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Secondary metastases, accounting for 90 % of cancer-related deaths, pose a formidable challenge in cancer treatment, with bone being a prevalent site. Importantly, tumours may relapse, often in the skeleton even after successful eradication of the primary tumour, indicating that tumour cells may lay dormant within bone for extended periods of time. This review summarises recent findings in the mechanisms underlying tumour cell dormancy and the role of bone cells in this process. Hematopoietic stem cell (HSC) niches in bone provide a model for understanding regulatory microenvironments. Dormant tumour cells have been shown to exploit similar niches, with evidence suggesting interactions with osteoblast-lineage cells and other stromal cells via CXCL12-CXCR4, integrins, and TAM receptor signalling, especially through GAS6-AXL, led to dormancy, with exit of dormancy potentially regulated by osteoclastic bone resorption and neuronal signalling. A comprehensive understanding of dormant tumour cell niches and their regulatory mechanisms is essential for developing targeted therapies, a critical step towards eradicating metastatic tumours and stopping disease relapse.
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Background: Several studies have examined return to play (RTP) and outcomes following the Latarjet procedure in contact athletes. Purpose: To investigate clinical outcomes affecting RTP following the Latarjet procedure in contact athletes. Study Design: Case series; Level of evidence, 4. Methods: A total of 67 contact athletes (72 shoulders) ≤35 years old who underwent Latarjet procedure for recurrent shoulder instability between January 1, 2018, and March 31, 2022, were retrospectively identified. Demographic information, medical history, surgical history, number of dislocations before surgery, and postoperative complications up to 6 months after surgery were reviewed. Outcomes evaluated included RTP, competition level, satisfaction, and patient-reported outcomes including visual analog scale for pain, American Shoulder and Elbow Surgeons (ASES) Score, and Disabilities of the Arm, Shoulder and Hand (DASH) scores. Results: There were a total of 67 patients (72 shoulders) included in the study with a mean age at surgery of 19.7 years for all shoulders. Of the total cohort, 46 patients (50 shoulders; [69.4%]) were available for follow-up by phone. Of the 46 patients contacted by phone, 22/46 were football players; 30/50 [60.0% of all shoulders]) were contact athletes and 19/46 [41.3%] limited contact athletes) were interviewed with a mean follow-up of 25.5 months (range, 10-49 months). Of 72 patients, 22 (30.6% of shoulders and 32.8% of patients) patients had prior shoulder surgery, most commonly arthroscopic stabilization. Only 1 patient experienced hardware failure, but this did not require reoperation. Sixteen of 46 (35%) athletes competed at the collegiate level, and 24/46 (52%) were high school athletes at the time of surgery; 34 of 46 patients (74%) returned to play, of which 30 of the 34 (88%) returned to playing at the same competition level; 15 of 22 (68%) football players returned to play. Only 4 of 51 (8%) reported subjective recurrent instability. Postoperative mean ASES score was 92.2, DASH score was 5.6, and visual analog scale for pain score was 4 (range, 0-50). A total of 43 of 46 (93%) patients reported improvement in quality of life after undergoing the Latarjet procedure for shoulder instability. Eight of 72 (11.1%) shoulders had unresolved pain or stiffness 6 months postoperatively, and 2 of 72 (2.8%) required revisions. Conclusion: Patient RTP, outcomes, and satisfaction were high following the Latarjet procedure in young contact athletes.
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Relatlimab (rela; anti-LAG-3) plus nivolumab (nivo; anti-PD-1) is safe and effective for treatment of advanced melanoma. We designed a trial (NCT03743766) where advanced melanoma patients received rela, nivo, or rela+nivo to interrogate the immunologic mechanisms of rela+nivo. Analysis of biospecimens from this ongoing trial demonstrated that rela+nivo led to enhanced capacity for CD8+ T cell receptor signaling and altered CD8+ T cell differentiation, leading to heightened cytotoxicity despite the retention of an exhaustion profile. Co-expression of cytotoxic and exhaustion signatures was driven by PRDM1, BATF, ETV7, and TOX. Effector function was upregulated in clonally expanded CD8+ T cells that emerged after rela+nivo. A rela+nivo intratumoral CD8+ T cell signature was associated with a favorable prognosis. This intratumoral rela+nivo signature was validated in peripheral blood as an elevated frequency of CD38+TIM3+CD8+ T cells. Overall, we demonstrated that cytotoxicity can be enhanced despite the retention of exhaustion signatures, which will inform future therapeutic strategies.
