Cancer DNA: The New Frontier for Preventing and Curing Cancer

By Jesica Levingston Mac Leod, PhD

 

DNA Biomarkers are the hot topic in oncology right now, and the more precise, easy and effective they may be to detect cancer, the better.  This cutting edge technique has its origins in the discovery that fetuses shed fragments of DNA into the bloodstreams of the mothers, so do normal and cancer cells. The strategy to search for the most accurate “bar code” for each type of cancer is been approach from a bunch of oncologists around the world.

Researchers from the National Cancer institute, MD, published this month in the Lancet, a correlative biomarker study for lymphoma. In the study publish by Roschewski and col., they detected circulating tumor DNA encoding the clonal immunoglobulin gene sequence (VDJ) in the serum of patients with diffuse large-B-cell lymphoma. The VDJ immunoglobulin genes contain unique sequences that are markers of clonality. Malignant cell VDJ gene sequences could be detected in the serum of patients with diffuse large B-cell lymphoma and used to predict clinical disease recurrence after treatment. For this, they used next-generation DNA sequencing to analyze cell-free circulating tumor DNA in patients assigned to one of three different treatment protocols during a period of 20 years. They concluded that “Surveillance circulating tumor DNA identifies patients at risk of recurrence before clinical evidence of disease in most patients and results in a reduced disease burden at relapse. Interim circulating tumor DNA is a promising biomarker to identify patients at high risk of treatment failure.”

Earlier this year, Hyman and col., reported the analysis of a biomarker (the mutant BRAF(V600E)) in 2 systemic histiocytic disorders characterized by accumulation and infiltration of histiocytes in multiple tissues of the body, leading to organ compromise. These researchers from Memorial Sloan Kettering Cancer Center, New York, showed that in plasma and urinary samples cell free DNA provides a reliable method to detect the mutation that is a biomarker for these disorders, and it can monitor response to therapy in these disorders.

In Australia, the group of doctors  Tie, Cosgrove and col., identified and validated 3 protein-based biomarkers in independent cohorts of colorectal cancer (n = 145 and n = 197), which could be translated to a reliable, non-invasive blood-based screening test. The biomarker “winners” were selected by Elisa kits, and they are the following proteins: Insulin like growth factor binding protein 2 (IGFBP2), Dickkopf-3 (DKK3), and Pyruvate kinase M2(PKM2). (3) Anyways, this article is bout DNA markers: So, in a follow up study Tie and col. detected circulating tumor DNA in a high proportion of treatment naïve metastatic colorectal cancer patients. Moreover, they described that early changes in circulating tumor DNA during first-line chemotherapy predict the later radiologic response.  On other notes, they also reported that the intake of aspirin is not associated with improvements in survival in colon cancer patients, yeah, bad news for the daily aspirin takers.

Studying the blood samples of healthy elders (“wellderlies”, adults age 80 plus), the team lead by doctor Eric Topol, at the SCRIP center, is trying to find the immune response that attacked and effectively destroyed cancer cells. There is a high probability that these healthy elders had had abnormal cell/cells in their bodies at some point of their lives, which they attacked and destroyed, generating immune memory and powerful anti-cancer antibodies. In fact, a member of the team, Doctor Brunie Felding, had discovered that one of the proteins recognized by “wellderly” antibodies was Apolipoprotein E, suggesting that antibodies against this protein may help develop a targeted therapy against highly-expressing ApolipoproteinE cancers.

These new discoveries, plus the recently  FDA approval of three new immuno-oncology therapy drugs, called PD-1 inhibitors,  are bright examples of the importance of cancer research funding and support from the public to the government officers.

One of the most influential bioinformaticians/molecular biologists, Dr. George Church, genetics professor at Harvard, thinks that “the DNA is the ultimate computer code and we are all computer programmers”. Therefore, the study of the DNA fragments can help to solve multiple problems… it is working for cancer therapy, and it could be useful to treat even the most common disease: aging.

Fasting Can Make You Healthier

 

By Jesica Levingston Mac leod, PhD

Believe it or not, breakthrough new research has shown that fasting could be good for you. The article was indeed featured in the Nature journal and the impact of this study relies on the conclusion that fasting promotes haematopoietic stem cell (HSC) function. Stem cells are good for you because they can differentiate into specialized cells and can divide to produce more stem cells.

I personally challenged myself by fasting during Ramadan. .Ramadan is one of the pillars of the Muslim religion. It consists of fasting during a month from sunrise to sunset in order to reflect the essence of piety and to be aware of the plight of the underprivileged. Other cultures include fasting in their practices. In the Jewish religion the fasting day is named Yom Kippur, the Day of Atonement. It is described as a Jewish festival without food, but full of praying, introspection and self-judgment.

During my fasting period, my friends noticed an off character onset of passive aggressiveness in me, and indeed I was pretty cranky… and super hungry. One of my favorite comedians, Luis CK, once said that we incorrectly overuse the “I am starving” phrase, while people in Africa are really dying for starvation… so I won’t say I was starving, but certainly I was in a glucose deprived state of mind, which was affecting my behavior.

The most challenging part for me was being dehydrated, as you should also fast liquids during Ramadan. Contrary to the great health guru; the actress Cameron Diaz, who taught in her book that drinking plenty of water is the basis for a healthy body, fasting liquids seemed counterproductive in my experience.

