SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b.

Chromatin remodeling proteins are frequently dysregulated in human cancer, yet little is known about how they control tumorigenesis. Here, we uncover an epigenetic program mediated by the NAD(+)-dependent histone deacetylase Sirtuin 6 (SIRT6) that is critical for suppression of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies. SIRT6 inactivation accelerates PDAC progression and metastasis via upregulation of Lin28b, a negative regulator of the let-7 microRNA. SIRT6 loss results in histone hyperacetylation at the Lin28b promoter, Myc recruitment, and pronounced induction of Lin28b and downstream let-7 target genes, HMGA2, IGF2BP1, and IGF2BP3. This epigenetic program defines a distinct subset with a poor prognosis, representing 30%-40% of human PDAC, characterized by reduced SIRT6 expression and an exquisite dependence on Lin28b for tumor growth. Thus, we identify SIRT6 as an important PDAC tumor suppressor and uncover the Lin28b pathway as a potential therapeutic target in a molecularly defined PDAC subset. PAPERCLIP.

Insight into ion dynamics in a NaClO4-doped polycaprolactone solid polymer electrolyte for solid state batteries.

Employing low Tg polymers has fundamental limitations in providing the desirable ionic conductivity at ambient temperature due to the freezing of chain dynamics. The stiffening of polymer chains and the formation of highly ordered systems due to the crosslinks have influenced the ionic conductivity. Ionic conductivity of 1.02 × 10-5 S cm-1 was attained for the system that presented a quantum mechanical tunnelling mode of ion transport. A Na-ion transference number of 0.31 was achieved for 30 wt% of NaClO4 salt in a polycaprolactone (PCL) matrix with an electrochemical stability window of 3.6 V at 25 °C. High crystallinity and limited availability of free Na+ ions in the electrolyte have resulted in lower ionic conductivity. PCL-NaClO4 exhibited brilliant thermal stability and mechanical properties. The influence of cathode materials MnO2, V2O5 and I2 on the discharge characteristics of an electrochemical cell in the configuration cathode |(70 wt%)PCL-NaClO4(30 wt%)|Na has been studied.

Inositol hexakisphosphate kinase 1 regulates neutrophil function in innate immunity by inhibiting phosphatidylinositol-(3,4,5)-trisphosphate signaling.

Inositol phosphates are widely produced throughout animal and plant tissues. Diphosphoinositol pentakisphosphate (InsP7) contains an energetic pyrophosphate bond. Here we demonstrate that disruption of inositol hexakisphosphate kinase 1 (InsP6K1), one of the three mammalian inositol hexakisphosphate kinases (InsP6Ks) that convert inositol hexakisphosphate (InsP6) to InsP7, conferred enhanced phosphatidylinositol-(3,4,5)-trisphosphate (PtdIns(3,4,5)P3)-mediated membrane translocation of the pleckstrin homology domain of the kinase Akt and thus augmented downstream PtdIns(3,4,5)P3 signaling in mouse neutrophils. Consequently, these neutrophils had greater phagocytic and bactericidal ability and amplified NADPH oxidase-mediated production of superoxide. These phenotypes were replicated in human primary neutrophils with pharmacologically inhibited InsP6Ks. In contrast, an increase in intracellular InsP7 blocked chemoattractant-elicited translocation of the pleckstrin homology domain to the membrane and substantially suppressed PtdIns(3,4,5)P3-mediated cellular events in neutrophils. Our findings establish a role for InsP7 in signal transduction and provide a mechanism for modulating PtdIns(3,4,5)P3 signaling in neutrophils.

Participation in a High-Structure General Chemistry Course Increases Student Sense of Belonging and Persistence to Organic Chemistry.

A parallel series of general chemistry courses for Life Science Majors was created in an effort to support students and improve general chemistry outcomes. We created a two-quarter enhanced general chemistry course series that is not remedial, but instead implements several evidence-based teaching practices including Process Oriented Guided Inquiry Learning (POGIL), Peer-Led Team Learning (PLTL), and the Learning Assistant (LA) model. We found that students who took enhanced general chemistry had higher persistence to the subsequent first organic chemistry course, and performed equally well in the organic course compared to their peers who took standard general chemistry. Students in the first enhanced general chemistry course also reported significantly higher belonging, although we were unable to determine if increased belonging was associated with the increased persistence to organic chemistry. Rather we found that the positive association between taking the enhanced general chemistry course and persistence to organic chemistry was mediated by higher grades received in the enhanced general chemistry course. Our findings highlight the responsibility we have as educators to carefully consider the pedagogical practices we use, in addition to how we assign student grades.

