Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population.

Although inactivation of the PTEN gene has been implicated in the development of resistance to the HER2 targeting antibody trastuzumab, the mechanisms mediating this resistance remain elusive. We generated trastuzumab resistant cells by knocking down PTEN expression in HER2 overexpressing breast cancer cell lines and demonstrate that development of trastuzumab resistance in these cells is mediated by activation of an IL6 inflammatory feedback loop leading to expansion of the cancer stem cell (CSC) population. Long term trastuzumab treatment generates highly enriched CSCs which display an EMT phenotype secreting over 100-fold more IL6 than parental cells. An IL6 receptor antibody interrupted this inflammatory feedback loop reducing the cancer stem cell population resulting in decreased tumor growth and metastasis in mouse xenographs. These studies demonstrate that trastuzumab resistance may be mediated by an IL6 inflammatory loop and suggest that blocking this loop may provide alternative strategy to overcome trastuzumab resistance.

Relationship Between Nutritional Factors and Hip Bone Density in Individuals with Chronic Stroke.

The aim of this study was to investigate the relationship between dietary habits and hip bone health in community-dwelling individuals with chronic stroke. The usual dietary intake of 94 individuals with chronic stroke (30 women, mean age: 59.0 years) was assessed by a 3-day food record within a single week. Dual-energy X-ray absorptiometry was used to measure bone mineral density (BMD) at both hips. The results showed that low hip bone mass was found in 59 and 50 of the participants on the affected and unaffected side, respectively. The mean hip BMD was also significantly lower on the affected side than the unaffected side (P < 0.001). The intake of total fat, carbohydrates, calcium, magnesium, iron, zinc, fiber, folic acid, vitamin B1, B2, B3, B6, C, and K was significantly lower than the respective recommended daily intake values (P < 0.05). Multiple regression analyses revealed that after adjusting for the effects of age, sex, body mass index, post-stroke duration, side of paresis, motor impairment, physical activity level, walking endurance, total calories intake, and total number of medications, intake of protein, fiber, and magnesium remained significantly associated with hip T score on the affected side, accounting for 4.2, 4.4, and 3.2% of the variance, respectively. On the other hand, intake of protein and fiber was independently associated with hip T score on the unaffected side, explaining 2.7 and 5.2% of the variance, respectively. The results highlighted the potential relevance of diet modification in maintaining bone health post stroke, which would require further study.

Plastic Surgery Response in Natural Disasters.

Disasters cause untold damage and are often unpredictable; however, with proper preparation, these events can be better managed. The initial response has the greatest impact on the overall success of the relief effort. A well-trained multidisciplinary network of providers is necessary to ensure coordinated care for the victims of these mass casualty disasters. As members of this network of providers, plastic surgeons have the ability to efficiently address injuries sustained in mass casualty disasters and are a valuable member of the relief effort. The skill set of plastic surgeons includes techniques that can address injuries sustained in large-scale emergencies, such as the management of soft-tissue injury, tissue viability, facial fractures, and extremity salvage. An approach to disaster relief, the types of disasters encountered, the management of injuries related to mass casualty disasters, the role of plastic surgeons in the relief effort, and resource management are discussed. In order to improve preparedness in future mass casualty disasters, plastic surgeons should receive training during residency regarding the utilization of plastic surgery knowledge in the disaster setting.

Cement-Induced Chemical Burn in a Middle-Aged Male: A Case Report and Review of Literature.

This case study reviews a 48-year-old Hispanic male working in construction who presented with left upper medial thigh pain, redness, and swelling after exposure to hazardous chemicals during cement processing. Initially diagnosed with cellulitis and adjacent myositis, the patient met sepsis criteria and received empiric antibiotics. However, negative cultures and an evolving wound appearance shifted the diagnosis towards bullous diseases and chemical injury. Occupational history and physical exam findings pointed towards injury secondary to chemical exposure, common in cement workers with inadequate protective gear. Cement burns, often insidious, are underreported due to their slow progression, mainly affecting the lower extremities. These burns involve chemical, mechanical, and hypersensitivity mechanisms that can mimic infection on imaging. This case highlights the importance of recognizing and managing cement burns promptly, emphasizing protective measures, decontamination, and potential early intervention by burn specialists.

