Day: 04/01/2023

Immunotherapy after Surgery Shows Long-Term Benefits for High-Risk Bladder Cancer

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Updated results from a large clinical trial confirm that, for some people with bladder cancer that can be removed with surgery, receiving immunotherapy immediately afterwards is an effective treatment.

In 2021, initial results from the same trial led the Food and Drug Administration (FDA) to approve the immune checkpoint inhibitor nivolumab (Opdivo) as a post-surgical (adjuvant) treatment for people with what is called high-risk bladder cancer.

That approval was based on data showing that, compared with treatment with a placebo, giving nivolumab for a year after surgery doubled the amount of time people lived without their disease recurring in or near the bladder or elsewhere in the body, a measure called disease-free survival.

The updated results, presented on February 17 at the 2023 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, included about 3 years of follow up. These results showed that people who received nivolumab had a median disease-free survival of 22 monthsExit Disclaimer, compared with about 11 months for those who received a placebo.

The picture looked even better for people whose tumors express a protein called PD-L1, which interacts with another protein targeted by nivolumab. That group of patients had a median disease-free survival of more than 52 months.

In the trial, nivolumab was given for a maximum of 1 year, said Matt Galsky, M.D., from the Icahn School of Medicine at Mt. Sinai, who presented the updated results at the ASCO symposium. 

“If you’re just suppressing cancer with a treatment, then potentially, once treatment stops, the cancer starts to grow again,” he said. The long-term survival free of disease seen in some of the study participants “might indicate that [immunotherapy] is actually eradicating the cancer in some patients.”

A lingering risk of recurrence

Bladder cancer that has invaded the bladder muscle or nearby lymph nodes can potentially be cured by surgical removal of the bladder and lymph nodes. But, in more than half of people who have this type of surgery, called radical cystectomy, cancer cells have already spread (metastasized) elsewhere in the body.

These deposits of metastatic cancer “are too small to be seen on [an imaging] scan,” said Dr. Galsky. “But over time those cancer cells grow and divide. And we want to try and avoid that if possible,” he explained.

The main strategy that clinical trials have tested to prevent bladder cancer from recurring, either at or near the original tumor or at distant locations, has been adjuvant therapy: chemotherapy or immunotherapy drugs given after surgery. 

Chemotherapy regimens based on the drug cisplatin are known to shrink tumors in people with bladder cancer that has metastasized at the time it’s diagnosed, explained Andrea Apolo, M.D., of the Genitourinary Malignancies Branch in NCI’s Center for Cancer Research. So these regimens are often used in bladder cancer that can be surgically removed, either before surgery (called neoadjuvant therapy) or afterward, as adjuvant therapy. 

But many people can’t tolerate cisplatin, she added. “And a lot of people prefer not to get chemotherapy because of the side effects,” she said.

Researchers have been searching for other adjuvant therapy options. A previous clinical trial tested a different immunotherapy called atezolizumab (Tecentriq) as an adjuvant therapy, but it did not improve disease-free survival. 

So for many years, explained Dr. Galsky, most people, following surgery for bladder cancer, underwent observation instead of adjuvant therapy. Observation is following patients with frequent imaging to try to catch a recurrence as early as possible.

But when a previous study found that nivolumab could shrink tumors in people with more advanced bladder cancer, researchers decided to test the drug as an adjuvant treatment in people without detectable metastases.

Preventing disease recurrence for years

The CheckMate 274 trial, which was funded by Bristol Myers Squibb and Ono Pharmaceutical, enrolled more than 700 people with high-risk, muscle-invasive bladder cancer who had undergone extensive surgery. Participants were eligible if they had received neoadjuvant cisplatin-based chemotherapy but not if they had received any adjuvant treatment. 

The researchers randomly assigned trial participants to receive up to a year of treatment with either nivolumab or a placebo. At the time of the ASCO presentation, participants had been followed for a minimum of 31 months. 

The incidence of side effects observed during the longer follow-up period was about the same as that seen during the initial 6 months of treatment. Around 18% of people who received nivolumab had at least one serious side effect, compared with 7% of those who received the placebo. Three of the 353 people who received nivolumab died of side effects attributed to the drug. 

Overall, after a median follow up of 36 months, people who received nivolumab lived about twice as long without their disease progressing than those who received a placebo. 

At the time of the initial publication, there was some evidence that people whose tumors expressed PD-L1 were benefitting more from nivolumab than those whose tumors lacked PD-L1. But it was too early to calculate their median disease-free survival.

