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The title compound (II), a key intermediate for the synthesis of the anti-psychotic drug olanzapine, is prepared by intramolecular cyclocondensation of [(nitrophenyl)amino]thiophenecarbonitrile (I) using tin powder and HCl a reducing system. [ABSTRACT FROM AUTHOR]

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are closely related conditions characterized by systemic inflammation, a predominant IL-6 signature, an excellent response to glucocorticoids, a tendency to a chronic and relapsing course, and older age of the affected population. This Review highlights the emerging view that these diseases should be approached as linked conditions, unified under the term GCA–PMR spectrum disease (GPSD). In addition, GCA and PMR should be seen as non-monolithic conditions, with different risks of developing acute ischaemic complications and chronic vascular and tissue damage, different responses to available therapies and disparate relapse rates. A comprehensive stratification strategy for GPSD, guided by clinical findings, imaging and laboratory data, facilitates appropriate therapy and cost-effective use of health-economic resources. Patients presenting with predominant cranial symptoms and vascular involvement, who usually have a borderline elevation of inflammatory markers, are at an increased risk of sight loss in early disease but have fewer relapses in the long term, whereas the opposite is observed in patients with predominant large-vessel vasculitis. How the involvement of peripheral joint structures affects disease outcomes remains uncertain and understudied. In the future, all cases of new-onset GPSD should undergo early disease stratification, with their management adapted accordingly. Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are increasingly viewed as parts of a single disease spectrum. In this Review, the authors outline how stratification of patients with GCA–PMR spectrum disease using clinical, imaging and laboratory data can to help guide therapy. Key points: Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are part of the same disease spectrum, which can be unified under the term GCA–PMR spectrum disease (GPSD). Management of GPSD is characterized by a paradoxical contrast between short-term steroid responsiveness and long-term damage related to both the disease itself and its treatment. Stratifying patients with GPSD according to clinical, imaging and laboratory features might help clinicians in personalizing the treatment to optimize the balance between effectiveness and safety. A strong inflammatory activation, as indicated by high levels of classic markers but also of alternative biomarkers such as YKL-40 and osteopontin, predicts an increased risk of disease relapse. Large-vessel involvement, peripheral arthritis and synovial hypertrophy in the shoulders are associated with a worse long-term outcome. There is a need for prospective inception cohort studies of GPSD mapping of anatomical sites of inflammation and evolution during disease course to long-term critical outcomes. [ABSTRACT FROM AUTHOR]

We show that topological defects in the language of Landau-Ginzburg models carry information about the RG flow between the non-compact orbifolds C/Zd. We show that such defects correctly implement the bulk-induced RG flow on the boundary. [ABSTRACT FROM AUTHOR]

The article presents the poem "Variations on the Great Figure #1" by Daniel Robbins. First Line: among the streetlights and rain; Last Line: complete disarray.

Using an effective field theory approach and the language of SU ( N ) -structures, we study higher derivative corrections to the supersymmetry constraints for compactifications of string or M-theory to Minkowski space. Our analysis is done entirely in the target space and is thus very general, and does not rely on theory-dependent details such as the amount of worldsheet supersymmetry. For manifolds of real dimension n < 4 we show that internal geometry remains flat and uncorrected. For n = 4 , 6 , Kähler manifolds with SU ( N ) -holonomy can become corrected to SU ( N ) -structure, while preserving supersymmetry, once corrections are included. [ABSTRACT FROM AUTHOR]

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, is an essential effector of B-cell receptor (BCR) signaling. Chronic activation of BTK-mediated BCR signaling is a hallmark of many hematological malignancies, which makes it an attractive therapeutic target. Pharmacological inhibition of BTK enzymatic function is now a well-proven strategy for the treatment of patients with these malignancies. We report the discovery and characterization of NX-2127, a BTK degrader with concomitant immunomodulatory activity. By design, NX-2127 mediates the degradation of transcription factors IKZF1 and IKZF3 through molecular glue interactions with the cereblon E3 ubiquitin ligase complex. NX-2127 degrades common BTK resistance mutants, including BTK C481S . NX-2127 is orally bioavailable, exhibits in vivo degradation across species, and demonstrates efficacy in preclinical oncology models. NX-2127 has advanced into first-in-human clinical trials and achieves deep and sustained degradation of BTK following daily oral dosing at 100 mg.

