Harnessing Oxylipins and Inflammation Modulation for Prevention and Treatment of Colorectal Cancer.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, ranking as the third most malignant. The incidence of CRC has been increasing with time, and it is reported that Westernized diet and lifestyle play a significant role in its higher incidence and rapid progression. The intake of high amounts of omega-6 (n - 6) PUFAs and low levels of omega-3 (n - 3) PUFAs has an important role in chronic inflammation and cancer progression, which could be associated with the increase in CRC prevalence. Oxylipins generated from PUFAs are bioactive lipid mediators and have various functions, especially in inflammation and proliferation. Carcinogenesis is often a consequence of chronic inflammation, and evidence has shown the particular involvement of n - 6 PUFA arachidonic acid-derived oxylipins in CRC, which is further described in this review. A deeper understanding of the role and metabolism of PUFAs by their modifying enzymes, their pathways, and the corresponding oxylipins may allow us to identify new approaches to employ oxylipin-associated immunomodulation to enhance immunotherapy in cancer. This paper summarizes oxylipins identified in the context of the initiation, development, and metastasis of CRC. We further explore CRC chemo-prevention strategies that involve oxylipins as potential therapeutics.

A Role for Lipid Mediators in Acute Myeloid Leukemia.

In spite of therapeutic improvements in the treatment of different hematologic malignancies, the prognosis of acute myeloid leukemia (AML) treated solely with conventional induction and consolidation chemotherapy remains poor, especially in association with high risk chromosomal or molecular aberrations. Recent discoveries describe the complex interaction of immune effector cells, as well as the role of the bone marrow microenvironment in the development, maintenance and progression of AML. Lipids, and in particular omega-3 as well as omega-6 polyunsaturated fatty acids (PUFAs) have been shown to play a vital role as signaling molecules of immune processes in numerous benign and malignant conditions. While the majority of research in cancer has been focused on the role of lipid mediators in solid tumors, some data are showing their involvement also in hematologic malignancies. There is a considerable amount of evidence that AML cells are targetable by innate and adaptive immune mechanisms, paving the way for immune therapy approaches in AML. In this article we review the current data showing the lipid mediator and lipidome patterns in AML and their potential links to immune mechanisms.

Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin.

R-spondin proteins sensitize cells to Wnt signalling and act as potent stem cell growth factors. Various membrane proteins have been proposed as potential receptors of R-spondin, including LGR4/5, membrane E3 ubiquitin ligases ZNRF3/RNF43 and several others proteins. Here, we show that R-spondin interacts with ZNRF3/RNF43 and LGR4 through distinct motifs. Both LGR4 and ZNRF3 binding motifs are required for R-spondin-induced LGR4/ZNRF3 interaction, membrane clearance of ZNRF3 and activation of Wnt signalling. Importantly, Wnt-inhibitory activity of ZNRF3, but not of a ZNRF3 mutant with reduced affinity to R-spondin, can be strongly suppressed by R-spondin, suggesting that R-spondin primarily functions by binding and inhibiting ZNRF3. Together, our results support a dual receptor model of R-spondin action, where LGR4/5 serve as the engagement receptor whereas ZNRF3/RNF43 function as the effector receptor.

The effect of erythropoiesis-stimulating agents in patients with therapy-refractory autoimmune hemolytic anemia.

BACKGROUND: Many patients with autoimmune hemolytic anemia (AIHA) do not respond to standard therapy and/or may develop severe complications which can be of fatal outcome. There is some evidence that erythropoiesis-stimulating agents (ESAs) may be helpful in the management of such patients. METHODS: We describe the effect of ESAs in 12 new patients with therapy-refractory AIHA (7 of warm type and 5 of cold type) and review 5 previously reported cases. Serological testing was performed using standard methods. RESULTS: All patients responded well to treatment with ESAs. At least 5 of the 17 patients demonstrated complete recovery, and none of the patients developed significant adverse reactions due to treatment with ESAs. CONCLUSION: The mechanism by which ESAs improves hemolysis in AIHA is not completely clear. In addition to increased production and prolonged RBC survival, it may inhibit eryptosis (programmed cell death). ESAs represent a new option in the treatment of decompensated and/or refractory AIHA of warm and cold type. However, more information is required to assess which patients can be treated with ESAs.

