A new understanding of the genetic process that can lead to cervical cancer may help improve diagnosis of potentially dangerous lesions for some women, and also raises a warning flag about the use of anti-viral therapies in certain cases – suggesting they could actually trigger the cancer they are trying to cure.

The analysis provides a clearer picture of the chromosomal and genetic changes that take place as the human papillomavirus sometimes leads to chronic infection and, in less than 1 percent of cases, to cervical cancer. It is the first to identify specific genes that are keys to this process.

Researchers say they want to emphasise, however, that the HPV vaccine commonly used by millions of women around the world is perfectly safe if done prior to infection with the virus. The concerns raised by this study relate only to viral therapies or possible use of a therapeutic vaccine after the virus has already been integrated into human cells.

‘It’s been known for decades that only women with prior infection with HPV get cervical cancer,’ said Andrey Morgun, an assistant professor and a leader of the study in the OSU College of Pharmacy. ‘In about 90 percent of cases it’s naturally eliminated, often without any symptoms. But in a small fraction of cases it can eventually lead to cancer, in ways that have not been fully understood.’

These findings by researchers from Oregon State University and a number of other universities or agencies in the United States, Norway and Brazil. Collaborators at OSU included Natalia Shulzhenko, an assistant professor in the OSU College of Veterinary Medicine.

The study found that some pre-cancerous lesions can acquire a higher level of chromosomal imbalances in just a small number of cells. These new features appear to do two things at the same time – finally eliminate the lingering virus that may have been present for many years, and set the stage for the beginning of invasive cancer.

So long as the virus is not eliminated, it helps to keep under control viral oncogenes that have been integrated into the patient’s genome, researchers said.

‘Some of what’s taking place here was surprising,’ Morgun said. ‘But with continued work it should help us improve diagnosis and early monitoring, to tell which lesions may turn into cancer and which will not.’

The study also concludes it could be dangerous to use antiviral treatments or therapeutic vaccines with women whose lesions already show signs of HPV integration.

This may help explain why use of the antiviral drug interferon had inconclusive results in the past, in some studies of its value in treating cervical cancer. Patients with existing HPV lesions may wish to discuss findings of this study with their physicians before starting such treatments, researchers said.

Other researchers using a similar analytical approach also found key driver genes in melanoma, according to the report. This approach may have value in identifying genomic changes that are relevant to a range of malignant tumors, scientists said. Oregon State University

Researchers at Case Western Reserve University have found that a single gene poses a double threat to disease: Not only does it inhibit the growth and spread of breast tumours, but it also makes hearts healthier.

In 2012, medical school researchers discovered the suppressive effects of the gene HEXIM1 on breast cancer in mouse models. Now they have demonstrated that it also enhances the number and density of blood vessels in the heart – a sure sign of cardiac fitness.

Scientists re-expressed the HEXIM1 gene in the adult mouse heart and found that the hearts grew heavier and larger without exercise. In addition, the animals’ resting heart rates decreased. The lowered heart rate indicates improved efficiency, and is supported by their finding that transgenic hearts are pumping more blood per beat. The team also discovered that untrained transgenic mice ran twice as long as those without any genetic modification.

‘Our promising discovery reveals the potential for HEXIM1 to kill two birds with one stone – potentially circumventing heart disease as well as cancer, the country’s leading causes of death,’ said Monica Montano, PhD, associate professor of pharmacology, member of the Case Comprehensive Cancer Center, who created the mice for the heart and breast cancer research and one of the lead researchers.

Hypertension and subsequent heart failure are characterised by a mismatch between the heart muscles’ need for oxygen and nutrients and blood vessels’ inability to deliver either at the rate required. This deficit leads to an enlarged heart that, in turn, often ultimately weakens and stops. The researchers showed that increasing blood vessel growth through the artificial enhancement of HEXIM1 levels improved overall function – HEXIM1 may be a possible therapeutic target for heart disease.

The study is the sixth from the team of Dr. Montano and Michiko Watanabe, PhD, professor of paediatrics, genetics, and anatomy at Case Western Reserve School of Medicine and director of Pediatric Cardiology Fellowship Research at Rainbow Babies and Children’s Hospital.
‘Our Cleveland-based collaborative research teams revealed that increasing HEXIM1 levels brought normal functioning hearts up to an athletic level, which could perhaps stand up to the physical insults of various cardiovascular diseases,’ Watanabe said.