Management of Sleep Apnea in Children with Chiari I Malformation: A Retrospective Study.

INTRODUCTION: The literature indicates that decompression of Chiari I malformations (CM-1) may resolve symptoms of sleep apnea. This study aims to identify the incidence of obstructive sleep apnea (OSA), central sleep apnea (CSA), and mixed sleep apnea in a cohort of pediatric CM-1 patients treated at our institution. We also assessed apnea-hypopnea index and symptomatology before and after surgery to investigate if Chiari decompression is a viable treatment for sleep apnea in CM-1 patients. Improvement relative to ENT surgical intervention was also considered. METHODS: We identified 75 patients who underwent polysomnography (PSG) from our database of 465 CM-1 patients. Sleep apnea diagnosis was based on the sleep physician's overall interpretation of the PSG. Symptomatology pre- and post-surgery was analyzed. RESULTS: Of the 75 CM-1 patients that underwent PSG, 23 were diagnosed with sleep apnea. Sixteen had OSA, 6 had CSA, and 1 had mixed apnea. Twelve OSA patients received ENT intervention. Eight improved and 2 further improved after Chiari decompression. Of the 4 patients that did not improve, one of those later improved following Chiari decompression. Of the 6 CSA patients, 2 underwent Chiari decompression, but only one improved. The mixed apnea patient underwent several ENT interventions that did not relieve symptoms but improved following Chiari decompression. DISCUSSION/CONCLUSIONS: Based on our results, sleep apnea in CM-1 patients may be obstructive, central, or mixed and is likely multifactorial. A multidisciplinary approach to the management of these patients is important, including neurosurgery, otolaryngology, and sleep medicine. Future prospective studies will lend further insight into this condition and its management.

Evidence that miR-152-3p is a positive regulator of SETDB1-mediated H3K9 histone methylation and serves as a toggle between histone and DNA methylation.

SETDB1 is a histone methyltransferase that converts H3K9me2 to H3K9me3. SETDB1 activity and H3K9me3 are crucial for the formation of obligately silenced heterochromatin such as that of centromeres. Here we show that a microRNA, miR-152-3p, is involved in the regulation of SETDB1 protein levels, but surprisingly, miR-152-3p plays a positive regulatory role for SETDB1 expression. Inhibition of miR-152-3p by anti-miR treatment resulted in a robust reduction in SETDB1 protein levels, though SETDB1 mRNA levels were unaffected. This was also accompanied by a blockade of the biochemical pathway proceeding from H3K9me2 to H3K9me3 as evidenced by quantitative nucleosome ELISA assays that showed that H3K9me2 accumulates in cells treated with an anti-miR that targets miR-152-3p. In addition, the action of a miR-152-3p mimic increased flux of the reaction leading to H3K9me3. We also performed site-directed mutagenesis of three predicted miR-152-3p target recognition sequences to yield three precise deletions. Deletion of one of the three sites recapitulated the positive regulatory aspect of the action of miR-152-3p upon SETDB1 expression in a luciferase reporter assay. Previous studies have shown that miR-152-3p negatively regulates DNMT1, the sole maintenance DNA methyltransferase which is required for levels of 5-methylcytosine levels within DNA. Our results shown that miR-152-3p positively regulates the production of H3K9me3 by regulating the production of SETDB1. Therefore, our findings provide strong evidence that miR-152-3p can serve as a toggle switch that regulates the balance between DNA methylation and H3K9 histone methylation in constitutive heterochromatin.

Ecological Limits as the Driver of Bird Species Richness Patterns along the East Himalayan Elevational Gradient.

Variation in species richness across environmental gradients results from a combination of historical nonequilibrium processes (time, speciation, extinction) and present-day differences in environmental carrying capacities (i.e., ecological limits affected by species interactions and the abundance and diversity of resources). In a study of bird richness along the subtropical east Himalayan elevational gradient, we test the prediction that species richness patterns are consistent with ecological limits using data on morphology, phylogeny, elevational distribution, and arthropod resources. Species richness peaks at midelevations. Occupied morphological volume is roughly constant from low elevations to midelevations, implying that more species are packed into the same space at midelevations compared with low elevations. However, variance in beak length and differences in beak length between close relatives decline with elevation, which is a consequence of the addition of many small insectivores at midelevations. These patterns are predicted from resource distributions: arthropod size diversity declines from low elevations to midelevations, largely because many more small insects are present at midelevations. Weak correlations of species mean morphological traits with elevation also match predictions based on resources and habitats. Elevational transects in the tropical Andes, New Guinea, and Tanzania similarly show declines in mean arthropod size and mean beak length and, in these cases, likely contribute to declining numbers of insectivorous bird species richness along these gradients. The results imply that conditions for ecological limits are met, although historical nonequilibrium processes are likely to also contribute to the pattern of species richness.

Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer.

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple αKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4α, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury, characterized by HNF-4α silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation. Moreover, IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy.

Impact of Guideline-Discordant Treatment on Cost and Health Care Utilization in Older Adults with Early-Stage Breast Cancer.

BACKGROUND: National Comprehensive Cancer Network (NCCN) guideline-based treatment is a marker of high-quality care. The impact of guideline discordance on cost and health care utilization is unclear. MATERIALS AND METHODS: This retrospective cohort study of Medicare claims data from 2012 to 2015 included women age ≥65 with stage I-III breast cancer receiving care within the University of Alabama at Birmingham Cancer Community Network. Concordance with NCCN guidelines was assessed for treatment regimens. Costs to Medicare and health care utilization were identified from start of cancer treatment until death or available follow-up. Adjusted monthly cost and utilization rates were estimated using linear mixed effect and generalized linear models. RESULTS: Of 1,177 patients, 16% received guideline-discordant treatment, which was associated with nonwhite race, estrogen receptor/progesterone receptor negative, human epidermal growth receptor 2 (HER2) positive, and later-stage cancer. Discordant therapy was primarily related to reduced-intensity treatments (single-agent chemotherapy, HER2-targeted therapy without chemotherapy, bevacizumab without chemotherapy, platinum combinations without anthracyclines). In adjusted models, average monthly costs for guideline-discordant patients were $936 higher compared with concordant (95% confidence limits $611, $1,260). For guideline-discordant patients, adjusted rates of emergency department visits and hospitalizations per thousand observations were 25% higher (49.9 vs. 39.9) and 19% higher (24.0 vs. 20.1) per month than concordant patients, respectively. CONCLUSION: One in six patients with early-stage breast cancer received guideline-discordant care, predominantly related to undertreatment, which was associated with higher costs and rates of health care utilization. Additional randomized trials are needed to test lower-toxicity regimens and guide clinicians in treatment for older breast cancer patients. IMPLICATIONS FOR PRACTICE: Previous studies lack details about types of deviations from chemotherapy guidelines that occur in older early-stage breast cancer patients. Understanding the patterns of guideline discordance and its impact on patient outcomes will be particularly important for these patients. This study found 16% received guideline-discordant care, predominantly related to reduced intensity treatment and associated with higher costs and rates of health care utilization. Increasing older adult participation in clinical trials should be a priority in order to fill the knowledge gap about how to treat older, less fit patients with breast cancer.

Common latitudinal gradients in functional richness and functional evenness across marine and terrestrial systems.

Functional diversity is an important aspect of biodiversity, but its relationship to species diversity in time and space is poorly understood. Here we compare spatial patterns of functional and taxonomic diversity across marine and terrestrial systems to identify commonalities in their respective ecological and evolutionary drivers. We placed species-level ecological traits into comparable multi-dimensional frameworks for two model systems, marine bivalves and terrestrial birds, and used global species-occurrence data to examine the distribution of functional diversity with latitude and longitude. In both systems, tropical faunas show high total functional richness (FR) but low functional evenness (FE) (i.e. the tropics contain a highly skewed distribution of species among functional groups). Functional groups that persist toward the poles become more uniform in species richness, such that FR declines and FE rises with latitude in both systems. Temperate assemblages are more functionally even than tropical assemblages subsampled to temperate levels of species richness, suggesting that high species richness in the tropics reflects a high degree of ecological specialization within a few functional groups and/or factors that favour high recent speciation or reduced extinction rates in those groups.

A confinement induced spectroscopic study of noble gas atoms using equation of motion architecture: Encapsulation within fullerene's voids.

