Abstract Number ‐ 170: Trends for Endovascular Mechanical Thrombectomy versus Intravenous Tissue Plasminogen Activator for Vertebrobasilar Stroke Treatment

Introduction Acute vertebrobasilar artery occlusion (VBAO) represents approximately 20% of patients presenting with acute ischemic stroke. The occlusion is caused by an embolus or underlying atherosclerotic disease plaque rupture forming an acute thrombus. Without treatment, VBAO’s mortality nears 80–90%, thus, effective and timely treatment strategies become paramount in managing the patients. Herein, we analyzed the age difference and outcomes in patients that underwent either Endovascular Mechanical Thrombectomy (MT) or intravenous (IV) tissue plasminogen activator (tPA). Methods National Inpatient Sample (NIS) was queried from years 2016 to 2018 using ICD‐10 diagnosis and procedure codes for occlusion or thrombosis of vertebral artery or basilar artery (I63.21, I63.22, I63.01, and I63.02), IV tPA (3E03317), and MT (03CG3ZZ, 03CG3Z6, 03CG3Z7, 03CG4Z6, 03CG4ZZ). Chi‐square test and was used for statistical analysis. Results From 2016 to 2018, there were 37,310 patients admitted with vertebrobasilar stroke. Out of these, IV tPA was administered in 2,530 (6.8%) admissions, whereas MT was done in 2,330 (6.2%) admissions. IV tPA was used significantly more than MT in age groups 65–84 and > = 85 years. MT was used significantly more than IV tPA in age groups 18–44 and 45–64 (Figure 1). There was no significant difference in their use between men and women. In large hospitals, MT was more common than IV tPA (8.1% vs 7%, p < 0.0001), and in small hospitals, IV tPA usage was significantly higher (3.8% vs 2%, p < 0.0001). All‐cause mortality rate was significantly higher in MT than IV tPA admissions (16.8% vs 8.1%, p < 0.0001). There was no significant difference in mean length of stay (LOS) between the two modalities (Figure 1). Conclusions We saw a trend of higher rate of mechcnical thrombectomy in younger age group (18‐64 years) than older, however, no sex difference was noted. All‐cause mortality rate was higher in the mechanical thrombectomy group than intravenous tissue plasminogen activator group. In addition, there was no difference in length of hospital stay

NOTCH pathway inactivation reprograms stem-like oral cancer cells to JAK-STAT dependent state and provides the opportunity of synthetic lethality

Background: We have recently provided the evidence of interconvertible cellular states, driving non-genetic heterogeneity among stem-like oral cancer cells (oral-SLCCs). Here, NOTCH pathway-activity status is explored as one of the possible mechanisms behind this stochastic plasticity. Methods: Oral-SLCCs were enriched in 3D-spheroids. Constitutively-active and inactive status of NOTCH pathway was achieved by genetic or pharmacological approaches. RNA sequencing and real-time PCR was performed for gene expression studies. in vitro cytotoxicity assessments were performed by AlamarBlue assay and in vivo effects were studied by xenograft growth in zebrafish embryo. Results: We have observed stochastic plasticity in oral-SLCCs, spontaneously maintaining both NOTCH-active and inactive states. While cisplatin refraction was associated with post-treatment adaptation to the active-state of NOTCH pathway, oral-SLCCs with inactive NOTCH pathway status showed aggressive tumor growth and poor prognosis. RNAseq analysis clearly suggested the upregulation of JAK-STAT pathway in NOTCH pathway-inactive subset. The 3D-spheroids with lower NOTCH-activity status displayed significantly higher sensitivity to JAK-selective drugs, Ruxolitinib or Tofacitinib or siRNA mediated downregulation of tested partners STAT3/4. Oral-SLCCs were programmed to adapt the inactive status of NOTCH pathway by exposing to γ-secretase inhibitors, LY411575 or RO4929097, followed by targeting with JAK-inhibitors, Ruxolitinib or Tofacitinib. This approach resulted in a very significant inhibition in viability of 3D-spheroids as well as xenograft initiation in Zebrafish embryos. Conclusion: Study revealed for the first time that NOTCH pathway-inactive state exhibit activation of JAK-STAT pathways, as synthetic lethal pair. Therefore, co-inhibition of these pathway may serve as novel therapeutic strategy against aggressive oral cancer

Telomere length-dependent transcription and epigenetic modifications in promoters remote from telomere ends.

Telomere-binding proteins constituting the shelterin complex have been studied primarily for telomeric functions. However, mounting evidence shows non-telomeric binding and gene regulation by shelterin factors. This raises a key question-do telomeres impact binding of shelterin proteins at distal non-telomeric sites? Here we show that binding of the telomere-repeat-binding-factor-2 (TRF2) at promoters ~60 Mb from telomeres depends on telomere length in human cells. Promoter TRF2 occupancy was depleted in cells with elongated telomeres resulting in altered TRF2-mediated transcription of distal genes. In addition, histone modifications-activation (H3K4me1 and H3K4me3) as well as silencing marks (H3K27me3)-at distal promoters were telomere length-dependent. These demonstrate that transcription, and the epigenetic state, of telomere-distal promoters can be influenced by telomere length. Molecular links between telomeres and the extra-telomeric genome, emerging from findings here, might have important implications in telomere-related physiology, particularly ageing and cancer

Correction: Telomere length-dependent transcription and epigenetic modifications in promoters remote from telomere ends.

[This corrects the article DOI: 10.1371/journal.pgen.1007782.]

Instantaneous Gelation of a Self-Healable Wide-Bandgap Semiconducting Supramolecular Mg(II)-Metallohydrogel: An Efficient Nonvolatile Memory Design with Supreme Endurance

An efficient strategy for room-temperature, atmospheric-pressure synthesis of a supramolecular metallohydrogel of the Mg(II) ion, i.e., Mg@3AP, using the metal-coordinating organic ligand 3-amino-1-propanol as a low-molecular-weight gelator (LMWG) in a water medium has been developed. Through a rheological analysis, we looked into the mechanical properties of the supramolecular Mg(II)-metallohydrogel. The self-healing nature of the metallohydrogel is confirmed along with the thixotropic characteristics. Investigation using field emission scanning electron microscopy revealed the hierarchical network of the supramolecular metallohydrogel. The EDX elemental mapping confirms the primary chemical constituents of the metallohydrogel. The possible metallohydrogel formation strategy has been analyzed through FT-IR spectroscopic studies. In this work, Schottky diode structures in a metal–semiconductor–metal geometry structures based on a magnesium(II) metallohydrogel (Mg@3AP) have been constructed, and charge transport behavior has been observed. Furthermore, here, it is demonstrated that the resistive random access memory (RRAM) device based on Mg@3AP exhibits bipolar resistive switching behavior at room temperature and ambient conditions. We have also looked into the switching mechanism through the formation (rupture) of conductive filaments between the metal electrodes to understand the process of resistive switching behavior. With a high on/off ratio (∼100), this RRAM device exhibits remarkable switching endurance over 10,000 switching cycles. These structures are suitable for use in nonvolatile memory design, neuromorphic computing, flexible electronics, and optoelectronics, among other fields, due to their simple fabrication procedures, reliable resistive switching behavior, and stability of the current system