Skin cancer: a team synthesises new drugs with surprising powers

Finding new, more effective and personalised treatments for cancer is the challenge of many researchers. A challenge that has been successfully met by a team from Inserm led by Stéphane Rocchi (Inserm Unit 1065, “Mediterranean Center for Molecular Medicine”), which has just synthesised and developed new drugs for melanoma. One of them, known as HA15, reduces the viability of melanoma cells without being toxic for normal cells. This work has just been published in the journal Cancer Cell.

Melanoma is a highly aggressive form of skin cancer. It affects melanocytes, the cells responsible for the synthesis of melanin, which gives the skin its colour. There are 3 stages of tumour progression: radial growth, in which the cells proliferate in a disordered manner in the epidermis, the vertical growth phase, which involves invasion of the dermis, and finally the metastatic phase, corresponding to the dissemination of the cancer cells in the peripheral tissues.

Although encouraging results have been obtained for treating the metastatic phase (using targeted therapies or immunotherapies), most patients will need additional treatments to prevent the tumour from coming back, and to prevent more metastases from developing. The identification of new drug candidates is therefore an unavoidable element for the establishment of effective biotherapies against this cancer, the incidence of which is doubling every ten years.

In this context, researchers from Nice discovered a new family of drugs, the Thiazole Benzensulfonamides (TZB), which have useful anticancer properties. “Initially this family of drugs was identified in type 2 diabetes, as it increased the sensitivity of cells to insulin. If we wanted to use it against cancer, we had to be able to eliminate this proinsulin activity,” explains Stéphane Rocchi. “Thus we started to modify its structure.”

After many attempts, the initial TZD structure was extensively modified thanks to a fruitful collaboration with Dr Benhida’s team from the Nice Institute of Chemistry, to obtain a formulation in which the “lead compound” was called HA15.

Their results show that HA15 reduces the viability of melanoma cells without being toxic for normal cells. HA15 induces stress in the endoplasmic reticulum, bringing about the death of the melanoma cells through apoptosis and autophagy.

In the mouse, this drug is highly effective in reducing the tumour volume without obvious toxicity in the rodent.

In humans, in collaboration with the Dermatology Department in Nice University Hospital, the researchers showed that the drugs were active on melanoma cells from biopsies taken from patients who were sensitive or resistant to targeted therapies.

Finally, HA15 is also effective on cell lines from other tumours such as cancer of the breast, colon, prostate, pancreas, and even gliomas and chronic myeloid leukaemias.

“The ultimate goal of this project is to use these new drugs to treat melanoma, and more generally in other types of cancers,” concludes Stéphane Rocchi, who hopes to start a phase I clinical trial soon.

This work has been the subject of two 2 patent applications filed by INSERM Transfert and a presentation to the MATWIN programme for technology transfer, and has received funding for maturation from Canceropole PACA and INSERM Transfert (Grand COPOC).

Stroke study prompts call for revised treatment guidelines

Doctors should rethink how they treat patients who have suffered the deadliest form of stroke, a clinical trial suggests.The study recommends a change in guidelines for treating any patients who have had a stroke caused by bleeding into the brain – known as intracerebral haemorrhage (ICH) – while regularly taking aspirin.

AVCAccident vasculaire cérébral ischémique (AVC)

(c) Inserm/Koulikoff Frédérique


Prof. Yvo Roos (Academic Medical Center Amsterdam) who initiated the study said: “Until now, a treatment known as platelet transfusion has been used by some doctors in the hope that it will aid recovery. It had been thought that platelets – blood cell fragments that play a vital role in blood clotting – could block ruptured blood vessels and prevent further bleeding into the brain in patients who are using anti-platelet therapy”.

However, the team from the Netherlands, France, UK has found that giving platelet transfusions to patients who had suffered an ICH while taking aspirin reduced their chances of recovery.


Prof. Charlotte Cordonnier (Inserm Unit 1171, Univ. Lille, CHU Lille) adds :”Each year, about two million adults worldwide suffer stroke caused by ICH, which accounts for half of all stroke deaths. Two out of five people die within one month, and a further two out of five become dependent on carers. One quarter of patients are taking aspirin before they suffer an ICH.”

