Phase Of Cycle Research Articles

Oncogene Downregulation by Mahanine Suppresses Drug-Sensitive and Drug-Resistant Lung Cancer and Inhibits Orthotopic Tumor Progression.

Background/Objectives: Lung cancer is one of the deadliest cancers, and drug resistance complicates its treatment. Mahanine (MH), an alkaloid from Murraya koenigii has been known for its anti-cancer properties. However, its effectiveness and mechanisms in treating non-small cell lung cancer (NSCLC) remain largely unexplored. The present study aimed to investigate MH's effect on drug-sensitive and drug-resistant NSCLC and its potential mechanism of action. Methods: We isolated MH from M. koenigii leaves and the purity (99%) was confirmed by HPLC, LC-MS and NMR. The antiproliferative activity of MH was determined using MTT and colony formation assays against drug-sensitive (A549 and H1299) and Taxol-resistant lung cancer cells (A549-TR). Western blot analysis was performed to determine MH's effects on various molecular targets. Anti-tumor activity of MH was determined against lung tumors developed in female NOD Scid mice injected with A549-Fluc bioluminescent cells (1.5 × 106) intrathoracically. Results: MH dose-dependently reduced the proliferation of all lung cancer cells (A549, H1299 and A549-TR), with IC50 values of 7.5, 5, and 10 µM, respectively. Mechanistically, MH arrested cell growth in the G0/G1 and G2/M phases of the cell cycle by inhibiting cyclin-dependent kinase 4/6 (CDK4/6) and cell division control 2 (CDC2) and induced apoptosis through the downregulation of B-cell leukemia/lymphoma 2 (BCL2) and B-cell lymphoma-extra large (BCL-XL). The apoptotic induction capacity of MH can also be attributed to its ability to inhibit pro-oncogenic markers, including mesenchymal-epithelial transition factor receptor (MET), phosphorylated protein kinase B (p-AKT), phosphorylated mammalian target of rapamycin (p-mTOR), survivin, rat sarcoma viral oncogene (RAS), myelocytomatosis oncogene (cMYC), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) levels. In vivo, MH (25 mg/kg b. wt.) significantly (p < 0.001) inhibited the growth of A549 lung cancer orthotopic xenografts in NOD Scid mice by 70%. Conclusions: Our study provides new mechanistic insights into MH's therapeutic potential against NSCLC.

Dissecting the role of transcription factor AP2-M in Babesia asexual replication.

Babesia spp. are obligate intracellular parasites that invade host cells to complete their asexual development and transmission. Here, we identified a transcription factor AP2-M (BXIN_0799) in Babesia sp. Xinjiang (Bxj), a member of the Apicomplexan AP2 family, which regulates gene expression related to red blood cell (RBC) invasion and cell cycle progression. Our genome-wide analysis of (Cut-Tag) data shows that AP2-M specifically recognized DNA motifs in the promoters of target genes. AP2-M target genes included other AP2 gene family members and epigenetic markers, which could modulate gene expression involved in RBC invasion, merozoite morphology, and cell cycle phases, as indicated by RNA sequencing, proteomics, and single-cell RNA sequencing (scRNA-seq) data from an ap2-m gene disrupted strain (AP2-M (-)). We conclude that AP2-M appeared to contribute to the process of red blood cell invasion, maintain merozoite morphology, and cell cycle progression through GS and MS phases.

Study on the balance and gait characteristics of subjects with generalized joint hypermobility residing in high-altitude using wearable devices: a cross-sectional study

