Early identification of recurrence in ovarian cancer: a comparison between the ovarian cancer metastasis index and CA-125 levels

Ovarian cancer (OC) is the second most common gynecologic malignancy. A clinical observational study was performed to investigate whether indicators that assess the risk of metastasis can identify recurrence earlier in OC patients. By successfully recruiting 41 patients with OC who underwent chemotherapy, we compared cancer antigen-125 (CA-125) and the ovarian cancer metastasis index (OCMI), which was previously developed by us in the clinic for this purpose. Our results showed that patients and their families generally took a sensible attitude toward disease progression and were willing to accept a new way to gain knowledge about the disease. Herein, the new way was the possibility of monitoring recurrence by introducing the OCMI into the clinic. Fifteen patients experienced recurrence during chemotherapy, implying treatment failure. For 53% of these patients, an abnormally high OCMI suggested a strong tendency toward metastasis at least one chemotherapy cycle prior to the pathological examination confirming recurrence. In comparison, the early recognition rate of recurrence using CA-125 levels was merely 13%. Furthermore, we found that the mean values of the OCMI no longer declined after the fourth chemotherapy cycle, implying that excessive chemotherapy brings no benefit to OC patients. In conclusion, our findings provide a novel and feasible approach to monitor the effectiveness of chemotherapy in the treatment of OC by assessing the potential risk of metastasis

A dimeric Smac/ diablo peptide directly relieves caspase-3 inhibition by XIAP. Dynamic and cooperative regulation of XIAP by Smac/Diablo

Caspase activation, the executing event of apoptosis, is under deliberate regulation. IAP proteins inhibit caspase activity, whereas Smac/Diablo antagonizes IAP. XIAP, a ubiquitous IAP, can inhibit both caspase-9, the initiator caspase of the mitochondrial apoptotic pathway, and the downstream effector caspases, caspase-3 and caspase-7. Smac neutralizes XIAP inhibition of caspase-9 by competing for binding of the BIR3 domain of XIAP with caspase-9, whereas how Smac liberates effector caspases from XIAP inhibition is not clear. It is generally believed that binding of Smac with IAP generates a steric hindrance that prevents XIAP from inhibiting effector caspases, and therefore small molecule mimics of Smac are not able to reverse inhibition of the effector caspases. Surprisingly, we show here that binding of a dimeric Smac N-terminal peptide with the BIR2 domain of XIAP effectively antagonizes inhibition of caspase-3 by XIAP. Further, we defined the dynamic and cooperative interaction of Smac with XIAP: binding of Smac with the BIR3 domain anchors the subsequent binding of Smac with the BIR2 domain, which in turn attenuates the caspase-3 inhibitory function of XIAP. We also show that XIAP homotrimerizes via its C-terminal Ring domain, making its inhibitory activity toward caspase-3 more susceptible to Smac

Causal association between serum 25-Hydroxyvitamin D levels and cutaneous melanoma: a two-sample Mendelian randomization study

BackgroundDespite numerous observational studies on the association between serum 25-Hydroxyvitamin D levels and cutaneous melanoma, causal inferences remain ambiguous due to confounding and reverse causality. This study aimed to elucidate the causal relationship between serum 25-Hydroxyvitamin D levels and melanoma incidence using Mendelian randomization (MR).MethodsA two-sample MR was conducted using genetic variants associated with serum 25-Hydroxyvitamin D levels as instrumental variables. Summary statistics for these variants were derived from genome-wide association studies, and those for melanoma risk were obtained from a comprehensive melanoma case-control study. Robustness of the results was assessed through sensitivity analyses, including the “leave-one-out” approach and tests for potential pleiotropy.ResultsThe MR analysis provided substantial evidence of a positive causal relationship between serum 25-Hydroxyvitamin D levels and the incidence of cutaneous melanoma, suggesting that each unit increase in serum 25-Hydroxyvitamin D levels corresponds with an increased risk of melanoma. Tests for pleiotropy showed minimal effects, and the sensitivity analysis confirmed no disproportionate influence by any individual single nucleotide polymorphism (SNP).ConclusionThe findings indicated a potentially causal positive association between serum 25-Hydroxyvitamin D levels and melanoma risk, challenging traditional beliefs about vitamin D’s role in melanoma. This emphasizes the need for a balanced and personalized approach to vitamin D supplementation and sun exposure, particularly in high-risk populations. These results should be interpreted with caution due to potential unrecognized pleiotropy and confounding factors. Future research should focus on validating these findings in diverse populations and exploring underlying biological mechanisms

