Survival Benefit from Multimodal Treatment for Patients with Atypical Teratoid Rhabdoid Tumor in a Surveillance, Epidemiology, and End Results Database Analysis.

INTRODUCTION: Atypical teratoid rhabdoid tumor (ATRT) is among the most aggressive central nervous system malignancies. Although rare, this tumor typically afflicts young children and results in mortality within months. Here, we aim to determine key clinical features and treatment options that impact the survival of patients with ATRT. METHODS: From the year 2000 to 2019, 363 patients with ATRT were identified from the Surveillance, Epidemiology, and End Results database. Univariate analysis was used to identify variables that had a significant impact on the primary endpoint of overall survival (OS). Multivariable analysis was then used to identify independent predictors of survival. RESULTS: The median OS of the entire cohort was 13 months. Univariate analysis identified ages between 1 and 3 years, ages between 4 and 17 years, years of diagnosis between 2010 and 2019, and the receipt of treatment to have a significant impact on survival. In multivariable analysis, ages between 1 and 3 years and receipt of treatment were the only significant independent predictors of survival. The median OS was significantly greater in patients who received surgical treatment, chemotherapy, or radiation when compared to those who did not receive any treatment. In general, the receipt of any combination of therapies improved the median OS significantly. The receipt of triple therapy had the greatest impact on survival. DISCUSSION: This study highlights the survival benefit of a multimodal approach in the treatment of ATRT. The use of triple therapy, including surgery, radiation, and chemotherapy, was found to have the greatest survival benefit for patients. Overall, these findings may guide future care for patients with ATRT.

Prognostic Factors of Survival for Grade 3 Solitary Fibrous Tumor/Hemangiopericytoma: A Population-Based Retrospective Surveillance, Epidemiology, and End Results Database Analysis.

INTRODUCTION: Grade 3 solitary fibrous tumor, previously known as anaplastic hemangiopericytoma, is a rare and highly malignant intracranial tumor with a limited understanding of its natural history and treatment outcomes. METHODS: We conducted a retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database spanning 2000-2019 to evaluate the clinical characteristics and treatment modalities that influence overall survival in this tumor entity. A cohort of 249 patients with intracranial grade 3 solitary fibrous tumors was identified. Univariate and multivariable Cox proportional hazard models were employed to determine significant prognostic factors for overall survival. Kaplan-Meier models were used to visualize survival curves, and a nomogram was constructed to predict survival probabilities at 6- and 12-month following diagnosis. RESULTS: Our findings indicated that patient age (<65 years), localized or regional disease burden, surgical resection, and radiation therapy were significant predictors of better overall survival. Combination therapies showed improved survival, with surgery and radiation therapy having the most significant impact. However, chemotherapy alone or in combination did not demonstrate a significant survival benefit, likely due to the limited sample size. The nomogram provided personalized prognostic predictions based on significant clinical factors. CONCLUSIONS: These data emphasize the importance of surgical resection and radiation therapy in the management of grade 3 solitary fibrous tumors, supporting the use of combination therapies to improve overall survival in this rare and aggressive intracranial neoplasm.

New Probe of the High-z Baryon Acoustic Oscillation Scale: BAO Tomography with CMB×LIM-Nulling Convergence.

Standard rulers such as the baryon acoustic oscillation (BAO) scale serve as workhorses for precision tests of cosmology, enabling distance measurements that probe the geometry and expansion history of our Universe. Aside from BAO measurements from the cosmic microwave background (CMB), most standard ruler techniques operate at relatively low redshifts and depend on biased tracers of the matter density field. In a companion paper [H. Fronenberg, A. S. Maniyar, A. R. Pullen, and A. C. Liu, companion paper, Phys. Rev. D 109, 123518 (2024).PRVDAQ2470-001010.1103/PhysRevD.109.123518], we explored the scientific reach of nulling estimators, where CMB lensing convergence maps are cross-correlated with linear combinations of similar maps from line intensity mapping to precisely null out the low-redshift contributions to CMB lensing. We showed that nulling estimators can be used to constrain the high redshift matter power spectrum and that this spectrum exhibits discernible BAO features. Here we propose using these features as a standard ruler at high redshifts that does not rely on biased tracers. Forecasting such a measurement at z∼5, we find that next-generation instruments will be able to constrain the BAO scale to 7.2% precision, while our futuristic observing scenario can constrain the BAO scale to 4% precision. This constitutes a fundamentally new kind of BAO measurement during early epochs in our cosmic history.

