Performance comparison of small-pixel CdZnTe radiation detectors with gold contacts formed by sputter and electroless deposition

Recent improvements in the growth of wide-bandgap semiconductors, such as cadmium zinc telluride (CdZnTe or CZT), has enabled spectroscopic X/γ-ray imaging detectors to be developed. These detectors have applications covering homeland security, industrial analysis, space science and medical imaging. At the Rutherford Appleton Laboratory (RAL) a promising range of spectroscopic, position sensitive, small-pixel Cd(Zn)Te detectors have been developed. The challenge now is to improve the quality of metal contacts on CdZnTe in order to meet the demanding energy and spatial resolution requirements of these applications. The choice of metal deposition method and fabrication process are of fundamental importance. Presented is a comparison of two CdZnTe detectors with contacts formed by sputter and electroless deposition. The detectors were fabricated with a 74 × 74 array of 200 μm pixels on a 250 μm pitch and bump-bonded to the HEXITEC ASIC. The X/γ-ray emissions from an 241Am source were measured to form energy spectra for comparison. It was found that the detector with contacts formed by electroless deposition produced the best uniformity and energy resolution; the best pixel produced a FWHM of 560 eV at 59.54 keV and 50% of pixels produced a FWHM better than 1.7 keV . This compared with a FWHM of 1.5 keV for the best pixel and 50% of pixels better than 4.4 keV for the detector with sputtered contacts

Distant Metastases From Childhood Differentiated Thyroid Carcinoma:Clinical Course and Mutational Landscape

Context: Distant metastases (DM) from childhood differentiated thyroid carcinoma (DTC) are uncommon and published studies are limited. Objective: This work aimed to describe the outcomes of patients with DM from childhood DTC and to evaluate the molecular landscape of these tumors. Methods: A retrospective study was conducted at a tertiary cancer center including patients with pediatric DTC (diagnosed at age Results: We identified 148 patients; 144 (97%) had papillary thyroid carcinoma (PTC) and 104 (70%) were female. Median age at DTC diagnosis was 13.4 years (interquartile range [IQR], 9.9-15.9 years). Evaluable individuals received a median of 2 (IQR, 1-3) radioactive iodine (RAI) treatments at a median cumulative administered activity of 238.0 mCi (IQR, 147.5-351.0 mCi). The oncogenic driver was determined in 64 of 69 PTC samples: RET fusion (38/64; 59%), NTRK1/3 fusions (18/64; 28%), and the BRAF V600E mutation (8/64; 13%). At last evaluation, 93% had persistent disease. The median overall and disease-specific survival after DTC diagnosis were 50.7 and 52.8 years, respectively. Eight (5%) PTC patients died of disease after a median of 30.7 years (IQR, 20.6-37.6 years). Conclusion: Childhood DTC with DM persists in most patients despite multiple courses of RAI, but disease-specific death is uncommon, typically occurring decades after diagnosis. Fusion genes are highly prevalent in PTC, and all identified molecular alterations have appropriate targeted therapies. Future studies should focus on expanding genotype-phenotype correlations, determining how to integrate molecularly targeted therapy into treatment paradigms, and relying less on repeated courses of RAI to achieve cure in patients with DM from childhood DTC

TAK1 and TBK1 are Differentially Required by GMP- and LMPP-like Leukemia Stem Cells

