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Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (αCTLA-4)–mediated toxicity upon disruption of gut homeostatic immunity. We found αCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of αCTLA-4–mediated irAEs, including colonic neutrophil accumulation and systemic interleukin-6 (IL-6) release. IL-6 blockade combined with antibiotic treatment reduced intestinal damage and improved αCTLA-4 therapeutic efficacy in inflammation-prone mice. Intestinal immune signatures were validated in biopsies from patients with ICB colitis. Our work provides new preclinical models of αCTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs.

International audience; Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.

Aim: To evaluate the female oncofertility attitude and knowledge of reproductive health professionals in China. Methods: An online survey was distributed to reproductive health professionals in Shanghai, China. Results: Female professionals were more likely to consider that cancer patients would want to preserve their fertility. Participants with higher educational background tended to have a more positive attitude toward oncofertility. The majority of the participants (71.0%) obtained a fair or low level of oncofertility knowledge, and only 25.3% of them received scores at the ‘good knowledge’ level. Conclusion: There are significant gaps in the current oncofertility knowledge among reproductive health professionals in China, suggesting an urgent, unmet need for establishing an interdisciplinary fertility preservation training and service system.

Immunotherapies such as anti-CTLA-4 immune checkpoint blockade (ICB) have revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by off-target tissue damage or immune-related adverse events (irAEs). At present, there is limited understanding of irAE mechanisms, hampering development of approaches to mitigate their damage. We addressed this problem by generating animal models of intestinal irAE. Our results show that disruption of homeostatic immunity by genetic predisposition to intestinal inflammation or acute gastrointestinal infection sensitizes mice to anti-CTLA-4-mediated intestinal toxicity. Inflammation-prone mice treated with anti-CTLA-4 showed neutrophil accumulation, systemic interleukin-6 (IL-6) release, and dysbiosis. Significantly, IL-6 blockade combined with antibiotic treatment improved anti-CTLA-4 therapeutic efficacy and reduced intestinal irAEs. Immune signatures were validated in biopsies from patients who developed colitis during ICB, supporting the utility of our models. This study provides new pre-clinical models, mechanistic insight into irAEs, and potential approaches to enhance ICB efficacy while mitigating irAEs. Citation Format: Yifan Zhou, Yusra B. Medik, Bhakti Patel, Daniel B. Zamler, Sijie Chen, Thomas Chapman, Sarah Schneider, Rachel L. Babcock, Taylor T. Chrisikos, Laura M. Kahn, Allison M. Dyevoich, Elizabeth M. Park, Alexandria P. Cogdill, Daniel H. Johnson, Sarah B. Johnson, Khalida M. Wani, Debora A. Ledesma, Courtney W. Hudgens, Jingjing Wang, Md Abdul Wadud Khan, Aron Y. Joon, Weiyi Peng, Haiyan S. Li, Reetakshi Arora, Ximing Tang, Maria Gabriela Raso, Xuegong Zhang, Wai Chin Foo, Michael T. Tetzlaff, Gretchen E. Diehl, Karen Clise-Dwyer, Elizabeth M. Whitley, Matthew M. Gubin, James P. Allison, Patrick Hwu, Nadim J. Ajami, Adi Diab, Jennifer A. Wargo, Stephanie S. Watowich. Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5545.

A variety of species of bacteria are known to colonize human tumours1–11, proliferate within them and modulate immune function, which ultimately affects the survival of patients with cancer and their responses to treatment12–14. However, it is not known whether antigens derived from intracellular bacteria are presented by the human leukocyte antigen class I and II (HLA-I and HLA-II, respectively) molecules of tumour cells, or whether such antigens elicit a tumour-infiltrating T cell immune response. Here we used 16S rRNA gene sequencing and HLA peptidomics to identify a peptide repertoire derived from intracellular bacteria that was presented on HLA-I and HLA-II molecules in melanoma tumours. Our analysis of 17 melanoma metastases (derived from 9 patients) revealed 248 and 35 unique HLA-I and HLA-II peptides, respectively, that were derived from 41 species of bacteria. We identified recurrent bacterial peptides in tumours from different patients, as well as in different tumours from the same patient. Our study reveals that peptides derived from intracellular bacteria can be presented by tumour cells and elicit immune reactivity, and thus provides insight into a mechanism by which bacteria influence activation of the immune system and responses to therapy. HLA peptidomic analysis identifies recurrent intracellular bacteria-derived peptides presented on HLA-I and HLA-II molecules in melanoma tumours, revealing how bacteria can modulate immune functions and responses to cancer therapies.

