DAMP-ing IBD: Extinguish the Fire and Prevent Smoldering.

In inflammatory bowel diseases (IBD), the most promising therapies targeting cytokines or immune cell trafficking demonstrate around 40% efficacy. As IBD is a multifactorial inflammation of the intestinal tract, a single-target approach is unlikely to solve this problem, necessitating an alternative strategy that addresses its variability. One approach often overlooked by the pharmaceutically driven therapeutic options is to address the impact of environmental factors. This is somewhat surprising considering that IBD is increasingly viewed as a condition heavily influenced by such factors, including diet, stress, and environmental pollution-often referred to as the "Western lifestyle". In IBD, intestinal responses result from a complex interplay among the genetic background of the patient, molecules, cells, and the local inflammatory microenvironment where danger- and microbe-associated molecular patterns (D/MAMPs) provide an adjuvant-rich environment. Through activating DAMP receptors, this array of pro-inflammatory factors can stimulate, for example, the NLRP3 inflammasome-a major amplifier of the inflammatory response in IBD, and various immune cells via non-specific bystander activation of myeloid cells (e.g., macrophages) and lymphocytes (e.g., tissue-resident memory T cells). Current single-target biological treatment approaches can dampen the immune response, but without reducing exposure to environmental factors of IBD, e.g., by changing diet (reducing ultra-processed foods), the adjuvant-rich landscape is never resolved and continues to drive intestinal mucosal dysregulation. Thus, such treatment approaches are not enough to put out the inflammatory fire. The resultant smoldering, low-grade inflammation diminishes physiological resilience of the intestinal (micro)environment, perpetuating the state of chronic disease. Therefore, our hypothesis posits that successful interventions for IBD must address the complexity of the disease by simultaneously targeting all modifiable aspects: innate immunity cytokines and microbiota, adaptive immunity cells and cytokines, and factors that relate to the (micro)environment. Thus the disease can be comprehensively treated across the nano-, meso-, and microscales, rather than with a focus on single targets. A broader perspective on IBD treatment that also includes options to adapt the DAMPing (micro)environment is warranted.

Basic moral sensitivity, moral disengagement, and defender self-efficacy as predictors of students' self-reported bystander behaviors over a school year: a growth curve analysis.

Though school children tend to view peer victimization as morally wrong most do not to intervene on the victim's behalf and some instead choose to aid the victimizer. The aim of this longitudinal study was to investigate how students' defending and pro-aggressive bystander behaviors evolved over the course of one school year and their association to basic moral sensitivity, moral disengagement, and defender self-efficacy. Three-hundred-fifty-three upper elementary school students (55% girls; 9.9-12.9 years of age) each completed self-report surveys at three points during one school year. Results from latent growth curve models showed that pro-aggressive bystander behavior remained stable over the year, whereas defending behavior decreased. Moreover, students who exhibited greater basic moral sensitivity were both less likely to be pro-aggressive and simultaneously more likely to defend. Students with defender self-efficacy were not only associated with more defending behavior at baseline but also were also less likely to decrease in defender behavior over time. Conversely, students reporting a higher degree of moral disengagement were linked to more pro-aggressive behavior, particularly when also reporting lower basic moral sensitivity. These short-term longitudinal results add important insight into the change in bystander behavior over time and how it relates to students' sense of morality. The results also highlight the practical necessity for schools to nurture students' sense of morality and prosocial behavior in their efforts to curb peer victimization.

Associated Factors of Patients' Survival in Out of Hospital Cardiac Arrest; a Cross-sectional Study.

