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Psychological functioning is shaped by how people navigate their environment. Accordingly, psychopathology is often caused and maintained by patterns of responding to the environment that do not meet situational demands. In particular, psychopathology is often expressed in an inflexible or intense manner of coping with stressful situations. Prior research on psychopathology and daily life stress is limited by an overreliance on negative affect reactivity, which neglects the myriad responses that can create problems in a person's life. In this study, we assessed a broad range of daily manifestations of psychopathology to examine daily psychopathology-stress associations. We conceptualized individual differences in functioning as psychopathology traits and daily fluctuations in the interrelated thoughts, behaviors, and emotions as psychopathology states, with traits and states corresponding to the same domains of functioning (i.e., antagonism, detachment, disinhibition, negative affectivity, anankastia, psychoticism). Data have been taken from two samples enriched for psychopathology ( N = 112, N = 294 participants) who completed daily assessments of stressors and psychopathological states ( n = 9,201, n = 4,292 days). We used multilevel structural equation models to examine average, within-person associations between stressors and psychopathological states and correlations between psychopathological traits and stress responses. Results showed that (a) most people experience increases in psychopathological states when stressed and (b) psychopathological traits relate to more consistent and stronger increases in psychopathological states. Our study suggests that psychopathology reflects how people cope with stressful situations, and what distinguishes people with high-trait psychopathology from those who experience typical upticks in psychopathology when stressed is the consistency and extremity of their responses. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Food colorants are frequently added to processed foods since color is an important tool in the marketing of food products, influencing consumer perceptions, preferences, and purchasing behavior. While synthetic dyes currently dominate the food colorant market, consumer concern regarding their safety and sustainability is driving a demand for their replacement with naturally derived alternatives. However, natural colorants are costly compared to their synthetic counterparts as the pigment content in the native sources is usually very low and extraction can be challenging. Recent advances in the engineering of microbial metabolism have sparked interest in the development of cell factories capable of producing natural colorants from renewable resources. This review summarizes major developments within metabolic engineering for the production of nature-identical food colorants by fermentation. Additionally, it highlights common applications, formulations, and physicochemical characteristics of prevalent pigment classes. Lastly, it outlines a workflow for accelerating the optimization of cell factories for the production or derivatization of nature-identical food colorants., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Irina Borodina reports a relationship with Novo Nordisk Foundation that includes: funding grants. Irina Borodina has patent #Methods for producing betalains in yeast (WO2022253815) pending to The Technical Univeristy of Denmark. Philip Tinggaard Thomsen has patent #Methods for producing betalains in yeast (WO2022253815) pending to The Technical Univeristy of Denmark. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Trauma-related intrusive memories (TR-IMs) possess unique phenomenological properties that contribute to adverse post-traumatic outcomes, positioning them as critical intervention targets. However, transdiagnostic treatments for TR-IMs are scarce, as their underlying mechanisms have been investigated separate from their unique phenomenological properties. Extant models of more general episodic memory highlight dynamic hippocampal-cortical interactions that vary along the anterior-posterior axis of the hippocampus (HPC) to support different cognitive-affective and sensory-perceptual features of memory. Extending this work into the unique properties of TR-IMs, we conducted a study of eighty-four trauma-exposed adults who completed daily ecological momentary assessments of TR-IM properties followed by resting-state functional magnetic resonance imaging (rs-fMRI). Spatiotemporal dynamics of anterior and posterior hippocampal (a/pHPC)-cortical networks were assessed using co-activation pattern analysis to investigate their associations with different properties of TR-IMs. Emotional intensity of TR-IMs was inversely associated with the frequency and persistence of an aHPC-default mode network co-activation pattern. Conversely, sensory features of TR-IMs were associated with more frequent co-activation of the HPC with sensory cortices and the ventral attention network, and the reliving of TR-IMs in the "here-and-now" was associated with more persistent co-activation of the pHPC and the visual cortex. Notably, no associations were found between HPC-cortical network dynamics and conventional symptom measures, including TR-IM frequency or retrospective recall, underscoring the utility of ecological assessments of memory properties in identifying their neural substrates. These findings provide novel insights into the neural correlates of the unique features of TR-IMs that are critical for the development of individualized, transdiagnostic treatments for this pervasive, difficult-to-treat symptom., (© 2024. The Author(s).)

