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Breast cancer bone metastasis is a major cause of mortality in patients with advanced breast cancer. Although decreased mineral density is a known risk factor for bone metastasis, the underlying mechanisms remain poorly understood because studying the isolated effect of bone mineral density on tumor heterogeneity is challenging with conventional approaches. Moreover, mineralized biomaterials are commonly utilized for clinical bone defect repair, but how mineralized biomaterials affect the foreign body response and wound healing is unclear. Here, we investigate how bone mineral affects tumor growth and microenvironmental complexity in vivo by combining single-cell RNA-sequencing with mineral-containing or mineral-free decellularized bone matrices. We discover that the absence of bone mineral significantly influences fibroblast and immune cell heterogeneity, promoting phenotypes that increase tumor growth and alter the response to injury or disease. Importantly, we observe that the stromal response to bone mineral content depends on the murine tumor model used. While lack of bone mineral induces tumor-promoting microenvironments in both immunocompromised and immunocompetent animals, these changes are mediated by altered fibroblast phenotype in immunocompromised mice and macrophage polarization in immunocompetent mice. Collectively, our findings suggest that bone mineral density affects tumor growth by impacting microenvironmental complexity in an organism-dependent manner., Competing Interests: Declaration of competing interest The authors 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. Published by Elsevier Ltd.)

Adult-onset foveomacular vitelliform dystrophy (AOFVD) is a rare condition affecting the macula that presents diagnostic and management challenges due to its varied manifestations and clinical overlap with other retinal disorders. As vitelliform lesions can occur in various conditions, such as Best disease and age-related macular degeneration, clinical presentation, multimodal imaging findings, and genetic testing can aid in accurate diagnosis. Although AOFVD typically affects both eyes, unilateral involvement can occur. This study presents four cases of unilateral AOFVD in female patients aged 43 to 66 years. Each patient was monitored for two years with fundoscopy and multimodal imaging, including color fundus photography, optical coherence tomography (OCT), OCT-angiography, fluorescein angiography, and fundus autofluorescence (FAF). All patients presented with a characterized solitary, subfoveal, yellow lesion on fundoscopy. FAF revealed intense hyperautofluorescence corresponding with the lesions. OCT revealed the accumulation of homogenous hyperreflective material between the retinal pigment epithelium and photoreceptors. No abnormal findings were observed in the fellow eyes. Subfoveal choroidal thickness was measured at 355 μm, 545 μm, 486 μm, and 669 μm in the affected eyes. While AOFVD typically manifests bilaterally, these cases demonstrate a unique unilateral presentation, highlighting the importance of comprehensive examination and differential diagnosis. Distinguishing cases with unilateral presentation from other conditions can be more challenging, so awareness of this unusual phenotype and its clinical characteristics must be raised. Choroidal thickness measurements provide additional insights into AOFVD pathophysiology, suggesting a potential association with the pachychoroid spectrum., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Spanos et al.)

Ovulation is essential for reproductive success, yet the underlying cellular and molecular mechanisms are far from clear. Here, we applied high-resolution spatiotemporal transcriptomics to map out cell type- and ovulation stage-specific molecular programs as function of time during follicle maturation and ovulation in mice. Our analysis revealed dynamic molecular transitions within granulosa cell types that occur in tight coordination with mesenchymal cell proliferation. We identified molecular markers for the emerging cumulus cell fate during the preantral-to-antral transition. We describe transcriptional programs that respond rapidly to ovulation stimulation and those associated with follicle rupture, highlighting the prominent roles of apoptotic and metabolic pathways during the final stages of follicle maturation. We further report stage-specific oocyte-cumulus cell interactions and diverging molecular differentiation in follicles approaching ovulation. Collectively, this study provides insights into the cellular and molecular processes that regulate mouse ovarian follicle maturation and ovulation with important implications for advancing therapeutic strategies in reproductive medicine., Competing Interests: Competing interests statement:The authors declare no competing interest.

