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Photodynamic Therapy (PDT) is an effective treatment modality for cancers, with Protoporphyrin IX (PPIX)-based PDT being the most widely used to treat cancers in patients. However, PDT is limited to superficial, thin (few mm in depth) lesions that can be accessed by visible wavelength light. Interstitial light-delivery strategies have been developed to treat deep-seated lesions (i.e. prostate cancer). The most promising of these are X-ray-induced scintillation nanoparticles, which have shown potential benefits for PDT of deep-seated tumors. Herein, the design and use of a new nanoscintillator-based radiation-activated PDT (radioPDT) system is investigated in the treatment of deep-seated tumors. Poly(ethylene glycol) methyl ether- block -poly(lactide- co -glycolide) (PEG-PLGA) nanospheres were loaded with a scintillator (LaF 3 :Ce3+) and photosensitizer (PPIX) to effect radioPDT. UV–Vis spectroscopy and electron microscopy studies demonstrated efficient encapsulation of nanoscintillators and PPIX (>90% efficiency) into the PEG-PLGA nanospheres. The nanoparticles were uniform in size and approximately 100 nm in diameter. They were highly stable and functional for up to 24 h under physiological conditions and demonstrated slow release kinetics. In vitro and in vivo toxicity studies showed no appreciable drug toxicity to human skin fibroblast (GM38), prostate cancer cells (PC3), and to C57/BL mice. Cell uptake studies demonstrated accumulation of the nanoparticles in the cytoplasm of PC3 cells. When activated, fluorescent resonant energy transfer (FRET) was evident via fluorescent spectroscopy and singlet oxygen yield. Determination of stability revealed that the nanoparticles were stable for up to 4 weeks. The nanoparticle production was scaled-up with no change in properties. This nanoparticle represents a unique, optimally designed therapeutic and diagnostic agent (theranostic) agent for radioPDT with characteristics capable of potentially augmenting radiotherapy for deep-seated tumors and integrating into current cancer radiotherapy. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Nanoparticle platforms are particularly attractive for theranostic applications due to their capacity for multifunctionality and multivalency. Some of the most promising nano-scale scaffold systems have been co-opted from nature including plant viruses such as cowpea mosaic virus (CPMV). The use of plant viruses like CPMV as viral nanoparticles is advantageous for many reasons; they are non-infectious and nontoxic to humans and safe for use in intravital imaging and drug delivery. The CPMV capsid icosahedral shape allows for enhanced multifunctional group display and the ability to carry specific cargoes. The native tropism of CPMV for cell-surface displayed vimentin and the enhanced permeability and retention effect allow them to preferentially extravasate from tumor neovasculature and efficiently penetrate tumors. Furthermore, CPMVs can be engineered via several straightforward chemistries to display targeting and imaging moieties on external, addressable residues and they can be loaded internally with therapeutic drug cargoes. These qualities make them highly effective as biocompatible platforms for tumor targeting, intravital imaging and cancer therapy. Depiction of CPMV as a theranostic tool for cancer cell imaging and therapy. Multifunctional CPMV nanoparticles (green circle) with externally-coupled fluorophore dye moieties (yellow spikes) carrying drug molecules as cargo (red star) home towards cancer cells over-expressing cell membrane-bound vimentin (+). The targeting and then retention of the functionalized nanoparticles to the tumor cells is theorized to be due to the efficiency of CPMV extravasation (purple arrows) into the stroma of the tumor by the EPR effect. Unlabelled Image [ABSTRACT FROM AUTHOR]

Background Autism spectrum disorder (ASD) is a developmental disorder defined by behavioral features that emerge during the first years of life. Research indicates that abnormalities in brain connectivity are associated with these behavioral features. However, the inclusion of individuals past the age of onset of the defining behaviors complicates interpretation of the observed abnormalities: they may be cascade effects of earlier neuropathology and behavioral abnormalities. Our recent study of network efficiency in a cohort of 24-month-olds at high and low familial risk for ASD reduced this confound; we reported reduced network efficiencies in toddlers classified with ASD. The current study maps the emergence of these inefficiencies in the first year of life. Methods This study uses data from 260 infants at 6 and 12 months of age, including 116 infants with longitudinal data. As in our earlier study, we use diffusion data to obtain measures of the length and strength of connections between brain regions to compute network efficiency. We assess group differences in efficiency within linear mixed-effects models determined by the Akaike information criterion. Results Inefficiencies in high-risk infants later classified with ASD were detected from 6 months onward in regions involved in low-level sensory processing. In addition, within the high-risk infants, these inefficiencies predicted 24-month symptom severity. Conclusions These results suggest that infants with ASD, even before 6 months of age, have deficits in connectivity related to low-level processing, which contribute to a developmental cascade affecting brain organization and eventually higher-level cognitive processes and social behavior. [ABSTRACT FROM AUTHOR]

