ObjectiveThe purpose of this study was to describe the clinicopathological characteristics and prognosis of primary small cell carcinoma of the breast (PSCCB) and compare PSCCB with breast invasive ...ductal carcinoma (IDC).DesignA retrospective cohort study.SettingData of patients with PSCCB and breast IDC were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2016.ParticipantsEighty-three patients with PSCCB and 410 699 patients with breast IDC were enrolled in the present cohort study.Materials and methodsPatients with PSCCB and breast IDC were identified from the SEER database between 2004 and 2016. The clinicopathological characteristics and survival of patients with PSCCB and IDC were compared. Propensity score matching (PSM) analysis was performed to adjust for differences in baseline characteristics when comparing overall survival (OS) and cancer-specific survival (CSS). Moreover, OS-/CSS-specific nomograms were established to predict the prognosis of PSCCB.ResultsCompared with IDC, PSCCB was significantly correlated with older age, male, higher pathological grade, higher TNM (tumour, node, metastases) stage, a higher proportion of triple-negative breast cancer, a lower proportion of ER/PR positivity and significantly worse clinical outcome. The median OS and CSS of patients with PSCCB were 23.0 m (95%CI 13.0 to 56.0) and 28.0 m (95%CI 18.0 to 66.0), respectively. The 5-year OS and CSS rates in the PSCCB group were 36.1% and 42.4%, respectively. In the matched cohort after PSM analysis, patients with PSCCB had significantly worse OS and CSS than IDC patients. Multivariate Cox regression analysis demonstrated that T stage and administration of chemotherapy were independent prognostic factors for both OS and CSS in patients with PSCCB. The C-index for OS-/CSS-specific nomogram was 0.75 (95%CI 0.66 to 0.85)/0.79 (95%CI 0.69 to 0.89), respectively. The calibration curve in the ROC analysis indicated that the predicted value was consistent with the actual observation value. Decision curve analysis suggested that the nomogram model has a significant positive net benefit from the risk of death and are better than the traditional TNM staging system.ConclusionPSCCB has distinct clinicopathological characteristics, and patients with PSCCB have significantly worse clinical outcomes than those with IDC.
We intended to explore the effect of level of frailty on, and relationship with, 1-, 3-, and 6-month postoperative emergency department visits, readmissions, and mortality. This is a prospective ...multicenter observational cohort study design. Patients aged 50 years or older treated for hip fracture (n = 245) were taken from Orthopedic wards in one medical center (n = 131) and one district hospital (n = 114) in Changhua County, Taiwan. Frailty was defined as measured by the validated Clinical Frailty Scale and categorized as robust, pre-frail, and frail. We used Kaplan-Meier analysis to estimate survival rates and Cox regression to estimate the risk of frailty associated with adverse outcomes. To examine the longitudinal associations between frailty and adverse outcome, the cross-lagged models were explored. Of the 245 patients, 55 (22.4%) were classified as frail, 113 (46.1%) as pre-frail, and 77 (31.4%) as robust. More cumulative events occurred for frail than for robust patients for each adverse outcome. Frailty has long-term effect on each adverse outcome after discharge, rather than the effect simultaneously. Targeting pre-frailty and frailty is essential for prevent adverse outcomes and improving the overall health of older adults after discharge for hip fracture.
Cancer heterogeneity is regarded as the main reason for the failure of conventional cancer therapy. The ability to reconstruct intra- and interpatient heterogeneity in cancer models is crucial for ...understanding cancer biology as well as for developing personalized anti-cancer therapy. Cancer organoids represent an emerging approach for creating patient-derived in vitro cancer models that closely recapitulate the pathophysiological features of natural tumorigenesis and metastasis. Meanwhile, cancer organoids have recently been utilized in the discovery of personalized anti-cancer therapy and prognostic biomarkers. Further, the synergistic combination of cancer organoids with organ-on-a-chip and 3D bioprinting presents a new avenue in the development of more sophisticated and optimized model systems to recapitulate complex cancer-stroma or multiorgan metastasis. Here, we summarize the recent advances in cancer organoids from a perspective of the in vitro emulation of natural cancer evolution and the applications in personalized cancer theranostics. We also discuss the challenges and trends in reconstructing more comprehensive cancer models for basic and clinical cancer research.
