Revitalizing zinc-ion batteries with advanced zinc anode design.

Rechargeable aqueous zinc-ion batteries (AZIBs) have attracted significant attention in large-scale energy storage systems due to their unique merits, such as intrinsic safety, low cost, and relatively high theoretical energy density. However, the dilemma of the uncontrollable Zn dendrites, severe hydrogen evolution reaction (HER), and side reactions that occur on the Zn anodes have hindered their commercialization. Herein, a state-of-the-art review of the rational design of highly reversible Zn anodes for high-performance AZIBs is provided. Firstly, the fundamental understanding of Zn deposition, with regard to the nucleation, electro-crystallization, and growth of the Zn nucleus is systematically clarified. Subsequently, a comprehensive survey of the critical factors influencing Zn plating together with the current main challenges is presented. Accordingly, the rational strategies emphasizing structural design, interface engineering, and electrolyte optimization have been summarized and analyzed in detail. Finally, future perspectives on the remaining challenges are recommended, and this review is expected to shed light on the future development of stable Zn anodes toward high-performance AZIBs.

Thermal-Stable Separators: Design Principles and Strategies Towards Safe Lithium-Ion Battery Operations.

Lithium-ion batteries (LIBs) are momentous energy storage devices, which have been rapidly developed due to their high energy density, long lifetime, and low self-discharge rate. However, the frequent occurrence of fire accidents in laptops, electric vehicles, and mobile phones caused by thermal runaway of the inside batteries constantly reminds us of the urgency in pursuing high-safety LIBs with high performance. To this end, this Review surveyed the state-of-the-art developments of high-temperature-resistant separators for highly safe LIBs with excellent electrochemical performance. Firstly, the basic properties of separators (e. g., thickness, porosity, pore size, wettability, mechanical strength, and thermal stability) in constructing commercialized LIBs were introduced. Secondly, the working mechanisms of advanced separators with different melting points acting in the thermal runaway stage were discussed in terms of improving battery safety. Thirdly, rational design strategies for constructing high-temperature-resistant separators for LIBs with high safety were summarized and discussed, including graft modification, blend modification, and multilayer composite modification strategies. Finally, the current obstacles and future research directions in the field of high-temperature-resistant separators were highlighted. These design ideas are expected to be applied to other types of high-temperature-resistant energy storage systems working under extreme conditions.

Dual-Regulation Strategy to Improve Anchoring and Conversion of Polysulfides in Lithium-Sulfur Batteries.

The sluggish reaction kinetics at the cathode/electrolyte interface of lithium-sulfur (Li-S) batteries limits their commercialization. Herein, we show that a dual-regulation system of iron phthalocyanine (FePc) and octafluoronaphthalene (OFN) decorated on graphene (Gh), denoted as Gh/FePc+OFN, accelerates the interfacial reaction kinetics of lithium polysulfides (LiPSs). Multiple in situ spectroscopy techniques and ex situ X-ray photoelectron spectroscopy combined with density functional theory calculations demonstrate that FePc acts as an efficient anchor and scissor for the LiPSs through Fe···S coordination, mainly facilitating their liquid-liquid transformation, whereas OFN enables Li-bond interaction with the LiPSs, accelerating the kinetics of the liquid-solid nucleation and growth of Li2S. This dual-regulation system promotes the smooth conversion reaction of sulfur, thereby improving the battery performance. A Gh/FePc+OFN-based Li-S cathode delivered an ultrahigh initial capacity of 1604 mAh g-1 at 0.2 C, with an ultralow capacity decay rate of 0.055% per cycle at 1 C over 1000 cycles.

Titanium silicalite as a radical-redox mediator for high-energy-density lithium-sulfur batteries.

