Anti-tumoral Immunity and Chemo-preventive Effectiveness of Herbal Extracts of Curcumin, Ginger, Clove and Amygdaline in Ehrlich Ascites Carcinoma-Challenging Mice.

BACKGROUND: Due to its systemic toxicity, traditional chemotherapy of tumors is being taken into consideration. Herbal therapy, containing phytochemical polyphenol derivatives such as Curcumin (Cur), Ginger (Gin), Cloves (Clov) and Amygdaline (Amyg), is one of the numerous complementary and alternative approaches as an anti-cancer therapy and holds great promise for cancer chemo-prevention with fewer side effects. AIM: The current study was designated to assess anti-tumoral immunity and anti-cancer and chemo-preventive effectiveness of herbal extracts of Cur, Ginger, Clov and Amyg in Ehrlich Ascites Carcinoma (EAC)-challenging mice. METHODS: Chemo-preventive efficacy of herbal extracts of Cur, Gin, Clov and Amyg were analyzed in vivo by examination of the apoptosis rate of EAC tumor cells by flow cytometry. The total numbers of EAC cells, splenocytes counts and leucocytes count with their differentials relative % in peripheral blood (PB) of EACchallenging mice were investigated. RESULTS: EAC-challenging mice treated with herbal extracts of Cur, Gin, Clov and Amyg showed a marked decline in EAC tumor cell count and a noticeable increase in apoptosis rate of EAC tumor cells, a remarkable decrease in serum level of cancer antigen 125 (CA-125) with an obvious increase in the number of splenocytes comparing to that in EAC-challenging mice treated with PBS alone. Moreover, the data indicated an insignificant change in the total leucocytes count and their differentials relative % of eosinophil, neutrophils, monocytes and lymphocytes in EAC-challenging mice treated with Cur and Amyg, but these parameters were markedly increased in EAC-challenging mice injected with Gin and Clov compared to that in EAC-challenging mice treated with PBS alone. CONCLUSION: To conclude, the herbal extracts of Cur, Gin, Clov and Amyg may have anti-tumoral immunity and anti-cancer potency and potential to reduce the resistance to cancer conventional chemotherapy and exert cancer chemo-protective approaches with low adverse effects. Further research is necessary to determine the regimen's toxicity on various tissues and organs and to connect the diagnostic and therapeutic approaches used in the regimen's biomedical use.

Effectiveness and Safety of Intrathecal Morphine for Pediatric Patients Undergoing Scoliosis Surgery: A Systematic Review and Meta-Analysis.

Adolescent idiopathic scoliosis (AIS) often necessitates spinal fusion surgery in pediatric patients, posing significant challenges in postoperative pain management. Standard care involves the administration of intravenous opioids perioperatively, often requiring high doses to achieve adequate analgesia following an operation. This increases the risk of adverse events, may delay recovery and prolong hospital stay, and increases the likelihood of future abuse and dependence. In this systematic review and meta-analysis, we assess the safety and effectiveness of intrathecal morphine (ITM) in pediatric patients undergoing posterior spinal fusion. Ovid Embase and MEDLINE were searched in October 2023 for articles that directly compared ITM use with standard pain management approaches for pediatric patients undergoing posterior spinal fusion. Our primary outcome was postoperative pain scores. Secondary outcomes included opioid usage details, adverse events, and blood loss. Of the 384 unique studies identified, nine studies (one randomized control trial, one prospective review, and seven retrospective reviews) met the inclusion criteria. The total number of patients within the ITM and control groups were 1384 and 676, respectively. Meta-analysis revealed significantly lower pain scores in the ITM group (standardized mean difference (SMD): -1.30 (-2.29, -0.31); p = 0.01). Similarly, ITM patients had significantly lower opioid usage, both intraoperatively (mean difference (MD): -0.71 mg/kg (-0.99, -0.44); p < 0.00001) as well as postoperatively (SMD: -2.10 (-3.48, -0.73); p = 0.003), and significantly lower blood loss (MD: -0.88 L (-1.34, -0.43); p = 0.0001). The occurrence of adverse events was similar across both groups. Our analysis of the available data demonstrates that a low to moderate dose of ITM is a safe and effective adjunct to improve standard postoperative care without increasing the risk of respiratory depression. When compared to control, ITM patients had superior analgesia while using fewer opioids had significantly reduced intraoperative blood loss when ITM was administered before spinal fusion, and had a similar complication profile. While further studies are warranted to establish optimal dosing, these findings underscore the potential of ITM as a valuable addition to multimodal pain management.