Tau, an important pathological protein of Alzheimer's disease (AD), can mediate the toxicity of amyloid β (Aβ). Thus, reduction of Tau with chemical molecules may offer a novel strategy for treating ...AD. Here, we designed and synthesized a series of multifunctional molecules that contained Tau-recognition moieties and E3 ligase-binding moieties to enhance Tau degradation. Among these molecules, TH006 had the highest activity of inducing Tau degradation by increasing its poly-ubiquitination. The decrement in Tau induced by TH006 could decrease the cytotoxicity caused by Aβ. Furthermore, TH006 could regulate the Tau level in the brain of an AD mouse model. Therefore, partial reduction of Tau with such multifunctional peptides may open up a novel therapeutic strategy for AD treatment.
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•Synthesized multifunctional PROTACs peptide TH006 effectively induces Tau degradation•TH006 increases poly-ubiquitination of Tau depending on VHL E3 ligase•Decrement of Tau induced by TH006 reduces the cytotoxicity caused by Aβ•TH006 can promote Tau reduction in primary neuron cells and 3xTg-AD mice
Tau, involved in Alzheimer's disease, is an intrinsically disordered protein which is difficult to be regulated. Chu et al. design and synthesize a multifunctional PROTACs peptide, TH006, to induce intracellular Tau degraded by increasing its poly-ubiquitination. Partial reduction of Tau induced by TH006 prevents cytotoxicity caused by Aβ.
Cell-penetrating peptides (CPPs) have been discovered to deliver chemical drugs, nucleic acids, and macromolecules to permeate cell membranes, creating a novel route for exogenous substances to enter ...cells. Up until now, various sequence structures and fundamental action mechanisms of CPPs have been established. Among them, arginine-rich peptides with unique cell penetration properties have attracted substantial scientific attention. Due to the positively charged essential amino acids of the arginine-rich peptides, they can interact with negatively charged drug molecules and cell membranes through non-covalent interaction, including electrostatic interactions. Significantly, the sequence design and the penetrating mechanisms are critical. In this brief synopsis, we summarize the transmembrane processes and mechanisms of arginine-rich peptides; and outline the relationship between the function of arginine-rich peptides and the number of arginine residues, arginine optical isomers, primary sequence, secondary and ternary structures, etc. Taking advantage of the penetration ability, biomedical applications of arginine-rich peptides have been refreshed, including drug/RNA delivery systems, biosensors, and blood-brain barrier (BBB) penetration. Understanding the membrane internalization mechanisms and design strategies of CPPs will expand their potential applications in clinical trials.
Stress reduction through contact with nature is well established, but far less is known about the contribution of contact parameters - duration, frequency, and nature quality. This study describes ...the relationship between duration of a nature experience (NE), and changes in two physiological biomarkers of stress - salivary cortisol and alpha-amylase. It is the first study to employ long-term, repeated-measure assessment and the first evaluation wherein study participants are free to choose the time of day, duration, and the place of a NE in response to personal preference and changing daily schedules. During an 8-week study period, 36 urban dwellers were asked to have a NE, defined as spending time in an outdoor place that brings a sense of contact with nature, at least three times a week for a duration of 10 min or more. Their goal was compliance within the context of unpredictable opportunity for taking a nature pill. Participants provided saliva samples before and after a NE at four points over the study period. Before-NE samples established the diurnal trajectory of each stress indicator and these were in line with published outcomes of more closely controlled experiments. For salivary cortisol, an NE produced a 21.3%/hour drop beyond that of the hormone's 11.7% diurnal drop. The efficiency of a nature pill per time expended was greatest between 20 and 30 min, after which benefits continued to accrue, but at a reduced rate. For salivary alpha-amylase, there was a 28.1%/h drop after adjusting for its diurnal rise of 3.5%/h, but only for participants that were least active sitting or sitting with some walking. Activity type did not influence cortisol response. The methods for this adaptive management study of nature-based restoration break new ground in addressing some complexities of measuring an effective nature dose in the context of normal daily life, while bypassing the limitations of a clinical pharmacology dose-response study. The results provide a validated starting point for healthcare practitioners prescribing a nature pill to those in their care. This line of inquiry is timely in light of expanding urbanization and rising healthcare costs.
