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A highly sensitive test for evaluation of solitary pulmonary nodules (SPN) involves a 5-phase, contrast enhanced CT evaluation which can be fraught with technical error. The goal of this study is to determine if qualitative evaluation of iodine maps with dual energy CT (DECT) can add value to SPN evaluation.100 patients had their SPN evaluated with traditional quantitative analysis and qualitative evaluation with iodine maps generated from DECT data acquired at 80 kVp and 140 kVp. Quantitative analysis served as the gold standard. Quantitative analysis was performed at 1, 2, 3, and 4 minutes. Qualitative Iodine maps analysis was performed at 1 and 2 minutes. Sensitivity and specificity were 63% and 95%, and 73% and 91%, respectively, at 1 and 2 minutes. Combined analysis resulted in sensitivity of 67% and specificity of 94%. Six of 7 false negatives on combined analysis were stable for 2 years and the seventh was lost to follow up after 1 year. Of 5 false positives on combined analysis; 2 were due to 'bleed-through of calcium' on iodine maps, 2 were positive on 3 and 4-minute quantitative analysis with one biopsy-proven adenocarcinoma. Qualitative analysis of Iodine maps generated using DECT data can be easily performed and may provide more effective evaluation of the solitary pulmonary nodule when combined with traditional analysis. This method warrants further investigation with larger patient populations, comparison with PET-CT, and evaluation of outcomes including long-term nodule stability and tissue diagnosis. [ABSTRACT FROM AUTHOR]

Objective: This study compared brain energy metabolism, as measured by cerebral concentrations of glutamate (Glu), glutamine (Gln), and N-acetyl aspartate (NAA), in older age bipolar depression (OABD) to that of psychiatrically healthy comparison subjects using proton (1H) magnetic resonance spectroscopy imaging at 4-Tesla. Metabolite levels were assessed in OABD subjects before and after 8 weeks of lamotrigine therapy with the goal of determining relationships between cerebral energy metabolism, depression symptom severity, and changes in depression symptom response.Methods: Individuals (n = 21, mean age: 62.0 ± 5.9 years) with bipolar disorder, current episode depressed, and a healthy comparison group (n = 14, mean age: 67.5 ± 8.8 years) were selected. Participants with bipolar disorder, current episode depressed, were treated in open label fashion with lamotrigine monotherapy for 8 weeks. All subjects were scanned with 1H magnetic resonance spectroscopy at 4T at baseline and again after 8 weeks to assess levels of cerebral metabolites in the anterior cingulate cortex and parieto-occipital cortex. Metabolite levels were examined as ratios relative to creatine (Cr). Response to 8 weeks of lamotrigine treatment in the bipolar disorder, current episode depressed group, was assessed as a continuous measure on the Montgomery-Asberg Depression Rating Scale.Results: NAA/Cr ratio in OABD was significantly lower by 14% (95% confidence interval: [1%, 26%]) than in comparison subjects at baseline. However, there were no associations between NAA/Cr, Glu/Cr, or Gln/Cr and either depression severity or lamotrigine treatment.Conclusion: Group differences in NAA suggest evidence for a deficit in cerebral energy metabolism in OABD. [ABSTRACT FROM AUTHOR]

Summary Background Indocyanine green angiography (ICGA) reduces ischemic complications by assessing mastectomy flap perfusion intraoperatively. However, outcomes of ICGA can be surgeon-dependent due to its relative novelty. We aimed to determine whether patient outcomes improved with the adoption of ICGA over time. Methods We conducted a single-institution retrospective study of mastectomy patients between March 2012 (date of ICGA introduction) and October 2016. We included patients who underwent immediate expander-based reconstruction with intraoperative ICGA, followed by second-stage permanent implant placement. Patients were chronologically sorted into 3 groups, of 45 patients each, based on the date of ICGA. Complications and reconstruction wait times (time between initial expander placement and subsequent final reconstruction) amongst the 3 groups were evaluated. Using the Cochran–Armitage test for trend, we tested the change in median adjusted expander fill volumes (expander fill volume in milliliter per gram of breast removed) over time. Results We identified 135 patients. Rates of ischemic complications significantly decreased (Group 1, 36%; Group 2, 22%; Group 3, 11%; p = 0.03), despite significantly increasing median adjusted expander fill volumes (Group 1, 0.46 mL/g; Group 2, 0.63 mL/g; Group 3, 0.76 mL/g; p = 0.003) over time. The rates of unexpected returns to the operating room across the 3 groups were not significantly different. The median reconstruction wait time was significantly reduced in the later groups (Group 1, 146 days; Group 2, 122 days; Group 3, 87 days; p = 0.01). Conclusions Outcomes for mastectomy with immediate expander-based reconstruction were found to improve with increasing case volume after implementation of ICGA. [ABSTRACT FROM AUTHOR]

