Between 2014 and 2016, the Gulf of Alaska experienced a prolonged and intense heatwave. The hot temperatures disrupted species interactions and stressed the Gulf of Alaska ecosystem past its tipping point. New research led by Dr Robert Suryan at the NOAA Alaska Fisheries Science Center suggests that this event may have left a long-standing mark on the Gulf of Alaska. Dr Suryan and his colleagues quantified the effects of the heatwave on all aspects of marine ecosystems. Their work highlights the importance of long-term ecosystem monitoring in tracking, predicting, and preparing for a changing climate.

The Northeast Pacific Marine Heatwave

The Northeast Pacific marine heatwave was the only marine heatwave recorded globally in recent decades that lasted through all four seasons and over consecutive years. A brief hiatus in 2016 was short-lived, with warming re-intensifying between late 2018 and 2019. The heatwave wasn’t just record-breaking in its duration and magnitude, but also in the diversity of habitats it affected, ranging from shoreline ecosystems to the deep ocean.

Some biological responses to the heatwave were apparent; tens of thousands of dead seabirds washed up on beaches, toxic algal blooms intensified and spread along the West Coast, and fewer humpback whales arrived in their breeding grounds in Hawaii.

Such marine heatwaves will only intensify as climate change continues. In 2016, 70% of the world’s oceans experienced intense or severe heatwaves, up from 30% in 2012. While the immediate effects of heatwaves can sometimes be apparent, few studies have evaluated the lingering impacts of heatwaves on whole ecosystems.

In 1989, another environmental disaster received international attention. The oil tanker Exxon Valdez spilled 11 million gallons of oil into the Gulf of Alaska. In response to this disaster, the Exxon Valdez Oil Spill Trustee Council and scientists established an extensive monitoring program to assess long-term recovery. Dr Robert Suryan, a marine biologist at the National Oceanic and Atmospheric Administration (NOAA) took advantage of this data to determine how the Gulf of Alaska has responded to and recovered from the Northeast Pacific marine heatwave.

Tracking Long-term Impacts

Dr Suryan and his collaborators showed that this Pacific heatwave left its mark on diverse ecosystems – from the shoreline to the open oceans. ‘As of 2022, the Gulf of Alaska ecosystem had yet to fully recover from the effects of this major heatwave,’ explains Dr Suryan. ‘The community composition, or proportion of species that make up the ecosystem, are distinct from what we observed prior to the heatwave.’

His team also showed how these ecosystem changes still affect Alaskan communities that depend on fisheries and nature-based tourism. Their research points to the importance of extensive monitoring to better understand and prepare for the long-term effects of climate change on sensitive ecosystems.

Dr Suryan and his team assessed nine ecosystem components that spanned the food web in the Gulf of Alaska. Specifically, they analysed 187 datasets that contained measurements of the abundance of primary producers, such as phytoplankton and zooplankton, shallow-water species including mussels and sea stars, fish, seabirds, and marine mammals.

With this wealth of long-term monitoring data across Gulf of Alaska species and ecosystems, Dr Suryan studied how specific species responded, which groups showed long-term effects or recovery responses for up to five years after the heatwave, and how the ecological community responded as a whole.

Varied Species Responses

To measure species response, Dr Suryan and other scientists looked at critical indicators including species abundance, size, growth rates, and signs of reproductive success. Many species showed prolonged negative responses to the heatwave, whereas others showed neutral or positive responses. ‘Some species did return to pre-heatwave levels soon after the heatwave; however, other species did not,’ says Dr Suryan.

For instance, the abundance of phytoplankton, a key primary producer, greatly decreased. Sea-stars, a prominent predator in shallow waters near the shore, also declined in abundance.

Populations of many fish species that form the diets of larger predatory species, such as cod and herring, dropped abruptly. There were fewer sea lion pups during the heatwave, and nesting seabird numbers also declined. Fewer humpback whales arrived in breeding grounds – a sustained decline that lasted beyond 2018.

On the other hand, the decline of some species helped others thrive. Mussel populations actually grew, giving a few coastal birds more to eat. Impacts on fisheries were also mixed. Declines in cod, herring and certain species of salmon left many fisheries struggling with closures and reduced quotas. In contrast, sablefish, pollock and other salmon species actually thrived during the heatwave.

Because some areas remained warmer than normal for almost five years after the beginning of the heatwave, many species were affected by warmer conditions for five years in a row. Consequently, some species of algae and whales struggled to return to their pre-heatwave levels of abundance.

