Adoptive cell therapy (ACT) of autologous tumor infiltrating lymphocytes (TIL) is an effective immunotherapy for patients with solid tumors, yielding objective response rates of around 40% in ...refractory patients with metastatic melanoma. Most clinical centers utilize bulk, randomly isolated TIL from the tumor tissue for
expansion and infusion. Only a minor fraction of the administered T cells recognizes tumor antigens, such as shared and mutation-derived neoantigens, and consequently eliminates the tumor. Thus, there are many ongoing effects to identify and select tumor-specific TIL for therapy; however, those approaches are very costly and require months, which is unreasonable for most metastatic patients. CD137 (4-1BB) has been identified as a co-stimulatory marker, which is induced upon the specific interaction of T cells with their target cell. Therefore, CD137 can be a useful biomarker and an important tool for the selection of tumor-reactive T cells. Here, we developed and validated a simple and time efficient method for the selection of CD137-expressing T cells for therapy based on magnetic bead separation. CD137 selection was performed with clinical grade compliant reagents, and TIL were expanded in a large-scale manner to meet cell numbers required for the patient setting in a GMP facility. For the first time, the methodology was designed to comply with both clinical needs and limitations, and its feasibility was assessed. CD137-selected TIL demonstrated significantly increased antitumor reactivity and were enriched for T cells recognizing neoantigens as well as shared tumor antigens. CD137-based selection enabled the enrichment of tumor-reactive T cells without the necessity of knowing the epitope specificity or the antigen type. The direct implementation of the CD137 separation method to the cell production of TIL may provide a simple way to improve the clinical efficiency of TIL ACT.
Overexpressed extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDAC) limits drug penetration into the tumor and is associated with poor prognosis. Here, we demonstrate that a ...pretreatment based on a proteolytic-enzyme nanoparticle system disassembles the dense PDAC collagen stroma and increases drug penetration into the pancreatic tumor. More specifically, the collagozome, a 100 nm liposome encapsulating collagenase, was rationally designed to protect the collagenase from premature deactivation and prolonged its release rate at the target site. Collagen is the main component of the PDAC stroma, reaching 12.8 ± 2.3% vol in diseased mice pancreases, compared to 1.4 ± 0.4% in healthy mice. Upon intravenous injection of the collagozome, ∼1% of the injected dose reached the pancreas over 8 h, reducing the level of fibrotic tissue to 5.6 ± 0.8%. The collagozome pretreatment allowed increased drug penetration into the pancreas and improved PDAC treatment. PDAC tumors, pretreated with the collagozome followed by paclitaxel micelles, were 87% smaller than tumors pretreated with empty liposomes followed by paclitaxel micelles. Interestingly, degrading the ECM did not increase the number of circulating tumor cells or metastasis. This strategy holds promise for degrading the extracellular stroma in other diseases as well, such as liver fibrosis, enhancing tissue permeability before drug administration.
The impact of social determinants on health status and outcomes has been widely established. However, it is recognized that health systems' ability to address community health needs may be limited. ...To better understand the interrelation between social determinants of health and health outcomes, health systems need to understand the health concerns and needs of populations. The aim of this study was to map the perceived health needs of Israel's northern periphery's diverse ethnic and religious communities and regional clusters by conducting a community health needs assessment (CHNA). The study employed a mixed-methods approach. We conducted a CHNA in the Galilee between November 2019 to January 2020 (n = 750). Additionally, we conducted focus groups using design thinking methodology to better understand the underlying causes of existing gaps between community and healthcare representatives (n = 42). Quantitative data was analyzed using multiple logistic regressions and qualitative data was analyzed using a content and thematic analysis. Galilee residents perceived sense of community (78%) as the major strength while cancer (53%) was perceived as the major health problem followed by heart disease and stroke (28.4%). The adjusted odds ratios for the association of each predictor with each perceived social and structural determinants of health among respondents indicated that Arab respondents were more likely to report race/ethnicity discrimination, domestic violence, lack of parks and recreation, neighborhood violence, limited places to exercise, school dropout and limited access to healthy food, as determinants affecting health than Jews. Conversely, Jews were more likely than Arabs to report access to mental health services, access to transportation, lack of job opportunities and access to a doctor's office as determinants affecting their health. Qualitative analysis revealed residents felt a 'lack of health security' as a result of problematic access to specialty and mental health services, especially for elderly populations. CHNA can inform the design of tailored interventions that will improve health for Galilee residents addressing their socioeconomic-cultural-geographical characteristics. The study's findings raise the need to create such tailored approaches to address the lack of health security felt by residents and improve not only health services provision but the social determinants affecting their health.
Medical students can assist in reducing healthcare disparities and promote health equity by engaging with rural communities and gaining insights into their unique healthcare needs. A two-arm ...student-delivered program was designed and implemented during COVID-19 in a social-geographic peripheral area to assist clinics with complex chronic and/or socially disadvantaged patients and improve preventive behavior in townships through home visits delivering community kits.
We conducted a pre-post design study which included weekly structured medical student reports and monthly structured telephone interviews with clinic directors and municipal partners. Students completed pre-post program survey on their knowledge, skills, and capabilities to address chronic patients from diverse cultural backgrounds (n = 73). The Wilcoxon-Signed-Rank test for related samples was used to determine differences.
Following the program, the knowledge and awareness levels of students about working in the community (P < 0.001) and their knowledge of common chronic diseases were significantly improved (Mean Difference (MD) = 0.31; p < 0.001). The program significantly increased students' interest to integrate into community care alongside a hospital (P = 0.012). Thematic analysis of student reports revealed improved insight into the role of primary care. Clinic directors (90%) were highly satisfied and reported that students became an integral part of the clinics' teams.
