Lifeboat Foundation

While immunotherapies have shown great promise in treating blood cancers, most clinical trials aimed at treating solid tumors such as pancreatic or lung cancer have failed. Researchers have long thought that solid tumors’ resistance to treatment is due to the tumor microenvironment—the cells and matrix that surround solid tumors—but the exact mechanisms behind this blockade were unclear, until now.

In a new study, University of Pennsylvania researchers reveal how the tumor microenvironment prevents T cells from attacking tumors. Using mouse models, they showed that cancer-associated fibroblasts along with extracellular matrix within the tumor microenvironment create a physical barrier to T cell entry, and these cells also actively suppress T cell function. When the researchers used CAR T cells to target and remove these fibroblasts, rather than targeting the tumor cells themselves, T cells were able to infiltrate and attack the tumor.

“The physical barrier and immunosuppressive environment derived from cancer-associated fibroblasts limits or traps T cells and prevents them from entering into the tumor,” says first author Zebin Xiao, a physician and postdoctoral researcher in the School of Veterinary Medicine. “We showed that targeting those fibroblasts can disrupt that barrier and has a very great tumor inhibition effect.”

Zachary Schug, Ph.D., assistant professor in the Molecular and Cellular Oncogenesis Program of the Ellen and Ronald Caplan Cancer Center at The Wistar Institute, has published a new paper in the journal Nature Cancer. Schug’s paper, titled “Acetate acts as a metabolic immunomodulator by bolstering T-cell effector function and potentiating antitumor immunity in breast cancer,” demonstrates a double-acting mechanism for fighting a particularly aggressive, difficult-to-treat form of breast cancer. Schug’s research shows how silencing a certain gene, ACSS2, may improve existing treatments for patients.

Triple-negative breast cancer, or TNBC, affects 10–15% of patients with breast cancer in the US. TNBC is called “triple-negative” because the cancer lacks an estrogen receptor, a progesterone receptor, and a HER2 (human epidermal growth factor) receptor. The absence of any of these receptors—receptors that when present in other forms of breast cancer, can be effectively targeted during treatment—makes treating TNBC quite difficult, and patients with TNBC have limited treatment options.

TNBC’s notorious aggression makes the technical challenge of finding a reliably effective treatment target all the more serious: compared to other breast cancers, TNBC grows faster and resists treatment more stubbornly. All these factors contribute to the fact that TNBC patients suffer from worse prognoses.

Conventional manufacturing methods such as soft lithography and hot embossing processes can be used to bioengineer microfluidic chips, albeit with limitations, including difficulty in preparing multilayered structures, cost-and labor-consuming fabrication processes as well as low productivity.

Materials scientists have introduced digital light processing as a cost-effective microfabrication approach to 3D print microfluidic chips, although the fabrication resolution of these microchannels are limited to a scale of sub-100 microns.

In a new report published in Microsystems and Nanoengineering, Zhuming Luo and a scientific team in biomedical engineering, and chemical engineering in China developed an innovative digital light processing method.

Summary: Researchers pioneered a groundbreaking method called “CHOOSE” to investigate genes tied to autism spectrum disorder (ASD) within human tissue. This technique allows for simultaneous examination of key transcriptional regulator genes linked to autism in a single organoid.

Utilizing CHOOSE, the team pinpointed mutations in 36 genes known to heighten autism risk, shedding light on how they influence brain development. The revelations from these organoids mirrored clinical observations, underscoring the potential of this method in advancing our understanding of neurodevelopmental disorders.

Our hope is for COVID-19 to never repeat itself,’ said the new program’s executive director.

A program run by a Canadian university is seeking to improve global health care for the most vulnerable by examining how artificial intelligence (AI) can enhance readiness for infectious disease epidemics in the Global South.

This is according to a report by CTV News published on Wednesday.