To explore and describe the experiences and perspectives of various stakeholders regarding the use of powered wheelchair standing devices (PWSDs).The purposive sample included: children aged 6 to 18 years who used a PWSD (n=8; diagnoses: cerebral palsy, spinal muscular atrophy, spina bifida, spinal cord injury), parents of children 18 years of age or younger who used a PWSD (n=12), rehabilitation professionals working with children who used a PWSD (n=12), and professionals working at companies manufacturing PWSDs (n=3). Data were gathered via face-to-face interviews conducted either in person or via ZoomThree main themes emerged in the data: (1) 'Stand-on-demand' revealed how participants perceived PWSDs as allowing children to stand whenever and wherever they wanted, thereby increasing participation; (2) 'It's more than weight-bearing' uncovered participants' perceptions of psychological and physical benefits from PWSD use; and (3) 'Ecosystems influencing PWSD acquisition and use' revealed child- and non-child-related factors perceived as influencing children's procurement and use of a PWSD.Use of a PWSD was perceived as providing a unique opportunity for children to stand whenever and wherever they desired. Findings suggest the possible transdiagnostic application of PWSDs. What this paper adds The ability to stand when desired was unique to powered wheelchair standing device (PWSD) use. Participants perceived numerous psychological and physical benefits from PWSD use. Child- and non-child-related factors influenced procurement and use of a PWSD.Explorar y describir las experiencias y las perspectivas de varias partes interesadas, incluido: niños/as, padres, y profesionales - sobre el uso de dispositivos de bipedestación en silla eléctrica (DBSE). MÉTODO: La muestra intencionada incluyó: niños/as de edades entre 6 y 18 años que utilizaron un DBSE (n=8; diagnósticos: parálisis cerebral, atrofia muscular espinal, espina bífida, lesión medular), padres de niños/as de 18 años o menos que usaban un DBSE (n=12=, profesionales de rehabilitación que trabajan con niños/as que usaban un DBSE (n=12), y profesionales que trabajan en empresas que fabrican los DBSEs (n=3). Los datos se recopilaron a través de entrevistas cara a cara realizadas en persona o mediante ZoomTres temas principales surgieron en los datos: (1) “De pie bajo demanda” reveló cómo los participantes percibían que los DBSE permitían a los/as niños/as a ponerse de pie cuando y donde querían, aumentando así la participación; (2) “es más que soportar peso” descubrió las percepciones de los participantes en cuanto a los beneficios psicológicos y físicos; y (3) “Los ecosistemas que influyen en la adquisición y uso de un DBSE” revelaron factores relacionados y no relacionados con el/la niño/a que se percibió como que influyen en la obtención y el uso de un DBSE. INTERPRETACIÓN: Se consideró que el uso de un DBSE brindaba una oportunidad única para que los/las niño/as se pongan de pie cuando y donde ellos desean. Los hallazgos sugieren una posible aplicación transdiagnóstica de los DBSEs.Explorar e descrever as experiências e perspectivas de vários envolvidos com relação ao uso de dispositivos para em cadeira de rodas motorizadas (DOCRMs). MÉTODO: Esta amostra proposital incluiu: crianças com idades de 6 a 18 anos que usavam um DOCRM (n=8; diagnósticos: paralisia cerebral, atrofia muscular espinhal, espinha bífida, lesão medular), pais de crianças com 18 anos ou menos que usavam um DOCRM (n=12), profissionais de reabilitação que trabalham com crianças que usavam um DOCRM (n=12), e profissionais que trabalham em uma companhia que produz DOCRMs (n=3). Os dados foram reunidos por meio de entrevistas face a face conduzidas pessoalmente ou via ZoomTrês temas principais emergiram nos dados: (1) ‘Ficar em pé sob demanda’ revelou como os participantes perceberam os DOCRMs como permitindo às crianças ficar em pé quando e onde quiserem, aumentando assim a participação; (2) ‘É mais do que descarga de peso’ descobriu as percepções dos participantes sobre os benefícios psicológicos e físicos do uso de DOCRMs; e (3) ‘Ecossistemas influenciando a aquisição e uso de DOCRMs’ revelaram fatores relacionados e não relacionados à criança percebidos como influenciando a procura e uso do DOCRM pelas crianças. INTERPRETAÇÃO: O uso de um DOCRM foi percebido como fornecendo uma oportunidade única para crianças ficarem em pé quando e onde quiserem. Os achados sugerem a possível aplicação transdiagnóstica de DOCRMs.

