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.

Analysis of the Relationship Between Periampullary Diverticulum and Recurrent Bile Duct Stones After Endoscopy on Magnetic Resonance Imaging of Magnetic Nanoparticles.

The objective of this work was to investigate the effect of magnetic resonance cholangiopancreatography (MRCP) based on super-paramagnetic iron oxide nanoparticles (SPIONs) on the recurrence diagnosis of periampullary diverticulum (PAD) and bile duct stone (BDS), so as to provide a scientific research basis for the recidivation factors of bile duct stones in clinic. Patients with PAD diagnosed in hospital from July 2019 to March 2021 (who had undergone endoscopic gallstone surgery) were selected for study in this work. They were rolled into two groups, the parapapillary group (123 cases) and the cholangiopancreatic duct directly opening in the diverticulum group (97 cases), according to the clinical classification. Then, 100 patients without PAD who had undergone bile duct node therapy were selected as the control group. The recidivation of BDS, serological index, and biliary pressure index before and after treatment were compared. The relationship between PAD and recidivation of bile duct stones was analyzed. The results showed that the average particle size, hydration kinetic particle size, effective time, and duration of polyethylene glycol (PEG)/polyethyleneimine (PEI)/poly aspartic acid-super-paramagnetic iron oxide nanoparticles(PASP-SPIONs) were better than PEG/PEI-SPIONs and SPIONs. The recidivation rate of BDS in Groups R and X was remarkably higher than the rate in control group (P < 0.05). Before treatment, common bile duct pressure in the control group was lower obviously than that in Groups R and X (P < 0.05). After treatment, the indexes including total bilirubin, direct bilirubin, and alkaline phosphatase in control group were lower than those in Groups R and X (P < 0.05). The incidence of complications in Groups R and X was much higher than in contrast to the control group (P < 0.05). Therefore, PEG/PEI/PASP-SPIONs had good contrast effect and could be used as magnetic resonance imaging contrast agent. Complications such as common bile duct pressure and infection were increased by PAD, which may be the main factor for the recidivation of BDS.

High methane emissions from thermokarst lakes on the Tibetan Plateau are largely attributed to ebullition fluxes.

Ebullition has been shown to be an important pathway for methane (CH4) emissions from inland waters. However, the CH4 fluxes and their magnitudes in thermokarst lakes remain unclear due to limited research data, especially on the Tibetan Plateau (TP). The magnitude and regulation of two CH4 pathways, ebullition and diffusion, were investigated in 32 thermokarst lakes on the TP during the summer of 2020. CH4 emissions from thermokarst lakes on the TP showed significant spatiotemporal heterogeneity. Diffusion fluxes in lakes averaged 2.6 mmol m-2 d-1 (ranging from 0.003 to 48.4 mmol m-2 d-1), and ebullition fluxes in lakes averaged 6.6 mmol CH4 m-2 d-1 (ranging from 0.002 to 140.0 mmol m-2 d-1). Together, these ebullition fluxes contributed 66.1 ± 24.9% (ranging 5.4 to 100.0%) to the total (diffusion + ebullition) CH4 emissions, indicating the importance of ebullition as a major CH4 transport mechanism on the TP. In general, thermokarst lakes with higher CH4 diffusion fluxes and ebullition fluxes occurred in alpine meadows (2.5 ± 5.3 mmol m-2 d-1; 8.2 ± 20.6 mmol m-2 d-1), followed by alpine steppes (0.6 ± 5.3 mmol m-2 d-1; 0.7 ± 10.8 mmol m-2 d-1) and desert steppes (0.2 ± 0.2 mmol m-2 d-1; 0.6 ± 0.8 mmol m-2 d-1). The organic matter contents in water and sediment were found to be important factors influencing the seasonal variations in CH4 diffusion fluxes. However, the ebullition CH4 fluxes did not show a clear seasonal variation pattern. Our findings highlight the importance of considering the large spatiotemporal variations in ebullition CH4 fluxes to improve the accuracy of large-scale estimations of CH4 fluxes in thermokarst lakes on the TP. Greater insight into these aspects will increase the understanding of CH4 dynamics in thermokarst lakes on the TP, which is essential for forecasting and climate impact assessments and to better constrain feedback to climate warming.

Risk assessment of potential thaw settlement hazard in the permafrost regions of Qinghai-Tibet Plateau.

