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Supplementary Figure S1-9 and Supplementary Tables S1-8

Mutations in IFN and MHC signaling genes endow immunotherapy resistance. Patients with colorectal cancer infrequently exhibit IFN and MHC signaling gene mutations and are generally resistant to immunotherapy. In exploring the integrity of IFN and MHC signaling in colorectal cancer, we found that optineurin was a shared node between the two pathways and predicted colorectal cancer patient outcome. Loss of optineurin occurs in early-stage human colorectal cancer. Immunologically, optineurin deficiency was shown to attenuate IFNGR1 and MHC-I expression, impair T-cell immunity, and diminish immunotherapy efficacy in murine cancer models and patients with cancer. Mechanistically, we observed that IFNGR1 was S-palmitoylated on Cys122, and AP3D1 bound with and sorted palmitoylated IFNGR1 to lysosome for degradation. Unexpectedly, optineurin interacted with AP3D1 to prevent palmitoylated IFNGR1 lysosomal sorting and degradation, thereby maintaining IFNγ and MHC-I signaling integrity. Furthermore, pharmacologically targeting IFNGR1 palmitoylation stabilized IFNGR1, augmented tumor immunity, and sensitized checkpoint therapy. Thus, loss of optineurin drives immune evasion and intrinsic immunotherapy resistance in colorectal cancer.Significance:Loss of optineurin impairs the integrity of both IFNγ and MHC-I signaling pathways via palmitoylation-dependent IFNGR1 lysosomal sorting and degradation, thereby driving immune evasion and intrinsic immunotherapy resistance in colorectal cancer. Our work suggests that pharmacologically targeting IFNGR1 palmitoylation can stabilize IFNGR1, enhance T-cell immunity, and sensitize checkpoint therapy in colorectal cancer.See related commentary by Salvagno and Cubillos-Ruiz, p. 1623.This article is highlighted in the In This Issue feature, p. 1601

Colorectal cancer includes an invasive stem-like/mesenchymal subtype, but its genetic drivers, functional, and clinical relevance are uncharacterized. Here we report the definition of an altered miRNA signature defining this subtype that includes a major genomic loss of miR-508. Mechanistic investigations showed that this miRNA affected the expression of cadherin CDH1 and the transcription factors ZEB1, SALL4, and BMI1. Loss of miR-508 in colorectal cancer was associated with upregulation of the novel hypoxia-induced long noncoding RNA AK000053. Ectopic expression of miR-508 in colorectal cancer cells blunted epithelial-to-mesenchymal transition (EMT), stemness, migration, and invasive capacity in vitro and in vivo. In clinical colorectal cancer specimens, expression of miR-508 negatively correlated with stemness and EMT-associated gene expression and positively correlated with patient survival. Overall, our results showed that miR-508 is a key functional determinant of the stem-like/mesenchymal colorectal cancer subtype and a candidate therapeutic target for its treatment.Significance: These results define a key functional determinant of a stem-like/mesenchymal subtype of colorectal cancers and a candidate therapeutic target for its treatment. Cancer Res; 78(7); 1751–65. ©2018 AACR.

This file contains supplementary tables 1-7 and the main information was described as follows. Table S1. All primers for real time PCR assay. Table S2. Differentially expressed genes between mesenchymal subtype and other non stem-like. Table S3. microRNA in stem-like/EMT CRC patients. Table S4. Full list of the predicted targets for the four key miRNAs. Table S5. Clinical information of 90 cases CRC patients (Renji cohort 1). Table S6. Clinical information of 100 cases CRC patients (Renji cohort 2). Table S7. Clinical information of 128 cases CRC patients (European cohort).