The results build on the team’s findings last year that showed increased levels of HEXIM1 suppressed the growth of breast cancer tumours. Using a well-known mouse model of breast cancer metastasis, researchers induced the gene’s expression by locally delivering a drug, hexamethylene-bisacetamide using an FDA-approved polymer. The strategy increased local HEXIM1 levels and inhibited the spread of breast cancer. The team is currently making a more potent version of the drug and intends to move to clinical trials within a few years. Case Western Reserve University School of Medicine

Chlamydia trachomatis is a human pathogen that is the leading cause of bacterial sexually transmitted disease worldwide with more than 90 million new cases of genital infections occurring each year. About 70 percent of women infected with Chlamydia remain asymptomatic and these bacteria can establish chronic infections for months, or even years. Even when it causes no symptoms, Chlamydia can damage a woman’s reproductive organs. In addition, standard antibacterial drugs are proving increasingly ineffective in complete eradication, as Chlamydia goes in to persistent mode, leading to asymptomatic chronic infection. Researchers at the Max Planck Institute for Infection Biology in Berlin (MPIIB) now show that Chlamydia infections can cause mutations in the host DNA by overriding the normal mechanisms by which their host prevents unregulated growth of genetically damaged cells that pave the way for the development of cancer.
Owing to their intracellular lifestyle Chlamydia depend on various host cell functions for their survival. Chlamydia manipulates the host cell mechanism to favour its growth, however the consequences of such alterations on the fate of host cells remains enigmatic. Even more worrying is mounting epidemiological evidence which links Chlamydia infections with the development of cervical and ovarian cancer. Cindrilla Chumduri, Rajendra Kumar Gurumurthy and Thomas F. Meyer, researchers at the Max Planck Institute for Infection Biology in Berlin, have now discovered that Chlamydia induces long-lasting effects on the genome and epi-genome of their host cells. Such changes are increasingly implicated in the development of a range of cancers.

The team found increased levels of DNA breaks in Chlamydia-infected cells. In normal cells, depending on the extent of damage, cells either ‘commit suicide’ or activate repair by special protein complexes in a process called the DNA Damage Response, which reseals the broken strands of DNA and makes sure the sequence of the genetic code has not been changed. Crucially, in Chlamydia-infected cells the DNA Damage Response was impaired, leading to an error-prone repair of the DNA breaks- a potential cause of mutations. Strikingly, despite the presence of extensive DNA damage, Chlamydia infected cells continued to proliferate, facilitated by additional pro-survival signals activated in the host cells by Chlamydia. The flip-side of this forced survival of damaged cells is an increased tendency to evade the normal mechanisms that eliminate cells carrying mutations that could lead to cancer. The team believe that this could be the first step on the path to carcinogenesis of the infected cells, due to uncontrolled cell growth in the presence of accumulating DNA damage – the hallmark of cancer.

The identification of infections as the origin of human cancers is important since it would allow early prevention of cancerogenesis by means of vaccination or antibiotic treatment. Such preventive strategies are currently successfully pursued against the cancer-inducing agents Human Papiloma Virus (HPV) and Helicobacter pylori, the etiological agents of cervical and gastric cancer, respectively. However, many infection-based cancer etiologies have not been firmly established and therefore cancer treatment is usually restricted to patients at an advanced stage and with an established cancer diagnosis. The department of Professor Meyer at MPIIB therefore vigorously pursues several lines of research to unequivocally assess the linkage between bacterial infections and cancer, apart from the well-known carcinogenic role of H. pylori. The current paper by Chumduri et al. constitutes one important mosaic piece, corroborating a potential link between female ascending Chlamydia infections and ovarian cancer in particular. Max Planck Society

Researchers with the UC Davis MIND Institute and Agilent Laboratories have found that Prader-Willi syndrome — a genetic disorder best known for causing an insatiable appetite that can lead to morbid obesity — is associated with the loss of non-coding RNAs, resulting in the dysregulation of circadian and metabolic genes, accelerated energy expenditure and metabolic differences during sleep.
The research was led by Janine LaSalle, a professor in the UC Davis Department of Medical Microbiology and Immunology who is affiliated with the MIND Institute. It is published online in Human Molecular Genetics.
‘Prader-Willi syndrome children do not sleep as well at night and have daytime sleepiness,’ LaSalle said. ‘Parents have to lock up their pantries because the kids are rummaging for food in the middle of the night, even breaking into their neighbours’ houses to eat.’
The study found that these behaviours are rooted in the loss of a long non-coding RNA that functions to balance energy expenditure in the brain during sleep. The finding could have a profound effect on how clinicians treat children with Prader-Willi, as well as point the way to new, innovative therapies, LaSalle said.
The leading cause of morbid obesity among children in the United States, Prader-Willi involves a complex, and sometimes contradictory, array of symptoms. Shortly after birth children with Prader-Willi experience failure to thrive. Yet after they begin to feed themselves, they have difficulty sleeping and insatiable appetites that lead to obesity if their diets are not carefully monitored.
The current study was conducted in a mouse model of Prader-Willi syndrome. It found that mice engineered with the loss of a long non-coding RNA showed altered energy use and metabolic differences during sleep.
Prader-Willi has been traced to a specific region on chromosome 15 (SNORD116), which produces RNAs that regulate gene expression, rather than coding for proteins. When functioning normally, SNORD116 produces small nucleolar (sno) RNAs and a long non-coding RNA (116HG), as well as a third non-coding RNA implicated in a related disorder, Angelman syndrome. The 116HG long non-coding RNA forms a cloud inside neuronal nuclei that associates with proteins and genes regulating diurnal metabolism in the brain, LaSalle said.
‘We thought the cloud would be activating transcription, but in fact it was doing the opposite,’ she said. ‘Most of the genes were dampened by the cloud. This long non-coding RNA was acting as a decoy, pulling the active transcription factors away from genes and keeping them from being expressed.’
As a result, losing snoRNAs and 116HG causes a chain reaction, eliminating the RNA cloud and allowing circadian and metabolic genes to get turned on during sleep periods, when they should be dampened down. This underlies a complex cycle in which the RNA cloud grew during sleep periods (daytime for nocturnal mice), turning down genes associated with energy use, and receded during waking periods, allowing these genes to be expressed. Mice without the 116HG gene lacked the benefit of this neuronal cloud, causing greater energy expenditure during sleep.
The researchers said that the work provides a clearer picture of why children with Prader-Willi syndrome can’t sleep or feel satiated and may change therapeutic approaches. For example, many such children have been treated with growth hormone because of short stature, but this actually may boost other aspects of the disease.
‘People had thought the kids weren’t sleeping at night because of the sleep apnea caused by obesity,’ said LaSalle. ‘What this study shows is that the diurnal metabolism is central to the disorder, and that the obesity may be as a result of that. If you can work with that, you could improve therapies, for example figuring out the best times to administer medications.’ UC Davis Department of Medical Microbiology and Immunology