[Treatment reality of esophageal cancer in the Federal State of Brandenburg : Comparison between squamous cell carcinoma and adenocarcinoma]. / Versorgungsrealität des Ösophaguskarzinoms im Bundesland Brandenburg : Ein Vergleich zwischen Plattenepithel- und Adenokarzinomen.

BACKGROUND: Clinical cancer registries are intended to reflect the reality of care through differentiated data analysis and, if necessary, to offer approaches for improving care. METHODS: For the years 2000-2018, the data of the Clinical Epidemiological Cancer Registry Brandenburg-Berlin were examined separately for adenocarcinoma and squamous cell carcinoma with respect to epidemiology and health care reality. RESULTS: Between 2000 and 2018 a total of 3207 esophageal cancers were documented in the cancer registry, of which 2182 were squamous cell carcinomas (ESCC), 843 adenocarcinomas (EAC) and 182 various others or missing histology. During the observation period there was a clear dominance of ESCC but with a significant increase in EAC in both sexes. Overall, the rate of new cases was 5 times higher for men than for women. The relative 5­year survival probability of all esophageal cancers was 17.4% in men and 22.5% in women. Patients with EAC survived significantly longer than those with ESCC. Radiotherapy and chemotherapy, individually or in combination, were mainly used as treatment methods. Surgery was performed on 19% of ESCC and 42% of EAC. CONCLUSION: The proportion of ESCC in Brandenburg is still significantly higher than EAC, with a significant increase for the latter, especially in men. Although locally advanced tumors have been significantly more common, modern neoadjuvant concepts have rarely been documented, and although the quality of the surgery is comparable to the international standard, surgery is carried out in relatively few patients.

[Pharmacologic thromboprophylaxis in critically ill patients]. / Perioperative Thromboseprophylaxe - Medikamentöse Thromboseprophylaxe in der Intensivmedizin.

Critical care patients have to be considered at high risk patients for thromboembolic events. The recommendations and guidelines support strongly a pharmacologic anticoagulant prophylaxis. Due to the fact that only very few data are available for this selected patient population there are still open questions concerning the ideal choice of drug and optimal dosages. Prophylactic administration of UFH, LMWH and Fondaparinux can be used safely and effectively. In case of acutely suspected or diagnosed HIT type II Argatroban seems to be a reasonable choice for anticoagulation. The new orally available anticoagulant drugs are not yet indicated in ICU patients.

Management of a severe bilateral pulmonary embolism as a complication of VITT following vaccination with AstraZeneca COVID-19 vaccine.

Since the start of vaccination against COVID-19 viral infection using adenovirus-based vector vaccine (eg, The Oxford-AstraZeneca vaccine, using the modified chimpanzee adenovirus ChAdOx1, and the Johnson & Johnson vaccine, using human adenovirus serotype 26), a rare, but potentially life-threatening complication called vaccine-induced thrombotic thrombocytopenia (VITT) was reported. As the number of cases increases every day, with the increase in the number of vaccinated people all over the world, this complication is a concern to the medical field. We report a case on the acute management of a patient who presented to us with life-threatening bilateral pulmonary embolism as a complication of VITT after the first dose of vaccination with Oxford-AstraZeneca vaccine against COVID-19.

[Reality of care of colorectal cancer in the State of Brandenburg : With special consideration of the number of hospital cases and certification as a colorectal cancer center]. / Die Versorgungsrealität des kolorektalen Karzinoms im Bundesland Brandenburg : Unter besonderer Berücksichtigung der Krankenhausfallzahlen und Zertifizierung als Darmkrebszentrum.

Analysis of the quality of care for colorectal cancer is an essential foundation for further development and is based on the comparison of the goals set and the actual quality of care. This publication presents the reality of care in the State of Brandenburg covering the complete spectrum of treating clinics based on the data of the clinical cancer register. This study analyzed the number of resected and examined lymph nodes, the quality of total mesorectal excision (TME), the residual tumor (R0) resection rate and the proportion of adjuvant therapy of colon cancer in Union internationale contre le cancer (UICC) stage III depending on the operation quota of hospitals and the certification as bowel cancer center according to Onkozert. Apart from the R status, the analyses showed no differences in the qualitative operation data from the clinical cancer register depending on the hospital volume.

Severe thrombocytopenia in a patient with metastatic renal cell carcinoma.