Summary Tumor cell extravasation is a key step during cancer metastasis, yet the precise mechanisms that regulate this dynamic process are unclear. We utilized a high-resolution time-lapse intravital imaging approach to visualize the dynamics of cancer cell extravasation in vivo. During intravascular migration, cancer cells form protrusive structures identified as invadopodia by their enrichment of MT1-MMP, cortactin, Tks4, and importantly Tks5, which localizes exclusively to invadopodia. Cancer cells extend invadopodia through the endothelium into the extravascular stroma prior to their extravasation at endothelial junctions. Genetic or pharmacological inhibition of invadopodia initiation (cortactin), maturation (Tks5), or function (Tks4) resulted in an abrogation of cancer cell extravasation and metastatic colony formation in an experimental mouse lung metastasis model. This provides direct evidence of a functional role for invadopodia during cancer cell extravasation and distant metastasis and reveals an opportunity for therapeutic intervention in this clinically important process. [ABSTRACT FROM AUTHOR]

• After 5 months of age, infants begin to prioritize attention to fearful over other facial expressions. • Amygdala and related early-maturing subcortical network, is important for emergence of this attentional bias. • Left amygdala volume associates positively with the emerging perceptual vigilance for fearful faces during infancy. • possible link from the prenatally defined variability in the amygdala size to social traits After 5 months of age, infants begin to prioritize attention to fearful over other facial expressions. One key proposition is that amygdala and related early-maturing subcortical network, is important for emergence of this attentional bias – however, empirical data to support these assertions are lacking. In this prospective longitudinal study, we measured amygdala volumes from MR images in 65 healthy neonates at 2–5 weeks of gestation corrected age and attention disengagement from fearful vs. non-fearful facial expressions at 8 months with eye tracking. Overall, infants were less likely to disengage from fearful than happy/neutral faces, demonstrating an age-typical bias for fear. Left, but not right, amygdala volume (corrected for intracranial volume) was positively associated with the likelihood of disengaging attention from fearful faces to a salient lateral distractor (r =.302, p =.014). No association was observed with the disengagement from neutral or happy faces in equivalent conditions (r =.166 and.125, p =.186 and.320, respectively). These results are the first to link the amygdala volume with the emerging perceptual vigilance for fearful faces during infancy. They suggest a link from the prenatally defined variability in the amygdala size to early postnatal emotional and social traits. [ABSTRACT FROM AUTHOR]

Blindsight is the ability of patients with primary visual cortex (V1) damage to process information in their clinically blind visual field in the absence of conscious awareness. In addition to those with localized V1 lesions, some patients exhibiting this phenomenon have had a cerebral hemisphere removed or disconnected from the rest of the brain for the treatment of drug-resistant epilepsy (hemispherectomy). Research into the underlying neural substrates of blindsight has long implicated the intact visual cortex in maintaining residual vision and supporting visuo-guided responses to stimuli presented ipsilaterally within the blind visual field while operating outside the geniculo-striate pathway. A recent study demonstrated functional reorganization in the dorsal visual areas of the intact hemisphere, thereby supporting its compensatory role in non-conscious vision. In this study, we used cortical thickness analysis to examine anatomical differences in the visual cortex of the intact hemisphere of three subjects with varying degrees of cortical damage and well documented blindsight: two with a right hemispherectomy (complete and partial), and one with a left V1 lesion. T1-weighted MRI data were obtained for the subjects while control data were chosen from publicly available NKI-dataset to match closely the acquisition parameters of our blindsight cases. Our results show significant increases in cortical thickness in the visual cortex of all blindsight subjects compared to healthy controls, irrespective of age-onset, etiology, and extent of the damage. Our findings add to accumulating evidence from behavioral, functional imaging, and tractography studies of cerebral compensation and reorganization. • Examined anatomical changes in the intact visual cortex of rare blindsight patients. • First comparison of hemispherectomy and lesion patients to a large control sample. • Blindsight subjects show significant increases in peri-calcarine cortical thickness. • Similar changes observed despite differences in etiology and age at time of lesion. • Increases are possible morphological signs of compensation underlying blindsight. [ABSTRACT FROM AUTHOR]

