Thyroid Hormone Levels Correlate With the Maturation of Implanted Pancreatic Endoderm Cells in Patients With Type 1 Diabetes.

BACKGROUND: Macroencapsulated pancreatic endoderm cells (PECs) can reverse diabetes in rodents and preclinical studies revealed that thyroid hormones in vitro and in vivo bias PECs to differentiate into insulin-producing cells. In an ongoing clinical trial, PECs implanted in macroencapsulation devices into patients with type 1 diabetes were safe but yielded heterogeneous outcomes. Though most patients developed meal responsive C-peptide, levels were heterogeneous and explanted grafts had variable numbers of surviving cells with variable distribution of endocrine cells. METHODS: We measured circulating triiodothyronine and thyroxine levels in all patients treated at 1 of the 7 sites of the ongoing clinical trial and determined if thyroid hormone levels were associated with the C-peptide or glucagon levels and cell fate of implanted PECs. RESULTS: Both triiodothyronine and thyroxine levels were significantly associated with the proportion of cells that adopted an insulin-producing fate with a mature phenotype. Thyroid hormone levels were inversely correlated to circulating glucagon levels after implantation, suggesting that thyroid hormones lead PECs to favor an insulin-producing fate over a glucagon-producing fate. In mice, hyperthyroidism led to more rapid maturation of PECs into insulin-producing cells similar in phenotype to PECs in euthyroid mice. CONCLUSION: These data highlight the relevance of thyroid hormones in the context of PEC therapy in patients with type 1 diabetes and suggest that a thyroid hormone adjuvant therapy may optimize cell outcomes in some PEC recipients.

Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes.

An open-label, first-in-human phase 1/2 study is being conducted to evaluate the safety and efficacy of pancreatic endoderm cells (PECs) implanted in non-immunoprotective macroencapsulation devices for the treatment of type 1 diabetes. We report an analysis on 1 year of data from the first cohort of 15 patients from a single trial site that received subcutaneous implantation of cell products combined with an immunosuppressive regimen. Implants were well tolerated with no teratoma formation or severe graft-related adverse events. After implantation, patients had increased fasting C-peptide levels and increased glucose-responsive C-peptide levels and developed mixed meal-stimulated C-peptide secretion. There were immunosuppression-related transient increases in circulating regulatory T cells, PD1high T cells, and IL17A+CD4+ T cells. Explanted grafts contained cells with a mature ß cell phenotype that were immunoreactive for insulin, islet amyloid polypeptide, and MAFA. These data, and associated findings (Shapiro et al., 2021), are the first reported evidence of meal-regulated insulin secretion by differentiated stem cells in patients.

The role of mitochondrial apoptotic pathway in islet amyloid-induced ß-cell death.

Islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), contributes to ß-cell death in type 2 diabetes. We previously showed that extracellular hIAPP aggregates promote Fas-mediated ß-cell apoptosis. Here, we tested if hIAPP aggregates can trigger the mitochondrial apoptotic pathway (MAP). hIAPP aggregation in Ad-hIAPP transduced INS-1 and human islet ß-cells promoted cytochrome c release, caspase-9 activation and apoptosis, which were reduced by Bax inhibitor. Amyloid formation in hIAPP-expressing mouse islets during culture increased caspase-9 activation in ß-cells. Ad-hIAPP transduced islets from CytcKA/KA and BaxBak ßDKO mice (models of blocked MAP), had lower caspase-9-positive and apoptotic ß-cells than transduced wild-type islets, despite comparable amyloid formation. Blocking Fas (markedly) and Bax or caspase-9 (modestly) reduced ß-cell death induced by extracellular hIAPP aggregates. These findings suggest a role for MAP in amyloid-induced ß-cell death and a potential strategy to reduce intracellular amyloid ß-cell toxicity by blocking cytochrome c apoptotic function.

The Teacher-Learner Contract (TLC): An Objectives-Based Checklist for Surgical Shadowing.

