Intrinsic Room-Temperature Ferromagnetism in New Halide Perovskite AgCrX3 (X: F, Cl, Br, I) Using Ab Initio and Monte Carlo Simulations.

Herein, we present a detailed comparative study of the structural, elastic, electronic, and magnetic properties of a series of new halide perovskite AgCrX3 (X: F, Cl, Br, I) crystal structures using density functional theory, mean-field theory (MFT), and quantum Monte Carlo (MC) simulations. As demonstrated by the negative formation energy and Born-Huang stability criteria, the suggested perovskite compounds show potential stability in the cubic crystal structure. The materials are ductile because the Pugh's ratio is greater than 1.75, and the Cauchy pressure (C12-C44) is positive. The ground state magnetic moments of the compound were calculated as 3.70, 3.91, 3.92, and 3.91 µB for AgCrF3, AgCrCl3, AgCrBr3, and AgCrI3, respectively. The GGA + SOC computed spin-polarized electronic structures reveal ferromagnetism and confirm the metallic character in all of these compounds under consideration. These characteristics are robust under a ±3% strained lattice constant. Using relativistic pseudopotentials, the total energy is calculated, which yields that the single ion anisotropy is 0.004 meV and the z-axis is the hard-axis in the series of AgCrX3 (X: F, Cl, Br, and I) compounds. Further, to explore room-temperature intrinsic ferromagnetism, we considered ferromagnetic and antiferromagnetic interactions of the magnetic ions in the compounds by considering a supercell with 2 × 2 × 2 dimensions. The transition temperature is estimated by two models, namely, MFT and MC simulations. The calculated Curie temperatures using MC simulations are 518.35, 624.30, 517.94, and 497.28 K, with ±5% error for AgCrF3, AgCrCl3, AgCrBr3, and AgCrI3 compounds, respectively. Our results suggest that halide perovskite AgCrX3 compounds are promising materials for spintronic nanodevices at room temperature and provide new recommendations. For the first time, we report results for novel halide perovskite compounds based on Ag and Cr atoms.

Synthesis, In Vitro Biological Evaluation and Molecular Modeling of Benzimidazole-Based Pyrrole/Piperidine Hybrids Derivatives as Potential Anti-Alzheimer Agents.

Benzimidazole-based pyrrole/piperidine analogs (1-26) were synthesized and then screened for their acetylcholinesterase and butyrylcholinesterase activities. All the analogs showed good to moderate cholinesterase activities. Synthesized compounds (1-13) were screened in cholinesterase enzyme inhibition assays and showed AChE activities in the range of IC50 = 19.44 ± 0.60 µM to 36.05 ± 0.4 µM against allanzanthane (IC50 = 16.11 ± 0.33 µM) and galantamine (IC50 = 19.34 ± 0.62 µM) and varied BuChE inhibitory activities, with IC50 values in the range of 21.57 ± 0.61 µM to 39.55 ± 0.03 µM as compared with standard allanzanthane (IC50 = 18.14 ± 0.05 µM) and galantamine (IC50 = 21.45 ± 0.21 µM). Similarly, synthesized compounds (14-26) were also subjected to tests to determine their in vitro AChE inhibitory activities, and the results obtained corroborated that all the compounds showed varied activities in the range of IC50 = 22.07 ± 0.13 to 42.01 ± 0.02 µM as compared to allanzanthane (IC50 = 20.01 ± 0.12 µM) and galantamine (IC50 = 18.05 ± 0.31 µM) and varied BuChE inhibitory activities, with IC50 values in the range of 26.32 ± 0.13 to 47.03 ± 0.15 µM as compared to standard allanzanthane (IC50 = 18.14 ± 0.05 µM) and galantamine (IC50 = 21.45 ± 0.21 µM). Binding interactions of the most potent analogs were confirmed through molecular docking studies. The active analogs 2, 4, 10 and 13 established numerous interactions with the active sites of targeted enzymes, with docking scores of -10.50, -9.3, -7.73 and -7.8 for AChE and -8.97, -8.2, -8.20 and -7.6 for BuChE, respectively.