It is well-known that regardless of the voltage/temperature/device structure, the hot carrier degradation (HCD) of classical logic transistors scales onto a single universal curve, offering a ...theory-agnostic approach to predict long-term degradation based on short-term accelerated tests. Based on the experimental results, it has been suggested that the HCD in power transistors e.g., laterally diffused MOS (LDMOS) is structurally and functionally so fundamentally different that an analogous universal scaling cannot apply. This article uses a tandem FET (two MOS) model of an LDMOS to explore the physical origin of the anomalous HCD degradation in power transistors and establish the general principle needed to restore the universality of the degradation kinetics. Interestingly, the empirical models used to evaluate HCD degradation in power transistors emerge naturally as approximations of the generalized approach. This article establishes the fact that the physics of HCD is universal and provides an example of nonclassical but predictive degradation in power transistors. This takes us a step closer to a generalized HCD model encompassing all the devices, including logic, memory, and power transistors.
Chemokines are a family of cytokines that orchestrate the migration and positioning of immune cells within tissues and are critical for the function of the immune system. CCR2 participates in liver ...pathology, including acute liver injury, chronic hepatitis, fibrosis/cirrhosis, and tumor progression, by mediating the recruitment of immune cells to inflammation and tumor sites. Although a variety of chemokines have been well studied in various diseases, there is no comprehensive review presenting the roles of all known chemokine ligands of CCR2 (CCL2, CCL7, CCL8, CCL12, CCL13, CCL16, and PSMP) in liver disease, and this review aims to fill this gap. The introduction of each chemokine includes its discovery, its corresponding chemotactic receptors, physiological functions and roles in inflammation and tumors, and its impact on different immune cell subgroups.
Research Summary
Strategic management has seen numerous studies analyzing interaction terms in nonlinear models since Hoetker's (Strat Mgmt J., 2007, 28(4), 331–343) best‐practice recommendations and ...Zelner's (Strat Mgmt J., 2009, 30(12), 1335–1348) simulation‐based approach. We suggest an alternative recentering approach to assess the statistical and economic importance of interaction terms in nonlinear models. Our approach does not rely on making assumptions about the values of the control variables; it takes the existing model and data as is and requires fewer computational steps. The recentering approach not only provides a consistent answer about statistical meaningfulness of the interaction term at a given point of interest, but also helps to assess the effect size using the template that we offer in this study. We demonstrate how to implement our approach and discuss the implications for strategy researchers.
Managerial Summary
In industry settings, the relationship between multiple corporate strategy‐related inputs and corporate performance is often nonlinear in nature. Furthermore, such relationships tend to vary for different types of firms represented within the broader population of firms in a given industry. It is thus imperative for managers to know how to take nonlinear relationships between related business factors into account when they make strategic decisions. We suggest a simple and easily implementable way of assessing and interpreting interactions in a nonlinear setting, which we term a recentering approach. We demonstrate how to apply our approach to a strategic management setting.
As foreseen by Keyes in the late 1960s, the self-heating effect has emerged as an important concern for device performance, output power density, run-time variability, and reliability of modern ...field-effect transistors. The self-heating effect is aggravated as the device footprint scales down for higher level of integration (low-power devices) or as the devices are operated in ultrahigh voltage regimes (high-power devices). In this article, we focus on the implications of self-heating on hot carrier degradation (HCD) of modern transistors by integrating within a coherent theoretical framework a broad range of experimental data scattered in the literature. We explain why system integration exacerbates transistor self-heating, while high-frequency digital operation ameliorates it, suggesting an opportunity for co-optimization. We conclude this article by discussing the various material-device-system design strategies to reduce HCD and suggesting open problems for further research.
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