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1.
Mol Cancer Ther ; 2023 Jan 24.
Article in English | MEDLINE | ID: mdl-36696581

ABSTRACT

Antibodies targeting IGF-1R induce objective responses in only 5-15% of children with sarcoma. Understanding mechanisms of resistance may identify combination therapies that optimize efficacy of IGF-1R-targeted antibodies. Sensitivity to the IGF1R-targeting antibody TZ-1 was determined in rhabdomyosarcoma (RMS) and Ewing sarcoma (EWS) cell lines. Acquired resistance to TZ-1 was developed and characterized in sensitive Rh41 cells. BRD4 inhibitor, JQ1 was evaluated as an agent to prevent acquired TZ-1 resistance in Rh41 cells. The phosphorylation status of RTKs was assessed. Sensitivity to TZ-1 in vivo was determined in Rh41 parental and TZ-1-resistant xenografts. Of 20 sarcoma cell lines, only Rh41 was sensitive to TZ-1. Cells intrinsically resistant to TZ-1 expressed multiple (>10) activated RTKs or a relatively less complex set of activated RTKs (~5). TZ-1 decreased the phosphorylation of IGF-1R, but had little effect on other pRTKs in all resistant lines. TZ-1 rapidly induced activation of RTKs in Rh41 that was partially abrogated by knockdown of SOX18 and JQ1. Rh41/TZ-1 cells selected for acquired resistance to TZ-1 constitutively expressed multiple activated RTKs. TZ-1 treatment caused complete regressions in Rh41 xenografts, and was significantly less effective against the Rh41/TZ-1 xenograft. Intrinsic resistance is a consequence of redundant signaling in pediatric sarcoma cell lines. Acquired resistance in Rh41 cells, is associated with rapid induction of multiple RTKs indicating a dynamic response to IGF-1R blockade and rapid development of resistance. The TZ-1 antibody had greater antitumor activity against Rh41 xenografts compared to other IGF-1R-targeted antibodies tested against this model.

2.
Infez Med ; 30(4): 563-569, 2022.
Article in English | MEDLINE | ID: mdl-36482963

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children typically results in similar symptoms with other viral respiratory agents including human adenoviruses (HAdVs). Mixed HAdV and SARS-CoV-2 infection (co-infection) in children might result in enhanced or reduced disease severity compared with single infections. The present study aims to investigate the rate of SARS-CoV2 and HAdV infection and also their coinfection and compare the two infections regarding their laboratory and clinical characteristics at hospital admission. A total of 360 combined oropharyngeal and nasopharyngeal swab samples from hospitalized children were examined by real-time PCR for the existence of the SARS-CoV-2 and HAdVs. The symptoms, the clinical characteristics and laboratory findings were retrieved and compared in SARS-CoV-2 and HAdVs positive cases. Of the total 360 suspected COVID-19 hospitalized children, 45 (12.5%) and 19 (5.3%) specimens were PCR-positive for SARS-CoV-2 and HAdV respectively. SARS-CoV-2 and HAdV co-infection was detected in 4 cases (1.1%). Regarding symptoms at hospital admission, fever in SARS-CoV-2 positive group was significantly higher than that in HAdV positive group [34 (85%) vs. 7 (46.7%), p = 0.012]. However, percentages of cases with sore throat, headache, fatigue, lymphadenopathy and conjunctivitis in HAdV positive group were significantly higher than those in SARS-CoV-2 positive group. SARS-CoV-2 and HAdV co-infected children showed mild respiratory symptoms. The present study revealed that SARS-CoV-2 positive children often appear to have a milder clinical course than children with respiratory HAdV infection and children co-infected with SARSCoV-2 and HAdV had less-severe disease on presentation.

3.
Phys Rev Lett ; 129(18): 186802, 2022 Oct 28.
Article in English | MEDLINE | ID: mdl-36374690

ABSTRACT

We present the first experimental evidence for the multifractality of a transport property at a topological phase transition. In particular, we show that conductance fluctuations display multifractality at the integer quantum Hall plateau-to-plateau transitions in high-mobility mesoscopic graphene devices. The multifractality gets rapidly suppressed as the chemical potential moves away from these critical points. Our combination of experimental study and multifractal analysis provides a novel method for probing the criticality of wave functions at phase transitions in mesoscopic systems, and quantum criticality in several condensed-matter systems.

