H2S-Powered Nanomotors for Active Therapy of Tumors by Inducing Ferroptosis and Lactate-Pyruvate Axis Disorders.

Disruption of the symbiosis of extra/intratumoral metabolism is a good strategy for treating tumors that shuttle resources from the tumor microenvironment. Here, we report a precision treatment strategy for enhancing pyruvic acid and intratumoral acidosis to destroy tumoral metabolic symbiosis to eliminate tumors; this approach is based on PEGylated gold and lactate oxidase-modified aminated dendritic mesoporous silica with lonidamine and ferrous sulfide loading (PEG-Au@DMSNs/FeS/LND@LOX). In the tumor microenvironment, LOX oxidizes lactic acid to produce pyruvate, which represses tumor cell proliferation by inhibiting histone gene expression and induces ferroptosis by partial histone monoubiquitination. In acidic tumor conditions, the nanoparticles release H2S gas and Fe2+ ions, which can inhibit catalase activity to promote the Fenton reaction of Fe2+, resulting in massive ·OH production and ferroptosis via Fe3+. More interestingly, the combination of H2S and LND (a monocarboxylic acid transporter inhibitor) can cause intracellular acidosis by lactate, and protons overaccumulate in cells. Multiple intracellular acidosis is caused by lactate-pyruvate axis disorders. Moreover, H2S provides motive power to intensify the shuttling of nanoparticles in the tumor region. The findings confirm that this nanomedicine system can enable precise antitumor effects by disrupting extra/intratumoral metabolic symbiosis and inducing ferroptosis and represents a promising active drug delivery system candidate for tumor treatment.

A convenient and practical index for predicting the induction response in adult patients with hemophagocytic lymphohistiocytosis: ferritin/platelet ratio.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome with high mortality rate. The response to induction therapy is an important factor affecting survival. The purpose is to investigate laboratory predictors for induction response in adult patients with HLH, which are convenient, practical, and timeliness. Clinical data from January 2017 to December 2020 was retrospectively analyzed, and 269 patients were included. Patients were divided into remission and non-remission groups according to their induction response, 177 in the remission group, and 92 in the non-remission group. We reviewed general characteristics and analyzed the predictive value of serum ferritin, triglycerides, alanine aminotransferase (ALT), and blood cells before and 1-4 weeks after induction therapy for induction response by univariate analysis, ROC curves, etc. There was a correlation between serum ferritin, ALT, leukocytes, neutrophils, hemoglobin, platelets, and induction response (P < 0.05). Serum ferritin and platelets 1-4 weeks after induction therapy, respectively, might be a good predictor for induction response in adults with HLH, with AUC values close to or greater than 0.7. We established a new clinical model of the ferritin/platelet ratio. The results showed that the ferritin/platelet ratio at 1-4 weeks after induction therapy might be a practical index for predicting induction response, which significantly improved the area under the ROC curve (AUC > 0.75). Patients with a ferritin/platelet ratio > 16.08 at 2 weeks after induction therapy may have a relatively poor induction response. Ferritin/platelet ratio after induction therapy can be a good predictor for induction response in adult patients with HLH.

Biological therapies for hemophagocytic lymphohistiocytosis: current knowledge and future perspectives.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome with a dismal prognosis. The underlying causes of HLH are diverse. However, the overabundance of cytokines was shared by all forms of HLH. Cytokine-targeted biotherapies have been increasingly used in HLH treatment. AREAS COVERED: In this review, we aim to provide an overview of biological treatment options for HLH. EXPERT OPINION: Biological therapies offer alternative treatment options for patients with refractory/relapsed HLH or who are intolerant to conventional chemotherapies. As a complement to traditional treatment, biological agents improve response rates, maintain more protracted periods of remission, and reduce treatment related toxicity. A combination of biological agents may be a promising direction for HLH treatment. However, they may induce HLH to deteriorate and even trigger HLH.

Proxalutamide reduces SARS-CoV-2 infection and associated inflammatory response.