Community-level Responses

Species responses to the heatwave led to new ecological community patterns within two years of the onset of the heatwave. Generally, the Gulf of Alaskan ecosystems differed from any community structures that had prevailed for at least fourteen years before the heatwave.

To measure community responses, Dr Suryan and his colleagues explored metrics that indicated changes in the abundance of biological populations, and species’ demographics, such as size, growth, and condition. Overall, the scientists noted that many different effects combined to drastically change relationships between species within the marine food web.

For example, large-scale declines in fish prey, including sand lance and capelin, meant far less food for their predators, leading to large-scale declines in the abundance of salmon, groundfish, birds, and mammals. Overall, over half of the 187 datasets showed a long-lasting response to the heatwave.

These community-level impacts coalesced to change the abundance and breeding success of various species at all levels of the marine food web, leading to different community structures. These results highlight the magnitude of the heatwave’s impacts, and demonstrate that the Gulf of Alaska ecosystem was not resilient enough to prevent large-scale community-level shifts.

The Human Dimension

Local communities in the Gulf of Alaska rely on fisheries and tourism to remain afloat. Unsurprisingly, fish species abundance and ecosystem changes significantly affected commercial fisheries and local communities.

We can think of commercial fisheries as another predator of fish. Like other marine predators, these fisheries need to adapt to fluctuations in prey abundance. In the case of reduced fish abundance, commercial fishery revenue suffers. Although fisheries can adjust the price and timing of product delivery, these changes can only temporarily buffer the impacts on local communities. Unfortunately, the fish species that were most negatively affected by the heatwave are also the most valuable, representing a substantial portion of total earnings for fishers in the region.

Similar to commercial fisheries, reductions in whale abundance led whale-watching tour operators to travel longer distances and concentrate on fewer whales, affecting tourist-dependent regions and placing additional stress on local communities and resources.

An Uncertain Recovery

In 2018, the Gulf of Alaska ecosystem still appeared distinct from its pre-heatwave years. A re-intensification of warming through fall 2018 and summer 2019 has meant that most species did not have enough time to rebound to pre-heatwave levels. This data also means we should be cautious when assessing observations that may point to recovery, such as increased whale sightings.

Additionally, increases in water temperature due to climate change, along with more frequent and intense heatwaves, mean that the Gulf of Alaska ecosystem will potentially continue changing from its pre-heatwave structure. Ecosystems have tipping points, beyond which they can no longer buffer disturbances. Climate change has the potential to push ecological communities past their upper limits.

Still, ecosystems have proven to be surprisingly resilient. The results of Dr Suryan’s study provide a foundation upon which he and other scientists can develop hypotheses to better understand why and how ecosystems will respond.

Underlying Mechanisms

The Gulf of Alaska has been severely affected by the marine heatwave, but Dr Suryan’s research shows that not every community and species responded similarly. While some groups were devastated, others thrived.

‘Whereas our analyses did not identify mechanisms of biological change, our results do provide a foundation on which to develop hypotheses and test mechanistic links to physical drivers of change,’ his team wrote in one of their recent papers.

The next step will be to explore these mechanisms, so that we can better predict how the changing climate will shape Alaskan ecosystems, in order to plan for and mitigate the most damaging effects.

‘This analysis is a good basis for future studies,’ says Dr Suryan. ‘What we need to do next is identify the mechanisms that cause species abundance fluctuations. For instance, understanding what forage fish and zooplankton species do well or poorly as water temperatures warm is critical for understanding how the marine mammals, seabirds and commercial fish stocks that feed on them will fare in this same environment.’

Of course, climate change is just one of many threats that Alaska must contend with. Predicting what ecosystems will look like in the future, and how the resources we depend on will be affected, requires an integrated approach that hinges on the continued collection of long-term monitoring data.

Following exposure to injury or infection, the body elicits a counteractive immune response which involves many different cell types and processes. Cytokines are substances secreted by cells which play a pivotal role in the regulation of this response. Professor Paige Lacy and colleagues in the Department of Medicine at the University of Alberta in Edmonton, Canada, have conducted extensive research into the exact mechanisms underpinning the regulation of cytokine release during the immune response with a particular focus on airway inflammatory disorders.

