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A major step towards individualized cancer therapy

新闻A major step towards individualized cancer therapy

The team opened a small window in eggshells and implanted ovarian tumour cells on top of the vascular membrane surrounding 10-day-old chicken embryos. Credit: Izumi Mindy Takamiya Fuyuhiko Tamanoi of Kyoto University's Institute for Integrated Cell-Material Sciences (iCeMS) and colleagues in the U.S. succeeded in establishing a powerful and convenient model to analyse human cancer. The researchers developed a chicken egg tumour model in which cultured ovarian cancer cells are transplanted on top of the membrane that surrounds a 10-day-old chicken embryo. An ovarian tumour forms on top of the membrane within three days of transplantation. The team had similar results when they used ovarian tumour samples taken directly from patients, showing that their chicken egg model provides a convenient system for replicating human cancer. This conclusion is supported by their detailed characterization of the tumour, demonstrating that it possesses all major cancer features. "We were surprised when the tumour was formed in three days," says Tamanoi." This is very rapid, considering that it takes weeks to do the same with mice. We can start using this model to test for anti-cancer drugs tailored to each cancer patient's needs. The process can be completed within one week," he says. This is a major step toward individualized medicine for cancer patients. Tamanoi's team, in collaboration with colleagues in France and Saudi Arabia, also developed a new type of biodegradable silica nanoparticle called biodegradable PMO, which is only 200 nanometres in size. The nanoparticles were loaded with the anti-cancer drug doxorubicin and were tested on human ovarian tumour established in the chicken egg. Researchers developed a faster and cheaper way to test cancer drugs to develop patient-specific treatments. Credit: Kyoto University iCeMS The biodegradable PMO carrying doxorubicin quickly eliminated the human ovarian tumours without affecting other organs in the chicken embryo. When a smaller amount of the drug, not enveloped in the nanoparticles, was injected in the egg, severe organ damage ensued. This indicates that the team's nanoparticles prevent anti-cancer drug side effects due to their ability to directly target the tumour. The chicken egg model has several advantages over existing models, such as mouse models, for testing anti-cancer therapies. The tumours form much more rapidly on the chicken embryonic membranes than in mice due to the rich nutrient environment and the incomplete immune system at this stage of embryonic development. Fertilized chicken eggs are also less expensive to use than immune-compromised mice making the model suitable for high throughput experiments.详情>>

2018-06-06 00:00:00
Abi darned: Data confirm Zytiga black-white effects, call for trial race inclusion

新闻Abi darned: Data confirm Zytiga black-white effects, call for trial race inclusion

