Solid variant of aneurysmal bone cyst of the heel: a case report

<p>Abstract</p> <p>Introduction</p> <p>An aneurysmal bone cyst is a benign but often rapidly expanding osteolytic multi-cystic osseous lesion that occurs as a primary, secondary, intra-osseous, extra-osseous, solid or conventional lesion. It frequently coexists with other benign and malignant bone tumors. Although it is considered to be reactive in nature, there is evidence that some aneurysmal bone cysts are true neoplasms. The solid variant of aneurysmal bone cyst is a rare subtype of aneurysmal bone cyst with a preponderance of solid to cystic elements. Such a case affecting the heel, an unusual site, is reported.</p> <p>Case presentation</p> <p>A 26-year-old Caucasian man presented with pain and swelling in his left lower extremity. A plain radiograph demonstrated an intra-osseous, solitary, eccentric mass in the front portion of the left heel. Computed tomography and magnetic resonance imaging scans showed that the lesion appeared to be sub-cortical, solid with a small cystic portion without the characteristic fluid-fluid level detection but with distinct internal septation. Bone images containing fluid-fluid levels are usually produced by aneurysmal bone cysts. The fluid-fluid level due to bleeding within the tumor followed by layering of the blood components based density differences, but it was not seen in our case. An intra-lesional excision was performed. Microscopic examination revealed fibrous septa with spindle cell fibroblastic proliferation, capillaries and extensive areas of mature osteoid and reactive woven bone formation rimmed by osteoblasts. The spindle cells had low mitotic activity, and atypical forms were absent. The histological features of the lesion were consistent with the solid variant of an aneurysmal bone cyst.</p> <p>Conclusion</p> <p>Solid aneurysmal bone cysts have been of great interest to pathologists because they may be mistaken for malignant tumors, mainly in cases of giant cell tumors or osteosarcomas, because of cellularity and variable mitotic activity. It is rather obvious that the correlation of clinical, radiological and histological findings is necessary for the differential diagnosis. The eventual diagnosis is based on microscopic evidence and is made when a predominance of solid to cystic elements is found. The present case is of great interest because of the nature of the neoplasm and the extremely unusual location in which it developed. Pathologists must be alert for such a diagnosis.</p

High Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers

BOS172722 (CCT289346) is a highly potent, selective, and orally bioavailable inhibitor of spindle assembly checkpoint kinase MPS1. BOS172722 treatment alone induces significant sensitization to death, particularly in highly proliferative triple-negative breast cancer (TNBC) cell lines with compromised spindle assembly checkpoint activity. BOS172722 synergizes with paclitaxel to induce gross chromosomal segregation defects caused by MPS1 inhibitor-mediated abrogation of the mitotic delay induced by paclitaxel treatment. In in vivo pharmacodynamic experiments, BOS172722 potently inhibits the spindle assembly checkpoint induced by paclitaxel in human tumor xenograft models of TNBC, as measured by inhibition of the phosphorylation of histone H3 and the phosphorylation of the MPS1 substrate, KNL1. This mechanistic synergy results in significant in vivo efficacy, with robust tumor regressions observed for the combination of BOS172722 and paclitaxel versus either agent alone in long-term efficacy studies in multiple human tumor xenograft TNBC models, including a patient-derived xenograft and a systemic metastasis model. The current target indication for BOS172722 is TNBC, based on their high sensitivity to MPS1 inhibition, the well-defined clinical patient population with high unmet need, and the synergy observed with paclitaxel

High Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers.

BOS172722 (CCT289346) is a highly potent, selective, and orally bioavailable inhibitor of spindle assembly checkpoint kinase MPS1. BOS172722 treatment alone induces significant sensitization to death, particularly in highly proliferative triple-negative breast cancer (TNBC) cell lines with compromised spindle assembly checkpoint activity. BOS172722 synergizes with paclitaxel to induce gross chromosomal segregation defects caused by MPS1 inhibitor-mediated abrogation of the mitotic delay induced by paclitaxel treatment. In in vivo pharmacodynamic experiments, BOS172722 potently inhibits the spindle assembly checkpoint induced by paclitaxel in human tumor xenograft models of TNBC, as measured by inhibition of the phosphorylation of histone H3 and the phosphorylation of the MPS1 substrate, KNL1. This mechanistic synergy results in significant in vivo efficacy, with robust tumor regressions observed for the combination of BOS172722 and paclitaxel versus either agent alone in long-term efficacy studies in multiple human tumor xenograft TNBC models, including a patient-derived xenograft and a systemic metastasis model. The current target indication for BOS172722 is TNBC, based on their high sensitivity to MPS1 inhibition, the well-defined clinical patient population with high unmet need, and the synergy observed with paclitaxel

Autophagy: A friend or foe in allergic asthma?

