Phase Ib clinical and pharmacodynamic study of the TIE2 kinase inhibitor rebastinib with paclitaxel or eribulin in HER2-negative metastatic breast cancer.

Purpose: Breast cancer cells disseminate to distant sites via Tumor Microenvironment of Metastasis (TMEM) doorways. The TIE2 inhibitor rebastinib blocks TMEM doorway function in the PyMT mouse model of breast cancer. We aimed to assess the safety and pharmacodynamics of rebastinib plus paclitaxel or eribulin in patients with HER2-negative metastatic breast cancer (MBC).

Hopelessness for family members of individuals with borderline personality disorder.

Family members and loved ones of individuals with Borderline Personality Disorder (BPD) can experience high levels of distress. Types of distress reported by family members include burden, grief, depression, guilt, and powerlessness. Hopelessness is a construct that has received little attention despite its potential relevance for this group.

Inhibition of ULK1/2 and KRAS controls tumor growth in preclinical models of lung cancer.

Mutational activation of occurs commonly in lung carcinogenesis and, with the recent U.S. Food and Drug Administration approval of covalent inhibitors of KRAS such as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC).

Combining VPS34 inhibitors with STING agonists enhances type I interferon signaling and anti-tumor efficacy.

An immunosuppressive tumor microenvironment promotes tumor growth and is one of the main factors limiting the response to cancer immunotherapy. We have previously reported that inhibition of vacuolar protein sorting 34 (VPS34), a crucial lipid kinase in the autophagy/endosomal trafficking pathway, decreases tumor growth in several cancer models, increases infiltration of immune cells and sensitizes tumors to anti-programmed cell death protein 1/programmed cell death 1 ligand 1 therapy by upregulation of C-C motif chemokine 5 (CCL5) and C-X-C motif chemokine 10 (CXCL10) chemokines. The purpose of this study was to investigate the signaling mechanism leading to the VPS34-dependent chemokine increase.

Inhibition of ULK1/2 and KRAS controls tumor growth in preclinical models of lung cancer.

Mutational activation of occurs commonly in lung carcinogenesis and, with the recent FDA approval of covalent inhibitors of KRAS such as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC). However, not all KRAS -driven NSCLCs respond to these inhibitors, and the emergence of drug resistance in those patients that do respond can be rapid and pleiotropic. Hence, based on a backbone of covalent inhibition of KRAS , efforts are underway to develop effective combination therapies.

Discovery of acyl ureas as highly selective small molecule CSF1R kinase inhibitors.

Based on the structure of an early lead identified in Deciphera's proprietary compound collection of switch control kinase inhibitors and using a combination of medicinal chemistry guided structure activity relationships and structure-based drug design, a novel series of potent acyl urea-based CSF1R inhibitors was identified displaying high selectivity for CSF1R versus the other members of the Type III receptor tyrosine kinase (RTK) family members (KIT, PDGFR-α, PDGFR-β, and FLT3), VEGFR2 and MET. Based on in vitro biology, in vitro ADME and in vivo PK/PD studies, compound 10 was selected as an advanced lead for Deciphera's CSF1R research program.

Discovery of vimseltinib (DCC-3014), a highly selective CSF1R switch-control kinase inhibitor, in clinical development for the treatment of Tenosynovial Giant Cell Tumor (TGCT).

Based on knowledge of kinase switch-control inhibition and using a combination of structure-based drug design and standard medicinal chemistry principles, we identified a novel series of dihydropyrimidone-based CSF1R kinase inhibitors displaying exquisite selectivity for CSF1R versus a large panel of kinases and non-kinase protein targets. Starting with lead compound 3, an SAR optimization campaign led to the discovery of vimseltinib (DCC-3014; compound 20) currently undergoing clinical evaluation for the treatment of Tenosynovial Giant Cell Tumor (TGCT), a locally aggressive benign tumor associated with substantial morbidity. 2021 Elsevier ltd.

Individuals who report having benefitted from dialectical behaviour therapy (DBT): a qualitative exploration of processes and experiences at long-term follow-up.

Background: Qualitative research in the area of DBT is limited, particularly at follow-up. The current study explored the follow-up experiences of individuals who previously received a diagnosis of borderline personality disorder and self-report having benefitted from DBT at the time of treatment.

Methods: Individuals who completed 12 months of standard DBT and were a minimum of two years post-completion were recruited.

Worldwide Assessment of the Mandibular First Molar Second Distal Root and Root Canal: A Cross-sectional Study with Meta-analysis.

Introduction: This study assessed the prevalence of radix entomolaris and 2 canals at the distal aspect of mandibular first molars among different geographic regions by means of cone-beam computed tomographic imaging.

Methods: Precalibrated observers from 23 worldwide geographic locations followed a standardized screening protocol to assess 5750 cone-beam computed tomographic images of mandibular first molars (250 per region), gathering demographic data and recording the presence of radix entomolaris and a second canal at the distal aspect of teeth. Intra- and interrater reliability tests were conducted and comparisons among groups were performed using proportions and odds ratio forest plots.

Vimseltinib: A Precision CSF1R Therapy for Tenosynovial Giant Cell Tumors and Diseases Promoted by Macrophages.

Macrophages can be co-opted to contribute to neoplastic, neurologic, and inflammatory diseases. Colony-stimulating factor 1 receptor (CSF1R)-dependent macrophages and other inflammatory cells can suppress the adaptive immune system in cancer and contribute to angiogenesis, tumor growth, and metastasis. CSF1R-expressing osteoclasts mediate bone degradation in osteolytic cancers and cancers that metastasize to bone.

Ripretinib and MEK Inhibitors Synergize to Induce Apoptosis in Preclinical Models of GIST and Systemic Mastocytosis.

