Combining CD38 antibody with CD47 blockade is a promising strategy for treating hematologic malignancies expressing CD38

BackgroundCD38 and CD47 are expressed in many hematologic malignancies, including multiple myeloma (MM), B-cell non-Hodgkin lymphoma (NHL), B-cell acute lymphoblastic leukemia (ALL), and B-cell chronic lymphocytic leukemia (CLL). Here, we evaluated the antitumor activities of CD38/CD47 bispecific antibodies (BsAbs).MethodsFive suitable anti-CD38 antibodies for co-targeting CD47 and CD38 BsAb were developed using a 2 + 2 “mAb-trap” platform. The activity characteristics of the CD38/CD47 BsAbs were evaluated using in vitro and in vivo systems.ResultsUsing hybridoma screening technology, we obtained nine suitable anti-CD38 antibodies. All anti-CD38 antibodies bind to CD38+ tumor cells and kill tumor cells via antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Five anti-CD38 antibodies (4A8, 12C10, 26B4, 35G5, and 65A7) were selected for designing CD38/CD47 BsAbs (IMM5605) using a “mAb-trap” platform. BsAbs had higher affinity and binding activity to the CD38 target than those to the CD47 target, decreasing the potential on-target potential and off-tumor effects. The CD38/CD47 BsAbs did not bind to RBCs and did not induce RBC agglutination; thus, BsAbs had much lower blood toxicity. The CD38/CD47 BsAbs had a greater ability to block the CD47/SIRPα signal in CD38+/CD47+ tumor cells than IMM01 (SIRPα Fc fusion protein). Through Fc domain engineering, CD38/CD47 BsAbs were shown to kill tumors more effectively by inducing ADCC and ADCP. IMM5605–26B4 had the strongest inhibitory effect on cellular CD38 enzymatic activity. IMM5605–12C10 had the strongest ability to directly induce the apoptosis of tumor cells. The anti-CD38 antibody 26B4 combined with the SIRPα-Fc fusion proteins showed strong antitumor effects, which were better than any of the mono-therapeutic agents used alone in the NCI-H929 cell xenograft model. The CD38/CD47 BsAbs exhibited strong antitumor effects; specifically, IMM5605–12C10 efficiently eradicated all established tumors in all mice.ConclusionA panel of BsAbs targeting CD38 and CD47 developed based on the “mAb-tarp” platform showed potent tumor-killing ability in vitro and in vivo. As BsAbs had lower affinity for binding to CD47, higher affinity for binding to CD38, no affinity for binding to RBCs, and did not induce RBC agglutination, we concluded that CD38/CD47 BsAbs are safe and have a satisfactory tolerability profile

Self-esteem and professional identity among male nurses and male nursing students: mediating roles of perceived prejudice and psychological distress

IntroductionThere are not enough nurses around the world, and there are even fewer male nurses. It has not been easy for men to become nurses because of stereotypes about the roles of men and women in the workplace, which lead to prejudice and discrimination. This study explored how the self-esteem of male nurses and male nursing students affects their professional identity in an environment where stereotypes and social prejudice exist. This study also examined the differences of relevant variables in different sociodemographic characteristics of the research subjects in a Chinese social context.MethodsBy purposive and snowball sampling, 464 male nurses and male nursing students were surveyed through questionnaires from November 2021 to January 2022. Data analysis was performed using SPSS 25.0 and PROCESS Macro 3.3.ResultsSelf-esteem could indirectly affect professional identity through perceived prejudice and psychological distress. Nonetheless, self-esteem still had a significant direct effect on professional identity. The total mediating effect accounted for 32.816% of the total effect, and the direct effect accounted for 67.184% of the total effect. Also of note was that 81.7% of participants reported experiencing psychological distress.DiscussionTo improve the professional identity of male nurses and male nursing students, nursing educators and administrators should do the following: protect and improve their self-esteem; take steps to reduce social prejudice against them; value their mental health and alleviate their psychological distress

Type A2 BTB Members Decrease the ABA Response during Seed Germination by Affecting the Stability of SnRK2.3 in Arabidopsis