Targeted and immunotherapy regimens have revolutionized the treatment of advanced melanoma patients. Despite this, only a subset of patients respond durably. Recently, combination strategies of BRAF/MEK inhibitors with immune checkpoint inhibitor monotherapy (��-CTLA-4 or ��-PD-1) have increased the rate of durable responses. Based on evidence from our group and others, these therapies appear synergistic, but at the cost of significant toxicity. We know from other treatment paradigms (e.g. hematologic malignancies) that combination strategies with multi-drug regimens (>4 drugs) are associated with more durable disease control. To better understand the mechanism of these improved outcomes, and to identify and prioritize new strategies for testing, we studied several multi-drug regimens combining BRAF/MEK targeted therapy and immunotherapy combinations in a Braf-mutant murine melanoma model (BrafV600E/Pten���/���). Short-term treatment with ��-PD-1 and ��-CTLA-4 monotherapies were relatively ineffective, while treatment with ��-OX40 demonstrated some efficacy [17% of mice with no evidence of disease, (NED), at 60-days]. Outcomes were improved in the combined ��-OX40/��-PD-1 group (42% NED). Short-term treatment with quadruplet therapy of immunotherapy doublets in combination with targeted therapy [dabrafenib and trametinib (DT)] was associated with excellent tumor control, with 100% of mice having NED after combined DT/��-CTLA-4/��-PD-1 or DT/��-OX40/��-PD-1. Notably, tumors from mice in these groups demonstrated a high proportion of effector memory T cells, and immunologic memory was maintained with tumor re-challenge. Together, these data provide important evidence regarding the potential utility of multi-drug therapy in treating advanced melanoma and suggest these models can be used to guide and prioritize combinatorial treatment strategies.

Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27 (IPN60090), which is currently in phase 1 clinical trials. Compound 27 attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans.

Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors such as the EGFR inhibitor (EGFRi), osimertinib, in non–small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here, we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2, that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTKs as the oncogenic driver. In EGFR-mutant osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation in vitro and caused tumor regression in vivo. Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFRi-resistant NSCLC. Significance: These findings highlight the discovery of IACS-13909 as a potent, selective inhibitor of SHP2 with drug-like properties, and targeting SHP2 may serve as a therapeutic strategy to overcome tumor resistance to osimertinib.

Background: Metastatic brain tumors are associated with significant morbidity and mortality. The current limited understanding of the mechanisms underlying brain metastasis has hindered the development of efficient diagnostics and therapeutics for this disease. Microbiota has emerged as a novel hallmark of cancer, with a prominent role in tumorigenesis, tumor immunity, and response to treatment. However, the role of the microbiota in tumor metastasis, and in particular brain metastasis, is poorly understood. We hypothesize that distinct microbial communities can alter the immune microenvironment in the brain and modulate the different steps of brain metastasis formation. Methods: To explore the role of gut microbiota in brain metastasis, we depleted gut microbiota in conventionally raised mice using a broad-spectrum non-absorbable antibiotic regimen. Subsequently, melanoma tumor cells were injected intracranially to evaluate the effect of gut microbiota depletion and associated immune changes on tumor growth. Tumor growth was measured through in vivo bioluminescent imaging and histology. Peripheral and tumor immune profiling was conducted through flow cytometry and immunohistochemistry. Results: Depletion of the gut microbiota in mice decreased tumor growth in the brain. Evaluation of the peripheral and tumor immune profiles suggested the underlying mechanisms to involve alterations in the circulating cytokine profiles and an increase in anti-tumor T cell activity. Conclusion: Our clinical studies suggest the association of distinct microbial communities with brain metastasis. Our pre-clinical findings demonstrate that the absence of gut microbiota can modulate the regulation of T cell activity to induce an anti-tumor response in the brain. Further studies, currently in progress, will determine the mechanistic role of dysbiotic microbiota and distinct microbial communities in this process. Citation Format: Golnaz Morad, Sarah B. Johnson, Jennifer A. Wargo. Gut microbiota-driven alterations in tumor immunity can modulate the growth of metastatic brain tumors [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P018.

