First-in-human clinical trial of personalized neoantigen vaccines as early intervention in untreated patients with lymphoplasmacytic lymphoma.

Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade B-cell lymphoma of the bone marrow. Despite a cumulative risk of progression, there is no approved therapy for patients in the asymptomatic phase. We conducted a first-in-human clinical trial of a novel therapeutic DNA idiotype neoantigen vaccine in nine patients with asymptomatic LPL. Treatment was well tolerated with no dose limiting toxicities. One patient achieved a minor response, and all remaining patients experienced stable disease, with median time to disease progression of 61+ months. Direct interrogation of the tumor microenvironment by single-cell transcriptome analysis revealed an unexpected dichotomous antitumor response, with significantly reduced numbers of clonal tumor mature B-cells, tracked by their unique BCR, and downregulation of genes involved in signaling pathways critical for B-cell survival post-vaccine, but no change in clonal plasma cell subpopulations. Downregulation of HLA class II molecule expression suggested intrinsic resistance by tumor plasma cell subpopulations and cell-cell interaction analyses predicted paradoxical upregulation of IGF signaling post vaccine by plasma cell, but not mature B-cell subpopulations, suggesting a potential mechanism of acquired resistance. Vaccine therapy induced dynamic changes in bone marrow T-cells, including upregulation of signaling pathways involved in T-cell activation, expansion of T-cell clonotypes, increased T-cell clonal diversity, and functional tumor antigen-specific cytokine production, with little change in co-inhibitory pathways or Treg. Vaccine therapy also globally altered cell-cell communication networks across various bone marrow cell types and was associated with reduction of protumoral signaling by myeloid cells, principally non-classical monocytes. These results suggest that this prototype neoantigen vaccine favorably perturbed the tumor immune microenvironment, resulting in reduction of clonal tumor mature B-cell, but not plasma cell subpopulations. Future strategies to improve clinical efficacy may require combinations of neoantigen vaccines with agents which specifically target LPL plasma cell subpopulations, or enable blockade of IGF-1 signaling or myeloid cell checkpoints.

Immortalized B Cells Transfected with mRNA of Antigen Fused to MITD (IBMAM): An Effective Tool for Antigen-Specific T-Cell Expansion and TCR Validation.

Peripheral mononuclear blood cells (PBMCs) are the most widely used study materials for immunomonitoring and antigen-specific T-cell identification. However, limited patient PBMCs and low-frequency antigen-specific T cells remain as significant technical challenges. To address these limitations, we established a novel platform comprised of optimized HLA-matched immortalized B cells transfected with mRNA of a prototype viral or tumor antigen conjugated to MHC class-I trafficking domain protein (MITD) to increase the efficiency of epitope expression in antigen-presenting cells (APCs) essential to expanding antigen-specific T cells. When applied to CMV as a model, the IBMAM platform could successfully expand CMV-specific T cells from low-frequency CMV PBMCs from seropositive donors. Additionally, this platform can be applied to the validation of antigen specific TCRs. Together, compared to using APCs with synthesized peptides, this platform is an unlimited, highly efficient, and cost-effective resource in detecting and expanding antigen-specific T cells and validating antigen-specific TCRs.

Continent-wide declines in shallow reef life over a decade of ocean warming.

Human society is dependent on nature1,2, but whether our ecological foundations are at risk remains unknown in the absence of systematic monitoring of species' populations3. Knowledge of species fluctuations is particularly inadequate in the marine realm4. Here we assess the population trends of 1,057 common shallow reef species from multiple phyla at 1,636 sites around Australia over the past decade. Most populations decreased over this period, including many tropical fishes, temperate invertebrates (particularly echinoderms) and southwestern Australian macroalgae, whereas coral populations remained relatively stable. Population declines typically followed heatwave years, when local water temperatures were more than 0.5 °C above temperatures in 2008. Following heatwaves5,6, species abundances generally tended to decline near warm range edges, and increase near cool range edges. More than 30% of shallow invertebrate species in cool latitudes exhibited high extinction risk, with rapidly declining populations trapped by deep ocean barriers, preventing poleward retreat as temperatures rise. Greater conservation effort is needed to safeguard temperate marine ecosystems, which are disproportionately threatened and include species with deep evolutionary roots. Fundamental among such efforts, and broader societal needs to efficiently adapt to interacting anthropogenic and natural pressures, is greatly expanded monitoring of species' population trends7,8.

Generation of a humanized afucosylated BAFF-R antibody with broad activity against human B-cell malignancies.

B-cell activating factor receptor (BAFF-R) is a mature B-cell survival receptor, which is highly expressed in a wide variety of B-cell malignancies but with minimal expression in immature B cells. These properties make BAFF-R an attractive target for therapy of B-cell lymphomas. We generated a novel humanized anti BAFF-R monoclonal antibody (mAb) with high specificity and potent in vitro and in vivo activity against B-cell lymphomas and leukemias. The humanized variants of an original chimeric BAFF-R mAb retained BAFF-R binding affinity and antibody-dependent cellular cytotoxicity (ADCC) against a panel of human cell lines and primary lymphoma samples. Furthermore, 1 humanized BAFF-R mAb clone and its afucosylated version, glycoengineered to optimize the primary mechanism of action, prolonged survival of immunodeficient mice bearing human tumor cell lines or patient-derived lymphoma xenografts in 3 separate models, compared with controls. Finally, the tissue specificity of this humanized mAb was confirmed against a broad panel of normal human tissues. Taken together, we have identified a robust lead-candidate BAFF-R mAb for clinical development.