BACKGROUND AND METHODS: A 63-year-old woman was transferred to our institution with suspected metastatic renal cell carcinoma (mRCC). Biopsies of the kidney and hepatic lesions proved partly sarcomatoid-differentiated clear cell carcinoma. Initially presenting with fever of unknown origin, the patient was empirically treated with antibiotics, but the patient's condition deteriorated and she developed progressive severe thrombocytopenia followed by mild anemia. Several blood tests were done to identify the cause of the thrombocytopenia. RESULTS: Radiologic imaging and clinical presentation showed rapidly progressive mRCC. Clinical and laboratory features were incompatible with severe sepsis, thrombotic thrombocytopenic purpura (TTP) or idiopathic thrombocytopenic purpura (ITP) and laboratory tests were negative for heparin-induced thrombocytopenia (HIT). The patient's current medication was changed to exclude potential drug-induced thrombocytopenia and the bone marrow was biopsied. The results showed massive bone marrow infiltration of RCC. CONCLUSIONS: Although very rare, bone marrow carcinosis can occur in patients with mRCC and may present a diagnostic challenge. It is associated with a very poor prognosis.

Crystal structure of the functional unit of interphotoreceptor retinoid binding protein.

Interphotoreceptor retinoid binding protein (IRBP), the major soluble component of the interphotoreceptor matrix, is critical to the function, integrity, and development of the vertebrate retina. Although its role is poorly understood, IRBP has been thought to protect 11-cis retinal and all-trans retinol while facilitating their exchange between the photoreceptors and retinal-pigmented epithelium. We determined the X-ray structure of one of the functional units, or modules, of Xenopus laevis IRBP to 1.8 A resolution by multiwavelength anomalous dispersion. The monomeric protein consists of two domains separated by a hydrophobic ligand binding site. A structural homology to the recently solved photosystem II D1 C-terminal-processing protease and the enoyl-CoA isomerase/hydratase family suggests the utility of a common fold used in diverse settings, ranging from proteolysis to fatty acid isomerization to retinoid transport.

The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size.

LGR4/5 receptors and their cognate RSPO ligands potentiate Wnt/ß-catenin signalling and promote proliferation and tissue homeostasis in epithelial stem cell compartments. In the liver, metabolic zonation requires a Wnt/ß-catenin signalling gradient, but the instructive mechanism controlling its spatiotemporal regulation is not known. We have now identified the RSPO-LGR4/5-ZNRF3/RNF43 module as a master regulator of Wnt/ß-catenin-mediated metabolic liver zonation. Liver-specific LGR4/5 loss of function (LOF) or RSPO blockade disrupted hepatic Wnt/ß-catenin signalling and zonation. Conversely, pathway activation in ZNRF3/RNF43 LOF mice or with recombinant RSPO1 protein expanded the hepatic Wnt/ß-catenin signalling gradient in a reversible and LGR4/5-dependent manner. Recombinant RSPO1 protein increased liver size and improved liver regeneration, whereas LGR4/5 LOF caused the opposite effects, resulting in hypoplastic livers. Furthermore, we show that LGR4(+) hepatocytes throughout the lobule contribute to liver homeostasis without zonal dominance. Taken together, our results indicate that the RSPO-LGR4/5-ZNRF3/RNF43 module controls metabolic liver zonation and is a hepatic growth/size rheostat during development, homeostasis and regeneration.

Resistance to activated protein C caused by factor V Leiden mutation and orthotopic liver transplantation.

BACKGROUND: Factor V (FV)-dependent resistance to activated protein C (APCR) is most likely caused by a point mutation in the FV gene, the so-called FV Leiden mutation (FV:Q506), which is a common risk factor predisposing to venous thromboembolism. Little is known about the role of FV:Q506 in recipients of human liver grafts and the significance of acquired APCR caused by orthotopic liver transplantation (OLT). METHODS: We screened blood samples of 720 patients who underwent OLT by genotyping for FV:Q506 and by testing for APCR with two highly FV-specific tests. Apart from the existing medical records, we obtained clinical data from 551 patients on thromboembolic events (TEs) by means of a questionnaire. RESULTS: We found 49 (6.8%) heterozygous carriers of FV:Q who did not show APCR after OLT. One patient, heterozygous for FV:Q506, displayed APCR after OLT. In 35 (4.9%) noncarriers of FV:Q we detected APCR after OLT. In comparison with noncarriers, carriers of FV:Q506 demonstrated more TE before transplantation (7% vs. 28%, P<0.0005; relative risk 4.0 [95% confidence interval, 2.3-6.9]); this was also true for Budd-Chiari syndrome (1.8% vs. 10%, P<0.005). At a median follow-up of 5 years (0, 13-12 years), we found a higher incidence of TE after transplantation in patients with "acquired" APCR (16.7% vs. 4,3%; P=0.01; relative risk 3.9 [95% confidence interval, 1.7-9.0]), which included one patient with life-threatening TE during the early postoperative phase. CONCLUSIONS: APCR caused by FV:Q506 before OLT is a risk factor for TE. OLT-related "acquired" APCR should be considered a risk factor for venous thromboembolism.

