Smart exosomes enhance PDAC targeted therapy.

Exosomes continue to attract interest as a promising nanocarrier drug delivery technology. They are naturally derived nanoscale extracellular vesicles with innate properties well suited to shuttle proteins, lipids, and nucleic acids between cells. Nonetheless, their clinical utility is currently limited by several major challenges, such as their inability to target tumor cells and a high proportion of clearance by the mononuclear phagocyte system (MPS) of the liver and spleen. To overcome these limitations, we developed "Smart Exosomes" that co-display RGD and CD47p110-130 through CD9 engineering (ExoSmart). The resultant ExoSmart demonstrates enhanced binding capacity to αvß3 on pancreatic ductal adenocarcinoma (PDAC) cells, resulting in amplified cellular uptake in in vitro and in vivo models and increased chemotherapeutic efficacies. Simultaneously, ExoSmart significantly reduced liver and spleen clearance of exosomes by inhibiting macrophage phagocytosis via CD47p110-130 interaction with signal regulatory proteins (SIRPα) on macrophages. These studies demonstrate that an engineered exosome drug delivery system increases PDAC therapeutic efficacy by enhancing active PDAC targeting and prolonging circulation times, and their findings hold tremendous translational potential for cancer therapy while providing a concrete foundation for future work utilizing novel peptide-engineered exosome strategies.

A Machine Learning Model for Prediction of Amputation in Diabetics.

BACKGROUND: Diabetic foot ulcer (DFU) and the resulting lower extremity amputation are associated with a poor survival prognosis. The objective of this study is to generate a model for predicting the probability of major amputation in hospitalized patients with DFU. METHODS: The National Inpatient Sample (NIS) database from 2008 to 2014 was used to select patients with DFU, who were then further divided by major amputation status. International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) and Agency for Healthcare Research and Quality (AHRQ) comorbidity codes were used to compare patient characteristics. For the descriptive statistics, the Student t test, the χ2 test, and the Spearman correlation were utilized. The five most predictive variables were identified. A decision tree model (CTREE) based on conditional inference framework algorithm and a random forest model were used to develop the algorithm. RESULTS: A total of 326 853 inpatients with DFU were identified, and 5.9% underwent major amputation. The top five contributory variables (all with P < .001) were gangrene (odds ratio [OR] = 11.8, 95% confidence interval [CI] = 11.5-12.2), peripheral vascular disease (OR = 2.9, 95% CI = 2.8-3.0), weight loss (OR = 2.6, 95% CI = 2.5-2.8), systemic infection (OR = 2.5, 95% CI = 2.4-2.53), and osteomyelitis (OR = 1.7, 95% CI = 1.6-1.73). The model performance of the training data was 77.7% (76.1% sensitivity and 79.3% specificity) and of the testing data was 77.8% (76.2% sensitivity and 79.4% specificity). The model was further validated with boosting and random forest models which demonstrated similar performance and area under the curve (AUC) (0.84, 95% CI = 0.83-0.85). CONCLUSION: Utilizing machine learning methods, we have developed a clinical algorithm that predicts the risk of major lower extremity amputation for inpatients with diabetes with 77.8% accuracy.

Timing of a Major Operative Intervention After a Positive COVID-19 Test Affects Postoperative Mortality: Results From a Nationwide, Procedure-matched Analysis.

