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The purpose of this review was to investigate the extent to which students with emotional and behavioral disorders (EBD) are adequately represented in and benefiting from college and career readiness (CCR) intervention research across race and gender groups. We conducted a secondary analysis of 14 intervention studies meeting the criteria for a prior systematic literature review examining CCR for U.S. students with and at risk for emotional and behavioral problems. We found that the majority (86%) of studies reported the race and gender of participants and more recent studies were more likely to have included this information. Students with EBD are more likely to be Black and identify as male, while the participants in our study samples were more likely to be White/Caucasian and identify as female. All studies reported gender exclusively within a gender binary. Furthermore, only three studies provided overall school or district demographics, allowing the reader to assess the extent to which the participants were representative of the school/district population. Finally, only two studies parceled out findings by race, making it difficult to assess the overall extent to which interventions for CCR are effective for students across race and gender groups. Given the high priority currently placed on preparing all students for college and career, these findings have important implications for practitioners, researchers, and policymakers. [ABSTRACT FROM AUTHOR]

Ecosystem restoration is a fundamental way of delivering nature‐based solutions to improve resilience in a changing climate and sustain biodiversity. Spatial analyses to identify where ecosystem restoration would yield targeted environmental benefits are critical to inform, and coordinate restoration initiatives at multiple scales to achieve national commitments and global goals. Here, we provide an optimization analysis for restoration potential of converted terrestrial ecosystems in Canada by integrating carbon storage and biodiversity benefits as key considerations. Our results show that converted landscapes are prevalent in southern anthropic regions of Canada, with the greatest potential for biodiversity benefits through forest and grassland restoration. At national scales, carbon density (tonnes C/km2) and total carbon storage (tonnes C) potential were greatest for wetland and forest restoration, respectively. When biodiversity and carbon were both included in an optimization framework, consistent priorities across all three restoration targets (50,000; 100,000; and 150,000 km2) comprised forest restoration in the St. Lawrence and Lake Erie Lowlands, with the Lake Manitoba Plains, Interlake Plains, and Manitoulin‐Lake Simcoe ecoregions also frequently identified. Our analysis will help decision‐makers identify where restoration of converted lands may support considerable gains in simultaneously achieving climate and biodiversity goals in Canada. [ABSTRACT FROM AUTHOR]

Presents the results of a content analysis of articles that were published in the "Journal of Multicultural Counseling and Development" (JMCD) during the last 15 years. The analysis identified the leading contributors (i.e., authors, institutions) to JMCD, evaluated the content of the articles, examined the type of articles, and highlighted the particular cultural groups that were studied most frequently. (GCP)

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Morbidity in advanced prostate cancer patients is largely associated with bone metastatic events. The development of novel therapeutic strategies is imperative in order to effectively treat this incurable stage of the malignancy. In this context, Akt signaling pathway represents a promising therapeutic target able to counteract biochemical recurrence and metastatic progression in prostate cancer. We explored the therapeutic potential of a novel dual PI3 K/mTOR inhibitor, X480, to inhibit tumor growth and bone colonization using different in vivo prostate cancer models including the subcutaneous injection of aggressive and bone metastatic (PC3) and non-bone metastatic (22rv1) cell lines and preclinical models known to generate bone lesions. We observed that X480 both inhibited the primary growth of subcutaneous tumors generated by PC3 and 22rv1 cells and reduced bone spreading of PCb2, a high osteotropic PC3 cell derivative. In metastatic bone, X480 inhibited significantly the growth and osteolytic activity of PC3 cells as observed by intratibial injection model. X480 also increased the bone disease-free survival compared to untreated animals. In vitro experiments demonstrated that X480 was effective in counteracting osteoclastogenesis whereas it stimulated osteoblast activity. Our report provides novel information on the potential activity of PI3 K/Akt inhibitors on the formation and progression of prostate cancer bone metastases and supports a biological rationale for the use of these inhibitors in castrate-resistant prostate cancer patients at high risk of developing clinically evident bone lesions. [ABSTRACT FROM AUTHOR]

