Delay In Progression Research Articles

Cell harvesting on robust smart thermosensitive pseudo-double networks prepared by one-step procedure

In this work, pseudo-double networks (pseudo-DN) based on N-vinyl caprolactam (VCL, major component, precursor of thermosensitive chains) and hexyl methacrylate (HMA, minor component, hydrophobic) have been prepared by using single step approach. The adjective pseudo refers to the fact that through the simultaneous copolymerization of VCL and HMA with different relative reaction kinetics, in the presence of an appropriate mixture of crosslinkers, networks with complex structures that tend towards DN-type structures are obtained. Hydrogels have been prepared with HMA/VCL molar ratios from 0 to 23.2 mol %. The series of hydrogels prepared show a composition-dependent behaviour in terms of thermosensitivity, swelling at temperatures below the Volume Phase Transition Temperature (VPTT) value, mechanical properties and performance during the cell culture experiments. More precisely, hydrogels with low percentages of HMA show elastic moduli under compression tests slightly lower than 1 MPa and presented a high thermal response (high swelling below the VPTT) allowing in addition the non-aggressive detachment of cell monolayer by controlled decrease of temperature. As the percentage of HMA increases, the elastic modulus increases, obtaining improved mechanical properties (reaching values in the range 1–3 MPa), thermosensitivity decreases (low swelling below VPTT) and a progressive delay in cell proliferation is also observed, being still cytocompatible. In this sense, hydrogels with low percentages of HMA (up 2.7 mol %) allow cell proliferation and transplantation similar to the control sample.

Cost-effectiveness analysis of dapagliflozin for people with chronic kidney disease in Malaysia.

Chronic kidney disease (CKD) is a global health concern which results in significant economic burden. Despite this, treatment options are limited. Recently, dapagliflozin has been reported have benefits in people with CKD. This study aimed to evaluate the cost-effectiveness of dapagliflozin as an add-on to standard of care (SoC) in people with CKD in Malaysia. A Markov model was adapted to estimate the economic and clinical benefits of dapagliflozin in people with Stage 2 to 5 CKD. The cost-effectiveness was performed based upon data from the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial supplemented with local costs and utility data whenever possible. In Malaysia, dapagliflozin in combination with SoC was the dominant intervention compared to SoC alone (RM 81,814 versus RM 85,464; USD19,762 vs USD20,644). Adding dapagliflozin to SoC in people with CKD increased life expectancy by 0.46 years and increased quality-adjusted life years (QALY) by 0.41 in comparison with SoC alone (10.01 vs. 9.55 years, 8.76 vs. 8.35 QALYs). This translates to a saving of RM8,894 (USD2,148) with every QALY gained. The benefits were due to the delay in CKD progression, resulting in lower costs of dialysis and renal transplantation. Results were robust to variations in assumptions over disease management costs as well as subgroup of population that would be treated and below the accepted willingness-to-pay thresholds of RM 46,000/QALY. The use of dapagliflozin was projected to improved life expectancy and quality of life among people with CKD, with a saving RM8,894 (USD2,148) for every quality-adjusted life-year gained and RM7,898 (USD1,908) saving for every life year gained.

Progression analysis versus traditional methods to quantify slowing of disease progression in Alzheimer’s disease