Prenatal and postnatal maternal psychological distress predicts various detrimental consequences on social, behavioral, and cognitive development of offspring, especially in girls. Maturation of white matter (WM) continues from prenatal development into adulthood and is thus susceptible to exposures both before and after birth. WM microstructural features of 130 children (mean age, 5.36 years; range, 5.04–5.79 years; 63 girls) and their association with maternal prenatal and postnatal depressive and anxiety symptoms were investigated with diffusion tensor imaging, tract-based spatial statistics, and regression analyses. Maternal questionnaires were collected during first, second, and third trimesters and at 3, 6, and 12 months postpartum with the Edinburgh Postnatal Depression Scale (EPDS) for depressive symptoms and Symptom Checklist-90 for general anxiety. Covariates included child's sex; child's age; maternal prepregnancy body mass index; maternal age; socioeconomic status; and exposures to smoking, selective serotonin reuptake inhibitors, and synthetic glucocorticoids during pregnancy. Prenatal second-trimester EPDS scores were positively associated with fractional anisotropy in boys (p <.05, 5000 permutations) after controlling for EPDS scores 3 months postpartum. In contrast, postpartum EPDS scores at 3 months correlated negatively with fractional anisotropy (p <.01, 5000 permutations) in widespread areas only in girls after controlling for prenatal second-trimester EPDS scores. Perinatal anxiety was not associated with WM structure. These results suggest that prenatal and postnatal maternal psychological distress is associated with brain WM tract developmental alterations in a sex- and timing-dependent manner. Future studies including behavioral data are required to consolidate associative outcomes for these alterations. [ABSTRACT FROM AUTHOR]

Bladder cancers, and specifically urothelial carcinoma, have few effective treatment options, and tumors typically develop resistance against standard of care chemotherapies leading to significant mortality. The development of alternative therapies with increased selectivity and improved tolerability would significantly impact this patient population. Here, we investigate a novel colchicine derivative, CR42-24, with increased selectivity for the βIII tubulin subtype as a treatment for urothelial carcinoma. βIII tubulin is a promising target due to its low expression in healthy tissues and its clinical association with poor prognosis. This study demonstrated that CR42-24 is selectively cytotoxic to several cancer cell lines at low nanomolar IC50, with high activity in bladder cancer cell lines both in vitro and in vivo. CR42-24 monotherapy in an aggressive urothelial carcinoma xenograft model results in effective control when treated early. We observed significant ablation of large tumors and patient-derived xenografts at low doses with excellent tolerability. CR42-24 was highly synergistic in combination with the standard of care chemotherapies gemcitabine and cisplatin, further increasing its therapeutic potential as a novel treatment for urothelial carcinoma. [ABSTRACT FROM AUTHOR]

Abstract: In pursuit of a single molecule with potential applications for both in vitro fluorescence microscopy and in vivo PET imaging, novel targeted 69/71Ga/68Ga-protoporphyrin IX (PPIX) probes were developed. Optical analysis, fluorescence microscopy and radiolabeling with gallium-68 were performed to confirm potential applications. The use of a targeted-PPIX ring, in conjunction with 69/71Ga or 68Ga, eliminates the need for the attachment of multiple imaging tags, allowing for either in vitro fluorescent-based evaluation or in vivo nuclear-based imaging. [Copyright &y& Elsevier]

