Blood-clotting protein may be SARS-CoV-2's hidden accomplice, helping it hide from antibodies and reach blood vessels

Amazing stuff!

Notice that the authors of this study could be considered to be "outsiders".

The lab leak hypothesis has never been disproven or refuted thanks to the secrecy and obstruction of the Communist Party of China! Was the SARS-Cov-2 just another naturally occurring coronavirus or something else?

Anthony Fauci made tremendous efforts to conceal and dismiss the lab leak hypothesis, because the Wuhan Institute of Virology (a dual research institute) did some research that was funded by the US government and US gain of function research was conducted there. How was this ever possible and approved!

"... The proposal offers a single mechanistic explanation for two features of COVID-19 that have long been treated as separate problems: the virus's ability to evade immunity and the vascular damage, microclotting and inflammation that characterize severe disease and long COVID. ...

SARS-CoV-2 is generally described as entering cells through the ACE2 receptor. But the spike protein carries clusters of positively charged lysine and arginine residues in its N-terminal domain (NTD) and receptor-binding domain (RBD).

In contrast, human fibrinogen is negatively charged at physiological pH. The authors argue this electrostatic attraction is more than incidental chemistry.

When fibrinogen binds the spike NTD, it can mask antigenic sites, providing a molecular shield against antibody detection. At the same time, the other end of the fibrinogen molecule, its gamma chain, engages endothelial receptors including the integrins αvβ3 and α5β1, platelet receptor GPIIb/IIIa and ICAM-1.

The result is a tether with the virus on one end and the blood vessel wall on the other. ..."

From the abstract:

"SARS-CoV-2 exploits multiple cellular entry routes. Beyond ACE2-mediated entry, we propose that the spike protein binds fibrinogen not only to facilitate immune evasion but also to position the receptor-binding domain for integrin-mediated uptake. This molecular bridge may enhance viral RNA delivery to endothelial cells. Targeting the spike protein–fibrinogen interface could open new therapeutic avenues for acute and post-COVID vascular disease."

Blood-clotting protein may be SARS-CoV-2's hidden accomplice, helping it hide from antibodies and reach blood vessels (This article was written by one of the authors of the research article below)

Fibrinogen as a Molecular Bridge Linking SARS-CoV-2 Immune Evasion and Endothelial Access? (no public access) "Fibrinogen as a Molecular Bridge Linking SARS-CoV-2 Immune Evasion and Endothelial Access?"

Visual abstract

Schizophrenia linked to body’s most prevalent white blood cell

Good news!

"In brief

• Stanford researchers discovered that neutrophils, a type of white blood cell, can produce the schizophrenia-associated protein C4A.
• This finding links the increased neutrophil count seen in schizophrenia patients to the disease’s underlying mechanisms.
• The research could lead to novel diagnostic methods and treatments by targeting neutrophil activity and protein production in schizophrenia.

The most common white blood cells in your body – immune cells called neutrophils – can make a protein nobody knew they were making ... That unexpected sighting joins a growing list of hints tying schizophrenia, a disorder of the brain, to events occurring elsewhere in our bodies. ...

Current treatments for schizophrenia are palliatives, Kalinowski said. They don’t stop disease progression or restore motivation or cognitive sharpness. ..."

From the significance and abstract:

"Significance

The number of C4A gene copies is associated with the risk of schizophrenia in genome-wide association studies of individuals with European ancestry.

Higher C4A gene expression is associated with higher levels of synaptic pruning in the brain.

We found that neutrophils from people with schizophrenia show C4 protein amounts that are positively correlated with the number of C4A gene copies.

Neutrophils may gain access to the central nervous system, during some critical periods in the development of schizophrenia. The role of neutrophils both outside the brain in the peripheral circulation and within the brain invites further exploration, potentially leading to new therapeutics.

Abstract

The lack of highly effective disease-modifying treatments for schizophrenia necessitates exploration of novel aspects of its pathophysiology, including attention to innate immune mechanisms outside the brain. 

C4 protein activation, associated with the complement cascade of innate immunity, associates with symptoms and predicts outcomes in schizophrenia. However, C4 protein activation does not coincide with expected changes to other proteins in the complement cascade, suggesting another source of C4 protein activation.

Studying a combination of fresh whole blood from 10 anonymous donors and a large set of publicly available microarray data, we show that C4 protein is found and expressed primarily in neutrophils and monocytes.

Then, we compared the correlation between C4 protein in neutrophils, classical monocytes, plasma, and the number of C4A gene copies. We determined the number of C4A genes using digital droplet PCR, C4 protein in neutrophils (15 patients/21 controls) and plasma (30 patients/38 controls) using Western blotting, and classical monocytes (30 patients/38 controls) using flow cytometry.

We found a large positive correlation between the number of C4A gene copies and the amount of C4 protein only in neutrophils and only in the schizophrenia group (Spearman’s rho = 0.63, 95% BCa CI: 0.12 to 0.89, P = 0.012).

Our results indicate a convergence of innate immunity mechanisms associated with schizophrenia. The involvement of innate immunity deserves further attention to determine whether it could be a target for therapy in schizophrenia."

Schizophrenia linked to body’s most prevalent white blood cell | Stanford Report

Peripheral complement C4 protein in schizophrenia: Association with gene copy number and immune cell subtypes (open access)

Fig. 2 Neutrophil C4 protein is positively correlated with the number of C4A gene copies in SZ.

Discovery could lead to new therapies for blood disorders

Good news!

"... investigators have revealed the detailed workings of a cell membrane protein that has essential roles in all animals. The discovery could lead to new therapeutic strategies for blood coagulation disorders, cancers and other conditions in which the protein, called a TMEM16 scramblase, works abnormally.

Scramblases operate within cell membranes, where they alter or “scramble” the normal layered arrangement of lipid molecules – an essential step in many biological processes. The scramblase TMEM16F also works as an ion channel, allowing small, charged molecules such as potassium or chloride ions through the membrane. ...

the researchers at last attained this goal by embedding the protein in liposomes – tiny lipid capsules – which allowed them to image its active and inactive structures at near-atomic-scale resolution. ...

