Publications by authors named "Linda Ye"

39 Publications

Evidence of two-dimensional flat band at the surface of antiferromagnetic kagome metal FeSn.

Nat Commun 2021 Sep 15;12(1):5345. Epub 2021 Sep 15.

Department of Physics, Massachusetts Institute of Technology, Cambridge, MA, USA.

The kagome lattice has long been regarded as a theoretical framework that connects lattice geometry to unusual singularities in electronic structure. Transition metal kagome compounds have been recently identified as a promising material platform to investigate the long-sought electronic flat band. Here we report the signature of a two-dimensional flat band at the surface of antiferromagnetic kagome metal FeSn by means of planar tunneling spectroscopy. Employing a Schottky heterointerface of FeSn and an n-type semiconductor Nb-doped SrTiO, we observe an anomalous enhancement in tunneling conductance within a finite energy range of FeSn. Our first-principles calculations show this is consistent with a spin-polarized flat band localized at the ferromagnetic kagome layer at the Schottky interface. The spectroscopic capability to characterize the electronic structure of a kagome compound at a thin film heterointerface will provide a unique opportunity to probe flat band induced phenomena in an energy-resolved fashion with simultaneous electrical tuning of its properties. Furthermore, the exotic surface state discussed herein is expected to manifest as peculiar spin-orbit torque signals in heterostructure-based spintronic devices.
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http://dx.doi.org/10.1038/s41467-021-25705-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443682PMC
September 2021

Hospitalizations in solid tumor phase I clinical trial patients: Incidence, pattern and clinical outcomes at an Australian phase I clinical trial unit.

Asia Pac J Clin Oncol 2021 Jun 28. Epub 2021 Jun 28.

Linear Clinical Research, Nedlands, Western Australia, Australia.

Background: Participation in early-phase clinical trials has become a prominent part of medical oncology patient management. We examined the incidence and pattern of hospitalizations in early-phase clinical trial patients and the associated clinical outcomes.

Method: We conducted a retrospective review of 194 patients with solid tumors treated on phase I clinical trials between July 2014 and October 2018 at a phase I trial unit. Unplanned hospitalizations occurring during the study period were characterized and correlated with treatment response and duration of trial participation.

Results: Among 194 patients, 104 hospitalizations were recorded involving 62 patients (31%). Nineteen percent of patients were hospitalized for cancer-related complications and 8% for treatment toxicity. No significant correlation was seen between the hospitalization and age, sex, tumor type, or trial drug. Best response to trial therapy was complete response, partial response, stable disease, and progressive disease in 5%, 11%, 37%, and 47% of patients, respectively. Median duration on trial was 86 days (range 0-1,412). Twenty-two patients (11%) remained on trial for more than 12 months. Overall, hospitalization did not impact treatment response or trial duration. However, cancer-related hospitalization was associated with significantly lower response (p < 0.001) and early patient attrition (p < 0.001). Resolution of the hospitalization event was associated with improved response (p = 0.002) and longer duration on trial (p < 0.001). The treatment related mortality was 0.5% (n = 1).

Conclusion: Approximately one third of patients required hospitalization, most commonly for cancer-related complications which correlated with poorer clinical outcomes. Hospitalizations related to treatment toxicity were infrequent. A significant proportion of patients derived significant therapeutic benefit. Phase I clinical trials provide a valuable treatment option for patients with cancer.
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http://dx.doi.org/10.1111/ajco.13622DOI Listing
June 2021

The Effect of Perioperative Blood Transfusion on Long-Term Survival Outcomes After Surgery for Pancreatic Ductal Adenocarcinoma: A Systematic Review.

Pancreas 2021 May-Jun 01;50(5):648-656

From the Department of Surgery, David Geffen School of Medicine at UCLA.

Objective: To evaluate survival outcomes associated with perioperative allogeneic red blood cell transfusion (RBCT) in patients with pancreatic ductal adenocarcinoma undergoing surgery.

Methods: PubMed, Embase, Cochrane, and Web of Science Core Collection were queried for English-language articles until May 28, 2020. Studies evaluating long-term outcomes of RBCT compared with no transfusion in adults with pancreatic ductal adenocarcinoma undergoing pancreatectomy were included. E-value sensitivity analysis assessed the potential for unmeasured confounders to overcome these findings.

Results: Of 4379 citations, 5 retrospective cohort studies were included. Three studies reported shorter recurrence-free survival by 1 to 5 months with RBCT. Two studies found shorter disease-specific survival by 5 to 13 months with RBCT. Overall survival was reduced by 5 to 7 months with RBCT in 3 studies. All multivariable findings associated with RBCT could be readily overcome unmeasured confounding on sensitivity analysis. Confounding in baseline characteristics resulted in high risk of bias.

Conclusions: Imprecision, unmeasured confounding, small effect sizes, and overall low quality of the available literature result in uncertainty regarding the effect of transfusion on recurrence-free survival, disease-specific survival, and overall survival in patients undergoing surgery for pancreatic cancer. Randomized trials are needed to determine if there is a causal relationship between transfusion and survival after pancreatic resection.
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http://dx.doi.org/10.1097/MPA.0000000000001825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375579PMC
January 2022

Management of Intraductal Papillary Mucinous Neoplasms-Watch and Wait or Operate?

JAMA Surg 2021 Sep;156(9):825-826

Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California.

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http://dx.doi.org/10.1001/jamasurg.2021.0951DOI Listing
September 2021

Direct Effects of Lipopolysaccharide on Human Pancreatic Cancer Cells.

Pancreas 2021 04;50(4):524-528

From the Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Objectives: Obesity, a risk factor for pancreatic adenocarcinoma (PDAC), is often accompanied by a systemic increase in lipopolysaccharide (LPS; metabolic endotoxemia), which is thought to mediate obesity-associated inflammation. However, the direct effects of LPS on PDAC cells are poorly understood.