Exploring how brain health strategy training informs the future of work.

Introduction: The workplace typically affords one of the longest periods for continued brain health growth. Brain health is defined by the World Health Organization (WHO) as the promotion of optimal brain development, cognitive health, and well-being across the life course, which we expanded to also include connectedness to people and purpose. This work was motivated by prior work showing individuals, outside of an aggregate setting, benefitted from training as measured by significant performance gains on a holistic BrainHealth Index and its factors (i.e., clarity, connectedness, emotional balance). The current research was conducted during the changing remote work practices emerging post-pandemic to test whether a capacity-building training would be associated with significant gains on measures of brain health and components of burnout. The study also tested the influence of utilization of training modules and days in office for individuals to inform workplace practices. Methods: We investigated whether 193 individuals across a firm's sites would improve on measures of brain health and burnout from micro-delivery of online tactical brain health strategies, combined with two individualized coaching sessions, and practical exercises related to work and personal life, over a six-month period. Brain health was measured using an evidenced-based measure (BrainHealth™ Index) with its components (clarity, connectedness, emotional balance) consistent with the WHO definition. Burnout was measured using the Maslach Burnout Inventory Human Services Survey. Days in office were determined by access to digital workplace applications from the firm's network. Regression analyses were used to assess relationships between change in BrainHealth factors and change in components of the Maslach Burnout Inventory. Results: Results at posttest indicated that 75% of the individuals showed gains on a composite BrainHealth Index and across all three composite factors contributing to brain health. Benefits were directly tied to training utilization such that those who completed the core modules showed the greatest gains. The current results also found an association between gains on both the connectedness and emotional balance brain health factors and reduced on burnout components of occupational exhaustion and depersonalization towards one's workplace. We found that fewer days in the office were associated with greater gains in the clarity factor, but not for connectedness and emotional balance. Discussion: These results support the value of a proactive, capacity-building training to benefit all employees to complement the more widespread limited offerings that address a smaller segment who need mental illness assistance programs. The future of work may be informed by corporate investment in focused efforts to boost collective brain capital through a human-centered, capacity-building approach. Efforts are underway to uncover the value of better brain health, i.e., Brainomics© - which includes economic, societal, and individual benefits.

Spontaneous Tissue Expander Migration in an Irradiated Field: A Case Report.

A 59-year-old woman with a history of bilateral breast cancer, bilateral mastectomy, and bilateral latissimus dorsi flap reconstruction with tissue expanders, before expansion, developed spontaneous unilateral tissue expander migration on the side that had been irradiated. During the operation to return the migrated tissue expander to the chest, the expander was found at the back with a seroma. The chest pocket had collapsed, and a subcutaneous tunnel inferior to the flap inset was encountered, indicating the path of migration. To our knowledge, this is the first case reported of spontaneous tissue expander dislodgement to the donor site. This case is unique in that the patient had bilateral procedures but developed tissue expander migration only on the irradiated side. This highlights the need during pocket creation to account for the fibrosis caused by radiation that can create a constricted pocket promoting migration.

Glycolytic network restructuring integral to the energetics of embryonic stem cell cardiac differentiation.