Toward Verification of DAG-Based Distributed Ledger Technologies through Discrete-Event Simulation.

As the potential of directed acyclic graph (DAG)-based distributed ledgers in IoT systems unfolds, a need arises to understand their intricate dynamics in real-world scenarios. It is well known that discrete event simulations can provide high-fidelity evaluations of protocols. However, there is a lack of public discrete event simulators capable of assessing DAG-based distributed ledgers. In this paper, a discrete-event-based distributed ledger simulator is introduced, with which we investigate a custom Python-based implementation of IOTA's Tangle DAG protocol. The study reveals the dynamics of Tangle (particularly Poisson processes in transaction dynamics), the efficiency and intricacies of the random walk in Tangle, and the quantitative assessment of node convergence. Furthermore, the research underscores the significance of weight updates without depth limitations and provides insights into the role, challenges, and implications of the coordinator/validator in DAG architectures. The results are striking, and although the findings are reported only for Tangle, they demonstrate the need for adaptable and versatile discrete event simulators for DAG architectures and tip selection methodologies in general.

Initial local resection versus early referral for spermatic cord sarcoma: Any impact on treatment timelines and oncological outcomes?

OBJECTIVES: Spermatic cord sarcomas are exceedingly rare, often misdiagnosed and subsequently improperly treated at local hospitals. This retrospective study looked at the oncological outcomes of spermatic cord sarcoma cases managed with curative intent resection at a tertiary referral sarcoma centre. We specifically studied how initial inadequate resections impact the oncologic outcomes compared to primary tumour resections at the reference centre. METHODS: One hundred eighteen consecutive patients affected by primary, localized spermatic cord sarcoma surgically managed at our reference centre from January 2001 through January 2021 were included. Primary endpoints were local relapse free (LRFS), distant metastasis free (DMFS) and overall survival (OS). These outcomes were evaluated with multi-nomial logistic regression and Cox proportional hazards regression models for a co-relation to known patient, tumour and treatment-related prognostic factors, including a prior inadequate resection and time from diagnosis to a complete oncologic resection as independent variables. Secondarily, we compared the above variables and treatment intervals among the subgroups of primary versus re-resection surgery. RESULTS: Over a median follow-up of 54 months (IQR 25-105), 12 patients (10.2%) developed local recurrence (LR) and 14 (11.6%) had distant metastasis (DM). 5-year local relapse (LRFS) and distant metastasis-free survival (DMFS) were 89.3% and 86.5%, respectively. Higher tumour grade and size were associated with a worse DMFS (p=<0.05). Likewise, marginal (R1) resection correlated with an inferior LRFS (p=< 0.05). Eighty-four patients (71.2%) had their initial diagnosis established on an inadequate surgical excision performed in a local hospital, followed by a re-excision at our centre (Re-resection group). During the same period, 34 (28.8%) were managed primarily with biopsy and treatment at our reference centre (Primary-resection group). The two groups had statistically significant differences in tumour size, histopathology, surgery duration, rate of postoperative complication and R0 resection (p < 0.005). Additionally, the difference in time intervals to achieve the treatment targets was statistically insignificant and did not correlate to the risk of recurrence as an independent variable. Residual disease was present in 51.2 % (n = 43) of the re-excision specimens. However, following a complete R0 resection, this did not correlate with a higher risk of recurrence (p = 0.481). CONCLUSION: Prompt referral to a tertiary centre, where multidisciplinary evaluation and sound oncologic resections are the standard of treatment, can align the OS and DFS of patients receiving incomplete surgery elsewhere to those treated primarily in referral centres. The primary determinant of prognosis remains surgical margin, tumour size and grade.

A machine learning driven automated system for safety data sheet indexing.