Identity dysfunction is considered core to psychopathology, contributing to emotional and interpersonal problems across psychiatric diagnoses. Despite its centrality in theories of personality and psychopathology, the empirical research on the structure of identity dysfunction is fragmented by a plethora of self-report measures assessing varied domains of identity dysfunction. This project examines conceptual domains of identity dysfunction in self-report assessments, with the goal of elucidating a clear structure of identity dysfunction to advance both theory and measurement. Toward this aim, we a) investigate the factor structure of identity dysfunction in existing self-report measures, using exploratory factor analysis and b) examine relationships between identity dysfunction and closely related constructs, using exploratory structural equation modeling. We assess responses from 632 young adults to 17 commonly used identity functioning self-report measures. In a series of exploratory factor analyses, we identified four content-domains of Identity Dysfunction (Self-Alienation, Susceptibility to External Influence, Self-Dysregulation, and Contingent Self-Esteem) and three content domains of Identity Clarity (Self-Consistency, Reflective Functioning, and Authentic Living). These content domains were largely well-represented by a single factor. In a series of exploratory structural equation models, emergent factors related similarly to personality, emotion dysregulation, and values and problems in interpersonal relationships.

The accumulation of day-to-day stressors can impact mental and physical health. How people respond to stressful events is a key mechanism responsible for the effects of stress, and individual differences in stress responses can either perpetuate or prevent negative consequences. Most research on daily stress processes has focused on affective responses to stressors, but stress responses can involve more than just affect (e.g., behavior, cognitions). Additionally, most research has studied the role of neuroticism in shaping those responses, but many other individual differences are associated with stress. In this study, we more broadly characterized daily stress processes by expanding the nomological networks of stress responses to include Big Five personality states. We also linked those stress responses to all Big Five traits, as well as individual differences in stress variety, severity, and controllability. We studied a sample of participants ( N = 1,090) who reported on stressful events, their appraisal of events in terms of severity and controllability, and their Big Five personality states daily for 8-10 days ( N = 8,870 observations). Multi-level structural equation models were used to separate how characteristics of the perceived stressful situation and characteristics of the person play into daily stress processes. Results showed that (1) all Big Five personality states shift in response to perceived stress, (2) all Big Five personality traits relate to average levels of perceived stress variety, severity, and controllability, (3) individual differences in personality and average perceived stress variety and perceived severity relate to the strength of personality state responses to daily stress, albeit in a more limited fashion. Our results point to new pathways by which stressors affect people in everyday life and begin to clarify processes that may explain individual differences in risk or resilience to the harmful effects of stress.

The desmoplastic reaction observed in many cancers is a hallmark of disease progression and prognosis, particularly in breast and pancreatic cancer. Stromal-derived extracellular matrix (ECM) is significantly altered in desmoplasia, and as such plays a critical role in driving cancer progression. Using fibroblast-derived matrices (FDMs), we show that cancer cells have increased growth on cancer associated FDMs, when compared to FDMs derived from non-malignant tissue (normal) fibroblasts. We assess the changes in ECM characteristics from normal to cancer-associated stroma at the primary tumor site. Compositional, structural, and mechanical analyses reveal significant differences, with an increase in abundance of core ECM proteins, coupled with an increase in stiffness and density in cancer-associated FDMs. From compositional changes of FDM, we derived a 36-ECM protein signature, which we show matches in large part with the changes in pancreatic ductal adenocarcinoma (PDAC) tumor and metastases progression. Additionally, this signature also matches at the transcriptomic level in multiple cancer types in patients, prognostic of their survival. Together, our results show relevance of FDMs for cancer modelling and identification of desmoplastic ECM components for further mechanistic studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rafaeva, Jensen, Horton, Zornhagen, Strøbech, Fleischhauer, Mayorca-Guiliani, Nielsen, Grønseth, Kuś, Schoof, Arnes, Koch, Clausen-Schaumann, Izzi, Reuten and Erler.)