OBJECTIVE: A lack of structure and communication in physician shadowing experiences may prevent medical students from accruing its potential benefits. In this study, we evaluated the use of an objectives-based surgical shadowing teacher-learner contract (TLC) on the outcomes of shadowing experiences. DESIGN: Cross-sectional study with 30 unique student-surgeon pairs who participated in a 1-time shadowing experience between December 2016 and May 2017. SETTING: Eight hospitals and clinics in Metro Vancouver, British Columbia, Canada. PARTICIPANTS: A convenience sample of preclinical medical students attending University of British Columbia and local surgeons from a variety of specialties were recruited by email. A random sample of 30 students was selected from a pool of interested students. RESULTS: Twenty-eight students and 18 surgeons completed the study. In general, students and surgeons reported that the TLC focused learning and improved communication between teachers and learners. Students also commented that using the TLC prompted them to reflect on their goals and consider how the shadowing experience might contribute to their overall medical education. Both students and surgeons found benefit in using the checklist (mean 3.5 ± 0.75 and mean 3.8 ± 1.1, respectively, where 1 was not useful and 5 was very useful). All participants rated the TLC as easy to use (mean 1.429 ± 1.271 and mean 1.333 ± 0.686, respectively, where 1 was not difficult and 5 was very difficult), and 80% of respondents said they would use the tool again. Participants who benefited the most were students with limited surgical shadowing experience and surgeons with less experience teaching preclerkship students. CONCLUSIONS: This study demonstrates that an objectives-based learning contract like the TLC can facilitate meaningful shadowing experiences for teachers and learners and may have longitudinal educational benefits. However, widespread implementation will require institutional support of this concept.

Devil's Club Falcarinol-Type Polyacetylenes Inhibit Pancreatic Cancer Cell Proliferation.

Natural falcarinol-type (FC-type) polyacetylenes are known to show anticancer activities. We studied the bioactivity of synthetic FC, 1,2-dihydrofalcarinol (FCH) and 3-acetoxyfalcarinol (FCA) and compared them with the natural bioactive polyacetylene [9,17-octadecadiene-12,14-diyne-1,11,16-triol,1-acetate] (DCA) isolated from Devil's club (DC) Oplopanax horridus. Antiproliferation activity of these polyacetylenes, along with DC inner stem bark 70% ethanol and water extracts, was tested on human pancreatic ductal adenocarcinoma cell lines PANC-1 and BxPC-3. Chemically synthesized FC and FCA showed consistent IC50 (50% inhibition concentration) and higher potency than DCA. FC and DCA's mechanism of action investigated by antibody array on apoptosis-associated genes, and cellular features confirmed by microscopy demonstrated that both compounds modulated genes related to pro-apoptosis, antiapoptosis, apoptosis, cell cycle, stress related, and death receptors. FC-type polyacetylenes with a terminal double bond (FC, FCA, and DCA) are potent inhibitors of pancreatic cancer cell proliferation compared to FCH with a terminal single bond. Liquid chromatography mass spectrometry confirmed the presence of FC and FCH in the inner stem bark of DC. For potential applications of FC-type polyacetylenes as anticancer agents, preparing them by chemical synthesis may provide an advantage over the labor intensive extraction process from raw plant material.

Enhanced recovery after surgery in colorectal surgery: Impact of protocol adherence on patient outcomes.

STUDY OBJECTIVES: There is growing evidence internationally to support Enhanced Recovery After Surgery (ERAS) pathways. The impact of pathway compliance and the relative importance of individual components, however, remains less clear. Our institution implemented a multimodal ERAS protocol for elective colorectal surgery in November 2013. The objectives of this study were to investigate the impact of the introduction of the pathway, the relationship between pathway adherence and patient outcomes, and the relative importance of individual components. DESIGN: This was a single-center, observational cohort study of elective colorectal surgical patients. SETTING: A tertiary care and academic teaching hospital in Canada. PATIENTS: Prospective data was collected from 495 consecutive major colorectal surgical patients following the ERAS launch. Retrospective data was also collected from a pre-ERAS cohort of 99. MEASUREMENTS: Adherence to 12 ERAS components were measured, along with American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP®) defined patient complications and hospital length of stay (LOS). Post-ERAS patients were divided in to two groups: high compliance (≥75% process adherence) and low compliance (<75% adherence). Outcomes were compared between groups. MAIN RESULTS: There was a significant reduction in both complication rate (31.5% vs 14.6%; p ≤0.05) and hospital mean LOS (10.1 vs 6.9 days; p ≤0.05) following introduction of the ERAS pathway. The high adherence group had a shorter mean LOS (5.7 vs 8.6 days; p ≤0.01) and lower rate of complications (11.2% vs 19.6%; p = 0.02) compared with the low compliance group. CONCLUSIONS: Higher adherence to the standardized ERAS protocol was associated with improved patient outcomes, including reduced pulmonary complications. The cause-effect relationship is complex and likely influenced by confounding factors. Our data provides feedback to aid ongoing innovation of our pathway locally and adds to the growing body of evidence supporting the value of ERAS in general.