A relativistic study of spectroscopic properties of the endohedral fullerenes Ng@C60q (where Ng = He, Ne and q=0,±1,±2 are the charges) associated with the C60 molecule has been done using the equation of motion coupled cluster (EOM-CC) methodology. Specific properties estimated are the transition energies, dipole oscillator strengths, and transition probabilities for the low-lying excitations 1s2(1S0) → 1snp (1P1) (n = 2, 3, 4) for He@C60q and 1s22s22p6 (1S0) → 1s22s22p5ns∕nd (1P1) (n = 3, 4) for Ne@C60q, which have been compared with those for the isolated atom to depict the confinement effect of the host molecule on the encapsulated atom. This is accomplished by introducing an effective potential to the atomic Hamiltonian induced by the fullerene moiety and its charge. The EOM-CC results have been compared with those estimated with the random phase approximation (and configuration interaction singles) to understand the effect of electron correlation under such confinement. The systematic and interesting behavior of the properties is highlighted indicating the effect of fullerene cage potential on the redistribution of electron density of the guest atom.

Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise.

BACKGROUND: Challenges in the diagnosis and classification of cholangiocarcinoma have made it difficult to quantify the true incidence of this highly aggressive malignancy. METHODS: We analyzed the Surveillance, Epidemiology, and End Results data to assess long-term trends in the age-standardized incidence of intrahepatic and extrahepatic cholangiocarcinoma between 1973 and 2012, correcting for systematic coding errors. Because intrahepatic cholangiocarcinoma (ICC) may frequently be misdiagnosed as cancer of unknown primary (CUP), we also analyzed trends in the incidence of CUP. RESULTS: Between 1973 and 2012, the reported U.S. incidence of ICC increased from 0.44 to 1.18 cases per 100,000, representing an annual percentage change (APC) of 2.30%; this trend has accelerated during the past decade to an APC of 4.36%. The incidence of extrahepatic cholangiocarcinoma increased modestly from 0.95 to 1.02 per 100,000 during the 40-year period (APC, 0.14%). The incidence of CUP with histologic features potentially consistent with cholangiocarcinoma decreased by 51% between 1973 and 2012 (APC, -1.87%), whereas the incidence of CUP with squamous or nonepithelial histologic features increased modestly (APC, 0.42%). CONCLUSION: The recognized incidence of ICC in the U.S. continues to rise, whereas the incidence of ECC is stable. The incidence of CUP has fallen dramatically during the same time period. IMPLICATIONS FOR PRACTICE: Clinical distinctions between cholangiocarcinoma (particularly intrahepatic cholangiocarcinoma [ICC]) and cancer of unknown primary (CUP) can be challenging. Recent discoveries have identified recurrent and potentially targetable genomic abnormalities in ICC, highlighting the importance of improving diagnosis. This study demonstrates that the incidence of ICC is increasing in the U.S., whereas the incidence of extrahepatic cholangiocarcinoma is stable. Concomitantly, the incidence of CUP has declined dramatically, suggesting that improved distinction between ICC and CUP may be a major driver of the increasing recognized incidence of ICC. The increasing incidence of ICC warrants further study of prevention and treatment approaches.

Unifying latitudinal gradients in range size and richness across marine and terrestrial systems.

Many marine and terrestrial clades show similar latitudinal gradients in species richness, but opposite gradients in range size-on land, ranges are the smallest in the tropics, whereas in the sea, ranges are the largest in the tropics. Therefore, richness gradients in marine and terrestrial systems do not arise from a shared latitudinal arrangement of species range sizes. Comparing terrestrial birds and marine bivalves, we find that gradients in range size are concordant at the level of genera. Here, both groups show a nested pattern in which narrow-ranging genera are confined to the tropics and broad-ranging genera extend across much of the gradient. We find that (i) genus range size and its variation with latitude is closely associated with per-genus species richness and (ii) broad-ranging genera contain more species both within and outside of the tropics when compared with tropical- or temperate-only genera. Within-genus species diversification thus promotes genus expansion to novel latitudes. Despite underlying differences in the species range-size gradients, species-rich genera are more likely to produce a descendant that extends its range relative to the ancestor's range. These results unify species richness gradients with those of genera, implying that birds and bivalves share similar latitudinal dynamics in net species diversification.

Early diversification of sperm size in the evolutionary history of the old world leaf warblers (Phylloscopidae).