Abstract Introduction The 21-gene recurrence score (RS) (Oncotype Dx, Genomic Health, Redwood City Ca) has not been validated in an older cohort with estrogen receptor (ER)-positive breast cancer. The objective of this study was to evaluate RS validity in a group of older women with ER-positive breast cancer. Methods Utilizing the Surveillance, Epidemiology, and End Results Program (SEER) database with available RS, we evaluated women with ER-positive breast cancer aged 18–69 and those 70 years of age and older from 2004 to 2014. We utilized multivariable logistic regression models to evaluate factors associated with RS testing as well as a high-risk categorization for those who underwent testing. Survival was analyzed using Kaplan Meier curves and Cox proportional hazard models. Results We identified 363,876 women aged 18–69 years and 147,107 women aged 70 years and older. A smaller proportion of patients in the older group (8%) underwent RS testing than in the younger group (18%). Of the patients who underwent testing, distribution of RS was similar between groups. High-risk categorization independently predicted a higher likelihood of death for older patients (hazard ratio 1.47, 95% confidence interval 1.15–1.90). Among patients with high-risk RS, chemotherapy was associated with a decreased risk of death in the younger group, but not in the older group. Conclusion Older women are less likely to receive RS testing, but when tested, older patients have a similar distribution of RS as compared to younger patients. While high-risk categorization in the older cohort was prognostic, chemotherapy was not associated with improved survival. [ABSTRACT FROM AUTHOR]

Background: Adequate lymph node evaluation (LNE) is recommended for surgically treated pancreatic adenocarcinoma because studies have shown an association between improved survival and adequate LNE. This study aimed to understand the mechanism of this association and determine whether LNE is a valuable quality metric.Methods: Using the linked Surveillance Epidemiology End Results Medicare database, we identified patients with surgically treated pancreatic adenocarcinoma from 2000 to 2010. Adequate LNE was defined as evaluation of ≥15 nodes. Survival was determined using Kaplan-Meier and Cox proportional hazards.Results: We identified 2629 patients who underwent resection for pancreatic adenocarcinoma. Overall, 33 % had adequate LNE. Adequate LNE was significantly associated with receipt of postoperative chemotherapy. A significant decrease in hazard of death was associated with adequate LNE (HR 0.86, p < 0.05). Receipt of postoperative chemotherapy was also significantly associated with decreased hazard of death (HR 0.77, p < 0.05). On unadjusted analysis, the survival benefit associated with adequate LNE was lost when stratified by receipt of postoperative chemotherapy.Conclusion: The survival benefit associated with LNE is in part derived from the fact that patients who receive adequate LNE are also more likely to receive chemotherapy. Thus, the use of lymph node counts has limitations as a quality metric. [ABSTRACT FROM AUTHOR]

Purpose: Pancreatitis--an inflammation of pancreas--is a severe and costly disease. Although many risk factors for pancreatitis are known, many pancreatitis cases, especially in elderly women, are of unknown etiology. Methods: Risk factors for acute pancreatitis (AP) and chronic pancreatitis (CP) were assessed in a prospective cohort (n = 36,436 women, aged ≤ 65 years). Exposures were self-reported at baseline. Pancreatitis was ascertained by linkage to Medicare claims (1986-2004) categorized by a physician as follows: "AP", one AP episode (n = 511) or "CP", 2+ AP or 1+ CP episodes (n = 149). Results: Multivariable odds ratios (ORs) and 95% confidence intervals for AP and CP were calculated using multinomial logistic regression. Alcohol use was not associated with AP or CP. Heavy smoking (40+ vs. 0 pack-years) was associated with a twofold increased OR for CP. For body mass index greater than or equal to 30 versus less than 25 kg/m2], the ORs were 1.35 (1.07-1.70) for AP (P trend = .009) and 0.59 (0.37-0.94) for CP (P trend = .01). ORs for AP and CP were increased for hormone replacement therapy use, heart disease, and hypertension. There were positive significant associations between protein and total fat intake for CP and AP. Conclusions: We identified factors associated with AP and CP that may be specific to older women. [ABSTRACT FROM AUTHOR]

