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"Kevin Bray"
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Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy
Macroautophagy is a key stress-response pathway that can suppress or promote tumorigenesis depending on the cellular context. Notably, Kirsten rat sarcoma (KRAS)-driven tumors have been reported to rely on macroautophagy for growth and survival, suggesting a potential therapeutic approach of using autophagy inhibitors based on genetic stratification. In this study, we evaluated whether KRAS mutation status can predict the efficacy to macroautophagy inhibition. By profiling 47 cell lines with pharmacological and genetic loss-of-function tools, we were unable to confirm that KRAS-driven tumor lines require macroautophagy for growth. Deletion of autophagy-related 7 (ATG7) by genome editing completely blocked macroautophagy in several tumor lines with oncogenic mutations in KRAS but did not inhibit cell proliferation in vitro or tumorigenesis in vivo. Furthermore, ATG7 knockout did not sensitize cells to irradiation or to several anticancer agents tested. Interestingly, ATG7-deficient and -proficient cells were equally sensitive to the antiproliferative effect of chloroquine, a lysosomotropic agent often used as a pharmacological tool to evaluate the response to macroautophagy inhibition. Moreover, both cell types manifested synergistic growth inhibition when treated with chloroquine plus the tyrosine kinase inhibitors erlotinib or sunitinib, suggesting that the antiproliferative effects of chloroquine are independent of its suppressive actions on autophagy.
Journal Article
Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning
T-cell-redirecting bispecific antibodies have emerged as a new class of therapeutic agents designed to simultaneously bind to T cells via CD3 and to tumor cells via tumor-cell-specific antigens (TSA), inducing T-cell-mediated killing of tumor cells. The promising preclinical and clinical efficacy of TSAxCD3 antibodies is often accompanied by toxicities such as cytokine release syndrome due to T-cell activation. How the efficacy and toxicity profile of the TSAxCD3 bispecific antibodies depends on the binding affinity to CD3 remains unclear. Here, we evaluate bispecific antibodies that were engineered to have a range of CD3 affinities, while retaining the same binding affinity for the selected tumor antigen. These agents were tested for their ability to kill tumor cells in vitro, and their biodistribution, serum half-life, and anti-tumor activity in vivo. Remarkably, by altering the binding affinity for CD3 alone, we can generate bispecific antibodies that maintain potent killing of TSA + tumor cells but display differential patterns of cytokine release, pharmacokinetics, and biodistribution. Therefore, tuning CD3 affinity is a promising method to improve the therapeutic index of T-cell-engaging bispecific antibodies.
Journal Article
Allogeneic CD20‐targeted γδ T cells exhibit innate and adaptive antitumor activities in preclinical B‐cell lymphoma models
Objectives Autologous chimeric antigen receptor (CAR) αβ T‐cell therapies have demonstrated remarkable antitumor efficacy in patients with haematological malignancies; however, not all eligible cancer patients receive clinical benefit. Emerging strategies to improve patient access and clinical responses include using premanufactured products from healthy donors and alternative cytotoxic effectors possessing intrinsic tumoricidal activity as sources of CAR cell therapies. γδ T cells, which combine innate and adaptive mechanisms to recognise and kill malignant cells, are an attractive candidate platform for allogeneic CAR T‐cell therapy. Here, we evaluated the manufacturability and functionality of allogeneic peripheral blood‐derived CAR+ Vδ1 γδ T cells expressing a second‐generation CAR targeting the B‐cell‐restricted CD20 antigen. Methods Donor‐derived Vδ1 γδ T cells from peripheral blood were ex vivo‐activated, expanded and engineered to express a novel anti‐CD20 CAR. In vitro and in vivo assays were used to evaluate CAR‐dependent and CAR‐independent antitumor activities of CD20 CAR+ Vδ1 γδ T cells against B‐cell tumors. Results Anti‐CD20 CAR+ Vδ1 γδ T cells exhibited innate and adaptive antitumor activities, such as in vitro tumor cell killing and proinflammatory cytokine production, in addition to in vivo tumor growth inhibition of B‐cell lymphoma xenografts in immunodeficient mice. Furthermore, CD20 CAR+ Vδ1 γδ T cells did not induce xenogeneic graft‐versus‐host disease in immunodeficient mice. Conclusion These preclinical data support the clinical evaluation of ADI‐001, an allogeneic CD20 CAR+ Vδ1 γδ T cell, and a phase 1 study has been initiated in patients with B‐cell malignancies (NCT04735471). The findings of our study demonstrate preclinical proof of concept for a CD20 CAR+ Vδ1 γδ T‐cell product, manufactured at clinical scale, in the treatment of CD20+ B‐cell malignancies. Complemented by innate and adaptive antitumor immunity, CD20 CAR+ Vδ1 γδ T cells have a unique advantage as an allogeneic CAR T‐cell product platform and, as a consequence, have the potential to improve clinical responses in eligible cancer patients. A phase 1 clinical study evaluating ADI‐001, an allogeneic CD20 CAR+ Vδ1 γδ T‐cell product, in relapsed/refractory B‐cell NHL patients has been initiated (NCT04735471).
