, ERBB3, CASP8, HLA-A, and TGFBR2. The authors also identified several cases with gene fusions involving the gene BCAR4, which produces a long noncoding RNA that has been shown to induce responsiveness to lapatinib, an oral drug that inhibits a key pathway in breast cancer. Therefore, BCAR4 may be a potential therapeutic target for cervical cancers with this alteration.
When analyzing the biology behind the molecular alterations in these tumors, the authors also found that nearly three-quarters of cervical cancers had genomic alterations in either one or both of the PI3K/MAPK and TGF-beta signaling pathways, which may also provide targets for therapy. The authors noted that an important question raised by this study is whether HPV-positive and HPV-negative tumors will respond differently to targeted therapies.
Elevated Levels of Belladonna in Certain Homeopathic Teething Products
Homeopathic teething products have not been evaluated or approved by the FDA for safety or effectiveness. The agency is unaware of any proven health benefit of the products, which are labeled to relieve teething symptoms in children. In September 2016, the FDA warned against the use of these products after receiving adverse event reports.
The FDA has announced that its laboratory analysis found inconsistent amounts of belladonna, a toxic substance, in certain homeopathic teething tablets, sometimes far exceeding the amount claimed on the label. The agency is warning consumers that homeopathic teething tablets containing belladonna pose an unnecessary risk to infants and children and urges consumers not to use these products.
In light of these findings, the FDA contacted Standard Homeopathic Company in Los Angeles, the manufacturer of Hyland’s homeopathic teething products, regarding a recall of its homeopathic teething tablet products labeled as containing belladonna, in order to protect consumers from inconsistent levels of belladonna. At this time, the company has not agreed to conduct a recall. The FDA recommends that consumers stop using these products marketed by Hyland’s immediately and dispose of any in their possession. In November 2016, Raritan Pharmaceuticals (East Brunswick, New Jersey) recalled three belladonna-containing homeopathic products, two of which were marketed by CVS.
According to FDA, consumers should seek medical care immediately if their child experiences seizures, difficulty breathing, lethargy, excessive sleepiness, muscle weakness, skin flushing, constipation, difficulty urinating, or agitation after using homeopathic teething products. The FDA also is encouraging health care professionals and consumers to report adverse events or quality problems experienced with the use of homeopathic teething products to the FDA’s MedWatch Adverse Event Reporting program:
1. Complete and submit the report online at www.fda.gov/medwatch/report.htm; or
2. Download and complete the form, then submit it via fax at 1-800-FDA-0178.
The Rooster Asian New Year Celebration
An online ad for Korean vodka, intrigued me, especially when there was no way to buy it in the U.S. After some research, it turned out two countries stocked it: Korea and Germany. Executive Director of Target Health Inc., Yong Joong Kim was contacted for advice. Luckily, for the newsletter, Y.J. Kim’s wife was heading to Korea for a visit.
Ingredients for two unbelievable vodka (Korean vodka) cocktails
3 jiggers of Korean vodka
1 cup of ruby red Tropicana grapefruit juice
3 jiggers of Frangelico
3 jiggers Ginger liqueur
1 teaspoon Campari in each glass, after all else is poured in
2 Martini picks (1 per glass)
6 Cocktail cherries, 3 on each pick (per glass)
1 Cara Cara orange, 1 circle cut in half, half per glass
2 spears watermelon (1 per glass)
2 spears cantaloupe (optional) – 1 per glass
This particular vodka cocktail is for Absolut Korean vodka only. Korean vodka comes with spices infused: coffee, almond, chili. ©Joyce Hays, Target Health Inc.
Special voyage needed to obtain this special vodka. ©Joyce Hays, Target Health Inc.
In Korea, Mrs Kim is receiving the Korean vodka from her father, who got it from her brother who made the purchase.
Here Mrs. Kim hands her husband, Yong Joong Kim the long sought after special Korean vodka, who brings it to THI in Manhattan and finally to yours truly, who now must come up with an extraordinary recipe saluting Asian Lunar New Year.
Above are the 4 basic alcoholic ingredients needed for this vodka cocktail: Absolut Korean (spiced) vodka, Canton Ginger Liqueur, Frangelico Liqueur, and after the above mixture is shaken with ice & with gusto, 1 teaspoon of Campari is gently dropped on the surface of the drink. I learned this secret from a friendly Italian master bartender, now Maitre D’ ©Joyce Hays, Target Health Inc.
You never want to use those bright red totally chemical cocktail cherries. Instead, shop around for slightly more expensive real cherries in their own syrup or sometimes infused in brandy, cognac or (above) bourbon. ©Joyce Hays, Target Health Inc.
After trying out several brands of juice (orange and grapefruit) plus some bubbly, we settled on the above ruby red with pulp. ©Joyce Hays, Target Health Inc.
Cut your fruit, before you do anything else. Cara cara oranges were used because they have peak flavor right now and because their color is really beautiful, as you can see above. ©Joyce Hays, Target Health Inc.
