Thyroid Hormone Replacement Therapy in Patients with Various Types of Cancer

Primary hypothyroidism is a common endocrine disorder that is effectively treated with l-thyroxine (T4) replacement. Preclinical and limited clinical evidence, however, indicates that T4 is a growth factor for a variety of cancers, acting at the thyroid hormone receptor on plasma membrane integrin αvβ3. T4 is the primary ligand for this receptor, whereas 3,5,3′-triiodo-l-thyronine (T3) is the principal intracellular thyroid hormone analogue. The evidence is reviewed here that T4 is a proliferative for breast, lung, kidney and prostate cancers and for glioblastoma, regulates cancer cell respiration and is a pro-angiogenic factor in established tumors. The recommendation is made that T3 be considered alternative replacement treatment for patients with primary hypothyroidism who also have cancer

Site-1 protease inhibits mitochondrial respiration by controlling the TGF-β target gene Mss51

The mitochondrial response to changes in cellular energy demand is necessary for cellular adaptation and organ function. Many genes are essential in orchestrating this response, including the transforming growth factor (TGF)-β1 target gene Mss51, an inhibitor of skeletal muscle mitochondrial respiration. Although Mss51 is implicated in the pathophysiology of obesity and musculoskeletal disease, how Mss51 is regulated is not entirely understood. Site-1 protease (S1P) is a key activator of several transcription factors required for cellular adaptation. However, the role of S1P in muscle is unknown. Here, we identify S1P as a negative regulator of muscle mass and mitochondrial respiration. S1P disruption in mouse skeletal muscle reduces Mss51 expression and increases muscle mass and mitochondrial respiration. The effects of S1P deficiency on mitochondrial activity are counteracted by overexpressing Mss51, suggesting that one way S1P inhibits respiration is by regulating Mss51. These discoveries expand our understanding of TGF-β signaling and S1P function

Evolution of the pore structure-transport relationship during catalyst reduction and sintering studied by integrated multi-scale porosimetry and multi-modal imaging

Catalyst pellet fabrication parameters significantly impact final product performance. Tabletted pellets are complex, hierarchical structures that evolve differently over various levels during subsequent processing. Multi-scale porosimetry and multi-modal imaging can, together, encompass all length-scales involved, and, therefore, fully characterise the evolving pellet structure during catalyst reduction and sintering. A random pore-bond network model has highlighted the key pellet structural features determining mass transport, and, thence, was predictive of the impact on mass transfer of controlled modifications to the void space for reduced and aged catalysts. Particular macroporosity, newly induced by reduction and sintering, was critical to mass transport out of proportion to its pore volume fraction. Combined X-ray tomography imaging and percolation modelling showed that reduction and sintering leads to a change (compared to the fresh state) in the initial pellet fabrication parameter that controls mass transport in pellets formed with roll-compacted feed

Targeted delivery of cisplatin to tumor xenografts via the nanoparticle component of nano-diamino-tetrac

Aim: Nano-diamino-tetrac (NDAT) targets a receptor on integrin alpha v beta 3; alpha v beta 3 is generously expressed by cancer cells and dividing endothelial cells and to a small extent by nonmalignant cells. The tetrac (tetraiodothyroacetic acid) of NDAT is covalently bound to a poly(lactic-co-glycolic acid) nanoparticle that encapsulates anticancer drugs. We report NDAT delivery efficiency of cisplatin to agent-susceptible urinary bladder cancer xenografts. Materials & methods: Cisplatin-loaded NDAT (NDAT-cisplatin) was administered to xenograft-bearing nude mice. Tumor size response and drug content were measured. Results: Intratumoral drug concentration was up to fivefold higher (p NDAT without cisplatin > cisplatin alone. Conclusion: NDAT markedly enhances cisplatin delivery to urinary bladder cancer xenografts and increases drug efficacy.NanoPharmaceuticals LLC (NY, USA)NanoPharmaceuticals LL

Toxicity and Surgical Complication Rates of Neoadjuvant Atezolizumab in Patients with Muscle-invasive Bladder Cancer Undergoing Radical Cystectomy: Updated Safety Results from the ABACUS Trial

