Advancing towards practice: A novel LC-MS/MS method for detecting retinol in dried blood spots.

BACKGROUND: To date, clinical laboratories face challenges in quantifying retinol from DBS samples. Disputes arise throughout the whole detection process, encompassing the storage condition, the release strategy as well as the selection of internal standards. METHODS: We incubated DBS with ascorbic acid solution. Then, retinol-d4 in acetonitrile was introduced to incorporate isotopic internal standard and promote protein precipitation. Afterward, sodium carbonate solution was added to ionize cytochromes (such as bilirubin), which amplified the difference of their hydrophobicity to retinol. Subsequently, cold-induced phase separation could be facilitated to separate retinol from the impurities. In the end, the upper layer was injected for LC-MS/MS analysis. RESULTS: By comparing the detected retinol content in whole blood and DBS samples prepared from the same volume, we confirmed the established pretreatment was capable to extract most of retinol from DBS (recovery >90 %). Thereafter, we verified that within DBS, retinol possessed satisfying stability without antioxidation. Indoor-light exposure and storage duration would not cause obvious degradation (<10 %). Following systematic validation, the established method well met the criteria outlined in the relevant guidelines. After comparing with detected DBS results to the paired plasma samples, 54 out of 60 met the acceptance limit for cross-validation of ±20 %. CONCLUSIONS: We realized precise quantification of retinol from one 3.2 mm DBS disc. By circumventing conventional antioxidation, liquid-liquid/solid-phase extraction and organic solvent evaporation, the pretreatment could be completed within 15 min consuming only minimal amounts of low-toxicity chemicals (ascorbic acid, acetonitrile, and sodium carbonate). We expect this contribution holds the potential to significantly facilitate the evaluation of patients' vitamin A status by using DBS samples in the future.

Bio-Skin-Inspired Flexible Pressure Sensor Based on Carbonized Cotton Fabric for Human Activity Monitoring.

With the development of technology, people's demand for pressure sensors with high sensitivity and a wide working range is increasing. An effective way to achieve this goal is simulating human skin. Herein, we propose a facile, low-cost, and reproducible method for preparing a skin-like multi-layer flexible pressure sensor (MFPS) device with high sensitivity (5.51 kPa-1 from 0 to 30 kPa) and wide working pressure range (0-200 kPa) by assembling carbonized fabrics and micro-wrinkle-structured Ag@rGO electrodes layer by layer. In addition, the highly imitated skin structure also provides the device with an extremely short response time (60/90 ms) and stable durability (over 3000 cycles). Importantly, we integrated multiple sensor devices into gloves to monitor finger movements and behaviors. In summary, the skin-like MFPS device has significant potential for real-time monitoring of human activities in the field of flexible wearable electronics and human-machine interaction.

Dispel some mist on circulating biopterins: measurement, physiological interval and pathophysiological implication.

BACKGROUND AND AIMS: Biopterins, including tetrahydrobiopterin (BH4), dihydrobiopterin (BH2), and biopterin (B), were crucial enzyme cofactors in vivo. Despite their recognized clinical significance, there remain notable research gaps and controversies surrounding experimental outcomes. This study aims to clarify the biopterins-related issues, including analytical art, physiological intervals, and pathophysiological implications. MATERIALS AND METHODS: A novel LC-MS/MS method was developed to comprehensively profile biopterins in plasma, utilizing chemical derivatization and cold-induced phase separation. Subsequently, apparently healthy individuals were enrolled to investigate the physiological ranges. And the relationships between biopterins and biochemical indicators were analyzed to explore the pathophysiological implications. RESULTS: The developed method was validated as reliable for detecting biopterins across the entire physiological range. Timely anti-oxidation was found to be essential for accurate assessment of biopterins. The observed overall mean ± SDs levels were 3.51 ± 0.94, 1.54 ± 0.48, 2.45 ± 0.84 and 5.05 ± 1.14 ng/mL for BH4, BH2, BH4/BH2 and total biopterins. The status of biopterins showed interesting correlations with age, gender, hyperuricemia and overweight. CONCLUSION: In conjunction with proper anti-oxidation, the newly developed method enables accurate determination of biopterins status in plasma. The observed physiological intervals and pathophysiological implications provide fundamental yet inspiring support for further clinical researches.

