Search

Treatment of hepatocellular carcinoma (HCC) with Y90 radioembolization segmentectomy (Y90-RE) demonstrates a tumor dose–response threshold, where dose estimates are highly dependent on accurate SPECT/CT acquisition, registration, and reconstruction. Any error can result in distorted absorbed dose distributions and inaccurate estimates of treatment success. This study improves upon the voxel-based dosimetry model, one of the most accurate methods available clinically, by using a deep convolutional network ensemble to account for the spatially variable uptake of Y90 within a treated lesion. A retrospective analysis was conducted in patients with HCC who received Y90-RE at a single institution. Seventy-seven patients with 103 lesions met the inclusion criteria: three or fewer tumors, pre- and post treatment MRI, and no prior Y90-RE. Lesions were labeled as complete (n = 57) or incomplete response (n = 46) based on 3-month post treatment MRI and divided by medical record number into a 20% hold-out test set and 80% training set with 5-fold cross-validation. Slice-wise predictions were made from an average ensemble of models and thresholds from the highest accuracy epochs across all five folds. Lesion predictions were made by thresholding all slice predictions through the lesion. When compared to the voxel-based dosimetry model, our model had a higher F1-score (0.72 vs. 0.2), higher accuracy (0.65 vs. 0.60), and higher sensitivity (1.0 vs. 0.11) at predicting complete treatment response. This algorithm has the potential to identify patients with treatment failure who may benefit from earlier follow-up or additional treatment. [ABSTRACT FROM AUTHOR]

Background: A healthy alveolar epithelium is critical to the gas exchange function of the lungs. As the major cell type of alveolar epithelium, alveolar type 2 (AT2) cells play a critical role in maintaining pulmonary homeostasis by serving as alveolar progenitors during lung injury, inflammation, and repair. Dysregulation of AT2 cells may lead to the development of acute and chronic lung diseases and cancer. The lack of clinically relevant AT2 cell models hampers our ability to understand pulmonary diseases. Here, we sought to establish reversibly immortalized mouse pulmonary alveolar type 2 cells (imPAC2) and investigate their potential in forming alveolar organoids to model pulmonary diseases. Methods: Primary mouse pulmonary alveolar cells (mPACs) were isolated and immortalized with a retroviral expression of SV40 Large T antigen (LTA). Cell proliferation and survival was assessed by crystal violet staining and WST-1 assays. Marker gene expression was assessed by qPCR, Western blotting, and/or immunostaining. Alveolar organoids were generated by using matrigel. Ad-TGF-β1 was used to transiently express TGF-β1. Stable silencing β-catenin or overexpression of mutant KRAS and TP53 was accomplished by using retroviral vectors. Subcutaneous cell implantations were carried out in athymic nude mice. The retrieved tissue masses were subjected to H & E histologic evaluation. Results: We immortalized primary mPACs with SV40 LTA to yield the imPACs that were non-tumorigenic and maintained long-term proliferative activity that was reversible by FLP-mediated removal of SV40 LTA. The EpCAM+ AT2-enriched subpopulation (i.e., imPAC2) was sorted out from the imPACs, and was shown to express AT2 markers and form alveolar organoids. Functionally, silencing β-catenin decreased the expression of AT2 markers in imPAC2 cells, while TGF-β1 induced fibrosis-like response by regulating the expression of epithelial-mesenchymal transition markers in the imPAC2 cells. Lastly, concurrent expression of oncogenic KRAS and mutant TP53 rendered the imPAC2 cells a tumor-like phenotype and activated lung cancer-associated pathways. Collectively, our results suggest that the imPAC2 cells may faithfully represent AT2 populations that can be further explored to model pulmonary diseases. [ABSTRACT FROM AUTHOR]

Effective and safe liver‐directed gene therapy has great promise in treating a broad range of liver diseases. While adenoviral (Ad) vectors have been widely used for efficacious in vivo gene delivery, their translational utilities are severely limited due to the short duration of transgene expression and solicitation of host immune response. Used as a promising polymeric vehicle for drug release and nucleic acid delivery, carboxymethyl chitosan (CMC) is biocompatible, biodegradable, anti‐microbial, inexpensive, and easy accessible. Here, by exploiting its biocompatibility, controlled release capability and anti‐inflammatory activity, we investigated whether CMC can overcome the shortcomings of Ad‐mediated gene delivery, hence improving the prospect of Ad applications in gene therapy. We demonstrated that in the presence of optimal concentrations of CMC, Ad‐mediated transgene expression lasted up to 50 days after subcutaneous injection, and at least 7 days after intrahepatic injection. Histologic evaluation and immunohistochemical analysis revealed that CMC effectively alleviated Ad‐induced host immune response. In our proof‐of‐principle experiment using the CCl4‐induced experimental mouse model of chronic liver damage, we demonstrated that repeated intrahepatic administrations of Ad‐IL10 mixed with CMC effectively mitigated the development of hepatic fibrosis. Collectively, these results indicate that CMC can improve the prospect of Ad‐mediated gene therapy by diminishing the host immune response while allowing readministration and sustained transgene expression. [ABSTRACT FROM AUTHOR]

