Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

Effective anti-tumor immune response against HCC is orchestrated by immune cell partnership network that functions through hepatic homeostatic pathways, not direct cytotoxicity.

The liver harbors a diverse array of immune cells during both health and disease. The specific roles of these cells in nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) remain unclear. Using a systems immunology approach, we demonstrate that reciprocal cell-cell communications function through dominant-subdominant pattern of ligand-receptor homeostatic pathways. In the healthy control, hepatocyte-dominated homeostatic pathways induce local immune responses to maintain liver homeostasis. Chronic intake of a Western diet (WD) alters hepatocytes and induces hepatic stellate cell (HSC), cancer cell and NKT cell-dominated interactions during NAFLD. During HCC, monocytes, hepatocytes, and myofibroblasts join the dominant cellular interactions network to restore liver homeostasis. Dietary correction during NAFLD results in nonlinear outcomes with various cellular rearrangements. When cancer cells and stromal cells dominate hepatic interactions network without inducing homeostatic immune responses, HCC progression occurs. Conversely, myofibroblast and fibroblast-dominated network orchestrates monocyte-dominated HCC-preventive immune responses. Tumor immune surveillance by 75% of immune cells successfully promoting liver homeostasis can create a tumor-inhibitory microenvironment, while only 5% of immune cells manifest apoptosis-inducing functions, primarily for facilitating homeostatic liver cell turnover rather than direct tumor killing. These data suggest that an effective immunotherapy should promote liver homeostasis rather than direct tumor killing.

Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein. and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

The quantum model of T-cell activation: Revisiting immune response theories.

Our understanding of the immune response is far from complete, missing out on more detailed explanations that could be provided by molecular insights. To bridge this gap, we introduce the quantum model of T-cell activation. This model suggests that the transfer of energy during protein phosphorylation within T cells is not a continuous flow but occurs in discrete bursts, or 'quanta', of phosphates. This quantized energy transfer is mediated by oscillating cycles of receptor phosphorylation and dephosphorylation, initiated by dynamic 'catch-slip' pulses in the peptide-major histocompatibility complex-T-cell receptor (pMHC-TcR) interactions. T-cell activation is predicated upon achieving a critical threshold of catch-slip pulses at the pMHC-TcR interface. Costimulation is relegated to a secondary role, becoming crucial only when the frequency of pMHC-TcR catch-slip pulses does not meet the necessary threshold for this quanta-based energy transfer. Therefore, our model posits that it is the quantum nature of energy transfer-not the traditional signal I or signal II-that plays the decisive role in T-cell activation. This paradigm shift highlights the importance of understanding T-cell activation through a quantum lens, offering a potentially transformative perspective on immune response regulation.

Spatiotemporal modeling of nano-delivered chemotherapeutics for synergistic microwave ablation cancer therapy.

BACKGROUND AND OBJECTIVE: The effectiveness of current microwave ablation (MWA) therapies is limited. Administration of thermosensitive liposomes (TSLs) which release drugs in response to heat has presented a significant potential for enhancing the efficacy of thermal ablation treatment, and the benefits of targeted drug delivery. However, a complete knowledge of the mechanobiological processes underlying the drug release process, especially the intravascular drug release mechanism and its distribution in response to MWA needs to be improved. Multiscale computational-based modeling frameworks, integrating different biophysical phenomena, have recently emerged as promising tools to decipher the mechanobiological events in combo therapies. The present study aims to develop a novel multiscale computational model of TSLs delivery following MWA implantation. METHODS: Due to the complex interplay between the heating procedure and the drug concentration maps, a computational model is developed to determine the intravascular release of doxorubicin from TSL, its transvascular transport into the interstitium, transport in the interstitium, and cell uptake. Computational models can estimate the interplays among liposome and drug properties, tumor perfusion, and heating regimen to examine the impact of essential parameters and to optimize a targeted drug delivery platform. RESULTS: Results indicated that the synergy of TSLs with MWA allows more localized drug delivery with lower side effects. The drug release rate and tumor permeability play crucial roles in the efficacy of TSLs during MWA treatment. The computational model predicted an unencapsulated drug lime around the ablated zone, which can destroy more cancer cells compared to MWA alone by 40%. Administration of TSLs with a high release rate capacity can improve the percentage of killed cancer cells by 24%. Since the heating duration in MWA is less than 15 min, the presented combination therapy showed better performance for highly permeable tumors. CONCLUSION: This study highlights the potential of the proposed computational framework to address complex and realistic scenarios in cancer treatment, which can serve as the future research foundation, including advancements in nanomedicine and optimizing the pair of TSL and MWA for both preclinical and clinical studies. The present model could be as a valuable tool for patient-specific calibration of essential parameters.