Cytokines and the Immune Response

Cytokines are intercellular messengers and purveyors of soluble regulatory signals which mediate the body’s response to injury due to pathogens, allergens and injury. Whilst cytokine release has been extensively studied, the precise mechanisms controlling this process are not yet fully understood, although it is acknowledged that the immune response is multifaceted and involves a complex system of different cell types, transport machinery and molecular pathways.

Over the past two decades, Professor Paige Lacy and her team in the Department of Medicine at the University of Alberta in Edmonton, Canada, have been investigating exactly how cytokines are synthesised, packaged, trafficked and released in response to external stimuli which cause cellular damage. Their work has identified many enzymes, membrane proteins, and receptors involved in these processes, and has revealed novel mechanisms of action in the regulation of the immune response in allergic airway inflammation and asthma.

Initially, Professor Lacy and colleagues reviewed published evidence to identify knowledge gaps relating to the mechanisms of cytokine release from immune cells. They explained that cytokine secretion by a range of cell types is a fundamental aspect of the immune response, and greatly influences the body’s reaction to stimuli.

Cytokine Secretion Pathways

Many different cells secrete cytokines, including epithelial cells, eosinophils, and macrophages. Epithelial cells are omnipresent, forming thin layers of lining tissue throughout the body, and are among the first cells to release cytokines in response to harmful signals. Epithelial cells work closely with the immune system by sending cues to initiate appropriate physiological reactions. Innate immune cells, such as macrophages and eosinophils, are naturally occurring cells which rapidly mobilise to the site of injury or infection, and can generate a wide range of cytokines. Collectively, these cells control pathogen invasion by recognising threats and producing toxic substances which kill harmful invaders, although the mechanisms relating to the movement of cytokines from epithelial cells prior to release remain to be fully determined.

Cytokines may be secreted via classical or non-classical pathways, which are defined depending upon the specific mode of action, and several pathways have been identified in specific immune cells. A major purpose of each pathway is to selectively regulate temporal cytokine release and to suitably terminate the response when necessary.

Most cytokine secretion, including from eosinophils, is via the classical pathway which is characterised by the packing and storage of cytokines in secretory granules within the cell prior to receptor-induced regulated release facilitated by membrane fusion. Alternatively, such as in macrophages, cytokines may be released immediately following synthesis which can ensue in a polarised manner. Furthermore, the process of cytokine secretion is customisable depending upon the required cell-specific immune function.

Eosinophils are highly granulated white blood cells which increase in abundance during an allergic response, and are capable of synthesising, storing, and secreting up to 35 different cytokines. Eosinophils have been observed in the airways of around half of asthma sufferers and may contribute to tissue damage. Cytokine secretion from eosinophils occurs predominantly via so-called piecemeal degranulation, where cytokines are recruited from larger storage granules and transported to the cell membrane in smaller vesicles, and degranulation may also occur via classical or compound exocytosis, as well as by lysis in dying cells.

Macrophages are derived from white blood cells predominantly found on mucosal surfaces including the airways and have a key role in wound healing and tissue repair. Cytokines within macrophages are continuously transported to the cell surface in preparation for release when these cells are activated.

Professor Lacy and her team summarised that the movement of cytokines through immune cells is dependent upon membrane-bound or cytoplasmic enzymes, proteins, trafficking molecules, and intracellular membrane receptors, which mediate transport, facilitate membrane fusion, and regulate secretion. Initiation of the secretion pathway occurs within minutes of encountering an agonist. However, the specific roles of certain enzymes and proteins and the importance of cellular structural rearrangements in cytokine release from innate immune cells had not yet been elucidated.

Determining Cytokine Secretion Mechanisms

Given the paucity of available information, Professor Lacy and colleagues attempted to determine which molecules regulate eosinophil degranulation within the context of airway inflammation. To do this, the team built upon an earlier study in which they discovered that asthma patients exhibited a higher expression and activity of a specific enzyme (Rab27a) within their eosinophils, and that this likely contributed to the physiological traits typically observed in asthma. Human and mouse eosinophils were isolated and subjected to various laboratory techniques to determine the presence, subcellular localisation, and polarisation of the selected molecule.

