Adipocyte autophagy limits gut inflammation by controlling oxylipin and IL-10.

Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, either through their function as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however, whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte-specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti-inflammatory energy substrates. Instead, Atg7-deficient adipose tissues exhibited an oxylipin imbalance, driven through an NRF2-mediated upregulation of Ephx1. This shift reduced secretion of IL-10 from adipose tissues, which was dependent on the cytochrome P450-EPHX pathway, and lowered circulating levels of IL-10 to exacerbate intestinal inflammation. These results suggest an underappreciated fat-gut crosstalk through an autophagy-dependent regulation of anti-inflammatory oxylipins via the cytochrome P450-EPHX pathway, indicating a protective effect of adipose tissues for distant inflammation.

Preclinical characterization of ISB 1342, a CD38 × CD3 T-cell engager for relapsed/refractory multiple myeloma.

Although treatment of multiple myeloma (MM) with daratumumab significantly extends the patient's lifespan, resistance to therapy is inevitable. ISB 1342 was designed to target MM cells from patients with relapsed/refractory MM (r/r MM) displaying lower sensitivity to daratumumab. ISB 1342 is a bispecific antibody with a high-affinity Fab binding to CD38 on tumor cells on a different epitope than daratumumab and a detuned scFv domain affinity binding to CD3ε on T cells, to mitigate the risk of life-threatening cytokine release syndrome, using the Bispecific Engagement by Antibodies based on the TCR (BEAT) platform. In vitro, ISB 1342 efficiently killed cell lines with different levels of CD38, including those with a lower sensitivity to daratumumab. In a killing assay where multiple modes of action were enabled, ISB 1342 showed higher cytotoxicity toward MM cells compared with daratumumab. This activity was retained when used in sequential or concomitant combinations with daratumumab. The efficacy of ISB 1342 was maintained in daratumumab-treated bone marrow patient samples showing lower sensitivity to daratumumab. ISB 1342 induced complete tumor control in 2 therapeutic mouse models, unlike daratumumab. Finally, in cynomolgus monkeys, ISB 1342 displayed an acceptable toxicology profile. These data suggest that ISB 1342 may be an option in patients with r/r MM refractory to prior anti-CD38 bivalent monoclonal antibody therapies. It is currently being developed in a phase 1 clinical study.

Morphogens and growth factor signalling in the myeloma bone-lining niche.

Multiple myeloma is a malignancy caused by the clonal expansion of abnormal plasma cells. Myeloma cells have proven to be incredibly successful at manipulating their microenvironment to promote growth and to evade modern therapies. They have evolved to utilise the integral signalling pathways of the bone and bone marrow to drive disease progression. The bone marrow is often described in the context of a single structure that fills the bone cavity and supports normal haematopoiesis. However, within that structure exists two anatomically different niches, the perivascular niche and the endosteal niche. These contain different cell types functioning to support normal immune and blood cell production as well as healthy bone. These cells secrete numerous signalling molecules that can influence myeloma cell biology and behaviour. The endosteal niche is home to specific bone cell lineages and plays a pivotal role in myeloma cell establishment and survival. This review will concentrate on some of the signalling pathways that are hijacked by myeloma cells to shape a favourable environment, and the different influences myeloma cells are exposed to depending on their spatial location within the bone marrow.

Longevity of SARS-CoV-2 immune responses in hemodialysis patients and protection against reinfection.

Patients with end stage kidney disease receiving in-center hemodialysis (ICHD) have had high rates of SARS-CoV-2 infection. Following infection, patients receiving ICHD frequently develop circulating antibodies to SARS-CoV-2, even with asymptomatic infection. Here, we investigated the durability and functionality of the immune responses to SARS-CoV-2 infection in patients receiving ICHD. Three hundred and fifty-six such patients were longitudinally screened for SARS-CoV-2 antibodies and underwent routine PCR-testing for symptomatic and asymptomatic infection. Patients were regularly screened for nucleocapsid protein (anti-NP) and receptor binding domain (anti-RBD) antibodies, and those who became seronegative at six months were screened for SARS-CoV-2 specific T-cell responses. One hundred and twenty-nine (36.2%) patients had detectable antibody to anti-NP at time zero, of whom 127 also had detectable anti-RBD. Significantly, at six months, 71/111 (64.0%) and 99/116 (85.3%) remained anti-NP and anti-RBD seropositive, respectively. For patients who retained antibody, both anti-NP and anti-RBD levels were reduced significantly after six months. Eleven patients who were anti-NP seropositive at time zero, had no detectable antibody at six months; of whom eight were found to have SARS-CoV-2 antigen specific T cell responses. Independent of antibody status at six months, patients with baseline positive SARS-CoV-2 serology were significantly less likely to have PCR confirmed infection over the following six months. Thus, patients receiving ICHD mount durable immune responses six months post SARS-CoV-2 infection, with fewer than 3% of patients showing no evidence of humoral or cellular immunity.