Climate warming could exacerbate the occurrence of thaw settlement hazard in the permafrost regions of the Qinghai-Tibet Plateau (QTP), which would threaten the stability of engineering infrastructure in cold regions. The risk associated with permafrost settlement, valuable for the regional sustainable development, remains poorly assessed or understood on the QTP. In this study, three common Geo-hazard indices were used to assess the settlement risks in the permafrost regions of the QTP, including the settlement index, the risk zonation index, and the allowable bearing capacity index. However, large spatial differences existed in simulating the risk maps by using the abovementioned Geo-hazard indices. Hence, we developed a combined index (Ic) by integrating the three indices to reduce the uncertainty of the simulations. The results indicated that the ground ice is a critical factor for assessing the settlement risk in permafrost regions. We also applied the Ic to assess the settlement risk along the Qinghai-Tibet Railway (QTR). The proportion of low-risk area along the QTR would be the highest (45.38%) for the future periods 2061-2080 under Representative Concentration Pathway 4.5. The medium-risk area combined with the high-risk area would be accounted for more than 40%, which were located at the boundary of the present permafrost regions. Therefore, the corresponding adaptation measures should be taken to reduce the potential economic losses caused by the high-risk regions to the infrastructure. Overall, the results would present valuable references for engineering design, construction and maintenance, and provide insights for early warning and prevention of permafrost thaw settlement hazard on the QTP.

Spatiotemporal characteristics of hydrothermal processes of the active layer on the central and northern Qinghai-Tibet plateau.

The spatial and temporal variations of the seasonal freeze-thaw cycles are important in understanding the ecological and hydrological processes and biogeochemical cycle associated with permafrost degradation caused by climate change, although observational data on the soil hydrothermal dynamics within the active layer of the permafrost region at the central and northern Qinghai-Tibet Plateau (QTP) are extremely scarce. In this study, soil temperature and moisture date from 11 observational sites along the Qinghai-Tibet Highway from 2010 to 2014 were used to analyze the freeze-thaw cycles of the active layer. The results revealed that mean annual ground surface temperature (MAGST) and mean annual temperature at the top of permafrost (TTOP) were the most closely related to the onset dates of soil freezing and thawing. The onset dates of soil freezing from bottom to top did not occur earlier than those from top to bottom. The differences between the onset dates of the two freezing directions and the proportion of bottom-up freezing depth increased with decreasing TTOP. The unfrozen water content of the cooling process was always higher than that of the warming process during the freezing stage. The hysteresis effect of the unfrozen water content could also be observed in the field experiment, and the maximum hysteresis levels occurred at their corresponding soil freezing points. Soil organic matter and soil moisture associated with vegetation cover are essential for water-heat exchanges between atmosphere and permafrost beneath active layer. We suggest that a better protected plant ecosystem, helps preserving the underlying permafrost on the Qinghai-Tibet Plateau.

Cloning, characterization and expression analysis of glutathione S-transferase from the Antarctic yeast Rhodotorula mucilaginosa AN5.

The gene for glutathione S-transferase (GST) in Antarctic sea-ice yeast Rhodotorula mucilaginosa AN5 was cloned and expressed in Escherichia coli and named RmGST. Sequence analysis showed that the RmGST gene contained a 843 bp open reading frame, which encoded 280 amino acid residues with a calculated molecular mass of 30.4 kDa and isoelectric point of 5.40. RmGST has the typical C- and N-terminal double domains of glutathione S-transferase. Recombinant RmGST (rRmGST) was expressed in E. coli to produce heterologous protein that had a high specific activity of 60.2 U/mg after purification. The apparent Km values of rRmGST for glutathione and 1-chloro-2,4-dinitrobenzene were 0.35 mM and 0.40 mM, respectively. Optimum enzyme activity was measured at 35 °C and at pH 7.0 and complete inactivation was observed after incubation at 55 °C for 60 min rRmGST tolerated high salt concentrations (1.0 M NaCl) and was stable at pH 3.0. Additionally, the recombinant protein nearly kept whole activity in Hg2+ and Mn2+, and could tolerate Ca2+, Cu2+, Mg2+, Cd2+, EDTA, thiourea, urea, Tween-80, H2O2 and Triton X-100. Real-time quantitative PCR showed that relative expression of the GST gene was significantly increased under Cu2+ and low temperature stress. These results indicate that rRmGST is a typical low thermostable enzyme, while its other characteristics, heavy metal and low temperature tolerance, might be related to its Antarctic home environment.

Cloning and functional characterization of a novel metallothionein gene in Antarctic sea-ice yeast (Rhodotorula mucilaginosa).

