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Updates found with 'cancerous tumors'

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Updates found with 'cancerous tumors'

New DNA nanorobots successfully target and kill off cancerous tumorsBY SARAH BUHRFeb 12, 2018Science fiction no more — in an article out today in Nature Biotechnology, scientists were able to show tiny autonomous bots have the potential to function as intelligent delivery vehicles to cure cancer in mice.These DNA nanorobots do so by seeking out and injecting cancerous tumors with drugs that can cut off their blood supply, shriveling them up and killing them.“Using tumor-bearing mouse models, we demonstrate that intravenously injected DNA nanorobots deliver thrombin specifically to tumor-associated blood vessels and induce intravascular thrombosis, resulting in tumor necrosis and inhibition of tumor growth, ” the paper explains.DNA nanorobots are a somewhat new concept for drug delivery. They work by getting programmed DNA to fold into itself like origami and then deploying it like a tiny machine, ready for action.DNA nanorobots, Nature Biotechnology 2018The scientists behind this study tested the delivery bots by injecting them into mice with human breast cancer tumors. Within 48 hours, the bots had successfully grabbed onto vascular cells at the tumor sites, causing blood clots in the tumor’s vessels and cutting off their blood supply, leading to their death.Remarkably, the bots did not cause clotting in other parts of the body, just the cancerous cells they’d been programmed to target, according to the paper.The scientists were also able to demonstrate the bots did not cause clotting in the healthy tissues of Bama miniature pigs, calming fears over what might happen in larger animals.The goal, say the scientists behind the paper, is to eventually prove these bots can do the same thing in humans. Of course, more work will need to be done before human trials begin.Regardless, this is a huge breakthrough in cancer research. The current methods of either using chemotherapy to destroy every cell just to get at the cancer cell are barbaric in comparison. Using targeted drugs is also not as exact as simply cutting off blood supply and killing the cancer on the spot. Should this new technique gain approval for use on humans in the near future it could have impressive affects on those afflicted with the disease
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MISSION CRITICALHEALTH, CANCER, MICROBIOLOGYHuman skin bacteria have cancer-fighting powersThe microbes make a compound that disrupts DNA formation in tumor cellsBY AIMEE CUNNINGHAM 3:49PM, FEBRUARY 28, 2018Staphylococcus epidermidis petri dishSKIN WIN Staphylococcus epidermidis, a species of bacteria that lives on human skin, grows here in a dish. Strains of this bacteria make a cancer-fighting compound that stops DNA synthesis.R. GALLO AND TERUAKI NAKATSUJI/UC SAN DIEGOSPONSOR MESSAGECertain skin-dwelling microbes may be anticancer superheroes, reining in uncontrolled cell growth. This surprise discovery could one day lead to drugs that treat or maybe even prevent skin cancer.The bacteria’s secret weapon is a chemical compound that stops DNA formation in its tracks. Mice slathered with one strain of Staphylococcus epidermidis that makes the compound developed fewer tumors after exposure to damaging ultraviolet radiation compared with those treated with a strain lacking the compound, researchers report online February 28 in Science Advances.The findings highlight “the potential of the microbiome to influence human disease, ” says Lindsay Kalan, a biochemist at the University of Wisconsin–Madison.Staphylococcal species are the most numerous of the many bacteria that normally live on human skin. Richard Gallo and his colleagues were investigating the antimicrobial powers of these bacteria when the team discovered a strain of S. epidermidis that made a compound — 6-N-hydroxyaminopurine, or 6-HAP for short — that looked a lot like one of the building blocks of DNA. “Because of that structure, we wondered if it interfered with DNA synthesis, ” says Gallo, a physician scientist at the University of California, San Diego. In a test tube experiment, 6-HAP blocked the enzyme that builds DNA chains and prevented the chains from growing.Mice treated with a strain of S. epidermidis that does not make the compound 6-HAP and then exposed to ultraviolet rays developed UV-induced tumors (left). The skin of mice who got a strain with the compound remained largely normal (right). T. NAKATSUJI ET AL/SCI ADV 2018Cancer cells have runaway growth, so the researchers thought the compound might inhibit those cells. Sure enough, 6-HAP stopped DNA formation in different tumor cells grown in the lab. But the compound was not able to do so in normal skin cells. Certain enzymes in normal skin cells deactivated 6-HAP, the researchers found, and the tumor cells tested appeared to lack those enzymes.Gallo and colleagues found that the compound had an effect both when injected and when applied topically. Among mice injected with skin cancer cells, some received a shot of 6-HAP while others got a dummy shot. Tumors grew