With the longer follow up, the researchers found that people whose tumors expressed PD-L1 lived more than twice as long without their disease progressing than the group as a whole.

“These results were impressive but not necessarily unexpected, given what we know about that protein and how [it] might relate to sensitivity to [nivolumab],” Dr. Galsky said. 

However, he added, “for all patients in the study, there was a benefit from [receiving] immunotherapy.” Under FDA’s approval, nivolumab can be used for anyone with high-risk bladder cancer, regardless of whether their tumors express PD-L1.

Pinpointing who needs adjuvant therapy

CheckMate 274 participants will continue to be followed to see if those who received nivolumab live longer, a measure called overall survival. 

The overall survival data will matter, explained Dr. Apolo. “We know we overtreat a lot of patients with adjuvant therapy,” she said. That is, many people who receive it may have been cured with surgery alone. “But we don’t know yet how to pinpoint who those people are.”

If it turns out that there’s no overall survival improvement from adjuvant immunotherapy, it would make more sense to wait until a cancer recurs or metastasizes to give it, she explained.

A planned NCI-supported trial will soon be looking at whether blood tests for circulating tumor DNA could predict which high-risk patients having surgery for bladder cancer actually need adjuvant therapy and who could safely skip it, Dr. Galsky said.

Although CheckMate 274 didn’t find that treatment with nivolumab decreased participants’ overall quality of life, those who received the drug did experience more side effects and the treatment caused several deaths. “So, if we can identify patients who absolutely don’t need treatment, that certainly makes sense,” said Dr. Galsky.

Other immunotherapy drugs are also being tested as adjuvant treatments for patients with high-risk bladder cancer, Dr. Apolo said. For example, NCI researchers recently finished treating participants in a trial called AMBASSADOR, which is comparing pembrolizumab (Keytruda) with observation after surgery.

In the future, researchers are also interested in testing whether giving nivolumab both before and after surgery can reduce the risk of recurrence even further, Dr. Galsky explained. A recent study found that giving pembrolizumab both before and after surgery reduced the risk of recurrence for some people with melanoma, an aggressive type of skin cancer.

“We’ll see if we see the same thing with bladder cancer,” Dr. Galsky said.

Oxford Vacmedix Ltd.: harnessing the power of immunotherapy to treat and monitor cancer

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A new platform built around recombinant overlapping peptides (ROPs) promises quicker and cheaper production of more effective therapeutic vaccines and diagnostics for cancer and viral infections.

Immunotherapy is a fast-growing approach for cancer treatment and the prevention of infections based on manipulation and direction of the patient’s immune system. It is a targeted therapy that is less toxic than chemotherapy and is usually suitable for combination with other treatments.

Vaccination against a cancer or pathogen can be achieved through injection of a preparation containing antigens that direct and stimulate T cells to attack anything bearing those antigen markers. However, there are two immune responses: one that produces antibodies and helper T cells, and another that produces killer T cells. For cancer, the killer T cell approach has been found to be much more effective. Unfortunately, many cancer vaccines are based on full-sized proteins produced by a tumor, which tend to generate antibodies and helper T cells rather than killer T cells.

Enter Oxford Vacmedix and its ROPs. Back in 2000, while at Harvard University, the company’s founder and CSO Shisong Jiang proposed that breaking a whole target protein into short but overlapping linear fragments would be much more effective for cellular immunity.

Although this approach is very effective, it requires the production of many different peptides. So in 2004, Jiang (then at Oxford University) and his team worked out a way to grow all the overlapping peptides together in bacteria, and in 2012 they spun out Oxford Vacmedix to exploit the technology.

The fragments, with an enzyme cleavage site between them, are linked into a single molecule encoded by a single gene for expression as a single protein. Once expressed, the protein can easily be split into the individual ROPs by enzyme cleavage ( in vitro or inside cells), which makes it easy to both deliver and manufacture.

The peptides can be produced synthetically but this can be slow and expensive. ROP production takes only 2–3 days at a time—a great improvement on synthetic production. “Vaccine can be designed and scaled up much more quickly, it is also more suitable than the pooled peptides strategy for applying for FDA [US Food and Drug Administration] registration,” said Jiang. “I have calculated that manufacturing overlapping peptides using a natural expression system is a thousand times cheaper and has the potential to significantly reduce the cost of vaccine development.”