Acute myeloid leukemia (AML) encompasses a diverse group of cancers that originate in the blood-forming tissues of the bone marrow. Aside from the M3 subtype (PML-RARA+), AML carries a 5-year survival rate of 28% for patients 20+ years of age. AML is the most common cancer of the hematopoietic system and is slightly more common in biological males; the average age at diagnosis is 68 years. Standard frontline treatment for AML is a 2-phase regimen of intensive chemotherapy (CTx) employing daunorubicin and cytarabine. Despite 60-70% of patients achieving complete remission (CR), at least half of CR-achieving patients experience relapse within 3 years from their diagnosis. Additionally, 30-40% of patients present with refractory AML, experiencing little to no benefit from frontline treatment. AML relapses when a pool of undetectable, CTx-resistant leukemia stem cells (LSCs) survives & proliferates after frontline CTx [1]. Notably, the poor performance status of many AML patients precludes use of the standard CTx regimen; while reduced-intensity CTx still offers therapeutic benefit, it is less effective at killing LSCs and, as a result, relapse is more likely. Goardon, et al. determined that AML patients harbor two types of LSCs: granulocyte-macrophage progenitor (GMP)-like LSCs and FLT3+ lymphoid-primed multipotential progenitor (LMPP)-like LSCs [2]. Eradication of both types of LSCs is necessary to maintain CR in AML. Our group and others have established that ~40% of AML patients express upregulated Toll-like receptor (TLR) signaling (TLR+). TLR+ disease is associated with specific genetic abnormalities, such as MLL rearrangements (MLL-r+), and is inversely associated with prognosis (Figure 1) [3,4]. TLR+ AML represents a challenging, treatment-sparse subset of an already difficult-to-treat disease. To study TLR+ AML, we utilize an MLL-r+ model using the MLL-AF9 oncogene. We have also demonstrated that both GMP- and LMPP-like LSCs require TLR-associated Ser/Thr protein kinases for their survival [5-7]. Specifically, GMP-like LSCs require TAK1 and LMPP-like LSCs require TBK1. The loss of either Tak1 or Tbk1 ablates the corresponding LSC pool and enriches for the opposite LSC pool in vitro and in vivo. Recently, our group determined that the genetic loss of Tak1 sensitizes mouse AML cells to TBK1 blockade in vitro. Strikingly, the loss of Tbk1 also seems to extend overall survival (OS) despite causing extramedullary AML. While mice given Tbk1NULL AML cells develop a subcutaneous tumor of AML cells (chloroma) near the pelvis, they survive longer than mice given control (Tbk1WT) AML cells. The clinical significance is unknown, but these data support our impression that the loss of Tbk1 forces AML cells to differentiate; this should be therapeutically favorable, as inducing the differentiation of AML cells is an effective treatment strategy. Theoretically, chloromas may form in Tbk1NULL AML due to the enrichment of GMP-like LSCs, which express higher levels of chemokine receptors. We hypothesize that the differentiation & eradication of LSCs can be induced by blocking TAK1/TBK1 in combination with standard CTx (and possibly targeted agents like Mylotarg®, Venclexta®, and/or Xospata®). We propose TAK1/TBK1 parallel blockade as augmentation to standard CTx, ideally allowing for a dose-reduction of CTx & promoting improved patient outcomes

Ripk3 signaling regulates HSCs during stress and represses radiation-induced leukemia in mice

Receptor-interacting protein kinase 3 (Ripk3) is one of the critical mediators of inflammatory cytokine-stimulated signaling. Here we show that Ripk3 signaling selectively regulates both the number and the function of hematopoietic stem cells (HSCs) during stress conditions. Ripk3 signaling is not required for normal homeostatic hematopoiesis. However, in response to serial transplantation, inactivation of Ripk3 signaling prevents stress-induced HSC exhaustion and functional HSC attenuation, while in response to fractionated low doses of ionizing radiation (IR), inactivation of Ripk3 signaling accelerates leukemia/lymphoma development. In both situations, Ripk3 signaling is primarily stimulated by tumor necrosis factor-α. Activated Ripk3 signaling promotes the elimination of HSCs during serial transplantation and pre-leukemia stem cells (pre-LSCs) during fractionated IR by inducing Mlkl-dependent necroptosis. Activated Ripk3 signaling also attenuates HSC functioning and represses a pre-LSC-to-LSC transformation by promoting Mlkl-independent senescence. Furthermore, we demonstrate that Ripk3 signaling induces senescence in HSCs and pre-LSCs by attenuating ISR-mediated mitochondrial quality control

Molecular responses of European flounder (Platichthys flesus) chronically exposed to contaminated estuarine sediments

