Exploring the utility of ultrasound to assess disuse atrophy in different muscles of the lower leg.

BACKGROUND: Skeletal muscle is a highly plastic tissue crucial for many functions associated with whole-body health across the life course. Magnetic resonance imaging (MRI) is the current gold standard for measuring skeletal muscle size. However, MRI is expensive, and access to facilities is often limited. B-mode ultrasonography (U/S) has been proposed as a potential alternative to MRI for the assessment of muscle size. However, to date, no work has explored the utility of U/S to assess disuse muscle atrophy (DMA) across muscles with different atrophy susceptibility profiles, an omission which may limit the clinical application of previous work. METHODS: To address this significant knowledge gap, 10 young men (22 ±  years, 24.1 ± 2.3 kg/m2) underwent 15-day unilateral leg immobilization using a knee-brace and air boot. Cross-sectional area (CSA) and muscle thickness (MT) of the tibialis anterior (TA) and medial gastrocnemius (MG) were assessed via U/S before and after immobilization, with CSA and muscle volume assessed via MRI. RESULTS: With both muscles combined, there were good correlations between each U/S and MRI measure, both before (e.g., CSAMRI vs. MTU/S and CSAU/S: r = 0.88 and 0.94, respectively, both P < 0.0001) and after (e.g., VOLMRI vs. MTU/S and CSAU/S: r = 0.90 and 0.96, respectively, both P < 0.0001) immobilization. The relationship between the methods was notably stronger for MG than TA at each time-point (e.g., CSAMRI vs. MTU/S: MG, r = 0.70, P = 0.0006; TA, r = 0.37, P = 0.10). There was no relationship between the degree of DMA determined by the two methods in either muscle (e.g., TA pre- vs. post-immobilization, VOLMRI: 136 ± 6 vs. 133 ± 5, P = 0.08; CSAU/S: 6.05 ± 0.3 vs. 5.92 ± 0.4, P = 0.70; relationship between methods: r = 0.12, P = 0.75). CONCLUSIONS: Both MTU/S and CSAU/S provide comparable static measures of lower leg muscle size compared with MRI, albeit with weaker agreement in TA compared to MG. Although both MTU/S and CSAU/S can discern differences in DMA susceptibility between muscles, neither can reliably assess degree of DMA. Based on the growing recognition of heterogeneous atrophy profiles between muscles, and the topical importance of less commonly studied muscles (i.e., TA for falls prevention in older adults), future research should aim to optimize accessible methods to determine muscle losses across the body.

Adipose microenvironment promotes hypersialylation of ovarian cancer cells.

Introduction: Ovarian and other peritoneal cancers have a strong tendency to metastasize into the surrounding adipose tissue. This study describes an effect of the adipose microenvironment on upregulation of sialic acid-containing glycans in ovarian cancer (OC). Heterogeneous populations of glycosylated OC tumors converged to a highly sialylated cell state that regulates tumorigenesis in an immune-dependent manner. Methods: We modeled the adipose microenvironment by conditioning growth media with human patient-derived adipose tissue. OC cell lines grown in the presence vs. absence of adipose conditioned media (ACM) were characterized by transcriptomics, western blotting, and chemical biology glycan labeling methods. Fluorescence-activated cell sorting was used to separate adipose-driven upregulation of hypersialylated ("SNA-high") vs. hyposialylated ("SNA-low") OC subpopulations. The two subpopulations were characterized by further transcriptomic and quantitative polymerase chain reaction analyses, then injected into a syngeneic mouse model. Immune system involvement was implicated using wild type and athymic nude mice with a primary endpoint of overall survival. Results: Adipose conditioning resulted in upregulation of sialyltransferases ST3GAL1, ST6GAL1, ST6GALNAC3, and ST8Sia1. In culture, OC cells displayed two distinct sialylated subpopulations that were stable for up to 9 passages, suggesting inherent heterogeneity in sialylation that is maintained throughout cell division and media changes. OC tumors that implanted in the omental adipose tissue exclusively reprogrammed to the highly sialylated subpopulation. In wild type C57BL/6 mice, only the hypersialylated SNA-high subpopulation implanted in the adipose, whereas the hyposialylated SNA-low subpopulation failed to be tumorigenic (p=0.023, n=5). In the single case where SNA-low established a tumor, post-mortem analysis revealed reprogramming of the tumor to the SNA-high state in vivo. In athymic nude mice, both subpopulations rapidly formed tumors, implicating a role of the adaptive immune system. Conclusions: These findings suggest a model of glycan-dependent tumor evolution wherein the adipose microenvironment reprograms OC to a tumorigenic state that resists the adaptive immune system. Mechanistically, adipose factors upregulate sialyltransferases. To our knowledge, this is the first demonstration of the effect of adipose microenvironment on OC tumor sialylation. Our results set the stage for translational applications targeting sialic acid pathways in OC and other peritoneal cancer tumorigenesis and metastasis.