Melatonin suppression by light involves different retinal photoreceptors in young and older adults.

Age-related sleep and circadian rhythm disturbances may be due to altered nonvisual photoreception. Here, we investigated the temporal dynamics of light-induced melatonin suppression in young and older individuals. In a within-subject design study, young and older participants were exposed for 60 min (0030-0130 at night) to nine narrow-band lights (range: 420-620 nm). Plasma melatonin suppression was calculated at 15, 30, 45, and 60 min time intervals. Individual spectral sensitivity of melatonin suppression and photoreceptor contribution were predicted for each interval and age group. In young participants, melanopsin solely drove melatonin suppression at all time intervals, with a peak sensitivity at 485.3 nm established only after 15 min of light exposure. Conversely, in older participants, spectral light-driven melatonin suppression was best explained by a more complex model combining melanopsin, S-cone, and M-cone functions, with a stable peak (~500 nm) at 30, 45, and 60 min of light exposure. Aging is associated with a distinct photoreceptor contribution to melatonin suppression by light. While in young adults melanopsin-only photoreception is a reliable predictor of melatonin suppression, in older individuals this process is jointly driven by melanopsin, S-cone, and M-cone functions. These findings offer new prospects for customizing light therapy for older individuals.

Deciphering cleaner and sustainable frontiers in scientific cow waste valorization: a review.

The forecasted global population growth is poised to create a greater exigency for livestock-derived food production, leading to a significant waste generation from the industrial-scale livestock operations, which necessitates to develop sustainable waste management solutions. The heightened demand for livestock and dairy products has driven a surge in cow waste (CW) production. While CW is typically used as organic fertilizer or solid fuel, improper disposal poses potential environmental hazards. Anaerobic digestion and composting transform CW into valuable products, such as biofuels and organic fertilizers, with the potential for electricity and heat generation, biochar production, and advanced friction materials. The CW contains essential inorganic and organic compounds vital for plant functions, including lignin, cellulose, hemicellulose, nitrogen, and minerals such as potassium, sulfur, iron, magnesium, copper, cobalt, and manganese. Additionally, the rich microbial diversity in cow dung drives the production of bioenergy carriers like biomethane and biohydrogen, promoting cost-effective energy generation and environmental sustainability. This review employs bibliometric analysis to explore the latest trends in CW applications, with a particular focus on innovative applications such as cellulose extraction, biochar production, microbial fuel cells, and nanoparticle synthesis. It further evaluates the environmental impacts of these technologies and assesses their potential to advance sustainable and cleaner frontiers in the valorization of CW.

Doppler Boosted Dust Emission and Cosmic Infrared Background-Galaxy Cross-Correlations: A New Probe of Cosmology and Astrophysics.

We identify a new cosmological signal, the Doppler-boosted cosmic infrared background (DB CIB), arising from the peculiar motion of the galaxies whose thermal dust emission source the cosmic infrared background (CIB). This new observable is an independent probe of the cosmic velocity field, highly analogous to the well-known kinematic Sunyaev-Zel'dovich (KSZ) effect. Interestingly, DB CIB does not suffer from the "KSZ optical depth degeneracy," making it immune from the complex astrophysics of galaxy formation. We forecast that the DB CIB effect is detectable in the cross-correlation of CCAT-Prime and DESI-like experiments. We show that it also acts as a new CMB foreground which can bias future KSZ cross-correlations, if not properly accounted for.

Optimized antiangiogenic reprogramming of the tumor microenvironment potentiates CD40 immunotherapy.

Cancer immunotherapies are increasingly combined with targeted therapies to improve therapeutic outcomes. We show that combination of agonistic anti-CD40 with antiangiogenic antibodies targeting 2 proangiogenic factors, vascular endothelial growth factor A (VEGFA) and angiopoietin 2 (Ang2/ANGPT2), induces pleiotropic immune mechanisms that facilitate tumor rejection in several tumor models. On the one hand, VEGFA/Ang2 blockade induced regression of the tumor microvasculature while decreasing the proportion of nonperfused vessels and reducing leakiness of the remaining vessels. On the other hand, both anti-VEGFA/Ang2 and anti-CD40 independently promoted proinflammatory macrophage skewing and increased dendritic cell activation in the tumor microenvironment, which were further amplified upon combination of the 2 treatments. Finally, combined therapy provoked brisk infiltration and intratumoral redistribution of cytotoxic CD8+ T cells in the tumors, which was mainly driven by Ang2 blockade. Overall, these nonredundant synergistic mechanisms endowed T cells with improved effector functions that were conducive to more efficient tumor control, underscoring the therapeutic potential of antiangiogenic immunotherapy in cancer.