BackgroundThe clinical meaningfulness of the effects of recently approved disease-modifying treatments (DMT) in Alzheimer’s disease is under debate. Available evidence is limited to short-term effects on clinical rating scales which may be difficult to interpret and have limited intrinsic meaning to patients. The main value of DMTs accrues over the long term as they are expected to cause a delay or slowing of disease progression. While awaiting such evidence, the translation of short-term effects to time delays or slowing of progression could offer a powerful and readily interpretable representation of clinical outcomes.MethodsWe simulated disease progression trajectories representing two arms, active and placebo, of a hypothetical clinical trial of a DMT. The placebo arm was simulated based on estimated mean trajectories of clinical dementia rating scale–sum of boxes (CDR-SB) recordings from amyloid-positive subjects with mild cognitive impairment (MCI) from Alzheimer’s Disease Neuroimaging Initiative (ADNI). The active arm was simulated to show an average slowing of disease progression versus placebo of 20% at each visit. The treatment effects in the simulated trials were estimated with a progression model for repeated measures (PMRM) and a mixed model for repeated measures (MMRM) for comparison. For PMRM, the treatment effect is expressed in units of time (e.g., days) and for MMRM in units of the outcome (e.g., CDR-SB points). PMRM results were implemented in a health economics Markov model extrapolating disease progression and death over 15 years.ResultsThe PMRM model estimated a 19% delay in disease progression at 18 months and 20% (~ 7 months delay) at 36 months, while the MMRM model estimated a 25% reduction in CDR-SB (~ 0.5 points) at 36 months. The PMRM model had slightly greater power compared to MMRM. The health economic model based on the estimated time delay suggested an increase in life expectancy (10 months) without extending time in severe stages of disease.ConclusionPMRM methods can be used to estimate treatment effects in terms of slowing of progression which translates to time metrics that can be readily interpreted and appreciated as meaningful outcomes for patients, care partners, and health care practitioners.

Apple Growing in Norway—Ecologic Factors, Current Fertilization Practices and Fruit Quality: A Case Study

This paper presents some features of apple production in Norway, the northernmost apple-growing country in the world. Acceptable growing conditions prevail along the fjords in western Norway and around the lakes in eastern Norway at 60° north. These specific mesic climate conditions are associated with very long summer days (18 h daylight mid-summer) and short winter days (6 h daylight), with frost rarely occurring in the spring along the fjord areas. The present apple-growing technique in Norway is similar to that of other developed apple-growing countries, taking into account that all local growing phases involve a considerable delay in progress (1.5–2 months). Therefore, high-density planting systems based on the use of dwarf rootstocks (mainly M.9) with imported early maturing international apple cultivars are used in most orchards. The most common soil type has high organic matter content (2–18%), which persists due to the cool climate and low mineralization, and a clay content of <15%, which results from the formation of the soil from bedrock. The increase in average temperatures caused by current climatic changes leads to a complex combination of different physiological effects on apples, which can have positive or negative effects on the phenology of the trees. The main advantage of Norwegian apple production is that the quality and aroma of the fruit meet the current demands of the local market.

Involvement of GSTP1 in low dose radiation-induced apoptosis in GM12878 cells

BackgroundLow-dose ionizing radiation-induced protection and damage are of great significance among radiation workers. We aimed to study the role of glutathione S-transferase Pi (GSTP1) in low-dose ionizing radiation damage and clarify the impact of ionizing radiation on the biological activities of cells. ResultsIn this study, we collected peripheral blood samples from healthy adults and workers engaged in radiation and radiotherapy and detected the expression of GSTP1 by qPCR. We utilized γ-rays emitted from uranium tailings as a radiation source, with a dose rate of 14 μGy/h. GM12878 cells subjected to this radiation for 7, 14, 21, and 28 days received total doses of 2.4, 4.7, 7.1, and 9.4 mGy, respectively. Subsequent analyses, including flow cytometry, MTS, and other assays, were performed to assess the ionizing radiation’s effects on cellular biological functions. In peripheral blood samples collected from healthy adults and radiologic technologist working in a hospital, we observed a decreased expression of GSTP1 mRNA in radiation personnel compared to the healthy controls. In cultured GM12878 cells exposed to low-dose ionizing radiation from uranium tailings, we noted significant changes in cell morphology, suppression of proliferation, delay in cell cycle progression, and increased apoptosis. These effects were partially reversed by overexpression of GSTP1. Moreover, low-dose ionizing radiation increased GSTP1 gene methylation and downregulated GSTP1 expression. Furthermore, low-dose ionizing radiation affected the expression of GSTP1-related signaling molecules. ConclusionsThis study shows that low-dose ionizing radiation damages GM12878 cells and affects their proliferation, cell cycle progression, and apoptosis. In addition, GSTP1 plays a modulating role under low-dose ionizing radiation damage conditions. Low-dose ionizing radiation affects the expression of Nrf2, JNK, and other signaling molecules through GSTP1.

