A Novel Protozoa Parasite-Derived Protein Adjuvant Is Effective in Immunization with Cancer Cells to Activate the Cancer-Specific Protective Immunity and Inhibit the Cancer Growth in a Murine Model of Colorectal Cancer.

Cancer-specific CD8+ cytotoxic T cells play important roles in preventing cancer growth, and IFN-γ, in addition to IL-12 and type I interferon, is critical for activating CD8+ cytotoxic T cells. We recently identified the capability of the amino-terminus region of dense granule protein 6 (GRA6Nt) of Toxoplasma gondii, an intracellular protozoan parasite, to activate IFN-γ production of microglia, a tissue-resident macrophage population. Therefore, in the present study, we examined whether recombinant GRA6Nt protein (rGRA6Nt) functions as an effective adjuvant to potently activate cancer-specific protective immunity using a murine model of MC38 colorectal cancer (CRC). When mice were immunized with non-replicable (either treated with mitomycin C or irradiated by X-ray) MC38 CRC cells in combination with rGRA6Nt adjuvant and received a challenge implantation of replication-capable MC38 tumor cells, those mice markedly inhibited the growth of the implanted tumors in association with a two-fold increase in CD8+ T cell density within the tumors. In addition, CD8+ T cells of the immunized mice secreted significantly increased amounts of granzyme B, a key mediator of the cytotoxic activity of CD8+ T cells, and IFN-γ in response to MC38 CRC cells in vitro when compared to the T cells from unimmunized mice. Notably, the protective effects of the immunization were specific to MC38 CRC cells, as the immunized mice did not exhibit a significantly inhibited growth of EL4 lymphoma tumors. These results indicate that rGRA6Nt is a novel and effective protein adjuvant when used in immunizations with non-replicable cancer cells to potently activate the protective immunity specifically against the cancer cells employed in the immunization.

Evaluating artificial intelligence software for delineating hemorrhage extent on CT brain imaging in stroke: AI delineation of ICH on CT.

BACKGROUND: The extent and distribution of intracranial hemorrhage (ICH) directly affects clinical management. Artificial intelligence (AI) software can detect and may delineate ICH extent on brain CT. We evaluated e-ASPECTS software (Brainomix Ltd.) performance for ICH delineation. METHODS: We qualitatively assessed software delineation of ICH on CT using patients from six stroke trials. We assessed hemorrhage delineation in five compartments: lobar, deep, posterior fossa, intraventricular, extra-axial. We categorized delineation as excellent, good, moderate, or poor. We assessed quality of software delineation with number of affected compartments in univariate analysis (Kruskall-Wallis test) and ICH location using logistic regression (dependent variable: dichotomous delineation categories 'excellent-good' versus 'moderate-poor'), and report odds ratios (OR) and 95 % confidence intervals (95 %CI). RESULTS: From 651 patients with ICH (median age 75 years, 53 % male), we included 628 with assessable CTs. Software delineation of ICH extent was 'excellent' in 189/628 (30 %), 'good' in 255/628 (41 %), 'moderate' in 127/628 (20 %), and 'poor' in 57/628 cases (9 %). The quality of software delineation of ICH was better when fewer compartments were affected (Z = 3.61-6.27; p = 0.0063). Software delineation of ICH extent was more likely to be 'excellent-good' quality when lobar alone (OR = 1.56, 95 %CI = 0.97-2.53) but 'moderate-poor' with any intraventricular (OR = 0.56, 95 %CI = 0.39-0.81, p = 0.002) or any extra-axial (OR = 0.41, 95 %CI = 0.27-0.62, p<0.001) extension. CONCLUSIONS: Delineation of ICH extent on stroke CT scans by AI software was excellent or good in 71 % of cases but was more likely to over- or under-estimate extent when ICH was either more extensive, intraventricular, or extra-axial.

A collaborative backbone resource for comparative studies of subterranean evolution: The World Asellidae database.