Stroke patients who participated in the clinical trial received standard stroke care, but they were also randomly assigned either the platelet transfusion or no extra treatment. Researchers found that platelet transfusions increased the risk of death and long-term disability compared with usual care.

It is unclear why patients given platelet transfusions were worse off than those who were not, researchers say. They suggest that the treatment may cause blood clots to form or trigger inflammation in the brain, worsening bleeding.

Prof. Rustam Al-Shahi Salman, of the University of Edinburgh’s School of Clinical Sciences, who co-led the study, said: “Our study shows that platelet transfusion seems harmful, and certainly is not beneficial, for people who take aspirin and have a stroke caused by bleeding into the brain. These findings should change clinical guidelines.”

Today, the study results are presented at the European Stroke Organisation Conference and are published in The Lancet.

HIV: Identification of key immune response receptors in patients spontaneously controlling infection

A small number of patients infected by HIV spontaneously control viral replication without antiretroviral therapy, and do not develop the disease. The ability of these rare patients, known as “HIV controllers”, to suppress HIV replication appears to be down to a highly effective immune response. Scientists from the Institut Pasteur and Inserm observed that CD4+ T immune cells in these patients, recruited from the ANRS CO21 CODEX cohort, were capable of recognizing tiny quantities of the virus. This highly sensitive detection is dependent on the expression of specific T cell receptors on the surface of immune cells, which target the HIV capsid protein with high affinity. The preferential expression of these receptors appears to keep the immune system on a constant state of alert, thereby enabling the patients to control HIV. These findings have been published in The Journal of Clinical Investigation.


© Institut Pasteur, Charles Dauguet

“HIV controller” patients represent less than 0.5% of all HIV-infected patients. They are proof that in some cases the human immune system can resist the harmful effects of HIV. They are able to maintain a population of functional auxiliary CD4+ T lymphocytes, whereas in patients that have gone on to develop the disease these cells are destroyed or rendered inactive. The patients enrolled in the HIV controller study were recruited from the ANRS CO21 CODEX cohort which includes the few HIV controller patients living in France. Scientists in the team led by Lisa Chakrabarti (Viral Pathogenesis Unit at the Institut Pasteur / Inserm unit U1108), in collaboration with Olivier Lambotte from Bicêtre Hospital, used the cohort to analyze the CD4+ T cell responses of these patients at molecular level.

To trigger the antiviral immune response, the CD4+ T cells of HIV controllers are able to produce numerous cytokines in response to very low doses of HIV antigens. The study revealed that these highly sensitive responses were due to the expression of particular T cell receptors (TCRs) on the surface of the controllers’ CD4+ T cells. In comparison, these TCRs were rarely found on the CD4+ T cells of patients receiving treatment. The scientists showed in particular that the TCRs targeting Gag293, the HIV capsid’s most highly conserved peptide, frequently shared the same sequence in HIV controllers. These “public” TCRs have a strong affinity for the Gag293 peptide, when this peptide is presented at the surface of immune cells. This strong affinity interaction ensures the highly sensitive detection of infected cells in HIV controllers. Transferring these TCRs to healthy cells reproduces the properties typically associated with CD4+ T cells in HIV controllers, with highly sensitive responses and the production of multiple cytokines.


Overall, this research shows that the expression of high-affinity TCRs is linked with spontaneous control of HIV infection. Immunotherapy strategies based on transferring or boosting these TCRs could help restore effective antiviral responses in patients that have gone on to develop the disease.

This research was funded by the ANRS (France REcherche Nord & Sud Sida-HIV Hépatites), the French National Research Agency (ANR), the Institut Pasteur, the Australian Research Council (ARC) and the Australian National Health and Medical Research Council (NHMRC).

Enhanced hippocampal-cortical coupling improves memory

For the first time, scientists in the Center for Interdisciplinary Research in Biology (CNRS/INSERM/Collège de France) have produced direct evidence that the long-term storage of memories involves a dialogue between two brain structures, the hippocampus and cortex, during sleep; by enhancing this dialogue, they succeeded in triggering the consolidation of memories that would otherwise have been forgotten. This work is published in Nature Neuroscience on 16 May 2016.

learing concept

(c) Fotolia

Since the 1950s, the principal theories on memory have posited that such traces are initially formed in the hippocampus and then gradually transferred to the cortex for long-term storage. Although supported by numerous experimental studies, this hypothesis had never yet been directly verified.