Methods: The expression of toll-like receptor 4, the receptor for LPS, was confirmed in PDAC cell lines. AsPC-1 and PANC-1 cells were exposed to LPS, and differential gene expression was determined by RNA sequencing. The activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway by LPS in PDAC cells was assessed by Western blotting.

Results: The expression of toll-like receptor 4 was confirmed in all PDAC cell lines. The exposure to LPS led to differential expression of 3083 genes (426 ≥5-fold) in AsPC-1 and 2584 genes (339 ≥5-fold) in PANC-1. A top canonical pathway affected by LPS in both cell lines was PI3K/Akt/mTOR. Western blotting confirmed activation of this pathway as measured by phosphorylation of the ribosomal protein S6 and Akt.

Conclusions: The exposure of PDAC cells to LPS led to differential gene expression. A top canonical pathway was PI3K/Akt/mTOR, a known oncogenic driver. Our findings provided evidence that LPS can directly induce differential gene expression in PDAC cells.
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http://dx.doi.org/10.1097/MPA.0000000000001790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097724PMC
April 2021

Intraoperative and postoperative outcomes of robot-assisted cholecystectomy: a systematic review.

Syst Rev 2021 04 23;10(1):124. Epub 2021 Apr 23.

Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Background: Rapid adoption of robotic-assisted general surgery procedures, particularly for cholecystectomy, continues while questions remain about its benefits and utility. The objective of this study was to compare the clinical effectiveness of robot-assisted cholecystectomy for benign gallbladder disease as compared with the laparoscopic approach.

Methods: A literature search was performed from January 2010 to March 2020, and a narrative analysis was performed as studies were heterogeneous.

Results: Of 887 articles screened, 44 met the inclusion criteria (range 20-735,537 patients). Four were randomized controlled trials, and four used propensity-matching. There were variable comparisons between operative techniques with only 19 out of 44 studies comparing techniques using the same number of ports. Operating room time was longer for the robot-assisted technique in the majority of studies (range 11-55 min for 22 studies, p < 0.05; 15 studies showed no difference; two studies showed shorter laparoscopic times), while conversion rates and intraoperative complications were not different. No differences were detected for the length of stay, surgical site infection, or readmissions. Across studies comparing single-port robot-assisted to multi-port laparoscopic cholecystectomy, there was a higher rate of incisional hernia; however, no differences were noted when comparing single-port robot-assisted to single-port laparoscopic cholecystectomy.

Conclusions: Clinical outcomes were similar for benign, elective gallbladder disease for robot-assisted compared with laparoscopic cholecystectomy. Overall, the rates of complications were low. More high-quality studies are needed as the robot-assisted technique expands to more complex gallbladder disease, where its utility may prove increasingly beneficial.

Systematic Review Registration: PROSPERO CRD42020156945.
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http://dx.doi.org/10.1186/s13643-021-01673-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067374PMC
April 2021

Clinical and Cost Outcomes of Robot-Assisted Inguinal Hernia Repair: A Systematic Review.

J Am Coll Surg 2021 05 23;232(5):746-763.e2. Epub 2021 Mar 23.

Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA; Veterans Health Administration, Greater Los Angeles Healthcare System, Los Angeles, CA; RAND Corporation, Santa Monica, CA; Olive View-UCLA Medical Center, Sylmar, CA.

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http://dx.doi.org/10.1016/j.jamcollsurg.2020.12.066DOI Listing
May 2021

The Current Lung Cancer Neoantigen Landscape and Implications for Therapy.

J Thorac Oncol 2021 06 10;16(6):922-932. Epub 2021 Feb 10.

National Centre for Asbestos Related Diseases, Faculty of Health and Medical Science, The University of Western Australia, Nedlands, Australia; Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Australia.

All tumors harbor unique mutant peptides, some of which are able to elicit T-cell-mediated immune responses. These are known as neoantigens. Lung cancers bear a heavy mutational burden and hence many potential neoantigens. Neoantigens are increasingly recognized as key mediators of tumor-specific immune activation and have been identified as potential targets for personalized cancer therapies. In this review, we discuss the current data on neoantigens in lung cancer and provide an overview of the recent advances in neoantigen-based immunotherapy. Furthermore, we look ahead to highlight the major opportunities and challenges for the clinical application of neoantigen-based treatment strategies for thoracic and other malignancies.
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http://dx.doi.org/10.1016/j.jtho.2021.01.1624DOI Listing
June 2021

Postoperative Physician Phone Calls as a Method to Decrease Urgent Care and Emergency Department Returns After Ambulatory General Surgery.

Am Surg 2020 Oct 25;86(10):1373-1378. Epub 2020 Oct 25.

Southern California Kaiser Permanente Medical Group, Woodland Hills, CA, USA.

Unplanned returns after ambulatory surgery pose a burden to patients and health care providers alike. We hypothesized that a postoperative phone call by a physician would decrease avoidable returns to urgent care (UC) or the emergency department (ED) in the week after anorectal (AR), laparoscopic cholecystectomy (LC), inguinal hernia repair (IHR), and umbilical hernia repair (UHR) operations. A retrospective analysis from 1/2011 to 12/2015 across 14 Kaiser hospitals was conducted to determine baseline UC/ED return rates of patients pre-call. Between 10/2017 and 06/2019, physicians placed phone calls to patients within postoperative days (PODs) 1-4. The cohorts were compared using chi-squared analysis with significance determined at < .05. In total, 276 patients received a call, with the majority placed on PODs 1-3. There were no statistically significant differences in return rates between the pre- and post-call groups. All of the AR, 50.0% of LC, 66.7% of IHR, and 50.0% of UHR patients returned prior to phone call placement. Our data indicate that a physician phone call does not help in decreasing UC/ED returns. However, it is noteworthy that many of the returns occurred pre-call placement. Future directions should be aimed at placing earlier postoperative phone calls.
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http://dx.doi.org/10.1177/0003134820964463DOI Listing
October 2020

Assessing the Burden of Nodal Disease for Breast Cancer Patients with Clinically Positive Nodes: Hope for More Limited Axillary Surgery.

