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Engagement of fathers in child welfare practice has been associated with improved outcomes for children, but they are not engaged equitably when compared to mothers. Within child death reviews, the Oregon Department of Human Services observed an overarching improvement opportunity regarding absent or minimal efforts to engage fathers. A multidisciplinary team, including fathers with lived expertise, completed a systems map to explore contributing factors. Learnings revealed caseworker bias and knowledge base, lack of legal paternal status, mothers' fears and/or withholding information, limited database access for contact information, and few local fatherinclusive or father-specific resources are among the salient barriers to father engagement.

Cyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of uncontrolled proliferation and increased survival. As a result, over the last two decades substantial efforts have been directed towards identification and development of pharmaceutical CDK inhibitors. Insights into the biological consequences of CDK inhibition in specific tumor types have led to the successful development of CDK4/6 inhibitors as treatments for certain types of breast cancer. More recently, a new generation of pharmaceutical inhibitors of CDK enzymes that regulate the transcription of key oncogenic and pro-survival proteins, including CDK9, have entered clinical development. Here, we provide the first disclosure of the chemical structure of fadraciclib (CYC065), a CDK inhibitor and clinical candidate designed by further optimization from the aminopurine scaffold of seliciclib. We describe its synthesis and mechanistic characterization. Fadraciclib exhibits improved potency and selectivity for CDK2 and CDK9 compared to seliciclib, and also displays high selectivity across the kinome. We show that the mechanism of action of fadraciclib is consistent with potent inhibition of CDK9-mediated transcription, decreasing levels of RNA polymerase II C-terminal domain serine 2 phosphorylation, the pro-survival protein Myeloid Cell Leukemia 1 (MCL1) and MYC oncoprotein, and inducing rapid apoptosis in cancer cells. This cellular potency and mechanism of action translate to promising anti-cancer activity in human leukemia mouse xenograft models. Studies of leukemia cell line sensitivity identify mixed lineage leukemia ( MLL ) gene status and the level of B-cell lymphoma 2 (BCL2) family proteins as potential markers for selection of patients with greater sensitivity to fadraciclib. We show that the combination of fadraciclib with BCL2 inhibitors, including venetoclax, is synergistic in leukemic cell models, as predicted from simultaneous inhibition of MCL1 and BCL2 pro-survival pathways. Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9- or CDK2-dependent cancers and as a rational combination with BCL2 inhibitors in hematological malignancies. Fadraciclib is currently in Phase 1 clinical studies in patients with advanced solid tumors ( NCT02552953 ) and also in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) ( NCT03739554 ) and relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) ( NCT04017546 ).

Engagement of fathers in child welfare practice has been associated with improved outcomes for children, but they are not engaged equitably when compared to mothers. Within child death reviews, the Oregon Department of Human Services observed an overarching improvement opportunity regarding absent or minimal efforts to engage fathers. A multidisciplinary team, including fathers with lived expertise, completed a systems map to explore contributing factors. Learnings revealed caseworker bias and knowledge base, lack of legal paternal status, mothers' fears and/or withholding information, limited database access for contact information, and few local fatherinclusive or father-specific resources are among the salient barriers to father engagement.

We describe an investigation into a Heartland virus (HRTV)—associated death in Tennessee with novel clinical and pathologic findings. HRTV can cause rapidly fatal, widely disseminated infection with multisystem organ failure in patients without substantial comorbidities. We identified viral antigen in multiple organ tissues where it was not detected previously.

In this book Edward McDonald takes a fresh look at issues of language in Chinese studies. He takes the viewpoint of the university student of Chinese with the ultimate goal of becoming 'sinophone': that is, developing a fluency and facility at operating in Chinese-language contexts comparable to their own mother tongue. While the entry point for most potential sinophones is the Chinese language classroom, the kinds of \"language\" and \"culture\" on offer there are rarely questioned, and the links between the forms of the language and the situations in which they may be used are rarely drawn. The author's explorations of Chinese studies illustrate the crucial link between becoming sinophone and developing a sinophone identity - learning Chinese and turning Chinese. Including chapters on: relating text to context in learning Chinese the social and political contexts of language learning myths about Chinese characters language reform and nationalism in modern China critical discourse analysis of popular culture ethnicity and identity in language learning. This book will be invaluable for all Chinese language students and teachers, and those with an interest in Chinese linguistics, linguistic anthropology, critical discourse analysis, and language education. Edward McDonald is currently Lecturer in Chinese at the University of Auckland, and has taught Chinese language, music, linguistics and semiotics at universities in Australia, China, and Singapore.