Purpose: The purpose of this study is to determine if inhibition of mitochondrial oxidative phosphorylation (OxPhos) is an effective strategy against MAPK pathway inhibitor (MAPKi)–resistant BRAF-mutant melanomas. Experimental Design: The antimelanoma activity of IACS-010759 (OPi), a novel OxPhos complex I inhibitor, was evaluated in vitro and in vivo. Mechanistic studies and predictors of response were evaluated using molecularly and metabolically stratified melanoma cell lines. 13C-labeling and targeted metabolomics were used to evaluate the effect of OPi on cellular energy utilization. OxPhos inhibition in vivo was evaluated noninvasively by [18F]-fluoroazomycin arabinoside (FAZA) PET imaging. Results: OPi potently inhibited OxPhos and the in vivo growth of multiple MAPKi-resistant BRAF-mutant melanoma models with high OxPhos at well-tolerated doses. In vivo tumor regression with single-agent OPi treatment correlated with inhibition of both MAPK and mTOR complex I activity. Unexpectedly, antitumor activity was not improved by combined treatment with MAPKi in vitro or in vivo. Signaling and growth-inhibitory effects were mediated by LKB1–AMPK axis, and proportional to AMPK activation. OPi increased glucose incorporation into glycolysis, inhibited glucose and glutamine incorporation into the mitochondrial tricarboxylic acid cycle, and decreased cellular nucleotide and amino acid pools. Early changes in [18F]-FAZA PET uptake in vivo, and the degree of mTORC1 pathway inhibition in vitro, correlated with efficacy. Conclusions: Targeting OxPhos with OPi has significant antitumor activity in MAPKi-resistant, BRAF-mutant melanomas, and merits further clinical investigation as a potential new strategy to overcome intrinsic and acquired resistance to MAPKi in patients.

The Hispanic American, the largest minority population in the United States, is at increased risk for obesity, diabetes and end-stage renal disease. Here we review genetic and environmental factors that might account for their increased risk for these conditions. Whereas many environmental and genetic factors have important roles in driving the increased risk for obesity and kidney disease in this population, a case is made that excessive intake of sugary beverages is a contributory cause. Studies focusing on decreasing intake of sugary beverages among the Hispanic American could potentially reduce renal and cardiovascular complications in this population.

It has been previously purported that higher relative affinity to the dopamine D4 receptor compared to D2 (i.e., D4/D2 affinity ratio > 1) may underlie unique antiaggression potency. Asenapine is a newer antipsychotic that also has D4/D2 affinity ratio > 1. It has demonstrated efficacy in reducing acute agitation in a placebo-controlled study. We performed a prospective naturalistic, pilot, proof of concept study on an inpatient psychiatric unit. Among patients with aggression at time of admission (≥ 12 on Refined Aggression Questionnaire [RAQ], or ≥ 2 on Modified Overt Aggression Scale [MOAS]), asenapine treatment was associated with a significant reduction in total aggression as measured by the MOAS (−14.7 ± 11.59 vs. −5.4 ± 10.12, P = 0.045), and particularly physical aggression (−8.0 ± 5.06 vs. −0.78 ± 2.40, P < 0.0001) compared to treatment that did not include asenapine. These data suggest that asenapine may be useful in the targeted treatment of aggression, and provide some support for the D4/D2 affinity ratio hypothesis.

Ovarian toxicity and infertility are major side effects of cancer therapy in young female cancer patients. We and others have previously demonstrated that doxorubicin (DOX), one of the most widely used chemotherapeutic chemicals, has a dose-dependent toxicity on growing follicles. However, it is not fully understood if the primordial follicles are the direct or indirect target of DOX. Using both prepubertal and young adult female mouse models, we comprehensively investigated the effect of DOX on all developmental stages of follicles, determined the impact of DOX on primordial follicle survival, activation, and development, as well as compared the impact of age on DOX-induced ovarian toxicity. Twenty-one-day-old CD-1 female mice were intraperitoneally injected with PBS or clinically relevant dose of DOX at 10 mg/kg once. Results indicated that DOX primarily damaged granulosa cells in growing follicles and oocytes in primordial follicles and DOX-induced growing follicle apoptosis was associated with the primordial follicle overactivation. Using the 5-day-old female mice with a more uniform primordial follicle population, our data revealed that DOX also directly promoted primordial follicle death and the DNA damage-TAp63α-C-CASP3 pathway was involved in DOX-induced primordial follicle oocyte apoptosis. Compared to 21-day- and 8-week-old female mice that were treated with the same dose of DOX, the 5-day-old mice had the most severe primordial follicle loss as well as the least degree of primordial follicle overactivation. Taken together, these results demonstrate that DOX obliterates mouse ovarian reserve through both primordial follicle atresia and overactivation and the DOX-induced ovarian toxicity is age dependent.