Developing a sustainable grease from jojoba oil with plant waste based nanoadditives for enhancement of rolling bearing performance.

This paper presents a novel grease from jojoba oil and activated carbon nanoparticles (ACNPs) extracted from banana peel waste. The raw jojoba oil and ACNPs are first characterized for structural properties. Samples of jojoba grease blended with 0.5 and 1.5 wt. % ACNPs are prepared and tested for physicochemical and tribological properties as compared to plain jojoba grease. Adding ACNPs to jojoba grease improves corrosion resistance from grade 2c to 1a while increasing the dropping point from 100 to 109 °C. ACNPs enhanced the viscosity of jojoba oil by up to 33% for testing temperature range of 40-100 °C. The load-carrying capacity of jojoba grease is increased by about 60% when blended with 1.5 wt.% ACNPs. The same blending decreased both the coefficient of friction and the wear scar diameter by 38% and 24%, respectively. A customized test rig is used to test the effectiveness of the grease samples in rolling bearing lubrication in terms of vibration levels and power consumption. The novel jojoba grease proved to show exceptional reductions power consumption reaching 25%. The vibration spectra show the absence of resonant peaks at high frequencies suggesting the capability of jojoba grease to form a stable full film lubrication.

Doxorubicin and folic acid-loaded zinc oxide nanoparticles-based combined anti-tumor and anti-inflammatory approach for enhanced anti-cancer therapy.

BACKGROUND: Zinc oxide nanoparticles (ZnONPs) have impressively shown their efficacy in targeting and therapy of cancer. The present research was designated to investigate the potential of ZnONP nanocomposites as a cancer chemotherapeutic-based drug delivery system and to assess the anti-tumor and anti-inflammatory effectiveness of ZnONP nanocomposites combination with systemic chemotherapeutic drugs doxorubicin (DOX) and folic acid (FA) in Ehrlich ascites carcinoma (EAC) tumor cell line both in vitro and in vivo. METHODS: Anti-tumor potential of ZnONP nanocomposites: ZnONPs, ZnONPs/FA, ZnONPs/DOX and ZnONPs/DOX/FA against EAC tumor cell line was evaluated in vitro by MTT assay. Anti-tumor and anti-inflammatory efficacy of ZnONP nanocomposites were analyzed in vivo by examination of the proliferation rate and apoptosis rate of EAC tumor cells by flow cytometry, splenocytes count, level of inflammatory markers interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), as well as liver and kidney function in EAC-challenged mice. RESULTS: In vitro results showed that ZnONP nanocomposites showed a high anti-proliferative potency against EAC tumor cells. Furthermore, the in vivo study revealed that the treatment EAC-challenged mice with ZnONPs, ZnONPs/DOX, ZnONPs/FA and ZnONPs/DOX/FA hindered the proliferation rate of implanted EAC tumor cells through lowering their number and increasing their apoptosis rate. Moreover, the treatment of EAC-challenged mice with ZnONPs/DOX/FA markedly decreased the level of IL-6 and TNF-α and remarkably ameliorated the liver and kidney damages that were elevated by implantation of EAC tumor cells, restoring the liver and kidney functions to be close to the naïve mice control. CONCLUSION: ZnONP nanocomposites may be useful as a cancer chemotherapeutic-based drug delivery system. ZnONP nanocomposites: ZnONPs/DOX, ZnONPs/FA and ZnONPs/DOX/FA regimen may have anti-inflammatory approaches and a great potential to increase anti-tumor effect of conventional chemotherapy, overcoming resistance to cancer systemic chemotherapeutics and reducing their side effects, offering a promising regimen for cancer therapy.

A reversible state of hypometabolism in a human cellular model of sporadic Parkinson's disease.