Lithium-sulfur (Li-S) batteries are receiving intense interest owing to their high energy densities, cost effectiveness, and the natural abundance of sulfur. However, practical applications are still limited by rapid capacity decay caused by multielectron redox reactions and complex phase transformations. Here, we include commercially available titanium silicalite-1 (TS-1) in carbon/sulfur cathodes, to introduce strong chemical interactions between the lithium polysulfides (LiPS) and TS-1 in a working Li-S battery. In situ UV-visible spectroscopy together with other experimental results confirm that incorporation of TS-1 mediators enables direct conversion between S82- and S3*- radicals during the discharge process, which effectively promotes the kinetic behaviors of soluble LiPS and regulates uniform nucleation and growth of solid sulfide precipitates. These features give our TS-1 engineered sulfur cathode an ultrahigh initial capacity of 1459 mA h g-1 at 0.1C. Moreover, the system has an impressively high areal capacity (3.84 mA h cm-2) and long cycling stability with a high sulfur loading of 4.9 mg cm-2. This novel and low-cost fabrication procedure is readily scalable and provides a promising avenue for potential industrial applications.

Interfacial Molecule Mediators in Cathodes for Advanced Li-S Batteries.

The complicated reactions at the cathode-electrolyte interface in Li-S batteries are a large barrier for their successful commercialization. Herein, we developed a molecular design strategy and employed three small molecules acting as interfacial mediators to the cathodes of Li-S batteries. The theoretical calculation results show that the incorporation of tris(4-fluorophenyl)phosphine (TFPP) has a strong binding performance. The experimental results demonstrate that the strong chemical interactions between polysulfides and the F, P atoms in TFPP not only modify the kinetics of the electrochemical processes in the electrolyte but also promote the formation of short-chain clusters (Li2Sx, x = 1, 2, 3, and 4) at the interface during the charge-discharge process. As a result, an optimized electrode exhibits a low capacity decay rate of 0.042% per cycle when the current rate is increased to 5 C over 1000 cycles.

3D CNTs/Graphene-S-Al3Ni2 Cathodes for High-Sulfur-Loading and Long-Life Lithium-Sulfur Batteries.

Lithium-sulfur batteries suffer from poor cycling stability at high areal sulfur loadings (ASLs) mainly because of the infamous shuttle problem and the increasing diffusion distance for ions to diffuse along the vertical direction of the cathode plane. Here, a carbon nanotube (CNT)/graphene (Gra)-S-Al3Ni2 cathode with 3D network structure is designed and prepared. The 3D network configuration and the Al in the Al3Ni2 provide an efficient channel for fast electron and ion transfer in the three dimensions, especially along the vertical direction of the cathode. The introduction of Ni in the Al3Ni2 is able to suppress the shuttle effect via accelerating reaction kinetics of lithium polysulfide species conversion reactions. The CNT/Gra-S-Al3Ni2 cathode exhibits ultrahigh cycle-ability at 1 C over 800 cycles, with a capacity degradation rate of 0.055% per cycle. Additionally, having high ASLs of 3.3 mg cm-2, the electrode delivers a high reversible areal capacity of 2.05 mA h cm-2 (622 mA h g-1) over 200 cycles at a higher current density of 2.76 mA cm-2 with high capacity retention of 85.9%. The outstanding discharge performance indicates that the design offers a promising avenue to develop long-life cycle and high-sulfur-loading Li-S batteries.

KIR 2D (L1, L3, L4, S4) and KIR 3DL1 protein expression in non-small cell lung cancer.

