“Cancer incidence is not a reliable measurement of cancer burden,” said Welch. “Rising incidence may not reflect rising true cancer occurrence but instead reflect overdiagnosis; that is, the detection of small cancers not destined to cause symptoms or death. Overdiagnosis can either be the result of purposely looking harder for the disease — that is, cancer screening — or from stumbling onto small cancers while testing patients for something else. It’s an issue that’s been around for years but this paper highlights that we can’t rely on cancer incidence alone.”

Welch and colleagues examined mortality and incidence patterns from 1975 through 2015 for selected cancers in the United States. The investigators used mortality data from the National Vital Statistics System, maintained by the National Center for Health Statistics, and incidence data from the Surveillance, Epidemiology, and End Results (SEER) Program.

The team illustrated mortality and incidence trends for each cancer and characterized the resulting “signatures.” In some cases, they found a desirable signature: for Hodgkin’s lymphoma and chronic myeloid leukemia (CML), mortality rates have declined, reflecting either gradual treatment improvements (for Hodgkin’s lymphoma) or rapid treatment improvements (CML). Another important example of a desirable signature is lung cancer, where both incidence and mortality have risen and fallen together — the rise and fall of cigarette smoking is followed, three decades later, by the rise and fall of lung cancer occurrence and lung cancer death.

The team also finds good news in rates of stomach, cervical and colorectal cancer, all three of which are simply less common than they were in 1975. The authors point out some likely explanations of these favorable trends, including the decline of a powerful risk factor for stomach cancer (the bacterium Helicobacter pylori) and better screening and treatment of precancerous lesions for cervical cancer.

The authors also provide examples of undesirable signatures, likely reflecting the problem of overdiagnosis. For thyroid cancer, kidney cancer, and melanoma, rates of cancer incidence appear to be rising steeply, but rates of cancer mortality are largely unchanged.

While Welch and colleagues laud the efforts of the federal government to track data and make them publicly accessible, they call for including a critical piece of information in cancer databases in the future: mode of cancer detection. Did the patient present with symptoms? Was the patient screened for cancer? Was their cancer detected by chance?

“Many people have assumed that additional screening is the best thing for population health, but in fact it may not be. You don’t test a population to health,” said Welch.

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A clinical trial funded by the National Institutes of Health has found that for these women, treatment with the antibiotic isoniazid to prevent TB was similarly safe if begun during pregnancy or 12 weeks after delivery. However, there was significantly greater risk of poor health outcomes and death for the fetuses and newborns of these women if isoniazid preventive therapy began during pregnancy than if it began 12 weeks after delivery. This finding is concerning and merits research into alternative approaches to TB preventive therapy in pregnant women, according to the study investigators. Their findings are reported in the Oct. 3 issue of The New England Journal of Medicine.

“Pregnant women are often excluded from clinical research, which leads to an information gap that can pose a danger to maternal and infant health,” said Anthony S. Fauci, M.D. “The findings reported today give women, health-care providers and policy makers high-quality data for weighing the risks and benefits of TB preventive therapy for pregnant women living with HIV who are taking antiretroviral therapy.” Dr. Fauci is Director of the National Institute of Allergy and Infectious Diseases, a component of NIH that co-funded the trial.

TB is the top infectious-disease killer worldwide and the leading cause of death for people living with HIV. Among women, TB mainly affects those of reproductive age. When active TB disease develops during pregnancy or in the weeks after birth, it is associated with poor health outcomes for both the mother and baby.

The study published today found that one or more of a set of poor health outcomes for fetuses and newborns occurred in 24% of pregnancies of women who began taking isoniazid during pregnancy and in 17% of pregnancies of women who began after delivery, a statistically significant difference. This set of poor health outcomes included stillbirth, spontaneous abortion, low birth weight, preterm delivery and congenital abnormalities. When these outcomes were evaluated individually, however, there was no statistically significant difference between the two groups. Nevertheless, the greater incidence of the set of poor pregnancy outcomes in women who began taking isoniazid during pregnancy without any reduction in the risk of TB or improvement in maternal or infant survival is troubling, the investigators conclude.

Medical experts have agreed that generally there is a net benefit to treating active TB during pregnancy and providing isoniazid to prevent active TB in people living with HIV. World Health Organization guidelines currently recommend initiating isoniazid preventive therapy in pregnant women with HIV based on data from nonpregnant adults. However, because pregnant women have previously been excluded from clinical trials of isoniazid preventive therapy, information about the safety, efficacy and appropriate timing of this approach to preventing TB in pregnant women living with HIV and taking antiretroviral therapy (ART) is lacking.

