Tag: Medication

Posted on

STAT+: Pharmalittle: We’re reading about a telehealth firm and patient safety, PBMs overcharging, and more

Good morning, everyone, and welcome to another working week. We hope the weekend respite was relaxing and invigorating because that oh-too-familiar routine of meetings, deadlines, and the like has returned with a vengeance. You knew this would happen, yes? To cope, we are relying, as always, on cups of stimulation. Our choice today is laced with traces of cocoa. Feel free to join us. Remember, no prescription is required. Meanwhile, here are some tidbits to help you along. Best of luck accomplishing your goals today and, of course, do keep in touch. …

Novo Nordisk, maker of Ozempic and Wegovy, lists the telehealth company LifeMD on its website as a provider that offers “legitimate medicine sourcing and patient support” for people seeking GLP-1 drugs. But some former employees describe LifeMD differently, as a company that has sought to maximize the volume of prescriptions it doles out at the expense of patient safety, STAT reports. Former workers told STAT that providers were pressed to expedite their work to a pace that was not clinically responsible, with two of them saying providers at times were expected to review the cases of 25 people per hour based only on electronic forms the patients filled out — the equivalent of spending about two minutes on each case.

A recent audit of Iowa Medicaid records revealed how pharmacy benefit managers are using complicated and sophisticated approaches for handling prescription drug claims that ultimately overcharge taxpayers, a finding that underscores controversy surrounding these crucial middlemen in the pharmaceutical supply chain, STAT explains. The audit found that one large pharmacy benefit manager appeared to have made more than $100 million by adjusting the amount of money paid to pharmacies without passing some of the savings back to managed care plans working on behalf of the state, according to Iowa officials. The review scrutinized records from 2019 through 2021.

Continue to STAT+ to read the full story…

Posted on

Patient journey mapping in an open-door psychiatric inpatient unit

BackgroundOpen-door policies in inpatient psychiatric care have been increasingly adopted to enhance patient autonomy and reduce coercive practices. However, systematic methods for evaluating patient experiences in these settings remain limited. This study applied Patient Journey Mapping in an acute psychiatric unit operating a structured, time-limited (6 hours/day) open-door policy to comprehensively analyze the hospitalization experience.MethodsAn exploratory sequential mixed-methods design was used. Qualitative data were first collected through focus groups with patients (n = 18), following GRAMMS guidelines, to identify critical touchpoints across the hospitalization journey. Quantitative data were then collected from patients (n = 32) using an adapted Likert-type ordinal scale to assess satisfaction with the identified touchpoints. Data were analyzed using content analysis methods.ResultsThe analysis delineated the main phases of hospitalization and identified key experiential touchpoints, including “Moments of Truth,” “Moments of Pain,” and “Wow Moments,” which substantially shaped patients’ perceptions of care quality. Open-door policies were perceived as supporting autonomy and reducing psychological distress. However, several challenges remained, particularly regarding the admission process, privacy during medication administration, and communication about structured activities.ConclusionPatient Journey Mapping provides a useful patient-centered approach for evaluating experiences in open-door psychiatric inpatient settings. The findings highlight opportunities to optimize service delivery, strengthen therapeutic environments, and support recovery-oriented practices in acute psychiatric care.
Posted on

STAT+: Telemedicine company touted by Novo Nordisk stressed profits over patient safety, ex-workers say

Novo Nordisk, maker of Ozempic and Wegovy, lists the telehealth company LifeMD on its website as a provider that offers “legitimate medicine sourcing and patient support” for people seeking GLP-1 drugs. But some former employees describe LifeMD differently, as a company that has sought to maximize the volume of prescriptions it doles out at the expense of patient safety.

Former workers told STAT that providers were pressed to expedite their work to a pace that was not clinically responsible, with two of them saying providers at times were expected to review the cases of 25 people per hour based only on electronic forms the patients filled out — the equivalent of spending about two minutes on each case.

The company also discouraged providers from asking what they felt were medically relevant questions to patients, so that they don’t “delay care,” former employees said.

Continue to STAT+ to read the full story…

Posted on

STAT+: State audit of Medicaid records points to methods used by PBMs to obscure drug costs

A recent audit of state Medicaid records revealed how pharmacy benefit managers are using complicated and sophisticated approaches for handling prescription drug claims that ultimately overcharge taxpayers, a finding that underscores controversy surrounding these crucial middlemen in the pharmaceutical supply chain.

