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The aim of this study was to evaluate the use of cathepsin-activated intraoperative near-infrared (NIR) imaging to detect insulinomas in dogs, a spontaneous large animal model for human disease. A prospective, pilot clinical trial was performed on dogs with naturally occurring insulinomas undergoing exploratory laparotomy. Each dog underwent routine preoperative diagnostic assessment, and a cathepsin-activated fluorophore (VGT-309) was administered intravenously 1-2 days preoperatively. All intraoperative findings with visible light and NIR imaging were recorded and mean NIR fluorescence intensity of tumors and grossly normal pancreas were quantified. Excision of any identified primary tumor and suspected metastatic lesions was performed. All excised tissues underwent histologic evaluation and immunohistochemistry (IHC) for cathepsin B expression. Descriptive statistics were calculated, and differential fluorescence intensity and cathepsin B expression between the pancreatic mass and adjacent grossly normal pancreatic tissue were assessed for statistical significance via paired t tests with p < 0.05 used for significance. Six dogs were enrolled. No adverse events occurred secondary to administration of the imaging agent. In situ, insulinomas had significantly greater mean fluorescence intensities than the surrounding pancreas, and the median tumor to background ratio was 1.906 (range 1.286-2.556). One dog had an occult pancreatic mass that was identified intraoperatively with NIR guidance. Background fluorescence of liver and lymph nodes was observed in all cases, and one dog was diagnosed with nodal and hepatic metastasis. Histologic tumor margins correlated with margins of NIR fluorescence. Cathepsin B expression was determined to be significantly greater in the pancreatic tumor compared to adjacent non-neoplastic pancreas via IHC, and there was no overlap in the range of median IHC-positive proportion values for these tissues. However, there was overlap in the range of IHC-positive proportion values for neoplastic pancreatic samples and lymph node and liver tissues. The findings of this pilot study support further investigation of cathepsin-activated NIR imaging to enhance intraoperative canine insulinoma localization and margin evaluation. Future studies are needed to further characterize and optimize the utility of targeted NIR imaging, particularly to identify metastatic lesions, for canine insulinoma, which may serve as an effective translational model for humans with pancreatic neuroendocrine tumors.

Case summary A 15-year-old male castrated domestic shorthair cat originally presented to its primary care veterinarian with a chief complaint of a multi-month history of decreased appetite, weight loss and mild weight-bearing lameness. On physical examination, over the right scapula there was mild-to-moderate muscle wasting and a palpable firm, bony mass measuring approximately 3.5 cm × 3 cm. A complete blood count, chemistry panel, urinalysis, urine culture and baseline thyroxine were clinically unremarkable. Further diagnostics included CT, which revealed a large, expansile, irregularly mineralized mass centered over the caudoventral scapula at the site of attachment of the infraspinatus muscle. Following wide surgical excision by means of complete scapulectomy the patient regained function of the limb and has been free of disease since. The clinical institution’s pathology service examined the resected scapula with associated mass and diagnosed an intraosseous lipoma. Relevance and novel information Intraosseous lipoma is a rare form of bone neoplasia that has only been reported once in the small animal veterinary literature. Histopathology, clinical signs and radiographic changes were consistent with what is described in human literature. It is hypothesized that these tumors occur because of invasively growing adipose tissue within the medullary canal following trauma. Considering the rarity of primary bone tumors in cats, intraosseous lipomas should be considered as a differential diagnosis in future cases with similar signs and history.

This study examines judicial decision-making in the Wisconsin circuit courts through the sentencing decisions of incarceration type and sentence length to describe the social construction of sentencing processes within the courtroom workgroup environment. An electronic and traditional mail survey design was utilized to gather information from judges about their sentencing practices to determine whether situated identity theory aids in the understanding of sentencing decisions. Analysis included independent t-tests and chi-square tests of independence to determine the connections between the independent variables of judicial characteristics, courtroom workgroup participants, and situated identity factors and the dependent variables of incarceration type and sentence length. The results demonstrated that sentencing decisions are social constructed within Wisconsin circuit courts. Limited support was found for the three hypotheses, but descriptive statistics illustrated courtroom participants and judicial situated identities aid in the development of sentencing practices and that situated identity theory is an appropriate tool to help decipher the social construction of judicial decision-making.