Transition to novel environments, such as groundwater colonization by surface organisms, provides an excellent research ground to study phenotypic evolution. However, interspecific comparative studies on evolution to groundwater life are few because of the challenge in assembling large ecological and molecular resources for species-rich taxa comprised of surface and subterranean species. Here, we make available to the scientific community an operational set of working tools and resources for the Asellidae, a family of freshwater isopods containing hundreds of surface and subterranean species. First, we release the World Asellidae database (WAD) and its web application, a sustainable and FAIR solution to producing and sharing data and biological material. WAD provides access to thousands of species occurrences, specimens, DNA extracts and DNA sequences with rich metadata ensuring full scientific traceability. Second, we perform a large-scale dated phylogenetic reconstruction of Asellidae to support phylogenetic comparative analyses. Of 424 terminal branches, we identify 34 pairs of surface and subterranean species representing independent replicates of the transition from surface water to groundwater. Third, we exemplify the usefulness of WAD for documenting phenotypic shifts associated with colonization of subterranean habitats. We provide the first phylogenetically controlled evidence that body size of males decreases relative to that of females upon groundwater colonization, suggesting competition for rare receptive females selects for smaller, more agile males in groundwater. By making these tools and resources widely accessible, we open up new opportunities for exploring how phenotypic traits evolve in response to changes in selective pressures and trade-offs during groundwater colonization.

Accuracy of artificial intelligence software for CT angiography in stroke.

OBJECTIVE: Software developed using artificial intelligence may automatically identify arterial occlusion and provide collateral vessel scoring on CT angiography (CTA) performed acutely for ischemic stroke. We aimed to assess the diagnostic accuracy of e-CTA by Brainomix™ Ltd by large-scale independent testing using expert reading as the reference standard. METHODS: We identified a large clinically representative sample of baseline CTA from 6 studies that recruited patients with acute stroke symptoms involving any arterial territory. We compared e-CTA results with masked expert interpretation of the same scans for the presence and location of laterality-matched arterial occlusion and/or abnormal collateral score combined into a single measure of arterial abnormality. We tested the diagnostic accuracy of e-CTA for identifying any arterial abnormality (and in a sensitivity analysis compliant with the manufacturer's guidance that software only be used to assess the anterior circulation). RESULTS: We include CTA from 668 patients (50% female; median: age 71 years, NIHSS 9, 2.3 h from stroke onset). Experts identified arterial occlusion in 365 patients (55%); most (343, 94%) involved the anterior circulation. Software successfully processed 545/668 (82%) CTAs. The sensitivity, specificity and diagnostic accuracy of e-CTA for detecting arterial abnormality were each 72% (95% CI = 66-77%). Diagnostic accuracy was non-significantly improved in a sensitivity analysis excluding occlusions from outside the anterior circulation (76%, 95% CI = 72-80%). INTERPRETATION: Compared to experts, the diagnostic accuracy of e-CTA for identifying acute arterial abnormality was 72-76%. Users of e-CTA should be competent in CTA interpretation to ensure all potential thrombectomy candidates are identified.

External Validation of e-ASPECTS Software for Interpreting Brain CT in Stroke.

OBJECTIVE: The purpose of this study was to test e-ASPECTS software in patients with stroke. Marketed as a decision-support tool, e-ASPECTS may detect features of ischemia or hemorrhage on computed tomography (CT) imaging and quantify ischemic extent using Alberta Stroke Program Early CT Score (ASPECTS). METHODS: Using CT from 9 stroke studies, we compared software with masked experts. As per indications for software use, we assessed e-ASPECTS results for patients with/without middle cerebral artery (MCA) ischemia but no other cause of stroke. In an analysis outside the intended use of the software, we enriched our dataset with non-MCA ischemia, hemorrhage, and mimics to simulate a representative "front door" hospital population. With final diagnosis as the reference standard, we tested the diagnostic accuracy of e-ASPECTS for identifying stroke features (ischemia, hyperattenuated arteries, and hemorrhage) in the representative population. RESULTS: We included 4,100 patients (51% women, median age = 78 years, National Institutes of Health Stroke Scale [NIHSS] = 10, onset to scan = 2.5 hours). Final diagnosis was ischemia (78%), hemorrhage (14%), or mimic (8%). From 3,035 CTs with expert-rated ASPECTS, most (2084/3035, 69%) e-ASPECTS results were within one point of experts. In the representative population, the diagnostic accuracy of e-ASPECTS was 71% (95% confidence interval [CI] = 70-72%) for detecting ischemic features, 85% (83-86%) for hemorrhage. Software identified more false positive ischemia (12% vs 2%) and hemorrhage (14% vs <1%) than experts. INTERPRETATION: On independent testing, e-ASPECTS provided moderate agreement with experts and overcalled stroke features. Therefore, future prospective trials testing impacts of artificial intelligence (AI) software on patient care and outcome are required before widespread implementation of stroke decision-support software. ANN NEUROL 2022;92:943-957.

