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Comment by Dr. Krishna Kumari Challa on May 6, 2024 at 9:52am

New mRNA cancer vaccine triggers fierce immune response to fight malignant brain tumour

Glioblastoma is among the most devastating diagnoses, with median survival around 15 months. The current standard of care involves surgery, radiation and some combination of chemotherapy.

In a first-ever human clinical trial of four adult patients, an mRNA cancer vaccine developed by scientists quickly reprogrammed the immune system to attack glioblastoma, the most aggressive and lethal brain tumour.

The results mirror those in 10 pet dog patients suffering from naturally occurring brain tumors whose owners approved of their participation, as they had no other treatment options, as well as results from preclinical mouse models. The breakthrough now will be tested in a Phase I pediatric clinical trial for brain cancer.

Reported May 1 in the journal Cell, the discovery represents a potential new way to recruit the immune system to fight notoriously treatment-resistant cancers using an iteration of mRNA technology and lipid nanoparticles, similar to COVID-19 vaccines, but with two key differences: use of a patient's own tumor cells to create a personalized vaccine, and a newly engineered complex delivery mechanism within the vaccine.

In less than 48 hours, the researchers could see these tumours shifting from what they refer to as 'cold'—immune cold, very few immune cells, very silenced immune response—to 'hot,' very active immune response.

The 10 pet dogs on which trials were done lived a median of 139 days, compared with a median survival of 30 to 60 days typical for dogs with the condition.

 RNA aggregates harness the danger response for potent cancer immunotherapy, Cell (2024). DOI: 10.1016/j.cell.2024.04.003. www.cell.com/cell/fulltext/S0092-8674(24)00398-2

Comment by Dr. Krishna Kumari Challa on May 4, 2024 at 11:38am

Most amniotic fluid cells are epithelial, but scientists knew very little about these cell populations. Everything changed when researchers started to look at the single cell level at what happened in the amniotic fluid.
used single-cell RNA sequencing to characterize the amniotic fluid of 12 patients and discovered subpopulations of epithelial cells that expressed markers typical of progenitors for the lung, kidney, and small intestine. The researchers cultured the tissue-specific progenitor cells, fed them a chemical cocktail to support growth, and watched as they proliferated, differentiated, and self-organized into 3D epithelial organoids. The mini-organs shared some transcriptomic and protein features found in their tissues of origin. For example, lung epithelial cells that developed and differentiated in culture had elevated expression of airway markers compared to their nondifferentiated counterparts. Similarly, kidney epithelial organoids expressed markers associated with renal tubules, which are integral components of the kidneys’ filtration system.

Although the amniotic fluid contained cells from other tissues, the researchers could not grow them into organoids, suggesting that they lack progenitor capabilities. Other research groups have successfully grown fetal organoids from somatic cells floating around the amniotic fluid, and the mini-organs generated using this approach are more complex.
reprogramming methods take up to 20 weeks to generate organoids. If the goal is to use organoids to inform prenatal interventions, timing is critical.
Part 3

Researchers re using these to study various diseases and find solutions to them.

More here: https://www.the-scientist.com/fetal-organoids-generated-from-human-...

Comment by Dr. Krishna Kumari Challa on May 4, 2024 at 11:35am

Scientists use patient cells to generate organoids that possess certain features and functions of the modeled organ while retaining the individual's genetic fingerprint. However, many of these platforms require lengthy dedifferentiation protocols to revert somatic cells into a state of pluripotency and then reprogram them to develop as another cell type. In contrast to organoids generated from pluripotent stem cells, primary organoids use tissue-specific stem cells or progenitor cells and therefore require minimal manipulation.3 While the organoid field is relatively advanced in terms of using adult tissues, researchers can only generate primary fetal organoids using tissue from terminated pregnancies. “This made it basically impossible to [generate organoids] compatible with the continuation of pregnancy, and therefore in a personalized medicine fashion”.
During gestation, the fetus floats in a protective pool of amniotic fluid.6 The yellowish liquid contains a concoction of nutrients and antibodies produced by the parent as well as less glamorous contributions from the fetus, including urine. It also includes fetal cells sloughed off during development, which doctors can extract and analyze for signs of disease.

