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Background: Osteocytes, composing over 90% of bone cells, are well known for their mechanosensing abilities. Aged osteocytes with impaired morphology and function are less efficient in mechanotransduction which will disrupt bone turnover leading to osteoporosis. The aim of this systematic review is to delineate the mechanotransduction mechanism at different stages in order to explore potential target for therapeutic drugs. Methods: A systematic literature search was performed in PubMed and Web of Science. Original animal, cell and clinical studies with available English full-text were included. Information was extracted from the included studies for review. Results: The 26 studies included in this review provided evidence that mechanical loading are sensed by osteocytes via various sensing proteins and transduced to different signaling molecules which later initiate various biochemical responses. Studies have shown that osteocyte plasma membrane and cytoskeletons are emerging key players in initiating mechanotransduction. Bone regulating genes expressions are altered in response to load sensed by osteocytes, but the genes involved different signaling pathways and the spatiotemporal expression pattern had made mechanotransduction mechanism complicated. Most of the included studies described the important role of osteocytes in pathways that regulate mechanosensing and bone remodeling. Conclusions: This systematic review provides an up-to-date insight to different steps of mechanotransduction. A better understanding of the mechanotransduction mechanism is beneficial in search of new potential treatment for osteoporotic patients. By delineating the unique morphology of osteocytes and their interconnected signaling network new targets can be discovered for drug development. Translational potential of this article: This systematic review provides an up-to-date sequential overview and highlights the different osteocyte-related pathways and signaling molecules during mechanotransduction. This allows a better understanding of mechanotransduction for future development of new therapeutic interventions to treat patients with impaired mechanosensitivity.

Simple Summary: The Aerococcus viridans bacterial lactate oxidase (LOX) is an enzyme absent in mammalian cells. LOX catalyzes lactate to pyruvate and hydrogen peroxide (H2O2), a function that was recently used for tumor microenvironment (TME) lactate removal and H2O2 production to induce cancer cell death. However, the functions of TME lactate other than being a metabolic intermediate or an energy source and the mechanism of LOX disruption of lactate-mediated cancer cell survival remain unknown. Our study aims at addressing these important cancer-related biological questions. We identified a novel onco-signaling nexus initiated by TME lactate activation of its cellular receptor hydroxycarboxylic acid receptor 1 (HCAR1) and amplified by HCAR-associated proteins that mediate the RAS and the PI3K pathways. This signaling model could explain many key survival strategies exerted by RAS, PI3K, and their effectors for cancer cell adaptation to TME changes, especially in the cells' use of lactate beyond an energy source. LOX was recently shown to inhibit cancer cell proliferation and tumor growth. The mechanism of this inhibition, however, has been exclusively attributed to LOX depletion of TME lactate, a cancer cell energy source, and production of H2O2, an oxidative stressor. We report that TME lactate triggers the assembly of the lactate receptor hydroxycarboxylic acid receptor 1 (HCAR1)-associated protein complex, which includes GRB2, SOS1, KRAS, GAB1, and PI3K, for the activation of both the RAS and the PI3K oncogenic signaling pathways in breast cancer (BCa) cells. LOX treatment decreased the levels of the proteins in the protein complex via induction of their proteasomal degradation. In addition, LOX inhibited lactate-stimulated expression of the lactate transporters MCT1 and MCT4. Our data suggest that HCAR1 activation by lactate is crucial for the assembly and function of the RAS and PI3K signaling nexus. Shutting down lactate signaling by disrupting this nexus could be detrimental to cancer cells. HCAR1 is therefore a promising target for the control of the RAS and the PI3K signaling required for BCa progression. Thus, our study provides insights into lactate signaling regulation of cancer progression and extends our understanding of LOX's functional mechanisms that are fundamental for exploring its therapeutic potential. [ABSTRACT FROM AUTHOR]

