Efficacy of MAGE-A4 long peptide as a universal immunoprevention cancer vaccine.

BACKGROUND: The clinical application of peptide vaccines in tumor immunotherapy holds significant promise. Peptide-based tumor vaccines are currently subject to certain limitations in clinical trials, including the challenge of inducing a sustained response from CD4+ T helper cells and cytotoxic T lymphocytes (CTL), as well as human leukocyte antigen (HLA) restrictions. METHODS: Through the utilization of biological information methodology, a screening process was conducted to identify three potential long peptides that are specifically targeted by the MAGE-A4 antigen. The candidate long peptides were subjected to in vitro testing using human peripheral blood lymphocytes as samples to evaluate their immunogenicity and immune function. The antitumor properties and preliminary mechanism of the long peptide vaccine were investigated through the use of a mouse model designed for the prevention of triple negative breast cancer (TNBC). RESULTS: Three predicted multi-epitope long peptides targeting MAGE-A4 have shown to have a strong immunogenicity, with a total positive rate of 72% across different HLA subtypes in Chinese populations. they can also increase the levels of the costimulatory factor CD137 and tumor necrosis factor-alpha (TNF-α), activate T cells, and boost the cytotoxic activity. Results from an animal study have revealed that the long-peptide vaccine, both on its own and in combination with R848, has displayed impressive anti-tumor and target-specific capabilities. Moreover, it has the ability to increase the expression of effector memory T cells and central memory T cells. CONCLUSIONS: This study was the first to screen three multi-epitope long peptides targeting MAGE-A4 and assess their immunogenicity, immune function, and potential as adjuvant peptides. The results showed that the MAGE-A4 long peptide vaccine can be used as a novel immunoprophylaxis method to prevent TNBC. Moreover, the proposed development model is capable of screening multiple target antigens, which lead to its clinical application.

Design of a single-center, phase II trial to explore the efficacy and safety of 'R-ISV-RO' treatment in advanced tumors.

Background: The authors' preclinical study has confirmed that RO adjuvant (composed of TLR 7 agonists [imiquimod/R837] and OX40 agonists) injected into local lesions induces the regression of both primary tumor and distant metastasis. The authors propose to realize local control and exert abscopal effect through an 'R-ISV-RO' in situ strategy plus anti-PD-1 monoclonal antibody in advanced tumors. Methods: This study is a single-center, exploratory, phase II trial to evaluate the efficacy and safety of R-ISV-RO plus anti-PD-1 monoclonal antibody in advanced tumors. 30 patients with one or more measurable extracerebral lesions that are accessible for radiation or injection will be enrolled. The primary endpoint is the objective response rate of target lesions. Discussion/Conclusion: The efficacy and safety of the novel strategy will be further validated through this clinical trial.Clinical trial registration: ChiCTR2100053870 (www.chictr.org.cn/).

[Box: see text].

iRGD-modified memory-like NK cells exhibit potent responses to hepatocellular carcinoma.

BACKGROUND: Cytokine-induced memory-like natural killer (CIML NK) cells have been found to possess potent antitumor responses and induce complete remissions in patients with leukemia. However, the poor infiltration of transferred NK cells is a major obstacle in developing adoptive cell immunotherapy for solid tumors. In our study, we explored the potential of using the tumor-penetrating peptide iRGD to deliver activated CIML NK cells deep into tumor tissues. METHODS: After being briefly stimulated with interleukin-12 (IL-12), IL-15, and IL-18, CIML NK cells were assessed for their phenotype and function with flow cytometry. The penetrating and killing capability of iRGD-modified CIML NK cells in tumor spheroids was revealed by confocal microscopy. The anti-tumor efficacy of these modified CIML NK cells was tested in hepatocellular carcinoma (HCC) xenograft mouse models. RESULTS: Treating NK cells with cytokines led to a substantial activation, which was evidenced by the upregulation of CD25 and CD137. After a resting period of six days, CIML NK cells were still able to display strong activation when targeting HepG2 and SK-Hep-1 HCC cell lines. Additionally, CIML NK cells produced increased amounts of cytokines (interferon-gamma and tumor necrosis factor alpha) and exhibited heightened cytotoxicity towards HCC cell lines. The iRGD modification enabled CIML NK cells to infiltrate multicellular spheroids (MCSs) and, consequently, to induce cytotoxicity against the target cancer cells. Moreover, the CIML NK cells modified with iRGD significantly decreased tumor growth in a HCC xenograft mouse model. CONCLUSION: Our findings demonstrate that CIML NK cells possess augmented potency and durability against HCC cell lines in vitro. Additionally, we have seen that the incorporation of iRGD to CIML NK cells facilitates enhanced infiltration and targeted destruction of MCSs. Moreover, the application of iRGD-modified CIML NK cells reveal remarkable anti-tumor efficacy against HCC in vivo.

