#New finding offers clues for blocking cancer gene A new study suggests a potential new way to block one of the most common cancer-causing genes, without causing severe side effects.
The Notch gene plays a role in many types of cancer. It's the most common cancer-causing gene in T-cell acute lymphoblastic leukemia.
About 60 percent of children and adults with T-cell leukemia harbor a Notch mutation. But drugs designed to block Notch have caused serious side effects such as severe diarrhea or skin cancers.
Now a team from the University of Michigan Comprehensive Cancer Center offers a potential new target to block Notch without the toxic effects.
Researchers found that a protein called Zmiz1 sticks to Notch triggering the gene to turn on its cancer function.
But Zmiz1 does not impact normal healthy Notch functions.""Notch controls the genes that cause cancer,
but it's also important for normal health. The challenge is to knock out the cancer function of Notch
but preserve its normal function,"says Mark Chiang, M d.,Ph d.,assistant professor of internal medicine at the University of Michigan Medical school."
"If you unstick Zmiz1 from Notch, the cancer cells die. And Zmiz1 seems to be selective in turning on the cancer functions of Notch,
"Chiang adds. The researchers found mice lived longer when Zmiz1 was deleted. The mice had normal body weight and no severe side effects from blocking Zmiz1.
Results of the study are published online in the journal Immunity.""Our goal is to develop a drug to sit right between Notch
We think this would block the Notch cancer pathway without causing toxic side effects, like we see with current Notch inhibitors,
While the majority of kids with T-cell leukemia are cured, about 20 percent will relapse. Those kids face a grim prognosis.
To date, no targeted therapies exist for these kids.""We need to develop therapies against Notch to help kids with relapsed cancer
and to cure kids with fewer toxicities or long-term effects, "Chiang says.""Our current treatments may often be curative,
but there can be a huge price to pay in late effects.""More research is needed before getting to this point with patients.
The most common approach is to make a sandwich of a"primary"antibody specific for a certain protein on a cell
and a"secondary"antibody connected to fluorophores. But if a protein is expressed at a low level,
In those cases, many fluorophores are attached to the secondary antibody to amplify the signal. However, there's a limit to that strategy
The bottlebrush structure could then serve as a new type of secondary antibody that could bind to thousands of fluorophores,
the brushes also could someday deliver cancer therapeutics s
#Researchers want to turn acid-loving microbes into safe drug-carriers Usually the microbe S. islandicus is found in hot and acidic volcanic springs,
This is relevant for different drugs as growth hormones, vaccines and insulin. Many diabetics need to daily inject insulin directly into their body,
and they would benefit greatly by taking insulin in a tablet instead. Not only is it easier to take a tablet than inject;
vaccines, etc. What did the researchers do in the lab? S. islandicus was grown for four days at 75 degrees Celsius.
they chose the most complex one known, Down syndrome cell adhesion molecule 1 (Dscam1), which controls the wiring of the brain in fruit flies.
#Researcher develops vaccine for fatal disease Over 200 million people in 74 countries suffer from schistosomiasis
and four times that many are at risk for the disease since they do not have access to clean water.
A recent discovery in the Texas Tech University Health Sciences Center (TTUHSC) research laboratory may make it possible to reduce the number of infections from this disease.
Afzal A. Siddiqui, Ph d.,has tested his new vaccine in animals and is now planning human trials.
Siddiqui, a Grover E. Murray Distinguished Professor at the TTUHSC School of medicine, received a patent from the U s. Patent and Trademark Office for his schistosomiasis vaccine.
The vaccine""Schistoshield"potentially can impact up to one billion people. The Bill & Melinda Gates Foundation and the National institutes of health have supported Siddiqui's research."
"We worked to get the patent to deter others from making money off this vaccine,
"This way, it can be made for $1 per vaccination and distributed to those in need.
An effective schistosomiasis vaccine has the potential to impact one billion people.""Praziquantel, a drug developed over 40 years ago,
is the only effective treatment available for schistosomiasis. However, re-infection frequently occurs following drug treatment.
An effective vaccine is critical toward providing long-term treatment. This schistosomiasis vaccine offers unique opportunities for organizations to market it as a method for completely eliminating this disease.
The vaccine's advantages make it easy to sell because it eliminates the instances of re-infection common with the current chemotherapeutic drug,
is easier and less expensive to distribute and can be administered with current chemotherapy regimen. Long-term vaccine efficacy will effectively reduce the transmission of schistosomiasis in endemic areas.
According to the World health organization there are no commercially available vaccines against schistosomiasis, which afflicts people in countries primarily in Asia, Africa and South america.