Amyloid formation reduces protein kinase B phosphorylation in primary islet ß-cells which is improved by blocking IL-1ß signaling.

Amyloid formation in the pancreatic islets due to aggregation of human islet amyloid polypeptide (hIAPP) contributes to reduced ß-cell mass and function in type 2 diabetes (T2D) and islet transplantation. Protein kinase B (PKB) signaling plays a key role in the regulation of ß-cell survival, function and proliferation. In this study, we used human and hIAPP-expressing transgenic mouse islets in culture as two ex vivo models of human islet amyloid formation to: 1. Investigate the effects of amyloid formation on PKB phosphorylation in primary islet ß-cells; 2. Test if inhibition of amyloid formation and/or interleukin-1ß (IL-1ß) signaling in islets can restore the changes in ß-cell phospho-PKB levels mediated by amyloid formation. Human and hIAPP-expressing mouse islets were cultured in elevated glucose with an amyloid inhibitor (Congo red) or embedded within collagen matrix to prevent amyloid formation. To block the IL-1ß signaling, human islets were treated with an IL-1 receptor antagonist (anakinra) or a glucagon-like peptide-1 agonist (exenatide). ß-cell phospho-PKB levels, proliferation, apoptosis, islet IL-1ß levels and amyloid formation were assessed. Amyloid formation in both cultured human and hIAPP-expressing mouse islets reduced ß-cell phospho-PKB levels and increased islet IL-1ß levels, both of which were restored by prevention of amyloid formation either by the amyloid inhibitor or embedding islets in collagen matrix, resulting in improved ß-cell survival. Furthermore, inhibition of IL-1ß signaling by treatment with anakinra or exenatide increased ß-cell phospho-PKB levels, enhanced proliferation and reduced apoptosis in amyloid forming human islets during 7-day culture. These data suggest that amyloid formation leads to reduced PKB phosphorylation in ß-cells which is associated with elevated islet IL-1ß levels. Inhibitors of amyloid or amyloid-induced IL-1ß production may provide a new approach to restore phospho-PKB levels thereby enhance ß-cell survival and proliferation in conditions associated with islet amyloid formation such as T2D and clinical islet transplantation.

Amyloid formation disrupts the balance between interleukin-1ß and interleukin-1 receptor antagonist in human islets.

OBJECTIVES: ß-cell dysfunction and apoptosis associated with islet inflammation play a key role in the pathogenesis of type 2 diabetes (T2D). Growing evidence suggests that islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), contributes to islet inflammation and ß-cell death in T2D. We recently showed the role of interleukin-1ß (IL-1ß)/Fas/caspase-8 apoptotic pathway in amyloid-induced ß-cell death. In this study, we used human islets in culture as an ex vivo model of amyloid formation to: (1) investigate the effects of amyloid on islet levels of the natural IL-1 receptor antagonist (IL-1Ra); (2) examine if modulating the IL-1ß/IL-1Ra balance can prevent amyloid-induced ß-cell Fas upregulation and apoptosis. METHODS: Isolated human islets (n = 10 donors) were cultured in elevated glucose (to form amyloid) with or without a neutralizing human IL-1ß antibody for up to 7 days. Parallel studies were performed with human islets in which amyloid formation was prevented by adeno-siRNA-mediated suppression of hIAPP expression (as control). ß-cell levels of IL-1Ra, Fas, apoptosis as well as islet function, insulin- and amyloid-positive areas, and IL-1Ra release were assessed. RESULTS: Progressive amyloid formation in human islets during culture was associated with alterations in IL-1Ra. Islet IL-1Ra levels were higher at early stages but were markedly reduced at later stages of amyloid formation. Furthermore, IL-1Ra release from human islets was reduced during 7-day culture in a time-dependent manner. These changes in IL-1Ra production and release from human islets during amyloid formation adversely correlated with islet IL-1ß levels, ß-cell Fas expression and apoptosis. Treatment with IL-1ß neutralizing antibody markedly reduced amyloid-induced ß-cell Fas expression and apoptosis, thereby improving islet ß-cell survival and function during culture. CONCLUSIONS: These data suggest that amyloid formation impairs the balance between IL-1ß and IL-1Ra in islets by increasing IL-1ß production and reducing IL-1Ra levels thereby promoting ß-cell dysfunction and death. Restoring the IL-1ß/IL-1Ra ratio may provide an effective strategy to protect islet ß-cells from amyloid toxicity in T2D.

