Brain network hypersensitivity underlies pain crises in sickle cell disease.

Sickle cell disease (SCD) is a genetic disorder causing painful and unpredictable Vaso-occlusive crises (VOCs) through blood vessel blockages. In this study, we propose explosive synchronization (ES) as a novel approach to comprehend the hypersensitivity and occurrence of VOCs in the SCD brain network. We hypothesized that the accumulated disruptions in the brain network induced by SCD might lead to strengthened ES and hypersensitivity. We explored ES's relationship with patient reported outcome measures (PROMs) as well as VOCs by analyzing EEG data from 25 SCD patients and 18 matched controls. SCD patients exhibited lower alpha frequency than controls. SCD patients showed correlation between frequency disassortativity (FDA), an ES condition, and three important PROMs. Furthermore, stronger FDA was observed in SCD patients with a higher frequency of VOCs and EEG recording near VOC. We also conducted computational modeling on SCD brain network to study FDA's role in network sensitivity. Our model demonstrated that a stronger FDA could be linked to increased sensitivity and frequency of VOCs. This study establishes connections between SCD pain and the universal network mechanism, ES, offering a strong theoretical foundation. This understanding will aid predicting VOCs and refining pain management for SCD patients.

Towards Understanding the Development of Breast Cancer: The Role of RhoJ in the Obesity Microenvironment.

Obesity is a growing pandemic with an increasing risk of inducing different cancer types, including breast cancer. Adipose tissue is proposed to be a major player in the initiation and progression of breast cancer in obese people. However, the mechanistic link between adipogenicity and tumorigenicity in breast tissues is poorly understood. We used in vitro and in vivo approaches to investigate the mechanistic relationship between obesity and the onset and progression of breast cancer. In obesity, adipose tissue expansion and remodeling are associated with increased inflammatory mediator's release and anti-inflammatory mediators' reduction.. In order to mimic the obesity micro-environment, we cultured cells in an enriched pro-inflammatory cytokine medium to which we added a low concentration of beneficial adipokines. Epithelial cells exposed to the obesity micro-environment were phenotypically transformed into mesenchymal-like cells, characterized by an increase in different mesenchymal markers and the acquisition of the major hallmarks of cancerous cells; these include sustained DNA damage, the activation of the ATR-Chk2 pathway, an increase in proliferation rate, cell invasion, and resistance to conventional chemotherapy. Transcriptomic analysis revealed that several genes, including RhoJ, CCL7, and MMP9, acted as potential major players in the observed phenomenon. The transcriptomics findings were confirmed in vitro using qRT-PCR and in vivo using high-fat-diet-fed mice. Our data suggests RhoJ as a potential novel molecular driver of tumor development in breast tissues and a mediator of cell resistance to conventional chemotherapy through PAK1 activation. These data propose that RhoJ is a potential target for therapeutic interventions in obese breast cancer patients.

Real-time Quantification of in vivo cerebrospinal fluid velocity using fMRI inflow effect.

In vivo estimation of cerebrospinal fluid (CSF) velocity is crucial for understanding the glymphatic system and its potential role in neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Current cardiac or respiratory gated approaches, such as 4D flow MRI, cannot capture CSF movement in real time due to limited temporal resolution and in addition deteriorate in accuracy at low fluid velocities. Other techniques like real-time PC-MRI or time-spatial labeling inversion pulse are not limited by temporal averaging but have limited availability even in research settings. This study aims to quantify the inflow effect of dynamic CSF motion on functional magnetic resonance imaging (fMRI) for in vivo, real-time measurement of CSF flow velocity. We considered linear and nonlinear models of velocity waveforms and empirically fit them to fMRI data from a controlled flow experiment. To assess the utility of this methodology in human data, CSF flow velocities were computed from fMRI data acquired in eight healthy volunteers. Breath holding regimens were used to amplify CSF flow oscillations. Our experimental flow study revealed that CSF velocity is nonlinearly related to inflow effect-mediated signal increase and well estimated using an extension of a previous nonlinear framework. Using this relationship, we recovered velocity from in vivo fMRI signal, demonstrating the potential of our approach for estimating CSF flow velocity in the human brain. This novel method could serve as an alternative approach to quantifying slow flow velocities in real time, such as CSF flow in the ventricular system, thereby providing valuable insights into the glymphatic system's function and its implications for neurological disorders.