Symptomatic schistosomiasis can result in increased susceptibility to sexually transmitted infections including HIV, which is prevalent in many countries plagued by schistosomiasis.
A person gets a schistosoma infection through contact with contaminated water. The parasite swims freely in open bodies of water.
Once contact is made with humans, the parasite burrows into the skin, matures into another stage,
and then migrates to the lungs and liver, where it matures into the adult form.
Siddiqui said detection of calcified schistosome eggs in Egyptian mummies from the 20th dynasty (1250 to1000 BC) tells us that schistosomiasis is an ancient disease."
"Major pathology of schistosomiasis is due to immunological reactions to schistosome eggs trapped in tissues, "Siddiqui said."
"Continuing infection causes enlargement of the liver and blood in urine. We see pictures of children from Africa with bulging bellies because of this disease."
"Despite mass treatment with drugs, infection rates continue to rise. An additional 800 million people are at risk of contracting schistosomiasis.
Durable and sustained reduction in the disease spectrum and transmission can only be obtained by long-term protection through vaccination.
Siddiqui has studied schistosomiasis for over 20 years working to develop this vaccine n
#Three-minute test detects common form of dementia that's hard to diagnose Although Lewy Body disease (LBD) is the second-most-common degenerative disease after Alzheimer's disease,
it's not exactly a household name. It affects more than 1. 3 million Americans, is recognized poorly,
and diagnosis is delayed often significantly. Patients with LBD simultaneously experience losses in cognitive function, mobility and behavior.
The late Robin williams had this form of dementia as did legendary NHL coach Alger Joseph"Radar"Arbour,
which also can cause visual hallucinations and make depression worse. Until now, there has been no way to assess or operationalize many of the cognitive and behavioral symptoms of LBD in clinical practice.
A leading neuroscientist at Florida Atlantic University has developed the"Lewy Body Composite Risk Score"(LBCRS) to quickly
and effectively diagnose LBD and Parkinson's disease dementia (PDD) in about three minutes. The LBCRS is a brief rating scale that can be completed by a clinician to assess clinical signs
and symptoms highly associated with the pathology of this disease. With this important tool, a clinician can assess
whether the patient has bradykinesia, rigidity, postural instability, or rest tremor without having to grade each extremity.
This simple, one-page survey provides structured yes/no questions for six non-motor features that are present in patients with LBD
but are much less commonly found in other forms of dementia. The LBCRS study,"Improving the Clinical Detection of Lewy Body Dementia with the Lewy Body Composite Risk Score,
"recently published in Alzheimer's & Dementia, the journal of the Alzheimer's Association, involved 256 patients who were compared with the clinical dementia rating
and gold standard measures of cognition, motor symptoms, function and behavior. The test was administered in a"real-world"clinic setting with patients who were referred from the community rather than in a research sample.
The clinic sample had a mixture of gender education, comorbidities, behavioral, affective, motor symptoms, and diagnoses.
The LBCRS was able to discriminate between Alzheimer's disease and LBD with 96.8 percent accuracy, and provided sensitivity of 90 percent and specificity of 87 percent.
For the study, caregivers completed evaluations to determine the presence and severity of non-cognitive symptoms observed in the patient and their impact on the caregiver.
Each patient was administered a 30-minute test battery at the time of the office visit to assess their cognitive status. The LBCRS was completed after all other rating scales were scored
and the diagnosis was presented to the patient and family.""Most patients never receive an evaluation by a neurologist skilled in the diagnosis of Lewy body dementia,
and significant delays and misdiagnoses occur in most patients with this disease, "said James E. Galvin, M d.,M p h,
. one of the most prominent neuroscientists in the country who developed the LBCRS, and a professor of clinical biomedical science in FAU's Charles E. Schmidt College of Medicine and a professor in FAU's Christine E. Lynn College of Nursing."
"This new tool has the potential to provide a clearer, more accurate picture for those patients who are unable to be seen by specialists,
hastening the correct diagnosis and reducing the strain and burden placed on patients and caregivers."
"Another important aspect of the LBCRS is its ability to improve the sensitivity of diagnosis,
The survey also increases the potential opportunity to receive appropriate symptomatic therapies in a timely fashion,
"Early detection of Lewy body dementias will be important to enable future interventions at the earliest stages
and differentiate LBD from healthy aging and other neurodegenerative diseases. Galvin has led efforts to develop a number of dementia screening tools,
including the Quick Dementia Rating system (QDRS), AD8, a brief informant interview to translate research findings to community settings.
He has done cross-cultural validation of dementia screening methods in comparison with Gold standard clinical evaluations and biomarker assays.
