Use of virtual consultations in an orthopaedic rehabilitation setting: how do changes in the work of being a patient influence patient preferences? A systematic review and qualitative synthesis.

OBJECTIVES: To systematically review qualitative studies reporting the use of virtual consultations within an orthopaedic rehabilitation setting and to understand how its use changes the work required of patients. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement, we conducted a systematic review of papers to answer the research question 'How do changes in the work of being a patient when using communication technology influence patient preferences?' Electronic databases were searched for studies meeting the inclusion criteria in April 2020. RESULTS: The search strategy identified 2057 research articles from the database search. A review of titles and abstracts using the inclusion criteria yielded 21 articles for full-text review. Nine studies were included in the final analysis. Six studies explored real-time video conferencing and three explored telephone consultations. The use of communication technology changes the work required of patients. Such changes will impact on expectations for care, resources required of patients, the environment of receiving care and patient-clinician interactions. This adjustment of the work required of patients who access orthopaedic rehabilitation using communication technology will impact on their experience of receiving care. It is proposed that changes in the work of being a patient will influence preferences for or against the use of communication technology consultations for orthopaedic rehabilitation. CONCLUSION: We found that the use of communication technology changes the work of being a patient. The change in work required of patients can be both burdensome (it makes it harder for patients to access their care) and beneficial (it makes it easier for patients to access their care). This change will likely to influence preferences. Keeping the concept of patient work at the heart of pathway redesign is likely to be a key consideration to ensure successful implementation. PROSPERO REGISTRATION NUMBER: CRD42018100896

Impact of different nitrogen emission sources on tree physiology as assessed by a triple stable isotope approach

The importance that nitrogen (N) deposition has in driving the carbon (C) sequestration of forests has recently been investigated using both experimental and modeling approaches. Whether increased N deposition has positive or negative effects on such ecosystems depends on the status of the N and the duration of the deposition. By combining d13C, d18O, d15N and dendrochronological approaches, we analyzed the impact of two different sources of NOx emissions on two tree species, namely: a broadleaved species (Quercus cerris) that was located close to an oil refinery in Southern Italy, and a coniferous species (Picea abies) located close to a freeway in Switzerland. Variations in the ci/ca ratio and the distinction between stomatal and photosynthetic responses to NOx emissions in trees were assessed using a conceptual model, which combines d13C and d18O. d15N in leaves, needles and tree rings was found to be a bioindicator of N input from anthropogenic emissions, especially at the oil refinery site.We observed that N fertilization had a stimulatory effect on tree growth near the oil refinery, while the opposite effect was found for trees at the freeway site. Changes in the ci/ca ratio were mostly related to variations in d13C at the freeway site and, thus, were driven by photosynthesis. At the oil refinery site they were mainly related to stomatal conductance, as assessed using d18O. This study demonstrates that a single method approach does not always provide a complete picture of which physiological traits are more affected by N emissions. The triple isotope approach combined with dendrochronological analyses proved to be a very promising tool for monitoring the ecophysiological responses of trees to long-term N deposition