Abstract: GATA binding protein 2 (GATA2) is a conserved zinc finger transcription factor that regulates the emergence and maintenance of complex genetic programs driving development and function of hematopoietic stem and progenitor cells (HSPCs). Patients born with monoallelic GATA2 mutations develop myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML), whereas acquired GATA2 mutations are reported in 3% to 5% of sporadic AML cases. The mechanisms by which aberrant GATA2 activity promotes MDS and AML are incompletely understood. Efforts to understand GATA2 in basic biology and disease will be facilitated by the development of broadly efficacious antibodies recognizing physiologic levels of GATA2 in diverse tissue types and assays. Here, we purified a polyclonal anti-GATA2 antibody and generated multiple highly specific anti-GATA2 monoclonal antibodies, optimized them for immunohistochemistry on patient bone marrow bioosy samples, and analyzed GATA2 expression in adults with healthy bone marrow, MDS, and acute leukemia. In healthy bone marrow, GATA2 was detected in mast cells, subsets of CD34+ HSPCs, E-cadherin-positive erythroid progenitors, and megakaryocytes. In MDS, GATA2 expression correlates with bone marrow blast percentage, positively correlates with myeloid dysplasia and complex cytogenetics, and is a nonindependent negative predictor of overall survival. In acute leukemia, the percent of GATA2+ blasts closely associates with myeloid lineage, whereas a subset of lymphoblastic and undifferentiated leukemias with myeloid features also express GATA2. However, the percent of GATA2+ blasts in AML is highly variable. Elevated GATA2 expression in AML blasts correlates with peripheral neutropenia and complex AML cytogenetics but, unlike in MDS, does not predict survival., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Bruton tyrosine kinase (BTK) is essential for B-cell receptor (BCR) signaling, a driver of chronic lymphocytic leukemia (CLL). Covalent inhibitors bind C481 in the active site of BTK and have become a preferred CLL therapy. Disease progression on covalent BTK inhibitors is commonly associated with C481 mutations. Here, we investigated a targeted protein degrader, NRX-0492, that links a noncovalent BTK-binding domain to cereblon, an adaptor protein of the E3 ubiquitin ligase complex. NRX-0492 selectively catalyzes ubiquitylation and proteasomal degradation of BTK. In primary CLL cells, NRX-0492 induced rapid and sustained degradation of both wild-type and C481 mutant BTK at half maximal degradation concentration (DC50) of ≤0.2 nM and DC90 of ≤0.5 nM, respectively. Sustained degrader activity was maintained for at least 24 hours after washout and was equally observed in high-risk (deletion 17p) and standard-risk (deletion 13q only) CLL subtypes. In in vitro testing against treatment-naïve CLL samples, NRX-0492 was as effective as ibrutinib at inhibiting BCR-mediated signaling, transcriptional programs, and chemokine secretion. In patient-derived xenografts, orally administered NRX-0492 induced BTK degradation and inhibited activation and proliferation of CLL cells in blood and spleen and remained efficacious against primary C481S mutant CLL cells collected from a patient progressing on ibrutinib. Oral bioavailability, >90% degradation of BTK at subnanomolar concentrations, and sustained pharmacodynamic effects after drug clearance make this class of targeted protein degraders uniquely suitable for clinical translation, in particular as a strategy to overcome BTK inhibitor resistance. Clinical studies testing this approach have been initiated (NCT04830137, NCT05131022).

Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoma of childhood (SETLC) is a rare, rapidly progressive, and often fatal disease of children and young adults characterized by monoclonal expansion of EBV-positive T cells in tissues or peripheral blood following infection with EBV. Its distinction from other EBV-positive T-cell lymphoproliferative disorders with overlapping features can be difficult, and particular diagnostic features may not be manifest until autopsy examination. We present the case of a 10-year-old boy with significant disability due to remote traumatic brain injury following non-accidental head trauma who died unexpectedly at home. Given the history of physical abuse and the potential for homicide charges, significant medicolegal implications arose with this case. Pathologic investigation ultimately revealed conclusive diagnostic features of SETLC including extensive proliferation of EBV-positive T cells in multiple organs. A natural manner of death was confirmed, thereby excluding delayed homicide related to complications of non-accidental head trauma.

Objectives: The epithelial associated mucus layer of vocal fold (VF) mucosa, plays an essential role in protecting and lubricating the tissue, as well as promoting normal voice quality. Serving as a habitat for laryngeal microbiota involved in the regulation of host immunity, VF mucus contributes to laryngeal health and disease. However, its unstable structure renders its' investigation challenging. We aim to establish a reproducible histological protocol to recover the natural appearance of the VF mucus layer for investigation., Methods: Using a murine model, we compared the suitability of multiple fixation methods-methacarn, formalin, and cryopreservation followed by post-fixation with formalin, paraformaldehyde (PFA), acetone, and two staining methods-Alcian Blue (pH 2.5)/Periodic Acid Schiff (AB/PAS) or PAS. Fixation and staining outcomes were evaluated based on the preservation of tissue morphology and mucus layer integrity. Mucin proteins, Muc1 and Muc4, were stained to validate the presence of mucus layer overlaying the VF mucosa., Results: Methacarn fixation followed by PAS staining was capable of preserving and displaying the smooth and continuous mucus layer, ensuring the determination of mucus thickness and mucin staining., Conclusions: Our study if the first to establish a histological protocol for the visualization of the in situ VF mucus layer whereby facilitating the study of VF mucus biology including VF surface hydration, ion/nutrients transports, biomechanical properties that maintains normal voice quality as well as VF pathophysiology and host-microbe interactions in the larynx., Level of Evidence: N/A., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Background Context: The North American Spine Society's (NASS) Evidence Based Clinical Guideline for the Diagnosis and Treatment of Low Back Pain features evidence-based recommendations for diagnosing and treating adult patients with nonspecific low back pain. The guideline is intended to reflect contemporary treatment concepts for nonspecific low back pain as reflected in the highest quality clinical literature available on this subject as of February 2016., Purpose: The purpose of the guideline is to provide an evidence-based educational tool to assist spine specialists when making clinical decisions for adult patients with nonspecific low back pain. This article provides a brief summary of the evidence-based guideline recommendations for diagnosing and treating patients with this condition., Study Design: This is a guideline summary review., Methods: This guideline is the product of the Low Back Pain Work Group of NASS' Evidence-Based Clinical Guideline Development Committee. The methods used to develop this guideline are detailed in the complete guideline and technical report available on the NASS website. In brief, a multidisciplinary work group of spine care specialists convened to identify clinical questions to address in the guideline. The literature search strategy was developed in consultation with medical librarians. Upon completion of the systematic literature search, evidence relevant to the clinical questions posed in the guideline was reviewed. Work group members utilized NASS evidentiary table templates to summarize study conclusions, identify study strengths and weaknesses, and assign levels of evidence. Work group members participated in webcasts and in-person recommendation meetings to update and formulate evidence-based recommendations and incorporate expert opinion when necessary. The draft guideline was submitted to an internal and external peer review process and ultimately approved by the NASS Board of Directors., Results: Eighty-two clinical questions were addressed, and the answers are summarized in this article. The respective recommendations were graded according to the levels of evidence of the supporting literature., Conclusions: The evidence-based clinical guideline has been created using techniques of evidence-based medicine and best available evidence to aid practitioners in the diagnosis and treatment of adult patients with nonspecific low back pain. The entire guideline document, including the evidentiary tables, literature search parameters, literature attrition flowchart, suggestions for future research, and all of the references, is available electronically on the NASS website at https://www.spine.org/ResearchClinicalCare/QualityImprovement/ClinicalGuidelines.aspx., (Copyright © 2020. Published by Elsevier Inc.)

