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Matrix metalloproteinases (MMPs) are important for many different types of cancer-related processes, including metastasis. Understanding the functional impact of changes in MMP activity during cancer treatment is an important facet not typically evaluated as part of preclinical research. With MMP activity being a critical component of the metastatic cascade, we designed a 3D hydrogel system to probe whether pharmacological inhibition affected human melanoma cell proteolytic activity; metastatic melanoma is a highly aggressive and drug-resistant form of skin cancer. The relationship between MMP activity and drug treatment is unknown, and therefore we used an in situ fluorogenic MMP sensor peptide to determine how drug treatment affects melanoma cell MMP activity in three dimensions. We encapsulated melanoma cells from varying stages of progression within PEG-based hydrogels to examine the relationship between drug treatment and MMP activity. From these results, a metastatic melanoma cell line (A375) and two inhibitors that inhibit RAF (PLX4032 and sorafenib) were studied further to determine whether changes in MMP activity led to a functional change in cell behavior. A375 cells exhibited increased MMP activity despite an overall decrease in metabolic activity with PLX4032 treatment. The changes in proteolytic activity correlated with increased cell elongation and increased single-cell migration. In contrast, sorafenib did not alter MMP activity or cell motility, showing that the changes induced by PLX4032 were not a universal response to small-molecule inhibition. Therefore, we argue the importance of studying MMP activity with drug treatment and its possible implications for unwanted side effects.

Background: This study evaluated the impact of diabetes mellitus (DM) and its treatments on cardiovascular outcomes in prostate cancer (PC) patients aged 66 years and older, with or without androgen deprivation therapy (ADT) exposure. Methods: Using the SEER-Medicare database (2009–2017), two cohorts were created: Cohort 1 included all PC patients enrolled in Medicare Parts A and B; Cohort 2 was a subset of Cohort 1 receiving ADT and enrolled in Medicare Part D. Exposures were DM and DM medications. Outcomes included cardiovascular events (CVEs), cardiovascular mortality (CVm), PC-specific mortality (PCsm), and all-cause mortality, analyzed using multivariable Fine-Gray and Cox models. Results: Cohort 1 included 150,647 PC patients (32% with DM, median age 72). DM was associated with higher risk of CVE (subdistribution hazard ratio [sHR] 1.20, 95% CI 1.17–1.22), CVm (sHR 1.35, 1.28–1.43), and all-cause mortality (adjusted HR [aHR] 1.22, 1.19–1.26) (all p < 0.001). Non-Hispanic Blacks (NHBs) and patients from lower socioeconomic (SES) and education areas experienced comparable or worse outcomes. In Cohort 2 (n = 14,938), DM patients on non-metformin therapies had higher all-cause mortality (aHR 1.33, 1.11–1.25; p = 0.002) than those on metformin, particularly in NHB and low education groups. Sensitivity analyses with follow-up limited to two years showed consistent results as overall. Conclusions: Diabetic PC patients, especially NHB, lower SES and lower education subgroups, were associated with worse cardiovascular and all-cause mortality outcomes. Metformin may be associated with better outcomes in these populations, warranting further research on the disparities in PC and diabetes, and cardioprotective effects of DM medications across different subpopulations.

Cyclodextrins are simple yet powerful molecules widely used in medicinal formulations and industry for their ability to stabilize and solubilize guest compounds. However, recent evidence shows that 2-hydroxypropyl-β-cyclodextrin (HPβCD) causes severe hearing loss in mice, selectively killing outer hair cells (OHC) within 1 week of subcutaneous drug treatment. In the current study, the impact of HPβCD on auditory physiology and pathology was explored further as a function of time and route of administration. When administered subcutaneously or directly into cerebrospinal fluid, single injections of HPβCD caused up to 60 dB threshold shifts and widespread OHC loss in a dose-dependent manner. Combined dosing caused no greater deficit, suggesting a common mode of action. After drug treatment, OHC loss progressed over time, beginning in the base and extending toward the apex, creating a sharp transition between normal and damaged regions of the cochlea. Administration into cerebrospinal fluid caused rapid ototoxicity when compared to subcutaneous delivery. Despite the devastating effect on the cochlea, HPβCD was relatively safe to other peripheral and central organ systems; specifically, it had no notable nephrotoxicity in contrast to other ototoxic compounds like aminoglycosides and platinum-based drugs. As cyclodextrins find expanding medicinal applications, caution should be exercised as these drugs possess a unique, poorly understood, ototoxic mechanism.