It contains 5 figures and 3 tables

The expression and biological role of IL33 in colon cancer is poorly understood. In this study, we show that IL33 is expressed by vascular endothelial cells and tumor cells in the human colon cancer microenvironment. Administration of human IL33 and overexpression of murine IL33 enhanced human and murine colon cancer cell growth in vivo, respectively. IL33 stimulated cell sphere formation and prevented chemotherapy-induced tumor apoptosis. Mechanistically, IL33 activated core stem cell genes NANOG, NOTCH3, and OCT3/4 via the ST2 signaling pathway, and induced phosphorylation of c-Jun N terminal kinase (JNK) activation and enhanced binding of c-Jun to the promoters of the core stem cell genes. Moreover, IL33 recruited macrophages into the cancer microenvironment and stimulated them to produce prostaglandin E2, which supported colon cancer stemness and tumor growth. Clinically, tumor IL33 expression associated with poor survival in patients with metastatic colon cancer. Thus, IL33 dually targets tumor cells and macrophages and endows stem-like qualities to colon cancer cells to promote carcinogenesis. Collectively, our work reveals an immune-associated mechanism that extrinsically confers cancer cell stemness properties. Targeting the IL33 signaling pathway may offer an opportunity to treat patients with metastatic cancer. Cancer Res; 77(10); 2735–45. ©2017 AACR.

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This file contains methods which were not included in the main text.

Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO. Funding: German Research Foundation (DFG).

Objective The aim was to describe initial outcomes of physician modified stent grafts using antegrade laser fenestrations and image fusion guidance (LEVAR) and company manufactured custom made (CM) stent grafts for the treatment of complex abdominal aortic aneurysms (CAAAs), thoraco-abdominal aortic aneurysms (TAAAs) and type I endoleaks (T1ELs). Methods This was a retrospective single centre study. All LEVAR and Zenith (Cook) CM stent graft procedures between 1 January 2012 and 31 December 2018 were reviewed. Endpoints included intra-operative adverse events (IOAEs), in hospital mortality, re-interventions, target vessel patency, and 12 month outcomes (overall survival, freedom from re-intervention, target vessel patency). Outcomes at 12 months were estimated using the Kaplan–Meier method. Results A hundred patients were identified and included in the study. All patients were deemed unfit for open repair. The cohort included 22 LEVAR and 78 CM stent grafts. LEVAR cases included painful aneurysms (n = 5), > 65 mm aneurysms (n = 10), anatomical constrains and/or presence of previous renal stents (n = 7) or cases declined by the manufacturer planning centre (n = 2). IOAEs were recorded in 41% of cases (n = 9) in the LEVAR group vs. 10% (n = 8, p = .002) in the CM group. The in hospital mortality rate in the LEVAR group was 9% (n = 2) vs. 4% (n = 3, p = .30) in the CM group. The median follow up duration was 22 months (7 – 38) in the LEVAR group and 28 months (11 – 78) in the CM group. The estimate of overall survival at one year was 91% in both groups. The freedom from re-intervention rate at one year was 58% in the LEVAR group vs. 87% in the CM group. The target vessel patency rates at one year were 95% in both groups. Conclusion In high risk patients deemed unfit for open repair, LEVAR may provide satisfactory 12 month overall survival and target vessel patency rates, though reported IOAE, mortality, and re-interventions rates were high thus requiring close and extensive follow up.

The integration of photonic materials with semiconductor nanocrystals by correlating the photonic stopband and bandgap energy is expected to afford hybrid materials with enhanced optoelectronic properties. Here, we report two photonic crystal–perovskite nanocrystal microbead hybrids synthesized through simple vacuum drying techniques. Photonic polystyrene microbeads combined with metal halide perovskite nanocrystals yield hybrids with expected photoluminescence maxima when excited above the bandgap energy but unexpectedly high photoluminescence quantum yields (as high as 198 %). These microbead hybrid systems also demonstrated better resistance to degradation in water over 30 days of immersion as compared to their colloidal counterparts.

Dye-sensitized photoelectrochemical cells have emerged as a potential candidate for solar-to-fuels conversion. Herein, we report a Cu(I)-based donor-chromophore-acceptor triad comprising a triphenylamine electron donor and dipyrido[3,2-a:2',3'-c]phenazine electron acceptor as the active material for photoanodes. Energy levels of this triad are carefully aligned for thermodynamically favorable photoinduced electron transfer. Once this triad is surface grafted onto zinc oxide nanowires, photoelectrochemical studies confirm the utility of this architecture for oxidative processes such as alcohol oxidation with modest yields.