BACKGROUND: Nature killer (NK) cells are the immune system's first line of defense against both viral infections and tumors. Killer cell immunoglobulin-like receptors (KIRs) are associated with susceptibility to different types of cancers. We investigated KIR 2D (L1, L3, L4, S4) and KIR 3DL1 protein expression and their association with survival in non-small cell lung cancer (NSCLC). METHODS: The expression of KIR 2D (L1, L3, L4, S4) (BC032422/ ADQ31987/ NP_002246/ NP_036446, ABCAM) and KIR 3DL1 (AA 1-444, ABCAM) protein was assessed by immunohistochemistry (IHC) in 62 NSCLC patients. RESULTS: KIR 2D (L1, L3, L4, S4) and KIR 3DL1 were expressed both on NSCLC tumor cells and tumor infiltrating lymphocytes (TILs). Fourteen samples (22.6%) stained positive for KIR 2D (L1, L3, L4, S4) on the tumor cells, and 10 (16.1%) had positive expression on the TILs. Thirty-three samples (53.2%) stained positive for KIR 3DL1 on the tumor cells, and 31 (50.0%) had positive expression on the TILs. Patients with negative KIR 2D (L1, L3, L4, S4) expression on tumor cells or TILs had longer overall survival (OS) than patients who are KIR 2D (L1, L3, L4, S4) positive on tumor cells (40.70 weeks, 95% CI 24.76-56.65 vs. 7.10 weeks, 95% CI 0.00-19.38, P = 0.014) or TILs (40.70 weeks, 95% CI 24.05-57.35 vs. 3.90 weeks, 95% CI 0.00-9.17, P < 0.001). Likewise, longer OS was significantly correlated with negative expression of KIR 3DL1 on tumor cells (62.30 weeks, 95% CI 0.00-177.37 vs. 13.10 weeks, 95% CI 3.42-22.78, P < 0.001) or TILs (62.30 weeks, 95% CI 0.00-152.05 vs. 12.10 weeks, 95% CI 2.61-21.59, P < 0.001). Cox regression analysis showed that KIR 2D (L1, L3, L4, S4) on TILs was correlated with OS (P = 0.032, Odds Ratio 2.628 95%CI 1.089-6.340). CONCLUSIONS: KIR 2D (L1, L3, L4, S4) and KIR 3DL1 expression was correlated with poor prognosis in NSCLC patients.

Hepatic Metastases is Associated with Poor Efficacy of Erlotinib as 2nd/3rd Line Therapy in Patients with Lung Adenocarcinoma.

BACKGROUND: Hepatocyte growth factor (HGF)-mediated mesenchymal-to-epithelial transition factor (MET) gene amplification is a common mechanism for acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). MET gene amplification has also been associated with hepatic metastases in patients with lung cancer. The aim of this study was to investigate whether hepatic metastases are associated with decreased efficacy of erlotinib in patients with adenocarcinoma. MATERIAL/METHODS: A cohort of 329 patients with stage IV lung adenocarcinoma, known EGFR mutation status, and who received treatment with erlotinib in the 2nd or 3rd line setting were enrolled into this study over a period of 4 years between January 2011 and January 2015. The cohort was stratified based on the presence or absence of hepatic metastases and the efficacy of erlotinib was defined based on disease control rate (DCR) and progression-free survival (PFS). RESULTS: Hepatic metastases were present in 220 of the 329 enrolled lung adenocarcinoma patients. EGFR-activating mutations (exon 19 deletion or an exon 21 L858R mutation) were identified in 113 (34.3%) patients. The DCR was significantly lower in the hepatic metastases group than in patients without hepatic metastases (39.5% vs. 51.4% P=0.045). In patients with hepatic metastases, median PFS was 2.3 months in the EGFR mutation-positive group versus 1.4 months in the EGFR mutation-negative group (95% CI 1.3-3.3 vs. 1.3-1.5; P=0.055). Of note, erlotinib therapy in patients with hepatic metastases was complicated by elevated alanine transaminase (ALT) levels. CONCLUSIONS: Hepatic metastasis in patients with lung adenocarcinoma predicts poor response to erlotinib as a 2nd/3rd line therapy. Combination therapy, for example with MET-TKI, may be a good choice for patients with liver metastases with poor prognosis.

Clinical evaluation of a novel method for the measurement of prostate-specific antigen, AccuPSA(TM) , as a predictor of 5-year biochemical recurrence-free survival after radical prostatectomy: results of a pilot study.

