Breast-to-brain metastasis is exacerbated with chemotherapy through blood-cerebrospinal fluid barrier and induces Alzheimer's-like pathology.

Control of breast-to-brain metastasis remains an urgent unmet clinical need. While chemotherapies are essential in reducing systemic tumor burden, they have been shown to promote non-brain metastatic invasiveness and drug-driven neurocognitive deficits through the formation of neurofibrillary tangles (NFT), independently. Now, in this study, we investigated the effect of chemotherapy on brain metastatic progression and promoting tumor-mediated NFT. Results show chemotherapies increase brain-barrier permeability and facilitate enhanced tumor infiltration, particularly through the blood-cerebrospinal fluid barrier (BCSFB). This is attributed to increased expression of matrix metalloproteinase 9 (MMP9) which, in turn, mediates loss of Claudin-6 within the choroid plexus cells of the BCSFB. Importantly, increased MMP9 activity in the choroid epithelium following chemotherapy results in cleavage and release of Tau from breast cancer cells. This cleaved Tau forms tumor-derived NFT that further destabilize the BCSFB. Our results underline for the first time the importance of the BCSFB as a vulnerable point of entry for brain-seeking tumor cells post-chemotherapy and indicate that tumor cells themselves contribute to Alzheimer's-like tauopathy.

What goes down must come up: role of the posteromedial cortices in encoding and retrieval.

The hypothesis that the neural network supporting successful episodic memory retrieval overlaps with the regions involved in episodic encoding has garnered much interest; however, the role of the posteromedial regions remains to be fully elucidated. Functional magnetic resonance imaging (fMRI) studies during successful encoding typically demonstrate deactivation of posteromedial cortices, whereas successful retrieval of previously encoded information has been associated with activation of these regions. Here, we performed an event-related fMRI experiment during an associative face-name encoding and retrieval task to investigate the topography and functional relationship of the brain regions involved in successful memory processes. A conjunction analysis of novel encoding and subsequent successful retrieval of names revealed an anatomical overlap in bilateral posteromedial cortices. In this region, a significant negative correlation was found: Greater deactivation during encoding was related to greater activation during successful retrieval. In contrast, the hippocampus and prefrontal cortex demonstrated positive activation during both encoding and retrieval. Our results provide further evidence that posteromedial regions constitute critical nodes in the large-scale cortical network subserving episodic memory. These results are discussed in relation to the default mode hypothesis, the involvement of posteromedial cortices in successful memory formation and retention, as well as potential implications for aging and neurodegenerative disease.

Radio-Pathomic Maps of Cell Density Identify Brain Tumor Invasion beyond Traditional MRI-Defined Margins.

BACKGROUND AND PURPOSE: Currently, contrast-enhancing margins on T1WI are used to guide treatment of gliomas, yet tumor invasion beyond the contrast-enhancing region is a known confounding factor. Therefore, this study used postmortem tissue samples aligned with clinically acquired MRIs to quantify the relationship between intensity values and cellularity as well as to develop a radio-pathomic model to predict cellularity using MR imaging data. MATERIALS AND METHODS: This single-institution study used 93 samples collected at postmortem examination from 44 patients with brain cancer. Tissue samples were processed, stained with H&E, and digitized for nuclei segmentation and cell density calculation. Pre- and postgadolinium contrast T1WI, T2 FLAIR, and ADC images were collected from each patient's final acquisition before death. In-house software was used to align tissue samples to the FLAIR image via manually defined control points. Mixed-effects models were used to assess the relationship between single-image intensity and cellularity for each image. An ensemble learner was trained to predict cellularity using 5 × 5 voxel tiles from each image, with a two-thirds to one-third train-test split for validation. RESULTS: Single-image analyses found subtle associations between image intensity and cellularity, with a less pronounced relationship in patients with glioblastoma. The radio-pathomic model accurately predicted cellularity in the test set (root mean squared error = 1015 cells/mm2) and identified regions of hypercellularity beyond the contrast-enhancing region. CONCLUSIONS: A radio-pathomic model for cellularity trained with tissue samples acquired at postmortem examination is able to identify regions of hypercellular tumor beyond traditional imaging signatures.