MicroRNA-145 replacement as a therapeutic tool to Improve TRAIL therapy

Pancreatic cancer (PanCa) is a third leading cause of cancer related deaths in US. Unlike other cancers, PanCa is highly resistant to TNF-related apoptosis-inducing ligand (TRAIL) that emerges as one of the most-promising therapy in clinical trials. Our group has previously identified microRNA-145 (miR-145) is downregulated in PanCa, the restoration of which inhibits tumor growth and enhances gemcitabine sensitivity. In this study, we have observed that miR-145 restoration in PanCa cells renders them sensitive to TRAIL treatment. Therefore, we have engineered unique superparamagnetic nanoparticles (SPs) for co-delivering miR-145 and TRAIL in PanCa for improving their therapeutic response to TRAIL. The results in this study demonstrate that acquired resistance to TRAIL in PanCa cells can overcome with the replacement of lost levels of miR-145 expression. Our SP nanoparticles were engineered to co-deliver miR-145 and TRAIL to PanCa cells, which resulted in simultaneous restoration of miR-145 and inhibition of acquired resistance to TRAIL. Combined actions of miR-145 and TRAIL markedly improve TRAIL-induced apoptotic effects in PanCa cells through the activation of an extrinsic apoptosis pathway pathway as indicated by activation of DR5, FLIP, FADD and enhanced expression of caspase-8/3. The co-delivery of miR-145 and TRAIL using SP nanoparticles inhibited tumorigenic characteristics of PanCa cells, which include proliferation, invasion, migration and clonogenicity. The results were reciprocated and got further confirmed with the inhibition of tumorsphere formation and in vivo tumorigencity in xenograft mice. Immunohistochemical staining of excised tumor tissues demonstrate an activation of death receptor pathway and subsequent expression of apoptotic markers. The study provides novel insights on two facades- how resistance of cancer cells to TRAIL-based pro-apoptotic therapies can be tackled, and how efficient intracellular delivery of TRAIL can be achieved. Our results suggest that acquired resistance to TRAIL can be overcome by co-delivery of miR-145 and pEGFP-TRAIL using SP nanoparticles

A Novel Approach to Target Tumor Immune Microenvironment and Improve Checkpoint Immunotherapies

Background: Pancreatic cancer remains 3rd deadliest disease, with less than 7-10% survival rate. Little progress has been seen in patient’s outcome due to high desmoplasia and chemo-resistance. Immunotherapy has shown promising results in cancers, except pancreatic cancer due to their characteristic fibrotic tumor microenvironment. The therapies are unable to penetrate fibrotic tumor leading to insufficient availability of therapeutic drugs at the tumor site. A recently identified mucin, MUC13 is aberrantly expressed in pancreatic tumors but not in normal pancreas, that makes it an excellent protein tumor target. This study is unique as it utilizes MUC13Ab for targeting the pancreatic tumor site and SPION nanoparticle system for delivering the stroma depleting drug (curcumin), which would help in improving immunotherapy response. Methods: The inhouse generated MUC13Ab have been conjugated with our recently developed novel patented superparamagnetic iron oxide nanoparticles (SPIONS). Conjugation efficiency of the SPION-Anti-MUC13 particles was seen through cell uptake studies, by measuring fluorescence intensity, Prussian blue staining. Invasion assay and migration assay was carried out on KPC cells. We have used female C57BL/6J black mice, orthotopic mice model for investigating targeting efficacy of MUC13-SPION-CUR. Immune checkpoint therapy (PDL-1 and CTLA-4) was administrated along with MUC13-SPION-CUR and conjugated with fluorescent indocyanine green (ICG) dye for monitoring the tumor growth. Further, immunostimulatory effect of the nano formulation was done using flow cytometry. Results: Our results showed that MUC13Ab conjugated SPIONS can efficiently internalize the PDAC cells. SPION-MUC13 using Indocyanine dye (ICG) specifically reached to the tumor site in an orthotopic syngeneic mouse model of PDAC as indicated by ICG fluorescence. Additionally, the combination formulation inhibited the tumor growth and showed more survival rate with CTLA-4. The combined treatment with CTLA-4 increased infiltration of total T cell population and CD8+T cells, reduced the population of myeloid-derived suppressor cells (MDSCs) by 43% (CD45+, CD3-, CD11b+, Ly6C high, Ly6G-) and T-Regulatory cells (Treg) by 23.8% (FoxP3+CD25+CD45+CD3+) in KrasG12D; LSL-Trp53R172H syngeneic mouse model of PDAC. Similar results were observed in SP-CUR-M13+PDL-1 group, which showed reduction in MDSCs (by 26.6%) and Tregs (by 0.1%) as compared with PDL-1 alone. Conclusion: The formulation softens up the tumors for therapies that resulted in improved response to checkpoint immunotherapies in a pancreatic orthotopic mice model. Therefore, this study indicates high significance of MUC13-SPIONS-CUR for achieving pancreatic tumor specific delivery of drugs. This study has a potential to reduce morbidity and mortality caused by the disease and improve survival in patients