Cardiac PET Myocardial Blood Flow Quantification Assessment of Early Cardiac Allograft Vasculopathy.

BACKGROUND: Positron emission tomography (PET) has demonstrated utility for diagnostic and prognostic assessment of cardiac allograft vasculopathy (CAV) but has not been evaluated in the first year after transplant. OBJECTIVES: The authors sought to evaluate CAV at 1 year by PET myocardial blood flow (MBF) quantification. METHODS: Adults at 2 institutions enrolled between January 2018 and March 2021 underwent prospective 3-month (baseline) and 12-month (follow-up) post-transplant PET, endomyocardial biopsy, and intravascular ultrasound examination. Epicardial CAV was assessed by intravascular ultrasound percent intimal volume (PIV) and microvascular CAV by endomyocardial biopsy. RESULTS: A total of 136 PET studies from 74 patients were analyzed. At 12 months, median PIV increased 5.6% (95% CI: 3.6%-7.1%) with no change in microvascular CAV incidence (baseline: 31% vs follow-up: 38%; P = 0.406) and persistent microvascular disease in 13% of patients. Median capillary density increased 30 capillaries/mm2 (95% CI: -6 to 79 capillaries/mm2). PET myocardial flow reserve (2.5 ± 0.7 vs 2.9 ± 0.8; P = 0.001) and stress MBF (2.7 ± 0.6 vs 2.9 ± 0.6; P = 0.008) increased, and coronary vascular resistance (CVR) (49 ± 13 vs 47 ± 11; P = 0.214) was unchanged. At 12 months, PET and PIV had modest correlation (stress MBF: r = -0.35; CVR: r = 0.33), with lower stress MBF and higher CVR across increasing PIV tertiles (all P < 0.05). Receiver-operating characteristic curves for CAV defined by upper-tertile PIV showed areas under the curve of 0.74 for stress MBF and 0.73 for CVR. CONCLUSIONS: The 1-year post-transplant PET MBF is associated with epicardial CAV, supporting potential use for early noninvasive CAV assessment. (Early Post Transplant Cardiac Allograft Vasculopahty [ECAV]; NCT03217786).

Brain network hypersensitivity underlies pain crises in sickle cell disease.

Sickle cell disease (SCD) is a genetic disorder causing blood vessel blockages and painful Vaso-occlusive crises (VOCs). VOCs, characterized by severe pain due to blocked blood flow, are recurrent and unpredictable, posing challenges for preventive strategies. In this study we propose explosive synchronization (ES), a phenomenon characterized by abrupt brain network phase transitions, as a novel approach to address this challenge. We hypothesized that the accumulated disruptions in the brain network induced by SCD might lead to strengthened ES and hypersensitivity. We explored ES's relationship with patient reported outcome measures (PROMs) and VOCs by analyzing EEG data from 25 SCD patients and 18 matched controls. SCD patients exhibited significantly lower alpha wave frequency than controls. SCD patients under painful pressure stimulation showed correlation between frequency disassortativity (FDA), an ES condition, and three important PROMs. Furthermore, patients who had a higher frequency of VOCs in the preceding 12 months presented with stronger FDA. The timing of VOC occurrence relative to EEG recordings was significantly associated to FDA. We also conducted computational modeling on SCD brain network to study FDA's role in network sensitivity. Stronger FDA correlated with higher responsivity and complexity in our model. Simulation under noisy environment showed that higher FDA could be linked to increased occurrence frequency of crisis. This study establishes connections between SCD pain and the universal network mechanism, ES, offering a strong theoretical foundation. This understanding will aid predicting VOCs and refining pain management for SCD patients.

