Clinical validation of circulating GDF15/MIC-1 as a marker of response to docetaxel and survival in men with metastatic castration-resistant prostate cancer.

BACKGROUND: Elevated circulating growth differentiation factor (GDF15/MIC-1), interleukin 4 (IL4), and IL6 levels were associated with resistance to docetaxel in an exploratory cohort of men with metastatic castration-resistant prostate cancer (mCRPC). This study aimed to establish level 2 evidence of cytokine biomarker utility in mCRPC. METHODS: IntVal: Plasma samples at baseline (BL) and Day 21 docetaxel (n = 120). ExtVal: Serum samples at BL and Day 42 of docetaxel (n = 430). IL4, IL6, and GDF15 levels were measured by ELISA. Monocytes and dendritic cells were treated with 10% plasma from men with high or low GDF15 or recombinant GDF15. RESULTS: IntVal: Higher GDF15 levels at BL and Day 21 were associated with shorter overall survival (OS) (BL; p = 0.03 and Day 21; p = 0.004). IL4 and IL6 were not associated with outcomes. ExtVal: Higher GDF15 levels at BL and Day 42 predicted shorter OS (BL; p < 0.0001 and Day 42; p < 0.0001). Plasma from men with high GDF15 caused an increase in CD86 expression on monocytes (p = 0.03), but was not replicated by recombinant GDF15. CONCLUSIONS: Elevated circulating GDF15 is associated with poor prognosis in men with mCRPC receiving docetaxel and may be a marker of changes in the innate immune system in response to docetaxel resistance. These findings provide a strong rationale to consider GDF15 as a biomarker to guide a therapeutic trial of drugs targeting the innate immune system in combination with docetaxel in mCRPC.

CD300f signalling induces inhibitory human monocytes/macrophages.

The CD300 glycoproteins are a family of related leucocyte surface molecules that regulate the immune response via their paired triggering and inhibitory receptors. Here we studied CD300f, an apoptotic cell receptor, and how it modulates the function of human monocytes and macrophages. We showed that CD300f signalling by crosslinking with anti-CD300f mAb (DCR-2) suppressed monocytes causing upregulation of the inhibitory molecule, CD274 (PD-L1) and their inhibition of T cell proliferation. Furthermore, CD300f signalling drove macrophages preferentially towards M2-type with upregulation of CD274, which was further enhanced by IL-4. CD300f signalling activates the PI3K/Akt pathway in monocytes. Inhibition of PI3K/Akt signalling resulting from CD300f crosslinking leads to downregulation of CD274 expression on monocytes. These findings highlight the potential use of CD300f blockade in cancer immune therapy to target immune suppressive macrophages in the tumour microenvironment, a known resistance mechanism to PD-1/PD-L1 checkpoint inhibitors.

Dendritic cells as cancer therapeutics.

The ability of immune therapies to control cancer has recently generated intense interest. This therapeutic outcome is reliant on T cell recognition of tumour cells. The natural function of dendritic cells (DC) is to generate adaptive responses, by presenting antigen to T cells, hence they are a logical target to generate specific anti-tumour immunity. Our understanding of the biology of DC is expanding, and they are now known to be a family of related subsets with variable features and function. Most clinical experience to date with DC vaccination has been using monocyte-derived DC vaccines. There is now growing experience with alternative blood-derived DC derived vaccines, as well as with multiple forms of tumour antigen and its loading, a wide range of adjuvants and different modes of vaccine delivery. Key insights from pre-clinical studies, and lessons learned from early clinical testing drive progress towards improved vaccines. The potential to fortify responses with other modalities of immunotherapy makes clinically effective "second generation" DC vaccination strategies a priority for cancer immune therapists.

Topoisomerases I and III inhibit R-loop formation to prevent unregulated replication in the chromosomal Ter region of Escherichia coli.