Introduction Sorafenib is the only drug approved by the Food and Drug Administration for metastatic hepatocellular carcinoma (HCC). Triptolide, a diterpene triepoxide, exhibits antineoplastic properties in multiple tumor cell types. In this study, we examined the effects of these agents and their combination on HCC in vitro and in vivo models. Methods HuH-7 and PLC/PRF/5 cells were treated with triptolide (50 nM), sorafenib (1.25 or 2.5 μM), or a combination of both. Cell viability assay (CCK-8), caspase 3&7 activation, and nuclear factor κB assays were performed. For in vivo studies, 40 mice were implanted with subcutaneous HuH7 tumors and divided into four treatment groups (n = 10); saline control, sorafenib 10 mg/kg PO daily (S), Minnelide (a prodrug of triptolide) 0.21 mg/kg intraperitoneally7 daily (M), and combination of both (C). Tumor volumes were assessed weekly. Results The combination of triptolide and sorafenib was superior to either drug alone in inducing apoptosis and decreasing viability, whereas triptolide alone was sufficient to decrease nuclear factor κB activity. After 2 weeks of treatment, tumor growth inhibition rates were S = 59%, M = 84%, and C = 93%, whereas tumor volumes in control animals increased by 9-fold. When crossed over to combination treatment, control mice tumor growth volumes plateaued over the following 4 weeks. Conclusion The combination of sorafenib and triptolide is superior to single drug treatment in increasing cell death and apoptosis in vitro. Combining sorafenib with Minnelide inhibited tumor growth with greater efficacy than single-agent treatments. Importantly, in vivo combination treatment allowed for using a lesser dose of sorafenib (10 mg/kg), which is less than 10% of currently prescribed dose for HCC patients. Therefore, combination treatment could have translational potential in the management of HCC. [ABSTRACT FROM AUTHOR]

Objectives Neoadjuvant chemoradiotherapy ( CRT) is a viable treatment strategy for patients with pancreatic cancer. This study was conducted to evaluate the Virginia Mason Protocol (5-fluorouracil, cisplatin, interferon-α and radiation) given in the neoadjuvant setting for the treatment of locally advanced pancreatic cancer. Methods A Phase II pilot study evaluating interferon-based neoadjuvant CRT in patients with locally advanced pancreatic cancer was performed. Results A total of 23 patients were enrolled. The mean age of the patients was 58.6 years. Of the 23 patients, seven (30.4%) completed all treatments. In the remaining 16 (69.6%) patients, treatment was interrupted as a result of toxicity. The most commonly reported effects of toxicity were leucopoenia/cytopoenia ( n = 19, 82.6%) and gastrointestinal effects ( n = 19, 82.6%). Surgical resection was successful in seven (30.4%) patients. Margins were negative in six (85.7%) of these seven patients. Positive lymph nodes were identified in three (42.9%) of seven patients. Overall survival was 11.5 months. Surgery provided improved survival (22.6 months) compared with CRT alone (8.8 months). Disease-free survival in resected patients was 17.2 months. Conclusions Interferon-based neoadjuvant CRT may allow for resection of locally advanced pancreatic cancer, but with significant toxicity. In the absence of surgical resection, survival remains dismal. [ABSTRACT FROM AUTHOR]

Although PKD is broadly expressed and involved in numerous cellular processes, its function in osteoclasts has not been previously reported. In this study, we found that PKD2 is the main PKD isoform expressed in osteoclastic cells. PKD phosphorylation, indicative of the activated state, increased after 2-3 days of treatment of bone marrow macrophages with M-CSF and RANKL, corresponding to the onset of preosteoclast fusion. RNAi against PKD2 and treatment with the PKD inhibitor CID755673 showed that PKD activity is dispensable for induction of bone marrow macrophages into tartrate-resistant acid phosphatase-positive preosteoclasts in culture but is required for the transition from mononucleated preosteoclasts to multinucleated osteoclasts. Loss of PKD activity reduced expression of DC-STAMP in RANKL-stimulated cultures. Overexpression of DC-STAMP was sufficient to rescue treatment with CID755673 and restore fusion into multinucleated osteoclasts. From these data, we conclude that PKD activity promotes differentiation of osteoclast progenitors through increased expression of DC-STAMP. [ABSTRACT FROM AUTHOR]

Background: Stapled pancreatic transection is widely used although pancreatic fistula remains a common post-surgical complication. Methods: We performed a meta-analysis of existing data regarding pancreatic fistula following stapled pancreatic transection, comparing bare metal staples to reinforced staple loads. Results: We identified ten manuscripts between 2007 and 2009 reporting outcomes following stapled division of the pancreas (five retrospective reviews, five prospective case series). A total of 483 stapled pancreatic resections are included in this meta-analysis. Of these, 234(48 %) were reinforced (REINF) and 249 (52 %) were bare staples (STPL). Out of 483 cases, there were a total of 100 documented pancreatic leaks (21 %). Sixty-one leaks were reported out of 249 STPL divisions (24 %), while 39 leaks were reported following REINF division (17 %). The overall relative risk of developing a pancreatic fistula following distal pancreatectomy was not significantly different comparing STPL to REINF when all studies were combined (RR 1.00, 95% CI 0.65-1.53). We further evaluated the data stratifying by study design (prospective or retrospective) and found that prospective studies reported a significantly higher risk of pancreatic fistula with STPL compared to REINF technique (RR 14.45, 95 % CI 3.15-66.21). Conclusion: Reinforced staples may be a preferred method of pancreatic stump closure following distal pancreatectomy. [ABSTRACT FROM AUTHOR]

