Pharmacological inhibition of BAP1 recruits HERC2 to competitively dissociate BRCA1-BARD1, suppresses DNA repair and sensitizes CRC to radiotherapy

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.

A three dimensional convolutional neural network pulmonary nodule detection algorithm based on the multi-scale attention mechanism / 生物医学工程学杂志

Early screening based on computed tomography (CT) pulmonary nodule detection is an important means to reduce lung cancer mortality, and in recent years three dimensional convolutional neural network (3D CNN) has achieved success and continuous development in the field of lung nodule detection. We proposed a pulmonary nodule detection algorithm by using 3D CNN based on a multi-scale attention mechanism. Aiming at the characteristics of different sizes and shapes of lung nodules, we designed a multi-scale feature extraction module to extract the corresponding features of different scales. Through the attention module, the correlation information between the features was mined from both spatial and channel perspectives to strengthen the features. The extracted features entered into a pyramid-similar fusion mechanism, so that the features would contain both deep semantic information and shallow location information, which is more conducive to target positioning and bounding box regression. On representative LUNA16 datasets, compared with other advanced methods, this method significantly improved the detection sensitivity, which can provide theoretical reference for clinical medicine.

Effect of metformin on colorectal carcinoma in type 2 diabetes mellitus patients: a Markov model analysis / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To evaluate the colorectal cancer (CRC) prevention effect of metformin in comparison with that of other T2DM medications from a Markov model perspective.</p><p><b>METHODS</b>Literature concerning CRC morbidity of T2DM patients with metformin or other diabetes medications treatment was reviewed in PubMed and Cochrane Library database from September 2010 to December 2016.</p><p><b>INCLUSION CRITERIA</b>(1)enrolled population was adult patients with T2DM but without CRC; (2) any of the parameters applied in our model was reported; (3) randomized clinical trials (RCTs), quasi-randomized trials, prospective or retrospective cohort studies. With CRC morbidity as endpoint, parameters were extracted to construct Markov model to assess CRC morbidity and cumulative tumor-free survival in each group over 11 years' follow-up period. Finally, Monte Carlo analysis was performed to evaluate the influence of parameter instability on the model.</p><p><b>RESULTS</b>Seven literatures were recruited and 10 000 patients were virtually allocated for each arm. In contrast with non-metformin group, T2DM patients treated with metformin had a lower rate of CRC(1.670% vs. 2.146%, P=0.016). Moreover, cumulative tumor-free survival of metformin group was, slightly but significantly, better than that of non-metformin group (10.908 years vs. 10.882 years, P=0.000).</p><p><b>CONCLUSIONS</b>T2DM patients treated with metformin have a lower morbidity of CRC and a better cumulative tumor-free survival than those of non-metformin group. Large scale RCTs are needed to illustrate the role of metformin in the prevention of CRC.</p>

Effects of percutaneous radiofrequency ablation and repeat hepatectomy for the treatment of solitary recurrent hepatocellular carcinoma with the diameter no more than 3 cm / 中华消化外科杂志

Objective To compare the efficacy of percutaneous radiofrequency ablation (PRFA) and repeat hepatectomy for solitary recurrent hepatocellular carcinoma (HCC) with the diameter≤3 cm. Methods The clinical data of 151 patients with recurrent HCC (diameter≤3 cm) who were admitted to the Cancer Center of Sun Yat-Sen University from January 1999 to December 2009 were retrospectively analyzed. Of all the patients, 79received PRFA (PRFA group) and 72 received repeat hepatectomy (repeat hepatectomy group). The survival rate, morbidity and recurrence of the tumor between the two groups were compared. All data were analyzed using t test, chi-square test or Log-rank test, and the survival of the patients were analyzed using the Kaplan-Meier method. Results The mobidities of the PRFA group and repeat hepatectomy group were 13% (10/79) and 36%(26/72), respectively, with a significant difference between the two groups (x2=11.411, P＜0.05). The cumulative 1-, 2-, 3-, 4-, 5-year survival rates were 89.7%, 75.2%, 67.1%, 61.5%, 56.6% in the PRFA group, and 86.0%, 67.6%, 53.6%, 44.1%, 40.2% in the repeat hepatectomy group, with no significant difference between the two groups (x2=1.610, P＞0.05). The cumulative 4-, 5-year survival rates of the PRFA group were significant higher than those in the repeat hepatectomy group (x2=4.682, 4. 196, P ＜ 0.05). The local tumor recurrence rate of the PRFA group was 5% (4/79), and the incisal margin recurrence rate was 3% (2/72) in the repeat hepatectomy group, with no significant difference between the two groups (x2=0.565, P＞0.05). Conclusion As a less invasive treatment method, PRFA is superior to repeat hepatectomy for solitary recurrent HCC with the diameter≤3 cm.