Fatal multiple organ dysfunction caused by commensal bacteria of urogenital tract infection in adult lung transplant recipients: two case reports.

BACKGROUND: Infection following lung transplantation has been the focus of clinical concerns. The colonization rate of commensal bacteria of the urogenital tract, including Mycoplasma hominis, Ureaplasma urealyticum (UU), and herpes simplex virus type-2 (HSV-2), is high, which may cause secondary infection after transplantation. CASE PRESENTATION: Twenty-three-year-old and 67-year-old women underwent lung transplantation for different causes. Shortly after the operation, they developed perineal skin ulcers, hypoxia, and intractable epilepsy. Subsequent computed tomography (CT) of the chest showed lung consolidation, and cranial CT showed shallowing sulci and gyri. UU and HSV-2 were detected in bronchoalveolar lavage fluid by next-generation sequencing, and HSV-2 was shown in the cerebrospinal fluid of both patients. Despite active treatment, both suffered irreversible brain function damage within 72 h of the seizure. CONCLUSIONS: Clinicians should know that commensal bacteria of urogenital tract infections can lead to fatal multiple organ dysfunction after lung transplantation.

[The early diagnostic value of urinary Sema3A for ICU adult patients with acute kidney injury].

OBJECTIVE: To research the early diagnosis value of Semaphorin3A as a biaomarker on acute kidney injury(AKI) in adult intensive care unit (ICU), and explore the relationship between Sema3A and sepsis. METHODS: The objects of the study are patients who were enrolled from July 2013 to December 2013 in XiangYa Hospital ICU. After admission and study enrollment, clinical data were recorded, and every 12 h serum, urinary samples were collected for Sema3A and neutrophil gelatinase associated lipocalin (NGAL) detected by enzyme linked immunosorbent assay (ELISA). According to the development of AKI, patients were divided into AKI group and non-AKI group. According to whether the AKI induced by sepsis, patients were divided into AKI-sepsis group, AKI-non-sepsis group, non-AKI-sepsis-group, non-AKI-and-non-sepsis group. The samples were selected in AKI group when AKI was diagnosed and 24 h before, the time when AKI diagnosed was counted as T (0) h, the other times were counted as T (-12) h, T (-24) h. In non-AKI group, the samples of the first three time points after admission were selected, and counted as T (0) h, T (-12) h, T (-24) h, respectively. Date was collected for statistical analysis. RESULTS: Compared with non-AKI group, AKI urinary Sema3A, urinary NGAL is higher, and the difference was statistically significant. In group AKI urinary Sema3A, urinary NGAL concentration change over time and there is an increasing trend, where the T (-24) h and T (0) h, T (-12) h and T (0) h respective comparison, the difference was statistically significant. Correlation Analysis: T (-24) h urinary Sema3A and urinary NGAL were positively correlated with serum creatinine, APACHE II. The AUC of urinary Sema3A with T (-12) h had the largest area of 0.885 (95% CI 0.774-0.997, P < 0.05); the AUC of urinary NGAL with T (-24) h had the largest area of 0.878 (95% CI 0.788-0.993, P < 0.05).There was no significant difference between sepsis group and non-sepsis group Sema3A, but there is significant difference between the two groups NGAL. There was no significant difference between S-AKI group and non-S-AKI group urinary Sema3A, but urinary NGAL were significantly different between the two groups. Compared with survival group, urinary Sema3A of death group was higher, and the difference was statistically significant. CONCLUSION: Urinary Sema3A can help early diagnose of adult AKI. Compared to urinary NGAL, the concentration of urinary Sema3A was not affected by sepsis, and will be more useful for prediction.

Mycobacterium smegmatis enhances shikonin-induced immunogenic cell death-an efficient in situ tumor vaccine strategy.

Tumor vaccines are a promising avenue in cancer immunotherapy. Despite the progress in targeting specific immune epitopes, tumor cells lacking them can evade treatment. Here, we aimed to construct an efficient in situ tumor vaccine Vac-SM, utilizing shikonin (SKN) to induce immunogenic cell death (ICD) and Mycobacterium smegmatis ( M. smegmatis) as an immune adjuvant to enhance in situ tumor vaccine efficacy. SKN demonstrated a dose-dependent and time-dependent cytotoxic effect on the tumor cell line as seen using the CCK-8 assay and induced ICD in tumor cells by detecting the expression of relevant indicators respectively. Compared to that in the control groups, in situ Vac-SM injection in mouse subcutaneous metastatic tumors significantly inhibited tumor growth and distant tumor growth and improved survival rates. M. smegmatis effectively induced bone marrow-derived dendritic cells (DC) maturation and activation and in vivo tumor-draining lymph nodes showed increased maturation of DC and a higher proportion of effector memory T-cell subsets with Vac-SM treatment, based on flow cytometry analysis results.Collectively, Vac-SM vaccine effectively induces ICD, improves antigen presentation by DC, activates a specific systemic antitumor T-cell immune response, exhibits favorable safety profile, and holds promise for clinical translation for local tumor immunotherapy.

