FTY720/Fingolimod mitigates paclitaxel-induced Sparcl1-driven neuropathic pain and breast cancer progression.

Paclitaxel is among the most active chemotherapy drugs for the aggressive triple negative breast cancer (TNBC). Unfortunately, it often induces painful peripheral neuropathy (CIPN), a major debilitating side effect. Here we demonstrate that in naive and breast tumor-bearing immunocompetent mice, a clinically relevant dose of FTY720/Fingolimod that targets sphingosine-1-phosphate receptor 1 (S1PR1), alleviated paclitaxel-induced neuropathic pain. FTY720 also significantly attenuated paclitaxel-stimulated glial fibrillary acidic protein (GFAP), a marker for activated astrocytes, and expression of the astrocyte-secreted synaptogenic protein Sparcl1/Hevin, a key regulator of synapse formation. Notably, the formation of excitatory synapses containing VGluT2 in the spinal cord dorsal horn induced by paclitaxel was also inhibited by FTY720 treatment, supporting the involvement of astrocytes and Sparcl1 in CIPN. Furthermore, in this TNBC mouse model that mimics human breast cancer, FTY720 administration also enhanced the anti-tumor effects of paclitaxel, leading to reduced tumor progression and lung metastasis. Taken together, our findings suggest that targeting the S1P/S1PR1 axis with FTY720 is a multipronged approach that holds promise as a therapeutic strategy for alleviating both CIPN and enhancing the efficacy of chemotherapy in TNBC treatment.

ORMDL mislocalization by impaired autophagy in Niemann-Pick type C disease leads to increased de novo sphingolipid biosynthesis.

Niemann-Pick type C1 (NPC1) disease is a rare neurodegenerative cholesterol and sphingolipid storage disorder primarily due to mutations in the cholesterol-trafficking protein NPC1. In addition to catabolic-derived sphingolipids, NPC1 dysfunction also leads to an increase in de novo sphingolipid biosynthesis, yet little is known about the cellular mechanism involved. Although deletion of NPC1 or inhibition of the NPC1 sterol binding domain enhanced de novo sphingolipid biosynthesis, surprisingly levels of the ORMDLs, the regulatory subunits of serine palmitoyltransferase (SPT), the rate-limiting step in sphingolipid biosynthesis, were also greatly increased. Nevertheless, less ORMDL was bound in the SPT-ORMDL complex despite elevated ceramide levels. Instead, ORMDL colocalized with p62, the selective autophagy receptor, and accumulated in stalled autophagosomes due to defective autophagy in NPC1 disease cells. Restoration of autophagic flux with N-acetyl-L-leucine in NPC1 deleted cells decreased ORMDL accumulation in autophagosomes and reduced de novo sphingolipid biosynthesis and their accumulation. This study revealed a previously unknown link between de novo sphingolipid biosynthesis, ORMDL, and autophagic defects present in NCP1 disease. In addition, we provide further evidence and mechanistic insight for the beneficial role of N-acetyl-L-leucine treatment for NPC1 disease which is presently awaiting approval from the Food and Drug Administration and the European Medicines Agency.

Highly Efficient and Scalable p-i-n Perovskite Solar Cells Enabled by Poly-metallocene Interfaces.

Inverted p-i-n perovskite solar cells (PSCs) are easy to process but need improved interface characteristics with reduced energy loss to prevent efficiency drops when increasing the active photovoltaic area. Here, we report a series of poly ferrocenyl molecules that can modulate the perovskite surface enabling the construction of small- and large-area PSCs. We found that the perovskite-ferrocenyl interaction forms a hybrid complex with enhanced surface coordination strength and activated electronic states, leading to lower interfacial nonradiative recombination and charge transport resistance losses. The resulting PSCs achieve an enhanced efficiency of up to 26.08% for small-area devices and 24.51% for large-area devices (1.0208 cm2). Moreover, the large-area PSCs maintain >92% of the initial efficiency after 2000 h of continuous operation at the maximum power point under 1-sun illumination and 65 °C.

Triple-tuned birdcage and single-tuned dipole array for quadri-nuclear head MRI at 7 T.

