Translating Biomarkers of Cholangiocarcinoma for Theranosis: A Systematic Review

Cholangiocarcinoma (CCA) is a rare disease with poor outcomes and limited research efforts into novel treatment options. A systematic review of CCA biomarkers was undertaken to identify promising biomarkers that may be used for theranosis (therapy and diagnosis). MEDLINE/EMBASE databases (1996–2019) were systematically searched using two strategies to identify biomarker studies of CCA. The PANTHER Go-Slim classification system and STRING network version 11.0 were used to interrogate the identified biomarkers. The TArget Selection Criteria for Theranosis (TASC-T) score was used to rank identified proteins as potential targetable biomarkers for theranosis. The following proteins scored the highest, CA9, CLDN18, TNC, MMP9, and EGFR, and they were evaluated in detail. None of these biomarkers had high sensitivity or specificity for CCA but have potential for theranosis. This review is unique in that it describes the process of selecting suitable markers for theranosis, which is also applicable to other diseases. This has highlighted existing validated markers of CCA that can be used for active tumor targeting for the future development of targeted theranostic delivery systems. It also emphasizes the relevance of bioinformatics in aiding the search for validated biomarkers that could be repurposed for theranosis

Hydrography and biogeochemistry of the north western Bay of Bengal and the north eastern Arabian Sea during winter monsoon

The north eastern Arabian Sea and the north western Bay of Bengal within the Indian exclusive economic zone were explored for their environmental characteristics during the winter monsoons of 2000 and 2001 respectively. The two regions were found to respond paradoxically to comparable intensities of the atmospheric forcing. There is an asymmetry in the net heat exchange of these two basins with atmosphere because of the varying thickness of barrier layer. During winter, the convective mixing in the Arabian Sea is driven by net heat loss from the ocean, whereas the Bay of Bengal does not contribute to such large heat loss to the atmosphere. It appears that the subduction of high saline Arabian Sea water mass is the mechanism behind the formation of a barrier layer in the northeast Arabian Sea; whereas that in the Bay of Bengal and the southeast Arabian Sea are already established as due to low saline water mass. The weak barrier layer in the Arabian Sea yields to the predominance of convective mixing to bring in nitrate-rich waters from the deeper layers to the surface, thereby supporting enhanced biological production. On the other hand, the river discharge into the Bay of Bengal during this period results in the formation of a thick and stable barrier layer, which insulates vertical mixing and provide oligotrophic condition in the Bay

Axonal Injury Partially Mediates Associations Between Increased Left Ventricular Mass Index and White Matter Damage

BACKGROUND AND PURPOSE: Left ventricular (LV) mass index is a marker of subclinical LV remodeling that relates to white matter damage in aging, but molecular pathways underlying this association are unknown. This study assessed if LV mass index related to cerebrospinal fluid (CSF) biomarkers of microglial activation (sTREM2 [soluble triggering receptor expressed on myeloid cells 2]), axonal injury (NFL [neurofilament light]), neurodegeneration (total-tau), and amyloid-β, and whether these biomarkers partially accounted for associations between increased LV mass index and white matter damage. We hypothesized higher LV mass index would relate to greater CSF biomarker levels, and these pathologies would partially mediate associations with cerebral white matter microstructure. METHODS: Vanderbilt Memory and Aging Project participants who underwent cardiac magnetic resonance, lumbar puncture, and diffusion tensor imaging (n=142, 72±6 years, 37% mild cognitive impairment [MCI], 32% APOE-ε4 positive, LV mass index 51.4±8.1 g/m2, NFL 1070±588 pg/mL) were included. Linear regressions and voxel-wise analyses related LV mass index to each biomarker and diffusion tensor imaging metrics, respectively. Follow-up models assessed interactions with MCI and APOE-ε4. In models where LV mass index significantly related to a biomarker and white matter microstructure, we assessed if the biomarker mediated white matter associations. RESULTS: Among all participants, LV mass index was unrelated to CSF biomarkers (P>0.33). LV mass index interacted with MCI (P=0.01), such that higher LV mass index related to increased NFL among MCI participants. Associations were also present among APOE-ε4 carriers (P=0.02). NFL partially mediated up to 13% of the effect of increased LV mass index on white matter damage. CONCLUSIONS: Subclinical cardiovascular remodeling, measured as an increase in LV mass index, is associated with neuroaxonal degeneration among individuals with MCI and APOE-ɛ4. Neuroaxonal degeneration partially reflects associations between higher LV mass index and white matter damage. Findings highlight neuroaxonal degeneration, rather than amyloidosis or microglia, may be more relevant in pathways between structural cardiovascular remodeling and white matter damage

