Novel lumbar plexus block versus femoral nerve block for analgesia and motor recovery after total knee arthroplasty.

This study aimed to compare the postoperative analgesic efficacy and motor recovery of a novel lumbar plexus block (LPB) with that of a femoral nerve block (FNB) after total knee arthroplasty (TKA). Forty patients who underwent TKA were randomised equally into an lumbar plexus and sciatic nerve (LS) group (receiving novel LPB) and an femoral and sciatic nerves (FS) group (receiving FNB). The assessed variables were the onset time of pain, time to the first analgesic request, pain scores, motor block at 6, 12, and 24 h after TKA, and the number of patients receiving successful blockade for each branch of the lumbar plexus. In the LS group, the femoral, lateral femoral cutaneous, genitofemoral, iliohypogastric, ilioinguinal, and obturator nerves were blocked in 18, 20, 16, 18, 15, and 19 patients. Compared to the FS group, the LS group had a significantly shorter onset time of pain and time to the first analgesic request, a significantly larger total postoperative dose of sufentanil, significantly higher numeric rating scale scores for both rest and dynamic pain at 6, 12, and 24 h, and faster motor recovery. Novel ultrasound-guided LPB has a high blocking success rate and provides inferior postoperative analgesia, but faster motor recovery after TKA than FNB.

A donor-acceptor (D-A) conjugated polymer for fast storage of anions.

Organic electrode materials have attracted a lot interest in batteries in recent years. However, most of them still suffer from low performance such as low electrode potential, slow reaction kinetics, and short cycle life. In this work, we report a strategy of fabricating donor-acceptor (D-A) conjugated polymers for facilitating the charge transfer and therefore accelerating the reaction kinetics by using the copolymer (p-TTPZ) of dihydrophenazine (PZ) and thianthrene (TT) as a proof-of-concept. The D-A conjugated polymer as p-type cathode could store anions and exhibited high discharge voltages (two plateaus at 3.82 V, 3.16 V respectively), a reversible capacity of 152 mAh g-1 at 0.1 A g-1 , excellent rate performance with a high capacity of 124.2 mAh g-1 at 10 A g-1 (≈50 C) and remarkable cyclability. The performance, especially the rate capability was much higher than that of its counterpart homopolymers without D-A structure. As a result, the p-TTPZ//graphite full cells showed a high output voltage (3.26 V), a discharge specific capacity of 139.1 mAh g-1 at 0.05 A g-1 and excellent rate performance. This work provides a novel strategy for developing high performance organic electrode materials through molecular design and will pave a way towards high energy density organic batteries.

Identification and Fungicide Screening of Fungal Species Associated with Walnut Anthracnose in Shaanxi and Liaoning Provinces, China.

Walnut is cultivated around the world for its precious woody nut and edible oil. Recently, walnut infected by Colletotrichum spp. resulted in a great yield and quality loss. In August and September 2014, walnut fruits with anthracnose were sampled from two commercial orchards in Shaanxi and Liaoning provinces, and five representative isolates were used in this study. To identify the pathogen properly, four genes per region (internal transcribed spacer, glyceraldehyde-3-phosphate dehydrogenase, actin, and chitin synthase) were sequenced and used in phylogenetic studies. Based on multilocus phylogenetic analysis, five isolates clustered with Colletotrichum fioriniae, including its ex-type, with 100% bootstrap support. The results of multilocus phylogenetic analyses, morphology, and pathogenicity confirmed that C. fioriniae was one of the walnut anthracnose pathogens in China. All 13 fungicides tested inhibited mycelial growth and spore germination. Flusilazole, fluazinam, prochloraz, and pyraclostrobin showed the strongest suppressive effects on the mycelial growth than the others, the average EC50 values ranged from 0.09 to 0.40 µg/ml, and there was not any significant difference (P < 0.05). Pyraclostrobin, thiram, and azoxystrobin were the most effective fungicides on spore germination (P < 0.05), and the EC50 values ranged from 0.01 to 0.44 µg/ml. Pyraclostrobin, azoxystrobin, fluazinam, flusilazole, mancozeb, thiram, and prochloraz exhibited a good control effect on walnut anthracnose caused by C. fioriniae, and preventive activities were greater than curative activities. Pyraclostrobin at 250 a.i. µg/ml and fluazinam at 500 a.i. µg/ml provided the highest preventive and curative efficacy, and the values ranged from 81.3 to 82.2% and from 72.9 to 73.6%, respectively. As a consequence, mancozeb and thiram could be used at the preinfection stage, and pyraclostrobin, azoxystrobin, flusilazole, fluazinam, and prochloraz could be used at the early stage for effective prevention and control of walnut anthracnose caused by C. fioriniae. The results will provide more significant instructions for controlling the disease effectively in northern China.