The audit of Iowa’s state Medicaid program found that one large pharmacy benefit manager appeared to have made more than $100 million by adjusting the amount of money paid to pharmacies without passing some of the savings back to managed care plans working on behalf of the state, according to Iowa officials. The review scrutinized records from 2019 through 2021.

The overall conclusion was similar to audit results conducted in a few other states, but in this instance, the auditors identified what amounted to creative accounting maneuvers, which not only made it possible to obscure the flow of money but evade prohibitions on a controversial pricing practice that is now outlawed in Iowa and some other states.

Continue to STAT+ to read the full story…

Posted on

Organ Aging Linked to Breakdown in Immune Cell Interaction and Senescent Neutrophil Clearance

We may age at different rates, but none of us escapes aging. A study in mice and in human cells by Stanford Medicine researchers has linked organ aging to the increased inability—with advancing age—of tissue resident macrophage (TRM) immune cells to clear aged neutrophils, another type of immune cell.

The study found that these TRMs appear to be central coordinators of age-related organ decline. Blocking a single receptor, EP2, on these cells preserved the youthfulness of multiple organs in mice, including the brain, heart, skeletal and heart muscle, liver, spleen, bone marrow, kidney, and colon. The receptor binds specifically to a hormone, prostaglandin E2, which is known to cause inflammation and pain in humans as well as in mice.

The researchers found that in mice, selectively disabling this receptor exclusively on tissue-resident macrophages genetically, or using an experimental selective EP2 antagonist drug, prevented chronic-inflammation-driven disorders of age—including frailty, excessive fat accumulation, and heart trouble—and also substantially slowed cognitive decline.

Research lead Katrin Andreasson, MD, the Edward F. and Irene Thiel Pimley Professor in Neurology and Neurological Sciences, said, “We’ve shown that when tissue-resident macrophages don’t have EP2 on their surfaces anymore or when that receptor is plugged up by a drug, this decline doesn’t happen … We’ve been trying to figure out why we age. Now we know at least one big reason for it.”

The discoveries help to clarify systemic inflammation’s significant contribution to aging and the debilities that accompany it. The findings also point to a pharmaceutical approach that could restrain our organs’ unavoidable march toward senescence and so extend overall health span.

Senior author Andreasson, together with first author Jessy Tan, PhD, an instructor in neurology, and colleagues reported on their findings in Science, in a paper titled “Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging.” In their research article summary, the team stated, “This work identifies EP2 signaling in TRMs as a central regulator of organ-wide aging through its control of senescent neutrophil clearance, reframing aging as a failure of active cellular clearance rather than passive degeneration.”

Aging is accompanied by parallel functional decline across organs, but the cellular drivers remain unclear, the authors wrote. “Although molecular hallmarks of aging have been identified, the cellular events that initiate and propel tissue decline remain poorly defined.”

The most abundant white blood cells in our immune system are neutrophils, which act as the body’s main first responders. Produced in bone marrow, new neutrophils are transferred to the bloodstream, where they circulate and attack bacterial, viral, or fungal pathogens that they encounter. Neutrophils are also extremely short-lived, surviving just 12–24 hours.

Some 90% of circulating neutrophils end up in the liver, spleen, and bone marrow, awaiting execution clearance by another type of immune cell. “Neutrophils are among the shortest-lived immune cells, aging within hours in the circulation and requiring continuous clearance,” the team noted.

This neutrophil clearance is critical. In aged animals, the vast bulk of neutrophils that never see combat undergo a fast transition to senescence, a zombie-like state in which they may injure, age, and inflame neighboring cells. And as we age, the neutrophil count rises, with senescent neutrophils constituting an ever higher percentage. “Senescent neutrophils are killing our tissues,” Andreasson said. “Clearance of these cells is essential for preventing chronic inflammation.”

That’s a job for macrophages. These cells comb the tissues for pathogens, signal other cells to lend a hand in the fight, and pump out growth factors that help repair damaged tissue. But first and foremost, Andreasson said, “They’re the body’s garbage collection crew. A lot of that garbage is defunct cells.” And a lot of those cells are neutrophils—to the tune of 100 billion a day.