TMEM16F’s rearrangement of cell membrane lipids enables platelet cells to clump together to make blood coagulate, and a mutation affecting the scramblase underlies Scott syndrome, a hemophilia-like bleeding disorder.

The protein is also involved in the formation of the placenta in pregnancy, bone development and immune functions; and it is exploited or suppressed in various cancers and infections. ..."

From the abstract:

"The ubiquitous transmembrane protein 16F (TMEM16F) Ca2+-activated channel and scramblase catalyzes phosphatidylserine externalization to enable blood coagulation, membrane fusion and brain immune surveillance.

Despite its importance, the molecular mechanisms underlying TMEM16F activation remain poorly understood.

Here, we obtained high-resolution cryo-electron microscopy structures of TMEM16F active in liposomes. In high-activity conditions, TMEM16F adopts two conformations, the canonical Ca2+-bound closed state and one where the upward rotation of the cytosolic domain leads to an X-shaped groove that forms a transmembrane pore and locally thins the membrane.

Using mutagenesis, functional assays and molecular dynamics simulations, we show that the X-shaped groove is active and mediates nonselective ion flux and lipid scrambling through distinct pathways; ions move within the protein-delimited pore, whereas lipids skirt the X-shaped groove.

Our findings provide a complete picture of TMEM16F Ca2+-dependent gating and demonstrate that imaging membrane proteins in a native-like environment can allow capturing otherwise inaccessible active states."

Discovery could lead to new therapies for blood disorders | Cornell Chronicle

Calcium dependent activation of the TMEM16F scramblase and ion channel (open access)

Fig. 1: Structure of purified TMEM16F reconstituted in liposomes.

Fig. 5: Activation of TMEM16F.

Leukemia cells use a sugar-coated protein to hide from the immune system

Good news! Cancer is history (soon)!

"Highlights

• Study reveals previously unrecognized way for cancer to evade the immune system. 
• Other cancers could also be using sugar-coated proteins to shield themselves from immune attack.
• Findings suggest CD43 is a potential target for new cancer immunotherapies.

...

Now, researchers have identified a key part of the cancer’s disguise: a protein called CD43 on the surface of leukemia cells that is coated so heavily in sugar molecules that it forms a physical barrier, shielding the cells from immune attack. ..."

From the abstract of the Perspective:

"Immune cells continually detect, engulf, and destroy invasive microbes and cancer cells. This process, called phagocytosis, is carried out by macrophages that must distinguish between proengulfment signals and inhibitory (“don’t-eat-me”) warnings.

Cluster of differentiation 47 (CD47), a cell-surface receptor, is the archetypal don’t-eat-me signal.

Many cancers upregulate CD47 expression to escape phagocytosis, and CD47 blockade promotes phagocytosis of cancer cells in mice.

However, CD47 blockers have not shown clinical benefits in patients with acute myeloid leukemia (AML), an aggressive cancer of blood immune cells. This discrepancy has raised the possibility that the molecular programs that inhibit phagocytosis differ between mice and humans. On page 174 of this issue, Chung et al. report that the mechanisms that control macrophage function in human and mouse cells are indeed different. They also identify cluster of differentiation 43 (CD43) as a potential target for human AML treatment."

From the editor's summary and abstract:

"Editor’s summary

Phagocytosis is a process used by immune cells called macrophages to destroy pathogens and cellular debris.

Tumor cells can evade killing by macrophage-mediated phagocytosis by deploying decoy signals to the immune system.

Chung et al. performed a CRISPR screen of human acute myeloid leukemia (AML) cells to identify phagocytic regulators ... 

The surface protein CD43 was found to be coated in a high-density shield of sialic acid residues that effectively functioned as a “don’t eat me” signal to limit immune clearance.

Inactivation of CD43 function restored the ability of macrophages to phagocytize AML. Strategies that disable sialylated glycans may therefore have potential to enhance phagocytosis and targeting of AML. ...

Structured Abstract

INTRODUCTION

Macrophages in the tumor microenvironment exert antitumorigenic effects through phagocytosis and/or direct tumoricidal activity.

Phagocytosis of tumor cells occurs through both antibody-dependent cellular phagocytosis (ADCP) and antibody-independent cellular phagocytosis (AICP) mechanisms. Despite the strong evidence that macrophages can mediate tumor control in acute myeloid leukemia (AML) and other diseases, therapeutic agents that enhance macrophage phagocytosis, including anti-CD47 neutralizing antibodies, have not led to improved clinical outcomes. Thus, a more comprehensive understanding of the tumor-intrinsic factors that suppress human macrophage phagocytosis is needed.

RATIONALE

To systematically identify the key pathways that regulate phagocytosis by human macrophages, we performed genome-scale knockout CRISPR screens in human AML cell lines cocultured with human monocyte-derived macrophages.

RESULTS

We performed in vitro genome-wide loss-of-function CRISPR screens to identify the major pathways that regulate ADCP and AICP by human macrophages. Unexpectedly, we found that the classic “don’t eat me” signal CD47 has minimal impact on human macrophage phagocytosis.

By contrast, CD47 strongly suppressed mouse macrophage phagocytosis. Additionally, we identified the major histocompatibility class I complex (MHC class I) as the most potent negative regulator of ADCP.

By integrating results from the AICP and ADCP screens, we discovered that the O-linked glycosylation and sialylation pathways negatively regulate both AICP and ADCP.

CD43, a heavily sialylated cell surface glycoprotein, was the major mediator of the inhibitory effects of the O-linked glycosylation and sialylation pathways.

The inhibitory activity of CD43 was dependent on its sialic acid residues and the length of its ectodomain but independent of the canonical sialic acid–binding receptors SIGLEC-1, SIGLEC-7, and SIGLEC-9. CD43 expression reduced the avidity of interactions between immune effector cells and leukemia cells, consistent with a model where CD43 forms a steric or electrostatic glycocalyx barrier that reduces interactions with the leukemia cell surface.

