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Overcoming PLK1 inhibitor resistance by targeting mevalonate pathway to impair AXL-TWIST axis in colorectal cancer

Biomed Pharmacother. 2021 Oct 23;144:112347. doi: 10.1016/j.biopha.2021.112347. Online ahead of print.

ABSTRACT

New therapeutic targets are revolutionizing colorectal cancer clinical management, opening new horizons in metastatic patients’ outcome. Polo Like Kinase1 (PLK1) inhibitors have high potential as antitumoral agents, however, the emergence of drug resistance is a major challenge for their use in clinical practice. Overcoming this challenge represents a hot topic in current drug discovery research. BI2536-resistant colorectal cancer cell lines HT29R, RKOR, SW837R and HCT116R, were generated in vitro and validated by IG50 assays and xenografts models by the T/C ratio. Exons 1 and 2 of PLK1 gene were sequenced by Sanger method. AXL pathway, Epithelial-to-Mesenchymal transition (EMT) and Multidrug Resistance (MDR1) were studied by qPCR and western blot in resistant cells. Simvastatin as a re-sensitizer drug was tested in vitro and the drug combination strategies were validated in vitro and in vivo. PLK1 gene mutation R136G was found for RKOR. AXL pathway trough TWIST1 transcription factor was identified as one of the mechanisms involved in HT29R, SW837R and HCT116R lines, inducing EMT and upregulation of MDR1. Simvastatin was able to impair the mechanisms activated by adaptive resistance and its combination with BI2536 re-sensitized resistant cells in vitro and in vivo. Targeting the mevalonate pathway contributes to re-sensitizing BI2536-resistant cells in vitro and in vivo, raising as a new strategy for the clinical management of PLK1 inhibitors.

PMID:34700228 | DOI:10.1016/j.biopha.2021.112347

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Gender and residence differences in the association between social support and subjective well-being among Chinese oldest-old: A national longitudinal study

Arch Gerontol Geriatr. 2021 Oct 3;98:104545. doi: 10.1016/j.archger.2021.104545. Online ahead of print.

ABSTRACT

OBJECTIVES: This study aimed to explore the gender and residence (rural/urban) differences in the associations between the specific dimensions of social support and subjective well-being (SWB) among the Chinese oldest-old.

METHODS: This study included 12,989 individuals aged ≥ 80 from 2011, 2014, and 2018 waves of the Chinese Longitudinal Healthy Longevity Survey. SWB was measured by ten items covering self-rated life satisfaction, positive emotions (optimism, happiness, personal control, and conscientiousness), and negative emotions (loneliness, anxiety, uselessness, depression, and boring feelings). Social support included the variables of marriage quality, living arrangements, contacts with others, children’s and siblings’ frequent visits and telecommunications, children and siblings living nearby, the main source of financial support, adequate financial support, social security and commercialized insurances, community social services, the caregiver when sick, and main medical expenses payer. Generalized estimating equation models were used to determine the effects of social support on the SWB.

RESULTS: Gender differences were found in the associations of living arrangements, contacts with others, children’s frequent visits and telecommunications, community social services, caregiver when sick, and main medical expenses payer with SWB. Residence differences were found in the associations of living arrangements, contacts with others, children’s frequent visits and telecommunications, siblings’ frequent visits, community social services, and main medical expenses payer with SWB.

CONCLUSIONS: There are gender and residence differences in the relationships between many dimensions of social support and SWB. Gender and residence-tailored interventions for social support are necessary to promote the well-being of the oldest old.

PMID:34700136 | DOI:10.1016/j.archger.2021.104545

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An annual study on plastic accumulation in surface water and sediment cores from the coastline of Tenerife (Canary Island, Spain)

Mar Pollut Bull. 2021 Oct 23;173(Pt B):113072. doi: 10.1016/j.marpolbul.2021.113072. Online ahead of print.