Sporadic Parkinson's Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors. Mitochondrial dysfunction is one contributing factor, but its role at different stages of disease progression is not fully understood. Here, we showed that neural precursor cells and dopaminergic neurons derived from induced pluripotent stem cells (hiPSCs) from sPD patients exhibited a hypometabolism. Further analysis based on transcriptomics, proteomics, and metabolomics identified the citric acid cycle, specifically the α-ketoglutarate dehydrogenase complex (OGDHC), as bottleneck in sPD metabolism. A follow-up study of the patients approximately 10 years after initial biopsy demonstrated a correlation between OGDHC activity in our cellular model and the disease progression. In addition, the alterations in cellular metabolism observed in our cellular model were restored by interfering with the enhanced SHH signal transduction in sPD. Thus, inhibiting overactive SHH signaling may have potential as neuroprotective therapy during early stages of sPD.

The Virulence Factor Macrophage Infectivity Potentiator (Mip) Influences Branched-Chain Amino Acid Metabolism and Pathogenicity of Legionella pneumophila.

Legionella pneumophila (Lp) is a common etiological agent of bacterial pneumonia that causes Legionnaires' disease (LD). The bacterial membrane-associated virulence factor macrophage infectivity potentiator (Mip) exhibits peptidyl-prolyl-cis/trans-isomerase (PPIase) activity and contributes to the intra- and extracellular pathogenicity of Lp. Though Mip influences disease outcome, little is known about the metabolic consequences of altered Mip activity during infections. Here, we established a metabolic workflow and applied mass spectrometry approaches to decipher how Mip activity influences metabolism and pathogenicity. Impaired Mip activity in genetically engineered Lp strains decreases intracellular replication in cellular infection assays, confirming the contribution of Mip for Lp pathogenicity. We observed that genetic and chemical alteration of Mip using the PPIase inhibitors rapamycin and FK506 induces metabolic reprogramming in Lp, specifically branched-chain amino acid (BCAA) metabolism. Rapamycin also inhibits PPIase activity of mammalian FK506 binding proteins, and we observed that rapamycin induces a distinct metabolic signature in human macrophages compared to bacteria, suggesting potential involvement of Mip in normal bacteria and in infection. Our metabolic studies link Mip to alterations in BCAA metabolism and may help to decipher novel disease mechanisms associated with LD.

Experience of the United Arab Emirates in the use of monoclonal antibody drug sotrovimab in high-risk vaccinated and unvaccinated patients with COVID-19: an observational cohort study.

OBJECTIVES: Monoclonal antibodies can slow COVID-19 progression. This study describes the experience of using sotrovimab in patients with COVID-19 at high risk for disease progression and hospitalisation within the United Arab Emirates (UAE). DESIGN: Observational cohort study. SETTING: A tertiary hospital in the Emirate of Sharjah, UAE. PARTICIPANTS: Patients with mild or moderate COVID-19 at high risk for disease progression. INTERVENTIONS: Infusion with a single 500 mg dose of the monoclonal antibody drug sotrovimab. PRIMARY AND SECONDARY OUTCOME MEASURES: Any adverse effect within 24 hours, disease progression within 5 days, emergency department visit within 10 days, hospital admission within 10 days or mortality within 28 days of infusion. RESULTS: 3227 high-risk COVID-19 patients were infused with sotrovimab during the mild (n=3107, 96.3%) or moderate (n=120, 3.7%) disease stages. The incidence of at least one outcome was recorded in 196 (6.1%) of the patients (60.7 per 1000 patients). The most common outcome was disease progression within 5 days of infusion in 129 patients (4.0%), followed by emergency department visits by 90 patients (2.8%) within 10 days. Twenty-nine (0.9%) patients were hospitalised within 10 days of infusion with only two deaths (0.1%). Patients infused with sotrovimab during the moderate disease stage had 11 times greater odds of developing at least one outcome compared with patients infused during the mild stage (adjusted OR, aOR 10.86, 95% CI 7.14 to 16.54). SARS-CoV-2 vaccinated (aOR 12.8, 95% CI 7.3 to 20.5) and unvaccinated (aOR 7.2, 95% CI 3.4 to 15.3) patients infused with sotrovimab during the moderate disease stage had similar odds of at least one outcome compared with patients infused during the mild stage. CONCLUSIONS: Among high-risk sotrovimab-infused COVID-19 patients, there were relatively low incidences of disease progression and hospitalisation. Regardless of vaccination history, monoclonal antibody intervention during the early stages of COVID-19 results in better outcomes.