In order to prove it, the scientists first recorded the activity of the hippocampus and cortex during sleep. They found a correlation between the oscillations observed in these two structures: when the hippocampus emitted sharp wave-ripples, the cortex in turn emitted delta waves and spindles like a series of questions and answers. To establish a link with memory, the scientists then trained rats to memorize the position of two identical objects in a room. During testing the next day, one of the objects had been moved and the rodents had to determine which one. Those that had spent 20 minutes in the room on the first day passed the test, while those that had only been there for three minutes failed. This difference was also reflected in the hippocampal-cortical coupling during sleep just after the initial exploration: coupling was more visible in rats that passed the test the next day. It was then necessary to prove that this was indeed the cause of memorization.

The scientists then developed a system for real-time detection of hippocampal sharp wave-ripples and immediate triggering of cortical delta waves and spindles, or in other words to generate coupling between these two structures on demand. They applied this system in rats that had been trained for just three minutes the first day, and were therefore not expected to remember the position of the objects the next day: these rodents passed the test perfectly. By contrast, if a variable delay was introduced between the hippocampal and cortical waves, the effect disappeared.
To better understand the mechanisms at play, the scientists also recorded cortical activity during learning, sleep and the test. They observed that selected neurons changed their activity in the context of coupling during sleep, and that the next day the cortex responded to the task by becoming more active in the vicinity of the object that had been moved.

By demonstrating the mechanisms underlying long-term memorization, this work may shed new light on certain memory disorders in humans. It might thus be possible to envisage overcoming certain memory deficits if they result from the same mechanism as that studied here. However, the ethical issues related to these techniques will need to be addressed and methods will have to be refined to enable selective action on the memories that need to be enhanced, before any clinical application can be envisaged. The team is now set to elucidate the dialogue between the hippocampus and cortex, notably when several memories need to be remembered, or not.

Early morning waking, a winning trend among the French

Setting one’s alarm an hour or two earlier to run, meditate, read or even cook is a trend that is attracting many followers in France, also known as “morningophiles.” Recommended by Hal Elrod in his book The Miracle Morning, this lifestyle, which started in the United States, extols the virtues of waking up very early in the morning, as a source of well-being and productivity.

Are there health benefits involved? Are we all equal when it comes to sleep? What are the risks associated with lack of sleep? Can we do anything about our internal clock?

Such are the questions that are often asked of Joëlle Adrien, neurobiologist and Inserm Research Director, in the Sleep and Alertness Management Workshops that she runs at Hôtel-Dieu Hospital in Paris. In her book Mieux Dormir et Vaincre l’Insomnie (Sleep Better and Overcome Insomnia), she explains the mechanisms of sleep (the ideal duration, the biological clock), explores the various sleep disorders and their remedies, and offers advice to improve the quality of sleep.

couple doing yoga

(c) Fotolia

Unemployment and health

In 2015, a study conducted by Pierre Meneton, entitled “Unemployment is associated with high cardiovascular event rate and increased all-cause mortality in middle-aged socially privileged individuals,” was published in the International Archives of Occupational and Environmental Health.

The results suggest that there may be an association between unemployment and poorer cardiovascular health, unlinked to other conventional risk factors, such as age.

Consult the scientific article to find out more


(c) Fotolia

Genetics and the gut microbiota together contribute to IBD

Modifications of the gut microbiota in chronic inflammatory bowel disease (Crohn’s disease and ulcerative colitis) are both the cause and consequence of these internal disorders. This has been shown a team of French researchers from Inserm, INRA[1], UPMC and AP-HP, who describe these mechanisms and propose new therapeutic approaches. Their work is published in Nature Medicine on 9 May 2016.

Harry Sokol

(c) Harry Sokol – Inserm

Transfer of the microbiota from Card9−/− mice is sufficient to induce the increased susceptibility to colitis observed in Card9−/− mice.