Early in the COVID-19 pandemic, data suggested that males had a higher risk of developing severe disease and that androgen deprivation therapy might be associated with protection. Combined with the fact that TMPRSS2 (transmembrane serine protease 2), a host entry factor for the SARS-CoV-2 virus, was a well-known androgen-regulated gene, this led to an upsurge of research investigating androgen receptor (AR)-targeting drugs. Proxalutamide, an AR antagonist, was shown in initial clinical studies to benefit COVID-19 patients; however, further validation is needed as one study was retracted. Due to continued interest in proxalutamide, which is in phase 3 trials, we examined its ability to impact SARS-CoV-2 infection and downstream inflammatory responses. Proxalutamide exerted similar effects as enzalutamide, an AR antagonist prescribed for advanced prostate cancer, in decreasing AR signaling and expression of TMPRSS2 and angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor. However, proxalutamide led to degradation of AR protein, which was not observed with enzalutamide. Proxalutamide inhibited SARS-CoV-2 infection with an IC50 value of 97 nM, compared to 281 nM for enzalutamide. Importantly, proxalutamide inhibited infection by multiple SARS-CoV-2 variants and synergized with remdesivir. Proxalutamide protected against cell death in response to tumor necrosis factor alpha and interferon gamma, and overall survival of mice was increased with proxalutamide treatment prior to cytokine exposure. Mechanistically, we found that proxalutamide increased levels of NRF2, an essential transcription factor that mediates antioxidant responses, and decreased lung inflammation. These data provide compelling evidence that proxalutamide can prevent SARS-CoV-2 infection and cytokine-induced lung damage, suggesting that promising clinical data may emerge from ongoing phase 3 trials.

Research progress on the role of PDGF/PDGFR in type 2 diabetes.

Platelet-derived growth factors (PDGFs) are basic proteins stored in the α granules of platelets. PDGFs and their receptors (PDGFRs) are widely expressed in platelets, fibroblasts, vascular endothelial cells, platelets, pericytes, smooth muscle cells and tumor cells. The activation of PDGFR plays a number of critical roles in physiological functions and diseases, including normal embryonic development, cellular differentiation, and responses to tissue damage. In recent years, emerging experimental evidence has shown that activation of the PDGF/PDGFR pathway is involved in the development of diabetes and its complications, such as atherosclerosis, diabetic foot ulcers, diabetic nephropathy, and retinopathy. Research on targeting PDGF/PDGFR as a treatment has also made great progress. In this mini-review, we summarized the role of PDGF in diabetes, as well as the research progress on targeted diabetes therapy, which provides a new strategy for the treatment of type 2 diabetes.

Pancoronary plaque characteristics and clinical outcomes in acute coronary syndrome patients with cancer history.

BACKGROUND AND AIMS: The prevalence of acute coronary syndrome (ACS) patients with cancer history is increasing and it is associated with higher mortality. However, there is limited evidence on the characteristics of coronary plaque in ACS patients with cancer history. This study explored the pancoronary plaque characteristics in ACS patients with cancer history by optical coherence tomography (OCT). METHODS: A total of 306 ACS patients treated by 3-vessel OCT at the time of percutaneous coronary intervention (PCI) were included, retrospectively. Patients were divided into two groups according to the presence or absence of cancer history: one group with cancer history (n = 98) and a matched group without cancer history (n = 208). RESULTS: A total of 314 culprit lesions and 514 nonculprit lesions were identified by OCT in this study. In culprit lesions, ACS patients with cancer history had higher incidence of thin cap fibroatheroma (TCFA) (p = 0.016), cholesterol crystals (p = 0.028), calcification (p = 0.001) and thrombus (p = 0.001), and had thinner fibrous cap thickness (FCT) (p = 0.011), greater maximum lipid arc (p = 0.042) and lipid index (p < 0.001), compared to matched ACS patients without cancer history. In nonculprit lesions, ACS patients with cancer history had higher prevalence of high-risk plaque (14.7% vs. 7.7%, p = 0.017), nonculprit rupture (14.7% vs. 6.3%, p = 0.003), and TCFA (52.2% vs. 28.3%, p < 0.001), and had higher incidence of calcification (p = 0.003), thrombus (p = 0.029), cholesterol crystals (p = 0.002) and microchannels (p = 0.029). These non-culprit lesions had longer lesion length (p = 0.001), thinner FCT (p < 0.001), greater maximum lipid arc (p = 0.016) and lipid index (p < 0.001). CONCLUSIONS: ACS patients with cancer history showed more high-risk plaque features in culprit and nonculprit lesions, compared with ACS patients without cancer history. Therefore, ACS patients with cancer history may have greater pancoronary vulnerability. This may predict a poorer prognosis for ACS patients with cancer history.