Type 1A topoisomerases (topos) are the only ubiquitous topos. E. coli has two type 1A topos, topo I (topA) and topo III (topB). Topo I relaxes negative supercoiling in part to inhibit R-loop formation. To grow, topA mutants acquire compensatory mutations, base substitutions in gyrA or gyrB (gyrase) or amplifications of a DNA region including parC and parE (topo IV). topB mutants grow normally and topo III binds tightly to single-stranded DNA. What functions topo I and III share in vivo and how cells lacking these important enzymes can survive is unclear. Previously, a gyrB(Ts) compensatory mutation was used to construct topA topB null mutants. These mutants form very long filaments and accumulate diffuse DNA, phenotypes that appears to be related to replication from R-loops. Here, next generation sequencing and qPCR for marker frequency analysis were used to further define the functions of type 1A topos. The results reveal the presence of a RNase HI-sensitive origin of replication in the terminus (Ter) region of the chromosome that is more active in topA topB cells than in topA and rnhA (RNase HI) null cells. The S9.6 antibodies specific to DNA:RNA hybrids were used in dot-blot experiments to show the accumulation of R-loops in rnhA, topA and topA topB null cells. Moreover topA topB gyrB(Ts) strains, but not a topA gyrB(Ts) strain, were found to carry a parC parE amplification. When a topA gyrB(Ts) mutant carried a plasmid producing topo IV, topB null transductants did not have parC parE amplifications. Altogether, the data indicate that in E. coli type 1A topos are required to inhibit R-loop formation/accumulation mostly to prevent unregulated replication in Ter, and that they are essential to prevent excess negative supercoiling and its detrimental effects on cell growth and survival.

Assessing the medical workforces perceived barriers to the prescription of risk-reducing medication for women at high-risk of breast cancer.

This study aims to determine the attitudes and barriers of Australian oncology health professionals towards using tamoxifen as a breast cancer risk-reducing medication (RRM). Our target group was health professionals involved in breast cancer risk assessment or treatment. Members of relevant medical organizations in Australia and New Zealand were invited to participate in a web-based survey assessing: their attitudes towards tamoxifen as a RRM; which health professionals they felt were responsible for initiating and monitoring women on RRM and their views on workforce issues related to RRM prescription. There were 100 respondents, including 33 genetic health professionals, 32 medical oncologists and 20 surgeons. Respondents perceived tamoxifen to be effective as a RRM (99%). However, only 41% of prescribing health professionals (n = 64) had ever prescribed tamoxifen as a RRM. Overall, survey respondents felt that the initiation of RRM was the role of specialists. Assessing a patient's risk of breast cancer was reported to be the role of cancer geneticists/familial cancer clinicians (74%) and medical oncologists (66%). Discussion about the use of RRM was reported to be the role of these same groups (84% and 85% respectively). Medical oncologists (83%) and breast physicians (70%) were most frequently considered to be responsible for initiating the prescription and monitoring women once commenced on RRM (72% and 71% respectively). Oncology health professionals express confidence in the effectiveness of tamoxifen as a RRM despite reporting low prescription rates. Findings demonstrate that these oncology health professionals felt that initiation of RRM was the role of cancer specialists, despite preventative medicine being seen as a primary care activity. If uptake among at-risk women increases, this will put a significant burden on cancer services and GPs will need to take on a greater role in the delivery of RRM.

Expression of phosphorylated-mTOR during the development of prostate cancer.

BACKGROUND: The PI3K pathway plays a significant role in the progression of prostate cancer (PCa) to an advanced stage. Mouse models suggest that the downstream effector molecule of the PI3K pathway, mTOR, is also important in the development of PCa, where it plays a pivotal role in forming precursor lesions such as high grade prostatic intraepithelial neoplasia (HGPIN). This study was conducted to determine the status of phosphorylated-mTOR (p-mTOR the activated state of mTOR) across the PCa progression model by looking at expression in normal prostate tissue, proliferative inflammatory atrophy (PIA), HGPIN, and PCa. METHODS: Expression of p-mTOR was evaluated by immunohistochemistry on tissue microarrays constructed from 120 archival formalin-fixed paraffin embedded radical prostatectomy tissue specimens. Levels of expression were recorded as the percentage of positive epithelial cells multiplied by the intensity of staining scored as 0-3. RESULTS: p-mTOR expression was found to increase across the progression model with mean staining in non-neoplastic samples of 40 compared to 98 in PIA, 107 in HGPIN, and 136 in cancer (P < 0.001), but without significant increase between HGPIN and PIA. Correlation of high p-mTOR expression with outcome in PCa showed a trend towards worse prognosis, but this was not statistically significant. CONCLUSIONS: This study demonstrates that p-mTOR signaling has a potential role in both the initiation and progression of PCa. These data provide support for further research into the possible use of rapamycin analogues in the treatment of PCa, and raise the possibility that mTOR might be a potential target for chemoprevention.