Decoding of the bioenergetic signature underlying embryonic stem cell cardiac differentiation has revealed a mandatory transformation of the metabolic infrastructure with prominent mitochondrial network expansion and a distinctive switch from glycolysis to oxidative phosphorylation. Here, we demonstrate that despite reduction in total glycolytic capacity, stem cell cardiogenesis engages a significant transcriptome, proteome, as well as enzymatic and topological rearrangement in the proximal, medial, and distal modules of the glycolytic pathway. Glycolytic restructuring was manifested by a shift in hexokinase (Hk) isoforms from Hk-2 to cardiac Hk-1, with intracellular and intermyofibrillar localization mapping mitochondrial network arrangement. Moreover, upregulation of cardiac-specific enolase 3, phosphofructokinase, and phosphoglucomutase and a marked increase in glyceraldehyde 3-phosphate dehydrogenase (GAPDH) phosphotransfer activity, along with apparent post-translational modifications of GAPDH and phosphoglycerate kinase, were all distinctive for derived cardiomyocytes compared to the embryonic stem cell source. Lactate dehydrogenase (LDH) isoforms evolved towards LDH-2 and LDH-3, containing higher proportions of heart-specific subunits, and pyruvate dehydrogenase isoforms rearranged between E1alpha and E1beta, transitions favorable for substrate oxidation in mitochondria. Concomitantly, transcript levels of fetal pyruvate kinase isoform M2, aldolase 3, and transketolase, which shunt the glycolytic with pentose phosphate pathways, were reduced. Collectively, changes in glycolytic pathway modules indicate active redeployment, which would facilitate connectivity of the expanding mitochondrial network with ATP utilization sites. Thus, the delineated developmental dynamics of the glycolytic phosphotransfer network is integral to the remodeling of cellular energetic infrastructure underlying stem cell cardiogenesis.

The Importance of Specific Workplace Environment Characteristics for Maximum Health and Performance: Healthcare Workers' Perspective.

OBJECTIVE: To examine the importance of specific workplace environment characteristics for maximum health and performance, assigned by healthcare employees, and how they relate to the nature of their work. METHODS: A cross-sectional mixed-method study was conducted with content analysis and robust regression models to examine the relationship between workplace environment characteristics and perceived importance in promoting health and performance. RESULTS: Our findings suggest that perceptions of key environment characteristics that safeguard health and performance in healthcare workplaces may vary by employee sex, setting, and nature of healthcare work involved. Theme and model descriptions of the influence of these factors on participant perceptions are provided. CONCLUSIONS: Employee feedback on workplace characteristics that impact health and performance could be instrumental in determining the priorities of workplace design.

Specific instructions are important for continuous bimanual drumming in adults with Down syndrome.

The present study examined continuous and discrete bimanual drumming in response to different instructions in 10 adults with Down syndrome, 10 mental age-matched and 10 chronological age-matched groups. For continuous drumming, participants hit two drums with both hands at the same time following verbal (e.g., "up" and "down"), visual (e.g., video of both drumsticks moving up and down together) and auditory (e.g., sound of both drums being hit, then symbol being hit) instructions for 10 s. For discrete drumming participants hit two drums with both hands at the same time once in response to the instructions described above. In general, for all groups spatial measures showed a performance advantage when using the visual metronome in continuous tasks but no advantage with any instructions for discrete tasks.

Upper extremity deep vein thrombosis with tourniquet use.

INTRODUCTION: Upper extremity deep vein thrombosis is an increasingly important clinical finding with significant morbidity and mortality. The condition may be under-diagnosed in trauma and surgery settings. PRESENTATION OF CASE: We present a case of upper extremity thrombosis with venous congestive symptoms secondary to the use of an operative tourniquet. A literature review and discussion of the causes of upper extremity deep vein thrombosis and the pathophysiological disturbances seen with tourniquet use are presented. DISCUSSION: Upper extremity deep venous thrombosis is uncommon. In this case the likely cause was operative tourniquet use. CONCLUSION: Operative tourniquet may be a risk factor in upper extremity deep vein thrombosis.

Effect of frequency of carbohydrate feedings on recovery and subsequent endurance run.