Measurement of Pro-Islet Amyloid Polypeptide (1-48) in Diabetes and Islet Transplants.

Context: Islet amyloid is a feature of ß-cell failure in type 2 diabetes (T2D) and type 1 diabetes (T1D) recipients of islet transplants. Islet amyloid contains islet amyloid polypeptide (IAPP; amylin), a circulating peptide that is produced in ß cells by processing of its precursor, proIAPP1-67, via an intermediate form, proIAPP1-48. Elevated proinsulin to C-peptide ratios in the plasma of persons with diabetes suggest defects in ß-cell prohormone processing. Objective: Determine whether plasma levels of precursor forms of IAPP are elevated in diabetes. Design, Setting, and Patients: We developed an immunoassay to detect proIAPP1-48 in human plasma, and we determined the ratio of proIAPP1-48 to mature IAPP in subjects with T1D, T2D, recipients of islet transplants, and healthy controls. Results: The proIAPP1-48 immunoassay had a limit of detection of 0.18 ± 0.06 pM and cross-reactivity with intact proIAPP1-67 <15%. Healthy individuals had plasma concentrations of proIAPP1-48 immunoreactivity of 1.5 ± 0.2 pM and a proIAPP1-48 to total IAPP ratio of 0.28 ± 0.03. Plasma concentrations of proIAPP1-48 immunoreactivity were not significantly different in subjects with T2D but were markedly increased in T1D recipients of islet transplants. Children and adults with T1D had reduced mature IAPP levels relative to age-matched controls but an elevated ratio of proIAPP1-48 to total IAPP. Conclusion: The ß cells in T1D and islet transplants have impaired processing of the proIAPP1-48 intermediate. The ratio of proIAPP1-48-to-IAPP immunoreactivity may have value as a biomarker of ß-cell stress and dysfunction.

Dual role of interleukin-1ß in islet amyloid formation and its ß-cell toxicity: Implications for type 2 diabetes and islet transplantation.

AIMS: Islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), contributes to ß-cell failure in type 2 diabetes, cultured and transplanted islets. We previously showed that biosynthetic hIAPP aggregates induce ß-cell Fas upregulation and activation of the Fas apoptotic pathway. We used cultured human and hIAPP-expressing mouse islets to investigate: (1) the role of interleukin-1ß (IL-1ß) in amyloid-induced Fas upregulation; and (2) the effects of IL-1ß-induced ß-cell dysfunction on pro-islet amyloid polypeptide (proIAPP) processing and amyloid formation. RESEARCH DESIGN AND METHODS: Human and h IAPP -expressing mouse islets were cultured to form amyloid without or with the IL-1 receptor antagonist (IL-1Ra) anakinra, in the presence or absence of recombinant IL-1ß. Human islets in which amyloid formation was prevented (amyloid inhibitor or Ad-prohIAPP-siRNA) were cultured similarly. ß-cell function, apoptosis, Fas expression, caspase-8 activation, islet IL-1ß, ß-cell area, ß-/α-cell ratio, amyloid formation, and (pro)IAPP forms were assessed. RESULTS: hIAPP aggregates were found to increase IL-1ß levels in cultured human islets that correlated with ß-cell Fas upregulation, caspase-8 activation and apoptosis, all of which were reduced by IL-1Ra treatment or prevention of amyloid formation. Moreover, IL-1Ra improved culture-induced ß-cell dysfunction and restored impaired proIAPP processing, leading to lower amyloid formation. IL-1ß treatment potentiated impaired proIAPP processing and increased amyloid formation in cultured human and h IAPP -expressing mouse islets, which were prevented by IL-1Ra. CONCLUSIONS: IL-1ß plays a dual role by: (1) mediating amyloid-induced Fas upregulation and ß-cell apoptosis; (2) inducing impaired proIAPP processing thereby potentiating amyloid formation. Blocking IL-1ß may provide a new strategy to preserve ß cells in conditions associated with islet amyloid formation.

