A Multicenter, 10-Year Experience With Hepatocellular Adenoma: Risk Factors and Disease Course.

BACKGROUND: Management of hepatocellular adenoma (HA) is marked by a paucity of recent studies. Long-term follow-up data from an equal access health care system may facilitate our understanding of the natural disease course of HA and identify modifiable risk factors. METHODS: A multi-institutional, retrospective review of patients with HA from 2008-2017 was performed. Patient demographics, disease characteristics, and clinical outcomes were analyzed. RESULTS: Of 124 patients identified, 94% were women with a mean age at diagnosis of 39.5 years (range 20-82). Median follow-up was 22.5 months (range 0-114) with thirty-four (27.4%) patients eventually undergoing hepatectomy. Mean BMI of the study population was 30.5 kg/m2 (range 16-72). Stratified by size, average BMI for adenomas ≥5 cm was 34 kg/m2 compared to 28 kg/m2 for those <5 cm (P < .05). The predominant symptom at presentation was abdominal pain (41.1%), while just 4% presented with acute rupture. Overall incidence of the malignancy was 2.5%. Among all patients, oral contraceptive use was documented in 74 (59.7%) patients, of whom 36 (29.0%) discontinued OC for at least six months. Regression after OC cessation occurred in seven patients (19.4%) while the majority (77.8%) remained stable. DISCUSSION: This decade-long review analyzing the impact of modifiable risk factors identifies a direct correlation between BMI and hepatocellular adenoma size. Rupture and malignant transformation are rare entities. Cessation of OC appears to be an effective strategy in the management of hepatic adenoma. Further investigations are warranted to determine if addressing modifiable risk factors such as BMI might induce further HA regression.

Predictors of Progression of Appendiceal Mucinous Neoplasm to Pseudomyxoma Peritonei.

Appendiceal mucinous neoplasm (AMN) can present with a spectrum of disease. Predicting factors in development of pseudomyxoma peritonei (PMP) from AMN could aid in management and treatment. The aim of this study was to determine factors predictive of PMP from AMN. This was a retrospective multicenter study of all patients diagnosed with AMN from 2006-2017. Diagnosis of PMP was compared by (1) patient demographics, (2) tumor characteristics, and (3) surgery. Secondary end points were disease-specific survival (DSS) and overall survival (OS).One-hundred thirty-eight patients with AMN were identified. Thirty-six patients (26.1%) had a ruptured appendix at presentation, and 12 patients (8.7%) were diagnosed with PMP during the study period. Eight patients presented with PMP at the time of surgery. No demographic factors were predictive of PMP. Operative approach and extent of initial resection did not correlate with PMP. Tumor rupture at presentation was the only factor associated with PMP, though only 14% of patients who presented with simple rupture eventually progressed to PMP.OS was not different between those who were diagnosed with PMP and those who were not. DSS was significantly lower for the group diagnosed with PMP (P = .007). Tumor rupture at presentation did not influence OS or DSS. The only factor found to be significantly associated with PMP was tumor rupture at presentation. Diagnosis of PMP did not affect OS but did lead to decreased DSS.In conclusion, though a majority of patients who presented with rupture did not go on to develop PMP, tumor rupture at presentation was the only factor significantly associated with PMP. Diagnosis of PMP did not affect OS at 5 years. In patients with AMN who present with a ruptured appendix on final pathology, we recommended continued surveillance, though overall risk of PMP is relatively low.

Surgical management of appendiceal mucinous neoplasm: Is appendectomy sufficient?

