A  few  years  ago,  Javier  Benítez, director  of  the Human Genetics Group at the CNIO,  received a  call  from Pablo  García  Pavía,  from  the  Cardiology  Unit  of  the  Puerta  de  Hierro University Hospital. This cardiologist was treating two brothers with a rare form of cancer, cardiac angiosarcoma (CAS). Could the experts in genetics do  something?  “At  that  time  we  tried  a  few  ideas,  but  unsuccessfully,”says Benítez. We have had to wait for modern genome analysis techniques to  discover  the  brothers’  genetic  problem.  The  finding  opens  a  way  to identify  CAS  families  who  are  carriers  of  a  mutation  in  the  gene
responsible  for  the disease. Family members  could  then  benefit  from an early diagnosis and the appropriate treatment.

Researchers  in  Benítez’s  group  recently  revaluated  the  case  of  the
brothers  with  CAS.  After  sequencing  their  exome  —  the  part  of  the
genome  that  is  translated  into  protein  and  therefore  the  one  that  most
influences the state of the organism, they  found that the cause of the
illness was a mutation in a gene called POT1.

The  identification  of  this  gene  led  them  directly  to  another  CNIO  group,
the  Telomere  and  Telomerase  Group,  headed  by  María  Blasco.  POT1  is
one of the proteins that comprise the protective shield around telomeres
—  the  structures  that  protect  the  tips  of  chromosomes —  and  it  has
recently  been  identified  as  responsible  for  other  forms  of  hereditary
cancer: melanoma  and  familial  glioma.  Blasco’s  group  is  not  only  one  of
the leading groups in  the field of  telomeres, but has also participated —
together with the groups headed by Carlos López-Otín and Elías Campo —
in  the  first  description  of  the mutation  of  this  gene  in  human  cancer
(chronic lymphocytic leukaemia).

Cardiac  angiosarcoma  is  a  rare  but  malignant  disease.  In  the  case  of
hereditary  CAS,  the  median  survival  expectancy  is  only  four  months
because  the  disease  is  diagnosed  at  an  advanced  stage.  Until  now,  no
related gene has been identified.

CNIO researchers also observed that hereditary CAS occurs in families with
a  high  incidence  of  other  types  of  cancer.  This  is  similar  to  what  is
observed in people affected by the so-called Li-Fraumeni syndrome, which
is caused by a mutation in the tumour suppressor gene — nicknamed the
genome  guardian — P53.  However,  POT1, but  not  P53, was  found
mutated in the families affected by CAS.

The  discovery  of  the  new  mutation  proved  to  be  even  more  significant
from  a  clinical  perspective,  given  that  it  identified  carriers  at  risk  of
developing cardiac angiosarcoma and possibly other tumours.

As  Benítez  explained,  “in  the  past,  we  simply  didn’t  have  anything  that
could  help  in  identifying  these  people  at  risk,  because  there  were  no
markers  for  familial  CAS  or  for  families  with  a  syndrome  similar  to  Li-
Fraumeni  without  P53  mutations.  This  study  uncovers  one  of  the  genes
that explains the high incidence of cancer in some of them.”

“The translation of these results into the clinic is immediate,” says Blasco.
“In fact, we are already helping families that carry this mutation.” CNIO

This new 5-part series of educational guides from Randox Quality Control explains how to improve laboratory performance through quality control.
It is easy for laboratories to get caught up in an abundance of QC statistics and forget the fundamental reason why QC exists in the first instance. QC is about detecting errors and ensuring that the results produced are accurate and reliable. With 70% of all medical decisions based on laboratory results, clinical lab specialists are not examining statistics, but real patients, real results and real lives. These five guides are individually titled as follows:
Designing an appropriate QC procedure for your lab – An effective QC strategy is not as complicated as one might think. It is vitally important that each and every laboratory has a well-designed QC procedure in place.
Troubleshooting QC errors – One analyte has been flagged as “out-of-control”, what is to be done next?
How often is Right for QC? – It is widely accepted that laboratories should perform QC at least every day of patient testing. However, is this adequate for every assay and for every laboratory?
Which QC is the Right QC? – When running internal QC, laboratories need to be assured of the accuracy of the results produced and, to ensure this, have confidence in the QC materials used.
The role of EQA in QC – External Quality Assessment plays an essential role in assuring laboratory quality by facilitating inter-laboratory performance comparison and enabling assessment of the complete testing process.
These guides are available as PDF documents on:www.slideshare.net/Acusera

Researchers funded by the National Institutes of Health have discovered the cellular switch that boosts the activity of sperm cells so that they can travel to the egg.  The finding may lead to new options for male contraception as well as treatments for infertility resulting from problems with sperm mobility.

Inside the male reproductive tract, mature sperm are capable of limited movement. This limited movement, however, is not enough to propel them toward the egg when they enter the female reproductive tract. To begin their journey, they must first be activated by the hormone progesterone, which is released by the egg.

The researchers report that the molecule to which progesterone must bind is the enzyme alpha/beta hydrolase domain containing protein 2 (ABHD2), found in the sperm cell’s outer membrane. The study was conducted by Melissa R. Miller and colleagues at the University of California, Berkley, the University of California, San Francisco, and Yale University School of Medicine in New Haven, Connecticut.

“This is an important advance in explaining how sperm become hypermotile in the female reproductive tract,” said Stuart Moss, Ph.D, director of the male reproductive health program at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, which funded the study.

“Developing new compounds that block ABHD2 ultimately may yield new contraceptive methods to prevent sperm from reaching the egg.”