Antitumor immunity and therapeutic properties of marine seaweeds-derived extracts in the treatment of cancer.

Marine seaweeds are important sources of drugs with several pharmacological characteristics. The present study aims to evaluate the antitumor and antitumor immunological potentials of the extracts from the brown alga Padina pavonica and the red alga Jania rubens, inhibiting the Egyptian marine coasts. Hep-G2 cell lines were used for assessment of the antitumor efficacy of Padina pavonica and Jania rubens extracts in vitro, while Ehrlich ascites carcinoma (EAC) cells were applied to gain more antitumor immunity and antitumor insights of P. pavonica and J. rubens extracts in vivo. In vitro antitumor potentials of P. pavonica and J. rubens extracts were analyzed against human liver cancer Hep-G2 cells by MTT and trypan blue exclusion assays. In vivo antitumor immunological potentials of P. pavonica and J. rubens extracts at low, high, and prophylactic doses were analyzed by blood counting and flow cytometry in mice challenged with Ehrlich ascites carcinoma (EAC) cells. In vitro results revealed that P. pavonica and J. rubens extracts caused significant decreases in the number and viability of Hep-G2 cells in a dose-dependent manner as compared to untreated Hep-G2 cells or Cisplatin®-treated Hep-G2 cells. In vivo findings showed that P. pavonica and J. rubens extracts at low, high, and prophylactic doses significantly reduced the number and viability of EAC tumor cells accompanied by increases in EAC apoptosis compared to naïve EAC mouse. Additionally, P. pavonica and J. rubens extracts at low and prophylactic doses remarkably increased both the total WBC count and the relative numbers of lymphocytes and decreased the relative numbers of neutrophils and monocytes. Flow cytometric analysis showed that P. pavonica and J. rubens extracts at the treatment and the prophylactic doses resulted in a significant increase in the phenotypic expressions of CD4+ T, CD8+ T, and CD335 cells compared to naïve EAC mouse. Overall, both extracts P. pavonica and J. rubens possess potential antitumor and antitumor immunological effects with less toxicity, opening new approaches for further studies of the chemical and biological mechanisms behind these effects.

[Reverse Takotsubo ou myocardite fulminante ? Succès de VA ECMO chez une patiente ayant une atteinte cardiaque liée COVID 19]. / Reverse TakoTsubo or Fulminant myocarditis ? Life saving VA ECMO in a COVID 19 patient.

A 45 years old female patient was admitted to our facility for COVID -19 infection complicated by fulminant cardiac injury and refractory cardiogemic shock. She had echographic findings of reverse takotsubo cardiomyopathy. She was successfully treated by VA-ECMO allowing complete revocery of the left ventricule function and weaning from support.

[Place of Linacs in extracranial stereotactic radiotherapy: Are they now equivalent to Cyberknife®?] / Place des Linacs dans la radiothérapie stéréotaxique extra crânienne : sont-ils désormais non inférieurs au Cyberknife® ?

Extracranial stereotactic radiotherapy has developed recently, since the years 1990-2000. Devices specifically dedicated to this type of treatment were then developed and shared the favors of radiation oncologists: Tomotherapy® and especially Cyberknife®, which offered the advantage of "tracking" with the possibility of real time motion correction, allowing an increase in the precision of targeting volumes. Recently, the latest generations of linear accelerators (Linac) have been developed, integrating much higher dose rates, an improved ballistic precision with a very short treatment duration time and the possibility of real time motion management (with notably the possibility of adaptive radiotherapy in real time with the development of "MLC tracking"). So are Linacs able to perform equivalent (not inferior) extracranial stereotactic radiotherapy treatments to those with Cyberknife®, the historical gold standard in this field? This article presents a comparison of these two treatment devices, by successively considering dose distributions in the irradiated volume, distant received doses from this volume (including the "integral dose"), problems linked to the duration of the sessions and those linked to motion management.

Mitochondrial metabolism in macrophages.

Mitochondria are considered to be the powerhouse of the cell. Normal functioning of the mitochondria is not only essential for cellular energy production but also for several immunomodulatory processes. Macrophages operate in metabolic niches and rely on rapid adaptation to specific metabolic conditions such as hypoxia, nutrient limitations, or reactive oxygen species to neutralize pathogens. In this regard, the fast reprogramming of mitochondrial metabolism is indispensable to provide the cells with the necessary energy and intermediates to efficiently mount the inflammatory response. Moreover, mitochondria act as a physical scaffold for several proteins involved in immune signaling cascades and their dysfunction is immediately associated with a dampened immune response. In this review, we put special focus on mitochondrial function in macrophages and highlight how mitochondrial metabolism is involved in macrophage activation.