BACKGROUND AND OBJECTIVES: Due to the rarity of appendiceal mucinous neoplasms (AMNs), there are few established treatment guidelines. The clinical course varies from incidental detection to progressive spread with pseudomyxoma peritonei (PMP). This study investigated the extent of resection on the prognosis and outcomes of AMNs. METHODS: This multicenter retrospective study evaluated patients with AMN who underwent surgery between 4/2006 to 9/2017. Primary endpoints included overall survival (OS) and disease-specific survival (DSS). Secondary endpoints included PMP incidence and treatment with cytoreductive surgery (CRS). RESULTS: Of the 138 patients with AMN, 70 patients (54%) underwent appendectomy, 26 (19%) cecectomy, and 37 (27%) right hemicolectomy. The median age was 59.7 years and 57 patients (41%) were male. Males were less likely to undergo cecectomy (P = .03). Rupture rates, tumor characteristics, and incidence of PMP were similar across surgery groups. Median follow-up was 61.3 months. Five-year OS and DSS for the total cohort were 94.9% and 98.6%, respectively, and remained similar across all surgery groups. CRS patients were more likely to undergo right hemicolectomy with no difference in survival by surgery type (P = .03). CONCLUSIONS: Patients with AMN have a good overall prognosis and there may be minimal benefit to performing extended surgical resection in these patients.

Pancreatectomy in Stage I pancreas cancer: national underutilization of surgery persists.

BACKGROUND: Pancreatectomy in early pancreas adenocarcinoma has been historically underutilized. This retrospective study examines recent trends in the use of pancreatectomy in clinical Stage I (T1-2N0M0) pancreas cancer. METHODS: Using the 2004-2014 National Cancer Database, patients with clinical Stage I pancreas cancer were identified. Patients who underwent surgery or failed to undergo surgery with no identifiable reason were included in analysis. Chi-square, binary logistic regression, and Kaplan Meier estimate were used to identify risk factors for failure to undergo surgery. RESULTS: 23,365 patients were identified. Pancreatectomy increased from 38.4% in 2004 to 52.3% in 2014 (p < 0.001). 50% (n = 11,922) of patients underwent surgery and 48.0% (n = 11,433) did not, of whom 6.8% had a prohibitive co-morbidity, and 36.1% (n = 8594) had no identifiable reason for the lack of operation. Failure to operate was associated with older age, African American race, residence in lower income and less educated areas, lack of insurance, and treatment at community hospitals (all p < 0.001). 5-year survival was maximized in patients who underwent surgery and chemotherapy at 28.1%. CONCLUSION: While utilization of surgery increased overtime, 36% of patients fail to undergo surgery without an identifiable reason. Future investigation is warranted to explain continuing underuse of surgery in early pancreas cancer.

Pasireotide is not effective in reducing the development of postoperative pancreatic fistula.

BACKGROUND: In a single trial, perioperative pasireotide demonstrated reduction in postoperative pancreatic fistula (POPF) following pancreatectomy, yet recent studies question the efficacy of this drug. METHODS: All patients who underwent pancreatic resection between January 2014 and August 2017 at a single institution were prospectively followed. Starting in February 2016, pasireotide was administered to all pancreatectomies. Pancreaticoduodenectomy (PD) patients were additionally risk-stratified using a validated clinical risk score. The primary endpoint was the development of clinically relevant POPF (CR-POPF), and was compared between patients who received pasireotide and controls. RESULTS: Of 116 patients, 87 patients (75%) underwent PD, and 43 patients (37.1%) received pasireotide. CR-POPF occurred in 28.4% patients. The use of pasireotide was not associated with reduced CR-POPF among the total cohort (25.6% vs. 30.1%, P = 0.599), distal pancreatectomy patients (P = 0.339), PD (P = 0.274), or PD patients with elevated risk scores (P = 0.073). Pasireotide did not decrease hospital length of stay, use of parenteral nutrition, delayed gastric emptying, surgical site wound infection, or readmission rate. CONCLUSION: Use of pasireotide after pancreatic resection does not decrease CR-POPF, nor is it associated with reduced length of stay or postoperative complications. A multi-center randomized trial is warranted to study its true effect on outcomes after pancreatectomy.

Long-Term Nononcologic Outcomes for Laparoscopic Liver Resection: Improvement over Open Hepatectomy?

