Citations

BACKGROUND: The current coronavirus disease 2019 (COVID-19) pandemic led to a significant disruption in the care of pain from chronic and subacute conditions. The impact of this cessation of pain treatment may have unintended consequences of increased pain, reduced function, increased reliance on opioid medications, and potential increased morbidity, due to the systemic impact of untreated disease burden. This may include decreased mobility, reduction in overall health status, and increase of opioid use with the associated risks. METHODS: The article is the study of the American Society of Pain and Neuroscience (ASPN) COVID-19 task force to evaluate the policies set forth by federal, state, and local agencies to reduce or eliminate elective procedures for those patients with pain from spine, nerve, and joint disease. The impact of these decisions, which were needed to reduce the spread of the pandemic, led to a delay in care for many patients. We hence review an emergence plan to reinitiate this pain-related care. The goal is to outline a path to work with federal, state, and local authorities to combat the spread of the pandemic and minimize the deleterious impact of pain and suffering on our chronic pain patients. RESULTS: The article sets forth a strategy for the interventional pain centers to reemerge from the current pandemic and to set a course for future events. CONCLUSIONS: The COVID-19 pandemic represents an overwhelming challenge to interventional pain physicians and their patients. In addition to urgent actions needed for disease mitigation, the ASPN recommends a staged return to pain management professionals’ workflow.

Ambiguity exists regarding the definition of a level III inferior vena cava tumor thrombus (IVC-TT), limiting comparisons between open and minimally-invasive series. We assessed 253 patients who underwent radical nephrectomy with IVC-TT from 2000-2015 and proposed a modified classification based on associations between intraoperative IVC clamp position and need for cardiopulmonary bypass with complications, length of stay, and blood transfusions. Predictive ability of the modified system was not meaningfully improved (AUCs 0.59–0.58; 0.61–0.61; 0.72–0.72). Nevertheless, we advocate for standardization of the border of a level III thrombus at or above the major hepatic veins to facilitate meaningful comparisons between techniques.

Abstract Background: Thalidomide and dexamethasone combination has been shown to be an effective therapy for multiple myeloma (MM). In newly diagnosed patients with MM, the combination results in overall response rates of over 70% of patients. However, a considerable number of patients do not respond and will need to proceed to other therapies. The ability to identify patients who are unlikely to respond to particular therapies will allow tailoring of therapeutic approaches and in turn will reduce unnecessary toxicity and morbidity from lack of rapid disease control. With the availability of new technology such as gene expression profiling (GEP), this has become a possibility. We employed this approach to identify genes that can reliably predict lack of response to the thalidomide dexamethasone combination. Methods: Patient samples from the Eastern Co-operative Oncology Group clinical trial (E1A00), that compared thalidomide-dexamethasone combination with dexamethasone, and patient samples from the phase II Mayo Clinic study of thalidomide and dexamethasone, both for newly diagnosed MM, were used for this study. Thirty newly diagnosed patients who were evaluable for response were included in the analysis. GEP was performed using the Affymetrix U133A microarray platform as per manufacturer’s recommendation. The Affymetrix output (CEL files) was imported into Genespring 7.2 (Agilent Technologies) microarray analysis software, normalized across chips using GCRMA followed by per gene normalization to median. For the purposes of this study, responses were defined as reduction in the serum paraprotein (or the urinary M protein in the absence of a serum M protein) of >=50% (PR), 25 to 49% (MR), increase of >=50% (PD) and stable disease for the remaining. Results: Five of the 30 patients had no response to the thalidomide Dexamethasone therapy. Using the class prediction tool available in Genespring (Support Vector Machines), we identified 25 genes that reliable predicted non responders (PD, NC) from the responders (MR, PR, and CR). See table for a list of predictive genes with identified genes. Conclusion: Using a combination of two datasets we have identified a set of genes that can be used to reliably predict lack of response to thalidomide and dexamethasone in patients with newly diagnosed MM. We think that this represents a step towards creation of custom microarrays spotted with genes that are capable of predicting lack of response (or response) for the purpose of tailoring therapy to the patient. Gene Predictive strength hypothetical protein FLJ20719 1.655 Tubulin alpha 6 1.653 SEC3-like 1 (S. cerevisiae) 1.649 Ribosomal protein L18 1.546 Ribosomal protein L4 1.432 Tubulin alpha 6 1.409 cleavage stimulation factor 1.393 Tubulin, alpha, ubiquitous 1.393 CD99 antigen 1.38 hmel2 1.346 Leptin receptor 1.291 Integrin-linked kinaseSMC4 structural maintenance of chromosomes 4-like 1 1.269 Cornichon homolog 1.255 Williams-Beuren syndrome chromosome region 5 1.217 Ubiquitin specific protease 1 1.2 Sarcoma antigen NY-SAR-91 1.2

