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Globular Glial Tauopathy (GGT) is a rare form of Frontotemporal Lobar Degeneration (FTLD) consisting of 4-repeat tau globular inclusions in astrocytes and oligodendrocytes. We present the pathological findings of GGT in a previously published case of a 73-year-old woman with behavioral symptoms concerning for right temporal variant frontotemporal dementia with initial and salient features of Geschwind syndrome. Clinically, she lacked motor abnormalities otherwise common in previously published GGT cases. Brain MRI showed focal right anterior temporal atrophy (indistinguishable from five FTLD-TDP cases) and subtle ipsilateral white matter signal abnormalities. Brain autopsy showed GGT type III and Alzheimer’s neuropathologic changes. .

Supplementary Figure 1 a. Doxorubicin resistance of DOXO-R C8 cells was further validated using the cell viability assay (SRB) following 48 hrs treatment with DOXO, n=4 independent experiment, 3 replicates/experiment. **p0.6 and pval

Table S18: Two-way ANOVA

Table S1: List of regions of genes with increased CNV (>= 0.5) and gene expression (>= 0.5) in DOXO-R cells compared to parental cells Table S2: List of all fold change and pvalue of DOXO-R C1 and C8 (vs parental cells) from gene expression analysis. Table S3. GSEA using the C5 module for the 1852 genes with gene expression fold change > 1.5 (pval < 0.05) in DOXO-R C1 and C8 Table S4. GSEA using the C5 module for the 407 genes with gene expression fold change > 1.5 (pval < 0.05) and CNV change > 0.5 Table S5: Mean LOG2FC of genes commonly up-regulated in C1 and C8 Table S6: Proteins that are significantly upregulated according to the following criteria. (i) only present in one or two of the Dox resistant cell lines (**) with at least 3 and 2 unique peptides, respectively. (ii) At least 1.5-fold upregulated in both cell lines with a maximum relative standard deviation (RSD) of 31% across control replicates and 25% RSD across resistant cell line replicates. Table S7: GSEA using the C5 module for the 98 overexpressed proteins in DOXO-R vs parental cells Table S8: mRNA fold change (POST vs PRE NAC) for 9 chemoresistant TNBC patients. Table S9: GSEA using the C5 module for NEO2 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis. Table S10: GSEA using the C5 module for NEO24 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis. Table S11: GSEA using the C5 module for NEO25 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis. Table S12: GSEA using the C5 module for NEO27 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis. Table S13: GSEA using the C5 module for NEO28 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis. Table S14: GSEA using the C5 module for NEO30 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis. Table S15: GSEA using the C5 module for NEO31 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis. Table S16: GSEA using the C5 module for NEO35 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis. Table S17: GSEA using the C5 module for NEO44 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis.

The major obstacle in successfully treating triple-negative breast cancer (TNBC) is resistance to cytotoxic chemotherapy, the mainstay of treatment in this disease. Previous preclinical models of chemoresistance in TNBC have suffered from a lack of clinical relevance. Using a single high dose chemotherapy treatment, we developed a novel MDA-MB-436 cell-based model of chemoresistance characterized by a unique and complex morphologic phenotype, which consists of polyploid giant cancer cells giving rise to neuron-like mononuclear daughter cells filled with smaller but functional mitochondria and numerous lipid droplets. This resistant phenotype is associated with metabolic reprogramming with a shift to a greater dependence on fatty acids and oxidative phosphorylation. We validated both the molecular and histologic features of this model in a clinical cohort of primary chemoresistant TNBCs and identified several metabolic vulnerabilities including a dependence on PLIN4, a perilipin coating the observed lipid droplets, expressed both in the TNBC-resistant cells and clinical chemoresistant tumors treated with neoadjuvant doxorubicin-based chemotherapy. These findings thus reveal a novel mechanism of chemotherapy resistance that has therapeutic implications in the treatment of drug-resistant cancer.Implications:These findings underlie the importance of a novel morphologic–metabolic phenotype associated with chemotherapy resistance in TNBC, and bring to light novel therapeutic targets resulting from vulnerabilities in this phenotype, including the expression of PLIN4 essential for stabilizing lipid droplets in resistant cells.

Nonfluent aphasia is a language disorder characterized by simplified sentence structures as well as word-level abnormalities such as a reduced use of verbs and function words. According to the predominant account of the disorder, both structural and word-level features are caused by a core deficit in the processing of syntax. Under this account, however, it remains unclear why nonfluent patients choose semantically richer verbs and may have an intact comprehension of verbs and function words.Here, we propose and test the hypothesis that the word-level features of nonfluency reflect a process that selects lexically richer words to increase the information content of sentences.We use a computational linguistic method to measure the information content of sentences in the language of patients with nonfluent primary progressive aphasia (nfvPPA) (n = 36) and healthy controls (n = 133). We measure sentence information using surprisal, a metric calculated by the average probability of occurrence of words in a sentence given their preceding context.We found that by packaging their structurally simple sentences with lower frequency words, nfvPPA patients produce sentences with similar surprisal as that of healthy speakers. Furthermore, we found that higher sentence surprisal in nfvPPA correlates with a lower function-to-all-word ratio, a lower verb-to-noun ratio, and a higher heavy-to-all-verb ratio.Surprisal is an effective quantitative index of sentence information. Using surprisal allows for testing an account of nonfluent aphasia that regards word-level features of nonfluency as adaptive rather than defective symptoms, a finding that may entail revisions in therapeutic approaches to nonfluent speech.