Prior studies of laparoscopic liver resection (LLR) have evaluated long-term outcomes in terms of cancer survival, but few have evaluated nononcologic outcomes. This study analyzes long-term nondisease-specific complications associated with LLR and open liver resection (OLR). We performed a retrospective single-institution review of patients undergoing liver resection for any reason from January 2005 to December 2014. Long-term complication was defined as any complication not related to the primary disease process, and occurring more than 90 days after surgery, emphasizing incisional hernia (IH) and small bowel obstruction (SBO). A total of 208 patients were included in the OLR group and 79 patients in the LLR group. Forty-one patients (19.6%) developed IH after OLR, whereas only six patients (7.5%) developed IH after LLR (P = 0.01). About 3.8 per cent of patients developed IH requiring surgical repair in both groups. Seven patients developed SBO (3.4%) after OLR; no patient developed SBO after LLR. Median time to development of complications was 13.8 months (range 3-54 months) after OLR compared with 8.5 months after LLR (range 6-36 months). Male gender, body mass index, prior abdominal surgery, and OLR were independent risk factors for development of long-term complications. There is a higher incidence of nondisease-specific complications after OLR than LLR.

Neural cell adhesion molecule NrCAM is expressed in the mammalian inner ear and modulates spiral ganglion neurite outgrowth in an in vitro alternate choice assay.

Neuron-glial-related cell adhesion molecule (NrCAM) is a neuronal cell adhesion molecule involved in neuron-neuron and neuron-glial adhesion as well as directional signaling during axonal cone growth. NrCAM has been shown to be involved in several cellular processes in the central and peripheral nervous systems, including neurite outgrowth, axonal pathfinding and myelination, fasciculation of nerve fibers, and cell migration. This includes sensory systems such as the eye and olfactory system. However, there are no reports on the expression/function of NrCAM in the auditory system. The aim of the present study was to elucidate the occurrence of NrCAM in the mammalian cochlea and its role in innervation of the auditory end organ. Our work indicates that NrCAM is highly expressed in the developing mammalian cochlea (position consistent with innervation). Moreover, we found that NrCAM, presented in stripe micropatterns, provide directional cues to neonatal rat inner ear spiral ganglion neurites in vitro. Our results are consistent with a role for NrCAM in the pathfinding of spiral ganglion dendrites toward their hair cell targets in the sensory epithelium.

Polymorphism in the innate immune receptor SIRPα controls CD47 binding and autoimmunity in the nonobese diabetic mouse.

The signal regulatory protein (SIRP) locus encodes a family of paired receptors that mediate both activating and inhibitory signals and is associated with type 1 diabetes (T1D) risk. The NOD mouse model recapitulates multiple features of human T1D and enables mechanistic analysis of the impact of genetic variations on disease. In this study, we identify Sirpa encoding an inhibitory receptor on myeloid cells as a gene in the insulin-dependent diabetes locus 13.2 (Idd13.2) that drives islet inflammation and T1D. Compared to T1D-resistant strains, the NOD variant of SIRPα displayed greater binding to its ligand CD47, as well as enhanced T cell proliferation and diabetogenic potency. Myeloid cell-restricted expression of a Sirpa transgene accelerated disease in a dose-dependent manner and displayed genetic and functional interaction with the Idd5 locus to potentiate insulitis progression. Our study demonstrates that variations in both SIRPα sequence and expression level modulate T1D immunopathogenesis. Thus, we identify Sirpa as a T1D risk gene and provide insight into the complex mechanisms by which disease-associated variants act in concert to drive defined stages in disease progression.

Role of somatostatin receptor-2 in gentamicin-induced auditory hair cell loss in the Mammalian inner ear.

Hair cells and spiral ganglion neurons of the mammalian auditory system do not regenerate, and their loss leads to irreversible hearing loss. Aminoglycosides induce auditory hair cell death in vitro, and evidence suggests that phosphatidylinositol-3-kinase/Akt signaling opposes gentamicin toxicity via its downstream target, the protein kinase Akt. We previously demonstrated that somatostatin-a peptide with hormone/neurotransmitter properties-can protect hair cells from gentamicin-induced hair cell death in vitro, and that somatostatin receptors are expressed in the mammalian inner ear. However, it remains unknown how this protective effect is mediated. In the present study, we show a highly significant protective effect of octreotide (a drug that mimics and is more potent than somatostatin) on gentamicin-induced hair cell death, and increased Akt phosphorylation in octreotide-treated organ of Corti explants in vitro. Moreover, we demonstrate that somatostatin receptor-1 knockout mice overexpress somatostatin receptor-2 in the organ of Corti, and are less susceptible to gentamicin-induced hair cell loss than wild-type or somatostatin-1/somatostatin-2 double-knockout mice. Finally, we show that octreotide affects auditory hair cells, enhances spiral ganglion neurite number, and decreases spiral ganglion neurite length.

