A better survival outcome is associated with low blood levels of squamous cell carcinoma antigen, or absence of tumour invasion either into the space between the lungs and chest wall or into blood vessels of individuals with a peripheral squamous cell carcinoma, a type of non-small cell lung cancer (NSCLC).

Lung cancer is the most common cause of cancer-related death worldwide and lung squamous cell carcinomas (SCC) account for 20-30% of all NSCLC. SCC can be classified as either central (c-SCC) or peripheral (p-SCC) depending on the primary location. While c-SCC is the most prevalent, the incidence of p-SCC is increasing and the clinical and biological behaviours of p-SCC remain unclear.

Researchers from Keio University School of Medicine and Saiseikai Utsunomiya Hospital in Japan evaluated several clinical and pathological variables in 280 patients with surgically removed p-SCC in order to identify potential prognostic factors.

Results show that low preoperative levels of squamous cell carcinoma antigen in the serum or either absence of tumour invasion into the pleura (the space between the lungs and chest wall) or tumour vasculature are independent prognostic factors for patients with any stage of p-SCC. These patients had an extended period without disease recurrence and longer overall survival. The same was also seen for the sub-group of patients with early stage I disease.

The authors note that “our study revealed that p-SCCs with pleural or vascular invasion or high serum SCC antigen are more likely to recur than those without it; even in stage I patients. Pleural and/or vascular invasion are thought to be essential steps in the progression and metastasis of p-SCCs and high serum SCC antigen may suggest micro-metastases at the time of surgery.” The authors propose that “patients with high serum SCC levels, vascular invasion or pleural invasion should have their tumour stage upgraded in order to reflect the clear differences in survival. Clinical trials should be performed to evaluate if postoperative chemotherapy would benefit these patients who typically may not receive chemotherapy because of their early stage.” International Association for the Study of Lung Cancer

It’s known that cholesterol levels typically rise as people age and that high cholesterol levels are associated with increased risk of cardiovascular disease. What’s less known is that cholesterol levels begin to decline the more a person ages. Recently, researchers from the University of Texas Medical Branch at Galveston and the University of Kentucky found that differences in one gene can influence a person’s cholesterol levels from midlife to late life.

The study analysed data from the blood samples of more than 590 people from the Framingham Heart Study Original Cohort. The specific gene, APOE, encodes proteins involved in maintaining cholesterol levels. People have different alleles, or variations, of APOE. Three of these alleles are APOE e2, APOE e3 and APOE e4. The APOE e4 allele is associated with an increased risk for several aging-related diseases, including Alzheimer’s disease and cardiovascular diseases such as stroke and coronary heart disease. The APOE e2 allele, on the other hand, is associated with a decreased risk for these diseases.

“The increased risk for cognitive and cardiovascular diseases among older adults who carry an APOE e4 allele may be due, in part, to the fact that these individuals are predisposed to having higher total cholesterol and lower HDL cholesterol from midlife through late life, compared to people with the APOE 3 variant,” said Brian Downer, lead author and UTMB Sealy Center on Aging postdoctoral fellow. “The decreased risk for these diseases associated with the APOE e2 allele may be due to the lower total cholesterol and higher HDL cholesterol across the life span. Further research is needed to determine if reducing total cholesterol and increasing HDL cholesterol decreases the risk for cognitive and vascular diseases among adults who carry APOE e4 alleles.”

Another surprising finding of the study is that higher cholesterol in older adults may be associated with longevity. The researchers observed that adults who lived past 90 years of age had higher total cholesterol during late life compared to adults who did not live past 80 or 90 years of age. This may have important implications for continuing the practice of prescribing cholesterol-lowering medications to older adults.

“The relationship between APOE, cholesterol and longevity is complex and it is important to continue conducting research in this area so that older adults know how to appropriately manage cholesterol levels during old age,” said Downer. One could argue that it may be harmful to prescribe medications to lower cholesterol based on evidence that low cholesterol and a decline in cholesterol in older adults is associated with increased mortality. However, further research will be needed to confirm whether a decline in cholesterol plays a direct role in mortality or if this decline is a result of changes that occur during the period of terminal decline prior to death. University of Texas Medical Branch at Galveston