BACKGROUND: Studies indicate that coronavirus disease 2019 (COVID-19) infection before or soon after operations increases mortality, but they do not comment on the appropriate timing for interventions after diagnosis. OBJECTIVE: We sought to determine what the safest time would be for COVID-19 diagnosed patients to undergo major operative interventions. METHODS: High-risk operations, between January 2020 and May 2021, were identified from the Veterans Affairs COVID-19 Shared Data Resource. Current Procedural Terminology (CPT) codes were used to exact match COVID-19 positive cases (n=938) to negative controls (n=7235). Time effects were calculated as a continuous variable and then grouped into 2-week intervals. The primary outcome was 90-day, all-cause postoperative mortality. RESULTS: Ninety-day mortality in cases and controls was similar when the operation was performed within 9 weeks or longer after a positive test; but significantly higher in cases versus controls when the operation was performed within 7 to 8 weeks (12.3% vs 4.9%), 5 to 6 weeks (10.3% vs 3.3%), 3 to 4 weeks (19.6% vs 6.7%), and 1 to 2 weeks (24.7% vs 7.4%) from diagnosis. Among patients who underwent surgery within 8 weeks from diagnosis, 90-day mortality was 16.6% for cases versus 5.8% for the controls ( P <0.001). In this cohort, we assessed interaction between case status and any symptom ( P =0.93), and case status and either respiratory symptoms or fever ( P =0.29), neither of which were significant statistically. CONCLUSIONS: Patients undergoing major operations within 8 weeks after a positive test have substantially higher postoperative 90-day mortality than CPT-matched controls without a COVID-19 diagnosis, regardless of presenting symptoms.

Nocturia is Associated with High Atherosclerotic Cardiovascular Disease Risk in Women: Results from the National Health and Nutrition Examination Survey.

Growing evidence has identified nocturia as a potential manifestation of several cardiovascular disease states. We aimed to determine whether a relationship exists between nocturia and global atherosclerotic cardiovascular disease (ASCVD) risk, defined by the American College of Cardiology/American Heart Association (ACC/AHA) ASCVD risk calculator, using a large nationally-representative study sample from the United States. We explored potential associations between nocturia and ASCVD risk in adults aged 40-79 years with no prior history of overt/known atherosclerotic disease from 7 consecutive cycles of the National Health and Nutrition Examination Survey. Subjects were classified by whether they met the ASCVD high-risk threshold following current ACC/AHA consensus guidelines (10-year major adverse cardiovascular event risk ≥ 20%). Logistic regression analyses were used to explore associations between nocturia (defined as ≥ 2 nocturnal voids) and ASCVD risk. The prevalence of nocturia and high ASCVD risk were 27.0% and 10.9%, respectively. Nocturia, older age, increased body mass index, and diuretic use were associated with high ASCVD risk on univariate logistic regression. After adjusting for age, body mass index, and diuretic use, nocturia remained associated with significantly greater odds of high ASCVD risk in females but not in males. Elicitation of nocturia on clinical history taking may serve to identify high cardiovascular risk in females. Future studies are needed to elucidate mechanisms underlying this association.

Higher comorbidities and early death in hospitalized African-American patients with Covid-19.

BACKGROUND: African-Americans/Blacks have suffered higher morbidity and mortality from COVID-19 than all other racial groups. This study aims to identify the causes of this health disparity, determine prognostic indicators, and assess efficacy of treatment interventions. METHODS: We performed a retrospective cohort study of clinical features and laboratory data of COVID-19 patients admitted over a 52-day period at the height of the pandemic in the United States. This study was performed at an urban academic medical center in New York City, declared a COVID-only facility, serving a majority Black population. RESULTS: Of the 1103 consecutive patients who tested positive for COVID-19, 529 required hospitalization and were included in the study. 88% of patients were Black; and a majority (52%) were 61-80 years old with a mean body mass index in the "obese" range. 98% had one or more comorbidities. Hypertension was the most common (79%) pre-existing condition followed by diabetes mellitus (56%) and chronic kidney disease (17%). Patients with chronic kidney disease who received hemodialysis were found to have lower mortality, than those who did not receive it, suggesting benefit from hemodialysis Age > 60 years and coronary artery disease were independent predictors of mortality in multivariate analysis. Cox proportional hazards modeling for time to death demonstrated a significantly high ratio for COPD/Asthma, and favorable effects on outcomes for pre-admission ACE inhibitors and ARBs. CRP (180, 283 mg/L), LDH (551, 638 U/L), glucose (182, 163 mg/dL), procalcitonin (1.03, 1.68 ng/mL), and neutrophil:lymphocyte ratio (8.3:10.0) were predictive of mortality on admission and at 48-96 h. Of the 529 inpatients 48% died, and one third of them died within the first 3 days of admission. 159/529patients received invasive mechanical ventilation, of which 86% died and of the remaining 370 patients, 30% died. CONCLUSIONS: COVID-19 patients in our predominantly Black neighborhood had higher in-hospital mortality, likely due to higher prevalence of comorbidities. Early dialysis and pre-admission intake of ACE inhibitors/ARBs improved patient outcomes. Early escalation of care based on comorbidities and key laboratory indicators is critical for improving outcomes in African-American patients.

Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases.

Pancreatic cancer remains one of the most difficult malignancies to treat. Minimal improvements in patient outcomes and persistently abysmal patient survival rates underscore the great need for new treatment strategies. Currently, there is intense interest in therapeutic strategies that target tyrosine protein kinases. Here, we employed kinome arrays and bioinformatic pipelines capable of identifying differentially active protein tyrosine kinases in different patient-derived pancreatic ductal adenocarcinoma (PDAC) cell lines and wild-type pancreatic tissue to investigate the unique kinomic networks of PDAC samples and posit novel target kinases for pancreatic cancer therapy. Consistent with previously described reports, the resultant peptide-based kinome array profiles identified increased protein tyrosine kinase activity in pancreatic cancer for the following kinases: epidermal growth factor receptor (EGFR), fms related receptor tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR-3), insulin receptor (INSR), ephrin receptor A2 (EPHA2), platelet derived growth factor receptor alpha (PDGFRA), SRC proto-oncogene kinase (SRC), and tyrosine kinase non receptor 2 (TNK2). Furthermore, this study identified increased activity for protein tyrosine kinases with limited prior evidence of differential activity in pancreatic cancer. These protein tyrosine kinases include B lymphoid kinase (BLK), Fyn-related kinase (FRK), Lck/Yes-related novel kinase (LYN), FYN proto-oncogene kinase (FYN), lymphocyte cell-specific kinase (LCK), tec protein kinase (TEC), hemopoietic cell kinase (HCK), ABL proto-oncogene 2 kinase (ABL2), discoidin domain receptor 1 kinase (DDR1), and ephrin receptor A8 kinase (EPHA8). Together, these results support the utility of peptide array kinomic analyses in the generation of potential candidate kinases for future pancreatic cancer therapeutic development.

Emerging Kinase Therapeutic Targets in Pancreatic Ductal Adenocarcinoma and Pancreatic Cancer Desmoplasia.

Kinase drug discovery represents an active area of therapeutic research, with previous pharmaceutical success improving patient outcomes across a wide variety of human diseases. In pancreatic ductal adenocarcinoma (PDAC), innovative pharmaceutical strategies such as kinase targeting have been unable to appreciably increase patient survival. This may be due, in part, to unchecked desmoplastic reactions to pancreatic tumors. Desmoplastic stroma enhances tumor development and progression while simultaneously restricting drug delivery to the tumor cells it protects. Emerging evidence indicates that many of the pathologic fibrotic processes directly or indirectly supporting desmoplasia may be driven by targetable protein tyrosine kinases such as Fyn-related kinase (FRK); B lymphoid kinase (BLK); hemopoietic cell kinase (HCK); ABL proto-oncogene 2 kinase (ABL2); discoidin domain receptor 1 kinase (DDR1); Lck/Yes-related novel kinase (LYN); ephrin receptor A8 kinase (EPHA8); FYN proto-oncogene kinase (FYN); lymphocyte cell-specific kinase (LCK); tec protein kinase (TEC). Herein, we review literature related to these kinases and posit signaling networks, mechanisms, and biochemical relationships by which this group may contribute to PDAC tumor growth and desmoplasia.

Transcriptome sequencing analysis reveals unique and shared antitumor effects of three statins in pancreatic cancer.