Inhibition of MMP-2 but not MMP-9 influences inner ear spiral ganglion neurons in vitro.

Matrix metalloproteinases (MMPs) play an important role in modeling of the extracellular matrix. There is increasing evidence that these proteases are important in neurite elongation and axonal guidance during development in the central nervous system and retina. Moreover, they are also expressed after acute injury and can be the key mediators of pathogenesis. However, the role of MMPs in the inner ear is largely unknown. Our group recently demonstrated that general inhibition of MMPs resulted in auditory hair cell loss in vitro. In the present study, we investigated the role of MMPs in inner ear spiral ganglion neuron (SGN) survival, neuritogenesis and neurite extension by blocking MMPs known to be involved in axonal guidance, neurite elongation, and apoptosis in other neuronal systems. Spiral ganglion (SG) explants from 5-day-old Wistar rats were treated with different concentrations of the general MMP inhibitor GM6001, a specific MMP-2 inhibitor, and a specific MMP-9 inhibitor, in vitro. The general inhibitor of MMPs and the specific inhibition of MMP-2 significantly reduced both the number of neurites that extended from SG explants, as well as the length of individual neurites. However, neither the general inhibitor of MMPs nor the specific inhibition of MMP-2 influenced SGN survival. Inhibition of MMP-9 had no influence on SGNs. The data suggest that MMPs, and more specifically MMP-2, influence the growth of developing afferent neurites in the mammalian inner ear in vivo.

Neural cell adhesion molecule L1 modulates type I but not type II inner ear spiral ganglion neurite outgrowth in an in vitro alternate choice assay.

L1, a neural cell adhesion molecule of the immunoglobulin superfamily, is widely expressed in the nervous system and important in axonal outgrowth, guidance, synapse formation, and signaling. Gene deletion studies emphasize the significance of L1 during development of the central nervous system and L1 is crucial for the topographic targeting of retinal axons. In contrast to the brain and retina, the role of L1 in the inner ear is largely unknown. While previous studies have localized L1 in the developing inner ear of the chicken and mouse, its function during the innervation of the cochlea still remains largely unclear. We therefore investigated the functional role of L1 in the mammalian inner ear. Our aim was to determine whether or not L1 can modulate type I and/or type II spiral ganglion neuron outgrowth using an in vitro alternate choice assay. We found that L1, presented in stripe micropatterns, provide directional cues to neonatal rodent type I but not type II inner ear spiral ganglion neurites. The results suggest that L1 may play a role in axonal pathfinding of type I spiral ganglion dendrites toward their inner hair cell targets but not of type II toward the outer hair cells.

Simvastatin protects auditory hair cells from gentamicin-induced toxicity and activates Akt signaling in vitro.

BACKGROUND: Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, known as statins, are commonly used as cholesterol-lowering drugs. During the past decade, evidence has emerged that statins also have neuroprotective effects. Research in the retina has shown that simvastatin, a commonly used statin, increases Akt phosphorylation in vivo, indicating that the PI3K/Akt pathway contributes to the protective effects achieved. While research about neuroprotective effects have been conducted in several systems, the effects of statins on the inner ear are largely unknown. RESULTS: We evaluated whether the 3-hydroxy-3-methylglutaryl-coenzyme A reductase is present within the rat cochlea and whether simvastatin is able to protect auditory hair cells from gentamicin-induced apoptotic cell death in a in vitro mouse model. Furthermore, we evaluated whether simvastatin increases Akt phosphorylation in the organ of Corti. We detected 3-hydroxy-3-methylglutaryl-coenzyme A reductase mRNA in organ of Corti, spiral ganglion, and stria vascularis by reverse transcriptase-polymerase chain reaction (RT-PCR). Moreover, we observed a dose-dependent and significant reduction of hair cell loss in organs of Corti treated with simvastatin in addition to gentamicin, as compared to samples treated with gentamicin alone. The protective effect of simvastatin was reversed by addition of mevalonate, a downstream metabolite blocked by simvastatin, demonstrating the specificity of protection. Finally, Western blotting showed an increase in organ of Corti Akt phosphorylation after simvastatin treatment in vitro. CONCLUSION: These results suggest a neuroprotective effect of statins in the inner ear, mediated by reduced 3-hydroxy-3-methylglutaryl-coenzyme A reductase metabolism and Akt activation.