Macrophages come in several subtypes. Tissue-resident macrophages are long-lived and ubiquitous. They take up residence in each of the body’s organs during fetal development and remain for their lifetimes in whatever organ they’ve inhabited, adapting their roles to fit that organ.

One of tissue-resident macrophages’ prime responsibilities is to swallow senescent cells. “A core TRM function is efferocytosis, the clearance of apoptotic, senescent, and damaged cells that is essential for preventing chronic inflammation,” they explained. Especially important targets for this operation, the study showed, are the potentially 100 billion neutrophils produced daily, which start showing signs of senescence within 8 to 12 hours after entering the bloodstream. (Neutrophils that haven’t arrived at senescence yet but have lived long enough and seen enough to put out “kill me now” flags of surrender on their cell surfaces are fair game.)

“Among primary TRM targets are neutrophils, the most abundantly produced immune cell, with more than 10 billion and 100 billion generated daily in mice and humans, respectively,” the investigator noted. “Uncleared aged neutrophils release proteases and extracellular traps that damage tissues, propagate inflammation, and promote aging, and are normally removed efficiently by TRMs in the liver, spleen, and bone marrow.”

But tissue-resident macrophages also grow old. As Andreasson and associates showed in a prior study, over the advancing years these long-lived cells become ever more prone to succumb to aging-associated inflammation and to propagate it. In their newly reported paper, they noted, “TRMs comprise 60–90% of macrophages in the brain, liver, lungs, heart, and kidneys, and their long lifespan makes them particularly vulnerable to aging, as they accumulate metabolic, oxidative, and inflammatory injury over years to decades.”

Immune cells produce hormones called prostaglandins. One of the five varieties of prostaglandin, called PGE2, can exert diverse effects on a cell, depending on which type of surface receptor is expressed on that cell’s surface. Of the various subtypes of receptors for PGE2, the EP2 receptor is highly pro-inflammatory. Tissue-resident macrophages are loaded with EP2.

Infection, injury, and toxic chemicals, including those produced by our aging bodies, increase PGE2 output. As the team’s prior work showed, that output grows substantially as we grow older. So does the concentration of EP2 on tissue-resident macrophages. “TRMs express the prostaglandin E2 (PGE2) receptor EP2, which suppresses macrophage metabolism and phagocytosis in aging,” the investigators noted.

This effectively creates a one-two punch. PGE2’s pro-inflammatory influence increases with age. The resulting unrelenting inflammatory PGE2 stimulation on tissue-resident macrophages, the new study showed, downshifts these cells’ ability to clear neutrophils. Senescent neutrophils then accumulate in tissues and blood.

Andreasson and her colleagues had previously shown that with aging, tissue-resident macrophages undergo a slow decay in their energy metabolism. “Once that starts, there’s a steady decline in a macrophage’s performance,” she said.

For their newly reported study, Andreasson’s lab bioengineered a mouse in which, at a time of the scientists’ choosing, the EP2 gene gets deleted—but only in tissue-resident macrophages. The results of their experiments showed that disappearance of EP2 from these cells reinvigorated the neutrophil-clearance process that PGE2 undermines.

For their experiments, the Stanford Medicine researchers studied younger normal mice, aged 6–8 months, which corresponds to late adolescence or early adulthood in humans, and they also studied older normal mice, at 23 to 25 months of age, whose human counterparts would be in their 60s or 70s. They also looked at older mice whose EP2-encoding gene had been deleted at 4 to 6 months of age (equivalent to their “teenage” years).

The team’s analyses identified 71 proteins, found in blood, whose levels were significantly altered in older normal mice. Of those proteins, 59 stayed at youthful levels in older mice whose tissue-resident macrophages lacked EP2. Many of these proteins originated in the liver. “The liver is one of the body’s most tissue-resident-macrophage-enriched organs and a major contributor to aging-related changes in blood chemistry,” Andreasson said. “It’s the central organ determining the body’s metabolic rate.”

The study showed that in normal old mice, smoldering senescent neutrophils accumulated in the liver, spleen, and bone marrow and, to a lesser extent, in many other organs the researchers looked at.

But the organs of older mice lacking EP2 on their tissue-resident macrophages retained the lower neutrophil numbers of youth. These mice looked younger, leaner, and more physically fit compared with control littermates. They evidenced less visceral fat and greater muscle mass. Their performance on tests of multiple organs’ function equaled that of young mice.

