Analysis of markers of cell division cycle, apoptosis and autophagy flux in glioblastoma

Glioblastomas are the most aggressive and most common type of primary brain neoplasms and are associated with poor prognosis despite advances in surgical and oncological treatments. Currently available treatments include surgical resection, fractionated external beam radiotherapy and chemotherapy. This study aimed to investigate markers of cell division cycle, apoptosis and autophagy flux in an attempt to identify biomarkers with prognostic and/or predictive significance. The cell cycle markers studied included: Mcm2, expressed throughout the cell cycle; Cyclin A, an S-phase cyclin; Geminin, a protein that prevents re-initiation; and Phosphohistone H3 (PHH3), a marker of mitosis. Apoptotic markers included two anti-apoptotic proteins, Bcl-2 and Bcl-xl; a pro-apoptotic protein, Bak; and a final executioner caspase, caspase 3. Markers of autophagy flux included LC3B, a ubiquitin like protein that form part of the core autophagy machinery; and p62, a mammalian autophagy receptor that binds ubiquitinated proteins. A total of 66 patients were recruited to the study between 2007 and 2009. Data were collected on patient demographics, pre-operative Karnofsky score, surgical and adjuvant treatment and survival. A tissue micro-array, constructed using glioblastoma tissue was immunohistochemically-stained using antibodies against a panel of markers against the molecules described above. A semiquantitative labelling index (LI) was calculated for cell cycle and apoptotic markers using an average of 18 high power fields (hpf) in three replicate cores. Staining scores were calculated for markers of autophagy flux on the basis of cytoplasmic staining intensity (1-3) and percentage of cells with nuclear staining (1<50%, 2>50%). Cell cycle marker LI were calculated from a cohort of 66 patients, who were further subdivided into two groups: Group 1 (n=50) underwent surgery and radiotherapy with 24 patients receiving temozolomide; and Group 2 (n=16) received surgical treatment only. In group 1, a LI, higher than the median value for Geminin and Cyclin A correlated with prolonged survival when tumours received adjuvant treatment (Kaplan Meier test, p=0.0046 and p =0.0063 respectively). In group 1, Mcm2 and PHH3 LI did not correlate significantly with survival. There was no relationship between patient survival and LI for any marker in group 2. A reduction in the LI of Mcm2, Geminin and Cyclin A was observed following administration of adjuvant treatment in three patients with recurrent glioblastoma. Apoptotic marker LI were calculated in 28 patients, due to limited tissue availability; values below the median for Bak expression conferred a survival advantage in these patients by Kaplan Meier analysis (p = 0.0039). LC3b and p62 staining scores were calculated in 45 patients and correlated significantly with each other. Whilst no significant correlation was observed between LC3b staining score and patient survival, p62 staining above the median conferred a survival disadvantage (Kaplan Meier analysis, p =0.017). Geminin and Cyclin A, each showed potential as independent prognostic markers in glioblastomas receiving adjuvant treatment. This may reflect the fact that geminin and cyclin A both estimate proliferating cell sub-populations sensitive to radiotherapy/chemotherapy. The addition of these markers could therefore contribute valuable prognostic information if added to the glioblastoma diagnostic panel. The association of high Bak expression with survival advantage suggests a possible, as yet unknown, role of this pro-apoptotic protein in glioblastoma oncogenesis. The association of high p62 expression with decreased survival confirms the important role of autophagy flux in glioblastoma resistance to treatment and suggests a target for future research and targeted therapy

Analysis of markers of cell division cycle, apoptosis and autophagy flux in glioblastoma