CHICAGO – A call for trials more inclusive of racial and ethnic minorities opened the annual meeting of the American Society of Clinical Oncology (ASCO), as researchers unveiled the first prospective study of the hormonal therapy Zytiga (abiraterone) from Johnson & Johnson for advanced prostate cancer (PC) in black men vs. white men. Findings ratified what clinicians already had observed retrospectively: Black men respond better to the drug than white men. "We've known this, but the reality is, the work hasn't been done" until now, said ASCO expert Robert Dreicer, a cancer specialist from the University of Virginia, who said that black men with the right access to care may respond "maybe better" than white. Called Abi Race, the study showed black men were more likely to have a decline in prostate-serum antigen (PSA), with a five-month longer median time to PSA worsening than white men (16.6 months vs. 11.5 months). The results are significant because black men are more than twice as likely to die of PC as white, and typically show worse treatment outcomes. Yet in most trials, the percentage of minority participants, including black patients, is disproportionally lower than the same racial group in the general population. Even in the study that led to Zytiga's approval, black men were underrepresented. (See BioWorld Today, April 29, 2011.) "African-American men are not really the problem here," said Duke University's Daniel George, the study's leader. "They were more than happy to participate in these studies once they were presented to them. A big part is access [and] presenting these studies to them at the right time." Anyway, he noted, "you don't have to be on a clinical trial to get abiraterone and to get docetaxel. What we need to be able to do is then help educate clinicians out there that these patients need to be treated and they need to be treated aggressively with standard-of-care therapies when they're most appropriate. I think when that happens, it's really equal by race. We do see similar outcomes." Enrolled in Abi Race were 100 men with metastatic, castration-resistant PC, of whom 50 self-identified as white and 50 as black. They were given a standard treatment regimen for PC – the oral CYP17 inhibitor Zytiga plus prednisone – until the cancer worsened or unacceptable side effects arose. Worsening was measured by way of imaging scans (radiographic progression-free survival, rPFS) and by testing for PSA level in the blood (PSA PFS). Researchers also looked at exploratory research on genetic ancestry, as well as on differences in genomic markers, metabolism and hormone levels by race. The time to radiographic disease progression was similar between the two cohorts, but the race differences turned up when researchers looked at PSA. Zytiga proved more effective at both lowering PSA and delaying PSA progression in black men than white; the median PSA PFS was 16.8 months in black men and 11.5 months in white. After Zytiga treatment, a greater percentage of black men than white men had a PSA decline of 90 percent or more (48 percent vs. 38 percent), 50 percent or more (76 percent vs. 66 percent), and 30 percent or more (86 percent vs. 76 percent). More white patients than black patients, eight vs. four, had no decline in the prognostic PC marker. Scans showed that black men did not have worse outcomes than white men, as the median rPFS was the same for black men and white (16.8 months). While most side effects were similar by race, fatigue appeared more often in white patients than black (40 percent vs. 26 percent). Twice as many black men than white showed low potassium levels (36 percent vs. 18 percent), a known complication of Zytiga's effect on adrenal hormones – and one that can threaten life if not corrected. "It took us almost three years to accrue this study," which received backing from J&J, George said. Duke and the Duke Cancer Network had trouble enrolling in the first year. "We went back to the sponsor, who gave us more funding to make it a multicenter study. Through the Prostate Cancer Clinical Trials Consortium, with support from the Prostate Cancer Foundation, which actually helped develop abiraterone, we were able to finish about 70 percent of the accrual in the last year." Sites mattered, he said. "They weren't necessarily the sites with the greatest number of African-American patients, but they had to have clinical champions and we had to have clinical infrastructure." Even then, "we had to put our Caucasian accrual on hold several times," he added. More analysis ahead "It's interesting that the white patients had a higher percentage of [treatment with] sipuleucel-T [Provenge, Dendreon Pharmaceuticals LLC], one of the therapies [where] we think there may also be a difference in outcome associated with race." Black patients in the study turned up higher rates of hypertension, hyperglycemia and hypercholesterolemia, "factors that would have excluded them from those large prospective phase III studies," he said. "We chose liberal criteria to allow patients on the study in order to maximize the eligibility for our populations." In the study, toxicity proved higher in black patients by 10 percent, with problems such as hyperglycemia, hyperkalemia and hot flashes – "all hormonal-based toxicities, through the adrenal gland, pancreas, or other mechanisms, suggesting perhaps a greater exposure rate to this medicine." Another 100-patient study exploring outcomes of treatment with Zytiga in combination with Erleada (apalutamide), also from Kenilworth, N.J.-based J&J, is underway, and researchers are co-leading an initiative to study all treatments of men with advanced PC through a global registry of 5,000 patients called Ironman. Earlier this year, J&J's Janssen Research & Development LLC won marketing clearance well ahead of its PDUFA date for Erleada, the first therapy to win U.S. regulators' go-ahead for patients with nonmetastatic, castration-resistant PC whose disease has quit responding to medical or surgical treatments that lower testosterone but has yet to spread. The company gained Erleada, a second-generation androgen receptor degrader also known as ARN-509, through its acquisition of Aragon Pharmaceuticals Inc., of San Diego, during the summer of 2013, in a deal initially valued at $650 million up front, with $350 million more in potential milestone payments. The drug was originally sourced from the University of California in 2009. (See BioWorld Today, June 18, 2013, and Feb. 15, 2018.) Clinicians will conduct molecular analysis of blood and tissue samples collected in the study which, George said, proves not only that such an experiment is possible but that "we absolutely need to do this."详情>>

