Treg-driven tumour control by PI3Kδ inhibition limits myeloid-derived suppressor cell expansion.

BACKGROUND: Recent studies have demonstrated that blocking the PI3Kδ signalling enzyme (by administering a small molecule inhibitor, PI-3065) can potently improve the anti-tumour T-cell response through direct inhibition of Tregs. This treatment also has a negative impact on MDSC numbers but the primary mechanism driving this effect has remained unclear. METHODS: The 4T1 breast cancer mouse model was used in combination with PI-3065 to gain insights into the effect of PI3Kδ inhibition on MDSCs. RESULTS: PI-3065 treatment resulted in a concomitant reduction in MDSC expansion and tumour size. However, targeting Tregs independent of PI-3065 was also associated with reduced tumour volume and MDSC numbers. Surgical removal of tumours resulted in a rapid and significant decline in MDSC numbers, whilst ex vivo studies using cells from PI-3065-treated mice demonstrated no direct effect of the inhibitor on MDSC activity. CONCLUSIONS: Our data suggest that MDSCs are not inhibited directly by PI-3065 treatment but that their reduced recruitment and immunosuppression within the tumour microenvironment is an indirect consequence of PI3Kδ-inhibition-driven tumour control. This indicates that PI3Kδ inhibition drives tumour immunity by breaking down multiple immunosuppressive pathways through both direct mechanisms (on Treg) and indirect mechanisms, secondary to tumour control (on MDSCs).

Circumflex to Left Atrial Appendage Fistula Associated With Watchman FLX Closure Device.

An 82-year-old man who had undergone Watchman FLX (Boston Scientific) device implantation presented with dyspnea. Multimodality evaluation demonstrated a small fistula from the proximal circumflex artery to the left atrial appendage. Anatomically, the left circumflex artery is close to the atrial appendage; therefore, it is plausible that fistula formation could be a late complication of implantation of the device.

Complete percutaneous coronary revascularization: An elegant solution to left ventricular dysfunction caused by severe coronary artery disease.

With increased complexity in both medical comorbidities and coronary anatomy, the proportion of surgically turndown patients and high-risk PCI will continue to rise. Impella-assisted complex PCI can be performed with high technical success and can improve quality of life, angina score, and potentially left ventricular ejection fraction.

Cardiomyopathy in Celiac Disease: A Systematic Review.

(1) Background: Cardiomyopathy in celiac disease or celiac cardiomyopathy (CCM) is a serious and potentially life-threatening disease that can occur in both adults and children. However, data supporting the causal relationship between celiac disease (CD) and cardiomyopathy (CMP) are still inconsistent. The aim of this study was to review and synthesize data from the literature on this topic and potentially reveal a more evidence-based causal relationship. (2) Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to search Medline, Embase, and Scopus databases from database inception until September 2023. A total of 1187 original articles were identified. (3) Results: We identified 28 CCM patients (19 adult and 9 pediatric) with a mean age of 27.4 ± 18.01 years. Adult patients with CCM were predominantly male (84.2%) while pediatric patients were predominantly female (75%). The most common comorbidities associated with CCM were anemia (75%) and pulmonary hemosiderosis (20%). In 35% of patients, CCM occurred before the diagnosis of CD, while in 48% of patients, CCM and CD were diagnosed at the same time. Diagnosis of CD preceded diagnosis of CCM in only 18% of patients. Diagnosis of CCM is often delayed with an average, from the onset of symptoms to diagnosis, of 16 months. All patients were treated with a gluten-free diet in addition to guideline-directed medical therapy. At 11-month follow-up, cardiovascular improvement was seen in 60.7% of patients. Pediatric mortality was 33.3%, while adult mortality was 5.3%. (4) Conclusions: Clinicians should be aware of the possible association between CD and CMP, and we recommend CD work-up in all patients with CMP who have concomitant anemia. While we identified only 28 cases in the literature, many cases might go unreported due to a lack of awareness regarding CCM. A high degree of clinical suspicion and a prompt diagnosis of CCM are essential to minimizing the risks of morbidity and mortality, as the combination of a gluten-free diet and guideline-directed medical therapy can improve clinical outcomes.

Spontaneous Coronary Artery Dissection in Patients with Autosomal Dominant Polycystic Kidney Disease: A Systematic Review of the Literature.