Study protocol of a multiphase optimization strategy trial (MOST) for delivery of smoking cessation treatment in lung cancer screening settings.

BACKGROUND: There is widespread agreement that the integration of cessation services in lung cancer screening (LCS) is essential for achieving the full benefits of LCS with low-dose computed tomography (LDCT). There is a formidable knowledge gap about how to best design feasible, effective, and scalable cessation services in LCS facilities. A collective of NCI-funded clinical trials addressing this gap is the Smoking Cessation at Lung Examination (SCALE) Collaboration. METHODS: The Cessation and Screening to Save Lives (CASTL) trial seeks to advance knowledge about the reach, effectiveness, and implementation of tobacco treatment in lung cancer screening. We describe the rationale, design, evaluation plan, and interventions tested in this multiphase optimization strategy trial (MOST). A total of 1152 screening-eligible current smokers are being recruited from 18 LCS sites (n = 64/site) in both academic and community settings across the USA. Participants receive enhanced standard care (cessation advice and referral to the national Quitline) and are randomized to receive additional tobacco treatment components (motivational counseling, nicotine replacement patches/lozenges, message framing). The primary outcome is biochemically validated, abstinence at 6 months follow-up. Secondary outcomes are self-reported smoking abstinence, quit attempts, and smoking reduction at 3 and 6 months. Guided by the Implementation Outcomes Framework (IOF), our evaluation includes measurement of implementation processes (reach, fidelity, acceptability, appropriateness, sustainability, and cost). CONCLUSION: We will identify effective treatment components for delivery by LCS sites. The findings will guide the assembly of an optimized smoking cessation package that achieves superior cessation outcomes. Future trials can examine the strategies for wider implementation of tobacco treatment in LDCT-LCS sites. TRIAL REGISTRATION: ClinicalTrials.gov NCT03315910.

African-centered coping, resilience, and psychological distress in Black prostate cancer patients.

OBJECTIVE: Blacks have the highest incidence and mortality rates for prostate cancer (PCa) in the U.S. Black PCa patients (PCaP) also report high psychological distress. Identifying culturally specific coping strategies that lower distress among Black PCaP could help improve psychological interventions for this group. African-centered coping (strategies unique to the structure of Black personality and the African-centered worldview) have been identified. We hypothesized that these coping strategies and resilience would be associated with lower psychological distress (anxiety and depression) in Black PCaP. METHODS: Black PCaP (N = 95) completed a survey assessing African-centered coping strategies, resilience, anxiety, and depression. Multiple regression was employed to examine African-centered coping strategies and resilience as predictors of psychological distress. RESULTS: Participants were aged M = 67 ± 9 years and 52% had late-stage PCa. Twenty percent met criteria for clinically significant anxiety, and 17% for depression. African-centered coping strategies were not associated with lower anxiety or depression, while resilience was associated with decreased anxiety (r = -0.45, p < 0.001) and depression (r = -0.54, p < 0.001). Mediation analyses did not support an indirect association among African-centered coping strategies, resilience, and anxiety and depression. CONCLUSIONS: Contrary to hypotheses, African-centered coping strategies were not associated with psychological distress. However, as predicted, greater resilience was associated with lower anxiety and depression. These findings support the relevancy of resilience in Blacks' psychological adjustment to PCa. It might be worthwhile to explore African-centered coping strategies that help Black PCaP cope with distress.