Throughout the 1950s, as anti-communism shaped immigration law, the Los Angeles Committee for the Protection of Foreign Born developed a leftist rhetoric of immigration justice that cast the quest for equal justice for the foreign-born as a test for the integrity of democracy and the Bill of Rights. While the group was marginalized by the anti-communist crackdowns of the postwar era, it managed to create a unique multi-racial, multi-ethnic coalition and crafted a rhetoric that knitted together ideas of migration as a basic right, universal due process, free speech for all non-citizens, and deportation as an inhumane and politically repressive state intervention. [ABSTRACT FROM AUTHOR]

Aims: Fibrinolysis plays a key transition step from haematoma formation to angiogenesis and fracture healing. Low-magnitude high-frequency vibration (LMHFV) is a non-invasive biophysical modality proven to enhance fibrinolytic factors. This study investigates the effect of LMHFV on fibrinolysis in a clinically relevant animal model to accelerate osteoporotic fracture healing. Methods: A total of 144 rats were randomized to four groups: sham control; sham and LMHFV; ovariectomized (OVX); and ovariectomized and LMHFV (OVX-VT). Fibrinolytic potential was evaluated by quantifying fibrin, tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) along with healing outcomes at three days, one week, two weeks, and six weeks post-fracture. Results: All rats achieved healing, and x-ray relative radiopacity for OVX-VT was significantly higher compared to OVX at week 2. Martius Scarlet Blue (MSB) staining revealed a significant decrease of fibrin content in the callus in OVX-VT compared with OVX on day 3 (p = 0.020). Mean tPA from muscle was significantly higher for OVX-VT compared to OVX (p = 0.020) on day 3. Mechanical testing revealed the mean energy to failure was significantly higher for OVX-VT at 37.6 N mm (SD 8.4) and 71.9 N mm (SD 30.7) compared with OVX at 5.76 N mm (SD 7.1) (p = 0.010) and 17.7 N mm (SD 11.5) (p = 0.030) at week 2 and week 6, respectively. Conclusion: Metaphyseal fracture healing is enhanced by LMHFV, and one of the important molecular pathways it acts on is fibrinolysis. LMHFV is a promising intervention for osteoporotic metaphyseal fracture healing. The improved mechanical properties, acceleration of fracture healing, and safety justify its role into translation to future clinical studies.

UnlabelledImmune cells promote the initial metastatic dissemination of carcinoma cells from primary tumors. In contrast to their well-studied functions in the initial stages of metastasis, the specific roles of immunocytes in facilitating progression through the critical later steps of the invasion-metastasis cascade remain poorly understood. Here, we define novel functions of neutrophils in promoting intraluminal survival and extravasation at sites of metastatic dissemination. We show that CD11b(+)/Ly6G(+) neutrophils enhance metastasis formation via two distinct mechanisms. First, neutrophils inhibit natural killer cell function, which leads to a significant increase in the intraluminal survival time of tumor cells. Thereafter, neutrophils operate to facilitate extravasation of tumor cells through the secretion of IL1β and matrix metalloproteinases. These results identify neutrophils as key regulators of intraluminal survival and extravasation through their cross-talk with host cells and disseminating carcinoma cells.SignificanceThis study provides important insights into the systemic contributions of neutrophils to cancer metastasis by identifying how neutrophils facilitate intermediate steps of the invasion-metastasis cascade. We demonstrate that neutrophils suppress natural killer cell activity and increase extravasation of tumor cells. Cancer Discov; 6(6); 630-49. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 561.

Objectives To identify factors associated with disease-specific survival (DSS) in intestinal and nonintestinal sinonasal adenocarcinoma. Design Retrospective review. Setting Surveillance Epidemiology and End Results database. Participants Adult patients with sinonasal adenocarcinoma. Main Outcome Measures DSS. Results We identified 325 patients; of these, 300 had the nonintestinal type and 25 had intestinal type histologies. The 5-year DSS rates for patients who had no treatment, radiation (RT), surgery, and surgery and postoperative RT were 42.5, 46.1, 85.6, and 72.6%, respectively (log-rank test; p

This article investigates how test-takers change their strategies to handle increased test difficulty. An adult sample reported their test-taking strategies immediately after completing the tasks in a reading test. Data were analyzed using structural equation modeling specifying a measurement-invariant, ability-moderated, latent transition analysis in M"plus" (Muthén & Asparouhov, 2011). It was found that almost half of the test-takers (47%) changed their strategies when encountering increased task-difficulty. The changes were characterized by augmenting comprehending-meaning strategies with score-maximizing and test-wiseness strategies. Moreover, test-takers' ability was the driving influence that facilitated and/or buffered the changes. The test outcomes, when reviewed in light of adjusted test-taking strategies, demonstrated a form of process-based validity evidence.

