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Abstract Background Hemorrhage is a common complication of nephrostomy and percutaneous nephrolithotripsy, and it is caused by surgical factors. Here we report a rare case of hemorrhage caused by sepsis-related coagulation dysfunction. Case presentation A 72-years-old male patient with bilateral ureteral calculi accompanied by hydronephrosis and renal insufficiency developed sepsis and hemorrhage on the third day after bilateral nephrostomy. After vascular injury was excluded by DSA, the hemorrhage was considered to be sepsis-associated coagulopathy(SAC/SIC), finally the patient recovered well after active symptomatic treatment. Conclusions In patients with sepsis and hemorrhage, SAC/SIC cannot be excluded even if coagulation function is slightly abnormal after surgical factors are excluded. For urologists who may encounter similar cases in their general urology practice, it is important to be aware of these unusual causes of hemorrhage.

Hepatic subcapsular hematoma (HSH) is an uncommon complication of pregnancy and is associated with elevated rates of maternal and foetal mortality. The rupture of an HSH is a critical situation that necessitates immediate and timely intervention to prevent loss of life. We present here, a case of a spontaneously ruptured massive HSH caused by preeclampsia. In addition, we conducted a comprehensive review of existing literature, encompassing 49 cases of HSH associated with pregnancy. If a pregnant woman with gestational hypertension experiences right upper abdominal pain with shoulder pain or radiating shoulder pain, it is crucial for her to have an urgent abdominal ultrasound because of the potential development of HSH and/or rupture. Our review of current literature suggests that opting for a caesarean section may offer notable advantages in preventing HSH rupture.

In order to promote the virtuous cycle of economic society, minimize the harm of red mud and manganese slag and maximize the efficiency of processing and utilization of red mud and manganese slag; in order to analyze the influence of red mud and manganese slag on the performance of matrix asphalt, this paper conducts multiple groups of compound proportion tests after fully mixing red mud and manganese slag, and finally determines the optimal compound proportion of 1：1.5. The red mud manganese slag compound modified asphalt binder was prepared by adding the powder-oil ratio of 0, 3%, 6%, 9%, 12%, 15%, 18%, 21% and 24% to the matrix asphalt by the external mixing method. Through the determination of three indexes of modified asphalt binder, the modification effect of different dosage on matrix asphalt is analyzed. From a large number of experimental data, it is concluded that when the mixing ratio is 15%, the three indexes of modified asphalt binder are the best. In this paper, the grey correlation theory is used to analyze the correlation between the dosage of the compound modifier and the penetration, ductility and softening point of the matrix asphalt. It is concluded that the addition of the compound modifier has the most obvious influence on the penetration at 10 ℃, followed by the penetration at 20 ℃, the softening point, the penetration at 25 ℃, the penetration at 30 ℃, the penetration at 15 ℃, the delay at 5 ℃ and the delay at 15 ℃. The adsorption process of red mud compound manganese slag and asphalt was qualitatively simulated by molecular dynamics theory, and the interaction energy between red mud compound manganese slag modified asphalt binder and matrix asphalt was quantitatively calculated, and the modification mechanism of modified asphalt was analyzed.

Triple-negative breast cancer (TNBC) is the most aggressive subtype with high metastasis and mortality rates. Given the lack of actionable targets such as ER and HER2, TNBC still remains an unmet therapeutic challenge. Despite harboring high CDK4/6 expression levels, the efficacy of CDK4/6 inhibition in TNBC has been limited due to the emergence of resistance. The resistance to CDK4/6 inhibition is mainly mediated by RB1 inactivation. Since our aim is to overcome resistance to CDK4/6 inhibition, in this study, we primarily used the cell lines that do not express RB1. Following a screening for activated receptor tyrosine kinases (RTKs) upon CDK4/6 inhibition, we identified the TAM (Tyro3, Axl, and MerTK) RTKs as a crucial therapeutic vulnerability in TNBC. We show that targeting the TAM receptors with a novel inhibitor, sitravatinib, significantly sensitizes TNBC to CDK4/6 inhibitors. Upon prolonged HER2 inhibitor treatment, HER2+ breast cancers suppress HER2 expression, physiologically transforming into TNBC-like cells. We further show that the combined treatment is highly effective against drug-resistant HER2+ breast cancer as well. Following quantitative proteomics and RNA-seq data analysis, we extended our study into the immunophenotyping of TNBC. Given the roles of the TAM receptors in promoting the creation of an immunosuppressive tumor microenvironment (TME), we further demonstrate that the combination of CDK4/6 inhibitor abemaciclib and sitravatinib modifies the immune landscape of TNBC to favor immune checkpoint blockade. Overall, our study offers a novel and highly effective combination therapy against TNBC and potentially treatment-resistant HER2+ breast cancer that can be rapidly moved to the clinic.