Tracking widespread climate-driven change on temperate and tropical reefs.

Warming seas, marine heatwaves, and habitat degradation are increasingly widespread phenomena affecting marine biodiversity, yet our understanding of their broader impacts is largely derived from collective insights from independent localized studies. Insufficient systematic broadscale monitoring limits our understanding of the true extent of these impacts and our capacity to track these at scales relevant to national policies and international agreements. Using an extensive time series of co-located reef fish community structure and habitat data spanning 12 years and the entire Australian continent, we found that reef fish community responses to changing temperatures and habitats are dynamic and widespread but regionally patchy. Shifts in composition and abundance of the fish community often occurred within 2 years of environmental or habitat change, although the relative importance of these two mechanisms of climate impact tended to differ between tropical and temperate zones. The clearest of these changes on temperate and subtropical reefs were temperature related, with responses measured by the reef fish thermal index indicating reshuffling according to the thermal affinities of species present. On low latitude coral reefs, the community generalization index indicated shifting dominance of habitat generalist fishes through time, concurrent with changing coral cover. Our results emphasize the importance of maintaining local ecological detail when scaling up datasets to inform national policies and global biodiversity targets. Scaled-up ecological monitoring is needed to discriminate among increasingly diverse drivers of large-scale biodiversity change and better connect presently disjointed systems of biodiversity observation, indicator research, and governance.

Prevalence of Depression in Podiatric Medical Students.

BACKGROUND: Although depression and depressive symptoms have been previously explored in various medical student cohorts, there has been a lack of formal investigation among podiatric medical students specifically. The purpose of this study was to identify the prevalence and related characteristics of depression and depressive symptoms in podiatric medical students. METHODS: A mixed-methods approach was used. Students at a podiatric medical college were asked to complete the Center for Epidemiologic Studies Depression Scale Revised survey electronically each year for 4 consecutive years. Focus group sessions were also conducted to further explore topics related to depression and depressive symptoms. RESULTS: Surveys were completed by 271 of 539 potential respondents (50.3%). A total of 34.7% of respondents screened positive for depression or depressive symptoms, defined as meeting or exceeding the criteria for subthreshold depressive symptoms on the Center for Epidemiologic Studies Depression Scale Revised. The prevalence was found to be lower in clinical students (third- and fourth-year students) and in students in committed relationships. Themes from the focus group sessions included the following: coping with stress, general health concerns, self-evaluation, action and preparation, and the use of campus resources. CONCLUSIONS: Depression and depressive symptoms were commonly encountered in this podiatric medical student cohort. Future investigations may consider specific treatment and prevention strategies.

The Lateral Column.

Lower extremity biomechanics is the cornerstone of podiatric medicine and surgery. The foot and ankle act as the interface between the ground and proximal segments, mediating internal and external moments Although the medial longitudinal arch has been widely researched, the details of the lateral longitudinal arch are less extensively delineated. The purpose of this review is to analyze the biomechanics of the lateral column as it relates to lower extremity biomechanics and function.

Rolipram, a Selective Phosphodiesterase 4 Inhibitor, Ameliorates Mechanical Hyperalgesia in a Rat Model of Chemotherapy-Induced Neuropathic Pain through Inhibition of Inflammatory Cytokines in the Dorsal Root Ganglion.

Chemotherapy-induced neuropathic pain is a significant side effect of chemotherapeutic agents and is the most common reason for stopping chemotherapy. The aim of the present study was to find the major site and mechanisms of action by which rolipram, a selective phosphodiesterase-4 inhibitor, alleviates paclitaxel-induced neuropathic pain. Chemotherapy-induced neuropathic pain was induced in adult male Sprague-Dawley rats by intraperitoneal injection of paclitaxel on four alternate days. Rolipram was administered systemically or locally into the lumbar spinal cord, L5 dorsal root ganglion, sciatic nerve, or skin nerve terminal. The mechanical threshold, the protein level of several inflammatory cytokines, and the cellular locations of phosphodiesterase-4 and interleukin-1ß in the dorsal root ganglion were measured by using behavioral testing, Western blotting, and immunohistochemistry, respectively. The local administration (0.03-mg) of rolipram in the L5 dorsal root ganglion ameliorated paclitaxel-induced pain behavior more effectively than did local administration in the other sites. Paclitaxel significantly increased the expression of inflammatory cytokines including tumor necrosis factor-α (2.2 times) and interleukin-1ß (2.7 times) in the lumbar dorsal root ganglion, and rolipram significantly decreased it. In addition, phosphodiesterase-4 and interleukin-1ß were expressed in the dorsal root ganglion neurons and satellite cells and paclitaxel significantly increased the intensity of interleukin-1ß (2 times) and rolipram significantly decreased it. These results suggest that the major site of action of rolipram on paclitaxel-induced neuropathic pain in rats was the dorsal root ganglion. Rolipram decreased the expression of inflammatory cytokines in the dorsal root ganglion. Thus, phosphodiesterase-4 inhibitors may ameliorate chemotherapy-induced neuropathic pain by decreasing expression of inflammatory cytokines in the dorsal root ganglion.