Effect of tumor heterogeneity on enhancing drug delivery to vascularized tumors using thermo-sensitive liposomes triggered by hyperthermia: A multi-scale and multi-physics computational model.

In this study, a novel multi-scale and multi-physics image-based computational model is introduced to assess the delivery of doxorubicin (Dox) loaded temperature-sensitive liposomes (TSLs) in the presence of hyperthermia. Unlike previous methodologies, this approach incorporates capillary network geometry extracted from images, resulting in a more realistic physiological tumor model. This model holds significant promise in advancing personalized medicine by integrating patient-specific tumor properties. The finite element method is employed to solve the equations governing intravascular and interstitial fluid flows, as well as the transport of therapeutic agents within the tissue. Realistic biological conditions and intricate processes like intravascular pressure, drug binding to cells, and cellular uptake are also considered to enhance the model's accuracy. The results underscore the significant impact of vascular architecture on treatment outcomes. Variation in vascular network pattern yielded changes of up to 38 % in the fraction of killed cells (FKCs) parameter under identical conditions. Pressure control of the parent vessels can also improve FKCs by approximately 17 %. Tailoring the treatment plan based on tumor-specific parameters emerged as a critical factor influencing treatment efficacy. For instance, changing the time interval between the administration of Dox-loaded TSLs and hyperthermia can result in a 48 % improvement in treatment outcomes. Additionally, devising a customized heating schedule led to a 20 % increase in treatment efficacy. Our proposed model highlights the significant effect of tumor characteristics and vascular network structure on the final treatment outcomes of the presented combination treatment.

Walnut Kernel Oil and Defatted Extracts Enhance Mesenchymal Stem Cell Stemness and Delay Senescence.

Decreased stemness and increased cellular senescence impair the ability of mesenchymal stem cells (MSCs) to renew themselves, change into different cell types, and contribute to regenerative medicine. There is an urgent need to discover new compounds that can boost MSCs' stemness and delay senescence. Therefore, this study aimed to investigate the impact of walnut kernel oil (WKO) and defatted (WKD) extracts on bone marrow (BM)-MSC stemness and senescence. Premature senescence and inflammation were induced in BM-MSCs using H2O2 and LPS, respectively. Phytochemical constituents of WKO and WKD extracts were detected by HPLC. The stemness (proliferation and migration), senescence-related markers (p53, p21, SIRT1, and AMPK), oxidative stress/antioxidant markers, inflammatory cytokines, and cell cycle of BM-MSCs were measured by MTT assay, qPCR, ELISA, and flow cytometry. WKO and WKD extracts improved rat BM-MSC stemness, as evidenced by (1) increased cell viability, (2) decreased apoptosis (low levels of Bax and caspase3 and high levels of Bcl2), (3) upregulated MMP9 and downregulated TIMP1 expression, and (4) cell cycle arrest in the G0/G1 phase and declined cell number in the S and G2/M phases. Additionally, WKO and WKD extracts reduced rat BM-MSC senescence, as indicated by (1) decreased p53 and p21 expression, (2) upregulated expression and levels of SIRT1 and AMPK, (3) reduced levels of ROS and improved antioxidant activity (higher activity of CAT, SOD, and GPx and upregulated expression of NrF2 and HO-1), and (4) declined levels of TNFα, IL1ß, and NF-κB. When compared to the WKO extract, the WKD extract had a greater impact on the induction of stemness and reduction of senescence of BM-MSCs due to its stronger antioxidant activity, which could be attributed to its higher levels of flavonoids and phenolic compounds, as detected by HPLC analysis. WKO and WKD extracts enhance rat BM-MSC stemness and protect them from senescence, suggesting their potential use as enhancers to increase MSCs' therapeutic efficacy.

The crosstalking immune cells network creates a collective function beyond the function of each cellular constituent during the progression of hepatocellular carcinoma.