Fasting is often indicated in general medical practice particularly prior to surgery or other procedures that require general anesthetics, because of the risk of pulmonary aspiration of gastric contents after induction of anesthesia (i.e., vomiting and inhaling the vomit, causing life-threatening aspiration pneumonia). One should also fast if undergoing a cholesterol or glucose test, as these measurements require a 12 hour fasting period so that a baseline can be established. These acute/short fasting periods are generally safe.

What more, a study in mice published in 2008 showed that short-term fasting (less than 48 hours) is effective in protecting normal cells but not cancer cells against high dose chemotherapy. The following year another study published in Science proved that caloric restriction delays disease onset and mortality in rhesus monkeys. In a human study, including 10 cancer patients under chemotherapy, Sadfie and collaborators  did not report significant side effects caused by fasting alone other than hunger and lightheadedness. In this study all patients voluntarily fasted for a total of 48 to 140 hours prior to and/or 5 to 56 hours following chemotherapy administered by their treating oncologists. In those patients whose cancer progression could be assessed, fasting did not prevent the chemotherapy-induced reduction of tumor volume or tumor markers. Fasting was well-tolerated and was associated with a self-reported reduction in multiple chemotherapy-induced side effects, suggesting that fasting in combination with chemotherapy is feasible, safe, and has the potential to ameliorate side effects caused by chemotherapies.

 

In the significant article that I mentioned before, Chen and collaborators showed that prolonged fasting (PF), exceeding 48 hours, activates a metabolic switch to lipid- and ketone-based catabolism and decreases circulating insulin-like growth factor-1 (IGF-1), which has been shown to reduce chemotoxicity (1) How? They couldn’t find an answer yet. However they clearly demonstrated that the decrease of circulating IGF-1 in the blood was accompanied by a reduction in protein kinase A (PKA) pathway activity in a variety of cell types. PKA has several functions in the cell, I.e. regulation of glycogen, sugar, and lipid metabolism and it regulates other proteins with a valuable role in stem cell stress resistance, self-renewal and pluripotency maintenance.

Interestingly, when Chen and collaborators exposed mice to cycles of prolonged fasting followed by challenges with cyclophosphamide (a drug used in chemotherapy), they noticed the reduction in the mortality and apoptosis (programmed cell death) of long- and short-term HSCs as well as multipotent progenitors in the bone marrow. In addition, multi-lineage differentiation was improved in these animals compared with fed mice, in vitro and in transplantation experiments. These positive effects of prolonged fasting were independent of the chemotherapy treatment, as they were also present in aged animals, which naturally exhibit a reduction in HSC function and multi-lineage potential. The effects of prolonged fasting could be reproduced in mice lacking the growth hormone receptor, which also have low levels of IGF-1. Transplantation experiments showed that low levels of IFG-1 in animals led to a reduction in IGF-1-mediated PKA signaling, both in haematopoietic cells and in associated stromal cells. Strikingly, the researchers could restore haematopoietic function by reducing the levels of either IGF-R1 or the PKA catalytic subunit. Conversely, the benefits were abolished if exogenous IGF-1 was added.

The scientific community is excited about these findings, and we hope understanding the positive effects of fasting can have implications in improving the quality of life of cancer patients… and all the humanity in general. On the other hand, I must cite one of the best Americans: “He that lives upon hope will die fasting”, Benjamin Franklin.

New Insight Into Breast Cancer Offers Therapeutic Hope

 

By Asu Erden

Triple negative breast cancers are highly aggressive malignancies. They do not express any of the hormone receptors usually used to target chemotherapies to treat this type of cancer and have a high relapse rate after treatment. As such, these cancers can come with a very poor prognosis and insight into their development is therefore direly needed. A study published this month by Chen et al. in the scientific journal Nature dissects the role of the XBP1 protein in the development of triple negative breast cancers. The team of scientists from Weill Cornell Medical College observed that XBP1 levels are higher in triple negative breast cancer cell lines. Of particular therapeutic relevance is their finding that depleting XBP1 leads to reduced tumor metastasis in both a mouse model of triple negative breast cancer and human cell lines derived from such cancers. These findings offer hope for the development of therapies aimed at treating this highly challenging cancer.

 

Cancers have high proliferative rates. This incurs a high energetic cost on cells by requiring the rapid synthesis of proteins. The resulting accumulation of unfolded proteins can in time lead to cellular stress. Studies have shown that the unfolded protein response (UPR) is activated in most breast cancers. The UPR is a cellular stress response mediated by the enzyme IRE1. The role of this enzyme is to cut up the Xbp1 mRNA into its mature form and allow the activated XBP1 protein to translocate to the nucleus. There, XBP1 acts as a transcription factor and allows the expression of a host of genes involved in the UPR.

 

To investigate the effects of anti-XBP1 treatment on cancer relapse, Chen et al. treated a breast cancer mouse model with a combination of XBP1 short-hairpin RNA (shRNA) and doxorubicin (a chemotherapeutic drug). XBP1 shRNA prevent the expression of the XBP1 gene. This combination therapy prevented tumor growth and relapse. Further probing revealed that XBP1 shRNA acts by targeting a specific tumor cell subset – human breast cancer stem cells – known to be involved in tumor relapse. Isolation of this cell population from triple negative breast cancer patients revealed increased levels of activated XBP1. Moreover, the silencing of XBP1 in these mammary gland cells resulted in reduced cell clumps, while overexpression of this gene resulted in increased cell clump formation and resistance to chemotherapeutic drugs.