EP2 deletion in addition reduced inflammation in the blood, liver, colon, heart, kidney, and hippocampus (a brain region tightly tied to memory and navigation ability) in the older mice. Their speed, balance, and forelimb grip strength resembled that of young animals.

Reducing EP2 activity in older mice also preserved their memory capabilities. These animals could thread their way through a maze or recall previously encountered objects almost as well as younger mice—and far better than similarly old mice with tissue-resident macrophages expressing functional EP2. “Reducing TRM EP2 signaling in aged mice preserved youthful mitochondrial fitness and prevented cognitive decline, frailty, sarcopenia, adiposity, cardiac impairment, and systemic inflammation,” they wrote in summary.

There are, today, no approved drugs that selectively shut down EP2 activity, although there are several that target PGE2. Non-steroidal anti-inflammatory painkillers work by blocking PGE2 production, Andreasson said. That’s how aspirin and similar drugs reduce pain, fever, swelling, and redness. But to greater or lesser degrees these drugs all block other vital prostaglandins. Even PGE2 has beneficial properties when it binds to receptors other than EP2, rather than the detrimental inflammatory one examined in this study.

As part of their study, the investigators treated otherwise normal 22-month-old mice for two months with an EP2-inhibiting experimental drug. The results showed that the treatment reduced total and senescent neutrophil counts in old mice toward youthful levels. In culture dishes, old age diminished—but the EP2-blocking drug likewise significantly restored—the mice’s tissue-resident macrophages’ ability to engulf and digest burnt-out neutrophils. “Together, these results demonstrate that pharmacologic EP2 inhibition partially reverses age-associated TRM dysfunction and senescent neutrophil accumulation, with strongest rescue in the liver,” they stated.

Finally, the team turned to a large human database characterizing different cell types in young, old, and diseased human livers. This database revealed the same age-related neutrophil buildup, increased neutrophil senescence, tissue-resident-macrophage decline, and heightened EP2 activity in older—and even more so, diseased—livers that the Stanford Medicine researchers had seen in mice. This was a first-time observation in human cells, according to Andreasson. “These human findings, while correlative, position the TRM EP2-efferocytosis axis as a candidate mechanism in human aging that warrants further functional testing,” they noted. “Specifically, future studies should assess whether the impaired clearance of senescent neutrophils also occurs in human TRMs and whether pharmacological EP2 blockade can restore this defect.”

Andreasson suggested that targeting neutrophil clearance may yield big therapeutic benefits. “We need to develop a safe drug that incapacitates EP2 without disrupting upstream events such as PGE2 production.”

The post Organ Aging Linked to Breakdown in Immune Cell Interaction and Senescent Neutrophil Clearance appeared first on GEN – Genetic Engineering and Biotechnology News.

Posted on

Circuit logic of oxytocin and vasopressin complementary actions

Oxytocin (OT) and vasopressin (VP) are evolutionarily conserved neuropeptides that regulate social behavior, emotional processing and physiological homeostasis. Although traditionally studied as individual modulators of affiliation, stress and autonomic function, emerging evidence indicates that their actions are best understood at the level of neural circuits. Advances in optogenetics, cell-type-specific electrophysiology and systems neuroscience have revealed that OT and VP act within distributed networks through receptor-defined microcircuits composed of excitatory and inhibitory neuronal populations, astrocytes and long-range projections. Within these circuits, OT and VP can exert complementary, synergistic or opposing effects depending on receptor localization, cellular identity and network state. Here, we synthesize recent circuit-level and electrophysiological evidence to propose a framework in which OT and VP operate as a coordinated neuromodulatory axis. We argue that the functional consequences of OT/VP signaling emerge not from peptide identity alone, but from their engagement of recurrent circuit motifs that redistribute excitation and inhibition across neural networks. These motifs provide a mechanistic substrate for regulating transitions between competing behavioral and physiological states, including social safety vs. threat, affiliation vs. avoidance, and parasympathetic vs. sympathetic dominance. We further discuss how disruption of receptor topology, synaptic integration and circuit architecture may contribute to neurodevelopmental, psychiatric and stress-related disorders. By shifting the focus from peptide-centric models to circuit-level mechanisms, this framework reconciles seemingly contradictory findings across brain regions and behavioral paradigms, and provides a foundation for the development of next-generation circuit-based therapeutic strategies targeting the oxytocin-vasopressin axis.
Posted on

Dendritic Cells Identified as Key Organizers of Anti-Tumor Immune Hubs

Not all immune activity inside a tumor is disorganized. In some patients, tumors contain tertiary lymphoid structures, or TLSs: organized clusters of immune cells that resemble lymph-node-like sites of local immune coordination. Their presence has been associated with improved survival and better responses to immunotherapy in several cancers, making them an increasingly important feature of the tumor microenvironment.