Metabolism in the Tumour-Bone Microenvironment.

PURPOSE OF REVIEW: For solid tumours such as breast and prostate cancer, and haematological malignancies such as myeloma, bone represents a supportive home, where the cellular crosstalk is known to underlie both tumour growth and survival, and the development of the associated bone disease. The importance of metabolic reprogramming is becoming increasingly recognised, particularly within cancer biology, enabling tumours to adapt to changing environments and pressures. This review will discuss our current understanding of metabolic requirements and adaptations within the tumour-bone microenvironment. RECENT FINDINGS: The bone provides a unique metabolic microenvironment, home to highly energy-intensive processes such as bone resorption and bone formation, both of which are dysregulated in the presence of cancer. Approaches such as metabolomics demonstrate metabolic plasticity in patients with advanced disease. Metabolic crosstalk between tumour cells and surrounding stroma supports disease pathogenesis. There is increasing evidence for a key role for metabolic reprogramming within the tumour-bone microenvironment to drive disease progression. As such, understanding these metabolic adaptations should reveal new therapeutic targets and approaches.

Adipokines, adiposity, and bone marrow adipocytes: Dangerous accomplices in multiple myeloma.

Obesity has become a global epidemic influencing the establishment and progression of a wide range of diseases, such as diabetes, cardiovascular disease, and cancer. In 2016, International Agency for Research on Cancer reported that obesity is now associated with 13 different cancers, one of which is multiple myeloma (MM), a destructive cancer of plasma cells that predominantly reside in the bone marrow. Obesity is the accumulation of excess body fat, which causes metabolic, endocrine, immunologic, and inflammatory-like changes. Obesity is usually associated with an increase in visceral and/or subcutaneous fat; however, an additional fat depot that also responds to diet-induced changes is bone marrow adipose tissue (BMAT). There have been several studies over the past few decades that have identified BMAT as a key driver in MM progression. Adipocytes secrete numerous adipokines, such as leptin, adiponectin, resistin, adipsin, and visfatin, which when secreted at normal controlled levels have protective properties. However, in obesity these levels of secretion change, coupled with an increase in adipocyte number and size causing a profound and lasting effect on the bone microenvironment, contributing to MM cell growth, survival, and migration as well as potentially fueling bone destruction. Obesity is a modifiable risk factor making it an attractive option for targeted therapy. This review discusses the link between obesity, monoclonal gammopathy of undetermined significance (a benign condition that precedes MM), and myeloma, and the contribution of key adipokines to disease establishment and progression.

Contributions of the Bone Microenvironment to Monoclonal Gammopathy of Undetermined Significance Pathogenesis.

PURPOSE OF REVIEW: MGUS (monoclonal gammopathy of undetermined significance) is a plasma cell disorder characterized by a moderate increase in serum monoclonal protein (≤ 3 g/dL), an increase in bone marrow plasma cell infiltration (≤ 10%) and the absence of any end-organ damage. Although MGUS is considered a benign condition, evidence for clinical consequences is increasing. In this review, we examine the most recent evidence regarding MGUS manifestations and risks and present an overview of MGUS population studies as related to bone disease. Data reveals important MGUS-related bone alterations that may contribute to disease pathogenesis. RECENT FINDINGS: MGUS patients present a rate of 1% per year risk of progression to the more aggressive multiple myeloma (MM) and therefore research has focused on the study of risk factors and the events leading to this progression. However, the exact health implications of MGUS itself and the mechanisms behind them remain unclear. It is now evident that the bone microenvironment plays a key role in hematologic cancers and other oncogenic processes leading to bone metastasis.

Prevention, Diagnosis, and Treatment of Implant Infection in the Distal Upper Extremity.

Implant related infection is relatively unusual in surgery to the hand and distal upper limb. When such infections occur, the consequences can be devastating. We review the latest guidance and research on the prevention, diagnosis, and management of implant-associated infections in the hand and distal upper limb.

Metformin and Prostate Cancer: a New Role for an Old Drug.