The trial reporting today, TB APPRISE (TB Ante vs. Postpartum PRevention with INH in HIV Seropositive mothers and their Exposed infants), sought to help fill this knowledge gap. The study began in August 2014 at 13 sites in Botswana, Haiti, India, South Africa, Tanzania, Thailand, Uganda and Zimbabwe. The investigators selected these countries in part because they have a high burden of TB — at least 60 of every 100,000 people have the disease.

Also known as IMPAACT P1078, the trial was conducted by the NIH-funded IMPAACT (International Maternal Pediatric Adolescent AIDS Clinical Trials) Network and was led by Amita Gupta, M.D., M.H.S. Dr. Gupta is a professor of medicine and international health at the Johns Hopkins School of Medicine and deputy director of the Johns Hopkins University Center for Clinical Global Health Education. The IMPAACT Network is co-funded by NIAID, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health, all part of NIH.

The TB APPRISE study team enrolled 956 pregnant women ages 18 years or older who were living with HIV and were at 14 to 34 weeks gestation. All but one of the women was taking ART at enrollment. None of the women had suspected active TB, recent known TB exposure, or TB treatment for more than 30 days in the previous year.

Study participants were assigned at random to begin taking daily oral isoniazid either during pregnancy or 12 weeks after delivery. The women who began treatment during pregnancy received tablets of 300 milligrams (mg) isoniazid to take daily from enrollment until their 28th week in the study, and then received identical placebo tablets to take daily until their 40th week after delivery. The women whose treatment was deferred received placebo tablets to take daily from enrollment until 12 weeks after delivery, and then received identical tablets of 300 mg isoniazid to take daily for 28 weeks. Neither the women nor the TB APPRISE investigators knew who was in the immediate treatment group or the deferred treatment group until the end of the trial.

The participants had follow-up visits with study staff every four weeks during pregnancy and delivery. There were 926 deliveries. Then the women and their infants were followed every four weeks after delivery for 48 weeks.

Adherence to the isoniazid treatment regimen was assessed based on self-report and pill counts. By those measures, roughly 88% of study participants completed at least 90% of the treatment regimen. There was no difference in adherence between the two treatment groups.

Some 15% of the women in both treatment groups either experienced serious side-effects or stopped taking isoniazid because the side effects were too difficult to tolerate. There was no statistically significant difference in the rate of these events between the two groups.

Two women in the immediate group and four in the deferred group died, all during the postpartum period, but only two of these women — one in each group — had taken isoniazid. Three women in each group developed TB. These differences were not statistically significant.

“The TB APPRISE study team is extremely grateful to the women who participated in this clinical trial,” said Dr. Gupta. “They have helped underscore the point that data from studies in non-pregnant women cannot always be extrapolated to pregnant women, so clinical trials must include pregnant women to accurately inform global health policy.”

For example, it is possible to study how a single atom is ionized and how an electron leaves the atom. The electron does not simply behave like a point-like particle, but its quantum-physical wave properties play an important role: the electron is actually an electron wave that oscillates on an extremely short time scale — and on a tiny length scale. It is a huge challenge to measure the cycle duration of such an oscillation, but It is even much more difficult to determine its phase: What exactly is the beat the electron oscillation follows? If an electron can be ionized in two different ways, will both electron waves oscillate in perfect unison, or will there be a small time delay (i.e. a phase shift)? A team from TU Wien (Vienna) and the CREOL College at the University of Central Florida has now developed a method to measure the phase of such electron waves. This enables a new, better view of important phenomena used in photosensors or photovoltaics.

Are the electrons or out of sync?

“Any wave consists of wave crests and wave troughs — and the phase of the wave tells us at which points in space and time they are located,” says Stefan Donsa, who developed the new measuring method, working on his dissertation in the research group of Prof. Joachim Burgdörfer (Institute for Theoretical Physics, TU Wien). “If two quantum waves overlap in such a way that each wave peak of one wave meets a wave peak of the other wave, then they add up. But if you shift one of the waves a little so that the wave crest of one wave is superimposed with the wave trough of the other wave, they can also cancel out.” Therefore, phase shifts play a very important role in quantum physics.