4.
ACS Biomater Sci Eng ; 2022 Jul 27.
Article in English | MEDLINE | ID: mdl-35895720

ABSTRACT

Soft electronic skin (soft-e-skin) capable of sensing touch and pressure similar to human skin is essential in many applications, including robotics, healthcare, and augmented reality. However, most of the research effort on soft-e-skin was confined to the lab-scale demonstration. Several hurdles remain challenging, such as highly complex and expensive fabrication processes, instability in long-term use, and difficulty producing large areas and mass production. Here, we present a robust 3D printable large-area electronic skin made of a soft and resilient polymer capable of detecting touch and load, and bending with extreme sensitivity (up to 150 kPa-1) to touch and load, 750 times higher than earlier work. The soft-e-skin shows excellent long-term stability and consistent performance up to almost a year. In addition, we describe a fabrication process capable of producing large areas and in large numbers, yet is cost-effective. The soft-e-skin consists of a uniquely designed optical waveguide and a layer of a soft membrane with an array of soft structures which work as passive sensing nodes. The use of a soft structure gives the liberty of stretching to the soft-e-skin without considering the disjoints among the sensing nodes. We have shown the functioning of the soft-e-skin under various conditions.

6.
NPJ Precis Oncol ; 6(1): 1, 2022 Jan 11.
Article in English | MEDLINE | ID: mdl-35017650

ABSTRACT

Rhabdomyosarcoma (RMS) is an aggressive pediatric tumor with a poor prognosis for metastasis and recurrent disease. Large-scale sequencing endeavors demonstrate that Rhabdomyosarcomas have a dearth of precisely targetable driver mutations. However, IGF-2 signaling is known to be grossly altered in RMS. The insulin receptor (IR) exists in two alternatively spliced isoforms, IR-A and IR-B. The IGF-2 signaling molecule binds both its innate IGF-1 receptor as well as the insulin receptor variant A (IR-A) with high affinity. Mitogenic and proliferative signaling via the canonical IGF-2 pathway is, therefore, augmented by IR-A. This study shows that RMS patients express increased IR-A levels compared to control tissues that predominantly express the IR-B isoform. We also found that Hif-1α is significantly increased in RMS tumors, portraying their hypoxic phenotype. Concordantly, the alternative splicing of IR adapts to produce more IR-A in response to hypoxic stress. Upon examining the pre-mRNA structure of the gene, we identified a potential hypoxia-responsive element, which is also the binding site for the RNA-binding protein CUG-BP1 (CELF1). We designed Splice Switching Oligonucleotides (SSO) against this binding site to decrease IR-A levels in RMS cell lines and, consequently, rescue the IR-B expression levels. SSO treatment resulted in a significant reduction in cell proliferation, migration, and angiogenesis. Our data shows promising insight into how impeding the IGF-2 pathway by reducing IR-A expression mitigates tumor growth. It is evident that Rhabdomyosarcomas use IR alternative splicing as yet another survival strategy that can be exploited as a therapeutic intervention in conjunction with already established anti-IGF-1 receptor therapies.