Metallothionein (MT) is a low-molecular-weight protein with a high metal binding capacity and plays a key role in organism adaptation to heavy metals. In this study, a metallothionein gene was successfully cloned and sequenced from Antarctic sea-ice yeast Rhodotorula mucilaginosa AN5. Nucleotide sequencing and analysis revealed that the gene had four exons interrupted by three introns. MTs complementary DNA (named as RmMT) had an open reading frame of 321 bp encoding a 106 amino acid protein with a predicted molecular weight of 10.3 kDa and pI of 8.49. The number of amino acids and distribution of cysteine residues indicated that RmMT was a novel family of fungal MTs. Quantitative real-time polymerase chain reaction analysis showed that RmMT expression was elevated under copper-induced stress. The RmMT gene was transferred into E. coli and the RmMT expressing bacteria showed improved tolerance to copper ion and increased accumulation of heavy metals, such as Cu2+ , Pb2+ , Zn2+ , Cd2+ , and Ag+ . Moreover, in vitro studies, purified recombinant RmMT demonstrated that it could be used as a good scavenger of superoxide anion, hydroxyl, and 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radicals. In summary, these results demonstrate that RmMT plays a key role in the tolerance and bioaccumulation of heavy metals.

Purification and characterization of a novel wild-type α-amylase from Antarctic sea ice bacterium Pseudoalteromonas sp. M175.

A novel wild-type α-amylase named wtAmy175 from Pseudoalteromonas sp. M175 strain was purified through ammonium sulphate precipitation, DEAE cellulose, and Sephadex G-75 sequentially (25.83-fold, 7.67%-yield) for biochemical characterization. SDS-PAGE and zymographic activity staining of purified enzyme showed a single band with a predicted molecular mass of about 61 kDa. The optimum temperature and pH for enzyme activity were 30 °C and 7.5, respectively. Additionally, the enzyme exhibited high activity and remarkable stability in 0-10 mM SDS. The values of Km and Vmax for soluble starch as substrate were 2.47 mg/ml and 0.103 mg/ml/min, respectively. Analysis of hydrolysis products of soluble starch and maltooligosaccharides showed that wtAmy175 cleaved the interior and the terminal α-1,4-glycosidic linkage in starch, and had transglycosylation activity. The result of fluorescence spectroscopy showed that wtAmy175 had strong binding affinity with soluble starch. In brief, this study discovered the first wild-type α-amylase so far with several distinctive properties of cold activity, SDS-resistance, and the mixed activity of α-amylase and α-glucosidase, suggesting that wtAmy175 possess high adaptive capability to endure harsh industrial conditions and would be an excellent candidate in detergent and textile industries.

Spatial variations and controlling factors of ground ice isotopes in permafrost areas of the central Qinghai-Tibet Plateau.

Ground ice is a distinctive feature of permafrost, and its thawing under climate change can alter the regional hydrological and biogeochemical cycles. Spatial variations and determinants of ground ice isotopes are critical to understand subsurface water cycling during freeze-thaw process in the context of climate change, while they are not well known in permafrost region due to lack of field investigation. We examined spatial distributions and controlling factors of ground ice isotopes using data of 8 soil profiles surveyed in permafrost areas of the Qinghai-Tibet Plateau (QTP). The stable isotope values (δ2H and δ18O) of subsurface water on the QTP were higher than those in Arctic tundra ecosystem and East Siberian permafrost region. Isotopic values of water components differed each other, and varied significantly among the sampling sites. The spatial distribution of isotopes was complex. Isotopes generally decreased with depth within the soil profile, implying a general isotope depth gradient across different permafrost-affected areas. Water source, evaporative and freeze-out fractionation, and cryoturbation affect soil water isotopes. Correlation analyses showed that δ2H and δ18O in soil water positively related to air temperature and soil temperature, while negatively related to soil moisture, depth, active layer thickness, vegetation coverage, elevation, and precipitation. Elevation and soil depth mainly controlled spatial distributions of ground ice isotopes. The results could provide a new insight into soil moisture movement and cycling during freeze-thaw process in the permafrost region of the QTP, which is helpful to understand subsurface water cycle mechanism in the context of permafrost degradation.

Exploring the contribution of precipitation to water within the active layer during the thawing period in the permafrost regions of central Qinghai-Tibet Plateau by stable isotopic tracing.