Purpose: The use of nitrogen-containing bisphosphonates (n-bis) is associated with necrosis of the jaws, also known as bisphosphonate-related osteonecrosis of the jaws (BRONJ); however, the pathophysiology is unknown. Matrix metalloproteinase-9 (MMP-9) expression is essential for normal bone healing and is also required for angiogenesis. N-bis alters MMP-9 expression in vitro and in vivo; therefore, we hypothesized that n-bis alters MMP-9 expression during oral wound healing after tooth extraction. Materials and Methods: A total accumulated dose of 2.25 mg/kg (n = 20) of Zoledronic acid (ZA) Zometa or saline (control, n = 20) was administered to Sprague–Dawley male rats. Next, both groups had maxillary molar teeth extracted. Rats were sacrificed at postoperative day 1, 3, 7, or 21. Western blotting or multiplex ELISA was used to evaluate proteins of interest. Real-time polymerase chain reaction was used to assess the relative quantities of target gene mRNA. MMP-9 enzymatic activity was assessed by zymography. Results: The ZA group showed a statistically significant reduction in bone mineralization rate 21 days after tooth extraction compared with the control group (Student t test, P = .005). Moreover, ZA-treated animals showed a statistically significant increase in MMP-9-specific mRNA at postoperative days 3 (P = .003), 7 (P < .0001), and 21 (P < .0001) and protein on postoperative days 3 (P = .005) and 7 (P < .0001). MMP-9 enzymatic activity was also increased in ZA-treated rats compared with control animals (Student t test, P = .014). We also evaluated the extraction sockets for the presence of tissue inhibitor of MMP-1 (TIMP1), which is an inhibitor of MMP-9 enzymatic activity. TIMP1-specific mRNA and protein were not significantly altered by ZA treatment at the times tested (P > .05). Receptor of NF-κB ligand (RANKL) is known to regulate the expression of MMP-9; we therefore assessed the RANKL expression in our experimental oral wound-healing model. The ZA-treated animals had significantly increased RANKL mRNA at postoperative days 3 (P = .02) and 21 (P = .004), while the protein expression was significantly increased at postoperative days 1 (P < .0001), 7 (P = .02), and 21 (P = .03) compared with the control group. Conclusions: ZA reduced bone mineralization within tooth extraction sockets, suggesting aberrant bone healing. ZA increases the amount and enzymatic activity of MMP-9, while apparently not altering the amount of TIMP1 within extraction sockets. RANKL is increased in ZA-treated rats, which suggests that increased MMP-9 expression is due, in part, to augmented RANKL expression. [Copyright &y& Elsevier]

Abstract: Condensed water particles are known to exist in the high latitude upper mesosphere during the summer months. However, the mechanism or mechanisms through which they nucleate remains uncertain. It is postulated here that particles of amorphous solid water (ASW, condensed water with a non-crystalline structure) may nucleate homogeneously in the summer mesosphere. Using classical nucleation theory and a one-dimensional model, it is shown that more than 105 cm−3 amorphous solid water particles can nucleate homogeneously under mesopause conditions. Furthermore, it is shown that homogeneous nucleation competes with heterogeneous nucleation on meteoric smoke particles when the cooling rate is >0.5K/h. The homogeneous nucleation of amorphous solid water could provide an explanation for the high density of ice particles (many thousands per cm3) thought to be required for electron depletions in the upper mesosphere. A parameterisation for homogeneous nucleation is presented which can be used in other mesospheric cloud models. [Copyright &y& Elsevier]