Ann Surg Oncol 2021 May 21;28(5):2609-2618. Epub 2020 Oct 21.

Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Background: Omission of axillary lymph node dissection (ALND) is accepted for patients with one or two positive sentinel nodes, and studies are focusing on clinically node-positive patients who have been downstaged with neoadjuvant chemotherapy (NAC). Evidence is lacking for patients with positive nodes who undergo surgery upfront. These patients are assumed to have a higher burden of nodal disease such that ALND remains the standard of care.

Methods: Patients who underwent ALND for breast cancer between 2010 and 2019 at the authors' institution were retrospectively identified. Those with clinical N1 disease were included in the study. Patients who received NAC and those who had surgery for sentinel node positive disease or axillary recurrence were excluded. Clinical and pathologic factors associated with nodal stage were evaluated.

Results: Of 111 patients who met the inclusion criteria, 61.3% had a palpable node on exam, and 41.4% ultimately had pN1 disease. Most of the tumors were estrogen receptor (ER)-positive (91.5%), and 21.7% of the tumors were invasive lobular cancers. Lobular histology, tumor size, and metastasis size were associated with higher nodal stage. In the multivariable analysis, the patients with nodal metastasis larger than 10 mm had significantly lower odds of having pN1 disease (odds ratio 0.12; 95% confidence interval 0.02-0.69; p = 0.02). In a subset analysis of patients with palpable nodes, tumor size and histology remained significantly associated with nodal stage.

Conclusion: More than 40% of breast cancer patients with clinically positive nodes had minimal nodal disease (pN1) at surgery. Additionally, palpable nodes on exam did not predict higher nodal stage. A subset of patients with clinically positive nodes may be identified who can potentially be spared the morbidity of ALND.
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http://dx.doi.org/10.1245/s10434-020-09228-5DOI Listing
May 2021

BAY61-3606 protects kidney from acute ischemia/reperfusion injury through inhibiting spleen tyrosine kinase and suppressing inflammatory macrophage response.

FASEB J 2020 Sep 15. Epub 2020 Sep 15.

Research Center of Traditional Chinese Medicine and Western Medicine Integration, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China.

Acute kidney injury (AKI) is a highly prevalent clinical syndrome with high mortality and morbidity. Previous studies indicated that inflammation promotes tubular damage and plays a key role in AKI progress. Spleen tyrosine kinase (Syk) has been linked to macrophage-related inflammation in AKI. Up to date, however, no Syk-targeted therapy for AKI has been reported. In this study, we employed both cell model of LPS-induced bone marrow-derived macrophage (BMDM) and mouse model of ischemia/reperfusion injury (IRI)-induced AKI to evaluate the effects of a Syk inhibitor, BAY61-3606 (BAY), on macrophage inflammation in vitro and protection of kidney from AKI in vivo. The expression and secretion of inflammatory cytokines, both in vitro and in vivo, were significantly inhibited even back to normal levels by BAY. The upregulated serum creatinine and blood urea nitrogen levels in the AKI mice were significantly reduced after administration of BAY, implicating a protective effect of BAY on kidneys against IRI. Further analyses from Western blot, immunofluorescence staining and flow cytometry revealed that BAY inhibited the Mincle/Syk/NF-κB signaling circuit and reduced the inflammatory response. BAY also inhibited the reactive oxygen species (ROS), which further decreased the formation of inflammasome and suppressed the mature of IL-1β and IL-18. Notably, these inhibitory effects of BAY on inflammation and inflammasome in BMDM were significantly reversed by Mincle ligand, trehalose-6,6-dibehenate. In summary, these findings provided compelling evidence that BAY may be an efficient inhibitor of the Mincle/Syk/NF-κB signaling circuit and ROS-induced inflammasome, which may help to develop Syk-inhibitors as novel therapeutic agents for AKI.
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http://dx.doi.org/10.1096/fj.202000261RRRDOI Listing
September 2020

Topological flat bands in frustrated kagome lattice CoSn.

Nat Commun 2020 Aug 10;11(1):4004. Epub 2020 Aug 10.

Department of Physics, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

Electronic flat bands in momentum space, arising from strong localization of electrons in real space, are an ideal stage to realize strongly-correlated phenomena. Theoretically, the flat bands can naturally arise in certain geometrically frustrated lattices, often with nontrivial topology if combined with spin-orbit coupling. Here, we report the observation of topological flat bands in frustrated kagome metal CoSn, using angle-resolved photoemission spectroscopy and band structure calculations. Throughout the entire Brillouin zone, the bandwidth of the flat band is suppressed by an order of magnitude compared to the Dirac bands originating from the same orbitals. The frustration-driven nature of the flat band is directly confirmed by the chiral d-orbital texture of the corresponding real-space Wannier functions. Spin-orbit coupling opens a large gap of 80 meV at the quadratic touching point between the Dirac and flat bands, endowing a nonzero Z invariant to the flat band. These findings demonstrate that kagome-derived flat bands are a promising platform for novel emergent phases of matter at the confluence of strong correlation and topology.
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http://dx.doi.org/10.1038/s41467-020-17465-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417556PMC
August 2020

Should All Patients With Pancreatic Cancer Receive Chemotherapy Before Surgery?

JAMA Surg 2020 09;155(9):840

Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles.