Quercetin as a promising intervention for rat osteoarthritis by decreasing M1-polarized macrophages via blocking the TRPV1-mediated P2X7/NLRP3 signaling pathway.

Osteoarthritis (OA) is characterized by an imbalance between M1 and M2 polarized synovial macrophages. Quercetin has shown protective effects against OA by altering M1/M2-polarized macrophages, but the underlying mechanisms remain unclear. In this study, rat chondrocytes were treated with 10 ng/mL of IL-1β. To create M1-polarized macrophages in vitro, rat bone marrow-derived macrophages (rBMDMs) were treated with 100 ng/mL LPS. To mimic OA conditions observed in vivo, a co-culture system of chondrocytes and macrophages was established. ATP release assays, immunofluorescence assays, Fluo-4 AM staining, Transwell assays, ELISA assays, and flow cytometry were performed. Male adult Sprague-Dawley (SD) rats were used to create an OA model. Histological analyses, including H&E, and safranin O-fast green staining were performed. Our data showed a quercetin-mediated suppression of calcium ion influx and ATP release, with concurrent downregulation of TRPV1 and P2X7 in the chondrocytes treated with IL-1β. Activation of TRPV1 abolished the quercetin-mediated effects on calcium ion influx and ATP release in chondrocytes treated with IL-1β. In the co-culture system, overexpression of P2X7 in macrophages attenuated the quercetin-mediated effects on M1 polarization, migration, and inflammation. Either P2X7 or NLRP3 knockdown attenuated IL-1β-induced M1/M2 polarization, migration, and inflammation. Moreover, overexpression of TRPV1 reduced the quercetin-mediated suppressive effects on OA by promoting M1/M2-polarized macrophages in vivo. Collectively, our data showed that quercetin-induced suppression of TRPV1 leads to a delay in OA progression by shifting the macrophage polarization from M1 to M2 subtypes via modulation of the P2X7/NLRP3 pathway.

Assessment of the impact of direct in vitro PFAS treatment on mouse spermatozoa.

Poly- and per-fluoroalkyl substances (PFAS) are synthetic environmentally persistent chemicals. Despite the phaseout of specific PFAS, their inherent stability has resulted in ubiquitous and enduring environmental contamination. PFAS bioaccumulation has been reported globally with omnipresence in most populations wherein they have been associated with a range of negative health effects, including strong associations with increased instances of testicular cancer and reductions in overall semen quality. To elucidate the biological basis of such effects, we employed an acute in vitro exposure model in which the spermatozoa of adult male mice were exposed to a cocktail of PFAS chemicals at environmentally relevant concentrations. We hypothesized that direct PFAS treatment of spermatozoa would induce reactive oxygen species generation and compromise the functional profile and DNA integrity of exposed cells. Despite this, post-exposure functional testing revealed that short-term PFAS exposure (3 h) did not elicit a cytotoxic effect, nor did it overtly influence the functional profile, capacitation rate, or the in vitro fertilization ability of spermatozoa. PFAS treatment of spermatozoa did, however, result in a significant delay in the developmental progression of the day 4 pre-implantation embryos produced in vitro. This developmental delay could not be attributed to a loss of sperm DNA integrity, DNA damage, or elevated levels of intracellular reactive oxygen species. When considered together, the results presented here raise the intriguing prospect that spermatozoa exposed to a short-term PFAS exposure period potentially harbor an alternate stress signal that is delivered to the embryo upon fertilization. PFAS are synthetic chemicals widely used in non-stick cookware, food packaging, and firefighting foam. Such extensive use has led to concerning levels of environmental contamination and reports of associations with a spectrum of negative health outcomes, including testicular cancer and reduced semen quality. To investigate the effects of PFAS on male reproduction, we incubated mouse sperm in a cocktail of nine PFAS at environmentally relevant concentrations before checking for a range of functional outcomes. This treatment strategy was not toxic to the sperm; it did not kill them or reduce their motility, nor did it affect their fertilization capacity. However, we did observe developmental delays among pre-implantation embryos created using PFAS-treated sperm. Such findings raise the intriguing prospect that PFAS-exposed sperm harbor a form of stress signal that they deliver to the embryo upon fertilization.