Clinician perspectives on communication and implementation challenges in precision oncology.

Aim: To describe patient communication challenges encountered by oncology clinicians, which represent a fundamental barrier to implementing precision oncology. Materials & methods: We conducted three focus groups including breast, melanoma and thoracic oncology clinicians regarding their precision oncology communication experiences. Transcripts were reviewed and coded using inductive thematic text analysis. Results: We identified four themes: varied definitions of precision oncology exist, clinicians and patients face unique challenges to precision oncology implementation, patient communication challenges engendered or heightened by precision oncology implementation and clinician communication solutions and training needs. Conclusion: This study elucidated clinicians' perspectives on implementing precision oncology and related communication challenges. Understanding these challenges and developing strategies to help clinicians navigate these discussions are critical for ensuring that patients reap the full benefits of precision oncology.

Lay abstract 'Precision oncology' has gained momentum as a term to describe cancer care that is optimized for an individual patient based on her/his unique characteristics. However, clinicians may encounter challenges with communication when delivering precision oncology care to patients and their families. We conducted three focus groups, or structured discussions, with breast, melanoma and thoracic oncology clinicians regarding their precision oncology communication experiences. Narrative transcripts of these discussions were analyzed by the research team to identify common themes. We identified four themes: varied definitions of precision oncology exist, clinicians and patients face unique challenges to precision oncology implementation, patient communication challenges engendered or heightened by precision oncology implementation, and clinician communication solutions and training needs. This study elucidated clinicians' perspectives on delivering precision oncology and related communication challenges. Understanding these challenges and developing strategies to help clinicians navigate these discussions are critical for ensuring that patients reap the full benefits of precision oncology.

Evaluating relationships between lung cancer stigma, anxiety, and depressive symptoms and the absence of empathic opportunities presented during routine clinical consultations.

OBJECTIVE: Empathic communication in clinical consultations is mutually constructed, with patients first presenting empathic opportunities (statements communicating emotions, challenges, or progress) to which clinicians can respond. We hypothesized that lung cancer patients who did not present empathic opportunities during routine consultations would report higher stigma, anxiety, and depressive symptoms than patients who presented at least one. METHODS: Audio-recorded consultations between lung cancer patients (N = 56) and clinicians were analyzed to identify empathic opportunities. Participants completed questionnaires measuring sociodemographic and psychosocial characteristics. RESULTS: Twenty-one consultations (38 %) did not contain empathic opportunities. Unexpectedly, there was a significant interaction between presenting empathic opportunities and patients' race on disclosure-related stigma (i.e., discomfort discussing one's cancer; F = 4.49, p = .041) and anxiety (F = 8.03, p = .007). Among racial minority patients (self-identifying as Black/African-American, Asian/Pacific Islander, or other race), those who did not present empathic opportunities reported higher stigma than those who presented at least one (t=-5.47, p = .038), but this difference was not observed among white patients (t = 0.38, p = .789). Additional statistically significant findings emerged for anxiety. CONCLUSION: Disclosure-related stigma and anxiety may explain why some patients present empathic opportunities whereas others do not. PRACTICE IMPLICATIONS: Clinicians should intentionally elicit empathic opportunities and encourage open communication with patients (particularly from diverse racial backgrounds).

Oncology Care Provider Training in Empathic Communication Skills to Reduce Lung Cancer Stigma.