Abundance of data on the role of inflammatory immune responses in the progression or inhibition of hepatocellular carcinoma (HCC) has failed to offer a curative immunotherapy for HCC. This is largely because of focusing on detailed specific cell types and missing the collective function of the hepatic immune system. To discover the collective immune function, we take systems immunology approach by performing high-throughput analysis of snRNAseq data collected from the liver of DIAMOND mice during the progression of nonalcoholic fatty liver disease (NAFLD) to HCC. We report that mutual signaling interactions of the hepatic immune cells in a dominant-subdominant manner, as well as their interaction with structural cells shape the immunological pattern manifesting a collective function beyond the function of the cellular constituents. Such pattern discovery approach recognized direct role of the innate immune cells in the progression of NASH and HCC. These data suggest that discovery of the immune pattern not only detects the immunological mechanism of HCC in spite of dynamic changes in immune cells during the course of disease but also offers immune modulatory interventions for the treatment of NAFLD and HCC.

From Reductionistic Approach to Systems Immunology Approach for the Understanding of Tumor Microenvironment.

The tumor microenvironment (TME) is a complex and dynamic ecosystem that includes a variety of immune cells mutually interacting with tumor cells, structural/stromal cells, and each other. The immune cells in the TME can have dual functions as pro-tumorigenic and anti-tumorigenic. To understand such paradoxical functions, the reductionistic approach classifies the immune cells into pro- and anti-tumor cells and suggests the therapeutic blockade of the pro-tumor and induction of the anti-tumor immune cells. This strategy has proven to be partially effective in prolonging patients' survival only in a fraction of patients without offering a cancer cure. Recent advances in multi-omics allow taking systems immunology approach. This essay discusses how a systems immunology approach could revolutionize our understanding of the TME by suggesting that internetwork interactions of the immune cell types create distinct collective functions independent of the function of each cellular constituent. Such collective function can be understood by the discovery of the immunological patterns in the TME and may be modulated as a therapeutic means for immunotherapy of cancer.

The Adaptation Model of Immunity: Signal IV Matters Most in Determining the Functional Outcomes of Immune Responses.

Current research in immunology and immunotherapy is fully influenced by the self-nonself model of immunity. This theoretical model suggests that alloreactivity results in graft rejection, whereas tolerance toward self-antigens expressed by malignant cells facilitates cancer development. Similarly, breakage of immunological tolerance toward self-antigens results in autoimmune diseases. Accordingly, immune suppression is recommended for the management of autoimmune diseases, allergy, and organ transplantation, whereas immune inducers are used for the treatment of cancers. Although the danger model, the discontinuity model, and the adaptation model are proposed for a better understanding of the immune system, the self-nonself model continues to dominate the field. Nevertheless, a cure for these human diseases remains elusive. This essay discusses current theoretical models of immunity, as well as their impacts and limitations, and expands on the adaptation model of immunity to galvanize a new direction for the treatment of autoimmune diseases, organ transplantation, and cancer.

SRA inhibition improves antitumor potency of antigen-targeted chaperone vaccine.

We have previously demonstrated that scavenger receptor A (SRA) acts as an immunosuppressive regulator of dendritic cell (DC) function in activating antitumor T cells. Here we investigate the potential of inhibiting SRA activity to enhance DC-targeted chaperone vaccines including one that was recently evaluated in melanoma patients. We show that short hairpin RNA-mediated SRA silencing significantly enhances the immunogenicity of DCs that have captured chaperone vaccines designed to target melanoma (i.e., hsp110-gp100) and breast cancer (i.e., hsp110-HER/Neu-ICD). SRA downregulation results in heightened activation of antigen-specific T cells and increased CD8+ T cell-dependent tumor inhibition. Additionally, small interfering RNA (siRNA) complexed with the biodegradable, biocompatible chitosan as a carrier can efficiently reduce SRA expression on CD11c+ DCs in vitro and in vivo. Our proof-of-concept study shows that direct administration of the chitosan-siRNA complex to mice promotes chaperone vaccine-elicited cytotoxic T lymphocyte (CTL) response, culminating in improved eradication of experimental melanoma metastases. Targeting SRA with this chitosan-siRNA regimen combined with the chaperone vaccine also leads to reprogramming of the tumor environment, indicated by elevation of the cytokine genes (i.e., ifng, il12) known to skew Th1-like cellular immunity and increased tumor infiltration by IFN-γ+CD8+ CTLs as well as IL-12+CD11c+ DCs. Given the promising antitumor activity and safety profile of chaperone vaccine in cancer patients, further optimization of the chitosan-siRNA formulation to potentially broaden the immunotherapeutic benefits of chaperone vaccine is warranted.