Loss of native rocky reef biodiversity in Australian metropolitan embayments.

Urbanisation of the coastal zone represents a key threat to marine biodiversity, including rocky reef communities which often possess disproportionate ecological, recreational and commercial importance. The nature and magnitude of local urban impacts on reef biodiversity near three Australian capital cities were quantified using visual census methods. The most impacted reefs in urbanised embayments were consistently characterised by smaller, faster growing species, reduced fish biomass and richness, and reduced mobile invertebrate abundance and richness. Reef faunal distribution varied significantly with heavy metals, local population density, and proximity to city ports, while native fish and invertebrate communities were most depauperate in locations where invasive species were abundant. Our study adds impetus for improved urban planning and pollution management practises, while also highlighting the potential for skilled volunteers to improve the tracking of changes in marine biodiversity values and the effectiveness of management intervention.

Parents' help-seeking processes for early childhood mental health problems.

BACKGROUND: Mental health problems affect up to one in five children and adolescents. Yet less than one quarter will access the appropriate professional help. This study explored parents' help-seeking processes for young children with mental health problems. METHODS: The present study followed up 442 6-year-old children of an original 733 infants (60% retention) who had been recruited from routine universal maternal and child health well-child appointments. An adapted help-seeking model was applied to a subsample of 84 children with mental health problems. RESULTS: Less than one third of parents whose child had a mental health problem accessed any type of professional service for their child's mental health. The majority of parents had highly positive help-seeking intentions, however, only one third of parents whose child had a mental health problem recognised their child's behavioural difficulties. Parents with more positive help-seeking intentions were more likely to access professional care for their child in need than parents who felt ambivalent about seeking help. Parent recognition that their child's behaviour was more difficult than average was a key barrier to accessing professional help when their child had a mental health problem. CONCLUSIONS: While most parents have positive help-seeking intentions, professionals aiding parent recognition of their young child's mental health difficulties could facilitate early intervention for children's mental health.

Effect of feedback on the quality of suicide prevention websites: randomised controlled trial.

There is concern regarding the quality of information about mental health problems on the internet. A trial was carried out to see whether sending feedback to website administrators about the quality of information on their website would lead to an improvement (ACTRN12609000449235). Fifty-two suicide prevention websites were identified by means of an online search. The quality of information about how to help someone who is suicidal was scored against expert consensus guidelines. Websites were randomised to receive feedback or serve as controls. The information on the websites varied greatly in quality. However, feedback did not lead to an improvement.

Desire for social distance from people with mental disorders.

The scientific literature on stigma has been confused because there are multiple components of stigma with different correlates. In order to make sense of this confusion, the present review focuses on research on the most commonly measured component: social distance. The review examines measurement of social distance; characteristics of people who desire greater social distance; experiences that affect social distance; characteristics of people that elicit social distance; the effects of psychiatric labelling; the effects of causal explanations for mental disorders; and interventions to reduce social distance. It is concluded that future research on social distance needs to focus on better evaluation of interventions and examine discriminatory and supportive behaviours in real life rather than in hypothetical situations.

Perceived helpfulness of websites for mental health information: a national survey of young Australians.

BACKGROUND: Despite the high risk of developing a mental disorder during adolescence, many young people fail to receive appropriate treatment from mental health professionals. Recent studies have found certain mental health information websites have improved mental health literacy and reduced symptoms of depression. However, studies exploring young people's perceptions of such resources still remain scarce. The current paper compared young people's preference for a website with self-help books and two face-to-face services-counselling and mental health services. The factors associated with believing in the perceived helpfulness of each intervention were also explored. METHOD: A national telephone survey was carried out with 3,746 people aged 12-25 years and 2005 co-resident parents. Perceived helpfulness of each intervention was assessed in relation to four vignettes (depression, social phobia, psychosis and depression with alcohol misuse). RESULTS: Approximately 71% of respondents rated websites and books as likely to be helpful, which was less than for counselling, but more than for mental health services. Predictors of rating a website as likely to be helpful were older age (18-25 years), belief in seeking help, less social distance from peers like the one in the vignette, and being presented with the vignettes depicting either social phobia or depression with alcohol misuse. Predictors of rating a book as helpful included belief in seeking help, awareness of the national depression initiative beyondblue, less social distance, being presented with the social phobia vignette, and the belief that the person in the vignette is 'weak not sick'. CONCLUSION: Most young people are open to the idea of accessing mental health information online, especially for disorders that are often perceived as behavioural problems. These young people also believe in help-seeking in general and are more willing to associate with peers who have mental health problems.