Background: Pancreatobiliary access following Roux-en-Y gastric bypass (RYGBP) is challenging. We reviewed 32 cases of surgical gastrostomy for complex transgastric upper gastrointestinal endoscopy.Methods: Retrospective review of prospectively collected database of patients with history of RYGBP that had surgical gastrostomy for pancreatobiliary and duodenal access at a single institution from 2004-2008. Indication for procedure, surgical findings, successful cannulation, and complications are reported.Results: Thirty patients (25 female), with age ranging from 27 to 72, underwent 32 procedures. The indications to access the gastric remnant were sphincter of Oddi dysfunction (13), pancreatitis (six), common bile duct stone/obstruction (five), cholangitis (three), pancreatic mass evaluation (two), gastrointestinal bleed (two), and cystic duct leak after cholecystectomy (one). Mean operative time was 200 min (98-338) and estimated blood loss (mean) 85 cc (10-500). Laparoscopic gastrostomy was attempted in 28 cases with one conversion to open (3.6%). Four planned open procedures were also performed. All 30 patients underwent successful endoscopy and 28 had an endoscopic retrograde cholangiopancreatography, all with successful cannulation of the pancreatobiliary tree (100%).Conclusions: Surgical gastrostomy is an effective means to gain access to the upper GI tract and pancreatobiliary tree following RYGBP. This technique should be considered when traditional endoscopic approaches are impossible. [ABSTRACT FROM AUTHOR]

Background: Guidelines for the current National Comprehensive Cancer Network recommend radical cholecystectomy, including hepatic resection and portal lymph node (LN) dissection, for patients with early stage gallbladder (GB) cancer. We sought to determine the survival benefit conferred by adequate LN evaluation. Methods: We used the surveillance, epidemiology and end results (SEER) neoplasm registry to identify patients who had an operation for GB cancer between 1988 and 2004. Patients were classified by stage of disease, operative procedure performed (cholecystectomy alone or radical resection), number of LNs evaluated (0, 1, >1), and receipt of radiation (RT). We included patients with T1B, T2, and T3 neoplasms who were LN positive or negative. Patients with T4 neoplasms and those with metastatic disease were excluded. Multivariate analysis included adjustment for age, race, sex, neoplasm grade, stage, operation performed, receipt of RT, and neoplasm registry. Results: We identified 4,614 patients who underwent operative treatment for stage 1–2B GB (including T1B–T3 and LN positive or negative) cancer between 1988 and 2004. Of 4,614 patients, 9.6% (442) had radical resection, whereas 90.4% (4,172) had cholecystectomy alone. Among patients undergoing radical resection, 56% had LNs evaluated as compared with 28% of patients after cholecystectomy. For patients with T1B and T2 neoplasms who underwent radical resection, pathologic evaluation of at least 1 LN was associated with a significant improvement in median overall survival (OS) compared with those who had no LN evaluated (123 months vs 22 months; P < .0001). Radical resection with no LN evaluation provided similar OS compared with cholecystectomy alone (22 months vs 23 months; P = NS). For patients with T3 neoplasms, radical resection, including pathologic evaluation of at least 1 LN, was also associated with improved OS compared with radical resection with no LN evaluation (12 months vs 7 months; P = .0014). Again, individuals who had radical resection without LN evaluation had similar OS compared with those who had cholecystectomy alone (7 months vs 6 months; P = NS). Individuals who had radical resection with LN evaluation were more likely to receive RT than those who had radical resection without LN evaluation (33.1% vs 19.1%; P = .002). In multivariate analysis (including adjustment for RT), however, LN evaluation was still associated with a decrease in mortality compared with no LN evaluated (HR = 0.611; 95% CI = 0.484, 0.770). The pathologic evaluation of additional LN (>1) did not provide any additional benefit compared with the evaluation of a single node (HR = 0.795; 95% CI = 0.571, 1.107). Radical resection alone (without LN evaluation) did not provide any benefit over cholecystectomy alone (HR = 1.098; 95% CI = 0.971, 1.241). Conclusion: LN evaluation is a critical component of radical resection for GB cancer. In the absence of LN evaluation, radical resection provides no benefit over cholecystectomy alone. [Copyright &y& Elsevier]

Background: Radical resection is recommended for selected patients with gallbladder (GB) cancer. We sought to determine whether radical resection improves survival for patients with early-stage cancer and to evaluate surgeon compliance with current treatment recommendations.Patients and Methods: Patients with stage 0, I, or II GB cancer who underwent surgical resection were identified from the Surveillance, Epidemiology, and End Results (SEER) tumor registry from 1988 through 2004. Patients were classified by surgical procedure performed (simple vs. radical resection) and adjuvant treatment given (radiation therapy [RT] vs. no RT). Unadjusted and adjusted overall survival (OS) and cancer-specific survival (CSS) were compared.Results: Of the 4,631 patients who underwent surgery for early-stage GB cancer from 1988 through 2004, 4,188 (90.4%) underwent cholecystectomy alone and 443 (9.6%) underwent radical surgery including hepatic resection. The proportion of patients having radical surgery for T1b, T2, and T3 cancers was 4.5%, 5.6%, and 16.3%, respectively. For patients with T1b/T2 cancer, radical resection was associated with significant improvement in adjusted CSS (p = 0.01) and OS (p = 0.03). For patients with T3 cancers, we noted no improvement in CSS or OS. Survival for patients with node-positive disease (stage 2b) was universally poor and not improved by radical resection. For all patients who underwent radical resection, node negativity, female sex, age <70, low grade, and RT predicted improved CSS and OS.Conclusions: Despite a significant survival advantage for patients with T1b/T2 GB cancer who undergo radical resection, this treatment is significantly underutilized. Ensuring delivery of recommended surgical treatment is vital to improving outcomes for patients with this disease. [ABSTRACT FROM AUTHOR]

