Background
Professionals need adequate tools to help patients with diabetes and depression. Although web programs integrating cognitive-behavioral therapy with diabetes education have shown good ...results, no similar approach has been performed as yet in Spain. The objective is to develop an Internet-based program for the treatment of mild-moderate depressive symptomatology in individuals with type 1 diabetes (WEB_TDDI1 study) based on Cognitive-behavioral therapy (CBT) and assess its results.
Methods
A 2-arm randomized controlled trial will be conducted. Adults with type 1 diabetes and mild-moderate depressive symptoms will be screened to participate in the study and randomly assigned to either the treatment group (TG) that will use a Web-based application for a specific 9-week intervention in depression and type 1 diabetes or the control group (CG) that will be on the waiting list during that time.
Results
Data on the primary variable (depressive symptoms) and secondary variables (treatment-related distress, anxiety, fear of hypoglycemia, quality of life, treatment adherence, coping strategies and glycemic control) will be collected from the TG at the beginning/baseline, at the end of treatment and at 3, 6 and 12 months after treatment. The CG will be assessed at the beginning and at the end of the TG intervention. On completion of the program by the TG, the treatment will then be carried out in the CG.
Conclusions
The new web application developed is expected to be effective for the treatment of mild-moderate depressive symptoms in adults with type 1 diabetes, reducing depressive symptoms and improving the rest of the analyzed variables.
Trial registration
Registry:
NCT03473704
(March 21, 2018); ClinicalTrials.gov.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Activation of the phosphoinositide 3-kinase (PI3K) pathway occurs frequently in breast cancer. However, clinical results of single-agent PI3K inhibitors have been modest to date. A combinatorial drug ...screen on multiple PIK3CA mutant cancers with decreased sensitivity to PI3K inhibitors revealed that combined CDK 4/6-PI3K inhibition synergistically reduces cell viability. Laboratory studies revealed that sensitive cancers suppress RB phosphorylation upon treatment with single-agent PI3K inhibitors but cancers with reduced sensitivity fail to do so. Similarly, patients’ tumors that responded to the PI3K inhibitor BYL719 demonstrated suppression of pRB, while nonresponding tumors showed sustained or increased levels of pRB. Importantly, the combination of PI3K and CDK 4/6 inhibitors overcomes intrinsic and adaptive resistance leading to tumor regressions in PIK3CA mutant xenografts.
•Synergy exists between inhibitions of CDK 4/6 and PI3K in PIK3CA mutant breast cancer.•CDK 4/6-PI3K inhibition is effective in several PIK3CA mutant xenograft tumor models.•Failure to suppress pRB correlates with resistance to PI3K inhibitors in patients.
PI3K inhibitors have only modest clinical efficacy in breast cancers with an aberrantly activated PI3K pathway. Vora et al. show that inhibiting CDK 4/6 overcomes intrinsic and adaptive resistance to PI3K inhibitors in these tumors and that reduction of phosphorylated RB is a good biomarker for the response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Localized angiopoietin-2 (Ang2) expression has been shown to function as a key regulator of blood vessel remodeling and tumor
angiogenesis, making it an attractive candidate for antiangiogenic ...therapy. A fully human monoclonal antibody (3.19.3) was
developed, which may have significant pharmaceutical advantages over synthetic peptide-based approaches in terms of reduced
immunogenicity and increased half-life to block Ang2 function. The 3.19.3 antibody potently binds Ang2 with an equilibrium
dissociation constant of 86 pmol/L, leading to inhibition of Tie2 receptor phosphorylation in cell-based assays. In preclinical
models, 3.19.3 treatment blocked blood vessel formation in Matrigel plug assays and in human tumor xenografts. In vivo studies with 3.19.3 consistently showed broad antitumor activity as a single agent across a panel of diverse subcutaneous
and orthotopic xenograft models. Combination studies of 3.19.3 with cytotoxic drugs or anti–vascular endothelial growth factor
agents showed significant improvements in antitumor activity over single-agent treatments alone with no apparent evidence
of increased toxicity. Initial pharmacokinetic profiling studies in mice and nonhuman primates suggested that 3.19.3 has a
predicted human half-life of 10 to 14 days. These studies provide preclinical data for 3.19.3 as a potential new antiangiogenic
therapy as a single agent or in combination with chemotherapy or vascular endothelial growth factor inhibitors for the treatment
of cancer. Mol Cancer Ther; 9(1); 145–56
The mammalian target of rapamycin (mTOR) is regulated by oncogenic growth factor signals and plays a pivotal role in controlling cellular metabolism, growth and survival. Everolimus (RAD001) is an ...allosteric mTOR inhibitor that has shown marked efficacy in certain cancers but is unable to completely inhibit mTOR activity. ATP-competitive mTOR inhibitors such as NVP-BEZ235 can block rapamycin-insensitive mTOR readouts and have entered clinical development as anti-cancer agents. Here, we show the degree to which RAD001 and BEZ235 can be synergistically combined to inhibit mTOR pathway activation, cell proliferation and tumor growth, both in vitro and in vivo. RAD001 and BEZ235 synergized in cancer lines representing different lineages and genetic backgrounds. Strong synergy is seen in neuronal, renal, breast, lung, and haematopoietic cancer cells harboring abnormalities in PTEN, VHL, LKB1, Her2, or KRAS. Critically, in the presence of RAD001, the mTOR-4EBP1 pathway and tumorigenesis can be fully inhibited using lower doses of BEZ235. This is relevant since RAD001 is relatively well tolerated in patients while the toxicity profiles of ATP-competitive mTOR inhibitors are currently unknown.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed ...cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations.