PURPOSE OF REVIEW: Since epidemiological studies first demonstrated a potential positive effect of metformin in reducing cancer incidence and mortality, there has been an increased interest in not only better understanding metformin's mechanisms of action but also in exploring its potential anti-cancer effects. In this review, we aim to summarise the current evidence exploring a role for metformin in prostate cancer therapy. RECENT FINDINGS: Preclinical studies have demonstrated a number of antineoplastic biological effects via a range of molecular mechanisms. Data from retrospective epidemiological studies in prostate cancer has been mixed; however, there are several clinical trials currently underway evaluating metformin's role as an anti-cancer agent. Early studies have shown benefits of metformin to inhibit cancer cell proliferation and improve metabolic syndrome in prostate cancer patients receiving androgen deprivation therapy (ADT). While the body of evidence to support a role for metformin in prostate cancer therapy is rapidly growing, there is still insufficient data from randomised trials, which are currently still ongoing. However, evidence so far suggests metformin could be a useful adjuvant agent, particularly in patients on ADT.

The Role of the Microenvironment in Prostate Cancer-Associated Bone Disease.

The bone is a common site for metastasis in patients with advanced prostate carcinoma, and provides a 'fertile' milieu which stimulates tumour growth and associated bone disease. For years, the concept of treatment strategies has remained targeting the tumour itself; however, the occurrence of chemoresistance remains a challenge now more than ever. The attraction of targeting the bone microenvironment in order to disrupt tumour localisation and proliferation stems from the idea that stromal cells are superiorly stable at a genetic level, thus decreasing the risk of resistance manifestation. In this review, we will discuss recent findings with regards to the pathogenesis of prostate cancer-induced bone disease and recent therapeutic strategies in an aim to evaluate the ever increasing role of the microenvironment in disease progression.

Margin index: a useful tool for the breast surgeon?

BACKGROUND: In breast conservation surgery (BCS) for breast cancer, the appropriate surgical margin is controversial. Margin index, a mathematical relationship between tumor size and closest margin, has been shown to be predictive of the probability of residual cancer after BCS for early stage breast cancer. We applied this tool to the same population of patients at our institution to evaluate its ability to predict residual disease after BCS. METHODS: We retrospectively reviewed a prospectively maintained database of women undergoing BCS between 1980 and 2010 at the University of Pennsylvania. A total of 246 women underwent re-excision because of close margins. Average margin index between groups with and without residual disease in the re-excision specimen was compared using the Student t-test. A receiver operating curve was created using logistic regression to assess the overall diagnostic ability of the margin index on the presence or absence of residual disease. RESULTS: Of patients who underwent re-excision, 29% of patients had residual disease. We analyzed several cutoff values for margin index, but none proved to be significant predictors of residual disease. Average margin index was significantly higher for patients without residual disease compared with patients with residual invasive cancer but not for patients with residual ductal carcinoma in situ. CONCLUSIONS: In women undergoing BCS for early stage breast cancer at our institution, margin index was not predictive of the presence of residual cancer on re-excision. We hypothesize that the predictive ability of a margin index is likely limited by several factors including the presence of ductal carcinoma in situ and the location and extent of the close margin.

Aversive conditioning increases short-term wariness but does not change habitat use in black bears associated with conflict.

Conflict between humans and black bears (Ursus americanus) occurs throughout North America with increasing public demand to replace lethal management with non-lethal methods, such as aversive conditioning (AC). AC aims to teach animals to associate negative stimuli with humans or their infrastructure. We sought to test the efficacy of AC using radio-collared black bears in Whistler, British Columbia, by monitoring individuals and assigning those in conflict with people to control or treatment groups. We measured wariness using overt reaction distance, displacement distance, and reaction to researchers before, during and after executing 3-5-day AC programs that consisted of launching projectiles at bears in the treatment group. We also assessed predictors of successful AC events (i.e., leaving at a run), changes in bear use of human-dominated habitat during the day and at night, and the effects of including a sound stimulus to signal the beginning and end of AC events. Among treated bears, overt reaction distance increased by 46.5% and displacement distance increased by 69.0% following AC programs, whereas both overt reaction distance and displacement distance decreased over time among control group bears. Each additional AC event during the previous 30 days increased likelihood of bear departure in response to researcher presence by 4.5%. The success of AC events varied among individuals, declined with distance to cover, and increased with exposure to previous AC events. Projectiles launched from guns were slightly more effective at causing bears to displace compared to those launched from slingshots, and sound stimuli decreased the likelihood of a successful AC event. AC did not alter diurnal use by bears of human-dominated habitat. Our results suggest that AC effectively increases short-term wariness in black bears but does not alter bear use of human-dominated spaces, highlighting the importance of proactive attractant management and prevention of food conditioning.