The transcriptional activity of Runx2 is determined by associations with co-repressors including histone deacetylase 7 (HDAC7). We previously found that bone morphogenic protein 2 (BMP2) induces export of HDAC7 from the nucleus. In this study we demonstrate that BMP2 specifically stimulates redistribution of HDAC7 but not HDAC 4, 5, or 6. HDAC7 subcellular redistribution in mesenchymal cells requires Crm1-mediated nuclear export, is associated with increased HDAC7 serine phosphorylation, and requires conserved serines in the HDAC7 amino terminus. The protein kinase D (PKD) inhibitor Gö6976 blocked both basal and BMP2-directed HDAC7 nuclear export. Protein kinase D1 (PKD1) associated with HDAC7 in a BMP2-enhanced manner, and a constitutively active form of PKD1 stimulated HDAC7 nuclear export. Furthermore, active PKD1 inhibited repression of Runx2-mediated transcription by HDAC7. Suppression of HDAC7 was not sufficient to rescue BMP2 induction of osteoblast marker genes in Gö6976-treated cells, indicating that PKD-dependent factors beyond attenuation of HDAC7-repressive activity are required for osteoblast differentiation. These results establish a novel pathway by which BMP signaling regulates Runx2 activity via PKD-dependent inhibition of HDAC7 transcriptional repression. [ABSTRACT FROM AUTHOR]

Abstract: Background: Pancreatic cancer cells express different mutations that increase the aggressiveness and confer resistance to conventional chemotherapy and radiotherapy. Molecules that selectively bind and inhibit these mutations are effective in other solid tumors and are now emerging as a complementary therapy in pancreatic cancer. The objective of this review is to describe the effect of drugs that inhibit specific mutations present in pancreatic cancer with special emphasis on clinical trials. Data sources: We reviewed the English-language literature (MedLine) addressing the role of drugs that target mutations present in pancreatic cancer. Both preclinical and clinical studies were included. Conclusions: Preclinical evidence supports the combination of conventional approved therapies plus drugs that block epidermal growth factor receptor and vascular growth endothelial factor or induce apoptosis. However, most of the current clinical evidence is limited to small phase I trials evaluating the toxicity and safety of these regimens. The results of additional randomized trials that are still undergoing will clarify the role of these drugs in pancreatic cancer. [Copyright &y& Elsevier]

To investigate the role of bone morphogenetic protein (BMP) signaling in osteoclastogenesis in vivo, we eliminated BMPRII in osteoclasts by creating a BMPRIIfl/fl;lysM-Cre mouse strain. Conditional knock-out (cKO) mice are osteopetrotic when compared with WT controls due to a decrease in osteoclast activity. Bone marrow macrophages (BMMs) isolated from cKOmice are severely inhibited in their capacity to differentiate into mature osteoclasts in the presence of M-CSF and receptor activator of NF-κB (RANK) ligand. We also show that BMP noncanonical (MAPK) and canonical (SMAD) pathways are utilized at different stages of osteoclast differentiation. BMP2 induces p38 phosphorylation in pre-fusion osteoclasts and increases SMAD phosphorylation around osteoclast precursor fusion. Phosphorylation of MAPKs was decreased in differentiated BMMs from cKO animals. Treating BMMs with the SMAD inhibitor dorsomorphin confirms the requirement for the canonical pathway around the time of fusion. These results demonstrate the requirement for BMP signaling in osteoclasts for proper bone homeostasis and also explore the complex signaling mechanisms employed by BMP signaling during osteoclast differentiation. [ABSTRACT FROM AUTHOR]