A histology section of axenic, genetically normal mice given the microbiota of genetically normal mice (left) or of Card9−/− mice (right), 12 days after induction of colitis. The colitis is much more severe in mice with the microbiota of Card9−/− mice.


Inflammatory bowel disease (IBD) is characterised by inappropriate inflammation of the digestive tract. It is characterised by inflammatory flare-ups of variable duration and frequency, depending on the patient. This group of diseases usually affects young adults, and its incidence is highest in industrialised countries. Researchers have already discovered susceptibility genes like NOD2, ATG16L1 or CARD9, but also suspect environmental factors and modifications of the gut flora, although when and how these factors are involved is not known.

The CARD9 gene encodes a protein involved in the immune system, and especially in the recognition of microorganisms. “The association between this predisposition gene, the immune system and bacteria deserved to be explored, given that all these factors are involved in IBD,” explains Harry Sokol, leader of this work.


To do this, his team used mice lacking this gene. The researchers found increased sensitivity in the gut of these mice when it was inflamed, with defective healing of the mucosa associated with an interleukin (IL) 22 deficiency and disruptions in the bacterial flora. Observations that did not really surprise them, given that “CARD9 protein expressed by cells of the immune system contributes to the production of IL22, involved in healing and protection of the gut mucosa, and in the recognition of microorganisms,” recalls Harry Sokol.

Except that on transplanting the gut flora from these genetically modified animals to other genetically intact mice but lacking a gut flora, the latter in turn became hypersensitive to gut inflammation. In addition, they also showed a defect in IL22 production. “In other words, the genetic defect in itself is not sufficient to induce the observed malfunctions. Alterations in the composition of the gut flora arising from the absence of CARD9 play a major role in gut hypersensitivity, and the functional defect in the IL22 pathway,” explains Harry Sokol.


The researchers therefore wanted to understand how this altered gut flora could confer these abnormalities on the recipient animal. They then observed that the bacteria present could not, or could only poorly convert tryptophan, an amino acid obtained from food, into an indole derivative that binds to lymphocytes and stimulates IL22 production. An observation that led the researchers to conclude that “Mutation of the CARD9 gene causes a modification of the gut flora mediated by a malfunction of the immune system. The flora loses its ability to produce indole derivatives, helping to exacerbate immunological abnormalities, especially in the IL22 pathway, conducive to inflammation.

These results show how all these mechanisms are interlinked—genetic, immune system and microbiota,” summarises Harry Sokol. “Thus, the abnormalities of the microbiota in IBD are both the cause and consequence of inflammation.”

But most importantly, the researchers showed that these mechanisms were reversible. By giving drugs that can mimic indole derivatives to mice lacking the CARD9 gene, they observed a remission in symptoms, and a return of the IL22 pathway to normal. Exciting results, but it remains to be shown that the same is true of humans. The researchers have already analysed the stools of about a hundred patients with IBD, and have observed a general decrease in the production of indole derivatives by the gut bacteria compared with healthy subjects. By combining this work with a genetic analysis to search for variants of susceptibility genes, they observed that this defect was particularly severe in patients showing a mutation in the CARD9 gene. The idea is now to compensate for this defect in patients. “We can already very easily find patients with a defect in the production of indole derivatives using a simple stool analysis. It may therefore be sufficient to supplement these patients with bacteria producing these derivatives, or directly administer the derivative in question to them.” Work already underway in the laboratory.


[1] “Interactions of commensals and probiotics with the host,” team, MICALIS Institute (Inra-AgroParisTech), Jouy en Josas

Confirmation that the Ebola virus persists in the semen of survivors of the epidemic

An international study, conducted by researchers from the Institute for Development Research (IRD), Inserm and Institut Pasteur and their Guinean partners (Donka University Hospital, Macenta Hospital, National Institute of Public Health, and University of Conakry, confirms that Ebola virus persists in the semen of survivors of the epidemic in Guinea, for up to 9 months after their recovery. These results, which recall the importance of monitoring survivors in order to prevent the risks of new epidemic outbreaks, are published in the Journal of Infectious Diseases on 3 May 2016.