Glioblastomas are the most aggressive and most common type of primary brain neoplasms and are associated with poor prognosis despite advances in surgical and oncological treatments. Currently available treatments include surgical resection, fractionated external beam radiotherapy and chemotherapy. This study aimed to investigate markers of cell division cycle, apoptosis and autophagy flux in an attempt to identify biomarkers with prognostic and/or predictive significance. The cell cycle markers studied included: Mcm2, expressed throughout the cell cycle; Cyclin A, an S-phase cyclin; Geminin, a protein that prevents re-initiation; and Phosphohistone H3 (PHH3), a marker of mitosis. Apoptotic markers included two anti-apoptotic proteins, Bcl-2 and Bcl-xl; a pro-apoptotic protein, Bak; and a final executioner caspase, caspase 3. Markers of autophagy flux included LC3B, a ubiquitin like protein that form part of the core autophagy machinery; and p62, a mammalian autophagy receptor that binds ubiquitinated proteins. A total of 66 patients were recruited to the study between 2007 and 2009. Data were collected on patient demographics, pre-operative Karnofsky score, surgical and adjuvant treatment and survival. A tissue micro-array, constructed using glioblastoma tissue was immunohistochemically-stained using antibodies against a panel of markers against the molecules described above. A semiquantitative labelling index (LI) was calculated for cell cycle and apoptotic markers using an average of 18 high power fields (hpf) in three replicate cores. Staining scores were calculated for markers of autophagy flux on the basis of cytoplasmic staining intensity (1-3) and percentage of cells with nuclear staining (1<50%, 2>50%). Cell cycle marker LI were calculated from a cohort of 66 patients, who were further subdivided into two groups: Group 1 (n=50) underwent surgery and radiotherapy with 24 patients receiving temozolomide; and Group 2 (n=16) received surgical treatment only. In group 1, a LI, higher than the median value for Geminin and Cyclin A correlated with prolonged survival when tumours received adjuvant treatment (Kaplan Meier test, p=0.0046 and p =0.0063 respectively). In group 1, Mcm2 and PHH3 LI did not correlate significantly with survival. There was no relationship between patient survival and LI for any marker in group 2. A reduction in the LI of Mcm2, Geminin and Cyclin A was observed following administration of adjuvant treatment in three patients with recurrent glioblastoma. Apoptotic marker LI were calculated in 28 patients, due to limited tissue availability; values below the median for Bak expression conferred a survival advantage in these patients by Kaplan Meier analysis (p = 0.0039). LC3b and p62 staining scores were calculated in 45 patients and correlated significantly with each other. Whilst no significant correlation was observed between LC3b staining score and patient survival, p62 staining above the median conferred a survival disadvantage (Kaplan Meier analysis, p =0.017). Geminin and Cyclin A, each showed potential as independent prognostic markers in glioblastomas receiving adjuvant treatment. This may reflect the fact that geminin and cyclin A both estimate proliferating cell sub-populations sensitive to radiotherapy/chemotherapy. The addition of these markers could therefore contribute valuable prognostic information if added to the glioblastoma diagnostic panel. The association of high Bak expression with survival advantage suggests a possible, as yet unknown, role of this pro-apoptotic protein in glioblastoma oncogenesis. The association of high p62 expression with decreased survival confirms the important role of autophagy flux in glioblastoma resistance to treatment and suggests a target for future research and targeted therapy

Frequency and Anatomical Distribution of Pulmonary Embolism on CT Pulmonary Angiography

Background: Pulmonary embolism, with its growing prevalence, has become a potentially life-threatening medical condition with crucial symptoms. However, prognosis is good if timely diagnosis is made and to the level of segmental and sub segmental arteries as well. Standard computed tomography pulmonary angiography (CTPA) is thus used to diagnose acute pulmonary embolism. Objective: The primary objective of the current study was to determine and investigate the anatomical distribution frequency of pulmonary emboli, where segmental, sub segmental, and lobar arteries on CT pulmonary angiography are included. Methodology: In a descriptive cross-sectional study, single-centered studies and CTPA scans of 98 patients were included. Data was obtained from Shalimar Hospital and University of Lahore – Teaching Hospital, Lahore, Pakistan. Sample size included patients of all age groups with suspected pulmonary embolism, with no differentiation of male or female samples. Results: According to statistics and analysis, the current study results indicated the presence of pulmonary embolism in 36 patients and its absence in 62 patients. Results indicated that amongst the 98 patients scanned, the highest frequency of pulmonary emboli was found in the pulmonary trunk and lobar artery in 8 patients (8.2%). Furthermore, CTPA of the participants detected pulmonary emboli in segmental and sub-segmental arteries of 5 patients (5.1%), with another 2 patients showing pulmonary emboli in only the sub-segmental artery (2.0%). Another 2-2 patients showed pulmonary emboli in lobar and segmental artery and lobar, segmental and sub-segmental artery respectively (2.0%, 2.0%). Conclusion: The largest number of pulmonary emboli were found in the pulmonary trunk, followed by emboli of segmental and lobar arteries in patients. It is concluded that CTPA evaluates pulmonary embolism with great precision and anatomical distribution localized main trunk, and pulmonary artery emboli along with lobar, segmental and sub-segmental artery emboli. Keywords: Computed Tomography Pulmonary Angiography (CTPA), pulmonary emboli, segmental artery, sub segmental artery, lobar arteries DOI: 10.7176/JHMN/100-02 Publication date:May 31st 202