2018-06-04 00:00:00

论文Personalized treatment of myocardial infarction and non-obstructive coronary arteries: an unmet need in a high-risk population

We appreciate the interest of Ciliberti et al. in our article about safety and prognostic relevance of invasive coronary provocative tests in patients presenting with myocardial infarction and non-obstructive coronary arteries (MINOCA).1 They raise concerns about the discharge therapy and the lack of any prognostic role of non-obstructive atherosclerosis. We agree that an optimal medical therapy might improve prognosis in MINOCA. However, no controlled trial has hitherto been conducted regarding pharmacological therapy in MINOCA. Recent retrospective data have suggested that statins, beta-blockers and renin–angiotensin–aldosterone (RAA) system antagonists might have favourable effects in MINOCA patients.2 However, besides being uncontrolled, this study included the whole heterogeneous population of MINOCA, and it is unclear whether the results might entirely be applied to MINOCA caused by vasomotor mechanisms. Indeed, the beneficial effects of statins in vasospastic angina patients are controversial,3 and no beneficial effects are expected from beta-blockers and RAA system antagonists. Importantly, in our study calcium-antagonist discontinuation during follow-up was a relevant prognostic variable, whereas no relation with clinical outcome was found with the use of other drugs.1展开>><<收起

European Heart Journal. Published: 29 May 2018  0
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Study identifies processes in the gut that drive fat build-up around the waist

新闻Study identifies processes in the gut that drive fat build-up around the waist

Credit: CC0 Public Domain Research by scientists at King's College London into the role the gut plays in processing and distributing fat could pave the way for the development of personalised treatments for obesity and other chronic diseases within the next decade. The research is published in Nature Genetics. In the largest study of its kind, scientists analysed the faecal metabolome (the community of chemicals produced by gut microbes in the faeces) of 500 pairs of twins to build up a picture of how the gut governs these processes and distributes fat. The King's team also assessed how much of that activity is genetic and how much is determined by environmental factors. The analysis of stool samples identified biomarkers for the build-up of internal fat around the waist. It's well known that this visceral fat is strongly associated with the development of conditions including type 2 diabetes, heart disease and obesity. By understanding how microbial chemicals lead to the development of fat around the waist in some, but not all the twins, the King's team hopes to also advance the understanding of the very similar mechanisms that drive the development of obesity. An analysis of faecal metabolites (chemical molecules in stool produced by microbes) found that less than a fifth (17.9 per cent) of gut processes could be attributed to hereditary factors, but 67.7 per cent of gut activity was found to be influenced by environmental factors, mainly a person's regular diet. This means that important changes can be made to the way an individual's gut processes and distributes fat by altering both their diet and microbial interactions in their gut. On the back of the study researchers have built a gut metabolome bank that can help other scientists engineer bespoke and ideal gut environments that efficiently process and distribute fat. The study has also generated the first comprehensive database of which microbes are associated with which chemical metabolites in the gut. This can help other scientists to understand how bacteria in the gut affect human health. Lead investigator Dr. Cristina Menni from King's College London said: 'This study has really accelerated our understanding of the interplay between what we eat, the way it is processed in the gut and the development of fat in the body, but also immunity and inflammation. By analysing the faecal metabolome, we have been able to get a snapshot of both the health of the body and the complex processes taking place in the gut.' Head of the King's College London's Twin Research Group Professor Tim Spector said: 'This exciting work in our twins shows the importance to our health and weight of the thousands of chemicals that gut microbes produce in response to food. Knowing that they are largely controlled by what we eat rather than our genes is great news, and opens up many ways to use food as medicine. In the future these chemicals could even be used in smart toilets or as smart toilet paper.' Dr. Jonas Zierer, first author of the study added: 'This new knowledge means we can alter the gut environment and confront the challenge of obesity from a new angle that is related to modifiable factors such as diet and the microbes in the gut. This is exciting, because unlike our genes and our innate risk to develop fat around the belly, the gut microbes can be modified with probiotics, with drugs or with high fibre diets.'详情>>