PURPOSE: The purpose of this work was to design and build a coil for quadri-nuclear MRI of the human brain at 7 T. METHODS: We built a transmit/receive triple-tuned (45.6 MHz for 2 $$ {}^2 $$ H, 78.6 MHz for 23 $$ {}^{23} $$ Na, and 120.3 MHz for 31 $$ {}^{31} $$ P) quadrature four-rod birdcage that was geometrically interleaved with a transmit/receive four-channel dipole array (297.2 MHz for 1 $$ {}^1 $$ H). The birdcage rods contained passive, two-pole resonant circuits that emulated capacitors required for single-tuning at three frequencies. The birdcage assembly also included triple-tuned matching networks, baluns, and transmit/receive switches. We assessed the performance of the coil with quality factor (Q) and signal-to-noise ratio (SNR) measurements, and performed in vivo multinuclear MRI and MR spectroscopic imaging (MRSI). RESULTS: Q measurements showed that the triple-tuned birdcage efficiency was within 33% of that of single-tuned baseline birdcages at all three frequencies. The quadri-tuned coil SNR was 78%, 59%, 44%, and 48% lower than that of single or dual-tuned reference coils for 1 $$ {}^1 $$ H, 2 $$ {}^2 $$ H, 23 $$ {}^{23} $$ Na, and 31 $$ {}^{31} $$ P, respectively. Quadri-nuclear MRI and MRSI was demonstrated in brain in vivo in about 30 min. CONCLUSION: While the SNR of the quadruple tuned coil was significantly lower than dual- and single-tuned reference coils, it represents a step toward truly simultaneous quadri-nuclear measurements.

High Heart Rate Variability Buffers the Effect of Attachment Insecurity on Sleep Quality.

OBJECTIVE: Sleep quality is an important health-protective factor. Psychosocial factors, including attachment orientation, may be valuable for understanding who is at risk of poor sleep quality and associated adverse health outcomes. High attachment anxiety is reliably associated with adverse health outcomes, whereas high attachment avoidance is associated with adverse health outcomes when co-occurring with poor self-regulatory capacity, indexed by heart rate variability (HRV). We examined the associations between attachment anxiety, attachment avoidance, HRV, and sleep quality. METHODS: Using longitudinal data from a sample of 171 older adults measured four times over 1 year ( M = 66.18 years old; 67.83% women), we separated the between-person variance (which we call "trait") and within-person variance (which we call "state") for attachment anxiety, attachment avoidance, and HRV (via the root mean square of successive differences). Sleep quality was measured with the Pittsburgh Sleep Quality Index. RESULTS: Higher trait attachment anxiety was associated with poorer global sleep quality ( B = 0.22, p = .005). Higher state attachment avoidance was associated with poorer sleep quality ( B = -0.13, p = .01), except for those with higher trait HRV. Higher state attachment anxiety was associated with poorer sleep quality ( B = -0.15, p = .002), except for those with higher or mean trait HRV. Higher trait attachment anxiety was associated with poorer sleep quality ( B = -0.31, p = .02), except for those with higher trait HRV. CONCLUSIONS: High trait HRV mitigated the adverse effects of attachment insecurity on sleep quality. Our results suggest that people with high trait HRV had greater self-regulation capacity, which may enable them to enact emotion regulation strategies effectively.

Physical pain among urban Native American emerging adults: Socio-cultural risk and protective factors.

