Epidermal proteomics demonstrates Elafin as a psoriasis-specific biomarker and highlights increased anti-inflammatory activity around psoriatic plaques.

BACKGROUND: Eczema and psoriasis are common diseases. Despite both showing active epidermal contribution to the inflammatory process, their molecular aetiology and pathological mechanisms are different. OBJECTIVE: Further molecular insight into these differences is therefore needed to enable effective future diagnostic and treatment strategies. The majority of our mechanistic and clinical understanding of psoriasis and eczema is derived from RNA, immunohistology and whole skin biopsy data. METHODS: In this study, non-invasive epidermal sampling of lesional, perilesional and non-lesional skin from diseased and healthy skin was used to perform an in depth proteomic analysis of epidermal proteins. RESULTS: Our findings confirmed the psoriasis-associated cytokine IL-36γ as an excellent protein biomarker for lesional psoriasis. However, ELISA and ROC curve analysis of 53 psoriasis and 42 eczema derived samples showed that the sensitivity and specificity were outperformed by elastase-specific protease inhibitor, elafin. Of note, elafin was also found upregulated in non-lesional psoriatic skin at non-predilection sites demonstrating inherent differences between the non-involved skin of healthy and psoriatic individuals. Mass spectrometry and ELISA analysis also demonstrated the upregulation of the anti-inflammatory molecule IL-37 in psoriatic perilesional but not lesional skin. The high expression of IL-37 surrounding psoriatic plaque may contribute to the sharp demarcation of inflammatory morphology changes observed in psoriasis. This finding was also specific for psoriasis and not seen in atopic dermatitis or autoimmune blistering perilesional skin. Our results confirm IL-36γ and add elafin as robust, hallmark molecules distinguishing psoriasis and eczema-associated inflammation even in patients under systemic treatment. CONCLUSIONS: Overall, these findings highlight the potential of epidermal non-invasive sampling and proteomic analysis to increase our diagnostic and pathophysiologic understanding of skin diseases. Moreover, the identification of molecular differences in healthy-looking skin between patients and healthy controls highlights potential disease susceptibility markers and proteins involved in the initial stages of disease.

Targeting lactate dehydrogenase B-dependent mitochondrial metabolism affects tumor initiating cells and inhibits tumorigenesis of non-small cell lung cancer by inducing mtDNA damage.

Once considered a waste product of anaerobic cellular metabolism, lactate has been identified as a critical regulator of tumorigenesis, maintenance, and progression. The putative primary function of lactate dehydrogenase B (LDHB) is to catalyze the conversion of lactate to pyruvate; however, its role in regulating metabolism during tumorigenesis is largely unknown. To determine whether LDHB plays a pivotal role in tumorigenesis, we performed 2D and 3D in vitro experiments, utilized a conventional xenograft tumor model, and developed a novel genetically engineered mouse model (GEMM) of non-small cell lung cancer (NSCLC), in which we combined an LDHB deletion allele with an inducible model of lung adenocarcinoma driven by the concomitant loss of p53 (also known as Trp53) and expression of oncogenic KRAS (G12D) (KP). Here, we show that epithelial-like, tumor-initiating NSCLC cells feature oxidative phosphorylation (OXPHOS) phenotype that is regulated by LDHB-mediated lactate metabolism. We show that silencing of LDHB induces persistent mitochondrial DNA damage, decreases mitochondrial respiratory complex activity and OXPHOS, resulting in reduced levels of mitochondria-dependent metabolites, e.g., TCA intermediates, amino acids, and nucleotides. Inhibition of LDHB dramatically reduced the survival of tumor-initiating cells and sphere formation in vitro, which can be partially restored by nucleotide supplementation. In addition, LDHB silencing reduced tumor initiation and growth of xenograft tumors. Furthermore, we report for the first time that homozygous deletion of LDHB significantly reduced lung tumorigenesis upon the concomitant loss of Tp53 and expression of oncogenic KRAS without considerably affecting the animal's health status, thereby identifying LDHB as a potential target for NSCLC therapy. In conclusion, our study shows for the first time that LDHB is essential for the maintenance of mitochondrial metabolism, especially nucleotide metabolism, demonstrating that LDHB is crucial for the survival and proliferation of NSCLC tumor-initiating cells and tumorigenesis.