The integrated on-chip isolation and detection of circulating tumour cells.

Circulating tumour cells (CTCs) are cancer cells shed from a primary tumour which intravasate into the blood stream and have the potential to extravasate into distant tissues, seeding metastatic lesions. As such, they can offer important insight into cancer progression with their presence generally associated with a poor prognosis. The detection and enumeration of CTCs is, therefore, critical to guiding clinical decisions during treatment and providing information on disease state. CTC isolation has been investigated using a plethora of methodologies, of which immunomagnetic capture and microfluidic size-based filtration are the most impactful to date. However, the isolation and detection of CTCs from whole blood comes with many technical barriers, such as those presented by the phenotypic heterogeneity of cell surface markers, with morphological similarity to healthy blood cells, and their low relative abundance (∼1 CTC/1 billion blood cells). At present, the majority of reported methods dissociate CTC isolation from detection, a workflow which undoubtedly contributes to loss from an already sparse population. This review focuses on developments wherein isolation and detection have been integrated into a single-step, microfluidic configuration, reducing CTC loss, increasing throughput, and enabling an on-chip CTC analysis with minimal operator intervention. Particular attention is given to immune-affinity, microfluidic CTC isolation, coupled to optical, physical, and electrochemical CTC detection (quantitative or otherwise).

Host-derived adiponectin is tumor-suppressive and a novel therapeutic target for multiple myeloma and the associated bone disease.

The contributions of the host microenvironment to the pathogenesis of multiple myeloma, including progression from the non-malignant disorder monoclonal gammopathy of undetermined significance, are poorly understood. In the present study, microarray analysis of a murine model requiring a unique host microenvironment for myeloma development identified decreased host-derived adiponectin compared with normal mice. In support, clinical analysis revealed decreased serum adiponectin concentrations in monoclonal gammopathy of undetermined significance patients who subsequently progressed to myeloma. We investigated the role of adiponectin in myeloma pathogenesis and as a treatment approach, using both mice deficient in adiponectin and pharmacologic enhancement of circulating adiponectin. Increased tumor burden and bone disease were observed in myeloma-bearing adiponectin-deficient mice, and adiponectin was found to induce myeloma cell apoptosis. The apolipoprotein peptide mimetic L-4F was used for pharmacologic enhancement of adiponectin. L-4F reduced tumor burden, increased survival of myeloma-bearing mice, and prevented myeloma bone disease. Collectively, our studies have identified a novel mechanism whereby decreased host-derived adiponectin promotes myeloma tumor growth and osteolysis. Furthermore, we have established the potential therapeutic benefit of increasing adiponectin for the treatment of myeloma and the associated bone disease.

Resistin expression correlates with steatohepatitis in morbidly obese patients.

BACKGROUND: Morbidly obese patients are at risk for nonalcoholic steatohepatitis (NASH) even in the absence of risk factors for liver disease. Unfortunately, NASH is usually not clinically evident, and a definitive, noninvasive test for NASH does not exist. Resistin, a cytokine originating from adipose tissue, is involved in insulin resistance and also initiates proinflammatory signaling from hepatic stellate cells. This study explores the relationship between resistin expression and liver pathology in bariatric surgery patients. METHODS: Blood samples from 30 patients undergoing bariatric surgery were collected. Total RNA was extracted and cDNA was synthesized. Quantitative RT-PCR was used to quantify relative gene expression using 18s rRNA gene as an internal control. Wedge liver biopsies from these patients were sectioned and stained. Based on a previously published scoring method, biopsies were assigned an overall NASH severity score and subscores for steatosis, inflammation, and fibrosis. Results were analyzed by using Student's t test. RESULTS: Resistin mRNA levels ranged from 0.5 to 9.7. A group of five patients with very high resistin expression (>4) was identified. These patients had a significantly higher average NASH score compared with the rest of the group (7.9 vs. 4.48, p = 0.019). Steatosis and inflammation scores were significantly higher in the high-resistin group (p < 0.05 for both comparisons). There also was a trend toward higher fibrosis score in this group, which approached statistical significance (p = 0.051). CONCLUSIONS: In morbidly obese patients, high resistin expression in serum is associated with hepatic steatosis, inflammation, and fibrosis. The development of elevated resistin expression may represent a link between obesity and the onset of steatohepatitis.

Pre-emptive replacement of water treatment components improves responsiveness to erythropoiesis-stimulating agents in maintenance haemodialysis patients: a quality improvement report.

