The “head them off at the pass” cliché endures for a good reason. It describes a hopeful scenario: the stalling or blocking of an unwelcome development at a strategic point. It is certainly the scenario favored by developers of inflammatory disease drugs. These developers would rather block a discrete step in a multistep inflammatory process—the equivalent of blocking a narrow mountain pass—than resort to a wider suppression of the immune system.
Unfortunately, conventional inflammatory disease drugs—the familiar steroidal and nonsteroidal drugs—frequently alter biological functions with system-wide effects. Such drugs give rise to adverse drug reactions. Also, when such drugs suppress immunity broadly, they weaken patients against infections.
Besides steroidal and nonsteroidal anti-inflammatories, there are now small-molecule drugs (such as Janus kinase inhibitors) and biologics (such as monoclonal antibodies against pro-inflammatory molecules). These medications are proving valuable in a range of applications, but there’s still room for improvement.
To stage even more targeted deployments, drug developers are exploiting the latest research about inflammatory pathways. Some developers are excited that disparate inflammatory conditions appear to share pathways and present the same targets. Conceivably, well-targeted drugs could have multiple indications. However, inflammatory pathways are intricate. Indeed, they can activate and resolve inflammatory processes in varied ways in different tissues and diseases. Still, drug developers are showing that if they can get the lay of the land, they can head inflammation off at the pass.
A wider reach and a tighter grasp
At IGM Biosciences, Mary Beth Harler, MD, is president of IGM autoimmunity and inflammation, a business unit tasked with realizing the potential of the company’s IgM antibody technology platform. Essentially, Harler’s unit is combining the strengths of IgM antibodies and IgG antibodies to inactivate pro-inflammatory cytokines and dampen inflammatory signals more effectively.
When faced with a pathogen, the immune system first produces nonspecific (but potent) IgM antibodies, and then, later, highly pathogen-specific IgG antibodies. The specificity of IgG is a major strength. It has already been harnessed by several drug developers. For example, AbbVie developed adalimumab (Humira), a recombinant monoclonal IgG antibody, to neutralize the inflammatory cytokine tumor necrosis factor alpha (TNF-a). The drug is used to treat arthritis, Crohn’s disease, ulcerative colitis, and psoriasis.
IgG antibodies, however, have just two antigen-binding sites, whereas IgM antibodies have ten. To make the most of IgG antibody specificity and IgM antibody potency, IGM Biosciences tried an unusual approach. “We graphed highly specific IgG binding sites onto an IgM molecule,” Harler says. “It equates to the difference between trying to pick something up with two fingers versus [ten fingers].”
More sites to bind ligands means more inflammatory cytokines neutralized per antibody—and not just cytokines like TNF-a. “I see a very rich field of validated targets that we can strongly consider,” Harler declares. She adds that pentameric antibodies could be produced that would be capable of neutralizing targets “that, frankly, were not accessible through more conventional IgG-based therapy.”
IGM Biosciences recently announced that its technology attracted an enthusiastic development partner. This partner, Sanofi, will pay IGM Biosciences $150 million upfront to collaborate in the creation, development, manufacture, and commercialization of IgM antibody agonists against three oncology targets and three immunology/inflammation targets. IGM Biosciences is eligible to receive potentially over $6 billion in aggregate development, regulatory, and commercial milestones.
Although the commercial potential of IgM antibodies is exciting, Harler has additional motivations. For example, she is motivated by scientific curiosity. She remarks, “The wealth of knowledge [about inflammatory pathways] that has been generated over the past two to three decades is breathtaking.” Diseases that may differ dramatically from one another, and even from patient to patient, often share the same inflammatory pathways, and they often present similar targets for potential therapies.
“If there is an organizing principle, it’s around the pathways,” Harler continues. “Autoimmune disease is almost system agnostic. It’s more about the pathways that may manifest in certain organ systems.”
Another motivation, Harler confides, is more personal. “I have a daughter who was diagnosed with ulcerative colitis at age 10,” she says. “The risk of a colectomy and a colostomy by age 20 for such a patient as my daughter is unacceptably high.”