Consensus statement on the processing, interpretation and reporting of temporal artery biopsy for arteritis.

Giant cell arteritis (GCA) is the most common systemic vasculitis in adults in Europe and North America, typically involving the extra-cranial branches of the carotid arteries and the thoracic aorta. Despite advances in noninvasive imaging, temporal artery biopsy (TAB) remains the gold standard for establishing a GCA diagnosis. The processing of TAB depends largely on individual institutional protocol, and the interpretation and reporting practices vary among pathologists. To address this lack of uniformity, the Society for Cardiovascular Pathology formed a committee tasked with establishing consensus guidelines for the processing, interpretation, and reporting of TAB specimens, based on the existing literature. This consensus statement includes a discussion of the differential diagnoses including other forms of arteritis and noninflammatory changes of the temporal artery.

Neurofluid coupling during sleep and wake states.

BACKGROUND: In clinical populations, the movement of cerebrospinal fluid (CSF) during sleep is a growing area of research with potential mechanistic connections in both neurodegenerative (e.g., Alzheimer's Disease) and neurodevelopmental disorders. However, we know relatively little about the processes that influence CSF movement. To inform clinical intervention targets this study assesses the coupling between (a) real-time CSF movement, (b) neuronal-driven movement, and (c) non-neuronal systemic physiology driven movement. METHODS: This study included eight young, healthy volunteers, with concurrently acquired neurofluid dynamics using functional Magnetic Resonance Imaging (MRI), neural activity using Electroencephalography (EEG), and non-neuronal systemic physiology with peripheral functional Near-Infrared Spectroscopy (fNIRS). Neuronal and non-neuronal drivers were assessed temporally; wherein, EEG measured slow wave activity that preceded CSF movement was considered neuronally driven. Similarly, slow wave oscillations (assessed via fNIRS) that coupled with CSF movement were considered non-neuronal systemic physiology driven. RESULTS AND CONCLUSIONS: Our results document neural contributions to CSF movement were only present during light NREM sleep but low-frequency non-neuronal oscillations were strongly coupled with CSF movement in all assessed states - awake, NREM-1, NREM-2. The clinical/research implications of these findings are two-fold. First, neuronal-driven oscillations contribute to CSF movement outside of deep sleep (NREM-3); therefore, interventions aimed at increasing CSF movement may yield meaningful increases with the promotion of NREM sleep more generally - a focus on NREM S3 may not be needed. Second, non-neuronal systemic oscillations contribute across wake and sleep stages; therefore, interventions may increase CSF movement by manipulating systemic physiology.

Limiting mitochondrial plasticity by targeting DRP1 induces metabolic reprogramming and reduces breast cancer brain metastases.

Disseminated tumor cells with metabolic flexibility to utilize available nutrients in distal organs persist, but the precise mechanisms that facilitate metabolic adaptations remain unclear. Here we show fragmented mitochondrial puncta in latent brain metastatic (Lat) cells enable fatty acid oxidation (FAO) to sustain cellular bioenergetics and maintain redox homeostasis. Depleting the enriched dynamin-related protein 1 (DRP1) and limiting mitochondrial plasticity in Lat cells results in increased lipid droplet accumulation, impaired FAO and attenuated metastasis. Likewise, pharmacological inhibition of DRP1 using a small-molecule brain-permeable inhibitor attenuated metastatic burden in preclinical models. In agreement with these findings, increased phospho-DRP1 expression was observed in metachronous brain metastasis compared with patient-matched primary tumors. Overall, our findings reveal the pivotal role of mitochondrial plasticity in supporting the survival of Lat cells and highlight the therapeutic potential of targeting cellular plasticity programs in combination with tumor-specific alterations to prevent metastatic recurrences.

mHealth hyperspectral learning for instantaneous spatiospectral imaging of hemodynamics.

