Search

We propose an internal calculus to check the satisfiability of a set of formulas in ${\boldsymbol {S4}}$. Our calculus directly supports model extraction and is designed so to implement a forward proof-search strategy that can be understood as a top-down construction of a model. We prove that the extracted models have minimal height.

Inflammatory bowel disease (IBD) affects a confined area of the intestine and, therefore, administration of drugs via oral route is preferable. However, obstacles such as changes in the pH along gastrointestinal tract (GIT), enzymatic activity, and intraluminal pressure may cause low drug availability in the target tissue when delivered orally. Previous studies have pointed out the benefits of using micron-sized particles for targeting inflamed intestinal mucosa and nanoparticles for delivery of anti-inflammatory agents to the affected epithelial cells. We hypothesized that by combining the benefits of micro- and nano- particles, we could create a more efficient delivery system for budesonide, a glucocorticosteroid commonly used for anti-inflammatory IBD therapy. The aim of this study was to develop a novel multistage system for oral delivery designed to increase concentrations budesonidein the inflamed intestinal tissue. The multistage system consists of Stage 1 mesoporous silicon microparticles (S1MP) loaded with stage 2 poly-lactic-glycolic acid (PLGA) budesonide-encapsulating nanoparticles (BNP). BNP were efficiently loaded into S1MP (loading efficiency of 45.9 ± 14.8%) due to the large pore volume and high surface area of S1MP and exhibited controlled release profiles with enhanced drug dissolution rate in biologically relevant pHs. Due to the robustness in acidic pH and their geometry, S1MP protected the loaded budesonide in the acidic (gastric) pH with only 20% release. This allowed for the prolonged release of the BNP in the higher pH conditions (intestinal pH). The sustained release of BNP could facilitate accumulation in the inflamed tissue, enabling BNP to penetrate inflamed mucosa and release active budesonide to the target site. The multistage systems of S1MP and BNP were further evaluated in three-dimensional (3D) in vitro model of IBD and were found to (1) increase accumulation of BNP in the inflamed areas, (2) restore the barrier function of Caco-2 inflamed monolayer, and (3) significantly reduce pro-inflammatory cytokine release almost to the level of the healthy control.

Objective: The focal length of available optical see-through (OST) head-mounted displays (HMDs) is at least 2 m; therefore, during manual tasks, the user eye cannot keep in focus both the virtual and real content at the same time. Another perceptual limitation is related to the vergence-accommodation conflict, the latter being present in binocular vision only. This paper investigates the effect of incorrect focus cues on the user performance, visual comfort, and workload during the execution of augmented reality (AR)-guided manual task with one of the most advanced OST HMD, the Microsoft HoloLens. Methods: An experimental study was designed to investigate the performance of 20 subjects in a connect-the-dots task, with and without the use of AR. The following tests were planned: AR-guided monocular and binocular, and naked-eye monocular and binocular. Each trial was analyzed to evaluate the accuracy in connecting dots. NASA Task Load Index and Likert questionnaires were used to assess the workload and the visual comfort. Results: No statistically significant differences were found in the workload, and in the perceived comfort between the AR-guided binocular and monocular test. User performances were significantly better during the naked eye tests. No statistically significant differences in performances were found in the monocular and binocular tests. The maximum error in AR tests was 5.9 mm. Conclusion: Even if there is a growing interest in using commercial OST HMD, for guiding high-precision manual tasks, attention should be paid to the limitations of the available technology not designed for the peripersonal space.

Background Venous percutaneous transluminal angioplasty (vPTA) in patients with multiple sclerosis (MS) and chronic cerebrospinal venous insufficiency (CCSVI) have shown contradictory results. The aim of the study is to evaluate the efficacy of the procedure in a randomized wait list control study. Methods 66 adults with neurologist-confirmed diagnosis of MS and sonographic diagnosis of CCSVI were allocated into vPTA-yes group (n = 31) or vPTA-not group (n = 35, control group). vPTA was performed immediately 15 days after randomization in the PTA-yes group and 6 months later in the control group. Evoked potentials (EPs), clinical-functional measures (CFMs), and upper limb kinematic measures (ULKMs) were measured at baseline (T0) and six months after in both groups, just before the venous angioplasty in the vPTA-not group (T1). Results Comparing the vPTA-yes and vPTA-not group, the CFM-derived composite functional outcome showed 11 (37%) versus 7 (20%) improved, 1 (3%) versus 3 (8%) stable, 0 versus 7 (20%) worsened, and 19 (61%) versus 18 (51%) mixed patients (χ2 = 8.71, df = 3, P = 0.03). Unadjusted and adjusted (for baseline confounding variables) odds ratio at 95% confidence interval were, respectively, 1.93 (1.3-2.8), P value 0.0007, and 1.85 (1.2-1.7), P value 0.002. EP- and ULKM-derived composite functional outcome showed no significant difference between the two groups. Conclusions Venous angioplasty can positively impact a few CFMs especially for the quality of life but achieving disability improvement is unlikely.

Objectives Revascularization according to the angiosome concept is of proven importance for limb salvage in chronic limb threatening ischaemia but it is not always practicable. Bifurcated bypasses could be considered as an option when an endovascular approach is not feasible or has already failed and a single bypass would not allow direct revascularization of the ischaemic area. Bifurcated bypasses are characterized by landing on two different arteries, the main artery (in direct continuity with the foot vessels) and the secondary one (perfusing the angiosome district). The aim of this study is to evaluate the safety and effectiveness of bifurcated bypass in chronic limb threatening ischaemia. Methods Thirty-five patients were consecutively treated with a bifurcated bypass for chronic limb threatening ischaemia from January 2014 to December 2019 in a single vascular surgery centre. Data from clinical records and operative registers were collected prospectively in an electronic database and retrospectively analysed. Primary and primary assisted bypass patency, amputation-free survival, morbidity and mortality rates at 12 and 24 months were analysed. Results Mean follow-up period was 25.1 months (range 2–72 months). Thirty-six bifurcated bypasses were performed on 35 patients (age 75.3 ± 7.2 years; 69.4% were male). According to Wound, Ischemia, foot Infection classification 22.2% belonged to stage 3 and 77.8% to stage 4 and the mean Rutherford’s class was 5.1 ± 0.7. Immediate technical success was 100%. Early mortality and morbidity rates were respectively 5.5%, and 33.3%; foot surgery was performed in 50% of cases with wound healing in all patients. Primary patency and primary assisted bypass patency were 96.7% and 100% at 6 months; 85.2% and 92% at 12 months, 59.9% and 73.4% at 24 months, respectively. Amputation-free survival at 12 and 24 months was, respectively, 95.6% and 78.8%. Overall survival rates at 12 and 24 months were respectively 94.4% and 91.6%. Conclusions Bifurcates bypass can provide good results in patients with chronic limb threatening ischaemia without endovascular option, especially in diabetic ones. Bifurcated bypass is a complex surgical solution, both to be planned and performed, and it is quite invasive for frail patients that should be accurately selected.

