Scientists have described a correlation between a key melanoma signaling pathway and a novel class of drugs being tested in the clinic as adjuvant therapy for advanced melanoma, providing useful information for a more effective use of this type of treatment.
About two years ago, scientists discovered that a certain class of receptors is capable of perceiving mechanical stimuli. Now they have begun to unravel the molecular mechanisms behind the discovery.
Cells produce insulin, for example, or generate antibodies. To perform these functions, cells need to produce large quantities of proteins. For this purpose, these cells activate a program, the unfolded protein response (UPR). Errors in the UPR are thought to play a decisive role in the development of diseases such as diabetes or cancer. A research team has now discovered a previously unknown mechanism that controls activation of the UPR.
Researchers investigating why some people suffer from motor disabilities report they may have dialed back evolution’s clock a few ticks by blocking molecular pruning of sophisticated brain-to-limb nerve connections in maturing mice.
For the first time, researchers reveal components of a G protein-coupled receptor (GPCR) named rhodopsin bound to a signaling molecule called arrestin, both crucial pieces of the body’s intricate cellular communication network. The new discovery further refines a landmark 2015 Nature article that first described the structure of the two molecules in complex together.
Engineers have found that an existing human protein is an ideal carrier for powerful molecules that can signal tumors to self-destruct.
New research provides insight into how changes that occur with age may predispose breast tissue cells to becoming cancerous. Specifically, the study demonstrates that regions in the genome where DNA methylation changes occur with age are particularly sensitive to disruption in cancer. This new data provides insight into how certain molecular changes with age in normal breast tissue itself may contribute to breast cancer risk.
A fast and practical molecular-scale imaging technique has been developed that could let scientists view never-before-seen dynamics of biological processes involved in neurodegenerative diseases such as Alzheimer’s disease and multiple sclerosis.
Researchers from the University of Copenhagen (Denmark), led by the Spanish researcher Guillermo Montoya, have discovered how Cpf1, a new molecular scissors unzip and cleave DNA. This member of the CRISPR-Cas family displays a high accuracy, capable of acting like a GPS in order to identify its destination within the intricate map of the genome. The high precision of Cpf1 will improve the use of this type of technology in repairing genetic damage and in other medical and biotechnological applications.
A scientific team from in the Novo Nordisk Foundation Center for Protein Research (NNF-CPR), at the University of Copenhagen, has succeeded in visualizing and describing how a new system for genome editing, known as Cpf1, works. This protein belongs to the Cas family and enables the cleavage of double stranded DNA, thus allowing the initiation of the genome modification process. The results of the study have been published in the journal Nature.
Guillermo Montoya, a researcher in the fields of biochemistry and molecular biology who led the study, explains that the new molecular scissors “will enable us to more safely modify and edit the instructions written in the genome, due to the utmost precision of the target DNA sequence recognition.”
The CRISPR Cas9 system for cutting and paste genome sequences is already being used to modify animal and plant genomes. Also to treat illnesses, such as cancer and retinal diseases, in humans and its applications are growing very fast.
X-Ray Crystallography Technique
Researchers across the world are trying to perfect this genome editing technique with the aim of making it yet more precise and efficient. To achieve this, they have also focused on other proteins that specifically cut DNA, such as Cpf1, whose manipulation can direct them to specific locations in the genome. Montoya’s team has achieved this using an X-ray Crystallography to decipher the molecular mechanisms controlling this process.
“We radiated the crystals of the Cpf1 protein using X-rays to be able to observe its structure at atomic resolution, enabling us to see all its components,” points out the co-author of this study. “X-ray diffraction is one of the main biophysical techniques used to elucidate biomolecular structures,” he continues.
In his opinion, “the main advantage of Cpf1 lies in its high specificity and the cleaving mode of the DNA, since it is possible to create staggered ends with the new molecular scissors, instead of blunt-ended breaks as is the case with Cas9, which facilitates the insertion of a DNA sequence.”