We found that CD43 is overexpressed in AML patient samples, and inhibition of CD43 with antibodies enhances phagocytosis of AML cell lines and patient-derived samples.

Finally, we found that CD43 not only restrains human macrophage phagocytosis but also human natural killer (NK) and human T cell cytotoxicity.

CONCLUSION

The cell surface glycoprotein CD43 is a potent inhibitor of innate and adaptive antileukemic immunity. The inhibitory activity of CD43 on immune cells is dependent on posttranslational sialic acid modifications that are added through the O-linked glycosylation and sialylation pathways. Thus, sialylated CD43 is a potential therapeutic target for the treatment of AML."

Leukemia cells use a sugar-coated protein to hide from the immune system | Broad Institute "Targeting this protein, called CD43, could offer a new path to treatment for leukemia and other cancers."

The sialic shield of leukemia cells (Perspective, no public access)

Sialylated CD43 forms a glyco-immune barrier that restrains antileukemic immunity (no public access)

Genome-scale phagocytosis screens identify sialylated CD43 as a potent inhibitor of antileukemic immunity.

Inexpensive detecting of multiple cancers and other diseases from a single blood sample by analyzing circulating DNA fragments

Good news! Will we soon have much better and cheaper health checkups?

"UCLA scientists have developed a simple and cost-effective blood test that, in early studies, shows promise in detecting multiple cancers, various liver conditions and organ abnormalities simultaneously by analyzing DNA fragments circulating in the bloodstream. The test, described in the journal Proceedings of the National Academy of Sciences, could offer a powerful and more affordable approach to early disease detection and comprehensive health monitoring. ..."

"Key takeaways

• In early studies, the blood test, developed by UCLA scientists, shows promise in detecting multiple cancers.
• The new method, called MethylScan, works by analyzing cell-free DNA, tiny fragments of genetic material released into the blood when cells die.
• In tests, MethylScan detected about 63% of cancers across all stages and roughly 55% of early-stage cancers. 

..."

From the significance and abstract:

"Significance

Cell-free DNA (cfDNA) in blood carries molecular signals from multiple organs, offering a powerful, noninvasive way to detect disease and monitor health. Current cfDNA methylation tests are costly and usually focus on a single condition.

We developed MethylScan, a low-cost assay that sequences cfDNA methylome from blood. In over 1,000 individuals, MethylScan shows robust performance across a range of clinical applications, including multicancer detection in the general population, liver cancer surveillance in high-risk individuals, liver disease classification, organ injury detection, and ancestry prediction, all from one blood sample. This versatile approach enables affordable, wide-ranging cfDNA tests that can identify various health conditions simultaneously, with the potential to transform early disease detection and health monitoring across diverse clinical settings.

Abstract

Plasma cell-free DNA (cfDNA), originating from multiple organs, holds significant potential for noninvasive diagnostics and prognostics. Current cfDNA methylation assays primarily focus on single clinical indications by targeting specific genomic loci. In contrast, comprehensive profiling of cfDNA methylome can enable simultaneous detection of multiple diseases by capturing organ-specific methylation signatures, thereby offering a holistic view of health, when disease etiology is unclear or when conventional biochemical diagnostics are unavailable. However, deep sequencing required for sensitive detection of methylation abnormalities remains prohibitively expensive, limiting widespread clinical use. To overcome this barrier, we developed MethylScan, a highly cost-effective approach for cfDNA methylome sequencing. We demonstrated its broad clinical utility in a cohort of 1,061 individuals across diverse applications, including multicancer detection in general population, liver cancer surveillance in high-risk individuals, liver disease classification, identification of organ abnormalities, and race prediction from cfDNA.

In multicancer detection (liver, lung, ovarian, and stomach cancers), MethylScan achieved an area under the receiver operating characteristic curve (AUROC) of 0.938 (95% CI: 0.920 to 0.954), with a sensitivity of 63.3% (95% CI: 58.9 to 67.9%) at 98.0% specificity for all cancer stages.

For early-stage cancers, the AUROC was 0.916 (95% CI: 0.890 to 0.940), with 55.3% sensitivity (95% CI: 49.1 to 62.1%) at the same specificity.

In liver cancer surveillance, MethylScan achieved an AUROC of 0.927 (95% CI: 0.889 to 0.959), with 79.6% sensitivity (95% CI: 70.6 to 87.8%) at 90.4% specificity.

The assay also demonstrated strong performance in additional diagnostic tasks, supporting its potential as a versatile platform for comprehensive cfDNA-based health monitoring."

Detecting multiple cancers and other diseases from a single blood sample

UCLA researchers develop low-cost blood test to detect multiple cancers and other diseases from a single sample (original news release)

Toward the simultaneous detection of multiple diseases with a highly cost-effective cell-free DNA methylome test (open access)

Fig. 1 Illustration of the principle of the MethylScan assay and the criteria of choosing target regions of the MethylScan panel. Shown are four genomic regions, of which the middle two regions have consistent unmethylated MSRE cutting sites in the background cfDNA and are therefore included in the MethylScan panel.

In Step 1, upon MSRE digestion, the background cfDNA in the two panel regions are removed.

In Step 2, the target panel specifically captures cfDNA from the panel regions, thereby enriching tumor cfDNA in the final sequencing pool.

Fig. 4 Study design. (A) overview of plasma samples. (B–F) the usage of plasma samples in five studies. (G) the usage of tissue samples.

New wound spray stops bleeding in one second

Good news!

"Researchers have developed a spray-on powder that turns into a wound-conforming gel when it comes in contact with blood. The breakthrough has the possibility of dramatically improving wound care in combat and other life-threatening situations. ...

