Tag: pubmed

Cell Signal. 2023 Sep 22:110901. doi: 10.1016/j.cellsig.2023.110901. Online ahead of print.

ABSTRACT

Cancer cachexia is a systemic inflammation-driven syndrome, characterized by muscle atrophy and adipose tissue wasting, with progressive weight loss leading to serious impairment of physiological function. Extracellular vesicles (EVs) derived from cancer cells play a significant role in adipocyte lipolysis, yet the mechanism remain uneclucidated. In this study, EVs derived from Lewis lung carcinoma (LLC) cells were extracted and characterized. 3 T3-L1 and HIB1B adipocytes were cultured with conditioned medium or EVs from LLC, and LLC cells were used to establish a cancer cachexia mouse model. EVs derived from LLC cells were taken up by 3 T3-L1 and HIB1B adipocytes, and derived exosomal EIF5A protein-induced lipolysis of adipocytes. High level of EIF5A was expressed in EVs from LLC cells, exosomal EIF5A is linked to lipid metabolism. Elevated expression of EIF5A is associated with shorter overall survival in lung cancer patients. Western blots, glycerol release and Oil red O staining assays were used to evaluate lipolysis of adipocytes. The reduction of lipolysis in 3 T3-L1 and HIB1B adipocytes is achieved through silencing EIF5A or treating with pharmacologic inhibitor GC7 in vitro, and suppressing the expression of EIF5A in LLC cells by infected with shRNA or GC7 treatment partly alleviated white and brown adipose tissue lipolysis in vivo. Mechanistically, EIF5A directly binds with G protein-coupled bile acid receptor 1 (GPBAR1) mRNA to promote its translation and then activates cAMP response element binding protein (CREB) signaling pathway to induce lipolysis. This study demonstrates that exosomal EIF5A from LLC cells, with hypusinated EIF5A, has a lipolytic effect on adipocyte and adipose tissues in cancer cachexia model. Exosomal EIF5A could be involved in lipolysis and these findings indicate that a novel regulator and potential target for cachexia treatment.

PMID:37743008 | DOI:10.1016/j.cellsig.2023.110901

Am J Obstet Gynecol MFM. 2023 Sep 22:101168. doi: 10.1016/j.ajogmf.2023.101168. Online ahead of print.

ABSTRACT

BACKGROUND: Continuous support during labor has many benefits, including lower use of obstetrical interventions. However, implementation remains limited. Insights into birth outcomes as well as peripartum costs are essential to assess whether continuous care by a maternity care assistant is a potentially (cost) effective program to provide for all women.

OBJECTIVE: Continuous care during labor, provided by maternity care assistants, will reduce the use of epidural analgesia and peripartum costs due to a reduction in interventions.

STUDY DESIGN: A randomized controlled trial, comparing continuous support during labor (intervention group) to care-as-usual (control group) with pre-specified intention-to-treat and per-protocol analyses. The primary outcome was epidural analgesia use. Secondary outcomes were use of other analgesia, referrals from midwife- to obstetrician-led care, modes of birth, hospital stay, sense of control (evaluated with the Labor Agentry Scale), maternal and neonatal adverse outcomes and peripartum costs. Data were collected using questionnaires. Anticipating incomplete adherence to providing continuous care, both intention-to-treat and per-protocol analyses were planned. Peripartum costs were estimated using a healthcare perspective. Mean costs per woman and cost differences between the intervention and control group were calculated.

RESULTS: The population consisted of 1076 women with 54 exclusions and 30 discontinuations, leaving 992 women to be analyzed (515 continuous care and 477 care-as-usual). Intention-to-treat analyses showed statistically non-significant differences between the intervention and control group for epidural use (RR 0.88, 95%-CI 0.74 to 1.04, p=0.14) and peripartum costs (mean difference € 185.83, 95%-CI -€ 204.22 to € 624.54). Per-protocol analyses showed statistically significant decreases in epidural analgesia (RR 0.64, 95%-CI 0.48 to 0.84, p=0.001), other analgesia (RR 0.59, 95%-CI 0.37 to 0.94, p=0.02), cesarean sections (RR 0.53, 95%-CI 0.29 to 0.95, p=0.03) and increase in spontaneous vaginal births (RR 1.09, 95%-CI 1.01 to 1.18, p=0.001) in the intervention group, but difference in total peripartum costs remained statistically non-significant (mean difference € 246.55, 95%-CI -€ 539.14 to € 13.50).