Role of Ultrasound in Flexor Tendon Injuries of the Hand: A New Insight.

This study was aimed at validating the diagnostic accuracy of ultrasound (US) scans in pre-operative evaluation of flexor tendon injuries in the hand and to determine its value in the management of such injuries and in the prediction of patient outcome. This descriptive cross-sectional prospective study included 35 patients with penetrating trauma to the volar aspect of the hand or wrist with questionable clinical findings. They had 50 injured tendons and were candidates for exploratory surgery versus physiotherapy. They underwent pre-operative US to guide their management. Ultrasound results were compared with the operative findings as the gold standard test. Patients were followed up postoperatively, and functional outcome was assessed and correlated with pre-operative sonographic findings. Our results indicate that sonographic examination of hand tendon injury has high accuracy in diagnosing complete or partial flexor injuries, with 100% accuracy, sensitivity and specificity in diagnosing full-thickness tears as well as tenosynovitis of hand flexor tendons. Zonal II injury was the most frequent among our study population and correlated with poorest functional outcome after rehabilitation at 3 mo follow-up. US of the hand is a fast, inexpensive and potentially indispensable dynamic tool for accurate assessment of flexor tendon injuries. It provides data on the extent of injury that effectively helps both set up an appropriate operative plan and predict the patient's functional outcome post-operatively, which in turn will have a direct impact on the patient's rehabilitation plan and lifestyle. Thus, it should be a fundamental part of the management of patients with tendon injuries.

Intraoperative neurophysiologic monitoring in idiopathic scoliosis surgery: a retrospective observational study of new neurologic deficits.

PURPOSE: Patients with adolescent idiopathic scoliosis undergoing corrective surgery are at risk for iatrogenic spinal cord injury and subsequent new neurologic deficits (NNDs). Intraoperative neurophysiologic monitoring (IONM) has been used to identify spinal cord injury; however, available data showing that IONM leads to improved clinical outcomes are inconclusive. This exploratory study aimed to examine the incidence of NNDs after idiopathic scoliosis surgery in two pediatric institutions in Canada with a focus on IONM use. METHODS: Charts of pediatric patients (10-18 yr) with adolescent idiopathic scoliosis who underwent scoliosis correction surgery were retrospectively identified from the operating room database. Data regarding incidence and severity (mild [isolated sensory deficit] vs severe [any motor deficit]) of NNDs as well as demographic and clinical characteristics were extracted. RESULTS: Of 547 patients reviewed, 359 (66%) underwent IONM and 186 (34%) underwent wake-up test. Neuromonitoring data were missing in two patients. Total incidence of NNDs was 4.9% (95% confidence interval [CI], 3.1 to 6.8). Compared with the wake-up test, patients undergoing IONM were less likely to develop NNDs (unadjusted odds ratio, 0.39; 95% CI, 0.18 to 0.86; P = 0.02). Nevertheless, subgroup analysis did not reveal a statistical difference in severity of those deficits (mild vs severe) with IONM vs wake-up test. Combined anterior and posterior approach was also significantly associated with increased risk of such deficits. CONCLUSION: This exploratory study revealed that IONM was associated with a reduced overall incidence of NNDs in idiopathic scoliosis correction; however, its impact on the severity of those deficits is questionable. As we were unable to adjust for confounding variables, further research is needed to determine the impact of IONM on NNDs.