Hyperspectral imaging acquires data in both the spatial and frequency domains to offer abundant physical or biological information. However, conventional hyperspectral imaging has intrinsic limitations of bulky instruments, slow data acquisition rate, and spatiospectral trade-off. Here we introduce hyperspectral learning for snapshot hyperspectral imaging in which sampled hyperspectral data in a small subarea are incorporated into a learning algorithm to recover the hypercube. Hyperspectral learning exploits the idea that a photograph is more than merely a picture and contains detailed spectral information. A small sampling of hyperspectral data enables spectrally informed learning to recover a hypercube from a red-green-blue (RGB) image without complete hyperspectral measurements. Hyperspectral learning is capable of recovering full spectroscopic resolution in the hypercube, comparable to high spectral resolutions of scientific spectrometers. Hyperspectral learning also enables ultrafast dynamic imaging, leveraging ultraslow video recording in an off-the-shelf smartphone, given that a video comprises a time series of multiple RGB images. To demonstrate its versatility, an experimental model of vascular development is used to extract hemodynamic parameters via statistical and deep learning approaches. Subsequently, the hemodynamics of peripheral microcirculation is assessed at an ultrafast temporal resolution up to a millisecond, using a conventional smartphone camera. This spectrally informed learning method is analogous to compressed sensing; however, it further allows for reliable hypercube recovery and key feature extractions with a transparent learning algorithm. This learning-powered snapshot hyperspectral imaging method yields high spectral and temporal resolutions and eliminates the spatiospectral trade-off, offering simple hardware requirements and potential applications of various machine learning techniques.

Immunohistochemical Expression Analysis of Caldesmon Isoforms in Colorectal Carcinoma Reveals Interesting Correlations with Tumor Characteristics.

Colorectal cancer is a notorious disease, with almost half of the patients succumbing to the disease. The prevalence and incidence rates of colorectal cancer are increasing in many parts of the world, highlighting the need to discover new biomarkers for diagnosis and therapy. Caldesmon (CaD), an actin-binding protein that plays a significant role in controlling cell motility, has emerged as a promising biomarker. The CALD1 gene encodes CaD as multiple transcripts that mainly encode two protein isoforms: High-molecular-weight (h-CaD), expressed in smooth muscle, and low-molecular-weight (l-CaD), expressed in nonsmooth muscle cells. Most studies have suggested an oncogenic role of CaD in colorectal cancer, but the exact subcellular localization of the two CaD isoforms in tumor cells and stroma have not been clarified yet. Here, we analyzed tissue samples from 262 colorectal cancer patients by immunohistochemistry analysis using specific antibodies for l-CaD and h-CaD. The results showed elevated cytoplasmic expression levels of l-Cad in 187/262 (71.4%) cases. l-Cad was expressed at low levels in the normal colon mucosa and was also consistently expressed in the cancer-associated stroma of all cases, suggesting that it could play a role in modulating the tumor microenvironment. l-CaD expression in cancer cells was associated with preinvasive stages of cancer. Survival analysis indicated that patients with high l-CaD expression in tumor cells could respond poorly to selective chemotherapeutic 5FU, but not combination chemotherapy. h-CaD was expressed in colonic and vascular smooth muscle cells as expected and to a lesser extent in the tumor-associated stroma, but it was not expressed in the cancer cells or normal colon mucosal epithelial cells. Collectively, these data clarify how the expression patterns of CaD isoforms in colorectal cancer can have applications in the management of colorectal cancer patients.

Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A.