PurposeTo investigate the characteristics of balance and gait functions in Generalized Joint Hypermobility (GJH) subjects residing in high-altitude areas.MethodsThis study included 61 university students (28 with GJH and 33 healthy controls) all from the high-altitude region of Linzhi, Tibet Autonomous Region. The Riablo™ wearable intelligent rehabilitation assessment and training system was used to assess static balance (with eyes open and closed) and gait function (during flat walking) in both groups.ResultsCompared to healthy subjects, GJH subjects exhibited significantly impaired balance, indicated by an increased distance of the center of pressure position from the ideal center of gravity(EO: P = 0.007, EC: P = 0.031) and greater amplitude of center of pressure displacements (EO: P = 0.043, EC: P = 0.032). Gait velocity(P = 0.007), stride length(P = 0.012), and swing stance phase of the gait cycle(P = 0.046) were significantly reduced in GJH subjects compared to healthy subjects. A significant increase in the flat-foot phase of the gait cycle(P = 0.022) was observed in GJH subjects compared to healthy subjects.ConclusionThe current study demonstrated that GJH subjects residing in high-altitude areas exhibit impairments in balance and gait, providing a basis for training and prevention strategies tailored for this population. And this study used the wearable intelligent rehabilitation evaluation and training system in high-altitude areas, providing methodological references for scientific research on balance and gait function under non laboratory conditions.Trial registrationControlled Trials No.102772023RT133, Registered 13 October 2023.

Estrogen predicts multimodal emotion recognition accuracy across the menstrual cycle.

Researchers have proposed that variation in sex hormones across the menstrual cycle modulate the ability to recognize emotions in others. Existing research suggests that accuracy is higher during the follicular phase and ovulation compared to the luteal phase, but findings are inconsistent. Using a repeated measures design with a sample of healthy naturally cycling women (N = 63), we investigated whether emotion recognition accuracy varied between the follicular and luteal phases, and whether accuracy related to levels of estrogen (estradiol) and progesterone. Two tasks assessed recognition of a range of positive and negative emotions via brief video recordings presented in visual, auditory, and multimodal blocks, and non-linguistic vocalizations (e.g., laughter, sobs, and sighs). Multilevel models did not show differences in emotion recognition between cycle phases. However, coefficients for estrogen were significant for both emotion recognition tasks. Higher within-person levels of estrogen predicted lower accuracy, whereas higher between-person estrogen levels predicted greater accuracy. This suggests that in general having higher estrogen levels increases accuracy, but that higher-than-usual estrogen at a given time decreases it. Within-person estrogen further interacted with cycle phase for both tasks and showed a quadratic relationship with accuracy for the multimodal task. In particular, women with higher levels of estrogen were more accurate in the follicular phase and middle of the menstrual cycle. We propose that the differing role of within- and between-person hormone levels could explain some of the inconsistency in previous findings.

DNA Replication and Polymer Chain Duplication Reshape the Genome in Space and Time

In eukaryotes, DNA replication constitutes a complex process whereby multiple origins are stochastically fired, and from which the replication machinery proceeds along chromosomes to achieve the faithful synthesis of two identical copies of the genome during the S phase of the cell cycle. Experimental evidence shows a functional correlation between the dynamics of replication and the spatial organization of the genome inside cell nuclei, suggesting that the process of replicating DNA may impact chromosome folding. However, the theoretical and mechanistic bases of such a hypothesis remain elusive. To address that question, we propose a quantitative, minimal framework that integrates the dynamics of replication along a polymer chain by accounting explicitly for the progression of the replication machinery and the resulting formation of sister chromatids. By systematically characterizing the 3D structural consequences of replication, and of possible interactions between active replication machineries, we show that the formation of transient loops may potentially impact chromosome organization across multiple temporal and spatial scales, from the level of individual origins to that of the global polymer chain. Comparison with available microscopy and chromosome conformation capture data in yeast suggests that a replication-dependent loop extrusion process may be acting , and may shape chromosomes as loose polymer bottle brushes during the S phase. Lastly, we explore the postreplication relative organization of sister chromatids and demonstrate the emergence of catenations and intertwined structures, which are regulated by the density of fired origins. Published by the American Physical Society 2024

Factors Related to Premenstrual Syndrome in Young Women at MTsN Labuhanbatu in 2024