Similarly, strategies to bypass or enhance the enzyme might provide therapies for treating infertility resulting from sperm that lack movement capability.

Before a sperm can transition to the hyper-active phase, calcium must pass through the cell’s outer membrane and enter the flagella, the tail-like appendage the cell uses to propel itself.  The sperm protein known as CatSper joins with similar proteins in the flagella to allow the entry of calcium.

When the researchers undertook the current study, it was not known whether progesterone interacted directly with CatSper to trigger the calcium influx, or acted on some other molecule (which, in turn, acted on CatSper). Before treating sperm with progesterone, the researchers exposed them to a chemical that inhibits a particular class of enzymes that they believed could include the candidate molecule that acted on CatSper. The hunch proved correct: the treated cells remained inactive after progesterone exposure, indicating that CatSper was not directly involved.

Working with modified progesterone, the researchers eventually isolated ABHD2 from the sperm tails. When the researchers inactivated ABHD2, exposure to progesterone failed to activate the sperm cells, confirming that ABHD2 is the molecular target for progesterone. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Cancer is a result of normal cellular functions going wildly awry on a genetic level. That fact has been known for some time, but increasing evidence is showing that the human microbiome, the diverse population of microorganisms within every person, may play a key role in either setting the stage for cancer or even directly causing some forms of it. A new study from the Perelman School of Medicine at the University of Pennsylvania, led by Erle S. Robertson, PhD and James C. Alwine, PhD, has identified, for the first time, an association between two microbial signatures and triple negative breast cancer (TNBC), the most aggressive form of the disease.

‘Viruses and other microorganisms probably have much more to do with cancer, at least the propagation of cancer and promotion of it, than is really known,’ said Alwine, a professor of Cancer Biology and associate director for core services at the Abramson Cancer Center. Using a microarray technology called PathoChip containing 60,000 molecular probes to identify all known viruses and pathogenic bacteria, fungi, parasites, and other microorganisms, Robertson, a professor of Microbiology and his colleagues screened tissue samples from 100 TNBC patients.

They also examined 40 matched and non-matched controls (matched controls are non-tumour tissue from TNBC patients; non-matched controls are breast tissue from healthy patients).

The team found a distinct microbial signature distinguishing TNBC tissue from normal samples, which could be further delineated into two broad clusters, one predominantly viral and the other predominantly bacterial, with some fungi and parasites.

‘If we look at this closely, we may also find some smaller clusters within those major groups that could give us some insights to unique identifiers for individuals in these clusters,’ stated Robertson, who is also associate director for global cancer research and co-leader of the tumour virology program at the Abramson Cancer Center. He explains that the team found ‘about 30 organisms that provide a specific type of signature to give us clues for developing a diagnostic tool.’ Co-authors Sagarika Banerjee, PhD, and Kristen Peck, from the Robertson lab, screened the organisms, and Michael Feldman, MD, PhD, and Natalie Shi from the department of Pathology and Laboratory Medicine, performed the pathology examinations to identify the TNBC cases.

Among the most prevalent viruses detected were Herpesviruses, Parapoxviruses, Retroviruses, Hepadnaviruses, Polyomaviruses, and Papillomaviruses. Significant bacterial signatures included Arcanobacterium, Brevundimonas, Sphingobacteria, and Geobacillus, while fungal species Pleistophora and Piedra and parasitic organisms Foncecaea and Trichuris were among the prominent ones identified. 

Alwine emphasizes that the detection of these and the other pathogens in TNBC tissues does not necessarily mean that they actually cause cancer. ‘There are a lot of different ways to look at this,’ he pointed out. ‘It’s possible that some of the organisms we’re looking at have a causative effect, but we don’t know that. We can’t say until it’s been thoroughly tested by many more experiments.’ One possibility is that the organisms could be adding something to the cellular microenvironment that helps damaged cells to become malignant or pushes them over the edge into cancer. Alternatively, certain organisms may simply find tumor tissue a favorable environment, without having any direct involvement at all with the cancer. ‘They might just be there because it’s a good place to hang out,’ Alwine said.

In either case, finding a distinct microbial signature associated with cancer raises the prospect of new diagnostic possibilities. ‘We’re looking at the signature as a potential for being able to diagnose cancer, possibly at an earlier stage,’ Alwine explained. Penn Medicine

There’s a typical ‘career’ for some allergic people, and it starts very early on the skin: babies develop atopic dermatitis, food allergies may follow, then comes asthma and later on hay fever. A group of scientists led by Ingo Marenholz and Young-Ae Lee at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), working with colleagues from several institutions, has now identified seven genetic risk loci for this course of disease. Two of these loci were previously unknown and mainly influence the connection between atopic dermatitis and asthma. According to the study, the regions that determine the risk for atopic dermatitis are mainly those that also determine the risk for the further development of the typical allergic career. This course of disease is also called the ‘atopic march.’ The scientists analysed data from nearly 20,000 people.
For their meta-analysis, the researchers concentrated on cases where atopic dermatitis preceded asthma. They included 12 studies with 2,428 patients and 17,034 healthy people. All of these studies were genome-wide association studies (GWAS) based on millions of genetic variants called Single Nucleotide Polymorphisms (SNPs).

It is the first GWAS for the atopic march and showed for the first time that there are specific genetic loci influencing the march’s unfortunate course. ‘Seen from a physician’s perspective, the prominent role of atopic dermatitis genes for later-onset of asthma is very interesting,“ says Young-Ae Lee. Max Delbrück Center for Molecular Medicine