Scientific characterization methods for better utilization of cattle dung and urine: a concise review.

Cattle are usually raised for food, manure, leather, therapeutic, and draught purposes. Biowastes from cattle, such as dung and urine, harbor a diverse group of crucial compounds, metabolites/chemicals, and microorganisms that may benefit humans for agriculture, nutrition, therapeutics, industrial, and other utility products. Several bioactive compounds have been identified in cattle dung and urine, which possess unique properties and may vary based on agro-climatic zones and feeding practices. Therefore, cattle dung and urine have great significance, and a balanced nutritional diet may be a key to improved quality of these products/by-products. This review primarily focuses on the scientific aspects of biochemical and microbial characterization of cattle biowastes. Various methods including genomics for analyzing cattle dung and gas chromatography-mass spectroscopy for cattle urine have been reviewed. The presented information might open doors for the further characterization of cattle resources for heterogeneous applications in the production of utility items and addressing research gaps. Methods for cattle's dung and urine characterization.

Clinical Validation of the Champagne Algorithm for Evoked Response Source Localization in Magnetoencephalography.

Magnetoencephalography (MEG) is a robust method for non-invasive functional brain mapping of sensory cortices due to its exceptional spatial and temporal resolution. The clinical standard for MEG source localization of functional landmarks from sensory evoked responses is the equivalent current dipole (ECD) localization algorithm, known to be sensitive to initialization, noise, and manual choice of the number of dipoles. Recently many automated and robust algorithms have been developed, including the Champagne algorithm, an empirical Bayesian algorithm, with powerful abilities for MEG source reconstruction and time course estimation (Wipf et al. 2010; Owen et al. 2012). Here, we evaluate automated Champagne performance in a clinical population of tumor patients where there was minimal failure in localizing sensory evoked responses using the clinical standard, ECD localization algorithm. MEG data of auditory evoked potentials and somatosensory evoked potentials from 21 brain tumor patients were analyzed using Champagne, and these results were compared with equivalent current dipole (ECD) fit. Across both somatosensory and auditory evoked field localization, we found there was a strong agreement between Champagne and ECD localizations in all cases. Given resolution of 8mm voxel size, peak source localizations from Champagne were below 10mm of ECD peak source localization. The Champagne algorithm provides a robust and automated alternative to manual ECD fits for clinical localization of sensory evoked potentials and can contribute to improved clinical MEG data processing workflows.

Feeding in Preterm Neonates With Antenatal Doppler Abnormalities: A Systematic Review and Meta-Analysis.

OBJECTIVES: In this systematic review and meta-analysis, we attempted to determine the most appropriate feed initiation and advancement practices in preterm neonates with antenatal Doppler abnormalities. METHODS: We included randomized controlled trials comparing different feed initiation and advancement practices in neonates with antenatal Doppler abnormalities. The databases of PubMed, Embase, Cochrane, CINAHL, Scopus, and Google Scholar were searched on February 25, 2022. The risk of bias was assessed using the Risk of Bias tool, version 2. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. RevMan 5.4 was used for data analysis. RESULTS: Of the 1499 unique records identified, 7 studies were eligible for inclusion (6 on feed initiation, 1 on feed advancement). Early enteral feeding did not increase NEC stage 2 or more [risk ratio (RR) 1.12, 95% confidence interval (CI) 0.71-1.78; 6 studies, 775 participants] and mortality (RR 0.83, 95% CI 0.47-1.48; 5 studies, 642 participants). A trend was noted towards an increase in feeding intolerance (RR 1.23, 95% CI 0.98-1.56; 5 studies, 715 participants). There was a significant reduction in age at full enteral feeds, duration of total parental nutrition, and rates of hospital-acquired infections. Rapid feed advancement decreased the age at full enteral feeds without affecting other outcomes. The overall certainty of the evidence was rated low. Heterogeneity was not significant. CONCLUSION: There is low-certainty evidence that early feed initiation in preterm neonates with antenatal Doppler abnormalities does not increase rates of NEC and mortality. There is insufficient data on the speed of feed advancement.