Premenstrual syndrome (PMS) is a complex and poorly understood condition consisting of one or more of a number of physical and psychological symptoms that begin in the luteal phase of the menstrual cycle. World Health Organization (WHO) in 2020 PMS has a higher prevalence in Asian countries compared to western countries. The purpose of this study was to determine the factors associated with Premenstrual syndrome in adolescent girls at MTsN 1 Labuhanbatu in 2024. This research design uses an analytic survey, namely research trying to explore how and why the phenomenon occurs. Then analyze the dynamics of the correlation between phenomena, both between related factors (Indipendent) and effect factors (Dependent). The approach used in this research is cross sectional. The population in this study was 291 people. The sample in this study amounted to 74 people. Data analysis used univariate analysis and bivariate analysis using the chi-square test. The results of statistical tests with stress categories obtained using the chi-square test at a confidence level of 95% are known that psig 0.000 is smaller than 0.05, the results of chi-square tests with consumption patterns at a confidence level of 95% are known that psig 0.000 is smaller than 0.05, the results of statistical tests with premenstrual syndrome incidence obtained using the chi-square test at a confidence level of 95% are known that psig 0.000 is smaller than 0.05. In conclusion, it is known that there is a relationship between stress, consumption patterns and exercise with the incidence of premenstrual syndrome in adolescent girls at MTsN 1 Labuhanbatu in 2024. It is suggested that the results of this study can add insight, knowledge and experience about premenstrual syndrome that can occur at any time.

Expression of Molecules Characterizing Metabolic and Cytotoxic Activity of Natural Killer Different Subpopulations of Peripheral Blood During Pregnancy

The functions of peripheral blood NK cells change significantly during pregnancy, which is mainly due to the inhibition of their cytotoxicity. The functional activity of NK cells is directly related to their metabolic status, but these changes in physiological pregnancy have not been studied. The aim of this work is to study the expression of Glut-1, CD94 and CD107a molecules characterizing metabolic and cytotoxic activity, as well as the mitochondrial mass of different subpopulations of peripheral blood NK cells in the I and III trimesters of physiological pregnancy. The object of the study was the peripheral blood of healthy women in the I and III trimesters of physiological pregnancy. The control group consisted of healthy non-pregnant women in the follicular phase of the menstrual cycle. The expression of Glut-1, CD94, CD107a molecules and the mitochondrial mass were analyzed by flow cytometry on regulatory (CD16–CD56bright), cytotoxic (CD16+CD56dim), minor cytotoxic (CD16hiCD56–) NK cells. It was found that in non-pregnant women, minor cytotoxic CD16hiCD56–NK have the highest expression of Glut-1, CD107a and the lowest expression of CD94 compared to other NK cell subpopulations. On regulatory CD16–CD 56bright and cytotoxic CD16+CD56dimNK, the expression of these molecules is comparable to each other. The mitochondrial mass is similar in all studied subpopulations. In the first trimester, the expression of Glut-1 increases on regulatory CD16–CD56brightNK, the mitochondrial mass and the expression of CD94, CD107a in all NK cells do not differ from non-pregnant ones. In the third trimester, the mitochondrial mass increases in cytotoxic CD16+CD56dimNK cells, but CD94 expression decreases compared to non-pregnant ones, and the expression CD94 in regulatory CD16–CD56brightNK increases compared to the first trimester. CD107a expression in minor cytotoxic CD16hiCD56–NK decreases, but in other subpopulations does not change compared to non-pregnant. The expression of Glut-1 does not change in all subpopulations. Thus, different subpopulations of peripheral blood NK cells are heterogeneous in the expression of Glut-1, CD107a, CD94. The expression of these molecules during physiological pregnancy varies by trimester. The obtained results are important for understanding the mechanisms of NK cell function regulations during pregnancy.

Blestriarene C exerts an inhibitory effect on triple-negative breast cancer through multiple signaling pathways.