Introduction: Chinese populations have an increasingly high prevalence of cardiac arrest. This study aimed to investigate the prehospital associated factors of survival to hospital admission and discharge among out-of-hospital cardiac arrest (OHCA) adult cases in Macao Special Administrative Region (SAR), China. Methods: Baseline characteristics as well as prehospital factors of OHCA patients were collected from publicly accessible medical records and Macao Fire Services Bureau, China. Demographic and other prehospital OHCA characteristics of patients who survived to hospital admission and discharge were analyzed using multivariate logistic regression analysis. Results: A total of 904 cases with a mean age of 74.2±17.3 (range: 18-106) years were included (78%>65 years, 62% male). Initial shockable cardiac rhythm was the strongest predictor for survival to both hospital admission (OR=3.57, 95% CI: 2.26-5.63; p<0.001) and discharge (OR=12.40, 95% CI: 5.70-26.96; p<0.001). Being male (OR=1.63, 95% CI:1.08-2.46; p =0.021) and the lower emergency medical service (EMS) response time (OR=1.62, 95% CI: 1.12-2.34; p =0.010) were also associated with a 2-fold association with survival to hospital admission. In addition, access to prehospital defibrillation (OR=4.25, 95% CI: 1.78-10.12; p <0.001) had a 4-fold association with survival to hospital discharge. None of these associations substantively increased with age. Conclusion: The major OHCA predictors of survival were initial shockable cardiac rhythm, being male, lower EMS response time, and access to prehospital defibrillation. These findings indicate a need for increased public awareness and more education.

Reactions of adolescent cyber bystanders toward different victims of cyberbullying: the role of parental rearing behaviors.

BACKGROUND: Group-based situations are common settings for cyberbullying, making bystander responses crucial in combating this issue. This study investigated how adolescent bystanders respond to various victims, including family members, friends, teachers, and celebrities. This study also examined how different parenting styles influenced children's cyber bystander involvement. METHODS: This study employed data from a cross-sectional school survey covering 1,716 adolescents aged 13-18 years from public and vocational schools in China collected in 2022. Logistic regression analyses were conducted to measure demographic characteristics, cyberbullying experiences, and parental rearing behaviors in predicting bystander reactions. RESULTS: The findings showed that middle school students preferred to "ask for help" while high school students tended to choose "call the police" when witnessing cyberbullying incidents. Bystanders growing up with parental rejection and overprotection, having previous cyberbullying victimization experiences, where the victims were disliked by them, exhibited fewer defensive reactions. CONCLUSIONS: This study has implications for future research and practices involving parental involvement in cyber bystander interventions, which could provide implications for future practice in designing specific intervention programs for cyberbullying bystander behavior. Future research and interventions against cyberbullying may provide individualized training including parents' positive parenting skills and parent-child interactions.

Parental Warmth, Friendship Quality, Empathy and Bystander Defending Behavior in Cyberbullying Among Adolescents in China.

Adolescents' bystander defending behavior in cyberbullying contributes to reducing the harm done to cyberbullying victims. This study examined the relationships and underlying mechanisms of parental warmth, friendship quality, empathy and bystander defending behavior in cyberbullying among 848 Chinese adolescents (43.986% girls, mean age = 14.960 years old [SD = 1.398]). The results showed that parental warmth, friendship quality and empathy were all positively correlated with bystander defending behavior in cyberbullying among adolescents. Both friendship quality and empathy played a mediating role between parental warmth and bystander defending behavior in cyberbullying, indicating that parental warmth was associated with increased bystander defending behavior through higher levels of friendship quality and empathy, respectively. Friendship quality and empathy also played a chain mediating role between these two, indicating that parental warmth was linked to increased bystander defending behavior by first associating with higher level of friendship quality and subsequently with greater empathy. These results suggest that high degrees of parental warmth, friendship quality and empathy may all increase the likelihood of bystander defending behavior in cyberbullying among adolescents. This study provides practical implications for improving adolescent bystander defending behavior in cyberbullying.

Endogenous bystander killing mechanisms enhance the activity of novel FAP-specific CAR-T cells against glioblastoma.