deCODE genetics, a global leader in analysing and understanding the human genome, havepublished four papers built on whole-genome sequence data from more than 100,000 people from across Iceland. The studies, written by a team of deCODE scientists together present the most detailed portrait of a population yet assembled using the latest for DNA reading technology.
“This work is a demonstration of the unique power sequencing gives us for learning more about the history of our species and for contributing to new means of diagnosing, treating and preventing disease,” said Kari Stefansson, founder and CEO of deCODE and lead author on the papers.
“It also shows how a small population such as ours, with the generous participation of the majority of its citizens, can advance science and medicine worldwide. In that sense this is very much more than a molecular national selfie. We’re contributing to important tools for making more accurate diagnostics for rare diseases; finding new risk factors and potential drug targets for diseases like Alzheimer’s; and even showing how the Y chromosome, a loner in the paired world of our genome, repairs itself as it passes from father to son. Other countries are now preparing to undertake their own large-scale sequencing projects, and I would tell them the rewards are great,” Dr Stefansson concluded.
The papers and their highlights:
“Large-scale whole-genome sequencing of the Icelandic population” demonstrates how deCODE is able to use comprehensive national genealogies to accurately impute even increasingly rare sequence data throughout the population, yielding new discoveries and key data for improving diagnostics.
“Identification of a large set of rare complete human knockouts.” For decades, genes have been knocked out or switched off in mice, as a model system for studying what genes do and how they might affect human health. But what if we could find people in whom genes had been switched off due to rare mutations? The scale and detail of deCODE’s data was used to identify more than a thousand knocked out genes, with nearly 8% of the 104,000 people studied having at least one gene knocked out in this way. The examination of health and other traits in these individuals should provide a unique way to study directly the effect of specific genes on human biology and potentially contribute to the development of new drugs and diagnostics.
“The Y-chromosome point mutation rate in humans” uses more than 50,000 years of male lineage to provide a much more detailed and accurate estimate of the mutation rate in the male sex chromosome. This rate can be used as a kind of evolutionary clock for dating events in the history and evolution of our species and its civilizations. It places the most recent common ancestor of all Y chromosomes in the world today as living some 239,000 years ago – nearly 100,000 years more recent than other estimates and much closer to that of the most recent common ancestor for all mitochondrial DNA, which is passed from mothers to offspring.
“Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease” presents a rare but powerful new risk factor that is also replicated in several European countries and the US. deCODE

Analysis of 607 small cell lung cancer (SCLC) lung tumours and neuroendocrine tumours (NET) identified common molecular markers among both groups that could reveal new therapeutic targets for patients with similar types of lung cancer, according to research.

This study examined the clinical specimens of 607 total cases of SCLC tumours (375) and lung NET (232), which included carcinoid, atypical carcinoid and large-cell neuroendocrine tumors. Biomarker testing was achieved through a combination of DNA sequencing (Next-Generation Sequencing (NGS) or Sanger-based); immunohistochemistry (IHC) to identify which proteins are present; and in situ hybridization (ISH) testing, a form of gene amplification, to determine if any of the markers that can cause cancer cells to grow or to become resistant to treatment are present.

Sequencing data were obtained from 201 total specimens (SCLC=115, NET=86). The 115 SCLC tumors harboured a wide spectrum of gene markers. Sequencing revealed mutations in p53 (57 percent), RB1 (11 percent), ATM, cMET (6 percent), PTEN (6 percent), BRAF (3 percent), SMAD4, KRAS (3 percent), ABL1, APB, CTNNB1, EGFR, FBXW7, FGFR2 (2 percent), HNF1A, HRAS, JAK3 (2 percent), MLH1 and PIK3CA (1 percent).

Multiple genes of interest were found in the NET group of 86 tumours, including 66 pulmonary neuroendocrine carcinomas and 20 carcinoid tumours. Among the neuroendocrine tumours, mutations were seen in p53 (44 percent), FGFR2 (9percent), ATM (9 percent), KRAS (6 percent) and PIK3CA (4 percent) as well as EGFR (2 percent) and BRAF (4 percent). Analysis of the carcinoid tumours revealed fewer markers, with notable mutations in p53 (11 percent), HRAS (11 percent), and BRAF (6 percent).

EGFR amplification was verified for 11 percent (5) of the 46 SCLC tumours tested. No SCLC tumours displayed amplification of cMET or HER2. The neuroendocrine tumours exhibited amplification of EGFR (13 percent), cMET (3 percent), and HER2 (4 percent) amplification, while the carcinoid tumours only showed amplification in EGFR (8 percent).

The overexpression of cKIT (64 percent vs. 37 percent), RRM1 (54 percent vs. 28 percent), TOP2A (91 percent vs. 48 percent), TOP01 (63 percent vs. 43 percent), and TS (46 percent vs. 25 percent) was found more frequently in SCLC tumours compared to lung NET, respectively (p=0.0001 for all). Low expression of PTEN was more often identified in SCLC tumours compared to lung NET (56 percent vs. 36 percent; p=0.001).