 

Chen’s team also further dissected the mechanism allowing XBP1 to promote the development of triple negative breast cancers. They unraveled the protein’s involvement in the hypoxia-induced cellular stress response. Hypoxia – a condition characterized by a deficiency in the amount of oxygen reaching cells – is a potent cellular stressor. It is also a central feature of many tumors. The hypoxia-induced factor 1a (HIF1a) is activated during the cellular response to hypoxia and is known to be upregulated in triple negative breast cancers. Chen et al. shed light on the interplay between XBP1 and HIF1a, which was hitherto unknown. They revealed that the two proteins cooperate in targeting specific DNA sequences and that XBP1 increases HIF1a activity. XBP1 therefore allows the hypoxia response, characteristic of cancers, to take place by promoting the cellular responses mediated by HIF1a.

 

The results from this study shed light on the mechanism through which XBP1 contributes to the development of triple negative breast cancers. Of particular note is Chen et al.’s silencing data. Therapies utilizing XBP1 silencing techniques, such as shRNAs, combined with chemotherapies could result in highly successful clearance of these cancers and significantly reduced chances of relapse.

 

Tumor-Suppressive microRNAs

 

By Thalyana Smith-Vikos

MicroRNAs (miRNAs) are short, noncoding RNAs that inhibit the expression of specific target genes. Certain classes of miRNAs have been identified as tumor suppressors, most notably miR-34. Studies have shown that miR-34 can be delivered as a tumor-static agent, including a 2012 report by Kasinski and Slack in Cancer Research. This report identifies miR-34 as a tumor suppressor in a Kras;p53 mouse model of lung cancer, the most potent cause of cancer deaths around the world. Tumors harvested from these mice had elevated levels of miR-34 targets, including Met and Bcl-2, indicating that miR-34 expression was inhibited. By adding exogenous miR-34, both tumor formation and progression of preformed tumors were prevented in the mice, and proliferation and invasion of lung tumor-derived epithelial cells were inhibited. This and other studies show promise for the use of miRNAs, especially miR-34, in clinical trials for cancer treatment and prevention.

Cancer Prevention: Affecting Epigenetic Changes with Diet

 

By Kelly Jamieson Thomas

Ending cancer needs to become a global health priority. Cancer, the leading cause of death worldwide, caused 8.2 million deaths in 2012. With 575,000 deaths attributable to cancer in 2010 in the United States, cancer-related deaths in the US are second only to those caused by heart disease, which caused 594,000. Bringing worldwide support behind ending cancer is one of the goals of World Cancer Day this February 4th. How can we end cancer? First and foremost, focus on prevention—the most viable option as a cure.

Historically, cancer has been perceived as a disease in which our genetic makeup dictates our likelihood of developing cancer. Presently, it has become broadly recognized that the initiation and progression of cancer is an intricate web of both genetic makeup and epigenetic events that alter our gene expression. Many studies have proven that epigenetic alterations are key components of the initiation and progression of cancer. These epigenetic processes—including DNA methylation, histone modification, and microRNA expression—are potentially reversible.

Global hypomethylation is a hallmark of almost all human cancers. CpG island hypermethylation and down-regulation is common for many genes involved in a broad range of functions that are deregulated in cancer. As a result, a breadth of research is now dedicated exclusively to understanding how epigenetic alterations are involved in the earliest stages of tumor progression in order to develop epigenetic-based cancer prevention strategies. NIH funding for epigenetic research has dramatically increased from approximately $500,000 to more than $13 million dollars. Support for pinpointing the relationship between diet, exercise, and cancer prevention is clearly on the rise.

Is it possible to affect epigenetic changes through our diet? Dietary compounds have been shown to elicit epigenetic changes in cancer cells. To fully understand how we can modulate cancer prevention through lifestyle, research must focus on how diet and bioactive food components specifically impact epigenetic processes. Antioxidants such as carotenoids and fiber found in many vegetables and fruit offer a variety of anti-cancer benefits. Increased dietary folate, a soluble form of B6 vitamin, consumption has been linked to a decrease in colorectal cancer through its affect on DNA methylation. Dietary phytochemicals, that act as anti-cancer agents (including polyphenols, genistein, sulforaphane, resveratrol, and curcumin) have been shown to act through epigenetic mechanisms.

Population studies are also instrumental in linking diet and cancer prevention. Through the American Cancer Society’s Cancer Prevention Study-3, more than 300,000 men and women ranging from 30-65 years old with no personal history of cancer are participating in an epidemiological cohort study to examine the interplay between genetics, lifestyle, behavior, environment, blood factors, and waist circumference in relation to cancer risk. Large epidemiological studies in combination with rigorous scientific studies help unravel the mechanisms of cancer initiation and progression.

Cancer prevention is the best way to ultimately cure the disease. To work towards cancer prevention, we must further explore how dietary modifications may achieve epigenetic reprogramming, resulting in the maintenance of normal gene expression and reversal of tumor progression.

 

A Dog’s Tale

By Sally Burn

2014 may be the Year of the Horse, but dogs have started the year as a scientist’s best friend, giving paws for thought in several recent papers. Freedman and colleagues barked up the right evolutionary trees to investigate canine evolutionary history, while Waller et al. report that puppy dog eyes give dogs a selective advantage when soliciting human care. Finally, a paper just published in Science sniffs out the genome secrets of an ancient transmissible dog cancer.