7.
J Obstet Gynaecol ; 42(2): 209-214, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34030601

ABSTRACT

The aim of this retrospective cohort study was to review rate of miscarriage following antenatal invasive diagnostic procedures from a unit where relatively low annual numbers of procedures are undertaken. Data were analysed for 201 chorionic villous samplings (CVSs) performed between January 2007 and June 2019 and 511 amniocenteses performed between January 2008 and June 2019, in singleton pregnancies. The miscarriage rates after CVS was 0% at 48 hours, 0.6% at 2 weeks and 2.5% up to 24 weeks of gestation. All four miscarriages following CVS had significant inherent high-risk features, therefore, it would be inappropriate to attribute these losses solely to the procedure itself. None of the women who had an amniocentesis had a miscarriage during the study period. We did not find a causal association between number of invasive procedures performed by an operator and miscarriage rate in our setting even with low annual numbers of invasive procedures.Impact StatementWhat is already known on this subject? Royal College of Obstetricians and Gynaecologists (RCOG) of UK recommends a minimum of at least 30 CVSs or amniocenteses procedures per year for a practitioner in order to maintain skills. A centre performing more fetal invasive procedures has lower miscarriage rates due to more experience of practitioners.What the results of this study add? This study is the first long-term audit data from a smaller fetal medicine unit with relatively low annual case load, suggesting that miscarriage risk may actually be lower than the current understanding. No additional risk of miscarriage or pregnancy loss following fetal invasive procedures even with relatively low annual numbers than that recommended by the RCOG.What the implications are of these findings for clinical practice and/or further research? The findings of this study are important in the era of non-invasive prenatal testing which will see the overall number of fetal invasive procedures decline with time. Competence in safely undertaking antenatal invasive procedure can possibly be maintained with lower annual procedure numbers. Units undertaking low number of antenatal invasive procedure must continuously audit their practice to ensure satisfactory standards and outcomes. More research is needed from smaller units to corroborate or refute the findings of this study.


Subject(s)
Abortion, Spontaneous , Chorionic Villi Sampling , Abortion, Spontaneous/epidemiology , Abortion, Spontaneous/etiology , Amniocentesis , Chorionic Villi Sampling/adverse effects , Diagnostic Tests, Routine , Female , Gestational Age , Humans , Perinatology , Pregnancy , Retrospective Studies , United Kingdom/epidemiology , Wales
8.
Eur J Midwifery ; 5: 53, 2021.
Article in English | MEDLINE | ID: mdl-34825132

ABSTRACT

INTRODUCTION: This study was undertaken because of the increasing rate of induction of labor (IOL) in our hospital and its associated higher caesarean section (CS) rates. The objective was to ascertain the incidence, indications, methods, outcome, and complications of IOL, in particular postpartum hemorrhage. METHODS: This was a prospective observational cohort study of women who underwent IOL in a medium-sized district general hospital. Blood loss was measured by the gravimetric method and correlated to postpartum hemoglobin level within 48 hours of birth. RESULTS: A total of 445 women needed IOL (incidence 33%). Common indications were: small for gestational age (SGA) or fetal growth restriction (FGR) (18%), spontaneous rupture of membrane (17%), reduced fetal movement (16%), prolonged pregnancy (15%), and diabetes (13%). In all, 67% women achieved spontaneous vaginal delivery and 18% underwent caesarean section. With regard to blood loss, 62 women (14%) had postpartum hemorrhage (PPH) of >1000 mL and 22 women (4.9%) had a blood loss >1500 mL. The caesarean section rate was higher than the overall emergency caesarean section rate in that year. Incidence of PPH in this cohort was higher than the normal incidence. CONCLUSIONS: Increasing trend of induction of labor (IOL) is due to the changing clinical policy on management of small for gestational age babies, spontaneous rupture of membrane, reduced fetal movement and other complications of pregnancy. There is conflicting evidence on the effect of IOL on caesarean section rates. IOL is a risk factor for PPH. Accurate measurement of blood loss is essential in detecting a fall in hemoglobin which in turn helps in the appropriate management of PPH.

9.
Sci Rep ; 11(1): 17052, 2021 08 23.
Article in English | MEDLINE | ID: mdl-34426596

ABSTRACT

Activation of a telomere length maintenance mechanism (TMM), including telomerase and alternative lengthening of telomeres (ALT), is essential for replicative immortality of tumor cells, although its regulatory mechanisms are incompletely understood. We conducted a microRNA (miRNA) microarray analysis on isogenic telomerase positive (TEP) and ALT cancer cell lines. Amongst nine miRNAs that showed difference in their expression in TEP and ALT cancer cells in array analysis, miR-708 was selected for further analysis since it was consistently highly expressed in a large panel of ALT cells. miR-708 in TEP and ALT cancer cells was not correlated with C-circle levels, an established feature of ALT cells. Its overexpression induced suppression of cell migration, invasion, and angiogenesis in both TEP and ALT cells, although cell proliferation was inhibited only in TEP cells suggesting that ALT cells may have acquired the ability to escape inhibition of cell proliferation by sustained miR-708 overexpression. Further, cell proliferation regulation in TEP cells by miR708 appears to be through the CARF-p53 pathway. We demonstrate here that miR-708 (i) is the first miRNA shown to be differentially regulated in TEP and ALT cancer cells, (ii) possesses tumor suppressor function, and (iii) deregulates CARF and p21WAF1-mediated signaling to limit proliferation in TEP cells.