RéSUMé: OBJECTIF: Les patients adolescents atteints de scoliose idiopathique subissant une chirurgie corrective sont à risque de lésions médullaires iatrogéniques et de nouveaux déficits neurologiques (NDN) subséquents. Le monitorage neurophysiologique peropératoire (MNP) a été employé pour identifier les lésions médullaires; cependant, les données disponibles montrant que le MNP entraîne de meilleurs pronostics cliniques ne sont pas concluantes. Cette étude exploratoire visait à examiner l'incidence des NDN après une chirurgie de scoliose idiopathique dans deux établissements pédiatriques au Canada en se concentrant sur l'utilisation du MNP. MéTHODE: Les dossiers des patients pédiatriques (10-18 ans) atteints de scoliose idiopathique ayant subi une chirurgie de correction de scoliose ont été rétrospectivement identifiés dans la base de données de salle d'opération. Les données concernant l'incidence et la gravité (légers [déficit sensoriel isolé] vs graves [tout déficit moteur]) des NDN ainsi que les caractéristiques démographiques et cliniques ont été extraites. RéSULTATS: Parmi les 547 patients passés en revue, 359 (66 %) ont eu un MNP et 186 (34 %) ont eu un test d'éveil ('wake-up test'). Les données de monitorage neurologique manquaient pour deux patients. L'incidence totale des NDN était de 4,9 % (intervalle de confiance [IC] de 95 %, 3,1 à 6,8). Par rapport au test d'éveil, les patients subissant un MNP étaient moins susceptibles de présenter des NDN (rapport de cotes non ajusté, 0,39; IC 95 %, 0,18 à 0,86; P = 0,02). Néanmoins, l'analyse des sous-groupes n'a pas révélé de différence statistique dans la gravité de ces déficits (légers vs graves) en comparant un MNP à un test d'éveil. Une association significative a également été relevée entre une approche combinée chirurgicale antérieure et postérieure et un risque accru de tels déficits. CONCLUSION: Cette étude exploratoire a indiqué que le MNP était associé à une incidence globale réduite de NDN lors d'une chirurgie de correction de scoliose idiopathique; toutefois, son impact sur la gravité de ces déficits est discutable. Comme nous n'avons pas été en mesure d'ajuster les données aux variables confondantes, d'autres recherches sont nécessaires pour déterminer l'impact du MNP sur les NDN.

Breast Cancer Cells in Microgravity: New Aspects for Cancer Research.

Breast cancer is the leading cause of cancer death in females. The incidence has risen dramatically during recent decades. Dismissed as an "unsolved problem of the last century", breast cancer still represents a health burden with no effective solution identified so far. Microgravity (µg) research might be an unusual method to combat the disease, but cancer biologists decided to harness the power of µg as an exceptional method to increase efficacy and precision of future breast cancer therapies. Numerous studies have indicated that µg has a great impact on cancer cells; by influencing proliferation, survival, and migration, it shifts breast cancer cells toward a less aggressive phenotype. In addition, through the de novo generation of tumor spheroids, µg research provides a reliable in vitro 3D tumor model for preclinical cancer drug development and to study various processes of cancer progression. In summary, µg has become an important tool in understanding and influencing breast cancer biology.

Simulated Microgravity Influences VEGF, MAPK, and PAM Signaling in Prostate Cancer Cells.

Prostate cancer is one of the leading causes of cancer mortality in men worldwide. An unusual but unique environment for studying tumor cell processes is provided by microgravity, either in space or simulated by ground-based devices like a random positioning machine (RPM). In this study, prostate adenocarcinoma-derived PC-3 cells were cultivated on an RPM for time periods of 3 and 5 days. We investigated the genes associated with the cytoskeleton, focal adhesions, extracellular matrix, growth, survival, angiogenesis, and metastasis. The gene expression of signaling factors of the vascular endothelial growth factor (VEGF), mitogen-activated protein kinase (MAPK), and PI3K/AKT/mTOR (PAM) pathways was investigated using qPCR. We performed immunofluorescence to study the cytoskeleton, histological staining to examine the morphology, and a time-resolved immunofluorometric assay to analyze the cell culture supernatants. When PC-3 cells were exposed to simulated microgravity (s-µg), some cells remained growing as adherent cells (AD), while most cells detached from the cell culture flask bottom and formed multicellular spheroids (MCS). After 3-day RPM exposure, PC-3 cells revealed significant downregulation of the VEGF, SRC1, AKT, MTOR, and COL1A1 gene expression in MCS, whereas FLT1, RAF1, MEK1, ERK1, FAK1, RICTOR, ACTB, TUBB, and TLN1 mRNAs were not significantly changed. ERK2 and TLN1 were elevated in AD, and FLK1, LAMA3, COL4A5, FN1, VCL, CDH1, and NGAL mRNAs were significantly upregulated in AD and MCS after 3 days. After a 5-day culture in s-µg, the PC-3 cells showed significant downregulations of VEGF mRNA in AD and MCS, and FN1, CDH1, and LAMA3 in AD and SCR1 in MCS. In addition, we measured significant upregulations in FLT1, AKT, ERK1, ERK2, LCN2, COL1A1, TUBB, and VCL mRNAs in AD and MCS, and increases in FLK1, FN1, and COL4A5 in MCS as well as LAMB2, CDH1, RAF1, MEK1, SRC1, and MTOR mRNAs in AD. FAK1 and RICTOR were not altered by s-µg. In parallel, the secretion rate of VEGFA and NGAL proteins decreased. Cytoskeletal alterations (F-actin) were visible, as well as a deposition of collagen in the MCS. In conclusion, RPM-exposure of PC-3 cells induced changes in their morphology, cytoskeleton, and extracellular matrix protein synthesis, as well as in their focal adhesion complex and growth behavior. The significant upregulation of genes belonging to the PAM pathway indicated their involvement in the cellular changes occurring in microgravity.

