Tailoring Multifunctional Small Molecular Photosensitizers to In Vivo Self-Assemble with Albumin to Boost Tumor-Preferential Accumulation, NIR Imaging, and Photodynamic/Photothermal/Immunotherapy.

Cancer immunotherapy has great potential in tumor eradication and metastasis suppression. However, systemic administration of immune adjuvants and inadequate specificity in cancer treatment, lead to restricted therapeutic benefits and potential immune-related side effects in clinical settings. In this report, the synthesis of various lengths of heptamethine cyanine small molecules to act as multifunctional photosensitizers (PS) for tumor-specific accumulation, near-infrared (NIR) fluorescent imaging, and photodynamic/photothermal/immunotherapy is optimized. In particular, it is demonstrated that C8, which contains eight carbons on two N-alkyl side chains, efficiently self-assembles with albumin to form nanosized dye-albumin complexes. This feature facilitates C8 in vivo self-assembly to remarkably improve its water-solubility, NIR fluorescent emission, long-term blood circulation, as well as tumor-specific accumulation. More importantly, C8 not only exhibits a superior phototherapeutic effect on primary tumors, but also elicits secretion of damage associated molecular patterns, cytokine secretion, dendritic cell maturation, and cytotoxic T lymphocytes activation, ultimately triggering a sufficient antitumor immune response to suppress growths of distant and metastatic tumors. Hence, this multifunctional small molecular PS is characterized with excellent tumor-preferential accumulation, imaging-guided laser irradiation, and phototherapy-induced in situ antitumor immune response, providing a prospective future of its use in tumor-targeting immunotherapy.

Blood Urea Nitrogen for Short-Term Prognosis in Patients with Cardiogenic Shock Complicating Acute Myocardial Infarction.

Purpose: Cardiogenic shock (CS) is the leading cause of death in patients with acute myocardial infarction (AMI). Our study aimed to evaluate the short-term prognostic value of admission blood urea nitrogen (BUN) in patients with CS complicating AMI. Materials and Methods: 218 consecutive patients with CS after AMI were enrolled. The primary endpoint was 30-day mortality. The association of admission BUN and 30-day mortality and major adverse cardiovascular event (MACE) was investigated by Cox regression. The integrated discrimination improvement (IDI) and net reclassification improvement (NRI) further examined the predictive value of BUN. Results: During a period of 30-day follow-up, 105 deaths occurred. Compared to survivors, nonsurvivors had significantly higher admission BUN (p < 0.001), creatinine (p < 0.001), BUN/creatinine (p = 0.03), and a lower glomerular filtration rate (p < 0.001). The area under the curve (AUC) of the 4 indices for predicting 30-day mortality was 0.781, 0.734, 0.588, and 0.773, respectively. When compared to traditional markers associated with CS, the AUC for predicting 30-day mortality of BUN, lactate, and left ventricular ejection fraction were 0.781, 0.776, and 0.701, respectively. The optimal cut-off value of BUN for predicting 30-day mortality was 8.95 mmol/L with Youden-Index analysis. Multivariate Cox analysis indicated BUN >8.95 mmol/L was an important independent predictor for 30-day mortality (HR 2.08, 95%CI 1.28-3.36, p = 0.003) and 30-day MACE (HR 1.85, 95%CI 1.29-2.66, p = 0.001). IDI (0.053, p = 0.005) and NRI (0.135, p = 0.010) showed an improvement in the accuracy for mortality prediction of the new model when BUN was included compared with the standard model of predictors in previous scores. Conclusion: An admission BUN >8.95 mmol/L was robustly associated with increased short-term mortality and MACE in patients with CS after AMI. The prognostic value of BUN was superior to other renal markers and comparable to traditional markers. This easily accessible index might be promising for early risk stratification in CS patients following AMI.

The 'diamond' approach to personalized drug treatment of heart failure with reduced ejection fraction.

Heart failure (HF) is a complex clinical syndrome with symptoms and signs due to cardiac dysfunction, leading to high hospitalization and morbidity. HF treatment has rapidly developed in recent decades, and breakthroughs have been made. Although conventional neurohormonal blockade therapies, including ß-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs), significantly improve the prognosis of patients with heart failure with reduced ejection fraction (HFrEF), mortality and rehospitalization remain high. Therefore, new therapies are needed. Previous studies demonstrated that ivabradine, angiotensin receptor-neprilysin inhibitor (ARNI), sodium-glucose cotransporter 2 (SGLT2) inhibitor, vericiguat, and omecamtiv mecarbil (OM) are beneficial for HFrEF. However, there is a lack of systematic review of the most optimal manner to use under various clinical conditions. This review summarizes the current knowledge regarding these therapies to give suggestions regarding clinical use timing, application scope, and optimal therapies under various conditions. Most importantly, we propose the HF diamond approach to express the necessity of conjunction of therapies. Different from the current guidelines, we suggest to use the diamond approach in an early and comprehensive manner at the beginning of ventricular remodeling in HFrEF to prevent further deterioration of HF and maximize the prognosis of patients.

