Immune mechanisms in the pathophysiology of hypertension.

Hypertension is a leading risk factor for morbidity and mortality worldwide. Despite current anti-hypertensive therapies, most individuals with hypertension fail to achieve adequate blood pressure control. Moreover, even with adequate control, a residual risk of cardiovascular events and associated organ damage remains. These findings suggest that current treatment modalities are not addressing a key element of the underlying pathology. Emerging evidence implicates immune cells as key mediators in the development and progression of hypertension. In this Review, we discuss our current understanding of the diverse roles of innate and adaptive immune cells in hypertension, highlighting key findings from human and rodent studies. We explore mechanisms by which these immune cells promote hypertensive pathophysiology, shedding light on their multifaceted involvement. In addition, we highlight advances in our understanding of autoimmunity, HIV and immune checkpoints that provide valuable insight into mechanisms of chronic and dysregulated inflammation in hypertension.

Impact and utility of follicular lymphoma GELF criteria in routine care: an Australasian Lymphoma Alliance study.

Follicular Lymphoma (FL) treatment initiation is largely determined by tumor burden and symptoms. In the pre-rituximab era, the Group d'Etude des Lymphomes Folliculaires (GELF) developed widely adopted criteria to identify high tumor burden FL patients to harmonize clinical trial populations. The utilization of GELF criteria (GELFc) in routine therapeutic decision-making is poorly described. This multicenter retrospective study evaluated patterns of GELFc at presentation and GELFc utilization in therapeutic decision-making in newly diagnosed, advanced stage rituximab-era FL. Associations between GELFc, treatment given, and patient survival were analyzed in 300 eligible cases identified between 2002-2019. 163 (54%) had ≥1 GELFc at diagnosis. The presence or cumulative number of GELFc did not predict PFS in patients undergoing watch-and-wait (WW) or those receiving systemic treatment. Of interest, in patients with ≥1 GELFc, 16/163 (10%) underwent initial watch-and-wait (comprising 22% of the watchand- wait cohort). In those receiving systemic therapy +/- radiotherapy, 74/215 (34%) met no GELFc. Our data suggest clinicians are using adjunctive measures to make decisions regarding treatment initiation in a significant proportion of patients. By restricting FL clinical trial eligibility only to those meeting GELFc, reported outcomes may not be applicable to a significant proportion of patients treated in routine care settings.

Modulating T Cell Phenotype and Function to Treat Hypertension.

Hypertension is the leading modifiable risk factor of worldwide morbidity and mortality because of its effects on cardiovascular and renal end-organ damage. Unfortunately, BP control is not sufficient to fully reduce the risks of hypertension, underscoring the need for novel therapies that address end-organ damage in hypertension. Over the past several decades, the link between immune activation and hypertension has been well established, but there are still no therapies for hypertension that specifically target the immune system. In this review, we describe the critical role played by T cells in hypertension and hypertensive end-organ damage and outline potential therapeutic targets to modulate T-cell phenotype and function in hypertension without causing global immunosuppression.

Amplification of the CXCR3/CXCL9 axis via intratumoral electroporation of plasmid CXCL9 synergizes with plasmid IL-12 therapy to elicit robust anti-tumor immunity.

Clinical studies have demonstrated that local expression of the cytokine IL-12 drives interferon-gamma expression and recruits T cells to the tumor microenvironment, ultimately yielding durable systemic T cell responses. Interrogation of longitudinal biomarker data from our late-stage melanoma trials identified a significant on-treatment increase of intratumoral CXCR3 transcripts that was restricted to responding patients, underscoring the clinical relevance of tumor-infiltrating CXCR3+ immune cells. In this study, we sought to understand if the addition of DNA-encodable CXCL9 could augment the anti-tumor immune responses driven by intratumoral IL-12. We show that localized IL-12 and CXCL9 treatment reshapes the tumor microenvironment to promote dendritic cell licensing and CD8+ T cell activation. Additionally, this combination treatment results in a significant abscopal anti-tumor response and provides a concomitant benefit to anti-PD-1 therapies. Collectively, these data demonstrate that a functional tumoral CXCR3/CXCL9 axis is critical for IL-12 anti-tumor efficacy. Furthermore, restoring or amplifying the CXCL9 gradient in the tumors via intratumoral electroporation of plasmid CXCL9 can not only result in efficient trafficking of cytotoxic CD8+ T cells into the tumor but can also reshape the microenvironment to promote systemic immune response.