Occult residual ovarian tissue at the time of minimally invasive risk reducing surgery in women with BRCA mutations.

OBJECTIVE: To describe extension of ovarian tissue beyond visible and National Comprehensive Cancer Network recommended margins among patients with BRCA mutations undergoing minimally invasive risk-reducing salpingo-oophorectomy. METHODS: A prospective study of patients with BRCA mutations who underwent minimally invasive risk-reducing bilateral salpingo-oophorectomy was conducted. Patient enrollment occurred between October 2021 and 2023. Tissue specimens were analyzed according to the Sectioning and Extensively Examining the Fimbriated End protocol. RESULTS: Twenty women with BRCA mutations were prospectively enrolled. All patients underwent minimally invasive surgery with 70% undergoing concurrent hysterectomy (n = 14). Approximately half of these procedures were performed with robotic assistance (n = 9, 45%). One patient was admitted overnight (5%); the other nineteen were discharged on the day of surgery (95%). One patient experienced a major complication and required readmission (5%). Extension of ovarian tissue beyond the visible ovary was noted on pathologic examination of six specimens (30%). In one patient this was observed on the left (17%), in three on the right (50%), and in two bilateral extension (33%) was noted. The distance ovarian stroma extended microscopically beyond the visible ovary was between 2 and 14 mm, with a median of 5 mm. Among patients with microscopic extension of ovarian tissue, the majority (n = 5, 83%) had a BRCA2 mutation. CONCLUSION: In women with BRCA mutations undergoing risk-reducing minimally invasive surgery, approximately one third had microscopic extension of ovarian stroma beyond the visible ovary. Current guidelines which recommend resection of at least 20 mm of tissue beyond the visible ovary are likely adequate in this population.

Generation of a biliary tract cancer cell line atlas reveals molecular subtypes and therapeutic targets.

Biliary tract cancers (BTCs) are a group of deadly malignancies encompassing intrahepatic and extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. Here, we present the integrative analysis of 63 BTC cell lines via multi-omics clustering and genome- scale CRISPR screens, providing a platform to illuminate BTC biology and inform therapeutic development. We identify dependencies broadly enriched in BTC compared to other cancers as well as dependencies selective to the anatomic subtypes. Notably, cholangiocarcinoma cell lines are stratified into distinct lineage subtypes based on biliary or dual biliary/hepatocyte marker signatures, associated with dependency on specific lineage survival factors. Transcriptional analysis of patient specimens demonstrates the prognostic significance of these lineage subtypes. Additionally, we delineate strategies to enhance targeted therapies or to overcome resistance in cell lines with key driver gene mutations. Furthermore, clustering based on dependencies and proteomics data elucidates unexpected functional relationships, including a BTC subgroup with partial squamous differentiation. Thus, this cell line atlas reveals potential therapeutic targets in molecularly defined BTCs, unveils biologically distinct disease subtypes, and offers a vital resource for BTC research.

Hard Candy Production and Quality Parameters: A review.