Aberrant forms of the anaplastic lymphoma kinase (ALK) have been implicated in the pathogenesis of multiple human cancers, where ALK represents a rational therapeutic target in these settings. In this study, we report the identification and biological characterization of X-376 and X-396, two potent and highly specific ALK small molecule tyrosine kinase inhibitors (TKIs). In Ambit kinome screens, cell growth inhibition studies, and surrogate kinase assays, X-376 and X-396 were more potent inhibitors of ALK but less potent inhibitors of MET compared to PF-02341066 (PF-1066), an ALK/MET dual TKI currently in clinical trials. Both X-376 and X-396 displayed potent antitumor activity with favorable pharmacokinetic and toxicity profiles. Similar levels of in vivo drug sensitivity were displayed by the three most common ALK fusion proteins in lung cancer (EML4-ALK variants E13;A20, E20;A20, and E6b;A20) as well as a KIF5B-ALK fusion protein. Moreover, X-396 could potently inhibit ALK kinases engineered with two point mutations associated with acquired resistance to PF-1066, L1196M, and C1156Y, when engineered into an E13;A20 fusion variant. Finally, X-396 displayed synergistic growth inhibitory activity when combined with the mTOR inhibitor rapamycin. Our findings offer preclinical proof-of-concept for use of these novel agents to improve therapeutic outcomes of patients with mutant ALK-driven malignancies. Cancer Res; 71(14); 4920-31. ©2011 AACR. [ABSTRACT FROM AUTHOR]

Importance: Ensartinib, an oral tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system efficacy for patients with ALK-positive non-small cell lung cancer (NSCLC)., Objective: To compare ensartinib with crizotinib among patients with advanced ALK-positive NSCLC who had not received prior treatment with an ALK inhibitor., Design, Setting, and Participants: This open-label, multicenter, randomized, phase 3 trial conducted in 120 centers in 21 countries enrolled 290 patients between July 25, 2016, and November 12, 2018. Eligible patients were 18 years of age or older and had advanced, recurrent, or metastatic ALK-positive NSCLC., Interventions: Patients were randomized (1:1) to ensartinib, 225 mg once daily, or crizotinib, 250 mg twice daily., Main Outcomes and Measures: The primary end point was blinded independent review committee-assessed progression-free survival (PFS). Secondary end points included systemic and intracranial response, time to central nervous system progression, and overall survival. Efficacy was evaluated in the intent-to-treat (ITT) population as well as a prespecified modified ITT (mITT) population consisting of patients with central laboratory-confirmed ALK-positive NSCLC., Results: A total of 290 patients (149 men [51.4%]; median age, 54 years [range, 25-90 years]) were randomized. In the ITT population, the median PFS was significantly longer with ensartinib than with crizotinib (25.8 [range, 0.03-44.0 months] vs 12.7 months [range, 0.03-38.6 months]; hazard ratio, 0.51 [95% CI, 0.35-0.72]; log-rank P < .001), with a median follow-up of 23.8 months (range, 0-44 months) for the ensartinib group and 20.2 months (range, 0-38 months) for the crizotinib group. In the mITT population, the median PFS in the ensartinib group was not reached, and the median PFS in the crizotinib group was 12.7 months (95% CI, 8.9-16.6 months; hazard ratio, 0.45; 95% CI, 0.30-0.66; log-rank P < .001). The intracranial response rate confirmed by a blinded independent review committee was 63.6% (7 of 11) with ensartinib vs 21.1% (4 of 19) with crizotinib for patients with target brain metastases at baseline. Progression-free survival for patients without brain metastases was not reached with ensartinib vs 16.6 months with crizotinib as a result of a lower central nervous system progression rate (at 12 months: 4.2% with ensartinib vs 23.9% with crizotinib; cause-specific hazard ratio, 0.32; 95% CI, 0.16-0.63; P = .001). Frequencies of treatment-related serious adverse events (ensartinib: 11 [7.7%] vs crizotinib: 9 [6.1%]), dose reductions (ensartinib: 34 of 143 [23.8%] vs crizotinib: 29 of 146 [19.9%]), or drug discontinuations (ensartinib: 13 of 143 [9.1%] vs crizotinib: 10 of 146 [6.8%]) were similar, without any new safety signals., Conclusions and Relevance: In this randomized clinical trial, ensartinib showed superior efficacy to crizotinib in both systemic and intracranial disease. Ensartinib represents a new first-line option for patients with ALK-positive NSCLC., Trial Registration: ClinicalTrials.gov Identifier: NCT02767804.

