Specific effects of bortezomib against experimental malignant pleural effusion: a preclinical study

BACKGROUND: We have previously shown that nuclear factor (NF)-κB activation of mouse Lewis lung carcinoma (LLC) specifically promotes the induction of malignant pleural effusions (MPE) by these cells. In the present studies we hypothesized that treatment of immunocompetent mice with bortezomib tailored to inhibit cancer cell NF-κB activation and not proliferation specifically inhibits MPE formation by LLC cells. RESULTS: Treatment of LLC cells with low concentrations of bortezomib (100 ng/ml) inhibited NF-κB activation and NF-κB-dependent transcription, but not cellular proliferation. Bortezomib treatment of immunocompetent C57BL/6 mice bearing LLC-induced subcutaneous tumors and MPEs significantly blocked tumor-specific NF-κB activation. However, bortezomib treatment did not impair subcutaneous LLC tumor growth, but was effective in limiting LLC-induced MPE. This specific effect was evidenced by significant reductions in effusion accumulation and the associated mortality and was observed with both preventive (beginning before MPE formation) and therapeutic (beginning after MPE establishment) bortezomib treatment. The favorable impact of bortezomib on MPE was associated with suppression of cardinal MPE-associated phenomena, such as inflammation, vascular hyperpermeability, and angiogenesis. In this regard, therapeutic bortezomib treatment had identical favorable results on MPE compared with preventive treatment, indicating that the drug specifically counteracts effusion formation. CONCLUSIONS: These studies indicate that proteasome inhibition tailored to block NF-κB activation of lung adenocarcinoma specifically targets the effusion-inducing phenotype of this tumor. Although the drug has limited activity against advanced solid lung cancer, it may prove beneficial for patients with MPE

Sequential treatment with teriparatide and strontium ranelate in a postmenopausal woman with atypical femoral fractures after long-term bisphosphonate administration

AbstrAct ObJEctIVE: Despite the existence of numerous case series, no evidenced-based medical management for atypical fractures associated with bisphosphonate (bP) treatment has been established. DEsIGN: We report the outcome of teriparatide (trP) administration followed by strontium ranelate (sr) in a woman with a complete and an incomplete contralateral atypical fracture of the femoral diaphysis (AFF) associated with bP treatment. the spontaneous complete AFF was managed with intramedullary nailing, discontinuation of bP and initiation trP. rEsULts: Eleven months later, she suffered a contralateral incomplete AFF. At the completion of the trP treatment, she had only slight discomfort in the femur with the incomplete AFF. bMD testing revealed increase of 7.61% at the lumbar spine (Ls) and 0.8% at the hip. Following trP, 1-year sr treatment resulted in further bMD increase of 9.2% at the Ls and 1.4% in the hip, while she does not report any pain. bone markers remain within the normal range. cONcLUsION: Our case indicates that sequential therapy with trP and sr in cases of AFF might be a rational treatment option. However, there is a need for additional information concerning the effect of trP and sr, given alone or sequentially, in these patients in order to incorporate these drugs into the management of AFF

Impact of minimal residual disease detection by next-generation flow cytometry in multiple myeloma patients with sustained complete remission after frontline therapy

Minimal residual disease (MRD) was monitored in 52 patients with sustained CR (≥2 years) after frontline therapy using next-generation flow (NGF) cytometry. 25% of patients initially MRD- reversed to MRD+. 56% of patients in sustained CR were MRD+; 45% at the level of 10−5; 17% at 10−6. All patients who relapsed during follow-up were MRD+ at the latest MRD assessment, including those with ultra-low tumor burden. MRD persistence was associated with specific phenotypic profiles: higher erythroblasts’ and tumor-associated monocytes/macrophages’ predominance in the bone marrow niche. NGF emerges as a suitable method for periodic, reproducible, highly-sensitive MRD-detection at the level of 10−6

