A Metascientific Review of the Evidential Value of Acceptance and Commitment Therapy for Depression.

In the past three-and-a-half decades, nearly 500 randomized controlled trials (RCTs) have examined Acceptance and Commitment Therapy (ACT) for a range of health problems, including depression. However, emerging concerns regarding the replicability of scientific findings across psychology and mental health treatment outcome research highlight a need to re-examine the strength of evidence for treatment efficacy. Therefore, we conducted a metascientific review of the evidential value of ACT in treating depression. Whereas reporting accuracy was generally high across all trials, we found important differences in evidential value metrics corresponding to the types of control conditions used. RCTs of ACT compared to weaker controls (e.g., no treatment, waitlist) were well-powered, with sample sizes appropriate for detecting plausible effect sizes. They typically yielded stronger Bayesian evidence for (and larger posterior estimates of) ACT efficacy, though there was some evidence of significance inflation among these effects. RCTs of ACT against stronger controls (e.g., other psychotherapies), meanwhile, were poorly powered, designed to detect implausibly large effect sizes, and yielded ambiguous-if not contradicting-Bayesian evidence and estimates of efficacy. Although our review supports a view of ACT as efficacious for treating depression compared to weaker controls, future RCTs must provide more transparent reporting with larger groups of participants to properly assess the difference between ACT and competitor treatments such as behavioral activation and other forms of cognitive behavioral therapy. Clinicians and health organizations should reassess the use of ACT for depression if costs and resources are higher than for other efficacious treatments. Clinical trials contributing effects to our synthesis can be found at https://osf.io/qky35.

Accuracy of Continuous Glucose Monitors for Inpatient Diabetes Management.

INTRODUCTION: In hospitalized patients, continuous glucose monitoring (CGM) may improve glycemic control, prevent hypoglycemic events, and reduce staff workload compared with point-of-care (POC) capillary glucose monitoring. METHODS: To evaluate CGM accuracy and safety of use in the inpatient setting, two versions of CGM sensors were placed on 43 and 34 adult patients with diabetes admitted to non-intensive care unit (ICU) medical wards, respectively. CGM accuracy relative to POC and safety of use were measured by calculating mean absolute relative difference (MARD) and by Clarke Error Grid (CEG) analysis. RESULTS: CGM version 2 had improved accuracy compared with CGM version 1 with MARD 17.7 compared with 21.4%. CGM accuracy did not change with POC value or with time of sensor wear. On CEG, 98.8% of paired values fell within acceptable zones A and B. CONCLUSION: Despite reduced accuracy compared with the outpatient setting, both versions of CGMs had acceptable safety profiles in the inpatient setting.

The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect.

Aerobic glycolysis in cancer cells, also known as the 'Warburg effect', is driven by hyperactivity of lactate dehydrogenase A (LDHA). LDHA is thought to be a substrate-regulated enzyme, but it is unclear whether a dedicated intracellular protein also regulates its activity. Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. A flexible loop within the amino terminus of FLCN controls movement of the LDHA active-site loop, tightly regulating its enzyme activity and, consequently, metabolic homeostasis in normal cells. Cancer cells that experience the Warburg effect show FLCN dissociation from LDHA. Treatment of these cells with a decapeptide derived from the FLCN loop region causes cell death. Our data suggest that the glycolytic shift of cancer cells is the result of FLCN inactivation or dissociation from LDHA. Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.

Mutation of the co-chaperone Tsc1 in bladder cancer diminishes Hsp90 acetylation and reduces drug sensitivity and selectivity.

The molecular chaperone Heat shock protein 90 (Hsp90) is essential for the folding, stability, and activity of several drivers of oncogenesis. Hsp90 inhibitors are currently under clinical evaluation for cancer treatment, however their efficacy is limited by lack of biomarkers to optimize patient selection. We have recently identified the tumor suppressor tuberous sclerosis complex 1 (Tsc1) as a new co-chaperone of Hsp90 that affects Hsp90 binding to its inhibitors. Highly variable mutations of TSC1 have been previously identified in bladder cancer and correlate with sensitivity to the Hsp90 inhibitors. Here we showed loss of TSC1 leads to hypoacetylation of Hsp90-K407/K419 and subsequent decreased binding to the Hsp90 inhibitor ganetespib. Pharmacologic inhibition of histone deacetylases (HDACs) restores acetylation of Hsp90 and sensitizes Tsc1-mutant bladder cancer cells to ganetespib, resulting in apoptosis. Our findings suggest that TSC1 status may predict response to Hsp90 inhibitors in patients with bladder cancer, and co-targeting HDACs can sensitize tumors with Tsc1 mutations to Hsp90 inhibitors.