Similar sentiments are no doubt widely shared, given that inflammation accompanies may chronic diseases. The Rand Corporation estimates that in 2014, nearly 60% of Americans had at least one chronic condition, 42% had more than one, and 12% of adults had five or more. According to the World Health Organization, three out of five people across the globe die due to chronic inflammatory diseases such as stroke, chronic respiratory diseases, heart disorders, cancer, obesity, and diabetes.
More than a mere framework
Engitix, a biotech firm based in London, focuses on how long-term chronic inflammation leads to the scarring and rigidity of tissue fibrosis. The company maintains fibrosis programs (sclerosing cholangitis, nonalcoholic steatohepatitis, and intestinal fibrostenosis in inflammatory bowel disease [IBD]) as well as solid tumor programs (pancreatic adenocarcinoma and hepatocellular carcinoma).
Despite the success of TNF-a-targeting drugs like adalimumab, “a significant number of patients with IBD, unfortunately, progress toward the most advanced or more serious complication of IBD, which is fibrostenotic disease,” says Giuseppe Mazza, PhD, the co-founder and CEO of Engitix. Intestinal fibrosis can lead to a narrowing of the intestines only addressable through surgery—no effective drugs currently exist.
To understand why some IBD patients progress to fibrosis, Engitix has turned its attention to the extracellular matrix (ECM), the network of collagen and other proteins that help structure tissues. “People have usually thought of the ECM as a scaffold, a bystander product, that keeps our tissue together,” Mazza says. “What we have discovered, together with, of course, other groups around the world, is that the ECM is a highly bioactive environment.”
According to Mazza, fibrotic disease caused by long-term chronic inflammation alters the ECM and stiffens tissues. He notes that the ECM also “plays a key role in driving the disease forward.”
Now in partnership with Takeda, Entigix is using its technology to study the ECM in healthy patients and in patients with IBD to identify both biomarkers and potential therapeutic targets.
“If we can understand this, we can combine anti-inflammatory therapy together with direct antifibrotic therapy to reverse or stabilize the disease,” Mazza states. The combination approach that Mazza has in mind incorporates existing therapies and ECM-based therapies. Some sort of combination approach will be necessary, he explains, because “complex diseases are not going to be treated by a single therapy.”
Edesa Biotech of Markham, Canada, has two drug candidates in later stage development. The first candidate is EB01, an inhibitor of secretory phospholipase A2. It is being evaluated as a topical treatment for chronic allergic contact dermatitis (ACD). ACD is a common, potentially debilitating condition and occupational illness.
The second candidate is EB05, a monoclonal antibody therapy that is being evaluated as a treatment for acute respiratory distress syndrome (ARDS). In ARDS, runaway inflammation leads to fluid filling the lungs. There are currently no drugs to treat the condition, and patients are typically supported with oxygen, with those who survive often dealing with fibrotic scarring of their lungs.
Initially, Edesa’s EB05 work focused on ARDS driven by influenza or chemical inhalation. Later, when COVID-19 emerged, Edesa recognized that the ARDS mechanism it uncovered also applied to COVID-19-driven ARDS. “It was obvious,” recalls Michael Brooks, PhD, president of Edesa, “that if there was good evidence for this mechanism in ARDS, then COVID-19 shouldn’t really be any different than influenza or chemical inhalation.”
Edesa found that the mechanism behind ARDS involved toll-like receptor 4 (TLR4), a signaling receptor that is widely expressed on immune cells. When TLR4 recognizes a foreign body, it triggers an inflammatory signaling cascade to clear out the pathogen. The problem, Brooks notes, is that TLR4 receptors also detect molecular motifs that result from cell death or tissue injury. These motifs are called damage-associated molecular patterns (DAMPS).
“There is a place that is sort of a point of no return,” Brooks remarks. “The damage starts to become the problem itself.” In other words, inflammation can cause damage that causes more inflammation.
Edesa’s EB05 aims to break the feedback loop in an unusual way. Instead of competing with DAMPS to prevent them from binding with TLR4, EB05 blocks the receptor’s dimerization, and hence its activation, regardless of DAMP binding.
Brooks asserts that EB05 “blocks activation of the receptor despite the amount of damage that’s surrounding the cell independent of the amount of extracellular signal.”
