Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment.

The tumor microenvironment (TME) influences cancer progression and therapy response. Therefore, understanding what regulates the TME immune compartment is vital. Here we show that microbiota signals program mononuclear phagocytes in the TME toward immunostimulatory monocytes and dendritic cells (DCs). Single-cell RNA sequencing revealed that absence of microbiota skews the TME toward pro-tumorigenic macrophages. Mechanistically, we show that microbiota-derived stimulator of interferon genes (STING) agonists induce type I interferon (IFN-I) production by intratumoral monocytes to regulate macrophage polarization and natural killer (NK) cell-DC crosstalk. Microbiota modulation with a high-fiber diet triggered the intratumoral IFN-I-NK cell-DC axis and improved the efficacy of immune checkpoint blockade (ICB). We validated our findings in individuals with melanoma treated with ICB and showed that the predicted intratumoral IFN-I and immune compositional differences between responder and non-responder individuals can be transferred by fecal microbiota transplantation. Our study uncovers a mechanistic link between the microbiota and the innate TME that can be harnessed to improve cancer therapies.

Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance.

The gut microbiota is a crucial regulator of anti-tumour immunity during immune checkpoint inhibitor therapy. Several bacteria that promote an anti-tumour response to immune checkpoint inhibitors have been identified in mice1-6. Moreover, transplantation of faecal specimens from responders can improve the efficacy of anti-PD-1 therapy in patients with melanoma7,8. However, the increased efficacy from faecal transplants is variable and how gut bacteria promote anti-tumour immunity remains unclear. Here we show that the gut microbiome downregulates PD-L2 expression and its binding partner repulsive guidance molecule b (RGMb) to promote anti-tumour immunity and identify bacterial species that mediate this effect. PD-L1 and PD-L2 share PD-1 as a binding partner, but PD-L2 can also bind RGMb. We demonstrate that blockade of PD-L2-RGMb interactions can overcome microbiome-dependent resistance to PD-1 pathway inhibitors. Antibody-mediated blockade of the PD-L2-RGMb pathway or conditional deletion of RGMb in T cells combined with an anti-PD-1 or anti-PD-L1 antibody promotes anti-tumour responses in multiple mouse tumour models that do not respond to anti-PD-1 or anti-PD-L1 alone (germ-free mice, antibiotic-treated mice and even mice colonized with stool samples from a patient who did not respond to treatment). These studies identify downregulation of the PD-L2-RGMb pathway as a specific mechanism by which the gut microbiota can promote responses to PD-1 checkpoint blockade. The results also define a potentially effective immunological strategy for treating patients who do not respond to PD-1 cancer immunotherapy.

Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells.

Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those cells1-7. Molecular differences in rare individual cells in the initial population enable certain cells to become resistant to therapy7-9; however, comparatively little is known about the variability in the resistance outcomes. Here we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing, to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies. We show that resistant clones emerging from single-cell-derived cancer cells adopt molecularly, morphologically and functionally distinct resistant types. These resistant types are largely predetermined by molecular differences between cells before drug addition and not by extrinsic factors. Changes in the dose and type of drug can switch the resistant type of an initial cell, resulting in the generation and elimination of certain resistant types. Samples from patients show evidence for the existence of these resistant types in a clinical context. We observed diversity in resistant types across several single-cell-derived cancer cell lines and cell types treated with a variety of drugs. The diversity of resistant types as a result of the variability in intrinsic cell states may be a generic feature of responses to external cues.

Identification of bacteria-derived HLA-bound peptides in melanoma.

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.

Stakeholder perspectives of pediatric powered wheelchair standing devices: a qualitative study.

AIM: To explore and describe the experiences and perspectives of various stakeholders regarding the use of powered wheelchair standing devices (PWSDs). METHOD: 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 Zoom® and analyzed using the constant comparative method. RESULTS: Three 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. INTERPRETATION: 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.

Doxorubicin obliterates mouse ovarian reserve through both primordial follicle atresia and overactivation.

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.

Female oncofertility attitude and knowledge: a survey of reproductive health professionals in Shanghai, China.

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.

Stigmatization of psychiatrists and general practitioners: results of an international survey.

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.

Developing and validating the Unhurried Conversations Assessment Tool (UCAT).

OBJECTIVE: Given the importance of unhurried conversations for providing careful and kind care, we sought to create, test, and validate the Unhurried Conversations Assessment Tool (UCAT) for assessing the unhurriedness of patient-clinician consultations. METHODS: In the first two phases, the unhurried conversation dimensions were identified and transformed into an assessment tool. In the third phase, two independent raters used UCAT to evaluate the unhurriedness of 100 randomly selected consultations from 184 videos recorded for a large research trial. UCAT's psychometric properties were evaluated using this data. RESULTS: UCAT demonstrates content validity based on the literature and expert review. EFA and reliability analyses confirm its construct validity and internal consistency. The seven formative dimensions account for 89.93% of the variance in unhurriedness, each displaying excellent internal consistency (α > 0.90). Inter-rater agreement for the overall assessment item was fair (ICC = 0.59), with individual dimension ICCs ranging from 0.26 (poor) to 0.95 (excellent). CONCLUSION: UCAT components comprehensively assess the unhurriedness of consultations. The tool exhibits content and construct validity and can be used reliably. PRACTICE IMPLICATIONS: UCAT's design and psychometric properties make it a practical and efficient tool. Clinicians can use it for self-evaluations and training to foster unhurried conversations.

Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration.

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.

Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties.

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.

Asenapine for the Control of Physical Aggression: A Prospective Naturalist Pilot Study.

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.

Hispanic Americans living in the United States and their risk for obesity, diabetes and kidney disease: Genetic and environmental considerations.

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.

Fat Preference: a novel model of eating behavior in rats.

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.

Review of psychiatric services to mentally disordered offenders around the Pacific Rim.

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.