Comparative evaluation of [(99m)tc]tilmanocept for sentinel lymph node mapping in breast cancer patients: results of two phase 3 trials.

BackgroundSentinel lymph node (SLN) surgery is used worldwide for staging breast cancer patients and helps limit axillary lymph node dissection. [(99m)Tc]Tilmanocept is a novel receptor-targeted radiopharmaceutical evaluated in 2 open-label, nonrandomized, within-patient, phase 3 trials designed to assess the lymphatic mapping performance.MethodsA total of 13 centers contributed 148 patients with breast cancer. Each patient received [(99m)Tc]tilmanocept and vital blue dye (VBD). Lymph nodes identified intraoperatively as radioactive and/or blue stained were excised and histologically examined. The primary endpoint, concordance (lower boundary set point at 90 %), was the proportion of nodes detected by VBD and [(99m)Tc]tilmanocept.ResultsA total of 13 centers contributed 148 patients who were injected with both agents. Intraoperatively, 207 of 209 nodes detected by VBD were also detected by [(99m)Tc]tilmanocept for a concordance rate of 99.04 % (p < 0.0001). [(99m)Tc]tilmanocept detected a total of 320 nodes, of which 207 (64.7 %) were detected by VBD. [(99m)Tc]Tilmanocept detected at least 1 SLN in more patients (146) than did VBD (131, p < 0.0001). In 129 of 131 patients with ≥1 blue node, all blue nodes were radioactive. Of 33 pathology-positive nodes (18.2 % patient pathology rate), [(99m)Tc]tilmanocept detected 31 of 33, whereas VBD detected only 25 of 33 (p = 0.0312). No pathology-positive SLNs were detected exclusively by VBD. No serious adverse events were attributed to [(99m)Tc]tilmanocept.Conclusion[(99m)Tc]Tilmanocept demonstrated success in detecting a SLN while meeting the primary endpoint. Interestingly, [(99m)Tc]tilmanocept was additionally noted to identify more SLNs in more patients. This localization represented a higher number of metastatic breast cancer lymph nodes than that of VBD

Human Galectin-9 Is a Potent Mediator of HIV Transcription and Reactivation.

Identifying host immune determinants governing HIV transcription, latency and infectivity in vivo is critical to developing an HIV cure. Based on our recent finding that the host factor p21 regulates HIV transcription during antiretroviral therapy (ART), and published data demonstrating that the human carbohydrate-binding immunomodulatory protein galectin-9 regulates p21, we hypothesized that galectin-9 modulates HIV transcription. We report that the administration of a recombinant, stable form of galectin-9 (rGal-9) potently reverses HIV latency in vitro in the J-Lat HIV latency model. Furthermore, rGal-9 reverses HIV latency ex vivo in primary CD4+ T cells from HIV-infected, ART-suppressed individuals (p = 0.002), more potently than vorinostat (p = 0.02). rGal-9 co-administration with the latency reversal agent "JQ1", a bromodomain inhibitor, exhibits synergistic activity (p<0.05). rGal-9 signals through N-linked oligosaccharides and O-linked hexasaccharides on the T cell surface, modulating the gene expression levels of key transcription initiation, promoter proximal-pausing, and chromatin remodeling factors that regulate HIV latency. Beyond latent viral reactivation, rGal-9 induces robust expression of the host antiviral deaminase APOBEC3G in vitro and ex vivo (FDR<0.006) and significantly reduces infectivity of progeny virus, decreasing the probability that the HIV reservoir will be replenished when latency is reversed therapeutically. Lastly, endogenous levels of soluble galectin-9 in the plasma of 72 HIV-infected ART-suppressed individuals were associated with levels of HIV RNA in CD4+ T cells (p<0.02) and with the quantity and binding avidity of circulating anti-HIV antibodies (p<0.009), suggesting a role of galectin-9 in regulating HIV transcription and viral production in vivo during therapy. Our data suggest that galectin-9 and the host glycosylation machinery should be explored as foundations for novel HIV cure strategies

Carotid Revascularization and Its Effect on Cognitive Function: A Prospective Nonrandomized Multicenter Clinical Study