Despite the important role of written language in everyday life, abnormalities in functional written communication have been sparsely investigated in Primary Progressive Aphasia (PPA). Prior studies have analyzed written language separately in the three variants of PPA – nonfluent (nfvPPA), logopenic (lvPPA), and semantic (svPPA) – but have rarely compared them to each other or to spoken language. Manual analysis of written language can be a time-consuming process. We developed a program which uses a language parser and quantifies content units (CU) and total units (U) in written language samples. The program was used to analyze written and spoken descriptions of the WAB Picnic scene, based on a pre-defined CU corpus. We then calculated the ratio of CU to U (CU/U Ratio) as a measure of content density. Our cohort included 115 participants (20 control participants for written, 20 control participants for spoken, 28 participants with nfvPPA, 30 with lvPPA, and 17 with svPPA). We compared written language between patients with PPA and control participants and written to spoken language in patients with the three variants of PPA. Finally, we analyzed CU and U in relation to the Progressive Aphasia Severity Scale Sum of Boxes and the Clinical Dementia Rating Sum of Boxes. Our program identified CU with a validity of 99.7% (95%CI 99.5 to 99.8) compared to manual annotation of the samples. All patients with PPA wrote fewer total units than controls (p<0.001). Patients with lvPPA (p=0.013) and svPPA (0.004) wrote fewer CU than controls. The CU/U Ratio was higher in nfvPPA and svPPA than controls (p=0.019 in both cases), but no different between lvPPA patients and controls (p=0.962). Participants with lvPPA (p<0.001) and svPPA (p=0.04) produced fewer CU in written samples compared to spoken. A two-way ANOVA showed all groups produced fewer units in written samples compared to spoken (p<0.001). However, the decrease in written CU compared to spoken was smaller than the decrease in written units compared to spoken in participants with PPA, resulting in a larger written CU/U Ratio when compared to spoken language (p<0.001). nfvPPA patients produced correlated written and spoken CU (R=0.5,p=0.009) and total units (R=0.64,p<0.001), but this was not the case for lvPPA or svPPA. Considering all PPA patients, fewer CU were produced in those with greater aphasia severity (PASS SoB, R=-0.24, p=0.04) and dementia severity (CDR SoB, R=-0.34, p=0.004). In conclusion, we observed reduced written content in patients with PPA compared to controls, with a preference for content over non-content units in patients with nfvPPA and svPPA. When comparing written to spoken language, we observed a similar “telegraphic” style in both modalities in patients with nfvPPA, which was different from patients with svPPA and lvPPA, who use significantly less non-content units in writing than in speech. Lastly, we show how our program provides a time-efficient tool, which could enable feedback and tracking of writing as an important feature of language and cognition.

The investigators aimed to describe the clinical experience of a single center reporting on neuropsychiatric findings among patients experiencing persistent symptoms as part of post-acute sequelae of SARS-CoV-2 (PASC) infection.Data were collected retrospectively (between February 2020 and May 2021) from a cohort (N=100) within a COVID-19 survivors study of patients with persistent symptoms enrolled after a short inpatient stay or who had been outpatients never hospitalized. Patients without confirmatory positive PCR or antibody diagnostic test results were grouped separately as presumptive cases (N=13).Of the 87 patients with confirmed SARS-CoV-2, 63 (72.4%) were female, and 65 (74.7%) were White. The mean age was 49.2 years (SD=14.9). The most prevalent symptoms after COVID-19 infection were fatigue, "brain fog," headache, anxiety, and sleep issues. Attention and executive function were frequently impaired. The mean Montreal Cognitive Assessment score was 26.0 (SD=2.8). Concentration and attention as well as memory issues were both significantly correlated with the complaint of brain fog.These preliminary findings suggest that post-acute sequelae of SARS-CoV-2 vary in frequency and duration with relation to premorbid history and that these conditions affect functional domains and patients' ability to return to work. Longitudinal research with larger cohorts is needed to characterize PASC and to optimize care, especially for vulnerable populations.