Dexamethasone Inhibits Spheroid Formation of Thyroid Cancer Cells Exposed to Simulated Microgravity.

Detachment and the formation of spheroids under microgravity conditions can be observed with various types of intrinsically adherent human cells. In particular, for cancer cells this process mimics metastasis and may provide insights into cancer biology and progression that can be used to identify new drug/target combinations for future therapies. By using the synthetic glucocorticoid dexamethasone (DEX), we were able to suppress spheroid formation in a culture of follicular thyroid cancer (FTC)-133 cells that were exposed to altered gravity conditions on a random positioning machine. DEX inhibited the growth of three-dimensional cell aggregates in a dose-dependent manner. In the first approach, we analyzed the expression of several factors that are known to be involved in key processes of cancer progression such as autocrine signaling, proliferation, epithelial-mesenchymal transition, and anoikis. Wnt/ß-catenin signaling and expression patterns of important genes in cancer cell growth and survival, which were further suggested to play a role in three-dimensional aggregation, such as NFKB2, VEGFA, CTGF, CAV1, BCL2(L1), or SNAI1, were clearly affected by DEX. Our data suggest the presence of a more complex regulation network of tumor spheroid formation involving additional signal pathways or individual key players that are also influenced by DEX.

Rolling element bearing fault identification using a novel three-step adaptive and automated filtration scheme based on Gini index.

For early detection of rolling element bearings (REBs) faults in contaminated signals, kurtosis-derived indices are involved in the filtration process prior to demodulation. However, they were found either sensitive to impulsive outliers or requiring many input arguments. In this study, a novel three-step adaptive and automated filtration scheme using Gini index (GI) is proposed as an alternative to kurtosis-based techniques to enhance the weak fault features and eliminate noise and interferences from the raw vibration signal. The proposed approach was tested using experimental signals with different bearing faults. The filtered signals were greatly denoised and the fault impulses were successfully isolated, which indicates the effectiveness of the proposed approach and the superiority of GI over kurtosis-derived indices as a criterion for proper filter design for REBs fault detection.

Short-Term Microgravity Influences Cell Adhesion in Human Breast Cancer Cells.

With the commercialization of spaceflight and the exploration of space, it is important to understand the changes occurring in human cells exposed to real microgravity (r-µg) conditions. We examined the influence of r-µg, simulated microgravity (s-µg, incubator random positioning machine (iRPM)), hypergravity (hyper-g), and vibration (VIB) on triple-negative breast cancer (TNBC) cells (MDA-MB-231 cell line) with the aim to study early changes in the gene expression of factors associated with cell adhesion, apoptosis, nuclear factor "kappa-light-chain-enhancer" of activated B-cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling. We had the opportunity to attend a parabolic flight (PF) mission and to study changes in RNA transcription in the MDA-MB cells exposed to PF maneuvers (29th Deutsches Zentrum für Luft- und Raumfahrt (DLR) PF campaign). PF maneuvers induced an early up-regulation of ICAM1, CD44 and ERK1 mRNAs after the first parabola (P1) and a delayed upregulation of NFKB1, NFKBIA, NFKBIB, and FAK1 after the last parabola (P31). ICAM-1, VCAM-1 and CD44 protein levels were elevated, whereas the NF-κB subunit p-65 and annexin-A2 protein levels were reduced after the 31st parabola (P31). The PRKCA, RAF1, BAX mRNA were not changed and cleaved caspase-3 was not detectable in MDA-MB-231 cells exposed to PF maneuvers. Hyper-g-exposure of the cells elevated the expression of CD44 and NFKBIA mRNAs, iRPM-exposure downregulated ANXA2 and BAX, whereas VIB did not affect the TNBC cells. The early changes in ICAM-1 and VCAM-1 and the rapid decrease in the NF-κB subunit p-65 might be considered as fast-reacting, gravity-regulated and cell-protective mechanisms of TNBC cells exposed to altered gravity conditions. This data suggest a key role for the detected gravity-signaling elements in three-dimensional growth and metastasis.