Progressing Bevacizumab-Induced Diffusion Restriction Is Associated with Coagulative Necrosis Surrounded by Viable Tumor and Decreased Overall Survival in Patients with Recurrent Glioblastoma.

BACKGROUND AND PURPOSE: Patients with recurrent glioblastoma often exhibit regions of diffusion restriction following the initiation of bevacizumab therapy. Studies suggest that these regions represent either diffusion-restricted necrosis or hypercellular tumor. This study explored postmortem brain specimens and a population analysis of overall survival to determine the identity and implications of such lesions. MATERIALS AND METHODS: Postmortem examinations were performed on 6 patients with recurrent glioblastoma on bevacizumab with progressively growing regions of diffusion restriction. ADC values were extracted from regions of both hypercellular tumor and necrosis. A receiver operating characteristic analysis was performed to define optimal ADC thresholds for differentiating tissue types. A retrospective population study was also performed comparing the overall survival of 64 patients with recurrent glioblastoma treated with bevacizumab. Patients were separated into 3 groups: no diffusion restriction, diffusion restriction that appeared and progressed within 5 months of bevacizumab initiation, and delayed or stable diffusion restriction. An additional analysis was performed assessing tumor O6-methylguanine-DNA-methyltransferase methylation. RESULTS: The optimal ADC threshold for differentiation of hypercellularity and necrosis was 0.736 × 10-3mm2/s. Progressively expanding diffusion restriction was pathologically confirmed to be coagulative necrosis surrounded by viable tumor. Progressive lesions were associated with the worst overall survival, while stable lesions showed the greatest overall survival (P < .05). Of the 40% of patients with O6-methylguanine-DNA-methyltransferase methylated tumors, none developed diffusion-restricted lesions. CONCLUSIONS: Progressive diffusion-restricted lesions were pathologically confirmed to be coagulative necrosis surrounded by viable tumor and associated with decreased overall survival. Stable lesions were, however, associated with increased overall survival. All lesions were associated with O6-methylguanine-DNA-methyltransferase unmethylated tumors.

The curve-shift paradigm in self-stimulation.

Eleven rats were trained to press a lever in an operant chamber in order to earn rewarding trains of cathodal rectangular pulses of fixed intensity and variable frequency. The rate-frequency functions were examined under administration of two neuroleptics (pimozide and chlorpromazine) and three manipulations that interfered with bar pressing (muscular relaxation with methocarbamol, increased lever weight, and limitation of maximum response rates by an F1 reinforcement schedule). Chlorpromazine, and pimozide at low dosages produced a near parallel shift of the rate-frequency functions on the logarithmic axis of pulses, suggesting that these drugs decreased the reinforcing efficacy of the stimulation. The three conditions that interfered with bar-pressing decreased the asymptotic rates and produced small or moderate lateral shifts. Changes in the reinforcing efficacy of the stimulation following the above manipulations were inferred from the shift in the number of pulses required at zero and half-maximal performance (theta 0 and M50 indices, respectively). In the cases of the manipulations that interfered with bar-pressing, M50 indicated a larger artifactual change in the efficacy of the stimulation, compared to theta 0. This phenomenon was mainly due to the fact that the asymptote of the altered functions was shifted towards higher pulse numbers.

[Comparative study of normal and psoriatic skin using a micromethod for detection of enzymatic activity]. / Etude comparée de la peau saine et psoriasique par une microméthode de détection d'activités enzymatiques.