Safety Data Sheets (SDS) are foundational to chemical management systems and are used in a wide variety of applications such as green chemistry, industrial hygiene, and regulatory compliance, among others within the Environment, Health, and Safety (EHS) and the Environment, Social, and Governance (ESG) domains. Companies usually prefer to have key pieces of information extracted from these datasheets and stored in an easy to access structured repository. This process is referred to as SDS "indexing". Historically, SDS indexing has always been done manually, which is labor-intensive, time-consuming, and costly. In this paper, we present an automated system to index the composition information of chemical products from SDS documents using a multi-stage ensemble method with a combination of machine learning models and rule-based systems stacked one after the other. The system specifically indexes the ingredient names, their corresponding Chemical Abstracts Service (CAS) numbers, and weight percentages. It takes the SDS document in PDF format as the input and gives the list of ingredient names along with their corresponding CAS numbers and weight percentages in a tabular format as the output. The system achieves a precision of 0.93 at the document level when evaluated on 20,000 SDS documents annotated for this purpose.

The Molecular Basis of Wnt/ß-Catenin Signaling Pathways in Neurodegenerative Diseases.

Defective Wnt signaling is found to be associated with various neurodegenerative diseases. In the canonical pathway, the Frizzled receptor (Fzd) and the lipoprotein receptor-related proteins 5/6 (LRP5/LRP6) create a seven-pass transmembrane receptor complex to which the Wnt ligands bind. This interaction causes the tumor suppressor adenomatous polyposis coli gene product (APC), casein kinase 1 (CK1), and GSK-3ß (glycogen synthase kinase-3 beta) to be recruited by the scaffold protein Dishevelled (Dvl), which in turn deactivates the ß-catenin destruction complex. This inactivation stops the destruction complex from phosphorylating ß-catenin. As a result, ß-catenin first builds up in the cytoplasm and then migrates into the nucleus, where it binds to the Lef/Tcf transcription factor to activate the transcription of more than 50 Wnt target genes, including those involved in cell growth, survival, differentiation, neurogenesis, and inflammation. The treatments that are currently available for neurodegenerative illnesses are most commonly not curative in nature but are only symptomatic. According to all available research, restoring Wnt/ß-catenin signaling in the brains of patients with neurodegenerative disorders, particularly Alzheimer's and Parkinson's disease, would improve the condition of several patients with neurological disorders. The importance of Wnt activators and modulators in patients with such illnesses is to mainly restore rather than overstimulate the Wnt/ß-catenin signaling, thereby reestablishing the equilibrium between Wnt-OFF and Wnt-ON states. In this review, we have tried to summarize the significance of the Wnt canonical pathway in the pathophysiology of certain neurodegenerative diseases, such as Alzheimer's disease, cerebral ischemia, Parkinson's disease, Huntington's disease, multiple sclerosis, and other similar diseases, and as to how can it be restored in these patients.

Oncologic outcomes of surgically managed primary pelvic soft tissue sarcoma; tumour biology or surgical constraints of the true pelvis?

BACKGROUND: Pelvic soft tissue sarcomas are rare. Potentially curative resection remains challenging due to anatomical constraints of true pelvis and tumour spread through various anatomical hiatus. We sought to review the oncological outcomes of surgically managed cases at our centre and determine whether outcomes differ for patients with localised (limited to pelvis) versus extensive disease (with extra-pelvic extension). METHODS: Sixty-seven patients who underwent surgical resection with curative intent at the centre for primary, non-metastatic, WHO intermediate to high-grade soft tissue sarcoma of the true pelvis from January 2012 through January 2020 were analysed. Establishment of the extent of disease was made by review of pre-treatment imaging and surgical notes. Oncologic endpoints examined were resection margin, recurrence rate, disease-free and overall survival. RESULTS: Rates of complete oncological resection and disease control were similar for tumours with localised or extensive disease. On logistic regression analysis, tumour grade, and a negative resection margin (R0) correlated with the risk of recurrence (p=<0.05). On further multinomial analysis, R0 resection was associated with improved local control, but not metastatic relapse (p = 0.003). 5-year local recurrence-free and distant metastasis-free survival were 61.3% and 67.1%, respectively. Five and 10-year overall survival were 64% and 36%, respectively. Age >50 years and high tumour grade were associated with a worse outcome (p < 0.05). CONCLUSIONS: When potentially curative surgery is performed for pelvic sarcoma, disease-extent does not influence oncologic outcomes. While a complete oncologic resection determines the risk of local recurrence, tumour grade and metastatic relapse remain primary prognostic determinants for overall survival.