Objectives: CAR-T cells are being investigated as a novel immunotherapy for glioblastoma, but clinical success has been limited. We recently described fibroblast activation protein (FAP) as an ideal target antigen for glioblastoma immunotherapy, with expression on both tumor cells and tumor blood vessels. However, CAR-T cells targeting FAP have never been investigated as a therapy for glioblastoma. Methods: We generated a novel FAP targeting CAR with CD3ζ and CD28 signalling domains and tested the resulting CAR-T cells for their lytic activity and cytokine secretion function in vitro (using real-time impedance, flow cytometry, imaging and bead-based cytokine assays), and in vivo (using a xenograft mimicking the natural heterogeneity of human glioblastoma). Results: FAP-CAR-T cells exhibited target specificity against model cell lines and potent cytotoxicity against patient-derived glioma neural stem cells, even when only a subpopulation expressed FAP, indicating a bystander killing mechanism. Using co-culture assays, we confirmed FAP-CAR-T cells mediate bystander killing of antigen-negative tumor cells, but only after activation by FAP-positive target cells. This bystander killing was at least partially mediated by soluble factors and amplified by IL-2 which activated the non-transduced fraction of the CAR-T product. Finally, a low dose of intravenously administered FAP-CAR-T cells controlled, without overt toxicity, the growth of subcutaneous tumors created using a mixture of antigen-negative and antigen-positive glioblastoma cells. Conclusions: Our findings advance FAP as a leading candidate for clinical CAR-T therapy of glioblastoma and highlight under-recognised antigen nonspecific mechanisms that may contribute meaningfully to the antitumor activity of CAR-T cells.

Effect of Cardiopulmonary Resuscitation Training for Layperson Bystanders on Outcomes of Out-of-Hospital Cardiac Arrest: A Prospective Multicenter Observational Study.

BACKGROUND: Effective bystander cardiopulmonary resuscitation (CPR) improves outcomes in out-of-hospital cardiac arrest (OHCA) patients. However, the effect of CPR training on the rate of return of spontaneous circulation (ROSC) among laypersons has yet to be thoroughly evaluated. METHODS: This prospective, multicenter observational study was conducted across 42 centers in Japan. We assessed OHCA patients who received bystander CPR from a layperson, excluding those performed by healthcare staff. The primary outcome was the ROSC rate. Secondary outcomes included pre-hospital ROSC, ROSC after hospital arrival, favorable neurological outcomes, and 30-day survival. Propensity score with inverse probability treatment weighting (IPTW) was used to adjust for confounders, including age, sex, presence or absence of witnesses, and past medical history. RESULTS: A total of 969 OHCA patients were included, divided into CPR-trained (n=322) and control (n=647). Before adjustment, the ROSC rate was higher in the trained group than the control (40.1% vs. 30.1%, P < 0.01). After IPTW adjustment, the trained group showed a significantly higher ROSC rate (36.7% vs. 30.6%; P = 0.02). All secondary outcomes in the trained group were significantly improved before adjustment. After IPTW adjustment, the trained group showed improved rates of pre-hospital ROSC and ROSC after hospital arrival (30.7% vs. 24.0%; P < 0.01, 23.9% vs. 20.7%; P = 0.04). There were no differences in neurological outcomes and 30-day survival. CONCLUSION: This study demonstrated that CPR training for laypersons was associated with increased ROSC rates in OHCA patients, indicating potential advantages of CPR training for non-healthcare professionals.

AAV gene replacement therapy for treating MPS IIIC: Facilitating bystander effects via EV-mRNA cargo.

MPS IIIC is a lysosomal storage disease caused by mutations in heparan-α-glucosaminide N-acetyltransferase (HGSNAT), for which no treatment is available. Because HGSNAT is a trans-lysosomal-membrane protein, gene therapy for MPS IIIC needs to transduce as many cells as possible for maximal benefits. All cells continuously release extracellular vesicles (EVs) and communicate by exchanging biomolecules via EV trafficking. To address the unmet need, we developed a rAAV-hHGSNATEV vector with an EV-mRNA-packaging signal in the 3'UTR to facilitate bystander effects, and tested it in an in vitro MPS IIIC model. In human MPS IIIC cells, rAAV-hHGSNATEV enhanced HGSNAT mRNA and protein expression, EV-hHGSNAT-mRNA packaging, and cleared GAG storage. Importantly, incubation with EVs led to hHGSNAT protein expression and GAG contents clearance in recipient MPS IIIC cells. Further, rAAV-hHGSNATEV transduction led to the reduction of pathological EVs in MPS IIIC cells to normal levels, suggesting broader therapeutic benefits. These data demonstrate that incorporating the EV-mRNA-packaging signal into a rAAV-hHGSNAT vector enhances EV packaging of hHGSNAT-mRNA, which can be transported to non-transduced cells and translated into functional rHGSNAT protein, facilitating cross-correction of disease pathology. This study supports the therapeutic potential of rAAVEV for MPS IIIC, and broad diseases, without having to transduce every cell.