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http://dx.doi.org/10.1001/jamasurg.2020.2302DOI Listing
September 2020

Detection of Low-level EGFR c.2369 C > T (p.Thr790Met) Resistance Mutation in Pre-treatment Non-small Cell Lung Carcinomas Harboring Activating EGFR Mutations and Correlation with Clinical Outcomes.

Pathol Oncol Res 2020 Oct 6;26(4):2371-2379. Epub 2020 Jun 6.

Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.

Increasing evidence points to the presence of low-level de novo T790M mutations in patients with non-small cell lung carcinoma (NSCLC) harboring activating EGFR mutations. We utilized digital PCR (dPCR), a highly sensitive gene mutation detection method, to detect pre-treatment T790M mutations in NSCLC tumor samples and correlated the T790M status with clinical features and patient outcomes. DNA extracted from pre-treatment NSCLC tumor tissue with known activating EGFR mutations, diagnosed between October 2010 and May 2017 at PathWest laboratory, was used to perform targeted dPCR for quantitative detection of T790M mutations. T790M was detected in 42 of 109 pre-treatment samples (38.5%). Median variant allele frequency was 0.14% (range 0.02-28.5%). Overall response rate to first generation EGFR tyrosine kinase inhibitors (TKI) was 67% regardless of T790M status. The median progression free survival was 10.7 (IQR 5.6-19.9) versus 6.7 (IQR 3.5-20.8) months in T790M negative and positive patients respectively. T790M positivity correlated with increased rate of early disease progression. It also correlated with increased mortality (HR 3.1 95%CI 1.2-8.1, p = 0.022) in patients who did not respond to TKI treatment. We detected a significant rate of low-level pre-treatment T790M mutations in NSCLC using highly sensitive dPCR. Low-level pre-treatment T790M did not impact treatment response rate or overall survival, but was associated with increased rate of early progression on TKI therapy.
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http://dx.doi.org/10.1007/s12253-020-00833-zDOI Listing
October 2020

Dirac fermions and flat bands in the ideal kagome metal FeSn.

Nat Mater 2020 Feb 9;19(2):163-169. Epub 2019 Dec 9.

Department of Physics, Massachusetts Institute of Technology, Cambridge, MA, USA.

A kagome lattice of 3d transition metal ions is a versatile platform for correlated topological phases hosting symmetry-protected electronic excitations and magnetic ground states. However, the paradigmatic states of the idealized two-dimensional kagome lattice-Dirac fermions and flat bands-have not been simultaneously observed. Here, we use angle-resolved photoemission spectroscopy and de Haas-van Alphen quantum oscillations to reveal coexisting surface and bulk Dirac fermions as well as flat bands in the antiferromagnetic kagome metal FeSn, which has spatially decoupled kagome planes. Our band structure calculations and matrix element simulations demonstrate that the bulk Dirac bands arise from in-plane localized Fe-3d orbitals, and evidence that the coexisting Dirac surface state realizes a rare example of fully spin-polarized two-dimensional Dirac fermions due to spin-layer locking in FeSn. The prospect to harness these prototypical excitations in a kagome lattice is a frontier of great promise at the confluence of topology, magnetism and strongly correlated physics.
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http://dx.doi.org/10.1038/s41563-019-0531-0DOI Listing
February 2020

Reforming Views About Residency Duty Hour Reform.

Ann Surg 2020 04;271(4):606-607

Department of Surgery, David Geffen School of Medicine at UCLA, , Los Angeles, CA.

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http://dx.doi.org/10.1097/SLA.0000000000003715DOI Listing
April 2020

de Haas-van Alphen effect of correlated Dirac states in kagome metal FeSn.

Nat Commun 2019 10 25;10(1):4870. Epub 2019 Oct 25.

Department of Physics, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

Primarily considered a medium of geometric frustration, there has been a growing recognition of the kagome network as a harbor of lattice-borne topological electronic phases. In this study we report the observation of magnetoquantum de Haas-van Alphen oscillations of the ferromagnetic kagome lattice metal FeSn. We observe a pair of quasi-two-dimensional Fermi surfaces arising from bulk massive Dirac states and show that these band areas and effective masses are systematically modulated by the rotation of the ferromagnetic moment. Combined with measurements of Berry curvature induced Hall conductivity, our observations suggest that the ferromagnetic Dirac fermions in FeSn are subject to intrinsic spin-orbit coupling in the d electron sector which is likely of Kane-Mele type. Our results provide insights for spintronic manipulation of magnetic topological electronic states and pathways to realizing further highly correlated topological materials from the lattice perspective.
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http://dx.doi.org/10.1038/s41467-019-12822-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814717PMC
October 2019

Immunotherapy strategies for mesothelioma - the role of tumor specific neoantigens in a new era of precision medicine.

Expert Rev Respir Med 2019 02 30;13(2):181-192. Epub 2018 Dec 30.

b National Centre for Asbestos Related Disease , University of Western Australia , Nedlands , Australia.

Introduction: Immunotherapy has long been considered a potential therapy for malignant mesothelioma and is currently being pursued as such. Some of the early phase clinical trials involving immunomodulators have demonstrated encouraging results and numerous clinical trials are underway to further investigate this treatment approach in various treatment settings and larger patient cohorts. Areas covered: This review summarizes the current and emerging clinical evidence for checkpoint blockade and other immunotherapeutic strategies in mesothelioma. The mesothelioma tumor immune microenvironment and mutational landscape are also discussed, including their impact on treatment strategies. We also provide an evaluation of the current evidence for neoantigen targeted personalized immunotherapy. Expert opinion: Immune checkpoint inhibitors work by unleashing the host immune response against probable neoantigens. Despite impressive activity in a small subset of patients and the potential for prolonged responses, most patients experience treatment failure. Neoantigen vaccines provide a potential complementary therapeutic strategy by increasing the immunogenic antigen load, which can lead to an increased tumor specific immune response. Further research is needed explore this treatment option in mesothelioma and technological advances are required to translate this concept into clinical practice.
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http://dx.doi.org/10.1080/17476348.2019.1563488DOI Listing
February 2019

Programmed death ligand-1 expression in non-small cell lung cancer in a Western Australian population and correlation with clinicopathologic features.