The Immunomodulatory Effects of Fluorescein-Mediated Sonodynamic Treatment Lead to Systemic and Intratumoral Depletion of Myeloid-Derived Suppressor Cells in a Preclinical Malignant Glioma Model.

Fluorescein-mediated sonodynamic therapy (FL-SDT) is an extremely promising approach for glioma treatment, resulting from the combination of low-intensity focused ultrasound (FUS) with a sonosensitizer. In the present study, we evaluated the efficacy and immunomodulation of SDT with fluorescein as the sonosensitizer in immunocompetent GL261 glioma mice for the first time. In vitro studies demonstrated that the exposure of GL261 cells to FL-SDT induced immunogenic cell death and relevant upregulation of MHC class I, CD80 and CD86 expression. In vivo studies were then performed to treat GL261 glioma-bearing mice with FL-SDT, fluorescein alone, or FUS alone. Perturbation of the glioma-associated macrophage subset within the immune microenvironment was induced by all the treatments. Notably, a relevant depletion of myeloid-derived suppressor cells (MDSCs) and concomitant robust infiltration of CD8+ T cells were observed in the SDT-FL-treated mice, resulting in a significant radiological delay in glioma progression and a consequent improvement in survival. Tumor control and improved survival were also observed in mice treated with FL alone (median survival 41.5 days, p > 0.0001 compared to untreated mice), reflecting considerable modulation of the immune microenvironment. Interestingly, a high circulating lymphocyte-to-monocyte ratio and a very low proportion of MDSCs were predictive of better survival in FL- and FL-SDT-treated mice than in untreated and FUS-treated mice, in which elevated monocyte and MDSC frequencies correlated with worse survival. The immunostimulatory potential of FL-SDT treatment and the profound modulation of most immunosuppressive components within the microenvironment encouraged the exploration of the combination of FL-SDT with immunotherapeutic strategies.

Estimation of the Physical Progress of Work Using UAV and BIM in Construction Projects

The delay in the physical progress of construction creates additional costs, missed deadlines, and quality issues. The research aimed to estimate the physical progress of the project by using unmanned aerial vehicles (UAVs) and building information modeling (BIM). The methodology comprised capturing 848 high-resolution images of the Civil Engineering Laboratory construction site at the National University of Jaen, Cajamarca, Peru, using the Phantom 4 RTK drone. The photographs were processed using Agisoft 2.0.1 software, resulting in a point cloud. This was then imported into ReCap Pro 2023 software, which was used to assess the quality of the points. The Revit 2023 software was subsequently utilized to establish the phase parameters, linking the BIM model with the point cloud, filtering the model, and eventually exporting it to the Power BI 2023 software. The work's estimated progress utilizing the proposed methodology was 42.82%, which was not statistically significant compared to the Public Works Information System (INFOBRAS) of 43.14%. This allows for the automation of customary processes, the identification of crucial issues, and prompt decision-making. The study's originality lies in the suggestion of integrating aerial imagery with drones and BIM modeling for the real-time and precise estimation of work progression. This method provides a precise and effective substitute for traditional techniques for gauging the tangible advancement of projects. Doi: 10.28991/CEJ-2024-010-02-02 Full Text: PDF

Socioeconomic Disparities in Research Participation: Bias in Plastic Surgery Residency Match.