Glycosylphosphatidylinositol (GPI) anchor protein modification in Plasmodium species is well known and represents the principal form of glycosylation in these organisms. The structure and ...biosynthesis of GPI anchors of Plasmodium spp. has been primarily studied in the asexual blood stage of P. falciparum and is known to contain the typical conserved GPI structure of EtN-P-Man3GlcN-PI. Here, we have investigated the circumsporozoite protein (CSP) for the presence of a GPI-anchor. CSP is the major surface protein of Plasmodium sporozoites, the infective stage of the malaria parasite. While it is widely assumed that CSP is a GPI-anchored cell surface protein, compelling biochemical evidence for this supposition is absent. Here, we employed metabolic labeling and mass-spectrometry based approaches to confirm the presence of a GPI anchor in CSP. Biosynthetic radiolabeling of CSP with 3H-palmitic acid and 3H-ethanolamine, with the former being base-labile and therefore ester-linked, provided strong evidence for the presence of a GPI anchor on CSP, but these data alone were not definitive. To provide further evidence, immunoprecipitated CSP was analyzed for presence of myo-inositol (a characteristic component of GPI anchor) using strong acid hydrolysis and GC-MS for a highly sensitive and quantitative detection. The single ion monitoring (SIM) method for GC-MS analysis confirmed the presence of the myo-inositol component in CSP. Taken together, these data provide confidence that the long-assumed presence of a GPI anchor on this important parasite protein is correct.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
Depression in people with diabetes is associated with poorer health outcomes. Although web programs integrating cognitive-behavioral therapy with diabetes education have shown good results, ...no similar approach has been implemented in Spain. This aim of this study was to administer an Internet-based cognitive-behavioral therapy program (CBT) for the treatment of mild-moderate depressive symptomatology in individuals with type 1 diabetes (WEB_TDDI1 study) and evaluate the efficacy of this program.
Research design and methods
A pre-post randomized controlled study was conducted. The sample comprised 65 people with type 1 diabetes and mild-moderate depressive symptoms: 35 treatment group (TG) and 30 control group (CG). The following effects of the nine-session program were analyzed: depression (Beck Depression Inventory Fast Screen, BDI-FS), metabolic variables (glycosilated hemoglobin, HbA1c), and other psychological variables including anxiety (State Trait Anxiety Inventory, STAI), fear of hypoglycemia (Fear of Hypoglycemia Questionnaire, FH-15), distress (Diabetes Distress Questionnaire (DDS), quality of life (Diabetes Quality of Life Questionnaire, DQOL),and treatment adherence (Diabetes Self-Care Inventory-Revised questionnaire, SCI-R).
Results
At the end of the treatment program, only 28 people were evaluated (TG=8; CG=20). However, a significant reduction was found in both groups in BDI-FS and STAI-T scores, which was significantly greater in the TG. Significant improvements were also found in the TG in DQOL, FH-15, DDS and SCI-R scores. The percentage change in these variables was also statistically significant in the TG versus the CG. However, no significant results were found in HbA1c.
Conclusions
The Internet-based cognitive-behavioral therapy program for the treatment of mild-moderate depressive symptomatology in people with type 1 diabetes (WEB_TDDI1 study) is effective in reducing depressive symptomatology in the sample that completed the study. Positive results are also produced in other variables associated with depression in this population such as diabetes-related distress, trait anxiety, fear of hypoglycemia, quality of life, and adherence to diabetes treatment. Although new studies would be necessary to support the results of this platform, the results obtained are positive and support the use of this platform as an appropriate treatment for this population.
Clinical trial registration
ClinicalTrials.gov; identifier NCT03473704.