Objectives: To examine adrenal cortex reserve in patients with rheumatic and musculoskeletal diseases (RMD) who relapse upon tapering of low glucocorticoid dose, despite concomitant treatment with disease-modifying anti-rheumatic drugs (DMARDs)., Methods: A morning standard dose of 250 mcg tetracosactide (Synacthen test) was given in 25 consecutive patients (13 rheumatoid arthritis, 2 psoriatic arthritis, 5 systemic lupus erythematosus, 2 dermatomyositis, 1 systemic sclerosis, 2 temporal arteritis) at the time of relapse upon small reductions (1-2 mg daily) of low prednisolone dose (<7.5 mg daily), while being on stable concomitant treatment with methotrexate, leflunomide, hydroxychloroquine, azathioprine, mycophenolate, tofacitinib, belimumab, anti-TNF, anti-IL-6 or anti-IL-1 regimens (n=14; 3; 9; 1; 2; 1; 1; 5; 2; 1, respectively). Sex-matched apparently healthy individuals (n=45) served as controls., Results: Baseline cortisol levels and time-integrated cortisol response to tetracosactide were lower in patients than controls (12.01±4.47 vs. 15.63±4.16 mcg/dl, p=0.001, and 1050±286 vs. 1284±182, p<0.001, respectively). No significant associations were observed between the cortisol response to tetracosactide and age, duration of disease or glucocorticoid treatment. An abnormal Synacthen test, indicative of adrenal insufficiency, presumably secondary to chronic glucocorticoid administration, was noted in 5/25 patients. The remaining 20 patients (80%) had normal Synacthen test demonstrating, however, lower cortisol response than controls, independently of age (β-coefficient=-0.373, p=0.033)., Conclusions: Patients with RMD in remission under DMARDs who relapse upon concomitant low glucocorticoid dose tapering should be tested for iatrogenic adrenal insufficiency. Whether a marginally normal Synacthen test should discourage further attempts to withdraw glucocorticoid treatment in these patients warrants further investigation.

Purpose: To determine the extent of treatment traces, the roughness depth, and the quantity of titanium nitride (TiN) removed from the surface of CAD/CAM abutments after treatment with various instruments., Materials and Methods: Twelve TiN coated CAD/CAM abutments were investigated for an in vitro study. In the test group (9), each abutment surface was subjected twice (150 g vs. 200 g pressure) to standardized treatment in a simulated prophylaxis measure with the following instruments: acrylic scaler, titanium curette, and ultrasonic scaler with steel tip. Three abutments were used as control group. Average surface roughness (Sa) and developed interfacial area ratio (Sdr) of treated and untreated surfaces were measured with a profilometer. The extent of treatment traces were analyzed by scanning electron microscopy., Results: Manipulation with ultrasonic scalers resulted in a significant increase of average surface roughness (Sa, P <.05) and developed interfacial area ratio (Sdr, P <.018). Variable contact pressure did not yield any statistically significant difference on Sa-values for all instruments ( P =.8). Ultrasonic treatment resulted in pronounced surface traces and partially detachment of the TiN coating. While titanium curettes caused predominantly moderate treatment traces, no traces or detectable substance removal has been determined after manipulation with acrylic curettes., Conclusion: Inappropriate instruments during regular plaque control may have an adverse effect on the integrity of the TiN coating of CAD/CAM abutments. To prevent defects and an increased surface roughness at the transmucosal zone of TiN abutments, only acrylic scaling instruments can be recommended for regular maintenance care.