Background:Checkpoint inhibitor therapy of cancer has led to markedly improved survival of a subset of patients in multiple solid malignant tumor types, yet the factors driving these clinical responses or lack thereof are not known. We have developed a mechanistic mathematical model for better understanding these factors and their relations in order to predict treatment outcome and optimize personal treatment strategies.Methods:Here, we present a translational mathematical model dependent on three key parameters for describing efficacy of checkpoint inhibitors in human cancer: tumor growth rate (α), tumor-immune infiltration (Λ), and immunotherapy-mediated amplification of anti-tumor response (µ). The model was calibrated by fitting it to a compiled clinical tumor response dataset (n = 189 patients) obtained from published anti-PD-1 and anti-PD-L1 clinical trials, and then validated on an additional validation cohort (n = 64 patients) obtained from our in-house clinical trials.Results:The derived parameters Λ and µ were both significantly different between responding versus nonresponding patients. Of note, our model appropriately classified response in 81.4% of patients by using only tumor volume measurements and within 2 months of treatment initiation in a retrospective analysis. The model reliably predicted clinical response to the PD-1/PD-L1 class of checkpoint inhibitors across multiple solid malignant tumor types. Comparison of model parameters to immunohistochemical measurement of PD-L1 and CD8+ T cells confirmed robust relationships between model parameters and their underlying biology.Conclusions:These results have demonstrated reliable methods to inform model parameters directly from biopsy samples, which are conveniently obtainable as early as the start of treatment. Together, these suggest that the model parameters may serve as early and robust biomarkers of the efficacy of checkpoint inhibitor therapy on an individualized per-patient basis.Funding:We gratefully acknowledge support from the Andrew Sabin Family Fellowship, Center for Radiation Oncology Research, Sheikh Ahmed Center for Pancreatic Cancer Research, GE Healthcare, Philips Healthcare, and institutional funds from the University of Texas M.D. Anderson Cancer Center. We have also received Cancer Center Support Grants from the National Cancer Institute (P30CA016672 to the University of Texas M.D. Anderson Cancer Center and P30CA072720 the Rutgers Cancer Institute of New Jersey). This research has also been supported in part by grants from the National Science Foundation Grant DMS-1930583 (ZW, VC), the National Institutes of Health (NIH) 1R01CA253865 (ZW, VC), 1U01CA196403 (ZW, VC), 1U01CA213759 (ZW, VC), 1R01CA226537 (ZW, RP, WA, VC), 1R01CA222007 (ZW, VC), U54CA210181 (ZW, VC), and the University of Texas System STARS Award (VC). BC acknowledges support through the SER Cymru II Programme, funded by the European Commission through the Horizon 2020 Marie Skłodowska-Curie Actions (MSCA) COFUND scheme and the Welsh European Funding Office (WEFO) under the European Regional Development Fund (ERDF). EK has also received support from the Project Purple, NIH (U54CA210181, U01CA200468, and U01CA196403), and the Pancreatic Cancer Action Network (16-65-SING). MF was supported through NIH/NCI center grant U54CA210181, R01CA222959, DoD Breast Cancer Research Breakthrough Level IV Award W81XWH-17-1-0389, and the Ernest Cockrell Jr. Presidential Distinguished Chair at Houston Methodist Research Institute. RP and WA received serial research awards from AngelWorks, the Gillson-Longenbaugh Foundation, and the Marcus Foundation. This work was also supported in part by grants from the National Cancer Institute to SHC (R01CA109322, R01CA127483, R01CA208703, and U54CA210181 CITO pilot grant) and to PYP (R01CA140243, R01CA188610, and U54CA210181 CITO pilot grant). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The objective of this study was to compute threshold values for the diameter of superficial spreading melanomas (SSMs) at which the radial growth phase (RGP) evolves into an invasive vertical growth phase (VGP). We examined reports from 1995 to 2019 of 834 primary SSMs. All the patients underwent complete surgical removal of the tumor and the diagnosis was confirmed after histologic examination. Machine learning was used to compute the thresholds. For invasive non-naevus-associated SSMs, a threshold for the diameter was found at 13.2 mm (n = 634). For the lower limb (n = 209) the threshold was at 9.8 mm, whereas for the upper limb (n = 117) at 14.1 mm. For the back (n = 106) and the trunk (n = 173), the threshold was at 16.2 mm and 17.1 mm, respectively. When considering non-naevus-associated and naevus-associated SSMs together (n = 834) a threshold for the diameter was found at 16.8 mm. For the lower limb (n = 248) the threshold was at 11.7 mm, whereas for the upper limb (n = 146) at 16.4 mm. For the back (n = 170) and the trunk (n = 236), the threshold was at 18.6 mm and 14.1 mm, respectively. Thresholds for various anatomic locations and for each gender were defined. They were based on the diameter of the melanoma and computed to suggest a transition from RGP to VGP. The transition from a radial to a more invasive vertical phase is detected by an increase of tumor size with a numeric cutoff. Besides the anamnestic, clinical and dermatoscopic findings, our proposed approach may have practical relevance in vivo during clinical presurgical inspections.

Augmented Reality (AR) headsets have become the most ergonomic and efficient visualization devices to support complex manual tasks performed under direct vision. Their ability to provide hands-free interaction with the augmented scene makes them perfect for manual procedures such as surgery. This study demonstrates the reliability of an AR head-mounted display (HMD), conceived for surgical guidance, in navigating in-depth high-precision manual tasks guided by a 3D ultrasound imaging system. The integration between the AR visualization system and the ultrasound imaging system provides the surgeon with real-time intra-operative information on unexposed soft tissues that are spatially registered with the surrounding anatomic structures. The efficacy of the AR guiding system was quantitatively assessed with an in vitro study simulating a biopsy intervention aimed at determining the level of accuracy achievable. In the experiments, 10 subjects were asked to perform the biopsy on four spherical lesions of decreasing sizes (10, 7, 5, and 3 mm). The experimental results showed that 80% of the subjects were able to successfully perform the biopsy on the 5 mm lesion, with a 2.5 mm system accuracy. The results confirmed that the proposed integrated system can be used for navigation during in-depth high-precision manual tasks.