Co-chaperones TIMP2 and AHA1 Competitively Regulate Extracellular HSP90:Client MMP2 Activity and Matrix Proteolysis.

The extracellular molecular chaperone heat shock protein 90 (eHSP90) stabilizes protease client the matrix metalloproteinase 2 (MMP2), leading to tumor cell invasion. Although co-chaperones are critical modulators of intracellular HSP90:client function, how the eHSP90:MMP2 complex is regulated remains speculative. Here, we report that the tissue inhibitor of metalloproteinases-2 (TIMP2) is a stress-inducible extracellular co-chaperone that binds to eHSP90, increases eHSP90 binding to ATP, and inhibits its ATPase activity. In addition to disrupting the eHSP90:MMP2 complex and terminally inactivating MMP2, TIMP2 loads the client to eHSP90, keeping the protease in a transient inhibitory state. Secreted activating co-chaperone AHA1 displaces TIMP2 from the complex, providing a "reactivating" mechanism for MMP2. Gene knockout or blocking antibodies targeting TIMP2 and AHA1 released by HT1080 cancer cells modify their gelatinolytic activity. Our data suggest that TIMP2 and AHA1 co-chaperones function as a molecular switch that determines the inhibition and reactivation of the eHSP90 client protein MMP2.

Evaluating the evidential value of empirically supported psychological treatments (ESTs): A meta-scientific review.

Empirically supported treatments (or therapies; ESTs) are the gold standard in therapeutic interventions for psychopathology. Based on a set of methodological and statistical criteria, the APA has assigned particular treatment-diagnosis combinations EST status and has further rated their empirical support as Strong, Modest, and/or Controversial. Emerging concerns about the replicability of research findings in clinical psychology highlight the need to critically examine the evidential value of EST research. We therefore conducted a metascientific review of the EST literature, using clinical trials reported in an existing online APA database of ESTs, and a set of novel evidential value metrics (i.e., rates of misreported statistics, statistical power, R-Index, and Bayes Factors). Our analyses indicated that power and replicability estimates were concerningly low across almost all ESTs, and individually, some ESTs scored poorly across multiple metrics, with Strong ESTs failing to continuously outperform their Modest counterparts. Lastly, we found evidence of improvements over time in statistical power within the EST literature, but not for the strength of evidence of EST efficacy. We describe the implications of our findings for practicing psychotherapists and offer recommendations for improving the evidential value of EST research moving forward. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Post-translational Regulation of FNIP1 Creates a Rheostat for the Molecular Chaperone Hsp90.

The molecular chaperone Hsp90 stabilizes and activates client proteins. Co-chaperones and post-translational modifications tightly regulate Hsp90 function and consequently lead to activation of clients. However, it is unclear whether this process occurs abruptly or gradually in the cellular context. We show that casein kinase-2 phosphorylation of the co-chaperone folliculin-interacting protein 1 (FNIP1) on priming serine-938 and subsequent relay phosphorylation on serine-939, 941, 946, and 948 promotes its gradual interaction with Hsp90. This leads to incremental inhibition of Hsp90 ATPase activity and gradual activation of both kinase and non-kinase clients. We further demonstrate that serine/threonine protein phosphatase 5 (PP5) dephosphorylates FNIP1, allowing the addition of O-GlcNAc (O-linked N-acetylglucosamine) to the priming serine-938. This process antagonizes phosphorylation of FNIP1, preventing its interaction with Hsp90, and consequently promotes FNIP1 lysine-1119 ubiquitination and proteasomal degradation. These findings provide a mechanism for gradual activation of the client proteins through intricate crosstalk of post-translational modifications of the co-chaperone FNIP1.

Extracellular Phosphorylation of TIMP-2 by Secreted c-Src Tyrosine Kinase Controls MMP-2 Activity.

The tissue inhibitor of metalloproteinases 2 (TIMP-2) is a specific endogenous inhibitor of matrix metalloproteinase 2 (MMP-2), which is a key enzyme that degrades the extracellular matrix and promotes tumor cell invasion. Although the TIMP-2:MMP-2 complex controls proteolysis, the signaling mechanism by which the two proteins associate in the extracellular space remains unidentified. Here we report that TIMP-2 is phosphorylated outside the cell by secreted c-Src tyrosine kinase. As a consequence, phosphorylation at Y90 significantly enhances TIMP-2 potency as an MMP-2 inhibitor and weakens the catalytic action of the active enzyme. TIMP-2 phosphorylation also appears to be essential for its interaction with the latent enzyme proMMP-2 in vivo. Absence of the kinase or non-phosphorylatable Y90 abolishes TIMP-2 binding to the latent enzyme, ultimately hampering proMMP-2 activation. Together, TIMP-2 phosphorylation by secreted c-Src represents a critical extracellular regulatory mechanism that controls the proteolytic function of MMP-2.