 

A Dog’s Tale Part I: The evolutionary history of dogs

Dogs and wolves share many traits but their exact evolutionary connection is unclear. A new paper out this month in PLoS Genetics attempts to address their phylogenetic relationship and reconstruct the early evolutionary history of man’s best friend. Adam Freedman and colleagues doggedly sequenced the genomes of three region-specific gray wolves, two basal dog breeds historically isolated from wolves, and a jackal outlier. Comparisons of these genomes (plus a boxer dog genome) revealed that modern wolves and dogs arose from a now-extinct common ancestor, contradicting the common notion that dogs simply descended from wolves that cozied up with humans. After the initial divergence, both the dog and wolf lineages went through severe population bottlenecks, resulting in increased disparity between their gene pools. The dog lineage was subsequently domesticated by hunter-gatherers, around 11-16 thousand years ago according to this new paper. Analysis was complicated by the fact that the genomes have not been in total isolation from one other, as extensive wolf-dog interbreeding has permitted further gene flow between the species. Such admixture and the extinction of the common ancestor have rendered the evolutionary history of dogs particularly hard to dissect, leading to vastly different conclusions from different research groups. Indeed, a study published last year concluded that population bottlenecks were not that significant during dog evolution. Another bone of contention has been the link between dietary adaptation and domestication. Grab yourself some kibble as we move on to that shaggy dog tale next…

 

A Dog’s Tale Part II: A dog’s dinner

The domestic dog is particularly fond of scraps from human tables. However, the human diet changed dramatically when we transitioned from hunter-gatherers to agriculturalists and so therefore did the digestive abilities of dogs. This was the conclusion of a study published in Nature in 2013, in which Erik Axelsson and colleagues discovered that dogs possess a number of gene variants associated with starch digestion. Compared to wolves, dogs have a seven-fold increase in copy number of AMY2B, a gene involved in the breakdown of starch. This was a necessary adaptation to share the starch-rich food of humans. The advent of agriculture was, they argued, a catalytic event in domestication as humans now had attractive scrapheaps, from which genetically-equipped wolves could steal tasty morsels. All of a sudden hanging with the humans was advantageous for survival and so the ancestor of modern dogs was born. In contrast, this month’s Freedman et al. study found that AMY2B copy number varies between dog breeds and is also high in some wolves, discrediting the notion of high AMY2B copy number being an explicitly dog trait. More specifically, AMY2B copy number is low in dog breeds not associated with agricultural societies, reaffirming their conclusion that domestication predated the onset of agriculture. The contrasting conclusions of the two papers demonstrate once again the difficulties in tracing canine evolution.

 

A Dog’s Tale Part III: Puppy dog eyes

Regardless of how they came to be able to digest our food, one thing we can be sure of is that dogs have a guaranteed mechanism for obtaining it: puppy dog eyes. Now researchers at the University of Portsmouth, UK, have found evidence that puppy dog eyes provide a selective advantage when soliciting human care. The team proposed that a key factor in dog domestication was human selection against aggression; they hypothesized that, in a process of co-evolution, dogs displaying pedomorphic (puppy-like) facial characteristics were preferentially selected by humans desiring increasingly tame canine companions. To test this hypothesis they used the speed of rehoming from shelters as a proxy for artificial selection. Humans stood in front of shelter pens and the facial expressions of the dog inmates were analyzed using a novel system called DogFACS (Dog Facial Action Coding System). As predicted, dogs who displayed puppy-like facial expressions were rehomed faster than those who did not. A key facial movement was the raising of the inner brow to make their eyes look bigger and more puppy-like. So next time you acquiesce and give doe-eyed Fido a superfluous treat, take solace in the fact that your weakness is just part of your DNA.

 

A Dog’s Tale Part IV: Transmissible dog cancer genome

Our final dog bulletin concerns the world’s oldest known cancer. Canine transmissible venereal tumor (CTVT) spreads when cancer cells pass between dogs during mating. Researchers at the Wellcome Trust Sanger Institute in Cambridge, UK, sequenced the cancer cells’ genome and published their findings last week in Science. They found that the cancer originated in a single dog around 11,000 years ago; the cancerous cells have been passed on ever since as a clonal lineage, long outliving the body from which they came and making CTVT the oldest known living cancer in the world. The cancerous cells still contain the genome of the dog in which the cancer arose, allowing the team to build up a genetic “identikit” of the first infected animal. The canine patient zero was a medium to large husky-like dog, with black or agouti fur. Mutation analysis pinpointed the origin to approximately 11,368 years ago. The cancer was initially contained within an isolated dog population but it became a worldwide problem around 500 years ago, possibly as a result of humans traveling the earth and taking four-legged companions with them. Some of these voyages may have been to sunny locales as the cancer’s genome bears hallmarks of exposure to ultraviolet light. The cancer cells have also undergone many other changes during their evolution, losing 646 genes and acquiring an estimated 1.9 million somatic substitution mutations – several hundred times the number found in most human cancers. Despite this accumulation of mutations the cancer cells have survived, illustrating just how robust mammalian somatic cell lines can be. Indeed, many of the mutations may have allowed the cancer to adapt to niche changes and thrive. While the cancer itself is rare, this study is of note as it chronicles the evolutionary history of a transmissible cancer. Further analysis of the cancer’s genome may therefore provide insights into the processes underlying cancer transmissibility.