A new study published in Science identifies a specialized immune cell population that helps build and sustain these structures. Researchers at the Icahn School of Medicine at Mount Sinai and collaborating institutions found that type 1 conventional dendritic cells, or cDC1s, act as central organizers of TLSs in cancer. The work helps explain how local anti-tumor immune responses are maintained within tumor tissue and points to potential strategies for improving immunotherapy.

Why TLSs matter in cancer immunity

TLSs are not normal anatomical lymph nodes. They arise in chronically inflamed tissues, including tumors, and can contain organized T-cell zones, B-cell follicles, germinal center-like regions, plasma cells, and specialized stromal networks. In cancer, their presence is often interpreted as evidence that the immune system is not only infiltrating the tumor but organizing a sustained local response.

Many tumors contain immune cells, but not all immune infiltrates are functionally productive. TLSs may provide a site where antigen presentation, T-cell activation, B-cell maturation, and antibody responses occur close to malignant cells. This could help explain why TLS-positive tumors are often associated with more favorable outcomes and greater sensitivity to immune checkpoint blockade.

Until now, however, it has been less clear what drives TLS formation and, just as importantly, what keeps these structures functional once they are established.

cDC1s as local immune architects

Dendritic cells are best known for antigen presentation: they capture tumor antigens and prime T-cell responses. This study expands that role. The researchers found that cDC1s do not only initiate anti-tumor immunity; they help organize the physical and functional immune architecture inside tumors.

“Our goal was to understand how these immune structures develop and persist inside tumors,” said lead author Raphael Mattiuz, PhD. “We found that a distinct subset of dendritic cells acts as the organizer, bringing together different immune cells and keeping the local anti-cancer response active.”

The team analyzed tumor samples from patients with lung, liver, colorectal, kidney, and ovarian cancers using multiplex imaging and spatial gene-expression approaches. These methods allowed them to map where dendritic cells were located, which immune cells surrounded them, and how those local neighborhoods related to TLS organization.

Across tumor types, mature dendritic cells accumulated within TLSs. The mechanistic work then focused on a mouse model of non-small cell lung cancer designed to reproduce mature TLS formation seen in human tumors. In this model, cDC1s were required both during the establishment of TLSs and later for their maintenance.

More than T-cell priming

The study suggests a two-stage role for cDC1s. Early in tumor development, TLS formation depended on IFNγ-driven maturation of cDC1s, migration to tumor-draining lymph nodes, and recruitment of primed T cells back into the tumor. As tumors progressed, however, the biology changed. TLSs could persist even when egress of T cells from tumor-draining lymph nodes was impaired, while cDC1s became retained within intratumoral stromal hubs enriched in CCR7 ligands.

This is clinically interesting because it positions cDC1s as tissue-resident coordinators of ongoing immunity, not merely transient antigen couriers. The researchers found that timed depletion of cDC1s after TLSs had formed disrupted TLS maintenance. Blocking their localization to stromal hubs had a similar effect.

The function of these cells also depended on antigen presentation. Genetic ablation of both MHC class I and II on cDC1s impaired TLS maintenance, T follicular helper cell preservation, germinal center formation, tumor-specific IgG production, and differentiation of progenitor exhausted CD8-positive T cells.

“We were surprised to see that these rare cells become permanent organizers within the tumor itself,” Mattiuz said. “They don’t just activate cancer-killing T cells. They also help coordinate antibody responses, allowing multiple parts of the immune system to work together where they’re needed most.”

Implications for immunotherapy

Checkpoint inhibitors have changed cancer care, but durable responses remain limited to a subset of patients. One reason is that reinvigorating T cells may not be enough if the tumor lacks the local immune organization needed to sustain productive responses. TLS biology offers a complementary framework: the issue may not only be whether immune cells are present, but whether they are organized into functional niches.

