Screening for tumour cells in the fallopian tubes of women at high-risk for ovarian cancer may help detect the cancer years before it develops further, suggests a new study co-led by researchers at Penn Medicine.
Work from Ronny Drapkin, MD, PhD, an associate professor of Pathology in Obstetrics & Gynecology at the Perelman School of Medicine at the University of Pennsylvania and director of gynaecologic cancer research at the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania, and others, has shown through human tumour studies and animal models that ovarian cancer can start in the fallopian tubes and secondarily move to the ovaries where it is clinically diagnosed. However, it was not clear how and when these cancers developed, or how to best detect them before they progressed to the ovaries. 
The new study traces the origins of high-grade serous ovarian carcinoma (HGSOC), the most frequent type of ovarian cancer that is often diagnosed at advanced stages, back to fallopian tube lesions known as ‘p53 signatures’ and serous tubal intraepithelial carcinomas (STICs) that harbor the TP53 gene mutations.
On average, the timing of the progression from the STICs to ovarian cancer in the five patients analysed was 6.5 years, with the cancer spreading to other areas quickly thereafter. The same TP53 gene mutations showed up in both the tube lesions and ovarian tumours of the women, all of whom also carried other high-risk mutations, such as BRCA or PTEN.
“These data provide much-needed insights into the etiology of ovarian cancer and have important implications for prevention, early detection and therapeutic intervention of the disease,” said Drapkin, who also serves as director of the Penn Ovarian Cancer Research Center. “It points us to a signature in the tubes to look for, and shows us a window of time to spot these cancers before they morph into something more sinister in the ovaries.”
Drapkin conducted early portions of the study while at the Dana-Farber Cancer Institute. Victor E. Velculescu, MD, PhD, of Johns Hopkins Kimmel Cancer Center, served as co-senior author.
The researchers performed next-generation sequencing on 37 samples taken from five patients’ STIC lesions, fallopian tube carcinomas, and ovarian cancers. Samples were also taken from metastases in the appendix, abdomen, and rectum in three patients. In addition, the team further analyzed isolated STIC lesions from four patients, three of whom had BRCA mutations and had their ovaries and tubes removed prophylactically. The fourth had her ovaries and tubes removed and a hysterectomy in the context of a pelvic mass surgery.
The researchers identified sequence changes in the TP53 tumor suppressor gene, a well-known driver gene in HGSOC, in all the patients. Those alterations were identical in all the samples from the same patient, including in the p53 (a tumor protein) signatures, the STIC lesions, and other carcinomas, suggesting that mutation of TP53 was among the earliest initiating events for HGSOC development, the authors said.
To recreate the timeline of the tumors, researchers used a mathematical model that estimates the interval between a “founder” cell of a tumor and the ancestral precursor cell in the lesions, using the mutation rates and cell division times observed in each patient.
In one patient, the time between STICs and ovarian cancer was two years.  For the four remaining patients, the time was, on average, 6.5 years. Importantly, in patients with metastatic lesions, the time between the initiation of ovarian cancer and development of metastases was rapid, with an average of two years, the researchers reported.
The study further supports the concepts behind the recommendation for BRCA carriers and non-carriers to remove the fallopian tubes, rather than the ovaries – which may significantly reduce their risk, as it eliminates the underlying cellular precursors of ovarian cancer, and that preservation of the ovaries provides long-term benefits, particularly for younger women.
Penn Medicine
www.pennmedicine.org/news/news-releases/2017/october/mutation-in-fallopian-tube-lesions-may-help-catch-ovarian-cancer-years-earlier

There is as yet no cure for Alzheimer’s disease. It is often argued that progress in drug research has been hampered by the fact that the disease can only be diagnosed when it is too late for an effective intervention. Alzheimer’s disease is thought to begin long before patients show typical symptoms like memory loss. Scientists have now developed a blood test for Alzheimer’s disease and found that it can detect early indicators of the disease long before the first symptoms appear in patients. The blood test would thus offer an opportunity to identify those at risk and may thereby open the door to new avenues in drug discovery.
One of the hallmarks of Alzheimer’s disease is the accumulation of amyloid-β plaques in the patient’s brain. The blood test, developed by Klaus Gerwert and his team at Ruhr University Bochum, Germany, works by measuring the relative amounts of a pathological and a healthy form of amyloid-β in the blood. The pathological form is a misfolded version of this molecule and known to initiate the formation of toxic plaques in the brain. Toxic amyloid-β molecules start accumulating in the patients’ body 15-20 years before disease onset. In the present study, Gerwert and colleagues from Germany and Sweden addressed whether the blood test would be able to pick up indications of pathological amyloid-β in very early phases of the disease.
The researchers first focused on patients in the early, so called prodromal stages of the disease from the Swedish BioFINDER cohort conducted by Oskar Hanson. They found that the test reliably detected amyloid-β alterations in the blood of participants with mild cognitive impairment that also showed abnormal amyloid deposits in brain scans.
In a next step, Gerwert and colleagues investigated if their assay was able to detect blood changes well ahead of disease onset. They used data from the ESTHER cohort study, which Hermann Brenner started in 2000 at DKFZ, comparing blood samples of 65 participants that were later in the follow-up studies diagnosed with Alzheimer’s disease with 809 controls. The assay was able to detect signs of the disease on average eight years before diagnosis in individuals without clinical symptoms. It correctly identified those with the disease in almost 70% of the cases, while about 9% of true negative subjects would wrongly be detected as positive. The overall diagnostic accuracy was 86%.
Currently available diagnostic tools for Alzheimer’s disease either involve expensive positron emission tomography (PET) brain scans, or analyse samples of cerebrospinal fluid that are extracted via lumbar puncture. The researchers suggest that their blood test serves as a cheap and simple option to pre-select individuals from the general population for further testing by these more invasive and costly methods to exclude the falsely positive subjects.
EMBOwww.embo.org/news/press-releases/2018/a-new-blood-test-useful-to-detect-people-at-risk-of-developing-alzheimer-s-disease