CONCLUSION: If the provision of continuous care given by maternity care assistants during labor can be secured, continuous care leads to more vaginal births and less epidural use, pain medication and cesarean sections, while not leading to a difference in peripartum costs compared to care-as-usual.

PMID:37742999 | DOI:10.1016/j.ajogmf.2023.101168

Sci Total Environ. 2023 Sep 22:167288. doi: 10.1016/j.scitotenv.2023.167288. Online ahead of print.

ABSTRACT

Limited information is available regarding the pollution status of organophosphate esters (OPEs) in the environment of the Yellow River estuary. Here, n = 51 sediment samples were collected from the Yellow River estuary in 2021, and further analyzed by using the integrated target, suspect, and feature fragment-dependent nontarget OPE screening strategy developed in our laboratory. Among the 30 target OPEs, 19 were detectable in at least one of the analyzed samples, with total concentrations (Σ₁₉OPEs) ranging from of 41.4 to 1930 ng/g dry weight (dw). On the basis of an in-house suspect compound database, we further tentatively identified 11 suspect OPEs, and they were semi-quantified. Furthermore, four other interesting findings were observed and described as follows: 1) a statistically significant difference existed in the concentrations of OPEs in sediment samples between the lower reaches of the Yellow River (n = 5 samples), and the Yellow River estuary (n = 46 samples) (unpaired t-test, p < 0.001); 2) tris(2,4-di-tert-butylphenyl)phosphate (TDTBPP) exhibited the greatest concentrations (ranging from 30.7 to 1920 ng/g dw) among all OPEs detected in the sediment samples; 3) samples from the north of the Yellow River estuary had higher OPE concentrations than those from the south; and 4) a suspect screening strategy allowed us to identify a novel OPE structure (tert-butyl)phenyl (ethyne-oxidane) bis(2,4-di-tert-butylphenyl) phosphate (TPBDTP) that exhibited a highly positive correlation relationship with TDTBPP (r = 0.749; p < 0.001). Overall, this study provided evidence that OPEs (especially TDTBPP) were ubiquitous in the sediment environment of the Yellow River estuary; thus, we emphasize that continuous monitoring of OPE pollution should be conducted in this region.

PMID:37742975 | DOI:10.1016/j.scitotenv.2023.167288

Sci Total Environ. 2023 Sep 22:167293. doi: 10.1016/j.scitotenv.2023.167293. Online ahead of print.

ABSTRACT

Magnesium-functionalized Magnolia grandiflora Linn leaf-derived biochar (MBC) capable of efficiently reclaiming phosphorus from urine was synthesized by slow co-pyrolysis. Four adsorption kinetic and seven adsorption isotherm models were fitted to the batch adsorption and desorption experimental data, and it was found that pseudo-first-order kinetic model and multilayer model with saturation best described the phosphate-phosphorus (PO₄^3--P) adsorption process by MBC. MBC and phosphorus-saturated MBC (P-MBC) were found to offer outstanding phosphorus adsorption and slow release properties, respectively. Based on material characterization, statistical physics, adsorption energy distribution and statistical thermodynamics, a multi-ionic, inclined orientation, entropy-driven spontaneous endothermic process of MBC on PO₄^3--P was proposed, involving physicochemical interactions (porous filling, electrostatic attraction, ligand exchange and surface precipitation). Further, seed germination and early seedling growth experiments proved that P-MBC can be used as a slow-release fertilizer. Overall, MBC offers prospective applications as an efficient phosphorus adsorbent and then as a slow-release fertilizer.