The application of mRNA-based gene transfer in mesenchymal stem cell-mediated cytotoxicity of glioma cells.

Since the tumor-oriented homing capacity of mesenchymal stem cells (MSCs) was discovered, MSCs have attracted great interest in the research field of cancer therapy mainly focused on their use as carries for anticancer agents. Differing from DNA-based vectors, the use of mRNA-based antituor gene delivery benefits from readily transfection and mutagenesis-free. However, it is essential to verify if mRNA transfection interferes with MSCs' tropism and their antitumor properties. TRAIL- and PTEN-mRNAs were synthesized and studied in an in vitro model of MSC-mediated indirect co-culture with DBTRG human glioma cells. The expression of TRAIL and PTEN in transfected MSCs was verified by immunoblotting analysis, and the migration ability of MSCs after anticancer gene transfection was demonstrated using transwell co-cultures. The viability of DBTRG cells was determined with bioluminescence, live/dead staining and real time cell analyzer. An in vivo model of DBTRG cell-derived xenografted tumors was used to verify the antitumor effects of TRAIL- and PTEN-engineered MSCs. With regard to the effect of mRNA transfection on MSCs' migration toward glioma cells, an enhanced migration rate was observed with MSCs transfected with all tested mRNAs compared to non-transfected MSCs (p<0.05). TRAIL- and PTEN-mRNA-induced cytotoxicity of DBTRG glioma cells was proportionally correlated with the ratio of conditioned medium from transfected MSCs. A synergistic action of TRAIL and PTEN was demonstrated in the current co-culture model. The immunoblotting analysis revealed the apoptotic nature of the cells death in the present study. The growth of the xenografted tumors was significantly inhibited by the application of MSCPTEN or MSCTRAIL/PTEN on day 14 and MSCTRAIL on day 28 (p<0.05). The results suggested that anticancer gene-bearing mRNAs synthesized in vitro are capable of being applied for MSC-mediated anticancer modality. This study provides an experimental base for further clinical anticancer studies using synthesized mRNAs.

Fluorescent cholangiography in laparoscopic cholecystectomy: the initial Canadian experience.

BACKGROUND: Bile duct injury remains a worrisome complication of laparoscopic cholecystectomy. Indocyanine Green (ICG) fluorescent cholangiography (FC) is a new approach that facilitates real-time intraoperative identification of biliary anatomy. This technology is hoped to improve the safety of dissection within Calot's triangle. METHOD: Demographics, intraoperative details, and subjective surgeon data were recorded for elective cholecystectomy cases involving ICG. Goals were to identify rates of bile duct identification, and assess the perceived benefit of the device. RESULTS: ICG was used in 12 biliary cases in Canada. Visualization rates of the cystic and common bile ducts were 100% and 83%, respectively. Also, 83% of surgeons felt that FC incorporated smoothly into the operation. No complications have been related to the technology. CONCLUSIONS: FC allows noninvasive real-time visualization of the extrahepatic biliary tree. This novel technique has received positive feedback in its initial Canadian use and will likely be a durable adjunct for minimally invasive surgery.

Statistical approaches and software for clustering islet cell functional heterogeneity.

Worldwide efforts are underway to replace or repair lost or dysfunctional pancreatic ß-cells to cure diabetes. However, it is unclear what the final product of these efforts should be, as ß-cells are thought to be heterogeneous. To enable the analysis of ß-cell heterogeneity in an unbiased and quantitative way, we developed model-free and model-based statistical clustering approaches, and created new software called TraceCluster. Using an example data set, we illustrate the utility of these approaches by clustering dynamic intracellular Ca(2+) responses to high glucose in ∼300 simultaneously imaged single islet cells. Using feature extraction from the Ca(2+) traces on this reference data set, we identified 2 distinct populations of cells with ß-like responses to glucose. To the best of our knowledge, this report represents the first unbiased cluster-based analysis of human ß-cell functional heterogeneity of simultaneous recordings. We hope that the approaches and tools described here will be helpful for those studying heterogeneity in primary islet cells, as well as excitable cells derived from embryonic stem cells or induced pluripotent cells.

