In Silico Tools to Extract the Drug Design Information Content of Degradation Data: The Case of PROTACs Targeting the Androgen Receptor.

Proteolysis-Targeting Chimeras (PROTACs) have recently emerged as a promising technology in the drug discovery landscape. Large interest in the degradation of the androgen receptor (AR) as a new anti-prostatic cancer strategy has resulted in several papers focusing on PROTACs against AR. This study explores the potential of a few in silico tools to extract drug design information from AR degradation data in the format often reported in the literature. After setting up a dataset of 92 PROTACs with consistent AR degradation values, we employed the Bemis-Murcko method for their classification. The resulting clusters were not informative in terms of structure-degradation relationship. Subsequently, we performed Degradation Cliff analysis and identified some key aspects conferring a positive contribution to activity, as well as some methodological limits when applying this approach to PROTACs. Linker structure degradation relationships were also investigated. Then, we built and characterized ternary complexes to validate previous results. Finally, we implemented machine learning classification models and showed that AR degradation for VHL-based but not CRBN-based PROTACs can be predicted from simple permeability-related 2D molecular descriptors.

Covered stenting and transcatheter embolization of splenic artery aneurysms in diabetic patients: A review of endovascular treatment of visceral artery aneurysms in the current era.

Diabetes mellitus is associated with both microvascular and macrovascular complications, which can result in visceral aneurysms as for example splenic artery aneurysms: in their management, an endovascular treatment, less invasive than surgery, is generally preferred. Endovascular treatment of splenic artery aneurysms can be based either on covered stenting (CS) or transcatheter embolization (TE). CS generally allows aneurysm exclusion with vessel preservation, while TE usually determines target artery occlusion with potential risk of distal ischemia. We performed a review of the existing literature on endovascular treatment of visceral artery aneurysms (VAAs) and psudoaneurysms (VAPAs) in the current era.

Endovascular Treatment of Visceral Artery Aneurysms and Pseudoaneurysms in 100 Patients: Covered Stenting vs Transcatheter Embolization.

PURPOSE: To retrospectively report a large single-center experience of visceral artery aneurysms (VAAs) and pseudoaneurysms (VAPAs) treated with covered stenting (CS) as the first therapeutic option vs transcatheter embolization (TE). METHODS: One hundred patients (mean age 59±14 years; 58 men) underwent 59 elective and 41 emergent endovascular procedures to treat 51 VAAs and 49 VAPAs. Seventy patients had TE and 30 received CS (27 Viabahn and 3 coronary stent grafts). Both TE and CS were performed in 10 cases. RESULTS: Technical success was 96% (97% CS, 96% TE), and 30-day clinical success was 83% (87% CS, 81.4% TE). Four major complications occurred; 30-day mortality was 7%, mainly due to septic shock following pancreatic surgery. The midterm follow-up was 20.8 months in the total population and 32.8 months in the CS group. More than 6 months after CS all aneurysms remained excluded; stent patency was achieved in 88%. Twelve CS patients with >3 years' follow-up had maintained stent patency. CONCLUSION: In endovascular treatment of visceral aneurysms, covered stenting was feasible in 30%. CS showed a slightly better efficacy than TE and good midterm patency. The Viabahn covered stent seems to be suitable for endovascular repair of tortuous visceral arteries affected by true or false aneurysms.

Orbital color Doppler ultrasound as noninvasive tool in the diagnosis of anterior-draining carotid-cavernous fistula.