Prognostic value of neutrophil-lymphocyte ratio in cardiogenic shock complicating acute myocardial infarction: A cohort study.

BACKGROUNDS: Cardiogenic shock (CS) is the most severe complication after acute myocardial infarction (AMI) with mortality above 50%. Inflammatory response is involved in the pathology of CS and AMI. In this study, we aimed to evaluate the prognostic value of admission neutrophil-lymphocyte ratio (NLR) in patients with CS complicating AMI. METHODS: Two hundred and seventeen consecutive patients with CS after AMI were divided into two groups according to the admission NLR cut-off value ≤7.3 and >7.3. The primary outcome was 30-day all-cause mortality and the secondary end-point was the composite events of major adverse cardiovascular events (MACE), including all-cause mortality, ventricular tachycardia/ventricular fibrillation, atrioventricular block, gastrointestinal haemorrhage and non-fatal stroke. Cox proportional hazard models were performed to analyse the association of NLR with the outcome. NLR cut-off value was determined by Youden index. RESULTS: Patients with NLR > 7.3 were older and presented with lower lymphocyte count, higher admission heart rate, B-type natriuretic peptide, leucocyte, neutrophil and creatinine (all P < .05). During a period of 30-day follow-up after admission, mortality in patients with NLR > 7.3 was significantly higher than in patients with NLR ≤ 7.3 (73.7% vs. 26.3%, P < .001). The incidence of MACE was also remarkably higher in patients with NLR > 7.3 (87.9% vs. 53.4%, P < .001). After multivariable adjustment, NLR > 7.3 remained an independent predictor for higher risk of 30-day mortality (HR 2.806; 95%CI 1.784, 4.415, P < .001) and MACE (HR 2.545; 95%CI 1.791, 3.617, P < .001). CONCLUSIONS: Admission NLR could be used as an important tool for short-term prognostic evaluation in patients with CS complicating AMI and higher NLR is an independent predictor for increased 30-day all-cause mortality and MACE.

A Mitochondria-Targeted Ferroptosis Inducer Activated by Glutathione-Responsive Imaging and Depletion for Triple Negative Breast Cancer Theranostics.

Ferroptosis is a new type of iron-dependent programmed cell death characterized by glutathione (GSH) depletion, selenoprotein glutathione peroxidase 4 (GPX4) inactivation, and lipid peroxides accumulation. Mitochondria, as the main source of intracellular energy supply and reactive oxygen species (ROS) generation, play a central role in oxidative phosphorylation and redox homeostasis. Therefore, targeting cancer-cell mitochondria and attacking redox homeostasis is expected to induce robust ferroptosis-mediated anticancer effects. In this work, a theranostic ferroptosis inducer (IR780-SPhF), which can simultaneously achieve the imaging and therapy of triple-negative breast cancer (TNBC) by targeting mitochondria is presented. It is developed from a mitochondria-targeting small molecule (IR780) with cancer-preferential accumulation, enabling it to react with GSH by nucleophilic substitution, resulting in mitochondrial GSH depletion and redox imbalance. More interestingly, IR780-SPhF exhibits GSH-responsive near-infrared fluorescence emission and photoacoustic imaging characteristics, further facilitating diagnosis and treatment with real-time monitoring of TNBC with a highly elevated GSH level. Both in vitro and in vivo results demonstrate that IR780-SPhF exhibits potent anticancer effect, which is significantly stronger than cyclophosphamide, a classic drug commonly recommended for TNBC patients in clinic. Hence, the reported mitochondria-targeted ferroptosis inducer may represent a promising candidate and a prospective strategy for efficient cancer treatment.

Leukocyte and its Subtypes as Predictors of Short-Term Outcome in Cardiogenic Shock Complicating Acute Myocardial Infarction: A Cohort Study.

BACKGROUND: Patients with cardiogenic shock (CS) complicating acute myocardial infarction (AMI) are at high risk of death. Inflammation is involved in both CS and AMI, and our present study aimed to investigate the changes of leukocyte and its subtypes as well as their prognostic value in patients with CS complicating AMI. METHODS: Data of 217 consecutive patients with CS complicating AMI were analyzed. The primary endpoint was 30-day all-cause mortality. The secondary endpoint was the composite events of major adverse cardiovascular events (MACE) including 30-day all-cause mortality, ventricular tachycardia/ventricular fibrillation, atrioventricular block, gastrointestinal hemorrhage and nonfatal stroke. The association of leukocyte and its subtypes with the endpoints was analyzed by Cox regression analysis. RESULTS: Leukocyte and its subtypes including neutrophil, eosinophil, lymphocyte, monocyte and basophil were all statistically significant between survivors and nonsurvivors (all P < 0.05). Among the leukocyte subtypes, eosinophil had the highest predictive value for 30-day all-cause mortality (AUC = 0.799) and the composite of leukocyte and its subtypes improved the predictive power (AUC = 0.834). The 30-day mortality and MACE K-M curves of leukocyte and its subtypes reveal a distinct trend based on the cut-off value determined by Youden Index (all log rank P < 0.001). After multivariable adjustment, high leukocyte (>11.6 × 109/L) (HR 1.815; 95%CI 1.134, 2.903; P = 0.013), low eosinophil (<0.3%) (HR 2.562; 95%CI 1.412, 4.648; P = 0.002) and low basophil (≤0.1%) (HR 1.694; 95%CI 1.106, 2.592; P = 0.015) were independently associated with increased risk of 30-day mortality. Similarly, high leukocyte (>11.6 × 109/L) (HR 1.894; 95%CI 1.285, 2.791; P = 0.001), low eosinophil (<0.3%) (HR 1.729; 95%CI 1.119, 2.670; P = 0.014) and low basophil (≤0.1%) (HR 1.560; 95%CI 1.101, 2.210; P = 0.012) were independently associated with increased risk of 30-day MACE. CONCLUSIONS: Leukocyte and its subtypes changed significantly in patients with CS complicating AMI. In addition to leukocyte, eosinophil and basophil also served as independent prognostic factors for 30-day outcomes. Moreover, as the composite of leukocyte and its subtypes increased the predictive power, thus leukocyte and its subtypes, especially eosinophil and basophil should be taken into consideration for the current risk stratification model.