Purpose: Metformin is associated with improved outcomes after external radiation and chemotherapy but has not been studied for Y-90 radiation segmentectomy (RS). This study evaluates the effect of metformin on tumor response after Y-90 RS in patients with hepatocellular carcinoma (HCC). Methods and Materials: A retrospective analysis of patients with HCC who underwent Y-90 RS between 2014–2018 was performed. Comparisons were made between all patients taking and not taking metformin, and diabetic patients taking and not taking metformin. Tumor response was analyzed with logistic regression to compare absolute and percent change in total tumor diameter (TTD) and modified Response Evaluation Criteria in Solid Tumors (mRECIST). Overall survival (OS) was evaluated using Kaplan–Meier estimation and log-rank analysis. Results: A total of 106 patients underwent 112 Y-90 RS, of which 40 were diabetic (38.8%) and 19 (18.4%) were on metformin. At baseline, the two groups of patients on metformin and not on metformin had no significant difference in age, Child–Pugh score, MELD score, ALBI grade, total tumor diameter, and size of dominant tumor. The only significant baseline difference was ECOG status. Uni- and multivariate analysis demonstrated a larger reduction in TTD and objective response by mRECIST criteria for patients undergoing Y-90 RS on metformin compared to those not on metformin. OS was similar between patients taking and not taking metformin (p = 0.912). Conclusion: Metformin may be associated with increased tumor response after Y-90 RS in patients with HCC. Level of Evidence: III, Retrospective Study. [ABSTRACT FROM AUTHOR]

Purpose: To compare the efficacies of glass and resin-based Yttrium-90 microspheres by comparing absorbed tumor dose (TD) with both tumor response (TR) and overall survival (OS) in patients with chemorefractory intrahepatic cholangiocarcinoma (ICC). Methods: Post-Y90 treatment bremsstrahlung SPECT/CT of 38 consecutive patients receiving 45 treatments (21 resin microspheres, 24 glass microspheres) were analyzed retrospectively. MIM software v6.9.4 (MIM Software Inc, Cleveland, OH) was used to calculate targeted tumors' dose volume histogram. Modified Response Evaluation Criteria in Solid Tumors was used to evaluate tumor response 3 months post-treatment. Kaplan Meier estimation was used for survival analysis. T-test was used to compare the devices on various dosimetric parameters. Results: Thresholds for TD to predict TR with ≥ 80% specificity were as follows: mean TD (Resin: 78.9 Gy; Glass: 254.7 Gy), maximum TD (Resin: 162.9 Gy; Glass: 591 Gy), minimum TD (Resin: 53.7 Gy; Glass: 149.1 Gy). Microsphere type had no effect on survival from first Y90 (Resin: 11.2 mo; Glass 10.9 mo [p = 0.548]). In patients receiving resin microspheres, mean TD ≥ 75 Gy or maximum TD ≥ 150 Gy was associated with median OS of 20.2 mo compared to 6.5 mo for those receiving less (p = 0.001, 0.002, respectively). For patients treated with glass microspheres, those receiving a mean TD ≥ 150 Gy had a median OS of 14.6 mo vs. 2.6 mo for those receiving less (p = 0.031). Conclusion: TD thresholds predictive of TR and OS differ significantly between glass and resin microspheres. However, microsphere type has no impact on survival in patients with chemorefractory ICC. Level of Evidence: Level 3, Retrospective Study. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of Y90 radiation segmentectomy (RS) vs. percutaneous microwave ablation (MWA) in patients with solitary HCC ≤ 4 cm. Methods: From 2014 to 2017, 68 consecutive treatment naïve patients were included (34 per treatment arm). Chi-square and t-test were used to evaluate differences in baseline demographics between groups. Objective response was evaluated using mRECIST and toxicity using CTCAE. Overall survival (OS) and progression free survival (PFS) in the targeted tumor and the remainder of liver from initial treatment was calculated using Kaplan–Meier estimation. Propensity score matching was then performed with n = 24 patients matched in each group. Similar outcome analysis was then pre-formed. Results: In the overall study population, both groups had similar baseline characteristics with the exception of larger lesions in the RS group. There was no difference in toxicity, objective tumor response, OS and non-target liver PFS between the MWA and RS group (p's > 0.05). In the matched cohort, the objective tumor response was 82.6% in MWA vs. 90.9%% in RS (p = 0.548). The mean OS in the MWA group (44.3 months) vs RS (59.0 months; p = 0.203). The targeted tumor mean PFS for the MWA groups was 38.6 months vs. 57.8 months in RS group (p = 0.005). There was no difference overall PFS and toxicity between the 2 matched groups. Conclusions: Our data suggest Y90 RS achieves similar tumor response and OS with a similar safety compared to MWA in the management of HCC lesions ≤ 4 cm. Additionally, targeted tumor PFS appears to be prolonged in the RS group with similar non-target liver PFS between RS and MWA group. [ABSTRACT FROM AUTHOR]