Epidémie d'Ebola en Guinée

(c)  IRD/ Eric Delaporte

PostEboGui: multidisciplinary monitoring of a cohort of Ebola survivors

The objective of the PostEboGui1 programme, which has been conducted in Guinea since November 2014, is to monitor, for 2 years, a cohort of over 700 adults and children who survived2 the most serious Ebola epidemic in West Africa, in 2014. The researchers are developing a multidisciplinary approach (clinical, virological, immunological, social, and public health) in order to identify the clinical and social sequelae of the epidemic, as well as the potential risks of reactivating the virus, or transmitting it sexually

In this study, the researchers monitored the first 450 patients from the PostEboGui programme, both men and women, for 1 year. They took specimens of body fluids (tears, saliva, faeces, vaginal fluids and semen), on the first day of the study, and every 3 months thereafter. In order to detect the presence of the Ebola virus in these fluids, the researchers used molecular biology techniques employing the polymerase chain reaction (PCR) and detection of ribonucleic acid (RNA), in hospitals in Guinea.


Presence of the virus in the semen for up to 9 months after recovery

The results relate to 98 specimens taken from 68 different people. Ebola virus was detected in 10 specimens taken from 8 men, for up to 9 months after recovery. In addition, the researchers showed that the persistence of the virus in semen decreases with time: the virus, present in 28.5% of samples taken between the 1st and 3rd months, was subsequently detected in only 16% between the 4th and 6th months, in 6.5% between the 7th and 9th months, 3.5% between the 10th and 12th months, and finally 0% after 12 months.


Improve survivor monitoring to limit resurgence of the epidemic

These results confirm those published in October 2015 in the New England Journal of Medicine on a cohort of survivors in Sierra Leone. They emphasise the need to recommend, at international level, the use of condoms by survivors in the months following their recovery.

Furthermore, the researchers insist on the importance of developing survivor monitoring, or even making it systematic, in order to limit the risks of a recrudescence of the epidemic.



Under the Ebola Task-Force, researchers are involved in monitoring survivors, especially in Guinea, from different aspects: surveillance of clinical and psychological sequelae, and risks of virus reactivation in patients who have recovered. They also focus on viral reservoirs in humans (the sites of “immune privilege” constituted by the eyes, brain and gonads).


In 2016, other research programmes will complete the scheme:

  • FORCE: This is a therapeutic trial conducted by Inserm in men showing traces of virus in the semen (treatment based on the antiviral agent favipiravir).
  • ContactEboGui: The objective of this project is to monitor people who have had contact with people who have been infected and declared cured (monitored under the PostEboGui programme), and who could have developed largely asymptomatic undiagnosed infections, in order to improve knowledge on the dynamic of the epidemic, and to identify the risks of secondary transmission and understand the routes of transmission.
  • Réservoir: This project is focused on the source of the epidemic, particularly the animal reservoir for the virus, in Guinea, Democratic Republic of the Congo, Cameroon, Congo and Gabon, in order to prevent future epidemics.

Research programmes initiated at the start of the epidemic in 2014 under the aegis of the French National Alliance for Life Sciences and Health (Aviesan) are also being pursued, in the areas of disease diagnosis, clinical trials, and human and social sciences.


1 Funded by the Interministerial Ebola Task-Force, IRD and INSERM, PostEboGui is conducted by the TransVIHMI joint international unit for translational research on HIV and infectious diseases, in partnership with the University of Conakry, the infectious disease department at Donka University Hospital, Macenta Hospital, INSP, and the Socio-Anthropological Analysis Laboratory of Guinea (LASAG) at Sonfonia University.

2   I.e. over half of the patients declared cured in the country.

Control of fertility: a new player identified

Individual small RNAs are responsible for controlling the expression of gonadoliberin or GnRH (Gonadotropin-Releasing Hormone), a neurohormone that controls sexual maturation, the appearance of puberty, and fertility in adults. This has just been demonstrated by the “Development and Plasticity of the Neuroendocrine Brain” team led by Vincent Prévot, Inserm Research Director (Jean-Pierre Aubert Research Centre, Lille). The involvement of microRNAs, transcribed from DNA, occurs around birth, and marks a key step in postnatal development. Failure of these microRNAs to act leads to the disruption or even total cessation of GnRH production by the hypothalamic neurons that synthesise it, and hence to infertility. In the most serious cases, sterility may result. Details of this work in mice are published in the 2 May 2016 issue of the journal Nature Neuroscience.