Hard candies are sugar confections comprising mainly water and sucrose. Corn syrup, colorants and flavors are also usually added to hard candy formulations. The production of hard candy requires heating of the ingredients to very high temperatures to reduce moisture content and subsequent cooling to obtain a solid matrix. Cooling of the mixtures achieves the final, well known glassy state of the products. In this glassy state, the system is kinetically stable and molecular mobility is restricted, providing longer shelf life to hard candies. There are, however, several factors affecting the final quality and consumer acceptance of hard candies. Production methods and parameters, initial formulations as well as storage conditions all play a crucial role in the physicochemical, textural and sensory properties of hard candies. Addition of colorants and flavors also plays a vital role in the final quality. Although hard candy production is a simple process with few production stages, even small changes in the method of production and process parameters may induce substantial changes in the final product characteristics. Additionally, storage conditions such as temperature and humidity can change the product properties leading to graining and stickiness which are the two major problems for hard candies during storage. Both production and storage conditions should therefore be carefully chosen and controlled for desirable hard candy properties. This review addresses the general production methods and considers process parameters and quality parameters of hard candy products. Moreover, a comprehensive review of the related hard candy literature is also presented. The majority of hard candy reviews focus on specific methods and processes, but this review will present a more general frame on the subject.

BRCA Status Dictates Wnt Responsiveness in Epithelial Ovarian Cancer.

The association of BRCA1 and BRCA2 mutations with increased risk for developing epithelial ovarian cancer is well established. However, the observed clinical differences, particularly the improved therapy response and patient survival in BRCA2-mutant patients, are unexplained. Our objective is to identify molecular pathways that are differentially regulated upon the loss of BRCA1 and BRCA2 functions in ovarian cancer. Transcriptomic and pathway analyses comparing BRCA1-mutant, BRCA2-mutant, and homologous recombination wild-type ovarian tumors showed differential regulation of the Wnt/ß-catenin pathway. Using Wnt3A-treated BRCA1/2 wild-type, BRCA1-null, and BRCA2-null mouse ovarian cancer cells, we observed preferential activation of canonical Wnt/ß-catenin signaling in BRCA1/2 wild-type ovarian cancer cells, whereas noncanonical Wnt/ß-catenin signaling was preferentially activated in the BRCA1-null ovarian cancer cells. Interestingly, BRCA2-null mouse ovarian cancer cells demonstrated a unique response to Wnt3A with the preferential upregulation of the Wnt signaling inhibitor Axin2. In addition, decreased phosphorylation and enhanced stability of ß-catenin were observed in BRCA2-null mouse ovarian cancer cells, which correlated with increased inhibitory phosphorylation on GSK3ß. These findings open venues for the translation of these molecular observations into modalities that can impact patient survival. SIGNIFICANCE: We show that BRCA1 and BRCA2 mutation statuses differentially impact the regulation of the Wnt/ß-catenin signaling pathway, a major effector of cancer initiation and progression. Our findings provide a better understanding of molecular mechanisms that promote the known differential clinical profile in these patient populations.

Mental Wellness Self-Care in Singapore With mindline.sg: A Tutorial on the Development of a Digital Mental Health Platform for Behavior Change.

BACKGROUND: Singapore, like the rest of Asia, faces persistent challenges to mental health promotion, including stigma around unwellness and seeking treatment and a lack of trained mental health personnel. The COVID-19 pandemic, which created a surge in mental health care needs and simultaneously accelerated the adoption of digital health solutions, revealed a new opportunity to quickly scale innovative solutions in the region. OBJECTIVE: In June 2020, the Singaporean government launched mindline.sg, an anonymous digital mental health resource website that has grown to include >500 curated local mental health resources, a clinically validated self-assessment tool for depression and anxiety, an artificial intelligence (AI) chatbot from Wysa designed to deliver digital therapeutic exercises, and a tailored version of the website for working adults called mindline at work. The goal of the platform is to empower Singapore residents to take charge of their own mental health and to be able to offer basic support to those around them through the ease and convenience of a barrier-free digital solution. METHODS: Website use is measured through click-level data analytics captured via Google Analytics and custom application programming interfaces, which in turn drive a customized analytics infrastructure based on the open-source platforms Titanium Database and Metabase. Unique, nonbounced (users that do not immediately navigate away from the site), engaged, and return users are reported. RESULTS: In the 2 years following launch (July 1, 2020, through June 30, 2022), the website received >447,000 visitors (approximately 15% of the target population of 3 million), 62.02% (277,727/447,783) of whom explored the site or engaged with resources (referred to as nonbounced visitors); 10.54% (29,271/277,727) of those nonbounced visitors returned. The most popular features on the platform were the dialogue-based therapeutic exercises delivered by the chatbot and the self-assessment tool, which were used by 25.54% (67,626/264,758) and 11.69% (32,469/277,727) of nonbounced visitors. On mindline at work, the rates of nonbounced visitors who engaged extensively (ie, spent ≥40 seconds exploring resources) and who returned were 51.56% (22,474/43,588) and 13.43% (5,853/43,588) over a year, respectively, compared to 30.9% (42,829/138,626) and 9.97% (13,822/138,626), respectively, on the generic mindline.sg site in the same year. CONCLUSIONS: The site has achieved desired reach and has seen a strong growth rate in the number of visitors, which required substantial and sustained digital marketing campaigns and strategic outreach partnerships. The site was careful to preserve anonymity, limiting the detail of analytics. The good levels of overall adoption encourage us to believe that mild to moderate mental health conditions and the social factors that underly them are amenable to digital interventions. While mindline.sg was primarily used in Singapore, we believe that similar solutions with local customization are widely and globally applicable.

