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"Chang, Jason"
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Enhanced CAR–T cell activity against solid tumors by vaccine boosting through the chimeric receptor
Chimeric antigen receptor–Tcell (CAR-T) therapy has been effective in the treatment of hematologic malignancies, but it has shown limited efficacy against solid tumors. Here we demonstrate an approach to enhancing CAR-T function in solid tumors by directly vaccine-boosting donor cells through their chimeric receptor in vivo. We designed amphiphile CAR-T ligands (amph-ligands) that, upon injection, trafficked to lymph nodes and decorated the surfaces of antigen-presenting cells, thereby priming CAR-Ts in the native lymph node microenvironment. Amph-ligand boosting triggered massive CAR-Texpansion, increased donor cell polyfunctionality, and enhanced antitumor efficacy in multiple immunocompetent mouse tumor models. We demonstrate two approaches to generalizing this strategy to any chimeric antigen receptor, enabling this simple non–human leukocyte antigen–restricted approach to enhanced CAR-T functionality to be applied to existing CAR-Tdesigns.
Journal Article
Innate immune recognition of glycans targets HIV nanoparticle immunogens to germinal centers
In vaccine design, antigens are often arrayed in a multivalent nanoparticle form, but in vivo mechanisms underlying the enhanced immunity elicited by such vaccines remain poorly understood. We compared the fates of two different heavily glycosylated HIV antigens, a gp120-derived mini-protein and a large, stabilized envelope trimer, in protein nanoparticle or “free” forms after primary immunization. Unlike monomeric antigens, nanoparticles were rapidly shuttled to the follicular dendritic cell (FDC) network and then concentrated in germinal centers in a complement-, mannose-binding lectin (MBL)–, and immunogen glycan–dependent manner. Loss of FDC localization in MBL-deficient mice or via immunogen deglycosylation significantly affected antibody responses. These findings identify an innate immune–mediated recognition pathway promoting antibody responses to particulate antigens, with broad implications for humoral immunity and vaccine design.
Journal Article
The Role of Matrix Metalloproteinase Polymorphisms in Ischemic Stroke
Stroke remains the fifth leading cause of mortality in the United States with an annual rate of over 128,000 deaths per year. Differences in incidence, pathogenesis, and clinical outcome have long been noted when comparing ischemic stroke among different ethnicities. The observation that racial disparities exist in clinical outcomes after stroke has resulted in genetic studies focusing on specific polymorphisms. Some studies have focused on matrix metalloproteinases (MMPs). MMPs are a ubiquitous group of proteins with extensive roles that include extracellular matrix remodeling and blood-brain barrier disruption. MMPs play an important role in ischemic stroke pathophysiology and clinical outcome. This review will evaluate the evidence for associations between polymorphisms in MMP-1, 2, 3, 9, and 12 with ischemic stroke incidence, pathophysiology, and clinical outcome. The role of polymorphisms in MMP genes may influence the presentation of ischemic stroke and be influenced by racial and ethnic background. However, contradictory evidence for the role of MMP polymorphisms does exist in the literature, and further studies will be necessary to consolidate our understanding of these multi-faceted proteins.
Journal Article
Circulating microRNAs as Potential Diagnostic and Prognostic Biomarkers in Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is the fifth most common cancer with high mortality, due to late diagnosis and limited treatment options. Blood miRNAs, which circulate in a highly stable, cell-free form, show promise as novel potential biomarkers for early detection of HCC. Whole miRNome profiling was performed to identify deregulated miRNAs between HCC and normal healthy (NH) volunteers. These deregulated miRNAs were validated in an independent cohort of HCC, NH and chronic Hepatitis B (CHB) volunteers and finally in a 3
rd
cohort comprising NH, CHB, cirrhotic and HCC volunteers to evaluate miRNA changes during disease progression. The associations between circulating miRNAs and liver-damage markers, clinicopathological characteristics and survival outcomes were analysed to identify prognostic markers. Twelve miRNAs are differentially expressed between HCC and NH individuals in all three cohorts. Five upregulated miRNAs (miR-122-5p, miR-125b-5p, miR-885-5p, miR-100-5p and miR-148a-3p) in CHB, cirrhosis and HCC patients are potential biomarkers for CHB infection, while miR-34a-5p can be a biomarker for cirrhosis. Notably, four miRNAs (miR-1972, miR-193a-5p, miR-214-3p and miR-365a-3p) can distinguish HCC from other non-HCC individuals. Six miRNAs are potential prognostic markers for overall survival.