This article was commissioned to collate and review forensic psychiatric services provided in a number of key Pacific Rim locations in the hope that it will assist in future dialogue about service development. The Board of the Pacific Rim College of Psychiatrists identified experts in forensic psychiatry from Australia, Canada, China, Hong Kong, Japan, Russia, Singapore, Taiwan, and the US. Each contributor provided an account of issues in their jurisdiction, including mental health services to mentally disordered offenders in prison, competence or fitness to stand trial, legal insanity as a defense at trial, diminished responsibility, and special forensic services available, including forensic hospitals and community forensic mental health services. Responses have been collated and are presented topic by topic and country by country within the body of this review. The availability of mental health screening and psychiatric in-reach or forensic liaison services within prisons differed considerably between countries, as did provisioning of community forensic mental health and rehabilitation services. Diversion of mentally disordered offenders to forensic, state, or hybrid hospitals was common. Legal constructs of criminal responsibility (insanity defense) and fitness to stand trial ("disability") are almost universally recognized, although variably used. Disparities between unmet needs and resourcing available were common themes. The legislative differences between contributing countries with respect to the mental health law and criminal law relating to mentally disordered offenders are relatively subtle. The major differences lie in operationalizing and resourcing forensic services.

A key component of clinical decision making with neurological patients is a good understanding of the most current theories of motor control in neurological rehabilitation. Current approaches recognize that movement emerges from an interaction between the individual, the task, and the environment in which the task is being carried out. It follows that movement is not the result of muscle-specific programs or stereotyped reflexes, but results from a dynamic interplay between perception, cognition and actions systems (Shumway-Cook & Woollacott, 2001). Numerous studies now support the motor learning approach or task-oriented approach to treating people affected by neurological disorders. This approach is defined as training or therapy where patients ''practice context-specific motor tasks and receive some form of feedback''(Teasell, Foley, Salter, & Jutai, 2008).Task specific training focuses on improvement of performance in functional tasks through goal directed movement and repetition. The emphasis of training is on function versus impairment. Increasing evidence also suggests that neural plastic changes are associated with task specific training (Richards, Stewart, Woodbury, Senesac, & Cauraugh, 2008), and learning is reported to be maximal for specific task related training (Goldstone, 1998).A major contributor to current theories of neurological rehabilitation is the evidence for brain plasticity, which refers to the brain's ability to reorganize itself in response to changes in behavioral demands (Rossini, Calautti, Pauri, & Baron, 2003). Both healthy and injured brains possess this capacity and therefore this ability is always active. With neuromotor interventions, neuroplastic changes and functional recovery have been demonstrated in the brain following ischemic stroke. An increasing number of researchers demonstrate changes in brain activation patterns following task-specific training (Richards et al., 2008). Evidence supports the components of task specific training which include ''real world'' or context specific activities, in a randomly ordered practice, with emphasis on repetition, and includes mass practice with the aim of reconstruction of the whole task (Hubbard, Parsons, Neilson, & Carey, 2009; Shumway-Cook & Woollacott, 2001).Clinical rehabilitation involves intensive work for patients with neurological disease or disorder. The authors have devised a collaborative approach to helping patients achieve functional real-world outcomes. Collaborations are encouraged between the physical, occupational, speech, and music therapists, each contributing unique research and clinical-based knowledge to the treatment team. For the purpose of this article, collaboration between physical and music therapies will be illustrated through three clinical vignettes.Neurologic Music TherapyThe practice of Neurologic Music Therapy (NMT) automatically incorporates the fundamental principles of motor rehabilitation. As the vignettes will clarify, NMT interventions emphasize goal-directed movement and repetition of functional tasks, while also providing immediate feedback on patient performance so that necessary adjustments can be made. By being based in motor control theories, NMT practice lends itself well to a collaborative treatment approach. Before entering into a discussion of collaborative rehabilitation techniques, a summary of the scientific foundations of Neurologic Music Therapy is in order.The principles and effectiveness of NMT techniques in the sensorimotor domain have been demonstrated by basic research. Music neuroscience researchers have found that intrinsic rhythmicity and temporality of music creates a framework for structuring learning and training to facilitate and shape neuroplasticity through synchronization and entrainment (Thaut, 2005).Entrainment is a key principle in sensorimotor rehabilitation in NMT and can be described as the magnet effect of auditory rhythm to synchronize and entrain movement patterns. …