PURPOSE: This study examined the effect of feeding pattern of a high glycemic index (GI) meal during a short-term recovery on subsequent endurance capacity. METHODS: Eight men ran at 70% .VO2max on a level treadmill for 90 min (T1) on two occasions, followed by 4-h recovery (R) and a further exhaustive run at the same speed (T2). During the R, subjects consumed a prescribed meal with a GI of 77 in either a "gorging" (GOR) or "nibbling" (NIB) intake pattern, providing 1.5 g carbohydrate (CHO) per kilogram body mass. In the GOR trial, the foods were consumed in a single bolus, 20 min after the end of T1. In the NIB trial, the same quantity of food was ingested in three equal portions; the first consumed 20 min after the end of T1 and the remainder at hourly intervals thereafter. RESULTS: The run time during T2 was similar between trials (GOR vs NIB: 68.1 +/- 8.2 vs 66.8 +/- 8.7 min, P > 0.05). However, CHO utilization was lower and fat utilization higher during T2 in the GOR trial compared with the NIB trial (GOR vs NIB: CHO: 94.4 +/- 11.4 vs 117.6 +/- 10.6 g, P < 0.05; FAT: 55.9 +/- 8.0 vs 44 +/- 8.6 g, P < 0.01). CONCLUSIONS: These results suggest that serial consumption of a high GI meal during a 4-h recovery increased the reliance on CHO oxidation for energy provision during a subsequent run when compared with a single feeding. However, there was no difference in the duration of the exhaustive run after the recovery between the GOR and NIB trials.

The impact of windows and daylight on acute-care nurses' physiological, psychological, and behavioral health.

OBJECTIVE: To investigate the physiological and psychological effects of windows and daylight on registered nurses. BACKGROUND: To date, evidence has indicated that appropriate environmental lighting with characteristics similar to natural light can improve mood, alertness, and performance. The restorative effects of windows also have been documented. Hospital workspaces generally lack windows and daylight, and the impact of the lack of windows and daylight on healthcare employees' well being has not been thoroughly investigated. METHODS: Data were collected using multiple methods with a quasi-experimental approach (i.e., biological measurements, behavioral mapping, and analysis of archival data) in an acute-care nursing unit with two wards that have similar environmental and organizational conditions, and similar patient populations and acuity, but different availability of windows in the nursing stations. RESULTS: Findings indicated that blood pressure (p < 0.0001) decreased and body temperature increased (p = 0.03). Blood oxygen saturation increased (p = 0.02), but the difference was clinically insignificant. Communication (p < 0.0001) and laughter (p = 0.03) both increased, and the subsidiary behavior indicators of sleepiness and deteriorated mood (p = 0.02) decreased. Heart rate (p = 0.07), caffeine intake (p = 0.3), self-reported sleepiness (p = 0.09), and the frequency of medication errors (p = 0.14) also decreased, but insignificantly. CONCLUSIONS: The findings support evidence from laboratory and field settings of the benefits of windows and daylight. A possible micro-restorative effect of windows and daylight may result in lowered blood pressure and increased oxygen saturation and a positive effect on circadian rhythms (as suggested by body temperature) and morning sleepiness. KEYWORDS: Critical care/intensive care, lighting, nursing, quality care, work environment.

Developmental enhancement of adenylate kinase-AMPK metabolic signaling axis supports stem cell cardiac differentiation.

BACKGROUND: Energetic and metabolic circuits that orchestrate cell differentiation are largely unknown. Adenylate kinase (AK) and associated AMP-activated protein kinase (AMPK) constitute a major metabolic signaling axis, yet the role of this system in guiding differentiation and lineage specification remains undefined. METHODS AND RESULTS: Cardiac stem cell differentiation is the earliest event in organogenesis, and a suitable model of developmental bioenergetics. Molecular profiling of embryonic stem cells during cardiogenesis revealed here a distinct expression pattern of adenylate kinase and AMPK genes that encode the AK-AMP-AMPK metabolic surveillance axis. Cardiac differentiation upregulated cytosolic AK1 isoform, doubled AMP-generating adenylate kinase activity, and increased AMP/ATP ratio. At cell cycle initiation, AK1 translocated into the nucleus and associated with centromeres during energy-consuming metaphase. Concomitantly, the cardiac AMP-signal receptor AMPKα2 was upregulated and redistributed to the nuclear compartment as signaling-competent phosphorylated p-AMPKα(Thr172). The cardiogenic growth factor TGF-ß promoted AK1 expression, while knockdown of AK1, AK2 and AK5 activities with siRNA or suppression by hyperglycemia disrupted cardiogenesis compromising mitochondrial and myofibrillar network formation and contractile performance. Induction of creatine kinase, the alternate phosphotransfer pathway, compensated for adenylate kinase-dependent energetic deficits. CONCLUSIONS: Developmental deployment and upregulation of the adenylate kinase/AMPK tandem provides a nucleocytosolic energetic and metabolic signaling vector integral to execution of stem cell cardiac differentiation. Targeted redistribution of the adenylate kinase-AMPK circuit associated with cell cycle and asymmetric cell division uncovers a regulator for cardiogenesis and heart tissue regeneration.