The efficacy of therapist-supported acceptance and commitment therapy-based bibliotherapy for psychological distress after stroke: a single-case multiple-baseline study.

BACKGROUND: Psychological distress is common after stroke, and affects recovery. However, there are few evidence-based psychological treatments. This study evaluates a bibliotherapy-based approach to its amelioration. AIMS: To investigate a stroke-specific self-management book, based on acceptance and commitment therapy (ACT), as a therapist-supported intervention for psychological distress after stroke. METHOD: The design was a single case, randomised non-concurrent multiple-baseline design (MBD). Sixteen stroke survivors, eight males and eight females (mean age 60.6 years), participated in an MBD with three phases: A (randomised-duration baseline); B (intervention); and follow-up (at 3 weeks). During the baseline, participants received therapist contact only. In the bibliotherapy intervention, participants received bi-weekly therapist support. The primary measures of psychological distress (General Health Questionaire-12; GHQ-12) and quality of life (Satisfaction with Life Scale; SWLS) were completed weekly. Secondary measures of mood, wellbeing and illness impact were completed pre- and post-intervention. RESULTS: Omnibus whole-group TAU-U analysis was statistically significant for each primary measure with a moderate effect size on both (0.6 and 0.3 for GHQ-12 and SWLS, respectively). Individual TAU-U analyses demonstrated that the majority of individuals exhibited positive change. All the secondary measures showed significant pre-post improvements. Eighty-one per cent of participants reported the book was helpful and 81% also found the ACT-based sections helpful. Relative risk calculations showed finding the book helpful was associated with improvement in GHQ-12 and SWLS scores. CONCLUSIONS: ACT-based bibliotherapy, with therapist support, is a promising intervention for psychological difficulties after stroke.

Mechanisms of RNA export and nuclear retention.

With the identification of huge amount of noncoding RNAs in recent years, the concept of RNA localization has extended from traditional mRNA export to RNA export of mRNA and ncRNA as well as nuclear retention of ncRNA. This review aims to summarize the recent findings from studies on the mechanisms of export of different RNAs and nuclear retention of some lncRNAs in higher eukaryotes, with a focus on splicing-dependent TREX recruitment for the export of spliced mRNA and the sequence-dependent mechanism of mRNA export in the absence of splicing. In addition, evidence to support the involvement of m6 A modification in RNA export with the coordination between the methylase complex and TREX complex as well as sequence-dependent nuclear retention of lncRNA is recapitulated. Finally, a model of sequence-dependent RNA localization is proposed along with the many questions that remain to be answered. This article is categorized under: RNA Export and Localization > RNA Localization RNA Export and Localization > Nuclear Export/Import.

Diffusion coefficients of electrorheological complex (dusty) plasmas.

Equilibrium molecular dynamics (EMD) simulations have been executed to investigate the parallel (D║) and perpendicular (D┴) diffusion coefficients for three-dimensional (3D) strongly coupled (SC) electrorheological complex (dusty) plasmas (ERCPs). The effects of uniaxial (z-axis) AC electric field (MT) on dust grains have been investigated along with various combinations of plasma parameters (Γ, κ). The new outcomes obtained by mean squared displacement of Einstein relation show diffusion coefficients for low-intermediate to high plasma couplings (Γ) for varying MT. The D║ and D┴ at MT = 0.01 agree well with earlier available data obtained from the Green-Kubo and Einstein relation for 3D SC-Yukawa systems. The simulation data show that D║ increased with an increase in moderate MT strength and that D┴ decreased for the intermediate to large MT strength. Both (D║ and D┴) remained nearly constant for low MT values. The investigations show that the current EMD scheme is more efficient for nonideal gas-like, liquid-like, and solid-like states of SC-ERCPs. It has been demonstrated that present simulation outcomes extended the MT range up to 0.01 ≤ MT ≤ 10 to understand the diffusive and rheological behaviors of dusty plasma systems.

A Survey and Ontology of Blockchain Consensus Algorithms for Resource-Constrained IoT Systems.