in all the mice, but the tumors in mice given the compound were about half the size of those in mice without the compound.The researchers then spread S. epidermidis on the backs of hairless mice subjected to UV rays. Some mice got a strain that makes 6-HAP; others got a strain that does not. After 12 weeks of being exposed periodically to UV rays, the first group of mice developed only one tumor each, while mice in the second group were saddled with four to six tumors.S. epidermidis strains might have gained the ability to stop DNA synthesis to prevent other bacteria from growing, Gallo says. In that way, the bacteria protect their homestead from other invading pathogens. “Perhaps we evolved to provide a safe haven for these organisms because they also benefit us when they’re doing this.” The researchers did a small study of existing genetic data from the human skin microbiome and estimate that 20 percent of the human population have S. epidermidis strains that make 6-HAP on their skin, Gallo says.More work needs to be done to understand how S. epidermidis makes 6-HAP and how much of the compound is on the skin, Kalan says. “It is important to understand how the microbiome interacts with its human host before we can begin to manipulate it for disease treatment.” One approach could be to develop probiotics for the skin — adding helpful bacteria to ward off infection or maybe even prevent cancer, she says.Along with skin cancer cells, 6-HAP was also able to block DNA synthesis in lymphoma cells, cancerous immune system cells. It’s too early to say, but there is potential for this secret weapon to slay more than one villain.
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HomeOur Story Blog Putting glioblastoma in its placePutting glioblastoma in its placePosted on March 16, 2018 | Sally Burn Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer, with a median survival time of just one year following diagnosis. Treatment is complicated by the considerable variability in GBM tumors – what works for one tumor often fails to work for another. Selecting the most appropriate treatment may soon, however, be easier, thanks to an improved GBM classification system, developed by Mount Sinai and Sema4 scientists and published in Cancer Research.A team of researchers, led by Sema4’s Head of Data Sciences Jun Zhu, PhD, reasoned that an improved GBM classification system could help clinicians to select the most pertinent therapy – a case of “know your enemy”. Some GBM tumors are dependent on the mitotic spindle checkpoint molecule BUB1B for their survival, so his team mined complex datasets to produce an innovative computational method to classify tumors based on their BUB1B dependency. In doing so, they uncovered new tumor subtypes and found that while BUB1B-sensitive tumors had a significantly worse prognosis, they were also predicted to be more responsive to many of the cancer drugs already in clinical use.The molecular subtypes identified in this new study appear to provide a more accurate estimate of prognosis and therapeutic response than existing classifications. One reason that previous classifications have failed to lead to effective personalized treatments is the high degree of intratumoral heterogeneity in GBM. Cells from different parts of the tumor may belong to different molecular subtypes and, therefore, subtype-specific therapies fail to eradicate all the cancerous cells. The BUB1B classification system, however, does not suffer the same defect.“It was a pleasant surprise to us that our subtype is stable for heterogeneous tumor cells within a GBM tumor and, thus, it is possible to kill all tumor cells instead of just a subgroup, ” says Dr. Zhu. “Preliminary results indicate that the stability is associated with certain genomic features, but more data are needed to understand why. More importantly, we also need to work out how to leverage the subtype information to develop mechanism-specific therapies.”“These findings underscore the significant potential we see to improve patient outcomes by investing in predictive modeling of even the most complex types of cancer, ” explains Eric Schadt, PhD, Sema4’s CEO and Dean for Precision Medicine at Icahn School of Medicine at Mount Sinai.The study was the result of a multidisciplinary collaboration between computational scientists and clinicians – a characteristic of many Sema4 research projects. Information generated from our integrative studies – such as the GBM project and a recent examination of lung cancer mutations – is the first step towards designing improved diagnostic tests and optimizing personalized cancer therapies. Currently, Sema4 offers the Oncology Hotspot Panel, which provides information on over 200 mutational hotspots associated with a range of cancers. As our knowledge of cancer genomics increases so too will our ability to expand this number, leading to improved diagnosis, treatment, and survival rates for cancers including glioblastoma. “We look forward to building on this collaborative project and moving toward development of a diagnostic test that could help physicians better understand and treat their patients’ glioblastoma cases, ” says Dr. Schadt.