Diamond LED substrate and novel quantum dots.

Nitride LED (e.g., GaN) has become the mainstream of blue light source. The blue light can be converted to white light by exciting a phosphor (e.g., Nichia's YAG or Osram's TAG) with the complementary yellow emission. However, GaN is typically deposited on sapphire (Al2O3) substrates formed by crystal pulling or hexagonal (e.g., 4 H or 6 H) SiC wafers condensed from SiC vapor. In either case, the nitride lattice is ridden (e.g., 10(9)/cm2) with dislocations. The high dislocation density with sapphire is due to the large (>13%) lattice mismatch; and with hexagonal SiC, because of intrinsic defects. Cubic (beta) SiC may be deposited epitaxially using a CVD reactor onto silicon wafer by diffusing the interface and by chemical gradation. A reactive echant (e.g., hydrogen or fluorine) can be introduced periodically to gasify mis-aligned atoms. In this case, large single crystal wafers would be available for the manufacture of high bright LED with superb electro-optical efficiency. The SiC wafer may be coated with diamond film that can eliminate heat in real time. As a result of lower temperature, the nitride LED can be brighter and it will last longer. The blue light of GaN LED formed on SiC on Diamond (SiCON) LED may also be scattered by using novel quantum dots (e.g., 33 atom pairs of CdSe) to form a broad yellow light that blend in with the original blue light to form sunlight-like white light. This would be the ideal source for general illumination (e.g., for indoor) or backlighting (e.g., for LCD).

Tandem dimerization of the human p53 tetramerization domain stabilizes a primary dimer intermediate and dramatically enhances its oligomeric stability.

Tetramerization of the human p53 tumor suppressor protein is required for its biological functions. However, cellular levels of p53 indicate that it exists predominantly in a monomeric state. Since the oligomerization of p53 involves the rate-limiting formation of a primary dimer intermediate, we engineered a covalently linked pair of human p53 tetramerization (p53tet) domains to generate a tandem dimer (p53tetTD) that minimizes the energetic requirements for forming the primary dimer. We demonstrate that p53tetTD self-assembles into an oligomeric structure equivalent to the wild-type p53tet tetramer and exhibits dramatically enhanced oligomeric stability. Specifically, the p53tetTD dimer exhibits an unfolding/dissociation equilibrium constant of 26 fM at 37 degrees C, or a million-fold increase in stability relative to the wild-type p53tet tetramer, and resists subunit exchange with monomeric p53tet. In addition, whereas the wild-type p53tet tetramer undergoes coupled (i.e. two-state) dissociation/unfolding to unfolded monomers, the p53tetTD dimer denatures via an intermediate that is detectable by differential scanning calorimetry but not CD spectroscopy, consistent with a folded p53tetTD monomer that is equivalent to the p53tet primary dimer. Given its oligomeric stability and resistance against hetero-oligomerization, dimerization of p53 constructs incorporating the tetramerization domain may yield functional constructs that may resist exchange with wild-type or mutant forms of p53.

Probing the impact of valency on the routing of arginine-rich peptides into eukaryotic cells.