The adaptation model of immunity: A new insight into aetiology and treatment of multiple sclerosis.

Current research and drug development for multiple sclerosis (MS) is fully influenced by the self-nonself (SNS) model of immunity, suggesting that breakage of immunological tolerance towards self-antigens expressed in the central nervous system (CNS) is responsible for pathogenesis of MS; thus, immune suppressive drugs are recommended for the management of the disease. However, this model provides incomplete understanding of the causes and pathways involved in the onset and progression of MS and limits our ability to effectively treat this neurological disease. Some pre-clinical and clinical reports have been misunderstood; some others have been underappreciated because of the lack of a theoretical model that can explain them. Also, current immunotherapies are guided according to the models that are not designed to explain the functional outcomes of an immune response. The adaptation model of immunity is proposed to offer a new understanding of the existing data and galvanize a new direction for the treatment of MS. According to this model, the immune system continuously communicates with the CNS through the adaptation receptors (AdRs) and adaptation ligands (AdLs) or co-receptors, signal IV, to support cell growth and neuroplasticity. Alterations in the expression of the neuronal AdRs results in MS by shifting the cerebral inflammatory immune responses from remyelination to demyelination. Therefore, novel therapeutics for MS should be focused on the discovery and targeting of the AdR/AdL axis in the CNS rather than carrying on with immune suppressive interventions.

Assessment of Knowledge, Attitudes, and Willingness Among People With and Without Heart Disease Relatives in Saudi Arabia Regarding Cardiopulmonary Resuscitation: A Cross-Sectional Study.

Background Cardiopulmonary resuscitation (CPR) is a life-saving procedure that can be performed in many situations where a person's breathing or heartbeat has stopped, such as during a heart attack, suffocation, near drowning, or electrical injuries. Despite its importance, to our knowledge, no research has been conducted yet in our community on the differences in CPR knowledge, attitudes, and willingness between those with and without heart disease relatives. Objective This study aimed to assess the level of knowledge, attitude, and willingness of people with and without heart disease relatives to perform CPR in a case of cardiac arrest. Methods A descriptive cross-sectional study was carried out between July 2023 and October 2023 among the Saudi Arabia population using a self-administered online questionnaire focusing on the sociodemographic characteristics of participants and the level of knowledge, attitude toward CPR, and the willingness to perform CPR in a case of cardiac arrest. Results This study included 799 participants, with 331 males (41.4%) and 468 females (58.6%). Age distribution was mainly in the range of 18-25 years (241 participants, 30.2%). Geographically, the highest proportion was from the southern region (214 participants, 26.8%). The majority had a university degree (533 participants, 66.7%). Employment status varied, with 401 participants (50.2%) working outside the medical field. Monthly income showed that 297 (37.2%) had an income ranging from 2,000 to 10,000 SAR. The average daily sleep duration varied, with the majority (64.7%) reporting six to nine hours of sleep. Also, 44.2% of participants reported exercising. Regarding smoking status, 80.9% reported not smoking. A family history of heart disease was reported by 46.4% of participants, whereas 16.3% reported a personal diagnosis of heart disease. Regarding knowledge, 40.8% correctly identified when CPR should be performed. Only 40.4% correctly identified the first step in a CPR situation, and only 22.9% identified the correct sequence of steps for performing CPR. Additionally, only 66.5% correctly identified the emergency hotline number "Red Crescent." Furthermore, only 8.9% knew the correct compression/ventilation ratio for adults during CPR. As for the attitude, a significant percentage (65.0%) had not taken a CPR course. However, the majority (84.6%) expressed a strong desire to learn CPR. Interestingly, the participants showed a positive attitude toward CPR education. Among the participants, 53.9% responded that they performed CPR when encountering a situation that required it, while 46.1% did not. Regarding the participants' willingness to perform CPR on different individuals, the majority (74.1%) expressed their readiness to perform CPR whenever needed. Conclusion The findings demonstrated knowledge gaps, with misconceptions about CPR. However, participants generally expressed a positive attitude toward CPR education and a willingness to learn. Factors such as age showed a weak association with knowledge level, while gender, region, education, employment, and family history of heart disease did not significantly impact knowledge. The study highlighted the need for improved CPR education and awareness. Hence, we recommend CPR courses to be implemented as a graduation prerequisite. In addition to that, linking some government services to a first aid course would positively impact the general population's practices in CPR and other emergencies.

