Researchers at Stanford University and in Mexico have found that scorpion venom contains two color-changing compounds that could help fight bacterial infections. The potential pharmacological treasures awaiting discovery in the toxins of scorpions, snakes, snails and other poisonous creatures could lead to countless medical advancements.
By analyzing the fossilized teeth of some of our most ancient ancestors, a team of scientists led by the universities of Bristol (UK) and Lyon (France) has discovered that the first humans significantly breastfed their infants for longer periods than their contemporary relatives.
The results, published in the journal Science Advances, provide the first insight into the practice of weaning that remains otherwise unseen in the fossil record.
The team sampled minute amounts from nearly 40 fossilized teeth of our South African fossil relatives, early Homo, Paranthropus robustus, and Australopithecus africanus.
They measured the proportions of their stable calcium isotopes in the tooth enamel, which are a function of the mother milk intake by infants.
By reconstructing the age at tooth enamel development, they show that early Homo offspring was breastfed in significant proportions until the age of around three to four years, which likely played a role in the apparition of traits that are specific to the human lineages, such as the brain development.
In contrast, infants of Paranthropus robustus, which became extinct around one million years ago and were a more robust species in terms of dental anatomy, as well as infants of Australopithecus africanus, stopped drinking sizeable proportions of mother milk in the course of the first months of life.
These differences in nursing behaviors likely come with major changes in the social structures of groups as well as the time between the birth of one child and the birth of the next.
One of the study’s lead authors, Dr. Theo Tacail from the University of Bristol’s School of Earth Sciences, said: “The practice of weaning — the duration of breastfeeding, age at non-milk food introduction and the age at cessation of suckling — differs among the modern members of the hominid family which includes humans and modern great apes: orangutan, gorillas, chimpanzees, and bonobos.
“The development of such behavioral differences likely play major roles in the evolution of the members of the human lineage, being associated for instance with size and structure of social groups, brain development, or demography.
“However, getting insights into these behavioral changes from fossils that are millions of years old is a challenge and, so far, little evidence allows discussing nursing practices in these fossil species.
“The findings stress the need for further exploration of calcium stables isotopes compositions in the fossil record in order to understand the co-evolution of weaning practices with other traits such as brain size or social behaviors.”
Enteroviral infections are common viral infections with usually rather few symptoms, and they are also believed to be linked to the onset of type 1 diabetes. Type 1 diabetes is a disorder in which the pancreatic insulin-producing beta-cells are destroyed, and it is more common in Finland than anywhere else in the world. A new study by the University of Turku and Tampere University supports the link between enteroviral infections and type 1 diabetes.
The goal of the new study by the research groups of Academy Professor at Turku Bioscience Centre Riitta Lahesmaa and Professor at Tampere University Heikki Hyöty was to understand the mechanisms that control the development of chronic enteroviral infection in the pancreas. The study also aimed at creating a comprehensive picture of the alterations caused by an enteroviral infection that could possibly have adverse health effects.
In the study, cutting-edge proteomic methods were utilized to measure how the infection influences the expression and secretion of thousands of different proteins in the cellular models of a chronic pancreatic enteroviral infection.
Having persisted for almost a year, the chronic enteroviral infections modified the cellular expression of numerous proteins that are key to cellular functions, such as proteins regulating energy metabolism. The infections also caused alterations in the secretion of several proteins.
– For example, the levels of proteins in the regulated secretory pathway participating in the secretion of hormones such as insulin in the beta-cells decreased with the chronic infection. The infections also clearly affected the levels of other proteins that are involved in the function and survival of beta-cells, says Dr. Niina Lietzén from the Turku Bioscience Centre.
– Interestingly, chronic infections that had been developed by using two different virus strains triggered partly very different responses. For example, major differences in the activation of immune responses were discovered between these two models. This indicates that the viruses have different kinds of abilities to manipulate the cellular defense systems, adds Hyöty.
Source: University of Turku
Why is it that you can remember the name of your childhood best friend that you haven’t seen in years yet easily forget the name of a person you just met a moment ago? In other words, why are some memories stable over decades, while others fade within minutes?
They believe that a blood test might one day be able to predict whether someone is likely to live 5 or 10 more years. The authors explain that this would help doctors make important treatment decisions.
For instance, they would be able to ascertain if an older adult is healthy enough to have surgery or help identify those in most need of medical intervention.
A test like this might also benefit clinical trials: Scientists could monitor how an intervention impacts mortality risk without having to run trials until enough people die.
Currently, blood pressure and cholesterol levels can give doctors an impression of a person’s likely lifespan. However, in older adults, these measures become less useful.
Counterintuitively, for people aged 85 or over, higher blood pressure and higher cholesterol levels are linked with lower mortality risk.
Scientists from Brunel University London in the United Kingdom and Leiden University Medical Center in the Netherlands set out to identify any biomarkers in the blood that might help tackle this issue.
The team initially identified metabolic markers associated with mortality. From this information, they created a scoring system to predict when a person might die.