Serum sCD25/ferritin ratio combined with MCP-1 is a valid predictor for identifying LAHS with HLH as the first manifestation.

PURPOSE: Lymphoma-associated haemophagocytic syndrome (LAHS) is a group of malignant diseases with rapid progression and a high mortality rate. Our study aimed to discover the significance of serum sCD25/ferritin ratio as well as cytokines in assisting the diagnosis of LAHS. METHODS: We retrospectively analyzed the clinical data of 82 patients with LAHS with hemophagocytic lymphohistiocytosis (HLH) as the first manifestation and divided them into B-LAHS group and T/NK-LAHS group according to lymphoma pathological diagnosis for comparison. And patients with LAHS were divided into responding group, non-responding group according to the assessment of efficacy after receiving DEP/L-DEP induction therapy for 2 weeks to compare possible valuable indicators. RESULTS: Serum sCD25/ferritin ratio and MCP-1 levels were significantly different between B-LAHS and T/NK-LAHS groups (P = 0.001, P = 0.022). An sCD25/ferritin ratio > 7.8 tended to suggest a diagnosis of B-LAHS (AUC = 0.71, 95% CI: 0.596-0.823), and the sCD25/ferritin ratio had better predictive value when combined with MCP-1 (AUC = 0.81, 95% CI: 0.699-0.922). The sCD25/ferritin ratio was also significantly different between the two groups responding or not responding to induction therapy (P = 0.002), yielding an optimal cutoff value of 11.48. An sCD25/ferritin ratio > 11.48 tended to suggest that the patient's LAHS was responsive to induction therapy. CONCLUSION: Our study reveals that serum sCD25/ferritin ratio combined with MCP-1 is a valid predictor for identifying LAHS with HLH as the first manifestation and may assist in predicting whether the lymphoma is of B-cell or T/NK-cell origin. The sCD25/ferritin ratio can also be used to predict the early response of LAHS after induction therapy.

Predictive Value of Cardiovascular Health Score for Health Outcomes in Patients with PCI: Comparison between Life's Simple 7 and Life's Essential 8.

The American Heart Association recently published an updated algorithm for quantitative assessments of cardiovascular health (CVH) metrics, namely Life's Essential 8 (LE8). This study aimed to compare the predictive value between Life's Simple 7 (LS7) and LE8 and predict the likelihood of major adverse cardiac events (MACEs) in patients undergoing percutaneous coronary intervention (PCI) to determine the utility of the LE8 in predicting CVH outcomes. A total of 339 patients with acute coronary syndrome (ACS) who had undergone PCI were enrolled to assess the CVH scores using the LS7 and LE8. Multivariable Cox regression analysis was employed to evaluate the predictive value of the two different CVH scoring systems at 2 years for MACEs. Multivariable Cox regression analysis revealed that both the LS7 and LE8 scores were protective factors for MACEs (HR = 0.857, [95%CI: 0.78-0.94], HR = 0.964, [95%CI: 0.95-0.98]; p < 0.05, respectively). Receiver operator characteristic analysis indicated that the area under the curve (AUC) of LE8 was higher than that of LS7 (AUC: 0.662 vs. 0.615, p < 0.05). Lastly, in the LE8 score, diet, sleep health, serum glucose levels, nicotine exposure, and physical activity were found to be correlated with MACEs (HR = 0.985, 0.988, 0.993, 0.994, 0.994, respectively). Our study established that LE8 is a more reliable assessment system for CVH. This population-based prospective study reports that an unfavorable cardiovascular health profile is associated with MACEs. Future research is warranted to evaluate the effectiveness of optimizing diet, sleep health, serum glucose levels, nicotine exposure, and physical activity in reducing the risk of MACEs. In conclusion, our findings corroborated the predictive value of Life's Essential 8 and provided further evidence for the association between CVH and the risk of MACEs.

Global profiling of AMG510 modified proteins identified tumor suppressor KEAP1 as an off-target.