Gastric cancer remains one of the most commonly diagnosed cancers in the world, with a relatively high mortality rate. Due to the heterogeneous course of the disease, its diagnosis and treatment are limited and difficult, and it is associated with a reduced prognosis for patients. That is why it is so important to understand the mechanisms underlying the development and progression of this cancer, with particular emphasis on the role of risk factors. According to the literature data, risk factors include: changes in the composition of the stomach and intestinal microbiota (microbiological dysbiosis and the participation of Helicobacter pylori), improper diet, environmental and genetic factors, and disorders of the body’s immune homeostasis. Therefore, the aim of this review is to systematize the knowledge on the influence of human microbiota dysbiosis on the development and progression of gastric cancer, with particular emphasis on the role of the immune system in this process.

Mutations in IFN and MHC signaling genes endow immunotherapy resistance. Patients with colorectal cancer infrequently exhibit IFN and MHC signaling gene mutations and are generally resistant to immunotherapy. In exploring the integrity of IFN and MHC signaling in colorectal cancer, we found that optineurin was a shared node between the two pathways and predicted colorectal cancer patient outcome. Loss of optineurin occurs in early-stage human colorectal cancer. Immunologically, optineurin deficiency was shown to attenuate IFNGR1 and MHC-I expression, impair T-cell immunity, and diminish immunotherapy efficacy in murine cancer models and patients with cancer. Mechanistically, we observed that IFNGR1 was S-palmitoylated on Cys122, and AP3D1 bound with and sorted palmitoylated IFNGR1 to lysosome for degradation. Unexpectedly, optineurin interacted with AP3D1 to prevent palmitoylated IFNGR1 lysosomal sorting and degradation, thereby maintaining IFNγ and MHC-I signaling integrity. Furthermore, pharmacologically targeting IFNGR1 palmitoylation stabilized IFNGR1, augmented tumor immunity, and sensitized checkpoint therapy. Thus, loss of optineurin drives immune evasion and intrinsic immunotherapy resistance in colorectal cancer. Significance: Loss of optineurin impairs the integrity of both IFNγ and MHC-I signaling pathways via palmitoylation-dependent IFNGR1 lysosomal sorting and degradation, thereby driving immune evasion and intrinsic immunotherapy resistance in colorectal cancer. Our work suggests that pharmacologically targeting IFNGR1 palmitoylation can stabilize IFNGR1, enhance T-cell immunity, and sensitize checkpoint therapy in colorectal cancer. See related commentary by Salvagno and Cubillos-Ruiz, p. 1623. This article is highlighted in the In This Issue feature, p. 1601

The unique and broadly applicable optoelectronic properties of metal-halide perovskite materials are determined by structural dimensionality. Conversion of scaffold supported carbonate salts to perovskite with microstructure retention has previously been shown to act as a gateway to unique morphologies. In the present work, calcium carbonate microstructures are electrochemically deposited on a transparent conducting oxide substrate. Through a series of ion-exchange reactions the microstructures are decorated with a layer of surface localized perovskite nanocrystals, indicating that this ion exchange process occurs at the microstructure surface. Throughout the conversion process, electron microscopy confirms that the microstructures retain their overall morphology while cubic perovskite nanocrystals exhibiting characteristic photoluminescence and photoblinking are formed at the interface. This work confirms a synthetic pathway in which perovskites can be made in shapes previously inaccessible, which may lead to enhanced optoelectronic properties.

In the paper a second order differential system with a periodic boundary data is considered. Using some variational methods sufficient conditions for the continuous dependence of trajectories on controls are proved. The obtained results are applied then to the optimal control problem governed by the above system and the cost functional of a Bolza-type. In the end of the paper, an example of periodic optimal control problem demonstrating the applicability of the results is presented.