“Those cells historically have been thought to be dead cells or cells that were shed from the lining of the amniotic fluid cavity.
Part 2

Comment by Dr. Krishna Kumari Challa on May 4, 2024 at 11:32am

Fetal Organoids Generated From Human Amniotic Fluid

A minimally invasive strategy for creating fetal organoids could facilitate precision medicine in the womb.

Moments after birth, a baby takes a first breath as the placenta, which has served as the fetus’ lungs during gestation, transfers responsibility to the baby's own organs. However, for patients born with congenital diaphragmatic hernia (CDH), a rare condition where the diaphragm fails to close, causing impaired lung development, entry into the world is more precarious. More severe cases of the disease lead to multiorgan damage, and approximately thirty percent of infants diagnosed with CDH never leave the hospital.

Diagnostic imaging and genetic screens help clinicians catch congenital fetal diseases in utero, but models for studying organ development and disease progression are limited. Over the last decade, organoids have become an increasingly popular platform for modeling organ function and disease. However, the generation of fetal organoids is complicated by ethical and legal restrictions on the harvesting of the human tissues needed to generate the mini-organs.

Now, reporting in Nature Medicine, researchers generated fetal organoids using cells derived from human amniotic and tracheal fluids. These mini-organs offer a minimally invasive approach for disease modeling during an active pregnancy and may eventually inform the development of personalized prenatal interventions.

Part 1

Comment by Dr. Krishna Kumari Challa on May 4, 2024 at 10:40am

Ice shelves fracture under weight of meltwater lakes, study shows

When air temperatures in Antarctica rise and glacier ice melts, water can pool on the surface of floating ice shelves, weighing them down and causing the ice to bend. Now, for the first time in the field, researchers have shown that ice shelves don't just buckle under the weight of meltwater lakes—they fracture.

As the climate warms and melt rates in Antarctica increase, this fracturing could cause vulnerable ice shelves to collapse, allowing inland glacier ice to spill into the ocean and contribute to sea level rise.

Ice shelves are important for the Antarctic Ice Sheet's overall health as they act to buttress or hold back the glacier ice on land. Scientists have predicted and modeled that surface meltwater loading could cause ice shelves to fracture, but no one had observed the process in the field, until now.

The new study, published in the Journal of Glaciology, may help explain how the Larsen B Ice Shelf abruptly collapsed in 2002. In the months before its catastrophic breakup, thousands of meltwater lakes littered the ice shelf's surface, which then drained over just a few weeks.

 Alison F. Banwell et al, Observed meltwater-induced flexure and fracture at a doline on George VI Ice Shelf, Antarctica, Journal of Glaciology (2024). DOI: 10.1017/jog.2024.31

Comment by Dr. Krishna Kumari Challa on May 4, 2024 at 10:24am

Mantle movements shape Earth's surface

The movement of tectonic plates shapes the rocky features of Earth's surface. Plates' convergence can form mountain ranges or ocean trenches, and their divergence can form oceanic ridges. But it's not just the plates themselves that influence Earth's topography. The mantle layer underneath exerts its own subtle influence, which can be seen even in places located far from tectonic plate edges, and is referred to as residual topography.

To better understand how the mantle affects topography,  researchers building on previous work focused on the oceans, created two new databases. The paper is published in the Journal of Geophysical Research: Solid Earth.

One compiles 26,725 measurements of crust thickness around the globe, the largest such database to date, along with estimates of seismic velocity. The other contains laboratory analysis of seismic velocity as a function of temperature, density, and pressure. Together these measurements helped disentangle crustal influences on topography from mantle influences to identify residual topography.