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Linfocitos T CD8-positivos , Proteína del Gen 3 de Activación de Linfocitos , Melanoma , Receptor de Muerte Celular Programada 1 , Humanos , Antígenos CD/metabolismo , Antígenos CD/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular , Citotoxicidad Inmunológica , Proteínas del Grupo de Alta Movilidad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Proteína del Gen 3 de Activación de Linfocitos/antagonistas & inhibidores , Melanoma/inmunología , Melanoma/tratamiento farmacológico , Melanoma/genética , Nivolumab/uso terapéutico , Nivolumab/farmacología , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Transducción de SeñalRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is one of the most recalcitrant cancers due to its late diagnosis, poor therapeutic response, and highly heterogeneous microenvironment. Nanotechnology has the potential to overcome some of the challenges to improve diagnostics and tumor-specific drug delivery but they have not been plausibly viable in clinical settings. The review focuses on active targeting strategies to enhance pancreatic tumor-specific uptake for nanoparticles. Additionally, this review highlights using actively targeted liposomes, micelles, gold nanoparticles, silica nanoparticles, and iron oxide nanoparticles to improve pancreatic tumor targeting. Active targeting of nanoparticles toward either differentially expressed receptors or PDAC tumor microenvironment (TME) using peptides, antibodies, small molecules, polysaccharides, and hormones has been presented. We focus on microenvironment-based hallmarks of PDAC and the potential for actively targeted nanoparticles to overcome the challenges presented in PDAC. It describes the use of nanoparticles as contrast agents for improved diagnosis and the delivery of chemotherapeutic agents that target various aspects within the TME of PDAC. Additionally, we review emerging nano-contrast agents detected using imaging-based technologies and the role of nanoparticles in energy-based treatments of PDAC. This article is categorized under: Implantable Materials and Surgical Technologies > Nanoscale Tools and Techniques in Surgery Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.
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Nanopartículas , Neoplasias Pancreáticas , Nanomedicina Teranóstica , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Nanopartículas/química , Nanopartículas/uso terapéutico , Microambiente Tumoral , Sistemas de Liberación de Medicamentos , Ratones , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/diagnóstico por imagenRESUMEN
Fluorescence correlation spectroscopy (FCS) is a cornerstone technique in optical microscopy to measure, for example, the concentration and diffusivity of fluorescent emitters and biomolecules in solution. The application of FCS to complex biological systems, however, is fraught with inherent intricacies that impair the interpretation of correlation patterns. Critical among these intricacies are temporal variations beyond diffusion in the quantity, intensity, and spatial distribution of fluorescent emitters. These variations introduce distortions into correlated intensity data, thus compromising the accuracy and reproducibility of the analysis. This issue is accentuated in imaging-based approaches such as pair correlation function (pCF) analysis due to their broader regions of interest compared with point-detector-based approaches. Despite ongoing developments in FCS, attention to systems characterized by a spatiotemporal-dependent probability distribution function (ST-PDF) has been lacking. To address this knowledge gap, we developed a new analytical framework for ST-PDF systems that introduces a dual-timescale model function within the conventional pCF analysis. Our approach selectively differentiates the signals associated with rapid processes, such as particle diffusion, from signals stemming from spatiotemporal variations in the distribution of fluorescent emitters occurring at extended delay timescales. To corroborate our approach, we conducted proof-of-concept experiments on an ST-PDF system, wherein the, initially, uniform distribution of fluorescent microspheres within a microfluidic channel changes into a localized accumulation of microspheres over time. Our framework is offering a comprehensive solution for investigating various phenomena such as biomolecular binding, sedimentation, and particle accumulation.
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INTRODUCTION: Recent studies have evaluated patient perception of physician attire; however, few studies have considered physician perceptions of workplace attire. This study aimed to assess current trends regarding attire preferences among surgeons. METHODS: A national, population-based survey was distributed via email and "X" (Twitter). Participants were asked to complete an online questionnaire regarding their perception of the white coat, preferred attire in clinical settings, and reasons for choice of attire. RESULTS: Of 481 participants, 172 (36%) were attendings, 164 (34%) were residents, 125 (26%) were medical students, and 20 (4%) were fellows. Those who practiced in the Midwest region were more likely to wear a white coat daily (35.1% versus 28.5% South, 23.5% Northeast, 20.0% West, P < 0.05). Late career surgeons (practicing >20 y) were more likely to wear a white coat in the hospital and wear it daily (56% versus 36% of middle-career surgeons, 34% early-career surgeons, and 26% in training, P < 0.05). Women surgeons more frequently wore a white coat in clinic (64% versus 54% men, P < 0.05), reported that wearing a white coat was influenced by their program's culture (61% versus 46% of men surgeons, P < 0.05), that they would stop wearing a white coat if other members of their department stopped (50% versus 35% of men, P < 0.05), and that they believe the white coat helps distinguish female doctors from nurses (61% versus 50% of men surgeons, P < 0.05). CONCLUSIONS: This study demonstrates generational, regional, and gender differences among surgeons in their perception of the white coat at a national level.