It is similar to finding the right rhythm in music: it is not enough for two musicians to play at the same tempo. Their beats must also coincide exactly in time, without any phase shift in between. For this you need a reference clock, such as a conductor or a metronome. The newly developed quantum measurement protocol uses something similar: one atomic process serves as a reference for the other.

One or two photons

“In computer simulations, we have studied helium atoms which are ionized by laser pulses at different energies,” says Iva Brezinova. “The helium atom can absorb a photon from the laser pulse and emit an electron. This electron then has a specific phase, which is extremely difficult to measure.”

The trick of the newly developed method is to add a second quantum effect as a clock — serving as a quantum metronome, so to speak. Instead of absorbing only one photon, the atom can also absorb two photons at once, under certain conditions. This double absorption leads to the same final result — an electron flying away with very specific energy. But this time this electron has a different phase, and this difference can be measured.

Complicated measurement protocols

In attosecond physics it is not possible to simply create a movie of a quantum physical system with a camera. Instead, complicated experimental protocols have to be used. Various such protocols are currently in use, but none of them has so far allowed direct measurement of the electron phase.

The new protocol, which has now been developed by the Viennese team, should make this possible. “Our new measurement protocol allows us to translate the information about the electron phase into its spatial distribution by combining very special laser pulses,” explains Stefan Donsa. “By using the correct type of laser pulses, phase information can be directly obtained from the angular distribution of the electrons.”

The newly proposed experimental protocol has now been published in the journal Physical Review Letters. Now experiments are to test the limits of this method, in order to see which quantum mechanical information can be obtained in practice using the new protocol.

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Nuclear shape abnormalities are frequently observed in human diseases like cancer. Specifically, nuclear abnormalities called micronuclei (small nuclear structures in proximity to the main nucleus) and nuclear blebs (protrusions of the main nucleus) can lead to a severe impact on genomic DNA integrity. These abnormalities have historically been used as a diagnostic and prognostic tool for several cancers, such as breast cancer. Nevertheless, the precise molecular mechanisms behind their formation are not fully understood.

Absence of MOF causes a stochastic loss of nuclear shape

In their latest study, the lab of Max Planck director Asifa Akhtar discovered a spontaneous accumulation of micronuclei and nuclear blebs in primary cells after the loss of the epigenetic regulatory enzyme called MOF. This well-characterized enzyme facilitates the accessibility of genetic material by modifying histones, which are the proteins on which the DNA is wrapped around within the nucleus. “MOF deposits acetyl-groups on the histones. This opens the chromatin, the packaging of the DNA, and enables gene activity and thus the encoding of proteins. We wondered what could be the link between the classical epigenetic regulator MOF and the abnormal nuclear blebs and micronuclei,” explains Asifa Akhtar.

To investigate this question, her team, led by PhD student Adam Karoutas, performed an unbiased identification of the full spectrum of proteins which are acetylated by MOF in the cell. Their analysis revealed that MOF targets not only histone proteins but also the nuclear lamina protein Lamin A/C. Furthermore, the team identified the MOF associated NSL complex responsible for Lamin A/C acetylation. Lamin A/C is one of the building blocks of the mesh-structured nuclear lamina that acts as a viscoelastic shell for the nucleus. The study revealed that loss of Lamin A/C acetylation results in softened nuclei that are prone to mechanical pressure and eventually to breaking. Nuclear blebs and micronuclei are far more likely to be formed under these conditions.

Genomic breakdown in the nucleus

“These nuclear blebs and segregated micronuclei pose a risk to the integrity of cell’s genetic material. When we sequenced the genomic DNA of the primary cells that lack MOF, we found a battle ground,” says Adam Karoutas, the first author of the publication.

The researchers saw that nuclear architecture collapse shreds parts of the cell’s chromosomes while other parts remain completely untouched. Segments of individual chromosomes were broken at many points and reassembled incorrectly. Whole parts were missing, while others were duplicated or reincorporated in the wrong orientation. Scientists and clinicians use the term “chromothripsis” (chromo for chromosome and thripsis is Greek for shattering) to describe this genomic disaster. “Such fatal events are associated with congenital diseases and occur in 20-30% of highly aggressive cancers. However, for the first time, we were able to observe chromothripsis in primary cells that lack only MOF,” says Adam Karoutas.