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Mesothelioma: The Role Of Asbestos And Gene Therapy In IndiaHomeStrand Gene WordMesothelioma: The Role of Asbestos and Gene Therapy in IndiaAsbestos has deep ties in the fabric of Indian industry and construction. Behind China, India is the second largest market for asbestos in the world, importing hundreds of millions of dollars worth of the material annually. The impact asbestos has on community and individual health is as vast as it is severe. As a versatile material favored by the construction and repair industries because of its heat and fire resistant properties, asbestos use saw its peak in the mid-20th century. However, people began noticing its alarming health effects, including mesothelioma, only decades after exposure to the toxin.Some of the effects from exposure include certain forms of cancer. Asbestos fibers often remain in the body for years, leading to irritation and the eventual development of malignant cells. Through further research and the development of clinical trials, aggressive cancers that are difficult to treat may stand a better chance with tumor profile-based targeted therapies and experimental treatments such as gene therapy.Asbestos Use in IndiaBeing the largest global importer of asbestos, much of India’s industry relies on the mineral’s production and use. Asbestos-containing products are manufactured in nearly 200 factories around India. The mineral can be found in a range of products, from cement and roofing to household appliances and automotive parts.Danger - Asbestos - Cancer and Lung Disease HazardMuch of India’s asbestos-related health issues can be attributed to occupational and secondhand exposure. Employees who work with the material in factories and shipyards, like those in Gujarat and Alang, are often the primary victims of diseases derived from asbestos exposure. The fibers produced by disturbed asbestos can stick to a worker’s attire, potentially entering their homes and communities. Those living near factories or construction sites are also at risk of airborne exposure, resulting in health complications that can be just as detrimental. Mesothelioma is one of the most significant byproducts of asbestos exposure. This rare form of cancer takes root in the mesothelium, or lining of the internal organs, and is known for its significantly low survival rate.Patients may not develop symptoms of mesothelioma for upwards of 10-50 years, and these symptoms are typically only discovered in the later stages of the disease. In addition, due to its rarity, mesothelioma can often be misdiagnosed or improperly treated. To fully understand the condition and how it develops, further clinical study and testing needs to be done. Innovative treatment methods and solutions could prove life changing for the majority of patients who do not survive more than a year after diagnosis.Gene Therapy, Targeted Therapy and Mesothelioma Even in its initial stages gene therapy has the potential to hugely benefit cancer patients like those suffering from mesothelioma. At its core, gene therapy works to replace mutated or cancerous cells, leading to correcting the gene completely and deactivating the mutation. In mesothelioma cases, the DNA of a cell is damaged by asbestos fibers, leading to uncontrolled growth and abnormalities.Mesothelioma patients most often receive treatment through some form of surgery, radiation, or chemotherapy. While a combination of these three treatments sees the highest success rates, the condition’s prognosis continues to be poor. Targeted therapy based on the mutation profile of the tumor is starting to become a reality for some patients (eg Erlotinib for tumors that carry an EGFR mutation) with some success in extending survival beyond one year, in some cases even up to five years. Gene therapy on the other hand is still in its experimental stages for mesothelioma, but is available now to patients through clinical trials. So far, much of the results have seen limited success with notable side effects or complications.However, researchers have uncovered the TP53 gene as an effective target in treating tumors through gene therapy. This gene comprises a key protein (p53) that regulates normal cell function within the body and is vital in preventing tumor growth. Almost every form of cancer linked to a poor prognosis has a mutation in this gene, making it an ideal target for therapy. Preclinical studies have focused on the common genetic mutation in mesothelioma which deactivates the p53 pathways. This study has been successful in restoring the pathways that prevent tumor growth, but so far researchers have not been able to use this therapy to greatly reduce tumor size.Mesothelioma in IndiaOn a global scale, the World Health Organization estimates asbestos was linked to an estimated 107, 000 deaths in 2004 alone. Although about 60 countries have banned the use of asbestos due to its threat to human health, India’s asbestos industry is worth billions of dollars and continues to grow. Around 80% of mesothelioma cases in the country involve men who experienced occupational exposure or those living in proximity to production.Yet, mesothelioma is a considerably new condition for India, with the first case being reported as recently as 2015. However, the crux of this cancer is that it will continually be diagnosed for years, even after asbestos has been fully banned. The epidemic of asbestos exposure in India will only come to a halt when the dangers associated with this mineral are fully investigated, and it has been proactively handled or disposed of.Until this time, it is important that evolving forms of cancer treatment, like targeted and gene therapy, are studied and implemented to help save the lives of those afflicted by mesothelioma. Targeted and gene therapy has the potential to greatly impact the way cancer care is approached, especially for patients with late stage diagnoses and where other forms of treatment would be too risky or ineffective. Further study into these treatment options provides hope in the cancer research community, and gives those who may face hazardous asbestos exposure the chance at a more promising future.Editor’s Note: We would like to thank the team at Mesothelioma + Asbestos Awareness Center for their contribution to this article.