Sperm morphological traits are highly variable among species and are commonly thought to evolve by post-copulatory sexual selection. However, little is known about the evolutionary dynamics of sperm morphology, and whether rates of evolutionary change are variable over time and among taxonomic groups. Here, we examine sperm morphology from 21 species of Old World leaf warblers (Phylloscopidae), a group of generally dull, sexually monochromatic birds, which are known to have high levels of extra-pair paternity. We found that sperm length differs markedly across species, spanning about 40% of the range observed across a larger selection of passerine birds. Furthermore, we found strong support for an 'early-burst' model of trait evolution, implying that the majority of divergence in sperm length has occurred early in the evolutionary history of this clade with subsequent evolutionary stasis. This large early divergence matches the early divergence reported in ecological traits (i.e. body size and feeding behaviour). Our findings demonstrate that rates of evolution in sperm morphology can change over time in passerine taxa, and that evolutionary stasis in sperm traits can occur even in species exhibiting characteristics consistent with moderate-to-high levels of sperm competition. It remains a major challenge to identify the selection mechanisms and possible constraints responsible for these variable rates of sperm evolution.

Prognosis and Clinicopathologic Features of Patients With Advanced Stage Isocitrate Dehydrogenase (IDH) Mutant and IDH Wild-Type Intrahepatic Cholangiocarcinoma.

BACKGROUND: Conflicting data exist regarding the prognostic impact of the isocitrate dehydrogenase (IDH) mutation in intrahepatic cholangiocarcinoma (ICC), and limited data exist in patients with advanced-stage disease. Similarly, the clinical phenotype of patients with advanced IDH mutant (IDHm) ICC has not been characterized. In this study, we report the correlation of IDH mutation status with prognosis and clinicopathologic features in patients with advanced ICC. METHODS: Patients with histologically confirmed advanced ICC who underwent tumor mutational profiling as a routine part of their care between 2009 and 2014 were evaluated. Clinical and pathological data were collected by retrospective chart review for patients with IDHm versus IDH wild-type (IDHwt) ICC. Pretreatment tumor volume was calculated on computed tomography or magnetic resonance imaging. RESULTS: Of the 104 patients with ICC who were evaluated, 30 (28.8%) had an IDH mutation (25.0% IDH1, 3.8% IDH2). The median overall survival did not differ significantly between IDHm and IDHwt patients (15.0 vs. 20.1 months, respectively; p = .17). The pretreatment serum carbohydrate antigen 19-9 (CA19-9) level in IDHm and IDHwt patients was 34.5 and 118.0 U/mL, respectively (p = .04). Age at diagnosis, sex, histologic grade, and pattern of metastasis did not differ significantly by IDH mutation status. CONCLUSION: The IDH mutation was not associated with prognosis in patients with advanced ICC. The clinical phenotypes of advanced IDHm and IDHwt ICC were similar, but patients with IDHm ICC had a lower median serum CA19-9 level at presentation. IMPLICATIONS FOR PRACTICE: Previous studies assessing the prognostic impact of the isocitrate dehydrogenase (IDH) gene mutation in intrahepatic cholangiocarcinoma (ICC) mainly focused on patients with early-stage disease who have undergone resection. These studies offer conflicting results. The target population for clinical trials of IDH inhibitors is patients with unresectable or metastatic disease, and the current study is the first to focus on the prognosis and clinical phenotype of this population and reports on the largest cohort of patients with advanced IDH mutant ICC to date. The finding that the IDH mutation lacks prognostic significance in advanced ICC is preliminary and needs to be confirmed prospectively in a larger study.

CYP11A1 microsatellite (tttta)n polymorphism in PCOS women from South India.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a condition with central feature of hyperandrogensism that affects 5-12 % of women worldwide. P450sec the cholesterol side chain cleavage enzyme encoded by CYP11A1 gene is instrumental in the synthesis of sex hormones. A promoter pentanucleotide repeat (tttta)(n) polymorphism of this gene is reported to be associated with several hormone related diseases including PCOS. Here we aimed to examine the involvement of CYP11A1 polymorphism with PCOS susceptibility in a case-control study conducted among South Indian women. METHODS: A total of 542 subjects comprised of 267 PCOS patients and 275 controls were recruited. DNA was extracted from blood and CYP11A1 (tttta)(n) polymorphism was genotyped by PCR-PAGE. RESULTS: Fifteen different alleles ranging between 2-16 repeats were identified in the studied group and the most frequent allele observed in controls was of 8 repeats. The presence of >8 repeat allele was common in patients (64 % vs. 38 %) and showed a three-fold risk for PCOS susceptibility than controls (OR = 2.93; p < 0.05). PCOS women with higher BMI were markedly elevated in early quartile (p < 0.05). CONCLUSION: CYP11A1 (tttta)(n) repeat polymorphism appeared to be a potential molecular marker for PCOS risk in our population. Gene-gene and gene-environmental interactions with respect to obesity may play a role in the early onset of this multifactorial condition. This is the first report from South India; however, replicative studies considering other probable causative factors for PCOS risk are warranted.

