Publications by authors named "Shourik Dutta"

4 Publications

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Magnetic resonance imaging accurately tracks kidney pathology and heterogeneity in the transition from acute kidney injury to chronic kidney disease.

Kidney Int 2021 01 8;99(1):173-185. Epub 2020 Sep 8.

Department of Radiology, Washington University in St. Louis, St. Louis, Missouri, USA.

Acute kidney injury (AKI) increases the risk for chronic kidney disease (CKD). However, there are few tools to detect microstructural changes after AKI. Here, cationic ferritin-enhanced magnetic resonance imaging (CFE-MRI) was applied to examine the heterogeneity of kidney pathology in the transition from AKI to CKD. Adult male mice received folic acid followed by cationic ferritin and were euthanized at four days (AKI), four weeks (CKD-4) or 12 weeks (CKD-12). Kidneys were examined by histologic methods and CFE-MRI. In the CKD-4 and CKD-12 groups, glomerular number was reduced and atubular cortical lesions were observed. Apparent glomerular volume was larger in the AKI, CKD-4 and CKD-12 groups compared to controls. Glomerular hypertrophy occurred with ageing. Interglomerular distance and glomerular density were combined with other MRI metrics to distinguish the AKI and CKD groups from controls. Despite significant heterogeneity, the noninvasive (MRI-based) metrics were as accurate as invasive (histological) metrics at distinguishing AKI and CKD from controls. To assess the toxicity of cationic ferritin in a CKD model, CKD-4 mice received cationic ferritin and were examined one week later. The CKD-4 groups with and without cationic ferritin were similar, except the iron content of the kidney, liver, and spleen was greater in the CKD-4 plus cationic ferritin group. Thus, our study demonstrates the accuracy and safety of CFE-MRI to detect whole kidney pathology allowing for the development of novel biomarkers of kidney disease and providing a foundation for future in vivo longitudinal studies in mouse models of AKI and CKD to track nephron fate.
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http://dx.doi.org/10.1016/j.kint.2020.08.021DOI Listing
January 2021

The CXCL5/CXCR2 axis is sufficient to promote breast cancer colonization during bone metastasis.

Nat Commun 2019 09 27;10(1):4404. Epub 2019 Sep 27.

Harper Cancer Research Institute, South Bend, IN, USA.

Bone is one of the most common sites for metastasis across cancers. Cancer cells that travel through the vasculature and invade new tissues can remain in a non-proliferative dormant state for years before colonizing the metastatic site. Switching from dormancy to colonization is the rate-limiting step of bone metastasis. Here we develop an ex vivo co-culture method to grow cancer cells in mouse bones to assess cancer cell proliferation using healthy or cancer-primed bones. Profiling soluble factors from conditioned media identifies the chemokine CXCL5 as a candidate to induce metastatic colonization. Additional studies using CXCL5 recombinant protein suggest that CXCL5 is sufficient to promote breast cancer cell proliferation and colonization in bone, while inhibition of its receptor CXCR2 with an antagonist blocks proliferation of metastatic cancer cells. This study suggests that CXCL5 and CXCR2 inhibitors may have efficacy in treating metastatic bone tumors dependent on the CXCL5/CXCR2 axis.
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http://dx.doi.org/10.1038/s41467-019-12108-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765048PMC
September 2019

Predictors of 30-day mortality after endovascular mechanical thrombectomy for acute ischemic stroke.

J Clin Neurosci 2018 Nov 23;57:38-42. Epub 2018 Aug 23.

Department of Neurological Surgery, University of Virginia Health System, Charlottesville, VA, United States. Electronic address:

Objective: The aims of this single-center, retrospective cohort study are to assess the outcomes of endovascular mechanical thrombectomy (EMT) for acute ischemic stroke (AIS) and determine predictors of 30-day mortality at an academic comprehensive stroke center (CSC).

Methods: We retrospectively collected data from consecutive patients who underwent EMT for AIS at our institution between April 2016 and January 2018. Primary outcome was defined as mortality within 30 days from EMT. Successful revascularization was defined as a modified Thrombolysis in Cerebral Infarction (mTICI) grade 2b-3. Statistical analyses were performed to identify predictors of 30-day mortality.

Results: The study cohort was comprised 57 patients (51% male) with mean age of 72 years. Intravenous tissue plasminogen activator was administered in 51%. The median Alberta Stroke Program Early Computed Tomography Score (ASPECTS) and National Institutes of Health Stroke Scale (NIHSS) score were 8 and 20, respectively. The 30-day mortality rate was 39%. Univariate analyses found that older age (mean 77 vs. 68 years, p = 0.022), higher baseline NIHSS score (median 23 vs. 19, p = 0.032), NIHSS score at 24 h after EMT (median 14.5 vs. 7.5, p < 0.001), and lower rates of successful revascularization (59% vs. 89%, p = 0.021) were associated with 30-day mortality.

Conclusion: We observed a moderate rate of 30-day mortality after EMT at an academic CSC. Older age, higher baseline NIHSS score, higher NIHSS score at 24 h after thrombectomy, and lower rates of successful revascularization were predictive of 30-day mortality in univariate analysis. Further efforts to identify modifiable risk factors of mortality are warranted.
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http://dx.doi.org/10.1016/j.jocn.2018.08.044DOI Listing
November 2018

Genetic ablation of Smoothened in pancreatic fibroblasts increases acinar-ductal metaplasia.

Genes Dev 2016 09 15;30(17):1943-55. Epub 2016 Sep 15.

Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;

The contribution of the microenvironment to pancreatic acinar-to-ductal metaplasia (ADM), a preneoplastic transition in oncogenic Kras-driven pancreatic cancer progression, is currently unclear. Here we show that disruption of paracrine Hedgehog signaling via genetic ablation of Smoothened (Smo) in stromal fibroblasts in a Kras(G12D) mouse model increased ADM. Smo-deleted fibroblasts had higher expression of transforming growth factor-α (Tgfa) mRNA and secreted higher levels of TGFα, leading to activation of EGFR signaling in acinar cells and increased ADM. The mechanism involved activation of AKT and noncanonical activation of the GLI family transcription factor GLI2. GLI2 was phosphorylated at Ser230 in an AKT-dependent fashion and directly regulated Tgfa expression in fibroblasts lacking Smo Additionally, Smo-deleted fibroblasts stimulated the growth of Kras(G12D)/Tp53(R172H) pancreatic tumor cells in vivo and in vitro. These results define a non-cell-autonomous mechanism modulating Kras(G12D)-driven ADM that is balanced by cross-talk between Hedgehog/SMO and AKT/GLI2 pathways in stromal fibroblasts.
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http://dx.doi.org/10.1101/gad.283499.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066238PMC
September 2016