“The high precision of this protein recognising the DNA sequence on which it is going to act functions like a GPS, directing the Cpf1 system within the intricate map of the genome to identify its destination. In comparison with other proteins used for this purpose, it is also very versatile and easy to be reprogrammed,” Montoya adds.
Genetic diseases and tumours
These properties make this system “particularly suitable for its use in the treatment of genetic diseases and tumours,” he affirms.
The team has previously worked with the French biotechnology company Celletics on the use of meganucleases -other proteins that can be redesigned to cut the genome in a specific location- to treat certain types of leukemia.
The new technology “can also be used to modify microorganisms, with the aim of synthesising the metabolites required in the production of drugs and biofuels,” adds Montoya.
This researcher, from Getxo (Biscay, Spain), says that there are many companies interested in this new technology. They are mostly from the biotechnology sector in the field of microorganism manipulation, but cannot be named due to confidentiality agreements.
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Based on a new molecular study of tissues biopsied from various parts of the upper digestive tract, researchers at Georgetown Lombardi Comprehensive Cancer Center have identified significant, if subtle, differences in gene mutations and other factors that could help in developing more tailored treatment options for cancer patients. This finding is notable because as the digestive tract winds its way down from the mouth to the rectum, a continuum of cancers can arise, each of which may be amenable to precision treatment.
In this study, the researchers focused primarily on small bowel adenocarcinomas (SBAs) and compared them with parts of the upper digestive tract that precede it and follow it — the gastroesophageal area and right-sided colon cancers, respectively. Each section of the gastrointestinal, or GI, tract plays a role in digestion of food and hence has distinct structural as well as molecular differences. The finding will be presented June 30, 2017, at the European Society for Medical Oncology gastrointestinal meeting in Barcelona, Spain.
“Our study was undertaken primarily because SBAs are greatly understudied, as well as increasing in incidence nationwide, and we wanted to determine what may make them unique,” says Mohamed E. Salem, MD, assistant professor of medicine at Georgetown Lombardi, and principal investigator for the study. “We really didn’t have good data on SBAs so we’ve been treating the tumors as if they were colon cancers and we really need to start treating them based on their unique properties.”
The investigators looked at 4,278 tumor samples from a tissue repository of patients with GI tract cancers. The researchers were able to clearly identify 531 SBAs; 2,674 gastroesophageal cancers; and 1,073 ride-sided colon cancers. Using a variety of genetic sequencing techniques, they ascertained how well the genes were expressed, or “turned on” to make proteins. They also calculated what is called the tumor mutational load, or TML, which can be a marker for how responsive a tumor is to immunotherapy — which, paradoxically, could indicate that immunotherapy more effective when a higher TML is found.
The researchers found a set of frequently mutated genes in SBAs that could be helpful to clinicians when they are looking to use targeted therapies that work best in cancers with specifics mutations. In this case, KRAS, BRAF, BRCA2 and a few other genes were identified in SBAs. Mutations to these genes can affect the choice of therapy as well as how to better target the mutations.
Next, the investigators compared the SBA mutations with mutations in the two other parts of the GI tract and found higher and lower mutation frequencies across a wide array of genes. They were able to discern that SBAs were more like colon than gastric cancers.
More importantly, though, they found about a two-fold higher PD-L1 expression level for gastroesophageal cancers compared to right-side colon cancers but did not find such a marked difference between those tumors and SBAs. PD-L1 is often used as a marker to indicate if a cancer might be responsive to immunotherapy, and usually the higher the PD-L1 level, the more responsive a cancer would be to certain immunotherapies.
“With this study we now have what I think is one of the biggest datasets on SBAs,” says Salem. “Previously, investigators studying the colon found very unique differences between the left and ride sides, and our study therefore took advantage of those findings by exploring the differences between ride-sided colon cancers and SBAs. We now see a continuum of molecular changes that occur as these regions of the digestive tract transition from one area to the other.”
The next step, says Salem, will be to try to correlate these findings with patient treatment outcomes, initially as a retrospective, or backward looking study, and then hopefully design a forward looking clinical trial to determine which treatments may be best for patients with SBAs.