The basic properties of blockchain, such as decentralization, security, and immutability, show promising potential for IoT applications. The main feature-decentralization of blockchain technology-depends on the consensus. However, consensus algorithms are mostly designed to work in extensive computational and communication environments for network security and immutability, which is not desirable for resource-restricted IoT applications. Many solutions are proposed to address this issue with modified consensus algorithms based on the legacy consensus, such as the PoW, PoS, and BFT, and new non-linear data structures, such as DAG. A systematic classification and analysis of various techniques in the field will be beneficial for both researchers and industrial practitioners. Most existing relevant surveys provide classifications intuitively based on the domain knowledge, which are infeasible to reveal the intrinsic and complicated relationships among the relevant basic concepts and techniques. In this paper, a powerful tool of systematic knowledge classification and explanation is introduced to structure the survey on blockchain consensus algorithms for resource-constrained IoT systems. More specifically, an ontology was developed for a consensus algorithm apropos of IoT adaptability. The developed ontology is subdivided into two parts-CONB and CONIoT-representing the classification of generic consensus algorithms and the ones that are particularly proposed for IoT, respectively. Guided by this ontology, an in depth discussion and analysis are provided on the major consensus algorithms and their IoT compliance based on design and implementation targets. Open research challenges and future research directions are provided.

Evaluation of outcomes in the management of primary sporadic desmoid-type fibromatosis at a specialist soft tissue sarcoma unit.

BACKGROUND: Desmoids are rare fibroblastic tumours whose treatment in any individual case presents a persistent challenge. We endeavoured to evaluate various clinicopathological factors contributing to tumour behaviour. METHODS: This is a retrospective review of 95 primary truncal sporadic fibromatosis managed between 2011 and 2020. We studied progression rate for wait and watch (WW) and recurrence rate for the surgically treated group as adverse events. Relevant event-free survivals and potential risk factors were analysed over a median follow-up of 27 months. RESULTS: 66 patients (69.5%) received watchful surveillance and 28 upfront surgery. 2-year progression-free survival in WW group (88.9%) was higher than RFS in the surgical group (77.1%) p = 0.02. Adverse event rate compared favourably, 28.8% in WW and 28.6% in surgical group. At final follow-up, rate of stable disease for WW was 47%, and the regression rate was 24.2%. On Cox regression analysis, meantime to progress was 14 ± 2.0 months, with larger tumour size as a significant prognostic indicator (p = 0.05). Surgical group's mean time to recurrence was 13.8 ± 2.76 months, with tumour location a significant contributing factor (p = 0.05). CONCLUSIONS: This study confirms to the safety of both treatment approaches. Adverse event rates remained comparable, but event-free survival was longer for the watchful surveillance group.

Recent Development in Coordination Compounds as a Sensor for Cyanide Ions in Biological and Environmental Segments.

Rapid detection of toxic ions has taken great attention in the last few decades due to its importance in maintaining a greener environment for human beings. The extreme toxicity of cyanide (CN-) ions is a great environmental concern as its continued industrial use generates interest in facile and sensitive methods for CN- ions detection. Since CN- ions act as a ligand in coordination chemistry which rapidly coordinates with suitable metals and forms complexes, this ability was mainly explored in its detection. It also attacks the central metal in coordination compounds and gives a fluorimetric response. Coordination compounds behave as a sensor for the detection of important ions like CN- ions and have gained great attention due to their facile synthesis, multianalyte detection, clear detection and low detection limit. Recently, considerable efforts have been devoted to the detection and quantification of hazardous multianalyte using a single probe. Cu2+ complexes are the main complexes used for CN- ions detection; however, the complexes of many other metals are also used as sensors. Four basic types of interaction have been discussed in coordination compound sensors for CN- detection. The performances of different sensors are compared with one another and the sensors which have the lowest detection limit are highlighted. This review comprises the progress made by coordination compounds as sensors for the detection of CN- ions in the last six years (2015-2021). To the best of our knowledge, there is no review on coordination compounds as a sensor for CN- ions during this period.

PUMILIO competes with AUF1 to control DICER1 RNA levels and miRNA processing.

