Safety, tolerability, pharmacokinetics and immunogenicity of an antibody-drug conjugate (SHR-A1201) in patients with HER2-positive advanced breast cancer: an open, phase I dose-escalation study.

SHR-A1201 is an antibody-drug conjugate (ADC) that combines trastuzumab with DM1 (a chemotherapeutic agent) using a chemical connector. This phase I study investigated the safety, tolerability and pharmacokinetics of SHR-A1201 in patients with human epidermal growth factor receptor 2-positive advanced breast cancer. This phase I study enrolled patients in a traditional 3 + 3 dose-escalation design to receive a single dose of SHR-A1201 (1.2 mg/kg, 2.4 mg/kg, 3.6 mg/kg or 4.8 mg/kg). The observation period of dose-limiting toxicity (DLT) was 21 days. A total of 12 patients were enrolled and received SHR-A1201. Most treatment-emergent adverse events (TEAEs) were grade 1 or 2 in severity, with elevated aspartate aminotransferase (75%), thrombocytopenia (75%), and nausea (66.7%) being reported most frequently. The common grade 3 TEAEs were thrombocytopenia and decreased lymphocyte count, and there were no grade 4 or above TEAEs. There were no serious adverse events or drug-related deaths. One DLT occurred in one patient treated with SHR-A1201 4.8 mg/kg (asymptomatic grade 3 increased γ-glutamyltransferase). The maximum tolerated dose of SHR-A1201 was not lower than that of T-DM1 (3.6 mg/kg). A total of 8.3% (1/12) of patients had ADA-positive reactions 504 h after administration, but no differences were observed in the type, incidence, or severity of TEAEs between patients with and without ADA. SHR-A1201 exhibited the pharmacokinetics characteristics of typical ADCs. An encouraging antitumor effect was observed in the 4.8 mg/kg dose group. SHR-A1201 was well tolerated and safe in patients with advanced HER2-positive breast cancer. The pharmacokinetics parameters showed a linear trend, and the immunogenicity results met the clinical expectations.

Identification of prognostic genes for early basal-like breast cancer with weighted gene co-expression network analysis.

BACKGROUND: Breast cancer (BC) has become the leading cause of death for women's malignancies and increasingly threatens the health of women worldwide. However, there is a lack of effective targeted drugs for basal-like BC. Therefore, biomarkers related to the prognosis of early BC need to be identified. METHODS: The RNA-seq data of 87 cases of early basal-like BC and 111 cases of normal breast tissue from The Cancer Genome Atlas were explored by the weighted gene co-expression network analysis method and Limma package. Then, intersected genes were identified, and hub genes were selected by the maximal clique centrality method. The prognostic effect of the hub genes was also evaluated in early basal-like BC. RESULTS: In total, 601 IGs were identified in this study. An APPI network was constructed, and the top 10 hub genes were selected, namely, cyclin B1, cyclin A2, cyclin-dependent kinase 1, cell division cycle 20, DNA topoisomerase II alpha, BUB1 mitotic checkpoint serine/threonine kinase, aurora kinase B (AURKB), cyclin B2, kinesin family member 11, and assembly factor for spindle microtubules. Only AURKB was found to be significantly associated with the overall prognosis of early basal-like BC. The immune cell infiltration analysis showed that the infiltration numbers of CD4 + T cells and naïve CD8 + T cells were positively correlated with the AURKB expression level, while those of naïve B cells and macrophage M2 cells were negatively correlated with the AURKB expression level in basal-like BC. CONCLUSION: AURKB might be a potential prognostic indicator in early basal-like BC.

Consistent expression of PD-L1 in tumor microenvironment with peripheral PD-1/PD-L1 in circulating T lymphocytes of operable breast cancer: a diagnostic test.

BACKGROUND: The expression of PD-L1 in the immune microenvironment can guide the application of immunosuppressants. In order to monitor the immune status of the body, repeated biopsies have to be taken. Our research aims to find new and convenient means to evaluate this indicator. METHODS: Eighty-three cases of newly diagnosed operable breast cancer without receiving preoperative treatment, were recruited from Beijing Shijitan Hospital between November 2018 and November 2019. The expression of PD-1/PD-L1 on circulating T lymphocytes was detected by flow cytometry and the expression of PD-L1 on immune cells in tumor microenvironment was detected by immunohistochemistry. RESULTS: The median percentage of positive PD-1 and PD-L1 expression on circulating T lymphocytes was 15.2% and 0.7%, respectively. The peripheral PD-1 had no relationship with clinicopathological characteristics, but the peripheral PD-L1 expression had a correlation with lymph node metastasis (p = 0.005) and Her-2 expression (p = 0.034) (p < 0.05). The positive rate of PD-L1 expression was 32.9% in tumor microenvironment. PD-L1 expression in tumor microenvironment had a significant correlation with PD-1/PD-L1 expression on circulating T lymphocytes, the correlation coefficients being 0.24 (p < 0.05) and 0.26 (p < 0.05), respectively. To predict the PD-L1 expression in tumor microenvironment, the area under the receiver operating characteristic curve was 0.65 and 0.66 for peripheral PD-1 and PD-L1, respectively. High level of peripheral PD-1/PD-L1 expression was associated with the odds ratios of 5.42 and 4.76 for positive PD-L1 expression in tumor microenvironment. CONCLUSION: Peripheral PD-1/PD-L1 expression had a significant consistency with PD-L1 expression in tumor microenvironment and could act as an alternative choice of tissue detection, for the patients intolerable of biopsy.