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Given the cost and unclear clinical impact of metagenomic next-generation sequencing (mNGS), laboratory stewardship may improve utilization. This retrospective observational study examines mNGS results from two academic medical centers employing different stewardship approaches. Eighty mNGS orders [54 cerebrospinal fluid (CSF) and 26 plasma] were identified from 2019 to 2021 at the University of Washington (UW), which requires director-level approval for mNGS orders, and the University of Utah (Utah), which does not restrict ordering. The impact of mNGS results and the relationship to traditional microbiology orders were evaluated. Nineteen percent (10/54) of CSF and 65% (17/26) of plasma studies detected at least one organism. Compared to CSF results, plasma results more frequently identified clinically significant organisms (31% vs 7%) and pathogens not detected by traditional methods (12% vs 0%). Antibiotic management was more frequently impacted by plasma versus CSF results (31% vs 4%). These outcome measures were not statistically different between study sites. The number and cumulative cost of traditional microbiology tests at UW were greater than Utah for CSF mNGS testing (UW: 46 tests, $6,237; Utah: 26 tests, $2,812; P < 0.05) but similar for plasma mNGS (UW: 31 tests, $3,975; Utah: 21 tests, $2,715; P = 0.14). mNGS testing accounted for 30%-50% of the total microbiology costs. Improving the diagnostic performance of mNGS by stewardship remains challenging due to low positivity rates and difficulties assessing clinical impact. From a fiscal perspective, stewardship efforts should focus on reducing testing in low-yield populations given the high costs of mNGS relative to overall microbiology testing expenditures. IMPORTANCE: Metagenomic next-generation sequencing (mNGS) stewardship practices remain poorly standardized. This study aims to provide actionable insights for institutions that seek to reduce the unnecessary usage of mNGS. Importantly, we highlight that clinical impact remains challenging to measure without standardized guidelines, and we provide an actual cost estimate of microbiology expenditures on individuals undergoing mNGS.
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Fluxes in human copper levels recently garnered attention for roles in cellular signaling, including affecting levels of the signaling molecule cyclic adenosine monophosphate. We herein apply an unbiased temporal evaluation of the signaling and whole genome transcriptional activities modulated by copper level fluctuations to identify potential copper sensor proteins responsible for driving these activities. We find that fluctuations in physiologically relevant copper levels modulate EGFR signal transduction and activation of the transcription factor CREB. Both intracellular and extracellular assays support Cu1+ inhibition of the EGFR phosphatase PTPN2 (and potentially PTPN1)-via ligation to the PTPN2 active site cysteine side chain-as the underlying mechanism. We additionally show i) copper supplementation drives weak transcriptional repression of the copper importer CTR1 and ii) CREB activity is inversely correlated with CTR1 expression. In summary, our study reveals PTPN2 as a physiological copper sensor and defines a regulatory mechanism linking feedback control of copper stimulated EGFR/CREB signaling and CTR1 expression.