Objective: This study evaluated the safety and preliminary efficacy of vorolanib, a novel tyrosine kinase inhibitor, for treatment of patients with advanced solid tumors., Methods: During dose escalation, patients received increasing doses of oral vorolanib (50-250 mg once daily) in cycles of four weeks for up to one year. During dose expansion, patients received recommended doses (100 and 200 mg) in 4-week cycles. The primary endpoint was to determine the safety and maximum tolerated dose and/or the recommended phase II dose (RP2D). The severity and type of adverse drug reactions (ADRs) were assessed using the Common Terminology Criteria for Adverse Events version 4.0. The second endpoint was preliminary efficacy in terms of objective response and progression-free survival (PFS)., Results: No dose-limiting toxicity occurred during dose escalation (50-250 mg). Five (26.3%) patients in the escalation cohort (n=19) and 12 (48.0%) in the expansion cohort (n=25) experienced grade 3 ADRs. The most common ADRs were hair color changes, fatigue, portal hypertension, hypertriglyceridemia, and proteinuria. During dose expansion, the patients treated with 200 mg and 100 mg (once daily) showed an objective response rate of 22.2% and 5.9%, respectively; the disease control rate was 88.9% and 73.3%, respectively; the median PFS was 9.9 [95% confidence interval (95% CI): 7.4-not reached] months and 3.8 (95% CI: 1.9-not reached) months, respectively., Conclusions: Oral vorolanib at a dose of 200 mg (once daily) exhibited an acceptable safety profile and favorable clinical benefit for patients with advanced solid tumors. The RP2D for vorolanib was determined to be 200 mg as a daily regimen., (Copyright © 2021 Chinese Journal of Cancer Research. All rights reserved.)

Purpose: Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non-small cell lung cancer (NSCLC). Patients and Methods: In dose escalation, ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK -positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were eligible. Results: Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK -positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60%, and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI-naïve patients was 80%, and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%. Conclusions: Ensartinib was active and generally well tolerated in patients with ALK -positive NSCLC. Clin Cancer Res; 24(12); 2771-9. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Morbidity in advanced prostate cancer patients is largely associated with bone metastatic events. The development of novel therapeutic strategies is imperative in order to effectively treat this incurable stage of the malignancy. In this context, Akt signaling pathway represents a promising therapeutic target able to counteract biochemical recurrence and metastatic progression in prostate cancer. We explored the therapeutic potential of a novel dual PI3 K/mTOR inhibitor, X480, to inhibit tumor growth and bone colonization using different in vivo prostate cancer models including the subcutaneous injection of aggressive and bone metastatic (PC3) and non-bone metastatic (22rv1) cell lines and preclinical models known to generate bone lesions. We observed that X480 both inhibited the primary growth of subcutaneous tumors generated by PC3 and 22rv1 cells and reduced bone spreading of PCb2, a high osteotropic PC3 cell derivative. In metastatic bone, X480 inhibited significantly the growth and osteolytic activity of PC3 cells as observed by intratibial injection model. X480 also increased the bone disease-free survival compared to untreated animals. In vitro experiments demonstrated that X480 was effective in counteracting osteoclastogenesis whereas it stimulated osteoblast activity. Our report provides novel information on the potential activity of PI3 K/Akt inhibitors on the formation and progression of prostate cancer bone metastases and supports a biological rationale for the use of these inhibitors in castrate-resistant prostate cancer patients at high risk of developing clinically evident bone lesions.

