Provoke (2023)
Mckenzie Witting
The 2023 worldwide total of 69 confirmed unprovoked cases is in line with the most recent five-year (2018-2022) average of 63 incidents annually. There were 14 confirmed shark-related fatalities this year, ten of which are assigned as unprovoked. This number is higher than the five-year annual global average of six unprovoked fatalities per year. Three of the unprovoked fatalities were due to bites from white sharks on surfers in Australia.
Annual fluctuations in shark-human interactions are expected. While the number of fatalities in 2023 was considerably higher than in 2022, there have been years in the past (2011) in which fatalities were also higher. The 2023 uptick in fatalities due to white sharks may reflect stochastic year-to-year variation, but it might also be the consequence of the increasing number of white sharks seen at aggregation sites near beaches that are popular with surfers (particularly in Australia). Year-to-year variability in oceanographic conditions influences the local abundance of sharks in the water, while weather patterns and economic conditions impact human activities along coastlines.
Consistent with long-term trends, the United States recorded the most unprovoked shark bites in 2023, with 36 confirmed cases. This is slightly lower than the 41 incidents recorded in 2022. The 36 cases represent 52% of the worldwide total.
New Caledonia reported three unprovoked bites, one of which was fatal. Egypt reported two unprovoked bites, including one fatality. The Bahamas and Mexico each reported one fatal unprovoked bite for 2023. Brazil reported three bites, none of which were fatal. South Africa reported two bites, neither of which were fatal. Costa Rica, Colombia, New Zealand, Seychelles, the Galapagos Islands and the Turks and Caicos Islands each reported single non-fatal incidents for 2023.
The total number of unprovoked shark bites worldwide remains extremely low. Fatalities saw an increase over the past year. Most of the fatalities in 2023 were due to white shark bites (three in Australia, one in California).
The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.
There are several endogenous molecules that can trigger migraine attacks when administered to humans. Notably, calcitonin gene-related peptide (CGRP) has been identified as a key player in a signalling cascade involved in migraine attacks, acting through the second messenger cyclic adenosine monophosphate (cAMP) in various cells, including intracranial vascular smooth muscle cells. However, it remains unclear whether intracellular cAMP signalling requires CGRP receptor activation during a migraine attack in humans. To address this question, we conducted a randomized, double-blind, placebo-controlled, parallel trial using a human provocation model involving the administration of CGRP and cilostazol in individuals with migraine pretreated with erenumab or placebo. Our study revealed that migraine attacks can be provoked in patients by cAMP-mediated mechanisms using cilostazol, even when the CGRP receptor is blocked by erenumab. Furthermore, the dilation of cranial arteries induced by cilostazol was not influenced by the CGRP receptor blockade. These findings provide clinical evidence that cAMP-evoked migraine attacks do not require CGRP receptor activation. This discovery opens up new possibilities for the development of mechanism-based drugs for the treatment of migraine.
Any person who publishes a libel of another which may tend to provoke a breach of the peace shall be punished, on conviction, by fine and imprisonment in the county jail, or hard labor for the county; the fine not to exceed in any case $500.00 and the imprisonment or hard labor not to exceed six months.
MIT researchers have now come up with a possible way to get around that obstacle. In a new study, they showed that when immunostimulatory prodrugs -- inactive drugs that require activation in the body -- are tuned for optimal activation timing, the drugs provoke the immune system to attack tumors without the side effects that occur when the active form of the drug is given.
The researchers designed prodrugs with bottlebrush-like structures based on a class of compounds called imidazoquinolines (IMDs). Mice treated with these bottlebrush prodrugs designed with optimized activation kinetics showed a significant reduction in tumor growth, with no side effects. The researchers hope that this approach could be used to boost immune system responses in cancer patients, especially when combined with other immunotherapy drugs or cancer vaccines.
"Our bottlebrush prodrug library enabled us to show an immunological effect of controlling immunotherapy kinetics, allowing us to boost immune responses while minimizing the side effects," says Sachin Bhagchandani, an MIT graduate student who is the lead author of the study. "This kind of approach opens up avenues for scientists who want to decouple toxicity from some promising immunotherapy agents."