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Transportador de Cobre 1 , Cobre , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Receptores ErbB , Proteína Tirosina Fosfatasa no Receptora Tipo 2 , Transducción de Señal , Receptores ErbB/metabolismo , Receptores ErbB/genética , Cobre/metabolismo , Humanos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Transportador de Cobre 1/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 2/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 1/genética , Transcripción Genética/efectos de los fármacosRESUMEN
Malaria was once endemic in the United States prior to its elimination in 1951. However, due to consistent introductions of travel-associated malaria cases and the presence of several native Anopheles species (Diptera: Culicidae) that are competent vectors of malaria, the potential for local (autochthonous) malaria transmission remains a persistent threat in the United States. While several intermittent cases of local malaria transmission have occurred in the United States in the decades since elimination, the emergence of autochthonous transmission in 4 states in 2023 demonstrates the continued risk for future outbreaks. Moreover, these recent examples also highlight significant gaps in current mosquito surveillance efforts that have predominantly focused on threats of arboviral disease, such that our understanding of Anopheles distributions relies only on historical records and offers limited insight into the ecological factors that influence their abundance. Herein, we summarize mosquito surveillance data collected over the last 20 years (2004-2023) across 59 Iowa counties to provide essential information into the spatial distribution, temporal abundance, and trap preferences of Anopheles species in the state. Further analyses of the 2 most abundant species, Anopheles punctipennis Say and Anopheles quadrimaculatus Say, reveal the additional influence of precipitation and forested habitats in defining An. punctipennis abundance. Together, we believe these results provide an increased understanding of previously neglected Anopheles species that have the potential for autochthonous malaria transmission in Iowa and that can be extended to other regions of the United States to enhance preparedness for future malaria outbreaks.
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PURPOSE: Papillary thyroid carcinoma detection has increased dramatically in the United States. However, the indolent nature of papillary thyroid microcarcinoma (mPTC) has led the American Thyroid Association (ATA) to advocate for more conservative management. The 2015 ATA recommendations advocated for observation or lobectomy for mPTC. However, the majority of mPTCs continue to be treated with more aggressive surgical management. In this study, we aim to understand the management of mPTC based on facility variables. MATERIALS AND METHODS: A retrospective observational study of patients diagnosed with mPTC between 2004 and 2018 was performed using the National Cancer Database incidence data. We collected data on patient sex, age, tumor size, race, ethnicity, geographic location, thyroid surgical volume at the facility, and treatment modality for mPTC were collected. Conservative and non-conservative treatment modalities based on patient and facility characteristics were compared both longitudinally and cross-sectionally between pre- and post-2015 ATA recommendations. RESULTS: Total thyroidectomy with or without radioactive iodine ablation (RAI) remains the treatment of choice regardless of patient and facility characteristics. Patients treated at low-volume facilities were actually more likely to be treated conservatively. CONCLUSIONS: Despite 2015 ATA recommendations advocating for observation or lobectomy for mPTC, patients with mPTC are still more likely to be treated with total thyroidectomy with or without RAI, especially at high-volume facilities.
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Colloidal and nanoparticle self-assembly enables the creation of ordered structures with a variety of electronic and photonic functionalities. The outcomes of the self-assembly processes used to synthesize such structures, however, strongly depend on the uniformity of the individual nanoparticles. Here, we explore the simplest form of particle size dispersity-bidispersity-and its impact on the self-assembly process. We investigate the robustness of self-assembling bcc-type crystals via isotropic interaction potentials in binary systems with increasingly disparate particle sizes by determining their terminal size ratio-the most extreme size ratio at which a mixed binary bcc crystal forms. Our findings show that two-well pair potentials produce bcc crystals that are more robust with respect to particle size ratio than one-well pair potentials. This suggests that an improved self-assembly process is accomplished with a second attractive length scale encoded in the particle-particle interaction, which stabilizes the second-nearest neighbor shell. In addition, we document qualitative differences in the process of ordering and disordering: in bidisperse systems of particles interacting via one-well potentials, we observe a breakdown of order prior to demixing, while in systems interacting via two-well potentials, demixing occurs first and bcc continues to form in parts of the droplet down to low size ratios.
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Background and Aims: Early biologic therapy treatment has demonstrated better outcomes in Crohn's disease (CD). We evaluated the impact of CD duration in patients with moderately to severely active CD treated with risankizumab therapy. Methods: This post hoc analysis evaluated clinical, endoscopic, and safety outcomes by baseline CD duration (<2, 2-5, >5-10, and >10 years) in patients from ADVANCE, MOTIVATE, and FORTIFY. Pooled induction analyses included patients who received intravenous 600-mg dose of risankizumab or placebo for 12 weeks. Maintenance analyses included patients who responded to induction risankizumab and received subcutaneous 180-mg or 360-mg dose of risankizumab for 52 weeks. Duration subgroups were compared using Cochrane-Armitage trend tests with nominal P values. Results: Among 527 patients who received risankizumab 600-mg induction therapy, higher outcome rates were observed at week 12 among patients with shorter vs longer baseline disease duration (for <2, 2-5, >5-10, and >10 years, clinical remission: 42.7%, 46.9%, 43.5%, and 33.2% [P = .046]; endoscopic response: 48.3%, 36.3%, 32.0%, and 33.4% [P = .025]). Among 298 patients receiving risankizumab (180 mg or 360 mg) maintenance therapy, shorter vs longer baseline disease duration was generally associated with numerically higher endoscopic outcome rates at week 52. Higher clinical remission and endoscopic outcome rates were generally observed with shorter disease duration with 180-mg risankizumab dose only. Adverse event rates were generally similar across duration subgroups. Conclusion: Clinical benefits of risankizumab are observed across disease duration subgroups; clinical and endoscopic outcome rates are higher with risankizumab initiation earlier in the disease course (ClinicalTrials.gov numbers: NCT03105128, NCT03104413, and NCT03105102).