Figure images Anglais

(c) Inserm/Prévot Vincent

Images showing the expression of the neurohormone GnRH (green) by the hypothalamic neurons that synthetize it in mice in which GnRH neurons have been genetically tagged by the Tomato gene (gene coding for a red fluorescent protein).


Reproductive function is determined by events that take place in the brain. Gametogenesis (the production of spermatozoa and oocytes) and the secretion of hormones by the ovaries and testes are heavily dependent on the hypophysis, a small gland located below the brain, to which it is connected by a capillary network. The latter is in turn controlled by a glandular “orchestra conductor” located at the base of the brain, the hypothalamus. During postnatal development, activation of a small number of highly specialised neurons (the GnRH neurons) in the hypothalamus leads to the synthesis of a hormone, gonadoliberin or GnRH (Gonadotropin Releasing Hormone), and this process leads to the appearance of puberty.

This step, known as “mini-puberty” constitutes the first activation of the reproductive axis by the brain. It occurs between the first and third months of life of the infant, and is important to the correct course of sexual maturation*. At puberty, GnRH stimulates the synthesis by the hypophysis of other hormones, which in turn enter the bloodstream to promote the growth of the gonads (ovaries and testes), and to subsequently ensure reproductive function.

The appearance of puberty remains one of the greatest scientific enigmas of the 21st century. In the last 30 years, the discovery of mutations in various parts of the genome in patients with disorders of puberty has made it possible to identify some genes involved in this process.

However, physicians and scientists believe that these genes are responsible for only a third of the disorders of puberty encountered in patients. The discovery of the involvement of microRNAs opens up considerable prospects for the medical management of these patients, from both a diagnostic and therapeutic point of view.

MicroRNAs are small non-coding RNAs transcribed from our DNA. In contrast to messenger RNAs (mRNA), they are not translated into proteins. Because of this, microRNAs are not part of the “coding genome,” but constitute what some people call the epigenome. Regulation of gene expression, e.g. expression of the GnRH gene, by microRNAs is therefore considered “epigenetic” regulation.

Research conducted in mice by Vincent Prévot’s team shows that birth induces a radical change in the expression of microRNAs in the hypothalamic GnRH neurons. This modification of the microRNA expression profile is essential to the inhibition of the expression of transcription factors (proteins that activate or inhibit gene expression) that have a repressive effect on GnRH expression. This inhibition of inhibitory factors allows increased production of GnRH, which is indispensable to infantile and juvenile sexual maturation, and the occurrence of puberty. Indeed, in the absence of microRNAs, the expression of transcription factors that inhibit GnRH expression increases, and leads to the extinction of GnRH synthesis in the brain, leading to the arrest of sexual maturation, absence of puberty, and complete sterility in adult individuals. Analysis of the GnRH gene in humans shows that analogous phenomena might occur in our own species. The mechanism elucidated by this team might therefore explain the absence of puberty and the occurrence of infertility in some patients for whom no mutation or polymorphism (variation in DNA sequence) has been identified in the coding genome.

Figure Anglais_fusion (c) Vincent Prévot Inserm

(c) Andrea Messina/Inserm

In terms of diagnosis, the study carried out by Vincent Prévot’s team in Lille shows the interest of analysing DNA segments from which microRNAs are transcribed, as well as the genome segments that encode their binding sites on the target genes.

“The work published today shows the importance of studying the genome sequences that will be transcribed into mRNA molecules, to which microRNAs bind in order to regulate their translation into protein,” add the researchers.

From a therapeutic standpoint, the interaction of microRNAs with the genes they regulate may be prevented or mimicked by the administration of small analogous molecules, for which the study done by Vincent Prévot’s team provides proof of concept.

This research received financial support from the French Medical Research Foundation (FRM).   

* This mini-puberty is seriously compromised in premature infants, who are more likely to develop disorders of puberty and adult infertility than infants born at full term.