Statins, a class of commonly prescribed cholesterol­lowering medications, have been revealed to influence the risk of multiple types of cancer. However, the antitumor effects of statins on pancreatic cancer and their differential efficacy among a variety of statins are not currently well­defined. The aim of the present study was therefore to identify and compare the genes and related biological pathways that were affected by each individual statin on pancreatic cancer. Two human pancreatic cancer cell lines, MiaPaCa2 and PANC1, were exposed to three statins, lovastatin, fluvastatin and simvastatin. The inhibitory effect of statins on pancreatic cancer cell proliferation was first validated. Next, RNA­seq analysis was used to determine the gene expression alterations in either low (2 µM) or high (20 µM) statin concentration­treated cancer cells. Marked differences in gene transcription profiles of both pancreatic cancer cell lines exposed to high concentration statins were observed. Notably, the high concentration statins significantly suppressed core­gene CCNA2­associated cell cycle and DNA replication pathways and upregulated genes involved in ribosome and autophagy pathways. However, the low concentration statin­induced gene expression alterations were only detected in MiaPaCa2 cells. In conclusion, a marked difference in the intra and inter cell­type performance of pancreatic cancer cells exposed to a variety of statins at low or high concentrations was reported herein, which may provide insights for the potential clinical use of statins in future pancreatic cancer therapeutics.

Repurposing metformin, simvastatin and digoxin as a combination for targeted therapy for pancreatic ductal adenocarcinoma.

Patients with pancreatic adenocarcinoma (PDAC) have a 5-year survival rate of 8%, the lowest of any cancer in the United States. Traditional chemotherapeutic regimens, such as gemcitabine- and fluorouracil-based regimens, often only prolong survival by months. Effective precision targeted therapy is therefore urgently needed to substantially improve survival. In an effort to expedite approval and delivery of targeted therapy to patients, we utilized a platform to develop a novel combination of FDA approved drugs that would target pancreaticoduodenal homeobox1 (PDX1) and baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) utilizing super-promoters of the target genes to interrogate an FDA approved drug library. We identified and selected metformin, simvastatin and digoxin (C3) as a novel combination of FDA approved drugs, which were shown to effectively target PDX1 and BIRC5 in human PDAC tumors in mice with no toxicity.

Clinicopathologic and Molecular Features of Mixed Neuroendocrine Non-Neuroendocrine Neoplasms of the Gallbladder.

Neuroendocrine neoplasms of the gallbladder are rare, comprising 0.5% of all neuroendocrine cancers and about 2% of gallbladder cancers. These neoplasms can also be found along with other malignant neoplasms of epithelial origin, mostly adenocarcinomas. Herein, we describe an unusual finding of a three-component mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) of the gallbladder. We also review the literature on 29 similar cases and summarize key features. We report on a 62-year-old woman who presented with right upper quadrant pain with a positive Murphy's sign. A clinical diagnosis of neoplasia was entertained and she underwent cholecystectomy. Gross examination of the specimen revealed a 5-cm exophytic mass at the gallbladder fundus. Histopathologic examination of the mass showed an infiltrating squamous cell carcinoma, an adjacent neuroendocrine carcinoma (each of these two components composed more than 30% of the neoplasm), and a superficial adenocarcinoma (composing 10% of the neoplasm). Gallbladder MiNENs present with similar symptoms and in the same age group as do carcinomas; however, their prognosis is often poor. Specific management and treatment guidelines have not been established since MiNENs are very rare.

Bifidobacterium spp: the promising Trojan Horse in the era of precision oncology.

Selective delivery of therapeutic agents into solid tumors has been a major challenge impeding the achievement of long-term disease remission and cure. The need to develop alternative drug delivery routes to achieve higher drug concentration in tumor tissue, reduce unwanted off-target side effects and thus achieve greater therapeutic efficacy, has resulted in an explosive body of research. Bifidobacterium spp. are anaerobic, nonpathogenic, Gram-positive bacteria, commensal to the human gut that are a possible anticancer drug-delivery vehicle. In this review, we describe Bifidobacterium's microbiology, current clinical applications, overview of the preclinical work investigating Bifidobacterium's potential to deliver anticancer therapy, and review the different strategies used up to date. Finally, we discuss both current challenges and future prospects.