Inhibition of γ-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce the pathogenic β-amyloid (Aβ) peptides, is an attractive approach to the ...treatment of Alzheimer disease. In addition to APP, however, several other γ-secretase substrates have been identified (e.g. Notch), and altered processing of these substrates by γ-secretase inhibitors could lead to unintended biological consequences. To study the in vivo consequences of γ-secretase inhibition, the γ-secretase inhibitor LY-411,575 was administered to C57BL/6 and TgCRND8 APP transgenic mice for 15 days. Although most tissues were unaffected, doses of LY-411,575 that inhibited Aβ production had marked effects on lymphocyte development and on the intestine. LY-411,575 decreased overall thymic cellularity and impaired intrathymic differentiation at the CD4-CD8-CD44+CD25+ precursor stage. No effects on peripheral T cell populations were noted following LY-411,575 treatment, but evidence for the altered maturation of peripheral B cells was observed. In the intestine, LY-411,575 treatment increased goblet cell number and drastically altered tissue morphology. These effects of LY-411,575 were not seen in mice that were administered LY-D, a diastereoisomer of LY-411,575, which is a very weak γ-secretase inhibitor. These studies show that inhibition of γ-secretase has the expected benefit of reducing Aβ in a murine model of Alzheimer disease but has potentially undesirable biological effects as well, most likely because of the inhibition of Notch processing.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The JAK1/2 inhibitor ruxolitinib has demonstrated significant benefits for patients with myeloproliferative neoplasms (MPN). However, patients often lose response to ruxolitinib or suffer disease ...progression despite therapy with ruxolitinib. These observations have prompted efforts to devise treatment strategies to improve therapeutic efficacy in combination with ruxolitinib therapy. Activation of JAK-STAT signaling results in dysregulation of key downstream pathways, notably increased expression of cell-cycle mediators including CDC25A and the PIM kinases.
Given the involvement of cell-cycle mediators in MPNs, we sought to examine the efficacy of therapy combining ruxolitinib with a CDK4/6 inhibitor (LEE011) and a PIM kinase inhibitor (PIM447). We utilized JAK2-mutant cell lines, murine models, and primary MPN patient samples for these studies.
Exposure of JAK2-mutant cell lines to the triple combination of ruxolitinib, LEE011, and PIM447 resulted in expected on-target pharmacodynamic effects, as well as increased apoptosis and a decrease in the proportion of cells in S-phase, compared with ruxolitinib. As compared with ruxolitinib monotherapy, combination therapy led to reductions in spleen and liver size, reduction of bone marrow reticulin fibrosis, improved overall survival, and elimination of disease-initiating capacity of treated bone marrow, in murine models of MPN. Finally, the triple combination reduced colony formation capacity of primary MPN patient samples to a greater extent than ruxolitinib.
The triple combination of ruxolitinib, LEE011, and PIM447 represents a promising therapeutic strategy with the potential to increase therapeutic responses in patients with MPN.
Abstract
The JAK-STAT pathway is an important signaling pathway downstream of multiple cytokine and growth factor receptors. It has been implicated in the pathogenesis of multiple human diseases. The ...genetic aberration of JAK2V617F and the associated activation of STAT in myeloproliferative neoplasia (MPN) is one example of the involvement of this pathway in human cancer. We have shown the combination benefits of combining ruxolitinib (Jak1, 2 inhibitor), with LGH447 (PIM inhibitor) and LEE011 (CDK4/6 inhibitor) in a Ba/F3-JAK2V617F-driven MPN model. This triple combination resulted in ∼99% reduction of total tumor burden and a ∼96% reduction of spleen weight. Furthermore, the triple combination of ruxolitinib, LGH447 and LEE011 reduced JAK2V617F allele burden by > 80%. To translate this combination from preclinical setting to the clinic, it is critical to evaluate dose to efficacy relationship for each agents and scheduling to efficacy correlation for this combination. Here, the preclinical doses for ruxolitinib, LGH447 and LEE011 were determined, based on their clinically achieved exposure. We then examined “intermittent dosing” of this combination in the same preclinical model. Our data suggest that the combination efficacy of ruxolitinib-LGH447-LEE011 is dependent on continuous administration of the agents. Finally, we examined the effect of dose reduction for each of the three agents on the combination efficacy in the Ba/F3-JAK2V617F-driven MPN model. By modifying the doses for ruxolitinib, LGH447 and LEE011 separately in the combination, our study reveals that the triple combination efficacy is most sensitive to LEE011 dose reduction, and it is least sensitive to LGH447 dose reduction. In summary, our studies aim to design novel preclinical approaches to inform and the design of clinical dose escalation in novel combination therapies.
Citation Format: Maria Pinzon-Ortiz, Xianhui Rong, Gary Vanasse, Z. Alexander Cao. Novel translational pharmacology approaches on dose reduction and alternative scheduling for the combination of JAK inhibitor, ruxolitinib, PIM inhibitor, LGH447, and CDK4/6 inhibitor, LEE011 in a preclinical model of myeloproliferative neoplasia. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3489. doi:10.1158/1538-7445.AM2015-3489
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