In situ fenestration of stent-graft represents a potential option for the treatment of aortic diseases in patients unsuitable for standard endovascular repair. The best fenestration strategy to restore perfusion of collateral vessels after their coverage by an endograft depends mainly on the anatomical area. Several tools are employed as fenestration devices, including needles, radiofrequency probes, and laser systems, used in conjunction with other instrumentation to provide enough support and stability during the procedure. In this systematic review, the approaches to reach the correct fenestration site both in human, animal, and in in vitro environments are described and discussed, highlighting advantages and limitations. Both commercial and dedicated solutions for the intraoperative modification of the fabric material are reported as well. The clinical interest in this procedure has so far encouraged researchers to develop and refine both methods and tools to solve the current limitations of this technique, intending to extend the indications for endovascular treatment to a broader range of patients.

Objective In recent years, manufacturers have developed new stent grafts with lower profiles to increase the endovascular aneurysm repair applicability. As reported by the current European Society for Vascular Surgery guidelines, long-term evaluation of such low-profile platforms is strongly recommended. This study aims to report outcomes beyond 5 years from a multicenter registry, including a real-world cohort of patients electively treated with low-profile stent grafts. Methods A retrospective data collection of patients who had undergone elective implantation of low-profile endograft ≤16 Fr. (Zenith LP, Ovation, Incraft) was performed in nine centers. The primary endpoint was a long-term primary clinical success. Secondary endpoints were survival rate, freedom from abdominal aortic aneurysm (AAA)-related death, freedom from type I to III endoleak, limb patency, and freedom from all reinterventions. The Kaplan-Meier curves were stratified for investigative devices. A multivariate analysis evaluated predictors of primary clinical success and reintervention rate. Results A total of 619 patients were enrolled (Ovation, n = 373; Incraft, n = 111; and Zenith LP, n = 135), with a mean follow-up of 56.8 ± 22.8 months. The overall primary and the secondary clinical success rate at 8 years was 72.1% and 93.8%, respectively. At 8 years, overall survival was 53.2%, freedom from AAA-related death was 94.4%, freedom from reintervention was 74%, freedom from type I/III endoleak was 86.9%, and limb patency was 90.4%. A significantly worse primary clinical success of the Zenith LP was recorded as dependent on more limb-related events. No differences between platforms were registered in the rate of AAA-related deaths, open conversion, sac enlargement, and type I/III endoleaks (P = .26). Multivariate analysis identified iliac tortuosity (hazard ratio, 2.053) and Zenith LP (hazard ratio, 3.818) as significant independent predictors of clinical failure and reintervention. Conclusion Low-profile stent grafts have acceptable long-term outcomes. Overall survival and AAA-related death were in line with those reported for traditional devices. Long-term surveillance and reintervention, when necessary, remain crucial to guarantee durability.

Insufficient delivery of systemically administered anticancer drugs to tumors can compromise therapeutic efficacy and develop drug delivery-based therapeutic resistance. Nanotherapeutics such as PEGylated liposomal doxorubicin (PLD) are designed to preferentially accumulate in tumors utilizing enhanced permeation and retention effect. However, their antitumor effects and resulting clinical outcomes are modest and heterogeneous among tumors. Here, we aimed to investigate whether the amount and efficacy of PLD delivered to tumors are tumor site dependent. We established orthotopic primary tumor or liver metastases models of murine breast cancer using 4 T1 cells. PLD showed significant therapeutic effects against tumors that grew in primary mammary sites but not in the liver. We found that differences in therapeutic efficacy were not because of the intrinsic biological resistance of cancer cells but rather were associated with tumor site-dependent differences in transport properties, such as the amount of PLD delivery, blood vessel function, relative vascular permeability, and mechanical pressure in tumors. Thus, transport properties in tumor is site dependent and can be used as phenotypic surrogate markers for tumor drug delivery and therapeutic efficacy.

Objective Hand-assisted laparoscopic surgery (HALS) for the treatment of abdominal aortic aneurysm (AAA) has shown promising initial results compared with traditional surgery, but its efficacy remains highly debated. The aim of this monocentric, retrospective study was to investigate differences in morbidity, mortality, and reintervention rates between endovascular aneurysm repair (EVAR) and HALS, in the medium- and long-term follow-up in a highly selected population. Methods We treated 977 patients consecutively for nonurgent AAA from January 2006 to December 2013; among them, 615 (62.9%) underwent open surgery, 173 (17.7%) HALS, and 189 (19.3%) EVAR. For this study, only patients treated with HALS or EVAR were considered. A subsequent selection process was carried out to identify the patients with clinical characteristics and aneurysm morphology amenable to either of these treatments. The final study cohort included 229 patients; 92 (40.2%) underwent HALS and 137 (69.8%) received EVAR. The two populations were homogeneous for clinical and demographic characteristics. Results The mean duration of follow-up was 57 ± 28 months (50 ± 24 months in the EVAR group and 67 ± 29 months in the HALS group; range, 2-110 months). No deaths and no statistically significant differences in severe complications or reinterventions were observed over the perioperative period (30 days). Length of stay was significantly shorter after EVAR, because the need for and length of stay in the intensive care unit were decreased. Three postoperative deaths (in-hospital mortality >30 days: HALS, 2.2%; EVAR, 0.7%; P = .7268) occurred owing to respiratory failure (two patients, one in each group) and multiorgan failure secondary to a bowel ischemia (one patient in the HALS group). Other deaths in the study population were not related to the procedure. In both groups, the major causes of death were cancer (24 cases [36.9%]), cardiovascular causes unrelated to AAA (16 [24.6%]), and chronic obstructive lung disease (10 [15.4%]). In the long-term follow-up period, there was a difference in the overall survival in favor of HALS when compared with EVAR (P = .011). Conclusions This retrospective, single-center study shows that, within a population of similar clinical and anatomic characteristics, treatment of AAA with EVAR or HALS does not result in significant differences in early morbidity and mortality. EVAR presents significantly shorter hospital and intensive care unit length of stay, whereas HALS presents a lower aneurysm-related reintervention rate and lower perioperative cost. The strict patient selection in this trial, as is generally the case with AAA treatment, is likely the key to success for both of these techniques.