© 2020 The Author(s) Background: There is conflicting data on the effect of carotid revascularization on cognitive function. Objective: To examine cerebral blood flow and cognitive function after carotid revascularization. Methods: Patients with unilateral, asymptomatic hemodynamically significant carotid artery stenosis (80% by computed tomography angiography or magnetic resonance angiography) were eligible. Cerebral blood flow was measured preoperatively and 1 month postoperatively using quantitative phase contrast magnetic resonance angiography. Preoperative flow impairment was defined as ipsilateral flow at least 20% less than contralateral flow (ie, an ipsilateral and/or contralateral flow ratio ≤0.8). Significant improvement in blood flow was defined as at least a 0.15 increase in flow ratio from pre- to postoperative. A control group was managed medically. Four cognitive domains were assessed at baseline, 1 month, and 6-12 months postoperatively. Results: Seventy-five patients were enrolled at 6 sites; 53 carotid endarterectomy, 11 carotid artery stenting, and 11 medical management only controls. Preoperative Trails B scores were similar between groups. Revascularization was associated with significant improvement in executive function (Trials B) while no improvement was observed in controls (P = .007). Of patients with improvement in middle cerebral artery (MCA) flow, 90% had improved Trails B scores compared to 46.5% of patients without MCA flow improvement (P = .01). Greater absolute improvement in mean Trails B scores was observed in patients with MCA flow improvement compared to those without (48 seconds versus 24.7 seconds, P = .001). Conclusions: In a cohort of patient with asymptomatic carotid stenosis, improvement in MCA flow following carotid revascularization is associated with improvement in executive functioning

Revisiting investability of heritage properties through indexation and portfolio frontier analysis

In recent years, the soaring prices of heritage properties in Georgetown, Penang have gained the attention of practitioners and investors. The practitioners claim that the prices of heritage properties within the core and buffer zones in Georgetown have increased more than 300% since the city was recognized as a UNESCO World Heritage site in 2008. Such heritage properties containing historical or art elements that lead to forming a diversified portfolio could exert a low correlation of returns with conventional assets. In addition, rehabilitation of heritage properties requires high restoration costs and conversion fees. Despite the above claims, there is an absence of empirical studies relating to heritage investability, particularly to prove whether the heritage properties are truly worth investing in. Thus, this study incorporates a self-developed heritage properties Index (PIHPI_HR) into the conventional investment portfolio for assessing diversification effects. This study has collected 853 units of transacted properties for constructing a 10-year price index (PIHPI_HR). Subsequently, its diversification effect was examined through the Efficient Frontier (EF), derived from the Modern Portfolio Theory (MPT). The findings have proven the optimization of the conventional portfolio by enabling investments in heritage properties where the return is higher than other investment assets at the same risk level. This study also unveiled the price movement of heritage properties together with their investment value, which is deemed to be useful for institutional investors and the public to formulate sustainable investment strategies in the future

Plasma levels of polychlorinated biphenyls (PCBs) and breast cancer mortality: The Carolina Breast Cancer Study

Background: It is unknown whether carcinogenic and endocrine disrupting polychlorinated biphenyls (PCBs) influence mortality following breast cancer. We examined plasma levels of 17 PCB congeners in association with mortality among women with breast cancer. Methods: Participants included 456 white and 292 black women in North Carolina who were diagnosed with primary invasive breast cancer from 1993 to 1996, and who had PCB and lipid measurements from blood samples obtained an average of 4.1 months after diagnosis. Over a median follow-up of 20.6 years, there were 392 deaths (210 from breast cancer). We used Cox regression to estimate covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and breast cancer-specific 5-year mortality, and 20-year mortality (conditional on 5-year survival) in association with tertiles and continuous ln-transformed lipid-adjusted PCB levels. Results: The highest (vs. lowest) tertiles of PCB74, PCB99, and PCB118 were associated with 5-year breast cancer-specific mortality HRs of 1.46 (95%CI = 0.86–2.47), 1.57 (95%CI = 0.90–2.73), and 1.86 (95%CI = 1.07–3.23), respectively. Additionally, one-ln unit increases in PCB74, PCB99, PCB118, and total PCBs were each associated with 33–40% increases in 5-year breast cancer-specific mortality rates. The PCBs were not, however, associated with longer-term breast cancer-specific mortality. For all-cause mortality, one-ln unit increases in PCB118, PCB146, PCB153, PCB182, PCB187, and total PCBs were associated with 20–37% increases in 20-year all-cause mortality rates among women who survived at least 5 years. Conclusion: PCBs may increase the risk of short-term breast cancer-specific mortality and long-term all-cause mortality among women with breast cancer

