Cancer is caused by the accumulation of genetic alterations and therefore has been historically considered to be irreversible. Intriguingly, several studies have reported that cancer cells can be ...reversed to be normal cells under certain circumstances. Despite these experimental observations, conceptual and theoretical frameworks that explain these phenomena and enable their exploration in a systematic way are lacking. In this review, we provide an overview of cancer reversion studies and describe recent advancements in systems biological approaches based on attractor landscape analysis. We suggest that the critical transition in tumorigenesis is an important clue for achieving cancer reversion. During tumorigenesis, a critical transition may occur at a tipping point, where cells undergo abrupt changes and reach a new equilibrium state that is determined by complex intracellular regulatory events. We introduce a conceptual framework based on attractor landscapes through which we can investigate the critical transition in tumorigenesis and induce its reversion by combining intracellular molecular perturbation and extracellular signaling controls. Finally, we present a cancer reversion therapy approach that may be a paradigm-changing alternative to current cancer cell-killing therapies.
Although fibroblasts are dormant in normal tissue, they exhibit explosive activation during wound healing and perpetual activation in pathologic fibrosis and cancer stroma. The key regulatory network ...controlling these fibroblast dynamics is still unknown. Here, we report that Twist1, a key regulator of cancer-associated fibroblasts, directly upregulates Prrx1, which, in turn, increases the expression of Tenascin-C (TNC). TNC also increases Twist1 expression, consequently forming a Twist1-Prrx1-TNC positive feedback loop (PFL). Systems biology studies reveal that the Twist1-Prrx1-TNC PFL can function as a bistable ON/OFF switch and regulates fibroblast activation. This PFL can be irreversibly activated under pathologic conditions, leading to perpetual fibroblast activation. Sustained activation of the Twist1-Prrx1-TNC PFL reproduces fibrotic nodules similar to idiopathic pulmonary fibrosis in vivo and is implicated in fibrotic disease and cancer stroma. Considering that this PFL is specific to activated fibroblasts, Twist1-Prrx1-TNC PFL may be a fibroblast-specific therapeutic target to deprogram perpetually activated fibroblasts.
A key step in sensory information processing involves modulation and integration of neuronal oscillations in disparate frequency bands, a poorly understood process. Here, we investigate how top-down ...input causes frequency changes in slow oscillations during sensory processing and, in turn, how the slow oscillations are combined with fast oscillations (which encode sensory input). Using experimental connectivity patterns and strengths of interneurons, we develop a system-level model of a neuronal circuit controlling these oscillatory behaviors, allowing us to understand the mechanisms responsible for the observed oscillatory behaviors. Our analysis discovers a circuit capable of producing the observed oscillatory behaviors and finds that a detailed balance in the strength of synaptic connections is the critical determinant to produce such oscillatory behaviors. We not only uncover how disparate frequency bands are modulated and combined but also give insights into the causes of abnormal neuronal activities present in brain disorders.
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•A computational neuronal circuit model of sensory cortex layers 2 and 3 is constructed•Cooperation of SST, VIP, and PV cells determines neuronal oscillation dynamics•The core structure regulating the top-down modulation of slow oscillation is found•The feedback between SST and VIP cells determines adaptability to top-down input
Lee et al. discover that precisely organized synaptic connectivity among cortical pyramidal cells and various classes of interneurons (expressing SST, VIP, and PV) enables sensitive frequency modulation of slow oscillations to encode top-down inputs and results in cross-frequency coupling with bottom-up-mediated fast oscillations.
Cancer is caused by the accumulation of multiple genetic mutations, but their cooperative effects are poorly understood. Using a genome-wide analysis of all the somatic mutations in colorectal cancer ...patients in a large-scale molecular interaction network, here we find that a giant cluster of mutation-propagating modules in the network undergoes a percolation transition, a sudden critical transition from scattered small modules to a large connected cluster, during colorectal tumorigenesis. Such a large cluster ultimately results in a giant percolated cluster, which is accompanied by phenotypic changes corresponding to cancer hallmarks. Moreover, we find that the most commonly observed sequence of driver mutations in colorectal cancer has been optimized to maximize the giant percolated cluster. Our network-level percolation study shows that the cooperative effect rather than any single dominance of multiple somatic mutations is crucial in colorectal tumorigenesis.