Developmental restructuring of the creatine kinase system integrates mitochondrial energetics with stem cell cardiogenesis.

Differentiation of pluripotent low-energy requiring stem cells into the high-energy expenditure cardiac lineage requires coordination of genomic programming and energetic system maturation. Here, in a murine embryonic stem cell cardiac differentiation model, emergence of electrical and beating activity in cardiomyocytes developing within embryoid bodies was coupled with the establishment of the mitochondrial network and expansion of the creatine kinase (CK) phosphotransfer system. Stem cell cardiogenesis was characterized by increased total CK activity, an isoform shift manifested by amplified muscle CK-M mRNA levels and protein content, and the appearance of cardiac-specific CK-MB dimers. Treatment of differentiating stem cells with BMP2, a cardiogenic growth factor, promoted CK activity. CK-M clustered around developing myofibrils, sarcolemma, and the perinuclear compartment, whereas CK-B was tightly associated with myofibrillar alpha-actinin, forming wire-like structures extending from the nuclear compartment to the sarcolemma. Developmentally enhanced phosphotransfer enzyme-anchoring protein FHL2 coalesced the myofibrillar CK metabolic signaling circuit, providing an energetic continuum between mitochondria and the nascent contractile machinery. Thus, the evolving CK-catalyzed phosphotransfer network integrates mitochondrial energetics with cardiogenic programming, securing the emergence of energy-consuming cardiac functions in differentiating embryonic stem cells.

Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells.

Cardiogenesis within embryos or associated with heart repair requires stem cell differentiation into energetically competent, contracting cardiomyocytes. While it is widely accepted that the coordination of genetic circuits with developmental bioenergetics is critical to phenotype specification, the metabolic mechanisms that drive cardiac transformation are largely unknown. Here, we aim to define the energetic requirements for and the metabolic microenvironment needed to support the cardiac differentiation of embryonic stem cells. We demonstrate that anaerobic glycolytic metabolism, while sufficient for embryonic stem cell homeostasis, must be transformed into the more efficient mitochondrial oxidative metabolism to secure cardiac specification and excitation-contraction coupling. This energetic switch was programmed by rearrangement of the metabolic transcriptome that encodes components of glycolysis, fatty acid oxidation, the Krebs cycle, and the electron transport chain. Modifying the copy number of regulators of mitochondrial fusion and fission resulted in mitochondrial maturation and network expansion, which in turn provided an energetic continuum to supply nascent sarcomeres. Disrupting respiratory chain function prevented mitochondrial organization and compromised the energetic infrastructure, causing deficient sarcomerogenesis and contractile malfunction. Thus, establishment of the mitochondrial system and engagement of oxidative metabolism are prerequisites for the differentiation of stem cells into a functional cardiac phenotype. Mitochondria-dependent energetic circuits are thus critical regulators of de novo cardiogenesis and targets for heart regeneration.

Infrared spectroscopy of hydrogen-bonded CHCl3-SO2 in the gas phase.

