An investigation of the immune epitopes of adeno-associated virus capsid-derived peptides among hemophilia patients.

Adeno-associated virus (AAV) is an optimal gene vector for monogenic disorders. However, neutralizing antibodies (Nabs) against AAV hinder its widespread application in gene therapy. In this study, we biosynthesized peptides recognized by the binding antibodies (Babs) from the sera containing high Nab titers against AAV2. We established four immunological methods to detect immune epitopes of the AAV2-derived peptides, including a Bab assay, Nab assay, B cell receptor (BCR) detecting assay, and immunoglobin-producing B cell enzyme-linked immunosorbent spot (B cell ELISpot) assay. Correlations among the epitopes determined by these four methods were analyzed using the serum samples and peripheral blood mononuclear cells (PBMC) from 89 patients with hemophilia A/B. As decoys, the peptides' ability to block the Nab of AAV2 particles was assessed using AAV transduction models both in vitro and in vivo. Overall, we provide insights into AAV2-capsid-derived peptide immune epitopes, involving the Nab, Bab, BCR, and B cell ELISpot assays, offering alternative immunological evaluation approaches and strategies to overcome Nab barriers in AAV-mediated gene therapy.

The predictive value of systemic immune-inflammatory markers before and after treatment for pathological complete response in patients undergoing neoadjuvant therapy for breast cancer: a retrospective study of 1994 patients.

PURPOSE: Systemic immune-inflammatory markers have a certain predictive role in pathological complete response (pCR) after neoadjuvant treatment (NAT) in breast cancer. However, there is a lack of research exploring the predictive value of markers after treatment. METHODS: This retrospective study collected data from 1994 breast cancer patients who underwent NAT. Relevant clinical and pathological characteristics were included, and pre- and post-treatment complete blood cell counts were evaluated to calculate four systemic immune-inflammatory markers: neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII). The optimal cutoff values for these markers were determined using ROC curves, and patients were classified into high-value and low-value groups based on these cutoff values. Univariate and multivariate logistic regression analyses were conducted to analyze factors influencing pCR. The factors with independent predictive value were used to construct a nomogram. RESULTS: After NAT, 383 (19.2%) patients achieved pCR. The area under the ROC curve is generally larger for post-treatment markers compared to pre-treatment markers. Pre-treatment NLR and PLR, as well as post-treatment LMR and SII, were identified as independent predictive factors for pCR, along with Ki-67, clinical tumor stage, clinical lymph node stage, molecular subtype, and clinical response. Higher pre-NLR (OR = 1.320; 95% CI 1.016-1.716; P = 0.038), pre-PLR (OR = 1.474; 95% CI 1.058-2.052; P = 0.022), post-LMR (OR = 1.532; 95% CI 1.175-1.996; P = 0.002), and lower post-SII (OR = 0.596; 95% CI 0.429-0.827; P = 0.002) are associated with a higher likelihood of achieving pCR. The established nomogram had a good predictive performance with an area under the ROC curve of 0.754 (95% CI 0.674-0.835). CONCLUSION: Both pre- and post-treatment systemic immune-inflammatory markers have a significant predictive role in achieving pCR after NAT in breast cancer patients. Indeed, it is possible that post-treatment markers have stronger predictive ability compared to pre-treatment markers.

Characteristics and outcomes of COVID-19 in Chinese immune thrombocytopenia patients: A prospective cohort study.

The coronavirus disease 2019 (COVID-19) pandemic has a significant impact on the immune system. This is the first and largest study on pre-existing immune thrombocytopenia (ITP) patients infected with COVID-19 in China. We prospectively collected ITP patients infected with COVID-19 enrolled in the National Longitudinal Cohort of Hematological Diseases (NICHE, NCT04645199) and followed up for at least 1 month after infection. One thousand and one hundred forty-eight pre-existing ITP patients were included. Two hundred and twelve (18.5%) patients showed a decrease in the platelet (PLT) count after infection. Forty-seven (4.1%) patients were diagnosed with pneumonia. Risk factors for a decrease in the PLT count included baseline PLT count <50 × 109/L (OR, 1.76; 95% CI, 1.25-2.46; p = 0.001), maintenance therapy including thrombopoietin receptor agonists (TPO-RAs) (OR, 2.27; 95% CI, 1.60-3.21; p < 0.001) and previous splenectomy (OR, 1.98; 95% CI, 1.09-3.61; p = 0.03). Risk factors for pneumonia included age ≥40 years (OR, 2.45; 95% CI, 1.12-5.33; p = 0.02), ≥2 comorbidities (OR, 3.47; 95% CI, 1.63-7.64; p = 0.001), maintenance therapy including TPO-RAs (OR, 2.14; 95% CI, 1.17-3.91; p = 0.01) and immunosuppressants (OR, 3.05; 95% CI, 1.17-7.91; p = 0.02). In this cohort study, we described the characteristics of pre-existing ITP patients infected with COVID-19 and identified several factors associated with poor outcomes.