The Safe Sport Allies bystander training: developing a multi-layered program for youth sport participants and their coaches to prevent harassment and abuse in local sport clubs.

Harassment and abuse represent a pervasive and critical problem in sport with far-reaching consequences. Survivors' testimonials underscore the profound and enduring impact of these experiences at individual, interpersonal, organizational and community level. Many of their stories reveal painful inaction from responsible adults in the sport organization, aggravating the harm. Other contributing factors to the harm inflicted include a culture of silence, lack of knowledge and understanding of what constitutes abuse, unawareness of reporting and supporting mechanisms, and fear of potential consequences. While effective bystander interventions have been developed outside the sport context, particularly targeting students in higher education, such initiatives have yet to be extensively adapted and assessed within the sport context. To address this gap, the Safe Sport Allies Erasmus+ collaborative partnership relied on the intervention mapping approach as a guiding framework to systematically develop a bystander training program (i.e., Safe Sport Allies) to train youth sport participants and youth sport coaches to act as effective bystanders. The current paper describes the comprehensive development process and provides an overview of implementation and evaluation possibilities. Throughout the paper, it is explained how each step of the Intervention Mapping approach shaped the Safe Sport Allies bystander training program. The program development, and the developed plans for implementation and evaluation are presented, shedding light on challenges encountered. The bystander training program developed in this paper and the implementation and evaluation plans can serve as an outline to build future interventions within this critical domain of safeguarding in sport.

Stimulating macropinocytosis of peptide-drug conjugates through DNA-dependent protein kinase inhibition for treating KRAS-mutant cancer.

KRAS-mutant cancers, due to their protein targeting complexity, present significant therapeutic hurdles. The identification of the macropinocytic phenotype in these cancers has emerged as a promising alternative therapeutic target. Our study introduces MPD1, an macropinocytosis-targeting peptide-drug conjugates (PDC), which is developed to treat KRAS mutant cancers. This PDC is specifically designed to trigger a positive feedback loop through its caspase-3 cleavable characteristic. However, we observe that this loop is hindered by DNA-PK mediated DNA damage repair processes in cancer cells. To counter this impediment, we employ AZD7648, a DNA-PK inhibitor. Interestingly, the combined treatment of MPD1 and AZD7648 resulted in a 100% complete response rate in KRAS-mutant xenograft model. We focus on the synergic mechanism of it. We discover that AZD7648 specifically enhances macropinocytosis in KRAS-mutant cancer cells. Further analysis uncovers a significant correlation between the increase in macropinocytosis and PI3K signaling, driven by AMPK pathways. Also, AZD7648 reinforces the positive feedback loop, leading to escalated apoptosis and enhanced payload accumulation within tumors. AZD7648 possesses broad applications in augmenting nano-sized drug delivery and preventing DNA repair resistance. The promising efficacy and evident synergy underscore the potential of combining MPD1 with AZD7648 as a strategy for treating KRAS-mutant cancers.

The roles of teacher and parental support on adolescent cyber-bystander behaviors: a path analysis.

Introduction: The role of bystanders in cyberbullying situations is critical, with the potential to significantly influence outcomes. Bystanders who demonstrate positive behaviors-such as reporting incidents or supporting victims-can help to mitigate the damaging effects of cyberbullying. Based on the Social Cognitive Theory, this study seeks to address the psychosocial mechanisms that underlie positive cyber-bystander behaviors. Methods: A total of 1,716 students in Grades 8-12 from three secondary schools in China participated in this study. Path analysis was utilized to delineate the relationships between internet self-efficacy, empathy, teacher and parental support, and cyber-bystander behaviors. Results: Adolescents who received greater support from teachers were more likely to demonstrate increased internet self-efficacy and empathy. In contrast, higher levels of parental warmth were associated with lower levels of internet self-efficacy. Teacher support and parental warmth exerted an indirect effect on positive bystander behaviors through empathy. Discussion: The importance of parental warmth paired with Internet self-efficacy in preventing online interpersonal violence and motivate active bystander behaviors is considerable. We recommend adopting a nuanced approach that differentiates between empathy and internet self-efficacy in cyber-bystander research.