Colorectal cancer is a common cancer with a poor prognosis in both males and females. The influence of bisphenol A (BPA), a widely used environmental contaminant, in colon cancer development and progression is not well identified, in spite of the fact that the most common mode of exposure to BPA is ingestion. The aim of this work is to elucidate the carcinogenic effects of BPA in the colon in vitro. We analyzed BPA's effects on human colon epithelial (HCoEpiC) and colon cancer (HCT116) cells. BPA exerted cytotoxic effects and augmented the 5FU cytotoxicity on both cell lines at high doses, while it did not show this effect at low doses. Therefore, we focused on studying the effects of low-dose (0.0043 nM) exposure on normal colonic epithelial cells for a long period of time (two months), which is more consistent with environmental exposure levels and patterns. BPA increased cellular invasiveness through collagen and the ability to anchorage-independent cell growth, as measured by colony formation in soft agar, which could support oncogenicity. To gain insights into the mechanism of these actions, we performed transcriptomic analysis using next-generation sequencing, which revealed 340 differentially expressed transcripts by BPA in HCT116 and 75 in HCoEpiC. These transcripts belong in many cancer-related pathways such as apoptosis, cell proliferation, signal transduction, and angiogenesis. Some of the significant genes (FAM83H, CXCL12, PITPNA, HMOX1, DGKZ, NR5A2, VMP1, and ID1) were confirmed by quantitative RT-PCR. Furthermore, BPA induced the phosphorylation of protein kinases such as JNK1/2/3, GSK-3α/ß, AMPKα1, AKT1/2/3, AMPKα2, HSP27, ß-catenin, STAT2, Hck, Chk2, FAK, and PRAS40 in HCoEpiC, as well as GSK-3α/ß, p53, AKT1/2/3, p70 S6 kinase, and WNK1 in HCT116. The majority of these proteins are involved in potential carcinogenic pathways. Taken together, these data suggest that BPA plays a role in colon carcinogenesis, and they provide insights into the molecular mechanisms of colon epithelial cell transformation by BPA. Increasing exposure to environmental toxins such as BPA can explain the increasing incidence of colorectal cancer.

Emerging role of caldesmon in cancer: A potential biomarker for colorectal cancer and other cancers.

Colorectal cancer (CRC) is a devastating disease, mainly because of metastasis. As a result, there is a need to better understand the molecular basis of invasion and metastasis and to identify new biomarkers and therapeutic targets to aid in managing these tumors. The actin cytoskeleton and actin-binding proteins are known to play an important role in the process of cancer metastasis because they control and execute essential steps in cell motility and contractility as well as cell division. Caldesmon (CaD) is an actin-binding protein encoded by the CALD1 gene as multiple transcripts that mainly encode two protein isoforms: High-molecular-weight CaD, expressed in smooth muscle, and low-molecular weight CaD (l-CaD), expressed in nonsmooth muscle cells. According to our comprehensive review of the literature, CaD, particularly l-CaD, plays a key role in the development, metastasis, and resistance to chemoradiotherapy in colorectal, breast, and urinary bladder cancers and gliomas, among other malignancies. CaD is involved in many aspects of the carcinogenic hallmarks, including epithelial mesenchymal transition via transforming growth factor-beta signaling, angiogenesis, resistance to hormonal therapy, and immune evasion. Recent data show that CaD is expressed in tumor cells as well as in stromal cells, such as cancer-associated fibroblasts, where it modulates the tumor microenvironment to favor the tumor. Interestingly, CaD undergoes selective tumor-specific splicing, and the resulting isoforms are generally not expressed in normal tissues, making these transcripts ideal targets for drug design. In this review, we will analyze these features of CaD with a focus on CRC and show how the currently available data qualify CaD as a potential candidate for targeted therapy in addition to its role in the diagnosis and prognosis of cancer.

Human CSF movement influenced by vascular low frequency oscillations and respiration.

Cerebrospinal fluid (CSF) movement through the pathways within the central nervous system is of high significance for maintaining normal brain health and function. Low frequency hemodynamics and respiration have been shown to drive CSF in humans independently. Here, we hypothesize that CSF movement may be driven simultaneously (and in synchrony) by both mechanisms and study their independent and coupled effects on CSF movement using novel neck fMRI scans. Caudad CSF movement at the fourth ventricle and hemodynamics of the major neck blood vessels (internal carotid arteries and internal jugular veins) was measured from 11 young, healthy volunteers using novel neck fMRI scans with simultaneous measurement of respiration. Two distinct models of CSF movement (1. Low-frequency hemodynamics and 2. Respiration) and possible coupling between them were investigated. We show that the dynamics of brain fluids can be assessed from the neck by studying the interrelationships between major neck blood vessels and the CSF movement in the fourth ventricle. We also demonstrate that there exists a cross-frequency coupling between these two separable mechanisms. The human CSF system can respond to multiple coupled physiological forces at the same time. This information may help inform the pathological mechanisms behind CSF movement-related disorders.