Breast cancer is the most common cancer worldwide, the leading cause of cancer death in women, and the fifth leading cause of cancer death. Triple negative breast cancer (TNBC), with high metastasis and mortality rates, is the most challenging subtype in breast cancer treatment. There is an urgent need to develop anti-TNBC drugs with significant efficacy, low side effects and good availability. In early drug screening, blestriarene C was found to have inhibitory effects on TNBC cells. In this article, we further explore the mechanisms associated with blestriarene C for breast cancer. In this article, we take the approach of network pharmacology combined with in vivo and in vitro experiments. Network pharmacology analysis was used to predict the active components in Baiji, and to investigate the hub targets and related mechanisms of BC in TNBC treatment. The mechanism of anti-TNBC in vitro was evaluated by CCK-8 assay, cell apoptosis and cell cycle assays, wound healing assay, WB assay, and molecular docking analysis. The inhibition effect in vivo was test in subcutaneous tumor models established in mice. Through network pharmacology analysis and experiments, we screened out BC as the main active ingredient, and found that BC could inhibit the Ras/ERK/c-Fos signaling pathway while downregulating the expression of HSP90AA1 and upregulating the expression of PTGS2, thereby promoting apoptosis, causing S-phase cycle arrest, and inhibiting the proliferation and migration of BT549 cells. The in vivo results illustrated that BC inhibited the growth of TNBC tumors and has a high safety profile. By integrating network pharmacology with in vitro and in vivo experiments, this study demonstrated that BC inhibited the proliferation and migration of TNBC cells by inhibiting the Ras/ERK/c-Fos signaling pathway, promoting apoptosis, and causing S-phase cycle arrest. This study provides new evidence for the use of BC as a novel drug for TNBC treatment.

Anticipatory and evoked visual cortical dynamics of voluntary temporal attention.

We can often anticipate the precise moment when a stimulus will be relevant for our behavioral goals. Voluntary temporal attention, the prioritization of sensory information at task-relevant time points, enhances visual perception. However, the neural mechanisms of voluntary temporal attention have not been isolated from those of temporal expectation, which reflects timing predictability rather than relevance. Here we use time-resolved steady-state visual evoked responses (SSVER) to investigate how temporal attention dynamically modulates visual activity when temporal expectation is controlled. We recorded magnetoencephalography while participants directed temporal attention to one of two sequential grating targets with predictable timing. Meanwhile, a co-localized SSVER probe continuously tracked visual cortical modulations both before and after the target stimuli. We find that in the pre-target period, the SSVER gradually ramps up as the targets approach, reflecting temporal expectation. Furthermore, we find a low-frequency modulation of the SSVER, which shifts approximately half a cycle in phase according to which target is attended. In the post-target period, temporal attention to the first target transiently modulates the SSVER shortly after target onset. Thus, temporal attention dynamically modulates visual cortical responses via both periodic pre-target and transient post-target mechanisms to prioritize sensory information at precise moments.

Technical performance differences in elite Olympic recurve archers

ABSTRACT The aim of this study was to identify technical differences in the shot cycle demonstrated by elite Olympic recurve archers in major tournaments. Participants were 30, world-ranked archers (15 men and 15 women) who competed in different World Cup series competitions in 2023. A video notational analysis system was designed, based on the shot cycle, to assess technical differences between the elite archers. For each archer, 18 shots were selected from an analysis of performance in individual or team competitions. Results showed that the execution of shot cycle phases varied among elite archers. Findings also revealed that these variations grouped into two styles of Olympic recurve archery: some displayed a common style and some a more complex style. The two styles were mainly different in movement complexity when raising the bow, loading and bow arm follow-through. In conclusion, the designed notational analysis system in recurve archery can be used by coaches and performance analysts for exploring skill adaptation of young archers in their development pathway. The observed technical differences in actions of the elite archers in this study could justify our re-definition of the ideal performance in this sport, re-directed towards skill adaptations, based on satisfying individual, environmental and task constraints.

Current oral contraceptive use affects explicit and implicit measures of depression in women.