Efficacy of Coral Sand for Removal of and Bacteriophage under Saturated Flow Conditions.

Knowledge of how effectively microbes are transported through porous media is useful for water resource/wastewater management. Despite much research having been done to characterize microbial contaminant transport through various sedimentary materials, very little study has been made on coral sand, such as constitutes the primary substrate of many Pacific atolls. We conducted a set of laboratory column experiments as a preliminary examination of how effective coral sand is at attenuating model pathogens J6-2 and MS2 bacteriophage (phage) under saturated flow conditions mildly representative of field conditions at the Bonriki freshwater lens, South Tarawa, Kiribati. The very poorly sorted gravelly sand coral substrate tested proved very effective at attenuating the bacterial tracer, and spatial removal rates of between 0.02 and 0.07 log cm were determined for J6-2. The ability to determine precise removal rates for MS2 phage was compromised by the use of a plastic apparatus, although the evidence weights toward coral sand being less effective at attenuating MS2 phage than it is . Further research is required to fully assess the ability of coral sand to remove pathogens and to explore how this medium could be engineered into cost-effective water/wastewater treatment solutions on Pacific atolls. The phage data from this work highlight the limitations of using plastic apparatus in experiments targeted at characterizing the fate and transport of viruses.

Randomized Controlled Trial of Thresholds for Drain Removal After Anatomic Lung Resection.

BACKGROUND: The criteria for chest drain removal after lung resections remain vague and rely on personal experience instead of evidence. Because pleural fluid resorption is proportional to body weight, a weight-related approach seems reasonable. We examined the feasibility of a weight-adjusted fluid output threshold concerning postoperative respiratory complications and the occurrence of symptomatic pleural effusion after chest drain removal. Our secondary objectives were the hospital length of stay and pain levels before and after chest drain removal. METHODS: This was a single-center randomized controlled trial including 337 patients planned for open or thoracoscopic anatomical lung resections. Patients were randomly assigned postoperatively into 2 groups. The chest drain was removed in the study group according to a fluid output threshold calculated by the 5 mL × body weight (in kg)/24 hours formula. In the control group, our previous traditional fluid threshold of 200 mL/24 hours was applied. RESULTS: No differences were evident regarding the occurrence of pleural effusion and dyspnea at discharge and 30 days postoperatively. In the logistic regression analysis, the surgical modality was a risk factor for other complications, and age was the only variable influencing postoperative dyspnea. Time to chest drain removal was identical in both groups, and time to discharge was shorter after open surgery in the test group. CONCLUSIONS: No increased postoperative complications occurred with this weight-based formula, and a trend toward earlier discharge after open surgery was observed in the test group.

Thoracic Outlet Syndrome: Single Center Experience on Robotic Assisted First Rib Resection and Literature Review.

Background: Thoracic outlet syndrome (TOS) is a pathological condition caused by a narrowing between the clavicle and first rib leading to a compression of the neurovascular bundle to the upper extremity. The incidence of TOS is probably nowadays underestimated because the diagnosis could be very challenging without a thorough clinical examination along with appropriate clinical testing. Beside traditional supra-, infraclavicular or transaxillary approaches, the robotic assisted first rib resection has been gaining importance in the last few years. Methods: We conducted a retrospective cohort analysis of all patients who underwent robotic assisted first rib resection due to TOS at Lucerne Cantonal Hospital and then we performed a narrative review of the English literature using PubMed, Cochrane Database of Systematic Reviews and Scopus. Results: Between June 2020 and November 2021, eleven robotic assisted first rib resections were performed due to TOS at Lucerne Cantonal Hospital. Median length of stay was 2 days (Standard Deviation: +/- 0.67 days). Median surgery time was 180 min (Standard Deviation: +/- 36.5). No intra-operative complications were reported. Conclusions: Robotic assisted first rib resection could represent a safe and feasible option in expert hands for the treatment of thoracic outlet syndrome.

Robotic vs. Transsternal Thymectomy: A Single Center Experience over 10 Years.