Assessment of sublethal and transgenerational effects of spirotetramat, on population growth of cabbage aphid, Brevicoryne brassicae L. (Hemiptera: Aphididae)

The cabbage aphid (Brevicoryne brassicae L.) is a devastating pest of cruciferous crops causing economic damage worldwide and notably owing to its increasing resistance to commonly used pesticides. Such resistance prompts the development of integrated pest management (IPM) programs that include novel pesticides being effective against the aphids. Spirotetramat is a novel insecticide used against sap-sucking insect pests, particularly aphids. This study evaluated the toxicity of spirotetramat to adult apterous B. brassicae after 72 h using the leaf dipping method. According to the toxicity bioassay results, the LC50 value of spirotetramat to B. brassicae was 1.304 mgL−1. However, the sublethal concentrations (LC5 and LC15) and transgenerational effects of this novel insecticide on population growth parameters were estimated using the age-stage, two-sex life table theory method. The sublethal concentrations (LC5; 0.125 mgL−1 and LC15; 0.298 mgL−1) of spirotetramat reduced the adult longevity and fecundity of the parent generation (F0). These concentrations prolonged the preadult developmental duration while decreasing preadult survival, adult longevity and reproduction of the F1 generation. The adult pre-reproductive period was also extended by spirotetramat treatment groups. Subsequently, the population growth parameters such as the intrinsic rate of increase r, finite rate of increase λ and net reproductive rate R0 of the F1 generation were decreased in spirotetramat treatment groups whereas, the mean generation time T of the F1 generation was not affected when compared to the control. These results indicated the negative effect of sublethal concentrations of spirotetramat on the performance of B. brassicae by reducing its nymphal survival, extending the duration of some immature stages and suppressing the population growth of B. brassicae. Overall, we demonstrated that spirotetramat is a pesticide showing both sublethal activities, and transgenerational effects on cabbage aphid; it may be useful for implementation in IPM programs against this aphid pest

Quality of life outcomes in incidental and operated meningiomas (QUALMS): a cross-sectional cohort study.

INTRODUCTION: Few studies have evaluated meningioma patients' longer-term health-related quality of life (HRQoL) following diagnosis and treatment, particularly in those with incidental, actively monitored tumours. METHODS: A single-center, cross-sectional study was completed. Adult patients with surgically managed or actively monitored meningioma with more than five years of follow-up were included. The patient-reported outcome measures RAND SF-36, EORTC QLQ-C30 and QLQ-BN20 were used to evaluate HRQoL. HRQoL scores were compared to normative population data. Outcome determinants were evaluated using multivariate linear regression analysis. RESULTS: 243 patient responses were analyzed, and the mean time from diagnosis was 9.8 years (range 5.0-40.3 years). Clinically relevant, statistically significant HRQoL impairments were identified across several SF-36 and QLQ-C30 domains. Increasing education level (β = 2.9, 95% CI 0.9 to 4.9), P = .004), employment (β = 7.7, 95% CI 2.2 to 13.1, P = .006) and absence of postoperative complications (β=-6.7, 95% CI -13.2 to (-)0.3, P = .041) were associated with a better QLQ-C30 summary score. Other tumour and treatment variables were not. CONCLUSION: This study highlights the longer-term disease burden of patients with meningioma nearly one decade after diagnosis or surgery. Patients with actively monitored meningioma have similar HRQoL to operated meningioma patients. Healthcare professionals should be mindful of HRQoL impairments and direct patients to sources of support as needed

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Effects of thumb size, pressure, position, nail, and skin on dielectric resonator glucose sensor