PMID:37742963 | DOI:10.1016/j.scitotenv.2023.167293

Sci Total Environ. 2023 Sep 22:167265. doi: 10.1016/j.scitotenv.2023.167265. Online ahead of print.

ABSTRACT

Africa is vulnerable to the impacts of climate change, particularly in terms of its agriculture and crop production. The majority of climate models project a negative impact of future climate change on crop production, with maize being particularly vulnerable. However, the magnitude of this change remains uncertain. Therefore, it is important to reduce the uncertainties related to the anticipated changes to guide adaptation options. This study uses a combination of local and large-scale empirical orthogonal function (EOF) predictors as a novel approach to model the impacts of future climate change on crop yields in West, East and Central Africa. Here a cross-validated Bayesian model was developed using predictors derived from the regional climate model REMO for the period 1982-2100. On average, the combined local and large-scale EOF predictors explained around 28 % of maize yield variability from 1982 to 2016 of the entire study regions. Notably, climate predictors played a significant role in West Africa, explaining up to 51 % of the maize yield variability. Large-scale climate EOF predictors contributed most to the explained variance, reflecting the role of regional climate in future maize yield variability. Under a high-emissions scenario (RCP8.5), maize yield is projected to decrease over the entire study region by 20 % by the end of the century. However, a minor increase is projected in eastern Africa. This study highlights the importance of incorporating climate predictors at various scales into crop yield modeling. Furthermore, the findings will offer valuable guidance to decision-makers in shaping adaptation options.

PMID:37742952 | DOI:10.1016/j.scitotenv.2023.167265

Hum Pathol. 2023 Sep 22:S0046-8177(23)00189-2. doi: 10.1016/j.humpath.2023.09.004. Online ahead of print.

ABSTRACT

Lymphocyte-rich hepatocellular carcinoma (LR-HCC), a newly proposed subtype of HCC, is characterized with abundant lymphocyte infiltration in the tumor. LR-HCC has a relatively good prognosis and is quite rare (< 1% of all HCC). We examined LR-HCC clinicopathological and molecular characteristics by analyzing 451 surgically resected HCC cases without any prior treatment history at our hospital between 2012 and 2021. Clinicopathological features of LR-HCC and other HCCs (non-LR-HCC) were compared. Neoplastic and nonneoplastic hepatocytes from LR-HCC (n = 4) were collected with a laser microdissection system; RNA was extracted, followed by microarray analysis to examine lymphocytic infiltration-related molecular targets. Immunohistochemical staining of identified molecular target was performed in LR-HCC and non-LR-HCC. CD3, CD20, and CD8 immunostaining was also performed in LR-HCCs. There were 28 cases of LR-HCC (6%). No statistically significant differences were found in clinicopathological features, except for gross type, between LR-HCC and non-LR-HCC cases. The LR-HCC 5-year survival rate was > 90%. Microarray analysis revealed high CCL20 expression in LR-HCC cases; immunohistochemical study showed significantly higher CCL20 expression in LR-HCC (P < 0.01) than in non-LR-HCC. CCR6, the only CCL20 receptor, was observed in infiltrating lymphocytes and HCC cells in LR-HCC. There were significantly more CD3-positive cells than CD20-positive cells (P < 0.0001) in tumor-infiltrating lymphocytes, most of which were CD8-positive T cells. In conclusion, there were no significant differences in clinicopathological characteristics between LR-HCC and non-LR-HCC, except for gross and LR microscopic features. CCL20 expression in LR-HCC may contribute to infiltration of large numbers of CD8-positive lymphocytes.

PMID:37742944 | DOI:10.1016/j.humpath.2023.09.004

Hum Pathol. 2023 Sep 22:S0046-8177(23)00187-9. doi: 10.1016/j.humpath.2023.09.002. Online ahead of print.