Eribis Peptide 94 (EP94) is an enkephalin analog with cardioprotective properties in ischemia and reperfusion. The aim of the present study was to define the optimal timing and dosing of the administration of EP94 during ischemia and reperfusion in a rat model. 172 anesthetized and mechanically ventilated male Sprague-Dawley rats were randomly assigned to different administration protocols of EP94 and subjected to 30 or 40 min of coronary artery occlusion followed by 2h of reperfusion. EP94 was administered intravenously at different doses and time intervals. Area at risk (AAR) and infarct size (IS) were determined by staining with Evans Blue (EB) and Triphenyl tetrazolium chloride (TTC), respectively. EP94 reduced IS/AAR when administered as a double bolus (0.5 µg/kg per dose), whereas single (1 μg/kg) or triple boluses (0.5 μg/kg per dose) did not confer any protection. Reduction of IS/AAR was of highest magnitude if EP94 was administered 5 and 0 min before the 30 min ischemic period (47% reduction, P<0.05), with declining cardioprotective effect with later administration during ischemia. When EP94 was administered after 15 and 20 min of a 40-min ischemic period, reduction of IS/AAR was of the same magnitude as when given after 5 and 10 min of a 30-min ischemic period. It is concluded that EP94 confers cardioprotection after double bolus administration. The effects are highly dependent on the timing of administration in relation to ischemia and reperfusion. Time of reperfusion from drug administration seems to be more critical than the total duration of ischemia., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In this placebo controlled double blind cross over study multiple daily dosing with 500 mg acetylic salicylic acid did not influence heart rate variability in 16 healthy male volunteers aged 25 (22-28) years (median; range) to a relevant extent (p > 0.05).

Adiponectin, an adipocyte-secreted hormone, is closely and inversely associated with insulin resistance and was recently found to be inversely and independently associated with endometrial cancer. Because insulin resistance in the setting of obesity has also been associated with the development of breast cancer, we have hypothesized that decreased adiponectin levels might underlie the association between breast cancer and obesity/insulin resistance. We evaluated the association of adiponectin with the occurrence of breast cancer in a case-control study comprising 174 women with newly diagnosed, histologically confirmed breast cancer and 167 controls. We found an inverse, fairly strong, and statistically significant association of serum adiponectin with breast cancer (odds ratio, 0.84; 95% confidence interval, 0.71-0.99). Importantly, despite a fairly robust inverse association of adiponectin with breast cancer risk among postmenopausal women (odds ratio, 0.82; 95% confidence interval, 0.67-1.00), no such significant association between adiponectin and breast cancer was found among premenopausal women. The observed associations were independent of possible effects of major components of the IGF system, leptin, body mass index, sociodemographic variables, and known risk factors for breast cancer. Future studies are needed to prove causality and provide further insights into both the mechanisms underlying the actions of this hormone and its potential role in breast cancer.

Objectives: Insulin-like growth factor I (IGF-I) and other components of the IGF system have been implicated in the etiology of several human malignancies. We have undertaken a case-control study among Greek women to explore the relation of major components of the IGF system (IGF-I, IGF-II and IGF-binding protein 3, IGFBP-3) with endometrial cancer risk., Methods: During a 1-year period (1999), 84 incident cases of histologically confirmed endometrial cancer were compared with 84 control women admitted to the same clinical department for small gynecological operations, mainly pelvic prolapse. Data were modeled through multiple logistic regression., Results: Endometrial cancer was positively associated with IGF-II and inversely with IGF-I. Both associations were statistically significant and they appear symmetrical around the null value. IGFBP-3 is positively associated with endometrial cancer risk, but this association does not reach statistical significance., Conclusions: This study adds to the gradually developing consensus that components of the IGF system play a central role in human carcinogenesis. It is possible that IGF-II, rather than IGF-I, is closely linked to the etiology of endometrial cancer, the form of cancer most strongly associated with obesity., (Copyright 2003 S. Karger AG, Basel)