OBJECTIVE: American Indian/Alaska Native (AI/AN) people have high rates of physical pain. Pain is understudied in urban-dwelling, AI/AN emerging adults, a group with unique socio-cultural risk and protective factors. We explore associations between socioeconomic disadvantage, additional socio-cultural factors, and pain among urban AI/AN emerging adults. METHODS: AI/AN participants aged 18-25 (N = 417) were recruited via social media. Regression models tested associations between socioeconomic disadvantage (income and ability to afford healthcare) and pain as well as additional socio-cultural factors (discrimination, historical loss, cultural pride and belonging, visiting tribal lands) and pain. Multi-group regression models tested whether associations between socio-cultural factors and pain differed between participants who were socioeconomically disadvantaged and those who were less disadvantaged. RESULTS: In the full sample, lower income (b = 1.00 - 1.48, p < .05), inability to afford healthcare (b = 1.00, p = .011), discrimination (b = 0.12, p = .001), and historical loss (b = 0.24, p = .006) were positively associated with pain, whereas visiting tribal lands was negatively associated with pain (b = -0.86 - -0.42, p < .05). In the multi-group model, visiting tribal lands 31+ days was negatively associated with pain only among the less socioeconomically disadvantaged group (b = -1.48, p < .001). CONCLUSIONS: Socioeconomic disadvantage may, in part, drive pain disparities among AI/AN emerging adults and act as a barrier to benefitting from visiting tribal lands. Results support a biopsychosocial approach to targeting pain in this population, including addressing socioeconomic challenges and developing culturally informed, strengths-based interventions.

Lactobacillus from the Altered Schaedler Flora maintain IFNγ homeostasis to promote behavioral stress resilience.

The gut microbiome consists of trillions of bacteria, fungi, and viruses that inhabit the digestive tract. These communities are sensitive to disruption from environmental exposures ranging from diet changes to illness. Disruption of the community of lactic acid producing bacteria, Lactobaccillacea, has been well documented in mood disorders and stress exposure. In fact, oral supplement with many Lactobacillus species can ameliorate these effects, preventing depression- and anxiety-like behavior. Here, we utilize a gnotobiotic mouse colonized with the Altered Schaedler Flora to remove the two native species of Lactobaccillacea: L. intestinalis and L. murinus. Using this microbial community, we found that the Lactobacillus species themselves, and not the disrupted microbial communities are protective from environmental stressors. Further, we determine that Lactobaccillacea are maintaining homeostatic IFNγ levels which are mediating these behavioral and circuit level responses. By utilizing the Altered Schaedler Flora, we have gained new insight into how probiotics influence behavior and provide novel methods to study potential therapies to treat mood disorders.

Stress-induced mucin 13 reductions drive intestinal microbiome shifts and despair behaviors.

Depression is a prevalent psychological condition with limited treatment options. While its etiology is multifactorial, both chronic stress and changes in microbiome composition are associated with disease pathology. Stress is known to induce microbiome dysbiosis, defined here as a change in microbial composition associated with a pathological condition. This state of dysbiosis is known to feedback on depressive symptoms. While studies have demonstrated that targeted restoration of the microbiome can alleviate depressive-like symptoms in mice, translating these findings to human patients has proven challenging due to the complexity of the human microbiome. As such, there is an urgent need to identify factors upstream of microbial dysbiosis. Here we investigate the role of mucin 13 as an upstream mediator of microbiome composition changes in the context of stress. Using a model of chronic stress, we show that the glycocalyx protein, mucin 13, is selectively reduced after psychological stress exposure. We further demonstrate that the reduction of Muc13 is mediated by the Hnf4 transcription factor family. Finally, we determine that deleting Muc13 is sufficient to drive microbiome shifts and despair behaviors. These findings shed light on the mechanisms behind stress-induced microbial changes and reveal a novel regulator of mucin 13 expression.

Enhancing sleep health in urban American Indian/Alaska Native adolescents: Implications for culturally tailored interventions.

BACKGROUND: Urban American Indian/Alaska Native (AI/AN) adolescents are vulnerable to sleep and other health-related disparities due to numerous social drivers, including historical trauma and relocation to urban areas. This study aims to identify strategies to increase protective factors and culturally tailor sleep health interventions for this population. METHODS: Using community-based participatory research, the NAYSHAW study conducted in-depth interviews with urban AI/AN adolescents aged 12-19 years to understand critical components needed for developing a culturally sensitive sleep health intervention. Data from two qualitative subsamples (N = 46) and parent surveys (N = 110) were analyzed, focusing on factors that affect sleep health behaviors, including parental involvement, technology, and traditional practices. RESULTS: Key findings include the detrimental impact of electronics use at night and protective effects of traditional practices on sleep. Parental involvement in sleep routines varied by adolescent's age. Adolescents desired sleep health education in interactive formats, whereas parents preferred workshops and digital applications for sleep health strategies. Findings suggest that interventions need to address electronics use and should also be culturally tailored to address the unique experiences of urban AI/AN adolescents. CONCLUSIONS: Results underscore the importance of utilizing community-based strategies to develop culturally tailored sleep interventions for underserved populations, specifically urban AI/AN adolescents. Integrating traditional practices with evidence-based sleep health strategies can provide a holistic approach to improving sleep and overall well-being. Parental education and involvement will be critical to the success of such interventions.