Mitigating sarcoplasmic reticulum stress limits disuse-induced muscle loss in hindlimb unloaded mice.

Muscle disuse in the hindlimb unloaded (HU) mice causes significant atrophy and weakness. However, the cellular and molecular mechanisms driving disuse-muscle atrophy remain elusive. We investigated the potential contribution of proteins dysregulation by sarcoplasmic reticulum (SR), a condition called SR stress, to muscle loss during HU. Male, c57BL/6j mice were assigned to ground-based controls or HU groups treated with vehicle or 4-phenylbutyrate (4-PBA), a potent inhibitor of SR stress, once a day for three weeks. We report that the 4-PBA reduced the SR stress and partly reversed the muscle atrophy and weakness in the HU mice. Transcriptome analysis revealed that several genes were switched on (n = 3688) or differentially expressed (n = 1184) due to HU. GO, and KEGG term analysis revealed alterations in pathways associated with the assembly of cilia and microtubules, extracellular matrix proteins regulation, calcium homeostasis, and immune modulation during HU. The muscle restoration with 4-PBA partly reversed these changes along with differential and unique expression of several genes. The analysis of genes among the two comparisons (HU-v vs. control and HU-t vs. HU-v.) shows 841 genes were overlapped between the two comparisons and they may be regulated by 4-PBA. Altogether, our findings suggest that the pharmacological suppression of SR stress may be an effective strategy to prevent disuse-induced muscle weakness and atrophy.

Evaluation of Galanin Expression in Colorectal Cancer: An Immunohistochemical and Transcriptomic Study.

Colorectal cancer (CRC) represents around 10% of all cancers, with an increasing incidence in the younger age group. The gut is considered a unique organ with its distinctive neuronal supply. The neuropeptide, human galanin, is widely distributed in the colon and expressed in many cancers, including the CRC. The current study aimed to explore the role of galanin at different stages of CRC. Eighty-one CRC cases (TNM stages I - IV) were recruited, and formalin-fixed paraffin-embedded samples were analyzed for the expression of galanin and galanin receptor 1 (GALR1) by immunohistochemistry (IHC). Galanin intensity was significantly lower in stage IV (n= 6) in comparison to other stages (p= 0.037 using the Mann-Whitney U test). Whole transcriptomics analysis using NGS was performed for selected samples based on the galanin expression by IHC [early (n=5) with high galanin expression and late (n=6) with low galanin expression]. Five differentially regulated pathways (using Absolute GSEA) were identified as drivers for tumor progression and associated with higher galanin expression, namely, cell cycle, cell division, autophagy, transcriptional regulation of TP53, and immune system process. The top shared genes among the upregulated pathways are AURKA, BIRC5, CCNA1, CCNA2, CDC25C, CDK2, CDK6, EREG, LIG3, PIN1, TGFB1, TPX2. The results were validated using real-time PCR carried out on four cell lines [two primaries (HCT116 and HT29) and two metastatic (LoVo and SK-Co-1)]. The current study shows galanin as a potential negative biomarker. Galanin downregulation is correlated with advanced CRC staging and linked to cell cycle and division, autophagy, transcriptional regulation of TP53 and immune system response.

Optimized protocol for stable isotope tracing and steady-state metabolomics in mouse HER2+ breast cancer brain metastasis.

Analyzing the metabolic dependencies of tumor cells is vital for cancer diagnosis and treatment. Here, we describe a protocol for 13C-stable glucose and glutamine isotope tracing in mice HER2+ breast cancer brain metastatic lesions. We describe how to inject cancer cells intracardially to generate brain metastatic lesions in mice. We then detail how to perform 13C-stable isotope infusion in mice with established brain metastasis. Finally, we outline steps for sample collection, processing for metabolite extraction, and analyzing mass spectrometry data. For complete details on the use and execution of this protocol, please refer to Parida et al. (2022).