Figure 1: Antigen presentation of ROP. MHC, major histocompatibility complex.

Oxford Vacmedix is currently developing two therapeutic vaccines. OVM-100 is a first-in-class human papillomavirus (HPV) vaccine aimed at cervical cancer, with an estimated market size of over £1 billion. OVM-200 is a first-in-class cancer vaccine that targets survivin, a protein that is expressed at high levels in many solid tumors, such as breast, lung, ovarian and colorectal, as well as blood cancers—a huge potential market. Data so far are compelling, with vaccinated mice showing greatly extended survival in tumor model systems. OVM is developing a large-scale good manufacturing practice (GMP)- compatible production process in China prior to transferring production to a contract manufacturing organization (CMO) in Europe.

Additionally, using ROPs as diagnostic reagents, Oxford Vacmedix in China is developing companion diagnostics for monitoring its therapeutic vaccines, and a test to identify chronic/latent infection in tuberculosis (TB). In the Elispot test (a widely used way of monitoring cellular immune responses), ROPs are added to a blood sample; if the subject already has strong immunity, the T cells respond vigorously by producing a cytokine that can be readily assayed. Tests of the TB prototype on more than 200 people have shown that it is comparable to gold-standard reagents and is early proof of the platform. “T cell immunity is instrumental in containing infections and tumors but, apart from TB, which is expensive, there are currently few diagnostic kits commercially available,” said William Finch, CEO of OVM. “This is a great medical need and we believe diagnostics for T cell immunity have a vast market.

Partnering outlook

Oxford Vacmedix is looking for a large pharmaceutical firm to codevelop its ROP technology, a suitable CMO for GMP-level production for its preclinical/phase 1 vaccine trials in Europe, and firms that can sequence tumor mutations against which it can design personalized vaccines (neoantigens). The company is also interested in collaborating with organizations that can provide checkpoint inhibitors suitable for combination with ROP vaccines.

“We are the first company to not only prove that overlapping peptides stimulate both helper and killer T cells, but also propose using them as vaccines to stimulate T cell immunity,” said Jiang. “Our high-performing ROP vaccines are easier and cheaper to design, scale up and quality-control than existing approaches—the potential impact on health care is enormous.”

Oxford Vacmedix is also looking to combine ROPs with other treatments, e.g. checkpoint inhibitors. As Jiang explained, “If you liken immunotherapy to a car, ROPs would be the steering wheel and checkpoint inhibitors like releasing the brake—the combination enables you to go very fast in the right direction.”

Why do animals living with humans evolve such similar features? A new theory could explain ‘domestication syndrome’

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In the 19th century, Charles Darwin was one of the first to notice something interesting about domesticated animals: different species often developed similar changes when compared to their ancient wild ancestors.

But why would a host of seemingly unrelated features repeatedly occur together in different domesticated animals?

Scientists call this collection of shared changes “domestication syndrome,” and the reason it occurs is still hotly debated.

In a new paper in Proceedings of the Royal Society B, we argue that currently popular explanations aren’t quite right—and propose a new explanation focused on big changes in the way domesticated animals live. Along the way, our theory also offers insights into the unexpected story of how we humans domesticated ourselves.

Shared changes under domestication

The most commonly shared change is tamer behavior. All domesticated animals are calmer than their wild ancestors naturally were.

That’s probably not very surprising. Ancient humans would’ve preferred docile animals, and likely selected breeding stock for tameness.

But other common changes don’t seem at all useful to humans—or to the animals themselves. Like shorter faces, smaller teeth, more fragile skeletons, smaller brains, and different colors in skin, fur, and feathers.

Not all domesticated animals share all these features. For example, dogs have many, and camels only a few.

But each change occurs in more than one domesticated species.

Wild self-domestication

Surprisingly, very similar changes sometimes also appear in wild animals, leading some scientists to think they “self-domesticated” in some way.

The bonobo (a great ape closely related to the chimpanzee) is one famous example of an animal that has undergone these changes without human intervention. Urban foxes are another.

Wild self-domestication is most common in isolated sub-populations, like on islands, and may overlap with a similar phenomenon known as the “island effect.”

Perhaps more surprisingly, modern humans also show features of domestication syndrome, when compared to our ancient ancestors. This suggests we also self-domesticated.

Some scientists argue these changes made us more sociable, helping us to develop complex languages and culture.