Surgical treatment, complications, reoperations, and healthcare costs among patients with clavicle fracture in England.

INTRODUCTION: The clinical and economic burden of clavicle fractures in England is not well documented. This study evaluated rates of surgical treatment, post-surgical complications, reoperations and costs in patients with clavicle fractures using the Clinical Practice Research Datalink (CPRD) database. METHODS: CPRD data were linked to National Health Service Hospital Episode Statistics data. Patients with a diagnosis of clavicle fracture between 2010-2018 were selected in CPRD (date of fracture = index date). Of those, patients with surgical intervention within 180 days from index fracture were identified. Rates of post-surgical complications (i.e., infection, non-union, and mal-union), reoperations (for device removal or for postoperative complications), post-operative costs and median time to reoperations were evaluated up to 2 years after surgery. RESULTS: 21,340 patients with clavicle fractures were identified (mean age 35.0 years(standard deviation (SD): 26.5), 66.7% male). Surgery was performed on 672 patients (3.2% of total cohort) at an average 17.1 (SD: 25.2) days post-fracture. Complications (i.e., infection, non-union, or malunion) affected 8.1% of surgically treated clavicle fracture patients; the rate of infection was 3.5% (95% CI, 1.7%- 5.2%), non-union 4.4% (95% CI, 2.4%-6.5%), and mal-union 0.3% (95% CI, 0%-0.7%). Adjusting for age, gender, comorbidities and time to surgery, the all-cause reoperation rate was 20.2% (13.2%-30.0%) and the adjusted rate of reoperation for implant removal was 17.0% (10.7%-25.9%)-84% of all-cause reoperations were thus performed for implant removal. Median time to implant removal was 254 days. The mean cost of reoperations for all causes was £5,000. The most expensive reoperations were for cases that involved infection (mean £6,156). CONCLUSIONS: Complication rates following surgical clavicle fracture care averaged 8.1%. However, reoperation rates exceed 20%, the vast majority of reoperations being performed for device removal. Technologies to alleviate secondary device removal surgeries would address a significant clinical unmet need.

Interhemispheric Auditory Cortical Synchronization in Asymmetric Hearing Loss.

OBJECTIVES: Auditory cortical activation of the two hemispheres to monaurally presented tonal stimuli has been shown to be asynchronous in normal hearing (NH) but synchronous in the extreme case of adult-onset asymmetric hearing loss (AHL) with single-sided deafness. We addressed the wide knowledge gap between these two anchoring states of interhemispheric temporal organization. The objectives of this study were as follows: (1) to map the trajectory of interhemispheric temporal reorganization from asynchrony to synchrony using magnitude of interaural threshold difference as the independent variable in a cross-sectional study and (2) to evaluate reversibility of interhemispheric synchrony in association with hearing in noise performance by amplifying the aidable poorer ear in a repeated measures, longitudinal study. DESIGN: The cross-sectional and longitudinal cohorts were comprised of 49 subjects (AHL; N = 21; 11 male, 10 female; mean age = 48 years) and NH (N = 28; 16 male, 12 female; mean age = 45 years). The maximum interaural threshold difference of the two cohorts spanned from 0 to 65 dB. Magnetoencephalography analyses focused on latency of the M100 peak response from auditory cortex in both hemispheres between 50 msec and 150 msec following monaural tonal stimulation at the frequency (0.5, 1, 2, 3, or 4 kHz) corresponding to the maximum and minimum interaural threshold difference for better and poorer ears separately. The longitudinal AHL cohort was drawn from three subjects in the cross-sectional AHL cohort (all male; ages 49 to 60 years; varied AHL etiologies; no amplification for at least 2 years). All longitudinal study subjects were treated by monaural amplification of the poorer ear and underwent repeated measures examination of the M100 response latency and quick speech in noise hearing in noise performance at baseline, and postamplification months 3, 6, and 12. RESULTS: The M100 response peak latency values in the ipsilateral hemisphere lagged those in the contralateral hemisphere for all stimulation conditions. The mean (SD) interhemispheric latency difference values (ipsilateral less contralateral) to better ear stimulation for three categories of maximum interaural threshold difference were as follows: NH (≤ 10 dB)-8.6 (3.0) msec; AHL (15 to 40 dB)-3.0 (1.2) msec; AHL (≥ 45 dB)-1.4 (1.3) msec. In turn, the magnitude of difference values were used to define interhemispheric temporal organization states of asynchrony, mixed asynchrony and synchrony, and synchrony, respectively. Amplification of the poorer ear in longitudinal subjects drove interhemispheric organization change from baseline synchrony to postamplification asynchrony and hearing in noise performance improvement in those with baseline impairment over a 12-month period. CONCLUSIONS: Interhemispheric temporal organization in AHL was anchored between states of asynchrony in NH and synchrony in single-sided deafness. For asymmetry magnitudes between 15 and 40 dB, the intermediate mixed state of asynchrony and synchrony was continuous and reversible. Amplification of the poorer ear in AHL improved hearing in noise performance and restored normal temporal organization of auditory cortices in the two hemispheres. The return to normal interhemispheric asynchrony from baseline synchrony and improvement in hearing following monoaural amplification of the poorer ear evolved progressively over a 12-month period.