Photochemical splitting of H2O to H2 and O2 is one approach to generate "solar fuels." Cu(II)-based electrocatalysts for water oxidation in aqueous solution have been studied previously, but photodriving these systems still remains a challenge. Light harvesting units can be employed for this purpose, that upon photoexcitation generate a high energy excited state and give rise to a charge separated state. In this work, a bis-diimine Cu(I)-based donor-chromophore-acceptor (D-C-A) system is synthesized, characterized, and applied as the light harvesting component of a photoanode. Here, this molecular assembly was integrated onto a zinc oxide (ZnO) nanowire surface on a fluorine-doped tin oxide (FTO) glass slide. Upon photoexcitation, chronoamperometric studies reveal that the integrated triad can inject electrons directly into the conduction band of zinc oxide generating oxidizing equivalents that are then transferred to a Cu(II) water oxidation catalyst in aqueous solution yielding O2 from H2O with a Faradaic efficiency of 76%.

A continuous nonlinear Fornasini–Marchesini system of fractional order with nonzero initial conditions is considered. The existence, uniqueness and continuous dependence of solutions on functional parameters are studied. Some results concerning single and mixed fractional derivatives of functions of two variables are presented.

Introduction. Over time, endovascular techniques of abdominal aortic aneurysm repair became the principal methods of treatment of this potentially fatal disease. Currently, endovascular aneurysm repair (EVAR) constitutes an effective alternative to open surgery, also in cases of aneurysm rupture. Low degree of invasiveness is the main advantage of this method. Introduction of a system enabling percutaneous stent-graft implantation appears to be the next step in the development of endovascular AAA surgery. Aim of the study is to evaluate the Prostar XL® closure device with regard to clinical effectiveness, safety, cost-effectiveness. Material and methods. The study included 100 patients (from January 2013 to December 2015) subject to endovascular abdominal aortic aneurysm repair in the infrarenal region of the aorta with the application of the Prostar Xl® closure device. Most patients were operated under epidural anaesthesia. Local anaesthesia (1% Lidocaine) was used in 36 patients due to comorbidities. A possible application of the closure system depended on a preoperative assessment of common femoral arteries using ultrasonography. Presence of atherosclerotic plaque on the anterior wall of the vessel disqualified the patient from percutaneous endovascular aneurysm repair (PEVAR). The main part of the procedure consisted of stent-graft implantation into the abdominal aortic aneurysm. In the final stage, puncture site on the anterior wall of common femoral arteries was closed using previously placed sutures of the Prostar XL system. The wound in the inguinal region was closed with a skin suture. Results. The analysis of obtained results demonstrated significantly shorter mean hospitalization times in patients treated with PEVAR compared to EVAR. Low rates and types of observed complications in the study group (PEVAR) compared to the control group (EVAR) are strongly in favour the percutaneous technique (PEVAR) of endovascular aortic abdominal aneurysm repair in the infrarenal region of the aorta, confirming its minimally invasive character.

Introduction Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) function as an immune checkpoint pathway that can be exploited by tumor cells to evade immuno-surveillance. The precise role of PD-1/PD-L1 inhibition of the immune response in GC is unknown. The study investigated PD-1 and PD-L1 expression on peripheral T-cells and its potential association with clinicopathological features in gastric cancer (GC) patients. Material and methods PD-1/PD-L1 expression on CD4(+) and CD8(+) T-cells from peripheral blood of 40 patients primarily diagnosed with advanced GC was evaluated by multicolor flow cytometry. Results The frequency of CD4(+)PD-1(+) and CD8(+)PD-1(+) cells in GC patients was higher than in the control group (p < 0.0001 and p < 0.01, respectively). Expression of PD-1 on CD8(+) cells in GC was higher than in the control group (p < 0.0001). The frequency of CD4(+)PD-L1(+) and CD8(+)PD-L1(+) cells was higher than in the control group (p < 0.0001). Expression of PD-L1 on CD4(+) and CD8(+) cells in GC was higher than in the control group (p < 0.0001). A higher frequency of CD4(+)PD-1(+) cells was found in diffuse-type compared to intestinal tumors (p < 0.029). A higher frequency of CD8(+)PD-1(+) cells was found in patients with poorly differentiated compared to well/moderately differentiated tumors (p < 0.019). Conclusions Downregulation of peripheral blood CD4(+) and CD8(+) lymphocytes can be associated with PD-1/PD-L1 expression. This can lead to attenuation of the general immune response in GC.