Seeking a solution to treating such injuries, researchers at the Korea Advanced Institute of Science and Technology (KAIST), one of whom is an Army Major, developed a powder that reacts with cations (particles with a positive electrical charge) like calcium in blood to turn into a gel state in just one second, sealing even deep and irregular wounds instantly.

The substance is made from three natural ingredients: alginate, a substance extracted from brown seaweed; gellan gum, a natural thickener made from bacteria through fermentation; and chitosan, a powder made from the exoskeletons of crustaceans and insects as well as from fungal cell walls. ..."

"... Accordingly, the research team developed a next-generation hemostatic agent in powder form that can be freely applied even to deep, large, and irregular wounds. They have secured versatility to respond to various types of wounds with a single powder. ..."

From the abstract:

"Rapid and effective bleeding control remains a clinical priority, particularly for deep or irregular wounds where conventional dressings are inadequate.

Here, an ionically responsive, powder-based hemostatic system (AGCL) composed of alginate, gellan gum, chitosan, and a glutaraldehyde crosslinker is presented. Upon contact with calcium ions in blood, AGCL rapidly forms an adhesive hydrogel network within ≈1 s, enabling ultrafast gelation and a high blood uptake ratio (≈725%).

The powder exhibits strong bioadhesion (>40 kPa), excellent sealing under mixed-mode loading, and robust storage stability for up to 24 months under ambient conditions. In vitro assays confirm minimal hemolysis (<3%), high cytocompatibility, and greater than 99% antibacterial efficacy.

In various bleeding models, AGCL significantly reduced blood loss and time to hemostasis compared to TachoSil, a clinical benchmark.

Furthermore, AGCL accelerated re-epithelialization, angiogenesis, and collagen deposition in murine skin and liver wound models, supporting high-quality tissue regeneration without systemic toxicity.

These results demonstrate that AGCL integrates rapid coagulation, strong adhesion, long-term biostability, and regenerative capacity in a single platform.

Its powder format offers distinct advantages in versatility, ease of application, and storability, making it a promising candidate for next-generation topical hemostats in trauma care, surgery, and emergency medicine."

New wound spray stops bleeding in one second

Hemostasis in 1 Second... Boosting Survival Rates for Soldiers​ (original news release)

An Ionic Gelation Powder for Ultrafast Hemostasis and Accelerated Wound Healing (open access)

Fig. 1 Fabrication and characterization of AGCL powder-type hemostatic material.

Pioneering new CAR T cell therapy reverses incurable blood cancer in 7 out of 11 patients (children and adults)

Good news! Cancer is history (soon)!

"Designer CAR Ts keep blood cancer at bay

Switching out letters in the genetic code of CAR T cells has put 7 out of 11 people with a type of blood cancer known as acute lymphoblastic leukemia into remission. The pioneering treatment uses CRISPR to make three base edits in the DNA of donor CAR T cells. These edits make it possible for the CAR T cells to seek out and destroy cancerous T cells while shielding themselves from attack from the immune system and chemotherapy. ..."

From the abstract:

"Abstract

Background

CD7 is an attractive target for chimeric antigen receptor (CAR) T-cell therapy in relapsed or refractory T-cell acute lymphoblastic leukemia (ALL). Supportive results of first-in-human studies of base-edited anti-CD7 CAR (BE-CAR7) T cells with triple C→T deamination-mediated knockouts of TCRαβ, CD52, and CD7 have been reported previously.

Methods

In a phase 1 study, we administered BE-CAR7 T cells to children (≤16 years of age) with relapsed or refractory T-cell ALL after they had undergone lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab. Adults with compassionate-use access arrangements were also eligible. Patients who had remission by day 28 after the BE-CAR7 T-cell infusion proceeded to allogeneic hematopoietic stem-cell transplantation. The primary outcome was safety. Secondary outcomes included duration of remission, disease-free survival, and overall survival.

Results

BE-CAR7 T cells were administered to 9 children, as well as to 2 adults who were treated under compassionate-use access arrangements. Lymphodepletion and BE-CAR7 infusions did not lead to unacceptable adverse events, and circulating CAR7 T cells were detected in all the patients.

Complications included cytokine release syndrome of grades 1 through 4, transient rashes, multilineage cytopenia, and opportunistic infections.

All the patients had complete morphologic remission with incomplete count recovery at day 28.

Nine patients (82%) had deep remission (according to flow cytometry or polymerase-chain-reaction assay) that allowed them to proceed to stem-cell transplantation, and 2 patients with quantifiable minimal residual disease in bone marrow received palliative care.
Transplantation eliminated remaining BE-CAR7 T cells and supported donor-derived, multilineage reconstitution.
Viral reactivations were frequent, and 3 patients had clinically significant virus-related complications after transplantation.
Overall, 7 of the 11 patients (64%) who received the investigational therapy were in ongoing remission at 3 to 36 months after transplantation, and leukemia with loss of CD7 expression was documented in 2 patients.

Conclusions

Universal BE-CAR7 T cells induced leukemic remission in patients with relapsed or refractory T-cell ALL, thus allowing successful allogeneic hematopoietic stem-cell transplantation in most of the patients. ..."

Nature Briefing: Cancer

Pioneering new treatment reverses incurable blood cancer in some patients

Universal Base-Edited CAR7 T Cells for T-Cell Acute Lymphoblastic Leukemia (no public access)

AI tool spots blood cell abnormalities missed by doctors

Good news! This seems to be an excellent example of applying machine learning & AI to medicine.

"Researchers have created a system called CytoDiffusion that uses generative AI – the same type of technology behind image generators such as DALL-E – to study the shape and structure of blood cells.

Unlike many AI models, which are trained to simply recognise patterns, CytoDiffusion ... could accurately identify a wide range of normal blood cell appearances and spot unusual or rare cells that may indicate disease.

Spotting subtle differences in blood cell size, shape and appearance is a cornerstone of diagnosing many blood disorders. But the task requires years of training, and even then, different doctors can disagree on difficult cases. ..."