In the context of bereavement, little is known about the mechanisms that differentiate normative adjustment patterns from those that may indicate potential psychopathology. This study aimed to replicate and extend previous work by (1) characterizing the trajectories of depressive symptoms from 3 to 12 months after the loss of a spouse, (2) examining whether (a) childhood maltreatment and attachment style predicted distinct depression trajectories, and (b) different depression trajectories were associated with the risk of prolonged grief at 12 months post‐loss. Recently bereaved individuals (N = 175) completed self‐report assessments at 3, 4, 6, and 12‐months post‐loss. Trajectories of depressive symptoms were estimated using group‐based trajectory modelling. Four distinct trajectories of depressive symptoms were identified: (1) resilience (minimal/no depression across time points; 45%), (2) moderate depression‐improved (alleviated to 'mild' by 12 months; 31%), (3) severe depression‐improved (alleviated to 'moderate' by 12 months; 15%), and (4) chronic depression ('severe' symptoms across time points; 9%). Higher childhood maltreatment predicted a greater likelihood of belonging to the 'severe depression‐improved' and 'chronic depression' groups than the 'resilient' and 'moderate depression‐improved' groups. Widow(er)s with higher attachment anxiety were more likely to belong to the 'severe depression‐improved' and 'chronic depression' groups than the 'resilient' group. The trajectory groups with persistent levels of depressive symptoms up until 6 months were more likely to exhibit prolonged grief at 12 months post‐loss. Changes from pre‐loss functioning cannot be estimated. Our findings provide insight into the early identification of post‐loss prolonged grief. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic caused major disruptions to healthcare services in 2020, delaying cancer diagnosis and treatment. While early-stage thyroid cancer often progresses slowly, it is crucial to determine whether treatment delays associated with the pandemic have impacted the clinical presentation and management of advanced-stage thyroid cancer. The purpose of our study was to determine the impact of the early COVID-19 pandemic on thyroid cancer presentation and treatment times. Utilizing the National Cancer Database, chi-squared tests and regression analyses were performed to compare patient demographic and clinical characteristics over time for 56,011 patients diagnosed with primary thyroid cancer who were treated at the Commission on Cancer-accredited sites in 2019 and 2020. We found that thyroid cancer diagnoses decreased between 2019 and 2020, with the biggest drop among patients with cT1 disease relative to other T stages. We also found that patients diagnosed with thyroid cancer in 2020 had similar treatment times to patients diagnosed in 2019, as measured by both the time between diagnosis and start of treatment and the time between surgery and start of radioactive iodine therapy. Overall, our study suggests that resources during the pandemic were allocated to patients with advanced thyroid disease, despite a decrease in diagnoses. [ABSTRACT FROM AUTHOR]

Compared with other health disciplines, there is a stagnation in technological innovation in the field of clinical neuropsychology. Traditional paper-and-pencil tests have a number of shortcomings, such as low-frequency data collection and limitations in ecological validity. While computerized cognitive assessment may help overcome some of these issues, current computerized paradigms do not address the majority of these limitations. In this paper, we review recent literature on the applications of novel digital health approaches, including ecological momentary assessment, smartphone-based assessment and sensors, wearable devices, passive driving sensors, smart homes, voice biomarkers, and electronic health record mining, in neurological populations. We describe how each digital tool may be applied to neurologic care and overcome limitations of traditional neuropsychological assessment. Ethical considerations, limitations of current research, as well as our proposed future of neuropsychological practice are also discussed. [ABSTRACT FROM AUTHOR]