PURPOSE: To investigate the role of orbital color Doppler ultrasound (OCDUS) in the diagnosis of carotid-cavernous fistula (CCF) with anterior drainage and particularly whether a negative OCDUS could avoid an invasive diagnostic cerebral angiography (DSA). MATERIALS AND METHODS: Twenty-two consecutive patients with ophthalmic signs suspecting CCF were submitted to ophthalmologic examination, OCDUS and DSA. CCF diagnosis with OCDUS was based on the finding of a reversed, arterialized and low-resistive-index (RI <0.5) blood flow in the superior ophthalmic vein (SOV). Sensibility, specificity, PPV, NPV, and accuracy of OCDUS were calculated considering both patients and eyes, using DSA as gold standard. RESULTS: DSA demonstrated 20 CCFs in 18 patients. Considering the patients, in 18/22 CCF diagnosis was positive at OCDUS and DSA while 4/22 were negative at both. Considering the eyes, in 24/43 CCF diagnosis was positive at both DSA and OCDUS (total eyes = 43, due to one case of SOV thrombosis). In 19/43 eyes diagnosis was negative at both OCDUS and DSA. So sensitivity, specificity, PPV, NPV, and accuracy of OCDUS in the patients and eyes analysis were all 100 %. CONCLUSIONS: OCDUS is a reliable, noninvasive tool in the diagnosis of CCF; a negative OCDUS could avoid an invasive DSA in patients suspected for anterior-draining CCF.

Hepatic steatosis after islet transplantation: Can ultrasound predict the clinical outcome? A longitudinal study in 108 patients.

Percutaneous intra-portal islet transplantation (PIPIT) is a less invasive, safer, and repeatable therapeutic option for brittle type 1 diabetes, compared to surgical pancreas transplantation. Hepatic steatosis is a consequence of the islet engraftment but it is curiously present in a limited number of patients and its meaning is controversial. The aims of this study were to assess hepatic steatosis at ultrasound (US) after PIPIT investigating its relationship with graft function and its role in predicting the clinical outcome. From 1996 to 2012, 108 patients underwent PIPIT: 83 type-1 diabetic patients underwent allo-transplantation, 25 auto-transplantation. US was performed at baseline, 6, 12, and 24 months, recording steatosis prevalence, first detection, duration, and distribution. Contemporaneously, steatotic and non-steatotic patients were compared for the following parameters: infused islet mass, insulin independence rate, ß-score, C-peptide, glycated hemoglobin, exogenous insulin requirement, and fasting plasma glucose. Steatosis at US was detected in 21/108 patients, 20/83 allo-transplanted and 1/25 auto-transplanted, mostly at 6 and 12 months. Infused islet mass was significantly higher in steatotic than non-steatotic patients (IE/kg: S=10.822; NS=6138; p=0.001). Metabolically, steatotic patients had worse basal conditions, but better islet function when steatosis was first detected, after which progressive islet exhaustion, along with steatosis disappearance, was observed. Conversely, in non-steatotic patients these parameters remained stable in time. Number of re-transplantations was significantly higher in steatotic than in non-steatotic patients (1.8 vs 1.1; p=0.001). Steatosis at US seems to be related to the islet mass and local overworking activity. It precedes metabolic alterations and can predict graft dysfunction addressing to therapeutic decisions before islet exhaustion. If steatosis does not appear, no conclusion can be drawn.

Quantification of waterborne pathogens and associated health risks in urban water.

Citizens are exposed to microbial hazards in urban waters. To quantify health risks associated with this exposure, pathogen concentrations in an urban river, lake, rainwater sedimentation pond, a pond in a park, and a wadi, were assessed. E. coli concentrations were variable in all locations, with mean values ranging between 1.2 × 10(2) (lake) and 1.7 × 10(4) (sedimentation pond) cfu (colony forming units)/100 mL. High concentrations of Campylobacter were found, being the lowest in the lake (4.2 × 10(1) gc (genomic copies)/L) and the highest in the wadi (1.7 × 10(4) gc/L). Cryptosporidium was not found in any sample. Low levels of adenovirus 40/41 were found in some samples in the river (1.8 × 10(1) gc/L) and lake (7.2 × 10° gc/L), indicating human fecal contamination. Legionella pneumophila was found in the sedimentation pond, with higher concentrations after rain events (1.3 × 10(2) gc/L). Cyanochlorophyll-a was found in the lake (7.0 × 10(-1) µg/L), the sedimentation pond (1.1 × 10° µg/L), and the pond in the park (2.9 × 10(1) µg/L), where low levels of microcystin were found (2.1 × 10° µg/L). Campylobacter data were used to estimate gastrointestinal risks from recreational exposure. This revealed risks above the annual disease incidence of campylobacteriosis in The Netherlands, being highest in the wadi and river. Measures are proposed to reduce the health risks.