Spontaneous coronary artery dissection (SCAD) is a spontaneous intimal tear of the coronary artery wall. A factor rarely associated with SCAD is autosomal dominant polycystic kidney disease (ADPKD). Using the PRISMA guidelines, we identified 10 unique cases of SCAD in ADPKD patients reported between 1998 and 2021. Ages ranged from 36 to 59 years, with an average of 44.6 years. The majority of patients were female (80%). Each case was diagnosed with a cardiovascular event: ST-elevation myocardial infarction (STEMI) in 40%, non-ST elevation myocardial infarction (NSTEMI) in 50%, and stable angina in 10%. Conservative management was used in 60% of cases. There is a significant gap in our understanding of the relationship between SCAD and ADPKD. Polycystin complex can lead to structural abnormalities in blood vessels, resulting in vascular leaks and vessel rupture. This suggests that ADPKD patients may have an elevated risk of arteriopathies, including coronary artery dissection.

The link between T cell activation and development of functionally useful tumour-associated high endothelial venules.

High endothelial venules (HEVs) are specialized postcapillary venules that specifically serve to recruit circulating lymphocytes to secondary lymphoid organs (SLOs) where cognate antigens can be encountered, and immune responses can be initiated. The presence of HEV-like vessels in primary human solid tumours and their association with lymphocyte infiltration and favourable clinical outcomes and response to immunotherapy have provided a rationale for therapeutically inducing these vessels in tumours for immunotherapeutic benefit. Here we specifically discuss evidence for a link between T-cell activation and development of useful tumour-associated HEV (TA-HEV). We discuss the molecular and functional features of TA-HEV, highlighting the benefits for promoting tumour immunity and the important unanswered questions that need to be addressed before TA-HEV induction can be optimized for immunotherapeutic benefit.

A Call to Action: Hypertensive Crises, Non-ST-Elevation Myocardial Infarction (NSTEMI), and Heart Failure in the Early Twenties.

A 21-year-old obese male with multiple hypertensive crises was diagnosed with non-ST-elevation myocardial infarction (NSTEMI), leading to heart failure due to uncontrolled hypertension and medication noncompliance. The patient's morbid obesity likely contributed to undiagnosed chronic hypertension, increasing the risk of atherosclerosis and cardiovascular diseases. Morbid obesity leads to increased interleukin-6 levels, promoting plaque accumulation and rupture. Obesity also triggers a pro-inflammatory and prothrombotic state, characterized by elevated levels of serum high-sensitivity C-reactive protein (hs-CRP), plasminogen activator inhibitor 1 (PAI-1), and other cytokines. This inflammatory state contributes to atherosclerosis development and renders plaques more prone to rupture. Additionally, obesity has been shown to increase the size of coronary thrombosis once the plaque ruptures. Treating obesity is crucial for the patient's well-being and reduces the burden on healthcare systems and society. Establishing a strong physician-patient relationship is essential for motivating lifestyle modifications, which are often the primary treatment approach for obesity and its complications.

A review of the risk and precipitating factors for spontaneous coronary artery dissection.

Introduction: Spontaneous coronary artery dissection (SCAD) accounts for 1%-4% of cases of acute coronary syndrome (ACS). SCAD is caused by separation occurring within or between any of the three tunics of the coronary artery wall. This leads to intramural hematoma and/or formation of false lumen in the artery, which leads to ischemic changes or infarction of the myocardium. The incidence of SCAD is higher in women than in men, with a ratio of approximately 9:1. It is estimated that SCAD is responsible for 35% of ACS cases in women under the age of 60. The high frequency is particularly observed during pregnancy and in the peripartum period (first week). Traditional risk factors are rare in patients with SCAD, except for hypertension. Patients diagnosed with SCAD have different combinations of risk factors compared with patients who have atherosclerotic changes in their coronary arteries. We presented the most common so-called "non-traditional" risk factors associated with SCAD patients. Risk factors and precipitating disorders which are associated with SCAD: In the literature, there are few diseases frequently associated with SCAD, and they are identified as predisposing factors. The predominant cause is fibromuscular dysplasia, followed by inherited connective tissue disorders, systemic inflammatory diseases, pregnancy, use of sex hormones or steroids, use of cocaine or amphetamines, thyroid disorders, migraine, and tinnitus. In recent years, the genetic predisposition for SCAD is also recognized as a predisposing factor. The precipitating factors are also different in women (emotional stress) compared with those in men (physical stress). Women experiencing SCAD frequently describe symptoms of anxiety and depression. These conditions could increase shear stress on the arterial wall and dissection of the coronary artery wall. Despite the advancement of SCAD, we can find significant differences in the clinical presentation between women and men. Conclusion: When evaluating patients with chest pain or other ACS symptoms who have a low cardiovascular risk, particularly female patients, it is important to consider the possibility of ACS due to SCAD, particularly in conditions often associated with SCAD. This will increase the recognition of SCAD and the timely treatment of affected patients.