Study Type - Diagnostic (validating cohort) Level of Evidence 1b What's known on the subject? and What does the study add? Nadir Ultrasensitive PSA levels has some value for predicting BCR following RD. AccuPSA assays lower limit of PSA quantification of <0.01 pg/ml greatly enhances sensitivity and specificity of nadir PSA to predict BCR following RP. Our pilot study shows an AccuPSA of 3 pg/ml has a sensitory and specificity of 100% and 75% respectively for predicting 5 year BCR following RP. OBJECTIVES • To conduct a proof of concept study to evaluate a novel digital single molecule immunoassay (AccuPSA(TM) ) that detects prostate-specific antigen (PSA) a thousandfold more sensitively than current PSA detection methods. • To determine the ability of the AccuPSA(TM) assay to predict 5-year biochemical recurrence (BCR)-free survival after radical prostatectomy (RP). PATIENTS AND METHODS • A total of 31 frozen serum specimens were obtained from specimen logs maintained at New York University Langone Medical Center and the Johns Hopkins University School of Medicine on men who had undergone RP. Those men without evidence of BCR had a minimum of 5 years' PSA follow-up. • In all cases, preoperative and pathological information were available, as was a serum specimen 3-6 months after RP, with a PSA level of <0.1 ng/mL measured by conventional PSA methods at the time of serum collection. • Specimens were tested using the AccuPSA(TM) method. • A Cox proportional hazard model and Kaplan-Meier analysis were used to determine whether AccuPSA(TM) predicted the risk of BCR. RESULTS • Overall, 11/31 (35.5%) men developed BCR. • Mean AccuPSA(TM) nadir levels were significantly different (P < 0.001) between the non-BCR group (2.27 pg/mL) and the BCR group (46.99 pg/mL). • Using a multivariate Cox proportional hazard model, AccuPSA(TM) nadir level was a significant predictor of BCR-free survival (P < 0.01). • Kaplan-Meier analysis of up to 5 years follow-up showed that 100% of men with AccuPSA(TM) nadir values <3 pg/mL did not develop BCR, whereas 62.5% of men with values >3 pg/mL developed BCR (P= 0.00024). • The sensitivity, specificity, positive predictive value and negative predictive value of the AccuPSA(TM) method was 100%, 75%, 69% and 100%, respectively. CONCLUSIONS • AccuPSA(TM) assay predicts 5-year BCR- free survival after RP. • Identifying a reliable predictor of BCR soon after RP has important implications for frequency of PSA testing, selection of candidates for adjuvant therapy, and reassuring a large subset of men that they are not at risk of recurrence. • Larger studies are needed to validate these findings.

Fifth-generation digital immunoassay for prostate-specific antigen by single molecule array technology.

BACKGROUND: Measurement of prostate-specific antigen (PSA) in prostate cancer patients following radical prostatectomy (RP) has been hindered by the limit of quantification of available assays. Because radical prostatectomy removes the tissue responsible for PSA production, postsurgical PSA is typically undetectable with current assay methods. Evidence suggests, however, that more sensitive determination of PSA status following RP could improve assessment of patient prognosis and response to treatment and better target secondary therapy for those who may benefit most. We developed an investigational digital immunoassay with a limit of quantification 2 logs lower than current ultrasensitive third-generation PSA assays. METHODS: We developed reagents for a bead-based ELISA for use with high-density arrays of femtoliter-volume wells. Anti-PSA capture beads with immunocomplexes and associated enzyme labels were singulated within the wells of the arrays and interrogated for the presence of enzymatic product. We characterized analytical performance, compared its accuracy with a commercially available test, and analyzed longitudinal serum samples from a pilot study of 33 RP patients. RESULTS: The assay exhibited a functional sensitivity (20% interassay CV) <0.05 pg/mL, total imprecision <10% from 1 to 50 pg/mL, and excellent agreement with the comparator method. All RP samples were well within the assay measurement capability. PSA concentrations following surgery were found to be predictive of prostate cancer recurrence risk over 5 years. CONCLUSIONS: The robust 2-log improvement in limit of quantification relative to current ultrasensitive assays and the validated analytical performance of the assay allow for accurate assessment of PSA status after RP.

Expanding pediatric orthopaedic trauma volume at a pediatric level 1 trauma hospital.