This study suggests that cDC1-directed therapies could help strengthen those niches. Potential strategies might include increasing cDC1 abundance, enhancing cDC1 maturation, improving their recruitment or retention in tumors, or combining cDC1 activation with checkpoint blockade, vaccines, radiotherapy, or other immune-modulating approaches.

The findings also add nuance to biomarker development. TLS presence is already being studied as a prognostic and predictive feature, but TLS quality may matter as much as TLS quantity. A tumor with cDC1-rich, antigen-presenting, germinal center-supporting TLSs may behave differently from a tumor with less mature or poorly maintained immune aggregates.

For medical oncology, this could eventually refine how TLSs are interpreted in pathology and translational studies. Rather than treating TLSs as a binary histological feature, future assays may need to assess their cellular composition, dendritic cell state, B-cell organization, and proximity to effector T-cell populations.

Still early, but mechanistically important

The work is not yet a clinical intervention. It does not show that activating cDC1s in patients will reliably generate TLSs or improve immunotherapy outcomes. Tumor type, antigenicity, stromal architecture, prior therapy, and immunosuppressive pathways will likely influence whether this biology can be therapeutically exploited.

Nevertheless, the study provides a clearer mechanistic target in a field that has often treated TLSs as useful but poorly controlled biomarkers. If cDC1s are required to form and maintain functional TLSs, then therapies aimed at dendritic cell biology may become a way to convert poorly organized tumor immune infiltrates into more coordinated anti-tumor responses.

The broader message is that effective cancer immunity is spatial as well as cellular. It is not only about having T cells, B cells, antibodies, or dendritic cells inside the tumor. It is about arranging them in the right place, in the right state, and for long enough to sustain pressure on malignant cells.

By identifying cDC1s as organizers of tumor-associated TLSs, the study offers a more concrete path toward therapies that help the immune system build its own infrastructure inside cancer.

The post Dendritic Cells Identified as Key Organizers of Anti-Tumor Immune Hubs appeared first on Inside Precision Medicine.

Posted on

Solving a 40-Year Mystery Could Advance Treatments for Neurodegenerative Diseases

A decades-long mystery surrounding one of the nervous system’s most important molecular machines has been solved, providing a structural blueprint that could accelerate the development of targeted therapies for several inherited neurodegenerative diseases.

In a study published in Science Advances, researchers at the University of California, Davis report the first complete structure of kinesin-1—a motor protein that transports neurotransmitters, proteins, and other essential cargo throughout nerve cells—in its inactive state. The findings reveal how the protein is switched off until needed and identify structural features that could serve as targets for future drugs.

Although kinesin-1 was the first member of the kinesin superfamily to be discovered and has been studied for more than 40 years, scientists have never fully understood how cells regulate its activity. The new study provides what the authors call “a structural answer,” revealing how motor activity and cargo binding are coordinated.

Kinesin-1 is essential for healthy neurons. The protein walks along microtubules using energy from ATP, carrying cargo from the cell body to distant parts of nerve cells. When this transport system fails, neurons cannot deliver the materials needed to function and survive, contributing to diseases including amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease type 2, and hereditary spastic paraplegia.

Using cryo-electron microscopy, the researchers captured the complete structure of kinesin-1 in its autoinhibited, or “off” state. They discovered that the protein folds into a compact configuration that simultaneously prevents the motor from moving and blocks cargo from attaching.

“This dual-inhibited kinesin architecture provides a comprehensive blueprint” for how the protein maintains its inactive state, the authors write. The structure also reveals distinct regulatory sites that can be unlocked to restore both movement and cargo transport.

The team also uncovered how the protein is activated. They propose that the microtubule-associated protein MAP7 binds kinesin-1 and triggers a series of structural changes that unfold the protein, releasing the motor domains and exposing the cargo-binding site. Once activated, kinesin can resume transporting essential cellular components through the neuron.

The findings have important implications for drug development because many disease-causing mutations disrupt kinesin-1’s ability to switch between its inactive and active states. Until now, researchers lacked the structural information needed to understand exactly how these mutations impair the protein or how they might be corrected.

With the complete structure now available, investigators can examine how specific mutations alter kinesin-1 and begin designing molecules that restore its normal function. Rather than replacing the defective protein, future therapies could stabilize its structure or correct the molecular interactions that prevent it from turning on.