Cell-based therapy is emerging as a promising strategy for treating a wide range of human diseases, such as diabetes, blood disorders, acute liver failure, spinal cord injury, and several types of cancer. Pancreatic islets, blood cells, hepatocytes, and stem cells are among the many cell types currently used for this strategy. The encapsulation of these "therapeutic" cells is under intense investigation to not only prevent immune rejection but also provide a controlled and supportive environment so they can function effectively. Some of the advanced encapsulation systems provide active agents to the cells and enable a complete retrieval of the graft in the case of an adverse body reaction. Here, we review various encapsulation strategies developed in academic and industrial settings, including the state-of-the-art technologies in advanced preclinical phases as well as those undergoing clinical trials, and assess their advantages and challenges. We also emphasize the importance of stimulus-responsive encapsulated cell systems that provide a "smart and live" therapeutic delivery to overcome barriers in cell transplantation as well as their use in patients.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with variable presentations and natural histories of disease. We hypothesized that different morphologic characteristics of PDAC tumors on diagnostic computed tomography (CT) scans would reflect their underlying biology. Experimental Design: We developed a quantitative method to categorize the PDAC morphology on pretherapy CT scans from multiple datasets of patients with resectable and metastatic disease and correlated these patterns with clinical/pathologic measurements. We modeled macroscopic lesion growth computationally to test the effects of stroma on morphologic patterns, hypothesizing that the balance of proliferation and local migration rates of the cancer cells would determine tumor morphology. Results: In localized and metastatic PDAC, quantifying the change in enhancement on CT scans at the interface between tumor and parenchyma (delta) demonstrated that patients with conspicuous (high-delta) tumors had significantly less stroma, higher likelihood of multiple common pathway mutations, more mesenchymal features, higher likelihood of early distant metastasis, and shorter survival times compared with those with inconspicuous (low-delta) tumors. Pathologic measurements of stromal and mesenchymal features of the tumors supported the mathematical model's underlying theory for PDAC growth. Conclusions: At baseline diagnosis, a visually striking and quantifiable CT imaging feature reflects the molecular and pathological heterogeneity of PDAC, and may be used to stratify patients into distinct subtypes. Moreover, growth patterns of PDAC may be described using physical principles, enabling new insights into diagnosis and treatment of this deadly disease.

BackgroundThe disruption of the stent component of the graft is an unusual complication of the endovascular abdominal aortic aneurysm repair (EVAR).Case presentationA 71-year-old man underwent EVAR followed by initial significant sac shrinkage. At 24 months, ultrasound and computed tomography showed sac growth associated with suprarenal stent graft separation from main body, without evidence of endoleak. A thoracic endograft was placed with complete relining of the previous graft.Conclusions.The report demonstrates un uncommon cause of endograft failure with suprarenal stent separation from a Zenith Cook main body and highlights the need for continuous follow-up.

Pre-exposure prophylaxis (PrEP) using antiretroviral oral drugs is effective at preventing HIV transmission when individuals adhere to the dosing regimen. Tenofovir alafenamide (TAF) is a potent antiretroviral drug, with numerous long-acting (LA) delivery systems under development to improve PrEP adherence. However, none has undergone preventive efficacy assessment. Here we show that LA TAF using a novel subcutaneous nanofluidic implant (nTAF) confers partial protection from HIV transmission. We demonstrate that sustained subcutaneous delivery through nTAF in rhesus macaques maintained tenofovir diphosphate concentration at a median of 390.00 fmol/106 peripheral blood mononuclear cells, 9 times above clinically protective levels. In a non-blinded, placebo-controlled rhesus macaque study with repeated low-dose rectal SHIVSF162P3 challenge, the nTAF cohort had a 62.50% reduction (95% CI: 1.72% to 85.69%; p=0.068) in risk of infection per exposure compared to the control. Our finding mirrors that of tenofovir disoproxil fumarate (TDF) monotherapy, where 60.00% protective efficacy was observed in macaques, and clinically, 67.00% reduction in risk with 86.00% preventive efficacy in individuals with detectable drug in the plasma. Overall, our nanofluidic technology shows potential as a subcutaneous delivery platform for long-term PrEP and provides insights for clinical implementation of LA TAF for HIV prevention.

Checkpoint inhibitor therapy of cancer has led to markedly improved survival of a subset of patients in multiple solid malignant tumor types, yet the factors driving these clinical responses or lack thereof are not known. Here we present a translational mathematical model dependent on three key parameters for describing efficacy of checkpoint inhibitors in human cancer: tumor growth rate (α), tumor immune infiltration (Λ), and immunotherapy-mediated amplification of anti-tumor response (µ). The model was validated by fitting it to a compiled clinical tumor response dataset (n = 189 patients) obtained from published anti-PD-1 and anti-PD-L1 clinical trials, and then validated on an additional validation cohort (n = 64 patients) obtained from our in-house clinical trials. The derived parameters Λ and µ were both significantly different between responding versus non-responding patients. Of note, our model appropriately classified response in 81.4% of patients by using only tumor volume measurements and within two months of treatment initiation in a retrospective analysis. The model reliably predicted clinical response to the PD-1/PD-L1 class of checkpoint inhibitors across multiple solid malignant tumor types. Comparison of model parameters to immunohistochemical measurement of PD-L1 and CD8+ T cells confirmed robust relationships between model parameters and their underlying biology, demonstrating reliable methods to inform model parameters directly from biopsy samples, which are conveniently obtainable as early as the start of treatment. Together, these results suggest that the model parameters may serve as early and robust biomarkers of the efficacy of checkpoint inhibitor therapy on an individualized per-patient basis.SIGNIFICANCECheckpoint inhibitors have revolutionized cancer immunotherapy, but only a subset of patients with solid tumors responds clinically. The ability to predict tumor responses a priori or soon after starting therapy would allow for personalized and timely adaptive clinical applications of checkpoint inhibitor- based immunotherapy in patients. By applying a mechanistic mathematical model, we show that checkpoint inhibitor therapeutic effectiveness is accurately predictable in most patients within two months after treatment initiation. Our method may be implemented directly into clinical practice, as it relies on standard-of-care imaging and pathology. If successful in prospective studies, this model will improve selection of cancer patients for checkpoint inhibitor therapy, and perhaps for other forms of humoral- or cell-based immunotherapy.