ABSTRACT

Sediment core samples from high tide lines and in submerged zones as well as surface water samples from eight beaches of Tenerife were analysed. Sampling was conducted over a period of one year in intervals of 5 weeks. The majority of particles were found in the high tide sediment (66%), followed by water samples (23%) and finally in sediment from submerged zones (11%). Regarding the particle amount per volume (items/L), accumulation in sediment samples was statistically higher compared to water samples. Mean values of items/L were higher in high tide sediments. In high tide and water samples, mostly white and transparent particles >1 mm were found. More than 70% were represented by fragments. In sediments from submerged zones, yellow and blue microparticles (<1 mm) were predominant and 61.9% consisted of fibres. Larger particles were mainly identified as PP, PE, PS, PTFE and PVC, while polymer types of smaller particles were more variable.

PMID:34700151 | DOI:10.1016/j.marpolbul.2021.113072

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Telomere length in dromedary camels (Camelus dromedarius) produced by somatic cell nuclear transfer (SCNT) and their age-matched naturally produced counterparts

Theriogenology. 2021 Oct 20;177:151-156. doi: 10.1016/j.theriogenology.2021.10.012. Online ahead of print.

ABSTRACT

There are controversial reports on the restoration of eroded telomere length in offspring produced by somatic cell nuclear transfer (SCNT) in different animal species. To the best of our knowledge, no earlier studies report the telomere length in naturally produced or cloned animals in any of the camelid species. Therefore, the present study was conducted to estimate the telomere length in dromedary camels produced by SCNT, the donor cells, and their age-matched naturally produced counterparts by Terminal Restriction Fragment (TRF) length analysis and real-time Q PCR T/S ratio methods. Genomic DNA was extracted from venous blood collected from 6 cloned animals and their age-matched counterparts. Using the southern blot technique, digested DNA was blotted onto a positively charged nylon membrane, and its hybridization was carried out using telomere (TTAGGG)n specific, DIG-labeled hybridization probe (Roche Diagnostics, Germany) at 42 °C for 4 h. Stringent washes were carried out at the same temperature, followed by a chemiluminescence reaction. The signals were captured using the Azure Biosystems C600 gel documentation system. A TeloTool program from MATLAB software with a built-in probe intensity correction algorithm was used for TRF analysis. The experiment was replicated three times, and the data, presented as mean ± SEM, were analyzed using a two-sample t-test (MINITAB statistical software, Minitab ltd, CV3 2 TE, UK). No difference was found in the mean telomere length of cloned camels when compared to their naturally produced age-matched counterparts. However, the telomere length was more (P < 0.05) than that of the somatic cells used for producing the SCNT embryos. A moderate positive Pearson correlation coefficient (r = 0.6446) was observed between the telomere lengths estimated by TRF and Q PCR T/S ratio method. In conclusion, this is the first study wherein we are reporting telomere length in naturally produced and cloned dromedary camels produced by somatic cell nuclear transfer. We found that telomere lengths in cloned camels were similar to their age-matched naturally produced counterparts, suggesting that the camel cytoplast reprograms the somatic cell nucleus and restores the telomere length to its totipotency stage.

PMID:34700072 | DOI:10.1016/j.theriogenology.2021.10.012

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MRI-based synthetic CT of the lumbar spine: Geometric measurements for surgery planning in comparison with CT

Eur J Radiol. 2021 Oct 13;144:109999. doi: 10.1016/j.ejrad.2021.109999. Online ahead of print.

ABSTRACT

PURPOSE: MRI is the imaging modality of choice for soft tissue-related spine disease. However, CT is superior to MRI in providing clear visualization of bony morphology. The purpose of this study is to test equivalency of MRI-based synthetic CT to conventional CT in quantitatively assessing bony morphology of the lumbar spine.

METHOD: A prospective study with an equivalency design was performed. Adult patients who had undergone MRI and CT of the lumbar spine were included. Synthetic CT images were generated from MRI using a deep learning-based image synthesis method. Two readers independently measured pedicle width, spinal canal width, neuroforamen length, anterior and posterior vertebral body height, superior and inferior vertebral body length, superior and inferior vertebral body width, maximal disc height, lumbar curvature and spinous process length on synthetic CT and CT. The agreement among CT and synthetic CT was evaluated using equivalency statistical testing.

RESULTS: Thirty participants were included (14 men and 16 women, range 20-60 years). The measurements performed on synthetic CT of pedicle width, spinal canal width, vertebral body height, vertebral body width, vertebral body length and spinous process length were statistically equivalent to CT measurements at the considered margins. Excellent inter- and intra-reader reliability was found for both synthetic CT and CT.