Abstract: Patients with a first episode of schizophrenia generally have increased phospholipid membrane breakdown products within the brain, while findings in chronic patients have been inconsistent. In this study we examine progressive changes in phosphorus membrane metabolites in the same patient group through the early years of schizophrenia in brain regions associated with the disease. Sixteen never-treated and medicated first episode schizophrenic patients were assessed at 10months and 52months after diagnosis. Sixteen matched volunteers were assessed at baseline and after 35months. Phospholipid membrane metabolism was assessed with phosphorous magnetic resonance spectroscopy in the thalamus, cerebellum, hippocampus, anterior/posterior cingulate, prefrontal cortex, parieto-occipital cortex, superior temporal gyrus and temporal pole. At 10months, glycerophosphocholine was increased in the anterior cingulate in patients as compared to controls. Glycerophosphocholine was decreased in the anterior cingulate and increased in the posterior cingulate and left superior temporal gyrus; glycerophosphoethanolamine was decreased in the left thalamus and increased in the left hippocampus within patients over time. At 52months, compared to controls phosphocholine was increased in the left thalamus and glycerophosphoethanolamine was increased in the left hippocampus. These results imply a gradual inclusion of brain regions in schizophrenia where an initial increase, followed by a decrease in phospholipid membrane metabolites was observed. This pattern, observed in the early years of schizophrenia, is consistent with excitotoxic neural membrane breakdown in these regions. [Copyright &y& Elsevier]

The physiological demands of pregnancy inevitably result in changes of both biochemical and hematological parameters as the fetus develops. Alterations in blood parameters have been observed to shift according to both trimester and species, to support fetal physiological needs and maternal basal requirements. Establishing normal reference ranges for each stage in gestation is important to facilitate diagnosis of underlying health concerns and prevent over-diagnosing abnormalities. Despite bottlenose dolphins (Tursiops truncatus) being one of the most highly studied cetaceans, the blood profile changes occurring as a result of pregnancy have not been previously described. A retrospective analysis was performed from blood samples obtained from 42 successful pregnancies from 20 bottlenose dolphins in a managed population over 30 years. Samples were compared to non-pregnant states and among trimesters of pregnancy. Blood profile fluctuations occurred throughout gestation, however significant alterations predominantly occurred between the 2nd and 3rd trimester. Hematological changes from the 2nd to the 3rd trimester included a decrease in lymphocytes, decrease in platelet count, and hemoconcentration with increased hematocrit and hemoglobin. Biochemical changes in the 3rd trimester included significant reductions in ALKP (alkaline phosphatase), ALT (alanine aminotransferase) and AST (aspartate aminotransferase) with significant increases observed in albumin, globulins, total protein, cholesterol, triglycerides and CO 2. It's important to note that despite significant shifts occurring between the 2nd and 3rd trimester, there was no significant change in platelets, hematocrit, hemoglobin, lymphocytes or CO 2 between non-pregnant and 3rd trimester blood samples. The normal reference ranges for each trimester established herein, will enable future identification of abnormalities occurring during pregnancy and help improve our understanding of factors potentially influencing a failed or successful pregnancy outcome. • HCT, HGB, RBC normally increase significantly during 3rd trimester. • Total WBC should remain consistent throughout all three trimesters. • Inflammatory hemogram of ALKP decreasing significantly in 3rd trimester is expected. • Total protein, albumin and globulins increase consistently throughout gestation. [ABSTRACT FROM AUTHOR]

• A large number of host proteins changes were observed during aspergillosis in dolphins. • 106 proteins were dramatically increased or decreased during aspergillosis in dolphins. • prepronociceptin; protamine P1, MHC and NADPH-ubiquinone oxido-reductases were mostly involved. • iTRAQ® is a valuable mass spectrometry technique to address proteins identification and their relative changes between distinct samples. Aspergillosis is a fungal infection caused by Aspergillus molds that can affect both humans and animals. Despite advances in diagnostics and therapy, medical management of this disease remains difficult. Expansion of the basic knowledge regarding its pathophysiology in animals is critical to aid in the identification of new biomarkers of infection for diagnosis and therapeutic targets. For such a purpose, proteomics can be used by addressing protein changes during various disease processes. In the present study, a mass spectrometry analysis based on isobaric tagging for relative and absolute quantitation (iTRAQ®) was applied for direct identification and relative quantitation of proteins in blood collected from 32 Aspergillus -diseased common bottlenose dolphins (Tursiops truncatus , 32 samples) in comparison with blood from 55 other dolphins (55 samples from 41 clinically-normal controls and from 14 cetaceans with miscellaneous non- Aspergillus inflammation diseases) and ten convalescent dolphins (28 samples). Sixty-six and 40 proteins were found to be ≥2.0-fold over- and underrepresented versus miscellaneous non- Aspergillus inflammatory dolphins, respectively, and most were confirmed vs. clinically-normal controls and convalescents. Many proteins which play a role in the adaptive immune response were identified, including MHC proteins and others involved in catalytic activity like the NADPH-ubiquinone oxido-reductases. Overall, iTRAQ® appears to be a convenient proteomic tool greatly suited for exploratory ex vivo studies focusing on pathophysiology. This technique should be considered as a preliminary step before validation of new diagnostic markers. [ABSTRACT FROM AUTHOR]