Preliminary results of contrast-enhanced sonography in the evaluation of the response of uveal melanoma to gamma-knife radiosurgery.

PURPOSE: Our aim was to prospectively analyze the use of contrast-enhanced ultrasound (CEUS) in the quantitative assessment of the response of uveal melanoma (UM) to gamma-knife radiosurgery (GKR), investigating whether changes in tumor vascularization precede thickness reduction, which on average occurs at 12 months after GKR. METHODS: Ten patients with UM treated with GKR underwent sonography (US) and CEUS at baseline and at 3, 6, and 12 months after GKR. The transverse diameter, thickness, and quantitative parameters of the UM (ie, area under the curve in the wash-in phase, wash-in perfusion index, peak enhancement, and wash-in rate) were calculated by using dedicated software and compared by using Wilcoxon's signed-rank test. RESULTS: The mean tumor thickness on US was significantly less at both 6 (6.6 mm) and 12 months after GKR (5.8 mm) than it was at baseline (8.3 mm; p < 0.05, both comparisons). Compared with baseline data, the median flow quantitative parameters on CEUS were significantly changed as follows: the peak enhancement (in arbitrary units [au]) at baseline was 5 × 10(6) ; 6 months after GKR, it was 2 × 10(1) (p < 0.05), and 12 months after GKR, it was 4 × 10(1) (p < 0.05). The wash-in rate (in au) at baseline was 1 × 10(6) ; 6 months after GKR, it was 2.1 (p < 0.05), and 12 months after GKR, it was 9.3 (p < 0.05). The wash-in perfusion index (in au) at baseline was 2 × 10(7) ; 6 months after GKR, it was 7 × 10(1) (p < 0.05), and 12 months after GKR, it was 1 × 10(2) (p < 0.05). The area under the curve during the wash-in phase (in au) at baseline was 1 × 10(8) ; 12 months after GKR, it was reduced to 6 × 10(2) (p < 0.05). CONCLUSIONS: At 6 months after GKR, a reduction of tumor thickness, as detected on US, occurred in 6 of the 10 patients, whereas a reduction in all the quantitative parameters measured on CEUS occurred in all 10 patients. However, a larger population is needed to investigate whether CEUS could become the first-choice technique for monitoring the response of UM to GKR.

Monitoring of central retinal artery and vein with color Doppler ultrasound during heart surgery as an alternative to transcranial Doppler ultrasonography: a case report.

Cardiac surgery can have severe neurologic complications. The noninvasive monitoring of intracranial circulation during heart surgery is usually performed with transcranial Doppler ultrasonography. We present the case of a 66-year-old man who underwent elective cardiac surgery for aortic valve replacement and coronary artery bypass graft, in whom monitoring was performed by simultaneously assessing blood flow velocity in the central retinal artery and vein.

Transcatheter Mitral Valve Implantation in Failed Transventricular Mitral Valve Repair.

An 84-year-old man presented with dyspnea at rest due to severe mitral regurgitation. He first underwent transventricular mitral valve repair with the Harpoon system, which relapsed owing to rupture of neochords. He was definitively treated with transcatheter mitral valve implantation of the Tendyne system 8 months later.

Apparent diffusion coefficient modifications in assessing gastro-oesophageal cancer response to neoadjuvant treatment: comparison with tumour regression grade at histology.