INTRODUCTION: Thymomas are the most common tumors of the mediastinum. Traditionally, thymectomies have been performed through a transsternal (TS) approach. With the development of robot-assisted thoracic surgery (RATS), a promising, minimally invasive, alternative surgical technique for performing a thymectomy has been developed. In the current paper, the oncological and surgical outcomes of the TS vs. RATS thymectomies are discussed. METHODS: For the RATS thymectomy, two 8 mm working ports and one 12 mm camera port were used. In the transsternal approach, we performed a median sternotomy and resected the thymic tissue completely, in some cases en bloc with part of the lung and/or, more frequently, a partial pericardiectomy with consequent reconstruction using a bovine pericardial patch. The decisions for using the TS vs. RATS methods were mainly based on the suspected tumor invasion of the surrounding structures on the preoperative CT scan and tumor size. RESULTS: Between January 2010 and November 2020, 149 patients were submitted for an anterior mediastinal tumor resection at our institution. A total of 104 patients met the inclusion criteria. One procedure was performed through a hemi-clamshell incision. A total of 81 (78%) patients underwent RATS procedures, and 22 (21.1%) patients were treated using a transsternal (TS) tumor resection. Thymoma was diagnosed in 53 (51%) cases. In the RATS group, the median LOS was 3.2 ± 2.8 days and the median tumor size was 4.4 ± 2.37 cm compared to the TS group, which had a median LOS of 9 ± 7.3 days and a median tumor size of 10.4 ± 5.3 cm. Both differences were statistically significant (p < 0.001). Complete resection was achieved in all patients. CONCLUSION: While larger and infiltrating tumors (i.e., thymic carcinomas) were usually resected via a sternotomy, the RATS procedure is a good alternative for the resection of thymomas of up to 9.5 cm, and the thymectomy is a strong approach for myasthenia gravis. The oncological outcomes and survival rates were not influenced by the chosen approach.

Surgical Site Infections Are Associated With Higher Blood Loss and Open Access in General Thoracic Practice.

Background: Surgical site infections (SSIs) are the most costly and second most frequent healthcare-associated infections in the Western world. They are responsible for higher postoperative mortality and morbidity rates and longer hospital stays. The aim of this study is to analyze which factors are associated with SSI in a modern general thoracic practice. Methods: Data were collected from our department's quality database. Consecutive patients operated between January 2014 and December 2018 were included in this retrospective study. Results: A total of 2430 procedures were included. SSIs were reported in 37 cases (1.5%). The majority of operations were video-assisted (64.6%). We observed a shift toward video-assisted thoracic surgery in the subgroup of anatomical resections during the study period (2014: 26.7%, 2018: 69.3%). The multivariate regression analysis showed that blood loss >100 ml (p = 0.029, HR 2.70) and open surgery (p = 0.032, HR 2.37) are independent risk factors for SSI. The latter was higher in open surgery than in video-assisted thoracic procedures (p < 0.001). In the subgroup of anatomical resection, we found the same correlation (p = 0.043). SSIs are also associated with significantly longer mean hospital stays (17.7 vs. 7.8 days, p < 0.001). Conclusion: As SSIs represent higher postoperative morbidity and costs, efforts should be made to maintain their rate as low as possible. In terms of prevention of SSIs, video-assisted thoracic surgery should be favored over open surgery whenever possible.

Stage III N2 non-small cell lung cancer treatment: decision-making among surgeons and radiation oncologists.

BACKGROUND: Stage III N2 non-small cell lung cancer (NSCLC) is a very heterogeneous disease associated with a poor prognosis. A number of therapeutic options are available for patients with Stage III N2 NSCLC, including surgery [with neoadjuvant or adjuvant chemotherapy (CTx)/neoadjuvant chemoradiotherapy (CRT)] or CRT potentially followed by adjuvant immunotherapy. We have no clear evidence demonstrating a significant survival benefit for either of these approaches, the selection between treatments is not always straightforward and can come down to physician and patient preference. The very heterogeneous definition of resectability of N2 disease makes the decision-making process even more complex. METHODS: We evaluated the treatment strategies for preoperatively diagnosed stage III cN2 NSCLC among Swiss thoracic surgeons and radiation oncologists. Treatment strategies were converted into decision trees and analysed for consensus and discrepancies. We analysed factors relevant to decision-making within these recommendations. RESULTS: For resectable "non-bulky" mediastinal lymph node involvement, there was a trend towards surgery. Numerous participants recommend a surgical approach outside existing guidelines as long as the disease was resectable, even in multilevel N2. With increasing extent of mediastinal nodal disease, multimodal treatment based on radiotherapy was more common. CONCLUSIONS: Both, surgery- or radiotherapy-based treatment regimens are feasible options in the management of Stage III N2 NSCLC. The different opinions reflected in the results of this manuscript reinforce the importance of a multidisciplinary setting and the importance of shared decision-making with the patient.

Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial.

RATIONALE: Sustained sepsis-associated immunosuppression is associated with uncontrolled infection, multiple organ dysfunction, and death. OBJECTIVES: In the first controlled biomarker-guided immunostimulatory trial in sepsis, we tested whether granulocyte-macrophage colony-stimulating factor (GM-CSF) reverses monocyte deactivation, a hallmark of sepsis-associated immunosuppression (primary endpoint), and improves the immunological and clinical course of patients with sepsis. METHODS: In a prospective, randomized, double-blind, placebo-controlled, multicenter trial, 38 patients (19/group) with severe sepsis or septic shock and sepsis-associated immunosuppression (monocytic HLA-DR [mHLA-DR] <8,000 monoclonal antibodies (mAb) per cell for 2 d) were treated with GM-CSF (4 microg/kg/d) or placebo for 8 days. The patients' clinical and immunological course was followed up for 28 days. MEASUREMENTS AND MAIN RESULTS: Both groups showed comparable baseline mHLA-DR levels (5,609 +/- 3,628 vs. 5,659 +/- 3,332 mAb per cell), which significantly increased within 24 hours in the GM-CSF group. After GM-CSF treatment, mHLA-DR was normalized in 19/19 treated patients, whereas this occurred in 3/19 control subjects only (P < 0.001). GM-CSF also restored ex-vivo Toll-like receptor 2/4-induced proinflammatory monocytic cytokine production. In patients receiving GM-CSF, a shorter time of mechanical ventilation (148 +/- 103 vs. 207 +/- 58 h, P = 0.04), an improved Acute Physiology and Chronic Health Evaluation-II score (P = 0.02), and a shorter length of both intrahospital and intensive care unit stay was observed (59 +/- 33 vs. 69 +/- 46 and 41 +/- 26 vs. 52 +/- 39 d, respectively, both not significant). Side effects related to the intervention were not noted. CONCLUSIONS: Biomarker-guided GM-CSF therapy in sepsis is safe and effective for restoring monocytic immunocompetence. Use of GM-CSF may shorten the time of mechanical ventilation and hospital/intensive care unit stay. A multicenter trial powered for the improvement of clinical parameters and mortality as primary endpoints seems indicated. Clinical trial registered with www.clinicaltrials.gov (NCT00252915).

A novel sternal closure technique with implants suitable for complex dehiscences.

A novel sternum stabilization implant system is presented in a complex clinical case with previous pseudarthroses. The authors used the advanced closure system Sternal Talon of KLS Martin group and arranged 1 double and 2 single implants in an atypical fashion to fit the patient's needs. One year later follow up has not revealed any recurrence of pain or pseudarthrotic signs such as crepitation.

Early inhibition of prostaglandin synthesis by n-3 fatty acids determinates histologic severity of necrotizing pancreatitis.

OBJECTIVE: Previously, we observed decreased histopathological severity of acute necrotizing pancreatitis (ANP) by parenteral nutrition with n-3 fatty acids. Thus, we now sequentially analyzed the impact of n-3 fatty acids on prostaglandin and leukotriene synthesis in ANP. METHODS: One hundred ninety-eight Sprague-Dawley rats (11 groups, n = 18) underwent intraductal glycodesoxycholat instillation and 6-hour cerulein infusion. Afterward, saline was infused in groups 2, 4, 6, 8, and 10, whereas groups 3, 5, 7, 9, and 11 received infusion rich in n-3 fatty acids (Omegaven, Fresenius Kabi, Bad Homburg, Germany). Animals were killed after 6 (group 1), 10 (groups 2 and 3), 14 (groups 4 and 5), 18 (groups 6 and 7), 22 (groups 8 and 9), and 26 hours (groups 10 and 11). The pancreas was histopathologically examined, and the pancreatic eicosanoid metabolism (prostaglandin E2, prostaglandin F1alpha [PGF1alpha], and leukotrienes) and lipid peroxidation (thiobarbituric acid-reactive substance, superoxide dismutase, and glutathione peroxidase) were analyzed. RESULTS: Between the 14th and 26th hours, histopathologic scores (edema, inflammation, bleeding, and necrosis) were reduced in the n-3 fatty acid group compared with the corresponding saline group. Pancreatic prostaglandin E2 and PGF1alpha were decreased between the 10th and 18th hour by n-3 fatty acids; PGF1alpha was reduced after 26 hours compared with the corresponding saline group. Lipid peroxidation was decreased by n-3 fatty acids after 14 hours (thiobarbituric acid-reactive substance); however, there was no difference concerning lipid peroxidation protective enzymes (glutathione peroxidase and superoxide dismutase). CONCLUSIONS: Parenteral therapy with n-3 fatty acids decreased histopathologic severity in ANP by early inhibition of prostaglandin (E2 and F1alpha) synthesis and reduction of lipid peroxidation.

