Hydrothermal 15N15N abundances constrain the origins of mantle nitrogen.

Nitrogen is the main constituent of the Earth's atmosphere, but its provenance in the Earth's mantle remains uncertain. The relative contribution of primordial nitrogen inherited during the Earth's accretion versus that subducted from the Earth's surface is unclear1-6. Here we show that the mantle may have retained remnants of such primordial nitrogen. We use the rare 15N15N isotopologue of N2 as a new tracer of air contamination in volcanic gas effusions. By constraining air contamination in gases from Iceland, Eifel (Germany) and Yellowstone (USA), we derive estimates of mantle δ15N (the fractional difference in 15N/14N from air), N2/36Ar and N2/3He. Our results show that negative δ15N values observed in gases, previously regarded as indicating a mantle origin for nitrogen7-10, in fact represent dominantly air-derived N2 that experienced 15N/14N fractionation in hydrothermal systems. Using two-component mixing models to correct for this effect, the 15N15N data allow extrapolations that characterize mantle endmember δ15N, N2/36Ar and N2/3He values. We show that the Eifel region has slightly increased δ15N and N2/36Ar values relative to estimates for the convective mantle provided by mid-ocean-ridge basalts11, consistent with subducted nitrogen being added to the mantle source. In contrast, we find that whereas the Yellowstone plume has δ15N values substantially greater than that of the convective mantle, resembling surface components12-15, its N2/36Ar and N2/3He ratios are indistinguishable from those of the convective mantle. This observation raises the possibility that the plume hosts a primordial component. We provide a test of the subduction hypothesis with a two-box model, describing the evolution of mantle and surface nitrogen through geological time. We show that the effect of subduction on the deep nitrogen cycle may be less important than has been suggested by previous investigations. We propose instead that high mid-ocean-ridge basalt and plume δ15N values may both be dominantly primordial features.

ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer.

Androgen receptor splice variant 7 (AR-V7) is crucial for prostate cancer progression and therapeutic resistance. We show that, independent of ligand, AR-V7 binds both androgen-responsive elements (AREs) and non-canonical sites distinct from full-length AR (AR-FL) targets. Consequently, AR-V7 not only recapitulates AR-FL's partial functions but also regulates an additional gene expression program uniquely via binding to gene promoters rather than ARE enhancers. AR-V7 binding and AR-V7-mediated activation at these unique targets do not require FOXA1 but rely on ZFX and BRD4. Knockdown of ZFX or select unique targets of AR-V7/ZFX, or BRD4 inhibition, suppresses growth of castration-resistant prostate cancer cells. We also define an AR-V7 direct target gene signature that correlates with AR-V7 expression in primary tumors, differentiates metastatic prostate cancer from normal, and predicts poor prognosis. Thus, AR-V7 has both ARE/FOXA1 canonical and ZFX-directed non-canonical regulatory functions in the evolution of anti-androgen therapeutic resistance, providing information to guide effective therapeutic strategies.

Clinical pilot of bacterial transcriptional profiling as a combined genotypic and phenotypic antimicrobial susceptibility test.