From the abstract:

"Blood cell morphology assessment via light microscopy constitutes a cornerstone of haematological diagnostics, providing crucial insights into diverse pathological conditions. This complex task demands expert interpretation owing to subtle morphological variations, biological heterogeneity and technical imaging factors that obstruct automated approaches.

Conventional machine learning methods using discriminative models struggle with domain shifts, intraclass variability and rare morphological variants, constraining their clinical utility.

We introduce CytoDiffusion, a diffusion-based generative classifier that faithfully models the distribution of blood cell morphology, combining accurate classification with robust anomaly detection, resistance to distributional shifts, interpretability, data efficiency and uncertainty quantification that surpasses clinical experts.

Our approach outperforms state-of-the-art discriminative models in

anomaly detection (area under the curve, 0.990 versus 0.916),

resistance to domain shifts (0.854 versus 0.738 accuracy) and

performance in low-data regimes (0.962 versus 0.924 balanced accuracy).

In particular, CytoDiffusion generates synthetic blood cell images that expert haematologists cannot distinguish from real ones (accuracy, 0.523; 95% confidence interval: [0.505, 0.542]), demonstrating good command of the underlying distribution.

Furthermore, we enhance model explainability through directly interpretable counterfactual heat maps.

Our comprehensive evaluation framework establishes a multidimensional benchmark for medical image analysis in haematology, ultimately enabling improved diagnostic accuracy in clinical settings."

AI tool spots blood cell abnormalities missed by doctors | University of Cambridge "An AI tool that can analyse abnormalities in the shape and form of blood cells, and with greater accuracy and reliability than human experts, could change the way conditions such as leukaemia are diagnosed."

Deep generative classification of blood cell morphology (open access)

Fig. 1: Overview of the diffusion-based classification model.

Fig. 4: Counterfactual visualizations for model explainability.

A new way to target aggressive blood cancer

Good news! Cancer is history (soon)!

"Researchers ... have found a new way to kill cancer cells of acute myeloid leukemia (AML), one of the most aggressive forms of blood cancer. ...

The new work shows that AML cells require a common molecule called heme to multiply and survive. Without heme, the cancer cells die of a type of cell death called cuproptosis.

“We’ve uncovered a fundamental weakness in AML cells,” ...

“By blocking AML cells from producing heme, we can switch on cuproptosis, a unique form of cell death, and effectively kill the cells most responsible for causing a cancer relapse.”

Cuproptosis is a form of cell death identified in 2022. It involves excessive levels of copper inside cells, which causes oxidative stress and ultimately leads to cell death. ..."

"Highlights

• Heme biosynthesis enzymes are variably suppressed in AML

• Heme levels are linked with altered leukemic transcriptional programs via BACH1

• Heme biosynthesis is a selective dependency in AML, both in vitro and in vivo

• Heme starvation disrupts complex IV, inducing copper accumulation and cuproptosis

Summary

The ubiquitous metabolite heme has diverse enzymatic and signaling functions in most mammalian cells. Through integrated analyses of mouse models, human cell lines, and primary patient samples, we identify de novo heme biosynthesis as a selective dependency in acute myeloid leukemia (AML).

The dependency is underpinned by a propensity of AML cells, and especially leukemic stem cells (LSCs), to downregulate heme biosynthesis enzymes (HBEs), which promotes their self-renewal.

Inhibition of HBEs causes the collapse of mitochondrial Complex IV and dysregulates the copper-chaperone system, inducing cuproptosis, a form of programmed cell death brought about by the oligomerization of lipoylated proteins by copper.

Moreover, we identify pathways that are synthetic lethal with heme biosynthesis, including glycolysis, which can be leveraged for combination strategies. Altogether, our work uncovers a heme rheostat that is connected to gene expression and drug sensitivity in AML and implicates HBE inhibition as a trigger of cuproptosis."

A new way to target aggressive blood cancer | News | ConnectSci

Peter Mac researchers uncover new way to target aggressive blood cancer (original news release)

Inhibition of heme biosynthesis triggers cuproptosis in acute myeloid leukemia

Graphical abstract

Ultrasound probe maps real-time blood flow across entire organs in 4D

Amazing stuff! Good news!

"Microcirculation – the flow of blood through the smallest vessels – is responsible for distributing oxygen and nutrients to tissues and organs throughout the body. Mapping this flow at the whole-organ scale could enhance our understanding of the circulatory system and improve diagnosis of vascular disorders. With this aim, researchers at the Institute Physics for Medicine Paris ... have combined 3D ultrasound localization microscopy (ULM) with a multi-lens array method to image blood flow dynamics in entire organs with micrometric resolution, reporting their findings in Nature Communications. ..."

"Researchers develop an ultrasound probe capable of visualising an entire organ in 4D

For the first time, whole-organ blood flow dynamics can be mapped at micrometric resolution using an ultrasound multi-lens probe — demonstrated in vivo in the heart, kidney, and liver.

Developed at Physics for Medicine Paris, this technology enables real-time 4D imaging of vascular dynamics across entire organs. ..."

From the abstract:

"Mapping microcirculation at the whole-organ scale in 3D is crucial for understanding vascular pathologies and improving diagnostics. Although 3D ultrasound localization microscopy (ULM) enables microscopic resolution by localizing intravenously injected microbubbles in small animal models, visualizing entire organs in large animals or humans remains challenging due to limited field of view, low sensitivity, and probe technological complexity.

Here, we demonstrate how a multi-lens array method overcomes these limitations. Combined with 3D ULM, it maps and quantifies large vascular volumes (up to 120 × 100 × 82 mm³) at high spatial resolution (125–200 µm) with a volumetric acquisition rate of 312 Hz, using low-cost technology.

This approach enables deeper insights into hemodynamics from large vessels to pre-capillary arterioles, by providing vast and rich datasets of whole-organ vascularization.

It could also facilitate diagnosis of microcirculation disorders and monitoring of small-vessel disease treatments by addressing key limitations of current imaging modalities."