Identification of VEGFs-related gene signature for predicting microangiogenesis and hepatocellular carcinoma prognosis.

Microangiogenesis is an important prognostic factor in various cancers, including hepatocellular carcinoma (HCC). The Vascular Endothelial Growth Factor (VEGF) has been shown to contribute to tumor angiogenesis. Recently, several studies have investigated the regulation of VEGF production by a single gene, with few researchers exploring all genes that affect VEGF production. In this study, we comprehensively analyzed all genes affecting VEGF production in HCC and developed a risk model and gene-based risk score based on VEGF production. Moreover, the model's predictive capacity on prognosis of HCCs was verified using training and validation datasets. The developed model showed good prediction of the overall survival rate. Patients with a higher risk score experienced poor outcomes compared to those with a lower risk score. Furthermore, we identified the immunological causes of the poor prognosis of patients with high-risk scores comparing with those with low-risk scores.

Lysosome targeting fluorescent probe for NAAA imaging and its applications in the drug development for anti-inflammatory.

N-acylethanolamine acid amidase (NAAA) is a nucleophilic lysosomal cysteine hydrolase, which primarily mediates the hydrolytic inactivation of endogenous palmitoylethanolamide (PEA), which further influences the inflammatory process by regulating peroxisome proliferator-activated receptor-α (PPAR-α). Herein, a novel lysosome (Lyso)-targeting fluorescent probe (i.e., PMBD) was designed and synthesized for detecting endogenous NAAA selectively and sensitively, allowing real-time visual monitoring of endogenous NAAA in living cells. Moreover, PMBD can target Lyso with a high colocalization in Lyso Tracker. Finally, a high-throughput assay method for NAAA inhibitor screening was established using PMBD, and the NAAA-inhibitory effects of 42 anti-inflammatory Traditional Chinese medicines were evaluated. A novel potent inhibitor of NAAA, ellagic acid, was isolated from Cornus officinalis, which can suppress LPS-induced iNOS upregulation and NO production in RAW264.7 cells that display anti-inflammatory activities. PMBD, a novel Lyso-targeting fluorescent probe for visually imaging NAAA, could serve as a useful molecular tool for exploring the physiological functions of NAAA and drug development based on NAAA-related diseases.

A near-infrared fluorescent probe based on a hemi-cyanine skeleton for detecting CES1 activity and evaluating pesticide toxicity.

A novel near-infrared (NIR) fluorescent probe CHC-CES1 based on a hemi-cyanine skeleton for detecting carboxylesterase 1 (CES1) activity was developed. Herein, CHC-CES1 could be specifically hydrolysed to CHC-COOH along with a significant NIR fluorescence signal enhancement at 670 nm. Systematic evaluation indicated that CHC-CES1 possessed an outstanding selectivity and sensitivity towards CES1, and possessed good chemical stability in complex biosamples. Finally, CHC-CES1 was successfully used for the real-time imaging of endogenous CES1 activity in living cells. Moreover, CHC-CES1 was applied to evaluate the inhibitory effects of various pesticides towards CES1, and visually revealed the inhibitory effect of combined residue pesticides.

Nanomodified Switch Induced Precise and Moderate Activation of CAR-T Cells for Solid Tumors.

Chimeric antigen receptor (CAR)-T cell therapy is a transformative treatment against advanced malignancies. Unfortunately, once administrated in vivo, CAR-T cells become out of artificial control, and fierce response to CAR-T therapy may cause severe adverse events, represented by cytokine-release syndrome and on-target/off-tumor effects. Here, a nanomodified switch strategy is developed, leading to sustained and precise "on-tumor only" activation of CAR-T cells. Here, original gelatinase-responsive nanoparticles (NPs) are used to selectively deliver the heterodimerizing switch, which is the key component of switchable CAR with separated activation modules. The "NanoSwitch" is tumor-specific, thus inactivated switchable CAR-T cells do little harm to normal cells, even if the normal cells express the target of CAR-T. Owing to the sustained-release effect of NPs, the CAR-T cells are activated smoothly, avoiding sudden release of cytokine. These data introduce NanoSwitch as a universal and applicable solution to safety problems of CAR-T therapy regardless of the target.