[Background] There are limited data on toxicity and surgical safety associated with neoadjuvant programmed death ligand 1 (PD-L1) inhibitors prior to radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC).[Objective] To present a comprehensive safety analysis of the largest neoadjuvant series, with focus on timing and severity of toxicity and surgical complications occurring after neoadjuvant atezolizumab in patients with MIBC enrolled in the ABACUS trial.[Design, setting, and participants] ABACUS (NCT02662309) is an open-label, multicenter, phase II trial for patients with histologically confirmed (T2-T4aN0M0) MIBC, awaiting RC. Patients either were ineligible or refused cisplatin-based neoadjuvant chemotherapy.[Intervention] Two cycles of neoadjuvant atezolizumab (1200 mg, every 3 wk) followed by RC.[Outcome measurements and statistical analysis] Description of atezolizumab toxicity profile in the neoadjuvant setting, impact on surgery, and delayed immune-mediated adverse events (AEs) were assessed.[Results and limitations] Ninety-five patients received treatment. Of them, 44% (42/95) had atezolizumab-related AEs during the neoadjuvant period (fatigue [20%], decreased appetite [6%], and transaminases increased [6%]). Treatment-related grade 3–5 AEs occurred in 11% (10/95) of patients during the study. Of the patients, 21% (20/95) received only one cycle of atezolizumab due to AEs; 92% (87/95) underwent RC. No surgery was delayed due to atezolizumab-related toxicities. Surgical complications occurred in 62% (54/87) of patients. Of these patients, 43% (37/87) and 20% (17/87) had minor (grade 1–2) and major (grade 3–5) complications, respectively. Thirteen of 87 (15%) patients had post-RC atezolizumab-related AEs, including adrenal insufficiency and transaminases increased. Three deaths occurred during the period of study-related interventions (one non–treatment-related aspiration pneumonia, one immune-related myocardial infarction, and one cardiogenic shock after RC). Not all surgical safety parameters were available.[Conclusions] Two cycles of neoadjuvant atezolizumab are well tolerated and do not seem to impact surgical complication rates. Owing to the long half-life, AEs may occur in the postoperative period, including endocrine abnormalities requiring attention and intervention.[Patient summary] Here, we report a comprehensive dataset of patients receiving neoadjuvant immune checkpoint inhibitors before radical cystectomy. Treatment with neoadjuvant atezolizumab is safe and does not seem to complicate surgery significantly.Queen Mary University of London was the Sponsor of the study. Roche granted QMUL funding for the study. J. Bull and M. Jacobson also provided financial support for aspects of the biomarker analysis. We acknowledge Cancer Research UK, the UK Experimental Cancer Medicine Network, and La Roche-Hoffmann for funding.Peer reviewe

Noninvasive prenatal screening in twin pregnancies with cell-free DNA using the IONA test: a prospective multicenter study.

BACKGROUND: In singleton pregnancies, studies investigating cell-free DNA in maternal blood have consistently reported high detection rate and low false-positive rate for the 3 common fetal trisomies (trisomies 21, 18, and 13). The potential advantages of noninvasive prenatal testing in twin pregnancies are even greater than in singletons, in particular lower need for invasive testing and consequent fetal loss rate. However, several organizations do not recommend cell-free DNA in twin pregnancies and call for larger prospective studies. OBJECTIVE: In response to this, we undertook a large prospective multicenter study to establish the screening performance of cell-free DNA for the 3 common trisomies in twin pregnancies. Moreover, we combined our data with that reported in published studies to obtain the best estimate of screening performance. STUDY DESIGN: This was a prospective multicenter blinded study evaluating the screening performance of cell-free DNA in maternal plasma for the detection of fetal trisomies in twin pregnancies. The study took place in 6 fetal medicine centers in England, United Kingdom. The primary outcome was the screening performance and test failure rate of cell-free DNA using next generation sequencing (the IONA test). Maternal blood was taken at the time of (or after) a conventional screening test. Data were collected at enrolment, at any relevant invasive testing throughout pregnancy, and after delivery until the time of hospital discharge. Prospective detailed outcome ascertainment was undertaken on all newborns. The study was undertaken and reported according to the Standards for Reporting of Diagnostic Accuracy Studies. A pooled analysis was also undertaken using our data and those in the studies identified by a literature search (MEDLINE, Embase, CENTRAL, Cochrane Library, and ClinicalTrials.gov) on June 6, 2020. RESULTS: A total of 1003 women with twin pregnancies were recruited, and complete data with follow-up and reference data were available for 961 (95.8%); 276 were monochorionic and 685 were dichorionic. The failure rate was 0.31%. The mean fetal fraction was 12.2% (range, 3%-36%); all 9 samples with a 3% fetal fraction provided a valid result. There were no false-positive or false-negative results for trisomy 21 or trisomy 13, whereas there was 1 false-negative and 1 false-positive result for trisomy 18. The IONA test had a detection rate of 100% for trisomy 21 (n=13; 95% confidence interval, 75-100), 0% for trisomy 18 (n=1; 95% confidence interval, 0-98), and 100% for trisomy 13 (n=1; 95% confidence interval, 3-100). The corresponding false-positive rates were 0% (95% confidence interval, 0-0.39), 0.10% (95% confidence interval, 0-0.58), and 0% (95% confidence interval, 0-0.39), respectively. By combining data from our study with the 11 studies identified by literature search, the detection rate for trisomy 21 was 95% (n=74; 95% confidence interval, 90-99) and the false-positive rate was 0.09% (n=5598; 95% confidence interval, 0.03-0.19). The corresponding values for trisomy 18 were 82% (n=22; 95% confidence interval, 66-93) and 0.08% (n=4869; 95% confidence interval, 0.02-0.18), respectively. There were 5 cases of trisomy 13 and 3881 non-trisomy 13 pregnancies, resulting in a computed average detection rate of 80% and a false-positive rate of 0.13%. CONCLUSION: This large multicenter study confirms that cell-free DNA testing is the most accurate screening test for trisomy 21 in twin pregnancies, with screening performance similar to that in singletons and very low failure rates (0.31%). The predictive accuracy for trisomies 18 and 13 may be less. However, given the low false-positive rate, offering first-line screening with cell-free DNA to women with twin pregnancy is appropriate in our view and should be considered a primary screening test for trisomy 21 in twins