Subject(s)
MicroRNAs/metabolism , Neoplasms/metabolism , Telomerase/genetics , A549 Cells , Cell Movement , Cell Proliferation , HEK293 Cells , Humans , MicroRNAs/genetics , Telomerase/deficiency
10.
Br J Hosp Med (Lond) ; 82(5): 1-7, 2021 May 02.
Article in English | MEDLINE | ID: mdl-34076518

ABSTRACT

Perioperative medicine can pose myriad challenges to professionalism and ethical practice. Medicine is a science, but definite end points, and predictable results and outcomes do not consistently occur. There is the potential for error during all steps of a patient's assessment and treatment. Examination findings, laboratory investigations, diagnosis, plans for and outcomes of surgery and long-term outcomes can all be uncertain and/or not meet expectations. Factors including pressures in the workplace, conflicts, ego, prescribed guidelines and pathways, the need to achieve healthcare targets, desire for autonomy and need to maintain multidisciplinary involvement in patient care can lead to an environment in which it is challenging for professionalism and ethics to thrive.


Subject(s)
Morals , Professionalism , Delivery of Health Care , Ethics, Medical , Humans , Workplace
11.
Phys Rev Lett ; 126(9): 096801, 2021 Mar 05.
Article in English | MEDLINE | ID: mdl-33750179

ABSTRACT

We report the discovery of electric-field-induced transition from a topologically trivial to a topologically nontrivial band structure in an atomically sharp heterostructure of bilayer graphene (BLG) and single-layer WSe_{2} per the theoretical predictions of Gmitra and Fabian [Phys. Rev. Lett. 119, 146401 (2017)PRLTAO0031-900710.1103/PhysRevLett.119.146401]. Through detailed studies of the quantum correction to the conductance in the BLG, we establish that the band-structure evolution arises from an interplay between proximity-induced strong spin-orbit interaction (SOI) and the layer polarizability in BLG. The low-energy carriers in the BLG experience an effective valley Zeeman SOI that is completely gate tunable to the extent that it can be switched on or off by applying a transverse displacement field or can be controllably transferred between the valence and the conduction band. We demonstrate that this results in the evolution from weak localization to weak antilocalization at a constant electronic density as the net displacement field is tuned from a positive to a negative value with a concomitant SOI-induced splitting of the low-energy bands of the BLG near the K(K^{'}) valley, which is a unique signature of the theoretically predicted spin-orbit valve effect. Our analysis shows that quantum correction to the Drude conductance in Dirac materials with strong induced SOI can only be explained satisfactorily by a theory that accounts for the SOI-induced spin splitting of the BLG low-energy bands. Our results demonstrate the potential for achieving highly tunable devices based on the valley Zeeman effect in dual-gated two-dimensional materials.

12.
ACS Nano ; 15(1): 916-922, 2021 Jan 26.
Article in English | MEDLINE | ID: mdl-33378173

ABSTRACT

Topological insulators, along with Chern insulators and quantum Hall insulator phases, are considered as paradigms for symmetry protected topological phases of matter. This article reports the experimental realization of the time-reversal invariant helical edge-modes in bilayer graphene/monolayer WSe2-based heterostructures-a phase generally considered as a precursor to the field of generic topological insulators. Our observation of this elusive phase depended crucially on our ability to create mesoscopic devices comprising both a moiré superlattice potential and strong spin-orbit coupling; this resulted in materials whose electronic band structure could be tuned from trivial to topological by an external displacement field. We find that the topological phase is characterized by a bulk bandgap and by helical edge-modes with electrical conductance quantized exactly to 2e2/h in zero external magnetic field. We put the helical edge-modes on firm ground through supporting experiments, including the verification of predictions of the Landauer-Büttiker model for quantum transport in multiterminal mesoscopic devices. Our nonlocal transport properties measurements show that the helical edge-modes are dissipationless and equilibrate at the contact probes. We achieved the tunability of the different topological phases with electric and magnetic fields, which allowed us to achieve topological phase transitions between trivial and multiple, distinct topological phases. We also present results of a theoretical study of a realistic model which, in addition to replicating our experimental results, explains the origin of the topological insulating bulk and helical edge-modes. Our experimental and theoretical results establish a viable route to realizing the time-reversal invariant Z2 topological phase of matter.