Introduction: Digital biomarkers may act as a tool for early detection of changes in cognition. It is important to understand public perception of technologies focused on monitoring cognition to better guide the design of these tools and inform patients appropriately about the associated risks and benefits. Health care systems may also play a role in the clinical, legal, and financial implications of such technologies. Objective: To evaluate public opinion on the use of passive technology for monitoring cognition. Methods: This was a one-time, Internet-based survey conducted in English and Spanish. Results: Within the English survey distributed in the USA (n = 173), 58.1% of respondents would be highly likely to agree to passive monitoring of cognition via a smartphone application. Thirty-eight percent of those with a higher degree of experience with technology were likely to agree to monitoring versus 20% of those with less experience with technology (p = 0.003). Sixty-two percent of non-health-care professionals were likely to agree to monitoring versus 45% of health-care workers (p = 0.012). There were significant concerns regarding privacy (p < 0.01). We compared the surveys answered in Spanish in Costa Rica via logistic regression (n = 43, total n = 216), adjusting for age, education level, health-care profession, owning a smartphone, experience with technology, and perception of cognitive decline. Costa Rican/Spanish-speaking respondents were 7 times more likely to select a high probability of agreeing to such a technology (p < 0.01). English-speaking respondents from the USA were 5 times more likely to be concerned about the impact on health insurance (p = 0.001) and life insurance (p = 0.01). Conclusions: Understanding public perception and ethical implications should guide the design of digital biomarkers for cognition. Privacy and the health-care system in which the participants take part are 2 major factors to be considered. It is the responsibility of researchers to convey the ethical and legal implications of cognition monitoring.

The major obstacle in successfully treating triple-negative breast cancer (TNBC) is resistance to cytotoxic chemotherapy, the mainstay of treatment in this disease. Previous preclinical models of chemoresistance in TNBC have suffered from a lack of clinical relevance. Using a single high dose chemotherapy treatment, we developed a novel MDA-MB-436 cell-based model of chemoresistance characterized by a unique and complex morphologic phenotype, which consists of polyploid giant cancer cells giving rise to neuron-like mononuclear daughter cells filled with smaller but functional mitochondria and numerous lipid droplets. This resistant phenotype is associated with metabolic reprogramming with a shift to a greater dependence on fatty acids and oxidative phosphorylation. We validated both the molecular and histologic features of this model in a clinical cohort of primary chemoresistant TNBCs and identified several metabolic vulnerabilities including a dependence on PLIN4, a perilipin coating the observed lipid droplets, expressed both in the TNBC-resistant cells and clinical chemoresistant tumors treated with neoadjuvant doxorubicin-based chemotherapy. These findings thus reveal a novel mechanism of chemotherapy resistance that has therapeutic implications in the treatment of drug-resistant cancer. Implications: These findings underlie the importance of a novel morphologic–metabolic phenotype associated with chemotherapy resistance in TNBC, and bring to light novel therapeutic targets resulting from vulnerabilities in this phenotype, including the expression of PLIN4 essential for stabilizing lipid droplets in resistant cells.

Summary Immune targeting of (glyco)protein tumor markers has been useful to develop cancer and virus vaccines. However, the ganglioside family of tumor-associated glycolipids remains intractable to vaccine approaches. Here we show that synthetic antigens mimicking the carbohydrate moiety of GD2 or GD3 gangliosides can be used as vaccines to activate a selective humoral and cellular immunity that is therapeutic against several cancers expressing GD2 or GD3. Adoptive transfer of T cells generated after vaccination elicits tumor-infiltrating lymphocytes of the γδ T cell receptor and CD8+ phenotypes; and affords a high therapeutic index. The glycomimetic vaccine principles can be expanded to target the family of tumor gangliosides and other carbohydrates expressed primarily in pathological states.

Neurodegenerative disorders are prevalent, complex and devastating conditions, with very limited treatment options currently available. While they manifest in many forms, there are commonalities that link them together. In this review, we will focus on neurotrophins – a family of related factors involved in neuronal development and maintenance. Neurodegenerative diseases often present with a neurotrophin imbalance, in which there may be decreases in trophic signaling through Trk receptors for example, and/or increases in pro-apoptotic activity through p75. Clinical trials with neurotrophins have continuously failed due to their poor pharmacological properties as well as the unavoidable activation of p75. Thus, there is a need for drugs without such setbacks. Small molecule neurotrophin mimetics are favorable options since they can selectively activate Trks or inactivate p75. In this review, we will initially present a brief outline of how these molecules are synthesized and their mechanisms of action; followed by an update in the current state of neurotrophins and small molecules in major neurodegenerative diseases. Although there has been significant progress in the development of potential therapeutics, more studies are needed to establish clear mechanisms of action and target specificity in order to transition from animal models to the assessment of safety and use in humans.

We present a case of a patient with diabetes with a pleural empyema originated from a pyomyositis process established after a central line procedure. This empyema later on extended into the spinal canal deriving into an epidural empyema, leading towards a spinal neurogenic shock and death. We discuss the anatomical substrate for this extension as well as the anatomopathological findings observed in the autopsy.