Natural killer cell response to chemotherapy-stressed cancer cells: Role in tumor immunosurveillance.

Natural killer (NK) cells are innate cytotoxic lymphoid cells that actively prevent neoplastic development, growth, and metastatic dissemination in a process called cancer immunosurveillance. An equilibrium between immune control and tumor growth is maintained as long as cancer cells evade immunosurveillance. Therapies designed to kill cancer cells and to simultaneously sustain host antitumor immunity are an appealing strategy to control tumor growth. Several chemotherapeutic agents, depending on which drugs and doses are used, give rise to DNA damage and cancer cell death by means of apoptosis, immunogenic cell death, or other forms of non-apoptotic death (i.e., mitotic catastrophe, senescence, and autophagy). However, it is becoming increasingly clear that they can trigger additional stress responses. Indeed, relevant immunostimulating effects of different therapeutic programs include also the activation of pathways able to promote their recognition by immune effector cells. Among stress-inducible immunostimulating proteins, changes in the expression levels of NK cell-activating and inhibitory ligands, as well as of death receptors on tumor cells, play a critical role in their detection and elimination by innate immune effectors, including NK cells. Here, we will review recent advances in chemotherapy-mediated cellular stress pathways able to stimulate NK cell effector functions. In particular, we will address how these cytotoxic lymphocytes sense and respond to different types of drug-induced stresses contributing to anticancer activity

Natural Killer Cell Response to Chemotherapy-Stressed Cancer Cells: Role in Tumor Immunosurveillance

Natural killer (NK) cells are innate cytotoxic lymphoid cells that actively prevent neoplastic development, growth, and metastatic dissemination in a process called cancer immunosurveillance. An equilibrium between immune control and tumor growth is maintained as long as cancer cells evade immunosurveillance. Therapies designed to kill cancer cells and to simultaneously sustain host antitumor immunity are an appealing strategy to control tumor growth. Several chemotherapeutic agents, depending on which drugs and doses are used, give rise to DNA damage and cancer cell death by means of apoptosis, immunogenic cell death, or other forms of non-apoptotic death (i.e., mitotic catastrophe, senescence, and autophagy). However, it is becoming increasingly clear that they can trigger additional stress responses. Indeed, relevant immunostimulating effects of different therapeutic programs include also the activation of pathways able to promote their recognition by immune effector cells. Among stress-inducible immunostimulating proteins, changes in the expression levels of NK cell-activating and inhibitory ligands, as well as of death receptors on tumor cells, play a critical role in their detection and elimination by innate immune effectors, including NK cells. Here, we will review recent advances in chemotherapy-mediated cellular stress pathways able to stimulate NK cell effector functions. In particular, we will address how these cytotoxic lymphocytes sense and respond to different types of drug-induced stresses contributing to anticancer activity

Thromboelastometry used for evaluation of blood coagulability in dogs with kidney diseases

Kidney diseases as protein-losing nephropathies are predisposing conditions for thrombosis/thromboembolism in dogs due to increased blood coagulability. The aim of this study was to use thromboelastometry for investigation of changes in haemostasis in dogs affected by renal proteinuria alone or concomitant with azotemia. The study was done at 55 client-owned, healthy (n = 34), proteinuric (n = 14), and proteinuric/azotemic (n = 7) dogs. Blood coagulation was assessed by means of standard coagulation profile and thromboelastometry (in-TEM, ex-TEM, and fib-TEM). In proteinuric dogs only the maximum clot firmness and maximum clot elasticity significantly increased (P P < 0.05) of the variables clotting time, clot formation time, α angle, maximum clot firmness and maximum clot elasticity. After correction for group affiliation, the linear regression analysis showed a non significant association between changes in proteinuria and thromboelastometric profiles. In conclusion, thromboelastometric changes indicating hypercoagulabilty were more consistently found in the dogs with proteinuria/azotemia, than in those with proteinuria alone, suggesting that the former dogs can be considered at higher thrombotic risk. This is the first study where thromboelastometry has been applied to the investigation of haemostatic changes in dogs with kidney diseases

Influence of Deposition Parameters on Hardness Properties of InconelTM 718 Processed by Laser Powder Bed Fusion for Space Applications

InconelTM 718 is widely used for commercial application in aerospace industry and additive manufacturing process allows for versatile design and manufacturing opportunities. In the present research, the results of a wide experimental campaign run on additive manufactured InconelTM 718 specimens obtained with different processing parameters are presented. In particular, the influence of process parameters (for both vertical and horizontal planes with respect to the building direction) on the hardness properties are investigated. A further investigation is performed on the optimal hardness testing procedure for additive manufacturing. The research is extended to as-built and heat-treated specimens. The new insight gained is that the orientation of the printing direction with respect to indentation direction can be responsible for scattering in hardness measurements and indentation size effect. As-built specimens show a strong anisotropy for in-plane and growth directions and an increment of hardness with respect to increasing energy density. The difference between hardness value with respect to the energy density and the measurements scattering are reduced by the heat treatment. A careful handling of hardness data is required when dealing with additive manufactured materials

TREM1/3 deficiency impairs tissue repair after acute kidney injury and mitochondrial metabolic flexibility in tubular epithelial cells