Tumor-associated macrophages (TAMs) are critical drivers of tumor progression and immunosuppression within the tumor microenvironment. The dominant TAM phenotype is broadly characterized as harboring M2-like macrophage properties, which are anti-inflammatory and pro-tumor, as opposed to M1-like macrophages, which possess tumoricidal and pro-inflammatory characteristics. The dependence of M2 TAMs on CSF1 receptor (CSF1R) kinase signaling has made CSF1R a desirable therapeutic target, and the need for highly selective therapies for use in combinations. Through an extensive medicinal chemistry campaign, we identified a series of orally bioavailable, highly potent, exquisitely selective inhibitors of CSF1R (IC50 < 10 nM) with excellent pharmacologic properties that are appropriate for evaluation as a cancer therapy. The aim of our study was to assess the biological impact of our lead CSF1R inhibitor (CSF1Ri) on macrophage populations and the consequent effect on T effector cells. In vitro biochemical activity was evaluated in various kinase assays comparing our CSF1Ri to BLZ945. The compound was evaluated using syngeneic murine models of colorectal cancer (MC38) and pancreatic adenocarcinoma (PANC02). Tumors were immune profiled using NanoString, immunohistochemistry and flow cytometric analysis establishing that there was a depletion of macrophages and a reduction in the relative amount of M2+ (CD206+MHCII-) cells, with a concomitant increase in M1+ (MHCII+CD206-) cells. Myeloid-derived suppressor cells (MDSCs), CD4, and CD8 cell infiltration were also altered with an elevation of cytotoxic immune cells. In conclusion, we have identified and characterized a novel potent and selective inhibitor of CSF1R with highly favorable PK/PD properties, that compares favorably to BLZ945. We also have clear evidence that our novel CSF1R inhibitors modulates TAM infiltration and phenotype altering the immune cell milieu toward a more favorable anti-tumor environment. Citation Format: Erika Suzuki, Jeffrey J. Kovacs, Nakia D. Spencer, Sonal Sonal, Ningping Feng, Angela L. Harris, Robert A. Mullinax, Andy M. Zuniga, Sarah B. Johnson, Mikhila Mahendra, Tin Oo Khor, Faika Mseeh, Zhen Liu, Jason P. Burke, Keith Mikule, Martin Tremblay, Timothy P. Heffernan, Philip Jones, Barbara Czako, Joseph R. Marszalek. Promoting an anti-tumor immune environment with a novel, exquisitely selective CSF1R inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-124.

Obesity is a growing problem in the United States of America, with more than a third of the population classified as obese. One factor contributing to this multifactorial disorder is the consumption of a high fat diet, a behavior that has been shown to increase both caloric intake and body fat content. However, the elements regulating preference for high fat food over other foods remain understudied. To overcome this deficit, a model to quickly and easily test changes in the preference for dietary fat was developed. The Fat Preference model presents rats with a series of choices between foods with differing fat content. Like humans, rats have a natural bias toward consuming high fat food, making the rat model ideal for translational studies. Changes in preference can be ascribed to the effect of either genetic differences or pharmacological interventions. This model allows for the exploration of determinates of fat preference and screening pharmacotherapeutic agents that influence acquisition of obesity.

The stigma of mental illness affects psychiatry as a medical profession and psychiatrists. The present study aimed to compare the extent and correlation patterns of perceived stigma in psychiatrists and general practitioners. An international multicenter survey was conducted in psychiatrists and general practitioners from twelve countries. Responses were received from N = 1,893 psychiatrists and N = 1,238 general practitioners. Aspects of stigma assessed in the questionnaire included perceived stigma, self-stigma (stereotype agreement), attitudes toward the other profession, and experiences of discrimination. Psychiatrists reported significantly higher perceived stigma and discrimination experiences than general practitioners. Separate multiple regression analyses showed different predictor patterns of perceived stigma in the two groups. Hence, in the psychiatrists group, perceived stigma correlated best with discrimination experiences and self-stigma, while in the general practitioners group it correlated best with self-stigma. About 17 % of the psychiatrists perceive stigma as a serious problem, with a higher rate in younger respondents. Against this background, psychiatry as a medical profession should set a high priority on improving the training of young graduates. Despite the number of existing antistigma interventions targeting mental health professionals and medical students, further measures to improve the image of psychiatry and psychiatrists are warranted, in particular improving the training of young graduates with respect to raising awareness of own stigmatizing attitudes and to develop a better profession-related self-assertiveness.