The expression and biological role of IL33 in colon cancer is poorly understood. In this study, we show that IL33 is expressed by vascular endothelial cells and tumor cells in the human colon cancer microenvironment. Administration of human IL33 and overexpression of murine IL33 enhanced human and murine colon cancer cell growth in vivo, respectively. IL33 stimulated cell sphere formation and prevented chemotherapy-induced tumor apoptosis. Mechanistically, IL33 activated core stem cell genes NANOG, NOTCH3, and OCT3/4 via the ST2 signaling pathway, and induced phosphorylation of c-Jun N terminal kinase (JNK) activation and enhanced binding of c-Jun to the promoters of the core stem cell genes. Moreover, IL33 recruited macrophages into the cancer microenvironment and stimulated them to produce prostaglandin E2, which supported colon cancer stemness and tumor growth. Clinically, tumor IL33 expression associated with poor survival in patients with metastatic colon cancer. Thus, IL33 dually targets tumor cells and macrophages and endows stem-like qualities to colon cancer cells to promote carcinogenesis. Collectively, our work reveals an immune-associated mechanism that extrinsically confers cancer cell stemness properties. Targeting the IL33 signaling pathway may offer an opportunity to treat patients with metastatic cancer. Cancer Res; 77(10); 2735–45. ©2017 AACR.

In the paper we consider a nonlinear control system governed by the Volterra integral operator. Using a version of the global implicit function theorem we prove that the control system under consideration is well-posed and robust, i.e. for any admissible control \(u\) there exists a uniquely defined trajectory \(x_{u}\) which continuously depends on control \(u\) and the operator \(u\mapsto x_{u}\) is continuously differentiable. The novelty of this paper is, among others, the application of the Bielecki norm in the space of solutions which allows us to weaken standard assumptions.

Visible light photosensitization of metal oxides to create heterostructures for the conversion of solar-to-chemical energy is a promising approach to produce solar fuels and other valuable chemicals. Carbon dots have recently been considered as suitable candidates to sensitize wide bandgap metal oxide semiconductors due to their low cost and tunable optical properties. While photocatalytic systems using carbon dots as sensitizers have been reported, transformations involving the production of value-added chemicals as well as the electron transfer mechanisms underpinning photocatalysis within such heterostructures remain underexplored. Here we report the sensitization of zinc oxide nanowires with carbon dots for the α-heteroarylation of 1-phenylpyrrolidine with 2-chlorobenzothiazole under visible light illumination at room temperature. The carbon dots improve the light absorption of the nanowires in the visible region of the spectrum affording the use of white light to drive catalysis. From optical spectroscopy and electrochemistry investigations of the resulting nanohybrid material, the photocatalytic properties are explained by the band alignment at the zinc oxide-carbon dot junction where a series of single-electron transfers creates the necessary potential to oxidize 1-phenylpyrrolidine. The resulting cascade of electron transfers into and from the carbon dots drives the α-heteroarylation to a 97% yield after 24 hrs.

Background We report a case of juxtarenal abdominal aortic aneurysm—anatomically unsuitable for conventional endovascular repair because of narrow distal aorta—successfully treated by endovascular repair facilitated by in situ laser fenestration. Methods and results An aortic stent graft was inserted to exclude a juxtarenal aneurysm: under image fusion guidance, antegrade in situ laser fenestration allowed to perfuse superior mesenteric artery and both renal arteries. After complementary insertion of an extended aortouni-iliac stent graft, retrograde in situ laser fenestration was performed to perfuse the contralateral left iliac artery, in order to overcome a narrow distal aorta. Postoperative course was uneventful. Six month's CT showed an excluded aneurysm, patency of the inserted stents and the absence of endoleak. Conclusions In situ laser fenestration seems to be an effective solution for endovascular therapy of complex juxtarenal aneurysms. In this case of narrow distal aorta it was a suitable alternative to overcome endovascular aneurysm repair anatomical restrictions and to prevent other additional open surgical interventions.