His team also has developed sophisticated statistical models to explore transition points in clinical cognitive, functional, behavioral and biological markers of disease in healthy aging, mild cognitive impairment, Alzheimer disease,
and Parkinson's disease e
#A molecular switch to stop inflammation Our immune system is vital to us and can sometimes overreact causing chronic illnesses,
such as for instance rheumatism and allergy. Now, researchers from Umeå University and University of Gothenburg have identified a molecular switch-MYSM1-that can suppress such an overreaction
and avoid inflammation. The study is published in the prestigious journal Immunity.""The discovery of MYSM1 is a major milestone in our understanding of how our immune system works,
and how its response could be controlled in order to prevent inflammatory diseases such as sepsis, "says Nelson O. Gekara,
research leader at MIMS, Molecular Infection Medicine Sweden at Umeå University. Our innate immune system is activated
when our body needs to protect itself against pathogens, for instance bacteria and viruses, as well as for tissue healing.
In some people, the immune system overreacts which can cause chronic inflammatory diseases and result in tumour development.
The innate immune system is activated by receptors that recognise certain molecular patterns found on microbes or dead cells.
Together with Professor Jonas A Nilsson at Sahlgrenska Cancer Center at the University of Gothenburg
For the first time, the researchers are now able to show that during infection or inflammation MYSM1 accumulates outside of the nucleus,
Therefore lack of MYSM1 in animal results in unrestrained activation of the innate immune system, leading to inflammatory diseases"says Nelson O. Gekara.
The hope is to find new therapeutics against infections and other inflammatory diseases e
#Study charts'genomic biography'of form of leukemia A new study by scientists at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard offers a glimpse of the wealth of information
that can be gleaned by combing the genome of a large collection of leukemia tissue samples. By analyzing genetic material in chronic lymphocytic leukemia (CLL) and normal tissue from more than 500 patients,
researchers identified dozens of genetic abnormalities that may drive the disease, including two that had never before been linked to human cancer.
They began to trace how some of these abnormalities affect the course of the disease and its susceptibility to treatment.
And they started tracking the evolutionary path of CLL as its ever-churning genome spawns new groups and subgroups of tumor cells in a single patient.
This type of information is critical as the treatment of CLL is geared increasingly to the unique genetic features of each patient's tumor.
Traditional chemotherapy regimens are now being supplemented by drugs that target the specific set of delinquent genes within cancer cells."
"Sequencing the DNA of CLL has taught us a great deal about the genetic basis of the disease,
"said Catherine Wu, MD, of Dana-Farber, the Broad Institute of MIT and Harvard, and Brigham and Women's Hospital, a senior author of the study, which is being published today by the journal Nature."
"Previous studies, however, were limited by the relatively small number of tumor tissue samples analyzed, and by the fact that those samples were taken at different stages of the treatment process,
from patients treated with different drug agents.""In our new study, we wanted to determine
similarly-treated group of patients provides the statistical power necessary to study the disease in all its genetic diversity-to draw connections between certain mutations and the aggressiveness of the disease,
and their role in helping the disease advance, "she continued.""Our results demonstrate the range of insights to be gained by this approach.""
and Brigham and Women's Hospital, a first author of the study.""The growing sample size allows us to start engaging deeply with the complex interplay between different mutations found in any individual tumor,
as well as reconstructs the evolutionary trajectories in which these mutations are acquired to allow the malignancy to thrive and overcome therapy."
"Wu and her team collected tumor and normal tissue samples from 538 patients with CLL, 278 of
whom had participated in a German clinical trial that helped determine the standard treatment for the disease.
They performed whole-exome sequencing (WES) on each sample, reading the genetic code letter by letter in sections of DNA that hold the code for making proteins.
and analyze large cohorts of tumor tissue samples with defined clinical status, "remarked Gad Getz, Phd, of the Broad Institute and Massachusetts General Hospital, co-senior author of the paper."
"Our work has enabled us to discover novel cancer genes, begin to chart the evolutionary path of CLL,
and demonstrate specific mutations affect patients'response to therapy. These discoveries will form the basis for precision medicine of CLL and other tumor types
#Massive screen of drug combinations may find treatment for resistant, BRAF-mutant melanoma A team of Massachusetts General Hospital (MGH) investigators has discovered a new combination of drugs that may be effective against one of the deadliest cancers, malignant melanoma.
The combination-pairing a drug targeted against mutations in the BRAF gene with a second drug that targets another important signaling pathway-was discovered through one of the largest screens of cancer drug combinations conducted to date.
Findings from the study conducted at the MGH Cutaneous Biology Research center and Center for Molecular Therapeutics have been published in the open-access journal PLOS ONE."