Backdoor Targeting of the Cancer Causing Protein K-Ras

 

Elaine To

When targeting a specific protein with a small molecule drug in order to treat a disease, scientists often use a molecule that mimics the natural substrate of the enzyme and targets the active site. However, this approach has met with limited success in the case of the oncogenic GTPase K-Ras. GTPases are regulatory proteins that act like binary switches for cellular pathways. In its “on” state, K-Ras is bound to GTP and activates signaling cascades responsible for cell growth, survival, and differentiation. When GTP gets hydrolyzed to GDP, K-Ras is turned “off.” Mutations that prolong the lifetime of GTP when bound to K-Ras, such as the G12C (glycine at position 12 is changed to cysteine) mutant, are highly oncogenic and lead to cancer. The high affinity of K-Ras for GTP and GDP makes drug targeting of the K-Ras active site difficult, but researchers Ostrem, Peters, et al. have discovered an alternate site on K-Ras that can be targeted for cancer therapies.

The researchers set out to find a small molecule that could specifically bind to the oncogenic G12C mutant protein while avoiding the wild type K-Ras by screening a disulfide library, which would be expected to react with the thiol group of the cysteine. Intact protein mass spectrometry revealed which compounds bound to the G12C mutant without targeting the wild type. The two strongest binders were unaffected by the presence of excess GDP, indicating that they do not compete with GDP for binding. X-ray crystallography showed that one of the strong binders was binding in a previously allosteric pocket of K-Ras.

In order to further characterize the novel allosteric site, the researchers examined libraries containing electrophiles, acrylamides, and vinyl sulphonamides for G12C K-Ras binding. Co-crystals of potent binders with K-Ras revealed that the switch-I and switch-II domains of the protein are disrupted, which also disturbs magnesium ion binding. Previously studied mutations in the residues that coordinate the magnesium ion result in a preference for GDP over GTP, thus the researchers tested the compounds for this activity as well. Indeed, exchange assays reveal a shift in K-Ras’s preference from GTP to GDP when the potent electrophiles are bound. Additionally, the compounds can block nucleotide exchange by exchange factors, though EDTA still effectively catalyzes the exchange of GDP for GTP.

It was also noted that the potent compounds occupied a position normally reserved for G60 when K-Ras is active. Known mutants of G60 have impaired binding to partner effector proteins such as Raf. Studies in cell lines show that compound binding impairs the association of K-Ras with Raf. Lastly, in order to show the effectiveness of the identified compounds as chemotherapeutic drugs, the researchers treat various cancer cell lines, some of which contain the G12C mutation. As expected, the cells with the mutation demonstrated significantly decreased viability in the presence of the compounds.

Overall, this is an elegant approach to small molecule drug development that fortuitously revealed a novel regulatory site of K-Ras. Drugs that target this site can be designed specifically for oncogenic mutations, and do not have to overcome the significant barrier of trying to out compete GDP and GTP for binding. The extensive crystal structure and enzymatic characterizations lay the groundwork for further drug development on K-Ras and may open up a whole new class of chemotherapeutic drugs.

The Most Scizzling Papers of 2013

 

The Scizzle Team

Bacteriophage/animal symbiosis at mucosal surfaces

The mucosal surfaces of animals, which are the major entry points for pathogenic bacteria, are also known to contain bacteriophages. In this study, Barr et al. characterized the role of these mucus associated phages. Phages were more commonly found on mucosal surfaces than other environments and adhere to mucin glycoproteins via hypervariable immunoglobulin like domains. Bacteriophage pre-treatment of mucus producing cells provided protection from bacterial induced death, but this was not the case for cells that did not produce mucus. These studies show that there may be a symbiotic relationship between bacteriophages and multicellular organisms which provides bacterial prey for the phages and antimicrobial protection for the animals.

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Interlocking gear system discovered in jumping insects

Champion jumping insects need to move their powerful hind legs in synchrony to prevent spinning. Burrows and Sutton studied the mechanism of high speed jumping in Issus coleoptratus juveniles and found the first ever example in nature of an interlocking gear system. The gears are located on the trochantera (leg segments close to the body’s midline) and ensure both hind legs move together when Issus is preparing and jumping. As the insect matures, the gear system is lost, leaving the adults to rely on friction between trochantera for leg synchronization.

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HIV-1 capsid hides virus from immune system

Of the two strains of HIV, HIV-1 is the more virulent and can avoid the human immune response, whereas HIV-2 is susceptible. This may be due to the fact that HIV-2 infects dendritic cells, which detect the virus and induce an innate immune response. HIV-1 cannot infect dendritic cells unless it is complexed with the HIV-2 protein Vpx, and even then the immune response isn’t induced until late in the viral life cycle, after integration into the host genome. Lahaye et al. found that only viral cDNA synthesis is required for viral detection by dendritic cells, not genome integration. Mutating the capsid proteins of HIV-1 showed that the capsid prevents sensing of HIV-1 cDNA until after the integration step. This new insight into how HIV-1 escapes immune detection may help HIV vaccine development.

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Transcription factor binding in exons affects protein evolution

Many amino acids are specified by multiple codons that are not present in equal frequencies in nature. Organisms display biases towards particular codons, and in this study Stamatoyannopoulos et al. reveal one explanation. They find that transcription factors bind within exonic coding sequences, providing a selective pressure determining which codon is used for that particular amino acid. These codons are called duons for their function as both an amino acid code and a transcription factor binding site.

