High-density lipoprotein cholesterol (HDL-C) is known as “good” cholesterol, because HDL particles removes excess cholesterol from arterial walls and transport them back to the liver. A research group has developed a practical test for the ability of HDL to accept cholesterol. This method could help to prevent and monitor cardiovascular disease, and it is simple enough to be used in everyday clinical situations.
The group members include Senior Researcher HARADA Amane (Central Research Laboratories, Sysmex Corporation), Project Associate Professor TOH Ryuji (Kobe University Graduate School of Medicine, Division of Evidence-Based Laboratory Medicine) in collaboration with a research team led by Professor HIRATA Ken-ichi (Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine).
Standard health checks measure HDL-C, the amount of cholesterol collected by HDL – they do not look at HDL’s capacity to accept cholesterol. However, HDL’s ability to extract and accept excess cholesterol that has accumulated in cells is a more effective marker in preventing and monitoring cardiovascular disease.
In order to measure HDL’s ability to extract cholesterol (efflux capacity), standard methods use cultured cells that contain cholesterol marked by radioisotopes. This procedure is complicated and takes several days, so it cannot be used in everyday clinical situations. In this study, researchers invented a simpler and faster way to measure HDL capacity.
The team marked cholesterol with fluorescent dye instead of radioactive isotopes and added it to blood serum samples from test subjects. They supplemented the HDL in the blood serum and evaluated the amount of cholesterol accepted by HDL by measuring the strength of the fluorescence . The team called the marker for this method cholesterol “uptake capacity”, as opposed to the conventional method that measures cholesterol “extraction” (efflux) capacity.
The research team is currently using this marker on a larger population to confirm the effect of decreased HDL capacity on the prevention and control of cardiovascular disease. The results of this study could help in creating strong core technology to develop drugs that improve HDL’s function.

Kobe University
www.kobe-u.ac.jp/research_at_kobe_en/NEWS/news/2017_07_10_01.html

Researchers at UC San Diego Moores Cancer Center, with colleagues from Memorial Sloan Kettering Cancer Center and Fox Chase Cancer Center, have determined that a specific region of the small bowel, called the duodenal-jejunal flexure or DJF, shows a high frequency of gastrointestinal stromal tumours (GISTs) with mutations of the NF1 gene.
The small bowel, where approximately 30 percent of all GISTs occur, is divided into three anatomically, histologically and functionally distinct segments: the duodenum, jejunum and ileum. Most small bowel GISTs are associated with KIT mutations. However, a subset of GISTs have mutations in other genes, such as NF1.
“Where the duodenum transitions into the jejunum, we are finding an over-representation of NF1-mutated GIST,” said Jason Sicklick, MD, surgical oncologist at Moores Cancer Center.
NF1 can be mutated both somatically (within tumour DNA) or in the germline (part of the hereditary condition called Neurofibromatosis type 1 [NF-1]). Patients with NF-1 are 34 times more likely to develop GIST than unaffected individuals.
“Genomic testing for some of these patients revealed occult germline NF1 mutations with no other obvious clinical symptoms of NF-1,” said Sicklick. “Anyone with a GIST should undergo tumour genetic testing. Currently only 8 to 15 percent of patients get tested. For those patients with NF1 mutations, there are implications for family members of patients who test positive for hereditary NF-1, as they also may be at increased risk of developing cancers, including GIST.”
According to the National Institutes of Health, NF-1 is a condition characterized by changes in skin colouring and the growth of tumours along nerves in the skin, brain and other parts of the body, such as the GI tract. The signs and symptoms of this condition vary widely among affected persons. NF-1 occurs in one in 3,000 to 4,000 individuals worldwide.
GIST represents the most common type of sarcoma in the GI tract, with an annual incidence of 6.8 cases per million people in the United States. These tumours start in special cells in the wall of the GI tract, called the interstitial cells of Cajal (ICCs). ICCs are sometimes dubbed the “pacemakers” of the GI tract because they signal the muscles in the digestive system to contract through peristalsis, moving food and liquid through the system.
Sicklick and colleagues at Moores Cancer Center are searching for a personalized approach to GIST tumours that become progressively resistant to treatment. Ultimately, more than 95 percent of patients with drug-resistant GIST succumb to their cancer, highlighting the necessity for alternative therapeutic targets.
“Patients with GIST should have their tumours profiled with next-generation sequencing panels,” said first author Adam Burgoyne, MD, PhD, medical oncologist at Moores Cancer Center. “We are uncovering a subset of patients, including patients with mutations of KIT, who have downstream mutations that may render them insensitive to conventional targeted therapy.”
Sicklick added: “This insight helps physicians to know which drugs will or won’t work in order to properly treat these deadly tumors. Of critical importance in NF1 mutant GIST, standard-of-care drug regimens aren’t effective.”
Sicklick’s recent GIST research has also identified new gene fusions and mutations associated with subsets of GIST patients. He and his team also provided the first evidence that the Hedgehog signalling pathway is central to the formation of GIST, which are frequently driven by the KIT oncogene.