Antimicrobial resistance is a growing health threat, but standard methods for determining antibiotic susceptibility are slow and can delay optimal treatment, which is especially consequential in severe infections such as bacteremia. Novel approaches for rapid susceptibility profiling have emerged that characterize either bacterial response to antibiotics (phenotype) or detect specific resistance genes (genotype). Genotypic and Phenotypic AST through RNA detection (GoPhAST-R) is a novel assay, performed directly on positive blood cultures, that integrates rapid transcriptional response profiling with the detection of key resistance gene transcripts, thereby providing simultaneous data on both phenotype and genotype. Here, we performed the first clinical pilot of GoPhAST-R on 42 positive blood cultures: 26 growing Escherichia coli, 15 growing Klebsiella pneumoniae, and 1 with both. An aliquot of each positive blood culture was exposed to nine different antibiotics, lysed, and underwent rapid transcriptional profiling on the NanoString platform; results were analyzed using an in-house susceptibility classification algorithm. GoPhAST-R achieved 95% overall agreement with standard antimicrobial susceptibility testing methods, with the highest agreement for beta-lactams (98%) and the lowest for fluoroquinolones (88%). Epidemic resistance genes including the extended spectrum beta-lactamase blaCTX-M-15 and the carbapenemase blaKPC were also detected within the population. This study demonstrates the clinical feasibility of using transcriptional response profiling for rapid resistance determination, although further validation with larger and more diverse bacterial populations will be essential in future work. GoPhAST-R represents a promising new approach for rapid and comprehensive antibiotic susceptibility testing in clinical settings.IMPORTANCEExposure to antibiotics causes differential transcriptional signatures in susceptible vs resistant bacteria. These differences can be leveraged to rapidly predict resistance profiles of Escherichia coli and Klebsiella pneumoniae in clinically positive blood cultures.

Development and evaluation of the Capability, Opportunity, and Motivation to deliver Physical Activity in School Scale (COM-PASS).

BACKGROUND: Teachers are recognized as 'key agents' for the delivery of physical activity programs and policies in schools. The aim of our study was to develop and evaluate a tool to assess teachers' capability, opportunity, and motivation to deliver school-based physical activity interventions. METHODS: The development and evaluation of the Capability, Opportunity, and Motivation to deliver Physical Activity in School Scale (COM-PASS) involved three phases. In Phase 1, we invited academic experts to participate in a Delphi study to rate, provide recommendations, and achieve consensus on questionnaire items that were based on the Capability, Opportunity, and Motivation Behavior (COM-B) model. Each item was ranked on the degree to which it matched the content of the COM-B model, using a 5-point scale ranging from '1 = Poor match' to '5 = Excellent match'. In Phase 2, we interviewed primary and secondary school teachers using a 'think-aloud' approach to assess their understanding of the items. In Phase 3, teachers (n = 196) completed the COM-PASS to assess structural validity using confirmatory factor analysis (CFA). RESULTS: Thirty-eight academic experts from 14 countries completed three rounds of the Delphi study. In the first round, items had an average rating score of 4.04, in the second round 4.51, and in the third (final) round 4.78. The final tool included 14 items, which related to the six constructs of the COM-B model: physical capability, psychological capability, physical opportunity, social opportunity, reflective motivation, and automatic motivation. In Phase 2, ten teachers shared their interpretation of COM-PASS via a 20-min interview, which resulted in minor changes. In Phase 3, CFA of the 3-factor model (i.e., capability, opportunity, and motivation) revealed an adequate fit to the data (χ2 = 122.6, p < .001, CFI = .945, TLI = .924, RMSEA = .066). The internal consistencies of the three subscale scores were acceptable (i.e., capability: α = .75, opportunity: α = .75, motivation: α = .81). CONCLUSION: COM-PASS is a valid and reliable tool for assessing teachers' capability, opportunity, and motivation to deliver physical activity interventions in schools. Further studies examining additional psychometric properties of the COM-PASS are warranted.

Real-World Incidence and Severity of Hypertension Caused by Abiraterone Acetate in Patients With Metastatic Prostate Cancer.