Ultrasound probe maps real-time blood flow across entire organs – Physics World

Major breakthrough in medical imaging just published in Nature Communications (original news release)

Multi-lens ultrasound arrays enable large scale three-dimensional micro-vascularization characterization over whole organs (open access)

Fig. 1: Definition, simulation study of the multi-lens array probe and comparison to conventional approaches.

Fig. 3: 3D Coronary mapping of an isolated porcine heart.

Researchers build bone marrow model entirely from human cells

Good news!

"Scientists have successfully engineered the first entirely human-made bone marrow system in a lab, a key development for advanced blood research."

"... Now, researchers have succeeded for the first time in recreating this cellular complexity in the laboratory using only human cells. The novel system could reduce the need for animal experiments for many applications ...

Typically, bone marrow research relies heavily on animal models and oversimplified cell cultures in the laboratory. Now, researchers from the Department of Biomedicine at the University of Basel and University Hospital Basel have developed a realistic model of the bone marrow engineered entirely from human cells. ..."

From the highlights and abstract:

"Highlights

• eVON model recapitulates molecular and cellular features of native BM endosteal niches

• Endosteal vasculature enhances human myelopoiesis in the eVON

• eVON preserves HSPC multilineage repopulating capacity

• VEGF-A, CXCL12, and SCF signaling are active and could be perturbed in the eVON

Summary

Endosteal bone marrow (BM) niches are crucial to sustain non-steady-state hematopoiesis but are challenging to be modeled in their cellular and molecular complexity in standardized, human settings.

We report a developmentally guided approach to generate a macro-scale organotypic model of BM endosteal niches (engineered vascularized osteoblastic niche [eVON]) based on human induced pluripotent stem cells and porous hydroxyapatite scaffolds. The eVON contains long-lasting vascular networks covered by pericytes and neural fibers within an osteogenic matrix.

Key niche signals (CXCL12, KITLG, and vascular endothelial growth factor A [VEGFA]) are expressed in human-specific patterns.

The system supports hematopoiesis in vitro and preserves hematopoietic stem and progenitor cell (HSPC) multilineage repopulation capacity in vivo.

eVON perturbations at cellular (removing vasculature) and molecular (deregulating VEGF-A and CXCL12 signaling) levels enabled the investigation of the contribution of endosteal vasculature to myelopoiesis.

The eVON faithfully captures phenotypic, structural, and functional features of human endosteal BM, enabling the study of pathophysiological interactions with hematopoietic cells."

Researchers build bone marrow model entirely from human cells | University of Basel

Macro-scale, scaffold-assisted model of the human bone marrow endosteal niche using hiPSC-vascularized osteoblastic organoids (open access)

Credits: The Flyover

Graphical abstract

Miraqules offers a nanotechnology that mimics blood clotting proteins

Good news! The Israeli Defense Forces might already be interested.

"... developed a nanotechnology in powder form that mimics blood clotting proteins. The blood clotting powder rapidly produces fibrous compounds at room temperature that are a high volume to ratio and can absorb blood quickly when applied. ...

Miraqules is looking to ramp up deployment and pilot programs heading into next year. It has already received potential interest from 10 different hospital chains in India and the Israeli Defense Forces. ..."

Miraqules will showcase its blood clotting technology at TechCrunch Disrupt 2025 | TechCrunch

Source

Source

Scientists make human blood in the lab — here’s how

Good news!

An Overlooked Protein May Advance Artificial Blood Production

Good news!

"... Recently, ... found that CXCL12, a signaling protein, may solve this problem.1 When the researchers exposed mice erythroblasts, or immature red blood cells, to CXCL12, they triggered enucleation. Their findings, reported in Science Signaling, may help advance efforts in making blood in the lab. ..."

"... deciphered a further intermediate step towards a complete understanding of the cellular processes: the molecular signal, chemokine CXCL12, triggers the expulsion of the nucleus by the red blood cell precursors, a key step in the development of red blood cells. ..."

From the editor's summary and abstract:

"Editor’s summary

Signaling by the chemokine CXCL12 through its receptor CXCR4 promotes cell migration during embryonic development and immune surveillance and to sites of infection and inflammation. Gutjahr et al. found that bone marrow–derived CXCL12 activated CXCR4 on mouse bone marrow erythroblasts, the precursors of red blood cells (erythrocytes), to promote erythroblast differentiation, rather than their migration, through pathways involving intracellular and nuclear CXCR4 signaling.

Knockout of CXCR4 selectively in erythroblasts inhibited erythrocyte generation in mice. These findings indicate that CXCL12-CXCR4 signaling promotes erythropoiesis, suggesting that it should be investigated for the treatment of erythrocyte pathologies. ...

Abstract

The chemokine CXCL12 signals through its receptor CXCR4 to induce the migration of all leukocyte types and multiple other cell types. Here, we report that CXCR4 is expressed in mouse erythroblasts, the bone marrow erythroid precursors, in which it stimulates erythrocyte generation instead of chemotaxis.

CXCR4 signaling promoted homeostatic erythroblast maturation and increased the expression of genes mainly involved in metabolism and chromatin organization. Consequently, genetic depletion of CXCR4 in erythroblasts inhibited late erythropoiesis and diminished bone marrow erythroid outputs.

Binding of CXCL12 to CXCR4 stimulated its rapid endocytosis and translocation together with Gαi or phosphorylated β-arrestin1 into distinct intracellular compartments, including the nuclear envelope and nucleus.

CXCL12 signaling promoted erythroblast elongation and the condensation and excentric positioning of nuclei and stimulated rapid perinuclear Ca2+ transients that immediately preceded erythroblast enucleation.

These findings highlight previously uncharacterized physiological roles for CXCR4 and bone marrow–derived CXCL12 in erythropoiesis."

An Overlooked Protein May Advance Artificial Blood Production | The Scientist "Making blood in the lab can be hard because scientists don’t know what triggers a key final step in red blood cell maturation. A new study may change that."

