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Objective: Nonrestorative sleep and sleep disorders are commonly reported in patients suffering from craniomandibular (CMD) and craniocervical dysfunctions (CCD). This study aimed to investigate polysomnographic characteristics and the reduction of pain before and after treatment in these patients.Methods: Seventy-four patients with sleep disorders and evident CMD and CCD were included. Manual therapy and an Aqualizer® were used in the therapeutic group. Polysomnographic measurements were conducted pre- and post-therapy.Results: The number of sleep stage alterations and the sleep stage index differed significantly between pre- and post-therapeutic measurements. Between both groups, these parameters were significantly different, as well (p = .001 and p = .012). The subjective perception of sleep quality improved in 81.6% post-therapy (p < .001).Discussion: Manual therapy and the application of an Aqualizer® may improve sleep quality in patients suffering from CMD and CCD. Pain may not be the main cause for the sleep disorders in CMD and CCD. [ABSTRACT FROM AUTHOR]

The assessment of the quality of life (QoL) of patients with chronic diseases before and after medical interventions has gained increasing importance in recent decades. Particularly for patients with visible keloid scars in the head and neck region, standardized measurement tools are either absent or have been shown to be insufficient. The aim of the present study was to create a new standardized questionnaire that is specific to auricular keloid patients and reflects their clinical symptoms and QoL. The Keloid Intervention Benefit Inventory 21 (KIBI-21) questionnaire was developed in two stages. First, a group of experts identified a pool of 26 questions and modified and supplemented the items through a comparison with existing QoL assessments so that they related to keloid-specific clinical symptoms and the QoL of patients with auricular keloids before and after a medical intervention. This questionnaire was distributed to 27 outpatients who had undergone medical interventions for visible auricular keloids. Second, a sequential statistical analysis was conducted. This included a single-item assessment and reduction, analysis for internal consistency, construct validity, and divergence validity as well as a factor analysis. The analyses were performed for the entire questionnaire and for the items in the subcategories General Health, Physical Symptoms, Self-Esteem, and Social Impact. The final version of this newly validated and standardized KIBI questionnaire consisted of 21 items, of which each item was assigned to only one subscale. The questionnaire showed a Cronbach's α of 0.84 with a good internal consistency. In the item correlation validity, strong associations were found in all subscales, except for the Social Impact Subscale. The keloid-specific QoL questionnaire KIBI-21 proved to be a reliable and reproducible instrument to assess the QoL and clinical symptoms in patients suffering from auricular keloids before and after a medical treatment. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that vascular endothelial growth factor (VEGF) is upregulated in patients with hereditary hemorrhagic telangiectasia (HHT). The use of Bevacizumab as an anti-angiogenic treatment agent seems promising. The purpose of the present in vitro study was to determine the efficacy and potential toxicity levels of bevacizumab on cell proliferation and VEGF concentrations in endothelial cells of HHT patients. In this in vitro study, endothelial cells from patients with HHT and HUVECs (control) were incubated with different concentration levels of bevacizumab (2, 4, 6, 8 or 10 mg/ml). After 24, 48 or 72 h, the cell proliferation was assessed by Alamar Blue® Assay and the VEGF levels in the cell culture supernatants were measured by VEGF-ELISA. All endothelial cells incubated with bevacizumab showed an initial decrease in cell proliferation. Cell proliferation recovered within 72 h in cell cultures incubated with concentration levels of up to 4 mg/ml bevacizumab, whereas those incubated with higher concentration levels showed a continuous decline in cell proliferation. VEGF expression decreased after 24 h in cell cultures incubated with bevacizumab concentration levels of 2 and 4 mg/ml but increased again after 48 h. Cell cultures incubated with bevacizumab concentration levels of 10 mg/ml showed a constant decline in VEGF expression without any tendency for recovery. Translating these results into daily clinical practice, the present study suggests that the intranasal submucosal injection of bevacizumab in HHT patients should not exceed a concentration level of 4 mg/ml. Overall, higher bevacizumab concentration levels not only reduce VEGF expression but pose a higher risk of toxic effects on endothelial cells as they jeopardize cell proliferation. [ABSTRACT FROM AUTHOR]