They found that the molecule selectively redistributed when the cells were stimulated with an agonist, which suggested that eosinophil cytokine release indeed occurred in a manner that was dependent on Rab27a. Further studies in eosinophils demonstrated a role for other intracellular enzymes and receptor proteins (Cdk5, VAMP-7). Professor Lacy and her team confirmed these findings by repeating the experiments in strains of mice which had been genetically modified to eliminate the proteins necessary for normal eosinophil function and observed that degranulation responses became defective. This research identified for the first time a direct role for specific regulatory molecules in inducing and controlling eosinophil degranulation in allergic inflammation and asthma.

Following these encouraging insights, Professor Lacy and her team endeavoured to further classify the proteins involved in the degranulation of eosinophils, since stimuli-induced activation of eosinophils is recognised as an exacerbating factor in the airway hyperresponsiveness associated with asthma. The researchers selected a vesicle-associated membrane protein (VAMP-7) which had previously been identified as an essential component of degranulation and confirmed that it was present in mouse eosinophils using fluorescence microscopy. Upon stimulation, isolated eosinophils translocate to gather at the edge of the cell, preparing for the release of granular contents.

Furthermore, genetically modified mice models lacking the chosen protein and mimicking allergic airway inflammation demonstrated a reduced incidence of degranulation and fewer cell-damaging products being released, suggesting a dysfunction in the eosinophil activation process, and confirming that eosinophil degranulation contributes to airway hyperresponsiveness. The fact that degranulation was not entirely abolished may be attributed to the small proportion of eosinophils that release their granular contents upon cell lysis, a recognised occurrence in allergic responses which depends on different signalling mechanisms. The researchers concluded that airway inflammation is at least partly mediated by degranulating eosinophils which can directly exacerbate the condition.

A Role for Cellular Structural Changes

To further investigate the mechanisms of cytokine secretion, Professor Lacy and colleagues proceeded to evaluate the intracellular storage sites of selected cytokines in eosinophils, and the pathways involved in their release. First, the team isolated human eosinophils from allergic or asthmatic participants and stimulated them to initiate cytokine trafficking. Fluorescence microscopy revealed altered eosinophil morphology and spatiotemporal increases in the levels of some cytokines following stimulation. Thereafter, the team deduced that membrane recycling pathways are likely employed by eosinophils to transport certain cytokines to the cell membrane for release, providing further insight into trafficking mechanisms within eosinophils.

This finding echoed that of earlier research conducted by Professor Lacy and her team investigating the mechanisms of cytokine secretion in macrophages, during which they reported that newly synthesised cytokines were also trafficked via a membrane recycling pathway. Delving further, the team continued to explore the mechanisms underlying the trafficking pathways and establish which mediators may be involved in the associated cellular structural changes. Using fluorescence microscopy techniques, dramatic alterations in the shape of cells were observed in the presence of a specific enzyme (Rac1), which was also associated with increased release of a selected cytokine and found to be vital for the final trafficking step prior to secretion within activated macrophages. Indeed, inhibition of the selected enzyme did not prevent cytokine synthesis in macrophages but did reduce transport and secretion, thus confirming, for the first time, its essential role in cytokine trafficking via the membrane recycling pathway.

Implications for Future Study

Understanding the various intercellular pathways involved in cytokine secretion is crucial for increasing our knowledge of cellular function in innate immunity and the associated ramifications for disease. Further studies surrounding the interrelationships of the regulatory pathways involved in the transport and secretion of cytokines and pro-inflammatory mediators may help to determine the underlying mechanisms unique to individual cell types. This is particularly prudent in the study of the mechanisms of cytokine release via non-classical pathways, since the theories surrounding this remain controversial.

More in-depth research to assess the secretion pathways of a wider range of cytokines and different cell types will undoubtedly prove highly beneficial in elucidating the underlying mechanisms of these phenomena. Using increasingly refined models of disease states has enabled Professor Lacy, her team, and collaborators to elicit the role of specific proteins in the degranulation of eosinophils in allergic inflammation using sophisticated gene targeting strategies. It is probable that complex multimodal mechanisms are involved in airway hyperresponsiveness involving synergistic product relationships, and experiments to decipher the contribution of individual components of eosinophil degranulation in asthmatic inflammation are warranted.

Perhaps most encouragingly, there is scope for exciting collaborations between scientific and clinical teams to apply the knowledge gained regarding the mechanisms of cytokine release in inflammatory disorders to the development of novel therapeutic targets.   