Veno-arterial extracorporeal membrane oxygenation for the treatment of obstructive shock caused by venous air embolism: A case report.

BACKGROUND: Venous air embolism (VAE) is a potentially lethal condition, with a reported incidence rate of about 0.13%, and the true incidence may be higher since many VAE are asymptomatic. The current treatments for VAE include Durant's maneuver, aspiration and removal of air through venous catheters, and hyperbaric oxygen therapy. For critically ill patients, use of cardiotonic drugs and chest compressions remain useful strategies. The wider availability of extracorporeal membrane oxygenation (ECMO) has brought a new option for VAE patients. CASE SUMMARY: A 53-year-old female patient with VAE presented to the emergency clinic due to abdominal pain with fever for 1 d and unconsciousness for 2 h. One day ago, the patient suffered from abdominal pain, fever, and diarrhea. She suddenly became unconscious after going to the toilet during the intravenous infusion of ciprofloxacin 2 h ago, accompanied by nausea and vomiting, during which a small amount of gastric contents were discharged. She was immediately sent to a local hospital, where cranial and chest computed tomography showed bilateral pneumonia as well as accumulated air visible in the right ventricle and pulmonary artery. The condition deteriorated despite endotracheal intubation, rehydration, and other treatments, and the patient was then transferred to our hospital. Veno-arterial ECMO was applied in our hospital, and the patient's condition gradually improved. The patient was successfully weaned from ECMO and extubated after two days. CONCLUSION: ECMO may be an important treatment for patients with VAE in critical condition.

A comprehensive pan-cancer analysis revealing SPAG6 as a novel diagnostic, prognostic and immunological biomarker in tumor.

Background: There have been studies on the role of sperm-associated antigen 6 (SPAG6) in cytoskeleton formation and growth cone stability, but it is also unknown how spag6 affect tumor growth and development. The aim of this study was to clarify the role of SPAG6 in pan-cancer, with some findings about thyroid carcinoma (THCA) validated through experiments. Methods: We examined the role of SPAG6 in pan-cancer, with the data being collected from databases. Further analysis was conducted to assess its correlations with prognosis, gene heterogeneity, stemness, and tumor immunity. The interacting proteins of SPAG6 were also identified, and gene ontology enrichment analysis was performed to determine its biological function. We preliminarily confirmed the role of SPAG6 via in vitro experiments and immunofluorescence staining. Results: This study found that SPAG6 expression was differentially expressed in cancers and at various tumor stages and grades. In stomach and esophageal carcinoma (STES), stomach adenocarcinoma (STAD), kidney renal clear cell carcinoma (KIRC), lung squamous cell carcinoma (LUSC), and adrenocortical carcinoma (ACC), SPAG6 expression was correlated with gender. SPAG6 expression was also found to be correlated with prognostic value, with low expression being associated with poor prognosis. Furthermore, SPAG6 expression was positively linked with immune-related cells in HNSC, chemokine receptors in LUSC, and immune checkpoint genes in THCA. Furthermore, SPAG6 overexpression suppressed the malignant phenotypes of THCA cells, manifested by slower proliferation and decreased migration. The different SPAG6 expression in THCA led to different malignant phenotypes, which are involved in the upregulation of DNA repair, MYC targets, peroxisome, and G2M checkpoint. Conclusions: SPAG6 plays a significant role as an oncogene and can be used as a marker to predict the prognosis of cancer. SPAG6 influences both the tumor immune infiltration and microenvironment, making it a promising immunotherapeutic target for tumor therapy.

Research on identification of flight cadets' cognitive load based on multi-source physiological data and CGAN-DBN model.