Incidence, Clinical Characteristics and Short-Term Prognosis in Patients With Cardiogenic Shock and Various Left Ventricular Ejection Fractions After Acute Myocardial Infarction.

The 2016 European Society of Cardiology Guidelines introduced a new term, mid-range left ventricular ejection fraction (mrEF) heart failure, however, the clinical characteristics and short-term outcomes in cardiogenic shock patients with mrEF after acute myocardial infarction remain unclear. This retrospective study analyzed the baseline characteristics, management, and outcomes according to the left ventricular ejection fraction (LVEF), reduced LVEF (rEF) ≤40%, mrEF 41% to 49%, and preserved LVEF (pEF) ≥50% in patients with acute myocardial infarction complicated by cardiogenic shock. The primary end point was 30-day all-cause mortality and the secondary end point was the composite events of major adverse cardiovascular events (MACEs). In 218 patients, 71 (32.6%) were patients with mrEF. Compared with those with pEF, patients with mrEF had some similar clinical characteristics to that of rEF. The 30-day all-cause mortality in patients with rEF, mrEF, and pEF were 72.7%, 56.3%, and 32.0%, respectively (p = 0.001). The 30-day MACE were 90.9%, 69.0%, and 60.2%, respectively (p = 0.001). After multivariable adjustment, patients with mrEF and rEF had comparable 30-day all-cause mortality (hazard ratio [HR] = 0.81, 95% confidence interval [CI] 0.50 to 1.33, p = 0.404), and pEF was associated with decreased risk of 30-day all-cause mortality compared with rEF (HR = 0.41, 95% CI 0.24 to 0.71, p = 0.001). In contrast, the risk of 30-day MACE in mrEF and pEF were lower than that of rEF (HR = 0.62, 95% CI 0.40 to 0.96, p = 0.031 and HR = 0.53, 95% CI 0.34 to 0.80, p = 0.003, respectively). In conclusion, 1/3 of patients with acute myocardial infarction complicated by cardiogenic shock were mrEF. The clinical characteristics and short-term mortality in patients with mrEF were inclined to that of rEF and the occurrence of early left ventricular systolic dysfunction is of prognostic significance.

Prognostic impact of mean heart rate by Holter monitoring on long-term outcome in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention.

BACKGROUND: Previous studies have shown elevated admission heart rate (HR) was associated with worse outcome in patients with myocardial infarction (MI). However, the prognostic value of mean heart rate (MHR) with Holter monitoring remains unclear. OBJECTIVES: Our present study aims to evaluate the impact of MHR by Holter monitoring on long-term mortality in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: 1013 STEMI patients were divided into four groups according to the quartiles of MHR by Holter monitoring, Q1 (< 66 bpm), Q2 66-72 bpm), Q3 (73-78 bpm), and Q4 (> 78 bpm). The endpoint was long-term all-cause mortality. The predictive value of admission HR, discharge HR, and MHR was compared with receiver operating characteristic (ROC) curves. RESULTS: Patients in Q4 were more likely to present with anterior MI, high Killip class, relatively lower admission blood pressure, significantly increased troponin I, B-type natriuretic peptide, and decreased left ventricular ejection fraction. During a median of 28.3 months follow up period, 91 patients (8.9%) died. The mortality in Q4 was significantly higher than in the other three groups (P < 0.001). After multivariate adjustment, Q4 was associated with a 1.0-fold increased risk of long-term all-cause mortality (HR = 2.096, 95% CI 1.190-3.691, P = 0.010). ROC analysis shows MHR with Holter (AUC = 0.672) was superior to admission HR (AUC = 0.556) or discharge HR (AUC = 0.578). CONCLUSIONS: MHR based on Holter monitoring provided important prognostic value and MHR > 78 bpm was independently associated with increased risk of long-term all-cause mortality in patients with STEMI, and its predictive validity was superior to admission or discharge HR.