KRAS inhibitor AMG510 covalently modifies the G12C residue and inactivates the KRAS/G12C function. Because there are many reactive cysteines in the proteome, it is important to characterize AMG510 on-target modification and off-targets. Here, we presented a streamlined workflow to measure abundant AMG510 modified peptides including that of KRAS/G12C by direct profiling, and a pan-AMG510 antibody peptide IP workflow to profile less abundant AMG510 off-targets. We identified over 300 off-target sites with three distinct kinetic patterns, expanding the AMG510 modified proteome involved in the nucleocytoplasmic transport, response to oxidative stress, adaptive immune system, and glycolysis. We found that AMG510 covalently modified cys339 of ALDOA and inhibited its enzyme activity. Moreover, AMG510 modified KEAP1 cys288 and induced NRF2 accumulation in the nuclear of NSCLC cells independent of KRAS/G12C mutation. Our study provides a comprehensive resource of protein off-targets of AMG510 and elucidates potential toxicological sideeffects for this covalent KRASG12C inhibitor.

PD-1 blockade and lenalidomide combination therapy for chronic active Epstein-Barr virus infection.

OBJECTIVES: Chronic active Epstein-Barr virus infection (CAEBV) is a prototype of EBV-associated T-or NK-cell lymphoproliferative diseases. It is a disease with poor outcome. Almost all current therapies are ineffective except of allogeneic hematopoietic stem cell transplantation. METHODS: We investigated the efficacy and safety of programmed death 1 (PD-1) blockade (Sintilimab), combined with lenalidomide, which is an immunomodulatory drug, in an open-label, single-center, prospective study involving CAEBV patients. PD1 blockade 2mg/kg was given every two weeks by intravenous infusion on day 1, and lenalidomide 5mg (age<18 years)/10mg (age ≥ 18 years) was given orally once a day on day 1-14. RESULTS: As of Nov 15, 2020, 34 patients were enrolled. As of the Feb 1, 2021 analysis cut-off date, 24 cases completed at least 3 courses and were assessed for efficacy. The overall response rate is 54.2% (13/24, 45.8% complete response; 8.3% partial response). EBV-DNA copies in PBMC decreased significantly (p = 0.002). The proportion of CD8+T cells in lymphocytes increased (p = 0.007). The comparative analysis between response group and non-response group showed the proportion of Effector Memory CD8+ T cells and cytokines of CTLs activation (IFN-γ, CD27, CD30, MIG, IP-10) increased significantly in Response-group after treatment. Whole-exome sequencing generated from peripheral blood and saliva samples reveal that Non-Response group had a higher somatic mutational load of copy number variation in background. With a median follow-up time of 17.8 months, 22 of 24 patients were alive with an estimated survival probability of 91.3% at 1 year. All 34 patients were assessed for safety evaluation. The possible drug-related adverse events were reported in 17 (50%) patients. CONCLUSIONS: PD-1 blockade combined with lenalidomide was an effective and safe therapy for CAEBV patients. The significant therapeutic effect and the different characteristics between response and non-response group, provides a possible predictive value for CAEBV treatment option.

Improved hemophagocytic lymphohistiocytosis index predicts prognosis of adult Epstein-Barr virus-associated HLH patients.

BACKGROUND: Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a common subtype of HLH with heterogeneous clinical presentations from self-limited to death, of which adults are worse than children. OBJECTIVE: To establish predictors of mortality risk in adult EBV-HLH patients for timely and appropriate treatment. METHODS: Patients with confirmed EBV-HLH admitted to Beijing Friendship Hospital from January 2015 to December 2019 were enrolled and statistical analysis of their laboratory test results was performed. RESULTS: Among 246 adult patients with EBV-HLH, the deceased were older (p < 0.05), with fewer blood cells (p < 0.05), poorer renal function (p < 0.01), higher levels of procalcitonin (PCT) (p < 0.01), as well as soluble interleukin-2 receptor (sCD25) (p < 0.01). The overall median survival time of patients was 135 days, 87 days for patients without transplantation and 294 days with transplantation (p < 0.001). A combined index of sCD25, PCT, and estimated glomerular filtration rate (eGFR) was obtained to predict prognosis, named the Improved HLH index (IH index), and patients were divided into three groups meeting IH- (i.e. sCD25 ≤ 18,000 pg/mL, PCT ≤ 1.8 ng/mL, eGFR ≥ 90 mL/min/1.73m2), IH1+ (i.e. only sCD25 > 18,000 pg/mL or only eGFR < 90 mL/min/1.73m2), and IH2+ (i.e. the rest), respectively. In patients with the HScore ≥ 169 or meeting HLH-04, those meeting IH2+ had significantly worse prognoses than those who met IH1+ or IH- (p < 0.001). In the group meeting IH + or IH2+, patients who received allo-HSCT had better prognoses than those who did not (p < 0.05), but there was still a significant difference in prognosis among the three groups in transplanted patients (p < 0.001). CONCLUSION: The IH index can early identify adult patients with a poor prognosis of EBV-HLH, initiating timely and appropriate treatment.KEY MESSAGESA combined index of sCD25, PCT, and eGFR was obtained to predict prognosis, named the Improved Hemophagocytic Lymphohistiocytosis index (IH index).IH index can early identify adult patients with a poor prognosis of EBV-HLH, initiating timely and appropriate treatment.