Moores Cancer Center
health.ucsd.edu/news/releases/Pages/2017-08-18-GIST-tumors-linked-NF1-mutations-genetic-testing-needed.aspx

Using fragments of circulating tumour DNA in blood, University of California San Diego School of Medicine researchers were able to identify theoretically targetable genetic alterations in 66 percent of patients with cancer of unknown primary (CUP), a rare disease with seven to 12 cases per 100,000 people each year.
In order to plan treatment for cancer in general, physicians first attempt to pinpoint the primary cancer — where the tumour first developed. In CUP, despite its spread throughout the body, the origin remains unknown, making treatment more difficult. The current standard of care is platinum-based combination chemotherapies with a median survival time of six to eight months.
In a study, researchers report that by sequencing circulating tumour DNA (ctDNA) derived from blood samples in 442 patients with CUP, they were able to identify at least one genetic alteration linked to cancer in 290 — 66 percent — of patients. Researchers used a screening test developed by Guardant Health that evaluates up to 70 genes. Based on known carcinogenic mutations, 99.7 percent of the 290 patients who had detectable tumour DNA in their bloodstream had genomic alterations that could hypothetically be targeted using existing FDA-approved drugs (as off-label use) or with therapies currently under investigation in clinical trials.
“By definition, CUP does not have a definite anatomical diagnosis, but we believe genomics is the diagnosis,” said Razelle Kurzrock, MD, director of the Center for Personalized Cancer Therapy at Moores Cancer Center at UC San Diego Health and senior author. “Cancer is not simple and CUP makes finding the right therapy even more difficult. There are multiple genes and abnormalities involved in different areas of the body. Our research is the first to show that evaluating circulating tumour DNA from a tube of blood is possible in patients with CUP and that most patients harbour unique and targetable alterations.”
“Another advantage of the liquid biopsy is that the location of the cancer does not matter,” said Shumei Kato, MD, assistant professor of medicine at UC San Diego School of Medicine and first author. “With a blood sample, we can analyse the DNA of tumours throughout the body to find targetable alterations. With tissue biopsies, we can only see genomic changes that are in that one site and that may not be the same as what is in different sites not biopsied, such as the lung or bone.”
Moores Cancer Centerhttp://tinyurl.com/y9lffvh3