Interfacial Assembly of 2D Graphene-Derived Ion Channels for Water-Based Green Energy Conversion.

The utilization of sustained and green energy is believed to alleviate increasing menace of global environmental concerns and energy dilemma. Interfacial assembly of 2D graphene-derived ion channels (2D-GDICs) with tunable ion/fluid transport behavior enables efficient harvesting of renewable green energy from ubiquitous water, especially for osmotic energy harvesting. In this review, various interfacial assembly strategies for fabricating diverse 2D-GDICs are summarized and their ion transport properties are discussed. This review analyzes how particular structure and charge density/distribution of 2D-GDIC can be modulated to minimize internal resistance of ion/fluid transport and enhance energy conversion efficiency, and highlights stimuli-responsive functions and stability of 2D-GDIC and further examines the possibility of integrating 2D-GDIC with other energy conversion systems. Notably, the presented preparation and applications of 2D-GDIC also inspire and guide other 2D materials to fabricate sophisticated ion channels for targeted applications. Finally, potential challenges in this field is analyzed and a prospect to future developments toward high-performance or large-scale real-word applications is offered.

Cellular crosstalk of macrophages and therapeutic implications in non-small cell lung cancer revealed by integrative inference of single-cell transcriptomics.

Introduction: Non-small cell lung cancer (NSCLC) exhibits heterogeneity with diverse immune cell infiltration patterns that can influence tumor cell behavior and immunotherapy. A comprehensive characterization of the tumor microenvironment can guide precision medicine. Methods: Here, we generated a single-cell atlas of 398170 cells from 52 NSCLC patients, and investigated the imprinted genes and cellular crosstalk for macrophages. Subsequently, we evaluated the effect of tumor cells on macrophages and verified the expression of marker genes using co-culture experiments, flow cytometry and RT-qPCR assays. Results: Remarkable macrophage adaptability to NSCLC environment was observed, which contributed to generating tumor-associated macrophages (TAMs). We identified 5 distinct functional TAM subtypes, of which the majority were SELENOP-positive macrophages, with high levels of SLC40A1 and CCL13. The TAMs were also involved in mediating CD8+ T cell activity and form intercellular interaction with cancer cells, as indicated by receptor-ligand binding. Indirect coculture of tumor cells SPC-A1 and THP-1 monocytes, produced M2-like TAMs that highly expressed several markers of SELENOP-positive macrophages. The abundance of this type TAMs seemed to be associated with poorer overall survival rates [hazard ratio (HR) = 1.34, 95% confidence interval (CI) = 0.98-1.83, p = 0.068] based on deconvolution of TCGA-LUAD dataset. Discussion: In summary, we provided a high-resolution molecular resource of TAMs, and displayed the acquired properties in the tumor microenvironment. Dynamic crosstalk between TAMs and tumor cells via multiple ligand-receptor pairs were revealed, emphasizing its role in sustaining the pro-tumoral microenvironment and its implications for cancer therapy.

Structural Isomers: Small Change with Big Difference in Anion Storage.

Organic electrode materials are promising for batteries. However, the reported organic electrodes are often facing the challenges of low specific capacity, low voltage, poor rate capability and vague charge storage mechanisms, etc. Isomers are good platform to investigate the charge storage mechanisms and enhance the performance of batteries, which, however, have not been focused in batteries. Herein, two isomers are reported for batteries. As a result, the isomer tetrathiafulvalene (TTF) could store two monovalent anions reversibly, deriving an average discharge voltage of 1.05 V and a specific capacity of 220 mAh g-1 at a current density of 2 C. On the other hand, the other isomer tetrathianaphthalene could only reversibly store one monovalent anion and upon further oxidation, it would undergo an irreversible solid-state molecular rearrangement to TTF. The molecular rearrangement was confirmed by electrochemical performances, X-ray diffraction patterns, nuclear magnetic resonance spectra, and 1H detected heteronuclear multiple bond correlation spectra. These results suggested the small structural change could lead to a big difference in anion storage, and we hope this work will stimulate more attention to the structural design for boosting the performance of organic batteries.