The diagnostic importance of multiple cytokines in adult hemophagocytic lymphohistiocytosis.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a category of immunological illnesses that cause out-of-control T cells and macrophages to release life-threatening cytokines. The HLH-2004 diagnostic criteria are the gold standard for HLH diagnosis, but there is a need to investigate the usefulness of various cytokines for HLH diagnosis. METHODS: Patients admitted to Beijing Friendship Hospital of Capital Medical University from January 2016 to December 2020 were included in this retrospective study, with 166 patients with confirmed HLH and 142 febrile patients requiring differential diagnosis completing the sum. Multiplex cytokine assays using multifactor liquid phase microarray technology-based multifactor liquid phase microarray technology were used to detect 33 cytokines. Twenty-eight cytokines detected using the Luminex analytical platform technology were ultimately included in the analysis. RESULTS: Interleukin-1 receptor antagonist (IL-1 RA), IL-18, interferon-γ (IFN-γ), and interferon-induced protein 10 (IP-10) regulated upon activation normal T cell expressed and secreted (RANTES), eotaxin, growth-related oncogene α (GRO-α), and macrophage inflammatory protein-1 α (MIP-1α) were higher in the HLH group than in the non-HLH group, and the differences were statistically significant. Among them, the area under the curve (AUC) for IL-18 for HLH diagnosis was reported for the first time as 82.69%, with a sensitivity of 76.32% and a specificity of 79.61%; the AUC of IL-1 RA was 72.34%, with a sensitivity of 62.71% and a specificity of 75.97%; and the AUC of IP-10 was 71.73%, with a sensitivity of 60.14% and a specificity of 75.15%. Moreover, the AUC of the combined diagnostic tests for IL-1 RA, IL-18, IFN-γ, IP-10, and RANTES was 99.6%, with a sensitivity of 95.8% and a specificity of 98.6%. CONCLUSION: Our study concluded that multiple cytokines are valid biological markers for the diagnosis of HLH. The findings of this study remain to be validated in an external dataset.

BME-free primary patient-specific organoids obtained with a one-day mimicking method to replicate the corresponding tumor for personalized treatment options.

Introduction: In cancer treatment, every minute counts. Due to the unpredictable behavior of cancer cells caused by continuous mutations, each cancer patient has a unique situation and may or may not respond to a specific drug or treatment. The process of finding an effective therapy can be time-consuming, but cancer patients do not have the luxury of time for trial and error. Therefore, a novel technology to fast generate a patient relevant organoid for the therapies selecting is urgently needed. Methods: Utilizing the new organoid technology by specially dissolving the mesenchyme in tumor tissues acquired from cancer patients, we realized the work of creating patient-specific organoids (PSO) within one day. Results: PSO properties reflect those of its respective original in vivo tumor tissue and can be utilized to perform various in vitro drug sensitivity tests to identify the most effective clinical treatment for patients. Additionally, PSO can aid in assessing the efficacy of immune cell therapies. Discussion: Organoid technology has advanced significantly in recent years. However, current cancer organoid methods involve creating 3D tumor tissue from 2D cancer cells or cell clusters, primarily for cancer research purposes aimed at investigating related molecular and cellular mechanisms of tumor development. These methods are research-driven, not tailored towards clinical applications, and cannot provide personalized information for individual patients. PSO filled the gap of clinic-driven and time-saving method for the personalized therapies selecting to the cancer patients.

Macrophage activation syndrome in adults: Characteristics, outcomes, and therapeutic effectiveness of etoposide-based regimen.