Patients with pancreatic ductal adenocarcinoma (PDAC) have a dismal 5-year survival rate of less than 10%, predominantly due to delayed diagnosis and a lack of effective treatment options. In the PDAC tumor microenvironment (TME), neutrophils are among the immune cell types that are most prevalent and are linked to a poor clinical prognosis. However, treatments that target tumor-associated neutrophils are limited despite recent developments in our understanding of neutrophil function in cancer. The feline sarcoma oncogene (FES) is a nonreceptor tyrosine kinase previously associated with leukemia and hematopoietic homeostasis. Here we describe a newly derived FES null mouse with no distinct phenotype and no defects in hematopoietic homeostasis including neutrophil viability. The immune cell composition and neutrophil population were analyzed with flow cytometry, colony-forming unit (CFU) assay, and a neutrophil viability assay, while the response to PDAC was examined with an in vivo cancer model. In an experimental metastasis model, the FES null model displayed a reduced PDAC hepatic metastatic burden and a reduction in neutrophils granulocytes. Accordingly, our results indicate FES as a potential target for PDAC TME modulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Strøbech, Giuriatti, Stagaard, De Sepulveda, Nielsen and Erler.)

X-linked hypophosphatemic rickets (XLH) and m.3243A>G mitochondrial disease share several clinical findings, including short stature, hearing impairment (HI), nephropathy, and hypertension. Here, we report on a case with the rare coincidence of these two genetic conditions. In early childhood, the patient presented with hypophosphatemia and bone deformities and was clinically diagnosed with XLH. This was genetically verified in adulthood with the identification of a de novo pathogenic deletion in phosphate-regulating endopeptidase homolog X-linked (PHEX). In addition, the patient developed HI and hypertension and when his mother was diagnosed with m.3243A>G, subsequent genetic testing confirmed the patient to carry the same variant. Over the next two decades, the patient developed progressive renal impairment however without nephrocalcinosis known to associate with XLH which could indicate an m.3243A>G-related kidney disease. Parallel with the progression of renal impairment, the patient developed hyperphosphatemia and secondary hyperparathyroidism. In conclusion, this case represents a complex clinical phenotype with the reversal of hypo- to hyperphosphatemia in XLH potentially mediated by the development of an m.3243A>G-associated nephropathy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Tumor-associated macrophages (TAM) are one of the most abundant cell types in many solid tumors and typically exert protumor effects. This has led to an interest in macrophage-depleting agents for cancer therapy, but approaches developed to date have had limited success in clinical trials. Here, we report the development of a strategy for TAM depletion in mouse solid tumor models using chimeric antigen receptor (CAR) T cells targeting the macrophage marker F4/80 (F4.CAR-T). F4.CAR-T cells effectively killed macrophages in vitro and in vivo without toxicity. When injected into mice bearing orthotopic lung tumors, F4.CAR-T cells infiltrated tumor lesions and delayed tumor growth comparably with PD-1 blockade, and significantly extended mouse survival. Antitumor effects were mediated by F4.CAR-T-produced IFNγ, which promoted upregulation of MHC molecules on cancer cells and tumor-infiltrating myeloid cells. Notably, F4.CAR-T promoted expansion of endogenous CD8 T cells specific for tumor-associated antigen and led to immune editing of highly antigenic tumor cell clones. Antitumor impact was also observed in mouse models of ovarian and pancreatic cancer. These studies provide proof of principle to support CAR T-cell targeting of TAMs as a means to enhance antitumor immunity., (©2022 American Association for Cancer Research.)