Non-supersymmetric heterotic model building

We investigate orbifold and smooth Calabi-Yau compactifications of the non-supersymmetric heterotic SO(16)xSO(16) string. We focus on such Calabi-Yau backgrounds in order to recycle commonly employed techniques, like index theorems and cohomology theory, to determine both the fermionic and bosonic 4D spectra. We argue that the N=0 theory never leads to tachyons on smooth Calabi-Yaus in the large volume approximation. As twisted tachyons may arise on certain singular orbifolds, we conjecture that such tachyonic states are lifted in the full blow-up. We perform model searches on selected orbifold geometries. In particular, we construct an explicit example of a Standard Model-like theory with three generations and a single Higgs field.Comment: 1+30 pages latex, 11 tables; v2: references and minor revisions added, matches version published in JHE

Association of Aortic Stiffness With Biomarkers of Neuroinflammation, Synaptic Dysfunction, and Neurodegeneration

OBJECTIVES: To test the hypothesis that increased aortic stiffening is associated with greater cerebrospinal fluid (CSF) evidence of core Alzheimer's disease pathology (Aβ, phosphorylated tau (p-tau)), neurodegeneration (total tau (t-tau)), synaptic dysfunction (neurogranin), neuroaxonal injury (neurofilament light (NFL)), and neuroinflammation (YKL-40, sTREM2), we analyzed pulse wave velocity (PWV) data and CSF data among older adults. METHODS: Participants free of stroke and dementia from the Vanderbilt Memory and Aging Project, an observational community-based study, underwent cardiac magnetic resonance to assess aortic pulse wave velocity (PWV, m/sec) and lumbar puncture to obtain CSF. Linear regressions related aortic PWV to CSF Aβ, p-tau, t-tau, neurogranin, NFL, YKL-40, and sTREM2 concentrations adjusting for age, race/ethnicity, education, apolipoprotein (APOE) ε4 status, Framingham Stroke Risk Profile, and cognitive diagnosis. Models were repeated testing PWV interactions with age, diagnosis, APOE-ε4, and hypertension on each biomarker. RESULTS: 146 participants were examined (72±6 years). Aortic PWV interacted with age on p-tau (β=0.31, p=0.04), t-tau, (β=2.67, p=0.05), neurogranin (β=0.94, p=0.04), and sTREM2 (β=20.4, p=0.05). Among participants over age 73 years, higher aortic PWV related to higher p-tau (β=2.4, p=0.03), t-tau (β=19.3, p=0.05), neurogranin (β=8.4, p=0.01), and YKL-40 concentrations (β=7880, p=0.005). Aortic PWV had modest interactions with diagnosis on neurogranin (β=-10.76, p=0.03) and hypertension status on YKL-40 (β=-18020, p<0.001). CONCLUSIONS: Among our oldest participants, age 74 years and older, greater aortic stiffening is associated with in vivo biomarker evidence of neuroinflammation, tau phosphorylation, synaptic dysfunction, and neurodegeneration, but not amyloidosis. Central arterial stiffening may lead to cumulative cerebral microcirculatory damage and blood flow delivery to tissue, resulting in neuroinflammation and neurodegeneration in more advanced age

Pheochromocytoma presenting as recurrent urinary tract infections : a case report

<p>Abstract</p> <p>Introduction</p> <p>Pheochromocytomas are rare, potentially fatal, neuroendocrine tumors of the adrenal medulla or extra-adrenal paraganglia. Their clinical presentation varies greatly from the classic triad of episodic headache, diaphoresis and tachycardia to include a spectrum of non-specific symptomatology.</p> <p>Case presentation</p> <p>A 43-year-old Caucasian woman was referred to us from primary care services with a three-month history of recurrent urinary tract infections on a background of hypertension, latent autoimmune diabetes of adulthood and autoimmune hypothyroidism. At 38 years she required insulin therapy. Despite medication compliance and dietary control, she reported a recent history of increased insulin requirements and uncontrolled hypertension with concomitant recurrent urinary tract infections. A renal ultrasound examination, to rule out underlying renal pathology, revealed an incidental 8cm right adrenal mass of both solid and cystic components. A subsequent computed tomography of her abdomen and pelvis confirmed a solid heterogeneous mass consistent with a pheochromocytoma. There were no other features suggestive of multiple endocrine neoplasia. Urinary collection over 24 hours revealed grossly elevated levels of catecholamines and metabolites. Following an open right adrenalectomy, our patient's insulin requirements were significantly reduced and her symptoms resolved. Two weeks post-operatively, an iodine-131-metaiodobenzylguanidine scintigraphy was negative for residual tumor and metastatic disease. Urinary catecholamine and metabolite concentrations were within the normal range at a follow-up six months later.</p> <p>Conclusion</p> <p>Pheochromocytoma is a rare catecholamine-producing tumor requiring a high index of suspicion for early diagnosis. Our case report serves to highlight the importance of considering pheochromocytoma as a differential diagnosis in the atypical setting of recurrent urinary tract infections and concomitant autoimmune disease.</p