Floater Stories: Assessing the Potential Benefits of Vitrectomy.

Symptomatic vitreous opacities (SVO, "floaters") in the mobile, aging vitreous that substantially interfere with daily visual activities (DVA) constitute degenerative vitreous syndrome (DVS). DVS is best distinguished from common "nuisance" floaters by use of "floater stories" written by presenting patients describing their symptoms. Here I discuss why vitreous opacity vitrectomy, though curative, has been adopted only belatedly and is still controversial, and I describe my long-term experience with its use for this disease.

FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma.

Genomic alterations that activate Fibroblast Growth Factor Receptor 2 (FGFR2) are common in intrahepatic cholangiocarcinoma (ICC) and confer sensitivity to FGFR inhibition. However, the depth and duration of response is often limited. Here, we conduct integrative transcriptomics, metabolomics, and phosphoproteomics analysis of patient-derived models to define pathways downstream of oncogenic FGFR2 signaling that fuel ICC growth and to uncover compensatory mechanisms associated with pathway inhibition. We find that FGFR2-mediated activation of Nuclear factor-κB (NF-κB) maintains a highly glycolytic phenotype. Conversely, FGFR inhibition blocks glucose uptake and glycolysis while inciting adaptive changes, including switching fuel source utilization favoring fatty acid oxidation and increasing mitochondrial fusion and autophagy. Accordingly, FGFR inhibitor efficacy is potentiated by combined mitochondrial targeting, an effect enhanced in xenograft models by intermittent fasting. Thus, we show that oncogenic FGFR2 signaling drives NF-κB-dependent glycolysis in ICC and that metabolic reprogramming in response to FGFR inhibition confers new targetable vulnerabilities.

Adipose microenvironment promotes hypersialylation of ovarian cancer cells.

Sialylation, the addition of negatively charged sialic acid sugars to terminal ends of glycans, is upregulated in most cancers. Hypersialylation supports multiple pro-tumor mechanisms such as enhanced migration and invasion, resistance to apoptosis and immune evasion. A current gap in knowledge is the lack of understanding on how the tumor microenvironment regulates cancer cell sialylation. The adipose niche is a main component of most peritoneal cancers' microenvironment. This includes ovarian cancer (OC), which causes most deaths from all gynecologic cancers. In this report, we demonstrate that the adipose microenvironment is a critical regulator of OC cell sialylation. In vitro adipose conditioning led to an increase in both ⍺2,3- and ⍺2,6-linked cell surface sialic acids in both human and mouse models of OC. Adipose-induced sialylation reprogramming was also observed in vivo from intra-peritoneal OC tumors seeded in the adipose-rich omentum. Mechanistically, we observed upregulation of at least three sialyltransferases, ST3GAL1, ST6GAL1 and ST3GALNAC3. Hypersialylated OC cells consistently formed intra-peritoneal tumors in both immune-competent mice and immune-compromised athymic nude mice. In contrast, hyposiaylated OC cells persistently formed tumors only in athymic nude mice demonstrating that sialylation impacts OC tumor formation in an immune dependent manner. To our knowledge, this is the first demonstration of the effect of adipose microenvironment on OC tumor sialylation. Our results set the stage for translational applications targeting sialic acid pathways in OC and other peritoneal cancers.