DICER1 syndrome is a cancer pre-disposition disorder caused by mutations that disrupt the function of DICER1 in miRNA processing. Studying the molecular, cellular and oncogenic effects of these mutations can reveal novel mechanisms that control cell homeostasis and tumor biology. Here, we conduct the first analysis of pathogenic DICER1 syndrome allele from the DICER1 3'UTR. We find that the DICER1 syndrome allele, rs1252940486, abolishes interaction with the PUMILIO RNA binding protein with the DICER1 3'UTR, resulting in the degradation of the DICER1 mRNA by AUF1. This single mutational event leads to diminished DICER1 mRNA and protein levels, and widespread reprogramming of miRNA networks. The in-depth characterization of the rs1252940486 DICER1 allele, reveals important post-transcriptional regulatory events that control DICER1 levels.

Recent Progress in Nanoparticles Based Sensors for the Detection of Mercury (II) Ions in Environmental and Biological Samples.

To maintain a green and sustainable environment for human beings, rapid detection of potentially toxic heavy metals like mercury (Hg(II)) has attracted great attention. Recently, sensors have been designed which can selectively detect Hg(II) over other common available cations and give a naked eye or fluorometric response. In the last two decades, the trend is shifting from bulky organic chemosensors toward nanoparticles due to their rapid response, low cost, eco-friendly and easy synthesis. In this review, promising nanoparticles-based sensors for Hg(II) detection are discussed. The nano-sensors are functionalized with nucleotide or other suitable materials which coordinate with Hg(II) ions and give clear color or fluorescence change. The operational mechanisms are discussed focusing on its four basic types. The nanoparticles-based sensors are even able to detect Hg in three different oxidation states (Hg(II), Hg(I) and Hg(0)). Recently, the trend has been shifted from ordinary nanoparticles to magnetic nanoparticles to simultaneously detect and remove Hg(II) ions from environmental samples. Furthermore, the nano-sensors for Hg(II) are compared with each other and with the reported organic chemosensors.

Sequence-dependent recruitment of SRSF1 and SRSF7 to intronless lncRNA NKILA promotes nuclear export via the TREX/TAP pathway.

The TREX-TAP pathway is vital for mRNA export. For spliced mRNA, the TREX complex is recruited during splicing; however, for intronless mRNA, recruitment is sequence dependent. However, the export of cytoplasmic long noncoding RNA (lncRNA) is poorly characterized. We report the identification of a cytoplasmic accumulation region (CAR-N) in the intronless lncRNA, NKILA. CAR-N removal led to strong nuclear retention of NKILA, and CAR-N insertion promoted the export of cDNA transcripts. In vitro RNP purification via CAR-N, mass spectrometry, and siRNA screening revealed that SRSF1 and SRSF7 were vital to NKILA export, and identified a cluster of SRSF1/7 binding sites within a 55 nucleotide sequence in CAR-N. Significant nuclear enrichment of NKILA was observed for NKILA lacking CAR-N or the cluster of binding sites in knock-in models. Depletion of TREX-TAP pathway components resulted in strong nuclear retention of NKILA. RNA and protein immunoprecipitation verified that SRSF1/7 were bound to NKILA and interacted with UAP56 and ALYREF. Moreover, NKILA lacking CAR-N was unable to inhibit breast cancer cell migration. We concluded that the binding of SRSF1/7 to clustered motifs in CAR-N facilitated TREX recruitment, promoting the export of NKILA, and confirmed the importance of NKILA localization to its function.

Prognostic Factors for Recurrence in Esophageal Cancer Patients Treated With Neoadjuvant Therapy and Surgery: A Single-institution Analysis.