Molecular responses to acute toxicant exposure can be effective biomarkers, however responses to chronic exposure are less well characterised. The aim of this study was to determine chronic molecular responses to environmental mixtures in a controlled laboratory setting, free from the additional variability encountered with environmental sampling of wild organisms. Flounder fish were exposed in mesocosms for seven months to a contaminated estuarine sediment made by mixing material from the Forth (high organics) and Tyne (high metals and tributyltin) estuaries (FT) or a reference sediment from the Ythan estuary (Y). Chemical analyses demonstrated that FT sediment contained significantly higher concentrations of key environmental pollutants (including polycyclic aromatic hydrocarbons (PAHs), chlorinated biphenyls and heavy metals) than Y sediment, but that chronically exposed flounder showed a lack of differential accumulation of contaminants, including heavy metals. Biliary 1-hydroxypyrene concentration and erythrocyte DNA damage increased in FT-exposed fish. Transcriptomic and 1H NMR metabolomic analyses of liver tissues detected small but statistically significant alterations between fish exposed to different sediments. These highlighted perturbance of immune response and apoptotic pathways, but there was a lack of response from traditional biomarker genes. Gene-chemical association annotation enrichment analyses suggested that polycyclic aromatic hydrocarbons were a major class of toxicants affecting the molecular responses of the exposed fish. This demonstrated that molecular responses of sentinel organisms can be detected after chronic mixed toxicant exposure and that these can be informative of key components of the mixture

Soy isoflavones, estrogen therapy, and breast cancer risk: analysis and commentary

There has been considerable investigation of the potential for soyfoods to reduce risk of cancer, and in particular cancer of the breast. Most interest in this relationship is because soyfoods are essentially a unique dietary source of isoflavones, compounds which bind to estrogen receptors and exhibit weak estrogen-like effects under certain experimental conditions. In recent years the relationship between soyfoods and breast cancer has become controversial because of concerns – based mostly on in vitro and rodent data – that isoflavones may stimulate the growth of existing estrogen-sensitive breast tumors. This controversy carries considerable public health significance because of the increasing popularity of soyfoods and the commercial availability of isoflavone supplements. In this analysis and commentary we attempt to outline current concerns regarding the estrogen-like effects of isoflavones in the breast focusing primarily on the clinical trial data and place these concerns in the context of recent evidence regarding estrogen therapy use in postmenopausal women. Overall, there is little clinical evidence to suggest that isoflavones will increase breast cancer risk in healthy women or worsen the prognosis of breast cancer patients. Although relatively limited research has been conducted, and the clinical trials often involved small numbers of subjects, there is no evidence that isoflavone intake increases breast tissue density in pre- or postmenopausal women or increases breast cell proliferation in postmenopausal women with or without a history of breast cancer. The epidemiologic data are generally consistent with the clinical data, showing no indication of increased risk. Furthermore, these clinical and epidemiologic data are consistent with what appears to be a low overall breast cancer risk associated with pharmacologic unopposed estrogen exposure in postmenopausal women. While more research is required to definitively allay concerns, the existing data should provide some degree of assurance that isoflavone exposure at levels consistent with historical Asian soyfood intake does not result in adverse stimulatory effects on breast tissue

Group B streptococcus serotype prevalence in reproductive-age women at a tertiary care military medical center relative to global serotype distribution

<p>Abstract</p> <p>Background</p> <p>Group B <it>Streptococcus </it>(GBS) serotype (Ia, Ib, II-IX) correlates with pathogen virulence and clinical prognosis. Epidemiological studies of seroprevalence are an important metric for determining the proportion of serotypes in a given population. The purpose of this study was to evaluate the prevalence of individual GBS serotypes at Madigan Healthcare System (Madigan), the largest military tertiary healthcare facility in the Pacific Northwestern United States, and to compare seroprevalences with international locations.</p> <p>Methods</p> <p>To determine serotype distribution at Madigan, we obtained GBS isolates from standard-of-care anogenital swabs from 207 women of indeterminate gravidity between ages 18-40 during a five month interval. Serotype was determined using a recently described molecular method of polymerase chain reaction by capsular polysaccharide synthesis (cps) genes associated with pathogen virulence.</p> <p>Results</p> <p>Serotypes Ia, III, and V were the most prevalent (28%, 27%, and 17%, respectively). A systematic review of global GBS seroprevalence, meta-analysis, and statistical comparison revealed strikingly similar serodistibution at Madigan relative to civilian-sector populations in Canada and the United States. Serotype Ia was the only serotype consistently higher in North American populations relative to other geographic regions (p < 0.005). The number of non-typeable isolates was significantly lower in the study (p < 0.005).</p> <p>Conclusion</p> <p>This study establishes PCR-based serotyping as a viable strategy for GBS epidemiological surveillance. Our results suggest that GBS seroprevalence remains stable in North America over the past two decades.</p