Mechanochemical Synthesis of Chromium(III) Complexes Containing Bidentate PN and Tridentate P-NH-P and P-NH-P' Ligands.

Chromium(III) complexes bearing bidentate {NH2(CH2)2PPh2: PN, (S,S)-[NH2(CHPh)2PPh2]: P'N} and tridentate [Ph2P(CH2)2N(H)(CH2)2PPh2: P-NH-P, (S,S)-(iPr)2PCH2CH2N(H)CH(Ph)CH(Ph)PPh2: P-NH-P'] ligands have been synthesized using a mechanochemical approach. The complexes {cis-[Cr(PN)Cl2]Cl (1), cis-[Cr(P'N)Cl2]Cl (2), mer-Cr(P-NH-P)Cl3 (3), and mer-Cr(P-NH-P')Cl3 (4)} were obtained in high yield (95-97%) via the grinding of the respective ligands andthe solid Cr(III) ion precursor [CrCl3(THF)3] with the aid of a pestle and mortar, followed by recrystallization in acetonitrile. The isolated complexes are high spin. A single-crystal X-ray diffraction study of 2 revealed a cationic chromium complex with two P'N ligands in a cis configuration with P' trans to P' with chloride as the counteranion. The X-ray study of 4 shows a neutral Cr(III) complex with the P-NH-P' ligand in a mer configuration. The difference in molecular structures and bulkiness of the ligands influence the electronic, magnetic, and electrochemical properties of the complexes as exhibited by the bathochromic shifts in the electronic absorption peaks of the complexes and the relative increase in the magnetic moment of 3 (4.19 µß) and 4 (4.15 µß) above the spin only value (3.88 µß) for a d3 electronic configuration. Complexes 1-4 were found to be inactive in the hydrogenation of an aldimine [(E)-1-(4-fluorophenyl)-N-phenylmethanimine] under a variety of activating conditions. The addition of magnesium and trimethylsilyl chloride in THF did cause hydrogenation at room temperature, but this occurred even in the absence of the chromium complex. The hydrogen in the amine product came from the THF solvent in this novel reaction, as determined by deuterium incorporation into the product when deuterated THF was used.

Drug Repurposing Using FDA Adverse Event Reporting System (FAERS) Database.

Drug repurposing is an emerging approach to reassigning existing pre-approved therapies for new indications. The FDA Adverse Event Reporting System (FAERS) is a large database of over 28 million adverse event reports submitted by medical providers, patients, and drug manufacturers and provides extensive drug safety signal data. In this review, four common drug repurposing strategies using FAERS are described, including inverse signal detection for a single disease, drug-drug interactions that mitigate a target ADE, identifying drug-ADE pairs with opposing gene perturbation signatures and identifying drug-drug pairs with congruent gene perturbation signatures. The purpose of this review is to provide an overview of these different approaches using existing successful applications in the literature. With the fast expansion of adverse drug event reports, FAERS-based drug repurposing represents a promising strategy for discovering new uses for existing therapies.

APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease.

Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do, they have a later age of onset, milder clinical course, and less severe neuropathological findings than people without this allele. The contrast is especially stark when compared with the major genetic risk factor for Alzheimer disease, APOE ε4, which has an age of onset several decades earlier, a more aggressive clinical course and more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Here, we demonstrate that brain exposure to APOE ε2 via a gene therapy approach, which bathes the entire cortical mantle in the gene product after transduction of the ependyma, reduces Aß plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE ε4. This result suggests a promising protective effect of exogenous APOE ε2 and reveals a cell nonautonomous effect of the protein on microglial activation, which we show is similar to plaque-associated microglia in the brain of Alzheimer disease patients who inherit APOE ε2. These data increase the potential that an APOE ε2 therapeutic could be effective in Alzheimer disease, even in individuals born with the risky ε4 allele.

A lower bound for set-coloring Ramsey numbers.