Next, the researchers compared the reliability of the scoring system with that of a model based on standard risk factors. To do this, they studied data from further 7,603 individuals, 1,213 of whom died during follow-up.
After whittling down a long list of metabolites, the researchers settled on 14 biomarkers independently associated with mortality.
Having higher concentrations of some of the 14 biomarkers — including histidine, leucine, and valine — is associated with decreased mortality.
Conversely, having lower concentrations of others — such as glucose, lactate, and phenylalanine — is associated with increased mortality.
The scientists demonstrated that the combination of biomarkers could predict mortality equally well in both males and females. They also tested their findings across several age groups, concluding that “[a]ll 14 biomarkers […] showed consistent associations with mortality across all strata.”
The biomarkers they identified are involved in a wide range of processes in the body, including fluid balance and inflammation. Also, scientists have already linked most of them to mortality risk in previous studies.
However, this was the first time that researchers have demonstrated their predictive power when combined into one model.
This study is just the next step along a path that might lead to a usable blood test. However, the study authors feel encouraged:
“A score based on these 14 biomarkers and sex leads to improved risk prediction as compared [with] a score based on conventional risk factors.”
A long path ahead
The authors do note certain limitations of their study. For example, they were only able to analyze hundreds of the thousands of metabolites present in human serum.
Including more metabolites in future analyses would, the authors predict, “result in [the] identification of many more mortality associated biomarkers and, hence, improved risk prediction.”
“There’s a hope that in the near future we can understand the biomarkers that can be modified, perhaps by helping people improve their lifestyle or through medication, to lower the risk of death before a significant deterioration of health.”
Study co-author Dr. Fotios Drenos
Although this exact test would not be suitable for use by the general public, it could eventually evolve and move into the public sphere in the same way that genetic testing has.
Perhaps, in the future, the question might not be, “How long will I live?” but rather, “Do I want to know?
Source: Medical News Today
Harvard University chemists have achieved what a new paper calls a “landmark in drug discovery” with the synthesis of halichondrin.
Researchers from the University of Montreal Hospital Research Centre (CRCHUM) have developed a two-step combination therapy to destroy cancer cells. In a study published in the journal Nature Communications, they show the superior therapeutic effectiveness of the “one-two punch” on cells of ovarian cancer patients, based on the manipulation of the state of cellular aging.
Within the pharmaceutical industry, 45% of clinical trials are completed late, or 70%-80% of studies are delayed or do not meet their timelines.
Due to these reasons, one of the main goals for a CRO is to create a mitigating strategy that overcomes the challenges that we commonly find in conducting a clinical study. They seek sites that fit with protocol specifications and requirements. It is these standards that have a direct impact on the quality of data collected, study timelines, and general project finances.
Step 1: Sponsor/CROs define site requirements and selection criteria
The first step in selecting appropriate sites for a study is to identify key site criteria from the study design. This data provides the fundamentals that will guide site selection. These criteria include:
- Staff qualifications: availability of staff, specialty, credentials, their performance in regulatory compliance, experience in clinical research, and experience in the indication studied.
- Facilities and equipment: adequate facility space, drug/device storage and security space, types of source documents, and equipment needed for the study.
- Site profile and timelines: site types (hospitals or clinics, academic sites, non-profit, government, and private sites), site Institutional Review Board (IRB) meeting schedules, and typical contract negotiation schedules.
- Population profile and access: availability and proximity of eligible participants, the incidence of diseases and conditions, ongoing trials that recruit similar patients, and recruitment capabilities (including resources for outreach).
- Previous Performance: Clinical trial experience including trials with similar enrollment timelines, enrollment target and complexity, and prior enrollment fees.
- Competence: Concurrent trials in the same indication/ targeting the same population profile that is ongoing or is scheduled to begin during the conduct of the study.
Step 2: Sponsor/CROs identify sites and collect information
Once the criteria are defined, identification of the sites will be done by:
- The internal database of the sponsor of previously used sites
- External database of CROs
- A site network organization that owns or manages a network of sites
- Online and offline directories
- Publications of recent clinical trials in the indication studied
- Publications on Clinicaltrials.gov
- Word of mouth referrals.
Sponsors & CROs generally request a feasibility questionnaire to identify population profiles according to the study protocol.
Step 3: Sponsor/CRO perform an evaluation
The sponsor and/or CRO evaluate through Pre-Study Visits (PSV), or Site selection Visits (SSV) carried out by Site Monitors, which is were the study is explained in more detail to the PI and center staff.
A questionnaire about the targeted population and the site is conducted to provide a report to the sponsor detailing the findings of the visit and the Monitor’s recommendations for final consideration of the site.
Once the information has been gathered, it is reviewed and evaluated to compare the sites objectively in a decision-making process.
It is important for site administration staff in charge of contracting and budgeting to be involved early in the conversation. It helps them understand one’s timeline and expectations. Setting expectations from the start will ensure a more efficient start-up and study conduct. If the sponsor does not have a pre-defined cost per patient, the site should provide a forecast budget that includes study setup cost, study conduct charges, closeout fees, and overhead percentage.