"We wanted to see whether very-large-scale screening across a diverse collection of cancer cell lines and a large number of drugs could yield new combinations for patients with cancer,
"says Adam Friedman, MD, Phd, of the CBRC and the MGH Cancer Center, who led the study."
"By conducting such a screen, we found one specific combination of agents that are already being used clinically that potentially could be used for a specific group of patients-those with BRAF-mutant cancers."
"Friedman notes that, even with the increasing number of drugs targeting specific molecular abnormalities that drive tumor growth,
most patients are treated only with one such drug at a time. Most of those treated with targeted-therapy drugs will relapse within a year,
often because their tumors have become resistant, and some tumors never respond to the targeted drugs.
While combining anticancer drugs appears a promising strategy, the sheer volume of drugs currently in use or in development-more than 500,
which could make up more than 100,000 two-drug combinations-makes testing each potential combination in clinical trials challenging.
This study utilized 36 well-characterized melanoma cell lines assembled by the MGH Center for Molecular Therapeutics to test all possible combinations of more than 100 oncology drugs,
looking for effects on the number and viability of tumor cells. While several combinations showed synergistic effects-with some drugs sensitizing the cells against several other drugs-most combinations increased the response of only one or two cell lines
implying that the vulnerability of an individual patient's tumor to these combinations depends on its unique genetic signature.
had synergistic effects against cell lines that were resistant to treatment with vemurafenib alone but not those sensitive to single-agent therapy.
and found significant synergistic effects against both tumor models.""We need to confirm this synergistic activity of vemurafenib
and cediranib across a broader range of melanoma models, investigate why the particular combination is effective,
and find biomarkers that predict which patients with BRAF-mutant melanoma should receive this combination,
who is a research fellow in Dermatology at Harvard Medical school.""What is really exciting is that these drugs are already in the clinic;
in fact a clinical trial for a similar combination is already underway at another research center. We may be able to quickly improve on the selection criteria for this trial
and identify patients whose tumors might respond.""He adds, "This study was actually a pilot project for a much larger effort within the Center for Molecular Therapeutics to map responses against drug combinations across hundreds of cancer cell lines, not just melanoma,
and look for novel combinations that will benefit subsets of patients regardless of the particular type of tumor they have.
Since our collection of cell lines is annotated completely genetically -which means that mutations and expression changes in each line's genes have been documented-we should be able to identify in advance patients who will benefit from specific combinations.
and do not in others is one of the top goals of oncology, and also one of the oldest. 126 years ago, The british physician, Stephen Paget, formulated his'seed and soil theory,
'In recent years, Héctor Peinado, Head of the Microenvironment and Metastasis Group at the Spanish National Cancer Research Centre (CNIO), David Lyden from Weill Cornell Medical College,
and Jaqueline Bromberg from the Memorial Sloan Kettering Cancer Center, have developed a theory that supports Paget's'seed
and pancreas cancer to the liver--metastasis is reduced in these organs. LAYING THE GROUNDWORK The researchers have discovered also the molecular signals that intercede in the reaction of the recipient tissue
inflammation is associated a process with cancer. These results represent the identification of potential new pharmacological targets,
"The study was performed using human and mouse tumour cell lines, preclinical mouse models, as well as plasma from cancer patients.
The latter served for the preliminary study of the predictive power of the integrins identified, that is,
and pancreas cancer seems to predict the organ where the metastasis will occur, "says Peinado."
which involves obtaining multiple cellular and preclinical models, as well as human samples. The search for these models has been carried out over the last three years with the participation of many teams,
and quickly develop tumors. The new work, published the week of November 2, 2015 in PNAS, suggests that Epha2 could be a new target for a subset of lung cancer,
and is the leading cause of cancer-related deaths worldwide.""Sometimes there are hundreds of mutations in the genes of a patient's tumors,
but you don't know whether they are drivers of the disease or byproducts,"says senior author Inder Verma, professor of genetics and holder of Salk's Irwin and Joan Jacobs Chair in Exemplary Life science."
"We found a new way by which to identify cancer suppressor genes and understand how they could be targeted for therapies."
"Two gene mutations in particular are known to spur the growth of human tumors: KRAS and p53. Though both genes have been studied heavily,
they are difficult to therapeutically target, so the Salk team decided to look at genes that might police KRAS and p53 instead.
The researchers narrowed in on the 4, 700 genes in the human genome related to cellular signaling--specifically,
and efficiently test the effect of these thousands of genes on tumor development. In animal models, the Salk team found that 16 of these cell-signaling genes produced molecules that had a significant effect on KRAS-and p53-related tumors.