2018-05-29 00:00:00
酒精、基因与心衰之间的新联系

新闻酒精、基因与心衰之间的新联系

The researchers investigated faulty versions of a gene called titin which are carried by one in 100 people or 600,000 people in the UK. Titin is crucial for maintaining the elasticity of the heart muscle, and faulty versions are linked to a type of heart failure called dilated cardiomyopathy. Now new research suggests the faulty gene may interact with alcohol to accelerate heart failure in some patients with the gene, even if they only drink moderate amounts of alcohol. The research was carried out by scientists from Imperial College London, Royal Brompton Hospital, and MRC London Institute of Medical Sciences, and published this week in the latest edition of the Journal of the American College of Cardiology. The study was supported by the Department of Health and Social Care and the Wellcome Trust through the Health Innovation Challenge Fund. In the first part of the study, the team analysed 141 patients with a type of heart failure called alcoholic cardiomyopathy (ACM). This condition is triggered by drinking more than 70 units a week (roughly seven bottles of wine) for five years or more. In severe cases the condition can be fatal, or leave patients requiring a heart transplant. The team found that the faulty titin gene may also play a role in the condition. In the study 13.5 per cent of patients were found to carry the mutation—much higher than the proportion of people who carry them in the general population. These results suggest this condition is not simply the result of alcohol poisoning, but arises from a genetic predisposition—and that other family members may be at risk too, explained Dr. James Ware, study author from the National Heart and Lung Institute at Imperial. This MRI image shows a heart with the condition alcohol cardiomyopathy. This is a form of heart failure, triggered by long-term excess alcohol, that causes the main pumping chamber of the heart (the large area on the bottom right of the …more "Our research strongly suggests alcohol and genetics are interacting—and genetic predisposition and alcohol consumption can act together to lead to heart failure. At the moment this condition is assumed to be simply due to too much alcohol. But this research suggests these patients should also be checked for a genetic cause—by asking about a family history and considering testing for a faulty titin gene, as well as other genes linked to heart failure," he said. He added that relatives of patients with ACM should receive assessment and heart scans—and in some cases have genetic tests—to see if they unknowingly carry the faulty gene. In a second part of the study, the researchers investigated whether alcohol may play a role in another type of heart failure called dilated cardiomyopathy (DCM). This condition causes the heart muscle to become stretched and thin, and has a number of causes including viral infections and certain medications. The condition can also be genetic, and around 12 per cent of cases of DCM are thought to be linked to a faulty titin gene. In the study the team asked 716 patients with dilated cardiomyopathy how much alcohol they consumed. None of the patients consumed the high-levels of alcohol needed to cause ACM. But the team found that in patients whose DCM was caused by the faulty titin gene, even moderately increased alcohol intake (defined as drinking above the weekly recommended limit of 14 units), affected the heart's pumping power. Compared to DCM patients who didn't consume excess alcohol (and whose condition wasn't caused by the faulty titin gene), excess alcohol was linked to reduction in heart output of 30 per cent. More research is now needed to investigate how alcohol may affect people who carry the faulty titin gene, but do not have heart problems, added Dr. Paul Barton, study co-author from the National Heart and Lung Institute at Imperial: "Alcohol and the heart have a complicated relationship. While moderate levels may have benefits for heart health, too much can cause serious cardiac problems. This research suggests that in people with titin-related heart failure, alcohol may worsen the condition. "An important wider question is also raised by the study: do mutations in titin predispose people to heart failure when exposed to other things that stress the heart, such as cancer drugs or certain viral infections? This is something we are actively seeking to address."详情>>