Objectives: To describe the clinical characteristics and outcomes of adult macrophage activation syndrome (MAS) patients and to provide experience for the treatment. Methods: Adult patients with MAS admitted to Beijing Friendship Hospital from December 2014 to September 2021 were enrolled in this study. Clinical data of patients were collected and analyzed. Results: A total of 118 adult MAS patients entered this study. MAS was the first manifestation in 43 (36.4%) patients, while 75 (63.6%) developed MAS after the diagnosis of autoimmune disease (AID) with a median diagnostic interval of 2 (0.5-359) months. Eighty-two patients were initially treated with glucocorticoid-based regimen; the overall response (OR) rate at the 2-week posttreatment was 37.8%. Forty-five patients switched to etoposide-based regimen, and the OR rate was 84.4%. Thirty-six patients were initially treated with etoposide-based regimen, and the OR rate at the 2-week posttreatment was 80.6%. Serum IL-18 (P = 0.021), IFN-γ (P = 0.013), IP-10 (P = 0.001), IL-10 (P = 0.041), IL-1RA (P < 0.001), and TNF-α (P = 0.020) levels of patients were significantly decreased in the remission phase than in the active phase. Levels of SDF-1α (P = 0.018) and IL-7 (P = 0.022) were higher in refractory patients, while the GRO-α level had a strong tendency toward statistical significance (P = 0.050). The probability of overall survival (OS) at 3, 6, and 36 months after HLH diagnosis were 89.8%, 89.0%, and 87.9%, retrospectively. The active MAS status at the 2-week post initial treatment [P = 0.009, HR = 15.281, 95% CI, (0.1.972, 118.430)] and baseline neutrophil count (Neu) <1.5 × 109/l [P = 0.017, HR = 3.678, 95% CI, (1.267, 10.672)] were negative prognostic factors. Conclusion: MAS typically occurs within 2 months after the onset of autoimmune disease in adults. SDF-1α, IL-7, and GRO-α could be used to predict refractory MAS. The etoposide-based regimen is effective and tolerable for adult MAS.

Association Between Dietary Intakes and Plaque Vulnerability Measured by Optical Coherence Tomography in Patients With Coronary Heart Disease: A Mediation Analysis of Inflammatory Factors.

Although studies have proven that diet has a critical role in preventing or delaying atherosclerosis and is far simpler to adjust and adhere to than other risk factors, the underlying mechanisms behind this effect remain not well comprehended. The purpose of this investigation was to determine the impact of inflammatory factors on the connection between dietary ingestion and coronary plaque fragility as measured via optical coherence tomography (OCT) in patients with coronary heart disease (CHD). This research eventually comprised 194 participants with CHD who met the inclusion and exclusion criteria. Semi-quantitative food frequency questionnaire (SQFFQ) was utilized to investigate dietary consumption status, serum levels of inflammatory biomarkers were analyzed using enzyme-linked immunosorbent assay, and OCT was employed to identify the plaque susceptibility of causative lesions in the body. Following correction for statistically meaningful possible confounders in univariate analysis, quartiles of soy and nuts, fruits and vitamin C were negatively associated with coronary plaque vulnerability. Conversely, the upper quartile group of sodium intake had 2.98 times the risk of developing vulnerable plaques compared with the most minimal quartile group. Meanwhile, we observed an inverse dose-response connection between vitamin C consumption and inflammatory biomarkers as well as plaque vulnerability. More importantly, tumor necrosis factor- α (TNF-α) and interleukin-6 (IL-6) were significant mediators of the connection between vitamin C and plaque vulnerability, suggesting that vitamin C may inhibit the atherosclerotic inflammatory process by decreasing the expression of IL-6 and TNF-α, thereby reducing the risk of vulnerable plaques. These new findings provide crucial clues to identify anti-inflammatory dietary components as effective therapeutic approaches in the management of CHD, while also providing some insights into their mechanisms of action.

Urinary protein biomarker panel predicts esophageal squamous carcinoma from control cases and other tumors.