What shapes the types of services terrorist and insurgent groups provide? Research on these organizations provides mounting evidence that understanding the nonviolent strategies of violent groups is critical to a complete picture of conflict dynamics. We add to this work, using a longitudinal measure of terrorist service provision coverage across a number of service sectors to evaluate hypotheses concerning the drivers of terrorist service provision to understand which services groups provide. Here, we are interested in understanding patterns of service provision: which groups provide services where, and whether and how that decision is reactive to the state context. Specifically we look to see if groups are likely to provide services as complements or substitutes to the state in the competition for constituents. We find terrorist groups challenge the state in service provision in less capital-intensive sectors, such as education, while avoiding competition in more capital-intensive sectors, such as healthcare. We also find service provision varies over a group's lifetime, likely in response to counterterrorism efforts. As a group ages and strengthens, it is also more likely to provide a broader array of services. Finally, we observe that service-providers tend to have longer lifespans. [ABSTRACT FROM AUTHOR]

Observing the structure and regeneration of the myelin sheath in peripheral nerves following injury and during repair would help in understanding the pathogenesis and treatment of neurological diseases caused by an abnormal myelin sheath. In the present study, transmission electron microscopy, immunofluorescence staining, and transcriptome analyses were used to investigate the structure and regeneration of the myelin sheath after end-to-end anastomosis, autologous nerve transplantation, and nerve tube transplantation in a rat model of sciatic nerve injury, with normal optic nerve, oculomotor nerve, sciatic nerve, and Schwann cells used as controls. The results suggested that the double-bilayer was the structural unit that constituted the myelin sheath. The major feature during regeneration was the compaction of the myelin sheath, wherein the distance between the 2 layers of cell membrane in the double-bilayer became shorter and the adjacent double-bilayers tightly closed together and formed the major dense line. The expression level of myelin basic protein was positively correlated with the formation of the major dense line, and the compacted myelin sheath could not be formed without the anchoring of the lipophilin particles to the myelin sheath. [ABSTRACT FROM AUTHOR]

What determines military effectiveness? Previous literature has examined factors such as military doctrine, culture, and capabilities, as well as regime type and civil–military relations, but has largely ignored military leadership quality. Competent military leaders positively influence battle outcomes by ensuring proper implementation of battleplans and quick reaction to an increasingly dynamic battlefield. This paper formally models the relationship between high-ranking military commanders and their immediate subordinates to examine the commander's ability to evaluate her personnel. I vary the ability of the subordinates to signal their commander to determine how different signaling structures influence what commanders may learn. This analysis reveals that commanders opt for less informative signals from subordinates as the military professionalizes, potentially impeding their ability to identify and remove incompetent subordinates. Leaving incompetent subordinates in command reduces the ability of the military to improve. Evidence from the US Army's leadership decisions after the Battle of Kasserine Pass and Operation Avalanche illustrates these results. [ABSTRACT FROM AUTHOR]

What determines military effectiveness? Though political scientists have studied the sources of military effectiveness, they have generally ignored the role of military leadership, a factor that historians have emphasized as crucial for effectiveness. This article presents the first rigorous examination of the proposition that militaries improve effectiveness by replacing low-performing leaders. The article tests three theories describing how militaries promote and demote leaders: (1) military leaders are promoted and demoted on the basis of combat performance; (2) political leaders fearful of coups do not demote low-performing military leaders, as a coup-proofing tactic; and (3) military leaders that belong to powerful interpersonal networks are less likely to be demoted and more likely to be promoted. Hypotheses are tested using new data on all American and German generals holding combat commands in the North African, Italian, and West European theaters in World War II and new data on the monthly combat performance of American and German divisions in these theaters. Analysis reveals that both armies replaced low-performing generals (coup-proofing motives did not prevent Hitler from demoting low performers) and that interpersonal networks in the US army did not block demotion of low performers. Also, the replacement of low-performing generals improved combat effectiveness in both armies. [ABSTRACT FROM AUTHOR]

Focuses on the medical examination in blood donation and its donee for safety blood transfusion. Guidelines for the medical examination of the blood; Factors contributing to health and well-being of the blood donated and the donor; Details of the test performed for the examination.