Retrospective analysis of clinical characteristics and outcomes of patients with carcinoma of unknown primary from three tertiary centers in Australia.

BACKGROUND: Carcinoma of unknown primary (CUP) remains an important tumor entity and a disproportionate cause of cancer mortality. Little is known about the contemporary clinical characteristics, treatment patterns, and outcomes of CUP patients based on updated international classification guidelines. We evaluated a contemporary CUP cohort to provide insight into current clinical practice and the impact of tissue of origin assignment, site-specific and empirical therapy in a real-world setting. METHODS: We conducted a retrospective cohort study of CUP patients, as defined by the updated European Society of Medical Oncology (ESMO) 2023 guidelines, across three tertiary referral centers in Australia between 2015 and 2022. We analyzed clinical characteristics, treatment patterns, and survival outcomes using the Kaplan-Meier method and Cox regression proportional hazard model between favorable and unfavorable risk groups. RESULTS: We identified a total of 123 CUP patients (n = 86 unfavorable, n = 37 favorable risk as per the 2023 ESMO guidelines). Sixty-four patients (52%) were assigned a tissue of origin by the treating clinician. Median progression free survival (PFS) was 6.8 (95% confidence interval (CI) 5.1-12.1) months and overall survival (OS) 10.2 (95% CI 6.0-18.5) months. Unfavorable risk (hazard ratio [HR] 2.9, p = 0.006), poor performance status (HR 2.8, p < 0.001), and non-squamous histology (HR 2.5, p < 0.05) were associated with poor survival outcome. A total of 70 patients (57%) proceeded to systemic therapy. In patients with non-squamous histology and unfavorable risk, site-specific therapy compared to empirical chemotherapy did not improve outcome (median OS 8.2 vs. 11.8 months, p = 0.7). CONCLUSIONS: In this real-world cohort, CUP presentations were heterogenous. Overall survival and rates of systemic treatment were poor. Poor performance status and unfavorable risk were associated with worse survival. For most patients, site-specific therapy did not improve survival outcome. Improved and timely access to diagnostic tests and therapeutics for this group of patients is urgently required.

Support roles, carer burden, and decision-making preferences of carers of older adults with cancer.

INTRODUCTION: Older adults with cancer value the perspectives of significant others and their carers regarding decision-making about treatment. Understanding the support provided by carers, and their perspectives on involvement in treatment decision-making, can help us improve our communication with patients and their supports. We aimed to describe the roles, burden, and decision-making preferences of carers of older adults with cancer. MATERIALS AND METHODS: We performed a cross-sectional survey of carers of older adults (≥65y) with cancer at three centres in Sydney, Australia. Type, frequency, and perspectives on providing care were evaluated using Likert scales. Preferred and perceived role in treatment decision-making by modified Control Preferences Scale, and carer burden by Zarit Burden Index (ZBI-12), were evaluated. Preferred role in decision-making and carer burden were compared between groups (culturally and linguistically diverse backgrounds [CALD], sex, and carer age ≥ 65) by chi-squared or t-tests. RESULTS: One-hundred and fourteen returned surveys were included (23 partially completed). Carer characteristics: median age 55y (range 24-90), female (74 %), child (49 %) and spouse (35 %) of the care-recipient. Care-recipient characteristics: median age 75y (range 65-96), receiving anti-cancer treatment (85 %), and CALD background (44 %). Carers were frequently involved in communication and information gathering (45 % -80 %) and supported instrumental activities of daily living (IADLs) (43 % - 81 %) more frequently than basic activities of daily living (ADLs) (2-13 %). Most (91 %) preferred to be present when treatment options were discussed. Their preferred role in treatment decision-making was passive in 66 %, collaborative in 30 %, and active in 4 %, with most (72 %) playing their preferred role. The preferred role was associated with carer age (p = 0.01) and CALD background (p = 0.04), with younger (<65y) carers and those caring for CALD older adults preferring a more passive role. Carer burden was 'low' in 29 %, 'moderate' in 31 %, and 'high' in 39 %, and providing psychological support was rated most challenging. DISCUSSION: Carers of older adults with cancer play varied support roles, particularly in communication and information gathering. Carers prefer to be present for discussions about treatment options, though favour a passive role in treatment decision-making, upholding patient autonomy. Understanding the communication preferences of carers is an important consideration when supporting the patient in deciding treatment options and direction of care.