Chemotherapy, one of the mainstays of cancer treatment, can unfortunately act as a double-edged sword. While achieving the intended aim of killing cancerous cells, it also generates an accumulation of cell debris, which in turn, promotes tumour growth by stimulating inflammation in the tumour microenvironment. Dr Dipak Panigrahy and his colleagues from Harvard Medical School, USA, have conducted several studies in mice showing that targeting the tumour cell debris-mediated surge of proinflammatory and protumourigenic factors provides a strategy for enhancing the efficacy of chemotherapy.

The Double-Edged Sword of Chemotherapy

With advances in genomics and drug discovery, chemotherapy is the frontline treatment for cancer now more than ever before. However, accumulating evidence from various animal models of the disease suggests that rather than simply killing the cancerous cells, chemotherapy can also initiate the recurrence of cancerous tumours. Unfortunately, the mechanisms behind this double-edged sword are still poorly understood. Working to resolve important questions about this critical issue is Dr Dipak Panigrahy, along with his colleagues at Harvard Medical School, USA.

Apoptosis is the process of programmed cell death, and this may trigger escape from tumour dormancy by causing a cellular stress response linked to inflammation. Dr Panigrahy and his colleagues argue that increased levels of spontaneous apoptotic cell death in the tumours of cancer patients are associated with poor prognosis in several cancer types.

5-fluorouracil (5-FU) is a chemotherapeutic drug used to treat colorectal cancer. It reduces tumour mass by causing cell death, creating tumour cell debris in the form of apoptotic cells and cell fragments. Observing that apoptotic tumour cells can stimulate specialised cells known as macrophages and the production of proinflammatory cytokines, Dr Panigrahy and his colleagues proposed that 5-FU may be a source of tumour growth stimulation. In 2019, the Panigrahy laboratory published an important study that clearly demonstrated that 5-FU generates cellular debris that causes tumour cells and host macrophages to release a tumour factor known as osteopontin (OPN).

In clinical settings, OPN expression is linked to poor 5-year survival in many cancer types. OPN is a well-characterised factor that has been linked to cancer progression and angiogenesis, which is the growth of new blood vessels that tumours need to grow. Conventional chemotherapy may contribute to tumour progression and relapse via cell debris, suggesting that treating the tumour-promoting activity of cell debris is critical for the prevention of tumour recurrence.

In the 2019 study, Dr Panigrahy examined the cytotoxic activity of 5-FU in mice that were previously inoculated with colorectal cancer cells. As predicted, the researchers observed increased cell death in tumours that were treated with 5-FU compared with size-matched control tumours. Furthermore, the study confirmed that systemic 5-FU treatment and tumour cell debris increase OPN levels and that debris-stimulated tumour growth is mediated by enhanced tumour angiogenesis. The most important finding, however, was that pharmacologic and genetic ablation of OPN inhibited debris-stimulated tumour growth. Dr Panigrahy and his colleagues demonstrated that a combination of neutralising antibodies to inhibit OPN and continued treatment of 5-FU dramatically inhibited tumour growth.

Chemotherapy-generated Debris and Ovarian Cancer Resurgence

Epithelial ovarian cancer, a major cause of death in women worldwide, is characterised by a high tumour recurrence, which can occur in up to 70% of patients. To ascertain whether chemotherapy-generated debris is biologically relevant in ovarian cancer, via a similar mechanism initiated by 5-FU and mediated by OPN in colorectal cancer, Dr Panigrahy and his colleagues treated mouse and human cell lines with cytotoxic platinum- or taxane-based chemotherapeutic agents used for treating ovarian cancer. As a consequence of the treatment, the colleagues observed a surge of proinflammatory cytokines and bioactive lipid molecules known as eicosanoids, released by macrophages, in the tumour microenvironment. The findings of this study were published in 2019 in the prestigious journal, the Proceedings of the National Academy of Sciences (PNAS).

The research team also observed that the presence of debris alone without macrophages in the culture medium resulted in minimal to undetectable levels of cytokines, confirming that the release of lipid mediators and cytokines is macrophage-dependent. The PNAS study showed that the combined pharmacological inhibition of the cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) pathways prevented the surge of both cytokines and lipid mediators by macrophages. These results confirmed that ovarian cancer patients may benefit from the suppression of eicosanoid and cytokine mediators, protecting the body from a therapy-induced debris-mediated cytotoxic and tumourigenic response.