Preliminary Experience with Three Alternative Motion Sensors for 0.55 Tesla MR Imaging.

Due to limitations in current motion tracking technologies and increasing interest in alternative sensors for motion tracking both inside and outside the MRI system, in this study we share our preliminary experience with three alternative sensors utilizing diverse technologies and interactions with tissue to monitor motion of the body surface, respiratory-related motion of major organs, and non-respiratory motion of deep-seated organs. These consist of (1) a Pilot-Tone RF transmitter combined with deep learning algorithms for tracking liver motion, (2) a single-channel ultrasound transducer with deep learning for monitoring bladder motion, and (3) a 3D Time-of-Flight camera for observing the motion of the anterior torso surface. Additionally, we demonstrate the capability of these sensors to simultaneously capture motion data outside the MRI environment, which is particularly relevant for procedures like radiation therapy, where motion status could be related to previously characterized cyclical anatomical data. Our findings indicate that the ultrasound sensor can track motion in deep-seated organs (bladder) as well as respiratory-related motion. The Time-of-Flight camera offers ease of interpretation and performs well in detecting surface motion (respiration). The Pilot-Tone demonstrates efficacy in tracking bulk respiratory motion and motion of major organs (liver). Simultaneous use of all three sensors could provide complementary motion information outside the MRI bore, providing potential value for motion tracking during position-sensitive treatments such as radiation therapy.

Patient Engagement in Provincial and Territorial Medical Association Decision-Making: A Rapid Scoping Review.

In recent years health systems have engaged patient partners in decision-making. Provincial and Territorial Medical Associations (PTMAs) are the sole bargaining agents for physicians. PTMA negotiations with governments are often seen as insular. Adding the patient perspective could add tremendous value to negotiating committees, etc. as PTMAs look to advocate for person-centered care provided by their members. Using rapid scoping review methodology, PubMed was searched for studies reporting on the use of patient partners in PTMA decision-making. Title and abstract screening were conducted by a single reviewer with full-text review screened by two reviewers. The search yielded 231 titles with 10 moving to full-text review and ultimately no titles meeting inclusion criteria. This empty scoping review has identified a paucity of literature reporting on patient engagement in PTMA decision-making. Further research is required to determine the utility of introducing patient partners in this capacity.

Severe Granulomatosis With Polyangiitis Treated With Low-Dose Cyclophosphamide, Rituximab, Glucocorticoids, and Plasma Exchange: A Case Report.

Granulomatosis with polyangiitis (GPA) is a systemic vasculitis that affects blood vessels and presents with vague constitutional symptoms, but more serious manifestations can develop, including pulmonary complications and glomerulonephritis. Currently, there are no definitive treatment guidelines. We present a case of a 66-year-old male with no previous medical history who was admitted for generalized constitutional symptoms for the past month. Imaging of the patient's brain revealed dural enhancement. Bronchoalveolar lavage was done and revealed diffuse alveolar hemorrhage (DAH). A kidney biopsy revealed granulomatosis with polyangiitis. The patient's hospital course was complicated by acute renal failure and required hemodialysis. Due to the patient's multi-organ involvement, the patient was treated aggressively with cyclophosphamide, rituximab, plasma exchange (PE), and steroids. GPA is a systemic vasculitis that can present with multi-organ involvement. A prompt diagnosis is necessary to initiate treatment and preserve organ function. More research is needed to determine which combination therapies are the best treatment modalities in cases of severe multi-organ system involvement.

Three-row MRI receive array with remote circuitry to preserve radiation transparency.