Static and dynamic mechanics of the murine lung after intratracheal bleomycin

<p>Abstract</p> <p>Background</p> <p>Despite its widespread use in pulmonary fibrosis research, the bleomycin mouse model has not been thoroughly validated from a pulmonary functional standpoint using new technologies. Purpose of this study was to systematically assess the functional alterations induced in murine lungs by fibrogenic agent bleomycin and to compare the forced oscillation technique with quasi-static pressure-volume curves in mice following bleomycin exposure.</p> <p>Methods</p> <p>Single intratracheal injections of saline (50 μL) or bleomycin (2 mg/Kg in 50 μL saline) were administered to C57BL/6 (<it>n </it>= 40) and Balb/c (<it>n </it>= 32) mice. Injury/fibrosis score, tissue volume density (TVD), collagen content, airway resistance (<it>R_N</it>), tissue damping (<it>G</it>) and elastance coefficient (<it>H</it>), hysteresivity (<it>η</it>), and area of pressure-volume curve (PV-A) were determined after 7 and 21 days (inflammation and fibrosis stage, respectively). Statistical hypothesis testing was performed using one-way ANOVA with LSD <it>post hoc </it>tests.</p> <p>Results</p> <p>Both C57BL/6 and Balb/c mice developed weight loss and lung inflammation after bleomycin. However, only C57BL/6 mice displayed cachexia and fibrosis, evidenced by increased fibrosis score, TVD, and collagen. At day 7, PV-A increased significantly and <it>G </it>and <it>H </it>non-significantly in bleomycin-exposed C57BL/6 mice compared to saline controls and further increase in all parameters was documented at day 21. <it>G </it>and <it>H</it>, but not PV-A, correlated well with the presence of fibrosis based on histology, TVD and collagen. In Balb/c mice, no change in collagen content, histology score, TVD, <it>H </it>and <it>G </it>was noted following bleomycin exposure, yet PV-A increased significantly compared to saline controls.</p> <p>Conclusions</p> <p>Lung dysfunction in the bleomycin model is more pronounced during the fibrosis stage rather than the inflammation stage. Forced oscillation mechanics are accurate indicators of experimental bleomycin-induced lung fibrosis. Quasi-static PV-curves may be more sensitive than forced oscillations at detecting inflammation and fibrosis.</p

Identifying Spatially Correlated Patterns between Surface Water and Frost Risk Using EO Data and Geospatial Indices

Frost is one the most significant hazards affecting various aspects of human lives including infrastructure, agriculture, economy and biodiversity. Water bodies are one of the key factors controlling temperature fluctuations and frost. This study introduces a contemporary method for identifying and spatially analyzing frost risk and also explores its spatial correlation with water bodies. The proposed technique is based on coupling freely distributed geospatial data with a time series of land surface temperature (LST) data from Moderate Resolution Imaging Spectroradiometer (MODIS) sensor. A region located in NW Greece, which annually suffers from very low temperatures and frost conditions and hosts important infrastructure and other human activities, was selected as a case study. In total, 5944 images were processed covering a 14-year long period. A frost frequency map of the study area was compiled along with two geospatial indices associated to distance from rivers/lakes (Hydro Distance Index&mdash;HDI) and from the seashore (Sea Distance Index&mdash;SDI). Their combined statistical and spatial correlation analysis indicated a protective buffer zone from frost at distances up to 20 km from sea and up to 5 km from lakes and rivers respectively, suggesting that the protective buffer zone depends on the water volume. Statistically, frost frequency was found to be positively correlated with both SDI (rs = 0.527) and HDI (rs = 0.145). Also, the effect of topography was examined in our analysis. Results showed that altitude and slope were moderately correlated to frost frequency; yet, the significance of the correlation was reported to be lower to SDI. Furthermore, the spatial autocorrelation analysis revealed a correspondence in the clustering of frost frequency maps with the HDI and SDI. Our findings demonstrate that water bodies are a major controlling factor for frost occurrence, by lowering frost frequency in water surrounding areas. Furthermore, it highlights the promising potential of our proposed methodology in quantifying frost effects, which can form a potentially useful tool assisting effective planning of protection measures and frost hazard mitigation in general

Longitudinal Analysis of Antibody Response Following SARS-CoV-2 Infection Depending on Disease Severity: A Prospective Cohort Study

Objective: Severe coronavirus disease 19 (COVID-19) is characterized by a dysregulated inflammatory response, with humoral immunity playing a central role in the disease course. The objective of this study was to assess the immune response and the effects of vaccination in recovered individuals with variable disease severity up to one year following natural infection. Methods: A prospective cohort study was conducted including patients with laboratory-confirmed COVID-19. Disease severity was classified as mild, moderate, and severe based on clinical presentation and outcomes. Anti-RBD (receptor binding domain) and neutralizing antibodies were evaluated at multiple timepoints during the first year after COVID-19 diagnosis. Results: A total of 106 patients were included; of them, 28 were diagnosed with mild, 38 with moderate, and 40 with severe disease. At least one vaccine dose was administered in 58 individuals during the follow-up. Participants with mild disease presented significantly lower anti-RBD and neutralizing antibodies compared to those with moderate and severe disease up to the 3rd and 6th months after the infection, respectively. After adjusting for covariates, in the third month, severe COVID-19 was associated with significantly higher anti-RBD (β: 563.09; 95% confidence intervals (CI): 257.02 to 869.17) and neutralizing (β: 21.47; 95% CI: 12.04 to 30.90) antibodies. Among vaccinated individuals, at the 12th month, a history of moderate disease was associated with significantly higher anti-RBD levels (β: 5615.19; 95% CI: 657.92 to 10,572.46). Conclusions: Severe COVID-19 is associated with higher anti-RBD and neutralizing antibodies up to 6 months after the infection. Vaccination of recovered patients is associated with a remarkable augmentation of antibody titers up to one year after COVID-19 diagnosis, regardless of disease severity