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Chromosome silencing

Down syndrome is caused by the most common chromosomal abnormality in live-born humans: Trisomy 21. The association of the syndrome with an extra (or partial extra) copy of chromosome 21 was established in 1959. In the subsequent fifty years a number of advances have been made using mouse models, but there are still many unanswered questions about exactly why the presence of this extra chromosome should lead to the observed defects. An ideal experimental strategy would be to turn off the extra chromosome in human trisomy 21 cells and compare the “corrected” version of these cells with the original trisomic cells. This is exactly what a team led by Jeanne Lawrence at the University of Massachusetts Medical School has done. Down syndrome is not the only human trisomy disorder: trisomy 13 (Patau syndrome) and trisomy 18 (Edward’s syndrome), for example, produce even more severe effects, with life expectancy usually under one to two years. Inducible chromosome silencing of cells from affected individuals could therefore also provide insights into the molecular and cellular etiology of these diseases.

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Grow your own brain

By growing organs in a dish researchers can easily monitor and manipulate the organs’ development, gaining valuable insights into how they normally develop and which genes are involved. Now, however, a team of scientists from Vienna and Edinburgh have found a way to grow embryonic “brains” in culture, opening up a whole world of research possibilities. Their technique, published in Nature, has also already provided a new insight into the etiology of microcephaly, a severe brain defect.

[box style=”rounded”]Scizzling extra: In general, 2013 was a great year for growing your own kidneyspotentially a limb and liver. What organ will be next? [/box]

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Sparking metastatic cell growth

A somewhat controversial paper published in Nature Cell Biology this year showed that the perivescular niche regulates breast tumor cells dormancy. The paper showed how disseminated breast tumor cells (DTC) are kept dormant and how they can be activated and aggressively metastasize. Based on the paper, this is due to the interaction of interaction with the microvascularate, where thrombospondin-1 (TSP-1) induces quiescence in DTC and TGF-beta1 and periosstin induces DTC growth. This work opens the door for potential therapeutic against tumor relapse.

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Fear memories inherited epigenetically

Scientists showed that behavioral experiences can shape mice epigenetically in a way that is transmittable to offspring.  Male mice conditioned to fear an odor showed hypomethylation for the respective odor receptor in their sperm; offspring of these mice showed both increased expression of this receptor, and increased sensitivity to the odor that their fathers had been conditioned on.  Does this suggest that memories can be inherited?

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Grid cells found in humans

Scientists have long studied rats in a maze, but what about humans?  An exciting paper last August demonstrated that we, like out rodent counterparts, navigate in part using hippocampal grid cells.  Initially identified in the entorhinal cortex of rats back in 2005, grid cells have the interesting activity pattern of firing in a hexagonal grid in the spatial environment and as such are thought to underlie the activity of place cells. Since then grid cells have been found in mice, rats, and monkeys, and fMRI data has suggested grid cells in humans.  This paper used electrophysiological recordings to document grid cell activity in humans.

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Sleep facilitates metabolic clearance

Sleep is vital to our health, but researchers have never been entirely sure why.  It turns out part of the function of sleep may be washing waste products from the brain, leaving it clean and refreshed for a new day of use.  Exchange of cerebral spinal fluid (CSF), which is the primary means of washing waste products from the brain, was shown to be significantly higher when animals were asleep compared to waking.  This improved flow was traced back to increased interstitial space during sleep, and resulted in much more efficient clearance of waste products.  Thus, sleep may be crucial to flushing metabolites from the brain, leaving it fresh and ready for another day’s work.

[box style = “rounded”] Robert adds: As a college student my friends and I always had discussions about sleep and it was also this mysterious black box of why we actually need to sleep. Studies could show the effects of lack of sleep such as poor cognition and worse memory but this paper linked it to an actual mechanism by which this happens. First of all I found it very impressive that the researchers trained mice to sleep under the microscope. On top of that showing the shrinkage of the neurons and the flow of cerebrospinal fluid which cleans out metabolites finally linked the cognitive aspects of sleep deprivation to the physical brain. [/box]

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Poverty impedes cognitive function

People who are struggling financially often find it difficult to escape poverty, in part due to apparently poor decision making.  Investigators demonstrated that part of this vicious cycle may arise from cognitive impairment as a direct result of financial pressures.  The researchers found that thinking about finances reduced performance on cognitive tasks in participants who were struggling, but not in those who were financially comfortable.  Furthermore, farmers demonstrated poorer cognitive performance before harvest, at a time of relative poverty, compared to after harvest when money was more abundant.

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Gut Behavior

2013 has definitely been the year of the gut microbiome! Studies have shown that diet affects the composition of trillions of microorganisms in the human gut, and there is also a great deal of evidence pointing towards the gut microbiome affecting an individual’s susceptibility to a number of diseases. Recently published in Cell, Hsiao and colleagues report that gut microbiota also affect behavior, specifically in autism spectrum disorder (ASD). Using a mouse model displaying ASD behavioral features, the researchers saw that probiotic treatment not only altered microbial composition, but also corrected gastrointestinal epithelial barrier defects and reduced leakage of metabolites, as demonstrated by an altered serum metabolomic profile. Additionally, a number of ASD behaviors were improved, including communication, anxiety, and sensorimotor behaviors. The researchers further showed that a particular metabolite abundant in ASD mice but lowered with probiotic treatment is the cause of certain behavioral abnormalities, indicating that gut bacteria-specific effects on the mammalian metabolome influence host behavior.
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Your skin – their home

A paper published in Nature examined the diversity of the fungal and bacterial communities that call our skin home. The analysis done in this study revealed that the physiologic attributes and topography of skin differentially shape these two microbial communities. The study opens the door for studying how the pathogenic and commensal fungal and bacterial communities interact with each other and how it affects the maintenance of human health.