MiR-497-5p inhibits cell proliferation and metastasis in hepatocellular carcinoma by targeting insulin-like growth factor 1.

BACKGROUND: MicroRNAs (miRNAs) play an important regulatory role in carcinogenesis and cancer progression. Aberrant expression of miR-497-5p has been reported in various human malignancies. However, the role of miR-497-5p in hepatocellular carcinoma (HCC) remains unclear. RESULTS: In this study, we found that miR-497-5p was downregulated in HCC tissues. The low level of miR-497-5p in HCC tumors was correlated with aggressive clinicopathological characteristics and predicted poor prognosis in HCC patients. The overexpression of miR-497-5p significantly inhibited HCC cell proliferation, colony formation, and metastasis in vitro and vivo. Bioinformatics analysis further identified insulin-like growth factor 1 (IGF1) as a novel target of miR-497-5p in HCC cells. CONCLUSION: Our study suggested that miR-497-5p regulates HCC cell survival, partially through downregulation of IGF1. Therefore, the miR-497-5p/IGF1 axis might serve as a novel therapeutic target in patients with HCC.

Natural killer cells: a review of biology, therapeutic potential and challenges in treatment of solid tumors.

Natural killer (NK) cells lead immune surveillance against cancer and early elimination of small tumors. Owing to their ability to engage tumor targets without the need of specific antigen, the therapeutic potential of NK cells has been extensively explored in hematological malignancies. In solid tumors, however, their role in the clinical arena remains poorly exploited despite a broad accumulation of preclinical data. In this article, we review our current knowledge of NK cells' biology, and highlight the challenges facing NK cell antitumor strategies in solid tumors. We further summarize the abundant preclinical attempts at overcoming these challenges, present past and ongoing clinical trial data and finally discuss the potential impact of novel insights on the development of NK cell-based therapies.

Catheter Directed Lysis and Thrombectomy Are Equally Effective for Extensive Deep Vein Thrombosis.

BACKGROUND: There is currently little consensus on the role of thrombectomy compared with catheter-directed lysis (CDL) for acute, extensive, proximal deep vein thrombosis (DVT). We sought to determine whether any differences in outcomes exist between thrombectomy and CDL in terms of postoperative venous patency, pulmonary emboli (PE), and bleeding/hematoma. METHODS: In an institutional review board-approved retrospective cohort study, patients from a single academic medical center with confirmed lower extremity DVT were divided into thrombectomy and CDL cohorts. Demographic information, comorbidities and laboratory data, postoperative patency, postoperative bleeding, postoperative PE, popliteal hematoma, and recurrence of DVT were collected. Type I error level was set at 0.05. RESULTS: Eighty-seven patients were identified, 51.7% received CDL, and 48.3% underwent thrombectomy. Patient comorbidities and hypercoagulable states were not significantly different among the groups. The two techniques did not have significantly different postoperative patency (P = 0.472), bleeding (P = 0.598), PE (P = 0.868), popliteal hematoma (P = 0.331), or recurrence of DVT (P = 0.835). CONCLUSIONS: In selecting optimum treatment for acute, extensive, proximal DVT, our retrospective cohort study found no significant differences among treatment groups in safety, efficacy, recurrence, and progression to PE. We conclude that modality of treatment should be decided based on hospital resources, surgeon experience, and comfort with each technique, patient's physiologic status, and associated costs.

Chimeric Antigen Receptor T-Cell Therapy: Reach to Solid Tumor Experience.