Resilience and associated factors in orphaned and separated adolescents in Kenya: Understanding the relationship with care environment and HIV risks.

Orphans are at higher risk of HIV infection and several important HIV risk factors than non-orphans; however, this may be due to a combination of related social, psychological, and economic factors, as well as care environment, rather than orphan status alone. Understanding these complex relationships may aid policy makers in supporting evidence-based, cost-effective programming for this vulnerable population. This longitudinal study uses a causal effect model to examine, through decomposition, the relationship between care environment and HIV risk factors in orphaned and separated adolescents and youths (OSAY) in Uasin Gishu County, Kenya; considering resilience, social, peer, or family support, volunteering, or having one's material needs met as potential mediators. We analysed survey responses from 1105 OSAY age 10-26 living in Charitable Children's Institutions (CCI) (orphanages) and family-based care settings (FBS). Follow-up time was 7-36 months. Care in CCIs (vs. FBS) was associated with a decreased likelihood of engaging in forced, exchange, and consensual sex. Excess relative risks (ERR) attributable to the indirect pathway, mediation, or interaction were not significant in any model. Care environment was not statistically associated with differences in substance use. Our findings support the direct, unmediated, association between institutional care and HIV risk factors.

Variability in the clinical management of fatty acid oxidation disorders: results of a survey of Canadian metabolic physicians.

INTRODUCTION: There is little robust empirical evidence on which to base treatment recommendations for fatty acid oxidation disorders. While consensus guidelines are important, understanding areas where there is a lack of consensus is also critical to inform priorities for future evaluative research. METHODS: We surveyed Canadian metabolic physicians on the treatment of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, and mitochondrial trifunctional protein (MTP) deficiency. We ascertained physicians' opinions on the use of different interventions for the long-term management of patients as well as for the management of acute illness, focusing on identifying interventions characterized by high variability in opinions. We also investigated factors influencing treatment decisions. RESULTS: We received 18 responses (response rate 45%). Participants focused on avoidance of fasting and increased meal frequency as interventions for the management of MCAD deficiency. For the long-chain disorders, avoidance of fasting remained the most consistently endorsed intervention, with additional highly endorsed treatments differing for VLCAD versus LCHAD/MTP deficiency. L-carnitine supplementation and restriction of dietary fat were characterized by high variability in physicians' opinions, as were several interventions specific to long-chain disorders. Social factors and patient characteristics were important influences on treatment decisions. CONCLUSIONS: Based on our findings we suggest that high priority treatments for rigorous effectiveness studies could include L-carnitine supplementation (MCAD and LCHAD/MTP deficiencies), restriction of dietary fat, and, for the long-chain disorders, feeding practices for breastfed infants and the use of various supplements (essential fatty acids, carbohydrates, cornstarch, multivitamins).

The role of chemotherapy in the treatment of advanced appendiceal cancers: summary of the literature and future directions.

Appendiceal cancer is rare and encompasses a diverse group of tumours ranging from low-grade appendiceal mucinous neoplasms to high-grade adenocarcinomas. Appendiceal cancers often spread to the peritoneal cavity causing extensive mucinous dissemination and peritoneal metastases. Prognosis varies with histological subtype. Cytoreductive surgery and heated intraperitoneal chemotherapy is well-established as the most effective treatment achieving long-term survival in some patients. Chemotherapy regimens used to treat appendiceal cancer are extrapolated from the colorectal cancer setting, but disease biology differs and outcomes are inferior. The role of chemotherapy in the treatment of appendiceal cancer remains poorly defined. There is an urgent need to develop novel tailored treatment strategies in the perioperative and unresectable setting. This review aims to evaluate the literature for patients who received intraperitoneal and systemic chemotherapy for appendiceal cancers.