Enhanced thermal, safety and anti-hygroscopicity performance of core-shell ammonium perchlorate with a double coating layer.

A new core-shell structure AP/Cu-DABT/Cu(Pa)2 (10 wt% each) (AP = ammonium perchlorate, DABT = 3,3'-diamino-5,5'-bis(1H-1,2,4-triazole), Pa = palmitic acid) with two coating layers was synthesized through two self-assembly reactions to improve the thermal decomposition performance, safety performance and moisture absorption resistance of AP. The results show that the surface of AP particles is uniformly and densely covered by Cu-DABT and Cu(Pa)2 coatings successively. Compared with pure AP, the HTD (high-temperature decomposition) peak temperature and activation energy of the AP/Cu-DABT/Cu(Pa)2 (10 wt% each) composite material were reduced by 74.7 °C and 117.67 kJ mol-1, respectively, and the heat release increased by 1421.02 J g-1. In addition, the burning rate and maximum flame temperature of the propellant containing the AP/Cu-DABT/Cu(Pa)2 (10 wt% each) composite were increased by 8.7 mm s-1 and 815.8 °C, respectively, compared with the propellant containing pure AP. Moreover, compared with pure AP, the contact angle of the AP/Cu-DABT/Cu(Pa)2 (10 wt% each) composite with water increased by 89.15°, and the water content decreased by 0.38 wt%. The impact sensitivity and friction sensitivity of the composite material were reduced by 16.9 cm and 96%, respectively. Analysis shows that the Cu-DABT coating plays a major role in improving the thermal properties of the composite material, the burning rate and flame temperature of the propellant, while the Cu(Pa)2 coating plays a major role in improving the hygroscopic performance and safety performance of the composite material. The composite material has good thermal decomposition properties, anti-hygroscopic properties and safety properties, so the composite material is very promising as a potential additive for solid propellants.

Clinical and Therapeutic Factors Vary by Prognosis in Patients with Pathological Complete Response After Neoadjuvant Therapy for Breast Cancer.

PURPOSE: To determine clinical predictors of recurrence and metastasis in patients with pathological complete response (pCR) after neoadjuvant chemotherapy (NCT). METHODS: Patients treated with NCT who achieved pCR (n=285) were classified into three groups according to pre-NCT clinical stage (cStage): group I (IIa-IIb), group II (IIIa), and group III (IIIb-IIIc). Survival was analysed using the Kaplan-Meier method. The relationships between clinicopathological factors and recurrence were determined using Cox regression analysis. RESULTS: The median follow-up was 31 months. The 3-year disease-free survival and overall survival rates in groups I, II, and III were 92.7%, 87.8%, and 66.7% (P < 0.01) and 98.6%, 98.3%, and 90.6% (P=0.370), respectively. Lymph node status and tumour size were independent risk factors for recurrence and metastasis after NCT. In the human epidermal growth factor receptor 2-positive subgroup, advanced cStage and lymph node metastasis were associated with recurrence (P < 0.01). In the hormone receptor-positive subgroup, disease-free survival rates differed for cStages I-II compared to cStage III (P=0.049) and clinical node status 0-2 compared to clinical node status 3 (P=0.037). CONCLUSION: Pre-NCT cStage predicted the prognosis of pCR for different breast cancer subtypes. Patients with advanced cStage, lymph node metastasis, and large tumour sizes had a higher risk of recurrence or metastasis.

Clinical Significance of Oncoplastic Breast-Conserving Surgery and Application of Volume-Displacement Technique.

ABSTRACT: Oncoplastic breast-conserving surgery for breast cancer has been continuously developing in recent years, and it has become an important part of breast cancer surgery. Its safety and aesthetics have been widely recognized by domestic and foreign experts. However, due to the complexity and diversity of individuals and diseases, and the need for integrating the thinking of breast surgery and plastic surgery, it is still a challenge for breast surgeons. This review summarizes the pros and cons of its clinical application through a comprehensive discussion of hot issues in oncoplastic breast-conserving surgery and introduces common volume-displacement techniques in the clinic for reference by doctors in daily work.

Tailoring neoadjuvant chemotherapy for patients with breast cancer who have achieved pathologic complete response.