So a clearer understanding of domestication syndrome in animals might improve our knowledge of human evolution too.

What causes domestication syndrome?

In recent years, two main possible explanations for domestication syndrome have dominated scientific discussion.

The first suggests it was caused when ancient humans selected animals for tamer behavior, which somehow triggered all of the other traits too.

This idea is supported by a famous long-running Russian fox-breeding experiment which began in 1959, in which caged foxes were selected only for tameness but developed the other “unselected” features as well.

The second hypothesis complements this first one. It suggests selection for tameness causes the other features because they’re all linked by genes controlling “neural crest cells.” These cells, found in embryos, form many animal features—so changing them could cause several differences at once.

More than selection for tameness

However, our new research suggests these two ideas oversimplify and obscure the complex evolutionary effects at play.

For one thing, there are problems with the famous Russian fox experiment. As other authors have noted, the experiment didn’t begin by taming wild foxes, but used foxes from a farm in Canada. And these pre-farmed foxes already had features of domestication syndrome.

What’s more, the experimenters didn’t only select for tameness. They bred other foxes for aggression, but the aggressive foxes also developed domestication syndrome features.

And in a similar experiment conducted in the 1930s, caged rats developed the same common changes, including tamer behavior, despite no deliberate selection for tameness, or aggression.

So, it seems domestication syndrome might not be caused by humans selecting animals for tameness. Instead, it might be caused by unintended shared effects from the new domestic environment.

A new hypothesis for domestication syndrome

Crucially, it’s not just new forces of selection, such as a human preference for tameness, that matters. The removal of pre-existing selection is just as important, because that’s what naturally shaped the wild ancestors in the first place. Adapting to the increased maternal stress that accompanies separation from infants (either for shared care or domestication) may be one of the drivers of domestication syndrome. Credit: Shutterstock

For example, domesticated animals are often protected from predators, so wild traits for avoiding them might be lost. Competition for mating partners is also often reduced, so wild reproductive features and behaviors could decline, or disappear.

Domesticated animals are also usually reliably fed. This might alter certain features, but would certainly change natural metabolism and growth.

In effect, we argue there are multiple selective changes at work on domesticated animals, not just “selection for tameness,” and that shared shifts in evolutionary selection would often cause shared changes in features. Even across different species.

Our new hypothesis highlights four ways that selection shaping wild animals is often disrupted by domestication. These are:

  1. less fighting between males
  2. fewer males for females to choose between
  3. more reliable food and fewer predators, and
  4. elevated maternal stress, which initially reduces the health and survival of offspring.

Several of these might resemble “selection for tameness,” but using this one term to describe them all is misleadingly vague, and obscures other changes in selection.

So how did we domesticate ourselves?

Well, one current theory is that sociable “beta males” began cooperating to kill alpha bullies. This changed how competition worked among males, leading to fewer big and aggressive males.

But our hypothesis suggests other effects also played a role. For example, our early ancestors evolved the capacity for shared infant care. In our chimpanzee relatives today, sharing care of an infant would likely trigger extreme stress for the mother—but our ancestors adapted to this increased stress and gained an effective survival strategy.

More reliable food access due to group foraging and sharing, plus collective defense against predators, might also have made us more sociable, more cooperative, and more complex, while promoting other changes commonly seen in non-human domesticated animals.

Whatever the specific drivers in each species, recognizing multiple selective pathways better explains the domestication syndrome, and reaffirms the complexity of evolutionary effects shaping all life on Earth.

Bobby Caldwell: Death from Fluoroquinolone Antibiotics

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Bobby Caldwell was a singer, songwriter, and guitarist of R&B, soul, jazz, and adult contemporary music who was perhaps best known for “What You Won’t Do for Love.”

In 2017, Caldwell was prescribed a fluoroquinolone antibiotic and suffered rupture of both Achilles tendons, followed by extensive nerve damage called peripheral neuropathy. He continued to perform, even though he had to do it in a wheelchair, with a cane, and with people to help him. In spite of the best medical treatment available, his condition continued to worsen. He lost much of his ability to control his muscles and was in great pain.
His health problems forced him to cancel his concerts after 2020, and on March 14, 2023 he died from complications of the antibiotic he received six years earlier.

Career in Singing and Songwriting
Caldwell was born in Manhattan and grew up in Miami, where his parents hosted a local variety television show called Suppertime. His mother was a real estate salesperson and one of her clients was reggae singer Bob Marley. Caldwell and Marley became friends.