Nowadays, ultrasound (US) is increasingly being chosen as imaging modality for both diagnostic and interventional applications, owing to its positive characteristics in terms of safety, low footprint, and low cost. The combination of this imaging modality with wearable augmented reality (AR) systems, such as the head-mounted displays (HMD), comes forward as a breakthrough technological solution, as it allows for hands-free interaction with the augmented scene, which is an essential requirement for the execution of high-precision manual tasks, such as in surgery. What we propose in this study is the integration of an AR navigation system (HMD plus dedicated platform) with a 3D US imaging system to guide a dissection task that requires maintaining safety margins with respect to unexposed anatomical or pathological structures. For this purpose, a standard scalpel was sensorized to provide real-time feedback on the position of the instrument during the execution of the task. The accuracy of the system was quantitatively assessed with two different experimental studies: a targeting experiment, which revealed a median error of 2.53 mm in estimating the scalpel to target distance, and a preliminary user study simulating a dissection task that requires reaching a predefined distance to an occult lesion. The second experiment results showed that the system can be used to guide a dissection task with a mean accuracy of 0.65 mm, with a mean angular error between the ideal and actual cutting plane of 2.07°. The results encourage further studies to fully exploit the potential of wearable AR and intraoperative US imaging to accurately guide deep surgical tasks, such as to guide the excision of non-palpable breast tumors ensuring optimal margin clearance.

Purpose: This study aimed to assess the diagnostic performances of multimodal imaging [i.e., white blood cell single-photon emission computed tomography/CT (99mTc-HMPAO-WBC SPECT/CT) and 18-fluoride-fluorodeoxyglucose positron emission tomography/CT ([18F]FDG PET/CT)] in patients with suspected infection after the Bentall procedure, proposing new specific diagnostic criteria for the diagnosis.Methods: Between January 2009 and December 2019, we selected within a cardiovascular infections registry, 76 surgically treated patients (27 women and 49 men, median 66 years, and range 29–83 years). All the patients underwent molecular imaging for a suspected infection after the replacement of the aortic valve and ascending aorta according to the Bentall procedure. We analyzed 98 scans including 49 99mTc-WBC and 49 [18F]FDG PET/CT. A total of 22 patients with very early/early suspected infection (99mTc labeled hexamethylpropylene amine oxime-WBC SPECT/CT (99mTc-HMPAO-WBC SPECT/CT) and [18F]FDG PET/CT imaging were calculated by using microbiology (n = 35) or clinical follow-up (n = 41) as final diagnosis. 99mTc-HMPAO-WBC scintigraphy and [18F]FDG PET/CT findings were compared with 95% CIs by using the McNemar test to those of echocardiography/CT, blood culture, and the Duke criteria.Results: Sensitivity, specificity, and accuracy of 99mTc-HMPAO-WBC were 86, 92, and 88%, respectively, with a slightly higher sensitivity for tube graft infection (TGI) as compared to isolated AV and combined AVTG. Overall, sensitivity, specificity, and accuracy of [18F]FDG PET/CT were 97, 73, and 90%, respectively. In 22 patients with suspected very early and early postsurgical infections, the two imaging modalities were concordant in 17 cases [10 true positive (TP) and 7 true negative (TN)]. [18F]FDG PET/CT presented a higher sensitivity than 99mTc-HMPAO-WBC scan. 99mTc-HMPAO-WBC scan correctly classified as negative three false-positive (FP) PET/CT findings.Conclusion: Our findings supported the use of 99mTc-HMPAO-WBC SPECT/CT and [18F]FDG PET/CT in patients with suspicion infection after the Bentall procedure early in the course of the disease onset to confirm the diagnosis and provide a comprehensive assessment of disease burden through the proposed criteria.

Intratumoral drug delivery is a promising approach for the treatment of glioblastoma multiforme (GBM)., Intratumoral drug delivery is a promising approach for the treatment of glioblastoma multiforme (GBM). However, drug washout remains a major challenge in GBM therapy. Our strategy, aimed at reducing drug clearance and enhancing site-specific residence time, involves the local administration of a multi-component system comprised of nanoparticles (NPs) embedded within a thermosensitive hydrogel (HG). Herein, our objective was to examine the distribution of NPs and their cargo following intratumoral administration of this system in GBM. We hypothesized that the HG matrix, which undergoes rapid gelation upon increases in temperature, would contribute towards heightened site-specific retention and permanence of NPs in tumors. BODIPY-containing, infrared dye-labeled polymeric NPs embedded in a thermosensitive HG (HG–NPs) were fabricated and characterized. Retention and distribution dynamics were subsequently examined over time in orthotopic GBM-bearing mice. Results demonstrate that the HG–NPs system significantly improved site-specific, long-term retention of both NPs and BODIPY, with co-localization analyses showing that HG–NPs covered larger areas of the tumor and the peri-tumor region at later time points. Moreover, NPs released from the HG were shown to undergo uptake by surrounding GBM cells. Findings suggest that intratumoral delivery with HG–NPs has immense potential for GBM treatment, as well as other strategies where site-specific, long-term retention of therapeutic agents is warranted.

The design of effective nanoformulations that target metastatic breast cancers is challenging due to a lack of competent imaging and image analysis protocols that can capture the interactions between the injected nanoparticles and metastatic lesions. Here, we describe the integration of in vivo whole-body PET-CT with high temporal resolution, ex vivo whole-organ optical imaging and high spatial resolution confocal microscopy to deconstruct the trafficking of injectable nanoparticle generators encapsulated with polymeric doxorubicin (iNPG-pDox) in pulmonary metastases of triple-negative breast cancer. We describe the details of image acquisition and analysis in a step-wise manner along with the development of a mouse model for metastatic breast cancer. The methods described herein can be easily adapted to any nanoparticle or disease model, allowing a standardized pipeline for in vivo preclinical studies that focus on delineating nanoparticle kinetics and interactions within metastases.

We report a translational toolbox of multiscale imaging and mathematical modeling exploring nanoscale drug transport in metastases., It is challenging to design effective drug delivery systems (DDS) that target metastatic breast cancers (MBC) because of lack of competent imaging and image analysis protocols that suitably capture the interactions between DDS and metastatic lesions. Here, we integrate high temporal resolution of in vivo whole-body PET-CT, ex vivo whole-organ optical imaging, high spatial resolution of confocal microscopy, and mathematical modeling, to systematically deconstruct the trafficking of injectable nanoparticle generators encapsulated with polymeric doxorubicin (iNPG-pDox) in pulmonary MBC. iNPG-pDox accumulated substantially in metastatic lungs, compared to healthy lungs. Intratumoral distribution and retention of iNPG-pDox varied with lesion size, possibly induced by locally remodeled microenvironment. We further used multiscale imaging and mathematical simulations to provide improved drug delivery strategies for MBC. Our work presents a multidisciplinary translational toolbox to evaluate transport and interactions of DDS within metastases. This knowledge can be recursively applied to rationally design advanced therapies for metastatic cancers.

