Search

Carcinoid tumors, one of the most common malignant lesions involving the appendix, are typically found incidentally during routine appendectomies. While up to 20% of acute appendicitis cases present with perforation, the incidence of perforation among patients with undiagnosed carcinoid tumors of the appendix is unknown. In addition, there is no consensus on the management of carcinoid tumors in the perforated appendix or its impact on prognosis. We present a case of a 42-year-old woman presented with perforated appendicitis. Final pathology demonstrated the presence of a 1.1 cm, well-differentiated grade 1 neuroendocrine tumor at the tip of the appendix extending into the subserosa, without evidence for lymphovascular invasion. Given the depth of tumor invasion and the relatively young age of the patient, the decision was made to perform an interval completion right hemicolectomy for lymph node sampling. Only a few cases have been reported in the available literature, and it remains unclear whether appendiceal perforation represents an independent negative prognostic factor for patient survival. Additional data from cohort studies are needed to determine the true incidence, prognosis, and optimal management of newly diagnosed carcinoid tumors in the perforated appendix. Furthermore, clear consensus guidelines are needed to identify the subgroup of patients who would benefit from interval or primary right hemicolectomy.

Abstract The current study retrospectively reviewed the cases of 68 patients who had undergone total laryngectomy and tracheoesophageal puncture (TEP) over a 16-year period. Fifty-one patients underwent primary TEP and [...]

Background: Intraperitoneal (IP) vancomycin is recommended as one of the treatment options for gram-positive coverage in the management of peritoneal dialysis (PD)-associated peritonitis. There is a lack of literature supporting the optimal dose and approach to vancomycin therapeutic drug-level monitoring.Methods: A retrospective chart review was conducted using the BC Renal Agency PROMIS Database and our hospital records from 1 June 2011 to 1 July 2019. Adult patients with PD-associated peritonitis who received IP vancomycin and had at least one serum vancomycin level drawn were included. All patients received a loading dose of 30 mg/kg, which was repeated every 3–5 days depending on PD modality. Serum vancomycin levels were drawn prior to the second vancomycin dose, then at the discretion of the prescriber. The primary end point was the rate of therapeutic serum vancomycin levels ≥15 mg/L.Results: Twenty-three episodes of PD-associated peritonitis in 20 patients met the eligibility criteria. Only 15/23 serum vancomycin levels were drawn appropriately after the first dose. Sixty per cent of these levels were subtherapeutic at <15 mg/L. All subsequent serum vancomycin levels were above the therapeutic target. Most peritonitis episodes (78%) achieved resolution of infection. Residual kidney function was not significantly correlated with serum vancomycin levels (p= 0.19).Conclusions: An IP vancomycin regimen of 30 mg/kg every 3–5 days resulted in subtherapeutic serum vancomycin levels in most patients following the loading dose but therapeutic levels thereafter. A large percentage of vancomycin levels were drawn inappropriately due to misalignment of outpatient follow-up visits and timing of blood work.

Outdoor free play is important for preschoolers' physical activity, health, and development. Certain temperamental characteristics are associated with obesity, nutrition, and sedentary behaviors in preschoolers, but the relationship between temperament and outdoor play has not been examined. This study examined whether there is an association between temperament and outdoor play in young children.

As in other organ transplant recipients, the authors demonstrate in 109 intestine organ transplant recipients that pretransplant donor-specific antibodies (DSAs) and persistent de novo DSA are associated with a worse outcome than in patients without DSAs. Supplemental digital content is available in the text.