Mod Pathol 2019 04 6;32(4):524-531. Epub 2018 Nov 6.

Sir Charles Gairdner Hospital, Perth, WA, Australia.

Immune checkpoint inhibition is an important therapeutic option in patients with non-small cell lung cancer. Programmed cell death ligand-1 (PD-L1) expression may serve as a predictive marker for anti-PD-1/PD-L1 therapies. The relationship between non-small cell lung cancer PD-L1 expression and clinicopathological characteristics remains unclear and there is no population level Australian data. We report the results of PD-L1 testing in patients with non-small cell lung cancer diagnosed at major Western Australian public hospitals served by a single state Pathology provider. We analyzed PD-L1 expression by immunohistochemistry in 241 non-small cell lung cancer specimens using the 22C3 clone on a Dako autostainer platform. Tumor cell PD-L1 expression was scored as Tumor Proportion Score and categorized using pre-specified subsets of  1%, 1-49% and  ≥  50% for correlation with clinicopathologic features. PD-L1 Tumor Proportion Score was  1% in 65 (27%) cases, 1-49% in 100 (41%) cases and  ≥  50% in 76 (32%) cases. PD-L1-positive rate was 92% in squamous cell carcinomas and 67% in adenocarcinomas. PD-L1 Tumor Proportion Score was higher in squamous cell carcinomas (p  =  0.004) and lower in adenocarcinomas (p  =  0.003). Of the 196 non-squamous carcinomas, 35% had rat sarcoma viral oncogene homolog (RAS) mutations, 13% had epidermal growth factor receptor (EGFR) mutations, 2% had anaplastic lymphoma kinase (ALK) translocations and 2% had ROS1 translocations. Tumor Proportion Score  ≥  50% was seen in 34% (23/68), 28% (7/25) and 25% (1/4) of RAS, EGFR mutant, and ALK translocated carcinomas, respectively. There was no significant correlation between PD-L1 expression and molecular or genetic abnormalities, or other parameters including age, gender, stage, and smoking status. In our patient cohort, PD-L1 Tumor Proportion Score was significantly higher in squamous cell carcinomas and lower in adenocarcinomas. The overall prevalence of Tumor Proportion Score  ≥  50% is consistent with that reported in clinical trials.
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http://dx.doi.org/10.1038/s41379-018-0173-9DOI Listing
April 2019

Ultrafast manipulation of mirror domain walls in a charge density wave.

Sci Adv 2018 10 19;4(10):eaau5501. Epub 2018 Oct 19.

Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Domain walls (DWs) are singularities in an ordered medium that often host exotic phenomena such as charge ordering, insulator-metal transition, or superconductivity. The ability to locally write and erase DWs is highly desirable, as it allows one to design material functionality by patterning DWs in specific configurations. We demonstrate such capability at room temperature in a charge density wave (CDW), a macroscopic condensate of electrons and phonons, in ultrathin 1-TaS. A single femtosecond light pulse is shown to locally inject or remove mirror DWs in the CDW condensate, with probabilities tunable by pulse energy and temperature. Using time-resolved electron diffraction, we are able to simultaneously track anti-synchronized CDW amplitude oscillations from both the lattice and the condensate, where photoinjected DWs lead to a red-shifted frequency. Our demonstration of reversible DW manipulation may pave new ways for engineering correlated material systems with light.
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http://dx.doi.org/10.1126/sciadv.aau5501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195337PMC
October 2018

Massive Dirac fermions in a ferromagnetic kagome metal.

Nature 2018 03 19;555(7698):638-642. Epub 2018 Mar 19.

Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

The kagome lattice is a two-dimensional network of corner-sharing triangles that is known to host exotic quantum magnetic states. Theoretical work has predicted that kagome lattices may also host Dirac electronic states that could lead to topological and Chern insulating phases, but these states have so far not been detected in experiments. Here we study the d-electron kagome metal FeSn, which is designed to support bulk massive Dirac fermions in the presence of ferromagnetic order. We observe a temperature-independent intrinsic anomalous Hall conductivity that persists above room temperature, which is suggestive of prominent Berry curvature from the time-reversal-symmetry-breaking electronic bands of the kagome plane. Using angle-resolved photoemission spectroscopy, we observe a pair of quasi-two-dimensional Dirac cones near the Fermi level with a mass gap of 30 millielectronvolts, which correspond to massive Dirac fermions that generate Berry-curvature-induced Hall conductivity. We show that this behaviour is a consequence of the underlying symmetry properties of the bilayer kagome lattice in the ferromagnetic state and the atomic spin-orbit coupling. This work provides evidence for a ferromagnetic kagome metal and an example of emergent topological electronic properties in a correlated electron system. Our results provide insight into the recent discoveries of exotic electronic behaviour in kagome-lattice antiferromagnets and may enable lattice-model realizations of fractional topological quantum states.
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http://dx.doi.org/10.1038/nature25987DOI Listing
March 2018

RNA-binding protein Rbpms is represented in human retinas by isoforms A and C and its transcriptional regulation involves Sp1-binding site.

Mol Genet Genomics 2018 Aug 8;293(4):819-830. Epub 2018 Feb 8.

Jules Stein Eye Institute, UCLA School of Medicine, 100 Stein Plaza, Los Angeles, CA, 90095, USA.