Breakthrough in Artificial Blood Production (original news release) "Scientists have been working on the artificial production of blood for several decades. Making a new discovery, researchers from the Institute for Cellular Biology and Immunology Thurgau at the University of Konstanz, in collaboration with Queen Mary University of London, have come an important step closer to this goal."

Intracellular and nuclear CXCR4 signaling promotes terminal erythroblast differentiation and enucleation (open access)

Fig. 5. CXCL12-stimulated erythroblast elongation, nuclear polarization, chromatin condensation, and enucleation.

Julia Christine Gutjahr (her last name means good year, source)

New blood Test detects HPV-associated head, neck cancer 10 years early and with highest accuracy 4 years early

Good news! Cancer is history (soon)!

"Human papillomavirus (HPV) causes an estimated 70 percent of head and neck cancers in the U.S., making it the most common cancer caused by the virus. Yet unlike cervical cancers caused by HPV, there is no screening test for HPV-associated head and neck cancers.

In a new ... study, ... researchers show that a novel liquid biopsy tool they developed, called HPV-DeepSeek, can identify HPV-associated head and neck cancer up to 10 years before symptoms appear.  ..."

From the abstract:

"Purpose

Early detection of HPV-associated oropharyngeal cancer (HPV+OPSCC), the most common HPV cancer in the United States, could reduce disease-related morbidity and mortality, yet currently, there are no early detection tests. Circulating tumor HPV DNA (ctHPVDNA) is a sensitive and specific biomarker for HPV+OPSCC at diagnosis. It is unknown if ctHPVDNA is detectable prior to diagnosis, and thus it’s potential as an early detection test.

Methods

Plasma samples from the MassGeneralBrigham biobank collected 1.3-10.8 years prior to diagnosis from HPV+OPSCC patients (n = 28) and age- and sex-matched controls (n = 28) were blinded and run on a newly developed and validated multi-feature HPV whole genome sequencing liquid biopsy assay and a validated HPV antibody assay.

Results

ctHPVDNA results were positive in 22/28 pre-diagnostic samples from HPV+OPSCC cases (sensitivity 79%) with a maximum lead time of 7.8 years. ctHPVDNA results were negative in all controls (0/28 controls, 100% specificity). Diagnostic accuracy was highest within four years of cancer diagnosis and was higher than HPV Ab detection within the same time frame (p-value 0.004). Application of a machine learning model trained and tested on an independent cohort of 306 cases and controls increased the sensitivity of detection to 27/28 cases (overall sensitivity 96%) and the maximum lead time to 10.3 years.

Conclusions

Circulating tumor HPV DNA can be detected in the blood years prior to diagnosis with HPV+OPSCC, with high specificity, in a case-control cohort of 56 participants. ctHPVDNA detection alone, or in combination with previously identified serological biomarkers may be a feasible approach to early detection of HPV+OPSCC."

Test detects HPV-associated head, neck cancer 10 years early — Harvard Gazette "Tool identifies disease before symptoms appear"

Circulating tumor human papillomavirus DNA whole genome sequencing enables human papillomavirus-associated oropharynx cancer early detection (no public access)

Nanoparticles detect and reduce artery plaques

Good news!

"A new generation of “theranostic” nanoparticles has been shown to both detect and reduce plaques in the arteries. Nanoparticles absorbed by immune cells in the arteries, where they work to lower inflammation and draw out harmful cholesterol, offer an entirely new way of not just diagnosing but fighting heart disease without drugs. ..."

"... The study used advanced imaging techniques to track the movement of the nanoparticles in pre-clinical models of heart disease. They were able to target inflamed plaques and significantly reduce both plaque size and inflammation.

"One of the key challenges in treating atherosclerosis is that inflammation fuels plaque build-up, creating a vicious cycle. Our nanoparticles help break that cycle, which could lead to better long-term outcomes for patients,” ...

In addition to their ability to shrink plaques, the nanoparticles have powerful imaging capabilities that allow for earlier detection of arterial disease. This could help cardiologists identify at-risk patients sooner and intervene with treatments before complications arise. ..."

From the highlights and abstract:

"Highlights

• Atherosclerosis is the deposition of fatty plaques in arteries and the main cause of heart attacks.

• Strategies to improve detection and reduce atherosclerotic plaques are needed.

• Multifunctional porphyrin-lipid nanoparticles (Por-NPs) have diagnostic and therapeutic properties.

• Por-NPs are internalized by macrophages and track to atherosclerotic plaques, visualized using multiple imaging modalities.

• Por-NPs exert atheroprotective effects in vitro in macrophages. They suppress inflammation and promote cholesterol efflux.

• Por-NPs exhibit therapeutic effects in two murine models of atherosclerosis and significantly reduce plaque size.

Abstract

Background

Porphyrin-lipid nanoparticles (Por-NPs) have unrealized potential for atherosclerosis. Por-NPs incorporate porphyrin-lipid which permits fluorescence imaging and chelates Copper-64 (64Cu) for positron emission tomography (PET) imaging. Their outer shell contains a short peptide ‘R4F’ that enables macrophage targeting and therapeutic effects. Accordingly, this study investigates the simultaneous diagnostic and therapeutic properties of Por-NPs in atherosclerosis.

Results

In vitro, Por-NPs were found to be internalized by immortalised bone marrow-derived macrophages (iBMDMs), visualized via fluorescence microscopy and flow cytometry.

Por-NPs also increased cholesterol efflux from [3H]-cholesterol-loaded iBMDMs, (49 %, P < 0.05).

Incubation of iBMDMs with Por-NPs reduced mRNA levels of inflammatory mediators Il1b (88 %), Il18 (54 %) Ccl5 (75 %) and Ccl17 (92 %), and protein secretion of IL-1β (69 %), CCL5 (82 %) and CCL17 (94 %), P < 0.05. Por-NPs suppressed inflammasome components Nlrp3 (69 %) and Asc (36 %), P < 0.05. Studies using siRNA deletion of SR-B1 and methyl-β-cyclodextrin, revealed the anti-inflammatory properties of Por-NPs were independent of SR-B1 and cholesterol efflux. However, Por-NPs suppressed activation of inflammatory transcription factor NF-κB (53 %, P < 0.05).