W artykule przedstawiono problem integracji muzułmanów oraz konsekwencje współczesnego kryzysu migracyjnego jako wyzwań, które stoją przed niemiecką i europejską dyplomacją. W odniesieniu do teoretycznych rozważań, przedstawiono koncepcje i modele polityki integracyjnej prowadzonej przez państwa zachodnioeuropejskie w warunkach przed kryzysem i obecnie. W opracowaniu zawarto krótki zarys historii napływu muzułmanów do Niemiec oraz procesy związane z ich integracją w tymże państwie. Przedstawiono także główne cechy obecnego kryzysu, wskazując na wyzwania, jakie niesie dla całej Unii Europejskiej, a w szczególności dla Niemiec jako kraju najbardziej zaangażowanego w proces przyjmowania uchodźców i imigrantów. Zwrócono uwagę na podstawowe problemy, z jakimi wiąże się przyjęcie migrantów; zarówno problemy wewnętrzne, jak i międzynarodowe. Podkreślono także kontekst polityczny, poparcie społeczeństwa dla rządzących oraz zagrożenia, jakie niesie kryzys migracyjny.

In the paper, a Lagrange optimal control problem governed by a fractional Dirichlet problem with the Riemann---Liouville derivative is considered. To begin with, based on some variational method, the existence and continuous dependence of solution to the aforementioned Dirichlet problem is investigated. Then, continuous dependence is applied to show the existence of optimal solution to the Lagrange problem. An important point is that the solution to Dirichlet problem does need to be unique; therefore, the above dependence should be understood as a continuity of some multifunction--the concept of the Kuratowski---Painleve limit of the sequence of sets is used to formulate this property.

This article is published with open access at Springerlink.com In the paper the optimization problem described by some nonlinear hyperbolic equation being continuous counterpart of the Fornasini-Marchesini model is considered. A theorem on the existence of at least one solution to this hyperbolic PDE is proved and some properties of the set of all solutions are established. The existence of a solution to an optimization problem under appropriate assumptions is themain result of this paper. Some application of the obtained results to the process of gas filtration is also presented.

Colorectal cancer includes an invasive stem-like/mesenchymal subtype, but its genetic drivers, functional, and clinical relevance are uncharacterized. Here we report the definition of an altered miRNA signature defining this subtype that includes a major genomic loss of miR-508. Mechanistic investigations showed that this miRNA affected the expression of cadherin CDH1 and the transcription factors ZEB1, SALL4, and BMI1. Loss of miR-508 in colorectal cancer was associated with upregulation of the novel hypoxia-induced long noncoding RNA AK000053. Ectopic expression of miR-508 in colorectal cancer cells blunted epithelial-to-mesenchymal transition (EMT), stemness, migration, and invasive capacity in vitro and in vivo. In clinical colorectal cancer specimens, expression of miR-508 negatively correlated with stemness and EMT-associated gene expression and positively correlated with patient survival. Overall, our results showed that miR-508 is a key functional determinant of the stem-like/mesenchymal colorectal cancer subtype and a candidate therapeutic target for its treatment. Significance: These results define a key functional determinant of a stem-like/mesenchymal subtype of colorectal cancers and a candidate therapeutic target for its treatment. Cancer Res; 78(7); 1751–65. ©2018 AACR.

Introduction Gastric cancer (GC) is one of the leading causes of cancer death worldwide. The membrane glycoprotein CD200, widely expressed on multiple cells/tissues, uses a structurally similar receptor (CD200R), delivering immunoregulatory signals. There is evidence that CD200/CD200R signaling suppresses anti-tumor responses in different types of malignancies. Little is known about the CD200/CD200R pathway in GC. The aim of the study was to evaluate the frequencies of CD200+ and CD200R+ lymphocytes in patients with GC. Material and methods Forty patients primarily diagnosed with GC and 20 healthy volunteers (control group) were enrolled. The viable peripheral blood lymphocytes underwent labeling with fluorochrome-conjugated monoclonal antibodies and were analyzed using a flow cytometer. Results In the GC group, the percentages of T CD3+, CD3+/CD4+, and CD3+/CD8+ cells expressing CD200 antigen were higher than in the control group (p < 0.00013, p < 0.0004, and p < 0.0006, respectively). In the GC group, the frequencies of T CD3+, CD3+/CD4+ and CD3+/CD8+ cells expressing CD200R were lower than in the control group (p < 0.0009, p < 0.004, and p < 0.002, respectively). The percentage of B CD19+/CD200+ lymphocytes was higher in GC patients than in the control group (p < 0.00005). Lower frequency of B CD19+/CD200R+ cells was observed in GC patients compared to the control group (p < 0.0001). No differences in the frequencies of CD200+ and CD200R+ lymphocytes were found in relation to either UICC stage or histological grading of the tumors. Conclusions For GC pathogenesis, deregulation of the CD200/CD200R axis is important. High percentages of lymphocytes with CD200 expression may contribute to the continuous T cell activation and development of chronic inflammation and influence gastric carcinogenesis.