Preparation of three structurally similar stationary phases with different ionizable terminal groups and evaluation of their retention performances under multiple modes in high performance liquid chromatography.

Three structurally similar silane reagents with different terminal groups were prepared and bonded to silica to obtain three structurally similar stationary phases (Sil-Ph-COOH, Sil-Phe and Sil-Ph-NH2). The prepared stationary phases were characterized through elemental analysis (EA) and Fourier Transform Infrared Spectroscopy (FT-IR). These three stationary phases provided acceptable retention repeatability (relative standard deviations between 0.08% and 0.13%) and high column efficiency (7.3 × 104 plates/m for uridine on Sil-Phe). The retention behavior of the three columns was investigated under different chromatographic conditions including different mobile phase ratio, salt concentration, pH etc. The retention mechanisms were explored by linear solvation energy relationships and Van't Hoff plots. Applications in separation under reversed phase liquid chromatography (RPLC), hydrophilic interaction liquid chromatography (HILIC) and ion exchange chromatography (IEC) mode were investigated. The results showed that the retention capacity of the stationary phases with different terminal groups to the analytes is very different, especially for carboxylic acids, because the surface charges of amino groups and carboxyl groups under weakly acidic conditions produce different electrostatic effects with dissociated carboxylic acids. Finally, the Sil-Phe column was employed to detect ibuprofen extracted from pharmaceutical ibuprofen capsules and vitamins extracted from vitamin tablets.

E3 ubiquitin ligase Siah1 aggravates NAFLD through Scp2 ubiquitination.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver disorders and accompanied by multiple metabolic dysfunctions. Although excessive lipid accumulation in hepatocytes has been identified as a crucial mediator of NAFLD development, the underlying mechanisms are very complicated and remain largely unknown. In this study, we reported that upregulated expression of the seven in absentia homolog 1 (Siah1) in the liver exacerbated NAFLD progression. Conversely, Siah1 downregulation markedly alleviated the high fat diet-induced accumulation of hepatic fat and expression of genes related to lipid metabolism in vitro and in vivo. The mechanistic study revealed that Siah1 interacted with sterol carrier protein 2 (Scp2) and promotes its ubiquitination and degradation, suggesting that Siah1 is an important activator of Scp2 ubiquitination in the context of NAFLD. Our results demonstrated that Siah1 regulated the lipid accumulation in NAFLD by interacting with Scp2. Thus, this study presents Siah1 as a promising therapeutic target in the development of NAFLD.

Single Crystals of a Highly Conductive Three-Dimensional Conjugated Coordination Polymer.

Conjugated coordination polymers (CCPs), which possess long-range planar π-d conjugation, are fascinating for various applications because they inherit the merits of both metal-organic frameworks (MOFs) and conducting polymers. However, only one-dimensional (1D) and two-dimensional (2D) CCPs have been reported so far. The synthesis of three-dimensional (3D) CCPs is challenging and even seems theoretically infeasible because conjugation implies 1D or 2D structure. Besides, the redox activity of the conjugated ligands and the π-d conjugation makes the synthesis of CCPs very complicated, and hence, single crystals of CCPs are rarely achieved. Herein, we reported the first 3D CCP and its single crystals with atomically precise structures. The synthesis process involves complicated in situ dimerization, deprotonation of ligands, oxidation/reduction of both ligands and metal ions, and precise coordination between them. The crystals contain in-plane 1D π-d conjugated chains and close π-π interactions between the adjacent chains that are bridged by another column of stacked chains, thus forming 3D CCP with high conductivity (400 S m-1 at room temperature and 3100 S m-1 at 423 K) and potential applications as cathodes in sodium-ion batteries with high capacity, rate capability, and cyclability.

The effect of ultrasound-guided intercostal nerve block on postoperative analgesia in thoracoscopic surgery: a randomized, double-blinded, clinical trial.

