Structure-Based Design of Selective Noncovalent CDK12 Inhibitors.

Cyclin-dependent kinase (CDK) 12 knockdown via siRNA decreases the transcription of DNA-damage-response genes and sensitizes BRCA wild-type cells to poly(ADP-ribose) polymerase (PARP) inhibition. To recapitulate this effect with a small molecule, we sought a potent, selective CDK12 inhibitor. Crystal structures and modeling informed hybridization between dinaciclib and SR-3029, resulting in lead compound 5 [(S)-2-(1-(6-(((6,7-difluoro-1H-benzo[d]imidazol-2-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]. Further structure-guided optimization delivered a series of selective CDK12 inhibitors, including compound 7 [(S)-2-(1-(6-(((6,7-difluoro-1H-benzo[d]imidazol-2-yl)methyl)amino)-9-isopropyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]. Profiling of this compound across CDK9, 7, 2, and 1 at high ATP concentration, single-point kinase panel screening against 352 targets at 0.1 µm, and proteomics via kinase affinity matrix technology demonstrated the selectivity. This series of compounds inhibits phosphorylation of Ser2 on the C-terminal repeat domain of RNA polymerase II, consistent with CDK12 inhibition. These selective compounds were also acutely toxic to OV90 as well as THP1 cells.

A method for going from 2D laparoscope to 3D acquisition of surface landmarks by a novel computer vision approach.

PURPOSE: This paper presents a method to use the Smart Trocars-our new surgical instrument recognition system-or any accurate localization system of surgical instrument for acquiring intraoperative surface data. Complex laparoscopic surgeries need a proper guidance system which requires registering the preoperative data from a CT or MRI scan to the intraoperative patient state. The Smart Trocar can be used to localize the instruments when it comes to contact with the soft tissue surface. METHOD: Two successive views through the laparoscope at different angles with the 3D localization of a fixed tool at one single location using the Smart Trocars can point out visible features during the surgery and acquire their location in 3D to provide a depth map in the region of interest. In other words, our method transforms a standard laparoscope system into a system with three-dimensional registration capability. RESULT: This method was initially tested on a simulation for uncertainty assessment and then on a rigid model for verification with an accuracy within 2 mm distance. In addition, an in vivo experiment on pig model was also conducted to investigate how the method might be used during a physiologic respiratory cycle. CONCLUSION: This method can be applied in a large number of surgical applications as a guidance system on its own or in conjunction with other navigation techniques. Our work encourages further testing with realistic surgical applications in the near future.

A simple questionnaire to detect chronic kidney disease patients from Long An province screening data in Vietnam.

BACKGROUND: The prevalence of chronic kidney disease (CKD) in rural Vietnam is unknown. We wished to determine the prevalence of CKD and determine whether a simple questionnaire was able to detect individuals at high risk of CKD before expensive confirmatory laboratory testing. METHODS: A cross sectional study was performed. We recruited 2037 participants from 13 communes of Long An province, Vietnam, for CKD screening with urine albumin/creatinine ratio (ACR) measured by immunoturbidimetric method and serum creatinine to estimate glomerular filtration rate (eGFR). CKD was defined as either ACR ≥ 30 mg/g or eGFR MDRD < 60 ml/min/1.73 m2. A two page questionnaire with 23 variables was administered to each participant with queries postulated to be correlated with risk of CKD. RESULTS: Of the 2037 participants, 260 (12.76%) were found to have CKD. Five questionnaire variables (age more than 50, measured hypertension, history of diabetes, history of hypertension, and history of a low salt diet) were correlated with CKD, and used to construct a risk score for CKD. CONCLUSIONS: CKD is common in Vietnam. Our questionnaire and risk score tool can be used to detect individuals with a higher likelihood of CKD, and who can then be more economically screened with routine laboratory confirmatory tests.

Image-guided simulation of tissue deformation using a mechanical model on a surgical application.

This paper presents a method for localizing the position of a liver and a tumor within the tissue during a minimally invasive liver operation. From pre-operative CT scans, the liver volume and its internal structures are segmented using image-processing techniques. Based on these segmentations, a three-dimensional mechanical model is built to compute the liver volume and internal structure displacement under boundary conditions such as external forces from the surgical instrument. This can help the surgeon understand the motion of internal structures when manipulating the liver. To validate our method, an experiment on a porcine liver explant was performed to assess the difference between actual tissue motion and the mechanical model.