The relationships between resilience, care environment, and social-psychological factors in orphaned and separated adolescents in western Kenya.

The relationships between care environment, resilience, and social factors in orphaned and separated adolescents and youths (OSAY) in western Kenya are complex and under-studied. This study examines these relationships through the analysis of survey responses from OSAY living in Charitable Children's Institutes (CCI) and family-based care settings (FBS) in Uasin Gishu County, Kenya. The associations between 1) care environment and resilience (measured using the 14-item Resilience Scale); 2) care environment and factors thought to promote resilience (e.g. social, family, and peer support); and 3) resilience and these same resilience-promoting factors, were examined using multivariable linear and logistic regressions. This cross-sectional study included 1202 OSAY (50.4% female) aged 10-26 (mean=16; SD=3.5). The mean resilience score in CCIs was 71 (95%CI=69-73) vs. 64 (95%CI=62-66) in FBS. OSAY in CCIs had higher resilience (ß=7.67; 95%CI=5.26-10.09), social support (ß=0.26; 95%CI=0.14-0.37), and peer support (ß=0.90; 95%CI=0.64-1.17) than those in FBS. OSAY in CCIs were more likely to volunteer than those in FBS (OR=3.72; 95%CI=1.80-7.68), except in the male subgroup. Family (ß=0.42; 95%CI=0.24-0.60), social (ß=4.19; 95%CI=2.53-5.85), and peer (ß=2.13; 95%CI=1.44-2.83) relationships were positively associated with resilience in all analyses. Volunteering was positively associated with resilience (ß=5.85; 95%CI=1.51-10.19). The factor most strongly related to resilience in both fully adjusted models was peer support. This study found a strong relationship between care environment and resilience. Care environment and resilience each independently demonstrated strong relationships with peer support, social support, and participating in volunteer activities. Resilience also had a strong relationship with familial support. These data suggest that resilience can be developed through strategic supports to this vulnerable population.

Moving on From Sipuleucel-T: New Dendritic Cell Vaccine Strategies for Prostate Cancer.

Tumors evade the immune system though a myriad of mechanisms. Using checkpoint inhibitors to help reprime T cells to recognize tumor has had great success in malignancies including melanoma, lung, and renal cell carcinoma. Many tumors including prostate cancer are resistant to such treatment. However, Sipuleucel-T, a dendritic cell (DC) based immunotherapy, improved overall survival (OS) in prostate cancer. Despite this initial success, further DC vaccines have failed to progress and there has been limited uptake of Sipuleucel-T in the clinic. We know in prostate cancer (PCa) that both the adaptive and the innate arms of the immune system contribute to the immunosuppressive environment. This is at least in part due to dysfunction of DC that play a crucial role in the initiation of an immune response. We also know that there is a paucity of DC in PCa, and that those there are immature, creating a tolerogenic environment. These attributes make PCa a good candidate for a DC based immunotherapy. Ultimately, the knowledge gained by much research into antigen processing and presentation needs to translate from bench to bedside. In this review we will analyze why newer vaccine strategies using monocyte derived DC (MoDC) have failed to deliver clinical benefit, particularly in PCa, and highlight the emerging antigen loading and presentation technologies such as nanoparticles, antibody-antigen conjugates and virus co-delivery systems that can be used to improve efficacy. Lastly, we will assess combination strategies that can help overcome the immunosuppressive microenvironment of PCa.

Patient satisfaction with telehealth consultations in medical oncology clinics: A cross-sectional study at a metropolitan centre during the COVID-19 pandemic.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has resulted in a widespread adoption of telehealth (phone and video consultations) in cancer care worldwide. The aim of this study was to determine patient satisfaction with telehealth consultations with their medical oncologist at a tertiary cancer centre in Sydney, Australia. METHODS: Patients who attended a routine telehealth appointment at the medical oncology outpatient clinic were recruited to complete a questionnaire containing 16 items, each on a 5-point Likert scale regarding satisfaction levels in various aspects of telehealth and their willingness to continue telehealth after the pandemic. Patients were also invited to provide suggestions for improvement. RESULTS: In total, 150 patients were invited to participate, and 103 valid questionnaires were returned. Median age was 63 years (range: 25-90), 49% of patients were male, 63% of patients had advanced cancer and 81% were on active treatment. In total, 95% of participants indicated that they were satisfied (score ≥4) with telehealth. 82% of participants preferred to continue telehealth consultations after the coronavirus disease 2019 pandemic, but ideally with a mix of telehealth and in-person consultations. Phone appointments (vs. video, p < 0.002), patients with advanced cancer (vs. early, p < 0.036) and pre-chemotherapy/immunotherapy/targeted therapy treatment reviews (vs. follow-up appointments, p < 0.001) were significantly associated with a willingness to continue telehealth. DISCUSSION: Patients were overwhelmingly satisfied with telehealth during the study period and were willing to continue telehealth for some appointments beyond the coronavirus disease 2019 pandemic. More research into the effectiveness, safety and implementation of telehealth to compliment traditional face-to-face services for patient-centred cancer care is required.

