Abstract
Background
People with musculoskeletal pain seek more healthcare than the general population, however little is known about the long-term effect on healthcare use. The aim of this study was ...to examine the consequences of number of musculoskeletal pain sites on long-term care-seeking and healthcare-related costs and explore how health anxiety influences this relationship.
Methods
We conducted a Danish population-based longitudinal cohort study of 4883 participants combining self-reported survey data from 2008 with ten-year follow-up data from national health registers. Using a causal inference framework, we examined associations between number of pain sites (range 0–7)/level of health anxiety (high/low level) and face-to-face healthcare contacts/healthcare-related costs. Data were analyzed using negative binomial regression with generalized estimating equations. Regression models were adjusted for sex, age, duration of pain, level of education, comorbidity, personality traits, risk of depression, marital status, physical job exposure, and previous healthcare utilization.
Results
For each additional pain site general healthcare contacts (Incidence Rate Ratio (IRR): 1.04 (95% CI: 1.03–1.05)), healthcare-related costs (IRR: 1.06 (95% CI: 1.03–1.08) and musculoskeletal healthcare contacts (IRR: 1.11 (95% CI:1.09–1.14) increased. Those with high levels of health anxiety at baseline had a slightly higher number of general healthcare contacts (IRR 1.06 (1.01–1.11), independent of number of pain sites. However, level of anxiety did not influence the effect of number of pain sites on any healthcare use or cost outcomes.
Conclusions
We found evidence for a causal association between increasing number of pain sites and greater healthcare use and cost, and high levels of health anxiety did not increase the strength of this association. This suggests that number of pain sites could be a potential target for biopsychosocial interventions in order to reduce the need for future care-seeking.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked desmoplasia and drug resistance due, in part, to poor drug delivery to extravascular tumor tissue. Here, we report that ...carcinoma-associated fibroblasts (CAFs) induce β5 integrin expression in tumor cells in a TGF-β dependent manner, making them an efficient drug delivery target for the tumor-penetrating peptide iRGD. The capacity of iRGD to deliver conjugated and co-injected payloads is markedly suppressed when β5 integrins are knocked out in the tumor cells. Of note, β5 integrin knock-out in tumor cells leads to reduced disease burden and prolonged survival of the mice, demonstrating its contribution to PDAC progression. iRGD significantly potentiates co-injected chemotherapy in KPC mice with high β5 integrin expression and may be a powerful strategy to target an aggressive PDAC subpopulation.
The MST1R (RON) kinase is overexpressed in >80% of human pancreatic cancers, but its role in pancreatic carcinogenesis is unknown. In this study, we examined the relevance of Mst1r kinase to Kras ...driven pancreatic carcinogenesis using genetically engineered mouse models. In the setting of mutant Kras, Mst1r overexpression increased acinar-ductal metaplasia (ADM), accelerated the progression of pancreatic intraepithelial neoplasia (PanIN), and resulted in the accumulation of (mannose receptor C type 1) MRC1+, (arginase 1) Arg+ macrophages in the tumor microenvironment. Conversely, absence of a functional Mst1r kinase slowed PanIN initiation, resulted in smaller tumors, prolonged survival and a reduced tumor-associated macrophage content. Mst1r expression was associated with increased production of its ligand Mst1, and in orthotopic models, suppression of Mst1 expression resulted in reduced tumor size, changes in macrophage polarization and enhanced T cell infiltration. This study demonstrates the functional significance of Mst1r during pancreatic cancer initiation and progression. Further, it provides proof of concept that targeting Mst1r can modulate pancreatic cancer growth and the microenvironment. This study provides further rationale for targeting Mst1r as a therapeutic strategy.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these ...compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 antitumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer.
KRAS-mutant pancreatic cancer models, including KRAS inhibitor-resistant models, show exquisite sensitivity to combined pan-ERBB and KRAS targeting, which provides the rationale for testing this drug combination in clinical trials.
Mucinous neoplasms of the appendix (MNA) are rare tumors which may progress from benign to malignant disease with an aggressive biological behavior. MNA is often diagnosed after metastasis to the ...peritoneal surfaces resulting in mucinous carcinomatosis peritonei (MCP). Genetic alterations in MNA are poorly characterized due to its low incidence, the hypo-cellularity of MCPs, and a lack of relevant pre-clinical models. As such, application of targeted therapies to this disease is limited to those developed for colorectal cancer and not based on molecular rationale.