Neuromedin U (NMU) is a highly conserved neuropeptide which regulates food intake and body weight. Transgenic mice lacking NMU are hyperphagic and obese, making NMU a novel target for understanding and treating obesity. Neuromedin U receptor 2 (NMUR2) is a high-affinity receptor for NMU found in discrete regions of the central nervous system, in particular the paraventricular nucleus of the hypothalamus (PVN), where it may be responsible for mediating the anorectic effects of NMU. We hypothesized that selective knock down of NMUR2 in the PVN of rats would increase their sensitivity to the reinforcing properties of food resulting in increased intake and preference for high-fat obesogenic food. To this end, we used viral-mediated RNAi to selectively knock down NMUR2 gene expression in the PVN. In rats fed a standard chow, NMUR2 knockdown produced no significant effect on food intake or body weight. However, when the same rats were fed a high-fat diet (45% fat), they consumed significantly more food, gained more body weight, and had increased feed efficiency relative to controls. Furthermore, NMUR2 knockdown rats demonstrated significantly greater binge-type food consumption of the high-fat diet and showed a greater preference for higher-fat food. These results demonstrate that NMUR2 signaling in the PVN regulates consumption and preference for high-fat foods without disrupting feeding behavior associated with non-obesogenic standard chow.

This article was commissioned to collate and review forensic psychiatric services provided in a number of key Pacific Rim locations in the hope that it will assist in future dialogue about service development. The Board of the Pacific Rim College of Psychiatrists identified experts in forensic psychiatry from Australia, Canada, China, Hong Kong, Japan, Russia, Singapore, Taiwan, and the US. Each contributor provided an account of issues in their jurisdiction, including mental health services to mentally disordered offenders in prison, competence or fitness to stand trial, legal insanity as a defense at trial, diminished responsibility, and special forensic services available, including forensic hospitals and community forensic mental health services. Responses have been collated and are presented topic by topic and country by country within the body of this review. The availability of mental health screening and psychiatric in-reach or forensic liaison services within prisons differed considerably between countries, as did provisioning of community forensic mental health and rehabilitation services. Diversion of mentally disordered offenders to forensic, state, or hybrid hospitals was common. Legal constructs of criminal responsibility (insanity defense) and fitness to stand trial ("disability") are almost universally recognized, although variably used. Disparities between unmet needs and resourcing available were common themes. The legislative differences between contributing countries with respect to the mental health law and criminal law relating to mentally disordered offenders are relatively subtle. The major differences lie in operationalizing and resourcing forensic services.

HOX genes encode a family of homeodomain-containing transcription factors involved in the determination of cell fate and identity during embryonic development. HOXB7 is overexpressed in more than 70% of breast cancers. Overexpression of HOXB7 in breast epithelial cells and induces epithelial-mesenchymal transition. In this study, we found that overexpression of the HOXB7 gene in breast cell lines increases cancer stem cell populations and promotes cell invasion, in contrast, knockdown of HOXB7 expression decreases the proportions of cancer stem cells. Colonogenic assay and xenograft transplantation experiments further confirmed that overexpression of HOXB7 in breast cancer cells increases their tumorigenecity both in vitro and in vivo. Mechanistically we found that HOXB7 strongly induces TGFβ2 expression and activates the canonical TGFβ/SMAD signaling pathways, which may be responsible for induction of EMT leading to expansion of cancer stem cell population. Overall, our results suggest that HOXB7 may be a critical factor which regulates the self-renewal and differentiation of breast cancer stem cells and therefore a potential therapeutic target in breast cancer. Citation Format: Shou Liu, Sarah Johnson, Hexin Chen. HOXB7 regulates breast cancer stem cells via induction of TGFβ2. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-54. doi:10.1158/1538-7445.AM2014-LB-54