The Sm2(Fe1−xMnx)14B (0 ≤ x ≤ 0.3) rare earth alloy was prepared by a reduction-diffusion method, and a corresponding reduction-diffusion model was established. The crystal structure, microscopic morphology, and magnetic properties were systematically characterized to investigate the effect of Mn doping. The results show that the diffusion of Sm into FeB proceeded with the formation of the Sm2Fe14B phase from the very beginning of the reaction. Sm2(Fe1−xMnx)14B alloy undergoes a transition from the ferromagnetic phase (x = 0) to the paramagnetic phase (x = 0.2), and the average magnetic moment of Fe decreases from 2.066 to 0.719 µB as observed by 57Fe Mössbauer spectroscopy. In addition, the Curie temperature decreases rapidly from 620 to 230 K. In other words, a wide temperature-regulation of TC can be achieved by adjusting the Mn content, which is attributed to the fact that Mn doping greatly weakens the atomic exchange interactions. These results provide value for potential applications of Re–Fe-based alloys in room temperature magnetic refrigeration.

Objective: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant gastrointestinal cancer with a 5-year survival rate of only 9%. Of PDAC patients, 15%-20% are eligible for radical surgery. Gemcitabine is an important chemotherapeutic agent for patients with PDAC; however, the efficacy of gemcitabine is limited due to resistance. Therefore, reducing gemcitabine resistance is essential for improving survival of patients with PDAC. Identifying the key target that determines gemcitabine resistance in PDAC and reversing gemcitabine resistance using target inhibitors in combination with gemcitabine are crucial steps in the quest to improve survival prognosis in patients with PDAC. Methods: We constructed a human genome-wide CRISPRa/dCas 9 overexpression library in PDAC cell lines to screen key targets of drug resistance based on sgRNA abundance and enrichment. Then, co-IP, ChIP, ChIP-seq, transcriptome sequencing, and qPCR were used to determine the specific mechanism by which phospholipase D1 (PLD1) confers resistance to gemcitabine. Results: PLD1 combines with nucleophosmin 1 (NPM1) and triggers NPM1 nuclear translocation, where NPM1 acts as a transcription factor to upregulate interleukin 7 receptor (IL7R) expression. Upon interleukin 7 (IL-7) binding, IL7R activates the JAK1/STAT5 signaling pathway to increase the expression of the anti-apoptotic protein, BCL-2, and induce gemcitabine resistance. The PLD1 inhibitor, Vu0155069, targets PLD1 to induce apoptosis in gemcitabine-resistant PDAC cells. Conclusions: PLD1 is an enzyme that has a critical role in PDAC-associated gemcitabine resistance through a non-enzymatic interaction with NPM1, further promoting the downstream JAK1/STAT5/Bcl-2 pathway. Inhibiting any of the participants of this pathway can increase gemcitabine sensitivity.