IMPORTANCE: Serum α-fetoprotein (AFP) is a biomarker for hepatocellular carcinomas (HCCs) associated with a more aggressive tumor phenotype and inferior outcomes after a liver transplant (LT). Data on the outcomes for patients with HCCs that do not produce AFP are limited. OBJECTIVE: To compare characteristics and outcomes among LT recipients with radiographically apparent HCC lesions with AFP-producing tumors or with tumors that do not produce AFP (hereafter referred to as non-AFP–producing tumors), and to identify factors influencing recurrence in LT recipients with non-AFP–producing tumors. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis at a university transplant center of 665 adults with HCC who underwent an LT during the period from 1989 to 2013. Of the 665 LT recipients, 457 (68.7%) had AFP-producing tumors, and 208 (31.3%) had non-AFP–producing tumors (the maximum AFP level before an LT was ≤10 ng/mL). Dates of study analysis were from August 2015 to June 2016. INTERVENTION: Liver transplant. MAIN OUTCOMES AND MEASURES: Recurrence-free survival and recurrence rates. RESULTS: Patients with non-AFP–producing tumors had radiographic tumor characteristics similar to those of patients with AFP-producing tumors, but, pathologically, they had fewer lesions (25% vs 35% with >2 lesions; P = .03), smaller cumulative tumor diameters (4.2 vs 5.0 cm; P = .02), fewer microvascular (17% vs 22%) and macrovascular (2% vs 9%) invasions (P &lt; .001), and fewer poorly differentiated tumors (15% vs 28%; P &lt; .001). Patients with non-AFP–producing tumors also had significantly superior recurrence-free survival at 1, 3, and 5 years (88%, 74%, and 67% vs 76%, 59%, and 51%, respectively; P = .002) and lower 5-year recurrence rates (8.8% vs 22%; P &lt; .001) than patients with AFP-producing tumors. When stratified by radiologic Milan criteria, 5-year survival was better, and recurrence lowest, among patients with non-AFP–producing tumors within the Milan criteria (71% survival and 6% recurrence), and survival was worse, and recurrence highest, for patients with AFP-producing tumors outside the Milan criteria (40% survival and 42% recurrence; P &lt; .001). Significant predictors of recurrence among patients with non-AFP–producing tumors include radiologic (>2 tumors [HR, 4.98; 95% CI, 1.72-14.4; P = .003]; cumulative diameter [1.70 per log SD; 1.12-2.59; P &lt; .001]; outside the Milan criteria [10.0; 3.7-33.3; P &lt; .001) and pathologic factors (>2 tumors [4.39; 1.32-14.6; P = .02]; cumulative diameter [2.32 per log SD; 1.43-3.77; P = .001]; microvascular [3.07; 1.02-9.24; P = .05] and macrovascular invasion [8.75; 2.15-35.6; P = .002]). CONCLUSIONS AND RELEVANCE: Nearly one-third of patients with radiographically apparent HCC have non-AFP–producing tumors that have more favorable pathologic characteristics, lower posttransplant recurrence, and superior survival compared with patients with AFP-producing tumors. Posttransplant HCC recurrence for patients with non-AFP–producing tumors is predicted by important radiologic and pathologic factors, and is negligible for patients within the Milan criteria. Stratifying patients by AFP status in addition to radiological criteria may improve the selection process for and the prioritization of transplant candidates.

Naturally occurring, thymic-derived Foxp3CD25CD4 regulatory T cells (nTregs) are pivotal for the maintenance of self-tolerance. nTregs, however, are sparse and lack alloantigen specificity, and these properties pose challenges for their use in clinical transplantation.

A major unmet challenge is to reduce the islet mass needed for insulin independence in type 1 diabetic recipients after islet transplantation. The recombinant homodimer of human annexin V, diannexin, has completed a Phase II Clinical Trial in Kidney Transplantation (NCT00615966).

BRAFV600EKis a frequent mutationally active tumor-specific kinase in melanomas that is currently targeted for therapy by the specific inhibitor PLX4032. Our studies with melanoma tumor cells that are BRAFV600EKand BRAFWTshowed that, paradoxically, while PLX4032 inhibited ERK12 in the highly sensitive BRAFV600EK, it activated the pathway in the resistant BRAFWTcells, via RAF1 activation, regardless of the status of mutations in NRAS or PTEN. The persistently active ERK12 triggered downstream effectors in BRAFWTmelanoma cells and induced changes in the expression of a wide-spectrum of genes associated with cell cycle control. Furthermore, PLX4032 increased the rate of proliferation of growth factor-dependent NRAS Q61L mutant primary melanoma cells, reduced cell adherence and increased mobility of cells from advanced lesions. The results suggest that the drug can confer an advantage to BRAFWTprimary and metastatic tumor cells in vivo and provide markers for monitoring clinical responses.

In tyrosinase-positive amelanotic melanoma cells, inactive tyrosinase accumulates in the endoplasmic reticulum. Based on studies described here, we propose that aberrant vacuolar proton ATPase (V-ATPase)-mediated proton transport in melanoma cells disrupts tyrosinase trafficking through the secretory pathway. Amelanotic but not melanotic melanoma cells or normal melanocytes display elevated proton export as observed by the acidification of the extracellular medium and their ability to maintain neutral intracellular pH. Tyrosinase activity and transit through the Golgi were restored by either maintaining the melanoma cells in alkaline medium (pH 7.4–7.7) or by restricting glucose uptake. The translocation of tyrosinase out of the endoplasmic reticulum and the induction of cell pigmentation in the presence of the ionophore monensin or the specific V-ATPase inhibitors concanamycin A and bafilomycin A1 supported a role for V-ATPases in this process. Because it was previously shown that V-ATPase activity is increased in solid tumors in response to an acidified environment, the appearance of hypopigmented cells in tyrosinase-positive melanoma tumors may indicate the onset of enhanced glycolysis and extracellular acidification, conditions known to favor metastatic spread and resistance to weak base chemotherapeutic drugs.