BACKGROUND: Abiraterone acetate (AA) is used in treatment of patients with metastatic prostate cancer. Despite the survival advantage, AA is associated with hypertension due to mineralocorticoid excess syndrome. OBJECTIVE: We conducted a single-center retrospective analysis to evaluate the real-world incidence and severity of AA-induced hypertension. METHODS: Electronic health records were used to collect baseline characteristics and prostate cancer history. Patient data, including blood pressure at each 4 (±2)-week interval, were collected for 24 weeks after the initiation of AA therapy. The primary endpoint was the incidence and severity of AA-induced hypertension. The secondary endpoints include effect of different prednisone dosing regimens and prostate cancer types on hypertensive incidence and the impact of clinical pharmacists' involvement in managing AA-induced hypertension. RESULTS: A total of 142 patients who met our inclusion criteria received AA for metastatic prostate cancer, 73 (51.4%) with metastatic castration-resistant prostate cancer (mCRPC), and 69 (48.6%) with metastatic castration-sensitive prostate cancer (mCSPC). Of all, 43.7% experienced all-grade hypertension, and 28.2% experienced grade 3-4 hypertension. There was no difference in incidence of hypertension between patients receiving 5 mg of prednisone daily and those receiving 5 mg of prednisone twice daily. All-grade hypertension occurred in 39.7% of mCRPC and 47.8% of mCSPC patients (P = 0.33). Thirty-two percent of patients were actively managed by a clinical pharmacist and had an overall trend of reduced hypertension severity after 12 weeks. CONCLUSION AND RELEVANCE: This single-center, retrospective cohort study found that real-world metastatic prostate cancer patients who received AA had substantially higher incidence and severity of hypertension compared with clinical trials regardless of prednisone dose. In patients with mCRPC and mCSPC, the role of prednisone dose in hypertension incidence and severity warrants further investigation. Overall, results indicate the need for closely monitoring hypertension and optimization of anti-hypertensive therapy by multidisciplinary teams in metastatic prostate cancer patients receiving AA.

Quality of life in the year after new diagnosis with advanced prostate cancer for Black and White individuals living in the US.

PURPOSE: To assess differences in baseline and longitudinal quality of life among Black and White individuals in the US with advanced prostate cancer. METHODS: Secondary analysis of data from the International Registry for Men with Advanced Prostate Cancer (IRONMAN) including US participants newly diagnosed with advanced prostate cancer and identifying their race as Black or White from 2017 to 2023. Participants completed the EORTC QLQ-C30 Quality of Life (QoL) Survey at study enrollment and every 3 months thereafter for up to 1 year of follow-up reporting 15 scale scores ranging from 0 to 100 (higher functioning and lower symptom scores represent better quality of life). Linear mixed effects models with race and month of questionnaire completion were fit for each scale, and model coefficients were used to assess differences in baseline and longitudinal QoL by race. RESULTS: Eight hundred and seventy-nine participants were included (20% identifying as Black) at 38 US sites. Compared to White participants at baseline, Black participants had worse constipation (mean 6.3 percentage points higher; 95% CI 2.9-9.8), financial insecurity (5.7 (1.4-10.0)), and pain (5.1 (0.9-9.3)). QoL decreased over time similarly by race; most notably, role functioning decreased by 0.7 percentage points (95% CI -0.8, -0.5) per month. CONCLUSION: There are notable differences in quality of life at new diagnosis of advanced prostate cancer for Black and White individuals, and quality of life declines similarly in the first year for both groups. Interventions that address specific aspects of quality of life in these patients could meaningfully improve the overall survivorship experience.

Burnout in healthcare workers in COVID-19-dedicated hospitals.

BACKGROUND: Considering the prolongation of the COVID-19 pandemic, the lack of studies on burnout, particularly in healthcare workers, needs to be addressed. This report aimed to identify the risk factors of burnout by comparing the level of burnout between nurses in general wards and those in COVID-19-dedicated wards in a national university hospital. METHODS: A survey based on the Korean version of Burnout Assessment Tool (BAT-K) was conducted on nurses between 10 January and 31 January 2022. The BAT-K consists of exhaustion, mental distance, cognitive impairment, emotional impairment and secondary symptoms. RESULTS: A total of 165 nurses, including 81 nurses from the COVID-19-dedicated ward, completed the questionnaire. The percentage of general-ward nurses with an emotional impairment score above the clinical cutoff was higher than that of COVID-19 ward nurses. General ward compared to the COVID-19 ward increased the risk of presenting with total-core symptoms. Two factors increased the risk regarding mental distance: short career length and underlying disease. CONCLUSIONS: In contrast to previous studies, the risk of burnout in the COVID-19-ward nurses was lower than that of the general ward nurses. The risk regarding mental distance was correlated with short career length and presence of an underlying disease.