The majority of gastrointestinal stromal tumors (GIST) harbor constitutively activating mutations in KIT tyrosine kinase. Imatinib, sunitinib, and regorafenib are available as first-, second-, and third-line targeted therapies, respectively, for metastatic or unresectable KIT-driven GIST. Treatment of patients with GIST with KIT kinase inhibitors generally leads to a partial response or stable disease but most patients eventually progress by developing secondary resistance mutations in KIT.

Worldwide Prevalence of a Lingual Canal in Mandibular Premolars: A Multicenter Cross-sectional Study with Meta-analysis.

Introduction: The presence of multiple root canals is an important morphologic aspect of mandibular premolars. This study aimed to perform a worldwide analysis on the prevalence of a lingual canal in mandibular premolars and to evaluate its influence on patients' demographics in 23 countries using cone-beam computed tomographic images.

Methods: Observers from 23 countries were instructed to evaluate cone-beam computed tomographic images of 300 first and 300 second premolars (13,800 teeth) regarding the presence of a lingual canal, canal configuration, and data related to patients' ethnicity, age, and sex following a standardized screening methodology.

Dialectical behaviour therapy: Implementation of an evidence-based intervention for borderline personality disorder in public health systems.

Dialectical behaviour therapy (DBT) is an intervention with demonstrated efficacy and effectiveness for individuals with borderline personality disorder. In recent years, research has shifted focus to the evaluation of DBT implementation in routine clinical settings. In this article, we consider the empirical evidence that guides clinicians and managers in health services with local implementation of DBT in community settings.

NTRK kinase domain mutations in cancer variably impact sensitivity to type I and type II inhibitors.

Tyrosine kinase domains dynamically fluctuate between two main structural forms that are referred to as type I (DFG-in) or type II (DFG-out) conformations. Comprehensive data comparing type I and type II inhibitors are currently lacking for NTRK fusion-driven cancers. Here we used a type II NTRK inhibitor, altiratinib, as a model compound to investigate its inhibitory potential for larotrectinib (type I inhibitor)-resistant mutations in NTRK.

Pulmonary Embolism in COVID-19 Treated with VA-ECLS and Catheter tPA.

Background: Novel coronavirus 2019 (COVID-19) has been the focus of the medical world since being declared a pandemic in March 2020. While the pathogenesis and heterogeneity of COVID-19 manifestations is still not fully understood, viral evasion of cellular immune responses and inflammatory dysregulation are believed to play essential roles in disease progression and severity.

Case Presentation: We present the first case of a patient with COVID-19 with massive pulmonary embolism treated successfully with systemic thrombolysis, VA-ECLS, and bail out catheter directed thrombolysis.

Dialectical behaviour therapy for adolescents: a comparison of 16-week and 24-week programmes delivered in a public community setting.

Background: Dialectical behaviour therapy for adolescents (DBT-A) is an intervention with a growing evidence base for treating adolescents with emotional and behavioural dysregulation. Previous studies have reported on varying lengths of treatment, however, and optimal treatment duration has not yet been identified. While the treatment developers initially proposed a 16-week programme, they have more recently recommended an extension to 24 weeks.

"Do Not Ignore Musculoskeletal Pain"-Initial Presentation of a Rare Malignant Disease: Case Report and Literature Review.

Gray zone lymphoma, also known as B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, is a rare malignancy with overlapping features of both diffuse large B-cell lymphoma and classical Hodgkin lymphoma. Most commonly mediastinal involvement is seen. Extranodal involvement is rare.

Life-Threatening Psoas Hematoma due to Retroperitoneal Hemorrhage in a COVID-19 Patient on Enoxaparin Treated With Arterial Embolization: A Case Report.

Respiratory failure is presumptively caused by microvascular thrombosis in some patients with coronavirus disease 2019 (COVID-19) requiring therapeutic anticoagulation. Anticoagulation treatment may cause life-threatening bleeding complications such as retroperitoneal hemorrhage. To the best of our knowledge, we report first case of a COVID-19 patient treated with therapeutic anticoagulation resulting in psoas hematoma due to lumbar artery bleeding.

Evaluating the national multisite implementation of dialectical behaviour therapy in a community setting: a mixed methods approach.

Background: The implementation of evidence-based interventions for borderline personality disorder in community settings is important given that individuals with this diagnosis are often extensive users of both inpatient and outpatient mental health services. Although work in this area is limited, previous studies have identified facilitators and barriers to successful DBT implementation. This study seeks to expand on previous work by evaluating a coordinated implementation of DBT in community settings at a national level.

Gonadal function protects against organ culture-induced vascular damage. Involvement of prostanoids.

Androgen deprivation induces vascular dysfunction in which altered release and action of prostanoids has been extensively studied. On the other hand, the vascular organ-culture system has been reported as a valid model for phenotypic changes that occur in several cardiovascular pathologies. Since there are no studies analyzing the impact of androgenic loss on vascular vulnerability during induced vascular damage, the objective of this study was to analyze the possible preventive role of male sex hormones on the organ culture-induced vascular damage in rat aorta.

A Phase I Study of LY3009120, a Pan-RAF Inhibitor, in Patients with Advanced or Metastatic Cancer.

Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in - and -mutated cell lines including -mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted of part A (dose escalation) and part B (dose confirmation) in patients with advanced/metastatic cancer.

A cost-effectiveness analysis of dialectical behaviour therapy for treating individuals with borderline personality disorder in the community.

Background/aims: This paper investigates the cost-effectiveness of dialectical behaviour therapy (DBT) for treating individuals with borderline personality disorder (BPD) in a community setting in Ireland, in the short term.

Methods: Resource utilisation and effectiveness data were collected as part of the National DBT Project, Ireland, and are incorporated into a cost-effectiveness analysis. The perspective taken was that of the service provider and payer.