CASI Pharmaceuticals (United States)

Tourette syndrome (TS), predominantly affecting children and adolescents aged 2-15 years, significantly impairs quality of life and social functioning. Shaoma Zhijing granules (SMZJG), a compound traditional Chinese medicine (TCM), has demonstrated comparable efficacy to tiapride (TIA) in alleviating TS symptoms with fewer adverse effects. To elucidate its tmaterial basis and mechanism of action, we employed iminodipropionitrile (IDPN) and 2, 5-dimethoxy-4-iodoarylamine (DOI) to induce a rat model of TS. SMZJG treatment significantly ameliorated IDPN- and DOI-induced stereotyped behavioral impairments and effectively counteracted the reduction in striatum volume. Notably, SMZJG was found to markedly correct neurotransmitter imbalances, suppress M1 microglial activation, and reduce the levels of interleukin-1α (IL-1α), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) in serum. These findings collectively suggest that SMZJG alleviates TS-associated behavioral disorders, potentially through mechanisms such as reducing striatal atrophy, modulating neurotransmitter imbalances, regulating abnormal neurotransmitter receptor expression, and decreasing microglial proliferation as well as levels of pro-inflammatory cytokines and chemokines in serum.

<div>Abstract<p><b>Purpose:</b> ENMD-2076 is a unique orally bioavailable Aurora kinase and VEGFR inhibitor. The purpose of this phase 1 study of ENMD-2076 was to determine the MTD, pharmacokinetic, and pharmacodynamic profiles and preliminary antitumor activity.</p><p><b>Experimental Design:</b> Patients with refractory advanced solid malignancies were treated with ENMD-2076 orally with continuous once daily dosing. Doses from 60 to 200 mg/m<sup>2</sup> were evaluated using a standard 3 (to 4) + 3 design. Pharmacokinetic parameters were studied on days 1, 28, and 30 to 35 of cycle 1. Expanded MTD cohorts included patients with ovarian cancer, colorectal cancer, and refractory solid tumors.</p><p><b>Results:</b> A total of 67 patients (46 F, 21M; ages 30–76) entered the study. Dose levels of 60, 80, 120, 200, and 160 mg/m<sup>2</sup> were evaluated. Two patients experienced grade 3 hypertension at 200 mg/m<sup>2</sup>, and additional grade 3 neutropenia events limited tolerability at this dose. An intermediate dose of 160 mg/m<sup>2</sup> was determined to be the MTD. The most common drug-related adverse events included hypertension, nausea/vomiting, and fatigue. The pharmacokinetics of ENMD-2076 were characterized by a rapid absorption phase (<i>T</i><sub>max</sub> 3–7.8 hours), a <i>t</i><sub>1/2</sub> of 27.3 to 38.3 hours after a single dose, and dose proportional exposure. Decreased plasma sVEGFR2 was observed posttreatment. Two patients with platinum refractory/resistant ovarian cancer had RECIST partial responses.</p><p><b>Conclusions:</b> ENMD-2076 was well tolerated, had a linear pharmacokinetic profile, and showed promising antitumor activity, particularly in ovarian cancer. The recommended phase 2 dose of ENMD-2076 is 160 mg/m<sup>2</sup> administered orally once daily with continuous dosing. <i>Clin Cancer Res; 17(4); 849–60. ©2010 AACR</i>.</p></div>