Rbpms (RNA-binding protein with multiple splicing) is a member of the RRM (RNA Recognition Motif) family of RNA-binding proteins, which is expressed as multiple alternatively spliced transcripts encoding different protein isoforms. We have shown earlier that Rbpms expression in the retina is restricted to retinal ganglion cells (RGCs), and have characterized this gene as a marker for RGCs. The aim of this study was to identify isoforms representing Rbpms in human retinas and to analyze its transcriptional regulation. We found that Rbpms is expressed as transcription variants 1 and 3 encoding isoforms A and C, respectively. These isoforms are encoded by the same first 6 exons but have different C-terminal ends encoded by exon 8 in variant 1 and exon 7 in variant 3. Computational analysis of the Rbpms 5' untranslated and flanking regions reveals the presence of three CpG islands and four predicted promoter regions (PPRs). The effect of PPR 1 (- 1672/- 1420) and PPR2 (- 330/- 79) on transcriptional activation was minimal, whereas PPR 3 (- 73/+ 177) and PPR4 (+ 274/+ 524) induced the expression by ~ 7 and ninefold compared to control, respectively. The maximum activity, a 30-fold increase above the control level, was obtained from the construct containing both PPRs 3 and 4. Site-directed mutagenesis of several cis-elements within PPR3 and PPR4 including five for Sp1, one for AP1, and two for NF-kB showed that mutation of the first three and especially the first GC box resulted in a threefold downregulation of gene expression. AP1, NF-kB, and two downstream Sp1 sites had no significant effect on expression level. The possible involvement of the GC box 1 at position - 54 in transcriptional regulation of Rbpms was corroborated by EMSA, which showed formation of a DNA-protein complex in the presence of the oligonucleotide corresponding to this Sp1-binding site.
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http://dx.doi.org/10.1007/s00438-018-1423-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033630PMC
August 2018

Heart-specific overexpression of the human short CLC-3 chloride channel isoform limits myocardial ischemia-induced ERP and QT prolongation.

Int J Cardiol 2016 Jul 30;214:218-24. Epub 2016 Mar 30.

Laboratory of Cardiovascular Phenomics, University of Nevada School of Medicine, Reno, NV 89557-0318, USA; Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557-0318, USA. Electronic address:

Introduction: Ischemia causes myocardial infarction and arrhythmias. Up-regulation of cardiac CLC-3 chloride channels is important for ischemic preconditioning-induced second-window protection against myocardial infarction. But its consequences in ischemia-induced electrical remodeling are still unknown.

Methods: The recently-characterized heart-specific overexpression of human short CLC-3 isoform (hsCLC-3(OE)) mice was used to study the effects of CLC-3 up-regulation on cardiac electrophysiology under ischemia/reperfusion conditions. In vivo surface electrocardiography (ECG) and intracardiac electrophysiology (ICEP) were used to compare the electrophysiological properties of age-matched wild-type (Clcn3(+/+)) and hsCLC-3(OE) mice under control and myocardial ischemia-reperfusion conditions.

Results: QT and QTc intervals of hsCLC-3(OE) mice were significantly shorter than those of Clcn3(+/+) mice under control, ischemia and reperfusion conditions. In the ICEP, ventricular effective refractory period (VERP) of hsCLC-3(OE) mice (26.7±1.7ms, n=6) was significantly shorter than that of Clcn3(+/+) mice (36.9±2.8ms, n=8, P<0.05). Under ischemia condition, both VERP (19.8±1.3ms) and atrial effective refractory period (AERP, 34.8±2.5ms) of hsCLC-3(OE) mice were significantly shorter than those of Clcn3(+/+) mice (35.2±3.0ms and 45.8±1.6ms, P<0.01, respectively). Wenckebach atrioventricular nodal block point (AVBP, 91.13±4.08ms) and 2:1 AVBP (71.3±3.8ms) of hsCLC-3(OE) mice were significantly shorter than those of Clcn3(+/+) mice (102.0±2.0ms and 84.1±2.8ms, P<0.05, respectively). However, no differences of ICEP parameters between hsCLC-3(OE) and Clcn3(+/+) mice were observed under reperfusion conditions.

Conclusion: Heart-specific overexpression of hsCLC-3 limited the ischemia-induced QT and ERP prolongation and postponed the advancements of Wenckebach and 2:1 AVBP. CLC-3 up-regulation may serve as an important adaptive mechanism against myocardial ischemia.
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http://dx.doi.org/10.1016/j.ijcard.2016.03.191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862918PMC
July 2016

Phenomics of Vascular Disease: The Systematic Approach to the Combination Therapy.

Curr Vasc Pharmacol 2015 ;13(4):433-40

Laboratory of Cardiovascular Phenomics, Department of Pharmacology, University of Nevada School of Medicine, Center for Molecular Medicine 303F, 1664 N Virginia Street/MS 318, Reno, Nevada 89557-0318, USA.

Vascular diseases are usually caused by multifactorial pathogeneses involving genetic and environmental factors. Our current understanding of vascular disease is, however, based on the focused genotype/phenotype studies driven by the "one-gene/one-phenotype" hypothesis. Drugs with "pure target" at individual molecules involved in the pathophysiological pathways are the mainstream of current clinical treatments and the basis of combination therapy of vascular diseases. Recently, the combination of genomics, proteomics, and metabolomics has unraveled the etiology and pathophysiology of vascular disease in a big-data fashion and also revealed unmatched relationships between the omic variability and the much narrower definition of various clinical phenotypes of vascular disease in individual patients. Here, we introduce the phenomics strategy that will change the conventional focused phenotype/genotype/genome study to a new systematic phenome/genome/proteome approach to the understanding of pathophysiology and combination therapy of vascular disease. A phenome is the sum total of an organism's phenotypic traits that signify the expression of genome and specific environmental influence. Phenomics is the study of phenome to quantitatively correlate complex traits to variability not only in genome, but also in transcriptome, proteome, metabolome, interactome, and environmental factors by exploring the systems biology that links the genomic and phenomic spaces. The application of phenomics and the phenome-wide associated study (PheWAS) will not only identify a systemically-integrated set of biomarkers for diagnosis and prognosis of vascular disease but also provide novel treatment targets for combination therapy and thus make a revolutionary paradigm shift in the clinical treatment of these devastating diseases.
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http://dx.doi.org/10.2174/1570161112666141014144829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397150PMC
May 2016

Prolyl hydroxylase domain protein 2 silencing enhances the survival and paracrine function of transplanted adipose-derived stem cells in infarcted myocardium.