We sequenced the whole exomes of 10 MCPs of appendiceal origin to identify genome-wide somatic mutations and copy number aberrations and validated significant findings in 19 additional cases.
Our study demonstrates that MNA has a different molecular makeup than colorectal cancer. Most tumors have co-existing oncogenic mutations in KRAS (26/29) and GNAS (20/29) and are characterized by downstream PKA activation. High-grade tumors are GNAS wild-type (5/6), suggesting they do not progress from low-grade tumors. MNAs do share some genetic alterations with colorectal cancer including gain of 1q (5/10), Wnt, and TGFβ pathway alterations. In contrast, mutations in TP53 (1/10) and APC (0/10), common in colorectal cancer, are rare in MNA. Concurrent activation of the KRAS and GNAS mediated signaling pathways appears to be shared with pancreatic intraductal papillary mucinous neoplasm.
MNA genome-wide mutational analysis reveals genetic alterations distinct from colorectal cancer, in support of its unique pathophysiology and suggests new targeted therapeutic opportunities.
We determine both the semigroup and spectral properties of a group of weighted composition operators on the little Bloch space. It turns out that these are strongly continuous groups of invertible ...isometries on the Bloch space. We then obtain the norm and spectra of the infinitesimal generator as well as the resulting resolvents which are given as integral operators. As a consequence, we complete the analysis of the adjoint composition group on the predual of the nonreflexive Bergman space and a group of isometries associated with a specific automorphism of the upper half-plane. Dedicated to Prof. Len Miller (PhD advisor to J. O. Bonyo) and Prof. Vivien Miller of Mississippi State University on their retirement
Background
Factors associated with development of medication-overuse headache (MOH) in migraine patients are not fully understood, but with respect to prevention, the ability to predict the onset of ...MOH is clinically important. The aims were to examine if personality characteristics, disability and physical activity level are associated with the onset of MOH in a group of migraine patients and explore to which extend these factors combined can predict the onset of MOH.
Methods
The study was a single-center prospective observational study of migraine patients. At inclusion, all patients completed questionnaires evaluating 1) personality (NEO Five-Factor Inventory), 2) disability (Migraine Disability Assessment), and 3) physical activity level (Physical Activity Scale 2.1). Diagnostic codes from patients’ electronic health records confirmed if they had developed MOH during the study period of 20 months. Analyses of associations were performed and to identify which of the variables predict onset MOH, a multivariable least absolute shrinkage and selection operator (LASSO) logistic regression model was fitted to predict presence or absence of MOH.
Results
Out of 131 participants, 12 % (
n
=16) developed MOH. Migraine disability score (OR=1.02, 95 % CI: 1.00 to 1.04), intensity of headache (OR=1.49, 95 % CI: 1.03 to 2.15) and headache frequency (OR=1.02, 95 % CI: 1.00 to 1.04) were associated with the onset of MOH adjusting for age and gender. To identify which of the variables predict onset MOH, we used a LASSO regression model, and evaluating the predictive performance of the LASSO-mode (containing the predictors MIDAS score, MIDAS-intensity and –frequency, neuroticism score, time with moderate physical activity, educational level, hours of sleep daily and number of contacts to the headache clinic) in terms of area under the curve (AUC) was weak (apparent AUC=0.62, 95% CI: 0.41-0.82).
Conclusion
Disability, headache intensity and frequency were associated with the onset of MOH whereas personality and the level of physical activity were not. The multivariable LASSO model based on personality, disability and physical activity is applicable despite moderate study size, however it can be considered as a weak classifier for discriminating between absence and presence of MOH.