Intratumoral Electroporation of Plasmid Encoded IL12 and Membrane-Anchored Anti-CD3 Increases Systemic Tumor Immunity.

Intratumoral delivery of plasmid IL12 via electroporation (IT-tavo-EP) induces localized expression of IL12 leading to regression of treated and distant tumors with durable responses and minimal toxicity. A key driver in amplifying this local therapy into a systemic response is the magnitude and composition of immune infiltrate in the treated tumor. While intratumoral IL12 typically increases the density of CD3+ tumor-infiltrating lymphocytes (TIL), this infiltrate is composed of a broad range of T-cell subsets, including activated tumor-specific T cells, less functional bystander T cells, as well as suppressive T regulatory cells. To encourage a more favorable on-treatment tumor microenvironment (TME), we explored combining this IL12 therapy with an intratumoral polyclonal T-cell stimulator membrane-anchored anti-CD3 to productively engage a diverse subset of lymphocytes including the nonreactive and suppressive T cells. This study highlighted that combined intratumoral electroporation of IL12 and membrane-anchored anti-CD3 plasmids can enhance cytokine production, T-cell cytotoxicity, and proliferation while limiting the suppressive capacity within the TME. These collective antitumor effects not only improve regression of treated tumors but drive systemic immunity with control of nontreated contralateral tumors in vivo. Moreover, combination of IL12 and anti-CD3 restored the function of TIL isolated from a patient with melanoma actively progressing on programmed cell death protein 1 (PD-1) checkpoint inhibitor therapy. IMPLICATIONS: This DNA-encodable polyclonal T-cell stimulator (membrane-anchored anti-CD3 plasmid) may represent a key addition to intratumoral IL12 therapies in the clinic.

Osteoporosis: A Small-Group Case-Based Learning Activity.

INTRODUCTION: Osteoporosis is the most common bone disease in the world. Approximately 50% of women and 20% of men over 50 will suffer an osteoporosis-related fracture. Future health care providers must be equipped to prevent, recognize, and treat osteoporosis-related fractures. METHODS: To supplement instruction on osteoporosis, we designed a case-based session. Groups of 10-12 second-year medical students worked with a single facilitator in a roundtable discussion. The 120-minute session integrated foundational sciences (pathology, physiology, pharmacology) and clinical disciplines (clinical skills, radiology, geriatrics, evidence-based medicine). Knowledge gains were assessed by performance on nine session-relevant multiple-choice questions (MCQs) on the final exam. Student satisfaction was assessed by an anonymous postsession survey. RESULTS: There were 121 students that participated, and their average performance on nine session-relevant final exam MCQs was 84%. After removal of a single outlier MCQ (15% correct), average performance on the remaining eight MCQs was 93%. A total of 107 students (88%) responded to the postsession survey. On a 5-point Likert scale, 101 of 107 students (94%) agreed or strongly agreed with the statement "The basic science-clinical combination lecture on osteoporosis followed by the small-group case discussion on osteoporosis prepared me adequately to understand the topic" (M = 4.56, SD = 0.63). DISCUSSION: We developed a case-based learning activity for preclinical medical students to enhance the clinical scaffolding of basic science and medical knowledge around osteoporosis. Students performed well on session-relevant exam questions, demonstrating competency in the educational objectives. Student satisfaction was high, with most students feeling well prepared.

Conservative Management of Placenta Accreta Using Helium Plasma Focused Radiofrequency Energy: A Surgical Technique.