Objective Oral squamous cell carcinoma (OSCC) represents 3%-4% of all cancers. Despite the increasing incidence of OSCC distant metastasis and poor prognosis, few animal models of OSCC distant metastasis have been reported. In this study, we established mouse models of OSCC lung metastasis by orthotopic and tail vein injection of new OSCC cell lines. Methods For the tail vein model, we used a novel cell line isolated from lung metastases reproduced in vivo after intravenous injection of HSC-3 GFP/luciferase cells and sorted for GFP expression (HSC-3 M1 GFP/luciferase). Lung metastases were assessed by imaging techniques and further confirmed by histology. For the orthotopic model, HSC-3 GFP/luciferase cells were injected into the tongue of athymic nude mice. The primary tumor and metastases were assessed by in vivo imaging, histology, and immunohistochemistry. Results The orthotopic model presented spontaneous lung metastases in 50% of the animals and lymph node metastases were present in 83% of cases. In the tail vein model, a lung metastasis rate of 60% was observed. Conclusions Lung metastases were successfully reproduced by orthotopic and tail vein injection. Since lymph node metastases were present, the orthotopic model with HSC-3 GFP/luciferase cells may be suitable to investigate metastatic dissemination in OSCC.

Background Virtual reality is becoming popular in the rehabilitation field thanks to the several advantages it can offer to patients and physicians. Indeed, serious games can: motivate and engage the patient; offer different levels of challenge and difficulty based on the patient baseline, and integrate objective measures of the patient's performance during each rehabilitation session. Objective We designed and implemented a serious game for shoulder rehabilitation based on real-time hand tracking. The aim was to maintain the medical benefits of traditional rehabilitation, while reducing human resources and costs and facilitating active patient participation. Methods Our software application provides the user with a shoulder horizontal adduction exercise. This exercise takes place in a 2D interactive game environment, controlled by hand movements on a desk pad. The hardware includes a standard desktop computer and screen, and the Leap Motion Controller: a hand tracking system. Changing the desk pad material allows the physiotherapist to vary the friction between the user hand and the supporting surface. Results Fourteen healthy volunteers and six rehabilitation experts tested our serious game. The results showed that the application is attractive, ergonomic and clinically useful. Conclusion Despite promising results, clinical validation is necessary to demonstrate the efficacy of the serious game.

Targeting the FATP4 transporter is an effective way to transport peptides and enhance oral bioavailability of peptide drugs., Low oral bioavailability of peptide drugs has limited their application to parenteral administration, which suffers from poor patient compliance. Here, we show that molecular targeting of the FATP4 transporter is an effective approach to specifically transport long-chain fatty acid (LCFA)–conjugated peptides across the enterocytic membrane and, thus, enables oral delivery of drug peptides. We packaged LCFA-conjugated exendin-4 (LCFA-Ex4) into liposomes and coated with chitosan nanoparticles to form an orally deliverable Ex4 (OraEx4). OraEx4 protected LCFA-Ex4 from damage by the gastric fluid and released LCFA-Ex4 in the intestinal cavity, where LCFA-Ex4 was transported across the enterocyte membrane by the FAPT4 transporter. OraEx4 had a high bioavailability of 24.8% with respect to subcutaneous injection and exhibited a substantial hypoglycemic effect in murine models of diabetes mellitus. Thus, molecular targeting of the FATP4 transporter enhances oral absorption of therapeutic peptides and provides a platform for oral peptide drug development.

Background Peritoneal carcinomatosis (PC) is a common manifestation of many gastrointestinal (GI) malignancies and is an advanced stage that is often associated with disseminated disease. Considerable progress has been made to achieve safe elimination of macroscopic disease using cytoreductive surgery (CRS) and more recently in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of microscopic disease or disease with minimal volume. The aim of this study was to assess the effects of such procedures on the quality of life (QoL), the long-term benefit and the functional status of the treated patients. Patients and methods Data from patients who underwent CRS-HIPEC for peritoneal metastasis (PM) at our center from November 2016 to November 2018 were analyzed retrospectively. The drugs administered were mitomycin and cisplatin. Quality of life (QoL) was assessed using the Euroquol-5D-5L and National Comprehensive Cancer Network Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index v2 questionnaires before CRS-HIPEC, and 1, 3 and 6 months after were administered. Results In our series, the survival efficacy of CRS plus HIPEC was confirmed in the treatment of primary and secondary peritoneal pathologies, particularly in ovarian cancer, although larger studies are needed to investigate its role in the pathology of gastric, colonic and rectal cancer. The QoL data were promising, with essentially stable values between the preoperative and the 1-month follow-up, but with incremental benefits from the second to the third month.

In the last years also in orthopedic surgery, there was an increasing interest in the development of surgical simulators using methods of additive manufacturing combined or not with augmented reality systems (hybrid simulators). Aim of this work was to evaluate the use of a new patient’s specific tibial plateau fractures simulator for surgical training of young resident surgeons in fracture fixation with an external fixator. The simulator is a realistic knee phantom including a patient-specific replica of a fractured tibia and fibula, obtained by CT segmentation and rapid prototyping techniques. Each training session started with the presentation, and planning, of the surgical case that it was followed by the external fixation session on the simulator. At the end of each session, all participants were asked to fill out a questionnaire, concerning the phantom realism and appropriateness as a teaching modality. The results of the Likert Questionnaire indicating that there is an overall significant agreement with the phantom realism and its appropriateness as a teaching modality.The solid model of the patient’s anatomy can faithfully reproduce the surgical complexity of the patient and it allows to generate surgical simulators with an increasing difficulty to perform structured training paths: from the "simple" case to the "complex" case. The use of simulators based on 3D models has proved to be a very useful tool both for didactic and surgical training purposes, allowing surgeons to perform a real procedure simulation outside the surgical room.

BackgroundDry eye disease (DED) affects more than 14% of the elderly population causing decrease of quality of life, high costs and vision impairment. Current treatments for DED aim at lubricating and controlling inflammation of the ocular surface. Development of novel therapies targeting different pathogenic mechanisms is sought-after. The aim of this study is to evaluate safety and efficacy of recombinant human nerve growth factor (rhNGF) eye drops in patients with DED.MethodsForty consecutive patients with moderate to severe DED were included in a phase IIa, prospective, open label, multiple-dose, clinical trial to receive rhNGF eye drops at 20 µg/mL (Group 1: G1) or at 4 µg/mL (Group 2: G2) concentrations, two times a day in both eyes for 28 days (NCT02101281). The primary outcomes measures were treatment-emerged adverse events (AE), Symptoms Assessment in Dry Eye (SANDE) scale, ocular surface staining and Schirmer test.ResultsOf 40 included patients, 39 completed the trial. Both tested rhNGF eye drop concentrations were safe and well tolerated. Twenty-nine patients experienced at least one AE (14 in G1 and 15 in G2), of which 11 had at least 1 related AE (8 in G1 and 3 in G2). Both frequency and severity of DED symptoms and ocular surface damage showed significant improvement in both groups, while tear function improved only in G1.ConclusionsThe data of this study indicate that rhNGF eye drops in both doses is safe and effective in improving symptoms and signs of DED. Randomised clinical trials are ongoing to confirm the therapeutic benefit of rhNGF in DED.Trial registration numberNCT02101281.