OBJECTIVES: To assess changes in apparent diffusion coefficient (ΔADC) and volume (ΔV) after neoadjuvant treatment (NT), and tumour regression grade (TRG) in gastro-oesophageal cancers (GEC), and to discriminate responders from non-responders. METHODS: Thirty-two patients with biopsy-proven locally-advanced GEC underwent diffusion weighted magnetic resonance imaging (DWI) pre- and post-NT. Lesion ADC, volume, ΔADC and ΔV were calculated. TRG 1-2-3 patients were classified as R; TRG 4-5 as non-responders. ΔADC-TRG and ΔV-TRG correlations, pre-NT and post-NT ADC, ΔADC and ΔV cut-off values for responders and non-responders were calculated. Two readers measured mean tumour ADCs and interobserver variability was calculated. (Spearman's and intraclass correlation coefficient [ICC]). RESULTS: The interobserver reproducibility was very good both for pre-NT (Spearman's rho = 0.8160; ICC = 0.8993) and post-NT (Spearman's rho = 0.8357; ICC = 0.8663). Responders showed lower pre-NT ADC (1.32 versus 1.63 × 10(-3) mm(2)/s; P = 0.002) and higher post-NT ADC (2.22 versus 1.51 × 10(-3) mm(2)/s; P = 0.001) than non-responders and ADC increased in responders (ΔADC, 85.45 versus -8.21 %; P = 0.00005). ΔADC inversely correlated with TRG (r = -0.71, P = 0.000004); no difference in ΔV between responders and non-responders (-50.92 % versus -14.12 %; P = 0.068) and no correlation ΔV-TRG (r = 0.02 P = 0.883) were observed. CONCLUSIONS: The ADC can be used to assess gastro-oesophageal tumour response to neoadjuvant treatment as a reliable expression of tumour regression. KEY POINTS: • DWI is now being used to assess many cancers. • Change in ADC measurements offer new information about oesophageal tumours. • ADC changes are more reliable than dimensional criteria in assessing neoadjuvant treatment. • Such ADC assessment could optimise management of locally advanced gastro-oesophageal cancers.

Drug-eluting stent patency at 6 months in the pedal artery of a patient with polyarteritis nodosa: a case report.

Drug-eluting stents are largely used in coronary arteries and more recently in tibial arteries owing to their potentially better outcomes compared with bare metal stents. A patient with polyarteritis nodosa and critical limb ischemia and a dorsal foot ulcer was previously unsuccessfully treated with multiple angioplasties and subsequently underwent implantation of a drug-eluting stent in the pedal artery. At 6 months, stent patency on color Doppler ultrasound and complete healing of the foot ulcer were observed.

Chamelogk: A Chromatographic Chameleonicity Quantifier to Design Orally Bioavailable Beyond-Rule-of-5 Drugs.

New chemical modalities in drug discovery include molecules belonging to the bRo5 chemical space. Because of their complex and flexible structure, bRo5 compounds often suffer from a poor solubility/permeability profile. Chameleonicity describes the capacity of a molecule to adapt to the environment through conformational changes; the design of molecular chameleons is a medicinal chemistry strategy simultaneously optimizing solubility and permeability. A default method to quantify chameleonicity in early drug discovery is still missing. Here we introduce Chamelogk, an automated, fast, and cheap chromatographic descriptor of chameleonicity. Moreover, we report measurements for 55 Ro5 and bRo5 compounds and validate our method with literature data. Then, selected case studies (macrocycles, nonmacrocyclic compounds, and PROTACs) are used to illustrate the application of Chamelogk in combination with lipophilicity (BRlogD) and polarity (Δ log kwIAM) descriptors. Overall, we show how Chamelogk deserves being included in property-based drug discovery strategies to design oral bioavailable bRo5 compounds.

Transarterial chemoembolization with drug-eluting beads preloaded with irinotecan as a first-line approach in uveal melanoma liver metastases: tumor response and predictive value of diffusion-weighted MR imaging in five patients.

Five patients with uveal melanoma metastatic to the liver (two to five lesions per patient) were prospectively enrolled and treated with transarterial chemoembolization with drug-eluting beads preloaded with irinotecan as a first-line therapy. An overall response rate of 80% was obtained per Response Evaluation Criteria In Solid Tumors. All patients were alive after mean follow-up durations of 10.6 months and 16.3 months, respectively, after the first treatment and the diagnosis of liver metastasis. The apparent diffusion coefficient values obtained by diffusion-weighted magnetic resonance imaging were significantly lower in lesions that showed a response. These findings are very promising and can constitute the background for further studies involving larger cohorts of patients.