Journal Article
Intratumourally injected alum-tethered cytokines elicit potent and safer local and systemic anticancer immunity
Anti-tumour inflammatory cytokines are highly toxic when administered systemically. Here, in multiple syngeneic mouse models, we show that the intratumoural injection of recombinantly expressed cytokines bound tightly to the common vaccine adjuvant aluminium hydroxide (alum) (via ligand exchange between hydroxyls on the surface of alum and phosphoserine residues tagged to the cytokine by an alum-binding peptide) leads to weeks-long retention of the cytokines in the tumours, with minimal side effects. Specifically, a single dose of alum-tethered interleukin-12 induced substantial interferon-γ-mediated T-cell and natural-killer-cell activities in murine melanoma tumours, increased tumour antigen accumulation in draining lymph nodes and elicited robust tumour-specific T-cell priming. Moreover, intratumoural injection of alum-anchored cytokines enhanced responses to checkpoint blockade, promoting cures in distinct poorly immunogenic syngeneic tumour models and eliciting control over metastases and distant untreated lesions. Intratumoural treatment with alum-anchored cytokines represents a safer and tumour-agnostic strategy to improving local and systemic anticancer immunity.
The intratumoural injection of recombinantly expressed cytokines bound tightly to the common vaccine adjuvant aluminium hydroxide leads to weeks-long retention of the cytokines in the tumours with minimal side effects, as shown in multiple syngeneic mouse models.
Journal Article
Engineered immunogen binding to alum adjuvant enhances humoral immunity
Adjuvants are central to the efficacy of subunit vaccines. Aluminum hydroxide (alum) is the most commonly used vaccine adjuvant, yet its adjuvanticity is often weak and mechanisms of triggering antibody responses remain poorly understood. We demonstrate that site-specific modification of immunogens with short peptides composed of repeating phosphoserine (pSer) residues enhances binding to alum and prolongs immunogen bioavailability. The pSer-modified immunogens formulated in alum elicited greatly increased germinal center, antibody, neutralizing antibody, memory and long-lived plasma cell responses compared to conventional alum-adsorbed immunogens. Mechanistically, pSer-immunogen:alum complexes form nanoparticles that traffic to lymph nodes and trigger B cell activation through multivalent and oriented antigen display. Direct uptake of antigen-decorated alum particles by B cells upregulated antigen processing and presentation pathways, further enhancing B cell activation. These data provide insights into mechanisms of action of alum and introduce a readily translatable approach to significantly improve humoral immunity to subunit vaccines using a clinical adjuvant.
Alum coupled to protein immunogens via site-specific phosphoserine-containing linkers enhances long-lived B cell responses and can selectively direct antibodies toward protective neutralizing epitopes.
Journal Article
Neurogenic stunned myocardium in subarachnoid hemorrhage
“Stunned myocardium,” characterized by reversible left ventricular dysfunction, was first described via animal models using transient coronary artery occlusion. However, this phenomenon has also been noted with neurologic pathologies and collectively been labeled “neurogenic stunned myocardium” (NSM). Neurogenic stunned myocardium resulting from subarachnoid hemorrhage (SAH) is a challenging pathology due to its diagnostic uncertainty. Traditional diagnostic criteria for NSM after SAH focus on electrocardiographic and echocardiographic abnormalities and troponemia. However, tremendous heterogeneity still exists. Traditional pathophysiological mechanisms for NSM encompassed hypothalamic and myocardial perivascular lesions. More recently, research on pathophysiology has centered on myocardial microvascular dysfunction and genetic polymorphisms. Catecholamine surging as a mechanism has also gained attention with particular focus placed on the role of adrenergic blockade in both the prehospital and acute settings. Management remains largely supportive with case reports acknowledging the utility of inotropes such as dobutamine and milrinone and intra-aortic balloon pump when NSM is accompanied by cardiogenic shock. Neurogenic stunned myocardium that follows SAH can result in many complications such as arrhythmias, pulmonary edema, and prolonged intubation, which can negatively impact long-term recovery from SAH and increase morbidity and mortality. This necessitates the need to accurately diagnose and treat NSM.