Background Osteosarcoma (OS) is an aggressive malignant neoplasm that still suffers from poor prognosis in the case of distal metastases or occurrence of multi-drug resistance. It is therefore crucial to find novel therapeutic options able to go beyond these limitations and improve patients’ survival. The objective of this study is to exploit the intrinsic properties of mesenchymal stromal cells (MSCs) to migrate and infiltrate the tumor stroma to specifically deliver therapeutic agents directly to cancer cells. In particular, we aimed to test the efficacy of the photoactivation of MSCs loaded with nanoparticles in vitro and in a murine in vivo ectopic osteosarcoma model. Methods AlPcS4@FNPs were produced by adding tetra-sulfonated aluminum phthalocyanine (AlPcS4) to an aqueous solution of positively charged poly-methyl methacrylate core-shell fluorescent nanoparticles (FNPs). The photodynamic therapy (PDT) effect is achieved by activation of the photosensitizer AlPcS4 in the near-infrared light with an LED source. Human MSCs were isolated from the bone marrow of five donors to account for inter-patients variability and used in this study after being evaluated for their clonogenicity, multipotency and immunophenotypic profile. MSC lines were then tested for the ability to internalize and retain the nanoparticles, along with their migratory properties in vitro. Photoactivation effect was evaluated both in a monolayer (2D) co-culture of AlPcS4@FNPs loaded MSCs with human OS cells (SaOS-2) and in tridimensional (3D) multicellular spheroids (AlPcS4@FNPs loaded MSCs with human OS cells, MG-63). Cell death was assessed by AnnexinV/PI and Live&Dead CalceinAM/EthD staining in 2D, while in the 3D co-culture, the cell killing effect was measured through ATP content, CalceinAM/EthD staining and TEM imaging. We also evaluated the effectiveness of AlPcS4@FNPs loaded MSCs as delivery systems and the ability of the photodynamic treatment to kill cancer cells in a subcutaneous mouse model of OS by bioluminescence imaging (BLI) and histology. Results MSCs internalized AlPcS4@FNPs without losing or altering their motility and viability in vitro. Photoactivation of AlPcS4@FNPs loaded MSCs induced high level of OS cells death in the 2D co-culture. Similarly, in the 3D co-culture (MSCs:OS ratios 1:1 or 1:3), a substantial decrease of both MSCs and OS cells viability was observed. Notably, when increasing the MSCs:OS ratio to 1:7, photoactivation still caused more than 40% cells death. When tested in an in vivo ectopic OS model, AlPcS4@FNPs loaded MSCs were able to decrease OS growth by 68% after two cycles of photoactivation. Conclusions Our findings demonstrate that MSCs can deliver functional photosensitizer-decorated nanoparticles in vitro and in vivo and inhibit OS tumor growth. MSCs may be an effective platform for the targeted delivery of therapeutic nanodrugs in a clinical scenario, alone or in combination with other osteosarcoma treatment modalities.

In pedicle screws placement using a free-hand technique or a fluoroscopic guided technique the main difficulties are facing to the bone morphology (i.e in deformity cases) and it could be easily reproduced in a patient’s specific spine simulator (we can choose the case). The aim of this work is to evaluate the use of 3D printed patient- specific models (3D printing) not only as a surgical planning tool but also as a surgical training tool in spine surgery and in particular in pedicle screws placement. The manufacturing of patient-specific physical replica involves the elaboration of CT dataset and rapid prototyping techniques. . Five resident surgeons were involved in different training sessions on simulators. To evaluate the exact screws position weperformed a CT evaluation of each instrumented simulators. Statistical analysis was conducted using SPSS software. A total of 120 pedicle screws were positioned, 90 screws were well-positioned and 30 screws were bad-positioned. There were a significant difference (p = 0.000008) between the bad-positioning screw rate of the “senior” resident (13/72) and those of “young” participants (17/48). Timeline analysis of pedicle instrumentation training showed the presence of a learning effect, with a lower error rate in the latest session (p=000001). We believe that the use of patient- specific surgical simulators, especially for those surgical tasks in which the complexity is mainly linked to the spine morphology (i.e. deformity), may represent a valid alternative to the use of cadavers that generally present a standard or otherwise poorly predictable anatomy.

Objective: This work presents a device for non-invasive wound parameters assessment, designed to overcome the drawbacks of traditional methods, which are mostly rough, inaccurate, and painful for the patient. The device estimates the morphological parameters of the wound and provides augmented reality (AR) visual feedback on the wound healing status by projecting the wound border acquired during the last examination, thus improving doctor-patient communication. Methods: An accurate 3D model of the wound is created by stereophotogrammetry and refined through self-organizing maps. The 3D model is used to estimate physical parameters for wound healing assessment and integrates AR functionalities based on a miniaturized projector. The physical parameter estimation functionalities are evaluated in terms of precision, accuracy, inter-operator variability, and repeatability, whereas AR wound border projection is evaluated in terms of accuracy on the same phantom. Results: The accuracy and precision of the device are respectively 2% and 1.2% for linear parameters, and 1.7% and 1.3% for area and volume. The AR projection shows an error distance, Monitoring Wound Healing with Contactless Measurements and Augmented Reality.

Objective: Aortic valve disease is the most common heart disease in the elderly calling for replacement with an artificial valve. The presented surgical robot aims to provide a highly controllable instrument for efficient delivery of an artificial valve by the help of integrated endoscopic vision. Methods: A robot (called ValveTech), intended for minimally invasive surgery (MIS) and consisting of a flexible cable driven manipulator, a passive arm, and a control unit has been designed and prototyped. The flexible manipulator has several features (e.g., stabilizing flaps, tiny cameras, dexterous introducer and custom cartridge) to help the proper valve placement. It provides 5 degrees of freedom for reaching the operative site via mini-thoracotomy; it adjusts the valve and expands it at the optimal position. The robot was evaluated by ten cardiac surgeons following a real surgical scenario in artificial chest simulator with an aortic mockup. Moreover, after each delivery, the expanded valve was evaluated objectively in comparison with the ideal position. Results: The robot performances were evaluated positively by surgeons. The trials resulted in faster delivery and an average misalignment distance of 3.8 mm along the aorta axis; 16.3 degrees rotational angle around aorta axis and 8.8 degrees misalignment of the valve commissure plane to the ideal plane were measured. Conclusion: The trials successfully proved the proposed system for valve delivery under endoscopic vision. Significance: The ValveTech robot can be an alternative solution for minimally invasive aortic valve surgery and improve the quality of the operation both for surgeons and patients.