Recent Advances in Smart Biomaterials for the Detection and Treatment of Autoimmune Diseases.

Autoimmune diseases are a group of debilitating illnesses that are often idiopathic in nature. The steady rise in the prevalence of these conditions warrants new approaches for diagnosis and treatment. Stimuli-responsive biomaterials also known as "smart", "intelligent" or "recognitive" biomaterials are widely studied for their applications in drug delivery, biosensing and tissue engineering due to their ability to produce thermal, optical, chemical, or structural changes upon interacting with the biological environment. This critical analysis highlights studies within the last decade that harness the recognitive capabilities of these biomaterials towards the development of novel detection and treatment options for autoimmune diseases.

Bacterial 1,4-α-glucan branching enzymes: characteristics, preparation and commercial applications.

The 1,4-α-glucan branching enzymes (GBEs) are ubiquitously distributed in animals, microorganisms and plants. These enzymes modify the structure of both starch and glycogen; changing the frequency and position of branches by forming new α-1,6-glucosidic linkages. In organisms, controlling the number and distribution of branches is an irreplaceable process that maintains the physiological state of starch and glycogen in the cell. The process is also the foundation for the industrial applications of GBEs. So far, a number of GBEs have been identified in eukaryotes and prokaryotes as researchers searched for GBEs with optimal properties. Among them, bacterial GBEs have received particular attention due to the convenience of heterologous expression and industrial applications of GBEs from bacteria than GBEs from other sources. The advantages of bacterial GBEs in potential applications stimulated the investigations of bacterial GBEs in terms of their structure and properties. However, full exploitation of GBEs in commercial applications is still in its infancy because of the disadvantages of currently available enzymes and of limited imagination with respect to future possibilities. Thus, in this review, we present an overview of the bacterial GBEs including their structure, biochemical properties and commercial applications in order to depict the whole picture of bacterial GBEs.

Low vasopressin and progression of neonatal sepsis to septic shock: a prospective cohort study.

The study objective was to analyze the association between low plasma vasopressin and progression of sepsis to septic shock in neonates < 34 weeks gestation. Septic neonates of < 34 weeks gestation were consecutively enrolled; moribund neonates and those with major malformations were excluded. Subjects were monitored for progression of sepsis to septic shock over the first 7 days from enrolment. Plasma vasopressin levels and inducible nitric oxide synthase levels were measured at the onset of sepsis (T0), severe sepsis (T1), and septic shock (T2). Primary outcome was plasma vasopressin levels at the point of sepsis in those who progressed to septic shock in comparison with matched nested controls in the non-progression group. Forty-nine (47%) enrolled subjects developed severe sepsis or septic shock. Plasma vasopressin levels (pg/ml) at the onset of sepsis were significantly low in those who progressed to septic shock (median (IQR), 31 (2.5-80) versus 100 (12-156); p = 0.02). After adjusting for confounders, vasopressin levels were independently associated with progression to septic shock (adjusted OR (95% CI), 0.97 (0.96, 0.99); p = 0.01).Conclusion: Preterm septic neonates who progressed to septic shock had suppressed vasopressin levels before the onset of shock. Low vasopressin levels were independently associated with progression to septic shock.What is known:• In animal sepsis models and adult septic patients, exuberant production of nitric oxide metabolites and low vasopressin levels have been reportedly associated with progression to septic shock.• Vasopressin levels have been variably reported as low as well as elevated in children with septic shock.What is New:• Preterm neonates who progressed from sepsis to septic shock had significantly lower levels of vasopressin before the onset of shock in comparison with those who did not progress.• Low vasopressin levels independently predicted the progression from sepsis to septic shock in this population.