Image informatics strategies for deciphering neuronal network connectivity

Brain function relies on an intricate network of highly dynamic neuronal connections that rewires dramatically under the impulse of various external cues and pathological conditions. Among the neuronal structures that show morphologi- cal plasticity are neurites, synapses, dendritic spines and even nuclei. This structural remodelling is directly connected with functional changes such as intercellular com- munication and the associated calcium-bursting behaviour. In vitro cultured neu- ronal networks are valuable models for studying these morpho-functional changes. Owing to the automation and standardisation of both image acquisition and image analysis, it has become possible to extract statistically relevant readout from such networks. Here, we focus on the current state-of-the-art in image informatics that enables quantitative microscopic interrogation of neuronal networks. We describe the major correlates of neuronal connectivity and present workflows for analysing them. Finally, we provide an outlook on the challenges that remain to be addressed, and discuss how imaging algorithms can be extended beyond in vitro imaging studies

The Effect of High Glucocorticoid Administration and Food Restriction on Rodent Skeletal Muscle Mitochondrial Function and Protein Metabolism

Glucocorticoids levels are high in catabolic conditions but it is unclear how much of the catabolic effects are due to negative energy balance versus glucocorticoids and whether there are distinct effects on metabolism and functions of specific muscle proteins.We determined whether 14 days of high dose methylprednisolone (MPred, 4 mg/kg/d) Vs food restriction (FR, food intake matched to MPred) in rats had different effects on muscle mitochondrial function and protein fractional synthesis rates (FSR). Lower weight loss (15%) occurred in FR than in MPred (30%) rats, while a 15% increase occurred saline-treated Controls. The per cent muscle loss was significantly greater for MPred than FR. Mitochondrial protein FSR in MPred rats was lower in soleus (51 and 43%, respectively) and plantaris (25 and 55%) than in FR, while similar decline in protein FSR of the mixed, sarcoplasmic, and myosin heavy chain occurred. Mitochondrial enzymatic activity and ATP production were unchanged in soleus while in plantaris cytochrome c oxidase activity was lower in FR than Control, and ATP production rate with pyruvate + malate in MPred plantaris was 28% lower in MPred. Branched-chain amino acid catabolic enzyme activities were higher in both FR and MPred rats indicating enhanced amino acid oxidation capacity.MPred and FR had little impact on mitochondrial function but reduction in muscle protein synthesis occurred in MPred that could be explained on the basis of reduced food intake. A greater decline in proteolysis may explain lesser muscle loss in FR than in MPred rats

Role of Alanine Racemase Mutations in Mycobacterium tuberculosis d-Cycloserine Resistance.

A screening of more than 1,500 drug-resistant strains of Mycobacterium tuberculosis revealed evolutionary patterns characteristic of positive selection for three alanine racemase (Alr) mutations. We investigated these mutations using molecular modeling, in vitro MIC testing, as well as direct measurements of enzymatic activity, which demonstrated that these mutations likely confer resistance to d-cycloserine

Supramolecular thermoplastics and thermoplastic elastomer materials with self-healing ability based on oligomeric charged triblock copolymers

Supramolecular polymeric materials constitute a unique class of materials held together by non-covalent interactions. These dynamic supramolecular interactions can provide unique properties such as a strong decrease in viscosity upon relatively mild heating, as well as self-healing ability. In this study we demonstrate the unique mechanical properties of phase-separated electrostatic supramolecular materials based on mixing of low molar mass, oligomeric, ABA-triblock copolyacrylates with oppositely charged outer blocks. In case of well-chosen mixtures and block lengths, the charged blocks are phase separated from the uncharged matrix in a hexagonally packed nanomorphology as observed by transmission electron microscopy. Thermal and mechanical analysis of the material shows that the charged sections have a T-g closely beyond room temperature, whereas the material shows an elastic response at temperatures far above this T-g ascribed to the electrostatic supramolecular interactions. A broad set of materials having systematic variations in triblock copolymer structures was used to provide insights in the mechanical properties and and self-healing ability in correlation with the nanomorphology of the materials