Some data suggest that increased depressive symptoms may occur in women using combined oral contraceptives (OCs). However, this idea is controversial and the existing evidence is conflicting. The present study compared negative affect in 53 healthy women (M age = 19.9 years) during intervals of active daily OC hormone intake and during the washout week of the contraceptive cycle when no exogenous estrogens or progestins are used. A prospective counterbalanced repeated-measures study design was employed. Depressive affect was evaluated using standard psychometric tests of explicit (self-perceived) and implicit negative affect. Implicit measures are considered less subject to bias related to social expectations, self-awareness, or willingness to disclose. Other than their usual OCs, participants were medication-free and had been using OCs for a median of 12 mo. We found that measures of implicit affect (e.g., Affect Misattribution Procedure, Emotional Stroop Test) displayed a more depressive-like pattern of performance during active hormone intake, particularly among a subgroup of OC users who reported experiencing high levels of depressive affect more generally. In contrast, participants' self-perceptions suggested that they perceived their negative symptoms to be greater during the 'off' phase of the OC cycle, when OC steroids are withdrawn and menses occurs. The present findings reinforce the possibility of depressive mood effects associated with OC usage, and highlight the utility of including implicit measures, but also illustrate the complexity of mood assessment in OC users.

Novel platinum nanoclusters (Pt NCs) induce mitochondrial apoptosis and damaging autophagy for the treatment of osteosarcoma—from the perspective of P53 mutation status in different cell lines

This study aimed to investigate the anticancer efficacy and underlying mechanism of novel platinum nanoclusters (Pt NCs) in osteosarcoma cell lines exhibiting distinct P53 expression profiles, namely MG-63 (P53−) and U2-OS (P53+). The findings revealed that Pt NCs exerted an inhibitory effect on proliferation, migration, and colony formation while promoting apoptosis in both MG-63 (P53−) and U2-OS (P53+) cells. The inhibitory effect on the malignant characteristics of MG-63 (P53−) cells was more obvious, indicating that the potential anticancer effect of Pt NCs was not dependent on P53. Animal experiments have substantiated the in vivo anticancer properties of Pt NCs, while also revealing their lower toxicity on cells and tissues. Pt NCs possess the ability to impede cell proliferation by inducing DNA damage and arresting the cell cycle in the G1 phase and possess the ability to promote BAX/Bcl-2/Caspase-3/mitochondrial apoptosis. Pt NCs may promote mitochondrial apoptosis by promoting damaging autophagy, thereby promoting cellular demise. This study has confirmed the P53-independent anticancer impact of Pt NCs on osteosarcoma in vitro and in vivo. Pt NCs may play a therapeutic role in more sensitive MG-63 (P53−) cells by promoting DNA damage to arrest the cell cycle, stimulating BAX/Bcl-2/Caspase-3/mitochondrial apoptosis, and initiating damaging autophagy.

Techno-economic optimization and feasibility of PCM-based seasonal thermal energy storage systems for district heating and cooling

Phase change materials (PCM) are an attractive seasonal thermal energy storage solution for load shifting due to relatively high energy density. Nevertheless, the choice of the right design parameters, such as storage size and phase-change temperature, is nontrivial, as these are tightly linked to the expected seasonal operation of the storage. This paper presents a combined design and operation optimization framework for sizing PCM-based seasonal thermal storage, which can capture dynamic behaviour of the storage in sensible and latent phases, and its impact on the efficiency of connected heat pumps and chillers. The proposed method, formulated as a mixed integer quadratically-constrained programming problem, was applied to a case study of heating-dominated district. It was found that the optimal PCM melting temperature equals to the heating demand supply temperature, thus removing the need of a heat pump to discharge the storage. The optimal operation of storage requires a full charging and discharging cycle of both latent and liquid phase. Higher CO2 emission price does not lead to a significant reduction of CO2 emissions, but the storage size does, leading to a higher heating coverage ratio of the storage, and consequently CO2 emissions and cost savings, which can be further enhanced with PV integration. The economic analysis indicates that, unless other benefits such as storage volume reduction are accounted for, PCM cost should drop by a factor 4 to make this solution economically viable for seasonal storage.

Melittin promotes the proliferation of Schwann cells in hyperglycemic environment by up‑regulating the Crabp2/Wnt/β‑catenin signaling pathway.