Circ Res 2013 Jul 21;113(3):288-300. Epub 2013 May 21.

Department of Cardiology, Daping Hospital.

Rationale: Transplantation of stem cells into damaged hearts has had modest success as a treatment for ischemic heart disease. One of the limitations is the poor stem cell survival in the diseased microenvironment. Prolyl hydroxylase domain protein 2 (PHD2) is a cellular oxygen sensor that regulates 2 key transcription factors involved in cell survival and inflammation: hypoxia-inducible factor and nuclear factor-κB.

Objective: We studied whether and how PHD2 silencing in human adipose-derived stem cells (ADSCs) enhances their cardioprotective effects after transplantation into infarcted hearts.

Methods And Results: ADSCs were transduced with lentiviral short hairpin RNA against prolyl hydroxylase domain protein 2 (shPHD2) to silence PHD2. ADSCs, with or without shPHD2, were transplanted after myocardial infarction in mice. ADSCs reduced cardiomyocyte apoptosis, fibrosis, and infarct size and improved cardiac function. shPHD2-ADSCs exerted significantly more protection. PHD2 silencing induced greater ADSC survival, which was abolished by short hairpin RNA against hypoxia-inducible factor-1α. Conditioned medium from shPHD2-ADSCs decreased cardiomyocyte apoptosis. Insulin-like growth factor-1 (IGF-1) levels were significantly higher in the conditioned medium of shPHD2-ADSCs versus ADSCs, and depletion of IGF-1 attenuated the cardioprotective effects of shPHD2-ADSC-conditioned medium. Nuclear factor-κB activation was induced by shPHD2 to induce IGF-1 secretion via binding to IGF-1 gene promoter.

Conclusions: PHD2 silencing promotes ADSCs survival in infarcted hearts and enhances their paracrine function to protect cardiomyocytes. The prosurvival effect of shPHD2 on ADSCs is hypoxia-inducible factor-1α dependent, and the enhanced paracrine function of shPHD2-ADSCs is associated with nuclear factor-κB-mediated IGF-1 upregulation. PHD2 silencing in stem cells may be a novel strategy for enhancing the effectiveness of stem cell therapy after myocardial infarction.
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http://dx.doi.org/10.1161/CIRCRESAHA.113.300929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744216PMC
July 2013

Impact of primary elvitegravir resistance-associated mutations in HIV-1 integrase on drug susceptibility and viral replication fitness.

Antimicrob Agents Chemother 2013 Jun 25;57(6):2654-63. Epub 2013 Mar 25.

Gilead Sciences, Inc, Foster City, California, USA.

Elvitegravir (EVG) is an effective HIV-1 integrase (IN) strand transfer inhibitor (INSTI) in advanced clinical development. Primary INSTI resistance-associated mutations (RAMs) at six IN positions have been identified in HIV-1-infected patients failing EVG-containing regimens in clinical studies: T66I/A/K, E92Q/G, T97A, S147G, Q148R/H/K, and N155H. In this study, the effect of these primary IN mutations, alone and in combination, on susceptibility to the INSTIs EVG, raltegravir (RAL), and dolutegravir (DTG); IN enzyme activities; and viral replication fitness was characterized. Recombinant viruses containing the six most common mutations exhibited a range of reduced EVG susceptibility: 92-fold for Q148R, 30-fold for N155H, 26-fold for E92Q, 10-fold for T66I, 4-fold for S147G, and 2-fold for T97A. Less commonly observed primary IN mutations also showed a range of reduced EVG susceptibilities: 40- to 94-fold for T66K and Q148K and 5- to 10-fold for T66A, E92G, and Q148H. Some primary IN mutations exhibited broad cross-resistance between EVG and RAL (T66K, E92Q, Q148R/H/K, and N155H), while others retained susceptibility to RAL (T66I/A, E92G, T97A, and S147G). Dual combinations of primary IN mutations further reduced INSTI susceptibility, replication capacity, and viral fitness relative to either mutation alone. Susceptibility to DTG was retained by single primary IN mutations but reduced by dual mutation combinations with Q148R. Primary EVG RAMs also diminished IN enzymatic activities, concordant with their structural proximity to the active site. Greater reductions in viral fitness of dual mutation combinations may explain why some primary INSTI RAMs do not readily coexist on the same HIV-1 genome but rather establish independent pathways of resistance to EVG.
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http://dx.doi.org/10.1128/AAC.02568-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3716146PMC
June 2013

Increased TMEM16A-encoded calcium-activated chloride channel activity is associated with pulmonary hypertension.

Am J Physiol Cell Physiol 2012 Dec 3;303(12):C1229-43. Epub 2012 Oct 3.

Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada 89557-0573, USA.