Fibroblast Cell-Based Therapy for Experimental Autoimmune Diabetes.

Type 1 diabetes (T1D) results from autoimmune destruction of insulin producing ß cells of the pancreatic islets. Curbing autoimmunity at the initiation of T1D can result in recovery of residual ß cells and consequently remission of diabetes. Here we report a cell-based therapy for autoimmune diabetes in non-obese diabetic (NOD) mice using dermal fibroblasts. This was achieved by a single injection of fibroblasts, expressing the immunoregulatory molecule indoleamine 2,3 dioxygenase (IDO), into peritoneal cavity of NOD mice shortly after the onset of overt hyperglycemia. Mice were then monitored for reversal of hyperglycemia and changes in inflammatory/regulatory T cell profiles. Blood glucose levels dropped into the normal range in 82% of NOD mice after receiving IDO-expressing fibroblasts while all control mice remained diabetic. We found significantly reduced islet inflammation, increased regulatory T cells, and decreased T helper 17 cells and ß cell specific autoreactive CD8+ T cells following IDO cell therapy. We further showed that some of intraperitoneal injected fibroblasts migrated to local lymph nodes and expressed co-inhibitory molecules. These findings suggest that IDO fibroblasts therapy can reinstate self-tolerance and alleviate ß cell autoreactivity in NOD mice, resulting in remission of autoimmune diabetes.

IDO-Expressing Fibroblasts Protect Islet Beta Cells From Immunological Attack and Reverse Hyperglycemia in Non-Obese Diabetic Mice.

Indoleamine 2,3-dioxygenase (IDO) induces immunological tolerance in physiological and pathological conditions. Therefore, we used dermal fibroblasts with stable IDO expression as a cell therapy to: (i) Investigate the factors determining the efficacy of this cell therapy for autoimmune diabetes in non-obese diabetic (NOD) mice; (ii) Scrutinize the potential immunological mechanisms. Newly diabetic NOD mice were randomly injected with either 10 × 10(6) (10M) or 15 × 10(6) (15M) IDO-expressing dermal fibroblasts. Blood glucose levels (BGLs), body weight, plasma kynurenine levels, insulitis severity, islet beta cell function, autoreactive CD8(+) T cells, Th17 cells and regulatory T cells (Tregs) were then investigated in these mice. IL-1ß and cleaved caspase-3 levels were assessed in islets co-cultured with IDO-expressing fibroblasts. BGLs in 83% mice treated with 15M IDO-expressing fibroblasts recovered to normal up to 120 days. However, only 17% mice treated with 10M IDO-expressing cells were reversed to normoglycemia. A 15M IDO-expressing fibroblasts significantly reduced infiltrated immune cells in islets and recovered the functionality of remaining islet beta cells in NOD mice. Additionally, they successfully inhibited autoreactive CD8(+) T cells and Th17 cells as well as increased Tregs in different organs of NOD mice. Islet beta cells co-cultured with IDO-expressing fibroblasts had reduced IL-1ß levels and cell apoptosis. Both cell number and IDO enzymatic activity contributes to the efficiency of IDO cell therapy. Optimized IDO-expressing fibroblasts successfully reverse the progression of diabetes in NOD mice through induction of Tregs as well as inhibition of beta cell specific autoreactive CD8(+) T cells and Th17 cells. J. Cell. Physiol. 231: 1964-1973, 2016. © 2016 Wiley Periodicals, Inc.

Why Canada needs networks to provide rural surgical care, including family doctors with essential surgical skills.