With some exceptions, surface chemistry had little effect on platelet and leukocyte activation, and cell deposition, by scanning electron microscopy after blood exposure and clotting times among a group of 12 unmodified and plasma modified tubings. All materials activated platelets and leukocytes to detectable levels, although some materials increased the value of one activation parameter but not another. Unmodified materials polyethylene PE, Pellethane® PEU, latex, nylon, and Silastic® and modified materials H2O plasma treated PE and PEU, CF4plasma treated PE, fluorinated PEU, NH4plasma treated PEU, polyethylene imine treated PEU, and heparin treated PEU were characterised by XPS and contact angle. The objective of this project was to define a series of assays for the evaluation of hemocompatibility of cardiovascular devices with a view to clarify the specific requirements of ISO109934, and to define an appropriate screening program for new blood contacting biomaterials. PE, PE–CF4, PE–H20, PEU–F, latex, and PEUheparin were the exceptions to the general observations, although each behaved differently. PE proved to be least reactive, whereas PE–CF4was most reactive by several assays. Platelet microparticle formation determined by flow cytometry, PTT, postblood exposure SEM, total SC5b9, C3a, and platelet and leukocyte loss cell counts were able to distinguish differences among these materials, and often, but not always, showed expected correlations. © 2001 John Wiley & Sons, Inc. J Biomed Mater Res 55: 447–459, 2001

Tyrosinase is essential for pigmentation and is a source of tumor-derived antigenic peptides and cellular immune response. Wild type tyrosinase in melanoma cells and certain albino mutants in untransformed melanocytes are targeted to proteolytic degradation by the 26 S proteasome due to retention of the misfolded protein in the endoplasmic reticulum and its subsequent retranslocation to the cytosol. Here, we demonstrate that the substrates DOPA and tyrosine induced in melanoma cells a transition of misfolded wild type tyrosinase to the native form that is resistant to proteolysis, competent to exit the endoplasmic reticulum, and able to produce melanin. Because the enzymatic activity of tyrosinase is induced by DOPA, we propose that proper folding of the wild type protein, just like mutant forms, is tightly linked to its catalytic state. Loss of pigmentation, therefore, in tyrosinase-positive melanoma cells is a consequence of tumor-induced metabolic changes that suppress tyrosinase activity and DOPA production within these cells.

Tyrosinase is a type I membrane glycoprotein essential for melanin synthesis. Mutations in tyrosinase lead to albinism due, at least in part, to aberrant retention of the protein in the endoplasmic reticulum and subsequent degradation by the cytosolic ubiquitin-proteasomal pathway. A similar premature degradative fate for wild type tyrosinase also occurs in amelanotic melanoma cells. To understand critical cotranslational events, the glycosylation and rate of translation of tyrosinase was studied in normal melanocytes, melanoma cells, an in vitrocell-free system, and semi-permeabilized cells. Site-directed mutagenesis revealed that all seven N-linked consensus sites are utilized in human tyrosinase. However, glycosylation at Asn-290 (Asn-Gly-Thr-Pro) was suppressed, particularly when translation proceeded rapidly, producing a protein doublet with six or sevenN-linked core glycans. The inefficient glycosylation of Asn-290, due to the presence of a proximal Pro, was enhanced in melanoma cells possessing 2–3-fold faster (7.7–10.0 amino acids/s) protein translation rates compared with normal melanocytes (3.5 amino acids/s). Slowing the translation rate with the protein synthesis inhibitor cycloheximide increased the glycosylation efficiency in live cells and in the cell-free system. Therefore, the rate of protein translation can regulate the level of tyrosinaseN-linked glycosylation, as well as other potential cotranslational maturation events.