Clinical evaluation of the IONA test: a non-invasive prenatal screening test for trisomies 21, 18 and 13.

OBJECTIVE: To evaluate the clinical accuracy of the IONA® test for aneuploidy screening. METHODS: This was a multicenter blinded study in which plasma samples from pregnant women at increased risk of trisomy 21 underwent cell-free DNA analysis utilizing the IONA test. For each sample, the IONA software generated a likelihood ratio and a maternal age-adjusted probability risk score for trisomies 21, 18 and 13. All results from the IONA test were compared against accepted diagnostic karyotyping. RESULTS: A total of 442 maternal samples were obtained, of which 437 had test results available for analysis and assessment of clinical accuracy. The IONA test had a detection rate of 100% for trisomies 21 (n = 43; 95% CI, 87.98-100%), 18 (n = 10; 95% CI, 58.72-100%) and 13 (n = 5; 95% CI, 35.88-100%) with cut-offs applied to likelihood ratio (cut-off > 1 considered high risk for trisomy) and probability risk score incorporating adjustment for maternal age (cut-off ≥ 1/150 considered high risk for trisomy). The false-positive rate (FPR) was 0% for trisomies 18 and 13 with both analysis outputs. For trisomy 21, a FPR of 0.3% was observed for the likelihood ratio, but became 0% with adjustment for maternal age. CONCLUSION: This study indicates that the IONA test is suitable for trisomy screening in a high-risk screening population. The result-interpretation feature of the IONA software should facilitate wider implementation, particularly in local laboratories, and should be a useful addition to the current screening methods for trisomies 21, 18 and 13. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd

Actions of Thyroid Hormones on Thyroid Cancers

L-Thyroxine (T4) is the principal ligand of the thyroid hormone analogue receptor on the extracellular domain of integrin αvβ3. The integrin is overexpressed and activated in cancer cells, rapidly dividing endothelial cells, and platelets. The biologic result is that T4 at physiological concentration and without conversion to 3,3’,5-triiodo-L-thyronine (T3) may stimulate cancer cell proliferation and cancer-relevant angiogenesis and platelet coagulation. Pro-thrombotic activity of T4 on platelets is postulated to support cancer-linked blood clotting and to contribute to tumor cell metastasis. We examine some of these findings as they may relate to cancers of the thyroid. Differentiated thyroid cancer cells respond to physiological levels of T4 with increased proliferation. Thus, the possibility exists that in patients with differentiated thyroid carcinomas in whom T4 administration and consequent endogenous thyrotropin suppression have failed to arrest the disease, T4 treatment may be stimulating tumor cell proliferation. In vitro studies have shown that tetraiodothyroacetic acid (tetrac), a derivative of T4, acts via the integrin to block T4 support of thyroid cancer and other solid tumor cells. Actions of T4 and tetrac or chemically modified tetrac modulate gene expression in thyroid cancer cells. T4 induces radioresistance via induction of a conformational change in the integrin in various cancer cells, although not yet established in thyroid cancer cells. The thyroid hormone receptor on integrin αvβ3 mediates a number of actions of T4 on differentiated thyroid cancer cells that support the biology of the cancer. Additional studies are required to determine whether T4 acts on thyroid cancer cells

Measurement of the t(t)over-bar production cross section in the dilepton channel in pp collisions at √s=8 TeV

The top-antitop quark (t (t) over bar) production cross section is measured in proton-proton collisions at root s = 8 TeV with the CMS experiment at the LHC, using a data sample corresponding to an integrated luminosity of 5.3 fb(-1). The measurement is performed by analysing events with a pair of electrons or muons, or one electron and one muon, and at least two jets, one of which is identified as originating from hadronisation of a bottom quark. The measured cross section is 239 +/- 2 (stat.) +/- 11 (syst.) +/- 6 (lum.) pb, for an assumed top-quark mass of 172.5 GeV, in agreement with the prediction of the standard model