Multivalency represents a critical parameter in cell biology responsible for the overall avidity of low-affinity interactions and the triggering of cellular events. Functions such as catalytic activity, cellular uptake, or localization are frequently linked to the oligomeric state of a protein. This study explores the impact of multivalency on the import and routing of peptides into cells. Specifically, cationic import sequences such as decaarginine, decalysine, and the HIV Tat peptide (GRKKRRQRRRAP, residues 48-59) as well as the nuclear localization sequence from SV40 large T-antigen were assembled into defined peptide oligomers by fusing them to the tetramerization domain of human p53 (residues 325-355, hp53(tet) domain). The resulting tetravalent peptides typically displayed between 10- and 100-fold enhancements in cellular import and intracellular routing properties in relation to their monomeric homologues. These peptides were not toxic to cells. Flow cytometry results and transfection assays indicated that tetravalent decaarginyl peptides (10R-p53(tet) and NLS-10R-p53(tet)) were the peptides most efficiently routed into cells. Their mechanism of import was subsequently examined on unfixed, viable cells using a combination of metabolic inhibitors, flow cytometry, and microscopy techniques. These studies revealed that tetravalent arginine-rich peptides bind to heparan sulfate on the cell surface, are internalized at 37 degrees C, but not at 4 degrees C, via a clathrin-mediated pathway, and accumulate into endosome-like acidic compartments. A fraction of these tetravalent peptides access the cytosol and accumulate in the nucleus of cells. This study concludes that the oligomerization of proteins harboring arginine-rich peptide chains may profoundly influence their ability to enter and be routed into cells.

The importance of valency in enhancing the import and cell routing potential of protein transduction domain-containing molecules.

Protein transduction domains (PTDs) are peptides that afford the internalization of cargo macromolecules (including plasmid DNA, proteins, liposomes, and nanoparticles). In the case of polycationic peptides, the efficiency of PTDs to promote cellular uptake is directly related to their molecular mass or their polyvalent presentation. Similarly, the efficiency of routing to the nucleus increases with the number of nuclear localization signals (NLS) associated with a cargo. The quantitative enhancement, however, depends on the identity of the PTD sequence as well as the targeted cell type. Thus the choice and multivalent presentation of PTD and NLS sequences are important criteria guiding the design of macromolecules intended for specific intracellular localization. This review outlines synthetic and recombinant strategies whereby PTDs and signal sequences can be assembled into multivalent peptide dendrimers and promote the uptake and routing of their cargoes. In particular, the tetramerization domain of the tumour suppressor p53 (p53tet) is emerging as a useful scaffold to present multiple routing and targeting moieties. Short cationic peptides fused to the 31-residue long p53tet sequence resulted in tetramers displaying a significant enhancement (up to 1000 fold) in terms of their ability to be imported into cells and delivered to the cell nucleus in relation to their monomeric analogues. The design of future polycationic peptide dendrimers as effective delivering vehicles will need to incorporate selective cell targeting functions and provide solutions to the issue of endosomal entrapment.

Wearable feedback systems for rehabilitation.

In this paper we describe LiveNet, a flexible wearable platform intended for long-term ambulatory health monitoring with real-time data streaming and context classification. Based on the MIT Wearable Computing Group's distributed mobile system architecture, LiveNet is a stable, accessible system that combines inexpensive, commodity hardware; a flexible sensor/peripheral interconnection bus; and a powerful, light-weight distributed sensing, classification, and inter-process communications software architecture to facilitate the development of distributed real-time multi-modal and context-aware applications. LiveNet is able to continuously monitor a wide range of physiological signals together with the user's activity and context, to develop a personalized, data-rich health profile of a user over time. We demonstrate the power and functionality of this platform by describing a number of health monitoring applications using the LiveNet system in a variety of clinical studies that are underway. Initial evaluations of these pilot experiments demonstrate the potential of using the LiveNet system for real-world applications in rehabilitation medicine.

Chemical analysis of raw, dry-roasted, and honey-roasted licorice by capillary electrophoresis.

In herbal medicine, licorice is usually processed using a roasting procedure which might modify the chemical compositions in licorice. To test this hypothesis, licorice root samples were roasted under various conditions (with or without honey) and subsequently extracted by refluxing with 95% ethanol. The analysis of chemical compositions of licorice root extracts was achieved by capillary electrophoresis. The running buffer has been optimized to be 50 mM sodium tetraborate (pH 9.01) containing 5 mM beta-cyclodextrin. Thermal decomposition of glycyrrhizin, which was a major ingredient in licorice, was first studied in detail, indicating the conversion of glycyrrhizin to glycyrrhetinic acid. The licorice extracts were then analyzed to indicate the above thermal conversion did occur in the licorice samples. This finding may shed some light on understanding the differences in the therapeutic values of raw versus roasted licorice in herbal medicine.