Integrated plastic surgery residency applicants have increased at a rate disproportionate to available positions. Research productivity has become a surrogate marker for competitiveness, and many applicants pursue it to distinguish themselves. To date, no study has investigated socioeconomic disparities in extended research experience (ERE) participation. A 35-question cross-sectional survey was distributed to applicants to United States-based integrated plastic surgery residency programs during the 2019-2022 application cycles. Summary tables, student t test, and chi-square tests were used for statistical analysis. A total of 161 responses (response rate: 20.9%) were recorded. Fifty-nine (40.7%) respondents participated in an ERE. The most common reason for ERE participation was strengthening one's application. The most common reason against participation was avoiding delays in career progression. A greater percentage of respondents from Northeastern medical schools participated in EREs (P = 0.019). There were no significant differences in debt burden between those who did or did not participate in an ERE. A greater percentage of applicants whose parents had advanced degrees participated in EREs (P = 0.053). There may be geographic and socioeconomic biases present in access to ERE for students interested in plastic surgery. The growing popularity of EREs may have unintended consequences for applicant diversity. As most plastic surgeons ultimately practice in nonacademic settings, applicants and plastic surgeons may consider the financial hardships and possible socioeconomic disparities in research opportunities before participating in or recommending them.

The effect of exercise training intervention for patients with abdominal aortic aneurysm on cardiovascular and cardiorespiratory variables: an updated meta-analysis of randomized controlled trials

ObjectiveThe purpose of this meta-analysis was to evaluate the effect of exercise training intervention in patients with abdominal aortic aneurysm (AAA).MethodsEight randomized controlled trials (RCTs) that recruited 588 AAA patients were extracted using 4 databases (PubMed, Embase, Wanfang Data, and Cochrane Library). Physiological and biochemistry parameters that included in this study are high-sensitivity C-reactive protein (hs-CRP), respiratory peak oxygen uptake rate (VO2peak), triglyceride (TG), total cholesterol (TC), anaerobic threshold (AT), the diameter of AAA, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), and matrix metalloproteinase-9 (MMP-9). Standard mean difference (SMD) was used to assess the between group effect.ResultsThis meta-analysis was synthesized with findings from RCTs and found that hs-CRP (SMD, − 0.56 mg/dL; 95% CI: − 0.90 to 0.22; P = 0.001), VO2peak (SMD, 0.4 mL/kg/min; 95% CI, 0.21 to 0.60; P < 0.001), TG (SMD, − 0.39 mg/dL; 95% CI: − 0.02 to 0.77; P = 0.04), and AT (SMD, 0.75 mL/kg/min; 95% CI, 0.54 to 0.96; P < 0.001) were significantly improved in the exercise groups, while the size of AAA (SMD, − 0.15; 95% CI: − 0.36 to 0.06; P = 0.15), TC (SMD, 0.16 mg/dL; 95% CI: − 0.10 to 0.42; P = 0.23), HDL/LDL ratio (SMD, − 0.06; 95% CI: − 0.32 to 0.20; P = 0.64), HDL (SMD, − 0.09; 95% CI: − 0.39 to 0.20; P = 0.54), LDL (SMD, 0.08; 95% CI: − 0.21 to 0.38; P = 0.59), and MMP-9 (SMD, − 0.23 mg/dL; 95% CI: − 0.53 to 0.06; P = 0.12) did not differ in the exercise groups compared with the controls.ConclusionExercise intervention improved some of the CVD risk factors but not all, hs-CRP, VO2peak and AT were significantly improved after exercise intervention, while, changes of MMP-9, the size of AAA, and the overall lipids profile were not. Exercise intervention provides an additional solution for improving cardiorespiratory capacity and health status among AAA patients, and might lead to a delay of AAA progression.