Hemorrhagic Fever with Renal Syndrome Complicated with Acute Pancreatitis and Capillary Cholangitis: A Case Report.

Hemorrhagic fever with renal syndrome (HFRS), caused by hanta viruses (HTNV), can be complicated by severe complications. Seventeen percent of the HFRS patients with abdominal pain had acute pancreatitis (AP). The reported prevalence of AP among HFRS patients has a conspicuous high mortality rate. Of note, acute capillary cholangitis (ACC) among HFRS patients presenting with abdominal pain appears extremely rare, particularly independent of HFRS patients complicated with AP. The main pathophysiological mechanism of HFRS complicated with AP and ACC may be that it preferentially damages the microvascular and induces plasma leakage. To date, the management of severe HFRS cases is mainly based on supportive treatment, including extracorporeal blood purification and mechanical ventilation. Here, we describe an exceptionally rare case of a 34-year man who developed HFRS with AP and ACC while improving from HTNV infection via antiviral and supportive treatment.

Advanced Pancreatic Cancer Patient Benefit From Personalized Neoantigen Nanovaccine Based Immunotherapy: A Case Report.

Personal neoantigen vaccines are considered to be effective methods for inducing, amplifying and diversifying antitumor T cell responses. We recently conducted a clinical study that combined neoantigen nanovaccine with anti-PD-1 antibody. Here, we reported a case with a clear beneficial outcome from this treatment. We established a process that includes comprehensive identification of individual mutations, computational prediction of new epitopes, and design and manufacture of unique nanovaccines for this patient. Nanovaccine started after a relapse in third-line treatment. We assessed the patient's clinical outcome and circulating immune response. In this advanced pancreatic cancer patient, the OS associated with the vaccine treatment was 10.5 months. A peptide-specific T-cell response against 9 of the 12 vaccine peptides could be detected sequentially. Robust neoantigen-specific T cell responses were also detected by IFN-γ ELISPOT and intracellular cytokine staining. In conclusion, sustained functional neoantigen-specific T cell therapy combined with immune checkpoint targeting may be well suited to help control progressive metastatic pancreatic cancer.

Benefits of an Immunogenic Personalized Neoantigen Nanovaccine in Patients with High-Risk Gastric/Gastroesophageal Junction Cancer.

Personalized neoantigen vaccines have shown strong immunogenicity in clinical trial, but still face various challenges in facilitating an efficient antitumor immune response. Here, a personalized neoantigen nanovaccine (PNVAC) platform for adjuvant cancer immunotherapy is generated. PNVAC triggers superior protective efficacy against tumor recurrence and promotes longer survival than free neoantigens, especially when combined with anti-PD-1 treatment in a murine tumor model. A phase I clinical trial (ChiCTR1800017319) is initiated to evaluate the safety, immunogenicity, and prophylactic effect of PNVAC on preventing tumor recurrence in patients with high-risk gastric/gastroesophageal junction cancer after adjuvant chemotherapy of postsurgical resection. The one- and two-year disease-free survival rates are significantly higher than historical record. PNVAC induces both CD4+ and CD8+ T cell responses as well as antigen-experienced memory T cell phenotype. Furthermore, the immune response is persistent and remains evident one year after the vaccination. This work provides a safe and feasible strategy for developing neoantigen vaccines to delay gastric cancer recurrence after surgery.

Rational design of a fluorescent probe for the detection of LAP and its application in drug-induced liver injury.

Drug-induced liver injury (DILI) has become a common adverse effect in routine clinical practice, which would further cause the disorder of enzymatic system that respond to multiple pathological progresses. Leucine aminopeptidase (LAP) is regarded as a biomarker in the early course of various liver diseases, in this work, a fluorescent probe NCPL was designed and synthesized for the detecting of LAP. NCPL possessed excellent properties including high selectivity, sensitivity and affinity toward LAP, it could real-time image the LAP activity in living cells and tissues. Additionally, the upregulation of LAP under the APAP-induced liver injury model was also illustrated by NCPL. In conclusion, NCPL as a novel tool could be used for the detection of LAP and monitoring liver function in clinic.

Corrigendum to "Rational design of a fluorescent probe for the detection of LAP and its application in drug-induced liver injury" [Spectrochim. Acta A Mol. Biomol. Spectrosc. 251 (2021) 119362].

The purpose of this corrigendum to the published work by the author Liu et al. (2021) is to correct the wrong use of Figures during the proof.