Aspirin-triggered Mediators as Optimal Chemopreventive Agents

Many studies suggest that the nonsteroidal anti-inflammatory drug (NSAID) aspirin is potent in counteracting the formation of tumours. Despite numerous reports confirming its beneficial properties in cancer prevention, the biochemical mechanisms behind this unique antitumour activity of aspirin compared with other NSAIDs remain poorly understood. Cyclooxygenase (COX)-1 and COX-2 are key targets of aspirin and are involved in the biosynthesis of proinflammatory lipids, such as prostaglandins. Dr Panigrahy and his colleagues published another study in 2019 showing that aspirin not only blocks the biosynthesis of prostaglandins, but also stimulates the endogenous production of anti-inflammatory mediators termed ‘aspirin-triggered specialised pro-resolving mediators’ (AT-SPMs), such as ‘aspirin-triggered resolvins’ (AT-RvDs) and ‘aspirin-triggered lipoxins’ (AT-LXs).

The research team demonstrated that treatment of mice with AT-RvDs or AT-LXs inhibited primary tumour growth by enhancing macrophage removal of tumour cell debris and inhibiting the production of macrophage-secreted proinflammatory cytokines. Following the publication of the 2019 study, AT-SPMs, including resolvins, have been considered in clinical studies for their tumour-preventing activity. Dr Panigrahy and his colleagues have shown that, given the risks associated with chronic low-dose aspirin intake, mediators such as aspirin-triggered resolvins and other AT-SPMs may be a more desirable therapeutic option, since they display more potent antitumour activity and are devoid of aspirin-related toxicity.

Resolvins Enhance Cancer Therapy by Clearing Cell Debris

As demonstrated in many studies by the Panigrahy team, dead and dying tumour cells greatly affect the tumour microenvironment. This leaves the medical profession with a dilemma between treating tumours with chemotherapy and minimising the effects of debris-induced tumour progression. Resolving this dilemma is paramount to preventing tumour recurrence after therapy.

In a study published in 2017, Dr Panigrahy and his colleagues demonstrated that apoptotic debris stimulates tumour growth through the action of phosphatidylserine (PS), a modified amino acid that is present on the surface of apoptotic cells. The study showed that blocking PS in the debris with a recombinant protein or an anti-PS neutralising antibody significantly inhibited debris-stimulated tumour growth in a dose-dependent manner.

The 2017 study adds further evidence in support of using specialised pro-resolving mediators, such as resolvins, to clear apoptotic debris. The novel approach alongside chemotherapy would greatly prevent tumour recurrence and enhance the benefits of cancer therapy. The observations were supported by the results of a 2019 study in which Dr Panigrahy and his colleagues demonstrated that the resolution of inflammation via resolvins, before surgery, inhibited the formation of new tumour growth, inducing robust anticancer T cell immunity in mice affected by Lewis lung carcinoma.

Resolution of Inflammation Halts Liver Cancer Progression

Building on the observations published in previous years, Dr Panigrahy and his colleagues recently published a new study on the effects of inflammation on the changes to the tumour microenvironment triggered by cytokine and eicosanoid storms during hepatocellular carcinoma (HCC). Aflatoxin B1 (AFB1), a mycotoxin produced by Aspergillus fungi, may play a causative role in 4.6 to 28.2% of all HCC cases worldwide. Aflatoxin-induced HCC is most prevalent in developing countries due to the regular consumption of food contaminated with aflatoxins.

HCC is associated with excessive production of proinflammatory cytokines, including TNF-α and IL-6, which lead to apoptotic cell death in multiple cell types. AFB1 can also negatively impact macrophages by impairing their ability to remove cell debris. By causing excessive production of oxidative stress, proinflammatory cytokines start a cascade that leads to DNA damage and new tumour growth, correlating with poor patient survival. Dr Panigrahy and his colleagues demonstrated that tumour cells killed by AFB1 stimulate primary HCC growth when co-injected in mice with a nontumourigenic inoculum of tumour cells and that the malignant growth is dependent on a macrophage-derived eicosanoid and cytokine storm that also involves mediators that promote the formation of new blood vessels.

Dr Panigrahy and colleagues demonstrated that dual COX-2/sEH inhibitors can be administered during and immediately after periods of high exposure to aflatoxins, resulting in a physiological switch from a pattern of inflammation to the resolution of inflammation. By targeting the debris-mediated eicosanoid and cytokine storm, via clearance of tumour cell debris, dual COX-2/sEH inhibition may provide an effective strategy for the prevention of AFB1-induced hepatocellular carcinoma.