Stable isotopic tracing has proven to be a useful tool for assessing surface water source dynamics and hydrological connectivity in permafrost regions. This study has investigated the contribution of precipitation to water within the active layer at three long-term observation sites, including Fenghuoshan (FHS), Hoh Xil (KKXL) and Wudaoliang (WDL), by using isotopic tracer technique and two-component mixing model. The results showed that precipitation was the predominant source for water within the active layer, permafrost and ground ice near permafrost table at the three sites. Precipitation in August was the predominant source for water within the active layer at FHS, and precipitation in September was the main source at KKXL and WDL. The variation of isotopic values at different levels indicated that the water sources within the active layer could vary as the depth increases. The evaporation fractionation of water within the active layer at WDL was noticeable at depths of 0-50 cm, and the evaporation intensity decrease gradually from late June to late September. The relationship of isotopic tracing values between precipitation and water within the active layer at depths of 0-50 cm becomes more significant as the amount of the recently-occurring precipitation increases. Moreover, the relatively higher d-excess in precipitation indicates that local recycled moisture has greater contribution to precipitation. The differences of d-excess in most water within the active layer, permafrost and ground ice near permafrost table revealed that there were isotopic fractionation when precipitation supplying to above-mentioned three water bodies. The precipitation event amounted to 8.1 mm at KKXL can exert 49% ±â€¯7.1% and 30.8% ±â€¯3.6% contribution to water within the active layer at depths of 0-10 cm and 10-20 cm, respectively. While the long-period contribution cannot be identified because of the impact of evaporation. The results would provide new insights into the contribution of precipitation to water within the active layer on the QTP, which is also helpful to improve process-based hydrological models in the permafrost regions.

Hydrochemical characteristics of ground ice in permafrost regions of the Qinghai-Tibet Plateau.

Ground ice is a distinctive feature of permafrost terrain. The vertical distribution and factors controlling the hydrochemistry of ground ice are important for studying soil moisture and salt migration during the freeze-thaw process in soil. These factors are also important components of hydrological cycles in cold regions. The hydrochemical characteristics of ground ice on the Qinghai-Tibetan Plateau (QTP) are not well known. We examined the characteristics of ground ice hydrochemistry using data from 9 soil profiles in permafrost regions of the central QTP. The isotopes and anion concentrations of subsurface water on the QTP were higher than those in Arctic polygonal ground regions. The spatial distribution of anions was complex. Well-developed hydrochemical depth gradients occurred within the soil profile. Isotopes decreased and anions increased with depth, suggesting general vertical patterns of soil hydrochemistry across different permafrost regions. Cl- and SO42- concentrations in soil water increased with depth, while NO3- concentration did not change with depth. Freeze-out fractionation, self-purification, and desalination greatly impact soil hydrochemistry. The major factors controlling variation of soil water chemistry were soil moisture, air temperature, and active layer thickness. The results could provide a framework for understanding ground ice origins and the moisture and salt migration pathways in the context of permafrost changes. This information could be useful in developing process-based permafrost hydrologic models.

[Operative treatment and curative effects of the deltoid ligament injuries of the ankle joint].

OBJECTIVE: To explore the operative methods and curative effects of the deltoid ligament injuries. METHODS: From 2002 to 2008, all 61 patients with ankle fractures complicated with deltoid ligament injuries were treated with open reduction and firm internal fixation. Among the patients, 39 patients were male and 22 patients were female, ranging in age from 14 to 71 years, with an average of 41 years. During the operation, the deltoid ligament was reconstructed to restore the medial and lateral stability of ankle joint. RESULTS: All the patients were followed up ranged from 5 to 30 months, with an average of 17 months. Fifty-nine patients had incision healed at the first stage; 2 patients had superficial infections at lateral malleolus, and healed at the 3rd week after changing dressings. The incisions at the internal medial malleolus were all healed at the first stage. According to Qi evaluation criteria, 35 patients got an excellent result, 13 good and 13 fair. CONCLUSION: The deltoid ligament should be treated properly in the treatment of ankle joint fractures when open reduction and firm internal fixation were emphasized.

One-stage reconstruction of complicated thumb injury with combination of microsurgical transplantations.

Complicated thumb loss of the hand still remains a great challenge to hand and microsurgeons. In this article, we report our technique and outcomes in 10 cases using one-stage microsurgical procedures. In each case, three tissue transplants in combination with a sequential vascular anastomoses was performed, i.e. the second toe for the thumb, the extensor digitorum brevis for thenar opponent muscle, and the anterolateral thigh flap for the first web space, and adjacent soft tissue defects. All the transplants survived eventually. After an average of 6 years follow-up, the results were very inspiring. Combined tissue transfer can hasten patient recovery and improve functional outcomes. However, this method needs meticulous technique and great experience in microsurgery.