BACKGROUND: Despite the clinical importance of assessing smoking history and advising patients who smoke to quit, patients with lung cancer often experience feelings of blame and stigma during clinical encounters with their oncology care providers (OCPs). Promoting empathic communication during these encounters may help reduce patients' experience of stigma and improve related clinical outcomes. This paper presents the evaluation of OCP- and patient-reported data on the usefulness of an OCP-targeted empathic communication skills (ECS) training to reduce the stigma of lung cancer and improve communication. RESEARCH QUESTION: What is the impact of the ECS intervention on OCPs' communication skills uptake and patient-reported outcomes (lung cancer stigma, satisfaction with communication, and perceived OCP empathy)? METHODS: Study subjects included 30 multidisciplinary OCPs treating patients with lung cancer who participated in a 2.25 h ECS training. Standardized Patient Assessments were conducted prior to and following training to assess ECS uptake among OCPs. In addition, of a planned 180 patients who currently or formerly smoked (six unique patients per OCP [three pretraining, three posttraining]), 175 patients (89 pretraining, 86 posttraining) completed post-OCP visit surveys eliciting feedback on the quality of their interaction with their OCP. RESULTS: OCPs exhibited an overall increase in use of empathic communication skills [t(28) = -2.37; P < .05], stigma-mitigating skills [t(28) = -3.88; P < .001], and breadth of communication skill use [t(28) = -2.91; P < .01]. Patients reported significantly higher overall satisfaction with communication post-ECS training, compared with pretraining [t(121) = 2.15; P = .034; Cohen d = 0.35]. There were no significant differences from pretraining to posttraining for patient-reported stigma or perceived OCP empathy. INTERPRETATION: Empathy-based, stigma-reducing communication may lead to improved assessments of tobacco use and smoking cessation for patients with smoking-related cancers. These findings support the dissemination and further testing of a new ECS model for training OCPs in best practices for assessment of smoking history and engagement of patients who currently smoke in tobacco treatment delivery.

C3d-positive donor-specific antibodies have a role in pretransplant risk stratification of cross-match-positive HLA-incompatible renal transplantation: United Kingdom multicentre study.

Anti-HLA-antibody characteristics aid to risk-stratify patients and improve long-term renal graft outcomes. Complement activation by donor-specific antibody (DSA) is an important characteristic that may determine renal allograft outcome. There is heterogeneity in graft outcomes within the moderate to high immunological risk cases (cross-match-positive). We explored the role of C3d-positive DSAs in sub-stratification of cross-match-positive cases and relate to the graft outcomes. We investigated 139 cross-match-positive living-donor renal transplant recipients from four transplant centres in the United Kingdom. C3d assay was performed on serum samples obtained at pretreatment (predesensitization) and Day 14 post-transplant. C3d-positive DSAs were found in 52 (37%) patients at pretreatment and in 37 (27%) patients at Day 14 post-transplant. Median follow-up of patients was 48 months (IQR 20.47-77.57). In the multivariable analysis, pretreatment C3d-positive DSA was independently associated with reduced overall graft survival, the hazard ratio of 3.29 (95% CI 1.37-7.86). The relative risk of death-censored five-year graft failure was 2.83 (95% CI 1.56-5.13). Patients with both pretreatment and Day 14 C3d-positive DSAs had the worst five-year graft survival at 45.5% compared with 87.2% in both pretreatment and Day 14 C3d-negative DSA patients with the relative risk of death-censored five-year graft failure was 4.26 (95% CI 1.79, 10.09). In this multicentre study, we have demonstrated for the first time the utility of C3d analysis as a distinctive biomarker to sub-stratify the risk of poor graft outcome in cross-match-positive living-donor renal transplantation.

The impact of social constraints on insomnia among African-American breast cancer survivors: The mediating role of fear of recurrence.

OBJECTIVE: Insomnia is a significant concern among African-American breast cancer survivors (BCS). Social constraints (SC)-receiving unsupportive or critical responses when expressing trauma-related emotions-and fear of recurrence (FOR) have been associated with insomnia. We examined FOR as a mediator in the relationship between SC and insomnia in African-American BCS. We hypothesized a direct effect of SC on insomnia, and an indirect effect of SC on insomnia through FOR. METHODS: Sixty-four African-American BCS completed a questionnaire assessing demographics, clinical characteristics, SC, FOR, and insomnia. Participants were an average of M = 8.41 (SD = 5.8) year survivors. The mediation was tested using PROCESS for SPSS. RESULTS: The direct effect of SC on insomnia was significant (direct effect = .17, SE = .08, P = .04). Moreover, the indirect effect of SC on insomnia through FOR was significant (indirect effect = .19, SE = .10, 95% CI = .05, .41). CONCLUSIONS: Experiencing SC from family and friends could produce cognitions that impact sleep for BCS, and FOR could be one of those cognitions. Family-based models of care that emphasize the emotional needs of survivors and families could be a relevant strategy to address the SC that impacts sleep.