Jeremiah Johnson, an MIT professor of chemistry, and Darrell Irvine, the Underwood-Prescott Professor with appointments in MIT's departments of Biological Engineering and of Materials Science and Engineering, are the senior authors of the paper, which appears today in Science Advances. Irvine is also an associate director of MIT's Koch Institute for Integrative Cancer Research and a member of the Ragon Institute of MGH, MIT, and Harvard.
Organic molecules known as IMDs bind to cell receptors called Toll-like receptors that are found on macrophages and other cells of the innate immune system. When activated, these cells begin producing cytokines and other inflammatory molecules.
In 1997, the FDA approved topical IMD drugs to treat certain types of skin cancer. Since then, many other IMD drugs have been tested in clinical trials for a variety of types of cancer, but none of these were approved, in part because the drugs produced too much systemic inflammation.
The MIT team set out to explore whether prodrugs of IMDs, which are inactivated until turned "on" in the tumor microenvironment, could reduce those side effects. In recent years, Johnson's lab has developed a novel type of prodrug platform shaped like a bottlebrush. These nanoscale, cylindrical structures consist of chains that extend from a central backbone, giving the molecule a bottlebrush-like structure. Inactivated drugs are bound along the bottlebrush backbone through cleavable linkers that define the rate of active IMD release.
The researchers generated and compared six bottlebrush prodrugs that only differed by their release rate, in order to investigate how prodrug activation kinetics impact antitumor responses. Using these bottlebrush prodrugs, the researchers hoped they could deliver active IMDs to tumors while avoiding release into the bloodstream.
"Our ability to synthesize six bottlebrush prodrugs with identical sizes and shapes uniquely allows us to isolate and study release kinetics as a key variable. Excitingly, we find that it is possible to identify prodrug structures that limit IMD exposure to the whole body, thereby avoiding toxicity, and that activate in tumors to give antitumor efficacy," Johnson says.
In preliminary studies in cells and mice, the researchers found that the fastest-activating prodrugs did cause immune-related side effects, including weight loss and elevated cytokine levels. However, the medium- and slow-releasing versions did not produce these effects.
The researchers then tested the IMD bottlebrush prodrugs in two different mouse models of colon cancer. Because the prodrugs are so small (approximately10 nanometers), they are able to efficiently accumulate in tumors. Once there, they get taken up by innate immune cells, where their linkers are cleaved. The resulting release of active IMDs causes immune cells to release cytokines and other molecules that create a pro-inflammatory environment. This series of events activates nearby T cells to attack the tumor.
In both models, mice treated with the bottlebrush prodrugs showed significantly slowed tumor growth. When the treatment was combined with a checkpoint blockade inhibitor -- another class of immunotherapy drug -- tumors were completely eliminated in about 20 percent of the mice.
While mice treated with the IMD used in this study, known as resiquimod, showed weight loss, elevated cytokine levels, and reduction in white blood cell count, as expected, mice given resiquimod bottlebrush prodrugs did not show any of these effects.
"Our molecules were able to safely reduce these effects by controlling how much of the active drug is released in the blood," Bhagchandani says. "If you minimize release of the active compound there, then you're able to get anti-tumor effects at the tumor site without the systemic side effects."
The findings suggest that the most promising use for IMD bottlebrush prodrugs could be to give them along with another drug that stimulates the immune response. Another possibility is using IMD bottlebrush prodrugs as adjuvants to enhance the immune system's response to cancer vaccines.
"The ability of the bottlebrush prodrug strategy to change both where the drug accumulates in the body and when it is active is very attractive for activating immune responses against cancer or other disease safely," Irvine says.
When Iranian women took off their government-mandated veils, spun them in the air, and set them on fire, dancing in the streets, they interjected new political subjectivities and demands into the realm of the possible, embodying a vision of freedom and sovereignty that is neither westernized nor policed by state-centered definitions of cultural authenticity. This energy, this joy, this assertion of life against death, this collective reorientation toward the feminized and marginalized as agents of revolutionary transformation, is difficult to sustain on the streets and to represent through visual cultural production. Artistic engagements with death, torture, grief, and martyrdom, which call attention to the tremendous violence meted out by the Iranian state against protesters and also build on religious and aesthetic tropes woven through hundreds of years of Iranian visual culture, have featured prominently in exhibitions such as Anonymously, Iran (2023), while comparatively little artistic energy has gone toward interpreting the revolutionary imagination that has inspired and buoyed the movement.
93ddb68554