Beneficial Effects of Low Frequency Vibration on Human Chondrocytes in Vitro.

BACKGROUND/AIMS: In articular cartilage, chondrocytes are the predominant cell type. A long-term stay in space can lead to bone loss and cartilage breakdown. Due to the poor regenerative capacity of cartilage, this may impair the crewmembers' mobility and influence mission activities. Beside microgravity other factors such as cosmic radiation and vibration might be important for cartilage degeneration. Vibration at different frequencies showed various effects on cartilage in vivo, but knowledge about its impact on chondrocytes in vitro is sparse. METHODS: Human chondrocytes were exposed to a vibration device, simulating the vibration profile occurring during parabolic flights, for 24 h (VIB) and compared to static controls. Phase-contrast microscopy, immunofluorescence, F-actin and TUNEL staining as well as quantitative real-time PCR were performed to examine effects on morphology, cell viability and shape as well as gene expression. The results were compared to earlier studies using semantic analyses. RESULTS: No morphological changes or cytoskeletal alterations were observed in VIB and no apoptotic cells were found. A reorganization and increase in fibronectin were detected in VIB samples by immunofluorescence technique. PXN, VCL, ANXA1, ANXA2, BAX, and BCL2 revealed differential regulations. CONCLUSION: Long-term VIB did not damage human chondrocytes in vitro. The reduction of ANXA2, and up-regulation of ANXA1, PXN and VCL mRNAs suggest that long-term vibration might even positively influence cultured chondrocytes.

Real Microgravity Influences the Cytoskeleton and Focal Adhesions in Human Breast Cancer Cells.

With the increasing number of spaceflights, it is crucial to understand the changes occurring in human cells exposed to real microgravity (r-µg) conditions. We tested the effect of r-µg on MCF-7 breast cancer cells with the objective to investigate cytoskeletal alterations and early changes in the gene expression of factors belonging to the cytoskeleton, extracellular matrix, focal adhesion, and cytokines. In the Technische Experimente unter Schwerelosigkeit (TEXUS) 54 rocket mission, we had the opportunity to conduct our experiment during 6 min of r-µg and focused on cytoskeletal alterations of MCF-7 breast cancer cells expressing the Lifeact-GFP marker protein for the visualization of F-actin as well as the mCherry-tubulin fusion protein using the Fluorescence Microscopy Analysis System (FLUMIAS) for fast live-cell imaging under r-µg. Moreover, in a second mission we investigated changes in RNA transcription and morphology in breast cancer cells exposed to parabolic flight (PF) maneuvers (31st Deutsches Zentrum für Luft- und Raumfahrt (DLR) PF campaign). The MCF-7 cells showed a rearrangement of the F-actin and tubulin with holes, accumulations in the tubulin network, and the appearance of filopodia- and lamellipodia-like structures in the F-actin cytoskeleton shortly after the beginning of the r-µg period. PF maneuvers induced an early up-regulation of KRT8, RDX, TIMP1, CXCL8 mRNAs, and a down-regulation of VCL after the first parabola. E-cadherin protein was significantly reduced and is involved in cell adhesion processes, and plays a significant role in tumorigenesis. Changes in the E-cadherin protein synthesis can lead to tumor progression. Pathway analyses indicate that VCL protein has an activating effect on CDH1. In conclusion, live-cell imaging visualized similar changes as those occurring in thyroid cancer cells in r-µg. This result indicates the presence of a common mechanism of gravity perception and sensation.