Noncommutative Euclidean spaces—otherwise known as Moyal spaces or quantum Euclidean spaces—are a standard example of a non-compact noncommutative geometry. Recent progress in the harmonic analysis of these spaces gives us the opportunity to highlight some of their peculiar features. For example, the theory of nonlinear partial differential equations has unexpected properties in this noncommutative setting. We develop elementary aspects of paradifferential calculus for noncommutative Euclidean spaces and give some applications to nonlinear evolution equations. We demonstrate how the analysis of some equations radically simplifies in the strictly noncommutative setting.

Human cancers often contain genetic alterations that disable G1/S checkpoint control and loss of this checkpoint is thought to critically contribute to cancer generation by permitting inappropriate proliferation and distorting fate-driven cell cycle exit. The identification of cell permeable small molecules that activate the G1/S checkpoint may therefore represent a broadly applicable and clinically effective strategy for the treatment of cancer. Here we describe the identification of several novel small molecules that trigger G1/S checkpoint activation and characterise the mechanism of action for one, CCT020312, in detail. Transcriptional profiling by cDNA microarray combined with reverse genetics revealed phosphorylation of the eukaryotic initiation factor 2-alpha (EIF2A) through the eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3/PERK) as the mechanism of action of this compound. While EIF2AK3/PERK activation classically follows endoplasmic reticulum (ER) stress signalling that sets off a range of different cellular responses, CCT020312 does not trigger these other cellular responses but instead selectively elicits EIF2AK3/PERK signalling. Phosphorylation of EIF2A by EIF2A kinases is a known means to block protein translation and hence restriction point transit in G1, but further supports apoptosis in specific contexts. Significantly, EIF2AK3/PERK signalling has previously been linked to the resistance of cancer cells to multiple anticancer chemotherapeutic agents, including drugs that target the ubiquitin/proteasome pathway and taxanes. Consistent with such findings CCT020312 sensitizes cancer cells with defective taxane-induced EIF2A phosphorylation to paclitaxel treatment. Our work therefore identifies CCT020312 as a novel small molecule chemical tool for the selective activation of EIF2A-mediated translation control with utility for proof-of-concept applications in EIF2A-centered therapeutic approaches, and as a chemical starting point for pathway selective agent development. We demonstrate that consistent with its mode of action CCT020312 is capable of delivering potent, and EIF2AK3 selective, proliferation control and can act as a sensitizer to chemotherapy-associated stresses as elicited by taxanes.

Deregulation of the cyclin‐dependent kinases (CDKs) has been implicated in the pathogenesis of multiple cancer types. Consequently, CDKs have garnered intense interest as therapeutic targets for the treatment of cancer. We describe herein the molecular and cellular effects of CCT068127, a novel inhibitor of CDK2 and CDK9. Optimized from the purine template of seliciclib, CCT068127 exhibits greater potency and selectivity against purified CDK2 and CDK9 and superior antiproliferative activity against human colon cancer and melanoma cell lines. X‐ray crystallography studies reveal that hydrogen bonding with the DFG motif of CDK2 is the likely mechanism of greater enzymatic potency. Commensurate with inhibition of CDK activity, CCT068127 treatment results in decreased retinoblastoma protein (RB) phosphorylation, reduced phosphorylation of RNA polymerase II, and induction of cell cycle arrest and apoptosis. The transcriptional signature of CCT068127 shows greatest similarity to other small‐molecule CDK and also HDAC inhibitors. CCT068127 caused a dramatic loss in expression of DUSP6 phosphatase, alongside elevated ERK phosphorylation and activation of MAPK pathway target genes. MCL1 protein levels are rapidly decreased by CCT068127 treatment and this associates with synergistic antiproliferative activity after combined treatment with CCT068127 and ABT263, a BCL2 family inhibitor. These findings support the rational combination of this series of CDK2/9 inhibitors and BCL2 family inhibitors for the treatment of human cancer. CCT068127 is a novel inhibitor of CDK2 and CDK9, which achieves potent inhibition of RB and RNA polymerase II phosphorylation in human colon cancer cells. MCL1 protein levels were rapidly decreased by CCT068127 treatment and associated with synergistic activity with the combination of CCT068127 and ABT263, a BCL2 family inhibitor. These findings support the rational combination of this series of CDK2/9 inhibitors and BCL2 family inhibitors for the treatment of human cancer.