Modern aircraft cockpit system is highly information-intensive. Pilots often need to receive a large amount of information and make correct judgments and decisions in a short time. However, cognitive load can affect their ability to perceive, judge and make decisions accurately. Furthermore, the excessive cognitive load will induce incorrect operations and even lead to flight accidents. Accordingly, the research on cognitive load is crucial to reduce errors and even accidents caused by human factors. By using physiological acquisition systems such as eye movement, ECG, and respiration, multi-source physiological signals of flight cadets performing different flight tasks during the flight simulation experiment are obtained. Based on the characteristic indexes extracted from multi-source physiological data, the CGAN-DBN model is established by combining the conditional generative adversarial networks (CGAN) model with the deep belief network (DBN) model to identify the flight cadets' cognitive load. The research results show that the flight cadets' cognitive load identification based on the CGAN-DBN model established has high accuracy. And it can effectively identify the cognitive load of flight cadets. The research paper has important practical significance to reduce the flight accidents caused by the high cognitive load of pilots.

In our study, a highly accurate cognitive load identification model for flight cadets was established by using multi-source physiological data. Moreover, it provides a theoretical basis for identifying the cognitive load of pilots through wearable physiological devices. Our intent is to catalyse further research and technological development.

Efficient Chemical Synthesis of Multi-Monoubiquitylated and Diubiquitylated Histones by the α-Halogen Ketone-Mediated Strategy.

The chemical synthesis of homogeneously ubiquitylated histones is a powerful approach to decipher histone ubiquitylation-dependent epigenetic regulation. Among the various methods, α-halogen ketone-mediated conjugation chemistry has recently been an attractive strategy to generate single-monoubiquitylated histones for biochemical and structural studies. Herein, we report the use of this strategy to prepare not only dual- and even triple-monoubiquitylated histones but also diubiquitin-modified histones. We were surprised to find that the synthetic efficiencies of multi-monoubiquitylated histones were comparable to those of single-monoubiquitylated ones, suggesting that this strategy is highly tolerant to the number of ubiquitin monomers installed onto histones. The facile generation of a series of single-, dual-, and triple-monoubiquitylated H3 proteins enabled us to evaluate the influence of ubiquitylation patterns on the binding of DNA methyltransferase 1 (DNMT1) to nucleosomes. Our study highlights the potential of site-specific conjugation chemistry to generate chemically defined histones for epigenetic studies.

Effects of Dietary Protein Level and Rumen-Protected Methionine and Lysine on Growth Performance, Rumen Fermentation and Serum Indexes for Yaks.

This study investigated the effects of the dietary protein level and rumen-protected methionine and lysine (RPML) on the growth performance, rumen fermentation, and serum indexes of yaks. Thirty-six male yaks were randomly assigned to a two by three factorial experiment with two protein levels, 15.05% and 16.51%, and three RPML levels: 0% RPML; 0.05% RPMet and 0.15% RPLys; and 0.1% RPMet and 0.3% RPLys. The trial lasted for sixty days. The results showed that the low-protein diet increased the DMI and feed conversion ratio of yaks. The diet supplemented with RPML increased the activities of IGF1 and INS and nutrient digestibility. The high-protein diet decreased the rumen butyrate concentration and increased the rumen isovalerate concentration. The low-protein diet supplemented with RPML increased the rumen pH and the concentrations of total volatile fatty acids, butyrate and NH3-N; the high-protein diet supplemented with a high level of RPML decreased the rumen pH and the concentrations of isobutyrate, isovalerate, propionate and NH3-N. The low-protein diet supplemented with RPML increased the total antioxidant capacity and glutathione peroxidase activity, along with the concentrations of malondialdehyde and amino acids such as aspartic acid, lysine, cysteine, etc. In conclusion, a low-protein diet supplemented with RPML is beneficial for rumen and body health, physiological response, and metabolic status in yaks.

Genetically engineered electrospinning contributes to spinal cord injury repair by regulating the immune microenvironment.