Caldwell started playing piano, guitar and many other instruments at age 12. Later he joined a Miami band called Katmandu and wrote many new songs for them. At 17, he joined a band in Las Vegas and then moved to Los Angeles. In the 1970’s, he was a rhythm guitarist for Little Richard. In 1978, at age 27, he recorded with TK Records in Miami and wrote and sang “What You Won’t Do for Love” which reached top ten on the Billboard magazine Hot 100 and Adult Contemporary charts.


https://www.youtube.com/embed/6jLy0bVuRyg


Fluoroquinolone Antibiotics and Ruptured Tendons
Fluoroquinolones include ciprofloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, prulifloxacin and rufloxacin. Ciprofloxacin (Cipro), levofloxacin (Levaquin), and moxifloxacin (Avelox) are still among the most widely prescribed antibiotic drugs in the U.S. to treat sinusitis, bronchitis, urinary tract infections, pneumonia, gastrointestinal infections like gastritis and diverticulitis and can save lives. These antibiotics are very effective in killing invading bacteria by damaging their DNA. However, they can also damage human DNA, potentially anywhere in the body (Consultant, 2017;57(9):541-542). They can cause long-lasting, disabling and potentially permanent damage involving tendons, muscles, joints, nerves, arteries and the heart.

They have been reported to cause pain and swelling of tendons that can lead to rupture (Int J Antimicrob Agents, 2009;33(3):194-200). Other side effects include headaches, rashes, aortic aneurysms, nerve damage, high blood sugar, and anxiety. The incidence of tendon ruptures after taking fluoroquinolones is 0.14-0.4 percent (Ann Pharmacother, 2007;41(11):1859-1866).

Overuse of Fluoroquinolones
Fluoroquinolones were first introduced in the 1970s and many of these antibiotics are still on the market today. Like many antibiotics, fluoroquinolones seem to be over prescribed. A study conducted by the CDC and published in 2018 found that 5.1 percent of outpatient fluoroquinolone prescriptions for adults were for conditions that didn’t need antibiotics at all, while almost 20 percent were for conditions that should have been treated with another antibiotic (Antimicrob Agents Chemother, Jul 2021;65(7):e00151-21).

Cautions About Fluoroquinolones
Bobby Caldwell died on March 14, 2023, apparently from heart failure caused by damage to his heart muscle from the fluoroquinolone antibiotic. Many of this class of antibiotics have been removed from the market, and warning labels are required on those that are still available.

If you take a fluoroquinolone antibiotic, realize that they can cause damage and pain in muscles, bones, joints, brain, peripheral nerves, skin, heart, blood vessels, and other tissues and damage thinking, vision, hearing, feeling, and muscle movement. They can damage your heart to cause irregular heartbeats, chest pain, or bursting of blood vessels called aortic aneurysms. Call your doctor immediately if you are taking a fluoroquinolone and you suffer tendon or muscle pain or weakness, joint pain or swelling, walking difficulty, feeling pins and needles, burning pain, tiredness, depression, problems with memory, sleeping, or any other unexpected effects. Cell damage can be permanent.

Fluoroquinolones are effective in curing very serious infections (even anthrax), and are cheap to manufacture. I think that fluoroquinolones should be used only in very sick patients in hospitals or for infections that have no other available treatment.

Central sleep apnea in a 38-year-old man

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A 38-year-old man presented to the pulmonology department with a 6-month history of snoring, witnessed breathing pauses during sleep and daytime sleepiness. He also noted changed sensation in his left hand. He had a history of hypertension, but no drug or alcohol use. On examination, his body mass index was 32.6, he had prickling dysesthesia and a sensation of muscular tension on the left arm and trunk, and symmetric hyperreflexia of the legs. Polysomnography showed an Apnea–Hypopnea Index (AHI) score of 88 and a central AHI of 56. A total AHI lower than 5 is considered normal, and greater than 15 suggests the need for continuous positive airway pressure (CPAP) therapy. Central sleep apnea (CSA) is defined by a central AHI of 5 or more with at least half of the total events being central.1 The patient’s symptoms improved with CPAP treatment.

Given the unexplained CSA and the neurologic findings, we performed brain magnetic resonance imaging, which showed a 2 cm cyst in the medulla oblongata (Figure 1). We performed microsurgical fenestration, and biopsy showed an arachnoid cyst. Fifteen months later, both apnea and dysesthesia had recovered. Polysomnography had improved substantially with a total AHI of 13, of which most events were obstructive. The patient no longer required CPAP.