Association Between Metabolic Syndrome, Its Components, and Knee Osteoarthritis in Premenopausal and Menopausal Women: A Pilot Study.

OBJECTIVE: This pilot study aimed to determine the correlation of metabolic syndrome (MetS), its components, and increased LDL (low-density lipoprotein) and total cholesterol levels with osteoarthritis (OA). In addition, our goal was to establish the association between MetS and the degree of handicap measured by the Lequesne index of functionality and severity of knee osteoarthritis. MATERIALS AND METHODS: The pilot study included 25 subjects with knee OA and 19 subjects without knee OA. All subjects were menopausal or premenopausal women. MetS was diagnosed according to the National Cholesterol Education Program, Adult Treatment Panel III. OA was diagnosed if Kellgren-Lawrence ≥ 2. RESULTS: MetS was detected in 80% of subjects with OA. In the non-OA group, MetS was detected in 26% of subjects. The difference in MetS prevalence between the two groups was significant (p=0.000). The presence of each MetS component was significant in the OA group, except for central obesity, which presence was marginally significant (p=0.054). Prevalence of increased total (p=0.019) and LDL cholesterol (p=0.000) was also significant in the OA group. A significant difference between OA and the non-OA group was detected in the prevalence of all five MetS components (p=0.016). In the OA group, the Lequesne index of functionality and severity of knee osteoarthritis was not significantly altered between subjects with and without MetS. CONCLUSION: Metabolic syndrome, its components, increased LDL, and total cholesterol are correlated with osteoarthritis in premenopausal and menopausal women. MetS is not correlated with the degree of handicap in the knee joint measured by the Lequesne index.

Three-dimensional Imaging Reveals Immune-driven Tumor-associated High Endothelial Venules as a Key Correlate of Tumor Rejection Following Depletion of Regulatory T Cells.

High endothelial venules (HEV) are specialized post capillary venules that recruit naïve T cells and B cells into secondary lymphoid organs (SLO) such as lymph nodes (LN). Expansion of HEV networks in SLOs occurs following immune activation to support development of an effective immune response. In this study, we used a carcinogen-induced model of fibrosarcoma to examine HEV remodeling after depletion of regulatory T cells (Treg). We used light sheet fluorescence microscopy imaging to visualize entire HEV networks, subsequently applying computational tools to enable topological mapping and extraction of numerical descriptors of the networks. While these analyses revealed profound cancer- and immune-driven alterations to HEV networks within LNs, these changes did not identify successful responses to treatment. The presence of HEV networks within tumors did however clearly distinguish responders from nonresponders. Finally, we show that a successful treatment response is dependent on coupling tumor-associated HEV (TA-HEV) development to T-cell activation implying that T-cell activation acts as the trigger for development of TA-HEVs which subsequently serve to amplify the immune response by facilitating extravasation of T cells into the tumor mass.

The hepatoprotective effect of aminoguanidine in acute liver injury caused by CCl4 in rats.

In this study, the hepatoprotective effect of aminoguanidine in acute liver damage caused by carbon tetrachloride-CCl4 at a dose of 1 mL/kg, i.p. was investigated in experimental rats. Ten days of preventive treatment with aminoguanidine before exposure to toxic CCl4, at a dose of 150 mg/kg, i.p., led to significant reduction in biochemical markers of acute liver injury-AST(p < 0.001), ALT (p < 0.01), SDH (p < 0.05) and reduction in pro-oxidative markers-H2O2 (p < 0.05), TOS (p < 0.01), TBARS, and LOOH (p < 0.001) in relation to rats treated only CCl4. Treatment with aminoguanidine resulted in a significant reduction in the consumption of antioxidant-GR (p < 0.01), GST, GPx, GSH (p < 0.001), and a decrease in pro-inflammatory-TNF-α (p < 0.01), IL-1ß, IL-6, NO and NGAL (p < 0.001) markers relative to animals exposed to CCl4 alone. Also, aminoguanidine pre-treatment leads to an increase in arginase activity (p < 0.001), and a decrease in citrulline concentration (p < 0.01), as well as polyamine catabolism enzyme activity-putrescin oxidase and spermine oxidase (p < 0.001) in comparison to the CCl4 group. Aminoguanidine led to a striking reduction of the necrotic field (p < 0.001), and a significant increase in the number of apoptotic hepatocytes (p < 0.001), as well as the proapoptotic markers-BAX and Caspase-3 (p < 0.05), compared to CCl4. The hepatoprotective mechanisms in CCl4 induce hepatotoxicity of aminoguanidine are based on the strong antioxidant effects, inhibition of pro-oxidative and pro-inflammatory mediators, as well as induction of damaged hepatocytes into apoptosis.