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Discovery of new male-female interaction can help control malaria

A study published in PLOS Biology provided the first demonstration of an interaction between a male allohormone and a female protein in insects.  The identification of a previously uncharacterized reproductive pathway in A. Gambiae has promise for the development of tools to control malaria-transmitting mosquito populations and interfere with the mating-induced pathway of oogenesis, which may have an effect on the development of Plasmodium malaria parasites.

[box style = “rounded”]Chris adds: “My friend chose this paper to present at journal club one week, because he thought it was well written, interesting etc etc. Unbeknownst to him, one of the paper’s authors was visiting us at the time. We sit down for journal club and one of the PIs comes in, sees the guy and exclaims (with mock exasperation) “you can’t be here!” Me and the presenter look at one another, confused. He presents journal club, and luckily enough, the paper is so well written, that he can’t really criticize it!” [/box]

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Using grapefruit to deliver chemotherapy

Published in Nature Communications, this paper describes how nanoparticles can be made from edible grapefruit lipids and used to deliver different types of therapeutic agents, including medicinal compounds, short interfering RNA, DNA expression vectors, and proteins to different types of cells. Grapefruit-derived nanovectors demonstrated the ability to inhibit tumor growth in two tumor animal models. Moreover, the grapefruit nanoparticles used in this study had no detectable toxic effects, could be manipulated or modified to target specific cells/ tissues, and were economical to create. Grapefruits may have a bad reputation for interfering with drugs, but perhaps in the future we will be using grapefruit products to deliver drugs more effectively!

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Getting CLARITY

In May, a new technique called CLARITY to effectively make tissue transparent through a new fixation technique was published in Nature. This new process has allowed them to clearly see neuron connection networks not possible before because they can now view the networks in thicker tissue sections. This new advancement will help researchers be able to better map the brain, but this new technology can also be to create 3-D images of other tissues such as cancer. This new ability allows us to gain better insight into the macroscopic networks within a specific tissue type.

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Crispier genome-editing

This year, the CRISPR technique was developed as an efficient gene-targeting method. The benefit of this method over the use of TALENS or a zinc-finger knockout is it allows for the rapid generation of mice that have multiple genetic mutations in just one step. The following review gives even more information on this new technique and compares its usefulness to that of TALENS and zinc-finger knockouts. Further, just couple of weeks ago, two back-to-back studies in Cell Stem Cell using the CRISPR-Cas9 system to cure diseases in mice and human stem cells.  In the first study the system was used in mice to correct the Crygc gene that causes cataracts; in the second study the CRSPR-Cas9 system was used to correct the CFTR locus in cultured intestinal stem cells of CF patients. These findings serve as a proof-of-concept that diseases caused by a single mutation can be “fixed” with genome editing using the CRISPR-Cas9 system.

What was your favorite paper this year? Let us know! And of course – use Scizzle to stay on top of your favorite topics and authors.

Too Young for Cancer?

 

Neeley Remmers

Officially, cancer awareness month is over, but honestly where this disease is concerned, we should constantly strive to increase cancer awareness amongst the general public. For this post, I have decided to highlight one area of cancer that gets very little attention, cancer in adolescents and young adults (persons ranging between the ages of 15-39 years) or AYAs for short. Like most, initially I had the bias that cancer in persons under the age of 50 and older than 12 rarely occurred. However, more than 72,000 AYAs learn they have cancer each year in the United States, a number up to seven times larger than the number of children under the age of 15 that are diagnosed with cancer (taken from American Cancer Society’s Facts and Figures). Cancers that are common in AYAs often are rare in the traditional adult oncology clinic—germ cell tumors, leukemias and lymphomas, melanoma, thyroid cancer, and sarcomas, but we are seeing more and more AYAs diagnosed with the more common adult cancers such as breast, colon, ovarian and prostate cancer as well. Unfortunately, AYAs face a number of unique medical issues that adults do not when seeking treatment for cancer. First and foremost, diagnosis often comes late because many physicians rarely think that an AYA displaying the signs and symptoms of cancer could actually have cancer. This alone makes treatment more difficult as cancers typically become more resistant to therapies as they advance.

In addition to receiving late diagnosis, it is becoming evident that cancers in AYAs are genetically different from those seen in either children or adults. This leads to AYA patients receiving treatments that may not be the most effective for their cancer. This is has become most evident in acute lymphoblastic leukemia (ALL) where recent clinical trials indicate that in some cases, AYA patients with ALL may have better outcomes when treated with pediatric regimens versus adult regimens. Work done by Dr. Christine Harrison of Newcastle University in the United Kingdom has shown that some AYAs with ALL have genetic changes that are typical of younger patients, whereas others have previously unknown alterations (Moorman et al., J Clinical Oncology. 2012). Another current, ongoing study done by a team lead by Dr. Cheryl Willman, director of the University of New Mexico Cancer Center, where tumor samples from 500 ALL tumors taken from children, teens, and AYAs has provided some indication that genetic differences do in fact occur in ALL based on patient age. For instance, some AYA tumors have genetic alterations that are often seen in older children with ALL who are at high risk of relapse. (AYAs and high-risk older pediatric patients tend to have worse outcomes than the vast majority of younger children with ALL.)