Regorafenib Induces Senescence and Epithelial-Mesenchymal Transition in Colorectal Cancer to Promote Drug Resistance.

Potential intrinsic resistance mechanisms to regorafenib were explored after short exposure (3 days) on five CRC cell lines (HCT-116, SW1116, LS-1034, SW480, Caco-2). The observation of senescence-like features led to the investigation of a drug-initiated phenotype switch. Following long-term exposure (12 months) of HCT-116 and SW480 cell lines to regorafenib, we developed resistant models to explore acquired resistance. SW480 cells demonstrated senescent-like properties, including a cell arrest in the late G2/prophase cell cycle stage and a statistically significant decrease in the expression of G1 Cyclin-Dependent Kinase inhibitors and key cell cycle regulators. A specific senescence-associated secretome was also observed. In contrast, HCT-116 treated cells presented early senescent features and developed acquired resistance triggering EMT and a more aggressive phenotype over time. The gained migration and invasion ability by long-exposed cells was associated with the increased expression level of key cellular and extracellular EMT-related factors. The PI3K/AKT pathway was a significant player in the acquired resistance of HCT-116 cells, possibly related to a PI3KCA mutation in this cell line. Our findings provide new insights into the phenotypic plasticity of CRC cells able, under treatment pressure, to acquire a stable TIS or to use an early senescence state to undergo EMT.

Anosognosia for theory of mind deficits: A single case study and a review of the literature.

Being aware of one's own ability to interact socially is crucial to everyday life. After a brain injury, patients may lose their capacity to understand others' intentions and beliefs, that is, the Theory of Mind (ToM). To date, the debate on the association between ToM and other cognitive deficits (in particular executive functions and behavioural disorders) remains open and data regarding awareness of ToM deficits are meagre. By means of an ad-hoc neuropsychological battery of tests, we report on a patient who suffers from ToM deficits and is not aware of these disorders, although aware of his other symptoms. The study is accompanied by a review of the literature (PRISMA guidelines) demonstrating that ToM deficits are independent of executive functions. Furthermore, an advanced lesion analysis including tractography was executed. The results indicate that: i) ToM deficits can be specific and independent of other cognitive symptoms; ii) unawareness may be specific for ToM impairment and not involve other disorders and iii) the medial structures of the limbic, monitoring and attentional systems may be involved in anosognosia for ToM impairment.

ABLATE: a score to predict complications and recurrence rate in percutaneous treatments of renal lesions.

RENAL score has been validated on predicting adverse events and relapses in percutaneous treatments of renal lesions. To better fit interventional issues a modified score (mRENAL) has been introduced, but the only difference from the RENAL score is on the dimensional parameter. However, it remains of surgical derivation while a specific interventional score is missing. This study aims to obtain a specific score (ABLATE) to better quantify the risk of complications and relapses in percutaneous kidney ablation procedures compared to the existing surgical scores. Taking inspiration from previous papers, a score was built to quantify the real difficulties faced in percutaneous treatment of renal lesions. The ABLATE score was used on 71 cryoablations to evaluate its predictivity of complications and relapses. Logistic regression was used to predict complication incidence; Cox-regression was used for relapses; ROC analysis was used to evaluate the accuracy of the different scores. Between January 2014 and November 2019, 71 lesions in 68 patients were treated. Overall, malignant histology was found in 62 lesions (87.3%). Mean and median RENAL, mRENAL, and ABLATE scores were 7.04 and 7, 7.19 and 7, and 5.11 and 4, respectively. Out of 71 treatments, we experienced 3 bleeding with anemia (4.2%), only 2 of which needed further treatment (2.82%). The mean and median RENAL, mRENAL, and ABLATE scores in those with complications were 7.66 and 7.01 (p = 0.69), 8.0 and 7.1 (p = 0.54), and 6.6 and 5.0 (p = 0.38), respectively. Out of 62 malignant lesions, we experienced 2 persistent and 6 recurrent lesions (3.2% and 8.4%, respectively). At Cox-regression analyses, mABLATE score outperformed both RENAL and mRENAL scores in predicting recurrences (HR 1.48; p < 0.001 vs. 1.41; p = 0.1 vs. 1.38: p = 0.07, respectively). The ABLATE score showed to be a better predictor of relapses than RENAL and mRENAL. The small number of complications conditioned a lack of statistic power on complications for all the scores. At the moment to quantify the risks in percutaneous kidney ablation procedures, surgical scores are used. A specific score better performs this task.