The researchers found that differences in the temperature and chemical structure of the mantle can cause swells and basins in the landscape distinct from those that form at the edges of tectonic plates. These features can rise or fall by up to 2 kilometers and stretch for hundreds to thousands of kilometers—all within the interior of plates.

Some of the highest swells (about 2 kilometers), which are thought to correspond to locations where the mantle is particularly hot, can be found in the Afar–Yemen–Red Sea region, western North America, and Iceland. Some of the deepest basins (deeper than about 1.5 kilometers), where the mantle is thought to be cooler, are in areas near the Black, Caspian, and Aral seas, as well as in the East European Plain. This pattern of swells and basins may control—to some extent—the locations where significant erosion and sedimentary deposition occur.

These topographical features can develop slowly over millions of years, but they nonetheless control important geological processes. According to the researchers, these findings could help explain the existence of magmatism found far from plate boundaries. They also could help scientists understand the elusive effects of flow in Earth's mantle on the surface through geologic time.

Simon N. Stephenson et al, Continental Residual Topography Extracted From Global Analysis of Crustal Structure, Journal of Geophysical Research: Solid Earth (2024). DOI: 10.1029/2023JB026735

Comment by Dr. Krishna Kumari Challa on May 4, 2024 at 10:02am

Genetics, not lack of oxygen, causes cerebral palsy in quarter of cases: Study

The world's largest study of cerebral palsy (CP) genetics has discovered genetic defects are most likely responsible for more than a quarter of cases in Chinese children, rather than a lack of oxygen at birth as previously thought.

The study, published in Nature Medicine, used modern genomic sequencing and found mutations were significantly higher in CP cases with birth asphyxia, indicating a lack of oxygen could be secondary to the underlying genetic defect. The results are consistent with smaller studies globally.

More than 1,500 Chinese children with CP were involved in this research project. 

24.5% of Chinese children in the study had rare genetic variations linked to cerebral palsy. This revelation mirrors  earlier findings in  Australian cerebral palsy cohort, where up to one-third of cases have genetic causes.

This research shows at least some babies who experience birth asphyxia and are diagnosed with CP may have improper brain development as a result of the underlying genetic variants rather than a lack of oxygen.

Crucially, clinically actionable treatments were found in 8.5% of cases with a genetic cause. It is exciting to see how genetic pathways to cerebral palsy inform tailored treatments for these individuals.

Cerebral palsy affects movement and posture and is the most common motor disability in children. The disorder is diagnosed in up to 2 per 1,000 children globally and is sometimes in association with epilepsy, autism and intellectual difficulties. Symptoms often emerge during infancy and early childhood and can range from mild to severe.

The research team identified 81 genes with causation mutations in the children with CP. These genes are known to play important roles in neural and embryonic development and may affect the molecular pathways responsible for respiration.

These results highlight the need for early genetic testing in children with cerebral palsy, especially those with risk factors like birth asphyxia, to ensure they receive the right medical care and treatment.

Yangong Wang et al, Exome sequencing reveals genetic heterogeneity and clinically actionable findings in children with cerebral palsy, Nature Medicine (2024). DOI: 10.1038/s41591-024-02912-z

Comment by Dr. Krishna Kumari Challa on May 3, 2024 at 11:11am

Centipedes used in traditional Chinese medicine offer leads for kidney treatment

A venomous, 8-inch centipede may be the stuff of nightmares, but it could save the life of those affected by kidney disease. Researchers report in the Journal of Natural Products that the many-legged critter—used in traditional Chinese medicine—contains alkaloids that in cell cultures reduced inflammation and renal fibrosis, which both contribute to kidney disease.

Some 1,500 species of animals are used in traditional Chinese medicine, but little is known about many of the secondary metabolites their bodies produce for specialized functions such as immobilizing prey. The few compounds that have been studied, such as toad venom for cancer treatment, have proved to be fruitful leads for drug development.

The researchers 

decided to examine the secondary metabolites produced by the Chinese red-headed centipede (Scolopendra subspinipes mutilans). The venomous centipede has been used for thousands of years in treatments for conditions including epilepsy, tuberculosis, burns and cardiovascular disease.

