Translational research : the journal of laboratory and clinical medicine
-
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.
-
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.
-
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.
-
This study aimed to assess the angiographic characteristics, feasibility and safety of the provocative test with acetylcholine (AChT), and the influence on further treatment and prognosis of Middle European patients in 5-year follow-up, especially focusing on those with a history of myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA). The AChPOL Registry was an ongoing prospective single-center registry that included patients undergoing AChT from December 2010 to March 2013 for further diagnostic evaluation of a suspicious variant angina or coronary microvascular spasm, based on the COVADIS criteria. AChT was injected in incremental doses of 25, 50, and 75µg into the right coronary artery and 25, 50, and 100 µg into the left coronary artery, and the patients were followed up for 5 years. ⋯ Interestingly, patients with a history of MINOCA had higher rates of MI and recurrent chest pain requiring hospitalization in the follow-up. We showed that AChT was safe in Middle European patients. In the follow-up patients with microvascular spasm and a history of MINOCA had the highest risk of MI and recurrent chest pain requiring hospitalization.
-
Although some evidence showed the activation of complement systems in COVID-19 patients, proinflammatory status and lectin pathway remain unclear. Thus, the present study aimed to demonstrate the role of MBL and ficolin-3 in the complement system activation and compared to pandemic Influenza A virus H1N1 subtype infection (H1N1pdm09) and control patients. A total of 27 lungs formalin-fixed paraffin-embedded samples (10 from H1N1 group, 6 from the COVID-19 group, and 11 from the control group) were analyzed by immunohistochemistry using anti-IL-6, TNF-alfa, CD163, MBL e FCN3 antibodies. ⋯ The genotypes AA for rs180040 (G/A), GG for rs1800451 (G/A) and CC for rs5030737 (T/C) showed a higher prevalence in the COVID-19 group. The intense activation of the lectin pathway, with particular emphasis on the MBL pathway, together with endothelial dysfunction and a massive proinflammatory cytokines production, possibly lead to a worse outcome in patients infected with SARS-Cov-2. Moreover, 3 SNPs of our study presented genotypes that might be correlated with high MBL tissue expression in the COVID-19 pulmonary samples.