Cistrome analysis of YY1 uncovers a regulatory axis of YY1:BRD2/4-PFKP during tumorigenesis of advanced prostate cancer.

Castration-resistant prostate cancer (CRPC) is a terminal disease and the molecular underpinnings of CRPC development need to be better understood in order to improve its treatment. Here, we report that a transcription factor Yin Yang 1 (YY1) is significantly overexpressed during prostate cancer progression. Functional and cistrome studies of YY1 uncover its roles in promoting prostate oncogenesis in vitro and in vivo, as well as sustaining tumor metabolism including the Warburg effect and mitochondria respiration. Additionally, our integrated genomics and interactome profiling in prostate tumor show that YY1 and bromodomain-containing proteins (BRD2/4) co-occupy a majority of gene-regulatory elements, coactivating downstream targets. Via gene loss-of-function and rescue studies and mutagenesis of YY1-bound cis-elements, we unveil an oncogenic pathway in which YY1 directly binds and activates PFKP, a gene encoding the rate-limiting enzyme for glycolysis, significantly contributing to the YY1-enforced Warburg effect and malignant growth. Altogether, this study supports a master regulator role for YY1 in prostate tumorigenesis and reveals a YY1:BRD2/4-PFKP axis operating in advanced prostate cancer with implications for therapy.

Assessment of left ventricular geometry in normotensive type II diabetic patients.

Background: Abnormalities of glucose metabolism are associated with abnormal left ventricular geometry (LV) independent of atherosclerosis. Abnormal LV geometry, a predictor of premature cardiovascular events, indicates presence of subclinical target organ damages. Screening for abnormal LV geometry in diseases of abnormal glucose metabolism is desirable as part of their management protocol. Aim: To assess the left ventricular geometry in normotensive type II diabetic patients. Cross-sectional, descriptive, hospital-based study. One hundred normotensive type II diabetic patients drawn from the Endocrinology and Family Medicine Clinics of a tertiary hospital were age- and gender-matched with 100 apparently healthy controls. Participants meeting the criteria and informed consent proceeded for clinical evaluation, biochemical assessment, electrocardiography, and echocardiography using the American Society of Echocardiography guideline. Materials and Methods: Data were analyzed using the Statistical Package for Social Sciences [SPSS] version 25.0 (Chicago Illinois, USA). Results: Mean age of study and control groups was (55.56 ± 9.89 versus 55.47 ± 10.7) years (χ2 = 0.062, P = 0.951). The mean duration of diabetes illness was 6.57 ± 6.26 years. Prevalence of abnormal LV geometry was 51% (study) versus 18% (control) FT, P < 0.001). Concentric remodeling was the predominant geometry in 36% of study versus 11% of controls, followed by eccentric hypertrophy in 11% (study) versus 4% (control) and concentric hypertrophy in 4% (study) versus 3% (control). Geometry was normal in 49% of study against 82% in the controls (FT, P < 0.001). Significant association existed between LV geometry and duration of diabetes (χ2 = 10.793, P = 0.005). Conclusion: Abnormal LV geometry is highly prevalent in normotensive diabetic patients.

Advances in organ-on-a-chip systems for modelling joint tissue and osteoarthritic diseases.

Joint-on-a-chip (JOC) models are powerful tools that aid in osteoarthritis (OA) research. These microfluidic devices apply emerging organ-on-a-chip technology to recapitulate a multifaceted joint tissue microenvironment. JOCs address the need for advanced, dynamic in vitro models that can mimic the in vivo tissue environment through joint-relevant biomechanical or fluidic integration, an aspect that existing in vitro OA models lack. There are existing review articles on OA models that focus on animal, tissue explant, and two-dimensional and three-dimensional (3D) culture systems, including microbioreactors and 3D printing technology, but there has been limited discussion of JOC models. The aim of this article is to review recent developments in human JOC technology and identify gaps for future advancements. Specifically, mechanical stimulation systems that mimic articular movement, multi-joint tissue cultures that enable crosstalk, and systems that aim to capture aspects of OA inflammation by incorporating immune cells are covered. The development of an advanced JOC model that captures the dynamic joint microenvironment will improve testing and translation of potential OA therapeutics.