Diffuse Gastric Ganglioneuromatosis: Novel Presentation of PTEN Hamartoma Syndrome-Case Report and Review of Gastric Ganglioneuromatous Proliferations and a Novel PTEN Gene Mutation.

Gastrointestinal ganglioneuromatous proliferations are rare, most often found in the colon, and are three types: polypoid ganglioneuromas, ganglioneuromatous polyposis, and diffuse ganglioneuromatosis. We present a case of diffuse ganglioneuromatosis in the posterior gastric wall in a nine-year-old female. To our knowledge, this is the first reported case of diffuse ganglioneuromatosis located in the stomach. Only six cases of gastric ganglioneuromatous proliferations have previously been reported, two in English and none were diffuse ganglioneuromatosis. A diagnosis of diffuse ganglioneuromatosis is relevant for patient care because, unlike sporadic polypoid ganglioneuromas or ganglioneuromatous polyposis, most are syndromic. Diffuse ganglioneuromatosis is commonly associated with neurofibromatosis type 1, multiple endocrine neoplasia type 2b, and Cowden Syndrome, one of the phenotypes of PTEN hamartoma tumor syndrome. The patient had the noted gastric diffuse ganglioneuromatosis, as well as other major and minor criteria for Cowden syndrome. Genetic testing revealed a novel frameshift mutation in the PTEN gene in the patient, her father, paternal aunt, and the aunt's son who is a paternal first cousin of the patient.

Detection and Analysis of Extracellular Hsp90 (eHsp90).

Heat Shock Protein 90 (Hsp90) is a ubiquitous molecular chaperone that comprises about 1-3% of the total cellular protein. Over the last decade, Hsp90 has been detected and studied in the extracellular space (extracellular or eHsp90) of normal and neoplastic cells. Once outside the cell, eHsp90 has been shown to interact with extracellular client proteins and promote their stabilization and function. Cell conditioned media are routinely collected to detect and quantify eHsp90, and determine its interactions with extracellular clients. Finally, targeting specifically the eHsp90 with pharmacologic inhibitors or antibodies that are unable to cross the plasma membrane has been beneficial in inhibiting tumor cell motility and invasion.

Phosphorylation and Ubiquitination Regulate Protein Phosphatase 5 Activity and Its Prosurvival Role in Kidney Cancer.

The serine/threonine protein phosphatase 5 (PP5) regulates multiple cellular signaling networks. A number of cellular factors, including heat shock protein 90 (Hsp90), promote the activation of PP5. However, it is unclear whether post-translational modifications also influence PP5 phosphatase activity. Here, we show an "on/off switch" mechanism for PP5 regulation. The casein kinase 1δ (CK1δ) phosphorylates T362 in the catalytic domain of PP5, which activates and enhances phosphatase activity independent of Hsp90. Overexpression of the phosphomimetic T362E-PP5 mutant hyper-dephosphorylates substrates such as the co-chaperone Cdc37 and glucocorticoid receptor in cells. Our proteomic approach revealed that the tumor suppressor von Hippel-Lindau protein (VHL) interacts with and ubiquitinates K185/K199-PP5 for proteasomal degradation in a hypoxia- and prolyl-hydroxylation-independent manner. Finally, VHL-deficient clear cell renal cell carcinoma (ccRCC) cell lines and patient tumors exhibit elevated PP5 levels. Downregulation of PP5 causes ccRCC cells to undergo apoptosis, suggesting a prosurvival role for PP5 in kidney cancer.

Can a Simulation Game Change Cystic Fibrosis Patients' Attitudes Toward Treatment Adherence?

OBJECTIVE: The authors hypothesized that playing a simulation game designed according to Multiple Identification Theory (MIT) would improve attitudes toward treatment adherence among adolescent cystic fibrosis (CF) patients. SUBJECTS AND METHODS: Study participants (n=16) were recruited from a large Midwestern children's hospital. As part of a within-group pilot study, they played "My Life with CF," an MIT simulation game. Their attitudes toward treatment adherence and general decision-making were assessed prior to playing the game. They were measured again immediately post-play and 1 month afterward. RESULTS: Statistically significant differences (P<0.05) were found immediately post-treatment on questionnaires concerning participants' holding present versus future-centered orientations and their attitudes toward adherence. One month post-treatment, significant differences were found regarding participants' attitudes toward adherence and whether luck or effort determines what happens to them in life. Effect sizes for all these differences ranged from large (r(2)=0.31) to very large (r(2)=0.94). CONCLUSION: The MIT-based "My Life with CF" game was effective at changing adolescent CF patients' attitudes toward adherence.