PURPOSE: Discovery of noninvasive urinary biomarkers for the early diagnosis of esophageal squamous carcinoma (ESCC). METHODS: We conducted proteomic analyses of 499 human urine samples obtained from healthy individuals (n = 321) and ESCC (n = 83), bladder cancer (n = 17), breast cancer (n = 12), colorectal cancer (n = 16), lung cancer (n = 33) and thyroid cancer (n = 17) patients from multiple medical centers. Those samples were divided into a discovery set (n = 247) and an independent validation set (n = 157). RESULTS: Among urinary proteins identified in the comprehensive quantitative proteomics analysis, we selected a panel of three urinary biomarkers (ANXA1, S100A8, TMEM256), and established a logistic regression model in the discovery set that can correctly classify the majority of ESCC cases in the validation sets with the area under the curve (AUC) values of 0.825. This urinary biomarker panel not only discriminates ESCC patients from healthy individuals but also differentiates ESCC from other common tumors. Notably, the panel distinguishes stage I ESCC patients from healthy individuals with AUC values of 0.886. On the analysis of stage-specific biomarkers, another combination panel of protein (ANXA1, S100A8, SOD3, TMEM256) demonstrated a good AUC value of 0.792 for stage I ESCC. CONCLUSIONS: Urinary biomarker panel represents a promising auxiliary diagnostic tool for ESCC, including early-stage ESCC.

A Study on Early Death Prognosis Model in Adult Patients with Secondary Hemophagocytic Lymphohistiocytosis.

Background: The mortality risks for secondary hemophagocytic lymphohistiocytosis in the induction stage and investigated prognostic factors need to be further discussed. Objective: The aim of this study is to establish a clinical model for predicting early death in adult patients with secondary hemophagocytic lymphohistiocytosis. Design, Participants, and Main Measures. The baseline characteristics, laboratory examination results, and 8-week survival rate of 139 adult sHLH patients diagnosed from January 2018 to December 2018 were analyzed retrospectively, and a prognostic model was constructed with low-risk (score 0-2), medium-risk (score 3), and high-risk (score ≥ 4) as parameters. Key Results. Univariate analysis confirmed that early death was not related to the type of HLH but significantly related to the patient's response to first-line treatment. The peripheral blood cell count was significantly decreased, C-reactive protein was higher, glutamyl transpeptidase and total bilirubin were higher, albumin was significantly lower, urea nitrogen was higher, hypocalcemia and hyponatremia, deep organ hemorrhage and D-dimer increased, cardiac function damage and HLH central involvement, sCD25 increased, and EB virus infection were predictive factors of early death. In the multivariate model, patients' response to first-line treatment was a good predictor of overall survival, and hypocalcemia and deep organ bleeding were associated with poor survival. The risk factors were scored and graded according to the risk ratio. The 8-week overall survival rates of the low-risk group (82 cases), medium-risk group (36 cases), and high-risk group (21 cases) were 85.4%, 52.8%, and 23.8%, respectively (P < 0.001). Conclusions: The early death of sHLH patients is closely related to some laboratory examination results. Attention should be paid to identify high-risk patients, choose effective first-line induction therapy, achieve deep remission as soon as possible, prevent deep organ bleeding, correct electrolyte disorders, and improve the early survival rate of sHLH patients.

EBV protection- and susceptibility-related HLA alleles and EBV status in the Chinese population: A single-center study.

BACKGROUND: Although most adults are infected by Epstein-Barr virus (EBV), some patients develop highly lethal diseases associated with EBV infection, including EBV-hemophagocytic lymphohistiocytosis (EBV-HLH), chronic active EBV infections (CAEBV), and lymphoma, the pathogeneses of which remain to be investigated. The human leukocyte antigen (HLA) complex may be associated with the viral infection pathway, and, therefore, HLA alleles may be associated with EBV-related diseases and subpopulations of infected cells, studies related to EBV-associated diseases, and subpopulations of infected cells that were conducted in China are scarce. METHODS: In this study, we analyzed the high-resolution HLA genotypes of 269 patients with EBV-associated diseases and 213 EBV-seronegative hematopoietic stem cell donors using PCR-SBT assay and elucidated the associations of HLA-A, -B, -C, -DRB1, and -DQB1 alleles with EBV-associated diseases in the Chinese population, Benjamini-Hochberg correction to adjust for multiple testing. HLA genotypes were also analyzed in patients with EBV-associated diseases showing EBV-infected lymphocyte subpopulations. RESULTS: We found that individuals carrying the following alleles showed the following levels of risks: HLA-DRB1*11 allele, reduced risk of EBV-related disease (OR [odds ratio]: 0.56; 95% confidence interval [95% CI]: 0.32-0.99; p < .05; Adjust p = .71); HLA-DQB1*06:02 allele, reduced risk (OR: 0.5699; 95% CI: 0.3486-0.9317; p < .05; Adjust p = .57); and HLA-B*15:01 allele, increased risk (OR: 1.763; 95% CI: 0.3486-0.9317; p < .05; Adjust p = .57). Patients with EBV-associated diseases showing the B*15:01 genotype had a higher risk of T-cell, NK-cell, and multicell infections than those with other genotype subgroups. CONCLUSIONS: These findings highlight the importance of HLA genotype for assessing EBV infectivity.

