Background: The T cell response against different tumors is improved by immunogenic cell death (ICD), indicating a role for ICD in augmenting antitumor immunity elicited by the anti-checkpoint antibody antiprogrammed death 1 (anti-PD-1). Methods: The effect of SR-4835 on breast cancer was analyzed by cell proliferation and ow cytometry. Calreticulin translocation and HMGB1 and ATP release were detected by ow cytometry, ELISA and luminescence assay, respectively. Immunogenicity in vitro was analyzed by co-culturing of SR-4835 treated cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of maturation of BMDCs and production of IL-6 in the supernatant were measured. The in vivo antitumor effect was analyzed by syngeneic mouse model followed by ow cytometry for TILs. Results: In the present study, we report a synergistic and durable immune-mediated antitumor response elicited by the combined treatment of SR-4835, a CDK12/13 speci c inhibitor, with PD-1 blockade in a murine model of 4T1 breast cancer. The developed combination therapy elicited antitumor activity in immunocompetent mouse tumor models. Furthermore, the SR-4835-treated tumor cells exhibited characteristics of ICD, including the release of high mobility group box 1 (HMGB1) and ATP and the translocation of surface calreticulin (CRT). This activity led to a significant T-cell dependent regression of tumors. The enhanced in ltration of T cells and dendritic cell (DC) activation in the tumors of mice treated with both SR-4835 and anti-PD-1 indicate that this combination treatment promotes an improved immune response and suggests a potential mechanism involving anti-PD-1 and SR-4835 activity that enhances anti-PD-1 effects. Conclusion: The results of the present study demonstrate the potential of CDK12/13 inhibition combined with checkpoint inhibition in breast cancer treatment.

Background: The T cell response against different tumors is improved by immunogenic cell death (ICD), indicating a role for ICD in augmenting antitumor immunity elicited by the anti-checkpoint antibody anti-programmed death 1 (anti-PD-1). Methods: The effect of SR-4835 on breast cancer was analyzed by cell proliferation and flow cytometry. Calreticulin translocation and HMGB1 and ATP release were detected by flow cytometry, ELISA and luminescence assay, respectively. Immunogenicity in vitro was analyzed by co-culturing of SR-4835 treated cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of maturation of BMDCs and production of IL-6 in the supernatant were measured. The in vivo antitumor effect was analyzed by syngeneic mouse model followed by flow cytometry for TILs.Results: In the present study, we report a synergistic and durable immune-mediated antitumor response elicited by the combined treatment of SR-4835, a CDK12/13 specific inhibitor, with PD-1 blockade in a murine model of 4T1 breast cancer. The developed combination therapy elicited antitumor activity in immunocompetent mouse tumor models. Furthermore, the SR-4835-treated tumor cells exhibited characteristics of ICD, including the release of high mobility group box 1 (HMGB1) and ATP and the translocation of surface calreticulin (CRT). This activity led to a significant T-cell dependent regression of tumors. The enhanced infiltration of T cells and dendritic cell (DC) activation in the tumors of mice treated with both SR-4835 and anti-PD-1 indicate that this combination treatment promotes an improved immune response and suggests a potential mechanism involving anti-PD-1 and SR-4835 activity that enhances anti-PD-1 effects. Conclusion: The results of the present study demonstrate the potential of CDK12/13 inhibition combined with checkpoint inhibition in breast cancer treatment.

Objective To explore the value of ultrasound in evaluating T/N staging of differentiated thyroid carcinoma (DTC). Methods The clinical data of 1206 patients with DTC in our hospital from January 2018 to December 2020 were retrospectively analyzed. Cervical ultrasound was performed before surgery, and the standard ultrasound images of thyroid nodules and cervical lymph nodes I to VII were retained. According to the 8th TNM staging guidelines of AJCC DTC, the T/N stages were assessed by preoperative ultrasonic data. Then, the sensitivity, specificity, negative predicted value, positive predicted value (PPV), and diagnostic value of ultrasound T/N staging were assessed using postoperative pathological staging as the reference. Results Ultrasonic T-stage had good consistency to pathological T stage in T4a and T4b tumors (kappa value>0.75), and moderate consistency to pathological T stage in T1, T2 and T3a tumors (kappa value between 0.4 and 0.75). ultrasonic T-stage had a sensitivity higher than 66%, except in T3b assessment (13/44, 29.5%, 95%CI: 16.1%-43.0%). All ultrasonic T-stage had specificity higher than 93%, except in T1b assessment (734/889, 82.6%, 95%CI: 80.1%-85.1%). The PPV of ultrasonic T1a to T4b was 94.3% (494/524), 61.0% (242/397), 54.4% (87/160), 34.3% (12/35), 20.3% (13/64), 100% (22/22) and 100% (4/4), respectively. The diagnostic accuracy values were 83% in T1a, 81% in T1b, 91% in T2, 98% in T3a, 93% in T3b, 99% in T4a and 100% in T4b. Nltrasonic N-stage had poor consistency to pathological N stage in any N stages (kappa value<0.3). The PPV of ultrasonic N0, N1, N1a and N1b was 61.0% (542/889), 55.2% (37/67), 48.2% (53/110), and 24.3% (34/140), respectively. Conclusion Ultrasound has a good consistency and high accuracy in assessing the T-stage of DTC. However, the consistency and accuracy were poor in N-staging. It has a certain reference value in reducing excessive surgical treatment of DTC.