Mycorrhizal roots slow the decay of belowground litters in a temperate hardwood forest.

There is increasing evidence that plant roots and mycorrhizal fungi, whether living or dead, play a central role in soil carbon (C) cycling. Root-mycorrhizal-microbial interactions can both suppress and enhance litter decay, with the net result dependent upon belowground nutrient acquisition strategies and soil nutrient availability. We measured the net effect of living roots and mycorrhizal fungi on the decay of dead roots and fungal hyphae in a hardwood forest dominated by either sugar maple (Acer saccharum) or white oak (Quercus alba) trees. Root and fungal litter were allowed to decompose within root-ingrowth bags and root-exclusion cores. In conjunction with root effects on decay, we assessed foraging responses and root induced changes in soil moisture, nitrogen (N) availability and enzyme activity. After 1 year, maple root production increased, and mycorrhizal fungal colonization decreased in the presence of decaying litter. In addition, we found that actively foraging roots suppressed the decay of root litter (- 14%) more than fungal litter (- 3%), and suppression of root decay was stronger for oak (- 20%) than maple roots (- 8%). Suppressive effects of oak roots on decay were greatest when roots also reduced soil N availability, which corresponded with reductions in hydrolytic enzyme activity and enhanced oxidative enzyme activities. These findings further our understanding of context-dependent drivers of root-mycorrhizal-microbial interactions and demonstrate that such interactions can play an underappreciated role in soil organic matter accumulation and turnover in temperate forests.

CD8+ T Cells Impact Rising PSA in Biochemically Relapsed Cancer Patients Using Immunotherapy Targeting Tumor-Associated Antigens.

The management of men with prostate cancer (PCa) with biochemical recurrence following local definitive therapy remains controversial. Early use of androgen deprivation therapy (ADT) leads to significant side effects. Developing an alternative, clinically effective, and well-tolerated therapy remains an unmet clinical need. INO-5150 is a synthetic DNA therapy that includes plasmids encoding for prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA), and INO-9012 is a synthetic DNA plasmid encoding for interleukin-12 (IL-12). This phase 1/2, open-label, multi-center study enrolled men with PCa with rising PSA after surgery and/or radiation therapy. Patients were enrolled into one of four treatment arms: arm A, 2 mg of INO-5150; arm B, 8.5 mg of INO-5150; arm C, 2 mg of INO-5150 + 1 mg of INO-9012; and arm D, 8.5 mg of INO-5150 + 1 mg of INO-9012. Patients received study drug with electroporation on day 0 and on weeks 3, 12, and 24, and they were followed for up to 72 weeks. Sixty-two patients were enrolled. Treatment was well tolerated. 81% (50/62) of patients completed all visits. 85% (53/62) remained progression-free at 72 weeks. PSA doubling time (PSADT) was increased when assessed in patients with day 0 PSADT ≤12 months. Immunogenicity was observed in 76% (47/62) of patients by multiple assessments. Analysis indicated that CD38 and perforin co-positive CD8 T cell frequency correlated with attenuated PSA rise (p = 0.05, n = 50).

The Prevalence and Pattern of Thyroid Dysfunction in HAART-Naïve HIV Patients in Enugu, Nigeria: A Cross-Sectional Comparative Study.