Continue reading “AI now used in the fight against global infectious diseases” »

Hospital staff spend a significant amount of time working to protect patients from acquiring infections while they are being cared for in the hospital. They employ various methods from hand hygiene to isolation rooms to rigorous environmental sanitation. Despite these efforts, hospital-onset infections still occur—the most common of which is caused by the bacterium Clostridioides difficile, or C. diff, the culprit of almost half a million infections in the U.S. each year.

Surprising findings from a study in Nature Medicine suggest that the burden of C. diff infection may be less a matter of hospital transmission and more a result of characteristics associated with the patients themselves.

The study team, led by Evan Snitkin, Ph.D. and Vincent Young, M.D., Ph.D., both members of the Departments of Microbiology & Immunology and Internal Medicine/Infectious Diseases at University of Michigan Medical School and Mary Hayden, M.D. of Rush University Medical Center, leveraged ongoing epidemiological studies focused on hospital-acquired infections that enabled them to analyze daily fecal samples from every patient within the intensive care unit at Rush University Medical Center over a nine-month period.

A startup by prominent biochemist David Liu seeks to turn hollowed out viruses into CRISPR-delivery vehicles.

Year 2023 😗

Data from patients with AMD, retinal dystrophies, and diabetic retinopathy indicate an important role of immune cells, including microglia, in the pathogenesis of these retinal diseases¹. The accumulation of drusen components provides an environment rich in chemoattractants for microglia and leads to their translocation to the subretinal space in AMD^2,4. The involvement of microglia in the activation of the NLRP3 inflammasome and the promotion of proinflammatory cytokine secretion has been confirmed in in vitro and animal studies^11,12,14. In patients with retinal dystrophies like retinitis pigmentosa, it has been shown that microglia become activated in response to signals from degenerating rod photoreceptors and migrate to the outer retinal layers⁴. There, they participate in the phagocytosis of debris and dying cells and secrete proinflammatory factors. Mouse models of retinal degeneration (e.g. rd1, rd7, rd8, and rd10 models) confirm many of these conclusions^9,10,13,15, but make it clear that the role of microglia may also be homeostatic, depending on both stimuli and anatomical location within the retina^7,20. Activated microglia are observed at all the stages of human diabetic retinopathy^3,8 and also feature prominently in many animal models of the disease^44,45. Finally, accumulations of activated microglia are also seen in a variety of animal models of retinal degeneration, including light-induced retinal degeneration and models based on complement dysregulation^34,46,47.

The pathways regulating immune surveillance, cell trafficking, and neuroinflammation in the retina are not well understood. A large number of molecules and processes have been implicated, ranging from chemokines involved in chemotaxis, cytokines involved in activation, factors that regulate oxidative stress and complement activation, and immunoregulatory proteins. In such a complex biological system, the unbiased nature of a forward genetics approach is particularly valuable in identifying genes affecting these immune cell processes. Furthermore, the accumulation of subretinal microglia, visible as or correlated with the accumulation of fundus spots, can serve as a marker for retinal pathology and thus as a screen for genes essential to retinal homeostasis. Our approach here has two important advantages relative to all prior forward genetics studies of the retina: 1. We are systematically applying a semiquantitative fundus spot scale to fundus photographs, and 2. Our pipeline is the only one in which all mice screened are G3 mice that have been pre-genotyped at all mutant loci. Our unbiased identification of 6 gene-phenotype associations to retinal pathology with strong literature support using our fundus spot scale screen is proof of concept supporting the efficacy of our approach. We identified other associations that had not been reported in the literature at the time of the screening. From those, we first concentrated our efforts on the gene Lipe, partly because the fundus spot scale was the only parameter leading to its identification.

Continue reading “Forward genetic screening using fundus spot scale identifies an essential role for Lipe in murine retinal homeostasis” »

Crispr used in mice to reverse vision loss 😀.

Qin and colleagues develop a genome-editing tool characterized by the versatility of prime editors and unconstrained PAM requirement of SpRY. In vivo gene corre.