Journal Article
Minocycline for acute stroke treatment: a systematic review and meta-analysis of randomized clinical trials
BackgroundVarious randomized-controlled clinical trials (RCTs) have investigated the neuroprotective role of minocycline in acute ischemic stroke (AIS) or acute intracerebral hemorrhage (ICH) patients. We sought to consolidate and investigate the efficacy and safety of minocycline in patients with acute stroke.MethodsLiterature search spanned through November 30, 2017 across major databases to identify all RCTs that reported following efficacy outcomes among acute stroke patients treated with minocycline vs. placebo: National Institute of Health Stroke Scale (NIHSS), Barthel Index (BI), and modified Rankin Scale (mRS) scores. Additional safety, neuroimaging and biochemical endpoints were extracted. We pooled mean differences (MD) and risk ratios (RR) from RCTs using random-effects models.ResultsWe identified 7 RCTs comprising a total of 426 patients. Of these, additional unpublished data was obtained on contacting corresponding authors of 5 RCTs. In pooled analysis, minocycline demonstrated a favorable trend towards 3-month functional independence (mRS-scores of 0–2) (RR = 1.31; 95% CI 0.98–1.74, p = 0.06) and 3-month BI (MD = 6.92; 95% CI − 0.92, 14.75; p = 0.08). In AIS subgroup, minocycline was associated with higher rates of 3-month mRS-scores of 0–2 (RR = 1.59; 95% CI 1.19–2.12, p = 0.002; I2 = 58%) and 3-month BI (MD = 12.37; 95% CI 5.60, 19.14, p = 0.0003; I2 = 47%), whereas reduced the 3-month NIHSS (MD − 2.84; 95% CI − 5.55, − 0.13; p = 0.04; I2 = 86%). Minocycline administration was not associated with an increased risk of mortality, recurrent stroke, myocardial infarction and hemorrhagic conversion.ConclusionsAlthough data is limited, minocycline demonstrated efficacy and seems a promising neuroprotective agent in acute stroke patients, especially in AIS subgroup. Further RCTs are needed to evaluate the efficacy and safety of minocycline among ICH patients.
Journal Article
Ultrasound identification of the cementoenamel junction and clinical correlation through ex vivo analysis
Accurately identifying periodontal landmarks via acoustic imaging is increasingly important. Here, we evaluated the accuracy of cementoenamel junction (CEJ) identification using ultrasound by comparing it to clinical methods in 153 extracted human teeth. The distance between the CEJ to a reference point was measured using two clinical methods (visual examination and tactile sensation) as well as ultrasound imaging. Statistical analyses were performed across all teeth and sub-groups, including tooth types (incisors, cuspids, and molars/premolars), and two classifications: A- vs. B- (visually detectable or undetectable CEJ, respectively); and CL-S vs. CL-D (shallow or deep cervical lesions). In A- or CL-S teeth, ultrasound measurements highly agreed with clinical measurements, showing a 1.72-mm 95% CI for A- and 1.99-mm 95% CI for CL-S compared to visual examination, and a 1.77-mm 95% CI for A- and a 2.10-mm 95% CI for CL-S compared to tactile sensation, respectively. For 80% of A- and 76% of CL-S teeth, the difference between ultrasound and visual examination was within ± 20%. For 81% of A- and 80% of CL-S teeth, the difference between ultrasound and tactile sensation was within ± 20%. The variance of ultrasound versus clinical CEJ identifications showed a significant correlation (
r
= 0.6607) to the cervical lesion depth. The errors between ultrasound and clinical measurements show no significant bias across different tooth types.
Journal Article