BACKGROUND: HIV/AIDS is a multi-system disease that has been associated with several endocrinopathies including thyroid dysfunction. Thyroid dysfunction in patients with HIV/AIDS, among other factors, may arise from the direct cytopathic effects of HIV on the thyroid gland in addition to the adverse effects of highly active anti-retroviral drugs (HAART). STUDY OBJECTIVE: The study aimed to determine the prevalence and pattern of thyroid dysfunction in HAART naïve HIV patients in Enugu. MATERIALS & METHODS: Study was cross sectional, casecontrol based, involving 250 HAART naïve HIV sero-positive patients and 250 HIV sero-negative subjects. Anthropometric measurements and physical examination were done. Assay for fT3, fT4, TSH (for thyroid function) was done using the Enzyme Linked Immunoassay (ELISA) method. Data was analyzed using the Statistical Package for Social Sciences (SPSS) version 23. RESULTS: The HAART naïve sero-positive cohorts comprised 112 males and 138 females while the control subjects consisted of 125 males and 125 females. Mean ages (years) of test and control groups were 38.84± 10.60 and 39.58 ±11.68 respectively. Prevalence of thyroid dysfunction among the study subjects was 36.4% and 7.6% in the controls. Subclinical hypothyroidism was the most common prevalent type of thyroid dysfunction in both test and control groups at 17.6% and 7.2% respectively. In the test group, sick euthyroid syndrome (17.2%) ranked second while in the controls, primary hypothyroidism (7.2%) was the second commonest dysfunction. CONCLUSION: Thyroid dysfunction was more common in HAART-naïve HIV sero-positive subjects than in the general population with subclinical hypothyroidism emerging as the commonest abnormality.

CONTEXTE: Le VIH/SIDA est une maladie multisystémique qui a été associée à plusieurs endocrinopathies, dont la thyroïde associée à plusieurs endocrinopathies, y compris le dysfonctionnement de la dysfunctionnement. Le dysfonctionnement thyroïdien chez les patients atteints du VIH/SIDA, entre autres facteurs, peut être due aux effets cytopathiques directs du cytopathiques directs du VIH sur la glande thyroïde, en plus des effets indésirables des médicaments antirétroviraux hautement actifs (HAART). OBJECTIF DE L'ÉTUDE: L'étude visait à déterminer la prévalence et le modèle de dysfonctionnement thyroïdien chez les patients VIH naïfs de traitement HAART à Enugu. MATÉRIEL ET MÉTHODES: L'étude était transversale, basée sur un cas-témoin, impliquant 250 patients séropositifs n'ayant jamais reçu de HAART et 250 patients séronégatifs et 250 sujets séronégatifs. Des mesures anthropométriques et un examen physique ont été effectués. Les dosages de fT3, fT4, TSH (pour la fonction thyroïdienne) a été effectué à l'aide de l'Enzyme Linked Immunoassay (ELISA). Les données ont été analysées en utilisant le progiciel statistiques pour sciences sociales (SPSS) version 23. RÉSULTATS: Les cohortes séropositives n'ayant jamais reçu de HAART comprenaient 112 hommes et 138 femmes, tandis que les sujets témoins comprenaient 125 hommes et 125 femmes. Les âges moyens (années) des groupes test et groupes témoins étaient respectivement de 38,84± 10,60 et 39,58 ±11,68. La prévalence du dysfonctionnement de la thyroïde parmi les sujets de l'étude était de 36,4 % et 7,6 % chez les témoins. L'hypothyroïdie subclinique était le type de dysfonctionnement thyroïdien le plus répandu dans les groupes test et témoin soit 17,6 % et 7,2 % respectivement. Dans le groupe test, le syndrome d'euthyroïdie maladive (17,2 %) arrivait en deuxième position, tandis que dans le groupe témoin, l'hypothyroïdie primaire (7,2 %) était le deuxième type de dysfonctionnement le plus courant. CONCLUSION: Les dysfonctionnements de la thyroïde étaient plus fréquents chez les personnes suivantes sujets séropositifs n'ayant jamais reçu de traitement antirétroviral que dans la population générale, l'hypothyroïdie subclinique apparaissant comme la l'anomalie la plus fréquente. MOTS-CLÉS: Prévalence, Modèle, HAART-naïf, patients VIH, dysfonctionnement de la thyroïde, Nigéria.