In the past, radiotherapy was primarily used to control local disease, but recent technological advances in accurate, high-dose ionizing radiation (IR) delivery have not only increased local tumor control but in some cases reduced metastatic burden. These “off target” therapeutic effects of IR at nonirradiated tumor sites, also known as abscopal effects, are thought to be mediated by tumor antigen–primed T cells that travel to metastatic sites and promote tumor regression. Similarly, early indications reveal that IR in combination with immune checkpoint inhibitors, such as ipilimumab (anti–CTLA-4) and nivolumab (anti–PD-1), can provide superior therapeutic responses. These observations suggest that local radiotherapy results in altered gene expression, exposure of new antigens, or cell death that can interact with immunotherapy. As such, radiotherapy enhancement of immune responses offers a promising synergy with the potential for substantial clinical benefit. This review focuses on the biology that underlies the mechanisms for the interaction between radiation-induced tumor cell death and enhanced immunologic response. Mol Cancer Res; 16(8); 1209–14. ©2018 AACR.

Augmented reality (AR) has been successfully providing surgeons an extensive visual information of surgical anatomy to assist them throughout the procedure. AR allows surgeons to view surgical field through the superimposed 3D virtual model of anatomical details. However, open surgery presents new challenges. This study provides a comprehensive overview of the available literature regarding the use of AR in open surgery, both in clinical and simulated settings. In this way, we aim to analyze the current trends and solutions to help developers and end/users discuss and understand benefits and shortcomings of these systems in open surgery. We performed a PubMed search of the available literature updated to January 2018 using the terms (1) "augmented reality" AND "open surgery", (2) "augmented reality" AND "surgery" NOT "laparoscopic" NOT "laparoscope" NOT "robotic", (3) "mixed reality" AND "open surgery", (4) "mixed reality" AND "surgery" NOT "laparoscopic" NOT "laparoscope" NOT "robotic". The aspects evaluated were the following: real data source, virtual data source, visualization processing modality, tracking modality, registration technique, and AR display type. The initial search yielded 502 studies. After removing the duplicates and by reading abstracts, a total of 13 relevant studies were chosen. In 1 out of 13 studies, in vitro experiments were performed, while the rest of the studies were carried out in a clinical setting including pancreatic, hepatobiliary, and urogenital surgeries. AR system in open surgery appears as a versatile and reliable tool in the operating room. However, some technological limitations need to be addressed before implementing it into the routine practice.

Purpose: Understanding the mechanism of radioresistance could help develop strategies to improve therapeutic response of patients with PDAC. The SMAD4 gene is frequently mutated in pancreatic cancer. In this study, we investigated the role of SMAD4 deficiency in pancreatic cancer cells' response to radiotherapy. Experimental Design: We downregulated SMAD4 expression with SMAD4 siRNA or SMAD4 shRNA and overexpressed SMAD4 in SMAD4 mutant pancreatic cancer cells followed by clonogenic survival assay to evaluate their effects on cell radioresistance. To study the mechanism of radioresistance, the effects of SMAD4 loss on reactive oxygen species (ROS) and autophagy were determined by flow cytometry and immunoblot analysis, respectively. Furthermore, we measured radioresistance by clonogenic survival assay after treatment with autophagy inhibitor (Chloroquine) and ROS inhibitor (N-acetyl-l-cysteine) in SMAD4-depleted pancreatic cancer cells. Finally, the effects of SMAD4 on radioresistance were also confirmed in an orthotopic tumor model derived from SMAD4-depleted Panc-1 cells. Results: SMAD4-depleted pancreatic cancer cells were more resistant to radiotherapy based on clonogenic survival assay. Overexpression of wild-type SMAD4 in SMAD4-mutant cells rescued their radiosensitivity. Radioresistance mediated by SMAD4 depletion was associated with persistently higher levels of ROS and radiation-induced autophagy. Finally, SMAD4 depletion induced in vivo radioresistance in Panc-1-derived orthotopic tumor model (P = 0.038). More interestingly, we observed that the protein level of SMAD4 is inversely correlated with autophagy in orthotopic tumor tissue samples. Conclusions: Our results demonstrate that defective SMAD4 is responsible for radioresistance in pancreatic cancer through induction of ROS and increased level of radiation-induced autophagy. Clin Cancer Res; 24(13); 3176–85. ©2018 AACR.

Transport processes in cancer are the focus of transport oncophysics (TOP). In the TOP approach, the sequential negotiation of transport barriers is critical to both drug delivery and metastasis development. New and creative therapeutic opportunities are currently emerging, stimulated by the study of cancer hallmarks with the TOP approach.

There is an increasing interest for a test assessing objectively the innate aptitude for surgery as a craft specialty to complement the current selection process of surgical residents. The aim of this study was to quantify the size of individuals with high, average, and low level of innate psychomotor skills among medical students. A volunteer sample of 155 medical students, without prior experience with surgical simulator, executed five tasks at a virtual simulator for robot-assisted surgery. They had to reach proficiency twice consecutively in each before moving to the next one. A weighting based on time and number of attempts needed to reach proficiency was assigned to each task. Nine students (5.8%) out of 155 significantly outperformed all the others on median (i.q.r.) weighted time [44.7 (42.2–47.3) min vs. 98.5 (70.8–131.8) min, p

Aptamers have the potential to be used as targeting ligands for cancer treatment as they form unique spatial structures. Methods: In this study, a DNA aptamer (T1) that accumulates in the tumor microenvironment was identified through in vivo selection and validation in breast cancer models. The use of T1 as a targeting ligand was evaluated by conjugating the aptamer to liposomal doxorubicin. Results: T1 exhibited a high affinity for both tumor cells and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Treatment with T1 targeted doxorubicin liposomes triggered apoptosis of breast cancer cells and PMN-MDSCs. Suppression of PMN-MDSCs, which serve an immunosuppressive function, leads to increased intratumoral infiltration of cytotoxic T cells. Conclusion: The cytotoxic and immunomodulatory effects of T1-liposomes resulted in superior therapeutic efficacy compared to treatment with untargeted liposomes, highlighting the promise of T1 as a targeting ligand in cancer therapy.