In vivo, in Apoe−/− mice, serial non-invasive PET imaging showed 64Cu-labelled Por-NPs localised in hearts and detected increases in plaque size longitudinally with high-cholesterol diet. Por-NP fluorescence was visualized in aortic sinus plaques, co-localised with CD68+ macrophages, and by fluorescence IVIS imaging in aortic arch plaque.

In two murine models, Por-NP-treated mice had smaller early-stage (22 %) and unstable plaques (52 %). Por-NP-treated mice had fewer circulating (32 %) and aortic (81 %) monocytes, and lower mRNA levels of aortic arch Rela (26 %) and Nfkb1 (27 %), P < 0.05.

Conclusions

Por-NPs detect plaques using multiple imaging modalities and exhibit atheroprotective effects, presenting as novel nanoscale theranostics for atherosclerosis."

Nanoparticles detect and reduce artery plaques

Nanoparticles engineered to suck the plaque out of arteries (original news release) "Researchers at SAHMRI are using specially designed nanoparticles to detect and help treat plaque build-up in arteries for the first time, offering a potential new approach to diagnosing and managing heart disease."

Theranostic porphyrin nanoparticles identify atherosclerosis via multimodal imaging and elicit atheroprotective effects (open access)

Graphical abstract

Platelets absorb precancerous and tumor DNA

Amazing stuff! Cancer is history (soon)!

"... a team reveals that as platelets cruise the bloodstream, they also absorb bits of DNA released by other body cells, including tumor cells. ... for so-called liquid biopsies that diagnose cancer through simple blood tests instead of more invasive sampling of tumor tissue. ...

The team even found that platelets absorb DNA from patients’ precancerous colon growths, which suggests they could be useful for early detection.  ..."

"... study ... demonstrates that platelets also act as scavengers, capturing and storing fragments of DNA that are circulating in the blood, including fetal DNA and mutated DNA from cancer cells. Analysis of platelet DNA via a simple blood test was found to reveal the presence of even “pre-cancerous” changes - indicating this may be a powerful technique for the early detection and prevention of cancer. ..."

From the editor's summary and abstract:

"Editor’s summary

Although platelets are best known for their role in blood clotting, they also contribute to host defense and homeostasis. Murphy et al. found that platelets could acquire DNA from nucleated cells by internalizing extracellular vesicles and taking up DNA not enclosed in a membrane, called cell-free DNA (cfDNA)  ... ... Human platelets isolated from pregnant individuals contain fetal DNA, and those from cancer patients contain DNA with tumor-associated mutations. Because there is a relatively low concentration of cfDNA in blood plasma, platelets might be an additional source to help overcome a current limitation in clinical diagnostics.  ...

Structured Abstract

INTRODUCTION

Platelets are the smallest and second most abundant cell type in our blood, contributing to a range of physiological processes, including hemostasis, vascular maintenance, and innate immunity. ...

RATIONALE

Given their known ability to sense and internalize exogenous nucleic acids, we hypothesized that platelets may sequester endogenous extracellular DNA during circulation. ... cell-free DNA (cfDNA) in plasma, which is immunostimulatory. ...

RESULTS

By using high resolution imaging and flow cytometry, we confirmed that platelets contain fractional quantities of DNA. To test whether platelets can acquire DNA after their release from megakaryocytes, we performed live cell imaging and coculture experiments, demonstrating transfer of mutant DNA from malignant cells to healthy donor platelets in vitro. We confirmed that cfDNA sequestration by platelets occurs in vivo ...

Uptake and release of DNA could be pharmacologically manipulated. Platelet-encapsulated DNA was protected from external deoxyribonuclease (DNase) degradation, and inhibiting platelet exocytosis increased the abundance of DNA obtained from platelets.

Lastly, we demonstrated that tumor-derived DNA was present in platelets of patients with advanced cancer, where cfDNA was in high abundance; in low–tumor burden disease; and also in those with premalignant colonic polyps. ..."

ScienceAdviser

Platelets shown to store DNA in study that could transform cancer screening (original news release) "Oxford-led study uncovers previously unknown function of platelets as DNA ‘vacuum cleaners’ in the blood, with profound implications for cancer diagnosis and prenatal screening."

Platelets sequester extracellular DNA, capturing tumor-derived and free fetal DNA

Platelets sequester cfDNA during circulation.

Scientists discover world's rarest blood type. Only one human being carries the 48th blood group

Amazing stuff!

"... scientists have identified the world’s rarest blood group, known as Gwada-negative. It's a blood group so rare that only one woman in the world is known to have it.

The existence of the unique blood type was first suspected in 2011 during a pre-surgical screening, when clinicians at France’s national blood agency, the Établissement Français du Sang (EFS), noticed something strange about a Guadeloupean woman’s blood: it reacted against every donor sample, including that of close family members.

Later tests revealed something astonishing, she carried antibodies that didn’t match any known blood group in the world. ...

The breakthrough came in 2019, when high-throughput DNA sequencing revealed a rare mutation in a gene called PIGZ. This particular gene encodes for an enzyme involved in the final step of producing glycosylphosphatidylinositol (GPI), a molecule essential for anchoring proteins to the surface of red blood cells. ...

This wasn’t just a rare blood type. It was a new blood type. A discovery so unique that there is no known compatible donor in the global registry. ...

In June 2025, the International Society of Blood Transfusion (ISBT) recognized Gwada as the 48th blood group. It is scientifically known as ERYR, or EMM-negative, but in honor of the patient’s Caribbean roots, it has been nicknamed Gwada-negative – “Gwada” being slang for "from Guadeloupe". ..."

French scientists discover world's rarest blood type