Dispositional shame and guilt as predictors of depressive symptoms and anxiety among adults with lung cancer: The mediational role of internalized stigma.

PURPOSE: The current study investigated whether dispositional tendencies to experience shame and guilt (i.e., shame- and guilt- proneness) were associated with higher levels of internalized stigma and, in turn, higher depressive symptoms and anxiety in adults with lung cancer. METHOD: Participants (N = 50, 56.0% female) were men and women who received a clinical consultation for lung cancer and completed validated questionnaires. Mediation modeling using bootstrapping was used to characterize relationships between shame- and guilt-proneness, lung cancer stigma, depressive symptoms, and anxiety. RESULTS: Higher guilt-proneness was associated significantly with higher anxiety (b = 0.69, SE=0.28, 95% CI [0.13, 1.26]) and higher shame-proneness was associated significantly with higher depressive symptoms (b = 0.56, SE = 0.19, 95% CI [0.18, 0.93]), beyond sociodemographic, medical, and smoking-related characteristics. Higher lung cancer stigma also significantly mediated the relationship between guilt-proneness and anxiety (indirect effect = 0.43, SE = .20, 95% CI [0.08, 0.89]) but not between shame-proneness and depressive symptoms. CONCLUSIONS: Shame- and guilt-proneness are associated significantly with depressive symptoms and anxiety, respectively, and the relationship between guilt-proneness and anxiety is explained in part by internalized stigma in a sample of newly diagnosed lung cancer patients. Findings carry implications for the early identification of lung cancer patients in need of additional supportive care services and highlight internalized stigma as a target for psychosocial intervention.

Real-world Independent Testing of e-ASPECTS Software (RITeS): statistical analysis plan.

Background: Artificial intelligence-based software may automatically detect ischaemic stroke lesions and provide an Alberta Stroke Program Early CT score (ASPECTS) on CT, and identify arterial occlusion and provide a collateral score on CTA. Large-scale independent testing will inform clinical use, but is lacking. We aim to test e-ASPECTS and e-CTA (Brainomix, Oxford UK) using CT scans obtained from a range of clinical studies. Methods: Using prospectively collected baseline CT and CTA scans from 10 national/international clinical stroke trials or registries (total >6600 patients), we will select a large clinically representative sample for testing e-ASPECTS and e-CTA compared to previously acquired independent expert human interpretation (reference standard). Our primary aims are to test agreement between software-derived and masked human expert ASPECTS, and the diagnostic accuracy of e-ASPECTS for identifying all causes of stroke symptoms using follow-up imaging and final clinical opinion as diagnostic ground truth. Our secondary aims are to test when and why e-ASPECTS is more or less accurate, or succeeds/fails to produce results, agreement between e-CTA and human expert CTA interpretation, and repeatability of e-ASPECTS/e-CTA results. All testing will be conducted on an intention-to-analyse basis. We will assess agreement between software and expert-human ratings and test the diagnostic accuracy of software.  Conclusions: RITeS will provide comprehensive, robust and representative testing of e-ASPECTS and e-CTA against the current gold-standard, expert-human interpretation.

Electroneutral polymersomes for combined cancer chemotherapy.