BACKGROUND: Intercostal nerve block (ICNB) is a very effective analgesic method. We aimed to explore the effect of preemptive analgesia with ultrasound-guided intercostal nerve block on postoperative analgesia in thoracoscopic surgery. METHODS: 126 patients, aged 18-70 years, with American Society of Anesthesiologists (ASA) physical status I-II and scheduled for thoracoscopic pulmonary resection were enrolled in this study. 119 patients were left for final analysis. Patients were randomly allocated to group ICNB and group CONTROL. Patients in CONTROL group were administered sufentanil with patient-controlled analgesia device after operation In group ICNB, patients received ropivacaine ICNB prior to surgery and patient-controlled analgesia device after operation. The primary outcome is visual analog scale pain score (VAS) at rest at 0,4, 8,16,24,48,72 and 168 h postoperatively and they were compared. Surgical outcomes and rescue analgesia requirement were also recorded. RESULTS: VAS scores were statistically significantly lower for ICNB group compared to control group at 0, 4, 8, 16, 24 and 48 h postoperatively. The duration of insertion of chest tube in ICBN group was shorter than that in control group, and the difference was statistically significant (4.69 ± 2.14 vs. 5.67 ± 2.86, P = 0.036). The postoperative hospital stay, incidence of nausea and vomiting and postoperative pulmonary infection rate in ICBN group were all lower than those in the control group, but there were no statistical differences. The frequency of rescue analgesia during 48 postoperative hours was different between the two groups (ICNB vs. Control; 9.83% vs. 31.03%, P = 0.004). CONCLUSIONS: For patients undergoing thoracoscopic surgery, ultrasound-guided ICNB is simple, safe, and effective for providing acute postoperative pain management during the early postoperative stage. TRIAL REGISTRATION: Chinese clinical trials: chictr.org.cn, ChiCTR1900021017. Registred on 25/01/2019.

Antimicrobial indole alkaloids from Tabernaemontana corymbosa.

Four unreported monoterpene indole alkaloids, tabernaecorymines B-E (1-4), together with twenty-one known indole alkaloids (5-25) were obtained from the stem bark of Tabernaemontana corymbosa. Their structures and absolute configurations were elucidated by extensive spectroscopy, quantum chemical calculations, DP4+ probability analyses and Mo2(OAc)4-induced electronic circular dichroism experiment. The antibacterial and antifungal activities of these compounds were evaluated and some of them showed significant activity against Staphylococcus aureus,Bacillus subtilis, Streptococcus dysgalactiae and Candida albicans.

A Recyclable and Scalable High-Capacity Organic Battery.

Redox organic electrode materials (OEMs) have attracted extensive attention for batteries due to the possibility to be designed with high performance. However, the practical application of OEMs requires rigor criteria such as low cost, recyclability, scalability and high performance etc. and hence seems still far away. Here, we demonstrate an OEM for high performance aqueous organic batteries. Quantification of the charge storage confirmed the storage of protons with fast reaction kinetics, thereby enabling the high performance at high mass loading. As a result, the laminated pouch cells delivered Ampere-hour-scale capacity with excellent cycling performance. Benefited from the small molecular nature and the stable both charged and discharged states, the electrodes can be recycled at any states of charge with high yields (more than 90 %). This work provides a substantial step in the practical applications of OEMs for the future sustainable batteries.

Preparation of MnO2-Carbon Materials and Their Applications in Photocatalytic Water Treatment.

Water pollution is one of the most important problems in the field of environmental protection in the whole world, and organic pollution is a critical one for wastewater pollution problems. How to solve the problem effectively has triggered a common concern in the area of environmental protection nowadays. Around this problem, scientists have carried out a lot of research; due to the advantages of high efficiency, a lack of secondary pollution, and low cost, photocatalytic technology has attracted more and more attention. In the past, MnO2 was seldom used in the field of water pollution treatment due to its easy agglomeration and low catalytic activity at low temperatures. With the development of carbon materials, it was found that the composite of carbon materials and MnO2 could overcome the above defects, and the composite had good photocatalytic performance, and the research on the photocatalytic performance of MnO2-carbon materials has gradually become a research hotspot in recent years. This review covers recent progress on MnO2-carbon materials for photocatalytic water treatment. We focus on the preparation methods of MnO2 and different kinds of carbon material composites and the application of composite materials in the removal of phenolic compounds, antibiotics, organic dyes, and heavy metal ions in water. Finally, we present our perspective on the challenges and future research directions of MnO2-carbon materials in the field of environmental applications.