We report the expression of melanocyte-related genes (MRG) in freshly resected, histopathologically confirmed, human breast cancer specimens and describe experiments illuminating similar observations ...on a variety of breast cancer cell lines including MDA-MB-435. This finding has implications for research on breast cancer, for clinical investigation of cancer patients presenting with metastases from occult primary tumors and for understanding aberrant differentiation in cancer cells. For example, higher expression of six MRG correlated inversely with propensity for metastatic spread in clones isolated from the human breast cancer cell line MDA-MB-435. Comparisons of MRG expression in cells growing in vitro with those seen in tumors generated by the same lines in vivo showed that the levels of activity of these genes are influenced by the surrounding environment. Also, silencing of expression of the melanocyte-related transcription factor MITF, by transduction of the non-metastatic clone NM2C5 with a construct expressing a specific anti-MITF shRNA, resulted in decreased production of 5 of the melanocyte-related proteins including TYRP1, Pmel 17, MART 1(Melan-A) and TYRP2, but no increase in metastatic capability. Hence MRG expression reproducibly ear-marked, but did not cause, metastatic incompetence. We also report cytogenetic and other data that conflict with the recent suggestion that MDA-MB-435 is of melanocytic origin and are more consistent with its original designation as being of mammary lineage. We conclude that detection of MRG expression profiles in freshly excised breast cancers and in cultured breast cancer cells reflects the operationally important clinical phenomenon of inappropriate gene expression in malignant neoplasms. Concomitantly, we suggest that the evidence we have obtained (i) collectively supports the continued widespread use of the MDA-MB-435 cell line in breast cancer and metastasis research and (ii) advances knowledge of the diversity of aberrant differentiation programs in malignant cells, which is valuable for making accurate diagnoses and treatment decisions in clinical oncology.
Pancreatic cancer is an aggressive disease associated with a poor 5-year overall survival. Most patients are ineligible for surgery due to late diagnosis and are treated primarily with chemotherapy ...with very limited success. Pancreatic cancer is relatively insensitive to chemotherapy due to multiple factors, including reduced bioavailability of drugs to tumor cells. One strategy to improve drug efficacy with reduced toxicity is the development of antibody-drug conjugates (ADC), which have now been used successfully to treat both solid and liquid tumors. Here, we evaluate the efficacy of TR1801-ADC, a newly developed ADC composed of a MET antibody conjugated to the highly potent pyrrolobenzodiazepine toxin-linker, tesirine.
We first evaluated MET expression and subcellular localization in pancreatic cancer cell lines, human tumors, and patient-derived xenografts (PDX). We then tested TR1801-ADC efficacy
in pancreatic cancer cell lines. Preclinical evaluation of TR1801-ADC efficacy was conducted on PDXs selected on the basis of their MET expression level.
We show that MET is highly expressed and located at the plasma membrane of pancreatic cancer cells. We found that TR1801-ADC induces a specific cytotoxicity in pancreatic cancer cell lines and a profound tumor growth inhibition, even in a gemcitabine-resistant tumor. We also noted synergism between TR1801-ADC and gemcitabine
and an improved response to the combination
.
Together, these results suggest the promise of agents such as TR1801-ADC as a novel approach to the treatment of pancreatic cancer.
Objectives
Medication‐overuse headache (MOH) is recognized as a biobehavioural disorder, warranting that both biological and psychological factors are targeted throughout treatment. A psychological ...factor of importance may be personality that could be used to tailor treatment if differences are found across headache diagnoses. The objectives were as follows: (a) To investigate if migraine patients and patients with MOH differed on personality traits, (b) To investigate if the two headache groups differed from a Danish normative sample, with respect to personality traits.
Materials and Methods
The NEO‐Five‐Factor Inventory was completed, and an age‐matched cohort of episodic migraine patients (n = 94) and MOH patients (n = 94) was included. Multivariate regression models and sex‐stratified comparisons were made on patients’ raw scores from five personality traits; neuroticism, extraversion, openness, agreeableness, and conscientiousness. The headache groups were also compared to personality traits from a Danish normative sample (n = 1032).
Results
MOH females obtained significantly lower scores on extraversion (24.4 ± 4.3 vs 27.1 ± 7.2, P < 0.01), openness (23.7 ± 3.9 vs 26.2 ± 6.4, P < 0.01), and conscientiousness (28.9 ± 3.7 vs 34.6 ± 5.8, P > 0.01) as compared to female migraineurs. Males showed no differences. Compared to the normative sample, both headache groups showed a lower score on extraversion (P < 0.01). Furthermore, MOH patients had statistically significant lower scores on conscientiousness while the migraine patients had a higher score.
Conclusion
Results suggests some personality trait differences between migraine and MOH patients. Especially, females showed different personality traits, where the MOH females appeared more introvert and less socially orientated. If confirmed in larger studies, this information could be used in personalized treatment in clinical practice.
PDF