Many different aberrations in the Anaplastic Lymphoma Kinase (ALK) were found to be oncogenic drivers in several cancers including neuroblastoma (NB), therefore ALK is now considered a critical player in NB oncogenesis and a promising therapeutic target. The ALK-inhibitor crizotinib has a limited activity against the various ALK mutations identified in NB patients. We tested: the activity of the novel ALK-inhibitor X-396 administered alone or in combination with Targeted Liposomes carrying ALK-siRNAs (TL[ALK-siRNA]) that are active irrespective of ALK gene mutational status; the pharmacokinetic profiles and the biodistribution of X-396; the efficacy of X-396 versus crizotinib treatment in NB xenografts; whether the combination of X-396 with the TL[ALK-siRNA] could promote long-term survival in NB mouse models. X-396 revealed good bioavailability, moderate half-life, high mean plasma and tumor concentrations. X-396 was more effective than crizotinib in inhibiting in vitro cell proliferation of NB cells and in reducing tumor volume in subcutaneous NB models in a dose-dependent manner. In orthotopic NB xenografts, X-396 significantly increased life span independently of the ALK mutation status. In combination studies, all effects were significantly improved in the mice treated with TL[ALK-siRNA] and X-396 compared to mice receiving the single agents. Our findings provide a rational basis to design innovative molecular-based treatment combinations for clinical application in ALK-driven NB tumors.

Purpose: Activating ALK mutations are present in almost 10% of primary neuroblastomas and mark patients for treatment with small-molecule ALK inhibitors in clinical trials. However, recent studies have shown that multiple mechanisms drive resistance to these molecular therapies. We anticipated that detailed mapping of the oncogenic ALK-driven signaling in neuroblastoma can aid to identify potential fragile nodes as additional targets for combination therapies., Experimental Design: To achieve this goal, transcriptome profiling was performed in neuroblastoma cell lines with the ALK(F1174L) or ALK(R1275Q) hotspot mutations, ALK amplification, or wild-type ALK following pharmacologic inhibition of ALK using four different compounds. Next, we performed cross-species genomic analyses to identify commonly transcriptionally perturbed genes in MYCN/ALK(F1174L) double transgenic versus MYCN transgenic mouse tumors as compared with the mutant ALK-driven transcriptome in human neuroblastomas., Results: A 77-gene ALK signature was established and successfully validated in primary neuroblastoma samples, in a neuroblastoma cell line with ALK(F1174L) and ALK(R1275Q) regulable overexpression constructs and in other ALKomas. In addition to the previously established PI3K/AKT/mTOR, MAPK/ERK, and MYC/MYCN signaling branches, we identified that mutant ALK drives a strong upregulation of MAPK negative feedback regulators and upregulates RET and RET-driven sympathetic neuronal markers of the cholinergic lineage., Conclusions: We provide important novel insights into the transcriptional consequences and the complexity of mutant ALK signaling in this aggressive pediatric tumor. The negative feedback loop of MAPK pathway inhibitors may affect novel ALK inhibition therapies, whereas mutant ALK induced RET signaling can offer novel opportunities for testing ALK-RET oriented molecular combination therapies., (©2015 American Association for Cancer Research.)

B cell acute lymphoblastic leukemia (B-ALL) is the most common hematological malignancy diagnosed in children, and blockade of the abnormally activated PI3Kδ displayed promising outcomes in B cell acute or chronic leukemias, but the mechanisms are not well understood. Here we report a novel PI3Kδ selective inhibitor X-370, which displays distinct binding mode with p110δ and blocks constitutively active or stimulus-induced PI3Kδ signaling. X-370 significantly inhibited survival of human B cell leukemia cells in vitro, with associated induction of G1 phase arrest and apoptosis. X-370 abrogated both Akt and Erk1/2 signaling via blockade of PDK1 binding to and/or phosphorylation of MEK1/2. Forced expression of a constitutively active MEK1 attenuated the antiproliferative activity of X-370. X-370 preferentially inhibited the survival of primary pediatric B-ALL cells displaying PI3Kδ-dependent Erk1/2 phosphorylation, while combined inhibition of PI3Kδ and MEK1/2 displayed enhanced activity. We conclude that PI3Kδ inhibition led to abrogation of both Akt and Erk1/2 signaling via a novel PI3K-PDK1/MEK1/2-Erk1/2 signaling cascade, which contributed to its efficacy against B-ALL. These findings support the rationale for clinical testing of PI3Kδ inhibitors in pediatric B-ALL and provide insights needed to optimize the therapeutic strategy.