Restoration of CD4+ T Cells during NAFLD without Modulation of the Hepatic Immunological Pattern Is Not Sufficient to Prevent HCC.

Predominant inflammatory immunological patterns as well as the depletion of CD4+ T cells during nonalcoholic fatty liver disease (NAFLD) are reported to be associated with the progression of hepatocellular carcinoma (HCC). Here, we report that an LRP-1 agonistic peptide, SP16, when administered during advanced NAFLD progression, restored the depleted CD4+ T cell population but did not significantly affect the inflammatory immunological pattern. This data suggests that restoration of CD4+ T cells without modulation of the hepatic immunological pattern is not sufficient to prevent HCC. However, SP16 administered early during NAFLD progression modulated the inflammatory profile. Future studies will determine if regulation of the inflammatory immune response by SP16 early in NAFLD progression will prevent HCC.

The adaptation model of immunity: Is the goal of central tolerance to eliminate defective T cells or self-reactive T cells?

The self-non-self model and the danger model are designed to understand how an immune response is induced. These models are not meant to predict if an immune response may succeed or fail in destroying/controlling its target. However, these immunological models rely on either self-antigens or self-dendritic cells for understanding of central tolerance, which have been discussed by Fuchs and Matzinger in response to Al-Yassin. In an attempt to address some questions that these models are facing when it comes to understanding central tolerance, I propose that the goal of negative selection in the thymus is to eliminate defective T cells but not self-reactive T cells. Therefore, any escape from negative selection could increase lymphopenia because of the depletion of defective naïve T cells outside the thymus, as seen in the elderly.

Distinct hepatic immunological patterns are associated with the progression or inhibition of hepatocellular carcinoma.

To discover distinct immune responses promoting or inhibiting hepatocellular carcinoma (HCC), we perform a three-dimensional analysis of the immune cells, correlating immune cell types, interactions, and changes over time in an animal model displaying gender disparity in nonalcoholic fatty liver disease (NAFLD)-associated HCC. In response to a Western diet (WD), animals mount acute and chronic patterns of inflammatory cytokines, respectively. Tumor progression in males and females is associated with a predominant CD8+ > CD4+, Th1 > Th17 > Th2, NKT > NK, M1 > M2 pattern in the liver. A complete rescue of females from HCC is associated with an equilibrium Th1 = Th17 = Th2, NKT = NK, M1 = M2 pattern, while a partial rescue of males from HCC is associated with an equilibrium CD8+ = CD4+, NKT = NK and a semi-equilibrium Th1 = Th17 > Th2 but a sustained M1 > M2 pattern in the liver. Our data suggest that immunological pattern-recognition can explain immunobiology of HCC and guide immune modulatory interventions for the treatment of HCC in a gender-specific manner.

Pattern recognition of tumor dormancy and relapse beyond cell-intrinsic and cell-extrinsic pathways.

In this thematic issue, several mechanisms of tumor dormancy and relapse are discussed. The reviews suggest mutual interactions and communications between malignant cells and other cells in their niche during tumor dormancy. Nevertheless, a complete understanding of tumor dormancy remains elusive. This is because we are getting lost in details of cell-intrinsic and cell-extrinsic molecular pathways without being able to discover the pattern of tumor dormancy. Here, we discuss some conceptual frameworks and methodological approaches that facilitate pattern recognition of tumor dormancy, and propose that settling on certain biological scale such as mitochondria would be the key to discover the pattern of tumor dormancy and relapse.

Multifaceted functions of chronic inflammation in regulating tumor dormancy and relapse.