BACKGROUND The BlueStar (Welldoc) digital health solution for people with diabetes incorporates data from multiple devices and generates coaching messages using artificial intelligence. The BlueStar app syncs glucose data from the G6 (Dexcom) real-time continuous glucose monitoring (RT-CGM) system, which provides a glucose measurement every 5 minutes. OBJECTIVE The objective of this real-world study of people with type 2 diabetes (T2D) using the digital health solution and RT-CGM was to evaluate change in glycemic control and engagement with the program over 3 months. METHODS Participants were current or former enrollees in an employer-sponsored health plan, were aged 18 years or older, had a T2D diagnosis, and were not using prandial insulin. Outcomes included CGM-based glycemic metrics and engagement with the BlueStar app, including logging medications taken, exercise, food details, blood pressure, weight, and hours of sleep. RESULTS Participants in the program that met our analysis criteria (n=52) were aged a mean of 53 (SD 9) years; 37% (19/52) were female and approximately 50% (25/52) were taking diabetes medications. The RT-CGM system was worn 90% (SD 8%) of the time over 3 months. Among individuals with suboptimal glycemic control at baseline, defined as mean glucose >180 mg/dL, clinically meaningful improvements in glycemic control were observed, including reductions in a glucose management indicator (–0.8 percentage points), time above range 181-250 mg/dL (–4.4 percentage points) and time above range >250 mg/dL (–14 percentage points; all <i>P</i><.05). Time in range 70-180 mg/dL also increased by 15 percentage points (<i>P</i>=.016) in this population, which corresponds to an increase of approximately 3.5 hours per day in the target range. Over the 3-month study, 29% (15/52) of participants completed at least one engagement activity per week. Medication logging was completed most often by participants (23/52, 44%) at a rate of 12.1 (SD 0.8) events/week, and this was closely followed by exercise and food logging. CONCLUSIONS The combination of an artificial intelligence–powered digital health solution and RT-CGM helped people with T2D improve their glycemic outcomes and diabetes self-management behaviors.

A 2017 umbrella review defined the technology-enabled self-management (TES) feedback loop associated with a significant reduction in A1C. The purpose of this 2021 review was to develop a taxonomy of intervention attributes in technology-enabled interventions; review recent, high-quality systematic reviews and meta-analyses to determine if the TES framework was described and if elements contribute to improved diabetes outcomes; and to identify gaps in the literature. We identified key technology attributes needed to describe the active ingredients of TES interventions. We searched multiple databases for English language reviews published between April 2017 and April 2020, focused on PwD (population) receiving diabetes care and education (intervention) using technology-enabled self-management (comparator) in a randomized controlled trial, that impact glycemic, behavioral/psychosocial, and other diabetes self-management outcomes. AMSTAR-2 guidelines were used to assess 50 studies for methodological quality including risk of bias. The TES Taxonomy was developed to standardize the description of technology-enabled interventions; and ensure research uses the taxonomy for replication and evaluation. Of the 26 included reviews, most evaluated smartphones, mobile applications, texting, internet, and telehealth. Twenty-one meta-analyses with the TES feedback loop significantly lowered A1C. Technology-enabled diabetes self-management interventions continue to be associated with improved clinical outcomes. The ongoing rapid adoption and engagement of technology makes it important to focus on uniform measures for behavioral/psychosocial outcomes to highlight healthy coping. Using the TES Taxonomy as a standard approach to describe technology-enabled interventions will support understanding of the impact technology has on diabetes outcomes.

O agôn entre autores implica, no mundo clássico, o agôn entre gêneros literários. Exemplo disso é o esforço de Platão, enquanto autor, de reivindicar um espaço próprio para a filosofia, distinguindo-a dos demais gêneros. Já em relação aos dramaturgos atenienses, a supremacia de Ésquilo, sugerida por Harold Bloom, talvez se dê justamente pela proximidade entre sua obra e a poesia épica, da qual Homero é o maior representante. Diante disso, Rãs, peça de Aristófanes que tem portema central o agôn poético, consiste em um objeto adequado para se pensar a angústia da influência na literatura grega clássica.Esta comunicação propõe-se um ato de desleitura da peça Rãs a partir de formulações teóricas e metodológicas de Harold Bloom. A princípio, faz-se uma síntese da teoria literária e da metodologia crítica de Bloom em sua versão atual, isto é, à luz das reconsiderações apresentadas pelo teórico em seu último livro The anatomyofinfluence(2012). Em seguida, opera-se uma desleitura intempestiva do texto grego à medida que se aplica, no procedimento exegético, categorias da narratologia moderna (e. g. metalepse narrativa) e da teoria da poesia romântica. Em uma primeira parte, limita-se a dar a ver, nas minucias do texto do poeta cômico, recursos metalépticos enquanto indícios do agôn entre Aristófanes e a tradição literária do quinto século a.C., no intuito de apresentá-lo como um poeta forte, uma vez que atinge a sexta razão revisionária: a apófrades. Numa segunda parte, propõe-se, a partir da concepção de amor literário de Bloom, que a peça Rãs possa ser lida como uma espécie de drama elegíaco em que o poeta Aristófanes, sob a máscara de Dioniso, desce ao Hades por Eurípides, o qual sua própria obra imortaliza justamente à medida que mimetiza e satiriza.