Screening potential immune signatures for early-stage basal-like/triple-negative breast cancer.

BACKGROUND: Breast cancer (BC) is a highly heterogeneous disease. Among the BC molecular subtypes, basal-like/triple-negative BC (TNBC) is characterized by a high propensity for relatively early metastases and a lack of available endocrine and targeted therapies. Therefore, this study aimed to discover potential signatures for predicting the immune response in early-stage basal-like/triple-negative BC. METHOD: A total of 86 cases of early-stage TNBC from the TCGA and 459 cases of normal breast tissue from GTEx were enrolled and analyzed to screen out differentially expressed genes (DEGs). Then, the prognostic effect and tumor immune cell infiltration relationship with the basal-like-specific DEGs were also evaluated. RESULTS: A total of 1556 DEGs, including 929 upregulated genes and 627 downregulated genes, were screened in early-stage basal-like BC. Two prognosis-associated DEGs, GAL and TTC36, were finally found to be basal-like BC specific. However, only GAL was significantly correlated with tumor immune-infiltrating cells, especially CD8+ T cells. The expressions of GAL and TTC36 were revalidated by using the GEO dataset. CONCLUSION: GAL might be an immune signature for the response to immune checkpoint therapy in early basal-like/triple-negative BC.

miR-509-3p Suppresses Migration, Invasion, and Epithelial- Mesenchymal Transition in Melanoma Cells by Targeting Collagen Triple Helix Repeat Containing 1.

BACKGROUND: microRNAs (miRNAs) are ubiquitously dysregulated in numerous tumor cell types, including melanoma cells. The anti-tumor effect of miR-509-3p was widely evaluated in various cancers. AIMS: To determine the functional role of miR-509-3p in melanoma. STUDY DESIGN: Cell culture study. METHODS: Expression of miR-509-3p in melanoma cell models were assessed by qRT-PCR. Cell migration and invasion were analyzed by wound healing and transwell assays, respectively. Expression levels of biomarkers of epithelial-mesenchymal transition were determined by Western blot. Luciferase vectors containing wildtype or mutant miR- 509-3p binding site were constructed, and then dual-luciferase reporter assay. RESULTS: Dysregulated miR-509-3p level was found in melanoma cells. Elevated miR-509-3p expression suppressed melanoma cell migration (P < .001) and invasion (P < .001) capacities. Epithelial-mesenchymal transition of melanoma cells was repressed by miR-509-3p, along with increased α-catenin/E-cadherin (P < .001) and decreased vimentin/ fibronectin (P < .001). CTHRC1 (collagen triple helix repeat containing 1) contained a potential binding site for miR-509-3p, and miR- 509-3p decreased protein expression of CTHRC1 in melanoma cells (P < .001). CTHRC1 promoted melanoma cell migration and invasion (P < .001), as well as contributed to epithelial-mesenchymal transition. Increased CTHRC1 expression attenuated miR-509-3p-induced inhibition of melanoma cell migration (P < .001), invasion, and epithelial- mesenchymal transition. CONCLUSION: miR-509-3p suppressed the biological function of melanoma cells through negatively regulating CTHRC1, shedding light on miR-509-3p as a potential candidate for melanoma therapeutics and treatments.

Overexpression of CD155 is associated with PD-1 and PD-L1 expression on immune cells, rather than tumor cells in the breast cancer microenvironment.