This work presents an extensive analysis of five uncertain variables of human thumb on a non-invasive glucose sensor made of a dielectric resonator antenna, operating at 4.899 GHz. A realistic 3D electromagnetic human thumb model is proposed, considering five uncertain variables namely, thumb size, pressure, position, nail length, and skin thickness. To the best of the authors' knowledge, this is the first work which presents such extensive treatment of the aforementioned variables altogether under a single framework. Moreover, the proposed sensor yields a 30 MHz shift of resonance frequency due to thumb displacement over an area of 10 mm×10 mm, which is the lowest among the reported microwave non-invasive glucose sensors

Design of Experiment (DOE) Analysis of System Level ESD Noise Coupling to High-Speed Memory Modules

This paper presents, for the first time, a comprehensive detailed design of experiment (DOE) based system level electrostatic discharge (ESD) coupling analysis of high-speed dynamic random access (DRAM) memory modules. The sensitive traces and planes on the high-speed DRAM modules (DDR3 and DDR4) against injected ESD noise are determined through full-wave numerical simulations of the memory modules using the developed 3D model of the ESD gun. The validity of the full-wave numerical setup is confirmed through measurements, prior to the DOE analysis. Besides, current distribution analysis of DRAMs, seven different DOE configurations based on the number of installed decoupling capacitors (decaps) and their values on memory modules, are analyzed. The findings of DOE analysis suggests that DDR4 is less susceptible (70&#8315;80 % less) to the coupled ESD noise compared to DDR3. In addition, the command address (CA) nets are most sensitive in both memory modules. The utilization of the maximum possible number of decaps covering low, medium and high frequency ranges, as well as separate power and ground layers in memory stack-up design, increase the robustness and immunity of memory modules for the transient ESD event. The suggested approach offers time-saving and financial advantages to high-speed memory community, with the robust design of the memory products at the design stage before the start of the production phase

Effect of the enhanced recovery after surgery (ERAS®) program on postoperative complications in the Whipple operation: A prospective cohort

Background: The Whipple operation treats pancreatic, bile duct, and intestinal malignancies. ERAS® usage in the Whipple surgery is seldom documented. So, this study examined how the ERAS® regimen affected postoperative complications in Whipple patients. Method: From January 2017 to December 2022, 97 patients were admitted to the general surgery department at Hayatabad Medical Complex, Peshawar, Pakistan, a tertiary care hospital. This study recruited Whipple patients. The prospective group was treated with ERAS methods, whereas the control group was handled using the non-ERAS treatment (Jan 2017–Dec 2018). The Whipple technique was performed on 18-year-olds with pancreatic, duodenum, and bile duct cancer. The present study's primary outcomes were CDC grading, surgical complications, 30-day readmission rate, 30-day re-operation for any reason, and hospital stay. SPSS 26.0 examined data. Results: This study has 97 patients. Both groups had equal comorbidities. The ERAS® technique minimized postoperative complications, as seen by the considerable drop in CDC grading (p = 0.003). Non-ERAS® patients had increased mortality (2 vs. 8). ERAS® also decreased stay duration (p = 0.001). ERAS® patients also had a lower readmission rate (p = 0.001). Conclusion: The Whipple procedure's ERAS® protocol has lowered postoperative complications, duration of stay, and readmission rates.&nbsp

Design of Robust Detection System for Printable Chipless RFID Tag Alphabet Letters

This work presents a novel chipless radio frequency identification (RFID) tag design method for Latin alphabets. Unlike the traditional complicated geometry tags, this new method uses a compact printable alphabet letters which additionally offers the advantage of efficient real time recognition of the transmitted data visually along with radio frequency (RF) waves. In this study, alphabet letters (a, b and c) are realized using copper etching on thin dielectric substrate (TLX-8) backed by a ground plane. The original signature of the radar cross section (RCS) frequency response reflected by letter, displays dips corresponding to the presence of individual letters. The tag has been simulated, fabricated and measured in a mono-static radar system using Vivaldi dual polarized antenna in frequency band ranging from 6 to 13 GHz. A robust detection has been reached with very good agreement between the experimental and simulated results in both co- and cross-polarizations