2018-05-28 00:00:00
高脂蛋白(a)水平的患者可受益于PCSK9抑制剂

新闻高脂蛋白(a)水平的患者可受益于PCSK9抑制剂

Lipoprotein(a) is a variant of LDL (low-density lipoprotein) cholesterol, and large amounts of data have shown that higher lipoprotein(a) levels are associated with an increased risk of cardiovascular events. Atherosclerosis patients with higher baseline lipoprotein(a) levels have a 26 percent greater risk of coronary death from heart attack than patients with the lowest lipoprotein(a) levels. To date, there have been limited therapies available that can effectively reduce lipoprotein(a) levels and reduce risk of cardiovascular events. In the latest analysis from the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, researchers found that PCSK9 inhibitors reduced lipoprotein(a) levels and that patients starting with higher Lp(a) levels appeared to derive greater absolute benefit from taking PSCK9 inhibitors. Their results were reported at the 86th Annual Congress of the European Atherosclerosis Society. "In addition to its effects for reducing LDL cholesterol, PCSK9 inhibition may emerge as an important option for patients with elevated lipoprotein(a) concentration," said first author Michelle L. O'Donoghue, MD, of the Department of Cardiovascular Medicine at Brigham and Women's Hospital. "We have identified a therapy, evolocumab treatment, that effectively reduces lipoprotein(a) concentration." The FOURIER trial was a randomized, double-blind, placebo-controlled trial, which evaluated adding evolocumab to the treatment regimen in over 27,000 patients with high LDL cholesterol levels. Evolocumab was found to significantly reduce Lp(a) levels and reduce risk of cardiovascular events. Patients with the higher baseline lipoprotein(a) levels benefited the most from evolocumab treatment, with a 24 percent decrease in the risk of heart attack, stroke or cardiovascular death. Patients with lower baseline lipoprotein(a) levels had a 15 percent reduction in risk with evolocumab treatment. "PSCK9 inhibitors may help us achieve a dual goal in treating cardiovascular patients: We might be able to reduce both LDL cholesterol levels and lipoprotein(a) levels with this treatment," said O'Donoghue. "This treatment was particularly effective for patients with higher Lp(a) levels, as these patients derived a greater absolute reduction in risk after evolocumab treatment."详情>>

2018-05-22 00:00:00
IDMC推荐扩大Tiziana公司Milciclib的2a临床试验

新闻IDMC推荐扩大Tiziana公司Milciclib的2a临床试验

Tiziana Life Sciences announces that the independent data monitor committee (IDMC) completed a second, interim analysis of tolerability data from the first eleven treated patients and recommended expansion of the initial cohort to continue enrolment of an additional 20 patients to complete the trial. This phase 2a multi-centre and multi-country clinical trial (CDKO-125A-010) in sorafenib-refractory or -intolerable patients with unresectable or metastatic hepatocellular carcinoma (HCC) is being conducted in Greece, Italy and Israel. Since, this was the first trial with milciclib in HCC patients, a second, interim analysis was scheduled following completion of treatment for the first 11 patients before initiating enrolment of the next 20 patients. Thus, demonstration of good tolerability with acceptable incidence of serious adverse events is an important milestone to initiate a phase 2b trial evaluating combination of milciclib with sorafenib (NexavarÒ; Bayer Germany (BAYN.GR)) in HCC patient. Milciclib treatment was well-tolerated with manageable drug-related toxicities. The IDMC concluded that there were no major signals of tolerability concerns and therefore favours proceeding to expand enrolment. Four patients have completed the study per protocol (6 cycles of treatment in 6 months). Two of these patients and their care provider opted to continue receiving milciclib at full dose as part of compassionate use. A third patient is awaiting ethical committee (EC) approval. Gabriele Cerrone, Chairman of Tiziana Life Sciences, commented: "Establishment of tolerability of milciclib as a single agent in HCC patients is a key pre-requisite to initiate the phase 2b trial to evaluate dosing, tolerability and clinical activity of milciclib in combination with sorafenib (NexavarÒ; Bayer Germany) in HCC patients. Tiziana Life Sciences CEO and CSO Kunwar Shailubhai said: "we are pleased with the conclusion of IDMC that milciclib treatment showed no major signals of tolerability concerns in sorafenib-refractory or -intolerable HCC patients. “These findings are consistent with the findings reported earlier on the long-term tolerability and clinical activity of milciclib in thymic carcinoma, thymoma1 and other solid cancers2. Results from these clinical studies strongly warrant further clinical development of milciclib for treatments of HCC and other cancers.” iziana Life Sciences plc is a UK biotechnology company that focuses on the discovery and development of novel molecules that treat human disease in oncology and immunology. The Company is focused on its lead compound Milciclib. The Company is also in clinical development of foralumab. Foralumab is the only fully human engineered anti-CD3 antibody in clinical development. This phase 2 compound has potential application in a wide range of autoimmune and inflammatory diseases, such as non-alcoholic steatohepatitis (NASH), primary biliary cholangitis (PBS), ulcerative colitis, multiple sclerosis, type-1 diabetes (T1D), inflammatory bowel disease (IBD), psoriasis and rheumatoid arthritis, where modulation of a T-cell response is desirable. Source: Company Press Release详情>>