Historical neighborhood redlining and bystander CPR disparities in out-of-hospital cardiac arrest.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is associated with low survival rates. Bystander cardiopulmonary resuscitation (CPR) is essential for improving outcomes, but its utilization remains limited, particularly among racial and ethnic minorities. Historical redlining, a practice that classified neighborhoods for mortgage risk in 1930s, may have lasting implications for social and health outcomes. This study sought to investigate the influence of redlining on the provision of bystander CPR during witnessed OHCA. METHODS: We conducted an analysis using data from the comprehensive Cardiac Arrest Registry to Enhance Survival (CARES), encompassing 736,066 non-traumatic OHCA cases across the United States. The Home Owners' Loan Corporation (HOLC) map shapefiles were utilized to categorize census tracts of arrests into four grades (A signifying "best", B "still desirable", C "declining", and D "hazardous"). Multivariable hierarchical logistic regression models were employed to predict the likelihood of CPR provision, adjusting for various factors including age, sex, race/ethnicity, arrest location, calendar year, and state of occurrence. Additionally, we accounted for the percentage of Black residents and residents below poverty levels at the census tract level. RESULTS: Among the 43,186 witnessed cases of OHCA in graded HOLC census tracts, 37.2% received bystander CPR. The rates of bystander CPR exhibited a gradual decline across HOLC grades, ranging from 41.8% in HOLC grade A to 35.8% in HOLC grade D. In fully adjusted model, we observed significantly lower odds of receiving bystander CPR in HOLC grades C (OR 0.89, 95% CI 0.81-0.98, p = 0.016) and D (OR 0.86, 95% CI 0.78-0.95, p = 0.002) compared to HOLC grade A. CONCLUSION: Redlining, a historical segregation practice, is associated with reduced contemporary rates of bystander CPR during OHCA. Targeted CPR training in redlined neighborhoods may be imperative to enhance survival outcomes.

Individual and contextual-level predictors of progression in the bystander intervention model.

The situational model of bystander behavior is a validated 5-step process for understanding intervention in bullying and sexual harassment, yet the individual-level and contextual-level factors that facilitate the progression from one step to the next are not well understood. The purpose of the current study was to examine whether individual characteristics (social-emotional skills, affective empathy, cognitive empathy, and personal attitudes toward bullying and sexual harassment) and contextual-level factors (school climate and perceived peer attitudes toward bullying and sexual harassment) explained the association between subsequent steps of the bystander intervention model. A sample of 788 high school students completed several validated measures of these constructs. Structural equation modeling analysis revealed that each step significantly and positively predicted the next step, and the addition of a direct path from accepting responsibility to helping improved model fit. The mediational model indicated that individual-level characteristics had significant direct effects on interpreting bullying and sexual harassment as problems, accepting responsibility, and helping, and indirect effects from noticing the bullying and sexual harassment to all subsequent steps except knowing. In contrast, contextual-level effects contributed to accepting responsibility in an inverse direction.

A Scoping Review of Bystander-Based Sexual Violence Prevention Training for College Students in Fraternities and Sororities.

Bystander-based sexual violence (SV) prevention trainings are offered on college campuses across the United States to meet federal Title IX requirements, as they have proven to be an effective strategy for violence prevention. Greek-affiliated students (fraternity and sorority members) are at a higher risk of sexual assault than their peers; however, few trainings consider the specific needs of this population, and program adaptations for this high-risk group may be needed. This scoping review identifies and describes the bystander trainings delivered to Greek-affiliated students in the US and Canada. An eight-database search was conducted following PRISMA-ScR guidelines. The review identified 81 unique sources, with 18 meeting the inclusion criteria. Eleven specific training programs were identified, encompassing qualitative, quantitative, and mixed-method studies. The thematic analysis revealed best practices, including the importance of peer leaders, interactive sessions, and tailored content to Greek culture, as well as barriers such as a lack of engagement and an inadequate session length. The review underscores the need for tailored interventions to effectively address the unique cultural characteristics and high-risk nature of Greek-affiliated students. These findings provide valuable insights for improving the design and implementation of bystander interventions to enhance their efficacy in preventing sexual violence within this population.