The set-coloring Ramsey number Rr,s(k) is defined to be the minimum n such that if each edge of the complete graph Kn is assigned a set of s colors from {1,…,r}, then one of the colors contains a monochromatic clique of size k. The case s=1 is the usual r-color Ramsey number, and the case s=r-1 was studied by Erdos, Hajnal and Rado in 1965, and by Erdos and Szemerédi in 1972. The first significant results for general s were obtained only recently, by Conlon, Fox, He, Mubayi, Suk and Verstraëte, who showed that Rr,s(k)=2Θ(kr) if s/r is bounded away from 0 and 1. In the range s=r-o(r), however, their upper and lower bounds diverge significantly. In this note we introduce a new (random) coloring, and use it to determine Rr,s(k) up to polylogarithmic factors in the exponent for essentially all r, s, and k.

Comparing the risk of deep vein thrombosis of two combined oral contraceptives: Norethindrone/ethinyl estradiol and drospirenone/ethinyl estradiol.

Background: Deep vein thrombosis (DVT) has been reported as an adverse event for patients receiving combined oral contraceptives. Norethindrone/ethinyl estradiol (NET/EE) and drospirenone/ethinyl estradiol (DRSP/EE) are two commonly prescribed combined hormonal oral contraceptive agents used in the United States, differing in their progestin component. Objective: The purpose of this study was to determine the association between the progestin component of a combined oral contraceptive and the risk of DVT in patients taking oral contraceptives for birth control using data derived from the FDA Adverse Event Reporting System (FAERS). Methods: The risk of DVT was compared between patients that had taken NET/EE with those that had taken the DRSP/EE COC formulation for birth control. In addition, age was assessed as a possible confounder and the outcome severity for those diagnosed with DVT were compared between the two groups. Finally, association rule mining was utilized to identify possible drug-drug interactions that result in elevated DVT risk. Results: DVT was the fourth most commonly adverse event reported for patients taking DRSP/EE accounting for 8558 cases and the seventeenth most commonly reported adverse event for NET/EE accounting for 298 cases. Age was found to be a significant confounder for users of DRSP/EE with regards to DVT risk across all age groups assessed: 2040 (ROR = 3.69, 95% CI 3.37-4.04) However, there was only a statistically significant elevated risk in patients over 40 years of age taking NET/EE (ROR = 1.98, 95% CI 1.36-2.88). Patients that had taken DRSP/EE and the corticosteroid prednisone simultaneously had an approximately 3-fold increase in DVT risk (ROR = 2.77, 95% CI 2.43-3.15) relative to individuals that had only taken DRSP/EE. Conclusion: Based on this analysis, there is a higher risk of developing DVT when taking DRSP/EE than when taking NET/EE as hormonal contraception. In addition, a possibly significant drug-drug interaction between different COC formulations and prednisone were identified. This interaction may result in elevated DVT risk due to a synergistic impairment of fibrinolysis and a decrease in plasmin production.

How denialist amplification spread COVID misinformation and undermined the credibility of public health science.

Denialist scientists played an outsized role in shaping public opinion and determining public health policy during the recent COVID pandemic. From early on, amplification of researchers who denied the threat of COVID shaped public opinion and undermined public health policy. The forces that amplify denialists include (1) Motivated amplifiers seeking to protect their own interests by supporting denialist scientists, (2) Conventional media outlets giving disproportionate time to denialist opinions, (3) Promoters of controversy seeking to gain traction in an 'attention economy,' and (4) Social media creating information silos in which denialists can become the dominant voice. Denialist amplification poses an existential threat to science relevant to public policy. It is incumbent on the scientific community to create a forum to accurately capture the collective perspective of the scientific community related to public health policy that is open to dissenting voices but prevents artificial amplification of denialists.

Glioblastoma extracellular vesicles modulate immune PD-L1 expression in accessory macrophages upon radiotherapy.

Glioblastoma (GBM) is the most aggressive brain tumor, presenting major challenges due to limited treatment options. Standard care includes radiation therapy (RT) to curb tumor growth and alleviate symptoms, but its impact on GBM is limited. In this study, we investigated the effect of RT on immune suppression and whether extracellular vesicles (EVs) originating from GBM and taken up by the tumor microenvironment (TME) contribute to the induced therapeutic resistance. We observed that (1) ionizing radiation increases immune-suppressive markers on GBM cells, (2) macrophages exacerbate immune suppression in the TME by increasing PD-L1 in response to EVs derived from GBM cells which is further modulated by RT, and (3) RT increases CD206-positive macrophages which have the most potential in inducing a pro-oncogenic environment due to their increased uptake of tumor-derived EVs. In conclusion, RT affects GBM resistance by immuno-modulating EVs taken up by myeloid cells in the TME.