Objective.Up to this point, 1.5 T linac-compatible coil array layouts have been restricted to one or two rows of coils because of the desire to place radiation-opaque circuitry adjacent to the coils and outside the window through which the linac beam travels. Such layouts can limit parallel imaging performance. The purpose of this work was to design and build a three-row array in which remotely located circuits permitted a central row of coils while preserving the radiolucent window.Approach.The remote circuits consisted of a phase shifter to cancel the phase introduced by the coaxial link between the circuit and coil, followed by standard components for tuning, matching, detuning, and preamplifier decoupling. Tests were performed to compare prototype single-channel coils with remote or local circuits, which were followed by tests comparing two and three-row arrays .Main results.The single-channel coil with the remote circuit maintained 85% SNR at depths of 30 mm or more as compared to a coil with local circuit. The three-row array provided similar SNR as the two-row array, along with geometry factor advantages for parallel imaging acceleration in the head-foot direction.Significance.The remote circuit strategy could potentially support future MR-linac arrays by allowing greater flexibility in array layout compared to those confined by local circuits, which can be leveraged for parallel imaging acceleration.

Beyond the Dichotomy: Creation and Validation of a Continuous Statewide Index of U.S. Honor Culture.

Honor cultures are characterized by a heightened sensitivity to reputation threats and strong expectations for the defense of honor. U.S. states vary in the extent to which they express the cultural norms of honor, but researchers have frequently relied upon a dichotomous classification that differentiates states as honor or dignity states. We created and validated a continuous, six-item index of honor norms and values across all U.S. states (Study 1). In Study 2, our honor index was correlated with historical variables theoretically associated with the genesis of honor cultures. In Study 3, we validated our honor index further by showing that it predicted several race-/ethnicity-specific outcomes that prior research has connected with honor (e.g., homicide rates, suicide rates). This new index equips researchers with a more nuanced understanding of U.S. honor cultures and a measure that can be used in future investigations.

The erector spinae plane block vs. usual care for treatment of mechanical back pain in the emergency department: a pilot study.

BACKGROUND: The ultrasound-guided erector spinae plane block (ESPB), traditionally utilized for thoracic regional pain control, has been reported as an effective analgesic option for mechanical back pain, renal colic, and rib fractures in the emergency department (ED). This pilot study aims to compare the effectiveness of the ESPB to usual analgesic treatment for patients presenting to the ED with mechanical back pain. METHODS: A prospective, single-blind randomized controlled trial was conducted at a Canadian community hospital from March 2020 to December 2022. Adult patients presenting to the ED with mechanical back pain of at least 7 out of 10 on the Numeric Pain Rating Scale (NPRS) were randomized to receive either the ESPB or usual care. The primary outcome was the difference in NPRS score reduction at ED discharge. Secondary outcomes included ED length of stay, ED opiate use, follow-up NPRS and Brief Pain Inventory (BPI) scores, back pain-related return ED visits, and ongoing opiate use. RESULTS: A total of 30 patients were enrolled, with 19 randomized to the ESPB cohort and 11 to the usual care cohort. The mean NPRS reduction at ED discharge was significantly higher in the ESPB group compared to the usual care group (5.4 vs. 2.2), with a difference of 3.2 (95% confidence interval 1.4-5.1). ED opiate use was lower in the ESPB group. The ESPB also resulted in a significant reduction in ED length of stay (160 min vs. 235 min). There were no reported adverse effects related to the research interventions. CONCLUSION: This pilot study suggests that the ESPB may be an effective opioid-sparing analgesic option for patients presenting to the ED with mechanical back pain. GOV IDENTIFIER: NCT05982483.