Pulmonary artery smooth muscle cells (PASMCs) are more depolarized and display higher Ca(2+) levels in pulmonary hypertension (PH). Whether the functional properties and expression of Ca(2+)-activated Cl- channels (Cl(Ca)), an important excitatory mechanism in PASMCs, are altered in PH is unknown. The potential role of Cl(Ca) channels in PH was investigated using the monocrotaline (MCT)-induced PH model in the rat. Three weeks postinjection with a single dose of MCT (50 mg/kg ip), the animals developed right ventricular hypertrophy (heart weight measurements) and changes in pulmonary arterial flow (pulse-waved Doppler imaging) that were consistent with increased pulmonary arterial pressure and PH. Whole cell patch experiments revealed an increase in niflumic acid (NFA)-sensitive Ca(2+)-activated Cl(-) current [I(Cl(Ca))] density in PASMCs from large conduit and small intralobar pulmonary arteries of MCT-treated rats vs. aged-matched saline-injected controls. Quantitative RT-PCR and Western blot analysis revealed that the alterations in I(Cl(Ca)) were accompanied by parallel changes in the expression of TMEM16A, a gene recently shown to encode for Cl(Ca) channels. The contraction to serotonin of conduit and intralobar pulmonary arteries from MCT-treated rats exhibited greater sensitivity to nifedipine (1 μM), an l-type Ca(2+) channel blocker, and NFA (30 or 100 μM, with or without 10 μM indomethacin to inhibit cyclooxygenases) or T16A(Inh)-A01 (10 μM), TMEM16A/Cl(Ca) channel inhibitors, than that of control animals. In conclusion, augmented Cl(Ca)/TMEM16A channel activity is a major contributor to the changes in electromechanical coupling of PA in this model of PH. TMEM16A-encoded channels may therefore represent a novel therapeutic target in this disease.
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http://dx.doi.org/10.1152/ajpcell.00044.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532492PMC
December 2012

Activation of volume regulated chloride channels protects myocardium from ischemia/reperfusion damage in second-window ischemic preconditioning.

Cell Physiol Biochem 2011 16;28(6):1265-78. Epub 2011 Dec 16.

Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada 89557-0318, USA.

Activation of volume regulated chloride channels (VRCCs) has been shown to be cardioprotective in ischemic preconditioning (IPC) of isolated hearts but the underlying molecular mechanisms remain unclear. Recent independent studies support that ClC-3, a ClC voltage-gated chloride channel, may function as a key component of the VRCCs. Thus, ClC-3 knockout (Clcn3(-/-)) mice and their age-matched heterozygous (Clcn3(+/-)) and wild-type (Clcn3(+/+)) littermates were used to test whether activation of VRCCs contributes to cardioprotection in early and/or second-window IPC. Targeted disruption of ClC-3 gene caused a decrease in the body weight but no changes in heart/body weight ratio. Telemetry ECG and echocardiography revealed no differences in ECG and cardiac function under resting conditions among all groups. Under treadmill stress (10 m/min for 10 min), the Clcn3(-/-) mice had significant slower heart rate (648±12 bpm) than Clcn3(+/+) littermates (737±19 bpm, n=6, P<0.05). Ex vivo IPC in the isolated working-heart preparations protected cardiac function during reperfusion and significantly decreased apoptosis and infarct size in all groups. In vivo early IPC significantly reduced infarct size in all groups including Clcn3(-/-) mice (22.7±3.7% vs control 40.1±4.3%, n=22, P=0.004). Second-window IPC significantly reduced apoptosis and infarction in Clcn3(+/+) (22.9±3.2% vs 45.7±5.4%, n=22, P<0.001) and Clcn3(+/-) mice (27.5±4.1% vs 42.2±5.7%, n=15, P<0.05) but not in Clcn3(-/-) littermates (39.8±4.9% vs 41.5±8.2%, n=13, P>0.05). Impaired cell volume regulation of the Clcn3(-/-) myocytes may contribute to the failure of cardioprotection by second-window IPC. These results strongly support that activation of VRCCs may play an important cardioprotective role in second-window IPC.
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http://dx.doi.org/10.1159/000335858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709186PMC
April 2012

Characterization of a critical role for CFTR chloride channels in cardioprotection against ischemia/reperfusion injury.

Acta Pharmacol Sin 2011 Jun;32(6):824-33

Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.

Aim: To further characterize the functional role of cystic fibrosis transmembrane conductance regulator (CFTR) in early and late (second window) ischemic preconditioning (IPC)- and postconditioning (POC)-mediated cardioprotection against ischemia/reperfusion (I/R) injury.

Methods: CFTR knockout (CFTR(-/-)) mice and age- and gender-matched wild-type (CFTR(+/+)) and heterozygous (CFTR(+/-)) mice were used. In in vivo studies, the animals were subjected to a 30-min coronary occlusion followed by a 40-min reperfusion. In ex vivo (isolate heart) studies, a 45-min global ischemia was applied. To evaluate apoptosis, the level of activated caspase 3 and TdT-mediated dUTP-X nick end labeling (TUNEL) were examined.

Results: In the in vivo I/R models, early IPC significantly reduced the myocardial infarct size in wild-type (CFTR(+/+)) (from 40.4% ± 5.3% to 10.4% ± 2.0%, n=8, P<0.001) and heterozygous (CFTR(+/-)) littermates (from 39.4% ± 2.4% to 15.4% ± 5.1%, n=6, P<0.001) but failed to protect CFTR knockout (CFTR(-/-)) mice from I/R induced myocardial infarction (46.9% ± 6.2% vs 55.5% ± 7.8%, n=6, P>0.5). Similar results were observed in the in vivo late IPC experiments. Furthermore, in both in vivo and ex vivo I/R models, POC significantly reduced myocardial infarction in wild-type mice, but not in CFTR knockout mice. In ex vivo I/R models, targeted inactivation of CFTR gene abolished the protective effects of IPC against I/R-induced apoptosis.

Conclusion: These results provide compelling evidence for a critical role for CFTR Cl(-) channels in IPC- and POC-mediated cardioprotection against I/R-induced myocardial injury.
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http://dx.doi.org/10.1038/aps.2011.61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217336PMC
June 2011
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