BACKGROUND: CD155 is an immune checkpoint protein in cancers and interacts with ligands to regulate the immune microenvironment. The expression of CD155 is correlated with the prognosis and pathological features of breast cancer. AIM: To investigate the expression status of CD155 and the association with exhausted CD4+ helper and CD8+ cytotoxic tumor infiltrating lymphocytes (TILs) and PD-L1 in the breast cancer microenvironment. METHODS: One hundred and twenty-six breast cancer patients with invasive ductal breast cancer were consecutively recruited into this study. Immunohistochemistry was used to detect the expression CD155, PD-L1 and PD-1 on tumor-infiltrating immune cells and tumor cells in the microenvironment. RESULTS: The proportion of patients with CD155 expression was higher in triple negative breast cancer (72.7%) than in Luminal A patients (22.2%, P < 0.05). Patients with positive CD155 expression had a higher percentage of CD4+/PD-1+ helper TILs (30%) than patients with negative CD155 expression (21%, P < 0.05). Patients with positive CD155 expression also had higher cell counts of exhausted CD4+ TILs [47 vs 20/high-power fields (HPF)] and unexhausted CD8+ TILs (30 vs 17/HPF) than patients with negative expression (P < 0.05). CD155 expression was correlated with increased PD-L1 expression in immune cells, 0.8% and 0.02% immune cells expressed PD-L1 in patients with positive and negative CD155 expression, respectively (P < 0.05). CONCLUSION: CD155 was related to an inhibitory immune breast cancer microenvironment. CD155 was associated with a high proportion of exhausted CD4+ and unexhausted CD8+ TILs and high PD-L1 expression in immune cells.

Lipid storage droplet protein 5 reduces sodium palmitate­induced lipotoxicity in human normal liver cells by regulating lipid metabolism­related factors.

Lipid storage droplet protein 5 (LSDP5) is specifically expressed in tissues with high oxidative metabolism such as liver and heart. The present study aimed to explored the role of LSDP5 in sodium palmitate­induced lipotoxicity in LO2 normal human liver cells. LO2 cells were treated with various concentrations of sodium palmitate (25, 50, 75, 100, 125 and 150 µmol/l) for 12, 24 and 48 h, and cell viability was determined by Cell Counting Kit­8. Subsequently, LO2 cells were exposed to 100 µmol/l sodium palmitate for 48 h to induce lipotoxicity (Model). Lipotoxicity Model LO2 cells were also transfected with pCMV5­LSDP5 overexpression vector, and reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) and apoptotic rates were measured. The contents of non­esterified fatty acid (NEFA), malondialdehyde (MDA) and superoxide dismutase (SOD) were also measured. The expression levels of LSDP5, and apoptosis­, mitochondrial­, lipid metabolism­related factors were detected using reverse transcription­quantitative polymerase chain reaction and western blot assays. The results indicated that sodium palmitate exposure inhibited cell viability and induced lipotoxicity in LO2 cells. LSDP5 overexpression decreased ROS and apoptotic rates, and reduced NEFA and MDA content. LSDP5 transfection rescued the loss of MMP and elevated SOD content in lipotoxicity Model LO2 cells. In addition, LSDP5 upregulated the expression levels of B­cell lymphoma­2, acetyl­CoA carboxylase1/2 and fatty acid synthase (Fas), whereas the expression levels of activated­caspase­3, Bcl­2­associated X protein, cytochrome c, cytochrome c oxidase subunits IV, carnitine palmitoyltransferase 1a and peroxisome proliferator­activated receptors α levels were downregulated. LSDP5 may produce a protective effect on sodium palmitate­induced lipotoxicity in LO2 cells by regulating lipid metabolism­related factors.

Notch Signaling: A Potential Therapeutic Target for Hematologic Malignancies.

Notch signaling is a well-conserved cell-fate determining factor in embryo development, and the dyregulation of this signaling is frequently observed in many types of cancers, including hematological malignancies. In this review, we briefly describe the Notch signaling pathway, and we primarily focus on the relationship between Notch and hematological malignancies. We also discuss the clinical development of promising agents including γ-secretase inhibitors (GSIs) and monoclonal antibodies (mAbs). Complete response has been observed among patients with T-cell acute lymphoblastic leukemia (T-ALL) when treated with GSIs. Furthermore, a recent study has suggested that targeting Zmiz1, a direct, selective cofactor of Notch1, rather than targeting Notch directly, maybe helpful to reduce the current target-related toxicities. Taken together, we summarize the role of Notch signaling in hematological malignancies and discuss the treatment strategies for these diseases through targeting Notch signaling.

Allergic transfusion reaction caused by the shrimp allergen of donor blood: a case report.

OBJECTIVE: The purpose of this report is to analyze the cause of allergic transfusion reaction. METHODS: The methods of immunoblot and immunonephelometry were applied to detect the levels of the immunoglobulins of IgA (Immunoglobulin A) and IgE (Immunoglobulin E) and the level of sIgE (specific Immunoglobulin E) to shrimp allergen both in the patient's pre and post transfusion blood samples, respectively. RESULTS: After transfusion, The level of sIgE to shrimp showed "increase" corresponding to the concentration of 0.70-3.5 IU/ml. CONCLUSION: The allergic transfusion reaction was very likely caused by passive transfer of shrimp antigen to the patient allergic to shrimp.