RéSUMé: CONTEXTE: Le bloc raboteux spina érectile guidé par ultrasons (ESPB), traditionnellement utilisé pour le contrôle de la douleur régionale thoracique, a été signalé comme une option analgésique efficace pour les maux de dos mécaniques, les coliques rénales et les fractures des côtes au service des urgences (ED). Cette étude pilote vise à comparer l'efficacité de l'ESPB au traitement analgésique habituel pour les patients présentant à l'urgence des douleurs dorsales mécaniques. MéTHODES: Un essai contrôlé randomisé prospectif en aveugle a été mené dans un hôpital communautaire canadien de mars 2020 à décembre 2022. Les patients adultes se présentant à l'urgence avec une douleur dorsale mécanique d'au moins 7 sur 10 sur l'échelle numérique d'évaluation de la douleur (NPRS) ont été randomisés pour recevoir soit la ESPB ou les soins habituels. Le critère de jugement principal était la différence dans la réduction du score NPRS à la sortie de l'urgence. Les critères de jugement secondaires comprenaient la durée du séjour à l'urgence, l'utilisation d'opiacés à l'urgence, les scores de suivi à l'INRP et au Brief Pain Inventory (BPI), les visites de retour à l'urgence liées à la douleur dorsale et l'utilisation continue d'opiacés. RéSULTATS: Au total, 30 patients ont été recrutés, dont 19 randomisés dans la cohorte de la DGPSE et 11 dans la cohorte de soins habituels. La réduction moyenne du NPRS à la sortie de l'urgence était significativement plus élevée dans le groupe ESPB que dans le groupe de soins habituels (5,4 vs. 2,2), avec une différence de 3,2 (intervalle de confiance à 95 % 1,4-5,1). La consommation d'opiacés aux urgences était plus faible dans le groupe ESPB. La ESPB a également entraîné une réduction significative de la durée du séjour aux urgences (160 min contre 235 min). Aucun effet indésirable lié aux interventions de recherche n'a été signalé. CONCLUSION: Cette étude pilote suggère que l'ESPB peut être une option analgésique efficace épargnant les opioïdes pour les patients se présentant à l'urgence avec des douleurs dorsales mécaniques.

CBCT-DRRs superior to CT-DRRs for target-tracking applications for pancreatic SBRT.

Objective.In current radiograph-based intra-fraction markerless target-tracking, digitally reconstructed radiographs (DRRs) from planning CTs (CT-DRRs) are often used to train deep learning models that extract information from the intra-fraction radiographs acquired during treatment. Traditional DRR algorithms were designed for patient alignment (i.e.bone matching) and may not replicate the radiographic image quality of intra-fraction radiographs at treatment. Hypothetically, generating DRRs from pre-treatment Cone-Beam CTs (CBCT-DRRs) with DRR algorithms incorporating physical modelling of on-board-imagers (OBIs) could improve the similarity between intra-fraction radiographs and DRRs by eliminating inter-fraction variation and reducing image-quality mismatches between radiographs and DRRs. In this study, we test the two hypotheses that intra-fraction radiographs are more similar to CBCT-DRRs than CT-DRRs, and that intra-fraction radiographs are more similar to DRRs from algorithms incorporating physical models of OBI components than DRRs from algorithms omitting these models.Approach.DRRs were generated from CBCT and CT image sets collected from 20 patients undergoing pancreas stereotactic body radiotherapy. CBCT-DRRs and CT-DRRs were generated replicating the treatment position of patients and the OBI geometry during intra-fraction radiograph acquisition. To investigate whether the modelling of physical OBI components influenced radiograph-DRR similarity, four DRR algorithms were applied for the generation of CBCT-DRRs and CT-DRRs, incorporating and omitting different combinations of OBI component models. The four DRR algorithms were: a traditional DRR algorithm, a DRR algorithm with source-spectrum modelling, a DRR algorithm with source-spectrum and detector modelling, and a DRR algorithm with source-spectrum, detector and patient material modelling. Similarity between radiographs and matched DRRs was quantified using Pearson's correlation and Czekanowski's index, calculated on a per-image basis. Distributions of correlations and indexes were compared to test each of the hypotheses. Distribution differences were determined to be statistically significant when Wilcoxon's signed rank test and the Kolmogorov-Smirnov two sample test returnedp≤ 0.05 for both tests.Main results.Intra-fraction radiographs were more similar to CBCT-DRRs than CT-DRRs for both metrics across all algorithms, with allp≤ 0.007. Source-spectrum modelling improved radiograph-DRR similarity for both metrics, with allp< 10-6. OBI detector modelling and patient material modelling did not influence radiograph-DRR similarity for either metric.Significance.Generating DRRs from pre-treatment CBCT-DRRs is feasible, and incorporating CBCT-DRRs into markerless target-tracking methods may promote improved target-tracking accuracies. Incorporating source-spectrum modelling into a treatment planning system's DRR algorithms may reinforce the safe treatment of cancer patients by aiding in patient alignment.