The Role of Social Problem-Solving and Prosocial Behavior in First Aid Willingness among Adolescents in Hungary.

First aid is a key factor in preventing further deterioration in an accident, saving lives, or improving treatment in emergencies. However, the reasons behind the willingness to provide first aid are still unclear. Therefore, this study aimed to investigate the role of social problem-solving and prosocial behavior in the dimension of first aid willingness. Self-administered questionnaires were used to evaluate the dimensions of first aid willingness (first aid willingness for peers, first aid willingness for strangers, knowledge, and negative emotions), social problem solving (positive problem orientation, negative problem orientation, rational problem solving, avoidance style, and impulsivity/carelessness) and prosocial behavior. A total of 497 school-aged students between the ages of 12 and 15 years (201 boys and 296 girls) participated in this study. Our results showed that positive problem orientation (p < 0.05) and rational problem solving (p < 0.001) are significant factors in determining first aid willingness for both peers and strangers. On the other hand, avoidance style orientation (p < 0.05) has a negative influence on the willingness to provide first aid to peers and strangers. Negative problem orientation (p < 0.001) only predicted negative emotions related to emergencies. Furthermore, prosocial behavior (p < 0.001) was more strongly associated with first aid willingness than social problem solving. Our study suggested that improving social competence could be a key factor in increasing first aid provision in real time, which could save lives in emergencies.

Transcriptional and functional remodeling of lung-resident T cells and macrophages by Simian varicella virus infection.

Introduction: Varicella zoster virus (VZV) causes varicella and can reactivate as herpes zoster, and both diseases present a significant burden worldwide. However, the mechanisms by which VZV establishes latency in the sensory ganglia and disseminates to these sites remain unclear. Methods: We combined a single-cell sequencing approach and a well-established rhesus macaque experimental model using Simian varicella virus (SVV), which recapitulates the VZV infection in humans, to define the acute immune response to SVV in the lung as well as compare the transcriptome of infected and bystander lung-resident T cells and macrophages. Results and discussion: Our analysis showed a decrease in the frequency of alveolar macrophages concomitant with an increase in that of infiltrating macrophages expressing antiviral genes as well as proliferating T cells, effector CD8 T cells, and T cells expressing granzyme A (GZMA) shortly after infection. Moreover, infected T cells harbored higher numbers of viral transcripts compared to infected macrophages. Furthermore, genes associated with cellular metabolism (glycolysis and oxidative phosphorylation) showed differential expression in infected cells, suggesting adaptations to support viral replication. Overall, these data suggest that SVV infection remodels the transcriptome of bystander and infected lung-resident T cells and macrophages.

The Effect of Bystander Features on Displaced Aggression in Provocative Situations among Male Juvenile Delinquents.

Two studies were conducted to explore the influence of bystander features of displaced aggression in provocative situations among male juvenile delinquents. Study 1 examined the differences in displaced aggression between provoked male juvenile delinquents in the presence or absence of bystanders. The results revealed that provoked male juvenile delinquents exhibited significantly higher levels of displaced aggression when bystanders were present compared to when they were not. Study 2 further manipulated the bystanders' trigger level and investigated the differences in displaced aggression exhibited by provoked male juvenile delinquents towards highly versus lowly triggered bystanders. The results indicated that after low provocation, male juvenile delinquents exhibited significantly higher levels of displaced aggression towards highly triggered bystanders compared to lowly triggered bystanders. These findings demonstrated that male juvenile delinquents exhibited a high level of displaced aggression towards bystanders in provocative situations, particularly with highly triggered bystanders. This study supported the personality and social model of displaced aggression, emphasizing that bystanders, especially those with high triggers, were more likely to become targets of displaced aggression. The current study provides references for subsequent criminal rehabilitation and crime prevention.

IL-6 knockdown in a model of the human bone marrow, abrogates DNA damage induction in bystander cells post-chemotherapy induced cytokine release syndrome.