AbstractRapid and functional bone‐tendon (B‐T) healing remains a difficulty in clinical practice. Tissue engineering has emerged as a promising strategy to address this problem. However, the majority of tissue engineering scaffolds are loaded with stem cells to enhance the regenerability in B‐T healing, which is complicated and inconvenient for clinical application. Accordingly, developing a cell‐free scaffold with chemotactic function and chondrogenic inducibility may be an effective approach. In this study, a collagen affinity peptide derived from the A3 domain of von Willebrand factor (a hemostasis factor) was fused into the C‐terminal of a stromal cell‐derived factor‐1α (SDF‐1α) to synthesize a recombinant SDF‐1α capable of binding collagen and chemotactic activity. The recombinant SDF‐1α was then tethered on the collagen fibers of a book‐shaped acellular fibrocartilage scaffold (BAFS), thus fabricating a novel scaffold (C‐SDF‐1α/BAFS) with chemotactic function and chondrogenic inducibility. In vitro tests determined that this scaffold was noncytotoxic and biomimetic, could attract stem cells migrating to the scaffold using sustainably released C‐SDF‐1α, and inducedthe interacting stem cells down the chondrogenic lineage. In vivo, the C‐SDF‐1α/BAFS significantly enhanced the B‐T healing in a rabbit partial patellectomy model, as shown by the larger cartilaginous metaplasia region, better fibrocartilage regeneration, additional bone formation, and improved biomechanical properties. Therefore, the findings of the study demonstrate that the C‐SDF‐1α/BAFS could potentially be applied for B‐T healing.

Abstract Introduction: Lung cancer is the leading cause of cancer death in the U.S. and in the world. In 2018, lung cancer alone resulted in 25.3% of all cancer deaths evaluated worldwide. Lung Adenocarcinoma (LUAD) is a major subtype of lung cancer and accounts for 40% of these tumors. Our group has recently discovered that about 20% of LUAD are characterized by abnormally high expression of the neuroendocrine transcription factor, ASCL1. In these tumors, ASCL1 orchestrates a network of genomic changes that create opportunities for treatment. We have shown that LUAD tumors expressing high ASCL1 have RET mRNA levels that are predictive of patient survival (p < 0.004), and, these tumors were susceptible to EGFR inhibitors, with having a functional interaction between RET and EGFR. We found EGFR inhibitor, Lapatinib, to have highest efficacy, indicating it to be a primary drug treatment for ASCL1+ (A+) LUAD. However, we and others have observed Lapatinib induces resistance to EGFR therapy over time, and, Lapatinib therapy associated by-pass signaling pathways have recently gained attention. Therefore, we hypothesize that for a long lasting therapy, it is important to identify additional drugs that in combination with EGFR inhibitor Lapatinib will eliminate A+ LUAD tumors. Methodology and Results: An in vitro preliminary screen of approx. 2000 FDA approved small molecule inhibitors done with A+ and A- LUAD cell lines in collaboration at NIH revealed potential candidates for alternative pathways, 80 of which showed a differential sensitivity to A+ LUAD as single agent. We identified best 28 drugs in total: 23 selected from this pre-screen (based on their effectiveness to A+LUAD lines) and 5 additional chosen based on their biological relevance to the disease, which may act upon putative compensatory pathways in EGFR therapy resistance. Our in vitro drug screening in HCC1833 ASCL1+ and ASCL1 knockdown lines has revealed 8 out of 28 drugs to synergize as per their IC50 and fixed ratios, with Lapatinib. From these 8 leads, we have confirmed a definite synergy of Lapatinib with DDR-1 7rh, an inhibitor of ECM receptor DDR-1, using Mac-Synergy-II software. DDR-1, Discoidin domain receptor-1, is a collagen receptor highly upregulated in NSCLC, and is associated with poor prognosis in LUAD. Our microarray data on lapatinib treated tumors from mice PDX has shown ECM signatures to be among top upregulated. Additionally, TM4SF1, a signaling molecule associated with DDR-1, was found to associate with poor outcome in A+LUAD (P=0.0001). Other synergistic drugs identified include, a K+ channel opener (Retigabine), Wnt signaling and Lyn kinase inhibitors (PRI-724, and Bafetinib), Tubulin inhibitor (Docetaxel) and 3 multi-tyrosine kinase inhibitors. Interestingly, Wnt pathway was found to be elevated in Lapatinib treated ASCL1+LUAD in our microarray data. Moreover, Wnt signaling in known to crosstalk with ECM and DDR-1 in other tumors. K+ channel dysfunction is associated with neuronal/neuroendocrine disorders and Lyn kinases are the predominant SRC kinases in brain tumors, indicating their possible involvement in ASCL1+ neuroendocrine tumor pathophysiology. Conclusion: Taken together this data reveals a potential involvement of ECM (DDR-1 receptor) and Wnt signaling in effect of Lapatinib, and the identified leads as path to novel combination therapies for A+ LUAD. Citation Format: Kshama Gupta, Farhad Kosari. Identification of the synergistic drugs in combination with EGFR therapy that can target ASCL1+ Lung Adenocarcinoma (A+ LUAD) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A143. doi:10.1158/1535-7163.TARG-19-A143