Objective Fenestrated and branched endovascular devices are increasingly used for complex aortic diseases, and despite the challenging nature of these procedures, early experiences from pioneering centers have been encouraging. The objectives of this retrospective study were to report our experience of intraoperative adverse events (IOAEs) during fenestrated and branched stent grafting and to analyze the impact on clinical outcomes. Methods Consecutive patients treated with fenestrated and branched stent grafting in a tertiary vascular center between February 2006 and October 2013 were evaluated. A prospectively maintained computerized database was scrutinized and updated retrospectively. Intraoperative angiograms were reviewed to identify IOAEs, and adverse events were categorized into three types: target vessel cannulation, positioning of graft components, and intraoperative access. Clinical consequences of IOAEs were analyzed to ascertain whether they were responsible for death or moderate to severe postoperative complications. Results During the study period, 113 consecutive elective patients underwent fenestrated or branched stent grafting. Indications for treatment were asymptomatic complex abdominal aortic aneurysms (CAAAs, n = 89) and thoracoabdominal aortic aneurysms (TAAAs, n = 24). Stent grafts included fenestrated (n = 79) and branched (n = 17) Cook stent grafts (Cook Medical, Bloomington, Ind), Ventana (Endologix, Irvine, Calif) stent grafts (n = 9), and fenestrated Anaconda (Vascutek Terumo, Scotland, UK) stent grafts (n = 8). In-hospital mortality rates for the CAAA and TAAA groups were 6.7% (6 of 89) and 12.5% (3 of 24), respectively. Twenty-eight moderate to severe complications occurred in 21 patients (18.6%). Spinal cord ischemia was recorded in six patients, three of which resolved completely. A total of 37 IOAEs were recorded in 34 (30.1%) patients (22 CAAAs and 12 TAAAs). Of 37 IOAEs, 15 (40.5%) resulted in no clinical consequence in 15 patients; 17 (45.9%) were responsible for moderate to severe complications in 16 patients, and five (13.5%) led to death in four patients. The composite end point death/nonfatal moderate to severe complication occurred more frequently in patients with IOAEs compared with patients without IOAEs (20 of 34 vs 12 of 79; P Conclusions In this contemporary series, IOAEs were relatively frequent during branched or fenestrated stenting procedures and were often responsible for significant complications.

SummaryLittle is known about how the immune system impacts human colorectal cancer invasiveness and stemness. Here we detected interleukin-22 (IL-22) in patient colorectal cancer tissues that was produced predominantly by CD4+ T cells. In a mouse model, migration of these cells into the colon cancer microenvironment required the chemokine receptor CCR6 and its ligand CCL20. IL-22 acted on cancer cells to promote activation of the transcription factor STAT3 and expression of the histone 3 lysine 79 (H3K79) methytransferase DOT1L. The DOT1L complex induced the core stem cell genes NANOG, SOX2, and Pou5F1, resulting in increased cancer stemness and tumorigenic potential. Furthermore, high DOT1L expression and H3K79me2 in colorectal cancer tissues was a predictor of poor patient survival. Thus, IL-22+ cells promote colon cancer stemness via regulation of stemness genes that negatively affects patient outcome. Efforts to target this network might be a strategy in treating colorectal cancer patients.