Quantitative systems pharmacology modeling of HER2-positive metastatic breast cancer for translational efficacy evaluation and combination assessment across therapeutic modalities.

HER2-positive (HER2+) metastatic breast cancer (mBC) is highly aggressive and a major threat to human health. Despite the significant improvement in patients' prognosis given the drug development efforts during the past several decades, many clinical questions still remain to be addressed such as efficacy when combining different therapeutic modalities, best treatment sequences, interindividual variability as well as resistance and potential coping strategies. To better answer these questions, we developed a mechanistic quantitative systems pharmacology model of the pathophysiology of HER2+ mBC that was extensively calibrated and validated against multiscale data to quantitatively predict and characterize the signal transduction and preclinical tumor growth kinetics under different therapeutic interventions. Focusing on the second-line treatment for HER2+ mBC, e.g., antibody-drug conjugates (ADC), small molecule inhibitors/TKI and chemotherapy, the model accurately predicted the efficacy of various drug combinations and dosing regimens at the in vitro and in vivo levels. Sensitivity analyses and subsequent heterogeneous phenotype simulations revealed important insights into the design of new drug combinations to effectively overcome various resistance scenarios in HER2+ mBC treatments. In addition, the model predicted a better efficacy of the new TKI plus ADC combination which can potentially reduce drug dosage and toxicity, while it also shed light on the optimal treatment ordering of ADC versus TKI plus capecitabine regimens, and these findings were validated by new in vivo experiments. Our model is the first that mechanistically integrates multiple key drug modalities in HER2+ mBC research and it can serve as a high-throughput computational platform to guide future model-informed drug development and clinical translation.

Adjuvant Radiotherapy After Minimally Invasive Surgery in Patients With Stage IA1-IIA1 Cervical Cancer.

To estimate whether adjuvant radiotherapy is necessary for patients with stage IA1-IIA1 cervical cancer after laparoscopic hysterectomy, 221 patients were retrospectively analyzed. Sixty-two of them were treated with laparoscopic hysterectomy and adjuvant radiotherapy (group A), 115 underwent open surgery (group B) and 44 received laparoscopic hysterectomy alone (group C). Results showed that the 3-year local recurrence-free survival (LRFS) rates of group A, B and C were 98.4%, 97.4% and 86.4%, respectively. The LRFS rates of group A and B surpassed C (A vs. B, p=0.634; A vs. C, p=0.011; B vs. C, p=0.006). The inter-group differences of 3-year overall survival (OS) and distant metastasis free survival (DMFS) were not statistically significant. In subgroup analysis of stage IB disease, the 3-year LRFS rates of group A, B and C were 100%, 98.8% and 83.1%, the 3-year OS rates of group A, B and C were 100%, 98.9% and 91.5%, respectively. The 3-year LRFS and OS rates of group A and B were significantly superior to group C (p<0.05). Our findings suggest that adjuvant radiotherapy can reduce the risk of recurrence for women with early-stage cervical cancer after laparoscopic hysterectomy and bring survival benefits for patients with stage IB disease.

Investigation on reproductive characteristics of Polygonatum cyrtonema / 中国中药杂志

The study is aimed to investigate the reproductive biology characteristics of Polygonatum cyrtonema, especially including phenology, flower bud differentiation, flowering timing, floral traits, pollen vigor and stigma receptivity. The results showed that P. cyrtonema forms inflorescence before the leaves spread. In the wild, P. cyrtonema is mainly pollinated by insects such as bumblebees, with a seed setting rate of 65.12%. The seed setting rate of indoor single plant isolation or self-pollination enclosed by parchment paper bag is 0, indicating that it is self-incompatible. In Lin'an city, seedlings begin to emerge from mid-March to early April(the temperature is higher than 7.5 ℃), buds begin to emerge from the end of March to mid-April, and then undergo the full bloom stage from mid-to-late April, and the final flowering stage from the end of April to mid-May. The whole flowering period lasts 36 to 45 days. There are obvious differences in the phenology of different provenances. The flowers come into bloom from the base to the top along the aboveground main axis, which usually contain 4-22 inflorescences with(2-) 4-10(-21) flowers per inflorescence. The flowering pe-riod for a single plant is 26-38 days. The single flower lasts about 20-25 days from budding to opening and withers 2 days after pollination, and then the ovary will gradually expand. If unpollinated, it will continue to bloom for 3-5 days and then wither. Flower development period is significantly related to pollen vigor and stigma remittance. The pollen viability is the highest when the flower is fully opened with anthers gathering on the stigma, and the receptivity is the strongest when the stigma protrudes out of the perianth and secretes mucus. The fruits and seeds ripen in October, and proper shading can ensure the smooth development and maturity of the seeds. This study provides a basis for the hybrid breeding and seed production of P. cyrtonema.