The desperate attempt of the cell’s DNA repair mechanisms to reassemble the fragments and repair the damage leads to mutations that eventually cause cell division and cell death to get out of control. In an attempt to understand the underlying molecular mechanisms behind this phenomenon, the researchers investigated the epigenetic landscape of the nuclear abnormalities. To their surprise, they found that it was totally different in nuclear blebs and micronuclei compared to their adjacent main nuclei.

An epigenetic mechanism on damage control

“While the main nuclei presented an equilibrium of regions of “loosely packed” and “tightly packed” DNA termed euchromatin and heterochromatin respectively, we observed that DNA within micronuclei and nuclear blebs was mainly in the heterochromatin state. This tighter and denser packed form of DNA is thought principally to suppress gene activity,” says Adam Karoutas.

The scientists termed this newly observed phenomenon as Heterochromatin Enrichment in Nuclear Abnormalities (HENA). Just like HENA decorating a hand, histone modifications were covering the DNA within nuclear abnormalities. “Most strikingly, HENA seems to have an impact on gene transcription. It shuts down the process by which DNA is used as a template to make RNA. Thus, genes which are “trapped” within nuclear abnormalities and are potentially damaged, are simply switched off rather than being expressed. We suggest that HENA may play a protective role in cells that accumulate nuclear abnormalities and could become carcinogenic,” explains Asifa Akhtar.

Preventing the road to catastrophe

The scientists hope that future work will determine the role played by the epigenetic mechanism HENA in diseases associated with nuclear abnormalities, such as cancer or upon ageing. Another promising line of research is the pharmacological alteration of Lamin A/C acetylation. “We tested histone deacetylase inhibitors. These are epigenetic drugs already used in cancer therapy. They function by increasing overall protein acetylation. In our first trials in mammalian cells, we observed an increase of Lamin A/C acetylation that rescued nuclear abnormalities compared to cells lacking MOF,” says Adam Karoutas. “How MOF-dependent Lamin A/C acetylation is regulated in living organisms is not understood. Thus, a complete characterization of this discovery in mouse models in different tissues or upon ageing would be the next logical step and provides an exciting possibility of unraveling the therapeutic potential in future.” says Asifa Akhtar.

Researchers say that the findings may have implications for how babies are screened for hearing loss and how mild-to-moderate hearing loss in children is managed by healthcare providers.

The structure and function of the auditory system, which processes sounds in the brain, develops throughout childhood in response to exposure to sounds. In profoundly deaf children, the auditory system undergoes a functional reorganisation, repurposing itself to respond more to visual stimuli, for example. However, until now relatively little was known about the effects of mild-to-moderate hearing loss during childhood.

A research team led by Dr Lorna Halliday, now at the MRC Cognition and Brain Sciences Unit, University of Cambridge, used an electroencephalogram (EEG) technique to measure the brain responses of 46 children who had been diagnosed with permanent mild-to-moderate hearing loss while they were listening to sounds.

Dividing the children into two groups — younger children (8-12 years) and older children (12-16 years) — the team found that the younger children with hearing loss showed relatively typical brain responses — in other words, similar to those of children with normal hearing. However, the brain responses of older children with hearing loss were smaller than those of their normally hearing peers.

To confirm these findings, the researchers re-tested a subset of the group of younger children from the original study, six years later. In the follow-up study, the researchers confirmed that as the children with hearing loss grew older, their brain responses changed. Responses that were present when the children were younger had either disappeared or grown smaller by the time the children were older. There was no evidence that the children’s hearing loss had worsened over this time, suggesting instead that a functional reorganisation was occurring.

“We know that children’s brains develop in response to exposure to sounds, so it should not be too surprising that even mild-to-moderate levels of hearing loss can lead to changes in the brain,” says Dr Axelle Calcus, lead author of the paper, from PSL University, Paris. “However, this does suggest that we need to identify these problems at an earlier stage than is currently the case.”

“Current screening programmes for newborn babies are good at picking up moderate-to-profound levels of hearing loss, but not at detecting mild hearing loss. This means that children with mild hearing impairment might not be detected until later in childhood, if at all,” says Dr Lorna Halliday from the University of Cambridge.

“Children with hearing problems tend to do less well than their peers in terms of language development and academic performance. Detecting even mild degrees of hearing impairment earlier could lead to earlier intervention that would limit these brain changes, and improve children’s chances of developing normal language.”

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