The transcription factor sex-determining region Y-box 2 (SOX2) in bladder cancer.

Sex-determining region Y-box 2 (SOX2) is a transcription factor with a central role in embryologic development. SOX2 is also an oncogene in several cancer types. Prior work by our group has shown SOX2 activity associates with cell cycle dysregulation in early-stage bladder cancer. The present study was thus undertaken to broadly investigate SOX2 in bladder cancer, with emphasis on associations with tumor stage, clinical outcomes, and tumorigenicity. Gene expression was quantified by immunohistochemistry in an established tissue microarray (n=303 cystectomy specimens, all stages) and whole tissue sections of noninvasive papillary urothelial carcinoma (n=25). Gene expression by RNA sequencing was evaluated in non-muscle invasive and muscle-invasive cohorts from publicly available repositories. By immunohistochemistry, SOX2 was expressed in 40% of whole tissue sections of noninvasive papillary carcinoma, which correlated with SOX2 expression by RNA sequencing (r=0.6, P=0.001, Spearman correlation). Expression tended to be focal (median H-score =6). SOX2 was expressed in only 9% of TMA cases, consistent with focal expression. SOX2 expression was substantially higher in muscle-invasive compared with noninvasive papillary urothelial carcinoma by RNA sequencing (P<0.001, Wilcoxon rank sum test). SOX2 expression associated with stage progression in lamina-propria invasive cancers (hazard ratio =2, P=0.05, Cox model, binary, RNA sequencing) but not noninvasive papillary cancers (P=0.5, Cox model, binary, RNA sequencing). SOX2 expression did not associate with overall survival in muscle-invasive carcinoma. Activity of SOX2 in bladder cancer was tested in vivo using murine allografts created with MB49 cells that express human SOX2 (MB49-SOX). MB49-SOX allografts expressed this protein focally by immunohistochemistry, much like human tumors. Compared with controls, MB49 allografts demonstrated larger tumor size (P=0.03, Wilcoxon rank sum test) and higher tumor burden in mesenteric metastases (P=0.009, Wilcoxon rank sum test). Though SOX2 expression is focal within tumors, it may drive tumorigenesis, increase growth rate, and promote aggressive features of bladder cancer, particularly stage progression of early-stage disease.

Sphingosine kinase 2 and p62 regulation are determinants of sexual dimorphism in hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality, and its incidence is increasing due to endemic obesity. HCC is sexually dimorphic in both humans and rodents with higher incidence in males, although the mechanisms contributing to these correlations remain unclear. Here, we examined the role of sphingosine kinase 2 (SphK2), the enzyme that regulates the balance of bioactive sphingolipid metabolites, sphingosine-1-phosphate (S1P) and ceramide, in gender specific MASH-driven HCC. METHODS: Male and female mice were fed a high fat diet with sugar water, a clinically relevant model that recapitulates MASH-driven HCC in humans followed by physiological, biochemical cellular and molecular analyses. In addition, correlations with increased risk of HCC recurrence were determined in patients. RESULTS: Here, we report that deletion of SphK2 protects both male and female mice from Western diet-induced weight gain and metabolic dysfunction without affecting hepatic lipid accumulation or fibrosis. However, SphK2 deficiency decreases chronic diet-induced hepatocyte proliferation in males but increases it in females. Remarkably, SphK2 deficiency reverses the sexual dimorphism of HCC, as SphK2-/- male mice are protected whereas the females develop liver cancer. Only in male mice, chronic western diet induced accumulation of the autophagy receptor p62 and its downstream mediators, the antioxidant response target NQO1, and the oncogene c-Myc. SphK2 deletion repressed these known drivers of HCC development. Moreover, high p62 expression correlates with poor survival in male HCC patients but not in females. In hepatocytes, lipotoxicity-induced p62 accumulation is regulated by sex hormones and prevented by SphK2 deletion. Importantly, high SphK2 expression in male but not female HCC patients is associated with a more aggressive HCC differentiation status and increased risk of cancer recurrence. CONCLUSIONS: This work identifies SphK2 as a potential regulator of HCC sexual dimorphism and suggests SphK2 inhibitors now in clinical trials could have opposing, gender-specific effects in patients.