The authors hope this discovery will aid in designing a molecule that would bind the mutant protein and correct its defect. They believe the study establishes “a clear foundation for future mutational studies” and provides “a powerful framework” for understanding how kinesin proteins are regulated across the broader superfamily.

While additional research is needed before therapies reach the clinic, the work provides the detailed structural roadmap that has long been missing. By revealing exactly how kinesin-1 is locked into its inactive state and how that lock can be released, the study identifies promising new targets for precision medicines aimed at restoring intracellular transport in neurodegenerative disease.

The post Solving a 40-Year Mystery Could Advance Treatments for Neurodegenerative Diseases appeared first on Inside Precision Medicine.

Posted on

Pancreatic Cancer Vaccine Triggers Immune Response Before Tumors Develop

Results from a Phase I clinical trial show early promise for a vaccine designed to prevent pancreatic cancer in people at high risk of developing the disease. Published in Cancer Discovery, the findings suggest it may be possible to intercept one of the most aggressive forms of cancer before it takes hold.

Pancreatic cancer is often diagnosed at advanced stages and grows rapidly, contributing to its poor survival rates. Yet the disease typically develops over many years from pancreatic cysts and other precursor lesions, creating a window of opportunity to intervene before those lesions turn into malignant tumors. 

“Individuals at high risk due to hereditary predisposition or to the presence of a concerning pancreatic lesion detected on imaging usually undergo surveillance to monitor for changes over time,” said Neeha Zaidi, MD, associate professor of oncology at Johns Hopkins Medicine and co-senior author of the study. “If there is a high enough concern for transformation to cancer or if early cancer is detected, the current standard of care is surgical resection. However, the chances of recurrence are up to 80%, and many precursor lesions to pancreatic cancer are microscopic and thus undetectable by imaging.”

More than 90% of pancreatic cancers are driven by mutations in the KRAS gene, which also appear in many precancerous lesions. Zaidi’s team developed a vaccine targeting the six most common KRAS mutations, with the goal of training the immune system to recognize and attack cells carrying these mutations before they become cancerous. 

The Phase I clinical trial evaluated the mKRAS-VAX vaccine in 20 participants with genetic predisposition to pancreatic cancer and a pancreatic abnormality identified through imaging. Patients received four doses of the vaccine over the course of 13 weeks and were monitored for side effects and immune responses for a median follow-up time of 16.5 months.

None of the patients developed pancreatic cancer or high-risk lesions during the study, and 90% of them developed a significant immune response to the vaccine. Memory cells against the six KRAS mutations were still detectable in the blood for as long as two years after vaccination. 

“This long-lasting response is particularly noteworthy when assessing for possible interception of cancer, which requires long-lasting immunity,” said Zaidi. “In addition, the vaccine was safe and well tolerated, supporting its use in larger cancer interception studies.”

Although the main goal of the study was to prove the vaccine’s safety, an exploratory imaging analysis found that pancreatic cysts completely regressed in five participants and partially regressed in three, while the remaining remained stable. 

The vaccine had previously been tested in pancreatic cancer patients who had undergone surgery and were at high risk of experiencing recurrence, where all participants remained disease free for at least five years. “We thought if we can see an immune response in patients with cancer, the vaccine should work even better in people who are at higher risk because of a family history, gene alteration or cyst on the pancreas,” said Zaidi.

Another trial is currently enrolling patients to study whether the immune response generated by the vaccine can infiltrate within precancerous lesions in addition to being detectable in the blood. If successful in larger clinical studies, the vaccine could offer the first interception strategy to reduce the number of pancreatic cancer cases. 

“Prevention and interception save lives and reduce the morbidity associated with cancer development and progression. This is especially important for cancers whose early-onset frequency is increasing and for which we do not have effective methods for early detection,” says Elizabeth Jaffee, MD, deputy director of the Johns Hopkins Kimmel Cancer Center, co-director of the Skip Viragh Center for Pancreatic Cancer, and associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy.

“This is just the beginning, but the findings suggest that the immune system is getting activated. We have more work to do, but this is a good start aimed at prevention, which no one had thought about doing before.”

The post Pancreatic Cancer Vaccine Triggers Immune Response Before Tumors Develop appeared first on Inside Precision Medicine.