Dual functionalized hyaluronic acid micelles loading paclitaxel for the therapy of breast cancer

Although many carriers for the delivery of chemotherapeutic drugs have been investigated, the disadvantages of passive targeting and uncontrolled drug release limit their utility. Herein, hyaluronic acid (HA) was hydrophobically modified to serve as a carrier for binding to cluster determinant 44 (CD44) overexpressed on tumor cell surfaces. Specifically, after deacetylation, HA was grafted to dodecylamine or tetradecylamine to afford amphiphilic zwitterionic polymer micelles, designated dHAD and dHAT, respectively, for the delivery of paclitaxel (PTX). The micelles were negatively charged at pH 7.4 and positively charged at pH 5.6, and this pH sensitivity facilitated PTX release under acidic conditions. The cell uptake efficiencies of the dHAD-PTX and dHAT-PTX micelles by MCF-7 cells after 4 h of incubation were 96.9% and 95.4%, respectively, and their affinities for CD44 were twice that of HA. Furthermore, the micelles markedly inhibited tumor growth both in vitro and in vivo, with IC50 values of 1.943 μg/mL for dHAD-PTX and 1.874 μg/mL for dHAT-PTX for MCF-7 cells; the tumor inhibition rate of dHAD-PTX (92.96%) was higher than that of dHAT-PTX (78.65%). Importantly, dHAD and dHAT micelles showed negligible systemic toxicity. Our findings suggest that these micelles are promising delivery vehicles for antitumor drugs

Mapping the Distribution of Water Resource Security in the Beijing-Tianjin-Hebei Region at the County Level under a Changing Context

The Beijing-Tianjin-Hebei (Jingjinji) region is the most densely populated region in China and suffers from severe water resource shortage, with considerable water-related issues emerging under a changing context such as construction of water diversion projects (WDP), regional synergistic development, and climate change. To this end, this paper develops a framework to examine the water resource security for 200 counties in the Jingjinji region under these changes. Thus, county-level water resource security is assessed in terms of the long-term annual mean and selected typical years (i.e., dry, normal, and wet years), with and without the WDP, and under the current and projected future (i.e., regional synergistic development and climate change). The outcomes of such scenarios are assessed based on two water-crowding indicators, two use-to-availability indicators, and one composite indicator. Results indicate first that the water resources are distributed unevenly, relatively more abundant in the northeastern counties and extremely limited in the other counties. The water resources are very limited at the regional level, with the water availability per capita and per unit gross domestic product (GDP) being only 279/290 m3 and 46/18 m3 in the current and projected future scenarios, respectively, even when considering the WDP. Second, the population carrying capacity is currently the dominant influence, while economic development will be the controlling factor in the future for most middle and southern counties. This suggests that significant improvement in water-saving technologies, vigorous replacement of industries from high to low water consumption, as well as water from other supplies for large-scale applications are greatly needed. Third, the research identifies those counties most at risk to water scarcity and shows that most of them can be greatly relieved after supplementation by the planned WDP. Finally, more attention should be paid to the southern counties because their water resources are not only limited but also much more sensitive and vulnerable to climate change. This work should benefit water resource management and allocation decisions in the Jingjinji region, and the proposed assessment framework can be applied to other similar problems.This study is supported by the National Key Research and Development Program of China (2016YFC0401401) and the National Natural Science Foundation of China (51609256, 51609122, 51522907, 51739011, and 51569026). Partial support is also from the Young Elite Scientists Sponsorship Program by the China Association for Science and Technology (2017QNRC001

Quantitative Analysis of Ubiquitinated Proteins in Human Pituitary and Pituitary Adenoma Tissues