A NIR fluorescent probe for fatty acid amide hydrolase bioimaging and its application in development of inhibitors.

Fatty acid amide hydrolase (FAAH) is primarily responsible for the inactivation of fatty acid ethanolamide (FAE) and is involved in a variety of biological functions related to diseases of the nervous system. Herein, we developed a highly selective and sensitive FAAH-activated near-infrared fluorescent probe named DAND and achieved the real-time detection and imaging of FAAH activity in complex biosystems. Moreover, a visual high-throughput screening method was established using DAND, piperine was identified as a novel inhibitor of FAAH. Based on the interaction of piperine with FAAH, a more potent FAAH inhibitor (11f) was designed and synthesized which possessed an IC50 value of 0.65 µM. Furthermore, 11f could attenuate the liposaccharide (LPS)-induced activation of BV2 cells, exhibiting an excellent anti-inflammatory activity. These results indicated that DAND could be used as a promising molecular tool for exploring FAAH activity and for rapidly screening potential FAAH inhibitors. In addition, piperine and its derivatives could serve as potential candidate drugs for the treatment of neurodegenerative diseases in the future.

Predictive values of diffusion-weighted imaging and perfusion-weighted imaging in evaluating the efficacy of transcatheter arterial chemoembolization for hepatocellular carcinoma.

This study explored the predictive values of diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) in evaluating the efficacy of transcatheter arterial chemoembolization (TACE) for patients with hepatocellular carcinoma (HCC). A total of 118 HCC patients treated with TACE were selected from April 2013 to November 2015. T1-weighted imaging (T1WI)/T2-weighted imaging (T2WI), DWI, and PWI were performed on all patients before and after TACE. Efficacy was evaluated according to modified Response Evaluation Criteria in Solid Tumors 1.1. Receiver operating characteristic curve was used to evaluate the diagnostic power of quantitative DWI and PWI parameters in evaluating the efficacy of TACE for HCC patients. Among the 118 HCC patients, there were 17 cases (14.4%) with complete response, 50 cases (42.4%) with partial response, 28 cases (23.7%) with stable disease, and 23 cases (19.5%) with progressive disease. There were 67 patients in the effective group (complete response + partial response) and 51 patients in the ineffective group (stable disease + progressive disease). Before TACE, there were significant differences in maximum tumor diameter (MTD), apparent diffusion coefficient (ADC), slow ADC (Dslow), fast ADC (Dfast), transfer constant of vessel at the maximum level (Ktrans), and rate constant of backflux (Kep) between the effective and ineffective groups (all P<0.05). After TACE, the effective group exhibited lower MTD, Dfast, and Kep and higher ADC and Dslow than the ineffective group (all P<0.05). Tumor regression rate negatively correlated with MTD, Ktrans, Kep, and Dfast but positively correlated with ADC and Dslow. Receiver operating characteristic curve analysis suggested that the area under the curve of ADC, Dslow, Dfast, Ktrans, and Kep were 0.869, 0.833, 0.812, 0.802, and 0.809, respectively. In conclusion, these results suggest that quantitative DWI and PWI parameters might be useful in evaluating the efficacy of TACE in the treatment of HCC patients.

[MSCT imaging research on atlanto-axial joint in rotary functional position].

OBJECTIVE: To provide quantitative foundation for the diagnosis of atlanto-axial rotatory subluxation by analyzing the various imaging features of normal atlanto-axial joints in neutral position and rotary functional position on the MSCT images. METHODS: Forty-one normal volunteers were examined by CT on the atlanto-axial joint in neutral position and rotary functional position. By the observation and measurement of atlanto-dental interval (ADI), lateral atlanta-dental space (LADS), VBLADS and rotating angle of atlas on dentate (RAAD), the imaging manifestations and anatomical characteristics were analyzed and compared. In order to compare VBLADS and RAAD and make a correlation analysis between different age groups, 51 normal volunteers were divided into two groups: age younger than 45 years old group and age older than or equal to 45 years old group. RESULTS: The dens in neutral position deviated in an angle range of (3.22±0.89)°. The articular facets of lateral atlantoaxial joint in rotary functional position had rotatory displacement and the range of the relative rotation angle was (33.85± 2.79)°. Through the correlation analysis of matching data, it could be concluded that there was no correlation between atlantoaxial relative rotation angle and VBLADS within a certain range. There were statistically differences of atlantoaxial relative rotation angle in rotary functional position between two groups. CONCLUSION: MSCT imaging in rotary functional position can clearly show the anatomical structure and rotation function of a normal atlanto-axial joint, so as to provide a theoretical basis for the diagnosis of atlanto axial rotatory subluxation.