Abstract VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors. Nevertheless, pancreatic adenocarcinoma (PAAD) cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways, thereby conferring resistance to VEGF inhibitors. Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD. The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth, and worse prognosis. In cells and mice with xenograft tumors, BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent manner. Mechanistically, as an RNA binding protein, BICC1 bounds to the 3’UTR of Lipocalin-2 (LCN2) mRNA and post-transcriptionally up-regulated LCN2 expression in PAAD cells. When its level is elevated, LCN2 binds to its receptor 24p3R, which directly phosphorylates JAK2 and activates JAK2/STAT3 signal, leading to increased production of an angiogenic factor CXCL1. Blocking of the BICC1/LCN2 signalling reduced the microvessel density and tumor volume of PAAD cell grafts in mice, and increased the tumor suppressive effect of gemcitabine. In conclusion, BICC1 plays a pivotal role in the process of VEGF-independent angiogenesis in pancreatic cancer, leading to resistance to VEGF inhibitors. BICC1/LCN2 signaling may serve as a promising anti-angiogenic therapeutic target for pancreatic cancer patients.

Abstract Background Chemoresistance is the main reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Thus, there is an urgent need to screen out new targets and compounds to reverse chemotherapeutic resistance. Methods We established a bio-bank of human PDAC organoid models, covering a representative range of PDAC tumor subtypes. We screened a library of 1304 FDA-approved compounds to identify candidates efficiently overcoming chemotherapy resistance. The effects of the compounds were evaluated with a CellTiter-Glo-3D assay, organoid apoptosis assay and in vivo patient-derived xenograft (PDX), patient-derived organoid (PDO) and LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) genetically engineered mouse models. RNA-sequencing, genome editing, sphere formation assays, iron assays and luciferase assays were conducted to elucidate the mechanism. Results High-throughput drug screening of chemotherapy-resistant PDOs identified irbesartan, an angiotensin ‖ type 1 (AT1) receptor antagonist, which could synergistically enhance the ability of chemotherapy to kill PDAC cells. In vitro and in vivo validation using PDO, PDX and KPC mouse models showed that irbesartan efficiently sensitized PDAC tumors to chemotherapy. Mechanistically, we found that irbesartan decreased c-Jun expression by inhibiting the Hippo/YAP1 pathway and further overcame chemotherapy resistance in PDAC. We also explored c-Jun, a potential target of irbesartan, which can transcriptionally upregulate the expression of key genes involved in stemness maintenance (SOX9/SOX2/OCT4) and iron metabolism (FTH1/FTL/TFRC). More importantly, we observed that PDAC patients with high levels of c-Jun expression demonstrated poor responses to the current standard chemotherapy regimen (gemcitabine plus nab-paclitaxel). Moreover, patients with PDAC had significant survival benefits from treatment with irbesartan plus a standard chemotherapy regimen in two-center retrospective clinical cohorts and patients with high c-Jun expression exhibited a better response to combination chemotherapy. Conclusions Irbesartan could be used in combination with chemotherapy to improve the therapeutic efficacy in PDAC patients with high levels of c-Jun expression. Irbesartan effectively inhibited chemotherapy resistance by suppressing the Hippo/YAP1/c-Jun/stemness/iron metabolism axis. Based on our findings, we are designing an investigator-initiated phase II clinical trial on the efficacy and safety of irbesartan plus a standard gemcitabine/nab-paclitaxel regimen in the treatment of patients with advanced III/IV staged PDAC and are hopeful that we will observe patient benefits.

Objective: The structural covariance network (SCN) alterations in patients with temporal lobe epilepsy and comorbid sleep disorder (PWSD) remain poorly understood. This study aimed to investigate changes in SCNs using structural magnetic resonance imaging. Methods: Thirty-four PWSD patients, thirty-three patients with temporal lobe epilepsy without sleep disorder (PWoSD), and seventeen healthy controls underwent high-resolution structural MRI imaging. Subsequently, SCNs were constructed based on gray matter volume and analyzed via graph-theoretical approaches. Results: PWSD exhibited significantly increased clustering coefficients, shortest path lengths, transitivity, and local efficiency. In addition, various distributions and numbers of SCN hubs were identified in PWSD. Furthermore, PWSD networks were less robust to random and target attacks than those of healthy controls and PWoSD patients. Conclusion: This study identifies aberrant SCN changes in PWSD that may be related to the susceptibility of patients with epilepsy to sleep disorders.