Stage migration in localized prostate cancer has no effect on the post-radical prostatectomy Kattan nomogram.

OBJECTIVE: To investigate the effect of prostate-specific antigen (PSA) testing on stage migration in an Australian population, and its consequences on the prognostic accuracy of the post-radical prostatectomy (RP) Kattan nomogram, as in North America widespread PSA testing has resulted in prostate cancer stage migration, questioning the utility of prognostic nomograms in this setting. PATIENTS AND METHODS: The study comprised 1008 men who had consecutive RP for localized prostate cancer between 1991 and 2001 at one institution. Two groups were assessed, i.e. those treated in 1991-96 (group 1, the early PSA era), and 1997-2001 (group 2, the contemporary PSA era). Differences in clinicopathological features between the groups were analysed by chi-squared testing and survival modelling. Individual patient data were entered into the post-RP Kattan nomogram and the efficacy assessed by receiver- operating characteristic curve analysis. RESULTS: Patients in group 2 had lower pathological stage disease (P = 0.01) and fewer cancers with Gleason score > or =8 (P < 0.001) than group 1. Multivariate analysis identified preoperative serum PSA level (P < 0.01) and Gleason score (P < 0.01) as strong predictors of biochemical relapse in both groups. In group 2 pathological stage was not significant, but margin involvement became highly significant (P = 0.004). There was no difference in the predictive accuracy of the Kattan nomogram between the groups (P = 0.253). CONCLUSIONS: These findings show a downward stage migration towards organ-confined disease after the introduction of widespread PSA testing in an Australian cohort. Despite this, the Kattan nomogram remains a robust prognostic tool in clinical practice.

Reliability and validity of the RS14 in orphaned and separated adolescents and youths in western Kenya.

PURPOSE: The 14-item Resilience Scale (RS14) is a tool designed to measure psychological resilience. It has been used effectively in diverse populations. However, its applicability is largely unknown for Sub-Saharan adolescent populations and completely unknown for orphaned and separated adolescents and youths (OSAY), a highly vulnerable population for whom resilience may be critical. This study assesses the RS14's psychometric properties for OSAY in Uasin Gishu County, Kenya. METHODS: Survey responses from a representative sample of 1016 OSAY (51.3% female) aged 10-25 (mean = 16; SD = 3.5) living in institutional and home-based environments in Uasin Gishu County were analyzed. The RS14's psychometric properties were assessed by examining internal consistency reliability, confirmatory factor analyses, and convergent validity using correlations between resilience and each of social support and depression. Sub-analyses were conducted by age and sex. RESULTS: Resilience scores ranged from 14-98 (mean = 66; SD = 19) with no sex-based significant difference. Resilience was higher for those aged ≥18 (mean = 69; range = 14-98) versus age <18 (mean = 65; range = 14-98). Internal consistency was good (Cronbach's α = .90). Confirmatory factor analysis indicated a 1-factor solution, though the model fit was only moderate. Resilience was positively correlated with social support in all ages (.22; p < .001) and negatively correlated with depression in individuals age <18 (-.22; p < .001). The relationship between resilience and depression in individuals age ≥18 was statistically significant only in females (-.17; p = .026). CONCLUSION: This study demonstrates reasonable evidence that the RS14 is both valid and reliable for measuring psychological resilience in the population of OSAY in western Kenya.