Introduction: Trauma reexperiencing is dominated by recollection of sensory-perceptual elements of the trauma, pointing to involvement of the sensory thalamus. This study examined posttraumatic stress symptoms in relation to volumes of thalamic nuclei that were grouped based on their predominant functions. We hypothesized that reexperiencing, controlling for other symptom dimensions, would correlate with volumes of thalamic nuclei involved in primary and higher-order sensory processing., Methods: Seventy-two trauma-exposed adults were interviewed with the Clinician Administered PTSD Scale for DSM-IV and underwent 3T magnetic resonance imaging. Scores were derived for reexperiencing, anxious arousal, dysphoric arousal, emotional numbing, and avoidance symptoms. These were entered as simultaneous predictors in five separate regression analyses, with age, sex, and total thalamus volume as covariates, predicting volumesf of five thalamus nuclear groupings corrected for intracranial volume: Specific sensory, associative-sensory, associative-cognitive, intralaminar, and motor groupings., Results: Reexperiencing symptoms were significantly positively correlated with volumes of the motor thalamic grouping, which included the ventral anterior, ventral lateral, and ventromedial nuclei. Anxious arousal was significantly negatively correlated with volumes of all five thalamic groupings., Conclusions: Reexperiencing symptoms were correlated with volumes of the motor thalamus, while anxious arousal symptoms were related to all thalamic subregion volumes. Thalamic nuclei involved in motor functions, including oculomotor control and motor planning, may be implicated in posttraumatic reexperiencing symptoms., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Serglycin is a proteoglycan highly expressed by immune cells, in which its functions are linked to storage, secretion, transport, and protection of chemokines, proteases, histamine, growth factors, and other bioactive molecules. In recent years, it has been demonstrated that serglycin is also expressed by several other cell types, such as endothelial cells, muscle cells, and multiple types of cancer cells. Here, we show that serglycin expression is upregulated in transforming growth factor beta (TGF-β) induced epithelial-mesenchymal transition (EMT). Functional studies provide evidence that serglycin plays an important role in the regulation of the transition between the epithelial and mesenchymal phenotypes, and it is a significant EMT marker gene. We further find that serglycin is more expressed by breast cancer cell lines with a mesenchymal phenotype as well as the basal-like subtype of breast cancers. By examining immune staining and single cell sequencing data of breast cancer tissue, we show that serglycin is highly expressed by infiltrating immune cells in breast tumor tissue., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with the author ADT., (Copyright © 2022 Tellez-Gabriel, Tekpli, Reine, Hegge, Nielsen, Chen, Moi, Normann, Busund, Calin, Mælandsmo, Perander, Theocharis, Kolset and Knutsen.)

While CRISPR screens are helping uncover genes regulating many cell-intrinsic processes, existing approaches are suboptimal for identifying extracellular gene functions, particularly in the tissue context. Here, we developed an approach for spatial functional genomics called Perturb-map. We applied Perturb-map to knock out dozens of genes in parallel in a mouse model of lung cancer and simultaneously assessed how each knockout influenced tumor growth, histopathology, and immune composition. Moreover, we paired Perturb-map and spatial transcriptomics for unbiased analysis of CRISPR-edited tumors. We found that in Tgfbr2 knockout tumors, the tumor microenvironment (TME) was converted to a fibro-mucinous state, and T cells excluded, concomitant with upregulated TGFβ and TGFβ-mediated fibroblast activation, indicating that TGFβ-receptor loss on cancer cells increased TGFβ bioavailability and its immunosuppressive effects on the TME. These studies establish Perturb-map for functional genomics within the tissue at single-cell resolution with spatial architecture preserved and provide insight into how TGFβ responsiveness of cancer cells can affect the TME., Competing Interests: Declaration of interests B.D.B. and A.W. have filed a patent application related to the Pro-Code technology., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Metastatic cancer spread is responsible for most cancer-related deaths. To colonize a new organ, invading cells adapt to, and remodel, the local extracellular matrix (ECM), a network of proteins and proteoglycans underpinning all tissues, and a critical regulator of homeostasis and disease. However, there is a major lack in tools to study cancer cell behavior within native 3D ECM. Here, an in-house designed bioreactor, where mouse organ ECM scaffolds are perfused and populated with cells that are challenged to colonize it, is presented. Using a specialized bioreactor chamber, it is possible to monitor cell behavior microscopically (e.g., proliferation, migration) within the organ scaffold. Cancer cells in this system recapitulate cell signaling observed in vivo and remodel complex native ECM. Moreover, the bioreactors are compatible with co-culturing cell types of different genetic origin comprising the normal and tumor microenvironment. This degree of experimental flexibility in an organ-specific and 3D context, opens new possibilities to study cell-cell and cell-ECM interplay and to model diseases in a controllable organ-specific system ex vivo., (© 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Pancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of only 8% largely due to late diagnosis and insufficient therapeutic options. Neutrophils are among the most abundant immune cell type within the PDAC tumor microenvironment (TME), and are associated with a poor clinical prognosis. However, despite recent advances in understanding neutrophil biology in cancer, therapies targeting tumor-associated neutrophils are lacking. Here, we demonstrate, using pre-clinical mouse models of PDAC, that lorlatinib attenuates PDAC progression by suppressing neutrophil development and mobilization, and by modulating tumor-promoting neutrophil functions within the TME. When combined, lorlatinib also improves the response to anti-PD-1 blockade resulting in more activated CD8 + T cells in PDAC tumors. In summary, this study identifies an effect of lorlatinib in modulating tumor-associated neutrophils, and demonstrates the potential of lorlatinib to treat PDAC.