Here’s a close up of the fruit I ended up using. Three dark cherries on each pick, half a slice of Cara cara, spear of watermelon. ©Joyce Hays, Target Health Inc.
1. Decide what fruit you want to use, then do all the cutting and slicing needed. This is a fun chance to be creative, in the shapes and lengths you make of the fruit.
2. Put all the fruit in each cocktail glass, so you’re free to arrange it any way you want. If you do this after the drink is poured, it’s much harder.
3. In a cocktail shaker, add all the ingredients except for the Campari
4. Shake vigourously.
5. Take cover off shaker and add as many ice cubes as will fit. Shake again with gusto
6. Pour the mixture, through the strainer, into each glass, about 1 inch from the top of the glass rim.
7. Pour a small amount of Campari into a small glass or measuring cup.
8. Place the drink in front of the lucky person about to take a sip. Now dip a teaspoon into the Campari, fill it, and carefully drop the Campari onto the surface of the drink. DO NOT STIR. WAIT until the Campari drops through the rest of the drink and falls to the bottom. There are photos below, that show the remarkable layers of color, this small amount of Campari adds to the already delicious Korean vodka drink
9. Okay, now sip and smile
The Rooster, a Korean vodka cocktail to celebrate the New Year with! We raise our glasses to Mr. and Mrs. Yong Joong Kim. We also raise our glasses to all of our wonderful Asian employees who contribute daily to the feeling of community at THI. ©Joyce Hays, Target Health Inc.
©Joyce Hays, Target Health Inc.
Like part of a rainbow, the color layers are so pretty. ©Joyce Hays, Target Health Inc.
Up close example of the separate layers of color that make a lovely presentation. ©Joyce Hays, Target Health Inc.
Here are the beautiful layers of color easy for you to achieve. ©Joyce Hays, Target Health Inc.
HAPPY NEW YEAR EVERYONE ! ©Joyce Hays, Target Health Inc.
Rice crackers or the Asian mix, above, are especially good with this cocktail. During one experiment with the Rooster, we had Ahi tuna & avocado sticks, which also went well with this drink. ©Joyce Hays, Target Health Inc.
From Our Table to Yours !
January 26, 2017
Lysergic acid diethylamide — more commonly known as ‘LSD’ or simply ‘acid’ — is one of the longest lasting and most potent hallucinogens, but researchers have never understood why LSD’s effects linger for 12 hours or more. The key to the drug’s psychedelic longevity lies in how it fits into receptors in the brain.
Lysergic acid diethylamide — more commonly known as “LSD” or simply “acid” — is one of the longest lasting and most potent hallucinogens, but researchers have never understood why LSD’s effects linger for 12 hours or more. The key to the drug’s psychedelic longevity lies in how it fits into receptors in the brain, as reported in a study appearing January 26 in Cell.
“When I was younger, and The Grateful Dead was still around, I would occasionally go to Grateful Dead concerts. A lot of people took LSD and similar drugs during concerts, and it would be interesting to be in the parking lot hearing people wondering when their LSD experience was going to end,” says Bryan Roth, a professor of pharmacology at University of North Carolina and a senior co-author on the study. “A lot of people who take the drug are not aware of just how long it lasts.”
Scientists from Roth’s lab at UNC captured crystallography images (images showing how a molecule’s atoms are arranged) of an LSD molecule bound to a human serotonin receptor and discovered that the LSD molecule was wedged into the receptor’s binding pocket at an angle no one had expected. On top of that, part of the receptor protein had folded in over the LSD like a lid, sealing the drug inside.
“Once LSD gets in the receptor, a lid comes over the LSD, so it’s basically trapped in the receptor and can’t get out,” says Roth. “LSD takes a really long time to get on the receptor, and then once it gets on, it doesn’t get off,” he added.
This finding explains why LSD trips last for a full day, even though LSD doses are extremely small — the average dose is 100 or so micrograms — and LSD molecules are cleared from the bloodstream in a couple of hours. Given that there has been a tentative resurgence in testing LSD for some medical conditions, understanding the mechanism of its potent and long-lasting actions may help drug developers design more effective psychiatric drugs with fewer side effects, the researchers say.
While speculative, the study’s results may help researchers think about how LSD micro-dosing could work. About 1 in 10 Americans have taken LSD at some point in their life, but increasingly, people are taking LSD at doses too small to cause hallucinations with the goal of boosting their creativity and countering depression. LSD micro-dosing has never been clinically tested, and many scientists have doubted that taking such small amounts of the drug would have any detectable effect. But when Roth’s group exposed live cells in a Petri dish to micro-dose-sized amounts of LSD, those tiny doses of LSD affected the receptors’ signaling. It’s as yet unknown how this signaling would translate into an effect on a person’s mood or perception, although the studies demonstrate LSD’s remarkably potent actions on cellular signaling.