Background The purpose of this study is to analyze potential predisposing factors for a higher risk of recurrence in our esophageal cancer patients managed with neoadjuvant chemotherapy, radiation therapy, and surgery, and to determine their impact on disease-free survival (DFS) and time to recurrence. Methods A total of 154 of 232 patients staged T1b to T4a managed electively at our institute from July 2005 through July 2015 with a tri-modality approach were retrospectively evaluated. Basic demographic, clinical, radiological, operative, and pathological disease-related parameters, along with waiting time for surgery and type of neoadjuvant modality used, were assessed as potential risk factors. The primary endpoint was the impact of these on the risk of recurrence. The secondary endpoint was to study their relation on DFS and time to recurrence. Results The recurrence rate in this particular study was 33.1% over a median follow-up of 35 months (interquartile range = 19-50.3). The median time to recurrence was 12 months, and 94% of recurrences occurred within two years. The median DFS was 33 months, and the one- and three-year DFS was 90% and 72%, respectively. On univariate and multivariate analysis, a complete pathological response (hazard ratio [HR]: 3.8, 95% confidence interval [CI]: 1.41-10.11), negative resection margins (HR: 5.9, 95% CI: 1.69-20.45), and a low nodal index (HR: 6.3, 95% CI: 1.37-28.67 for an index of 0.1-0.2; and HR: 15.2, 95% CI: 0.96-241.73 for an index of >0.2) were found as statistically significant (P = < 0.05) for risk to recurrence. In addition to these three, a low comorbidity index (P = 0.03; HR: 3.5; 95% CI: 1.16-10.52) was an individual positive predictor of DFS. Conclusions A complete pathological response, low nodal index, and margin-negative resection were the identified predictors of freedom from recurrence, with a better DFS and a low comorbidity index as additional indicators of prolonged DFS.

Risk factors and patterns of recurrence after curative resection in Gastroesophageal Junction Adenocarcinoma.

OBJECTIVES: We looked at risk factors and patterns of recurrence following surgical treatment of Gastro-Oesophageal Junction carcinoma (GOJC). METHODS: Electronic medical records of patients with GOJC undergoing resection with curative intent between Jan 2009 and June 2017 at Shaukat Khanum Memorial Cancer Hospital were reviewed. GOJ cancer was classified as per Siewert classification. Clinical and operative details were studied and data was analysed using SPSS 20. RESULTS: During the study period, we identified 78 patients with GOJ adenocarcinoma (38 patients with GOJ Type-I, 16 with Type-II tumors and 24 patients with GOJ Type-III tumors). Median age was 56 years ± 1.1. Male to female distribution was 72 versus 28%. Carbo-Pacli /5-FU based XRT verses Magic protocol (p<0.015) and advanced pathological T.-stage (p-value<0.032) were found to be statistically significant risk factors for recurrence. After a median follow up of 17.8 months+/- 1.5, 20 patients developed recurrence of which five had local recurrence, three had regional recurrence, eight had distant metastases and four had both local and distant metastases. CONCLUSION: The incidence of recurrence following curative resection of GOJC is 25%. Type of neoadjuvant treatment, waiting time for surgery and advanced T-stage are a risk factor for recurrence.

XAB2 depletion induces intron retention in POLR2A to impair global transcription and promote cellular senescence.

XAB2 is a multi-functional protein participating processes including transcription, splicing, DNA repair and mRNA export. Here, we report POLR2A, the largest catalytic subunit of RNA polymerase II, as a major target gene down-regulated after XAB2 depletion. XAB2 depletion led to severe splicing defects of POLR2A with significant intron retention. Such defects resulted in substantial loss of POLR2A at RNA and protein levels, which further impaired global transcription. Treatment of splicing inhibitor madrasin induced similar reduction of POLR2A. Screen using TMT-based quantitative proteomics identified several proteins involved in mRNA surveillance including Dom34 with elevated expression. Inhibition of translation or depletion of Dom34 rescued the expression of POLR2A by stabilizing its mRNA. Immuno-precipitation further confirmed that XAB2 associated with spliceosome components important to POLR2A expression. Domain mapping revealed that TPR motifs 2-4 and 11 of XAB2 were critical for POLR2A expression by interacting with SNW1. Finally, we showed POLR2A mediated cell senescence caused by XAB2 deficiency. Depletion of XAB2 or POLR2A induced cell senescence by up-regulation of p53 and p21, re-expression of POLR2A after XAB2 depletion alleviated cellular senescence. These data together support that XAB2 serves as a guardian of POLR2A expression to ensure global gene expression and antagonize cell senescence.