The incidence of abnormal placentation has escalated due to the increase in cesarean sections. Adherent placentas are associated with significant maternal morbidity and mortality and often result in cesarean hysterectomy due to life-threatening hemorrhage. The purpose of these case reports is to describe conservative management of placenta accreta by utilizing a helium plasma device to fulgurate the placental bed. Placenta accreta is associated with a 7% mortality rate and 60% morbidity rate. Conservative treatment for uterine preservation include embolization, placenta left in-situ, uterine balloon tamponade, and methotrexate. Complications of these options include hemorrhage, endometritis, and morbidly adherent placentas (MAP) recurrence in subsequent pregnancies. The helium plasma device utilizes radiofrequency (RF) to ionize helium into a plasma beam capable of coagulating and fulgurating tissue with high precision and minimal thermal spread. This instrument is Food and Drug Administration (FDA) approved for surgical coagulation and fulguration, but has not been evaluated in the treatment of placenta accreta at the time of a cesarean section. The helium plasma device was used to fulgurate the placenta accreta at 40% power 4 L/min gas flow for 30 seconds, providing adequate hemostasis to the 12.76 cc of retained placental bed. Estimated blood loss was 560 cc. The patient remained hemodynamically stable and had no complications at follow up. The device provided efficient management of placenta accreta. This approach offers a safer alternative management of abnormal placentation and avoiding a cesarean hysterectomy. This novel surgical technique allows women with morbidly adherent placentas to maintain reproductive capability.

Quantitative Interactome Proteomics Reveals a Molecular Basis for ATF6-Dependent Regulation of a Destabilized Amyloidogenic Protein.

Activation of the unfolded protein response (UPR)-associated transcription factor ATF6 has emerged as a promising strategy to reduce the secretion and subsequent toxic aggregation of destabilized, amyloidogenic proteins implicated in systemic amyloid diseases. However, the molecular mechanism by which ATF6 activation reduces the secretion of amyloidogenic proteins remains poorly defined. We employ a quantitative interactomics platform to define how ATF6 activation reduces secretion of a destabilized, amyloidogenic immunoglobulin light chain (LC) associated with light-chain amyloidosis (AL). Using this platform, we show that ATF6 activation increases the targeting of this destabilized LC to a subset of pro-folding ER proteostasis factors that retains the amyloidogenic LC within the ER, preventing its secretion. Our results define a molecular basis for the ATF6-dependent reduction in destabilized LC secretion and highlight the advantage for targeting this UPR-associated transcription factor to reduce secretion of destabilized, amyloidogenic proteins implicated in AL and related systemic amyloid diseases.

Prospective comparison of valve regurgitation quantitation by cardiac magnetic resonance imaging and transthoracic echocardiography.

BACKGROUND: Both transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) imaging allow quantification of chronic aortic regurgitation (AR) and mitral regurgitation (MR). We hypothesized that CMR measurement of regurgitant volume (RVol) is more reproducible than TTE. METHODS AND RESULTS: TTE and CMR performed on the same day in 57 prospectively enrolled adults (31 with AR, 26 with MR) were measured by 2 independent physicians. TTE RVol(AR) was calculated as Doppler left ventricular outflow minus inflow stroke volume. RVol(MR) was calculated by both the proximal isovelocity surface area method and Doppler volume flow at 2 sites. CMR RVol(AR) was calculated by phase-contrast velocity mapping at the aortic sinuses and RVol(MR) as total left ventricular minus forward stroke volume. Intraobserver and interobserver variabilities were similar. For AR, the Bland-Altman mean interobserver difference in RVol was -0.7 mL (95% confidence interval [CI], -5 to 4) for CMR and -9 mL (95% CI, -53 to -36) for TTE. The Pearson correlation was higher (P=0.001) between CMR (0.99) than TTE readers (0.89). For MR, the Bland-Altman mean difference in RVol between observers was -4 mL (95% CI, -21 to 13) for CMR compared with 0.7 mL (95% CI, -30 to 32) for the proximal isovelocity surface area and -10 mL (95% CI, -76 to 56) for TTE volume flow at 2 sites. Correlation was similar for CMR (0.94) versus TTE readers (0.90 for the proximal isovelocity surface area). CONCLUSIONS: Compared with TTE, CMR has lower intraobserver and interobserver variabilities for RVol(AR), suggesting CMR may be superior for serial measurements. Although RVol(MR) is similar by TTE and CMR, variability in measured RVol by both approaches suggests that caution is needed in clinical practice.