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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

In the paper, we consider a bipolynomial fractional Dirichlet-Laplace problem with a functional parameter u. The main goal is to prove theorems on the existence and continuous dependence of...

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.