General strain theory has been tested critically, but the development of the theory has lagged because tests of the full model are rare, and the integration and specification of conditioning variables that affect crime and deviance are not clear. This test of general strain theory used a young adult sample (n=679) of university students to complete a comprehensive analysis of the main tenets of general strain theory with the specific inclusion of conditioning variables such as self-esteem, self-efficacy, and delinquent peers, and expansion of the traditional measures of affective states, coping strategies, and types of deviant and criminal behaviors. General support for the theory was confirmed. The results show that perceptions of success and fairness, a more traditional measure of strain, are not related to crime and deviance, but the more subjective measure of stress, consistent with general strain theory, does have a relationship with crime and deviance. Implications based on these findings are presented. [PUBLICATION ABSTRACT]

Hyer et al . generate a potent and specific small-molecule inhibitor of the E1 ubiquitin-activating enzyme UBE1 that has antitumor activity in mice against a wide variety of tumor types. The ubiquitin–proteasome system (UPS) comprises a network of enzymes that is responsible for maintaining cellular protein homeostasis. The therapeutic potential of this pathway has been validated by the clinical successes of a number of UPS modulators, including proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Here we identified TAK-243 (formerly known as MLN7243) as a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE), the primary mammalian E1 enzyme that regulates the ubiquitin conjugation cascade. TAK-243 treatment caused depletion of cellular ubiquitin conjugates, resulting in disruption of signaling events, induction of proteotoxic stress, and impairment of cell cycle progression and DNA damage repair pathways. TAK-243 treatment caused death of cancer cells and, in primary human xenograft studies, demonstrated antitumor activity at tolerated doses. Due to its specificity and potency, TAK-243 allows for interrogation of ubiquitin biology and for assessment of UAE inhibition as a new approach for cancer treatment.

Background Elevated brain iron deposition is recognized as a characteristic of normal aging and neurodegenerative diseases, particularly Alzheimer's disease (AD), where it correlated with amyloid‐β plaques and neurofibrillary tangles. Our study aimed to investigate the relationship between longitudinal changes in hippocampal iron deposition and episodic memory, and how this relationship is impacted by AD pathology and APOE4 allele carriership. Method We measured longitudinal changes in brain iron levels using quantitative susceptibility mapping (QSM)‐MRI (see Figure 1), in a cohort of old adults at risk of AD (N =143, 102 females, 41 males; mean age = 67.7 ± 5.0 years; longitudinal duration = 2.7 ± 0.4 years). Cognition was assessed using the RBANS. Plasma was collected from all participants at a single time point (Time 2, T2) and p‐tau181 measured using in‐house single‐molecule arrays. We examined the relationship between iron accumulation and memory, the mediating effect of plasma p‐tau181. We also investigated how APOE4 status moderates the relationship between iron deposition and plasma p‐tau181. Result Hippocampal iron levels demonstrated a significant increase over time (t(142)=2.45, Cohen's d=0.21, p = 0.016). Changes in iron levels were significantly negatively correlated with memory performance (β=‐0.223, p = 0.009, Figure 2A), and positively associated with plasma p‐tau181 (β=0.217, p = 0.011, Figure 2B). Plasma p‐tau181 were also negatively associated memory (β=–0.207, p = 0.015, Figure 2C). Furthermore, p‐tau181 mediated the relationship between hippocampal iron increases and memory performance, accounted for 16.2% of the total association (β = −0.034, p = 0.045, CI: −0.09 to ‐0.004, Figure 2D). APOE4 status moderated the impact of increased hippocampal iron on plasma p‐tau181 levels (β =0.431, p = 0.021, CI: 0.06 to 0.8, Figure 3). Conclusion These findings underscore the unique effect of hippocampal iron accumulation on cognition, which is additionally impacted by AD pathology. Further, we find a novel association in APOE4 carriers, wherein increases in iron interact with AD pathology, which highlights the need for early detection and intervention strategies tailored to APOE4 carriers. This work deepens our understanding of the interplay among iron dysregulation, tau pathology, and APOE4, offering a promising avenue for precision‐based approaches to AD risk assessment and therapeutic development.

The uses and methodology of factor analysis are widely debated and discussed, especially the issues of rotational use, methods of confirmatory factor analysis, and adequate sample size. The variety of perspectives and often conflicting opinions can lead to confusion among researchers about best practices for using factor analysis. The focus of the present review is to clarify terminology, identify key issues, and clarify areas of debate regarding best practices and functions of factor analytic procedures., The conclusions and implications drawn should be useful to researchers in education, psychology, and cognate social fields who employ factor analytic procedures or evaluate research using factor analytic methods.