Abstract
Oxygen supplementation is crucial for awake tracheal intubation (ATI) using a flexible bronchoscope in patients with an anticipated difficult airway. However, the modality of optimal oxygen ...delivery remains unclear. This retrospective study compared high-flow nasal oxygen (HFNO) and conventional low-flow oxygen supply during ATI. We applied inverse probability of treatment weighting (IPTW) to account for biases due to clinical characteristic differences between the groups. The primary endpoint was the lowest oxygen saturation during ATI. The secondary endpoints were incidence of desaturation, multiple attempts, failure rate, and procedural duration. After IPTW adjustment, the lowest oxygen saturation in the HFNO group during ATI was significantly higher than that in the conventional oxygenation group (99.3 ± 0.2 vs. 97.5 ± 0.5,
P
< 0.001). Moreover, the HFNO group had fewer cases with multiple attempts than the conventional oxygenation group (3% vs. 16%,
P
= 0.007). There were no significant differences between the two groups in the incidence of desaturation, failure and procedural duration. Our findings suggest that HFNO was associated with improved lowest oxygen saturation and a lower rate of multiple attempts during ATI. Therefore, we recommend using HFNO for safer oxygen delivery and improved quality of procedure during ATI.
Cancer, recognized as a primary cause of death worldwide, has profound health implications and incurs a substantial social burden. Numerous efforts have been made to develop cancer treatments, among ...which anticancer peptides (ACPs) are garnering recognition for their potential applications. While ACP screening is time-consuming and costly, in silico prediction tools provide a way to overcome these challenges. Herein, we present a deep learning model designed to screen ACPs using peptide sequences only. A contrastive learning technique was applied to enhance model performance, yielding better results than a model trained solely on binary classification loss. Furthermore, two independent encoders were employed as a replacement for data augmentation, a technique commonly used in contrastive learning. Our model achieved superior performance on five of six benchmark datasets against previous state-of-the-art models. As prediction tools advance, the potential in peptide-based cancer therapeutics increases, promising a brighter future for oncology research and patient care.
Purpose
Ischemia-reperfusion injury is inevitable during donor organ harvest and recipient allograft reperfusion in kidney transplantation, and affects graft outcomes. Dexmedetomidine, an ...α2-adrenoreceptor agonist, has renoprotective effects against ischemia-reperfusion injury. We investigated the effects of intraoperative dexmedetomidine infusion on renal function and the development of delayed graft function after elective living donor kidney transplantation in a randomized controlled trial.
Methods
A total of 104 patients were randomly assigned to receive either an intraoperative infusion of dexmedetomidine 0.4 μg·kg
-1
·hr
-1
or 0.9% saline. The primary outcome was the serum creatinine level on postoperative day (POD) 7. Secondary outcomes were renal function and the degree of inflammation and included the following variables: serum creatinine level and estimated glomerular filtration rate up to six months; incidence of delayed graft function; and levels of serum cystatin C, plasma interleukin (IL)-1β, and IL-18 during the perioperative period.
Results
The mean (standard deviation) serum creatinine level on POD 7 was comparable between the groups (dexmedetomidine
vs
control: 1.11 0.87 mg·dL
-1
vs
1.06 0.73 mg·dL
-1
; mean difference, 0.05; 95% confidence interval, -0.27 to 0.36;
P
= 0.77). Delayed graft function occurred in one patient in each group (odds ratio, 1.020;
P
> 0.99). There were no significant differences in the secondary outcomes between the groups (all
P
> 0.05).
Conclusions
Intraoperative dexmedetomidine infusion did not produce any beneficial effects on renal function or delayed graft function in patients undergoing elective living donor kidney transplantation.