Inactivation of the retinoblastoma tumor suppressor protein (pRb) has been implicated in melanoma cells, but the molecular basis for this phenotype has not yet been elucidated, and the status of additional family members (p107 and p130, together termed pocket proteins) or the consequences on downstream targets such as E2F transcription factors are not known. Because cell cycle progression is dependent on the transcriptional activity of E2F family members (E2F1–E2F6), most of them regulated by suppressive association with pocket proteins, we characterized E2F–pocket protein DNA binding activity in normal versus malignant human melanocytes. By gel shift analysis, we show that in mitogen-dependent normal melanocytes, external growth factors tightly controlled the levels of growth-promoting free E2F DNA binding activity, composed largely of E2F2 and E2F4, and the growth-suppressive E2F4–p130 complexes. In contrast, in melanoma cells, free E2F DNA binding activity (E2F2 and E2F4, to a lesser extent E2F1, E2F3, and occasionally E2F5), was constitutively maintained at high levels independently of external melanocyte mitogens. E2F1 was the only family member more abundant in the melanoma cells compared with normal melanocytes, and the approximately fivefold increase in DNA binding activity could be accounted for mostly by a similar increase in the levels of the dimerization partner DP1. The continuous high expression of cyclin D1, A2, and E, the persistent cyclin-dependent kinase 4 (CDK4) and CDK2 activities, and the presence of hyperphosphorylated forms of pRb, p107, and p130, suggest that melanoma cells acquired the capacity for autonomous growth through inactivation of all three pocket proteins and release of E2F activity, otherwise tightly regulated in normal melanocytes by external growth factors.

To determine whether epithelial ion transport abnormalities in cystic fibrosis (CF) might reflect abnormal regulation of intracellular Ca2+levels, cytosolic free calcium (Cai2+) was measured using fura-2 or quin2 in suspensions of normal or CF nasal epithelial cells derived from primary cell culture. The basal Cai2+level measured with fura-2 in CF nasal epithelia was 155 ± 9 nM (n = 5), a value not significantly different from normal nasal epithelia (143 ± 16 nM, n = 5). Total cell calcium was measured by atomic absorption spectroscopy and no differences were observed between CF (6.3 ± 0.5 nmol/mg protein; n = 3) and normal (6.2 ±1.2 nmol/mg protein; n = 3) nasal epithelial cells. Placing Na+loaded cells in a low (10 mM) extracellular Na+solution resulted in a rapid increase in Cai2+consistent with Ca2+uptake via a plasmalemmal Na+-Ca2+exchanger. The level of Cai2+achieved by this low Na+maneuver was not significantly different in CF cells compared to normal cells. Neither isoproterenol (10-5M) nor forskolin (10-6M) had any effect on Cai2+in normal or CF nasal epithelial cells. Thus, it appears that differences in cell Cai2+, as measured by fluorescent chelators in suspensions of cultured cells, do not account for the abnormalities in basal or isoproterenol stimulated ion transport in CF tissues. (Pediatr Res 24: 79–84, 1988)

Peptides produced by Staphylococcus epidermidispromote dissemination of this bacterium from biofilms, leading to systemic infection in catheterized patients.

Antibiotics alter the normal intestinal flora and increase susceptibility to infection by highly resistant bacteria.

Targeted delivery of antifibrotic compounds stems scar formation.

Growth hormone–releasing hormone directly stimulates fibroblasts to accelerate wound healing.

A protein transduction domain peptide enhances the cellular uptake of Foxp3 protein for the treatment of autoimmune and allergic disorders.

Valproic acid coaxes transplanted neural stem cells to differentiate into neurons that boost repair of spinal cord injury in mice.

A new microfluidic device allows for easy isolation of neutrophils for genomic and proteomic analyses.

Creation of a bioartificial lung is successful for transplantation in the treatment of end-stage lung disease.

Vaccination with α-lactalbumin provides prophylaxis against breast cancer in tumor-prone mouse models.

Detecting an enzyme expressed by a subset of monocytes confers an ability to monitor rejection of transplanted hearts.

Interleukin-33 attenuates sepsis by promoting neutrophil migration to the site of infection and facilitating bacterial clearance.

Magnetic nanoparticles carrying a therapeutic agent can be specifically targeted to stents to prevent re-occlusion of blood vessels.

Combination therapy with TRAIL and all-trans-retinyl acetate prevents the progression of premalignant intestinal polyps into colon cancer.

Skin-associated bacterial communities hold promise for forensic identification.

Tumor visualization with activatable cell-penetrating peptides during surgery allows more complete tumor removal.

Chemical permeation enhancers increase the effectiveness of lidocaine derivatives, conferring prolonged analgesia without motor impairment.

A new system for the efficient delivery of siRNAs in vivo facilitates gene silencing.

The death receptor Fas may contribute to obesity-induced inflammation and the pathogenesis of type 2 diabetes mellitus.