Cancer drops sparse chemical hints of its presence early on, but unfortunately, many of them are in a class of biochemicals that could not be detected thoroughly, until now.
Researchers at the Georgia Institute of Technology have engineered a chemical trap that exhaustively catches what are called glycoproteins, including minuscule traces that have previously escaped detection.
Glycoproteins are protein molecules bonded with sugar molecules, and they’re very common in all living things. Glycoproteins come in myriad varieties and sizes and make up important cell structures like cell receptors. They also wander around our bodies in secretions like mucus or hormones.
But some glycoproteins are very, very rare and can serve as an early signal, or biomarker, indicating there’s something wrong in the body – like cancer. Existing methods to reel in glycoproteins for laboratory examination are relatively new and have had big holes in their nets, so many of these molecules, especially those very rare ones produced by cancer, have tended to slip by.
 “These tiny traces are critically important for early disease detection,” said principal investigator Ronghu Wu, a professor in Georgia Tech’s School of Chemistry and Biochemistry. “When cancer is just getting started, aberrant glycoproteins are produced and secreted into body fluids such as blood and urine. Often their abundances are extremely low, but catching them is urgent.”
This new chemical trap, which took Georgia Tech chemists several years to develop and is based on a boronic acid, has proven extremely effective in lab tests including on cultured human cells and mouse tissue samples.
“This method is very universal,” said first author Haopeng Xiao, a graduate research assistant. “We get over 1,000 glycoproteins in a really small lab sample.”
In comparison tests with existing methods, the chemical trap, a complex molecular construction reminiscent of an octopus, captured exponentially more glycoproteins, especially more of those trace glycoproteins.
Wu, Xiao and Weixuan Chen, a former Georgia Tech postdoctoral researcher, who was also first author of the study alongside Xiao.
For chemistry whizzes, here’s a short summary of how the researchers made the octopus. They took a good thing and doubled then tripled down on it.
Those who recall high school chemistry class may still know what boric acid is, as do people who use it to kill roaches. Its chemical structure is an atom of boron bonded with three hydroxyl groups (H3BO3).
Boronic acids are a family of organic compounds that build on boric acid. There are many members of the boronic acid family, and they tend to bond well with glycoproteins, but their bonds can be less reliable than needed.
“Most boronic acids let too many low-abundance glycoproteins get away,” Wu said. “They can catch glycoproteins that are in high abundance but not those in low abundance, the ones that tell us more valuable things about cell development or about human disease.”
But the Georgia Tech chemists were able to leverage the strengths of boronic acids to develop a glycoprotein capturing method that works exceptionally well.
First, they tested several boronic acid derivatives and found that one called benzoboroxole strongly bound with each sugar component on the glycopeptide. (“Peptide” refers to the basic chemical composition of a protein.) 
Then they stitched many benzoboroxole molecules together with other components to form a "dendrimer," which refers to the resulting branch- or tentacle-like structure. The finished large molecule resembled an octopus ready to go after those sugar components.
In its middle, similarly positioned to an octopus’s head, was a magnetic bead, which acted as a kind of handle. Once the dendrimer caught a glycoprotein, the researchers used a magnet to grab the bead and pull out their chemical octopus along with its ensnared glycopeptides (e.g. glycoproteins).
“Then we washed the dendrimer off with a low pH solution, and we had the glycoproteins analysed with things like mass spectrometry,” Wu said.
The researchers have some ideas about how medical laboratory researchers could make practical use of the new Georgia Tech method to detect odd biomolecules emitted by cancer, such as antigens. For example, the chemical octopus could improve detection of prostate-specific antigens (PSA) in prostate cancer screenings.
“PSA is a glycoprotein. Right now, if the level is very high, we know that the patient may have cancer, and if it’s very low, we know cancer is not likely,” Wu said. “But there is a gray area in between, and this method could lead to much more detailed information in that gray area.”
The researchers also believe that developers could leverage the chemical invention to produce targeted cancer treatments. Immune cells could be trained to recognize the aberrant glycoproteins, track down their source cancer cells in the body and kill them.