Characteristics of human parainfluenza virus type 4 infection in hospitalized children in Korea.

BACKGROUND: The characteristics of human parainfluenza virus type 4 (hPIV4) infection are not thoroughly understood. We therefore clarified the characteristics of hPIV4 in Korea. METHOD: From January 2013 to December 2017, children admitted with respiratory tract infection at the Department of Pediatrics in Chung-Ang University Hospital were enrolled in the study. Nasopharyngeal aspirate specimens were obtained from patients and tested for hPIV types by multiplex reverse transcription polymerase chain reaction. We retrospectively reviewed subject medical records, focusing on epidemiological and clinical characteristics. RESULTS: Of the 12 423 NPA specimens, 8,406 were positive by multiplex reverse transcription polymerase chain reaction for nine respiratory viruses, and 1,018 were positive for one of the four types of hPIV: 1,018 specimens led to the detection of 1,029 hPIVs; 3ss (31.3%) were positive for hPIV1, 120 (11.7%) were positive for hPIV2, 356 (34.6%) were positive for hPIV3, and 231 (22.4%) were positive for hPIV4. Of the hPIV-positive patients, the mean age was 2.3 years (range, 0.1-12.7 years), 225 (97.4%) had no underlying disease, and 178 (77.1%) had a fever with a duration of 4.1 ± 2.3 days and a peak temperature of 39.0 ± 0.7 ℃. The most common diagnosis in hPIV4 infection was pneumonia (44.2%), followed by bronchiolitis (26.0%) and upper respiratory tract infection (24.3%). Only 2.2% of patients were diagnosed with croup. Although the most prevalent overall type of hPIV was hPIV3, hPIV4 generally caused acute respiratory tract infection in summer and early fall in an irregular annual pattern. CONCLUSIONS: Human parainfluenza virus type 4 is an important common pathogen of respiratory tract infections in pediatric patients in Korea.

Dacomitinib, but not lapatinib, suppressed progression in castration-resistant prostate cancer models by preventing HER2 increase.

BACKGROUND: Despite overexpression of the ErbB (EGFR/HER2/ErbB3/ErbB4) family in castration-resistant prostate cancer (CRPC), some inhibitors of this family, including the dual EGFR/HER2 inhibitor lapatinib, failed in Phase II clinical trials. Hence, we investigated mechanisms of lapatinib resistance to determine whether alternate ErbB inhibitors can succeed. METHODS: The CWR22 human tumour xenograft and its CRPC subline 22Rv1 and sera from lapatinib-treated CRPC patients from a previously reported Phase II trial were used to study lapatinib resistance. Mechanistic studies were conducted in LNCaP, C4-2 and 22Rv1 cell lines. RESULTS: Lapatinib increased intratumoral HER2 protein, which encouraged resistance to this treatment in mouse models. Sera from CRPC patients following lapatinib treatment demonstrated increased HER2 levels. Investigation of the mechanism of lapatinib-induced HER2 increase revealed that lapatinib promotes HER2 protein stability, leading to membrane localisation, EGFR/HER2 heterodimerisation and signalling, elevating cell viability. Knockdown of HER2 and ErbB3, but not EGFR, sensitised CRPC cells to lapatinib. At equimolar concentrations, the recently FDA-approved pan-ErbB inhibitor dacomitinib decreased HER2 protein stability, prevented ErbB membrane localisation (despite continued membrane integrity) and EGFR/HER2 heterodimerisation, thereby decreasing downstream signalling and increasing apoptosis. CONCLUSIONS: Targeting the EGFR axis using the irreversible pan-ErbB inhibitor dacomitinib is a viable therapeutic option for CRPC.

All-solid-state VUV frequency comb at 160 nm using high-harmonic generation in nonlinear femtosecond enhancement cavity.