Autophagy is a major self-degradative process through which cytoplasmic material, including damaged organelles and proteins, are delivered and degraded in the lysosome. Autophagy represents a dynamic recycling system that produces new building blocks and energy, essential for cellular renovation, physiology, and homeostasis. Principal autophagy triggers include starvation, pathogens, and stress. Autophagy plays also a pivotal role in immune response regulation, including immune cell differentiation, antigen presentation and the generation of T effector responses, the development of protective immunity against pathogens, and the coordination of immunometabolic signals. A plethora of studies propose that both impaired and overactive autophagic processes contribute to the pathogenesis of human disorders, including infections, cancer, atherosclerosis, auto-immune and neurodegenerative diseases. Autophagy has been also implicated in the development and progression of allergen-driven airway inflammation and remodeling. Here, we provide an overview of recent studies pertinent to the biology of autophagy and molecular pathways controlling its activation, we discuss autophagy-mediated beneficial and detrimental effects in animal models of allergic diseases and illuminate new advances on the role of autophagy in the pathogen-esis of human asthma. We conclude contemplating the potential of targeting autophagy as a novel therapeutic approach for the management of allergic responses and linked asthmatic disease. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article

TFEB signaling attenuates NLRP3-driven inflammatory responses in severe asthma

Background: NLRP3-driven inflammatory responses by circulating and lung-resident monocytes are critical drivers of asthma pathogenesis. Autophagy restrains NLRP3-induced monocyte activation in asthma models. Yet, the effects of autophagy and its master regulator, transcription factor EB (TFEB), on monocyte responses in human asthma remain unexplored. Here, we investigated whether activation of autophagy and TFEB signaling suppress inflammatory monocyte responses in asthmatic individuals. Methods: Peripheral blood CD14+ monocytes from asthmatic patients (n = 83) and healthy controls (n = 46) were stimulated with LPS/ATP to induce NLRP3 activation with or without the autophagy inducer, rapamycin. ASC specks, caspase-1 activation, IL-1β and IL-18 levels, mitochondrial function, ROS release, and mTORC1 signaling were examined. Autophagy was evaluated by LC3 puncta formation, p62/SQSTM1 degradation and TFEB activation. In a severe asthma (SA) model, we investigated the role of NLRP3 signaling using Nlrp3−/− mice and/or MCC950 administration, and the effects of TFEB activation using myeloid-specific TFEB-overexpressing mice or administration of the TFEB activator, trehalose. Results: We observed increased NLRP3 inflammasome activation, concomitant with impaired autophagy in circulating monocytes that correlated with asthma severity. SA patients also exhibited mitochondrial dysfunction and ROS accumulation. Autophagy failed to inhibit NLRP3-driven monocyte responses, due to defective TFEB activation and excessive mTORC1 signaling. NLRP3 blockade restrained inflammatory cytokine release and linked airway disease. TFEB activation restored impaired autophagy, attenuated NLRP3-driven pulmonary inflammation, and ameliorated SA phenotype. Conclusions: Our studies uncover a crucial role for TFEB-mediated reprogramming of monocyte inflammatory responses, raising the prospect that this pathway can be therapeutically harnessed for the management of SA. © 2022 European Academy of Allergy and Clinical Immunology and John Wiley &amp; Sons Ltd

Accuracy of commercial devices and methods for noninvasive estimation of aortic systolic blood pressure a systematic review and meta-analysis of invasive validation studies

Background: Although compelling evidence has established the physiological and clinical relevance of aortic SBP (a-SBP), no consensus exists regarding the validity of the available methods/techniques that noninvasively measure it. Objectives: The systematic review and meta-analysis aimed to determine the accuracy of commercial devices estimating a-SBP noninvasively, which have been validated by invasive measurement of a-SBP. Moreover their optimal mode of application, in terms of calibration, as well as specific technique and arterial site of pulse wave acquisition were further investigated. Methods: The study was performed according to the PRISMA guidelines; 22 eligible studies were included, which validated invasively 11 different commercial devices in 808 study participants. Results: Overall, the error in a-SBP estimation (estimated minus actual value) was -4.49mmHg [ 95% confidence interval (CI): -6.06 to -2.92 mmHg]. The estimated (noninvasive) a-SBP differed from the actual (invasive) value depending on calibration method: by -1.08mmHg (95% CI: -2.81, 0.65 mmHg) and by -5.81mmHg (95% CI: -7.79, -3.84 mmHg), when invasively and noninvasively measured brachial BP values were used respectively; by -1.83 mmHg, (95% CI: -3.32, -0.34 mmHg), and by 7.78mmHg (95% CI: -10.28, -5.28 mmHg), when brachial mean arterial pressure/DBP and SBP/DBP were used, respectively. Conclusion: Automated recording of waveforms, calibrated noninvasively by brachial mean arterial pressure/DBP values seems the most promising approach that can provide relatively more accurate, noninvasive estimation of a-SBP. It is still uncertain whether a specific device can be recommended as 'gold standard'; however, a consensus is currently demanding