The Arabidopsis genome comprises eighty genes encoding BTB (broad-complex, tramtrack, and bric-a-brac) family proteins that are characterized with the BTB domain and that potentially serve as substrate adaptors for cullin-based E3-ligases. In addition to the BTB domain, most BTB proteins also contain various other interaction motifs that probably act as target recognition elements. Here, we report three members of the BTB-A2 subfamily that distinctly only contain the BTB domain, BTB-A2.1, BTB-A2.2, and BTB-A2.3, that negatively regulates abscisic acid (ABA) signaling in Arabidopsis. BTB-A2.1, BTB-A2.2, and BTB-A2.3 encoded cytoplasm- and nucleus-localized proteins and displayed highly overlapping expression patterns in Arabidopsis tissues. Disruption of these three genes, but not single or double mutants, resulted in a decrease in ABA-induced inhibition of seed germination. Further analyses demonstrated the expression levels of these three genes were up-regulated by ABA, and their mutation increased ABA signalling. Importantly, protein-protein interaction assays showed that these three BTB-A2 proteins physically interacted with SnRK2.3. Moreover, biochemical and genetic assays indicated that BTB-A2.1, BTB-A2.2, and BTB-A2.3 decreased the stability of SnRK2.3 and attenuated the SnRK2.3 responsible for the ABA hypersensitive phenotype of seed germination. This report thus reveals that BTB-A2s serve as negative regulators for balancing the intensity of ABA signaling during seed germination

Macrophage, Co-cultured with Irradiated Lung Cancer Cells, Plays a Role in Triggering Secondary Bystander Effects on Epithelial Cells

Microbeam particles can precisely target sub-cellular organs and hence has become an advantageous tool in studying the mechanisms of low dose radiation responses including radiation-induced bystander effect (RIBE). Besides nuclei, mitochondria and endoplasmic reticulum in cytoplasm may be involved in RIBE as potential radiation targets. When only one or few cells in a population with million cells were irradiated with microbeam particles through either nuclei or cytoplasm, DNA damage could be observed in thousands of other nonirradiated cells, which hints that radiation induced signals could be transferred from one cell to other cells. But so far no direct evidence to show that any cell plays a role as an intermediate between irradiated cells and nonirradiated cells. Here we found when macrophage U937 cells were co- cultured with lung cancer cells NCI-H446 irradiated with either y-rays or carbon ions, this U937 became a bystander signal transmitter and could further induce DNA damage in its neighboring bronchial epithelial cells BEAS-2B. Interestingly, U937 cells were only activated by y-irradiated NCI-H446 cells so that the secondary injuries in BEAS-2B cells under carbon ions irradiation were weaker than y-rays. Both TNF-a and IL-1α were involved in y-irradiation induced abscopal effect but only TNF-α contributed to carbon irradiation-induced response. Further assay disclosed that IL-1α but not TNF-α was largely responsible for the activation of macrophages and micronucleus formation in BEAS-2B cells. These data suggest that macrophage as a transmitter plays an important role in the abscopal effect of photon irradiation, while carbon ion irradiation has conspicuous advantage due to its reduced abscopal injury.15th International Congress of Radiation Researc

Retroperitoneal laparoscopic debridement and drainage of infected retroperitoneal necrosis in severe acute pancreatitis

Objective: To explore the effect of retroperitoneal laparoscopic debridement and drainage on infected necrosis in severe acute pancreatitis. Materials and methods: This retrospective study included 18 patients with severe acute pancreatitis (SAP) undergoing retroperitoneal laparoscopic debridement and drainage from May 2006 to April 2012 in our hospital. All patients had infected retroperitoneal necrosis and single or multiple peritoneal abscesses. Eleven patients transferred to our hospital were treated with the retroperitoneal laparoscopic debridement and drainage within 24–72 hours after admission. Conservative treatments were given to eight patients. Retroperitoneal laparoscopic debridement and drainage were applied 3–11 days after admission. Results: All patients had infection of necrotic pancreas or peripancreatic tissues. Twelve patients had organ failure. Three patients underwent secondary surgery. Laparotomy with debridement and drainage were applied to one patient who had a huge lesser sac abscess 7 days after first surgery. The other two patients were given secondary retroperitoneal laparoscopic debridement and drainage. One case was complicated by retroperitoneal hemorrhage, four cases had pancreatic leakage, and no intestinal fistula was found. The patients' heart rate, respiration, temperature, and white blood cell count were significantly improved 48 hours after surgery compared with those prior to surgery (p<0.05). The average length of stay in hospitals was 40.8 days (range, 6–121 days), and the drainage tube indwelling time was 44.4 days (range, 2–182 days). Conclusion: Retroperitoneal laparoscopic debridement and drainage is an SAP surgical treatment with a minimally invasive procedure and a good effect, and can be applied for infected retroperitoneal necrosis in early SAP