Ibrutinib restores immune cell numbers and function in first-line and relapsed/refractory chronic lymphocytic leukemia

© 2020 The Authors Ibrutinib positively modulates many T-cell subsets in chronic lymphocytic leukemia (CLL). To understand ibrutinib\u27s effects on the broader landscape of immune cell populations, we comprehensively characterized changes in circulating counts of 21 immune blood cell subsets throughout the first year of treatment in patients with relapsed/refractory (R/R) CLL (n = 55, RESONATE) and previously untreated CLL (n = 50, RESONATE-2) compared with untreated age-matched healthy donors (n = 20). Ibrutinib normalized abnormal immune cell counts to levels similar to those of age-matched healthy donors. Ibrutinib significantly decreased pathologically high circulating B cells, regulatory T cells, effector/memory CD4+ and CD8+ T cells (including exhausted and chronically activated T cells), natural killer (NK) T cells, and myeloid-derived suppressor cells; preserved naive T cells and NK cells; and increased circulating classical monocytes. T-cell function was assessed in response to T-cell receptor stimulation in patients with R/R CLL (n = 21) compared with age-matched healthy donors (n = 18). Ibrutinib significantly restored T-cell proliferative ability, degranulation, and cytokine secretion. Over the same period, ofatumumab or chlorambucil did not confer the same spectrum of normalization as ibrutinib in multiple immune subsets. These results establish that ibrutinib has a significant and likely positive impact on circulating malignant and nonmalignant immune cells and restores healthy T-cell function

The Use of Single-Sided NMR to Study Moisture Behaviour in an Activated Carbon Fibre/Phenolic Composite

Nuclear Magnetic Resonance (NMR) has been shown to be a useful technique to study the form and content of water in polymer composites. Composites using activated carbon fibres with phenolic resin have complex water absorption behaviour which would benefit from such investigation; however, the presence of the conductive fibres can make NMR problematic. In this study, single-sided NMR has been successfully used on such material by developing a method for sample-to-sample compensation for the effect of conductivity. Transverse relaxation curves showed water to be primarily in two states in the resin, corresponding to "bound" and "mobile" molecules. In addition, two much less bound states were identified in the composite, associated firstly with water adsorbed on to the fibre surface and secondly with clusters of water molecules moving more freely within the fibre pores

Electrical control over single hole spins in nanowire quantum dots

Single electron spins in semiconductor quantum dots (QDs) are a versatile platform for quantum information processing, however controlling decoherence remains a considerable challenge. Recently, hole spins have emerged as a promising alternative. Holes in III-V semiconductors have unique properties, such as strong spin-orbit interaction and weak coupling to nuclear spins, and therefore have potential for enhanced spin control and longer coherence times. Weaker hyperfine interaction has already been reported in self-assembled quantum dots using quantum optics techniques. However, challenging fabrication has so far kept the promise of hole-spin-based electronic devices out of reach in conventional III-V heterostructures. Here, we report gate-tuneable hole quantum dots formed in InSb nanowires. Using these devices we demonstrate Pauli spin blockade and electrical control of single hole spins. The devices are fully tuneable between hole and electron QDs, enabling direct comparison between the hyperfine interaction strengths, g-factors and spin blockade anisotropies in the two regimes

A quantum spin transducer based on nano electro-mechancial resonator arrays

Implementation of quantum information processing faces the contradicting requirements of combining excellent isolation to avoid decoherence with the ability to control coherent interactions in a many-body quantum system. For example, spin degrees of freedom of electrons and nuclei provide a good quantum memory due to their weak magnetic interactions with the environment. However, for the same reason it is difficult to achieve controlled entanglement of spins over distances larger than tens of nanometers. Here we propose a universal realization of a quantum data bus for electronic spin qubits where spins are coupled to the motion of magnetized mechanical resonators via magnetic field gradients. Provided that the mechanical system is charged, the magnetic moments associated with spin qubits can be effectively amplified to enable a coherent spin-spin coupling over long distances via Coulomb forces. Our approach is applicable to a wide class of electronic spin qubits which can be localized near the magnetized tips and can be used for the implementation of hybrid quantum computing architectures