CONCLUSIONS: Equivalency of MRI-based synthetic CT to CT was demonstrated on geometrical measurements in the lumbar spine. In combination with the soft tissue information of the conventional MRI, this provides new possibilities in diagnosis and surgical planning without ionizing radiation.

PMID:34700094 | DOI:10.1016/j.ejrad.2021.109999

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Fetal Reduction and Twins

Am J Obstet Gynecol MFM. 2021 Oct 23:100521. doi: 10.1016/j.ajogmf.2021.100521. Online ahead of print.

ABSTRACT

Infertility treatments have benefited millions of couples to have their own children, but resultant multiple pregnancies with their increased morbidity and mortality have been a significant complication. Fetal reduction (FR) was developed to ameliorate those. Over 30 years of publications show that FR has been highly successful in substantially reducing both mortality and morbidity. As with most radically new techniques, initial cases were in the “nothing to lose” category. With experience, indications liberalize, and quality of life issues increase as a proportion of cases. Overall risks for twins are not twice singletons; they are about 4 – 5 x higher. In experienced hands, the combination of genetic testing by CVS followed by FR has made most multiples behave statistically as if they were originally the lower number. Use of microarray analysis to better determine fetal genetic health before deciding on which fetus(es) to keep or reduce further improves pediatric outcomes. With increasing experience and lower average starting numbers, the proportion of FRs to a singleton has increased considerably. Twins to a singleton FR now constitute an increasing proportion of cases performed. Data on such cases show improved outcomes, and we believe FR should be at least discussed and offered to all patients with a dichorionic twin pregnancy or higher. With increasing reliance upon elective single embryo transfer (eSET), monochorionic twins have substantially increased which have much higher complication rates than dichorionic twins. Furthermore, monochorionic twins cannot be readily, safely reduced so the adverse perinatal statistics of eSET are a major set-back for good outcomes. While eSET is appropriate for some, we believe that for many couples, transfer of 2 embryos is generally a more rational approach.

PMID:34700026 | DOI:10.1016/j.ajogmf.2021.100521

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Identification of characteristic volatiles and metabolomic pathway during pork storage using HS-SPME-GC/MS coupled with multivariate analysis

Food Chem. 2021 Oct 20;373(Pt A):131431. doi: 10.1016/j.foodchem.2021.131431. Online ahead of print.

ABSTRACT

Previous researches have been conducted evaluating the volatile compounds of pork. However, data regarding the changes in volatiles and metabolic pathways during pork storage were inadequately investigated. Herein, a headspace solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC/MS) coupled multivariate analysis was proposed for characterizing the profiles of volatile compounds and metabolic pathways during pork storage. A total of 37 metabolites, including aldehydes, ketones, alcohols etc. were successfully identified. Multivariate statistical analysis revealed a substantial variation in metabolite phenotype among samples over the pork storage period, with 12 characteristic metabolites and 5 potential characteristic metabolites screened as biomarkers. Moreover, three metabolomic pathways analysis and transformation between each other (thermal reactions, lipid metabolism and amino acid metabolism) reveals the underlying mechanisms of metabolites change of pork. Therefore, the present study may provide insight into future understanding of the variation in the pork metabolite profiles.

PMID:34700034 | DOI:10.1016/j.foodchem.2021.131431

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Operative outcomes for wide awake local anesthesia versus regional and general anesthesia for flexor tendon repair

Hand Surg Rehabil. 2021 Oct 23:S2468-1229(21)00596-X. doi: 10.1016/j.hansur.2021.10.312. Online ahead of print.