BACKGROUND: Trauma continues to be the leading cause of morbidity and mortality among children. There is a perception among pediatric orthopaedists that the volume of pediatric orthopaedic trauma care is increasing. We hypothesized that the change in trauma volume was greater than the local and regional population change. METHODS: This retrospective analysis (1996 to 2006) of our institution's trauma registry analyzed changes in general trauma and orthopaedic trauma admissions, surgical volumes, patient and population demographics, and hospital reimbursement. RESULTS: For the decade, the local pediatric population increased annually by only 2% to 3%. During that same period, there was an increase in the proportion of patients treated from outside the immediate county, from 13% in 1996 to 28% in 2006. Total general trauma patient admissions increased at an average of 10% per year from 1996 to 2006, whereas total orthopaedic trauma admissions and orthopaedic trauma admissions requiring operative treatment increased by an annual average of 18%. Orthopaedic trauma admissions as a percentage of total trauma admissions steadily increased from 26% in 1996 to 45% in 2006. During 2005 and 2006, an average total of 1216 orthopaedic trauma cases per year were performed generating an average 10,465 work relative value units per year. Between 1996 and 2005, the hospital's gross charges for pediatric orthopaedic trauma increased by an average of 26% annually; however, the percentage of total charges collected decreased from 67% in 1999 to 28% in 2005. CONCLUSIONS: Pediatric orthopaedic trauma at this level 1 trauma center increased dramatically and more rapidly than the local population over the last decade, increasing the demand for physician and hospital resources. Physicians, hospitals, and the communities they serve face financial and logistical problems of providing care for an expanding volume of pediatric orthopaedic trauma patients with decreasing reimbursements, changing referral patterns and a decreasing population of pediatric orthopaedic specialists. Care of the pediatric orthopaedic trauma patient could become a national crisis. LEVEL OF EVIDENCE: Economic analysis-level III.

Potent activity of indolequinones against human pancreatic cancer: identification of thioredoxin reductase as a potential target.

The indolequinone ES936 {5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione} was previously developed in our lab as an antitumor agent against pancreatic cancer. The objective of this study was to identify indolequinones with improved potency against pancreatic cancer and to define their mechanisms of action. Pancreatic cancer cell lines PANC-1, MIA PaCa-2, and BxPC-3 were used in in vitro assays [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) and clonogenic assays]; indolequinones displayed potent cytotoxicity against all three cell lines, and two specific classes of indolequinone were particularly potent agents. These indolequinones induced caspase-dependent apoptosis but no redox cycling or oxidative stress in MIA PaCa-2 and BxPC-3 cells. Selected indolequinones were also screened against the NCI-60 cell line panel and were found to be particularly effective against colon, renal, and melanoma cancer cells. A potential target of these indolequinones was identified as thioredoxin reductase. Indolequinones were found to be potent inhibitors of thioredoxin reductase activity both in pancreatic cancer cells and in cell-free systems. The mechanism of action of the indolequinones was shown to involve metabolic reduction, loss of a leaving group to generate a reactive electrophile resulting in alkylation of the selenocysteine residue in the active site of thioredoxin reductase. In vivo efficacy of the indolequinones was also tested in the MIA PaCa-2 pancreatic tumor xenograft in nude mice, and lead indolequinones demonstrated high efficacy and low toxicity. Inhibition of thioredoxin reductase represents a potential novel target in pancreatic cancer and may provide a biomarker of effect of lead indolequinones in this type of cancer.

Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma.

The modest response of patients with head and neck squamous cell carcinoma (HNSCC) and non-small cell lung carcinoma (NSCLC) to epithelial growth factor receptor tyrosine kinase inhibitors such as gefitinib and erlotinib indicates the need for the development of biomarkers to predict response. We determined gefitinib sensitivity in a panel of HNSCC cell lines by a 5-day 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and confirmed these responses with analysis of downstream signaling by immunoblotting and cell cycle arrest. Basal gene expression profiles were then determined by microarray analysis and correlated with gefitinib response. These data were combined with previously reported NSCLC microarray results to generate a broader predictive index. Common markers of resistance between the two tumor types included genes associated with the epithelial to mesenchymal transition. We confirmed that increased protein expression of vimentin combined with the loss of E-cadherin, claudin 4, and claudin 7 by immunoblotting was associated with gefitinib resistance in both HNSCC and NSCLC cell lines. In addition, the loss of the Ca(2+)-independent cell-cell adhesion molecules EpCAM and TROP2 in resistant lines was confirmed by immunofluorescence. Tumor xenografts derived from the gefitinib-sensitive UM-SCC-2 were growth-delayed by gefitinib, whereas the gefitinib-resistant 1483 xenografts were unaffected. These data support a role for epithelial to mesenchymal transition in establishing gefitinib resistance for both HNSCC and NSCLC, and indicate that clinical trials should address whether these biomarkers will be useful for patient selection.