An easy-plane FeSi3.5 composite with excellent magnetic properties and loss properties at MHz were proposed. The easy-plane FeSi3.5 composite has ultra-low loss at 10 MHz and 4 mT, about 372.88 kW/m3. In order to explore the reason that the Pcv of easy-plane FeSi3.5 composite is ultra-low, a none easy-plane FeSi3.5 composite, without easy-plane processing as a control group, measured the microstructure, and the magnetic and loss properties. We first found that the real reason why magnetic materials do not work properly at MHz due to overheat is dramatical increase of the excess loss and the easy-plane composite can greatly re-duce the excess loss by loss measurement and separation. The total loss of none easy-plane FeSi3.5 composite is much higher than that of easy-plane FeSi3.5 composite, where the excess loss is a major part in the total loss and even over 80% in the none easy-plane FeSi3.5 composite. The easy-plane FeSi3.5 composite can greatly reduce the total loss compared to the none easy-plane FeSi3.5 composite, from 2785.8 kW/m3 to 500.42 kW/m3 (3 MHz, 8 mT), with the main reduction being the excess loss, from 2435.2 kW/m3 to 204.93 kW/m3 (3 MHz, 8 mT), reduced by 91.58%. Furthermore, the easy-plane FeSi3.5 composite also has excellent magnetic properties, high permeability and ferromagnetic resonance frequencies. This makes the easy-plane FeSi3.5 composite become an excellent soft magnetic composite and it is possible for magnetic devices to operate properly at higher frequencies, especially at the MHz band and above.

ObjectiveThis study aimed to investigate white matter (WM) microstructural alterations and their relationship correlation with disease severity in anti-NMDA receptor (NMDAR) encephalitis. Multivariate pattern analysis (MVPA) was applied to discriminate between patients and healthy controls and explore potential imaging biomarkers.MethodsThirty-two patients with anti-NMDAR encephalitis and 26 matched healthy controls underwent diffusion tensor imaging. Tract-based spatial statistics and atlas-based analysis were used to determine WM microstructural alterations between the two groups. MVPA, based on a machine-learning algorithm, was applied to classify patients and healthy controls.ResultsPatients exhibited significantly reduced fractional anisotropy in the corpus callosum, fornix, cingulum, anterior limb of the internal capsule, and corona radiata. Moreover, mean diffusivity was increased in the anterior corona radiata and body of the corpus callosum. On the other hand, radial diffusivity was increased in the anterior limb of the internal capsule, cingulum, corpus callosum, corona radiata, and fornix. WM changes in the cingulum, fornix, and retrolenticular part of the internal capsule were correlated with disease severity. The accuracy, sensitivity, and specificity of fractional anisotropy-based classification were each 78.33%, while they were 67.71, 65.83, and 70% for radial diffusivity.ConclusionWidespread WM lesions were detected in anti-NMDAR encephalitis. The correlation between WM abnormalities and disease severity suggests that these alterations may serve a key role in the pathophysiological mechanisms of anti-NMDAR encephalitis. The combination of tract-based spatial statistics and MVPA may provide more specific and complementary information at the group and individual levels.

Abstract Background Malnutrition and muscle wasting are common features frequently observed in pancreatic ductal adenocarcinoma (PDAC) patients with cancer cachexia. They are associated with reduced survival and quality of life. Nutrition therapy is an important part of multimodal cancer care in PDAC. However, due to the complexity of nutrition assessment, only 30–60% of patients with nutritional risks receive nutritional treatment at present. It is important to identify biomarkers that may be used to improve management of PDAC‐associated malnutrition. Serum insulin‐like growth factor binding protein 2 (IGFBP2) has emerged as a potential serum biomarker in a variety of tumours. However, its association with malnutrition and muscle wasting in PDAC is unclear. Methods We evaluated the tumour IGFBP2 expression and serum IGFBP2 level in 98 PDAC patients using immunohistochemistry and enzyme‐linked immunosorbent assay and analysed the correlation between them. Furthermore, we explored the relationship between IGFBP2 of both tumour and serum and nutritional status (Patient‐Generated Subjective Global Assessment and skeletal muscle index). Pan02 IGFBP2 stable transfection cell lines, Pan02 PLV‐IGFBP2 cells, and PLKO‐IGFBP2 cells were injected subcutaneously into the flank of C57BL/6 mouse. Serum IGFBP2 levels, food intake, and body weight of these mice were measured. The degree of muscle atrophy is characterized by haematoxylin and eosin, Oil Red O, and Masson's trichrome staining. The mRNA and protein expression of several essential muscle‐related signal proteins such as atrogin‐1 and muscle RING finger 1 was measured. Results Among 98 patients, we found that tumour IGFBP2 expression is related to plasma IGFBP2 levels (rs = 0.562, P