Targeting CD300f to enhance hematopoietic stem cell transplantation in acute myeloid leukemia.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) significantly reduces the rate of relapse in acute myeloid leukemia (AML) but comes at the cost of significant treatment-related mortality. Despite the reduction in relapse overall, it remains common, especially in high-risk groups. The outcomes for patients who relapse after transplant remains very poor. A large proportion of the morbidity that prevents most patients from accessing allo-HSCT is due to toxic nonspecific conditioning agents that are required to remove recipient hematopoietic stem and progenitor cells (HSPCs), allowing for successful donor engraftment. CD300f is expressed evenly across HSPC subtypes. CD300f has transcription and protein expression equivalent to CD33 on AML. We have developed an anti-CD300f antibody that efficiently internalizes into target cells. We have generated a highly potent anti-CD300f antibody-drug conjugate (ADC) with a pyrrolobenzodiazepine warhead that selectively depletes AML cell lines and colony forming units in vitro. The ADC synergizes with fludarabine, making it a natural combination to use in a minimal toxicity conditioning regimen. Our ADC prolongs the survival of mice engrafted with human cell lines and depletes primary human AML engrafted with a single injection. In a humanized mouse model, a single injection of the ADC depletes CD34+ HSPCs and CD34+CD38-CD90+ hematopoietic stem cells. This work establishes an anti-CD300f ADC as an attractive potential therapeutic that, if validated in transplant models using a larger cohort of primary AML samples, will reduce relapse rate and toxicity for patients with AML undergoing allo-HSCT.

Long-term care facility National Healthcare Safety Network enrollment challenges, 2016.

The Centers for Medicare & Medicaid Services has a national goal to increase the number of long-term care facilities reporting Clostridium difficile infection data to the Centers for Disease Control and Prevention. A partnership between the Tennessee Department of Health and the quality improvement organization, Qsource, helped facilitate successful enrollment into the National Healthcare Safety Network for nursing homes in the state of Tennessee.

Physiotherapists utilizing diagnostic ultrasound in shoulder clinics. How useful do patients find immediate feedback from the scan as part of the management of their problem?

AIMS: Physiotherapists are beginning to utilize diagnostic ultrasound imaging in upper limb/shoulder clinics. The aim of the present study was to receive feedback on the views of the patients concerning the usefulness of the information obtained immediately from the scan in the management of their problem. METHODS: A questionnaire was offered to all patients attending a physiotherapist-led upper limb/shoulder clinic who underwent ultrasound imaging as part of a shoulder assessment over a 6-month period. A total of 103 patients completed a questionnaire for analysis. RESULTS: Patients rated the ultrasound scan to be of benefit in all aspects. Regarding the ability to understand their shoulder problem better and in feeling reassured about their problem, 97% of patients either strongly agreed or agreed that this was the case. Concerning the capability of managing their problem, 89% of patients strongly agreed or agreed that they felt more able to do this. In total, 96% of patients evaluated the ultrasound scan to be of very high/high value to them. CONCLUSION: Patients highly rate the information gained from ultrasound imaging in a physiotherapy-led upper limb/shoulder clinic and felt that it assisted them in the understanding, reassurance and management of their problem.

Effects of embryonic exposure to ethanol on zebrafish visual function.

Across a variety of species, including humans, it has been shown that embryos exposed to ethanol display eye abnormalities as well as deficiencies in visual physiology and behavior. The purpose of this study was to examine the effects of embryonic exposure to ethanol on visual function in zebrafish. Visual function was assessed physiologically, via electroretinogram (ERG) recordings, and behaviorally, by measuring visual acuity with the optomotor response. Zebrafish larvae were exposed to 1.5% ethanol at various times during development, including the period of maximal eye development. The results show that ethanol effects on visual function were most pronounced when exposure occurred during eye development. ERG recordings from ethanol-exposed larvae differed from normal subjects both in shape of the response waveform and in visual thresholds under both light and dark adaptation; the differences were more pronounced under lower levels of adaptation. Also, ethanol-exposed larvae displayed lower visual acuity as determined from the optomotor response. These results indicate embryonic ethanol exposure affects visual function particularly when exposure occurs during eye development. In addition, these findings illustrate the usefulness of the zebrafish as a viable animal model for studying Fetal Alcohol Syndrome (FAS).