Study registration
www.ClinicalTrials.gov
(NCT03327389); registered 31 October 2017.
Many clinical trials for cancer precision medicine have yielded unsatisfactory results due to challenges such as drug resistance and low efficacy. Drug resistance is often caused by the complex ...compensatory regulation within the biomolecular network in a cancer cell. Recently, systems biological studies have modeled and simulated such complex networks to unravel the hidden mechanisms of drug resistance and identify promising new drug targets or combinatorial or sequential treatments for overcoming resistance to anticancer drugs. However, many of the identified targets or treatments present major difficulties for drug development and clinical application. Nanocarriers represent a path forward for developing therapies with these “undruggable” targets or those that require precise combinatorial or sequential application, for which conventional drug delivery mechanisms are unsuitable. Conversely, a challenge in nanomedicine has been low efficacy due to heterogeneity of cancers in patients. This problem can also be resolved through systems biological approaches by identifying personalized targets for individual patients or promoting the drug responses. Therefore, integration of systems biology and nanomaterial engineering will enable the clinical application of cancer precision medicine to overcome both drug resistance of conventional treatments and low efficacy of nanomedicine due to patient heterogeneity.
Recent studies show how systems biology and nanomaterial engineering can overcome the challenges of each field of study to achieve cancer precision medicine. Integration of systems biology and nanomaterial engineering can resolve the problem of drug resistance and heterogeneity in cancer patients, and realize the power of precision medicine for the treatment of cancer.
The main objective of this study was to induce and evaluate drug-dose-dependent outer retinal degeneration in cynomolgus monkeys by application of N-methyl-N-nitrosourea (MNU).
Intravitreal temporary ...tamponade induced outer retinal degeneration with MNU solutions (2-3 mg ml
) after vitrectomy in five cynomolgus monkeys. Optical coherence tomography (OCT), fundus autofluorescence (FAF), full-field electroretinography (ffERG), and visual evoked potentials (VEP) were performed at baseline and weeks 2, 6, and 12 postoperatively. At week 12, OCT angiography, histology, and immunohistochemistry were performed.
Outer retinal degeneration was observed in four monkeys, especially in the peripheral retina. Anatomical and functional changes occurred at week 2 and persisted until week 12. FAF images showed hypoautofluorescence dots, similar to AF patterns seen in human retinitis pigmentosa. Hyperautofluorescent lesions in the pericentral area were also observed, which corresponded to the loss of the ellipsoid zone on OCT images. OCT revealed thinning of the outer retinal layer adding to the loss of the ellipsoid zone outside the vascular arcade. Histological findings confirmed that the abovementioned changes resulted from a gradual loss of photoreceptors from the perifovea to the peripheral retina. In contrast, the inner retina, including ganglion cell layers, was preserved. Functionally, a decrease or extinction of scotopic ffERGs was observed, which indicated rod-dominant loss. Nevertheless, VEPs were relatively preserved.
Therefore, we can conclude that temporary exposure to intravitreal MNU tamponade after vitrectomy induces rod-dominant outer retinal degeneration in cynomolgus monkeys, especially in the peripheral retina.
Cancer reversion, converting the phenotypes of a cancer cell into those of a normal cell, has been sporadically observed throughout history. However, no systematic analysis has been attempted so far.
...To investigate this from a systems biological perspective, we have constructed a logical network model of colorectal tumorigenesis by integrating key regulatory molecules and their interactions from previous experimental data. We identified molecular targets that can reverse cancerous cellular states to a normal state by systematically perturbing each molecular activity in the network and evaluating the resulting changes of the attractor landscape with respect to uncontrolled proliferation, EMT, and stemness. Intriguingly, many of the identified targets were well in accord with previous studies. We further revealed that the identified targets constitute stable network motifs that contribute to enhancing the robustness of attractors in cancerous cellular states against diverse regulatory signals.
The proposed framework for systems analysis is applicable to the study of tumorigenesis and reversion of other types of cancer.
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