Pharmaceutical Business Review
2018-05-18 00:00:00

论文心血管风险的血脂、载脂蛋白和炎性生物标志物

Cardiovascular diseases (CVD) are the first cause of death in the world. CVD risk is influenced by multiple factors, some non‐modifiable such as age, sex and genetic background, and others modifiable. Great progress has been made over the last decades in the identification of biomarkers of incident or recurrent CV risk and surrogate endpoints of CV outcomes. We present the current state of knowledge for CV biomarkers in plasma including lipids, apolipoproteins, inflammation‐related, and emerging omics‐based biomarkers. Clinically validated surrogate endpoints for CV outcomes include plasma low‐density lipoprotein (LDL)‐cholesterol reduction, and plasma triglyceride reduction is a likely relevant surrogate endpoint. High‐density lipoprotein (HDL)‐cholesterol is not a validated surrogate endpoint, but is a useful biomarker of CV risk. CV risk biomarkers of interest include apolipoprotein B and non‐HDL‐cholesterol, lipoprotein (a), C‐reactive protein and recently genetic and protein‐based risk scores and gut microbiota‐derived trimethylamine oxide levels. This article is protected by copyright. All rights reserved.展开>><<收起

Accepted manuscript online: 15 May 2018  0
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论文生物标志物作为药物开发的工具:发现、验证、鉴定和使用

The 21st Century Cures Act, approved in the USA in December 2016, has encouraged the establishment of the national Precision Medicine Initiative and the augmentation of efforts to address disease prevention, diagnosis and treatment on the basis of a molecular understanding of disease. The Act adopts into law the formal process, developed by the FDA, of qualification of drug development tools, including biomarkers and clinical outcome assessments, to increase the efficiency of clinical trials and encourage an era of molecular medicine. The FDA and European Medicines Agency (EMA) have developed similar processes for the qualification of biomarkers intended for use as companion diagnostics or for development and regulatory approval of a drug or therapeutic. Biomarkers that are used exclusively for the diagnosis, monitoring or stratification of patients in clinical trials are not subject to regulatory approval, although their qualification can facilitate the conduct of a trial. In this Review, the salient features of biomarker discovery, analytical validation, clinical qualification and utilization are described in order to provide an understanding of the process of biomarker development and, through this understanding, convey an appreciation of their potential advantages and limitations.展开>><<收起

Nature Reviews Rheumatology,Published: 14 May 2018  0
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论文精准医学时代的囊性纤维化

The treatment of people with cystic fibrosis (CF) has been transformed by the availability of drugs that target the basic chloride defect in the disease. The use of drugs that target specific molecular defects embodies the goals of precision medicine, which incorporate preventive and therapeutic strategies and takes into account differences among individuals. However, the entirety of CF care, from diagnosis to understanding the clinical phenotype and developing a therapeutic strategy, depends on taking into account individual characteristics to achieve optimal outcomes. Future therapies are likely to be even more individualized ushering in a new era of precision medicine.展开>><<收起

Paediatric Respiratory Reviews,2018,25:64-72  0
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