Protein ubiquitination is an important post-translational modification that is associated with multiple diseases, including pituitary adenomas (PAs). Protein ubiquitination profiling in human pituitary and PAs remains unknown. Here, we performed the first ubiquitination analysis with an anti-ubiquitin antibody (specific to K-ε-GG)-based label-free quantitative proteomics method and bioinformatics to investigate protein ubiquitination profiling between PA and control tissues. A total of 158 ubiquitinated sites and 142 ubiquitinated peptides in 108 proteins were identified, and five ubiquitination motifs were found. KEGG pathway network analysis of 108 ubiquitinated proteins identified four statistically significant signaling pathways, including PI3K-AKT signaling pathway, hippo signaling pathway, ribosome, and nucleotide excision repair. R software Gene Ontology (GO) analysis of 108 ubiquitinated proteins revealed that protein ubiquitination was involved in multiple biological processes, cellular components, and molecule functions. The randomly selected ubiquitinated 14-3-3 zeta/delta protein was further analyzed with Western blot, and it was found that upregulated 14-3-3 zeta/delta protein in nonfunctional PAs might be derived from the significantly decreased level of its ubiquitination compared to control pituitaries, which indicated a contribution of 14-3-3 zeta/delta protein to pituitary tumorigenesis. These findings provided the first ubiquitinated proteomic profiling and ubiquitination-involved signaling pathway networks in human PAs. This study offers new scientific evidence and basic data to elucidate the biological functions of ubiquitination in PAs, insights into its novel molecular mechanisms of pituitary tumorigenesis, and discovery of novel biomarkers and therapeutic targets for effective treatment of PAs

Heat Transfer Coefficient Estimation and Performance Evaluation of Shell and Tube Heat Exchanger Using Flue Gas

In the past few decades, water and air were commonly used as working fluid to evaluate shell and tube heat exchanger (STHE) performance. This study was undertaken to estimate heat transfer coefficients and evaluate performance in the pilot-scale twisted tube-based STHE using the flue gas from biomass co-combustion as working fluid. Theoretical calculation along with experimental results were used to calculate the specific heat of flue gas. A simplified model was then developed from the integration of two heat transfer methods to predict the overall heat transfer coefficient without tedious calculation of individual heat transfer coefficients and fouling factors. Performance including water and trailer temperature, heat load, effectiveness, and overall heat transfer coefficient were jointly investigated under variable operating conditions. Results indicated that the specific heat of flue gas from co-combustion ranging between 1.044 and 1.338 kJ/kg·K while specific heat was increased by increasing flue gas temperature and decreasing excess air ratio. The developed mathematical model was validated to have relatively small errors to predict the overall heat transfer coefficient. A flue gas mass flow rate of 61.3–98.8 kg/h, a water flow rate of 13.7–14.1 L/min, and a parallel arrangement of two water-to-air heaters in an empty trailer were found to be optimal conditions for space heating purpose. In addition, a lower poultry litter feeding rate decreased heat loss of flue gas and increased heat gain of water, while a lower water flow rate also provided a lower maximum possible heat transfer rate with a higher actual heat transfer rate to quickly achieve heat equilibrium that ultimately improves the performance. This study demonstrates the possibility of collecting residual heat from the flue gas using the pilot-scale STHE system while outlining a systematic approach and process for evaluating its performance

Design and Evaluation of the Lab-Scale Shell and Tube Heat Exchanger (STHE) for Poultry Litter to Energy Production

Poultry litter is one type of biomass and waste generated from the farming process. This study performed a performance and process analysis of poultry litter to energy using the lab-scale shell and tube heat exchanger (STHE) system along with a Stirling engine and a swirling fluidized bed combustor (SFBC). The effects of tube shape, flow direction, and water flow rates on water and trailer temperature changes were investigated during the poultry litter co-combustion process. Energy flow analysis and emissions were also studied. Results showed that the water outlet temperature of 62.8 ° C in the twisted tube was higher than the straight tube case (58.3 ° C ) after 130 min of the co-combustion process. It was found that the counter-current direction had higher water temperature changes, higher logarithmic mean temperature difference (LMTD), and higher trailer temperature changes than the co-current direction. A water flow rate of 4.54 L/min showed adequate heat absorption in the lab-scale STHE system and heat rejection in the trailer. Results indicated that the lab-scale STHE system has a conversion efficiency of 42.3% and produces hot water (at about 63.9 ° C ) along with lower emissions. This research study confirmed that poultry litter can be used to generate energy (e.g., hot water and electricity) by using a lab-scale biomass conversion system for space heating applications