Introduction: Spinal cord injury (SCI) is associated with microenvironment imbalance, thereby resulting in poor regeneration and recovery of the spinal cord. Gene therapy can be used to balance the inflammatory response, however target genes cannot exist in localized injured areas. Methods: A genetically engineered electrospun scaffold (GEES) to achieve long-term immunoregulation and nerve repair was constructed. By combining the microfluidic and electrospinning techniques, interleukin-10 plasmid (pIL10) was loaded into lipid nanoparticles (LNPs) (pIL10-LNP), which was encapsulated to the nerve growth factor (NGF). Immunofluorescence staining, qRT-PCR, ELISA, flow cytometry, and other tests were employed to comprehensively assess the role of GEES in modulating macrophage polarization and facilitating neural repair. Results: The results showed that the scaffold released >70% of the pIL10-LNP within 10 d and continued slow release within 30 d. In vitro cell experiments have demonstrated that GEES effectively stimulates macrophages to secrete anti-inflammatory cytokines and facilitates the differentiation of neural stem cells into neuronal cells. In rat T9 SCI model, the GEES significantly inhibited the inflammatory response in the acute and chronic phases of SCI by transfecting local tissues with slow-release pIL10-LNP to promote the release of the anti-inflammatory factor IL10, thereby creating a favorable microenvironment. With the addition of NGF, the repair and regeneration of nerve tissues was effectively promoted, and the post-SCI motor function of rats improved. Discussion: GEES can regulate post-SCI immune responses through continuous and effective gene delivery, providing a new strategy for the construction of electrospun scaffolds for nerve repair in gene therapy.

Mineral-element-chelating activity of food-derived peptides: influencing factors and enhancement strategies.

Mineral elements including calcium, iron, and zinc play crucial roles in human health. Their deficiency causes public health risk globally. Commercial mineral supplements have limitations; therefore, alternatives with better solubility, bioavailability, and safety are needed. Chelates of food-derived peptides and mineral elements exhibit advantages in terms of stability, absorption rate, and safety. However, low binding efficiency limits their application. Extensive studies have focused on understanding and enhancing the chelating activity of food-derived peptides with mineral elements. This includes obtaining peptides with high chelating activity, elucidating interaction mechanisms, optimizing chelation conditions, and developing techniques to enhance the chelating activity. This review provides a comprehensive theoretical basis for the development and utilization of food-derived peptide-mineral element chelates in the food industry. Efforts to address the challenge of low binding rates between peptides and mineral elements have yielded promising results. Optimization of peptide sources, enzymatic hydrolysis processes, and purification schemes have helped in obtaining peptides with high chelating activity. The understanding of interaction mechanisms has been enhanced through advanced separation techniques and molecular simulation calculations. Optimizing chelation process conditions, including pH and temperature, can help in achieving high binding rates. Methods including phosphorylation modification and ultrasonic treatment can enhance the chelating activity.

A flexible, stretchable and wearable strain sensor based on physical eutectogels for deep learning-assisted motion identification.

Physical eutectogels as a newly emerging type of conductive gel have gained extensive interest for the next generation multifunctional electronic devices. Nevertheless, some obstacles, including weak mechanical performance, low self-adhesive strength, lack of self-healing capacity, and low conductivity, hinder their practical use in wearable strain sensors. Herein, lignin as a green filler and a multifunctional hydrogen bond donor was directly dissolved in a deep eutectic solvent (DES) composed of acrylic acid (AA) and choline chloride, and lignin-reinforced physical eutectogels (DESL) were obtained by the polymerization of AA. Due to the unique features of lignin and DES, the prepared DESL eutectogels exhibit good transparency, UV shielding capacity, excellent mechanical performance, outstanding self-adhesiveness, superior self-healing properties, and high conductivity. Based on the aforementioned integrated functions, a wearable strain sensor displaying a wide working range (0-1500%), high sensitivity (GF = 18.15), rapid responsiveness, and excellent stability and durability (1000 cycles) and capable of detecting diverse human motions was fabricated. Additionally, by combining DESL sensors with a deep learning technique, a gesture recognition system with accuracy as high as 98.8% was achieved. Overall, this work provides an innovative idea for constructing multifunction-integrated physical eutectogels for application in wearable electronics.

Clinical value of auditory nerve enhancement in idiopathic sudden sensorineural hearing loss: a retrospective study.

