Targeting Bruton tyrosine kinase (BTK) by ibrutinib is an effective treatment for patients with relapsed/refractory mantle cell lymphoma (MCL). However, both primary and acquired resistance to ...ibrutinib have developed in a significant number of these patients. A combinatory strategy targeting multiple oncogenic pathways is critical to enhance the efficacy of ibrutinib. Here, we focus on the BCL2 anti-apoptotic pathway. In a tissue microarray of 62 MCL samples, BCL2 expression positively correlated with BTK expression. Increased levels of BCL2 were shown to be due to a defect in protein degradation because of no or little expression of the E3 ubiquitin ligase FBXO10, as well as transcriptional upregulation through BTK-mediated canonical nuclear factor-κB activation. RNA-seq analysis confirmed that a set of anti-apoptotic genes (for example, BCL2, BCL-XL and DAD1) was downregulated by BTK short hairpin RNA. The downregulated genes also included those that are critical for B-cell growth and proliferation, such as BCL6, MYC, PIK3CA and BAFF-R. Targeting BCL2 by the specific inhibitor ABT-199 synergized with ibrutinib in inhibiting growth of both ibrutinib-sensitive and -resistant cancer cells in vitro and in vivo. These results suggest co-targeting of BTK and BCL2 as a new therapeutic strategy in MCL, especially for patients with primary resistance to ibrutinib.
Background
KIT inhibitors, such as toceranib (TOC), and vinblastine (VBL) have not been prospectively compared in the treatment of macroscopic mast cell tumors (MCTs). Also, it is unknown whether VBL ...or TOC is superior for treating MCT without c‐kit mutations.
Hypothesis/Objectives
To determine the value of KIT genotyping and localization in treatment decisions for dogs with macroscopic MCT. We hypothesized that c‐kit mutated MCT would have a better response to TOC than VBL.
Animals
Eighty‐eight client‐owned dogs with macroscopic MCT.
Methods
Prospective, randomized trial. Dogs were randomized to TOC (2.75 mg/kg EOD) or VBL (2.5 mg/m2 weekly × 4 then EOW) by KIT localization and c‐kit mutation status using an adaptive randomization scheme.
Results
Sixty dogs were allocated to TOC and 28 to VBL. Of the dogs receiving TOC, 20% had c‐kit mutations, compared to 30% receiving VBL (P = 0.74). Overall response rates were 46% (TOC) and 30% (VBL) (odds ratio = 1.56 0.62–3.92; P = 0.28). Median progression‐free survival (PFS) for dogs receiving VBL was 78 days (7–1,521) and for TOC 95.5 (14–990); hazard ratio (HR) = 1.34 0.72–2.50; P = 0.36. Median overall survival (OS) was 241.5 days (10–1,521) for the VBL group and 159 (20–990) for the TOC group; HR = 0.80 (0.45–1.41; P = 0.44).
Conclusions and Clinical Importance
Neither PFS nor OS was significantly different between treatment groups. As the proportion of dogs with c‐kit mutations was not different between treatment groups in this population of dogs, c‐kit mutation status did not predict treatment response.
Background: There is no standard first line treatment for mantle cell lymphoma. Patients and methods: This was a multicenter phase II pilot study of rituximab and modified hyper-fractionated ...cyclophosphamide, vincristine doxorubicin, dexamethasone (modified R-hyperCVAD) administered every 28 days for four to six cycles followed by rituximab maintenance therapy consisting of four weekly doses every 6 months for 2 years. Unlike traditional hyperCVAD regimens, no methotrexate or cytarabine was administered. Results: Of 22 patients, the overall response rate was 77% and the complete response rate was 64%. With a median follow-up time of 37 months in surviving patients, the median PFS was 37 months and the median OS was not reached. The achievement of a molecular remission did not correlate with improved outcome. The major toxicity was expected myelosuppression. Two patients died during induction treatment. There were no major adverse effects during maintenance therapy. Conclusion: In a multicenter trial, modified R-hyperCVAD was tolerable and effective induction therapy for untreated MCL. Maintenance rituximab appeared to prolong PFS without increasing toxicity.
Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart and kidney failure in patients with type 2 diabetes, possibly due to diuretic effects. Previous non-placebo-controlled ...studies with SGLT2 inhibitors observed changes in volume markers in healthy individuals and in patients with type 2 diabetes with preserved kidney function. It is unclear whether patients with type 2 diabetes and signs of kidney damage show similar changes. Therefore, a post hoc analysis was performed on two randomized controlled trials (
= 69), assessing effects of dapagliflozin 10 mg/day when added to renin-angiotensin system inhibition in patients with type 2 diabetes and urinary albumin-to-creatinine ratio ≥30 mg/g. Blood and 24-h urine was collected at the start and the end of treatment periods lasting six and 12 weeks. Effects of dapagliflozin compared to placebo on various markers of volume status were determined. Fractional lithium excretion, a marker of proximal tubular sodium reabsorption, was assessed in 33 patients. Dapagliflozin increased urinary glucose excretion by 217.2 mmol/24 h (95% confidence interval (CI): from 155.7 to 278.7,
< 0.01) and urinary osmolality by 60.4 mOsmol/kg (from 30.0 to 90.9,
< 0.01), compared to placebo. Fractional lithium excretion increased by 19.6% (from 6.7 to 34.2;
< 0.01), suggesting inhibition of sodium reabsorption in the proximal tubule. Renin and copeptin increased by 46.9% (from 21.6 to 77.4,
< 0.01) and 33.0% (from 23.9 to 42.7,
< 0.01), respectively. Free water clearance (FWC) decreased by -885.3 mL/24 h (from -1156.2 to -614.3,
< 0.01). These changes in markers of volume status suggest that dapagliflozin exerts both osmotic and natriuretic diuretic effects in patients with type 2 diabetes and kidney damage, as reflected by increased urinary osmolality and fractional lithium excretion. As a result, compensating mechanisms are activated to retain sodium and water.
Abstract
The ongoing digitization of engineering processes and the increasing prevalence of smart products create possibilities for new business models and services. Digital twins enable the ...collection of all required data about a smart product in order to make these possibilities a reality. This paper describes a flexible approach towards a digital product twin that is tightly integrated with existing product models while being lightweight and easy to integrate with existing IT solutions.
Limited evidence exists on whether subclinical hypothyroidism suggested by mildly elevated TSH levels affect neurodevelopment and growth in preterm infants. The objective of this study was to ...determine the association between gestational age adjusted TSH percentiles and neurodevelopmental outcomes among preterm infants.
Univariate linear regression analysis was conducted to determine, in infants born less than thirty-two weeks gestational age, the correlation between the TSH percentile on the last newborn screen and neurodevelopmental assessment scores and growth outcomes at eighteen to twenty-two months of corrected age.
Seventy-four patients were enrolled in the study with a mean gestational age of 28.8 weeks. There was no correlation between the last TSH percentile value and Bayley-III cognitive composite score or other neurodevelopmental or growth outcomes.
In a cohort of preterm infants, higher TSH percentiles suggesting potential subclinical hypothyroidism did not predict any adverse effect on neurodevelopmental or growth outcomes.
Pulse oximetry screening (POS) is an effective tool to detect critical congenital heart disease (CCHD) in asymptomatic term infants, but its value in the neonatal intensive care unit (NICU) requires ...further clarification.
A retrospective review of 1005 babies without previously diagnosed CCHD admitted to a level III NICU was performed to assess the risk for missed CCHD and performance of POS.
Of the 1005 NICU patients, 812 had documented POS and none failed POS. In 812 patients, 547 had delayed POS because of the use of supplemental oxygen. In 259/812 patients, POS was delayed until the baby was >2 weeks old. CCHD was excluded by echocardiography, irrespective of POS, in 287/1005 patients.
POS can be performed in the NICU with minimal adverse effects. However, in many NICU patients CCHD is confirmed or excluded before POS, and POS will frequently be performed after CCHD would have been expected to become symptomatic.
Abstract
Industrial Data Analytics needs access to huge amounts of data, which is scattered across different IT systems. As part of an integrated reference kit for Industrial Data Analytics, there is ...a need for a data backend system that provides access to data. This system needs to have solutions for the extraction of data, the management of data and an analysis pipeline for those data. This paper presents an approach for this data backend system.
In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells ...adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosurvival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients' clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target.
Understanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development. See related commentary by Zhang et al., p. 2017. This article is highlighted in the In This Issue feature, p. 2007.
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