It is almost axiomatic in medicine that the study of rare disorders informs the understanding of more common, widespread ailments. Researchers from the Perelman School of Medicine at the University of Pennsylvania who study an inherited disorder of skin, hair follicles, nails, sweat glands, and teeth called hypohidrotic ectodermal dysplasia (HED) have identified a mechanism that may also be disrupted in male pattern baldness, a more common condition.
About one in 5,000 to 10,000 people are thought to have HED, although this may be an underestimate of its actual prevalence as this condition is not always diagnosed correctly. HED is most frequently caused by mutations in the EDA, EDAR, EDARRAD and WNT10A genes. In addition to its association with HED, mutations in WNT10A are the most common genetic defect observed in people who are born missing one or more teeth, but do not display other characteristics of the disease. These milder WNT10A mutations occur surprisingly frequently, in about 1 to 2 percent of the population. Interestingly, a variant of the WNT10A gene associated with lower levels of its protein’s expression has been linked to a greater likelihood of male pattern baldness, according to a recent genome-wide association study.
“By analysing mice with the WNT10A mutation, as well as tissues from human patients with WNT10A mutations, we found that WNT10A regulates the proliferation, but not the maintenance, of stem cells in hair follicles,” said Sarah Millar, PhD, vice chair for Basic Research in the Department of Dermatology. “Together with a previously published genome-wide association study, our findings suggest that lower levels of WNT10A may contribute to male pattern baldness in some individuals.”
The team made mouse models for WNT10A-associated HED by deleting the Wnt10a gene.  The mutant mice displayed the same symptoms as HED patients with severe loss of function mutations in the WNT10A gene. Long-term absence of WNT10A leads to miniaturization of hair follicle structures and enlargement of the associated sebaceous glands, a phenomenon that is also observed in male pattern baldness.
Millar’s group and her clinical collaborators, including Emily Chu, MD, PhD, an assistant professor of Dermatology and John McGrath, MD, from King’s College, London, also discovered that cracking and scaling of palm and foot sole skin in WNT10A patients is due to decreased expression of a structural protein called Keratin 9, which is specifically expressed in these regions of skin and contributes to its mechanical integrity.
“Our studies took us back and forth between human patients and our mouse model,” said Millar. “Our goal was to find what happened to cellular components affected by the WNT10A mutation to make better treatments.”
Millar’s group showed that decreased proliferation and Keratin 9 expression in the absence of WNT10A resulted from failure of signalling through a well-characterized pathway that stabilizes a protein called beta-catenin, allowing it to enter the cell nucleus and activate gene transcription.
These findings indicate that small molecule drugs that activate the beta-catenin pathway downstream of WNT10A could potentially be used to treat hair thinning and palm and sole skin defects in WNT10A patients. These agents may also be useful for preventing hair loss in a subgroup of people with male pattern baldness.

Penn Medicine
www.pennmedicine.org/news/news-releases/2017/june/inherited-rare-skin-disease-informs-treatment-of-common-hair-disorders

Gastric carcinoma is one of the most common causes of cancer-related deaths, primarily because most patients present at an advanced stage of the disease. The main cause of this cancer is the bacterium Helicobacter pylori, which chronically infects around half of all humans. However, unlike tumour viruses, bacteria do not deposit transforming genes in their host cells and how they are able to cause cancer has so far remained a mystery. An interdisciplinary research team at the Max Planck Institute in Berlin in collaboration with researchers in Stanford, California, has now discovered that the bacterium sends stem cell renewal in the stomach into overdrive – and stem cell turnover has been suspected by many scientists to play a role in the development of cancer. By showing that the stomach contains two different stem cell types, which respond differently to the same driver signal, they have uncovered a new mechanism of tissue plasticity. It allows tuning tissue renewal in response to bacterial infection.
While it has long been recognized that certain viruses can cause cancer by inserting oncogenes into the host cell DNA, the fact that some bacteria can also cause cancer has been slower to emerge and much harder to prove. While it is now clear that most cases of stomach cancer are linked to chronic infections with H. pylori, the mechanism remains unknown.
Thomas F. Meyer and his colleagues at the Max Planck Institute for Infection Biology in Berlin have spent many years investigating this bacterium and the changes it induces in the cells of the stomach epithelium. In particular, they were puzzled how malignancy could be induced in an environment in which cells are rapidly replaced. They suspected that the answer might lie in the stem cells found at the bottom of the glands that line the inside of the stomach, which continually replace the remaining cells ‘from the bottom up’ – and which are the only long-lived cells in the stomach. Michael Sigal, a clinical scientist of the Charité – Universitätsmedizin Berlin, who joined the Max Planck team, overturned the established dogma to show that H. pylori not only infects the surface cells, which are about to be sloughed off, but that some of the bacteria manage to invade deep into the glands and reach the stem cell compartment. They have now found that these stem cells do indeed respond to the infection by increasing their division – producing more cells and leading to the characteristic thickening of the mucosa observed in affected patients.
They used different transgenic mice to trace cells expressing particular genes, as well as all their daughter cells. The results indicate that the stomach glands contain two different stem cell populations. Both respond to a signalling molecule called Wnt, which maintains stem cell turnover in many adult tissues. Crucially, they discovered that myofibroblast cells in the connective tissue layer directly underneath the glands produce a second stem cell driver signal, R-spondin, to which the two stem cell populations responded differently. It is this signal, which turned out to control the response to H. pylori: following infection, the signal is ramped up, silencing the more slowly cycling stem cell population and putting the faster cycling stem cell population into overdrive.
These findings substantiate the rising awareness that chronic bacterial infections are strong promoters of cancer.

Max Planck Societyhttp://tinyurl.com/yaar3gcy