The Dual Role of High Endothelial Venules in Cancer Progression versus Immunity.

Secondary lymphoid organs (SLOs) are important initiators and regulators of immunity. To carry out this function, the blood vasculature must deliver oxygen and nutrients and recruit circulating lymphocytes into the SLO parenchyma, where they encounter cognate antigen. High endothelial venules (HEVs) are specialised postcapillary venules that specifically serve this function and are found in all SLOs except spleen. It is becoming clear that alterations to HEV network density and/or morphology can result in immune activation or, as recently implicated, in providing an exit route for tumour cell dissemination and metastases. In this review, the structural plasticity of HEVs, the regulatory pathways underpinning this plasticity, and the relevance of these pathways to cancer progression will be discussed.

Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3.

BACKGROUND: Despite striking successes, immunotherapies aimed at increasing cancer-specific T cell responses are unsuccessful in most patients with cancer. Inactivating regulatory T cells (Treg) by inhibiting the PI3Kδ signaling enzyme has shown promise in preclinical models of tumor immunity and is currently being tested in early phase clinical trials in solid tumors. METHODS: Mice bearing 4T1 mammary tumors were orally administered a PI3Kδ inhibitor (PI-3065) daily and tumor growth, survival and T cell infiltrate were analyzed in the tumor microenvironment. A second treatment schedule comprised PI3Kδ inhibitor with anti-LAG3 antibodies administered sequentially 10 days later. RESULTS: As observed in human immunotherapy trials with other agents, immunomodulation by PI3Kδ-blockade led to 4T1 tumor regressor and non-regressor mice. Tumor infiltrating T cells in regressors were metabolically fitter than those in non-regressors, with significant enrichments of antigen-specific CD8+ T cells, T cell factor 1 (TCF1)+ T cells and CD69- T cells, compatible with induction of a sustained tumor-specific T cell response. Treg numbers were significantly reduced in both regressor and non-regressor tumors compared with untreated tumors. The remaining Treg in non-regressor tumors were however significantly enriched with cells expressing the coinhibitory receptor LAG3, compared with Treg in regressor and untreated tumors. This striking difference prompted us to sequentially block PI3Kδ and LAG3. This combination enabled successful therapy of all mice, demonstrating the functional importance of LAG3 in non-regression of tumors on PI3Kδ inhibition therapy. Follow-up studies, performed using additional cancer cell lines, namely MC38 and CT26, indicated that a partial initial response to PI3Kδ inhibition is an essential prerequisite to a sequential therapeutic benefit of anti-LAG3 antibodies. CONCLUSIONS: These data indicate that LAG3 is a key bottleneck to successful PI3Kδ-targeted immunotherapy and provide a rationale for combining PI3Kδ/LAG3 blockade in future clinical studies.

Immune Remodeling of the Extracellular Matrix Drives Loss of Cancer Stem Cells and Tumor Rejection.

The nature of the tumor microenvironment (TME) influences the ability of tumor-specific T cells to control tumor growth. In this study, we performed an unbiased comparison of the TME of regulatory T-cell (Treg)-replete and Treg-depleted carcinogen-induced tumors, including Treg-depleted responding (regressing) and non-responding (growing) tumors. This analysis revealed an inverse relationship between extracellular matrix (ECM) and T-cell infiltrates where responding tumors were T-cell rich and ECM poor, whereas the converse was observed in non-responder tumors. For this reason, we hypothesized that the ECM acted as a barrier to successful T-cell infiltration and tumor rejection. However, further experiments revealed that this was not the case but instead showed that an effective T-cell response dramatically altered the density of ECM in the TME. Along with loss of ECM and high numbers of infiltrating T cells, responder tumors were distinguished by the development of lymphatic and blood vessel networks with specialized immune function. ECM-rich tumors exhibited a stem cell-like gene expression profile and superior tumor-initiating capacity, whereas such features were absent in responder tumors. Overall, these findings define an extended role for an effective immune response, not just in direct killing of tumor cells but in widescale remodeling of the TME to favor loss of ECM, elimination of cancer stem cells, and propagation of adaptive immunity.