Background/aims: Dehydroepiandrosterone (DHEA) is generally considered to have beneficial effects in humans. There is, however, limited information concerning the role of lifestyle variables, including diet, on blood DHEA levels. We have undertaken a study of DHEA determinants in a general population sample of adult Greeks., Methods: The sample consisted of 620 apparently healthy men and women aged 35-65 years, from all over Greece, participating in the EPIC study. Plasma DHEA was determined by radioimmunoassay. Nutritional intakes were ascertained through an interviewer-administered validated food frequency questionnaire, which also contained information on lifestyle variables. Statistical analyses were undertaken through simple cross-tabulations and by modelling the data through multiple regression., Results: DHEA declines sharply with age and there is some evidence that the decline may be sharper in men than in women. Protein intake was significantly inversely associated with plasma levels of DHEA, whereas other dietary factors, energy expenditure and anthropometric variables were unrelated to this hormone. Alcohol intake and tobacco smoking tended to be positively related to DHEA, but the respective associations were not statistically significant., Conclusion: There has been a growing interest in replacement of DHEA in ageing adults. If confirmed, our results would indicate that a reduction in protein intake could have qualitatively similar effects., (Copyright 2003 S. Karger AG, Basel)

Background/aim: Because leptin is a hormone associated with obesity and reproduction, we attempted to examine whether there is a relationship between leptin and endometrial cancer., Methods: Cases were 84 women with histologically confirmed incident endometrial cancer, whereas controls were 84 women admitted to the same hospital for small surgical operations. The serum leptin levels were determined in fasting morning blood samples by using radioimmunoassay. The mean values of leptin levels among cases and controls were compared with simple t test, and the data were further analyzed using multiple logistic regression procedures., Results: The serum leptin levels were 36.7 +/- (SD) 25.7 ng/ml among cases and 26.9 +/- 19.8 ng/ml among controls (p = 0.006). After adjustment for known risk factors of endometrial cancer, components of the insulin-like growth factor system did not confound the association of leptin with endometrial cancer, but this association was eliminated, when the body mass index was adjusted for. Thus, the odds ratio for an increment of 1 SD of blood leptin was 1.52 (p = 0.03) before adjustment for body mass index, but only 1.13 (p = 0.62) after adjustment for it., Conclusions: In a case-control study of incident endometrial cancer in Greece, we found evidence that leptin is strongly positively associated with endometrial cancer. It cannot be conclusively inferred, however, whether leptin elevation, as a consequence of obesity, plays a role in endometrial carcinogenesis or whether it is a simple correlate of obesity., (Copyright 2002 S. Karger AG, Basel)

Objectives: To assess whether age at menarche, age at menopause, parity, and selected blood hormones are associated with risk of hepatocellular carcinoma among women., Design: Case-control., Sample: and setting Data collected from 50 cases of hepatocellular carcinoma among women and 62 female controls with minor trauma or surgical conditions who attended one of three hospitals in Athens, Greece between 1995 and 1998., Methods: Researchers collected information on Reproductive variables and assayed sera samples for blood hormone levels and for chronic infection with Hepatitis B and C viruses. RESULTS Individuals with hepatocellular carcinoma had a lower mean age at menarche and a significantly higher mean age at menopause. After adjusting for potential confounding, age at menopause remained an important and significant predictor, increasing the risk of hepatocellular carcinoma 24% for each later year of menopause (P < 0.001). For each year that menarche was delayed, risk of hepatocellular carcinoma declined 21% (P = 0.100). Mean levels of insulin-like growth factor-1 and its binding protein were significantly reduced in cases compared with controls, while levels of oestradiol, testosterone and sex hormone binding globulin were somewhat higher among the cases., Conclusions: This study provides indirect, but converging evidence that steroid hormones in general, and oestrogens in particular, play an important role in the aetiology of hepatocellular carcinoma among women.