Assessing the Delay, Cost, and Quality Risks of Claims on Construction Contract Performance

Conflicts are frequent within the complex professional environment of the construction industry. If claims cannot be overcome amicably, they result in disputes that lead to litigation. Identification of the causes of these claims and their impact on the duration, cost, and quality of the final project is expected to facilitate the prevention of unsuccessful performance of construction contracts. The novelty of this study is that after codifying the most common causes of construction contract claims derived from the extant literature, they are further investigated in terms of their probability of occurrence and the perceived impact they have on the project completion time, its total cost, and quality. Based on calculated relative importance indices from expert opinion, this paper proposes probability and severity of impact values for 39 common causes of claims in the construction industry. These can be applied to calculate their risk values for stakeholders in public construction contracts to plan mitigation measures for contractual claims. The findings show that the top five highest risk causes of contractual claims in the Greek construction industry are changes in quantities, work, or scope, design quality deficiencies or errors, payment delays, delays in work progress, and the financial failure of the contractor.

The Experience of Multilingual Doctoral Students Related to Academic Success: A Descriptive Qualitative Study

When multilingual students face the challenge of writing a doctoral capstone or dissertation, delays in academic progress may occur. The aim of this study was to identify writing challenges multilingual doctoral students face and provide recommendations regarding learner-centered resources to support timely academic success, as literature regarding multilingual students and language diversity in the doctoral environment is limited.&lt;em&gt; &lt;/em&gt;A qualitative descriptive design was used for this study, and six multilingual DNP and PhD alumni participated. Data were collected using semi-structured audio interviews and analyzed using iterative content analysis.&lt;em&gt; &lt;/em&gt;The findings support the need for community and culture to support language identity and doctoral writing development. Findings also support that early diagnostics of writing issues and opportunities for editorial feedback help support multilingual doctoral students.&lt;em&gt; &lt;/em&gt;Findings also suggest a need for faculty and academic team development regarding the impacts of language diversity and culture on academic writing. Ultimately the goal is to help all graduate students preserve and share their identity in their writing.

An update on managing patients with multiple sclerosis in primary care.

Multiple sclerosis (MS) is an immune-mediated inflammatory condition of the central nervous system causing periods of recurring inflammation and ultimately progression of symptoms over time. MS is a common cause of disability in younger patients. Evidence-based treatment for patients with MS early in their disease course prevents relapses and delays progression. Early treatments for MS were classified as immune-modulating; newer developments that suppress the immune system are more effective in preventing future relapses and progression but carry risks. The increased use of immunosuppressant therapies for patients with MS makes it imperative for clinicians to understand potential risks, benefits, and serious adverse reactions related to these therapies.

Fabry-specific treatment in Australia: time to align eligibility criteria with international best practices.

Disease-specific therapy aims to improve symptoms, stabilise current disease and delay progression in patients with Fabry disease. In Australia, treatment access is subject to eligibility criteria initially established in 2004. Patients and their clinicians question why these criteria have remained unchanged despite significant progress in disease understanding. Appraise the clinical quality of the Australian treatment access criteria. The Fabry Australia Medical Advisory Committee (N = 6) used the Appraisal of Guidelines for REsearch and Evaluation Global Rating Scale (AGREE II GRS) to assess the clinical quality of the current treatment eligibility criteria. They reviewed the literature, developed 17 clinical statements to help guide reforms of the eligibility criteria and achieved consensus (achievement of ≥75% agreement in the range 5-7 on a 7-point Likert scale) through anonymous voting. The findings were applied to develop proposals for revised classification and treatment initiation criteria. The current treatment eligibility criteria underperformed on the AGREE II GRS. They are pragmatic but out-of-step with contemporary data. Consensus was achieved on all 17 proposed clinical statements. There was strong agreement to differentiate classical male Fabry patients to facilitate timelier access to Fabry-specific treatment. There was also agreement on the value of adopting relevant organ involvement criteria in classical female patients and patients with non-classical disease. Australian access criteria are misaligned with current clinical evidence. The clinical statements and proposed classification and initiation criteria should prompt discussions to support more equitable access to treatment and better align Australian practice with contemporary evidence and international guidelines.