Prevention and early detection of ovarian cancer: mission impossible?

Epithelial ovarian cancer is neither a common nor a rare disease. In the United States, the prevalence of ovarian cancer in postmenopausal women (1 in 2,500) significantly affects strategies for prevention and detection. If chemoprevention for ovarian cancer were provided to all women over the age of 50, side effects would have to be minimal in order to achieve an acceptable ratio of benefit to risk. This ratio might be improved by identifying subsets of individuals at increased risk or by bundling prevention of ovarian cancer with treatment for other more prevalent conditions. Approximately 10% of ovarian cancers are familial and relate to mutations of BRCA1, BRCA2, and mismatch repair genes. More subtle genetic factors are being sought in women with apparently sporadic disease. Use of oral contraceptive agents for as long as 5 years decreases the risk of ovarian cancer in later life by 50%. In one study, fenretinide (4-HPR) delayed development of ovarian cancer in women at increased risk of developing breast and ovarian cancer. Accrual to confirmatory studies has been prohibitively slow and prophylactic oophorectomy is recommended for women at increased genetic risk. Vaccines may have a role for prevention of several different cancers. Breast and ovarian cancers express mucins that could serve as targets for vaccines to prevent both cancers. Early detection of ovarian cancer requires a strategy with high sensitivity (> 75% for stage I disease) and very high specificity (> 99.6%) to achieve a positive predictive value of 10%. Transvaginal sonography (TVS) has achieved these values in some studies, but is limited by the cost of annual screening in a general population. Two-stage strategies that incorporate both serum markers and TVS promise to be more cost-effective. An algorithm has been developed that calculates risk of ovarian cancer based on serial CA125 values and refers patients at highest risks for TVS. Use of the algorithm is currently being evaluated in a trial with 200,000 women in the United Kingdom that will critically test the ability of a two-stage screening strategy to improve survival in ovarian cancer. Whatever the outcome, additional serum markers will be required to detect all patients in an initial phase of screening. More than 30 serum markers have been evaluated alone and in combination with CA125. Recent candidates include: HE4, mesothelin, M-CSF, osteopontin, kallikrein(s) and soluble EGF receptor. Proteomic approaches have been used to define a distinctive pattern of peaks on mass spectroscopy or to identify a limited number of critical markers that can be assayed by more conventional methods. Several groups are placing known markers on multiplex platforms to permit simultaneous assay of multiple markers with very small volumes of serum. Mathematical techniques are being developed to analyze combinations of marker levels to improve sensitivity and specificity. In the future, serum markers should improve the sensitivity of detecting recurrent disease as well as facilitate earlier detection of ovarian cancer.

ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, alone and in combination with radiation and chemotherapy as a new therapeutic strategy in non-small cell lung cancer.

The epidermal growth factor receptor is overexpressed in a majority of non-small cell lung cancers and has been associated with a poor prognosis. Preclinical studies have shown that ZD1839, an oral anilinoquinazoline, targets the epidermal growth factor receptor-associated tyrosine kinase, reversibly inhibiting critical downstream signaling and resulting in cancer cell growth arrest. Potent antitumor effects have been observed in human lung tumor xenograft models. Preclinical studies have shown additive to synergistic effects when ZD1839 is combined with radiation or chemotherapy in colon, head and neck, and non-small cell lung cancers. Phase I clinical trials have shown modest dose-related toxicity, and antitumor activity has been reported in a variety of malignancies including lung cancer. Future studies will certainly combine ZD1839 with chemotherapy or radiation. ZD1839 also may be effective as a chemoprevention agent because premalignant lesions often overexpress epidermal growth factor receptor.