Tumour-infiltrated cortex participates in large-scale cognitive circuits.

The extent to which tumour-infiltrated brain tissue contributes to cognitive function remains unclear. We tested the hypothesis that cortical tissue infiltrated by diffuse gliomas participates in large-scale cognitive circuits using a unique combination of intracranial electrocorticography (ECoG) and resting-state functional magnetic resonance (fMRI) imaging in four patients. We also assessed the relationship between functional connectivity with tumour-infiltrated tissue and long-term cognitive outcomes in a larger, overlapping cohort of 17 patients. We observed significant task-related high gamma (70-250 Hz) power modulations in tumour-infiltrated cortex in response to increased cognitive effort (i.e., switch counting compared to simple counting), implying preserved functionality of neoplastic tissue for complex tasks probing executive function. We found that tumour locations corresponding to task-responsive electrodes exhibited functional connectivity patterns that significantly co-localised with canonical brain networks implicated in executive function. Specifically, we discovered that tumour-infiltrated cortex with larger task-related high gamma power modulations tended to be more functionally connected to the dorsal attention network (DAN). Finally, we demonstrated that tumour-DAN connectivity is evident across a larger cohort of patients with gliomas and that it relates to long-term postsurgical outcomes in goal-directed attention. Overall, this study contributes convergent fMRI-ECoG evidence that tumour-infiltrated cortex participates in large-scale neurocognitive circuits that support executive function in health. These findings underscore the potential clinical utility of mapping large-scale connectivity of tumour-infiltrated tissue in the care of patients with diffuse gliomas.

An Ex Vivo Model of Ovarian Cancer Peritoneal Metastasis Using Human Omentum.

Ovarian cancer is the deadliest gynecologic malignancy. The omentum plays a key role in providing a supportive microenvironment to metastatic ovarian cancer cells as well as immune modulatory signals that allow tumor tolerance. However, we have limited models that closely mimic the interaction between ovarian cancer cells and adipose-rich tissues. To further understand the cellular and molecular mechanisms by which the omentum provides a pro-tumoral microenvironment, we developed a unique 3D ex vivo model of cancer cell-omentum interaction. Using human omentum, we are able to grow ovarian cancer cells within this adipose-rich microenvironment and monitor the factors responsible for tumor growth and immune regulation. In addition to providing a platform for the study of this adipose-rich tumor microenvironment, the model provides an excellent platform for the development and evaluation of novel therapeutic approaches to target metastatic cancer cells in this niche. The proposed model is easy to generate, inexpensive, and applicable to translational investigations.

Reactivity umpolung (reversal) of ligands in transition metal complexes.

The success and power of homogeneous catalysis derives in large part from the wide choice of transition metal ions and their ligands. This tutorial review introduces examples where the reactivity of a ligand is completely reversed (umpolung) from Lewis basic/nucleophilic to acidic/electrophilic or vice versa on changing the metal and co-ligands. Understanding this phenomenon will assist in the rational design of catalysts and the understanding of metalloenzyme mechanisms. Labelling a metal and ligand with Seebach donor and acceptor labels helps to identify whether a reaction involving the intermolecular attack on the ligand is displaying native reactivity or reactivity umpolung. This has been done for complexes of nitriles, carbonyls, isonitriles, dinitrogen, Fischer carbenes, alkenes, alkynes, hydrides, methyls, methylidenes and alkylidenes, silylenes, oxides, imides/nitrenes, alkylidynes, methylidynes, and nitrides. The electronic influence of the metal and co-ligands is discussed in terms of the energy of (HOMO) d electrons. The energy can be related to the pKLACa (LAC is ligand acidity constant) of the theoretical hydride complexes [H-[M]-L]+ formed by the protonation of pair of valence d electrons on the metal in the [M-L] complex. Preliminary findings indicate that a negative pKLACa indicates that nucleophilic attack by a carbanion or amine on the ligand will likely occur while a positive pKLACa indicates that electrophilic attack by strong acids on the ligand will usually occur when the ligand is nitrile, carbonyl, isonitrile, alkene and η6-arene.