Background: We looked at long-term follow-up of spine stapling with Nitinol Staples. This was a cohort of all adolescent idiopathic scoliosis (AIS) patients with curves at high risk to progress based on curve magnitude, premenarchal status in all females, failure of brace treatment, and skeletal immaturity., Methods: This is a single surgeon retrospective review of consecutive AIS patients treated with Nitinol staples for progressive scoliosis. Fourteen patients, 16 curves from 2005 to 2008 were eligible. Minimum curve for stapling was 30 degrees. Standard preoperative, intraoperative, and postoperative data were collected. All patients were followed for a minimum of 36 months and to skeletal maturity. Three groups were: improved (group 1), correction of any amount; minimal progression (group 2), progression ≤10 degrees; and failure (group 3), ≥10 degrees of progression., Results: A total of 13 thoracic curves and 2 compensatory lumbar curves met the inclusion criteria (94%). Average follow-up was 61 months. The mean preoperative main thoracic curve was 35 degrees. All but 1 patients progressed at least 9 degrees in a brace prior to stapling. Females were all premenarchal, 10 patients were Risser 0 and 3 Risser 1. The average number of vertebrae stapled per curve was 6. Group 1 included 6 curves (40%). Group 2, 5 curves (33%). Group 3, 4 curves (27%). Three patients went on to uncomplicated fusion. Final curve measurement at the end of follow-up or before fusion (P=0.0037), curve progression (P≤0.001), and percentage of coronal correction on first postoperative standing radiograph (P=0.042) were the significant differences between groups 1+2 (successful) versus group 3 (failures). In total, 73% of this group either progressed ≤10 degrees or improved., Conclusions: This is the first study that follows AIS patients treated with spine stapling to skeletal maturity. Staples likely changed natural history in some of our patients. Initial percentage of correction on first standing postoperative PA x-rays was the only predictor of success. Stapling was safe without any long-term complications., Level of Evidence: Level III-retrospective study.

Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683).

The purpose of this study was to investigate the acute effects of performing paired-set (PS) vs. traditional-set (TS) training over 3 consecutive sets, on volume load and electromyographic fatigue parameters of the latissimus dorsi, biceps brachii, pectoralis major, and triceps brachii muscles. Fifteen trained men performed 2 testing protocols (TS and PS) using 10 repetition maximum loads. The TS protocol consisted of 3 sets of bench press (BP) followed by 3 sets of wide-grip seated row (SR). The PS consisted of 3 sets of BP and 3 sets of SR performed in an alternating manner. Volume load was calculated as load × repetitions. The electromyographic signal, time (CRMS) and frequency (Cf5) domain, parameters were recorded during SR. Under the PS protocol, sets of SR were performed immediately after the sets of BP. A 2-minute rest interval between the completion of the set of SR and the subsequent set of BP was implemented (e.g., between PSs). Under the TS protocol, 2-minute rest intervals were implemented between all sets. BP and SR volume loads decreased significantly from set 1 to set 2 and from set 2 to set 3 under both conditions. Volume load was greater for all sets of both exercises under PS as compared with TS. Muscle fatigue indices were greater under PS as compared with TS. In general, these results indicate that as compared with TS, PS produced a greater training volume in less time and may induce greater fatigue and thereby provide an enhanced training stimulus.

Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound 1 , a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound 1 bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein-ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound 26 is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 μM and Bcl-xL at >99 μM, and induces cleaved caspase-3 in MV4-11 cells with an IC 50 of 3 μM after 6 h., Competing Interests: The authors declare no competing financial interest.