Edesa reported positive initial results from a Phase II/III clinical trial of EB05 in COVID-19 ARDS patients in September 2021, which showed a greater than 68% reduction in risk of death compared with placebo over 28 days. Edesa is still recruiting patients and shifting into a Phase III confirmatory trial with EB05.
A gene expression profile test
Besides driving therapeutic development, molecular pathway knowledge can guide therapeutic selection. For example, Castle Biosciences is developing a gene expression profile (GEP) test to predict the response to systemic therapy in patients with moderate-to-severe psoriasis, atopic dermatitis, and related inflammatory skin conditions. It’s an approach that could bring greater efficiency to a process that is too often reactive rather than proactive, says Robert Cook, PhD, Castle’s senior vice president of research and development.
“Trial and error has been the primary way that clinicians are trying to implement these therapies,” he says. “For atopic dermatitis, Dupixent (dupilumab) is a newer therapy that has been very effective, but it’s not effective for everyone. A lot of clinicians may focus on Dupixent at treatment outset, but they learn later on that they need to switch gears.”
In the United States, about 18 million patients receive atopic dermatitis and psoriasis diagnoses each year. A subset of these patients—about 450,000 patients—have moderate to severe disease and are eligible for systemic therapies. These are the patients Castle hopes to help.
In April, Castle announced that its GEP test was the subject of a new poster paper. The paper described how samples were collected via a noninvasive skin scraping technique and evaluated via the quantitative real-time polymerase chain reaction technique. The paper also reported that the test was able to process sufficient RNA to reproducibly assess gene expression.
Castle hopes to identify biomarkers that could be used to guide treatment decisions. According to Cook, the company has launched an observational trial aiming to enroll 4,800 patients with atopic dermatitis or psoriasis across 52 participating centers. More than 140 patients have been enrolled so far.
“With those patient samples, we can begin expanding the discovery process to identify the relevant biomarkers,” he declares. “We expect to launch the test by the end of 2025.”
Restoring immune homeostasis
Atopic dermatitis is also important to Brickell Biosciences. Although the condition isn’t a primary target for the company’s new lead drug candidate, a DYRK1a inhibitor, it presents an excellent opportunity for the company to test its technology.
“We chose atopic dermatitis, not because we necessarily want to enter that space, but because the condition affects a large patient population and causes visible inflammation,” says Monica Luchi, MD, a rheumatologist and chief medical officer at Brickell. “You can see it on the skin.”
Therapies based on DYRK1a could potentially treat much more than skin inflammation—including diseases such as rheumatoid arthritis, type 1 diabetes, and Alzheimer’s.
DYRK1a—dual-specificity tyrosine-phosphorylation-regulated kinase 1A—is an enzyme with two important roles in inflammatory processes. In the innate immune system, the inhibition of DYRK1a prevents TLR4 pathway signaling that releases pro-inflammatory cytokines. In the adaptive immune system, inhibition of DYRK1a can restore immune homeostasis between regulatory and pro-inflammatory T cells. Without sufficient or effective regulatory T cells, Luchi relates, “the pro-inflammatory cells can actually kind of run amok.”
Brickell has several DYRK1A inhibitors in development, the most advanced of which, BBI-02, will enter a first-in-human Phase Ib clinical trial before summer’s over, Luchi notes. BBI-02 could treat atopic dermatitis, rheumatoid arthritis, and type 1 diabetes. Another DYRK1a inhibitor, a “next-generation kinase inhibitor” that Brickell hopes will treat neuroinflammatory diseases such as Alzheimer’s disease and Pick’s disease, is still in the experimental characterization phase.
The trick to taking these new therapies from bench to bedside, Luchi remarks, is to understand that while different diseases may share inflammatory pathways and even targets such as DYRK1a, the specific ways inflammation manifests in each condition—and even each patient—can vary dramatically.
“We thought that we understood all these diseases by subdividing them,” she observes. “We’re learning that even within the subdivisions, there are other diseases.”
In this specific predicament, U.S. officials have to choose a strategy to deliver the aid without the perception of benefiting Hamas, a group the U.S. and Israel both classify as a terrorist organization.