Therapeutic Intervention Using Autologous Exosomes for Treatment of Early-Stage Pancreatic Cancer

Background: Pancreatic cancer (PanCa) is the third deadliest cancer in United States with a poor survival rate. Despite extensive research efforts, there is not any substantial progress in cancer therapeutics; major challenges lie with inherent drug toxicity, ineffectiveness, and resistance due to impediments against intracellular drug delivery. From a therapeutic delivery standpoint, novel delivery vehicles are required that are both biocompatible and non-immunogenic for a patient in order to maximize the chances of cure. This is possible by utilizing an autologous biological material, which can be applied as a personalized medicine to match the individual circumstances and molecular profile of the patient. One such approach has been optimized in our lab, which utilizes exosomes from the matched tumor adjacent normal (NAT) area following surgical resection. Using exosomes as a scaffold, our objective is to deliver therapeutics safely and effectively to the patient tumor site. Results: NAT derived exosomes showed effective size and zeta potential (size: 44.12 ± 0.89; Zeta potential: -14.9 mV), which is ideal for drug delivery purposes. The purification of exosomes was confirmed using proteins isolated from exosomes through Western blotting for expression of exosomal markers, such as CD63 expression. Immunofluorescence for CD63 expression confirmed the efficient delivery of exosomes in PanCa cells. Our results indicated high drug loading capacity of NAT derived exosomes as demonstrated using drug, Ormeloxifene (ORM) though UPLC. Exo-ORM treatment efficiently delivered ORM into the cancer cells and inhibited the cancer cell characteristics, such as, proliferation compared with ORM alone. Additionally, NAT derived exosomes showed enhanced expression of tumor suppressor microRNA, miR-145, suggestive of their therapeutic importance. We observed restoration of lost miR-145 levels in PanCa cells on incubation with NAT derived exosomes for 48hrs. This further indicates their relevance for their utilization in the development of an anti-cancer therapy. Conclusion: Our observations offer importance of the utilization of NAT derived exosomes for personalized medicine as a therapeutic delivery vehicle in PanCa

Superconducting-coil--resistor circuit with electric field quadratic in the current

It is shown for the first time that the observed [Phys. Lett. A 162 (1992) 105] potential difference Phi_t between the resistor and the screen surrounding the circuit is caused by polarization of the resistor because of the kinetic energy of the electrons of the superconducting coil. The proportionality of Phi_t to the square of the current and to the length of the superconducting wire is explained. It is pointed out that measuring Phi_t makes it possible to determine the Fermi quasimomentum of the electrons of a metal resistor.Comment: 2 pages, 1 figur

