Translational research : the journal of laboratory and clinical medicine
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Rectal cancer remains a challenging disease to treat. Therapy for locally advanced rectal cancer (LARC), the most frequent presentation, has evolved to include a multimodal approach of radiation, chemotherapy, and surgery. While this approach improves local disease control, the distant recurrence rate is nearly 30% and treatment-related morbidity is substantial, thus underscoring the need for new therapeutic approaches with better efficacy and lower side effects. ⋯ We also address the role of current immunotherapies in colorectal cancer and highlight where novel immunotherapy approaches are currently being evaluated in LARC. Finally, we address important future directions in LARC immunotherapy including the need to define optimal therapeutic sequencing, predictive biomarkers, strategies to limit treatment-related side effects and the potential of gut microbiome manipulation to improve outcomes. In summary, this review provides a framework to guide future research and inform immunotherapy trial design so as to advance rectal cancer care.
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Systemic sclerosis (SSc) is an idiopathic autoimmune disease with a heterogeneous clinical phenotype ranging from limited cutaneous involvement to rapidly progressive diffuse SSc. The most severe SSc clinical and pathologic manifestations result from an uncontrolled fibrotic process involving the skin and various internal organs. The molecular mechanisms responsible for the initiation and progression of the SSc fibrotic process have not been fully elucidated. ⋯ Currently, there are no effective disease-modifying therapies for SSc-associated tissue fibrosis. Therefore, extensive investigation has been conducted to examine whether tyrosine kinase inhibitors (TKIs) may exert antifibrotic effects. Here, we review the role of receptor and nonreceptor tyrosine kinases in the pathogenesis of the frequently progressive cutaneous and systemic fibrotic alterations in SSc, and the potential of TKIs as SSc disease-modifying antifibrotic therapeutic agents.
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Diabetes mellitus (DM) is a devastating metabolic disease. Recently, the cross-talk between insulin-secreting-β-cells and various organs has sparked much interest. SerpinB1 emerged as a novel hepatokine inducing β-cell proliferation. ⋯ Higher serum serpinB1 levels were found to be associated with lower susceptibility for T2DM. Conclusively, serpinB1 is associated with various aspects of β-cell dysfunction, glycemic-control, and dyslipidemia with a possible role in β-cell compensation in obese nondiabetic subjects. The results of the current study shed lights on potential novel roles of serpinB1 in T2DM besides its action as an inducer for β-cell proliferation.
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Currently, clinicians rely on clinical nomograms to stratify progression risk at the time of diagnosis in patients with prostate cancer (CaP). However, these tools may not accurately distinguish aggressive potential in low-grade CaP. The current study determined the diagnostic potential of 3 molecular markers (ROCK1, RUNX3, and miR-301a) in terms of their ability to identify which low-grade tumors are likely to progress. ⋯ Expressions of ROCK1 and miR-301a were found to be significantly higher in Gleason 6 and 7 CaP as compared to BPH, while an inverse trend was observed with RUNX3. Further, incorporation of all 3 molecular markers significantly improved clinical nomograms' diagnostic accuracy and correlated with disease progression. Hence, in conclusion, the inclusion of these 3 molecular markers identified aggressive phenotype and predicted disease progression in low-grade CaP tumors at the time of diagnosis.
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Acute kidney injury (AKI) diagnosis relies on plasma creatinine concentration (Crpl), a relatively insensitive, surrogate biomarker of glomerular filtration rate that increases only after significant damage befalls. However, damage in different renal structures may occur without increments in Crpl, a condition known as subclinical AKI. Thus, detection of alterations in other aspects of renal function different from glomerular filtration rate must be included in an integral diagnosis of AKI. ⋯ Predisposed animals showed a reduced response to the FST (namely, reduced furosemide-induced diuresis and K+ excretion), whereas nonpredisposed animals showed no alteration, compared to the controls. Computational modeling of epithelial transport of solutes and water along the nephrons applied to experimental data suggested that proximal tubule transport was only minimally reduced, the sodium-chloride symporter was upregulated by 50%, and the renal outer medullary potassium channel was downregulated by 85% in predisposed animals. In conclusion, serial coupling of the FST and computational modeling may be used to detect and localize subclinical tubular alterations.