Activating KRAS mutations are present in 25% of human cancer. Although oncogenic Ras was deemed “undruggable” in the past, recent efforts led to the development of pharmacological inhibitors targeting the KRASG12C mutant, which have shown promise in early clinical trials. The development of allele-specific K-RasG12C inhibitors marked a new chapter in targeting oncogenic KRAS mutant in cancer. However, drug resistance against these new drugs will likely limit their efficacy in the clinic. Genome-wide approaches have been used to interrogate the mechanisms of resistance to K-RasG12C inhibitors, which would facilitate the development of therapeutics overcoming drug resistance. This article reviews the latest progress in resistance to K-RasG12C-targeted therapies and aims to provide insight in future research targeting drug resistance in cancer.

An effective porosity is defined as the ratio of volume of interconnected pore space to total volume of a porous sample. It controls the magnitude of fluid flow and is a key parameter in the assessment of recoverable resources. However, its accurate measurement in tight formations is challenging, due to their complex pore structure and lithofacies heterogeneity. In this study, porosities of sixteen lacustrine shale samples from the second Member of the Kongdian Formation (Ek2) in the Cangdong Sag, Bohai Bay Basin were measured and compared using multiple methods and sample sizes to compare and contrast the effective porosity results. The methods included helium pycnometry (HP; cubes of 1 cm3 and grains at 500-841 μm), water immersion porosimetry (WIP; cubes), mercury intrusion porosimetry (MIP; cubes), and nuclear magnetic resonance (NMR; cubes). Finally, samples were completely sealed using paraffin for bulk density measurements to evaluate the extent of potential clay swelling in shale samples involving probing fluids. Results from the HP, WIP, and MIP methods for skeletal density, bulk density, and effective porosity with cubic samples were compared. While very similar skeletal densities were found for all three methods, a lower bulk density, and therefore lower porosity, from the MIP approach can be attributed to the experimental conditions (e.g., vacuum efficiency, applied pressure, wettability of water/helium vs. mercury) and the probable presence of pores with diameters larger than 50 μm not measurable by MIP. Furthermore, the HP porosity of granular samples with 500-841 μm grain sizes can be regarded as approaching the total porosity. The complicated relationship between WIP and NMR porosities may result from the heat-induced volatilization of moisture in pores during NMR tests, and countercurrent imbibition of water replacing the residual hydrocarbons during the saturation process for sample preparation in both tests. The swelling behavior of the lacustrine Ek2 shale with water is not significant because of the low content of expansive clay minerals. In summary, the WIP and HP methods are recommended for effective porosity measurement, whereas the NMR and MIP methods are invaluable for the measurement of pore-size distribution, with additional information on the effective porosity.

Abstract The mitochondrial deoxynucleotide triphosphate (dNTP) is maintained by the mitochondrial deoxynucleoside salvage pathway and dedicated for the mtDNA homeostasis, and the mitochondrial deoxyguanosine kinase (DGUOK) is a rate‐limiting enzyme in this pathway. Here, we investigated the role of the DGUOK in the self‐renewal of lung cancer stem‐like cells (CSC). Our data support that DGUOK overexpression strongly correlates with cancer progression and patient survival. The depletion of DGUOK robustly inhibited lung adenocarcinoma tumor growth, metastasis, and CSC self‐renewal. Mechanistically, DGUOK is required for the biogenesis of respiratory complex I and mitochondrial OXPHOS, which in turn regulates CSC self‐renewal through AMPK‐YAP1 signaling. The restoration of mitochondrial OXPHOS in DGUOK KO lung cancer cells using NDI1 was able to prevent AMPK‐mediated phosphorylation of YAP and to rescue CSC stemness. Genetic targeting of DGUOK using doxycycline‐inducible CRISPR/Cas9 was able to markedly induce tumor regression. Our findings reveal a novel role for mitochondrial dNTP metabolism in lung cancer tumor growth and progression, and implicate that the mitochondrial deoxynucleotide salvage pathway could be potentially targeted to prevent CSC‐mediated therapy resistance and metastatic recurrence.