ABSTRACT

Molecular research on large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) has progressed significantly. However, there are still fewer molecular markers related to prognostic/therapeutic strategies for these conditions compared to those for adenocarcinoma. We therefore investigated the molecular characteristics of neuroendocrine carcinomas (NECs). We enrolled patients surgically diagnosed with NECs between 2011 and 2019, with complete follow-up records. All were analyzed using whole exome sequencing and p53/Rb immunohistochemistry (IHC). A total of 92 cases, comprising 45 pure SCLC, 15 combined SCLC, 27 pure LCNEC, and 5 combined LCNEC, were included. TP53 (78.3%) and RB1 (34.8%) were the most common molecular alterations, followed by KMT2D, LRP1B, FAT3, NCOR2, SPTA1, and NOTCH1. The mutation frequency for EGFR was 10.9%. Sixteen patients with LCNEC who had TP53/RB1 co-alterations were SCLC-like, while the remaining were NSCLC-like. There was no statistically significant difference between the groups regarding overall survival (OS; p=0.458) and progression-free survival (PFS; p=0.157). The frequency of the loss of Rb expression by IHC in SCLC-like LCNEC was 100%. Significant pathway alterations unique to SCLC included Notch and AMPK, while HIF-1 was enriched exclusively in LCNEC. NCOR2 mutation was linked to worse OS (p=0.029) and PFS (p=0.015), while wild-type SPTA1 was associated with poor PFS (p=0.018). IHC for Rb was reliable for predicting LCNEC molecular subtypes, indicating its clinical value. NCOR2 and SPTA1 alterations were identified as prognostic factors that may provide therapeutic targets for patients with NEC.

PMID:37742943 | DOI:10.1016/j.humpath.2023.09.002

Mod Pathol. 2023 Sep 22:100336. doi: 10.1016/j.modpat.2023.100336. Online ahead of print.

ABSTRACT

Phosphaturic mesenchymal tumors (PMT) are uncommon neoplasms that cause hypophosphatemia/osteomalacia mainly by secreting fibroblast growth factor 23. We previously identified FN1::FGFR1/FGF1 fusions in nearly half of PMTs, and frequent KL (Klotho or α-Klotho) overexpression only in those with no known fusion. Here, we studied a larger cohort of PMTs for KL expression and alterations. By FN1 break-apart FISH and reappraisal of previous RNA sequencing data, 6 tumors previously considered “fusion-negative” (defined by negative results of FISH for FN1::FGFR1 fusion and FGF1 break-apart and/or of RNA sequencing) were reclassified as fusion-positive PMTs, including one containing a novel FN1::ZACN fusion. The final cohort of fusion-negative PMTs included 33 tumors from 32 patients, which occurred in bone (N=18), soft tissue (10), sinonasal tract (4) and brain. In combination with previous work, RNA sequencing, RNA in situ hybridization, and immunohistochemistry showed largely concordant results and demonstrated KL/α-Klotho overexpression in 17 of the 28 fusion-negative and none of the 10 fusion-positive PMTs studied. Prompted by a patient in this cohort harboring germline KL upstream translocation with systemic α-Klotho overexpression and multifocal PMTs, FISH was performed and revealed KL rearrangement in 16 of the 33 fusion-negative PMTs (one also with amplification), including 14 of the 17 cases with KL/α-Klotho overexpression and none of the 11 KL/α-Klotho-low fusion-negative and 11 fusion-positive cases studied. Whole genomic sequencing confirmed in 2 FISH-positive cases translocation and inversion, respectively, involving KL upstream region, warranting further investigation into the mechanism whereby these rearrangements may lead to KL upregulation. Methylated DNA immunoprecipitation and sequencing suggested no major role of promoter methylation in KL regulation in PMT. Interestingly, KL-high/-rearranged cases seemed to form a clinicopathologically homogeneous group, showing a predilection for skeletal/sinonasal locations and typically matrix-poor, cellular solitary fibrous tumor-like morphology. Importantly, FGFR1 signaling pathways were upregulated in fusion-negative PMTs regardless of the KL status compared with non-PMT mesenchymal tumors by gene set enrichment analysis, perhaps justifying FGFR1 inhibition in treating this subset of PMTs.