The anaplastic lymphoma kinase (ALK) and the c-Met receptor tyrosine kinase play essential roles in the pathogenesis in multiple human cancers and present emerging targets for cancer treatment. Here, we describe CM-118, a novel lead compound displaying low nanomolar biochemical potency against both ALK and c-Met with selectivity over>90 human kinases. CM-118 potently abrogated hepatocyte growth factor (HGF)-induced c-Met phosphorylation and cell migration, phosphorylation of ALK, EML4-ALK, and ALK resistance mutants in transfected cells. CM-118 inhibited proliferation and/or induced apoptosis in multiple c-Met- and ALK-addicted cancer lines with dose response profile correlating target blockade. We show that the CM-118-induced apoptosis in c-Met-amplified H1993 NSCLC cells involved a rapid suppression of c-Met activity and c-Met-to-EGFR cross-talk, and was profoundly potentiated by EGFR inhibitors as shown by the increased levels of apoptotic proteins cleaved-PARP and Bim as well as reduction of the survival protein Mcl-1. Bim-knockdown or Mcl-1 overexpression each significantly attenuated apoptosis. We also revealed a key role by mTOR in mediating CM-118 action against the EML4-ALK-dependent NSCLC cells. Abrogation of EML4-ALK in H2228 cells profoundly reduced signaling capacity of the rapamycin-sensitive mTOR pathway leading to G 1 cell cycle arrest and mitochondrial hyperpolarization, a metabolic perturbation linked to mTOR inhibition. Depletion of mTOR or mTORC1 inhibited H2228 cell growth, and mTOR inhibitors potentiated CM-118's antitumor activity in vitro and in vivo. Oral administration of CM-118 at a wide range of well tolerated dosages diminished c-Met- and ALK phosphorylation in vivo, and caused tumor regression or growth inhibition in multiple c-Met- and ALK-dependent tumor xenografts in mice. CM-118 exhibits favorable pharmacokinetic and drug metabolism properties hence presents a candidate for clinical evaluation.

Receptor tyrosine kinases (RTK), such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and fms-like tyrosine kinase 3 (FLT3), are expressed in malignant tissues and act in concert, playing diverse and major roles in angiogenesis, tumor growth, and metastasis. With the exception of a few malignancies, seemingly driven by a single genetic mutation in a signaling protein, most tumors are the product of multiple mutations in multiple aberrant signaling pathways. Consequently, simultaneous targeted inhibition of multiple signaling pathways could be more effective than inhibiting a single pathway in cancer therapies. Such a multitargeted strategy has recently been validated in a number of preclinical and clinical studies using RTK inhibitors with broad target selectivity. SU14813, a small molecule identified from the same chemical library used to isolate sunitinib, has broad-spectrum RTK inhibitory activity through binding to and inhibition of VEGFR, PDGFR, KIT, and FLT3. In cellular assays, SU14813 inhibited ligand-dependent and ligand-independent proliferation, migration, and survival of endothelial cells and/or tumor cells expressing these targets. SU14813 inhibited VEGFR-2, PDGFR-beta, and FLT3 phosphorylation in xenograft tumors in a dose- and time-dependent fashion. The plasma concentration required for in vivo target inhibition was estimated to be 100 to 200 ng/mL. Used as monotherapy, SU14813 exhibited broad and potent antitumor activity resulting in regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines. Treatment in combination with docetaxel significantly enhanced both the inhibition of primary tumor growth and the survival of the tumor-bearing mice compared with administration of either agent alone. In summary, SU14813 inhibited target RTK activity in vivo in association with reduction in angiogenesis, target RTK-mediated proliferation, and survival of tumor cells, leading to broad and potent antitumor efficacy. These data support the ongoing phase I clinical evaluation of SU14813 in advanced malignancies.

To improve the antitumor properties and optimize the pharmaceutical properties including solubility and protein binding of indolin-2-ones, a number of different basic and weakly basic analogues were designed and synthesized. 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (12b or SU11248) has been found to show the best overall profile in terms of potency for the VEGF-R2 and PDGF-Rbeta tyrosine kinase at biochemical and cellular levels, solubility, protein binding, and bioavailability. 12b is currently in phase I clinical trials for the treatment of cancers.