ABSTRACT

Operative repair of flexor tendons after traumatic injury may be performed under general anesthesia (GA), regional blocks, or a wide-awake local anesthesia no tourniquet (WALANT) technique. To our knowledge there are currently no large-scale reports evaluating outcomes of flexor tendon repair in patients where wide-awake anesthesia was utilized in comparison to regional anesthesia (RA) and general anesthesia. We performed a retrospective analysis of patients who underwent treatment for flexor tendon injuries at a tertiary referral center for hand surgery over a two-year period. A total of 151 patients were included (53 WALANT, 57 RA, and 41 GA) and a total of 251 tendons were repaired (63 WALANT, 104 RA and 84 GA). No statistically significant difference was observed in rates of tendon rupture, adhesions, infection, or hand function. Flexor tendon repair under WALANT is found to be safe and presents comparable operative and functional outcomes to more traditional anesthetic techniques. Additional advantages, including the ability to test the repair intraoperatively, patient education, and the potential for boosting theatre efficiency. Further studies, preferably utilizing a randomized trial methodology, may further elucidate the benefits and risks of WALANT versus regional and general anesthesia.

PMID:34700023 | DOI:10.1016/j.hansur.2021.10.312

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Changes in appendicitis treatment during the COVID-19 pandemic – A systematic review and meta-analysis

Int J Surg. 2021 Oct 23:106148. doi: 10.1016/j.ijsu.2021.106148. Online ahead of print.

ABSTRACT

BACKGROUND: During the COVID-19 pandemic in 2020 a decrease of emergency consultations and modification in treatment of numerous medical conditions were observed. Aim of this paper was to evaluate the effect of the COVID-19 pandemic on incidence, treatment strategies, severity, length of hospital stay and time of presentation in adults and children with acute appendicitis.

METHODS: A systematic literature search of Pubmed, Embase and Cochrane databases was performed, and eligible studies used to perform a meta-analysis.

RESULTS: 46 suitable studies were identified with an overall reduction of appendicitis cases by 20.9% in adults and an increase of 13.4% in children. The rate of open appendectomies increased without statistical significance in both groups (adults: 8.5% vs. 7.1%, P = 0.32; children: 7.1% vs. 5.3%, P = 0.13), whereas the rate of antibiotic treatment increased significantly (P = 0.007; P = 0.03). Higher rates of complicated appendicitis were observed in adults (adults: OR 2.00, P < 0.0001; children: OR 1.64, P = 0.12). Time to first consultation did not change significantly (adults: 52.3 vs. 38.5 h – P = 0.057; children: 51.5 vs. 32.0 h – P = 0.062) and length of stay was also not lengthened during the pandemic (adults: 2.9 vs. 2.7 days, P = 0.057; children: 4.2 vs. 3.7 days, P = 0.062).

CONCLUSION: The COVID-19 pandemic of 2020 had major impact on incidence and treatment strategies of acute appendicitis. Results of this meta-analysis might be another hint to support the theory that appendicitis is not a progressive disease and surgeons can safely consider antibiotic therapy for acute uncomplicated appendicitis.

PMID:34700020 | DOI:10.1016/j.ijsu.2021.106148

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Treatment and control of modifiable cardiovascular risk factors among patients with diabetes mellitus and hypertension in Inner Mongolia: A cross-sectional study

J Clin Hypertens (Greenwich). 2021 Oct 26. doi: 10.1111/jch.14375. Online ahead of print.

ABSTRACT

The authors assessed treatment and control of blood glucose, blood pressure (BP), and blood lipids among patients from Inner Mongolia with diabetes mellitus (DM) and hypertension (HTN) and identified the modifiable factors associated with treatment and achievement of blood glucose, BP, and blood lipid targets. The authors used a multistage stratified cluster sampling method according to geographical location and level of economic development in Inner Mongolia. Among patients with DM and HTN, the crude rates of fasting plasma glucose (FPG) treatment and control was 30.76% and 4.73%, respectively. Crude rates of BP treatment and control were 50.81% and 8.70%, respectively. The authors found that treatment rates of HTN and DM and control rates of BP and FPG showed a gradually increasing trend with increased age. Among patients with DM and HTN, the likelihood of treatment for HTN and DM was significantly increased among participants who were older, non-Mongolian, male, obese, smokers, and those with previous cardiovascular disease. The authors found that control of BP, FPG, and low-density lipoprotein cholesterol was far from optimal among study participants. Medical and health departments in Inner Mongolia should take appropriate measures to reduce the burden of DM and HTN in the population, such as by promoting and improving the quality of HTN and DM treatment to achieve control goals and reduce the risk of cardiovascular disease.

PMID:34699679 | DOI:10.1111/jch.14375