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GEN News HighlightsMore »May 10, 2018Cancer Drug Resistance Predicted by CRISPR ScreensSource: Cambridge UniversityScientists at the Institute of Cancer Research (ICR) in the U.K. have harnessed CRISPR-Cas9 genome-editing technology to uncover why some tumors are resistant to poly(ADP-ribose) polymerase inhibitors (PARPi), such as olaparib and talazoparib. The studies, headed by Chris Lord, Ph.D., professor of Cancer Genomics at ICR, found that mutations in the PARP1 gene prevent the enzyme from being trapped by the drugs when it binds to DNA, resulting in resistance to PARPi therapy in vitro and animal models in vivo, as well as in an ovarian cancer patient who had developed resistance to olaparib.The researchers hope that their results will help clinicians select the most appropriate treatments and drug regimens for patients with breast and ovarian cancer. "PARPi are hugely exciting new drugs which are especially effective in women with BRCA mutations—but unfortunately, as with many other treatments, it is common for cancer cells to eventually develop resistance, ” comments co-researcher Stephen Pettitt, Ph.D., staff scientist in cancer genomics at the ICR. “Our study has discovered one of the reasons why resistance to PARPi such as olaparib might occur. Testing for the mutations we have identified could offer even more personalized treatment for women with breast and ovarian cancer, by allowing doctors to judge whether and for how long olaparib should be used."The ICR team, together with colleagues in the U.K., U.S., and Bulgaria, report on their findings in Nature Communications, in a paper entitled “Genome-Wide and High-Density CRISPR-Cas9 Screens Identify Point Mutations in PARP1 Causing PARP Inhibitor Resistance.”The PARP enzyme PARP1 acts as DNA damage sensor, which attaches to and coordinates the repair of single- or double-stranded breaks in DNA. Drugs that target PARP1 and PARP2 cause the death of cancer cells that already have defects in genes, such as the tumor suppressors BRCA1 or BRCA2, because this double deficit in repair mechanisms is effectively lethal to the cells. Studies have shown that as well as blocking the catalytic activity of PARP1, most clinical PARPi cause cytotoxicity by trapping PARP1 where it binds to DNA at the sites of DNA damage.To try and understand the mechanisms of PARPi toxicity in even greater detail, the ICR researchers developed genome-wide, high-density CRISPR-Cas9 “tag-mutate-enrich” mutagenesis screens. The approach involved generating mutations in specific sections of the PARP1 gene, and tagging the mutated proteins so that the effects on cancer cell response to drug therapy could be tracked. Using this method the team could generate and identify near full-length mutant forms of PARP1 that cause resistance to PARPi both in vitro and in tumor-bearing animal models. Mice with PARP1-mutant tumors were more resistant to therapy with talazoparib, whereas the drug delayed tumor growth and increased survival in control animals.Specific mutations in the DNA-binding region of the PARP1 gene were found to disrupt the ability of the enzyme protein to bind to DNA, and so prevented PARPi from trapping them at the site of DNA damage. Interestingly, even mutations at sites on the PARP1 gene that are not known to be directly involved with DNA binding caused PARPi resistance, suggesting that they may also prevent PARP1 trapping. Further analyses suggested that these mutations may affect amino acids that are involved in hydrogen-bonding interactions that act to bridge the DNA-binding and catalytic domains of the protein, which could ultimately impact on PARP1 trapping. “Our genetic screens also uncovered several clusters of mutations that suggest that regions of PARP1 outside the DNA-binding domain can influence trapping, observations that are consistent with inter-domain interactions being critical for PARP1 binding and activation, ” the authors state.More surprisingly, some cancer cells with mutant BRCA1 were resistant to PARP1 inhibitors, even when the enzyme couldn't carry out DNA repair. The team's analyses suggested that some residual BRCA1 function may be retained in these cells, which is enough to support cell survival even when PARP1 is mutated. “Our experiments also showed that PARP1 mutation can be tolerated in certain BRCA1 mutant, PARPi-sensitive tumour cells, ” the researchers comment. “This suggests that PARP1 trapping still underlies the increased cytotoxicity of PARPi in these tumour cells but that some residual BRCA1 function allows these cells to tolerate PARP1 mutations.