The present study aimed to explore the effect of melittin (MLT) on the growth of Schwann cells (SCs) in high glucose conditions and to understand the mechanisms involved. The goal was to provide a theoretical basis for using MLT in the treatment of diabetic peripheral neuropathy (DPN). The CCK‑8 assay was used to measure cell activity at different concentrations of glucose and MLT. Flow cytometry was employed to analyze the effect of MLT on cell cycle phases and apoptosis in SCs under high glucose conditions. To identify differentially expressed proteins, 4D label‑free quantitative proteomics with liquid chromatography‑mass spectrometry was used, followed by biological analysis to explore potential mechanisms. PCR, western blotting and immunofluorescence were conducted to confirm these mechanisms. Melittin (0.2 µg/ml) increased the proliferation of SCs in a high glucose environment. Flow cytometry showed that after MLT treatment, the proportion of cells in the G2/M+S phase increased and the combined ratio of early and late apoptosis decreased under high glucose conditions. Proteomics identified 1,784 proteins with significant changes in expression; 725 were upregulated, and 1,059 were downregulated. Kyoto Encyclopedia of Genes and Genomes analysis indicated that the differentially expressed proteins were mainly involved in metabolic pathways and neurodegenerative disease pathways. PCR, western blotting and immunofluorescence confirmed the increase in Crabp2, Wnt3a, C‑Jun, CDK4, CyclinD1 and proliferating cell nuclear antigen. In high glucose conditions, MLT protects SCs from glucose toxicity by upregulating the Crabp2/Wnt/β‑catenin signaling pathway, potentially providing a new treatment for DPN.

Targeting cancer-associated fibroblasts/tumor cells cross-talk inhibits intrahepatic cholangiocarcinoma progression via cell-cycle arrest

BackgroundCancer-associated fibroblasts (CAFs), mainly responsible for the desmoplastic reaction hallmark of intrahepatic Cholangiocarcinoma (iCCA), likely have a role in tumor aggressiveness and resistance to therapy, although the molecular mechanisms involved are unknown. Aim of the study is to investigate how targeting hCAF/iCCA cross-talk with a Notch1 inhibitor, namely Crenigacestat, may affect cancer progression.MethodsWe used different in vitro models in 2D and established new 3D hetero-spheroids with iCCA cells and human (h)CAFs. The results were confirmed in a xenograft model, and explanted tumoral tissues underwent transcriptomic and bioinformatic analysis.ResultshCAFs/iCCA cross-talk sustains increased migration of both KKU-M213 and KKU-M156 cells, while Crenigacestat significantly inhibits only the cross-talk stimulated migration. Hetero-spheroids grew larger than homo-spheroids, formed by only iCCA cells. Crenigacestat significantly reduced the invasion and growth of hetero- but not of homo-spheroids. In xenograft models, hCAFs/KKU-M213 tumors grew significantly larger than KKU-M213 tumors, but were significantly reduced in volume by Crenigacestat treatment, which also significantly decreased the fibrotic reaction. Ingenuity pathway analysis revealed that genes of hCAFs/KKU-M213 but not of KKU-M213 tumors increased tumor lesions, and that Crenigacestat treatment inhibited the modulated canonical pathways. Cell cycle checkpoints were the most notably modulated pathway and Crenigacestat reduced CCNE2 gene expression, consequently inducing cell cycle arrest. In hetero-spheroids, the number of cells increased in the G2/M cell cycle phase, while Crenigacestat significantly decreased cell numbers in the G2/M phase in hetero but not in homo-spheroids.ConclusionsThe hCAFs/iCCA cross-talk is a new target for reducing cancer progression with drugs such as Crenigacestat.Graphical abstract

A Recurrent Deep Network for Gait Phase Identification from EMG Signals During Exoskeleton-Assisted Walking