The basement membrane (BM) is a special type of extracellular matrix and presents the major barrier cancer cells have to overcome multiple times to form metastases. Here we show that BM stiffness is a major determinant of metastases formation in several tissues and identify netrin-4 (Net4) as a key regulator of BM stiffness. Mechanistically, our biophysical and functional analyses in combination with mathematical simulations show that Net4 softens the mechanical properties of native BMs by opening laminin node complexes, decreasing cancer cell potential to transmigrate this barrier despite creating bigger pores. Our results therefore reveal that BM stiffness is dominant over pore size, and that the mechanical properties of 'normal' BMs determine metastases formation and patient survival independent of cancer-mediated alterations. Thus, identifying individual Net4 protein levels within native BMs in major metastatic organs may have the potential to define patient survival even before tumour formation. The ratio of Net4 to laminin molecules determines BM stiffness, such that the more Net4, the softer the BM, thereby decreasing cancer cell invasion activity.

Background: Patients with B-cell neoplasms in remission are monitored with regular physician visits at the hospital. The current standard follow-up procedure is not evidence-based or individualized to patient needs. To improve and individualize the follow-up, we investigated the feasibility of a shared care follow-up initiative, with alternating physician visits and nurse-led telephone consultations and assessments based on patient-reported outcome (PRO) data., Methods: Patients ≥18 years diagnosed with B-cell neoplasms were eligible for the study when they were in remission and stable without treatment for at least 6 months. Patients were assigned to alternating visits with physicians and nurse-led telephone consultations. The nurse-led telephone consultations were based on PROs, which were collected with the European Organization for Research and Treatment of Cancer questionnaire (EORTC-QLQ-C30), the Myeloproliferative Neoplasm - Symptom Assessment Form, and the Hospital Anxiety and Depression Scale. Patients completed questionnaires before every nurse-led consultation. We also applied the Patient Feedback Form to survey patient acceptance of the requirement of questionnaire completion. We applied descriptive statistics, in terms of counts (n) and proportions (%), to describe the study population and all endpoints., Results: Between February 2017 and December 2018, 80 patients were enrolled. Adherence, measured as the recruitment rate, was 96% (80/83), and the drop-out rate was 6% (5/80). During the study period, 3/80 (4%) patients relapsed, and 5/80 (6%) patients returned to the standard follow-up, because they required closer medical observation. Relapses were diagnosed based on unscheduled visits requested by patients (n = 2) and patient-reported symptoms reviewed by the nurse (n = 1). The response rate to questionnaires was 98% (335/341). A total of 58/79 (74%) patients completed the Patient Feedback Form; 51/57 (89%) patients reported improved communication with health care professionals; and 50/57 (88%) patients reported improved recollection of symptoms as a result of completing questionnaires., Conclusion: Based on patient adherence, a low relapse rate, and positive patient attitudes towards completing questionnaires, we concluded that a shared care follow-up, supported by PROs, was a feasible alternative to the standard follow-up for patients with B-cell disease in remission.

The ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumor microenvironment that suppresses and excludes cytotoxic CD8 + T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immunoprotective role of the metastatic tumor microenvironment in pancreatic cancer is not completely understood. In this study, we find that macrophage-derived granulin contributes to cytotoxic CD8 + T-cell exclusion in metastatic livers. Granulin expression by macrophages was induced in response to colony-stimulating factor 1. Genetic depletion of granulin reduced the formation of a fibrotic stroma, thereby allowing T-cell entry at the metastatic site. Although metastatic PDAC tumors are largely resistant to anti-PD-1 therapy, blockade of PD-1 in granulin-depleted tumors restored the antitumor immune defense and dramatically decreased metastatic tumor burden. These findings suggest that targeting granulin may serve as a potential therapeutic strategy to restore CD8 + T-cell infiltration in metastatic PDAC, thereby converting PDAC metastatic tumors, which are refractory to immune checkpoint inhibitors, into tumors that respond to immune checkpoint inhibition therapies. Significance: These findings uncover a mechanism by which metastatic PDAC tumors evade the immune response and provide the rationale for targeting granulin in combination with immune checkpoint inhibitors for the treatment of metastatic PDAC. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4253/F1.large.jpg Cancer Res; 78(15); 4253-69. ©2018 AACR ., (©2018 American Association for Cancer Research.)