Affinity-Tuned ErbB2 or EGFR Chimeric Antigen Receptor T Cells Exhibit an Increased Therapeutic Index against Tumors in Mice.

Target-mediated toxicity is a major limitation in the development of chimeric antigen T-cell receptors (CAR) for adoptive cell therapy of solid tumors. In this study, we developed a strategy to adjust the affinities of the scFv component of CAR to discriminate tumors overexpressing the target from normal tissues that express it at physiologic levels. A CAR-expressing T-cell panel was generated with target antigen affinities varying over three orders of magnitude. High-affinity cells recognized target expressed at any level, including at levels in normal cells that were undetectable by flow cytometry. Affinity-tuned cells exhibited robust antitumor efficacy similar to high-affinity cells, but spared normal cells expressing physiologic target levels. The use of affinity-tuned scFvs offers a strategy to empower wider use of CAR T cells against validated targets widely overexpressed on solid tumors, including those considered undruggable by this approach.

Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma.

Chimeric antigen receptors (CARs) are synthetic molecules designed to redirect T cells to specific antigens. CAR-modified T cells can mediate long-term durable remissions in B cell malignancies, but expanding this platform to solid tumors requires the discovery of surface targets with limited expression in normal tissues. The variant III mutation of the epidermal growth factor receptor (EGFRvIII) results from an in-frame deletion of a portion of the extracellular domain, creating a neoepitope. We chose a vector backbone encoding a second-generation CAR based on efficacy of a murine scFv-based CAR in a xenograft model of glioblastoma. Next, we generated a panel of humanized scFvs and tested their specificity and function as soluble proteins and in the form of CAR-transduced T cells; a low-affinity scFv was selected on the basis of its specificity for EGFRvIII over wild-type EGFR. The lead candidate scFv was tested in vitro for its ability to direct CAR-transduced T cells to specifically lyse, proliferate, and secrete cytokines in response to antigen-bearing targets. We further evaluated the specificity of the lead CAR candidate in vitro against EGFR-expressing keratinocytes and in vivo in a model of mice grafted with normal human skin. EGFRvIII-directed CAR T cells were also able to control tumor growth in xenogeneic subcutaneous and orthotopic models of human EGFRvIII(+) glioblastoma. On the basis of these results, we have designed a phase 1 clinical study of CAR T cells transduced with humanized scFv directed to EGFRvIII in patients with either residual or recurrent glioblastoma (NCT02209376).

Patient-specific vascularized tumor model: Blocking monocyte recruitment with multispecific antibodies targeting CCR2 and CSF-1R.

Tumor-associated inflammation drives cancer progression and therapy resistance, often linked to the infiltration of monocyte-derived tumor-associated macrophages (TAMs), which are associated with poor prognosis in various cancers. To advance immunotherapies, testing on immunocompetent pre-clinical models of human tissue is crucial. We have developed an in vitro model of microvascular networks with tumor spheroids or patient tissues to assess monocyte trafficking into tumors and evaluate immunotherapies targeting the human tumor microenvironment. Our findings demonstrate that macrophages in vascularized breast and lung tumor models can enhance monocyte recruitment via CCL7 and CCL2, mediated by CSF-1R. Additionally, a multispecific antibody targeting CSF-1R, CCR2, and neutralizing TGF-ß (CSF1R/CCR2/TGF-ß Ab) repolarizes TAMs towards an anti-tumoral M1-like phenotype, reduces monocyte chemoattractant protein secretion, and blocks monocyte migration. This antibody also inhibits monocyte recruitment in patient-specific vascularized tumor models. In summary, this vascularized tumor model recapitulates the monocyte recruitment cascade, enabling functional testing of innovative therapeutic antibodies targeting TAMs in the tumor microenvironment.