Integrating medical students into the community through primary-care clinics and home visits in diverse communities, exposed students to the interwoven effect of clinical and social determinants on health and improve their knowledge of common chronic diseases. Participation in the program encouraged students to consider a career in community care.
Antibiotic-resistant pathogens are a growing global issue, leading to untreatable infectious diseases in both humans and animals. Personalized bacteriophage (phage) therapy, the use of specific ...anti-bacterial viruses, is currently a leading approach to combat antibiotic-resistant infections. The implementation of phage therapy has primarily been focused on humans, almost neglecting the impact of such infections on the health and welfare of companion animals. Pets also have the potential to spread resistant infections to their owners or the veterinary staff through zoonotic transmission. Here, we showcase personalized phage-antibiotic treatment of a cat with a multidrug-resistant
implant-associated infection post-arthrodesis surgery. The treatment encompassed a tailored combination of an anti-
phage and ceftazidime, precisely matched to the pathogen. The phage was topically applied to the surgical wound while the antibiotic was administered intramuscularly. After two treatment courses spanning 7 and 3 weeks, the surgical wound, which had previously remained open for five months, fully closed. To the best of our knowledge, this is the first case of personalized phage therapy application in felines, which provides further evidence of the effectiveness of this approach. The successful outcome paves the way for personalized phage-antibiotic treatments against persistent infections therapy in veterinary practice.
The essential micronutrient selenium is found in proteins as selenocysteine (Sec), the only genetically encoded amino acid whose biosynthesis occurs on its cognate tRNA in humans. In the final step ...of selenocysteine formation, the essential enzyme SepSecS catalyzes the conversion of Sep-tRNA to Sec-tRNA. We demonstrate that SepSecS mutations cause autosomal-recessive progressive cerebellocerebral atrophy (PCCA) in Jews of Iraqi and Moroccan ancestry. Both founder mutations, common in these two populations, disrupt the sole route to the biosynthesis of the 21st amino acid, Sec, and thus to the generation of selenoproteins in humans.
Melanoma has the highest propensity to metastasize to the brain compared to other cancers, as brain metastases are found frequently high in patients who have prolonged survival with visceral ...metastasis. Once disseminated in the brain, melanoma cells communicate with brain resident cells that include astrocytes and microglia. Microglia cells are the resident macrophages of the brain and are the main immunological cells in the CNS involved in neuroinflammation. Data on the interactions between brain metastatic melanoma cells and microglia and on the role of microglia‐mediated neuroinflammation in facilitating melanoma brain metastasis are lacking. To elucidate the role of microglia in melanoma brain metastasis progression, we examined the bidirectional interactions between microglia and melanoma cells in the tumor microenvironment. We identified the molecular and functional modifications occurring in brain‐metastasizing melanoma cells and microglia cells after the treatment of each cell type with supernatants of the counter cell type. Both cells induced alteration in gene expression programs, cell signaling, and cytokine secretion in the counter cell type. Moreover, melanoma cells exerted significant morphological changes on microglia cells, enhanced proliferation, induced matrix metalloproteinase‐2 (MMP‐2) activation, and cell migration. Microglia cells induced phenotypic changes in melanoma cells increasing their malignant phenotype: increased melanoma proliferation, MMP‐2 activity, cell migration, brain endothelial penetration, and tumor cells ability to grow as spheroids in 3D cultures. Our work provides a novel insight into the bidirectional interactions between melanoma and micoglia cells, suggesting the contribution of microglia to melanoma brain metastasis formation.
What's new?
Activated microglia are found in metastatic brain lesions of several tumors. However, their role in tumorigenesis and metastasis remains controversial. Here, the authors found that brain‐metastasizing melanoma cells and microglia cells induced reciprocal alteration in their gene expression pattern, cell signaling, and cytokine secretion. Moreover, melanoma cells exerted significant morphological changes on microglia cells, enhanced proliferation, induced matrix metalloproteinase‐2 activation and cell migration. Microglia cells induced phenotypic changes in melanoma cells increasing their malignant phenotype. The work provides a novel insight into the bidirectional interactions between melanoma and microglia cells, suggesting the contribution of microglia to melanoma brain metastasis formation.
Arid environments are characterized by rare rain events that are highly variable, as a result of which plant populations often exhibit episodic recruitment and mortality dynamics. However, direct ...records and observations of such events are rare because of the slow development of woody species. In this study, we described how a decrease in annual precipitation affected acacia tree population dynamics in two hydrological regime types: small wadis and salt flats. This study combines 15 years of continuous, yearly field monitoring of individual acacia trees and data from a historical Corona satellite image, which has extended the time scope of the research. Results indicate that the annual mortality of acacia trees in small wadis reflects the cumulative effective rain events in the preceding five years, whereas the population on the salt flats was not affected by annual rainfall fluctuations. Moreover, in small wadis, rain events of less than 8 mm did not increase acacia tree survival rates. The mortality pattern and dynamics of each plot was unique, suggesting unsynchronized mortality and recruitment episodes on a regional scale. Mortality in all plots was documented both in “old” trees (i.e., recognized in 1968) and “new” trees (not recognized in 1968), but varied highly between plots. More than 50% of the dead trees recorded at the sites had died during the previous dry period (2000–2010). Combining field monitoring and historical satellite image data provided a unique database of acacia population dynamics. This record revealed the response of the acacia population to climate fluctuations and a period of episodic mortality.
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