PMID:37742927 | DOI:10.1016/j.modpat.2023.100336

Mod Pathol. 2023 Sep 22:100335. doi: 10.1016/j.modpat.2023.100335. Online ahead of print.

ABSTRACT

Tumor cell fraction (TCF) estimation is a common clinical task with well-established large inter-observer variability. It thus provides an ideal testbed to evaluate potential impacts of employing a computer-aided diagnostic (TCFCAD) tool to support pathologists’ evaluation. During a National Slide Seminar event, pathologists (n=69) were asked to visually estimate TCF in 10 regions of interest (ROI) from hematoxylin and eosin (H&E) colorectal cancer images intentionally curated for diverse tissue compositions, cellularity, and stain intensities. Next, they re-evaluated the same ROIs while being provided a TCFCAD created overlay highlighting predicted tumor versus non-tumor cells, together with the corresponding TCF percentage. Participants also reported confidence levels in their assessments using a 5-tiers scale, indicating no confidence to high confidence, respectively. The TCF ground truth (GT) was defined by manual cell-counting by experts. When assisted, inter-observer variability significantly decreased, showing estimates converging to the GT. This improvement remained even when TCFCAD predictions deviated slightly from the GT. The standard-deviation of estimated TCF to the GT across ROIs was 9.9% vs 5.8% with TCFCAD, p < 0.0001. The intraclass correlation coefficient increased from 0.8 to 0.93 (CI95% [0.65, 0.93] vs [0.86, 0.98]) and pathologists stated feeling more confident when aided (3.67 ± 0.81 vs. 4.17 ± 0.82 with CAD). TCFCAD estimation support demonstrated improved scoring accuracy, inter-pathologist agreement and scoring confidence. Interestingly, pathologists also expressed more willingness to use such a CAD tool at the end of the survey, highlighting the importance of training/education to increase adoption of CAD systems.

PMID:37742926 | DOI:10.1016/j.modpat.2023.100335

J Pain. 2023 Sep 22:S1526-5900(23)00541-2. doi: 10.1016/j.jpain.2023.09.011. Online ahead of print.

ABSTRACT

The ATP-gated channel P2X7 is encoded by a gene enriched for common nonsynonymous variants. Many of these variants have functional cellular effects, and some been implicated in chronic pain. In this study, we first systematically characterized all 17 common nonsynonymous variants using whole-cell patch clamp electrophysiology. Then, we analyzed these variants for statistical association with chronic pain phenotypes using both individual P2RX7 variants as predictors and cumulative allele counts of same-direction cellular effect in univariate models. Association and validation analyses were conducted in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) cohort (N=3260) and in the Complex Persistent Pain Conditions (CPPC) cohort (N= 900), respectively. Our results showed an association between allele A of rs7958311 and an increased risk of chronic pelvic pain, with convergent evidence for contribution to fibromyalgia and irritable bowel syndrome (IBS), confirmed in meta-analysis. This allelic variant produced a unique cellular phenotype: a gain-of-function (GOF) in channel opening, and loss-of-function (LOF) in pore opening. Computational study using a 12-state Markov model of ATP binding to the P2X7 receptor suggested that this cellular phenotype arises from an increased ATP binding affinity and an increased open channel conductance combined with a loss of sensitization. Cumulative allele count analysis did not provide additional insights. In conclusion, our results go beyond reproducing association for rs7958311 with chronic pain and suggest that its unique combination of GOF in channel and LOF in pore activity may explain why it is likely the only common P2RX7 variant with contribution to chronic pain. PERSPECTIVE: This study characterizes all common P2RX7 variants using cellular assays and statistical association analyses with chronic pain, with Markov state modeling of the most robustly associated variant.

PMID:37742908 | DOI:10.1016/j.jpain.2023.09.011