In patients with relapsed diffuse large B-cell lymphoma (DLBCL), high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is standard treatment. Here, we aim to identify factors associated with survival in patients undergoing ASCT. A total of 369 patients with relapsed DLBCL undergoing ASCT from 2000 to 2012 were identified in the Danish National Lymphoma Registry. Information on clinical and socioeconomic factors was obtained from medical records and national registries. Factors associated with survival were assessed using a Cox's proportional hazards model. Median overall survival was 6.8 years, median progression-free survival was 2.6 years, and treatment-related mortality at Day 100 was 6%. Factors associated with a significant adverse impact on survival were age, primary refractory disease, prolonged hospitalization during salvage treatment, and performance status >0 prior to conditioning therapy. Reconsideration of ASCT for those patients may be required in order to select the right patients for this toxic procedure.

Macrophages are one of the most abundant immune cells in the tumour microenvironment of solid tumours and their presence correlates with reduced survival in most cancers. Macrophages are present at all stages of tumour progression and stimulate angiogenesis, tumour cell invasion, and intravasation at the primary site. At the metastatic site, macrophages and monocytes prepare for the arrival of disseminated tumour cells and promote their extravasation and survival by inhibiting immune-mediated clearance or by directly engaging with tumour cells to activate prosurvival signalling pathways. In addition, macrophages promote the growth of disseminated tumour cells at the metastatic site by organising the formation of a supportive metastatic niche. The development of agents inhibiting the recruitment or the protumorigenic effector functions of macrophages in both the primary tumour and at the metastatic site is a promising strategy to improve cancer survival in the future., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Tumor-associated macrophages (TAM) and myofibroblasts are key drivers in cancer that are associated with drug resistance in many cancers, including pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the molecular mechanisms by which TAM and fibroblasts contribute to chemoresistance is unclear. In this study, we found that TAM and myofibroblasts directly support chemoresistance of pancreatic cancer cells by secreting insulin-like growth factors (IGF) 1 and 2, which activate insulin/IGF receptors on pancreatic cancer cells. Immunohistochemical analysis of biopsies from patients with pancreatic cancer revealed that 72% of the patients expressed activated insulin/IGF receptors on tumor cells, and this positively correlates with increased CD163 + TAM infiltration. In vivo, we found that TAM and myofibroblasts were the main sources of IGF production, and pharmacologic blockade of IGF sensitized pancreatic tumors to gemcitabine. These findings suggest that inhibition of IGF in combination with chemotherapy could benefit patients with PDAC, and that insulin/IGF1R activation may be used as a biomarker to identify patients for such therapeutic intervention. Cancer Res; 76(23); 6851-63. ©2016 AACR., (©2016 American Association for Cancer Research.)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating metastatic disease for which better therapies are urgently needed. Macrophages enhance metastasis in many cancer types; however, the role of macrophages in PDAC liver metastasis remains poorly understood. Here we found that PDAC liver metastasis critically depends on the early recruitment of granulin-secreting inflammatory monocytes to the liver. Mechanistically, we demonstrate that granulin secretion by metastasis-associated macrophages (MAMs) activates resident hepatic stellate cells (hStCs) into myofibroblasts that secrete periostin, resulting in a fibrotic microenvironment that sustains metastatic tumour growth. Disruption of MAM recruitment or genetic depletion of granulin reduced hStC activation and liver metastasis. Interestingly, we found that circulating monocytes and hepatic MAMs in PDAC patients express high levels of granulin. These findings suggest that recruitment of granulin-expressing inflammatory monocytes plays a key role in PDAC metastasis and may serve as a potential therapeutic target for PDAC liver metastasis.