Background: The pathogenesis of idiopathic sudden sensorineural hearing loss remains unclear, and no substantial breakthroughs have been achieved in its treatment. Therefore, we conducted this study with the aim to investigate the clinical features and prognostic factors of patients with idiopathic sudden sensorineural hearing loss and auditory nerve enhancement by using three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) magnetic resonance imaging (MRI) of the inner ear. Methods: We retrospectively analyzed the clinical data of adult patients, who experienced sudden unilateral deafness and were admitted to the Department of Otolaryngology, Shandong Provincial ENT Hospital, between December 2020 and July 2021. Patients were divided into an auditory nerve enhancement group and a normal inner ear group, according to 3D-FLAIR MRI findings. Differences in sex, age, side, disease course, underlying diseases, dizziness/vertigo, vestibular function, degree of deafness, hearing classification, and treatment efficacy were analyzed. Results: Of the 112 cases of sudden idiopathic deafness, 16.07% exhibited enhancement of the auditory nerve on inner-ear 3D-FLAIR MRI. Statistically significant differences in the degree and type of hearing loss were detected between the two groups (p < 0.05). The rates of abnormal results in the caloric, vestibular-evoked myogenic potential, and video head impulse tests were higher in the auditory nerve enhancement group. The cure rate (11.1%) in patients with auditory nerve enhancement was lower than that in patients with normal inner ear MRI findings (28.7%); however, the difference was not statistically significant. Conclusion: Findings from 3D-FLAIR MRI scans of the inner ear indicated that patients with sudden deafness and auditory nerve enhancement experienced severe hearing loss, aggravated vestibular function injury, and a significantly decreased cure rate. Prompt treatment, ideally within 2 weeks of disease onset, can facilitate hearing recovery.

Alpha-Hederin induces incomplete autophagic injury in non-small cell lung cancer by interfering with the lysosomal acidification.

Lung cancer is the most common oncological disease worldwide, with non-small cell lung cancer accounting for approximately 85% of lung cancer cases. α-Hederin is a monodesmosidic triterpenoid saponin isolated from the leaves of Hedera helix L. or Nigella sativa and has been extensively studied for its antitumor activity against a variety of tumor cells. It has been suggested that α-Hederin is a potential regulator of autophagy and has high promise for application. However, the specific mechanism and characteristics of α-Hederin in regulating autophagy are not well understood. In this study, we confirmed the potential of α-Hederin application in lung cancer treatment and comprehensively explored the mechanism and characteristics of α-Hederin in regulating autophagy in lung cancer cells. Our results suggest that α-Hederin is an incomplete autophagy inducer that targets mTOR to activate the classical autophagic pathway, inhibits lysosomal acidification without significantly affecting the processes of autophagosome transport, lysosome biogenesis, autophagosome and lysosome fusion, and finally leads to impaired autophagic flux and triggers autophagic damage in NSCLC.

Impacts of micron-sized aeration bubble on sludge properties and hydraulic dynamics in relation to membrane fouling alleviation.

This investigation elucidates the influence of micron-scale aeration bubbles on the improvement of anti-fouling characteristics within submerged membrane bioreactors (sMBRs). A systematic examination of sludge properties, hydraulic dynamics, and fouling tendencies revealed that the application of microbubble aeration, specifically at dimensions of 100 µm, 80 µm, and 30 µm, significantly reduced sludge electrostatic repulsion and augmented particle size distribution, as opposed to the utilization of coarse bubble aeration of 1 mm. Notably, the employment of 100 µm bubbles achieved a significant reduction in the proportion of smaller particles (<10 µm) and sludge viscosity, thereby facilitating a more homogenous and vigorous turbulence at the membrane interface. These optimized conditions were instrumental in the substantial reduction of membrane fouling, which was corroborated by the diminished rate of fouling, reduced resistance accumulation, and lesser foulant deposition. The investigation identified sludge particle size, turbulent kinetic energy, and shear stress as the predominant factors influencing the development of membrane fouling. The findings underscore the pronounced advantages of employing 100 µm-sized bubbles in aeration strategies, providing enhanced understanding for the optimization of aeration parameters to improve sMBR efficiency and maintenance.