Figure 1:

Magnetic resonance imaging scan of the brain of a 38-year-old man with central sleep apnea. The images — gadolinium-enhanced T1-weighted sagittal (A) and T2-weighted axial views (B) — show a 2 cm cyst in the medulla oblongata (arrow) with left dorsolateral compression of the dorsal respiratory group including the solitary tract nucleus (asterisk), which is known to play a role in ventilatory drive.1

The AHI is calculated by adding all apneas and hypopneas and dividing by total sleep time. In central events, there is a reduction of airflow without respiratory effort, whereas obstructive events are accompanied by a high breathing effort.1 Central sleep apnea is uncommon and is associated with heart failure with Cheyne–Stokes breathing, stroke, opioid use, structural cerebral anomalies and treatment of obstructive sleep apnea with CPAP.1 When CSA is unexplained, neuroimaging is indicated to look for a structural cause at the cervicomedullary junction, such as a space-occupying lesion or Chiari malformation, which can be cured with surgery

Meminductor: Researchers discover new circuit element

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Dr. H. Rusty Harris, associate professor in the Department of Electrical and Computer Engineering at Texas A&M University, has identified a new circuit element known as a meminductor.

A circuit element is an electrical component used to help direct and control the flow of electricity through an electrical circuit. The classical three are known as the resistor, capacitor and inductor. Two additional circuit elements, the memristor and the memcapacitor, were only discovered in the past 15 years. These newer circuit elements are known as the mem- versions of their classical counterparts, and their current and voltage properties are dependent on previous values of current or voltage in time, like a memory.

“Those two discoveries set the world a little bit on its head as far as electrical engineering,” Harris said. “All of the sudden, we thought we had three, but now we found these two others. And so that led us to think, ‘OK, there’s got to be more then, but how do we understand what they are? How do we map all of these things relative to each other?’ And it turns out, there is a relationship between each of the resistors and its family and each of the capacitors and its family.”

Harris and his student created a two-terminal passive system—comprised primarily of an electromagnet interacting with a pair of permanent magnets—to examine the magnetic flux density and magnetizing field strength of the inductor circuit element. With the help of this tool, Harris was able to prove the existence of the pinched hysteresis curve within the inductor leading to its mem- state, or memory-like nature, by the same definition that the memristor and memcapacitor were realized.

https://www.youtube.com/embed/rs_vR0S0zmY?color=white The motion of the winding for the negative half-cycle of current results in gradually smaller winding volumes being occupied by the ferromagnetic core thus resulting in lower values of inductance. Credit: Scientific Reports (2023). DOI: 10.1038/s41598-022-24914-y

The researchers published their findings in the February issue of the journal Scientific Reports.

“New discovery is very exciting,” Harris said. “And the student-professor interaction on this project was beautiful. During our brainstorming sessions, we fed off each other—I learned new things based on my discussion with him, and he learned new things based on my experience.”

Plastic transistor amplifies biochemical sensing signal

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The molecules in our bodies are in constant communication. Some of these molecules provide a biochemical fingerprint that could indicate how a wound is healing, whether or not a cancer treatment is working or that a virus has invaded the body. If we could sense these signals in real time with high sensitivity, then we might be able to recognize health problems faster and even monitor disease as it progresses.

Now Northwestern University researchers have developed a new technology that makes it easier to eavesdrop on our body’s inner conversations.

While the body’s chemical signals are incredibly faint—making them difficult to detect and analyze—the researchers have developed a new method that boosts signals by more than 1,000 times. Transistors, the building block of electronics, can boost weak signals to provide an amplified output. The new approach makes signals easier to detect without complex and bulky electronics.

By enabling amplification of weak biochemical signals, the new approach brings modern medicine one step closer to real-time, on-site diagnostics and disease monitoring.

The research was published Saturday in the journal Nature Communications.

“If we could reliably measure biochemical signals in the body, we could incorporate those sensors into wearable technologies or implants that have a small footprint, less burden and don’t require expensive electronics,” said Northwestern’s Jonathan Rivnay, the study’s senior author. “But extracting high-quality signals has remained a challenge. With limited power and space inside the body, you need to find ways to amplify those signals.”