13.
Front Immunol ; 12: 689966, 2021.
Article in English | MEDLINE | ID: mdl-34566957

ABSTRACT

Background: Most of the explanatory and prognostic models of COVID-19 lack of a comprehensive assessment of the wide COVID-19 spectrum of abnormalities. The aim of this study was to unveil novel biological features to explain COVID-19 severity and prognosis (death and disease progression). Methods: A predictive model for COVID-19 severity in 121 patients was constructed by ordinal logistic regression calculating odds ratio (OR) with 95% confidence intervals (95% CI) for a set of clinical, immunological, metabolomic, and other biological traits. The accuracy and calibration of the model was tested with the area under the curve (AUC), Somer's D, and calibration plot. Hazard ratios with 95% CI for adverse outcomes were calculated with a Cox proportional-hazards model. Results: The explanatory variables for COVID-19 severity were the body mass index (BMI), hemoglobin, albumin, 3-Hydroxyisovaleric acid, CD8+ effector memory T cells, Th1 cells, low-density granulocytes, monocyte chemoattractant protein-1, plasma TRIM63, and circulating neutrophil extracellular traps. The model showed an outstanding performance with an optimism-adjusted AUC of 0.999, and Somer's D of 0.999. The predictive variables for adverse outcomes in COVID-19 were severe and critical disease diagnosis, BMI, lactate dehydrogenase, Troponin I, neutrophil/lymphocyte ratio, serum levels of IP-10, malic acid, 3, 4 di-hydroxybutanoic acid, citric acid, myoinositol, and cystine. Conclusions: Herein, we unveil novel immunological and metabolomic features associated with COVID-19 severity and prognosis. Our models encompass the interplay among innate and adaptive immunity, inflammation-induced muscle atrophy and hypoxia as the main drivers of COVID-19 severity.


Subject(s)
COVID-19 , SARS-CoV-2 , Severity of Illness Index , Adult , Blood Coagulation , Body Mass Index , COVID-19/blood , COVID-19/immunology , COVID-19/metabolism , Cytokines/blood , Extracellular Traps/immunology , Female , Hemoglobins/analysis , Humans , Male , Metabolome , Middle Aged , Muscular Atrophy , Neutrophils/immunology , Phenotype , Prognosis , Serum Albumin, Human/analysis , T-Lymphocytes/immunology , Valerates/blood
14.
Nanoscale Adv ; 2(9): 3858-3864, 2020 Sep 16.
Article in English | MEDLINE | ID: mdl-36132768

ABSTRACT

Non-radiative processes like energy and charge transfer in 0D-2D semiconductor quantum dot (QD)-transition metal dichalcogenides (TMDs) and other two-dimensional layered materials, like graphene and analogs, leading to strong quenching of the photoluminescence (PL) of the usually highly emissive QDs, have been widely studied. Here we report control of the emission efficiency of core QDs placed in close proximity to the monolayers of MoS2. The QDs are transferred in the form of a high-density compact monolayer with the dot-dot separation, δ as well as the MoS2-QD separation, d, being controlled through chemical methods. While at larger separations we observe some quenching due to non-radiative processes, at smaller separations we observe enhanced emission from QDs on MoS2 as compared to the reference despite the presence of significant non-radiative charge transfer. Interestingly, at small separations δ, we see evidence of strong dot-dot interactions and a significant red shift of QD PL which enhances spectral overlap with the B exciton of MoS2. However, we observe significant reduction of PL quenching of QDs relative to longer δ and d cases, despite increased probability of non-radiative resonant energy transfer to MoS2, due to the enhanced spectral overlap, as well as charge transfer. Significantly we observe that simultaneously the intensity of the B exciton of MoS2 increases significantly suggesting the possibility of coherent and resonant radiative energy exchange between the 0D excitons in QDs and the 2D B exciton in MoS2. Our study reveals interesting nanoscale light-matter interaction effects which can suppress quenching of QDs leading to potential applications of these nanoscale materials in light emitting and photonic devices.