Efficacy of bilateral temporal artery biopsies and sectioning of the entire block of tissue for the diagnosis of temporal arteritis.

Giant cell arteritis (GCA) is a systemic vasculitis of medium and large sized blood vessels. The incidence is greater in women as compared to men (3:1) and most often occurs in the elderly. The most common symptoms are unilateral headaches, visual disturbances and scalp tenderness. If untreated, GCA may result in irreversible blindness. Prompt treatment is necessary to prevent progression of the disease, but accurate diagnosis is vital to prevent unwarranted side effects of the therapy. Temporal artery biopsy (TAB) remains the gold standard for diagnosis. TAB is an invasive procedure that can require up to 40 minutes to perform but is important for pathological confirmation. Variation amongst centers and practitioners exists in the type of biopsies performed. In 2013, a survey of over 1000 specialists showed that 37% recommended unilateral biopsy alone, 29% recommended initial unilateral biopsy with biopsy of the contralateral side if the first side is negative, 18% recommended bilateral biopsy in all cases, and 16% stated that their preference depended upon the degree of suspicion. Studies have shown that bilateral TAB can enhance diagnostic accuracy by 3 to 12.7%. Furthermore, temporal arteritis can involve the artery in a discontinuous fashion and there is no standardization of the number of sections or levels that should be examined in a segment of temporal artery. This study aims to shed light on the benefits of a bilateral temporal artery biopsy as well as to determine the optimum level for block sectioning for the diagnosis of temporal arteritis.

Coupling between cerebrovascular oscillations and CSF flow fluctuations during wakefulness: An fMRI study.

It is commonly believed that cerebrospinal fluid (CSF) movement is facilitated by blood vessel wall movements (i.e., hemodynamic oscillations) in the brain. A coherent pattern of low frequency hemodynamic oscillations and CSF movement was recently found during non-rapid eye movement (NREM) sleep via functional MRI. This finding raises other fundamental questions: 1) the explanation of coupling between hemodynamic oscillations and CSF movement from fMRI signals; 2) the existence of the coupling during wakefulness; 3) the direction of CSF movement. In this resting state fMRI study, we proposed a mechanical model to explain the coupling between hemodynamics and CSF movement through the lens of fMRI. Time delays between CSF movement and global hemodynamics were calculated. The observed delays between hemodynamics and CSF movement match those predicted by the model. Moreover, by conducting separate fMRI scans of the brain and neck, we confirmed the low frequency CSF movement at the fourth ventricle is bidirectional. Our finding also demonstrates that CSF movement is facilitated by changes in cerebral blood volume mainly in the low frequency range, even when the individual is awake.

Metabolic diversity within breast cancer brain-tropic cells determines metastatic fitness.

HER2+ breast cancer patients are presented with either synchronous (S-BM), latent (Lat), or metachronous (M-BM) brain metastases. However, the basis for disparate metastatic fitness among disseminated tumor cells of similar oncotype within a distal organ remains unknown. Here, employing brain metastatic models, we show that metabolic diversity and plasticity within brain-tropic cells determine metastatic fitness. Lactate secreted by aggressive metastatic cells or lactate supplementation to mice bearing Lat cells limits innate immunosurveillance and triggers overt metastasis. Attenuating lactate metabolism in S-BM impedes metastasis, while M-BM adapt and survive as residual disease. In contrast to S-BM, Lat and M-BM survive in equilibrium with innate immunosurveillance, oxidize glutamine, and maintain cellular redox homeostasis through the anionic amino acid transporter xCT. Moreover, xCT expression is significantly higher in matched M-BM brain metastatic samples compared to primary tumors from HER2+ breast cancer patients. Inhibiting xCT function attenuates residual disease and recurrence in these preclinical models.