Georgia Institute of Technologywww.news.gatech.edu/2018/05/04/chemical-octopus-catches-sneaky-cancer-clues-trace-glycoproteins

Researchers from Case Western Reserve University School of Medicine have discovered how unusually long pieces of RNA work in skin cells. The RNA pieces, called “long non-coding RNAs” or “lncRNAs,” help skin cells modulate connective tissue proteins, like collagen, and could represent novel therapeutic targets to promote skin repair.
In a recent study, researchers identified specific lncRNAs that control genes and behaviour of mouse skin cells. The team found 111 lncRNAs that work with a highly conserved protein network called the Wnt/β-catenin pathway. The Wnt/β-catenin pathway serves as a signalling hub that helps cells across species adjust gene expression in response to their environment. The new study connects this important pathway to a new form of genetic control—lncRNAs.
“LncRNAs are a newly discovered class of genes, and we’ve been working to elucidate their functions and mechanisms as they appear to be critical for human health,” said Ahmad Khalil, PhD, assistant professor of genetics and genome sciences and member of the Case Comprehensive Cancer Center at Case Western Reserve University School of Medicine. “Our findings show that the Wnt/β-catenin pathway activates certain lncRNAs to directly control gene expression in skin fibroblast cells.”
The team studied skin cells, called dermal fibroblasts, that help hair follicles develop, wounds heal, and generally maintain the structural integrity of skin. Fibroblasts orchestrate these important functions with the help of the Wnt/β-catenin pathway, among others. Sustained activation of the Wnt/β-catenin pathway can cause fibroblasts to overproduce connective tissue proteins, like collagen, causing harmful skin fibrosis. According to the new study, lncRNAs serve as an intermediary between Wnt/β-catenin and fibroblast genes.
The researchers showed fibroblasts genetically modified to overproduce β-catenin had 8-14 times higher levels of two specific lncRNAs when compared to control fibroblasts. The researchers named the lncRNAs Wincr1 and Wincr2—Wnt signalling induced non-coding RNA.” The lncRNA levels correlated with significantly higher levels of proteins that help fibroblasts move and contract. The findings suggest disrupting lncRNA levels could change how fibroblasts function in skin.  The study adds to a growing body of evidence that lncRNAs could represent a new arena for drug developers. LncRNAs are intriguing therapeutic targets—recent studies by Khalil and others have implicated lncRNAs defects in all kinds of diseases, including infertility and cancer.
Said Atit, “Specific lncRNAs that operate downstream of the Wnt/β-catenin pathway could serve as drug targets for chronic and acute skin fibrosis conditions.” The researchers are now working to understand how lncRNAs work in various animal models, and how their dysfunction may promote disease.
Case Western Reserve University School of Medicinehttps://tinyurl.com/yan5xss9

Blood stem cells give rise to all of our blood cells: the red blood cells that transport oxygen, the platelets that enable blood coagulation, and our immune cells that protect us from infections. Immune cells can, in turn, be divided into two groups; one that consists of cells with a very short life expectancy and a natural but rather unspecific ability to counteract infections (myeloid cells), and another that, in contrast, consists of very long-lived cells (lymphocytes) that specialize in combatting specific bacteria and viruses.
“The ability of blood stem cells to form all types of blood cells is a fundamental property that is also utilized in connection with bone marrow transplants. An increased understanding of these processes is crucial as immune cells in patients who undergo bone marrow transplants are regenerated very slowly, which results in a long period of immune sensitivity”, says David Bryder who was in charge of the study.
Despite the fact that all of our genes have been mapped, it is still largely unknown how the genes are controlled. What a cell can and cannot do is governed entirely by how the cell uses its genome. David Bryder and his colleagues have searched for genes expressed in immature blood cells but which disappear in connection with their further maturation. They then discovered the HLF gene, which caught their attention for two reasons: one, the gene controls what parts of our DNA are to be used, and two, the gene is directly involved in a rare but very aggressive type of blood cancer.
“Our studies revealed that if the immature blood cells are unable to shut down the HLF gene at the correct stage of development, the lymphocytes – the long-lived immune cells – are unable to form. As a result, you will only have one type of immune defence.”
A single cell must undergo a variety of changes to become cancerous. However, the earliest changes may involve the HLF gene, which give rise to a precursor to leukemia. Patients with leukemia in which the HLF gene is involved have a very poor prognosis, but it has been difficult to generate reliable models for studying the emergence, development and possible treatment of these leukemia more thoroughly. The researchers’ long-term goal is now to identify the mechanisms that can be used to break down these aggressive leukemia.
“The knowledge and experimental model systems we developed concerning how HLF affects blood cell development enables us to map the order of gene mutations that lead to HLF-generated leukemia, which is an important next step towards our goal”, concludes David Bryder.
Lund Universityhttps://tinyurl.com/yd2xl6b2