Background and Aims Vacuolar H+‐ATP complex (V‐ATPase) is a multisubunit protein complex required for acidification of intracellular compartments. At least five different factors are known to be essential for its assembly in the endoplasmic reticulum (ER). Genetic defects in four of these V‐ATPase assembly factors show overlapping clinical features, including steatotic liver disease and mild hypercholesterolemia. An exception is the assembly factor vacuolar ATPase assembly integral membrane protein (VMA21), whose X‐linked mutations lead to autophagic myopathy. Approach and Results Here, we report pathogenic variants in VMA21 in male patients with abnormal protein glycosylation that result in mild cholestasis, chronic elevation of aminotransferases, elevation of (low‐density lipoprotein) cholesterol and steatosis in hepatocytes. We also show that the VMA21 variants lead to V‐ATPase misassembly and dysfunction. As a consequence, lysosomal acidification and degradation of phagocytosed materials are impaired, causing lipid droplet (LD) accumulation in autolysosomes. Moreover, VMA21 deficiency triggers ER stress and sequestration of unesterified cholesterol in lysosomes, thereby activating the sterol response element‐binding protein–mediated cholesterol synthesis pathways. Conclusions Together, our data suggest that impaired lipophagy, ER stress, and increased cholesterol synthesis lead to LD accumulation and hepatic steatosis. V‐ATPase assembly defects are thus a form of hereditary liver disease with implications for the pathogenesis of nonalcoholic fatty liver disease.

In the cognate nephrology literature, a few recent publications from major academic centers in the United States have suggested that the incidence of contrast nephropathy was exaggerated and overstated. These investigators have concluded that intravenous contrast material administration was not associated with an increased risk of acute kidney injury (AKI), emergent dialysis, and short-term mortality in a cohort of patients with diminished renal function. As a contrarian opinion, we first describe a clear cut case of contrast-nephropathy resulting in AKI requiring hemodialysis treatment managed in the Renal Unit of the Mayo Clinic Health System, Northwestern Wisconsin, in the Spring of 2017. We subsequently revisit the overwhelming evidence-base in the English literature that supports the enormous impact of contrast-nephropathy as a clinical syndrome. We finally posit that these recent repudiations of the existence and significance of contrast-nephropathy as a significant clinical entity represent an overreach in statistical expertise. There is no basis for a requiem song over contrast-nephropathy