Rivnay is a professor of biomedical engineering at Northwestern’s McCormick School of Engineering. Xudong Ji, a post-doctoral researcher in Rivnay’s laboratory, is the paper’s first author.

While they communicate vital information packed with potential to guide diagnoses and treatment, many chemical sensors produce weak signals. In fact, health care professionals often cannot decipher these signals without removing a sample (blood, sweat, saliva) and running it through high-tech laboratory equipment. Usually, this equipment is expensive and perhaps even located off-site. And results can take an excruciatingly long time to return.

Rivnay’s team, however, aims to sense and amplify these hidden signals without ever leaving the body.

Other researchers have explored electrochemical sensors for biosensing using aptamers, which are single strands of DNA engineered to bind to specific targets. After successfully binding to a target of interest, aptamers act like an electronic switch, folding into a new structure that triggers an electrochemical signal. But with aptamers alone, the signals are often weak and highly susceptible to noise and distortion if not tested under ideal and well-controlled conditions.

To bypass this issue, Rivnay’s team equipped an amplifying component onto a traditional electrode-based sensor and developed an electrochemical transistor-based sensor with new architecture that can sense and amplify the weak biochemical signal. In this new device, the electrode is used to sense a signal, but the nearby transistor is dedicated to amplifying the signal. The researchers also incorporated a built-in, thin-film reference electrode to make the amplified signals more stable and reliable.

“We combine the power of the transistor for local amplification with the referencing you get from well-established electrochemical methods,” Ji said. “It’s the best of both worlds because we’re able to stably measure the aptamer binding and amplify it on site.”

To validate the new technology, Rivnay’s team turned to a common cytokine, a type of signaling protein, that regulates immune response and is implicated in tissue repair and regeneration. By measuring the concentration of certain cytokines near a wound, researchers can assess how quickly a wound is healing, if there is a new infection or whether or not other medical interventions are required.

In a series of experiments, Rivnay and his team were able to amplify the cytokines’ signal by three-to-four orders of magnitude compared with traditional electrode-based aptamer sensing methods. Although the technology performed well in experiments to sense cytokine signaling, Rivnay says it should be able to amplify signals from any molecule or chemical, including antibodies, hormones or drugs, where the detection scheme uses electrochemical reporters.

“This approach is broadly applicable and doesn’t have a specific use case,” Rivnay said. “The big vision is to implement our concept into implantable biosensors or wearable devices that can both sense a problem and then respond it.”

The study is titled “Organic electrochemical transistors as on-site signal amplifier for electrochemical aptamer-based sensing.”

Indian man is world’s first person to contract plant fungus infection

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It was later found that he had been infected with Chondrostereum purpureum – the same fungus that causes silver leaf disease in plants.

STORY HIGHLIGHTS

The case resembles the events occurring in the hit show ‘The Last of Us’ – which is itself inspired by a real-life bacteria that turns ants into ‘zombies’ and can wipe out entire colonies

A 61-year-old Indian man from eastern Kolkata city became the first in the world to catch an infection from a plant fungus.

Doctors claimed that this is the first case of human infection by the microorganism, saying that it demonstrates the crossover of plant pathogen into humans when working in close contact with plant fungi.

The man, who worked as a plant mycologist and whose identity has not been revealed, had gone to Apollo Multispeciality Hospitals after complaining of hoarse voice, cough, fatigue, and difficulty in swallowing and anorexia for three months, according to journal Medical Mycology Case Reports.

While undergoing medical check-up, the CT-scan of his neck revealed that the man had a paratracheal abscess.

His pus samples were then sent for testing to the WHO Collaborating Centre for Reference & Research on Fungi of Medical Importance.

It was later found that he had been infected with Chondrostereum purpureum – the same fungus that causes silver leaf disease in plants.

“Chondrostereum purpureum is a plant fungus that causes silver leaf disease in plants, particularly those in the rose family. This is the first instance of a plant fungus causing disease in a human. Conventional techniques (microscopy and culture) failed to identify the fungus,” the report added.

“Only through sequencing could the identity of this unusual pathogen be revealed. This case highlights the potential of environmental plant fungi to cause disease in humans and stresses the importance of molecular techniques to identify the causative fungal species,” it said.

The infection has alarmed health experts as it defied their understanding of the possibility of plant fungus infecting human beings. 

Notably, the case resembles the events occurring in the hit show ‘The Last of Us’ – which is itself inspired by a real-life bacteria that turns ants into ‘zombies’ and can wipe out entire colonies.