Immune checkpoint inhibitors (ICI) are increasingly used to treat solid tumors. With growing use, numerous toxicities have been recognized, many of which are believed to be secondary to dysregulated autoimmune inflammatory responses. Although PD-L1 antibody toxicities in the lower gastrointestinal tract, including diarrhea and colitis, are widely described, adverse effects in the upper gastrointestinal tract are rarely reported. We describe a patient with severe esophagitis, gastritis, and duodenitis following atezolizumab treatment for urothelial cancer. A 71-year-old male with metastatic invasive papillary urothelial carcinoma was admitted to The University of Chicago Hospitals for Klebsiella urosepsis. Eight weeks prior to admission he was enrolled in a clinical trial of anti-PD-L1 antibody atezolizumab and completed two cycles of therapy. On the current admission, the patient developed dysphagia as well as odynophagia that gradually progressed to inability to tolerate even liquids.He denied abdominal pain or diarrhea. Esophagogastroduodenoscopy was performed that was notable for severe, circumferential LA Grade D esophagitis, diffuse gastritis, and severe duodenitis with multiple cratered duodenal ulcers. Biopsies obtained from the esophagus showed deep ulcerations with involvement of the underlying smooth muscle, consistent with drug-induced injury. The only other potential offending medication was an NSAID, which he used infrequently. A GMS histochemical stain and immunostains for HSV and CMV were negative. The patient was started on twice daily PPI with improvement in both dysphagia and odynophagia. Follow-up EGD, however, could not be performed as the patient subsequently expired following a cardiac arrest. Immune checkpoint inhibitors are increasingly used to treat solid tumors. It is, therefore, important to recognize their toxicities. While colitis secondary to these agents is well-described, upper GI toxicities have rarely been reported. We believe, therefore, that this case report will help serve to alert gastroenterologists and oncologists of their little reported, but potentially severe proximal gut toxicities.

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is a significant public health burden, with up to 30% of the US population affected. The prevalence of NAFLD among inflammatory bowel disease (IBD) patients is unknown. Understanding risk factors for NAFLD in IBD patients has implications in the treatment of these patients. The purpose of this study was to determine the prevalence of NAFLD among IBD patients and to identify risk factors associated with NAFLD development. Methods Embase and MEDLINE databases were searched using Medical Subject Headlines to find studies that assessed the prevalence of NAFLD among IBD patients. Twenty-seven English-language research abstracts/articles were identified between January 2005 and April 2018. Meta-analyses were performed using random-effects models. Prevalence of NAFLD among IBD patients was compared with prevalence of NAFLD in the general population. Results Based on data pooled from all 27 studies, the prevalence of NAFLD among IBD patients was 32% (95% CI, 24%–40%) with substantial heterogeneity (I2 = 98%). The prevalence of NAFLD among IBD patients (32%) is statistically significantly higher than the prevalence of NAFLD in the general population (25.2%; P < 0.001). Factors associated with the development of NAFLD among IBD patients included age, BMI, diabetes, IBD duration, and prior history of bowel resection. Conclusions There is a higher prevalence of NAFLD among IBD patients compared with the general population. Previous treatment regimens may be a risk factor for the development of NAFLD. Future studies are needed to further clarify these risk factors and determine screening recommendations.

The purpose is to explore the effect of iris image acquisition and real-time detection systems based on Convolutional Neural Network (CNN) and improve the efficiency of iris real-time detection. Based on existing iris data acquisition and detection systems, this study uses the light field focusing algorithm to collect iris data in live, introduces CNN in Deep Learning (DL) algorithm, and designs an iris image acquisition and live detection system based on CNN. Afterward, Radial Basis Function (RBF)-Support Vector Machines (SVM) algorithm is used to classify iris feature information. Based on Field Programmable Gate Array (FPGA), a system for iris image acquisition, processing, and display is constructed. Finally, the performance of the constructed system and algorithm are analyzed through simulation experiments. The research results show that the proposed algorithm can automatically select the qualified iris images in live, significantly improve the recognition accuracy of the whole iris recognition system, and the average time of live quality evaluation for each frame image is less than 0.05 s. The focal point of the investigation involves the exploration of a CNN-based iris image acquisition and real-time detection system, with an emphasis on enhancing the efficiency of real-time iris detection. The innovation of this research lies in the integration of deep learning algorithms and light-field focusing techniques, applied to the reconstruction of a FPGA system. Further, the proposed algorithm is compared with Super-Resolution Using Very Deep Convolutional Networks (VDSR), Deeply Recursive Convolutional Network (DRCN), Residual Dense Network (RDN), and Bicubic. The comparison analysis suggests that the recognition accuracy of the proposed algorithm is the highest, close to 100%. Additionally, the proposed algorithm is compared with the Image Quality Evaluation-based Algorithm (IQA) and the Feature Extraction-based Algorithm (FEA), showing that the proposed RBF-SVM algorithm has higher classification accuracy (96.38%) and lower Average Classification Error Rate (ACER) (3.69%). The research results can provide a reference for live iris image detection and data acquisition.

The development of e-commerce has greatly changed the development of social retail formats. Business-to-consumer (B2C) e-commerce model is important. Due to the characteristics of high consumer trust and commodities dominated by electronic products and brand commodities, the income and profits generated are also very considerable. Therefore, the major e-commerce giants have increased the development of B2C formats. Logistics service capability and level have become an important driving force for the development of B2C e-commerce. How to optimize the inventory of B2C e-commerce and realize the organic balance between the economy and service capacity of the whole logistics chain has become a very urgent problem faced by major e-commerce giants. From the perspective of big data, first, the overview of the dataset used is analyzed based on the real operation data of a business to consumer (B2C) e-commerce platform.