Pathogenic and commensal microbes induce various levels of inflammation and metabolic disease in the host. Inflammation caused by infection leads to increased production of reactive oxygen species (ROS) and subsequent oxidative DNA damage. These in turn cause further inflammation and exacerbation of DNA damage, and pose a risk for cancer development. Helicobacter pylori-mediated inflammation has been implicated in gastric cancer in many previously established studies, and Fusobacterium nucleatum presence has been observed with greater intensity in colorectal cancer patients. Despite ambiguity in the exact mechanism, infection-mediated inflammation may have a link to cancer development through an accumulation of potentially mutagenic DNA damage in surrounding cells. The multiple DNA repair pathways such as base excision, nucleotide excision, and mismatch repair that are employed by cells are vital in the abatement of accumulated mutations that can lead to carcinogenesis. For this reason, understanding the role of DNA repair as an important cellular mechanism in combatting the development of cancer will be essential to characterizing the effect of infection on DNA repair proteins and to identifying early cancer biomarkers that may be targeted for cancer therapies and treatments.

Infection with the Gram-negative, microaerophilic bacterium Helicobacter pylori induces an inflammatory response and oxidative DNA damage in gastric epithelial cells that can lead to gastric cancer (GC). However, the underlying pathogenic mechanism is largely unclear. Here, we report that the suppression of Nei-like DNA glycosylase 2 (NEIL2), a mammalian DNA glycosylase that specifically removes oxidized bases, is one mechanism through which H. pylori infection may fuel the accumulation of DNA damage leading to GC. Using cultured cell lines, gastric biopsies, primary cells, and human enteroid-derived monolayers from healthy human stomach, we show that H. pylori infection greatly reduces NEIL2 expression. The H. pylori infection–induced down-regulation of NEIL2 was specific, as Campylobacter jejuni had no such effect. Using gastric organoids isolated from the murine stomach in co-culture experiments with live bacteria mimicking the infected stomach lining, we found that H. pylori infection is associated with the production of various inflammatory cytokines. This response was more pronounced in Neil2-knockout (KO) mouse cells than in WT cells, suggesting that NEIL2 suppresses inflammation under physiological conditions. Notably, the H. pylori–infected Neil2-KO murine stomach exhibited more DNA damage than WT. Furthermore, H. pylori–infected Neil2-KO mice had greater inflammation and more epithelial cell damage. Computational analysis of gene expression profiles of DNA glycosylases in gastric specimens linked the reduced Neil2 level to GC progression. Our results suggest that NEIL2 down-regulation is a plausible mechanism by which H. pylori infection impairs DNA damage repair, amplifies the inflammatory response, and initiates GC.

Colorectal cancer (CRC) is the third most prevalent cancer, while the majority (80–85%) of CRCs are sporadic and are microsatellite stable (MSS), and approximately 15–20% of them display microsatellite instability (MSI). Infection and chronic inflammation are known to induce DNA damage in host tissues and can lead to oncogenic transformation of cells, but the role of DNA repair proteins in microbe-associated CRCs remains unknown. Using CRC-associated microbes such as Fusobacterium nucleatum (Fn) in a coculture with murine and human enteroid-derived monolayers (EDMs), here, we show that, among all the key DNA repair proteins, NEIL2, an oxidized base-specific DNA glycosylase, is significantly downregulated after Fn infection. Fn infection of NEIL2-null mouse-derived EDMs showed a significantly higher level of DNA damage, including double-strand breaks and inflammatory cytokines. Several CRC-associated microbes, but not the commensal bacteria, induced the accumulation of DNA damage in EDMs derived from a murine CRC model, and Fn had the most pronounced effect. An analysis of publicly available transcriptomic datasets showed that the downregulation of NEIL2 is often encountered in MSS compared to MSI CRCs. We conclude that the CRC-associated microbe Fn induced the downregulation of NEIL2 and consequent accumulation of DNA damage and played critical roles in the progression of CRCs.

Extracellular matrix (ECM) stiffness is correlated to malignancy and invasiveness of cancer cells. Although the mechanism of change is unclear, mechanical signals from the ECM may affect physical properties of cells such as their density profile. The current methods, such as Percoll density‐gradient centrifugation, are unable to detect minute density differences. A magnetic levitation device is developed (i.e., MagDense platform) where cells are levitated in a magnetic gradient allowing them to equilibrate to a levitation height that corresponds to their unique cellular density. In application of this system, MDA‐MB‐231 breast and A549 lung cancer cells are cultured and overall differences in cell density are observed in response to increasing collagen fiber density. Overall, density values are significantly more spread out for MDA‐MB‐231 cells extracted from the 1.44 mg mL−1 collagen gels compared to those from 0.72 mg mL−1 collagen, whereas no significant difference with A549 cell lines is observed. The MagDense platform can determine differences in cellular densities under various microenvironmental conditions. The imaging of cancer cells in a magnetic levitation device serves as a unique tool to observe changes in phenotypic properties of cancer cells as they relate to micromechanical cues encoded by the ECM.