SUMMARY: Time is long overdue for action to improve rural surgical services in Canada. In this issue of CJS, a proposed curriculum for the provision of enhanced surgical skills (ESS) to rural family physicians offers an opportunity to fortify a seamless network of high-quality surgical care for rural Canada. It is supported and enhanced by the best available evidence and measured advice from specialists and generalists alike. Publication of this curriculum proposal provides for essential dialogue with general surgeons. We discuss why we must play an active role in the development, teaching and evaluation of ESS, or we will have minimal influence and limited grounds on which to criticize its outcome or celebrate the opportunity of success it promises.

Therapeutic potential of CAR-T cell-derived exosomes: a cell-free modality for targeted cancer therapy.

Chimeric antigen receptor (CAR)-based T-cell adoptive immunotherapy is a distinctively promising therapy for cancer. The engineering of CARs into T cells provides T cells with tumor-targeting capabilities and intensifies their cytotoxic activity through stimulated cell expansion and enhanced cytokine production. As a novel and potent therapeutic modality, there exists some uncontrollable processes which are the potential sources of adverse events. As an extension of this impactful modality, CAR-T cell-derived exosomes may substitute CAR-T cells to act as ultimate attackers, thereby overcoming some limitations. Exosomes retain most characteristics of parent cells and play an essential role in intercellular communications via transmitting their cargo to recipient cells. The application of CAR-T cell-derived exosomes will make this cell-based therapy more clinically controllable as it also provides a cell-free platform to diversify anticancer mediators, which responds effectively to the complexity and volatility of cancer. It is believed that the appropriate application of both cellular and exosomal platforms will make this effective treatment more practicable.

Joint position paper on rural surgery and operative delivery.

Our professional organizations have prepared this paper as part of an integrated, multidisciplinary plan to ensure the availability of well-trained practitioner teams to sustain safe, effective and high-quality rural surgical and operative delivery services. Without these robust local (or nearby) surgical services, sustaining rural maternity care is much more difficult. This paper describes the "network model" as a health human resources solution to meet the surgical needs, including operative delivery, of rural residents; outlines necessary policy directions for achieving this solution; and poses a series of enabling recommendations.

Nos organisations professionnelles ont préparé cet article dans le cadre d'un plan multidisciplinaire intégré visant à assurer la disponibilité d'équipes soignantes bien formées pour offrir des services obstétricaux interventionnels et chirurgicaux sécuritaires, efficaces et de grande qualité en milieu rural. Sans de tels solides services chirurgicaux locaux (ou de proximité), il est beaucoup plus difficile d'assurer les soins obstétricaux en milieu rural. Cet article décrit le « modèle en réseau ¼ comme une solution au chapitre des ressources humaines en santé pour répondre aux besoins chirurgicaux des populations rurales, y compris pour les services obstétricaux interventionnels. On y décrit aussi les orientations politiques nécessaires à l'application de cette solution et on formule une série de recommandations préparatoires.

Inhibition of Human Pancreatic Cancer Cell Proliferation by Devil's Club Oplopanax horridus and Its Polyacetylene Bioactive Compound.

Devil's club Oplopanax horridus (DC) is a close relative of ginseng; its inner root and stem bark extract showed antiproliferation activity on human leukemia, ovarian, breast and colon cancer cells. We study here the effects of DC 70% ethanol extract alone, or in combination with cisplatin, gemcitabine, and paclitaxel on pancreatic endocrine HP62 and pancreatic ductal carcinoma PANC-1 and BxPC-3 cells. Antiproliferation activity assay, cell cycle analysis by flow cytometry, apoptosis-related markers by antibody array, and RT-PCR assay were used for this study. DC extract inhibited proliferation of HP62 with IC50 (50% inhibition concentration) at 0.037±0.002% (v/v), PANC-1 at 0.0058 ± 0.0004% and BxPC-3 at 0.021 ± 0.003%. DC at 0.0033% combined with 1 nM of paclitaxel showed inhibition synergy on PANC-1 cells with a combination index of 0.44. Apoptosis focused antibody array profile indicated upregulation of cytochrome C, claspin, cIAP-2 and HTRA2/Omi apoptosis-related markers in DC-treated HP62 and PANC-1. Our data suggest that DC acts through targeting the intrinsic mitochondrial apoptosis pathway in the pancreatic cancer cells. The high antiproliferation potency of DC on PANC-1 is potentially useful as an adjunct therapy for treating pancreatic cancer, which is known for developing resistance to conventional chemotherapeutics.