15.
Ultrasound ; 27(4): 205, 2019 Nov.
Article in English | MEDLINE | ID: mdl-31762777
16.
Heliyon ; 5(6): e01956, 2019 Jun.
Article in English | MEDLINE | ID: mdl-31294108

ABSTRACT

Every river dam activity has definite beneficial effects but cannot circumvent its negative impact in the long run. The Panchet dam has been commissioned as a multipurpose river valley project under the authority of Damodar Valley Corporation (DVC) across the river Damodar at the border of West Bengal and Jharkhand states of India in 1959 to overcome some problems like flood control, supply of irrigation, domestic and industrial water, hydroelectric power generation etc. But it has now become a threat to the surrounding people, due to rapid sedimentation and reduction in its water holding capacity. Human risk assessment of the dam thus claims importance and such an effort is executed in this work using Delphi Questionnaire and two Multi-Criteria Decision-Making (MCDM) methods viz. Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) and Weighted Aggregated Sum Product Assessment (WASPAS). At first 9 human risk alternatives (A1-A9) of the dam are identified using Delphi Questionnaire and rated them in order to prioritize using TOPSIS and WASPAS methods. Risk prioritization results of TOPSIS and WASPAS show somewhat differences. The integrated 'Mean-Rank' method is applied to provide final priority ranking of the risk alternatives and the result is: A3 > A9 > A8 > A4, A6 > A1 > A7 > A5 > A2 (when WASPAS parameter λ = 0); A3 > A9 > A4, A8 > A2 > A6 > A1 > A5, A7 (when WASPAS parameter λ = 1); A3 > A9 > A8 > A4, A6 > A1 > A2 > A5 > A7 (when WASPAS parameter λ = 0.5). In all cases, A3 (Population Displacement) alternative ranks first and is identified as the top most risk prone alternative among all. The risk of displacement of people due to further inundation of land is rising gradually. This has motivated us for assessment of other human risks of the dam in the work.

18.
Ultrasound ; 27(2): 75-76, 2019 May.
Article in English | MEDLINE | ID: mdl-31037090
19.
J Phys Condens Matter ; 31(14): 145603, 2019 Apr 10.
Article in English | MEDLINE | ID: mdl-30734721

ABSTRACT

We report an investigation of metal-insulator transition (MIT) using conductivity and magnetoconductance (MC) measurements down to 0.3 K in Nd0.7La0.3NiO3 films grown on crystalline substrates of LaAlO3 (LAO), SrTiO3 (STO), and NdGaO3 (NGO) by pulsed laser deposition. The film grown on LAO experiences a compressive strain and shows metallic behavior with the onset of a weak resistivity upturn below 2 K which is linked to the onset of weak localization contribution. Films grown on STO and NGO show a cross-over from a positive temperature coefficient (PTC) resistance regime to negative temperature coefficient (NTC) resistance regime at definite temperatures. We establish that a cross-over from PTC to NTC on cooling does not necessarily constitute a MIT because the extrapolated conductivity at zero temperature [Formula: see text] though small (<10 S cm-1) is finite, signaling the existence of a bad metallic state and absence of an activated transport. The value of [Formula: see text] for films grown on NGO is reduced by a factor of 40 compared to that for films grown on STO. We show that a combination of certain physical factors makes substituted nickelate (that are known to exhibit first-order Mott type transition), undergo a continuous transition as seen in systems undergoing disorder/composition driven Anderson transition. The MC measurement also supports the above observation and shows that at low temperatures, there exists a positive MC that arises from the quantum interference which co-exists with a spin-related negative MC that becomes progressively stronger as the electrons approach a strongly localized state in the film grown on NGO.

20.
Ultrasound ; 27(1): 5, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30774693
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