Journal Article
Glutamine deprivation stimulates mTOR-JNK-dependent chemokine secretion
The non-essential amino acid, glutamine, exerts pleiotropic effects on cell metabolism, signalling and stress resistance. Here we demonstrate that short-term glutamine restriction triggers an endoplasmic reticulum (ER) stress response that leads to production of the pro-inflammatory chemokine, interleukin-8 (IL-8). Glutamine deprivation-induced ER stress triggers colocalization of autophagosomes, lysosomes and the Golgi into a subcellular structure whose integrity is essential for IL-8 secretion. The stimulatory effect of glutamine restriction on IL-8 production is attributable to depletion of tricarboxylic acid cycle intermediates. The protein kinase, mTOR, is also colocalized with the lysosomal membrane clusters induced by glutamine deprivation, and inhibition of mTORC1 activity abolishes both endomembrane reorganization and IL-8 secretion. Activated mTORC1 elicits
IL8
gene expression via the activation of an IRE1-JNK signalling cascade. Treatment of cells with a glutaminase inhibitor phenocopies glutamine restriction, suggesting that these results will be relevant to the clinical development of glutamine metabolism inhibitors as anticancer agents.
Glutamine deprivation is currently being tested as a therapeutic strategy in cancer. Shanware
et al.
show that in cultured cells, glutamine deprivation stimulates IL-8 secretion by triggering endoplasmic reticulum stress, and suggest that the potential of this effect to influence tumour development should be examined.
Journal Article
Young patient with thunderclap headache, seizure activity, and fixed eye deviation
PATIENT PRESENTATION A 39-year-old female with a history of iron deficiency anemia presented to the emergency department (ED) with a 3-hour history of severe headache followed by acute-onset projectile non-bilious, non-bloody vomiting, acute mental status change, and seizure-like activity. Initial laboratory test results were significant for anemia (hemoglobin = 5.2 g/dL, hematocrit = 21%) and elevated platelets (426.5). Continued hypoperfusion can result in ischemic tissue damage, resulting in acute neurologic symptoms such as seizures, headaches, altered mental status, and increased intracranial pressure.
Journal Article
Atomic-scale oxygen-vacancy engineering in Sub-2 nm thin Al2O3/MgO memristors
Ultrathin (sub-2 nm) Al2O3/MgO memristors were recently developed using an in vacuo atomic layer deposition (ALD) process that minimizes unintended defects and prevents undesirable leakage current. These memristors provide a unique platform that allows oxygen vacancies (VO) to be inserted into the memristor with atomic precision and study how this affects the formation and rupture of conductive filaments (CFs) during memristive switching. Herein, we present a systematic study on three sets of ultrathin Al2O3/MgO memristors with VO-doping via modular MgO atomic layer insertion into an otherwise pristine insulating Al2O3 atomic layer stack (ALS) using an in vacuo ALD. At a fixed memristor thickness of 17 Al2O3/MgO atomic layers (∼1.9 nm), the properties of the memristors were found to be affected by the number and stacking pattern of the MgO atomic layers in the Al2O3/MgO ALS. Importantly, the trend of reduced low-state resistance and the increasing appearance of multi-step switches with an increasing number of MgO atomic layers suggests a direct correlation between the dimension and dynamic evolution of the conducting filaments and the VO concentration and distribution. Understanding such a correlation is critical to an atomic-scale control of the switching behavior of ultrathin memristors.