Dynamic proteomic change of tumor and immune organs in an immune-competent hepatocellular carcinoma mouse model.

Subcutaneous implantation of a human cancer cell line in immune-deficient mice (CDX) is a commonly used tool in preclinical studies for the assessment of potential anti-cancer drugs. As immunotherapy is transforming cancer treatment, tumor models in immunocompetent mice are necessary for us to understand the immune aspects of tumor biology. However, the systemic immune response to the implantation of cancer cells at proteome level is unclear. In this study, we characterized the dynamic proteomic changes of subcutaneous tumors and 5 immune organs (draining lymph node, mesenteric lymph node, spleen, thymus and marrow) at six time points after implantation using a Hepa1-6 derived allograft mouse model. Our data suggest that interaction of the implanted tumor cells with mouse immune system followed the trajectory of "tumor rejection" to "immune evasion" in that the tumor gained the ability to evade the immune system for growth. Furthermore, anti-PDL2 antibody was validated here as an optional immunotherapy strategy to inhibit the growth of Hepa1-6 subcutaneous tumors. These findings from our study provided valuable information for the understanding of tumor and immune interaction and shed light on the rational design for clinical cancer treatment and other preclinical experiments.

LM22B-10 promotes corneal nerve regeneration through in vitro 3D co-culture model and in vivo corneal injury model.

Corneal nerve wounding often causes abnormalities in the cornea and even blindness in severe cases. In this study, we construct a dorsal root ganglion-corneal stromal cell (DRG-CSC, DS) co-culture 3D model to explore the mechanism of corneal nerve regeneration. Firstly, this model consists of DRG collagen grafts sandwiched by orthogonally stacked and orderly arranged CSC-laden plastic compressed collagen. Nerve bundles extend into the entire corneal stroma within 14 days, and they also have orthogonal patterns. This nerve prevents CSCs from apoptosis in the serum withdrawal medium. The conditioned medium (CM) for CSCs in collagen scaffolds contains NT-3, IL-6, and other factors. Among them, NT-3 notably promotes the activation of ERK-CREB in the DRG, leading to the growth of nerve bundles, and IL-6 induces the upregulation of anti-apoptotic genes. Then, LM22B-10, an activator of the NT-3 receptor TrkB/TrkC, can also activate ERK-CREB to enhance nerve growth. After administering LM22B-10 eye drops to regular and diabetic mice with corneal wounding, LM22B-10 significantly improves the healing speed of the corneal epithelium, corneal sensitivity, and corneal nerve density. Overall, the DS co-culture model provides a promising platform and tools for the exploration of corneal physiological and pathological mechanisms, as well as the verification of drug effects in vitro. Meanwhile, we confirm that LM22B-10, as a non-peptide small molecule, has future potential in nerve wound repair. STATEMENT OF SIGNIFICANCE: The cornea accounts for most of the refractive power of the eye. Corneal nerves play an important role in maintaining corneal homeostasis. Once the corneal nerves are damaged, the corneal epithelium and stroma develop lesions. However, the mechanism of the interaction between corneal nerves and corneal cells is still not fully understood. Here, we construct a corneal stroma-nerve co-culture in vitro model and reveal that NT-3 expressed by stromal cells promotes nerve growth by activating the ERK-CREB pathway in nerves. LM22B-10, an activator of NT-3 receptors, can also induce nerve growth in vitro. Moreover, it is used as eye drops to enhance corneal epithelial wound healing, corneal nerve sensitivity and density of nerve plexus in corneal nerve wounding model in vivo.