A Multifunctional Cosolvent Pair Reveals Molecular Principles of Biomass Deconstruction.

The complex structure of plant cell walls resists chemical or biological degradation, challenging the breakdown of lignocellulosic biomass into renewable chemical precursors that could form the basis of future production of green chemicals and transportation fuels. Here, experimental and computational results reveal that the effect of the tetrahydrofuran (THF)-water cosolvents on the structure of lignin and on its interactions with cellulose in the cell wall drives multiple synergistic mechanisms leading to the efficient breakdown and fractionation of biomass into valuable chemical precursors. Molecular simulations show that THF-water is an excellent "theta" solvent, such that lignin dissociates from itself and from cellulose and expands to form a random coil. The expansion of the lignin molecules exposes interunit linkages, rendering them more susceptible to depolymerization by acid-catalyzed cleavage of aryl-ether bonds. Nanoscale infrared sensors confirm cosolvent-mediated molecular rearrangement of lignin in the cell wall of micrometer-thick hardwood slices and track the disappearance of lignin. At bulk scale, adding dilute acid to the cosolvent mixture liberates the majority of the hemicellulose and lignin from biomass, allowing unfettered access of cellulolytic enzymes to the remaining cellulose-rich material, allowing them to sustain high rates of hydrolysis to glucose without enzyme deactivation. Through this multiscale analysis, synergistic mechanisms for biomass deconstruction are identified, portending a paradigm shift toward first-principles design and evaluation of other cosolvent methods to realize low cost fuels and bioproducts.

Melatonin suppression is exquisitely sensitive to light and primarily driven by melanopsin in humans.

INTRODUCTION: Light elicits a range of non-visual responses in humans. Driven predominantly by intrinsically photosensitive retinal ganglion cells (ipRGCs), but also by rods and/or cones, these responses include melatonin suppression. A sigmoidal relationship has been established between melatonin suppression and light intensity; however, photoreceptoral involvement remains unclear. METHODS AND RESULTS: In this study, we first modelled the relationships between alpha-opic illuminances and melatonin suppression using an extensive dataset by Brainard and colleagues. Our results show that (a) melatonin suppression is better predicted by melanopic illuminance compared to other alpha-opic illuminances, (b) melatonin suppression is predicted to occur at levels as low as ~1.5 melanopic lux (melanopsin-weighted irradiance 0.2 µW/cm2 ), (c) saturation occurs at 305 melanopic lux (melanopsin-weighted irradiance 36.6 µW/cm2 ). We then tested this melanopsin-weighted illuminance-response model derived from Brainard and colleagues' data and show that it predicts equally well melatonin suppression data from our laboratory, although obtained using different intensities and exposure duration. DISCUSSION: Together, our findings suggest that melatonin suppression by monochromatic lights is predominantly driven by melanopsin and that it can be initiated at extremely low melanopic lux levels in experimental conditions. This emphasizes the concern of the non-visual impacts of low light intensities in lighting design and light-emitting devices.

The multi-receptor inhibitor axitinib reverses tumor-induced immunosuppression and potentiates treatment with immune-modulatory antibodies in preclinical murine models.

Cancer immunotherapies have significantly improved the prognosis of cancer patients. Despite the clinical success of targeting inhibitory checkpoint receptors, including PD-1 and/or CTLA-4 on T cells, only a minority of patients derive benefit from these therapies. New strategies to improve cancer immunotherapy are therefore needed. Combination therapy of checkpoint inhibitors with targeted agents has promisingly shown to increase the efficacy of immunotherapy. Here, we analyzed the immunomodulatory effects of the multi-receptor tyrosine kinase inhibitor axitinib and its efficacy in combination with immunotherapies. In different syngeneic murine tumor models, axitinib showed therapeutic efficacy that was not only mediated by VEGF-VEGFR inhibition, but also through the induction of anti-cancer immunity. Mechanistically, a significant reduction of immune-suppressive cells, including a decrease of tumor-promoting mast cells and tumor-associated macrophages was observed upon axitinib treatment. Inhibition of mast cells by axitinib as well as their experimental depletion led to reduced tumor growth. Of note, treatment with axitinib led to an improved T cell response, while the latter was pivotal for the therapeutic efficacy. Combination with immune checkpoint inhibitors anti-PD-1 and anti-TIM-3 and/or agonistic engagement of the activating receptor CD137 resulted in a synergistic therapeutic efficacy. This demonstrates non-redundant immune activation induced by axitinib via modulation of myeloid and mast cells. These findings provide important mechanistic insights into axitinib-mediated anti-cancer immunity and provide rationale for clinical combinations of axitinib with different immunotherapeutic modalities.