Optional Exam Retakes Reduce Anxiety but may Exacerbate Score Disparities Between Students with Different Social Identities.

Use of high-stakes exams in a course has been associated with gender, racial, and socioeconomic inequities. We investigated whether offering students the opportunity to retake an exam makes high-stakes exams more equitable. Following the control value theory of achievement emotions, we hypothesized that exam retakes would increase students' perceived control over their performance and decrease the value of a single exam attempt, thereby maximizing exam performance. We collected data on exam scores and experiences with retakes from three large introductory biology courses and assessed the effect of optional exam retakes on gender, racial/ethnic, and socioeconomic disparities in exam scores. We found that Black/African American students and those who worked more than 20 h a week were less likely to retake exams. While exam retakes significantly improved student scores, they slightly increased racial/ethnic and socioeconomic disparities in scores partly because of these differences in participation rates. Most students reported that retake opportunities reduced their anxiety on the initial exam attempt. Together our results suggest that optional exam retakes could be a useful tool to improve student performance and reduce anxiety associated with high-stakes exams. However, barriers to participation must be examined and reduced for retakes to reduce disparities in scores.

SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy that frequently exhibits isocitrate dehydrogenase (IDH1/IDH2) mutations. Mutant IDH (IDHm) ICC is dependent on SRC kinase for growth and survival and is hypersensitive to inhibition by dasatinib, but the molecular mechanism underlying this sensitivity is unclear. We found that dasatinib reduced p70 S6 kinase (S6K) and ribosomal protein S6 (S6), leading to substantial reductions in cell size and de novo protein synthesis. Using an unbiased phosphoproteomic screen, we identified membrane-associated guanylate kinase, WW, and PDZ domain containing 1 (MAGI1) as an SRC substrate in IDHm ICC. Biochemical and functional assays further showed that SRC inhibits a latent tumor-suppressing function of the MAGI1-protein phosphatase 2A (PP2A) complex to activate S6K/S6 signaling in IDHm ICC. Inhibiting SRC led to activation and increased access of PP2A to dephosphorylate S6K, resulting in cell death. Evidence from patient tissue and cell line models revealed that both intrinsic and extrinsic resistance to dasatinib is due to increased phospho-S6 (pS6). To block pS6, we paired dasatinib with the S6K/AKT inhibitor M2698, which led to a marked reduction in pS6 in IDHm ICC cell lines and patient-derived organoids in vitro and substantial growth inhibition in ICC patient-derived xenografts in vivo. Together, these results elucidated the mechanism of action of dasatinib in IDHm ICC, revealed a signaling complex regulating S6K phosphorylation independent of mTOR, suggested markers for dasatinib sensitivity, and described a combination therapy for IDHm ICC that may be actionable in the clinic.

Deciphering the Effect of Microstructural Modification in Sodium Alginate-Based Solid Polymer Electrolyte by Unlike Anions.

Microstructure modification in sodium alginate (NaAlg)-based solid polymer electrolytes by the perchlorate (ClO4-) and acetate (CH3COO-) anions of sodium salts has been reported. ClO4- participates in the structure-breaking effect via inter/intramolecular hydrogen bond breaking, while CH3COO- changes the amorphous phase, as evident from X-ray diffraction studies. The larger size and negative charge delocalization of ClO4- have a plasticizing effect, resulting in a lower glass transition temperature (Tg) compared to CH3COO-. Decomposition temperature is strongly dependent on the type of anion. Scanning electron microscopy images showed divergent modifications in the surface morphology in both electrolyte systems, with variations in salt content. The mechanical properties of the NaAlg-NaClO4 electrolyte systems are better than those of the NaAlg-CH3 COONa system, indicating weak interactions in the latter. Although most of the studies focus on the cation influence on conductivity, the interaction of the anion and its size certainly have an influence on the properties of solid polymer electrolytes, which will be of interest in the near future for sodium ion-based electrolytes in energy storage devices.