The emerging cytokine tissue inhibitor of metalloproteinases-1 (TIMP-1) correlates with the progression of inflammatory diseases, including cancer. However, the effects of TIMP-1 on immune cell activation and underlying molecular mechanisms are largely unknown. Unbiased ligand-receptor-capture-screening revealed TIMP-1-interaction with Amyloid Precursor Protein (APP) family members, namely APP and Amyloid Precursor-like Protein-2 (APLP2), which was confirmed by pull-down assays and confocal microscopy. We found that TIMP-1 triggered glucose uptake and proinflammatory cytokine expression in human monocytes. In cancer patients, TIMP-1 expression positively correlated with proinflammatory cytokine expression and processes associated with monocyte activation. In pancreatic cancer, TIMP-1 plasma levels correlated with the monocyte activation marker sCD163, and the combined use of both clinically accessible plasma proteins served as a powerful prognostic indicator. Mechanistically, TIMP-1 triggered monocyte activation by its C-terminal domain and via APP as demonstrated by in vitro interference, in silico docking, and the employment of recombinant TIMP-1 variants. Identification of TIMP-1 as a trigger of monocyte activation opens new therapeutic perspectives for inflammatory diseases. [ABSTRACT FROM AUTHOR]

Background/aim: Transforming growth factor-β (TGF-β) plays a significant role in the formation of different cancer subtypes. There is evidence that TGF-β pathways promote cancerogenic cell characteristics but also have tumor-suppressor capabilities. The tyrosine kinase inhibitors nilotinib, dasatinib, erlotinib, gefitinib, and everolimus are approved as targeted therapies for several tumor entities, including head and neck squamous cell carcinoma (HNSCC). This study aimed to investigate the effects of these substances on the expression levels of TGFβ1 and TGF-β receptor type 2 (TGFβR2) in HPV-negative and HPV-positive SCC cell cultures., Materials and Methods: Expression patterns of TGFβ1 and TGFβR2 were determined using enzyme-linked immunosorbent assay (ELISA) in three HNSCC cell lines (i.e., HNSCC-11A, HNSCC-14C, and CERV196). These cells were incubated with nilotinib, dasatinib, erlotinib, gefitinib, and everolimus (20 μmol/l) and compared to a chemonaive control. An assessment of concentration levels was conducted after 24, 48, 72, and 96 h of treatment., Results: Statistically significant changes in the expression levels of TGFβ1 and TGFβR2 were found in all tested cell cultures (p<0.05) compared to the negative control. An increase in TGFβ-R2 expression was detected after treatment with most of the tested tyrosine kinase inhibitors, whereas a reduction in TGFβ1 was observed. The addition of everolimus had the opposite effect on both TGFβR2 and TGF-B1- expression., Conclusion: Expression of TGFβ1 and TGFβR2 was detected in all cultured HNSCC cell lines. Nilotinib, dasatinib, erlotinib, gefitinib, and everolimus had an impact on the expression levels of TGFβ1 and TGFβR2 in vitro., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: The treatment of auricular keloids is challenging, as they tend to recur; further, the treatment may impact quality of life and implies cosmetic and functional impairment for each patient. There is no standardized therapeutic concept established, and the literature is lacking long-term results of available treatment modalities. Methods: Patients suffering from auricular keloids were included in the study. All patients had undergone surgical resection, intralesional injection of triamcinolone acetonide (TAC), and the application of an individual pressure splint. Quality of life (QoL) was assessed using the keloid intervention benefit inventory 21 (KIBI-21). Further analysis was carried out for patients without (group 1) and with (group 2) recurrence of the keloid. Results: In total, 50 keloids with a mean follow-up period of 59 months (range 6-137 months) could be analyzed. In nine cases (18%), a keloid recurrence was found during the observation period. The assessment of QoL differed significantly between study groups at P = 0.04, as well as for the subcategories General Health (GH) and Physical Health (PH). No differences were found for the categories Social Impact (SI) and Self-Esteem (SE). Conclusions: The multimodal subsequent treatment regimen consisting of surgical resection, intralesional TAC injection, and the application of an individual magnetic pressure splint shows good results concerning long-term recurrence rates. The treatment method shows positive effects on the QoL, especially in the measured categories GH and PH., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Sex disparity in cancer is so far inadequately considered, and components of its basis are rather unknown. We reveal that male versus female pancreatic cancer (PC) patients and mice show shortened survival, more frequent liver metastasis, and elevated hepatic metastasis-promoting gene expression. Tissue inhibitor of metalloproteinases 1 (TIMP1) was the secreted factor with the strongest male-biased expression in patient-derived pancreatic tumors. Male-specific up-regulation of systemic TIMP1 was demonstrated in PC mouse models and patients. Using TIMP1-competent and TIMP1-deficient PC mouse models, we established a causal role of TIMP1 in determining shortened survival and increased liver metastasis in males. Observing TIMP1 expression as a risk parameter in males led to identification of a subpopulation exhibiting increased TIMP1 levels (T1HI males) in both primary tumors and blood. T1HI males showed increased risk for liver metastasis development not only in PC but also in colorectal cancer and melanoma. This study reveals a lifestyle-independent sex disparity in liver metastasis and may open new avenues toward precision medicine., Competing Interests: Disclosures:   O. Prokopchuk reported grants from DZIF (grant TI07.001) during the conduct of the study. K. Steiger reported personal fees from Roche outside the submitted work; in addition, K. Steiger had a patent to a radiopharmaceutical issued and is a member of the advisory board of TRIMT. No other disclosures were reported., (© 2021 Hermann et al.)