Impact of taurolidin and octreotide on liver metastasis and lipid peroxidation after laparoscopy in chemical induced ductal pancreatic cancer.

BACKGROUND: There is controversial discussion whether metastasis initiated by laparoscopy with carbon dioxide might be prevented by instillation of taurolidin or radical scavengers like the somatostatin analogue Octreotide. Therefore we evaluated the effects of laparoscopic lavage with taurolidin and Octreotide on liver metastasis after staging laparoscopy in ductal pancreatic cancer. METHODS: In 60 Syrian hamsters pancreatic adenocarcinoma was induced by weekly subcutanous injection of 10 mg N-nitrosobis-2-oxopropylamin/kg body weight for 10 weeks. In the 16th week laparoscopic staging biopsy by use of carbon dioxide was performed. Finally animals underwent abdominal irrigation with saline (gr.1, n = 20), taurolidin (0.5%) (gr.2, n = 20) or Octreotide (gr.3, n = 20). In week 25 animals were sacrificed, pancreas and liver were analysed. RESULTS: Size of pancreatic carcinomas was decreased in the taurolidin gr. compared to the other two groups. Furthermore the number of liver metastasis per animal was reduced after lavage with taurolidin (2 +/- 2) and Octreotide (2.5 +/- 2) compared to saline irrigation (4 +/- 4) (p < 0.05). Additionally the incidence of port site metastases was significantly reduced in the taurolidin group. Activity of antioxidative enzyme superoxide dismutase (SOD) was increased while concentration of products of lipidperoxidation was decreased in non-metastatic liver after taurolidin irrigation compared to saline or Octreotide irrigation. CONCLUSIONS: Taurolidin irrigation during laparoscopy might be a new concept to reduce the number of liver metastasis and port site metastases in pancreatic cancer.

Effects of octreotide on lipid peroxidation in pancreas and plasma in acute hemorrhagic necrotizing pancreatitis in rats.

BACKGROUND: The therapeutic effects of octreotide in acute hemorrhagic necrotizing pancreatitis (ANP) have always been considered to be due to the inhibition of the exocrine pancreatic secretion in order to reduce pancreatic autodigestion. In this experimental study we analyzed whether octreotide has also antioxidative effects on acute pancreatitis. METHODS: 40 male Wistar rats were randomized into four groups (n = 10). Group 1 underwent a laparotomy. Groups 2-4 received an injection of natrium taurocholate into the pancreatic duct to induce acute pancreatitis. One hour later group 2 was injected 1 ml NaCl solution intraperitoneally, while groups 3 and 4 received 0.1 or 0.2 mg octreotide, respectively. The severity of ANP was examined histologically. The lipid peroxide level as well as the activity of glutathione peroxidase and superoxide dismutase were measured in plasma and pancreatic tissue samples. RESULTS: High-dose octreotide decreased the lipid peroxide level in plasma (2.1 +/- 0.53 vs. 4.69 +/- 1.35 nmol/l; p < 0.05) and pancreatic tissue samples 4.67 +/- 1.37 vs. 13.20 +/- 2.93 nmol/ml; p < 0.05) compared to the pancreatitis control group. Low-dose octreotide, however, did not reduce lipid peroxidation. CONCLUSION: Octreotide seems to have a dose-dependent antioxidative effect in natrium taurocholate-induced pancreatitis in rats.