Preparation of three regioisomeric ionic liquid stationary phases and investigation of their retention behavior.

The structural properties of ionic liquid stationary phases have a considerable effect on their separation selectivity. However, the difference of the chromatographic retention behavior of different regioisomeric ionic liquid stationary phases has rarely been investigated. In this study, three regioisomeric ionic liquid silane reagents were prepared by photoinitiated ene-click chemistry and bonded to silica by one-pot method to fabricate three new stationary phases (Sil-C2Im-C8, Sil-C6Im-C4, and Sil-C9Im-C1). All three stationary phases showed promising retention repeatability and efficiency. The retention behavior of the three stationary phases was investigated under various chromatographic conditions. The retention mechanism was further investigated by the linear energy solvation relationship and Van't Hoff plots. The stationary phases exhibited mixed-mode retention mechanisms. The π-π, hydrogen bonding, ion-exchange, and hydrophilic interactions with analytes were the weakest when the imidazole ions were embedded in the innermost part of the alkyl chains, while the interactions were the strongest when the imidazole ions were embedded in the middle of the alkyl chains. The three stationary phases provided great but different separation performances towards nucleosides, nucleobases, aromatic acids, alkyl benzenes, and polycyclic aromatic hydrocarbons due to the influence of imidazole ion position.

The Value of Radiotherapy in Patients With Resectable Stage IIIA Non-Small-Cell Lung Cancer in the Era of Individualized Treatment: A Population-Based Analysis.

INTRODUCTION: No consensus has been achieved on the benefit of radiotherapy for resected stage IIIA NSCLC patients. The division of stage IIIA has changed significantly in 2017. This study aims to explore the effects of radiotherapy on the survival of patients with resectable stage IIIA NSCLC in the new era. PATIENTS AND METHODS: Patients diagnosed with NSCLC between 2010 and 2018 were identified in the 8th edition TNM classification from the Surveillance, Epidemiology, and End Results database. A nomogram was developed by integrating all independent predictors for lung cancer-specific survival (LCSS). The Propensity Score Matching (PSM) and subgroup analysis were applied to mitigate potential bias. Survival analyses were conducted using the Kaplan Meier curves and Cox proportional hazards regression. RESULTS: A total of 2632 stage IIIA NSCLC patients were enrolled. The C-index of the nomogram for the prediction of LCSS was 0.636 (95% CI, 0.616-0.656). In the group of patients with N2 stage who featured more than 5 positive regional lymph nodes, compared with non-PORT, PORT did prolong postoperative survival time (50 vs. 31 months; P= .005). N2 patients with visceral pleural invasion (VPI), older (age >65), or had a larger tumor (size >3 cm) could also benefit from adjuvant radiotherapy. CONCLUSION: Treatment protocol for stage IIIA NSCLC patients should be individualized. Based on our findings, N2 patients with more than 5 positive regional lymph nodes, VPI, larger tumor size (greater than 3 cm), and older (age above 65) could benefit from adjuvant radiotherapy. Further well-designed randomized trials are warranted.

Preparation of spherical silica hydroxyl-functionalized covalent organic polymer composites for mixed-mode liquid chromatography.

Covalent organic polymers are an emerging class of amorphous microporous materials that have raised increasing concerns in analytical chemistry due to their unique structural and surface chemical properties. However, the application of covalent organic polymers as mixed-mode stationary phases in chromatographic separations has rarely been reported. Herein, novel spherical silica hydroxyl-functionalized covalent organic polymer composites were successfully prepared via a layer-by-layer approach. The structure and morphology of the materials were carefully characterized by elemental analysis, Fourier-transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, X-ray diffraction, thermogravimetric analysis, Brunauer-Emmett-Teller, and contact angle measurements. Baseline separations of various alkylbenzenes, polycyclic aromatic hydrocarbons, and nucleosides and bases were achieved on the prepared stationary phase under reversed-phase/hydrophilic interaction mode. The column efficiencies of 23 853 and 36 580 plates/m were obtained for butylbenzene and uracil, respectively, and the relative standard deviation of the retention time for continuous injections was less than 1.38% (n = 10), suggesting satisfactory column efficiency and repeatability. Additionally, this novel stationary phase realized the complete separation of the endocrine-disrupting chemicals in river water. This work affords a new route for synthesizing covalent organic polymers-based mixed-mode stationary phase and further reveals their great potential in chromatographic separation.