Summary: The deregulation of the actin cytoskeleton has been extensively studied in metastatic dissemination. However, the post-dissemination role of the actin cytoskeleton dysregulation is poorly understood. Here, we report that fascin, an actin-bundling protein, promotes lung cancer metastatic colonization by augmenting metabolic stress resistance and mitochondrial oxidative phosphorylation (OXPHOS). Fascin is directly recruited to mitochondria under metabolic stress to stabilize mitochondrial actin filaments (mtF-actin). Using unbiased metabolomics and proteomics approaches, we discovered that fascin-mediated mtF-actin remodeling promotes mitochondrial OXPHOS by increasing the biogenesis of respiratory Complex I. Mechanistically, fascin and mtF-actin control the homeostasis of mtDNA to promote mitochondrial OXPHOS. The disruption of mtF-actin abrogates fascin-mediated lung cancer metastasis. Conversely, restoration of mitochondrial respiration by using yeast NDI1 in fascin-depleted cancer cells is able to rescue lung metastasis. Our findings indicate that the dysregulated actin cytoskeleton in metastatic lung cancer could be targeted to rewire mitochondrial metabolism and to prevent metastatic recurrence. : Lin et. al. show that fascin, a pro-metastasis actin-bundling protein, promotes mitochondrial oxidative phosphorylation and metabolic stress resistance in lung adenocarcinoma by remodeling mitochondrial actin filaments and regulating the homeostasis of mitochondrial DNA. Keywords: fascin, actin, mitochondria, NSCLC, metastasis, metastatic colonization, OXPHOS

Abstract The emergence of drug resistance continues to be a major hurdle towards improving patient outcomes for the treatment of Multiple Myeloma. MTI-101 is a first-in-class peptidomimetic that binds a CD44/ITGA4 containing complex and triggers necrotic cell death in multiple myeloma cell lines. In this report, we show that acquisition of resistance to MTI-101 correlates with changes in expression of genes predicted to attenuate Ca2+ flux. Consistent with the acquired resistant genotype, MTI-101 treatment induces a rapid and robust increase in intracellular Ca2+ levels in the parental cells; a finding that was attenuated in the acquired drug resistant cell line. Mechanistically, we show that pharmacological inhibition of store operated channels or reduction in the expression of a component of the store operated Ca2+ channel, TRPC1 blocks MTI-101 induced cell death. Importantly, MTI-101 is more potent in specimens obtained from relapsed myeloma patients, suggesting that relapse may occur at a cost for increased sensitivity to Ca2+ overload mediated cell death. Finally, we demonstrate that MTI-101 is synergistic when combined with bortezomib, using both myeloma cell lines and primary myeloma patient specimens. Together, these data continue to support the development of this novel class of compounds for the treatment of relapsed myeloma.

Interleukin-35 (IL-35) is an immune suppressive cytokine produced by T-cells. Here, the authors show that IL-35 is overexpressed by human pancreatic cancer cells and show, in a mouse model, that IL-35 promotes metastasis in an autocrine/paracrine manner via induction of ICAM-1 expression.