LSD’s ability to fit in and let the receptor’s “lid” close over it depends on the specific chemical structures of both the drug and the receptor. When the team exposed cells with mutant receptors that had floppier lids to LSD, the LSD bound more quickly and also exited the receptor much faster. Those short LSD binding events produced very different signaling patterns than the longer binding events.
“I think it’s important for the pharmaceutical industry to understand that even if you modify just one tiny aspect of any compound, you may affect the way the entire compound sits in the receptor, and that affects the compound’s performance,” says study first author Daniel Wacker, a postdoctoral fellow at UNC.
The researchers stressed that they do not advocate LSD use, as it is an illegal and potentially dangerous drug. However, its potential medical applications, and its enormous impact on pop culture, warrant an understanding of its modes of action and ways in which they can be modified.
A separate study on LSD, published January 26 in Current Biology, found that one of the receptors the team tested plays a role in peoples’ experience of music while on LSD.
This research was supported by the National Institutes of Health, the National Institute of Mental Health, a Terman Faculty Fellowship, and the Michael Hooker Distinguished Chair of Pharmacology.
Materials provided by Cell Press. Note: Content may be edited for style and length.
- Daniel Wacker, Sheng Wang, John D. McCorvy, Robin M. Betz, A.J. Venkatakrishnan, Anat Levit, Katherine Lansu, Zachary L. Schools, Tao Che, David E. Nichols, Brian K. Shoichet, Ron O. Dror, Bryan L. Roth. Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell, 2017; 168 (3): 377 DOI: 10.1016/j.cell.2016.12.033
Source: Cell Press. “Structure of LSD and its receptor explains its potency.” ScienceDaily. ScienceDaily, 26 January 2017. <www.sciencedaily.com/releases/2017/01/170126132541.htm>.
January 25, 2017
Devastating tsunamis could be halted before hitting the Earth’s shoreline by firing deep-ocean sound waves at the oncoming mass of water, new research has proposed.
Devastating tsunamis could be halted before hitting Earth’s shoreline by firing deep-ocean sound waves at the oncoming mass of water, new research has proposed.
Dr Usama Kadri, from Cardiff University’s School of Mathematics, believes that lives could ultimately be saved by using acoustic-gravity waves (AGWs) against tsunamis that are triggered by earthquakes, landslides and other violent geological events.
AGWs are naturally occurring sounds waves that move through the deep ocean at the speed of sound and can travel thousands of metres below the surface.
AGWs can measure tens or even hundreds of kilometres in length and it is thought that certain lifeforms such as plankton, that are unable to swim against a current, rely on the waves to aid their movement, enhancing their ability to find food.
In a paper published in the journal Heliyon, Dr Kadri proposes that if we can find a way to engineer these waves, they can be fired at an incoming tsunami and will react with the wave in such a way that reduces its amplitude, or height, and causes its energy to be dissipated over a large area.
By the time the tsunami reaches the shoreline, Dr Kadri writes, the reduced height of the tsunami would minimise the damage caused to both civilians and the environment.
Dr Kadri also believes that this process of firing AGWs at a tsunami could be repeated continuously until the tsunami is completely dispersed.
“Within the last two decades, tsunamis have been responsible for the loss of almost half a million lives, widespread long-lasting destruction, profound environmental effects and global financial crisis,” Dr Kadri said.
“Up until now, little attention has been paid to trying to mitigate tsunamis and the potential of acoustic-gravity waves remains largely unexplored.”
The devastating tsunami that was generated in the Indian Ocean in 2004 after a magnitude 9 earthquake has been recorded as one of the deadliest natural disasters in recent history after it caused over 230,000 deaths in 14 countries.
The energy released on Earth’s surface by the earthquake and subsequent tsunami was estimated to be the equivalent of over 1,500 times that of the Hiroshima atomic bomb.
In order to use AGWs in tsunami mitigation, engineers will firstly need to devise highly accurate AGW frequency transmitters or modulators, which Dr Kadri concedes would be challenging.
It may also be possible to utilise the AGWs that are naturally generated in the ocean when a violent geological event, such as an earthquake, occurs — essentially using nature’s natural processes against itself.
Indeed, Dr Kadri has already shown that naturally occurring AGWs could be utilised in an early tsunami detection system by placing detection systems in the deep ocean.
Dr Kadri continued: “In practice, generating the appropriate acoustic-gravity waves introduces serious challenges due to the high energy required for an effective interaction with a tsunami. However, this study has provided proof-of-concept that devastating tsunamis could be mitigated by using acoustic-gravity waves to redistribute the huge amounts of energy stored within the wave, potentially saving lives and billions of pounds worth of damage.”
- Usama Kadri. Tsunami mitigation by resonant triad interaction with acoustic–gravity waves. Heliyon, 2017; 3 (1): e00234 DOI: 10.1016/j.heliyon.2017.e00234
Source: Cardiff University. “Novel mechanism to stop tsunamis in their tracks proposed.” ScienceDaily. ScienceDaily, 25 January 2017. <www.sciencedaily.com/releases/2017/01/170125093743.htm>.