A molecular association between chloroform and sulfur dioxide in the gas phase at room temperature was studied by Fourier transform infrared spectroscopy. Since the intensity of the CH-stretching fundamental vibration of monomer chloroform is very weak but much stronger upon complexation, a simple subtraction procedure isolated the CH-stretching vibration spectrum of the complex. The presence of a 1:1 complex was confirmed by two dilution series, where the monomer concentrations were varied. The molecular association manifested itself as a shift of the peak absorbance of the CH-stretching vibration of CHCl3-SO2 by +7 cm(-1) and of the CD-stretching vibration of CDCl3-SO2 by +5 cm(-1) to higher wave numbers compared to monomer chloroform, accompanied by a considerable broadening of the band contour. In agreement with previous ab initio calculations, this indicates a "blueshifting" or more appropriately, a "C-H contracting" hydrogen bond between chloroform and sulfur dioxide. An estimate of the complex concentration was made based on ab initio calculations for the integrated band strength and the measured spectrum. With this estimate, the equilibrium constant Kp (295 K)=0.014 (po=10(5) Pa) for the dimerization was calculated, providing one of the very few cases where the formation of a hydrogen-bonded gas phase complex at room temperature could be quantitatively studied by infrared spectroscopy.

LEDGF/p75 determines cellular trafficking of diverse lentiviral but not murine oncoretroviral integrase proteins and is a component of functional lentiviral preintegration complexes.

Human immunodeficiency virus type 1 (HIV-1), feline immunodeficiency virus (FIV), and Moloney murine leukemia virus (MoMLV) integrases were stably expressed to determine their intracellular trafficking. Each lentiviral integrase localized to cell nuclei in close association with chromatin while the murine oncoretroviral integrase was cytoplasmic. Fusions of pyruvate kinase to the lentiviral integrases did not reveal transferable nuclear localization signals. The intracellular trafficking of each was determined instead by the transcriptional coactivator LEDGF/p75, which was required for nuclear localization. Stable small interfering RNA expression eliminated detectable LEDGF/p75 expression and caused dramatic, stable redistribution of each lentiviral integrase from nucleus to cytoplasm while the distribution of MoMLV integrase was unaffected. In addition, endogenous LEDGF/p75 coimmunoprecipitated specifically with each lentiviral integrase. In vitro integration assays with preintegration complexes (PICs) showed that endogenous LEDGF/p75 is a component of functional HIV-1 and FIV PICs. However, HIV-1 and FIV infection and replication in LEDGF/p75-deficient cells was equivalent to that in control cells, whether cells were dividing or growth arrested. Two-long terminal repeat circle accumulation in nondividing cell nuclei was also equivalent to that of LEDGF/p75 wild-type cells. Virions produced in LEDGF/p75-deficient cells had normal infectivity. We conclude that LEDGF/p75 fully accounts for cellular trafficking of diverse lentiviral, but not oncoretroviral, integrases and is the main lentiviral integrase-to-chromatin tethering factor. While lentiviral PIC nuclear import is unaffected by LEDGF/p75 knockdown, this protein is a component of functional lentiviral PICs. A role in HIV-1 integration site distribution merits investigation.

Tyrosine-sulfated peptides functionally reconstitute a CCR5 variant lacking a critical amino-terminal region.

Entry of most primary human immunodeficiency virus, type 1 (HIV-1) isolates into their target cells requires the cellular receptor CD4 and the G protein-coupled chemokine coreceptor CCR5. An acidic, tyrosine-rich, and tyrosine-sulfated domain of the CCR5 amino terminus plays a critical role in the ability of CCR5 to serve as an HIV-1 coreceptor, and tyrosine-sulfated peptides based on this region physically associate with the HIV-1 envelope glycoprotein gp120 and slow HIV-1 entry into CCR5-expressing cells. Here we show that the same tyrosine-sulfated peptides, but not their unsulfated analogs, can restore the HIV-1 coreceptor activity of a CCR5 variant lacking residues 2-17 of its amino terminus. Additionally, these sulfated peptides restored the ability of this CCR5 variant to mobilize calcium in response to the chemokines macrophage inflammatory factors 1alpha and 1beta. These observations show that a tyrosine-sulfated region of the CCR5 amino terminus can function independently to mediate association of chemokines and the HIV-1 envelope glycoprotein with the remaining domains of CCR5.