Combination cancer chemotherapy provides an important treatment tool, both as an adjuvant and neoadjuvant treatment, this shift in focus from mono to combination therapies has led to increased interest in drug delivery systems (DDS). DDSs, such as polymersomes, are capable of encapsulating large amounts of multiple drugs with both hydrophilic and hydrophobic properties simultaneously, as well as offering a mechanism to combat multi drug resistant cancers and poor patient tolerance of the cytotoxic compounds utilised. In this article, we report the formulation and evaluation of a novel electroneutral polymersome capable of high encapsulation efficacies for multiple drugs (Doxorubicin, 5-Fluorouracil and leucovorin). The in-vivo biodistribution of the polymersome were established and they were found to accumulate largely in tumour tissue. Polymersome encapsulating the three chemotherapeutic drugs were assessed both in-vitro (BxPC-3 cell line) and in-vivo (following intratumoral and intravenous administration) and compared with the same concentration of the three drugs in solution. We report better efficacy and higher maximum tolerated dose for our combination drug loaded polymersomes in all experiments. Furthermore, intratumorally injected combination drug loaded polymersomes exhibited a 62% reduction in tumour volume after 13 days when compared with the free combination solutions. A smaller differential of 13% was observed for when treatment was administered intravenously however, importantly less cardiotoxicity was displayed from the polymersomal DDS. In this study, expression of a number of survival-relevant genes in tumours treated with the free chemotherapy combination was compared with expression of those genes in tumours treated with the polymersomes harbouring those drugs and the significance of findings is discussed. STATEMENT OF SIGNIFICANCE: The shift in focus from mono to combination chemotherapies has led to an increased interest in the role of drug delivery systems (DDS). Liposomes, although commercialized for mono therapy, have lower loading capacities and stability than their polymeric counterpart, polymersomes. Polymersomes are growing in prevalence as their advantageous properties are better understood and exploited. Here we present a novel polymersome for the encapsulation of three anticancer compounds. This is the first time this particular polymersome has been used to encapsulate these three compounds with both an in-vitro and in-vivo evaluation carried out. This work will be of interest to those in the field of combination therapy, drug delivery, drug toxicity, multidrug resistance, liposomes, DDS and polymersomes.

Clinical risk stratification of paediatric renal transplant recipients using C1q and C3d fixing of de novo donor-specific antibodies.

INTRODUCTION: We have previously shown that children who developed de novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) had greater decline in allograft function. We hypothesised that patients with complement-activating DSA would have poorer renal allograft outcomes. METHODS: A total of 75 children developed DSA in the original study. The first positive DSA sample was subsequently tested for C1q and C3d fixing. The primary event was defined as 50% reduction from baseline estimated glomerular filtration rate and was analysed using the Kaplan-Meier estimator. RESULTS: Of 65 patients tested, 32 (49%) and 23 (35%) tested positive for C1q and C3d fixing, respectively. Of the 32 C1q-positive (c1q+) patients, 13 (41%) did not show concomitant C3d fixing. The mean fluorescence intensity values of the original immunoglobulin G DSA correlated poorly with complement-fixing positivity (C1q: adjusted R 2 0.072; C3d: adjusted R 2 0.11; p < 0.05). C1q+ antibodies were associated with acute tubulitis [0.75 ± 0.18 (C1q+) vs. 0.25 ± 0.08 (C1q-) episodes per patient (mean ± standard error of the mean; p < 0.05] but not with worse long-term renal allograft dysfunction (median time to primary event 5.9 (C1q+) vs. 6.4 (C1q-) years; hazard ratio (HR) 0.74; 95% confidence ratio (CI) 0.30-1.81; p = 0.58]. C3d-positive (C3d+) antibodies were associated with positive C4d histological staining [47% (C3d+) vs. 20% (C3d-); p = 0.04] and with significantly worse long-term allograft dysfunction [median time to primary event: 5.6 (C3d+) vs. 6.5 (C3d-) years; HR 0.38; 95% CI 0.15-0.97; p = 0.04]. CONCLUSION: Assessment of C3d fixing as part of prospective HLA monitoring can potentially aid stratification of patients at the highest risk of long-term renal allograft dysfunction.

A Restorative Yoga Intervention for African-American Breast Cancer Survivors: a Pilot Study.