BACKGROUND: We retrospectively examined whether different cycles of chemotherapy affected the prognosis of patients who achieved a pathologic complete response (pCR). METHODS: We reviewed data from patients who achieved pCR after neoadjuvant chemotherapy (NACT) between 2008 and 2018. In total, 286 patients were divided into three groups: group one (n=148, 52%) completed standard chemotherapy cycles before surgery, group two (n=81, 28%) did not complete standard chemotherapy cycles before surgery or received chemotherapy after surgery, and group three (n=57, 20%) did not complete standard chemotherapy cycles before surgery but completed them after surgery. Recurrence-free survival (RFS) was estimated using the Kaplan-Meier method, and differences between groups were evaluated by the log-rank test. Cox proportional hazards regression analysis was adjusted for different NACT groups, age, Ki-67 levels, and clinical stages. RESULTS: After a median follow-up of 26 months, there were no significant differences in RFS among the NACT groups (P=0.14). Multivariate analysis showed that Ki-67 ≥40% (P=0.03) and clinical stage (IIIB + IIIC) (P=0.002) might be risk factors for recurrence in patients with pCR. There were no significant differences in survival among subgroups according to Ki-67 levels and clinical stages. CONCLUSIONS: Our study suggests that, even with pCR, patients with baseline stage IIIB or IIIC or Ki-67 levels ≥40% may have an increased risk of recurrence. The RFS of patients with pCR was not associated with the completion of standard chemotherapy cycles, even in high-risk patients. Therefore, the prevention of excessive chemotherapeutic treatment by de-escalation is necessary for patients with pCR.

Characterization of binding interactions of anthraquinones and bovine ß-lactoglobulin.

Anthraquinones, a class of naturally occurring polyphenolic compounds, exhibit a wide range of bioactivities. However, most free anthraquinones are lipophilic bioactive compounds. Bovine ß-lactoglobulin (ßLG), a major whey protein, has a high affinity for small hydrophobic compounds. In this study, the interactions between anthraquinones (rhein, emodin, and chrysophanol) and ßLG were investigated by using fluorescence, circular dichroism (CD), Fourier-transform infrared spectroscopy (FTIR), and docking studies. These anthraquinones bound to the site near Trp19-Arg124 on ßLG with a binding constant (Ka) between 103 and 105 L mol-1 to form complexes, which changed the secondary structure of ßLG, inducing an α-helix to ß-sheet structure transition. The order of binding increased with an increasing polarity in the order of rhein > emodin > chrysophanol. In addition, the degree of radical scavenging capacity masking increased with an increasing binding affinity. Complexation with ßLG significantly increases the hydrosolubility of anthraquinones.

Circular RNA regulatory network reveals cell-cell crosstalk in acute myeloid leukemia extramedullary infiltration.

BACKGROUND: Acute myeloid leukemia can develop as myoblasts infiltrate into organs and tissues anywhere other than the bone marrow, which called extramedullary infiltration (EMI), indicating a poor prognosis. Circular RNAs (circRNAs) are a novel class of non-coding RNAs that feature covalently closed continuous loops, suggesting their potential as micro RNA (miRNA) "sponges" that can participate in biological processes and pathogenesis. However, investigations on circRNAs in EMI were conducted rarely. In this study, the overall alterations of circRNAs and their regulatory network between EMI and non-EMI AML were delineated. METHODS: CircRNA and whole genome microarrays derived from EMI and non-EMI AML bone marrow mononuclear cells were carried out. Functional analysis was performed via Gene Ontology and KEGG test methods. The speculated functional roles of circRNAs were based on mRNAs and predicted miRNAs that played intermediate roles. Integrated bioinformatic analysis was conducted to further characterize the circRNA/miRNA/mRNA regulatory network and identify the functions of distinct circRNAs. The Cancer Genome Atlas (TCGA) data were acquired to evaluate the poor prognosis of distinct target genes of circRNAs. Reverse transcription-quantitative polymerase chain reaction was conducted to identify the expression of has_circRNA_0004520. Connectivity map (CMap) analysis was further performed to predict potential therapeutic agents for EMI. RESULTS: 253 circRNAs and 663 genes were upregulated and 259 circRNAs and 838 genes were downregulated in EMI compared to non-EMI AML samples. GO pathways were enriched in progress including cell adhesion (GO:0030155; GO:0007155), migration (GO:0016477; GO:0030334), signal transduction (GO:0009966; GO:0007165) and cell-cell communication. Overlapping circRNAs envolved in pathways related to regulate cell-cell crosstalk, 17 circRNAs were chosen based on their putative roles. 7 target genes of 17 circRNAs (LRRK1, PLXNB2, OLFML2A, LYPD5, APOL3, ZNF511, and ASB2) indicated a poor prognosis, while overexpression of PAPLN and NRXN3 indicated a better one based on data from TCGA. LY-294002, trichostatin A and SB-202190 were identified as therapeutic candidates for EMI by the CMap analysis. CONCLUSION: Taken together, this study reveals the overall alterations of circRNA and mRNA involved in EMI and suggests potential circRNAs may act as biomarkers and targets for early diagnosis and treatment of EMI.