Chapter 1: The Burden of Heart Failure

Heart failure (HF) affects an estimated 6 million American adults, and the prevalence continues to increase, driven in part by the aging of the population and by increases in the prevalence of diabetes. In recent decades, improvements in the survival of patients with HF have resulted in a growing number of individuals living longer with HF. HF and its comorbidities are associated with substantial impairments in physical functioning, emotional well-being, and quality of life, and also with markedly increased rates of morbidity and mortality. As a result, the management of patients with HF has a substantial economic impact on the health care system, with most costs arising from hospitalization. Clinicians have an important role in helping to reduce the burden of HF through timely diagnosis of HF as well as increasing access to effective treatments to minimize symptoms, delay progression, and reduce hospital admissions. Prevention and early diagnosis of HF will play a fundamental role in efforts to reduce the large and growing burden of HF. Recent advances in pharmacotherapies for HF have the potential to radically change the management of HF, offering the possibility of improved survival and quality of life for patients.

Setbacks, Shutdowns, and Overruns

We investigate optimal project management in a setting plagued by an indefinite number of setbacks that are discovered en route to project completion. The contractor can cover up delays in progress due to shirking either by making false claims of setbacks or by postponing the reports of real ones. The sponsor optimally induces work and honest reporting via a soft deadline and a reward for completion that specifies a bonus for early delivery. Late‐stage setbacks trigger randomization between minimally feasible project extension and (inefficient) cancellation. Because extensions may be granted repeatedly, arbitrarily large overruns in schedule and budget are possible after which the project may still be canceled.

Endosulfine alpha maintains spindle pole integrity by recruiting Aurora A during mitosis

BackgroundThe maintenance of spindle pole integrity is essential for spindle assembly and chromosome segregation during mitosis. However, the underlying mechanisms governing spindle pole integrity remain unclear.MethodsENSA was inhibited by siRNA or MKI-2 treatment and its effect on cell cycle progression, chromosome alignment and microtubule alignment was observed by immunohistochemical staining and western blotting. PP2A-B55α knockdown by siRNA was performed to rescue the phenotype caused by ENSA inhibition. The interaction between ENSA and Aurora A was detected by in situ PLA. Furthermore, orthotopic implantation of 4Tl-luc cancer cells was conducted to confirm the consistency between the in vitro and in vivo relationship of the ENSA-Aurora A interaction.ResultsDuring mitosis, p-ENSA is localized at the spindle poles, and the inhibition of ENSA results in mitotic defects, such as misaligned chromosomes, multipolar spindles, asymmetric bipolar spindles, and centrosome defects, with a delay in mitotic progression. Although the mitotic delay caused by ENSA inhibition was rescued by PP2A-B55α depletion, spindle pole defects persisted. Notably, we observed a interaction between ENSA and Aurora A during mitosis, and inhibition of ENSA reduced Aurora A expression at the mitotic spindle poles. Injecting MKI-2-sensitized tumors led to increased chromosomal instability and downregulation of the MASTL-ENSA-Aurora A pathway in an orthotopic breast cancer mouse model.ConclusionsThese findings provide novel insights into the regulation of spindle pole integrity by the MASTL-ENSA-Aurora A pathway during mitosis, highlighting the significance of ENSA in recruiting Aurora A to the spindle pole, independent of PP2A-B55α.