Tumor-derived protein tissue inhibitor of metalloproteinases-1 (TIMP1) correlates with poor prognosis in many cancers, including highly lethal pancreatic ductal adenocarcinoma (PDAC). The noncanonical signaling activity of TIMP1 is emerging as one basis for its contribution to cancer progression. However, TIMP1-triggered progression-related biological processes are largely unknown. Formation of neutrophil extracellular traps (NET) in the tumor microenvironment is known to drive progression of PDAC, but factors or molecular mechanisms initiating NET formation in PDAC remain elusive. In this study, gene-set enrichment analysis of a human PDAC proteome dataset revealed that TIMP1 protein expression most prominently correlates with neutrophil activation in patient-derived tumor tissues. TIMP1 directly triggered formation of NETs in primary human neutrophils, which was dependent on the interaction of TIMP1 with its receptor CD63 and subsequent ERK signaling. In genetically engineered PDAC-bearing mice, TIMP1 significantly contributed to NET formation in tumors, and abrogation of TIMP1 or NETs prolonged survival. In patient-derived PDAC tumors, NETs predominantly colocalized with areas of elevated TIMP1 expression. Furthermore, TIMP1 plasma levels correlated with DNA-bound myeloperoxidase, a NET marker, in the blood of patients with PDAC. A combination of plasma levels of TIMP1 and NETs with the clinically established marker CA19-9 allowed improved identification of prognostically distinct PDAC patient subgroups. These observations may have a broader impact, because elevated systemic levels of TIMP1 are associated with the progression of a wide range of neutrophil-involved inflammatory diseases. SIGNIFICANCE: These findings highlight the prognostic relevance of TIMP1 and neutrophil extracellular traps in highly lethal pancreatic cancer, where a noncanonical TIMP1/CD63/ERK signaling axis induces NET formation. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/13/3568/F1.large.jpg., (©2021 American Association for Cancer Research.)

Objective : Nonrestorative sleep and sleep disorders are commonly reported in patients suffering from craniomandibular (CMD) and craniocervical dysfunctions (CCD). This study aimed to investigate polysomnographic characteristics and the reduction of pain before and after treatment in these patients. Methods : Seventy-four patients with sleep disorders and evident CMD and CCD were included. Manual therapy and an Aqualizer® were used in the therapeutic group. Polysomnographic measurements were conducted pre- and post-therapy. Results : The number of sleep stage alterations and the sleep stage index differed significantly between pre- and post-therapeutic measurements. Between both groups, these parameters were significantly different, as well ( p  = .001 and p = .012). The subjective perception of sleep quality improved in 81.6% post-therapy ( p  < .001). Discussion : Manual therapy and the application of an Aqualizer® may improve sleep quality in patients suffering from CMD and CCD. Pain may not be the main cause for the sleep disorders in CMD and CCD.