Led by Yoshito Kishi, Morris Loeb Professor of Chemistry Emeritus in Harvard’s Department of Chemistry and Chemical Biology, researchers have now synthesized sufficient quantities of E7130, a drug candidate from the halichondrin class, to enable for the first time rigorous studies of its biological activity, pharmacological properties, and efficacy, all conducted in collaboration with researchers at Japanese pharmaceutical company Eisai.
The molecule has undergone unusually rapid development and is already being tested in Phase I clinical trial in Japan, under a license from Harvard’s Office of Technology Development (OTD) to Eisai. The company hopes to begin a second clinical trial in the U.S. in due course. The Kishi Lab’s results, driven to completion through an intense, three-year research collaboration with Eisai, are published today in Scientific Reports, an open-access Nature journal. The paper reports the total synthesis of the highly potent halichondrin molecule E7130 — 11.5 grams of it, with 99.81 percent purity —and characterizes its mode of action. In preclinical studies, the research team has identified it not only as a microtubule dynamics inhibitor, as was previously recognized but also as a novel agent to target the tumor microenvironment.
“We spent decades on basic research and made very dramatic progress,” said Kishi, whose laboratory has, since 1978, received significant and sustaining support from the National Cancer Institute (NCI) of the National Institutes of Health to study the synthesis of natural products.
The structure of the complete E7130 molecule derived by total synthesis is particularly challenging to replicate because it has 31 chiral centers, asymmetrical points that must each be correctly oriented. In other words, there are roughly 4 billion ways to get it wrong.
When the natural product was first identified 33 years ago by Japanese researchers, it sparked an immediate interest. “At that time, they realized the halichondrins looked exceedingly potent,” recalls Takashi Owa, chief medicine creation officer and chief discovery officer for Eisai’s oncology business group and a co-author of the paper. Over time, NCI investigators testing tiny amounts of it recognized that it was affecting the formation of microtubules, which are essential to cell division. “Due to the very unique structure of the natural product, many people were interested in the mode of action, and the investigators wanted to do a clinical study,” Owa explains. “But a lack of drug supply prevented them from doing it. So 30 years have passed, very, unfortunately, but Professor Kishi is a pioneer in this field.”
Over the years, the Kishi Lab advanced methods of convergent synthesis, which enables complex molecules to be assembled from subunits rather than constructed linearly. Another innovation, now known as the Nozaki-Hiyama-Kishi reaction, protected the highly reactive functional groups while they were being assembled. And in 1992, Kishi and his colleagues achieved the first total synthesis of a halichondrin molecule (halichondrin B). The process required a sequence of more than 100 chemical reactions and produced less than a 1 percent overall yield. It was a major achievement, however, and a simplified version of that molecule, eribulin, became a drug that treats metastatic breast cancer and liposarcoma, now marketed by Eisai. Since then, Kishi’s lab has been engaged in basic research on organic synthesis, including the discovery and development of new reactions that can be used at a late stage of synthesis.
“In 1992, it was unthinkable to synthesize a gram quantity of a halichondrin,” Kishi says, “but three years ago we proposed it to Eisai. Organic synthesis has advanced to that level, even with molecular complexity that was untouchable several years ago. We are very delighted to see our basic chemistry discoveries have now made it possible to synthesize this compound at a large scale.”
“It’s a really unprecedented achievement of total synthesis, a special one,” says Owa. “No one has been able to produce halichondrins on a 10-gram scale. One milligram, that’s it. They have completed a remarkable total synthesis, enabling us to initiate a clinical trial of E7130.”
The team’s Scientific Reports paper describes the results of studies conducted in vitro and in vivo, in animal models, that shed light on the molecule’s complex mode of action. The team showed that E7130 can increase intratumoral CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts, components of the tumor microenvironment that may be involved in the transformation to malignancy.
“Professor Kishi’s expertise provided us with such an exciting and unique opportunity to test the molecule in our systems,” says Owa. “I have never experienced this kind of very efficient and rapid successful collaboration. Just a three-year collaboration took this from the discovery stage to the clinical development of such a complex molecule having a very unique mechanism and mode of action. To me, this is a kind of track record in drug development.
“The collaboration between scientists at Eisai and Harvard is an example of academia and industry working together successfully to accelerate the development of a new class of therapeutics that may address important unmet medical needs,” says Vivian Berlin, managing director of strategic partnerships in Harvard’s OTD. “The collaborative spirit and transparency of the relationship contributed enormously to the success of the project.”
“Without OTD,” Owa adds, “this collaboration could never have happened. Harvard OTD has been a core for the bridging industry and Harvard researchers and facilitating discussions about how to build a win-win relationship.”
Research for the new publication, titled “A landmark in drug discovery based on complex natural product synthesis,” was conducted jointly by researchers at Harvard and Eisai. Harvard’s OTD has protected the intellectual property associated with this project, which is now exclusively licensed to Eisai for the commercial development of therapeutics.
Source: Harvard University