Objective: To investigate whether the three principal components of the insulin-like growth factor (IGF) system, IGF-1, IGF-2 and IGF binding protein-3 (IGFBP-3), are associated with survival from childhood leukemia., Patients and Methods: 116 children, 0--14 years old, with newly diagnosed and bone-marrow-biopsy-confirmed acute childhood leukemia between 1993 and 1996 were followed up until death or March 31, 1998. IGF-1, IGF-2 and IGFBP-3 were measured at diagnosis and clinical data, including presence of hepatosplenomegaly and number of white blood cells, were available., Results: After controlling for gender, age, indicators of clinical severity and the other measured components of the IGF system there was a statistically significant (p < 0.05) inverse association of IGFBP-3 with survival. An increment of one standard deviation in IGFBP-3 was associated with a 65% reduction of the death hazard among the children with leukemia. Neither IGF-1 nor IGF-2 was associated with survival in this data set., Conclusion: The presented empirical evidence in conjunction with the fact that IGFBP-3 modulates IGF-1 and IGF-2 bioavailability and is likely to have proapoptotic effects makes this compound a plausible independent predictor of survival from childhood leukemia., (Copyright 2001 S. Karger AG, Basel)

Objective: Liver disease in men has been associated with an imbalance of serum estradiol and testosterone. We have evaluated whether serum estradiol and testosterone levels are altered in male liver cancer patients as a result of a specific effect of the disease or because of the associated liver damage., Methods: We have performed a hospital-based case-control study in Greece. The study subjects were all men; 73 patients with hepatocellular carcinoma (HCC), 25 with metastatic liver cancer (MLC) patients and 111 control subjects. Serum estradiol, testosterone and sex hormone binding globulin (SHBG) levels were measured for each subject. Data were analyzed by multiple linear regression., Results: Mean serum estradiol levels were significantly higher among HCC patients as well as among patients with MLC compared to controls. Mean serum testosterone levels were significantly lower among HCC patients as well as among patients with MLC compared to controls. The mean SHBG levels did not differ significantly between the groups. After controlling for the degree of liver damage, the elevated serum estradiol and reduced serum testosterone levels among HCC and MLC patients were no longer significant., Conclusions: Changes in sex steroid levels among patients with liver damage are due to the liver damage per se and not to specific disease processes., (Copyright 2001 S. Karger AG, Basel.)

The insulin-like growth factor (IGF) axis has important autocrine, paracrine, and endocrine roles in the promotion of growth. Alterations of the IGF system have recently been implicated in the pathogenesis of several malignancies, but the relation to hepatocellular carcinoma (HCC) risk is unclear. To address this issue, we used an immunoradiometric assay to quantify IGF-1 levels in serum samples in a hospital-based, case-control study in Greece. The study subjects were all men and included 53 patients with HCC positive for hepatitis B and/or hepatitis C virus infections, 20 virus-negative HCC patients, 25 virus-negative patients with metastatic liver cancer (MLC), and 111 virus-negative control subjects. Data were analyzed by multiple linear regression, using IGF-1 as the dependent variable. The mean value of IGF-1 was 65.9 ng/ml among virus-positive HCC patients, 79.5 ng/ml among virus-negative HCC patients, 110.8 ng/ml among patients with MLC, and 174.7 ng/ml among hospital controls. After controlling for the degree of liver damage, as assessed by prothrombin time and serum albumin level, the reduction in IGF-1 level among HCC patients was found to be more than could be attributed to liver damage alone. This finding may have both diagnostic and pathophysiological implications., (Copyright 2000 Wiley-Liss, Inc.)

Objectives: Because both breast cancer and the hormone leptin are associated with obesity and reproductive phenomena in women, we have examined whether there is a relationship between leptin and breast cancer among premenopausal and postmenopausal women. We have also evaluated in this dataset the association of IGF-I with breast cancer., Methods: Seventy-five cases, diagnosed during mammographic screening, with incident breast cancer were matched for age and type of permanent residence with seventy-five controls from those screened negative in the same study base., Results: There was no evidence for an association between IGF-I and either premenopausal or postmenopausal breast cancer risk or between leptin and postmenopausal breast cancer. Among premenopausal women, however, there was a strong and statistically significant inverse association of leptin with breast cancer., Conclusion: We did not confirm the positive association, reported from other investigations, of IGF-I with premenopausal breast cancer risk. We have found evidence, however, that leptin may be inversely related to breast cancer risk among premenopausal women. The latter finding is not biologically implausible and deserves to be examined in additional datasets.