…”In parallel with their screening studies, the researchers analyzed cells from an ovarian cancer patient who had developed olaparib resistance. They identified a specific mutation in the patient's PARP1 gene that meant the enzyme could still be recruited to sites of DNA damage, but didn’t bind well to the DNA, so wasn’t trapped by the drug. “…we also observed a PARP1 mutation that abolished trapping in a patient with de novo resistance to olaparib, suggesting that such mutations can arise in patients and could potentially contribute to resistance.”The team says that the finding that PARP1 mutations outside of the DNA-binding domains can still influence PARP1 trapping, and so PARPi resistance “…reinforces the importance of trapped PARP1 as a cytotoxic DNA lesion and suggests that PARP1 mutations are also tolerated in cells with a pathogenic BRCA1 mutation where they result in distinct sensitivities to chemotherapeutic drugs compared to other mechanisms of PARPi resistance.”They further suggest that their "tag-mutate-enrich” approach could, in principle, be used to generate full-length mutants of any gene associated with a particular disease. “This could be employed in the analysis of other resistance mutations observed in patients being treated with targeted therapies in order to annotate likely drivers and passengers of resistance." "The evolution of cancers into drug-resistant forms is a major challenge we face in getting cancer treatments to work, ” states Dr. Lord. “Studies like this can tell us how and why drug resistance occurs, and give us new ways of predicting the likely response to new-style targeted drugs. We hope our research will help doctors use the best drug right from the outset, respond quickly to early signs of resistance, and work out the best ways to combine treatments to overcome drug resistance.Charles Swanton, Ph.D., Cancer Research UK's chief clinician, adds, “This ambitious study using state-of-the-art molecular technologies shows new ways in which tumors become resistant to PARPi, a family of drugs discovered and developed by Cancer Research UK–funded scientists. Importantly, this resistance may influence the success of future treatment options, so increasing our understanding of how resistance occurs means we may be able to design even better therapies and predict how well a patient may respond to future treatment.""Studies like this, which build on the development of PARPi as a brand new treatment option for some women with breast cancer, could help take us a step closer to an even more personalized approach to treating the disease, " noted Baroness Delyth Morgan, chief executive at Breast Cancer Now, which partly funded the study. “It is vital that we understand exactly how and when cancer cells begin to adapt to and resist treatment, so that we can remain one step ahead of often elusive cancer cells.”
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Tumor-Induced Generation of Splenic Erythroblast-like Ter-Cells Promotes Tumor ProgressionYanmei Han9, Qiuyan Liu9, Jin Hou9, Yan Gu, Yi Zhang, Zhubo Chen, Jia Fan, Weiping Zhou, Shuangjian Qiu, Yonghong Zhang, Tao Dong, Ning Li, Zhengping Jiang, Ha Zhu, Qian Zhang, Yuanwu Ma, Lianfeng Zhang, Qingqing Wang, Yizhi Yu, Nan Li, Xuetao Cao10, 'Correspondence information about the author Xuetao CaoEmail the author Xuetao Cao9These authors contributed equally10Lead ContactPublication stage: In Press Corrected ProofPlumX MetricsDOI: https://doi.org/10.1016/j.cell.2018.02.061SummaryHighlights•Ter-119+CD45− erythroblast-like cells were induced in spleen of tumor-bearing mice•TGF-β and Smad3 activation are important in the generation of splenic Ter-cells•Splenic Ter-cells produce artemin, and high serum artemin predicts poor prognosis•Blockade of artemin or its receptor GFRα3 signaling inhibits tumor progressionSummaryIdentifying tumor-induced leukocyte subsets and their derived circulating factors has been instrumental in understanding cancer as a systemic disease. Nevertheless, how primary tumor-induced non-leukocyte populations in distal organs contribute to systemic spread remains poorly defined. Here, we report one population of tumor-inducible, erythroblast-like cells (Ter-cells) deriving from megakaryocyte-erythroid progenitor cells with a unique Ter-119+CD45−CD71+ phenotype. Ter-cells are enriched in the enlarged spleen of hosts bearing advanced tumors and facilitate tumor progression by secreting neurotrophic factor artemin into the blood. Transforming growth factor β (TGF-β) and Smad3 activation are important in Ter-cell generation. In vivo blockade of Ter-cell-derived artemin inhibits hepatocellular carcinoma (HCC) growth, and artemin deficiency abolishes Ter-cells’ tumor-promoting ability. We confirm the presence of splenic artemin-positive Ter-cells in human HCC patients and show that significantly elevated serum artemin correlates with poor prognosis. We propose that Ter-cells and the secreted artemin play important roles in cancer progression with prognostic and therapeutic implications.
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