2-Heptanol inhibits Botrytis cinerea by accelerating amino acid metabolism and retarding membrane transport.

During the postharvest storage of tomatoes, they are susceptible to infection by Botrytis cinerea, leading to significant economic losses. This study evaluated the antifungal potential of 2-heptanol (2-HE), a volatile biogenic compound, against B. cinerea and explored the underlying antifungal mechanism. The results indicated that 2-HE effectively suppressed the growth of B. cinerea mycelia both in vivo and in vitro and stimulated the activities of antioxidative enzymes, including superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) in tomatoes. Furthermore, 2-HE reduced spore viability, compromised membrane integrity, and resulted in increased levels of extracellular nucleic acids, protein content, and membrane lipid peroxidation. Transcriptomic analysis revealed that 2-HE disrupted the membrane transport system and enhanced amino acid metabolism, which led to intracellular nutrient depletion and subsequent B. cinerea cell death. Additionally, the 2-HE treatment did not negatively impact the appearance or quality of the tomatoes. In conclusion, the findings of this study offer insights into the use of 2-HE as a biocontrol agent in food and agricultural applications.

Protein Lactylation Profiles Provide Insights into Molecular Mechanisms Underlying Metabolism in Yak.

Protein lysine lactylation, a recently discovered post-translational modification (PTM), is prevalent across tissues and cells of diverse species, serving as a regulator of glycolytic flux and biological metabolism. The yak (Bos grunniens), a species that has inhabited the Qinghai-Tibetan Plateau for millennia, has evolved intricate adaptive mechanisms to cope with the region's unique geographical and climatic conditions, exhibiting remarkable energy utilization and metabolic efficiency. Nonetheless, the specific landscape of lysine lactylation in yaks remains poorly understood. Herein, we present the first comprehensive lactylome profile of the yak, effectively identifying 421, 308, and 650 lactylated proteins in the heart, muscles, and liver, respectively. These lactylated proteins are involved in glycolysis/gluconeogenesis, the tricarboxylic acid cycle, oxidative phosphorylation, and metabolic process encompassing carbohydrates, lipids, and proteins during both anaerobic and aerobic glucose bio-oxidation, implying their crucial role in material and energy metabolism, as well as in maintaining homeostasis in yaks.

Evaluating the Clinical Characteristics and Prognosis of Advanced Non-Small Cell Lung Cancer with Exon 20 Insertions.

BACKGROUND: Epidermal growth factor receptor exon 20 insertion (EGFR ex20ins), an uncommon mutation in non-small cell lung cancer (NSCLC), can induce poor patient response to EGFR tyrosine kinase inhibitors (EGFR-TKI). However, the clinical features and prognosis of patients with EGFR ex20ins are not clearly understood. This study investigated the clinical characteristics and prognosis of advanced NSCLC patients with EGFR ex20ins. METHODS: Advanced NSCLC patients treated at Fujian Cancer Hospital were consecutively recruited from June 1, 2014 to December 20, 2021 and retrospectively examined. EGFR ex20ins was identified by polymerase chain reaction (PCR) or next-generation sequencing (NGS). The clinical characteristics, treatment methods, and patient outcomes were retrieved from the hospital database. The progression-free survival (PFS)  and overall survival (OS) were assessed by Kaplan-Meier analysis. RESULTS: Fourteen mutation subtypes of EGFR ex20ins were identified in the 24 enrolled patients, with EGFR ex20ins mutation more prevalent in non-smoking women. A763_Y764insFQEA and A767_V769dup (12.5% for both) were the most common mutation subtypes. Notably, no significant differences in PFS and OS were found between the first-line targeted therapy group [PFS: 257 days, 95% confidence interval (CI): 116-397 days; OS: not reached] and chemotherapy-based combination therapy group (PFS: 182 days, 95% CI: 156-207 days; OS: 998 days, 95% CI: 674-1321 days). TP53 mutation was the commonest concomitant mutation (62%), followed by EGFR amplification (25%). Chemotherapy combined with immunotherapy improved the prognosis of patients with high PD-L1 expression. CONCLUSION: For NSCLC patients with EGFR ex20ins, limited therapeutic benefits can be gleaned from either EGFR-TKIs or chemotherapy-based combination therapy.