We realized a solid-state-based vacuum ultraviolet frequency comb by harmonics generation in an external enhancement cavity. Optical conversions were so far reported by only using gaseous media. We present a theory that allows the most suited solid generation medium to be selected for specific target harmonics by adapting the material's bandgap. We experimentally use a thin AlN film grown on a sapphire substrate to realize a compact frequency comb high-harmonic source in the Deep Ultraviolet (DUV) / Vacuum Ultraviolet (VUV) spectral range. By extending our earlier VUV source [Opt. Express26, 21900 (2018)] with the enhancement cavity, a sub-Watt level Ti:sapphire femtosecond frequency comb is enhanced to 24 W stored average power, its 3rd, 5th, and 7th harmonics are generated, and the targeted 5th harmonic's power at 160 nm increased by two orders of magnitude. The emerging nonlinear effects in the solid medium, together with suitable intra-cavity dispersion management, support optimal enhancement and stable locking. To demonstrate the realized frequency comb's spectroscopic ability, we report on the beat measurement between the 3rd harmonic beam and a 266 nm CW laser reaching about 1 MHz accuracy.

1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) reduces hepatic injury in concanavalin A-treated mice.

1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG), a chemically synthesized monoacetyldiaglyceride, is one of the constituents in Sika deer antlers and has been known traditionally as having immunomodulatory effects. However, the mechanism by which PLAG controls neutrophil migration, which evokes liver injury in the hepatitis animal model, remains largely unknown. This study was designed to evaluate the immunomodulatory effects of PLAG on cytokine secretion and neutrophil migration in vivo and in vitro. Concanavalin A (Con A) induced leukocyte infiltration in the liver and increased plasma cytokine levels. Pretreatment with PLAG reduced the levels of interleukin (IL)-4, IL-6, IL-10, and CXCL2, but maintained interferon (IFN)-γ levels and modulated neutrophil recruitment toward the liver. Furthermore, the mRNA and protein levels of IL-4 and CXCL2 in liver tissue were also decreased in the Con A-treated mice. Liver histology analyses showed that PLAG reduced Con A-induced hepatic necrosis, which was accompanied by leukocyte infiltration. The in vitro studies revealed that PLAG reduced IL-4 secretion in Con A stimulated T cell and blocked signal transducer and activator of transcription 6 (STAT6) Con A induced hepatocyte. PLAG attenuated IL-4 induced activation of atypical protein kinase C (PKC)/STAT6 in hepatocytes and inhibited neutrophil migration toward the liver tissue through suppression of IL-8/vascular cell adhesion molecule (VCAM) expression. These results suggest that PLAG could mitigate excess neutrophil migration into liver tissue and potentially have a therapeutic effect on immune-mediated liver injury.

Phase II trial of palbociclib in patients with metastatic urothelial cancer after failure of first-line chemotherapy.

BACKGROUND: The majority of urothelial cancers (UC) harbor alterations in retinoblastoma (Rb) pathway genes that can lead to loss of Rb tumour suppressor function. Palbociclib is an oral, selective inhibitor of CDK 4/6 that restores Rb function and promotes cell cycle arrest. METHODS: In this phase II trial, patients with metastatic platinum-refractory UC molecularly selected for p16 loss and intact Rb by tumour immunohistochemistry received palbociclib 125 mg p.o. daily for 21 days of a 28-day cycle. Primary endpoint was progression-free survival at 4 months (PFS4) using a Simon's two-stage design. Next-generation sequencing including Rb pathway alterations was conducted. RESULTS: Twelve patients were enrolled and two patients (17%) achieved PFS4 with insufficient activity to advance to stage 2. No responses were seen. Median PFS was 1.9 months (95% CI 1.8-3.7 months) and median overall survival was 6.3 months (95% CI 2.2-12.6 months). Fifty-eight percent of patients had grade ≥3 hematologic toxicity. There were no CDKN2A alterations found and no correlation of Rb pathway alterations with clinical outcome. CONCLUSIONS: Palbociclib did not demonstrate meaningful activity in selected patients with platinum-refractory metastatic UC. Further development of palbociclib should only be considered with improved integral biomarker selection or in rational combination with other therapies.