Prostate cancer (PCa) may be initiated by CD133+/CD44+ expressing stem cell-like cells (PCSC), which are also thought to drive metastasis. Platelets also contribute to metastasis via tumor cell-induced platelet aggregation (TCIPA), which in part enhances cancer cell invasion. Moreover, activated platelets secrete stromal derived growth factor-1α (SDF-1α) that can mobilize CSCs via the CXCR4 receptor. However, the potential reciprocal interactions between CSCs and platelets have not been investigated. To characterize the mechanisms behind PCSC-platelet interaction. Fluorescence Activated Cell Sorting was utilized to separate DU145 and PC3 PCa cells into CD133+/CD44+, CD133+/CD44-, CD44+/CD133-, and CD133-/CD44- subpopulations and to measure their CXCR4 surface expression. PCa subpopulation TCIPA experiments were performed using aggregometry and immunoblot was used to measure prothrombin. Platelet SDF-1α secretion was measured by ELISA. Modified-Boyden chamber assays were used to assess the role of SDF-1α:CXCR4 pathway in platelet-PCSC interactions. DU145 and PC3 expressing both CD133 and CD44 stem cell markers accounted for only small fractions of total cells (DU145: CD133+/CD44+ 3.44 ± 1.45% vs. CD133+/CD44- 1.56 ± 0.45% vs. CD44+/CD133- 68.19 ± 6.25% vs. CD133-/CD44- 20.36 ± 4.51%). However, CD133+ subpopulations induced the greatest amount of aggregation compared to CD44+/CD133- and double-negative DU145, and this aggregation potency of CD133+ PCa cells corresponded with high levels of prothrombin expression. Additionally, CD133+ subpopulations expressed significantly higher level of CXCR4 compared to CD133-/CD44- and CD44+/CD133-. Disruption of SDF-1α:CXCR4 pathway reduced platelet-induced PCSC invasion. CD133+/CD44+ and CD133+/CD44- PCSCs have highest platelet aggregation potency, which could be attributed to their increased prothrombin expression. Reciprocally, platelet-derived SDF-1α stimulates PCSC invasion. • Little is known about the interaction between PCSC and platelets. • Study assess PCSC induced TCIPA and the role of SDF-1α:CXCR4 in platelet-induced PCSC invasion. • PCSCs induce TCIPA through thrombin generation and their invasion is facilitated in part by platelet-derived SDF-1α. [ABSTRACT FROM AUTHOR]

Background Clear-cell renal cell carcinoma (ccRCC) exhibits suppressed mitochondrial function and preferential use of glycolysis even in normoxia, promoting proliferation and suppressing apoptosis. ccRCC resistance to therapy is driven by constitutive hypoxia-inducible factor (HIF) expression due to genetic loss of von Hippel-Lindau factor. In addition to promoting angiogenesis, HIF suppresses mitochondrial function by inducing pyruvate dehydrogenase kinase (PDK), a gatekeeping enzyme for mitochondrial glucose oxidation. Objective To reverse mitochondrial suppression of ccRCC using the PDK inhibitor dichloroacetate (DCA). Design, setting, and participants Radical nephrectomy specimens from patients with ccRCC were assessed for PDK expression. The 786-O ccRCC line and two animal models (chicken in ovo and murine xenografts) were used for mechanistic studies. Outcome measurements and statistical analysis Mitochondrial function, proliferation, apoptosis, HIF transcriptional activity, angiogenesis, and tumor size were measured in vitro and in vivo. Independent-sample t -tests and analysis of variance were used for statistical analyses. Results PDK was elevated in 786-O cells and in ccRCC compared to normal kidney tissue from the same patient. DCA reactivated mitochondrial function (increased respiration, Krebs cycle metabolites such as α-ketoglutarate [cofactor of factor inhibiting HIF], and mitochondrial reactive oxygen species), increased p53 activity and apoptosis, and decreased proliferation in 786-O cells. DCA reduced HIF transcriptional activity in an FIH-dependent manner, inhibiting angiogenesis in vitro. DCA reduced tumor size and angiogenesis in vivo in both animal models. Conclusions DCA can reverse the mitochondrial suppression of ccRCC and decrease HIF transcriptional activity, bypassing its constitutive expression. Its previous clinical use in humans makes it an attractive candidate for translation to ccRCC patients. Patient summary We show that an energy-boosting drug decreases tumor growth and tumor blood vessels in animals carrying human kidney cancer cells. This generic drug has been used in patients for other conditions and thus could be tested in kidney cancer that remains incurable. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum disorder is a complex neurodevelopmental disorder characterized by impaired social interaction and communication, repetitive behaviors, and restricted interests. Gray matter differences linked to autism spectrum disorder have been studied using a variety of structural imaging methods, but yielded little consensus; the extent to which disparate results reflect differences in methodology or heterogeneity within autism spectrum disorder is not yet clear. Moreover, very few studies have examined gray matter changes as a function of age in autism spectrum disorder.Method: A detailed investigation of gray matter structural development was performed via voxel-based morphometry, cortical thickness, and cortical surface area analyses in 38 autism spectrum disorder versus 46 typically developing children.Results: Relative to typically developing children, the autism spectrum disorder group showed gray matter increases most prominently in the frontal and temporal lobes (including regions such as medial frontal gyrus, Broca's area and posterior temporal cortex), as well as certain parietal and occipital subcortical regions. Gray matter decreases were found only near the temporoparietal junction. Subcortical gray matter increases were found in the putamen and caudate nucleus, while decreases were found in cerebellum. There were age-dependent GM differences in distributed regions including prefrontal cortex, primary sensorimotor cortex, and temporoparietal junction.Conclusion: The results underline the distributed nature of gray matter structural differences in autism spectrum disorder and provide a more comprehensive characterization of autism spectrum disorder-related cortical and subcortical gray matter structural differences during childhood and adolescent development. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Incisional biopsies, including the diagnostic core needle biopsy (CNB), routinely performed before surgical excision of breast cancer tumors are hypothesized to increase the risk of metastatic disease. In this study, we experimentally determined whether CNB of breast cancer tumors results in increased distant metastases and examine important resultant changes in the primary tumor and tumor microenvironment associated with this outcome. METHOD: To evaluate the effect of CNB on metastasis development, we implanted murine mammary 4T1 tumor cells in BALB/c mice and performed CNB on palpable tumors in half the mice. Subsequently, emulating the human scenario, all mice underwent complete tumor excision and were allowed to recover, with attendant metastasis development. Tumor growth, lung metastasis, circulating tumor cell (CTC) levels, variation in gene expression, composition of the tumor microenvironment, and changes in immunologic markers were compared in biopsied and non-biopsied mice. RESULTS: Mice with biopsied tumors developed significantly more lung metastases compared to non-biopsied mice. Tumors from biopsied mice contained a higher frequency of myeloid-derived suppressor cells (MDSCs) accompanied by reduced CD4+ T cells, CD8+ T cells, and macrophages, suggesting biopsy-mediated development of an increasingly immunosuppressive tumor microenvironment. We also observed a CNB-dependent up-regulation in the expression of SOX4, Ezh2, and other key epithelial-mesenchymal transition (EMT) genes, aswell as increased CTC levels among the biopsy group. CONCLUSION: CNB creates an immunosuppressive tumor microenvironment, increases EMT, and facilitates release of CTCs, all of which likely contribute to the observed increase in development of distant metastases. [ABSTRACT FROM AUTHOR]