When aiding people in war zones, you can’t just send money, a development strategy called “cash transfers” that has become increasingly popular due to its efficiency. Sending money can boost the supply of locally produced goods and services and help people on the ground pay for what they need most. But injecting cash into an economy so completely cut off from the world would only stoke inflation.
So the aid must consist of goods that have to be brought into Gaza, and services provided by people working as part of an aid mission. Humanitarian aid can include food and water; health, sanitation and hygiene supplies and services; and tents and other materials for shelter and settlement.
Due to the closure of the border with Israel, aid can arrive in Gaza only via the Rafah crossing on the Egyptian border.
The U.S. Agency for International Development, or USAID, will likely turn to its longtime partner on the ground, the United Nations Relief and Works Agency, or UNRWA, to serve as supply depots and distribute goods. That agency, originally founded in 1949 as a temporary measure until a two-state solution could be found, serves in effect as a parallel yet unelected government for Palestinian refugees.
USAID will likely want to tap into UNRWA’s network of 284 schools – many of which are now transformed into humanitarian shelters housing two-thirds of the estimated 1 million people displaced by Israeli airstrikes – and 22 hospitals to expedite distribution.
Since Biden took office, total yearly U.S. assistance for the Palestinian territories has totaled around $150 million, restored from just $8 million in 2020 under the Trump administration. During the Obama administration, however, the U.S. was providing more aid to the territories than it is now, with $1 billion disbursed in the 2013 fiscal year.
The United Nations Relief and Works Agency is a U.N. organization. It’s not run by Hamas, unlike, for instance, the Gaza Ministry of Health. However, Hamas has frequently undermined UNRWA’s efforts and diverted international aid for military purposes.
Humanitarian aid professionals regularly have to contend with these trade-offs when deciding to what extent they can work with governments and local authorities that commit violent acts. They need to do so in exchange for the access required to help civilians under their control.
Similarly, Biden has had to make concessions to Israel while brokering for the freedom to send humanitarian aid to Gaza. For example, he has assured Israel that if any of the aid is diverted by Hamas, the operation will cease.
This promise may have been politically necessary. But if Biden already believes Hamas to be uncaring about civilian welfare, he may not expect the group to refrain from taking what they can.
Security best practices
What can be done to protect the security of humanitarian aid operations that take place in the midst of dangerous conflicts?
Under International Humanitarian Law, local authorities have the primary responsibility for ensuring the delivery of aid – even when they aren’t carrying out that task. To increase the chances that the local authorities will not attack them, aid groups can give “humanitarian notification” and voluntarily alert the local government as to where they will be operating.
Under the current agreement between the U.S., Israel and Egypt, the convoy will raise the U.N. flag. International inspectors will make sure no weapons are on board the vehicles before crossing over from Arish, Egypt, to Rafah, a city located on the Gaza Strip’s border with Egypt.
The aid convoy will likely cross without militarized security. This puts it at some danger of diversion once inside Gaza. But whether the aid convoy is attacked, seized or left alone, the Biden administration will have demonstrated its willingness to attempt a humanitarian relief operation. In this sense, a relatively small first convoy bearing water, medical supplies and food, among other items, serves as a test balloon for a sustained operation to follow soon after.
In that case, the presence of U.S. armed forces might provoke attacks on Gaza-bound aid convoys by Hamas and Islamic jihad fighters that otherwise would not have occurred. Combined with the mobilization of two U.S. Navy carrier groups in the eastern Mediterranean Sea, I’d be concerned that such a move might also stoke regional anger. It would undermine the Biden administration’s attempts to cool the situation.
On U.N.-approved missions, aid delivery may be secured by third-party peacekeepers – meaning, in this case, personnel who are neither Israeli nor Palestinian – with the U.N. Security Council’s blessing. In this case, tragically, it’s unlikely that such a resolution could conceivably pass such a vote, much less quickly enough to make a difference.
Topher L. McDougal does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.
“The majority of wound infections often manifest themselves immediately postoperatively, so close followup should take place […]”
Credit: 2023 Barbarewicz et al.