Clinicopathological Evaluation of Patients with Hormone Receptor–Positive HER2-Negative Metastatic Breast Cancer Progressing on Endocrine Treatment: A Real-World Retrospective Study from a Regional Cancer Center

Metastatic breast cancer (MBC) is an incurable disease with the primary aim of treatment being the improvement of the patient's quality of life and the delay of disease progression. A substantial proportion of patients with hormone receptor (HR)-positive MBC eventually experience progression despite endocrine treatment. As endocrine resistance remains a significant challenge, we aim to comprehend the intricate relationship between clinicopathological characteristics and the utility of various parameters as predictive markers for hormonal treatment response. This study, conducted at a single center, is ambispective in nature and includes hormone receptor (HR)-positive, human epidermal growth factor 2–negative MBC patients who progressed while on endocrine treatment, selected through purposeful sampling. Nominal data were analyzed in terms of frequency distribution, and continuous variables were represented as median/mean ± standard deviation. Spearman's correlation test and chi-square test were employed to examine variable dependencies. Data comparisons were performed using the independent t-test, one-way analysis of variance, or Mann–Whitney's test. The majority of our study participants (n = 44, 64.70%) presented with de novo metastasis, while the remainder (n = 24, 35.29%) were patients who progressed from early-stage breast cancer to metastasis. The overall mean age of our study population at presentation was 47 ± 11 years. Patients with upfront stage 4 tumors presented at an older age, exhibited grade 2 tumors, had a higher frequency of bone-only metastasis, and experienced longer progression-free survival (PFS) compared to patients who progressed from the early stage to metastasis. Multiple visceral involvements had a significant negative impact on PFS in contrast to cases with single visceral or bone-only involvement. No significant associations with PFS were observed for the Ki-67 index, first-line chemotherapy, or endocrine therapy. The extent of metastasis to various organs emerged as the most influential factor in determining PFS. Consequently, we propose the necessity for larger prospective studies aimed at identifying superior or additional biomarkers.

Changing the trajectory of Alzheimer’s disease: What is a meaningful delay in disease progression?

AbstractBackgroundRecent trials of anti‐amyloid therapies have shown it is possible to change the course of early symptomatic Alzheimer’s disease (AD). However, the limited durations of these trials with the associated limited decline in the patient populations have left questions about the clinical meaningfulness of the observed treatment differences. Through progression analysis, one can quantify trial results in terms of time delay of progression. Compared to treatment differences on clinical scales, time delays are arguably more interpretable to patients and their families. However, it is yet to be established what constitutes a meaningful time delay in AD progression.MethodAssess how different hypothetical delays in disease progression in early symptomatic AD translate into treatment differences on the Clinical Dementia Rating Sum of Boxes (CDR‐SB) based on published results placebo‐arm trajectories in recent anti‐amyloid trials. Estimates are compared to published estimates of minimal clinically important differences (MCIDs) in AD and meaningful delays in progression in other diseases.ResultBased on placebo arms from six recent trials of anti‐amyloid antibodies, a 6‐month delay over 18 months (33% slowing) corresponded to treatment differences on CDR‐SB between ‐0.5 and ‐0.8, a 12‐month delay (67% slowing) corresponded to treatment differences between ‐1.0 and ‐1.7, and completely stopping progression (18‐month delay) corresponded to treatment differences between ‐1.6 and ‐2.3 (Figure 1, Table 1). Observed treatment effects in the EMERGE, CLARITY‐AD and TRAILBLAZER‐ALZ trials are consistent with approximately 4‐6 months delay of progression (22‐30% slowing, Figure 1). Established MCIDs in CDR‐SB in early AD range between 1.0 and 1.6, suggesting that a 12‐month delay or 67% slowing of disease progression in an 18‐month trial would be considered borderline in terms of clinical meaningfulness.ConclusionQuantifying treatment effects in progressive diseases such as AD in terms of time delays or slowing of progression may offer a more meaningful interpretation of the treatment effects. Based on the trajectories of placebo group in recent trials, we found that treatment effects matching conventionally used MCIDs in AD would correspond to a very substantial slowing of disease (&gt;67%), suggesting that current MCIDs for CDR‐SB are likely inflated.