Long-term sequelae of acute kidney injury (AKI) are associated with incomplete recovery of renal function and the development of chronic kidney disease (CKD), which can be mediated by aberrant innate immune activation, mitochondrial pathology, and accumulation of senescent tubular epithelial cells (TECs). Herein, we show that the innate immune receptor Triggering receptor expressed on myeloid cells-1 (TREM-1) links mitochondrial metabolism to tubular epithelial senescence. TREM-1 is expressed by inflammatory and epithelial cells, both players in renal repair after ischemia/reperfusion (IR)-induced AKI. Hence, we subjected WT and TREM1/3 KO mice to different models of renal IR. TREM1/3 KO mice displayed no major differences during the acute phase of injury, but increased mortality was observed in the recovery phase. This detrimental effect was associated with maladaptive repair, characterized by persistent tubular damage, inflammation, fibrosis, and TEC senescence. In vitro, we observed an altered mitochondrial homeostasis and cellular metabolism in TREM1/3 KO primary TECs. This was associated with G2/M arrest and increased ROS accumulation. Further exposure of cells to ROS-generating triggers drove the cells into a stress-induced senescent state, resulting in decreased wound healing capacity. Treatment with a mitochondria anti-oxidant partly prevented the senescent phenotype, suggesting a role for mitochondria herein. In summary, we have unraveled a novel (metabolic) mechanism by which TREM1/3 deficiency drives senescence in TECs. This involves redox imbalance, mitochondrial dysfunction and a decline in cellular metabolic activities. These finding suggest a novel role for TREM-1 in maintaining tubular homeostasis through regulation of mitochondrial metabolic flexibility

Multiple regression model to analyze the total LOS for patients undergoing laparoscopic appendectomy

The rapid growth in the complexity of services and stringent quality requirements present a challenge to all healthcare facilities, especially from an economic perspective. The goal is to implement different strategies that allows to enhance and obtain health processes closer to standards. The Length Of Stay (LOS) is a very useful parameter for the management of services within the hospital and is an index evaluated for the management of costs. In fact, a patient's LOS can be affected by a number of factors, including their particular condition, medical history, or medical needs. To reduce and better manage the LOS it is necessary to be able to predict this value

Inhibition of bromodomain and extra-terminal (BET) proteins increases NKG2D ligand MICA expression and sensitivity to NK cell-mediated cytotoxicity in multiple myeloma cells. role of cMYC-IRF4-miR-125b interplay

Background: Anticancer immune responses may contribute to the control of tumors after conventional chemotherapy and different observations have indicated that chemotherapeutic agents can induce immune responses resulting in cancer cell death and immune-stimulatory side effects. Increasing experimental and clinical evidence highlight the importance of Natural Killer (NK) cells in immune responses toward Multiple Myeloma (MM) and combination therapies able to enhance the activity of NK cells against MM are showing promise in treating this hematologic cancer. The epigenetic readers of acetylated histones Bromodomain and Extra-Terminal (BET) proteins are critical regulators of gene expression. In cancer, they can upregulate transcription of key oncogenes such as cMYC, IRF4, BCL-2 and others. In addition, the activity of these proteins can regulate the expression of osteoclastogenic cytokines during cancer progression. Here, we investigated the effect of BET-bromodomain proteins inhibition, on the expression of Natural Killer (NK) cell-activating ligands in Multiple Myeloma (MM) cells. Methods: Five MM cell lines [SKO-007(J3), U266, RPMI-8226, ARP-1, JJN3] and CD138+ MM cells isolated from MM patients were used to investigate the activity of BET bromodomain inhibitors (BETi) (JQ1 and I-BET-151) and of the selective BRD4-degrader PROTAC (Proteolysis Targeting Chimera) (ARV-825), on the expression and function of several NK cell activating ligands (NKG2DLs and DNAM-1Ls), using Flow Cytometry, Real-Time PCR, transient transfections and degranulation assays. Results: Our results indicate that inhibition of BET proteins via small molecule inhibitors or their degradation via a hetero-bifunctional Proteolysis Targeting Chimera (PROTAC) probe can enhance the expression of MICA, a ligand of the NKG2D receptor, in human MM cell lines and primary malignant plasma cells, rendering myeloma cells more efficient to activate NK cell degranulation. Noteworthy, similar results were obtained using selective CBP/EP300 bromodomain inhibition. Mechanistically, we found that BETi-mediated inhibition of cMYC correlates with the upregulation of miR-125b-5p and the downregulation of the cMYC/miR-125b-5p target gene IRF4, a transcriptional repressor of MICA. Conclusions: These findings provide new insights on the immuno-mediated antitumor activities of BETi and further elucidate the molecular mechanisms that regulate NK cell-activating ligand expression in MM

Using ultrasonography for verifying feeding tube placements in cats

IntroductionThis study aimed to investigate the use of ultrasonography for verifying feeding tube placement in hospitalized cats compared with radiographic evaluation.MethodsThis prospective investigation was performed on client-owned cats. The position of the feeding tube was checked using right lateral thoracic radiography and ultrasonography. Ultrasound examinations were performed using a high-frequency linear transducer and a microconvex transducer. The examination was performed in three steps: transverse and longitudinal planes of the left side of the animal’s neck to identify the feeding tube in the esophagus, and a longitudinal angled plane of the epigastrium to identify the tube at the lower esophageal sphincter.ResultsA total of 25 cats were included in this study. Assessing the correct positioning of the feeding tubes using a right lateral thoracic radiograph revealed that the tube was in the distal esophagus in 12/25 cats and reached the stomach in 13/25 cases.DiscussionIn all cats, both ultrasonography and right lateral chest radiography identified the feeding tube at the esophageal level. For stomach, ultrasonography demonstrated good values of diagnostic performance compared to radiography, with excellent reliability and validity in terms of sensitivity and predictive value. Ultrasonography is a valid tool for confirming tube placement in the esophagus and is almost as efficient as radiology