A breakthrough non-invasive test can detect whether transplanted kidneys are in the process of being rejected, as well as identify patients at risk for rejection weeks to months before they show symptoms, according to a study.
By measuring just three genetic molecules in a urine sample, the test accurately diagnoses acute rejection of kidney transplants, the most frequent and serious complication of kidney transplants, says the study’s lead author, Dr. Manikkam Suthanthiran, the Stanton Griffis Distinguished Professor of Medicine at Weill Cornell Medical College and chief of transplantation medicine, nephrology and hypertension at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
‘It looks to us that we can actually anticipate rejection of a kidney several weeks before rejection begins to damage the transplant,’ Dr. Suthanthiran says.
The test may also help physicians fine-tune the amount of powerful immunosuppressive drugs that organ transplant patients must take for the rest of their lives, says Dr. Suthanthiran, whose laboratory developed what he calls the ‘three-gene signature’ of the health of transplanted kidney organs.
‘We have, for the first time, the opportunity to manage transplant patients in a more precise, individualised fashion. This is good news since it moves us from the current one-size-fits-all treatment model to a much more personalised plan,’ he says, noting that too little immunosuppression leads to organ rejection and too much can lead to infection or even cancer.
Such a test is sorely needed to help improve the longevity of kidney transplants and the lives of patients who receive these organs, says study co-author Dr. Darshana Dadhania, associate professor of medicine and medicine in surgery at Weill Cornell Medical College and associate attending physician at NewYork-Presbyterian Hospital.
Dr. Dadhania says that the primary blood test now used to help identify rejection — creatinine, which measures kidney function — is much less specific than the three-gene signature.
‘Creatinine can go up for many reasons, including simple dehydration in a patient, and when this happens we then need to do a highly invasive needle-stick biopsy to look at the kidney and determine the cause. Our goal is to provide the most effective care possible for our transplant patients, and that means individualizing their post transplant care,’ she says. ‘Using an innovative biomarker test like this will eliminate unnecessary biopsies and provide a yardstick to measure adequate immunosuppression to keep organs — and our patients — healthy.’
Although a number of researchers have tried to develop blood or urine-based tests to measure genes or proteins that signify kidney organ rejection, Dr. Suthanthiran and his research team were the first to create a gene expression profile urine test — an advance that was reported in NEJM in 2001 and, with an update also in NEJM, in 2005.
The research team measured the levels of messenger RNA (mRNA) molecules produced as genes are being expressed, or activated, to make proteins. To do this, they developed a number of sophisticated tools to measure this genetic material. ‘We were told we would never be able to isolate good quality mRNA from urine,’ he says. ‘Never say never.’
He and his colleagues found that increased expression of three mRNAs can determine if an organ will be, or is being, rejected. The mRNAs (18S ribosomal (rRNA)–normalized CD3ε mRNA, 18S rRNA–
The signature test consists of adding levels of the three mRNAs in urine into a composite score. Tracked over time, a rising score can indicate heightened immune system activity against a transplanted kidney, Dr. Suthanthiran says. A score that stays the same suggests that the patient is not at risk for rejection.
‘We were always looking for the most parsimonious model for an organ rejection biomarker test,’ Dr. Suthanthiran says. ‘Minimising the number of genes that we test for is just more practical and helps to give us a clearer path towards diagnosis and use in the clinic.’

Physicians can tailor a patient’s use of multiple immunosuppressive drugs by lowering the doses steadily, and monitoring the patient’s composite score over time. Any increase would suggest a somewhat higher dose of therapy is needed to keep the organ safe. EurekAlert normalised interferon-inducible protein 10 (IP-10) mRNA, and 18S rRNA) indicate that killer T immune cells are being recruited to the kidney in order to destroy what the body has come to recognise as alien tissue.