Biology subjects

Cardenas, J. C.

Publications and source records attributed to Cardenas, J. C..

3 recordsLinked to original sources

bioRxiv2022

Radiofrequency ablation remodels the tumor microenvironment and promotes systemic immunomodulation in pancreatic cancer

Background and AimsPancreatic ductal adenocarcinoma (PDAC) is characterized by resistance to therapy. A major contributing factor to therapeutic failure is profound desmoplasia and a well-documented hypoxic tumor microenvironment (TME). In PDAC, several therapeutic approaches, including chemotherapy and radiation alone or combined with immune checkpoint inhibitors, have shown minimal therapeutic success, placing an imperative need for the discovery and application of innovative treatments. Endoscopic ultrasound guided radiofrequency ablation (EUS-RFA) is a promising immunomodulator therapy for PDAC. In this work, we hypothesized RFA promotes local and systemic stromal and immunomodulating effects that can be identified for new combination therapeutic strategies. MethodsTo test our hypothesis, a syngeneic PDAC mouse model was performed by symmetrically injecting 100k murine KPC cells in bilateral flanks of C57BL/6 female mice. RFA treatment initiated when tumors reached 200-500 mm3 and was performed only in the right flank. The left flank tumor (non-RFA contralateral side) was used as a paired control for further analysis. ResultsRFA promoted a significant reduction in tumor growth rate 4 days after treatment in RFA treated and non-RFA side contralateral tumors from treated mice when compared to controls. Histological analysis revealed a significant increase in expression of cleaved Caspase3 in RFA treated tumors. In addition, collagen deposition and CD31+ cells were significantly elevated in RFA side and non-RFA contralateral tumors from RFA treated mice. Proteome profiling showed changes in C5a and IL-23 in RFA responsive tumors, indicating a role of RFA in modulating intratumoral inflammatory responses. ConclusionsThese data indicate RFA promotes local and systemic anti-tumor responses in a syngeneic mouse model of PDAC implicating RFA treatment for local tumors as well as metastatic disease. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

cancer biology↗

bioRxiv2021

Necroptosis inhibition counteracts axonal degeneration, cognitive decline and key hallmarks of aging, promoting brain rejuvenation.

Age is the main risk factor for the development of neurodegenerative diseases. In the aged brain, axonal degeneration is an early pathological event, preceding neuronal dysfunction, and cognitive disabilities in humans, primates, rodents, and invertebrates. Necroptosis mediates degeneration of injured axons, but whether necroptosis triggers neurodegeneration and cognitive impairment along aging is unknown. Here we show that the loss of the necroptotic effector Mlkl was sufficient to delay age-associated axonal degeneration and neuroinflammation, protecting against decreased synaptic transmission and memory decline in aged mice. Moreover, short-term pharmacologic inhibition of necroptosis in aged mice reverted structural and functional hippocampal impairment, both at the electrophysiological and behavioral level. Finally, a quantitative proteomic analysis revealed that necroptosis inhibition leads to an overall improvement of the aged hippocampal proteome, including a subclass of molecular biofunctions associated with brain rejuvenation, such as long-term potentiation and synaptic plasticity. Our results demonstrate that necroptosis contributes to the age-dependent brain degeneration, disturbing hippocampal neuronal connectivity, and cognitive function. Therefore, necroptosis inhibition constitutes a potential geroprotective strategy to treat age-related disabilities associated with memory impairment and cognitive decline.

neuroscience↗

bioRxiv2020

Control of mammalian brain aging by the unfolded protein response (UPR)

Aging is the major risk factor for the development of dementia and neurodegenerative disorders, and the aging brain manifests severe deficits in buffering capacity by the proteostasis network. Accordingly, we investigated the significance of the unfolded protein response (UPR), a major signaling pathway that copes with endoplasmic reticulum (ER) stress, to normal mammalian brain aging. Genetic disruption of ER stress sensor IRE1 accelerated cognitive and motor dysfunction during aging. Exogenous bolstering of the UPR by overexpressing an active form of the transcription factor XBP1 restored synaptic and cognitive function in addition to reducing cell senescence. Remarkably, proteomic profiling of hippocampal tissue indicated that XBP1s expression corrected age-related alterations in synaptic function. Collectively, our data demonstrate that strategies to manipulate the UPR sustain healthy brain aging. One Sentence SummaryThe IRE1/XBP1 pathway dictates when and how brain function declines during aging.

neuroscience↗