Hydrogels are biocompatible polymers that are tunable to the system under study, allowing them to be widely used in medicine, bioprinting, tissue engineering, and biomechanics. Hydrogels are used to mimic the three-dimensional microenvironment of tissues, which is essential to understanding cell–cell interactions and intracellular signaling pathways (e.g., proliferation, apoptosis, growth, and survival). Emerging evidence suggests that the malignant properties of cancer cells depend on mechanical cues that arise from changes in their microenvironment. These mechanobiological cues include stiffness, shear stress, and pressure, and have an impact on cancer proliferation and invasion. The hydrogels can be tuned to simulate these mechanobiological tissue properties. Although interest in and research on the biomedical applications of hydrogels has increased in the past 25 years, there is still much to learn about the development of biomimetic hydrogels and their potential applications in biomedical and clinical settings. This review highlights the application of hydrogels in developing pre-clinical cancer models and their potential for translation to human disease with a focus on reviewing the utility of such models in studying glioblastoma progression.

The accumulation of Helicobacter pylori infectioninduced oxidative DNA damage in gastric epithelial cells is a risk factor for developing gastric cancer (GC); however, the underlying mechanisms remain poorly understood. Here we report that the suppression of NEIL2, an oxidized base-specific mammalian DNA glycosylase, is one such mechanism via which H. pylori infection may fuel the accumulation of DNA damage during the initiation and progression of GC. Using a combination of cultured cell lines and primary cells, we show that expression of NEIL2 is significantly down-regulated after H. pylori infection; such down-regulation was also seen in human gastric biopsies. The H. pylori infection-induced down-regulation of NEIL2 is specific, as Campylobacter jejuni has no such effect. Using gastric organoids isolated from the murine stomach in co-culture studies with live bacteria mimicking the infected stomach lining, we found that H. pylori infection was associated with IL-8 production; this response was more pronounced in Neil2 knockout (KO) mouse cells compared to wild type (WT) cells, suggesting that NEIL2 suppresses inflammation under physiological conditions. Interestingly, DNA damage was significantly higher in Neil2 KO mice compared to WT mice. H. pylori-infected Neil2 KO mice showed higher inflammation and more epithelial cell damage. Computational analysis of gene expression profiles of repair genes in gastric specimens showed the reduction of Neil2 level is linked to the GC progression. Taken together, our data suggest that down-regulation of NEIL2 is a plausible mechanism by which H. pylori infection derails DNA damage repair, amplifies the inflammatory response and initiates GCs.

mTOR complex 1 (mTORC1) integrates inputs from multiple pathways, such as PI3K/Akt, AMPK, Ca2+, and cAMP/PKA, and senses diverse signals to regulate cell growth, protein translation, and proliferation. Although the subcellular compartmentalization of signaling pathways can enhance signal specificity and efficiency, the spatial regulation of mTORC1 and its specific functions are still poorly understood. A pool of mTORC1 associated with the outer mitochondrial membrane has previously been identified but the function of mitochondrial mTORC1 is largely unknown. Previous studies have linked mTORC1 inhibition to changes in mitochondrial metabolism through its effect on transcription or translation, but a direct role for mTORC1 at the mitochondria is not yet elucidated. By targeting our FRET‐based mTORC1 activity reporter, TORCAR, to the outer mitochondrial membrane, we found that treating cells with platelet‐derived growth factor leads to a gradual increase in mitochondrial mTORC1 activity, and that this response is abrogated with rapamycin pre‐treatment. In pursuit of identifying the function of mTORC1 at the outer mitochondrial membrane, we have also developed a genetically encodable peptide‐based mTORC1 inhibitor, TerminaTOR, targeted to the outer mitochondrial membrane for specific subcellular inhibition of mTORC1. Using these molecular tools, we set out to examine whether mitochondrial mTORC1 activity is critical for mitochondria‐governed cellular homeostasis. We hypothesize that mitochondrial mTORC1 plays a critical role in altering mitochondrial metabolism upon stimulation with growth factor. We aim to further elucidate the functions of this activity by selectively inhibiting mitochondrial mTORC1 using mitochondria‐targeted TerminaTOR and quantifying changes in mitochondrial metabolism. We will also identify mitochondrial proteins that may interact with mTORC1 to contribute to these metabolic changes. This research will increase our understanding of the role that mTORC1 may play in diseases associated with altered metabolism or mitochondrial dysfunction.

It is important for students to acquire and maintain healthy lifestyle behaviors during university education. This study investigates healthy lifestyle behaviors and related factors in university students. A total of 869 associate degree students participated in the study. Data were collected with the Data Registration Form created by the researchers and the Health Promotion Lifestyle Profile-II (HPLP-II). The mean HPLP-II total score of the study group was 127.9±19.9. Students who stay with their families, whose economic status and general health perceptions are good/very good, and who do not smoke had higher health responsibility scores (p<0.05). The mean physical activity scores of students who were male, whose parents had higher education, and who had a good/very good general health perception were higher (p<0.05). The nutrition scores of the students who were studying in the second grade, who were staying with their families, who were non-smokers, who were overweight and obese, and who had a good/very good general health perception were found to be higher (p<0.05). Those with good/very good general health perception had higher interpersonal relations and personal development scores, and female students had higher interpersonal relations scores (p<0.05). The stress management scores of the second-grade students with good/very good general health perception were higher (p<0.05). It is important to implement lifestyle interventions to improve the health of university students. Considering socio-demographic factors in health promotion programs to be implemented may help develop healthy lifestyle behaviors.