Lower limb exoskeletons represent a relevant tool for rehabilitating gait in patients with lower limb movement disorders. Partial assistance exoskeletons adaptively provide the joint torque needed, on top of that produced by the patient, for a correct and stable gait, helping the patient to recover an autonomous gait. Thus, the device needs to identify the different phases of the gait cycle to produce precisely timed commands that drive its joint motors appropriately. In this study, EMG signals have been used for gait phase detection considering that EMG activations lead limb kinematics by at least 120 ms. We propose a deep learning model based on bidirectional LSTM to identify stance and swing gait phases from EMG data. We built a dataset of EMG signals recorded at 1500 Hz from four muscles from the dominant leg in a population of 26 healthy subjects walking overground (WO) and walking on a treadmill (WT) using a lower limb exoskeleton. The data were labeled with the corresponding stance or swing gait phase based on limb kinematics provided by inertial motion sensors. The model was studied in three different scenarios, and we explored its generalization abilities and evaluated its applicability to the online processing of EMG data. The training was always conducted on 500-sample sequences from WO recordings of 23 subjects. Testing always involved WO and WT sequences from the remaining three subjects. First, the model was trained and tested on 500 Hz EMG data, obtaining an overall accuracy on the WO and WT test datasets of 92.43% and 91.16%, respectively. The simulation of online operation required 127 ms to preprocess and classify one sequence. Second, the trained model was evaluated against a test set built on 1500 Hz EMG data. The accuracies were lower, yet the processing times were 11 ms faster. Third, we partially retrained the model on a subset of the 1500 Hz training dataset, achieving 87.17% and 89.64% accuracy on the 1500 Hz WO and WT test sets, respectively. Overall, the proposed deep learning model appears to be a valuable candidate for entering the control pipeline of a lower limb rehabilitation exoskeleton in terms of both the achieved accuracy and processing times.

TRIP13 is Critical for the Survival of B-cell Lymphomas and Myeloid Leukemias In Vitro

Hematologic malignancies represent a diverse group of blood tumors accounting for approximately 10% of all cancer cases in the US. Based on the site of manifestation, presumed cell of origin, genetic abnormalities, and clinical features, we recognize more than 100 clinically important subtypes of hematologic malignancies broadly categorized into three main groups: leukemia, lymphoma, and multiple myeloma. While the prognosis for patients with specific subtypes of hematologic malignancies, such as Hodgkin lymphomas or chronic lymphocytic leukemia has significantly improved over the last several years, other subtypes such as acute myeloid leukemia or non-Hodgkin lymphomas still present with significant treatment challenges. A better understanding of molecular drivers of tumor maintenance is needed to improve existing therapies. Thyroid hormone receptor interactor 13 (TRIP13) is an AAA + ATPase that plays an important yet poorly understood role in the regulation of the mammalian cell cycle. The TRIP13 gene is highly expressed in various human tumors including colorectal carcinoma and glioblastoma, and it seems to promote tumorigenesis. Recently, we identified TRIP13 as a gene overexpressed in Peripheral T-cell lymphomas where it plays a critical role in tumor maintenance by regulating the G2-M phase of the cell cycle. However, the biological activities of TRIP13 in non-T cell hematologic malignancies have not been investigated to date. Here we used shRNA-mediated knockdown and a small molecule inhibitor to downregulate TRIP13 in B-cell lymphoid and myeloid lineages. We found genetic downregulation inhibited the proliferation of both B-cell lymphomas and acute myeloid leukemia cell lines in vitro. The pharmacologic inhibition of TRIP13 effectively induced the G0/G1 cell cycle arrest and apoptosis of B-cell lymphomas. Altogether these data demonstrate that TRIP13 is critical for the maintenance of hematologic malignancies of B-cell and myeloid malignancies in vitro. Thus, TRIP13 might be a good target in the treatment of various types of hematologic malignancies.

Budget impact analysis of TPMT and NUDT15 pharmacogenomic testing for 6-mercaptopurine in pediatric acute lymphoblastic leukemia patients.