In this case, it is said that the 61-year-old made a full recovery after receiving two antifungal medications for two months.

Vitamin B12, probiotics and calcium: Why yogurt can be better than home-made curd?

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Home-made curd does not have good bacteria in required concentration. A probiotic curd or yoghurt comes packed with good bacteria that improve digestion, eliminate waste from the body faster and indirectly aid weight loss, say nutritionists.

Often we wonder which is better, curd or yoghurt? Truth be told, there’s not much of a difference except that curd is set at home by curdling milk with lemon juice, while yoghurt is prepared in a conditioned environment, where it is fermented with artificial acids in a standardised set-up, so that it tastes the same everyday and has the same amount of good bacteria. The bacteria in home-made curd varies on a day-to-day basis.

“Yoghurt is formed as there is a chemical reaction between lactic acid bacteria and casein. When you add active bacteria strains of lactobacillus bulgaris or streptococcus thermophilus to milk fermentation, the process starts,” explains Dr Charu Dua, Chief Clinical Nutritionist, Amrita Hospital, Faridabad. “The key benefit comes from probiotics or good bacteria. Now certain strands of this bacteria need to be present in sufficient amounts in your curd for it to be an effective metabolism booster. Home-made curd does not have it in required concentration. A probiotic curd or yoghurt comes packed with good bacteria, be it Lactobacillus bulgaricus, Streptococcus thermophilus, Lactobacillus casei and Bifidus. They improve digestion and eliminate waste from the body faster, flushing out toxins,” says Ritika Samaddar, Regional head, Department of Clinical Nutrition and Dietetics, Max Healthcare. “We do not know how much of the good bacteria in home-made curd reach our intestines alive and survive the stomach juices and bile. Yogurt has these live strains,” adds Dr Dua.

All curd/yoghurts are not healthy. “Watch out for flavoured varieties with added sugar and excessive processing. They could be high on calories,” she warns.

Probiotic curd/yogurt is a must inclusion in your daily diet because it is rich in protein, which lends satiety, besides being a storehouse of calcium, Vitamin B12, riboflavin, phosphorus and magnesium. “Calcium restricts the creation of cortisol, which stops the body from gaining weight. So, in that sense curd can help in fighting cortisol. Besides, curd is a great addition for the lactose-intolerant,” says Samaddar. Lactobacillus bulgaricus converts the lactose present in milk into lactic acid, so no stressors remain. Probiotic curd is rich in minerals such as potassium and magnesium, which make it easier for the excess water in the cells to escape and reach the bladder with ease, maintaining blood pressure levels.

“Calcium is good for bone health. The protein is good for vegetarians. Overall, it manages gut health, relieving symptoms of irritable bowel disease and healing ulcerative colitis,” says Dr Dua.

How should probiotic infused curd/yogurt be had? “It can be had at any time of the day and night, possibly after meals. People fear having it after sunset, thinking the curd may sour or that they may catch a cold. But none of this is true. It is a great digestive aid and can easily be had thrice a day. It keeps you fit,” adds Samaddar.

But Dr Dua argues that “curd by default is warm, hence adding water is advised in summers.” There are creative ways of including it in your diet. “Greek yoghurt, basically hung yoghurt, is made after straining whey water from regular curd. It is thicker and creamier. Can be used as dips and healthy bread spreads and as an alternative to butter/ mayonnaise. Then there is kefir or fermented milk. Kefir requires multiple fermentation processes unlike curd which is fermented at one go. The texture of kefir is liquid, more like our buttermilk. Choose frozen yogurts as a replacement for ice cream,” adds Dr Dua.

Brain MRI showing indicating central sleep apnoea

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Central sleep apnoea (CSA) is a breathing disturbance with repetitive periods of inadequate ventilation and compromised gas exchange. This disorder can lead to important comorbidity and increased risk of adverse cardiovascular conditions. Sleep-related complaints like snoring, witnessed breathing pauses during sleep and daytime sleepiness with Apnoea–Hypopnea Index (AHI) greater than 5 were regarded as CSA. The neurological findings like brain magnetic resonance imaging (MRI) revealed a 2 cm cyst in the medulla oblongata (A and B) in this case. In unexplained cases of CSA, neuroimaging is required to investigate structural causes at the cervico-medullary junction, such as a space-occupying lesion or Chiari malformation, which can be cured with a surgical procedure