Chimeric antigen receptor (CAR) modified T-cell therapy, a unique platform technology highlighting precision medicine through utilization of molecular biology and cell-based therapeutics has shown unprecedented rates in patients with hematological malignancies such as acute lymphocyte leukemia, non-Hodgkin's lymphoma and multiple myeloma (MM). With the approval of CD19-targeted CAR T-cells by the Food and Drug Administration in acute lymphoblastic leukemia (ALL) and NHL, this technology is positioned for aggressive expansion to combination therapeutic opportunities and proof of principle towards utility in other malignant disorders. However, despite the impressive results seen with hematological malignancies, CAR T-cells have shown limited efficacy in solid tumors with several unsuccessful preclinical studies. Regardless, these attempts have provided us with a better understanding of the imminent challenges specific to solid tumors even if they have not so far led to expanded clinical treatment opportunities outside ALL/NHL/MM. This review summarizes our current understanding of CAR T-cell mechanism of action, while presenting the major limitations of CAR T-cell derived treatments in solid tumors. We further discuss recent findings and present new potential strategies to overcome the challenges facing solid tumor targeting by CAR T-cell platforms.

BIRC5 is a target for molecular imaging and detection of human pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer mortality with a dismal overall survival rate and an urgent need for detection of minute tumors. Current diagnostic modalities have high sensitivity and specificity for larger tumors, but not for minute PDAC. In this study, we test the feasibility of a precision diagnostic platform for detecting and localizing minute human PDAC in mice. This platform includes: 1) defining BIRC5 as an early PDAC-upregulated gene and utilizing an enhanced BIRC5 super-promoter to drive expression of dual Gaussia luciferase (GLuc) and sr39 thymidine kinase (sr39TK) reporter genes exponentially and specifically in PDAC; 2) utilizing a genetically-engineered AAV2RGD to ensure targeted delivery of GLuc and sr39TK specifically to PDAC; 3) using serologic GLuc and sr39TK microPET/CT imaging to detect and localize minute human PDAC in mice. The study demonstrates feasibility of a precision diagnostic platform using an integrated technology through a multiple-stage amplification strategy of dual reporter genes to enhance the specificity and sensitivity of detection and localization of minute PDAC tumors and currently undetectable disease.

Interleukin 10-Mediated Response and Correlated Anemia in a Patient with Advanced Non-Small Cell Lung Carcinoma.

Anemia in cancer patients is associated with poor quality of life, reduced response to therapy, and decreased overall survival. We describe a case of a 56-year old woman with advanced metastatic non-small cell lung carcinoma who demonstrated marked response to a novel combinational immunotherapy approach involving a long-acting PEGylated construct of recombinant human Interleukin-10 with Nivolumab, an anti-PD-L1 checkpoint inhibitor. While on treatment, the patient developed severe anemia and hyper-ferritinemia requiring RBC transfusion support. Here we discuss a possible novel immune mechanism of IL10-mediated anemia in correlation with tumor response.

Closing the Disparity in Pancreatic Cancer Outcomes: A Closer Look at Nonmodifiable Factors and Their Potential Use in Treatment.

OBJECTIVES: African Americans (AAs) have disproportionately higher incidence and lower survival rates from pancreatic cancer compared with whites. Historically, this disparity has been attributed to modifiable risk factors. Recent studies suggest that nonmodifiable aspects may also play an important role. We review these new contributions as potential targets for closing the disparity. METHODS: A PubMed search was conducted to review studies of nonmodifiable elements contributing to pancreatic cancer disparities in AAs. RESULTS: Several nonmodifiable risks are associated with the racial disparity in pancreatic cancer. SSTR5 P335L, Kaiso, and KDM4/JMJD2A demonstrate differential racial expression, increasing their potential as therapeutic targets. Many social determinants of health and their associations with diabetes, obesity, and the microbiome are partially modifiable risk factors that significantly contribute to outcomes in minorities. Barriers to progress include the low minority inclusion in research studies. CONCLUSIONS: Genomics, epigenetics, the microbiome, and social determinants of health are components that contribute to the pancreatic cancer disparity in AAs. These factors can be researched, targeted, and modified to improve mortality rates. Closing the disparity in pancreatic cancer will require an integrated approach of personalized medicine, increased minority recruitment to studies, and advanced health care/education access.