Employers are increasingly focused on addressing the behavioral health issues of their employees and families. The high prevalence of behavioral health disorders in employees and their dependents has increased total health and disability costs as well as impacted productivity. These circumstances have stimulated the behavioral health focus and prompted new innovative strategies to address it. Ultimately, employers need a healthy and productive workforce in today’s increasingly competitive global economy.

Induced pluripotent stem cells (iPSCs) are a recently developed technology in which fully differentiated cells such as fibroblasts from individual CF patients can be repaired with [wildtype] CFTR, and reprogrammed to differentiate into fully differentiated cells characteristic of the proximal and distal airways. Here, we review properties of different epithelial cells in the airway, and the in vitro genetic roadmap which iPSCs follow as they are step-wise differentiated into either basal stem cells, for the proximal airway, or into Type II Alveolar cells for the distal airways. The central theme is that iPSC-derived basal stem cells, are penultimately dependent on NOTCH signaling for differentiation into club cells, goblet cells, ciliated cells, and neuroendocrine cells. Furthermore, given the proper matrix, these cellular progenies are also able to self-assemble into a fully functional pseudostratified squamous proximal airway epithelium. By contrast, club cells are reserve stem cells which are able to either differentiate into goblet or ciliated cells, but also to de-differentiate into basal stem cells. Variant club cells, located at the transition between airway and alveoli, may also be responsible for differentiation into Type II Alveolar cells, which then differentiate into Type I Alveolar cells for gas exchange in the distal airway. Using gene editing, the mutant CFTR gene in iPSCs from CF patients can be repaired, and fully functional epithelial cells can thus be generated through directed differentiation. However, there is a limitation in that the lung has other CFTR-dependent cells besides epithelial cells. Another limitation is that there are CFTR-dependent cells in other organs which would continue to contribute to CF disease. Furthermore, there are also bystander or modifier genes which affect disease outcome, not only in the lung, but specifically in other CF-affected organs. Finally, we discuss future personalized applications of the iPSC technology, many of which have already survived the "proof-of-principle" test. These include (i) patient-derived iPSCs used as a "lung-on-a-chip" tool for personalized drug discovery; (ii) replacement of mutant lung cells by wildtype lung cells in the living lung; and (iii) development of bio-artificial lungs. It is hoped that this review will give the reader a roadmap through the most complicated of the obstacles, and foster a guardedly optimistic view of how some of the remaining obstacles might one day be overcome.

MKC-1 is an orally available cell cycle inhibitor with downstream targets that include tubulin and the importin-β family. We conducted an open-label Phase II study with MKC-1 in patients with advanced pancreatic cancer. Eligibility criteria included unresectable or metastatic pancreatic cancer, performance status of 1 or better, and failure of at least one prior regimen of chemotherapy. MKC-1 was administered orally, twice daily, initially at 100 mg/m(2) dosing for 14 consecutive days of a 28-day cycle. This schedule was modified during the trial to fixed and continuous dosing of 150 mg per day. 20 of an original target of 33 patients were accrued, with a median age of 61 (range 44-81). No objective responses were observed, with one patient demonstrating stable disease. Overall survival was 101 days from the start of MKC-1 administration, and median time to progression was 42 days. The most common adverse events listed as related or possibly related to MKC-1 administration were hematologic toxicities and fatigue. One patient developed grade 5 (fatal) pancytopenia. Grade 3 and 4 events included cytopenias (lymphopenia, anemia), hyperbilirubinemia, pneumonia, mucositis, fatigue, infusion reaction, anorexia, and hypoalbuminemia. MKC-1 administration was associated with substantial toxicity and did not demonstrate sufficient activity in patients with advanced pancreatic cancer to justify further exploration in this patient population.