Background: The meniscal roots play a vital role in maintaining proper knee kinematics. Neglected meniscal root tears place excess stress on the articular cartilage and increase the risk of premature osteoarthritis. As opposed to medial meniscal root tears, lateral meniscal posterior root tears (LMPRTs) are more likely to be associated with anterior cruciate ligament (ACL) pathology. Failure to identify and address meniscal root tears may place undue loads on ACL grafts and lead to inferior post-surgical outcomes. Purpose: To examine preoperative knee magnetic resonance imaging (MRI) radiologist interpretations for the identification of lateral meniscal root pathology in children and adolescents. Methods: We performed a retrospective review of children and adolescents that underwnent knee arthroscopy between 3/1/2010 and 4/1/2020 and had an arthroscopically confirmed LMPRT. Arthroscopic findings were compared to the reading radiologist’s preoperative MRI interpretations. LMPRTs were graded using the LaPrade classification. ANOVA was performed to assess if body mass index (BMI), open physes, time from injury to MRI, time from MRI to surgery, MRI magnet field strength, musculoskeletal radiologist designation, insurance type and tear grade were associated with the preoperative MRI identification of a LMPRT. Results: During the study period, 1285 knee arthroscopies were performed. 607 of which were ACL reconstructions. 54 children were found to have a LMPRT arthroscopically and all were associated with an ACL tear 54/607 (9%). One patient had 2 preoperative MRIs for a total of 55 MRIs in 54 pateints. Average age was 16 years (range 14-21). Preoperative MRI diagnosis of a LMPRT was made in only 14/55 (25%) and missed in 22/55 (40%). In 19/55 (35%), pathology of the lateral meniscus nonspecific to the root was mentioned. Lateral joint line tenderness was present in 23/54 (46%). There was no statistical significance found in regards to patient BMI, skeletal maturity, time from injury to MRI, time from MRI to surgery, MRI magnet strength, if the radiologist was musculoskeletal fellowship-trained, or insurance type, with a reliable diagnosis. (Table) Conclusion: The final interpretation of preoperative MRIs did not provide a clear definitive diagnosis of a LMPRT in 75 % in patients. As the intraoperative management of LMPRTs can be involved and diverge from standard meniscal work, preoperative diagnosis would be advantageous. All LMPRTs in this study were associated with a concomitant ACL tear. Surgeons caring for ACL tears in children and adolescents should be prepared to treat a LMPRT regardless of a inconclusive MRI interpretation for meniscal root pathology.

Category: Arthroscopy; Ankle; Sports; Trauma Introduction/Purpose: The deltoid ligament complex is the main stabilizing structure of the ankle mortise and is often disrupted in rotational ankle injuries. Current treatment involves open techniques for the acute repair of the superficial deltoid layer, however, repair or reconstruction of the deep deltoid ligament (DDL) has proven to be challenging using open techniques. Our described arthroscopically-assisted technique allows for better intra-articular visualization and durable reconstruction of the ruptured DDL with suture and knotless bone anchors. The goal of this new, minimally invasive approach is to facilitate a faster and more reliable recovery and prevent long-term dysfunction and degeneration from medial and rotational ankle instability. We believe it has the potential to provide improved immediate ankle stability and decrease overall surgical morbidity compared to open treatments. Methods: Case of a 48-year-old male with ligamentous-equivalent Massioneuve fracture with medial clear space (MCS) measuring 11 millimeters. Arthroscopy revealed unstable syndesmosis and rupture of the DDL. After syndesmotic fixation, there was persistent MCS widening on stress exam. Arthroscopically-assisted DDL reconstruction was performed using an accessory anteromedial (AAM) portal between the tibialis anterior tendon and posterior tibial tendon. Needle localization identified the sagittal midpoint of the medial wall of the talus, inferior to articular cartilage. Anchor sites at both the medial talar wall and midportion of the distal medial malleolus (insertion and origin of the DDL, respectively) were then drilled via the AAM portal under arthroscopic and fluoroscopic guidance respectively at the isometric point. A suture anchor was placed into the talus and tails were loaded and secured to the medial malleolus with a bioabsorbable anchor. Ankle mortise was stable to stress exam and there were no restraints to physiologic motion. Results: The patient was kept non-weight bearing on his right lower extremity for a total of 6 weeks postoperatively and was seen in the clinic for routine follow-up visits at 2 weeks, 6 weeks, and 3 months post-procedure. Sutures were removed at 2 weeks, without any wound complications, and he was transitioned from splint to a short leg cast. He required only three days of oral narcotic analgesia. Weight-bearing in a controlled ankle motion (CAM) boot and physical therapy were both initiated at 6 weeks post-op. Radiographs at each follow-up visit were without abnormalities. At 3 months post-op, he was graduated from the CAM boot into a lace-up ankle brace, without any complaints of ankle pain or instability. The patient progressed well with full weight-bearing and physical therapy and was seen for a final visit at 5 months post-op with stable MCS. No complications were encountered. Conclusion: Acute DDL rupture is a common occurrence in ankle fractures and can be diagnosed radiographically and by arthroscopy. Known sequelae of untreated DDL disruption include medial instability and late valgus collapse. This case report demonstrates a novel, minimally invasive technique to successfully reconstruct the DDL, which may minimize the surgical morbidity compared to open dissection methods and allow for decreased recovery time postoperatively. This approach may also be utilized for cases of chronic instability. Future work includes larger case series with long-term follow-up and refinement of the technique as instrumentation advances.