It is well established that widely expressed PTK7 is essential for vertebrate tissue morphogenesis. In cancer, the functionality of PTK7 is selectively regulated by membrane type-1 matrix metalloproteinase (MT1-MMP), ADAMs (a disintegrin domain and metalloproteinases), and γ-secretase proteolysis. Here, we established that the full-length membrane PTK7, its Chuzhoi mutant with the two functional MT1-MMP cleavage sites, and its L622D mutant with the single inactivated MT1-MMP cleavage site differentially regulate cell motility in a two-dimensional versus three-dimensional environment. We also demonstrated that in polarized cancer cells, the levels of PTK7 expression and proteolysis were directly linked to the structure and kinetics of cell protrusions, including lamellipodia and invadopodia. In the functionally relevant and widely accepted animal models of metastasis, mouse and chick embryo models, both the overexpression and knock-out of PTK7 in HT1080 cells abrogated metastatic dissemination. Our analysis of human tissue specimens confirmed intensive proteolysis of PTK7 in colorectal cancer tumors, but not in matching normal tissue. Our results provide convincing evidence that both PTK7 expression and proteolysis, rather than the level of the cellular full-length PTK7 alone, contribute to efficient directional cell motility and metastasis in cancer. [ABSTRACT FROM AUTHOR]

Pannexin 1 (Panx1) is a channel-forming glycoprotein expressed in different cell types of mammalian skin. We examined the role of Panx1 in melanoma tumorigenesis and metastasis since qPCR and Western blots revealed that mouse melanocytes exhibited low levels of Panx1 while increased Panx1 expression was correlated with tumor cell aggressiveness in the isogenic melanoma cell lines (B16-F0, -F10, and -BL6). Panx1 shRNA knockdown (Panx1-KD) generated stable BL6 cell lines, with reduced dye uptake, that showed a marked increase in melanocyte- like cell characteristics including higher melanin production, decreased cell migration and enhanced formation of cellular projections. Western blotting and proteomic analyses using 2D-gel/mass spectroscopy identified vimentin and β-catenin as two of the markers of malignant melanoma that were down-regulated in Panx1-KD cells. Xenograft Panx1-KD cells grown within the chorioallantoic membrane of avian embryos developed tumors that were significantly smaller than controls. Mouse-Alu qPCR of the excised avian embryonic organs revealed that tumor metastasis to the liver was significantly reduced upon Panx1 knockdown. These data suggest that while Panx1 is present in skin melanocytes it is up-regulated during melanoma tumor progression, and tumorigenesis can be inhibited by the knockdown of Panx1 raising the possibility that Panx1 may be a viable target for the treatment of melanoma. [ABSTRACT FROM AUTHOR]