BACKGROUND: Data show that yoga is effective for improving health-related outcomes in breast cancer survivors. While breast cancer is the most commonly diagnosed cancer among African-American women (AAW), AAW are less likely to engage in yoga compared to other ethnic groups. The goals of the current study were to assess the feasibility of an 8-week restorative yoga program among African-American breast cancer survivors (AA BCS). Specifically, study aims were to (1) measure changes in study outcomes in a restorative yoga (RY) group compared to a wait list control group, (2) assess adherence to the RY program, and (3) assess program satisfaction among study participants. METHODS: Thirty-three AA BCS were randomly assigned to either the RY intervention (n = 18) or wait list control group (n = 15). RY classes met once per week for 8 weeks. Pre- and post-testing assessments were measured at 0 and 8 weeks (immediately post-intervention). RESULTS: Depression scores at follow-up were significantly lower in the yoga group (M = 4.78, SD = 3.56) compared to the control group (M = 6.91, SD = 5.86). No significant group differences were observed for sleep quality, fatigue, or perceived stress. Yoga program participants completing baseline assessments demonstrated 61% adherence to the yoga classes. Average rating of the yoga program was "very useful." Recommendations for future yoga programs were provided. CONCLUSIONS: This study suggests that yoga has a beneficial effect on depression in AA BCS. There is, however, a need to further explore the benefits of yoga among minority breast cancer survivors using a study with larger sample sizes.

Cholesteryl to improve the cellular uptake of polymersomes within HeLa cells.

The need to develop a greater understanding of drug delivery systems has arisen through the development of alternative biological based therapeutics. Drug delivery systems need to adapt and respond to this increasing demand for cellular transportation of highly charged species. Polymersomal drug delivery systems have displayed great potential and versatility for such a task. In this manuscript we present the synthesis, characterisation and biological evaluation of six amphiphilic random co polymers with varying amounts of cholesteryl (0-39%wt) before the subsequent formation into polymersomes. The polymersomes were then analysed for size, zeta potential, encapsulation efficiency, release kinetics and cellular uptake. Results confirmed that the polymersome containing 12%wt cholesteryl polymer displayed a ten-fold increase in cellular uptake of Fitc-CM-dextran when compared to un-encapsulated drug, crossing the cellular membrane via endocytosis. The size of these vehicles ranged between 100 and 500nm, zeta potential was shown to be neutral at -0.82mV ±0.2 with encapsulation efficiencies in the region of 60%. The ease of adaptability and preparation of such systems renders them a viable alternative to liposomal drug delivery systems.

Recent advances in amphiphilic polymers for simultaneous delivery of hydrophobic and hydrophilic drugs.

Nanomedicine has evolved with the use of biological compounds such as proteins, peptides and DNA. These hydrophilic and often highly charged compounds require a delivery system to allow effective transport and release at the site of action. These new biological therapeutics have not replaced the more traditional smaller molecule, but instead are working synergistically to the benefit of the end user. To that end, drug delivery systems are now required to encapsulate both larger hydrophilic compounds as well as the smaller and generally more hydrophobic compound. This review highlights the emerging role in drug delivery of amphiphilic polymers that by their very nature can associate with compounds of differing physicochemical properties, in particular the role of micelles, polymersomes and nanocapsules.

A charge neutral, size tuneable polymersome capable of high biological encapsulation efficiency and cell permeation.

The field of therapeutics is evolving to include a greater proportion of higher molecular weight, hydrophilic biological compounds. To cater for this new era in healthcare the concomitant development of appropriate drug delivery systems is essential to aid cellular permeation. In this manuscript we present the synthesis, characterisation and biological evaluation of a charge neutral polymersome (Ps) based drug delivery system (DDS) using an amphiphilic pegylated random copolymer. A detailed dynamic light scattering study revealed that the hydrodynamic diameter of the Ps can be tailored to a specific size simply by varying the quantities and ratios used during the preparation step. The zeta potential of this new drug delivery system was determined to be -0.095 ± 0.037 mV, the encapsulation efficiency of Fitc-CM-Dextran (4 KDa) was 70%, the uptake of Fitc-CM-Dextran by Hela cells was increased 4-fold when encapsulated within the polymersomal system. The facile preparation, high loading capacity and size tuneable nature of this Ps renders it a promising alternative to the ever growing array of currently available Ps.