Molecular profiling of these lung cancer subtypes is not routinely performed, however, numerous mutations were found to be in common with non-small cell lung cancer tumours. Specifically, an EGFR mutation was noted in one small cell lung cancer specimen and one neuroendocrine specimen, an ALK rearrangement was detected in a neuroendocrine tumor, and HER2 amplification was seen in a neuroendocrine specimen.

“Even cancers that appear to be very similar can be dramatically different at the molecular level, and these differences may reflect unique vulnerabilities that could positively impact therapeutic options and decisions,” said Stephen V. Liu, MD, senior study author and Assistant Professor of Medicine in the Division of Hematology/Oncology at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC. “We are pleased that this research confirms these rarer subtypes; it calls for additional investigation on a larger scale. Once confirmed, molecular profiling of small cell tumours and NET could become standard, as it is currently for non-small cell lung cancers, which will be especially important as more molecularly targeted chemotherapy agents are developed.” ASTRO

Highlighting a potential target in the treatment of multiple sclerosis (MS) and Alzheimer’s disease, new research suggests that triggering a protein found on the surface of brain cells may help slow the progression of these and other neurological diseases.

Working with mice, two research teams at Washington University School of Medicine in St. Louis independently linked the protein to the ability to clear debris from the brain. Such waste builds up both as a by-product of daily mental activities and as a result of misdirected immune system attacks on brain cells. If too much debris is present in the brain for too long, it can contribute to neurological disease.

In one study, scientists showed that Alzheimer’s brain plaques build up more slowly in mice that have a defective version of the TREM2 protein. In another, researchers showed that mice lacking the same protein had trouble cleaning up debris in the brain produced by damage to a protective coating on nerve cells. The problem is thought to occur in MS and other neurological disorders.

“We’ve been very interested in identifying ways to control naturally occurring mechanisms that help clean and repair the brain, and these new studies provide clear evidence that TREM2 could be just such a target,” said Laura Piccio, MD, PhD assistant professor of neurology and senior author of one of the studies.

Scientists are looking for ways to activate the protein to slow or prevent  damage caused by neurological disorders.

Previous studies have linked rare forms of the TREM2 gene to early-onset dementia and increased risk of Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

Scientists knew the protein was found on brain cells called microglia, which help maintain and repair the central nervous system. The new studies are among the first to provide clear evidence that the protein plays an integral role in at least some of these processes.

In Alzheimer’s disease, amyloid beta, a by-product of brain metabolism that is normally cleared from the brain, builds up to form plaques. Researchers in the laboratories of Marco Colonna, MD, the Robert Rock Belliveau MD Professor of Pathology, and John Cirrito, PhD, associate professor of neurology, bred mice lacking the gene with mice genetically engineered to have an Alzheimer’s-like condition.

First author Yaming Wang, PhD, a postdoctoral research scholar, monitored the build-up of amyloid plaques in the mice offspring as they aged and found that the absence of the gene significantly accelerated the accumulation of the plaques.

“We found that microglia cluster around amyloid plaques when TREM2 is present, presumably because the cells are getting ready to absorb the plaques and break them down,” said Colonna. “When TREM2 is absent, this clustering does not occur.”

In MS, misdirected immune cell attacks damage myelin, a protective coating on nerve cells, leaving myelin fragments in brain tissue. Failure to promptly remove this debris can worsen damage caused by the condition and inhibit repair mechanisms.

For the MS study, Piccio and colleagues at the John L. Trotter MS Center at Washington University School of Medicine and Barnes-Jewish Hospital gave a compound called cuprizone to mice that lacked the TREM2 gene. Cuprizone causes loss of myelin in a manner somewhat similar to that seen in people with MS.

“When we give normal mice this chemical, they can clear most of the myelin fragments from the brain,” Piccio said. “But when we gave cuprizone to mice that did not have the gene and looked at their brains four, six and 12 weeks later, we could still see evidence of damaged myelin.”

Motor coordination in these mice also was significantly more impaired after cuprizone exposure. This may reflect enhanced damage to brain cells resulting from the lingering presence of damaged myelin in the brain.

Colonna and his colleagues showed that TREM2 detects molecules associated with amyloid beta and with damaged neurons. They believe that the protein helps keep microglia from self-destructing as debris is cleared from the brain.

“This is a mechanism that is very common in immune cells,” he explained. “When a signal activates immune cells and they start attacking an invader or working to repair an injury, they start using energy very rapidly. If the cells do not receive a second signal confirming the need for their services, this increased energy usage will kill them.” University of Washington in St. Louis