Abstract: To evaluate the accumulation conditions and gas-bearing properties of shale gas in the Lower Cambrian Niutitang Formation, northwestern Hunan Province, the first shale gas parameter well (Well Changye-1) that takes the Niutitang Formation as the target horizon in the Hunan Province was selected preferably and drilled, cumulatively revealing the thickest dark shale horizon of the Niutitang Formation among the single-well drillings in China, with a true vertical thickness of 674.5m. Through analyzing the core samples in terms of organic geochemistry, rock mineralogy and reservoir properties, the black shale horizons in the Niutitang Formation of Well Changye-1 have high organic carbon content (average 3.9%), moderate maturity (equivalent Ro average 2.6%), high brittle mineral content (quartz content average 50.1%), low clay mineral content (average 32.4%), low porosity (1.7%) and low permeability (1.32×10-3mD), and well-developed meso to micro-pores and fractures, indicating good conditions for shale gas accumulation. Field desorption and laboratory isothermal adsorption measurements on core samples show that Well Changye-1 has good gas-bearing properties, and gas content generally increases with depth. The black shale horizons at the depth of 1100-1250m have an average organic carbon content up to 10.1%, total gas content of 0.5-2.1m3/t and 3.7-6.4m3/t, and this is the most favorable depth for shale gas development, indicating that the Niutitang Formation has good a prospect for shale gas exploration. Due to huge sedimentary thickness, the black shale in the middle-lower part of the Niutitang Formation should be given priority for exploration. Key words: shale gas, gas-bearing properties, Niutitang Formation, Well Changye-1, northwestern Hunan

The fucose salvage pathway is a two-step process in which mammalian cells transform L-fucose into GDP-L-fucose, a universal fucose donor used by fucosyltransferases to modify glycans. Emerging evidence indicates the fucose salvage pathway and the fucosylation of proteins are altered during melanoma progression and metastasis. However the underlying mechanisms are not completely understood. Here, we report that the fucose salvage pathway inhibits invadopodia formation and extracellular matrix degradation by promoting α-1,2 fucosylation. Chemically or genetically increasing the fucose salvage pathway decreases invadopodium numbers and inhibits the proteolytic activity of invadopodia in WM793 melanoma cells. Inhibiting fucosylation by depleting fucokinase abrogates L-fucose-mediated inhibition of invadopodia, suggesting dependence on the fucose salvage pathway. The inhibition of invadopodium formation by L-fucose or ectopically expressed FUK could be rescued by treatment with α-1,2, but not α-1,3/α-1,4 fucosidase, implicating an α-1,2 fucose linkage-dependent anti-metastatic effect. The expression of FUT1, an α-1,2 fucosyltransferase, is remarkably down-regulated during melanoma progression, and the ectopic expression of FUT1 is sufficient to inhibit invadopodium formation and ECM degradation. Our findings indicate that the fucose salvage pathway can inhibit invadopodium formation, and consequently, invasiveness in melanoma via α-1,2 fucosylation. Re-activation of this pathway in melanoma could be useful for preventing melanoma invasion and metastasis.

Fucosylation is a post-translational modification of glycans, proteins, and lipids that is responsible for many biological processes. Fucose conjugation via α(1,2), α(1,3), α(1,4), α(1,6), and O’- linkages to glycans, and variations in fucosylation linkages, has important implications for cancer biology. This review focuses on the roles that fucosylation plays in cancer, specifically through modulation of cell surface proteins and signaling pathways. How L-fucose and serum fucosylation patterns might be used for future clinical diagnostic, prognostic, and therapeutic approaches will be discussed.

Background. Breast cancer is the most common malignancy in women. There is increasing evidence suggesting that ORAI1, components of store-operated calcium channel, play a pivotal role in breast cancer progression and metastasis. Methods. A total of 384 female patients with breast cancer were included in this study. We selected five representative tagging ORAI1 SNPs from HapMap database with minimum allele frequency (MAF) >10%. Genotyping was performed using TaqMan allelic discrimination assay. Chi-square (χ2) test was used to analyze statistical differences among control and patient groups in genotype and allelic frequencies. Results. Two of the ORAI1 SNPs (rs12320939 and rs12313273) were associated with estrogen receptors positive in breast cancer patients under the recessive model. When the Bonferroni correction was performed, the significance still existed. In addition, rs12320939 also associated with the lymph nodal involvement. Conclusion. We showed that genetic polymorphisms of ORAI1 associated strongly with lymph nodal involvement and estrogen receptors (ERs) positive breast cancer patients in a Taiwanese population.