Framework Dimensional Control Boosting Charge Storage in Conjugated Coordination Polymers.

Conjugated coordination polymers (CCPs) with extended π-d conjugation, which can effectively promote long-range delocalization of electrons and enhance conductivity, are superior to traditional metal-organic frameworks (MOFs) and attracted great attention for potential applications in chemical sensors, electronics, energy conversion/storage devices, etc. However, the precise construction of CCPs is still challenging due to the complex and uncontrollable reactions of CCPs. Herein, two different framework dimensions of CCPs are controllably realized by employing the same ligand (2,3,5,6-tetraaminobenzoquinone (TABQ)) and the same metal (copper) as center ions. The manipulation of reaction leads to different valences of ligands and metal ions, different coordination geometries, and thereby 1D-CuTABQ and 2D-CuTABQ frameworks, respectively. High performance of charge storage is hence achieved involving the storage of both cations and anions, and therein, 2D-CuTABQ shows a high reversible capacity of ≈305 mAh g-1 , good rate capability and high capacity retention (≈170 mAh g-1 after 2000 cycles at 5 A g-1 with 0.01% decay per cycle), which outperforms 1D-CuTABQ and almost all of the reported MOFs as cathodes for batteries. These results highlight the delicate structural control of CCPs for high-performance batteries and other various applications.

Grafting (S)-2-Phenylpropionic Acid on Coordinatively Unsaturated Metal Centers of MIL-101(Al) Metal-Organic Frameworks for Improved Enantioseparation.

Chiral metal-organic frameworks (cMOFs) are emerging chiral stationary phases for enantioseparation owing to their porosity and designability. However, a great number of cMOF materials show poor separation performance for chiral drugs in high-performance liquid chromatography (HPLC). The possible reasons might be the irregular shapes of MOFs and the low grafting degree of chiral ligands. Herein, MIL-101-Ppa@SiO2 was synthesized by a simple coordination post-synthetic modification method using (S)-(+)-2-Phenylpropionic acid and applied as the chiral stationary phase to separate chiral compounds by HPLC. NH2-MIL-101-Ppa@SiO2 prepared via covalent post-synthetic modification was used for comparison. The results showed that the chiral ligand density of MIL-101-Ppa@SiO2 was higher than that of NH2-MIL-101-Ppa@SiO2, and the MIL-101-Ppa@SiO2 column exhibited better chiral separation performance and structural stability. The binding affinities between MIL-101-Ppa@SiO2 and chiral compounds were simulated to prove the mechanism of the molecular interactions during HPLC. These results revealed that cMOFs prepared by coordination post-synthetic modification could increase the grafting degree and enhance the separation performance. This method can provide ideas for the synthesis of cMOFs.

KRAS G12D mutation eliminates reactive oxygen species through the Nrf2/CSE/H 2S axis and contributes to pancreatic cancer growth.

In pancreatic cancer, KRAS G12D can trigger pancreatic cancer initiation and development. Rapid tumor growth is often accompanied by excess intracellular reactive oxygen species (ROS) production, which is unfavorable to tumor. However, the regulation of intracellular ROS levels in KRAS mutant pancreatic cancer remains unclear. In this study, we establish BxPC3 stable cell strains expressing KRAS wild type (WT) and G12D mutation and find unchanged ROS levels despite higher glycolysis and proliferation viability in KRAS mutant cells than KRAS WT cells. The key hydrogen sulfide (H 2S)-generating enzyme cystathionine-γ-lyase (CSE) is upregulated in KRAS mutant BxPC3 cells, and its knockdown significantly increases intracellular ROS levels and decreases cell glycolysis and proliferation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is activated by KRAS mutation to promote CSE transcription. An Nrf2 binding site (‒47/‒39 bp) in the CSE promoter is verified. CSE overexpression and the addition of NaHS after Nrf2 knockdown or inhibition by brusatol decreases ROS levels and rescues cell proliferation. Our study reveals the regulatory mechanism of intracellular ROS levels in KRAS mutant pancreatic cancer cells, which provides a potential target for pancreatic cancer therapy.