A similar comparative study has begun for AYAs with colorectal cancer by Dr. Anna Franklin at MD Anderson and her team of colleagues at MD Anderson and Colorado, and preliminary results from this study also indicate that genetic differences occur between tumors from AYAs versus tumors from adults. However, this phenomenon is not seen in all types of tumors affecting AYAs. For example, genetic differences were not seen in breast cancer cases even though AYAs are diagnosed with more aggressive subtype than older patients; however, the reasoning for this discrepancy is not yet fully understood. More research is needed to gain a better understanding of AYA tumor biology. These biological differences may require different treatment strategies in AYAs as compared to children or adults to achieve the best possible outcomes.

Finally, AYAs have more long-term health effects that arise from either latent cancer cells or are a side-effect of their treatment. Some of these health effects include being put at a higher risk for developing cataracts, hearing loss, chronic pain, limb amputation, hypopituitarism, loss of bone mass, and cardiac problems to name a few. Survivors of AYA cancers, like their pediatric counterparts, are also at increased risk for life-threatening problems such as second primary cancers and psychiatric issues such as post-traumatic stress disorder and depression. Unfortunately, many AYA survivors are often unaware of or underestimate their heightened risk for these late health effects; the same is true of many of the doctors and health care providers these survivors see after leaving the confines of active cancer treatment and follow-up.

The reality of AYA cancer is that this is a highly understudied field that is in need of more researchers and clinicians help fill the knowledge gaps to improve treatments for this patient group. Additionally, greater awareness amongst AYAs and physicians alike is needed so we can begin to diagnose their cancers while they are still at an early stage and the importance of realizing that AYA survivors are at a much higher risk for additional health complications later in life.

The information for this post was taken from the NCI website www.cancer.gov under their page dedicated to cancers in adolescents and young adults.

A Marvellous Month of Science

 

Stephanie Swift

Fungal extracts prevent hepatitis C virus infection

Credit: ti-wago (Flickr)
Credit: Tiwago (Flickr)

Hepatitis C virus (HCV) is a huge cause of liver cancer, but current treatments are very expensive and not that great. Since HCV is a cunning little virus capable of quickly evolving drug resistance, simultaneously attacking it at several key points during its life cycle has the best chance of resolving infection. Researchers in Japan have now created and screened a library of 300 natural drugs isolated from fungi found on seaweed, mosses and other plants, and tested their ability to shut down HCV infection. One of their best hits, sulochrin, repelled several strains of hepatitis C virus, and was free from any toxic side effects. When they combined sulochrin with the traditional HCV drug, telaprevir, results were even better. Although any potential off-target effects of sulochrin still have to be ruled out, this research highlights that the natural world is a tremendously rich source of new drugs that should continue to be mined.

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Unwinding shielded DNA attacks the root cause of prostate cancer

Credit: axshuzaifa (Flickr)
Credit: Huzaifa Das (Flickr)

Most organs in the human body, including the prostate gland, contain a tiny population of stem cells that replace old defunct cells with shiny new ones. If these stem cells get damaged, they can become carcinogenic machines, dividing uncontrollably to form a tumor. Such cancer stem cells are thought to be the driving force that creates prostate tumors. Cancer stem cells are very difficult to kill, since they have excellent inbuilt safety features, one of which is very tightly coiled DNA that rebuffs normal treatments. Researchers at the University of York have now shown that treating prostate cancer stem cells with drugs that unwind and relax DNA sensitizes them to common chemotherapies, allowing them to be destroyed and ultimately preventing tumor relapse.

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Chilly temperatures help cancers to grow

Credit: ssoosay (Flickr)
Credit: Surian Soosay (Flickr)

At low temperatures the human body has a hard time, entering a state of thermal stress where only the most vital systems, like the brain, are left switched on. Now, a paper published in PNAS suggests that cold has yet another disadvantage – it changes the way cancer cells grow and spread, at least in mice. Mice living in a relatively cold environment (around 22°C) had cancers that grew more quickly and aggressively than mice living at a nice thermally comfortable temperature (around 30°C). Both the cold and the comfortable mice had the same numbers of potential cancer-fighting immune T cells when they were healthy, but when they got sick, the T cells in the comfortable mice were quicker and better at burrowing into the tumour to attack it. They also secreted more cancer-fighting substances than the cells from cold mice. In the tumors of cold mice, there were greater numbers of suppressive cells capable of shutting down normal immune responses. Cold temperatures, then, shifted the body’s response from fighting the tumor to accepting it. This suggests that the benefits of heat therapy for cancer may have been largely overlooked. Adapted from an article originally published on The Conversation.

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Common chemotherapy drug helps oncolytic viruses kill tumors

Credit: Bryan Brandenburg (Flickr)
Credit: Bryan Brandenburg (http://bryanbrandenburg.net)

There is a lot of excitement in the world of cancer immunotherapy over the potential utility of oncolytic viruses – that is, viruses that specifically infect and destroy cancer cells with the help of the immune system. Since a tumor is essentially a big chunk of overgrown tissue, the immune system often continues to see it as a normal part of the body (although sometimes, the sneaky tumor simply makes itself invisible to the immune system). Even after immune-activating oncolytic virus treatment, properly re-educating the immune system to see the tumor as a malignant intruder is a very difficult process. Researchers at McMaster Immunology Research Centre now show that administering an oncolytic virus together with a chemotherapy drug that triggers the immune system as it kills cancer cells finally allows the tumor to be recognized as a threat. Once that biological brake has been removed, cancer-fighting immune cells can pour into the tumor and secrete cancer-busting substances. Such exciting new combination therapies can help retrain the immune system to identify developing