EGFR-TKIs have limited efficacy in NSCLC patients with EGFR ex20ins. Combining chemotherapy with immunotherapy may represent a promising treatment approach for individuals with positive ex20ins and high PD-L1 expression.

Experimental study on fractal dimension of energy dissipation and crack growth in saturated tuff at different strain rates.

In order to investigate the effects of strain rate and water saturation on the energy dissipation and crack growth of tuff, uniaxial compression tests were carried out on dry and water saturated tuff with different strain rates using an electro-hydraulic servo press and a 50 mm diameter split Hopkinson pressure rod (SHPB) device. High-speed camera and Image J image analysis software were used to obtain the crack growth process of the specimen under impact load, and fractal dimension was introduced to quantitatively study the crack growth degree. The results show that more than 90% of the energy is stored in the specimen as elastic energy when it reaches the peak stress under static load. The average total energy of water-saturated specimens is 67.55% of that of dry specimens. The average energy dissipation density of water-saturated specimens under 0.3 MPa, 0.4 MPa and 0.5 MPa air pressure is 0.79, 0.91 and 0.92 times of that of dry specimens, respectively. Water-saturated specimens will deteriorate and thus reduce their energy storage and energy absorption effects. The reflected energy, transmitted energy, absorbed energy and incident energy are linear, logarithmic and linear functions, respectively, and the energy absorptivity and specific energy absorptivity of water-saturated specimens are lower than those of dry specimens. Due to the existence of "stefan" effect, the increase of energy dissipation density of water-saturated specimen at high strain rate is greater than that of dry specimen. The mean fractal dimension of water-saturated specimens under 0.3 MPa, 0.4 MPa and 0.5 MPa is 1.09, 1.05 and 1.16 times that of dry specimens. At the same strain rate, the number and width of cracks in water-saturated specimens are larger than that in dry specimens. Water-saturated behavior reduces the energy absorption capacity of tuff, increases the fractal dimension of crack growth, and significantly reduces the resistance of water-saturated rock to external loads.

BOLERO-5: a phase II study of everolimus and exemestane combination in Chinese post-menopausal women with ER + /HER2- advanced breast cancer.

BACKGROUND: The global BOLERO-2 trial established the efficacy and safety of combination everolimus (EVE) and exemestane (EXE) in the treatment of estrogen receptor positive (ER +), HER2-, advanced breast cancer (ABC). BOLERO-5 investigated this combination in a Chinese population (NCT03312738). METHODS: BOLERO-5 is a randomized, double-blind, multicenter, placebo controlled, phase II trial comparing EVE (10 mg/day) or placebo (PBO) in combination with EXE (25 mg/day). The primary endpoint was progression-free survival (PFS) per investigator assessment. Secondary endpoints included PFS per blinded independent review committee (BIRC), overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), pharmacokinetics, and safety. RESULTS: A total of 159 patients were randomized to EVE + EXE (n = 80) or PBO + EXE (n = 79). By investigator assessment, treatment with EVE + EXE prolonged median PFS by 5.4 months (HR 0.52; 90% CI 0.38, 0.71), from 2.0 months (PBO + EXE; 90% CI 1.9, 3.6) to 7.4 months (EVE + EXE; 90% CI 5.5, 9.0). Similar results were observed following assessment by BIRC, with median PFS prolonged by 4.3 months. Treatment with EVE + EXE was also associated with improvements in ORR and CBR. No new safety signals were identified in BOLERO-5, with the incidence of adverse events in Chinese patients consistent with the safety profile of both drugs. CONCLUSION: The efficacy and safety results of BOLERO-5 validate the findings from BOLERO-2, and further support the use of EVE + EXE in Chinese post-menopausal women with ER + , HER2- ABC. NCT03312738, registered 18 October 2017.