“The majority of wound infections often manifest themselves immediately postoperatively, so close followup should take place […]”
BUFFALO, NY- October 20, 2023 – A new research perspective was published in Oncoscience (Volume 10) on October 4, 2023, entitled, “Diagnosis and management of postoperative wound infections in the head and neck region.”
In everyday clinical practice at a department for oral and maxillofacial surgery, a large number of surgical procedures in the head and neck region take place under both outpatient and inpatient conditions. The basis of every surgical intervention is the patient’s consent to the respective procedure. Particular attention is drawn to the general and operation-specific risks.
Particularly in the case of soft tissue procedures in the facial region, bleeding, secondary bleeding, scarring and infection of the surgical area are among the most common complications/risks, depending on the respective procedure. In their new perspective, researchers Filip Barbarewicz, Kai-Olaf Henkel and Florian Dudde from Army Hospital Hamburg in Germany discuss the diagnosis and management of postoperative infections in the head and neck region.
“In order to minimize the wound infections/surgical site infections, aseptic operating conditions with maximum sterility are required.”
Furthermore, depending on the extent of the surgical procedure and the patient‘s previous illnesses, peri- and/or postoperative antibiotics should be considered in order to avoid postoperative surgical site infection. Abscesses, cellulitis, phlegmone and (depending on the location of the procedure) empyema are among the most common postoperative infections in the respective surgical area. The main pathogens of these infections are staphylococci, although mixed (germ) patterns are also possible.
“Risk factors for the development of a postoperative surgical site infection include, in particular, increased age, smoking, multiple comorbidities and/or systemic diseases (e.g., diabetes mellitus type II) as well as congenital and/ or acquired immune deficiency [10, 11].”
Continue reading the paper: DOI:https://doi.org/10.18632/oncoscience.589
Correspondence to: Florian Dudde
Keywords: surgical site infection, head and neck surgery
Oncoscience is a peer-reviewed, open-access, traditional journal covering the rapidly growing field of cancer research, especially emergent topics not currently covered by other journals. This journal has a special mission: Freeing oncology from publication cost. It is free for the readers and the authors.
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G77 Nations, China, Push Back On U.S. "Loss And Damage" Climate Fund In Days Leading Up To UN Summit
As was the case in primary school with bringing in presents, make sure you bring enough for the rest of the class, otherwise people get ornery...
This age old rule looks like it could be rearing its head in the days leading up to the UN COP 28 climate summit, set to take place in the United Arab Emirates in about six weeks.
At the prior UN COP 27, which took place in Egypt last year, the U.S. pushed an idea for a new World Bank "loss and damage" climate slush fund to help poor countries with climate change. But the G77 nations plus China, including many developing countries, are pushing back on the idea, according to a new report from the Financial Times.
The goal was to arrange how the fund would operate and where the money would come from for the "particularly vulnerable" nations who would have access to it prior to the upcoming summit in UAE.
But as FT notes, Pedro Luis Pedroso Cuesta, the Cuban chair of the G77 plus China group, has said that talks about these details were instead "deadlocked" over issues of - you guessed it - where the money is going and the governance of the fund.
The U.S.'s proposal for the fund to be governed by the World Bank has been rejected by the G77 after "extensive" discussions, the report says. Cuesta has said that the nations seek to have the fund managed elsewhere, but that the U.S. wasn't open to such arrangements.
Cuesta said: “We have been confronted with an elephant in the room, and that elephant is the US. We have been faced with a very closed position that it is [the World Bank] or nothing.”
Christina Chan, a senior adviser to US climate envoy John Kerry, responded: “We have been working diligently at every turn to address concerns, problem-solve, and find landing zones.” She said the U.S. has been "clear and consistent" in their messaging on the need for the fund.
Cuesta contends that the World Bank, known for lending to less affluent nations, lacks a "climate culture" and often delays decision-making, hindering quick responses to climate emergencies like Pakistan's recent severe flooding.
The G77 coalition voiced concerns about the World Bank's legal framework potentially limiting the fund's ability to accept diverse funding sources like philanthropic donations or to access capital markets.
With just days left before the UN COP 28 summit, the World Bank insists that combating climate change is integral to its mission and vows to collaborate on structuring the fund.