MicroRNA-145 replacement as a therapeutic tool to Improve TRAIL therapy

Pancreatic cancer (PanCa) is a third leading cause of cancer related deaths in US. Unlike other cancers, PanCa is highly resistant to TNF-related apoptosis-inducing ligand (TRAIL) that emerges as one of the most-promising therapy in clinical trials. Our group has previously identified microRNA-145 (miR-145) is downregulated in PanCa, the restoration of which inhibits tumor growth and enhances gemcitabine sensitivity. In this study, we have observed that miR-145 restoration in PanCa cells renders them sensitive to TRAIL treatment. Therefore, we have engineered unique superparamagnetic nanoparticles (SPs) for co-delivering miR-145 and TRAIL in PanCa for improving their therapeutic response to TRAIL. The results in this study demonstrate that acquired resistance to TRAIL in PanCa cells can overcome with the replacement of lost levels of miR-145 expression. Our SP nanoparticles were engineered to co-deliver miR-145 and TRAIL to PanCa cells, which resulted in simultaneous restoration of miR-145 and inhibition of acquired resistance to TRAIL. Combined actions of miR-145 and TRAIL markedly improve TRAIL-induced apoptotic effects in PanCa cells through the activation of an extrinsic apoptosis pathway pathway as indicated by activation of DR5, FLIP, FADD and enhanced expression of caspase-8/3. The co-delivery of miR-145 and TRAIL using SP nanoparticles inhibited tumorigenic characteristics of PanCa cells, which include proliferation, invasion, migration and clonogenicity. The results were reciprocated and got further confirmed with the inhibition of tumorsphere formation and in vivo tumorigencity in xenograft mice. Immunohistochemical staining of excised tumor tissues demonstrate an activation of death receptor pathway and subsequent expression of apoptotic markers. The study provides novel insights on two facades- how resistance of cancer cells to TRAIL-based pro-apoptotic therapies can be tackled, and how efficient intracellular delivery of TRAIL can be achieved. Our results suggest that acquired resistance to TRAIL can be overcome by co-delivery of miR-145 and pEGFP-TRAIL using SP nanoparticles

Novel therapy targeting mutant-KRASG12D and galectin-1 in pancreatic cancer

Introduction: In pancreatic ductal adenocarcinoma (PDAC), low patient survival rate remains a problem. The activating point mutation of KRAS on codon-12 is present in 70–95% of PDAC cases and so far, no success has been achieved to inhibit KRAS. KRASG12D regulates cell proliferation, differentiation, apoptosis; recent preliminary and published studies show high Galectin-1 (Gal-1) levels in both PDAC and stromal cells, which modulate tumor microenvironment and metastasis. Therefore, we have developed a novel combination therapy for PDAC by targeting mutated KRASG12D and Gal-1 to target both proliferation and metastasis in PDAC. This includes the delivery of KRASG12D inhibiting siRNA (siKRASG12D) using a superparamagnetic iron oxide nanoparticle (SPION) and a galectin inhibitor. Methods: Our patented SPION nano-formulation was used to deliver siKRASG12D and investigated in conjunction with Gal-1 inhibitor for its anticancer efficacy. Particles were investigated for size, physico-chemical characterization (Dynamic light scattering), hemocompatibility (hemolysis assay) and the complexation of siKRAS (gel retardation assay). Cellular internalization and uptake of the particles were investigated. Anti-cancer efficacy was determined using in vitro functional assays for cell viability (MTT), migration (Boyden chambers), invasion (Matrigel), clonogenicity, tumor spheroid formation, and in a mouse model. Results: Our results demonstrate optimal particle size/zeta potential of SP-siKRAS formulation. SP-siKRAS efficiently internalized in PDAC cells and suppressed KRASG12D as well as its downstream targets, YAP and PDL-1. Combined targeting of siKRAS and Gal-1 inhibited cell proliferation. It inhibited cell proliferation, clonogenicity, migration, and invasion of PDAC cells. This resulted in activation of death related mechanisms, such as Bax, bcl-2, PARP cleavage in KRASG12D cells. Interestingly, the formulation was highly effective in inhibiting KRASG12D and growth of tumor spheroid in 3D cell models, which recapitulate the heterogeneity and pathophysiology of PDAC. This further provides a clinical validation demonstrating potential of SP-siKRAS particles to efficiently silence KRAS expression. SP-siKRAS also exhibited hemocompatibility and stability suggesting its potential of silencing KRAS without being toxic to the body. The formulation efficiently exhibited KRasG12D silencing and inhibited tumor growth and metastasis in nude mice. Conclusion: This gene therapy targeting KRAS G12D mutation with a Gal-1 inhibition has a potential to modulate the oncogenic network and tumor microenvironment resulting in the repression of growth, metastasis, chemoresistance, and improvement in patient survival. This study will develop a novel sustainable therapeutic approach to target PDAC growth and improve patient survivability