Transcriptomic dynamics governing serotonergic dysregulation in the dorsal raphe nucleus following mild traumatic brain injury.

Mild traumatic brain injury (mTBI) is a leading cause of disability in the United States, with neuropsychiatric disturbances such as depression, anxiety, PTSD, and social disturbances being common comorbidities following injury. The molecular mechanisms driving neuropsychiatric complications following neurotrauma are not well understood and current FDA-approved pharmacotherapies employed to ameliorate these comorbidities lack desired efficacy. Concerted efforts to understand the molecular mechanisms of and identify novel drug candidates for treating neurotrauma-elicited neuropsychiatric sequelae are clearly needed. Serotonin (5-HT) is linked to the etiology of neuropsychiatric disorders, however our understanding of how various forms of TBI directly affect 5-HT neurotransmission is limited. 5-HT neurons originate in the raphe nucleus (RN) of the midbrain and project throughout the brain to regulate diverse behavioral phenotypes. We hypothesize that the characterization of the dynamics governing 5-HT neurotransmission after injury will drive the discovery of novel drug targets and lead to a greater understanding of the mechanisms associated with neuropsychiatric disturbances following mild TBI (mTBI). Herein, we provide evidence that closed-head mTBI alters total DRN 5-HT levels, with RNA sequencing of the DRN revealing injury-derived alterations in transcripts required for the development, identity, and functional stability of 5-HT neurons. Further, using gene ontology analyses combined with immunohistological analyses, we have identified a novel mechanism of transcriptomic control within 5-HT neurons that may directly influence 5-HT neuron identity/function post-injury. These studies provide molecular evidence of injury-elicited 5-HT neuron dysregulation, data which may expedite the identification of novel therapeutic targets to attenuate TBI-elicited neuropsychiatric sequelae.

Strain in the Midbrain: Impact of Traumatic Brain Injury on the Central Serotonin System.

Traumatic brain injury (TBI) is a pervasive public health crisis that severely impacts the quality of life of affected individuals. Like peripheral forms of trauma, TBI results from extraordinarily heterogeneous environmental forces being imparted on the cranial space, resulting in heterogeneous disease pathologies. This has made therapies for TBI notoriously difficult to develop, and currently, there are no FDA-approved pharmacotherapies specifically for the acute or chronic treatment of TBI. TBI is associated with changes in cognition and can precipitate the onset of debilitating psychiatric disorders like major depressive disorder (MDD), generalized anxiety disorder (GAD), and post-traumatic stress disorder (PTSD). Complicating these effects of TBI, FDA-approved pharmacotherapies utilized to treat these disorders often fail to reach the desired level of efficacy in the context of neurotrauma. Although a complicated association, decades of work have linked central serotonin (5-HT) neurotransmission as being involved in the etiology of a myriad of neuropsychiatric disorders, including MDD and GAD. 5-HT is a biogenic monoamine neurotransmitter that is highly conserved across scales of biology. Though the majority of 5-HT is isolated to peripheral sites such as the gastrointestinal (GI) tract, 5-HT neurotransmission within the CNS exerts exquisite control over diverse biological functions, including sleep, appetite and respiration, while simultaneously establishing normal mood, perception, and attention. Although several key studies have begun to elucidate how various forms of neurotrauma impact central 5-HT neurotransmission, a full determination of precisely how TBI disrupts the highly regulated dynamics of 5-HT neuron function and/or 5-HT neurotransmission has yet to be conceptually or experimentally resolved. The purpose of the current review is, therefore, to integrate the disparate bodies of 5-HT and TBI research and synthesize insight into how new combinatorial research regarding 5-HT neurotransmission and TBI may offer an informed perspective into the nature of TBI-induced neuropsychiatric complications.