The researchers mixed a sample of dried centipede powder with ethanol to extract numerous compounds from the animals and then separated and identified the constituents with techniques such as chromatography and spectrometry. The team found 12 new quinoline and isoquinoline alkaloids, including some with unusual molecular structures, along with a half dozen other alkaloids that had previously been detected in this species or in plants.

In cell cultures, some of the alkaloids showed anti-inflammatory behavior, while a portion also reduced renal fibrosis. This buildup of connective tissue is associated with chronic kidney disease and is stimulated by inflammation. Finally, the researchers identified a protein that plays a role in renal fibrosis and that was targeted by the most effective dual-function alkaloid. This information could provide a lead for developing treatments for kidney disease, according to the researchers.

Bin-Yuan Hu et al, Structurally Diverse Alkaloids with Anti-Renal-Fibrosis Activity from the Centipede Scolopendra subspinipes mutilans, Journal of Natural Products (2024). DOI: 10.1021/acs.jnatprod.4c00044

Comment by Dr. Krishna Kumari Challa on May 3, 2024 at 10:57am

The team tested its E. coli-based delivery system in mouse models of pancreatic ductal adenocarcinoma, or PDAC, the most common and lethal form of pancreatic cancer, which was the focus of the study.

Mice treated with the therapeutic-laden bacteria experienced delayed tumour growth and significantly longer survival compared with mice that received other treatments. Postmortem analyses also showed that tumors treated with the nano-drug-carrying E. coli had the greatest infiltration of cancer-fighting immune cells among all treatments.

Zhaoting Li et al, Nanodrug-bacteria conjugates-mediated oncogenic collagen depletion enhances immune checkpoint blockade therapy against pancreatic cancer, Med (2024). DOI: 10.1016/j.medj.2024.02.012

Part2

Comment by Dr. Krishna Kumari Challa on May 3, 2024 at 10:55am

Nano-drugs hitching a ride on bacteria could help treat pancreatic cancer

Many pancreatic tumors are like malignant fortresses, surrounded by a dense matrix of collagen and other tissue that shields them from immune cells and immunotherapies that have been effective in treating other cancers. Employing bacteria to infiltrate that cancerous fortification and deliver these drugs could aid treatment for pancreatic cancer, according to newly published findings from a team of researchers.

The paper is published in the journal Med.

Tumor collagen is a tough barrier

Pancreatic cancer is well known for its deadliness and has among the lowest five-year survival rates among common cancers. While there are several drivers behind the disease's dismal prognosis, one that's the focus of this study is the matrix surrounding many pancreatic tumors, which acts as an effective barrier against treatment.

The barrier is a collection of collagen, connective tissue, proteins that facilitate fibrosis and other cells. Recent studies have highlighted the role of this barrier in counteracting treatment attempts with immunotherapies—treatments that work by spurring on or tamping down the patient's immune system—such as immune checkpoint inhibitors. Analyzing patient tumour samples, the research team found genetic evidence that a specific type of collagen, called oncogenic collagen, is indeed a barrier to immunotherapy-based treatments.

That really dense extracellular matrix, made up of immunosuppressive cells, collagens and other cells is a critical problem if we want to use immunotherapies against these pancreatic cancers.

So researcher s  applied a bacterium that could both penetrate through the tough collagen barrier and deliver immunotherapeutic "nano-drugs."

The team chose a strain of the bacterium Escherichia coli with a track record of safe use in humans and known affinity for low-oxygen environments such as tumors to serve as a drug delivery vehicle. They engineered "protein cages" containing a pair of drugs—one breaks down collagen and the other is an anticancer immune checkpoint inhibitor—and attached them to the E. coli.

E. coli has great motility, meaning it can move by itself, and it actively targets hypoxic environments like tumors. And the researchers found that it was able to penetrate deep into the tumor site to deliver drugs.

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