Endovascular Repair of 40 Visceral Artery Aneurysms and Pseudoaneurysms with the Viabahn Stent-Graft: Technical Aspects, Clinical Outcome and Mid-Term Patency.

PURPOSE: Endovascular repair of true visceral artery aneurysms (VAAs) and pseudoaneurysms (VAPAs) with stent-grafting (SG) can simultaneously allow aneurysm exclusion and vessel preservation, minimizing the risk of ischemic complications. Our aim was to report a single-center experience on SG of visceral aneurysms, focusing on technical aspects, clinical outcome and mid-term patency. MATERIALS AND METHODS: Consecutive patients affected by VAAs-VAPAs and submitted to endovascular treatment were retrospectively reviewed, and SG cases with the self-expandable peripheral Viabahn stent-graft were analyzed (2003-2017). Aneurysm type, patient number, SG clinical setting, procedural data, peri-procedural complications, technical success, 30-day clinical success, 30-day mortality and follow-up period (aneurysm exclusion, stent-graft patency, ischemic complications) were analyzed. RESULTS: SG was performed in 40 patients (24 VAPAs/16 VAAs) and in 44 procedures (25 in emergency, 19 in elective treatments), via transfemoral in 37 cases (transaxillary in 7 cases). One peri-procedural complication was recorded (a splenic artery dissection successfully converted to transcatheter embolization). The overall technical and clinical success rates were, respectively, 96 and 84%, with excellent trend in elective treatments (both 100%). Overall 30-day mortality was 12.5% (septic shock after pancreatic surgery). Stent-graft thrombosis occurred in 2 patients within 3 months, with aneurysm exclusion and without ischemic complications. Stent-graft patency and aneurysm exclusion were confirmed at 6, 12 and 36 months in 18, 12 and 7 patients, respectively. CONCLUSION: SG of VAAs and VAPAs was safe and effective, particularly in elective treatments. The Viabahn stent-graft, flexible and without shape memory, is suitable for endovascular repair of tortuous visceral arteries.

Allo- and auto-percutaneous intra-portal pancreatic islet transplantation (PIPIT) for diabetes cure and prevention: the role of imaging and interventional radiology.

Although the life expectancy of patients with type 1 diabetes mellitus (T1DM) has improved since the introduction of insulin therapy, the acute life-threatening and long-term complications from diabetes mellitus are significant causes of both mortality and morbidity. Percutaneous intra-portal pancreatic islet transplantation (PIPIT) is a minimally invasive, repeatable procedure which allows a ß-cell replacement therapy through a liver islet engraftment, leading to insulin release and glycaemic control restoration in patients with diabetes. Allo-PIPIT, in which isolated and purified islets from cadaveric donor are used, does not require major surgery, and is potentially less expensive for the recipient. In case of long-term T1DM, islet-after-kidney (IAK) transplantation can simultaneously cure diabetes and chronic renal failure, while islet-transplant-alone (ITA) is performed in brittle, short-term T1DM, based on the infusion of an adequate islet mass and on a steroid-free immunosuppressive regimen according to the Edmonton protocol. Results of the Collaborative Islet Transplant Registry (CITR) demonstrate that allo-PIPIT reduces episodes of hypoglycemia and diabetic complications, and improves quality of life of diabetic patients. Auto-PIPIT, in which the own patient's islets are used, has been investigated as a preventive treatment for pancreatogenic diabetes in patients who undergo extensive pancreatectomy for malignant and non-malignant disease. This Review outlines the role of imaging and interventional radiology in allo- and auto-PIPIT.