Journal Article
Perceptions of the Emergency Medicine Resident Selection Process by Program Directors Following the Transition to a Pass/Fail USMLE Step 1
Beginning January 26th, 2022, the National Board of Medical Examiners transitioned scoring of the United States Medical Licensing Examination (USMLE) Step 1 from a 3-digit score to pass/fail. In the past, the Step 1 score has been weighted heavily by program directors (PDs) as one of the most important metrics when assessing medical student's competitiveness.
The objective of this study was to evaluate the perceptions of emergency medicine (EM) PDs on the transition to a pass/fail USMLE Step 1 exam, and to elicit the opinions of EM PDs on the USMLE examinations' ability to predict resident performance.
A survey consisting of ranking and multiple-choice questions was sent to EM PDs. The multiple-choice questions were asked to determine EM PDs level of confidence in the ability of Step 1 and Step 2 Clinical Knowledge (CK) to predict a student's ability to succeed in residency. The ranking questions focused on assessing each program's current resident selection practices in comparison to expected selection criteria changes following a transition to pass/fail Step 1. R studio and MATLAB were used for statistical analysis, and a P value <0.05 was considered significant.
The survey was completed by 57 (20.21%) EM PDs. When asked if Step 1 and Step 2 CK are accurate predictors of a resident's ability to perform clinically within EM, only 10.5% of PDs answered 'yes' to Step 1 being predictive, compared to 31.6% for Step 2 CK. Regarding selection criteria, the top quartile of attributes (standardized letters of evaluation [1st], away rotations [2nd], clerkship grades [3rd] and Step 2 CK score [4th]) remained the same following the transition.
Our results indicate that the top quartile of attributes might remain the same, despite most PDs agreeing that Step 2 CK is a better predictor of a resident's performance.
Journal Article
Autophagy Suppresses RIP Kinase-Dependent Necrosis Enabling Survival to mTOR Inhibition
mTOR inhibitors are used clinically to treat renal cancer but are not curative. Here we show that autophagy is a resistance mechanism of human renal cell carcinoma (RCC) cell lines to mTOR inhibitors. RCC cell lines have high basal autophagy that is required for survival to mTOR inhibition. In RCC4 cells, inhibition of mTOR with CCI-779 stimulates autophagy and eliminates RIP kinases (RIPKs) and this is blocked by autophagy inhibition, which induces RIPK- and ROS-dependent necroptosis in vitro and suppresses xenograft growth. Autophagy of mitochondria is required for cell survival since mTOR inhibition turns off Nrf2 antioxidant defense. Thus, coordinate mTOR and autophagy inhibition leads to an imbalance between ROS production and defense, causing necroptosis that may enhance cancer treatment efficacy.
Journal Article
Atomic-scale oxygen-vacancy engineering in Sub-2 nm thin Al 2 O 3 /MgO memristors
Ultrathin (sub-2 nm) Al 2 O 3 /MgO memristors were recently developed using an in vacuo atomic layer deposition (ALD) process that minimizes unintended defects and prevents undesirable leakage current. These memristors provide a unique platform that allows oxygen vacancies (V O ) to be inserted into the memristor with atomic precision and study how this affects the formation and rupture of conductive filaments (CFs) during memristive switching. Herein, we present a systematic study on three sets of ultrathin Al 2 O 3 /MgO memristors with V O -doping via modular MgO atomic layer insertion into an otherwise pristine insulating Al 2 O 3 atomic layer stack (ALS) using an in vacuo ALD. At a fixed memristor thickness of 17 Al 2 O 3 /MgO atomic layers (∼1.9 nm), the properties of the memristors were found to be affected by the number and stacking pattern of the MgO atomic layers in the Al 2 O 3 /MgO ALS. Importantly, the trend of reduced low-state resistance and the increasing appearance of multi-step switches with an increasing number of MgO atomic layers suggests a direct correlation between the dimension and dynamic evolution of the conducting filaments and the V O concentration and distribution. Understanding such a correlation is critical to an atomic-scale control of the switching behavior of ultrathin memristors.
Journal Article