Inflammation is a double-edged sword exhibiting multifaceted functions. On one hand, it either induces tumor cell apoptosis, or establishes tumor dormancy by inhibiting tumor cell proliferation; on the other hand, it either facilitates the tumorigenesis process or reawakens dormant tumor cells, resulting in disease recurrences. Each outcome would depend on the balance between type I and type II inflammation as well as the duration of inflammation being acute or chronic. In this essay, we provide a critical review of the empirical evidence suggesting that chronic inflammation, dominated by type I inflammatory cells and cytokines as a result of trauma and microbiome dysbiosis, could facilitate the carcinogenesis process in normal cells and retain nascent transformed cells in a dormant state. On the other hand, an elevated type II inflammation along with inefficient resolution of type I inflammation following trauma or major surgeries could delay the wound healing process and promote the growth and reawakening of dormant tumor cells, resulting in disease recurrences. Finally, cytokines exhibiting type I and II inflammatory functions, simultaneously, tend to promote tumor recurrence when become chronic. Therefore, the risk of reawakening dormant tumor cells should be considered in cancer survivors who experience major surgeries and trauma, or suffer from chronic inflammatory diseases.

Engineering T Cells to Express Tumoricidal MDA-7/IL24 Enhances Cancer Immunotherapy.

Antigen-specific immunotherapy can be limited by induced tumor immunoediting (e.g., antigen loss) or through failure to recognize antigen-negative tumor clones. Melanoma differentiation-associated gene-7/IL24 (MDA-7/IL24) has profound tumor-specific cytotoxic effects in a broad spectrum of cancers. Here we report the enhanced therapeutic impact of genetically engineering mouse tumor-reactive or antigen-specific T cells to produce human MDA-7/IL24. While mock-transduced T cells only killed antigen-expressing tumor cells, MDA-7/IL24-producing T cells destroyed both antigen-positive and negative cancer targets. MDA-7/IL24-expressing T cells were superior to their mock-engineered counterparts in suppressing mouse prostate cancer and melanoma growth as well as metastasis. This enhanced antitumor potency correlated with increased tumor infiltration and expansion of antigen-specific T cells as well as induction of a Th1-skewed immunostimulatory tumor environment. MDA-7/IL24-potentiated T-cell expansion was dependent on T-cell-intrinsic STAT3 signaling. Finally, MDA-7/IL24-modified T-cell therapy significantly inhibited progression of spontaneous prostate cancers in Hi-Myc transgenic mice. Taken together, arming T cells with tumoricidal and immune-potentiating MDA-7/IL24 confers new capabilities of eradicating antigen-negative cancer cell clones and improving T-cell expansion within tumors. This promising approach may be used to optimize cellular immunotherapy for treating heterogeneous solid cancers and provides a mechanism for inhibiting tumor escape. SIGNIFICANCE: This research describes a novel strategy to overcome the antigenic heterogeneity of solid cancers and prevent tumor escape by engineering T lymphocytes to produce a broad-spectrum tumoricidal agent.

Distal Transradial Access for Diagnostic Cerebral Angiography and Neurointervention: Systematic Review and Meta-analysis.

BACKGROUND: Radial artery access for cerebral angiography is traditionally performed in the wrist. Distal transradial access in the anatomic snuffbox is an alternative with several advantages. PURPOSE: Our aim was to review the safety and efficacy of distal transradial access for diagnostic cerebral angiography and neurointerventions. DATA SOURCES: We performed a comprehensive search of the literature using PubMed, Scopus, and EMBASE. STUDY SELECTION: The study included all case series of at least 10 patients describing outcomes associated with distal transradial access for diagnostic cerebral angiography or a neurointervention. DATA ANALYSIS: Random-effects models were used to obtain pooled rates of procedural success and complications. DATA SYNTHESIS: A total of 7 studies comprising 348 (75.8%) diagnostic cerebral angiograms and 111 (24.2%) interventions met the inclusion criteria. The pooled success rate was 95% (95% CI, 91%-98%; I2 = 74.33). The pooled minor complication rate was 2% (95% CI, 1%-4%; I2 = 0. No major complications were reported. For diagnostic procedures, the combined mean fluoroscopy time was 13.53 [SD, 8.82] minutes and the mean contrast dose was 74.9 [SD, 35.6] mL. LIMITATIONS: A small number of studies met the inclusion criteria, all of them were retrospective, and none compared outcomes with proximal transradial or femoral access. CONCLUSIONS: Early experience with distal transradial access suggests that it is a safe and effective alternative to proximal radial and femoral access for performing diagnostic cerebral angiography and interventions. Additional studies are needed to establish its efficacy and compare it with other access sites.