Abstract Background Nodal positivity is a predictor of poor survival following resection for intrahepatic cholangiocarcinoma (ICC). The aim of this study was to evaluate the impact of surgical resection on survival in patients with lymph node (LN) positive ICC. Methods An augmented version of the Surveillance, Epidemiology, and End Results program database was utilized to identify patients with LN-positive ICC without distant metastases from 2000 to 2014. Patients were stratified by treatment: chemotherapy alone or surgical resection with/without chemotherapy. Survival was evaluated using Kaplan–Meier and Cox proportional hazard models. Results 169 patients who underwent treatment for LN-positive ICC were identified. 88% underwent surgical resection and 12% underwent chemotherapy alone. The median survival for patients who underwent surgical resection was not different from patients treated with chemotherapy alone (19 months 95% Confidence Interval (CI) 17–33 versus 20 months CI 10–27, p = 0.323). A cox-proportional hazard ratio model demonstrated that black race was associated with worse survival (p < 0.05), while surgical resection was not independently associated with survival. Conclusion Surgical resection for patients with LN-positive ICC may not improve survival compared to chemotherapy alone. Pathologic LN evaluation should be performed prior to surgical resection, to improve patient selection and ensure receipt of optimal therapy. [ABSTRACT FROM AUTHOR]

Study Objective: The purpose of this study was to compare the efficacy of bilateral ultrasound guided thoracic paravertebral catheters to a thoracic epidural after open pancreatic surgery.Design: This was a prospective non-blinded randomized controlled trial.Setting: Academic hospital operating room, postoperative recovery area, and ward.Patients: 53 patients aged 18 and above who had open pancreatic surgery.Interventions: Patients received either bilateral thoracic paravertebral block at T8 with an infusion of 0.2% ropivacaine or thoracic epidural analgesia at T7/8 with an infusion of 0.125% bupivacaine with hydromorphone 6 μg/mL.Measurements: Pain scores, opioid use, length of recovery room and hospital stay, adverse events, and incidence of nausea and vomiting.Main Results: There was no difference in baseline demographics between the two groups. There were no significant differences in pain scores between the two groups in each of the first five days after surgery. There was no difference in length of stay nor nausea and vomiting. There was significantly less modality related adverse events in the paravertebral group compared to the epidural group (p = 0.02).Conclusions: The use of thoracic paravertebral catheters provided comparable analgesia and less modality related adverse events when compared to a thoracic epidural in patients undergoing open pancreaticoduodenectomy. [ABSTRACT FROM AUTHOR]

Studies using kinase inhibitors have shown that the protein kinase D (PRKD) family of serine/threonine kinases are required for formation and function of osteoclasts in culture. However, the involvement of individual protein kinase D genes and their in vivo significance to skeletal dynamics remains unclear. In the current study we present data indicating that protein kinase D3 is the primary form of PRKD expressed in osteoclasts. We hypothesized that loss of PRKD3 would impair osteoclast formation, thereby decreasing bone resorption and increasing bone mass. Conditional knockout (cKO) of Prkd3 using a murine Cre/Lox system driven by cFms-Cre revealed that its loss in osteoclast-lineage cells reduced osteoclast differentiation and resorptive function in culture. Examination of the Prkd3 cKO mice showed that bone parameters were unaffected in the femur at 4 weeks of age, but consistent with our hypothesis, Prkd3 conditional knockout resulted in 18 % increased trabecular bone mass in male mice at 12 weeks and a similar increase at 6 months. These effects were not observed in female mice. As a further test of our hypothesis, we asked if Prkd3 cKO could protect against bone loss in a ligature-induced periodontal disease model but did not see any reduction in bone destruction in this system. Together, our data indicate that PRKD3 promotes osteoclastogenesis both in vitro and in vivo. • Protein kinase D3 is the major isoform of protein kinase D expressed in osteoclasts • Deletion of Prkd3 in osteoclasts inhibited their differentiation and resorptive function in culture • Prkd3 conditional knockout altered osteoclast morphology and increased trabecular bone mass specifically in male cKO mice at 12 weeks and 6 months [ABSTRACT FROM AUTHOR]

Purpose: Guidelines regarding the prevention, detection, and management of surgical site infections (SSI) have been published previously.(1-3) This document is intended to update prior guidelines based on the current literature and to provide a concise summary of relevant topics. [ABSTRACT FROM AUTHOR]