Cell cycle-correlative bystander effects are co-mediated by DNA-PKcs and ATM kinase after high LET carbon ions irradiation

Radiation-induced bystander effects (RIBE) was demonstrated with accumulated evidence. Recently, several studies have focused on the role of DNA damage and repair in the bystander response, but the heavy ions induced, especially cell cycle-correlative RIBE are still largely unclear. Our present study found that G2/M phase cells had the largest contribution to the RIBE induced by carbon ions irradiation and identified a pivotal role for DNA-PKcs and ATM in this process as two independent factors.平成26年度放射線医学総合研究所重粒子線がん治療装置等共同利用研究報告

Role of Endoplasmic Reticulum and Mitochondrion in Proton Microbeam Radiation-Induced Bystander Effect

It is well known that mitochondria and endoplasmic reticulum (ER) plays important roles in radiation responses, but their functions in radiation-induced bystander effect (RIBE) are largely unknown. This study found that, when a small portion of cells in the population of human lung fibroblast MRC-5 cells were precisely irradiated through either nuclear or cytoplasm with counted microbeam protons, the yield of micronucleus (MN) in the nonirradiated cells neighboring to irradiated cells was increased and the levels of intracellular reactive oxygen species (ROS) in the whole population were also significantly increased after irradiation. The mito/ER-tracker assay illustrates that the mitochondria was obviously activated after nuclear irradiation and the mass of ER approached to a higher level after cytoplasmic irradiation. Moreover, the above radiation induced ROS was diminished by rotenone, an inhibitor of mitochondria activation, but it was not influenced by siRNA interference of BiP, an ER regulation protein. For nuclear irradiation, rotenone enhanced radiation-induced ER expression, and BiP siRNA eliminated radiation-induced activation of mitochondria. However, these phenomena were not observed for cytoplasmic irradiation. Bystander MN was reduced by rotenone but enhanced by BiP siRNA. When the cells were treated with both rotenone and BiP siRNA, the MN yield was reduced for nuclear irradiation but was enhanced for cytoplasmic irradiation. Our results suggest that the cell organelles of mitochondria and ER have different roles in RIBE with respect to nuclear and cytoplasmic irradiations, and the function of ER is a prerequisite for mitochondrial activation

Cell cycle-correlative bystander effects are co-mediated by DNA-PKcs and ATM kinase after high LET carbon ions irradiation.

Radiation-induced bystander effects (RIBE) wasdemonstrated with accumulated evidence. Recently,several studies have focused on the role of DNAdamage and repair in the bystander response, but the heavy ions induced, especially cell cycle-correlative RIBE are still largely unclear. Our present study found that G2/M phase cells had the largest contribution to the RIBE induced by carbon ions irradiation and identified a pivotal role for DNA-PKcs and ATM in this process as two independent factors

PICK1 inhibits the malignancy of nasopharyngeal carcinoma and serves as a novel prognostic marker

Abstract Although many important advances have been made in the treatment of nasopharyngeal carcinoma (NPC) in recent years, local recurrence and distant metastasis remain the main factors affecting NPC prognosis. Biomarkers for predicting the prognosis of NPC need to be urgently identified. Here, we used whole-exon sequencing (WES) to determine whether PICK1 mutations are associated with the prognosis of NPC. Functionally, PICK1 inhibits the proliferation and metastasis of NPC cells both in vivo and in vitro. Mechanistically, PICK1 inhibited the expression of proteins related to the Wnt/β-catenin signaling pathway. PICK1 restrained the nuclear accumulation of β-catenin and accelerated the degradation of β-catenin through the ubiquitin-proteasome pathway. The reduced PICK1 levels were significantly associated with poor patient prognosis. Hence, our study findings reveal the mechanism by which PICK1 inactivates the Wnt/β-catenin signaling pathway, thereby inhibiting the progression of NPC. They support PICK1 as a potential tumor suppressor and prognostic marker for NPC