PEGylation of lysine residues reduces the pro-migratory activity of IGF-I.

BACKGROUND: The insulin-like growth factor (IGF) system is composed of ligands and receptors which regulate cell proliferation, survival, differentiation and migration. Some of these functions involve regulation by the extracellular milieu, including binding proteins and other extracellular matrix proteins. However, the functions and exact nature of these interactions remain incomplete. METHODS: IGF-I variants PEGylated at lysines K27, K65 and K68, were assessed for binding to IGFBPs using BIAcore, and for phosphorylation of the IGF-IR. Furthermore, functional consequences of PEGylation were investigated using cell viability and migration assays. In addition, downstream signaling pathways were analyzed using phospho-AKT and phospho-ERK1/2 assays. RESULTS: IGF-I PEGylated at lysines 27 (PEG-K27), 65 (PEG-K65) or 68 (PEG-K68) was employed. Receptor phosphorylation was similarly reduced 2-fold with PEG-K65 and PEG-K68 in 3T3 fibroblasts and MCF-7 breast cancer cells, whereas PEG-K27 showed a more than 10- and 3-fold lower activation for 3T3 and MCF-7 cells, respectively. In addition, all PEG-IGF-I variants had a 10-fold reduced association rate to IGF binding proteins (IGFBPs). Functionally, all PEG variants lost their ability to induce cell migration in the presence of IGFBP-3/vitronectin (VN) complexes, whereas cell viability was fully preserved. Analysis of downstream signaling revealed that AKT was preferentially affected upon treatment with PEG-IGF-I variants whereas MAPK signaling was unaffected by PEGylation. CONCLUSION: PEGylation of IGF-I has an impact on cell migration but not on cell viability. GENERAL SIGNIFICANCE: PEG-IGF-I may differentially modulate IGF-I mediated functions that are dependent on receptor interaction as well as key extracellular proteins such as VN and IGFBPs.

Differential subcellular and extracellular localisations of proteins required for insulin-like growth factor- and extracellular matrix-induced signalling events in breast cancer progression.

BACKGROUND: Cancer metastasis is the main contributor to breast cancer fatalities as women with the metastatic disease have poorer survival outcomes than women with localised breast cancers. There is an urgent need to develop appropriate prognostic methods to stratify patients based on the propensities of their cancers to metastasise. The insulin-like growth factor (IGF)-I: IGF binding protein (IGFBP):vitronectin complexes have been shown to stimulate changes in gene expression favouring increased breast cancer cell survival and a migratory phenotype. We therefore investigated the prognostic potential of these IGF- and extracellular matrix (ECM) interaction-induced proteins in the early identification of breast cancers with a propensity to metastasise using patient-derived tissue microarrays. METHODS: Semiquantitative immunohistochemistry analyses were performed to compare the extracellular and subcellular distribution of IGF- and ECM-induced signalling proteins among matched normal, primary cancer and metastatic cancer formalin-fixed paraffin-embedded breast tissue samples. RESULTS: The IGF- and ECM-induced signalling proteins were differentially expressed between subcellular and extracellular localisations. Vitronectin and IGFBP-5 immunoreactivity was lower while ß1 integrin immunoreactivity was higher in the stroma surrounding metastatic cancer tissues, as compared to normal breast and primary cancer stromal tissues. Similarly, immunoreactive stratifin was found to be increased in the stroma of primary as well as metastatic breast tissues. Immunoreactive fibronectin and ß1 integrin was found to be highly expressed at the leading edge of tumours. Based on the immunoreactivity it was apparent that the cell signalling proteins AKT1 and ERK1/2 shuffled from the nucleus to the cytoplasm with tumour progression. CONCLUSION: This is the first in-depth, compartmentalised analysis of the distribution of IGF- and ECM-induced signalling proteins in metastatic breast cancers. This study has provided insights into the changing pattern of cellular localisation and expression of IGF- and ECM-induced signalling proteins in different stages of breast cancer. The differential distribution of these biomarkers could provide important prognostic and predictive indicators that may assist the clinical management of breast disease, namely in the early identification of cancers with a propensity to metastasise, and/or recur following adjuvant therapy.