Pharmacogenomic testing identifies gene polymorphisms impacting drug metabolism, aiding in optimizing treatment efficacy and minimizing toxicity, thus potentially reducing healthcare utilization. 6-Mercaptopurine metabolism is affected by thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) polymorphisms. We sought to estimate the budget impact of preemptive pharmacogenomic testing for these genes in pediatric acute lymphoblastic leukemia (ALL) patients from an institutional perspective. A Markov model was constructed to model the first cycle of the maintenance phase of chemotherapy for pediatric ALL patients transitioning between one of three health states: stable, moderately myelosuppressed, and severely myelosuppressed over 16 weeks, with each health state's associated costs derived from the literature. The patient's likelihood to experience moderate or severe myelosuppression based on metabolism phenotype was calculated from the literature and applied on a weekly basis, and the marginal budget impact of preemptive pharmacogenomic testing vs. no pharmacogenomic testing was calculated. One-way sensitivity analysis was conducted to assess parameter influence on results. Preemptive pharmacogenomic testing of TPMT and NUDT15 provided savings of up to $26 028 per patient during the maintenance phase. In the sensitivity analysis, the cost of outpatient management of moderate myelosuppression had the greatest impact on the budget, resulting in cost savings ranging from $8592 to $30 129 when the minimum and maximum costs of management were used in the model. Preemptive pharmacogenomic testing for TPMT and NUDT15 polymorphisms before initiation of maintenance therapy for pediatric ALL patients yielded considerable cost savings.

Statistical Study of the Occurrence of Coronal Holes in the Solar Corona During Solar Cycle 24

In this article we look at: (a) the occurrence of coronal holes as a function of the different phases of solar cycle 24, (b) the variability of the annual number of coronal holes from 2009 to 2019, (c) the distribution of polar and non-polar coronal holes, irrespective of the phase but also as a function of the different phases of the cycle. From the phase minimum to the descending phase of solar cycle 24, the occurrences of coronal holes observed on the solar disc are 38%, 24%, 9% and 29% respectively. The annual number of coronal holes observed on the solar disc does not always follow the expected evolution of the two components of the solar magnetic field and the annual number of sunspots. Regardless of the phase of the solar cycle, the majority of coronal holes, around 65%, are located in the polar regions. During the early and late phases of the solar cycle, polar coronal holes predominate, whereas during the ascending phase and phase maximum, non-polar coronal holes predominate. The number of polar coronal holes is highest during the minimum phase of the solar cycle and lowest during the maximum phase. During the phases of the solar cycle, coronal hole activity appears to be in phase opposition with sunspot activity. There is a fairly good correlation between variations in the number of polar coronal holes and the expected evolution of the poloidal component of the solar magnetic field.

The Effect of the Oral Contraceptive Pill on Acute Glycaemic Response to an Oral Glucose Bolus in Healthy Young Women: A Randomised Crossover Study.

Background/Objective: The oral contraceptive pill (OCP) is widely used by women worldwide, yet the influence of the OCP on carbohydrate metabolism remains under-investigated, with existing studies being few and largely cross-sectional. The study objective was to assess, for the first time, the effect of the combined OCP on postprandial glycaemic response to an oral glucose bolus, using a randomised crossover design. Methods: The effect of a combined monophasic OCP phase on glucose homeostasis and metabolic profile was investigated in 21 healthy young women, who were regular users of either androgenic or anti-androgenic OCP formulations. Plasma glycaemic markers (glucose, insulin and C-peptide) were assessed prior to a 60 g glucose drink (fasting) and for a further 4 h postprandially; once during the "active" (hormone-containing) pill phase and once during the "inactive" (hormone-free) pill phase of the OCP usage cycle. Results: Despite no change in fasting values, in androgenic pill users, postprandial glucose and insulin responses to an oral glucose bolus were ~100% and ~50% greater, respectively, during the active versus inactive phase. In contrast, in anti-androgenic pill users there was no significant change in response between the two OCP usage cycle phases. Conclusions: These findings highlight an acute, but potentially detrimental, influence of the combined OCP on glucose homeostasis, particularly in users of formulations containing androgenic progestogens. Given the high global prevalence of OCP use and increasingly common prolonged active pill regimens, which may continue for months, years or even decades, potential cumulative effects of such changes on metabolic risk demand further investigation.