Of these 16 molecules one especially stood out: the Epha2 enzyme, originally discovered in the lab of another Salk scientist, Tony Hunter.
but the team discovered that its absence let KRAS-associated tumors grow much more aggressively."
"With a mutation in KRAS, a tumor forms in 300 days. But without Epha2, the KRAS mutation leads to tumors in half the time, 120 to 150 days,"says Verma,
who is also an American Cancer Society Professor of Molecular biology.""This molecule Epha2 is having a huge effect on restraining cancer growth
when KRAS is mutated.""Mutated KRAS is a common culprit in approximately 10 to 20 percent of all cancers, particularly colon cancer and human lung cancer."
"Since activating Epha2 led to the suppression of both cell signaling and cell proliferation, we believe that the enzyme might serve as a potential drug target in KRAS-dependent lung adenocarcinoma,
"says Narayana Yeddula, a Salk research associate and first author of the paper. A 10-year national project called the Cancer Genome Atlas mapped the genomes of hundreds of patients for over 20 different cancers
and uncovered a number of related genetic mutations, though the role of these mutations has not been understood well in lung cancer (especially adenocarcinoma,
which makes up almost a quarter of all lung cancers). From the Cancer Genome Atlas data, the Salk team found that genetic alterations of Epha2 were detected in 54 out of 230 patients with adenocarcinoma.
The team also found, surprisingly, that the loss of Epha2 activated a pathway commonly associated with cancer (dubbed Hedgehog) that promotes tumor growth."
"Oddly, among human lung cancer patients with Epha2 mutations, around 8 percent of patients actually have high Epha2 expression.
So, in some instances, Epha2 is not suppressing tumors and may be context-dependent. Therefore, we need to carefully evaluate the molecule's function
when designing new therapeutics,"adds Yifeng Xia, a Salk staff researcher involved in the work k
#Cancer cells use secret tunnels to communicate and smuggle cancer signals their neighbors A new discovery published in the Nov. 2015 issue of The FASEB Journal shows that cancer cells use previously unknown channels to communicate with one another and with adjacent non-cancerous cells.
Not only does this cast an important light on how cancer metastasizes and recruits cellular material from healthy cells,
but it also suggests that these physical channels might be exploitable to deliver drug therapies."
"I hope that the tools we have developed, especially the mouse model, will be used by academics to isolate healthy cells modified by tumors,
and by the pharmaceutical industry in the quest for novel anticancer drugs that block tumor-organ communication,
"said Anne Burtey, Ph d.,study author from the Department of Biomedicine, at the University of Bergen in Bergen, Norway."
"I also hope the knowledge we provide here is paving the way to engineer'super-spreading'agents,
with increased abilities to diffuse within tumors and even reach the healthy cells involved in tumor progression."
"To make this discovery, Burtey and colleagues studied the exchange of molecules between cells, by color-coding them with red or blue cellular fluorescent'dyes'or'tags.'
suggesting that this protein is a key regulator of cell-cell communication in cancer. Live cell imaging confirmed that the transfer is contact-dependent.
or use them to deliver lifesaving therapies
#New research opens door to understanding human tonsil cancer Researchers at Simon Fraser University and the BC Cancer Agency have developed a groundbreaking method to identify
and separate stem cells that reside in the tonsils. Their research, which sheds new light on the fight against oral cancer, is published today in the journal Stem Cell Reports.
While stem cells in many other body tissues have been studied well, little is known about these stem cells,
says researcher Catherine Kang, a Phd student in the Department of Biomedical Physiology and Kinesiology and lead author of the paper.
Ninety per cent of human tonsil cancers show evidence of HPV (human papillomavirus) infection. But little is known about its role in causing these cancers.
Researchers suspect it is a key player, as HPV is the major risk factor for cervical cancer.
Kang, who is working with BPK professor Miriam Rosin, director of the BC Oral Cancer Prevention Program,
and UBC professor Connie Eaves of the Terry Fox Laboratory, was interested in finding out why the tonsil is particularly susceptible to HPV
and wondered if it might have something to do with the stem cells of the tissue that coats the tonsils.
and made them incorporate a cancer-causing gene normally transmitted by HPV, the cells grew abnormally in a special tissue culture system,
and created what one might imagine what the beginning stages of human tonsil cancer would look like."
as it is the first stage of human cancer development that researchers need to learn how to detect
Cancer of oropharynx, or the tonsils in particular, is an important health concern with rising incidence worldwide, especially in men.
The researchers, including Dr. Raj Kannan of the BC Cancer Agency's Terry Fox Laboratory,
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