Hypo-responsiveness to erythropoiesis-stimulating agents (ESAs) has been associated with increased mortality. We examined the effect of water treatment component replacement on declining ESA responsiveness in the absence of chemical or microbiological standards failure. Pre-emptive renewal of the water treatment system supplying 802 standard-flux haemodialysis patients resulted in a significant rise in haemoglobin from (mean ± SD) 12.1 ± 1.2 to 12.3 ± 1.0 g/dl (p < 0.0001), accompanied by a significant decrease in prescribed dose of darbepoetin alfa from 47.9 ± 27.3 to 44.7 ± 27.6 µg/week (p < 0.0001). ESA responsiveness improved significantly from 0.060 ± 0.041 to 0.055 ± 0.040 µg/kg/g · dl(-1) (p < 0.0001) and the number of patients no longer requiring ESA therapy increased threefold. These benefits were derived in the absence of haemolysis or significant changes in water quality. Renewal of water system components should be conducted even in the absence of proven microbiological and chemical failure.

Breast-specific gamma imaging influences surgical management in patients with breast cancer.

Breast-specific gamma imaging (BSGI) is a physiologic breast imaging modality that provides more sensitive detection of breast lesions than mammography or ultrasound, and appears to have greater specificity than breast MRI. The purpose of this study was to evaluate how often BSGI changed surgical management in patients with breast cancer. Charts were reviewed from 218 consecutive eligible patients who had preoperative evaluation with BSGI or MRI before surgery for breast cancer from January 2008 to May 2010. Patients who were initially considered eligible for breast-conserving therapy (BCT) were evaluated to determine how many ultimately had mastectomies. Patients who underwent mastectomy because of personal choice or ineligibility for BCT were excluded. Management was changed to mastectomy in 11.9% of those who had BSGI and 28.9% of those who had MRI. Review of pathology demonstrated that all patients who underwent mastectomies were not candidates for breast conservation. 15.4% of patients who underwent BCT based on BSGI findings required a single re-excision due to positive surgical margins. 14.4% required mastectomy. In the MRI group, 18.8% required a single re-excision, and 6.3% required mastectomy. Evaluation with BSGI changed management to mastectomy in a substantial proportion of patients believed to be eligible for BCT following standard imaging. BSGI is effective in evaluation of extent of disease in patients with breast cancer, and is comparable to MRI in terms of its influence on surgical management.

What do we tell patients about elective total hip replacement in the UK? An analysis of patient literature.

BACKGROUND: Although hip information literature is given to people following total hip replacement (THR) almost routinely, little evaluation has been conducted on it to date. Our aim was therefore to analyse and evaluate the literature provided to patients by occupational therapists concerning elective hip surgery in the UK. METHODS: This was a pragmatic, descriptive analysis of information leaflets routinely given to patients undergoing primary total hip replacement (THR). The literature was collected as part of a national survey of occupational therapy practice. In the absence of a suitable evaluation tool, the patient leaflets were compared using a checklist devised by the researchers. The three areas of interest were: accessibility including presentation of information, breadth of information covered and specific activities of daily living described. RESULTS: 111 information leaflets and booklets were examined. These ranged from hospital publications which were professionally printed to those produced by individual departments. There was a variation in the readability of the leaflets ranging from 13% to 83%; the mean was 45% (SD 15). There was also variation in the content ranging from those covering surgery and possible complications, to those including diet and hip exercises. The most commonly covered activity of daily living was advice on sitting (99; 89%); the least commonly covered was work (26; 23%). Only 3 (2.7%) booklets had involved patients in their production and only 22 (20%) signposted obtaining information in another language or in Braille. CONCLUSIONS: There was a range of literature in terms of presentation and content given to people who had a total hip replacement (THR). Although some booklets and leaflets scored highly, some did not meet basic standards such as providing contact details for help, using good quality diagrams, suggesting further reading or involving patients in their design. These results highlight important and fundamental deficiencies in the literature routinely provided.

"Wherever There's Men, it can Happen": Constructions of Violence Against Women by Young Adults in Ireland.

Given the growing concern about perpetration of violence against women (VAW) amongst young adults, this article examines how a sample (n = 27) of Irish young adults (18-24 years) construct the term VAW. Participants drew on personal experiences to describe the term and were cognisant of the gendered perpetration of domestic, psychological, and sexual violence. A group of participants, however, constructed narrow understandings of VAW that did not align with their routinized experiences of unwanted touching and sexual microaggressions. We call for initiatives to enable young adults to name and link together different forms of VAW.