Aim: The aim of this study was to compare the strength and degree of inflammation in small intestinal anastomoses in rabbits after repeated preoperative treatment with the TNF-α antibody, adalimumab (Humira®), compared to placebo., Method: Thirty-three New Zealand white female rabbits were randomized to three weeks of weekly subcutaneous injections of adalimumab (n = 24) or placebo (n = 9). After this treatment regime, two end to end anastomoses were performed in the ileum. Following euthanasia on postoperative day 5 the anastomoses were evaluated for minimal tensile strength (MITS) and histological parameters of wound healing using a modified Verhofstad Scale., Results: There were no statistically significant differences between the adalimumab and placebo groups in terms of MITS or histological parameters. Multiple regression analyzes revealed that there was no association between MITS and treatment, numbers of sutures, length of surgery, preoperative weight gain, postoperative weight loss or histological score. On the day of surgery the median serum concentration of adalimumab was 5.4 μg/ml (3.4-8.6)., Conclusion: Repeated preoperative treatment with adalimumab had no significant influence on MITS or histological score in anastomoses in the small intestine of the rabbits.

Electrospinning technology has been widely recognized because of its ability to synthesize nanoscale fibers that are structurally similar to fibrillar structure of the natural extracellular matrix (ECM). Rendering the nanofiber surface to be biofunctional is critical for the successful application of the electrospinning technology in biomedical applications. Limitations in typical conjugation chemistry and physical adsorption procedures might be overcome by using polydopamine (pDA) coating inspired by adhesive proteins secreted by marine mussels. This perspective paper attempts to highlight an emerging area of the unique combination of electrospinning with pDA surface functionalization. The scientific progress and understandings of pDA coating chemistry mechanisms, coating processes and characterization with aids of nanoscale analytical techniques are reviewed and discussed. The intrinsic biomimetic morphological characteristics of the electrospun nanofibers united with the unique advantages of the pDA associated bio-functionalization have endowed a range of successful applications, especially in the interesting and important field of bioengineering.

Objective: Obesity, insulin resistance, and diabetes disproportionately affect African-American (AA) women. Abnormal adipose tissue free fatty acid (FFA) release is associated with these conditions. Resting energy expenditure (REE) and sex predict FFA release in Caucasians, but whether this is true in AA is unknown. The sex-specific relationships between FFA release, REE, and race was compared., Design and Methods: 100 adults (47% AA, 50% male, age 32 ± 8 years [mean ± SD]) from three different centers underwent duplicate measures of FFA release ([U-13C] palmitate) and REE (indirect calorimetry). Body composition was determined by DXA and abdominal imaging., Results: AA participants had lower REE, but similar FFA concentrations and flux compared with Caucasian participants. The significant predictors of palmitate release were REE, sex, and race. REE and FFA flux were correlated in both sexes and both races. In a multiple linear regression analysis with palmitate flux as the dependent variable and REE, sex, race, total fat mass, fat-free mass, and insulin as independent variables, REE was the only independent predictor of FFA release in men. Both REE and race predicted palmitate flux in women., Conclusions: FFA flux is related to REE, but the relationship differs in AA and Caucasian women., (Copyright © 2013 The Obesity Society.)

Objective: IL-27 belongs to the IL-12 family of cytokines and is recognized for its role in Th cell differentiation and as an inhibitor of tumor angiogenesis. The purpose of this study was to investigate the effect of IL-27 on proliferation of lymphatic endothelial cells to gain insight into the interplay between the immune system and development of the lymphatic system., Methods: IL-27-stimulated signal transduction in human dermal lymphatic endothelial cells was measured by western blotting and synthesis of CXCL10 and CXCL11 by use of RT-PCR and ELISA. Proliferation was measured using MTT and BrdU kits and the role of STAT1 and chemokines was determined by use of siRNA and recombinant proteins., Results: Stimulation of lymphatic endothelial cell cultures with IL-27 induced JAK dependent phosphorylation of STAT1 and STAT3 and inhibited lymphatic endothelial cell proliferation and migration. Expression of CXCL10 and CXCL11, both STAT1 target genes, was profoundly up-regulated upon IL-27 stimulation, and recombinant CXCL10 and CXCL11 inhibited FGF-2-induced proliferation in vitro. siRNA targeting of STAT1 almost completely abrogated CXCL10 and CXCL11 expression as well as the proliferative effect of IL-27., Conclusions: IL-27 function as an anti-lymphangiogenic regulator in vitro by up-regulating chemokines and interfering with the mitogenic effect of growth factors through STAT1 activation., (© 2013 John Wiley & Sons Ltd.)