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OBJECTIVE: Sexual and gender diverse (SGD) individuals are at heightened risk for intimate partner aggression (IPA) perpetration relative to their heterosexual and cisgender peers. Alcohol is a well-established cause of IPA perpetration in cisgender, heterosexual couples; however, minimal research has investigated the alcohol-IPA perpetration link in SGD couples. The relative lack of work in this area is a major barrier to addressing this health disparity. SGD individuals experience unique stressors related to their and/or their partner's intersecting minoritized identities that are critical to understanding alcohol-IPA etiology and informing culturally affirming intervention programming. METHOD: We advance prior work by members of the authorship team (see Parrott et al., 2023a; Shorey et al., 2019) to propose an integrative theoretical model that invokes (1) the I3 Model to organize risk and resilience factors at the individual and dyadic level, and (2) Alcohol Myopia Theory to explain the mechanism by which proximal alcohol use facilitates IPA as a function of individual differences in those factors. RESULTS: This integrative model provides a framework to understand how the confluence of stigma, minority stressors, proximal alcohol use, and other factors contribute to IPA perpetration in SGD couples. DISCUSSION: Application of this integrative model has potential to facilitate more rigorous research (e.g., intensive longitudinal designs, dyadic analysis) focused on putative risk and resilience factors across the social ecology. Further, the model provides guidance for intervention development by identifying how individual (e.g., minority stress), relationship (e.g., relationship functioning), and structural factors (e.g., SGD stigma) interactively contribute to alcohol-facilitated IPA perpetration.
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The evolution of complete blood count (CBC) methodology from manual calculations to sophisticated high throughput hematology analyzers is the focus of this article. In recent years, hematology testing has greatly benefitted from the combination of various technologies with automated neural networks. In addition to an increasing complexity of the laboratory instrumentation, there is a demand on point of care CBC testing with its benefits and drawbacks. This article highlights exciting advancements of hematology testing from the past to the present and into the future.
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Hematología , Humanos , Recuento de Células Sanguíneas/instrumentación , Hematología/instrumentación , Hematología/tendencias , Pruebas Hematológicas/instrumentación , Pruebas Hematológicas/tendencias , Redes Neurales de la ComputaciónRESUMEN
Adverse childhood experiences (ACEs) are prevalent and associated with common problems among adults with substance use disorders (SUDs), including posttraumatic stress disorder (PTSD) symptoms and compulsive behaviors. Most studies consider cumulative ACEs when examining their associations with health and behavioral outcomes. We tested whether patterns of ACEs related to SUD symptoms, PTSD symptoms, and compulsive behaviors among adults receiving treatment for substance use. We identified latent classes of ACEs using medical record data from 721 patients in residential SUD treatment and conducted Wald chi-square tests to assess whether these latent classes differed in alcohol and drug use disorder symptoms, PTSD symptoms, compulsive sexual behavior, and compulsive gambling. We identified four latent classes: high ACEs (15.1%), maltreatment (12.4%), household problems (22.3%), and low ACEs (49.1%). There were significant differences across latent classes in drug use disorder symptoms, PTSD symptoms, and compulsive sexual behavior, χ2(1, N = 721) = 37.42-107.07, ps < .001. Participants in the high ACEs and household problems classes had more drug use disorder symptoms than those in the low ACEs class. Relative to all other classes, individuals in the low ACEs class had the lowest PTSD symptoms and those in the high ACEs class had the highest PTSD symptoms. Findings indicate that adults with SUDs who have more ACEs have the highest risk for PTSD symptoms and compulsive sexual behavior. Screening for ACEs while considering ACE patterns and frequency may benefit treatment planning for SUD patients with comorbid concerns such as PTSD symptoms and compulsive sexual behavior.