We used a semiquantitative micromethod for detection of enzymatic activity (APIZYM) which allows a fast and simultaneous study of 67 hydrolase and dehydrogenase activities on dermo-epidermic skin samples. This wide investigated field led to the determination of the enzymatic profile (called zymogram) of the samples under study. This method was applied to normal skin and to psoriatic and uninvolved psoriatic skin; our results exhibited the good reproductibility of the method and the homogeneity of the studied samples. The enzymatic activities of the psoriatic skin are, in mean, twice those of normal skin. The uninvolved psoriatic skin showed reactions close to those of the normal skin. These observed variations of those different activities are perfectly similar to literature datas. The APIZYM method, thanks to its easy utilization and its fiability seems extremely interesting in the study of zymogram of cutaneous samples. The use of APIZYM in observations on naevus and malignant melanoma is to be exposed in a following publication.

Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline.

BACKGROUND: Previous cross-sectional fMRI studies in subjects with prodromal Alzheimer disease (AD) have reported variable results, ranging from hypoactivation, similar to patients with AD, to paradoxically increased activation or hyperactivation compared to cognitively normal older individuals. We have hypothesized that subjects in early phases of prodromal AD may experience a period of hippocampal hyperactivation, followed by loss of hippocampal activation as the disease progresses. METHODS: We studied 51 older individuals without dementia (Clinical Dementia Rating [CDR] at baseline of 0, n = 21, and 0.5, n = 30) with longitudinal clinical and neuropsychological assessments, as well as fMRI during a face-name associative memory paradigm. Whole brain and region-of-interest analyses were applied to the longitudinal fMRI data. RESULTS: Subjects classified as CDR 0 at baseline showed no difference in fMRI activity over 2 years, whereas those who were CDR 0.5 at baseline demonstrated a decrease in fMRI activity in the right hippocampus (p < 0.001). Dividing the subjects on the basis of their clinical and neuropsychological change over the 2 years, we found that subjects with more rapid decline demonstrated both the highest hippocampal activation at baseline, and the greatest loss of hippocampal activation. These findings remained significant after accounting for age, hippocampal volume, and APOE epsilon4 carrier status. CONCLUSIONS: Clinical decline is associated with loss of hippocampal activation in older subjects. Longitudinal fMRI provides a reliable indicator of brain activation over time, and may prove useful in identifying functional brain changes associated with cognitive decline on the trajectory toward clinical Alzheimer disease.

Parity-violating electron scattering from 4He and the strange electric form factor of the nucleon.

We have measured the parity-violating electroweak asymmetry in the elastic scattering of polarized electrons from 4He at an average scattering angle = 5.7 degrees and a four-momentum transfer Q2 = 0.091 GeV2 . From these data, for the first time, the strange electric form factor of the nucleon G(E)s can be isolated. The measured asymmetry of A(PV) = (6.72 +/- 0.84(stat) +/- 0.21(syst) x 10(-6) yields a value of G(E)s = -0.038 +/- 0.042(stat) +/- 0.010(syst), consistent with zero.

Precision measurement of the weak mixing angle in Møller scattering.

We report on a precision measurement of the parity-violating asymmetry in fixed target electron-electron (Møller) scattering: A(PV) = [-131 +/- 14(stat) +/- 10(syst)] x 10(-9), leading to the determination of the weak mixing angle sin2(thetaW(eff) = 0.2397 +/- 0.0010(stat) +/- 0.0008(syst), evaluated at Q2 = 0.026 GeV2. Combining this result with the measurements of sin2(thetaW(eff) at the Z0 pole, the running of the weak mixing angle is observed with over 6sigma significance. The measurement sets constraints on new physics effects at the TeV scale.

[Tyrosinases of the pigmented portions of the eye in 4 species of rodent]. / Les tyrosinases des parties pigmentées de l'aeil chez quatre espèces de Rongeurs

Ocular tyrosinases of choroid from adult Rabbit, Rat, Hamster and Guinea pig are separated by gel electrophoresis. A single tyrosinase is found in all mammalian species investigated, it is present in pigmented strains and lacking in albino ones. Molecular weights of those enzymes, as determined by polyacrilamide gradient gel electrophoresis, are about 67,000. Involvement of ocular mammalian tyrosinases in in vitro L tyrosine oxidation has been demonstrated.