Following infection or exposure to therapeutic agents, an aggressive immune response may result, termed cytokine storm (CS) or cytokine release syndrome. Here the innate immune system becomes uncontrolled, leading to serious consequences including possible death. Patients surviving CS are at greater risk for de novo tumorigenesis, but it is unclear if any specific cytokines are directly responsible for this outcome. De novo tumorigenesis has been observed in donated cells exposed to CS following haematopoietic stem cell transplant (HSCT). Modelling HSCT, we firstly demonstrated the release of CS levels from the HS-5 human bone marrow stromal cell line, post-exposure to chemotherapy. We then exposed the TK6 lymphoblast cell line to healthy and storm doses of IL-6 and measured increased genotoxicity via the micronucleus assay. During HSCT, haematopoietic cells are exposed to a complex mix of cytokines, so to determine if IL-6 was integral in a chemotherapy-induced bystander effect, we attempted to inhibit IL-6 from HS-5 cells using resatorvid or siRNA, treated with chlorambucil or mitoxantrone, and then co-cultured with bystander TK6 cells. Whilst resatorvid did not reduce IL-6 and did not reduce micronuclei in the bystander TK6 cells, siRNA inhibition reduced IL-6 to healthy in vivo levels, and micronuclei aligned with untreated controls. Our data suggests that exposure to high IL-6 (in the absence of inflammatory cells) has potential to induce genetic damage and may contribute to de novo tumorigenesis post-CS. We suggest that for individuals with a pro-inflammatory profile, anti-IL-6 therapy may be an appropriate intervention to prevent complications post-CS.

Efficient Induction of Apoptosis in Lung Cancer Cells Using Bismuth Sulfide Nanoparticles.

Background: The use of nanomaterial-based radiosensitizers to improve the therapeutic ratio has gained attraction in radiotherapy. Increased radiotoxicity applied to the tumor region may result in adverse impact on the unexposed normal cells to the radiation, a phenomenon known as radiation-induced bystander effect (RIBE). Objectives: This study aimed to investigate the effect of Bi2S3@BSA nanoparticles (NPs) as radiosensitizers on the enhancement of bystander response in non-irradiated cells. Materials and Methods: Lung carcinoma epithelial cells were exposed to 6 MV x-ray photons at different doses of 2 and 8 Gy, with and without Bi2S3@BSA NPs. The irradiated-cell's conditioned medium (ICCM) was collected and incubated with MCR-5 human fetal lung fibroblasts. Results: This study showed that ICCM collected from 2-Gy-irradiated A549 cells in the presence of Bi2S3@BSA NPs reduced the cell viability of MCR-5 bystander cells more than ICCM collected from irradiated cells without NPs (P<0.05), whereas such a difference was not observed after 8-Gy radiation. The mRNA expression of the BAX and XPA genes, as well as the cell death rate in MCR-5 bystander cells, revealed that the Bi2S3@BSA NPs significantly improved bystander response at 2-Gy (P<0.05), but the efficacy was not statistically significant after 8-Gy Irradiation. Conclusion: The results indicated that the presence of NPs did not affect bystander response enhancement at higher concentrations. These findings highlighted the potential use of radiation-enhancing agents and their benefits in radiotherapy techniques with high doses per fraction.

Upregulation of iNOS/NO in Cancer Cells That Survive a Photodynamic Challenge: Role of No in Accelerated Cell Migration and Invasion.

Anti-tumor photodynamic therapy (PDT) is a unique modality that employs a photosensitizer (PS), PS-exciting light, and O2 to generate cytotoxic oxidants. For various reasons, not all malignant cells in any given tumor will succumb to a PDT challenge. Previous studies by the authors revealed that nitric oxide (NO) from inducible NO synthase (iNOS/NOS2) plays a key role in tumor cell resistance and also stimulation of migratory/invasive aggressiveness of surviving cells. iNOS was the only NOS isoform implicated in these effects. Significantly, NO from stress-upregulated iNOS was much more important in this regard than NO from preexisting enzymes. Greater NO-dependent resistance, migration, and invasion was observed with at least three different cancer cell lines, and this was attenuated by iNOS activity inhibitors, NO scavengers, or an iNOS transcriptional inhibitor. NO diffusing from PDT-targeted cells also stimulated migration/invasion potency of non-targeted bystander cells. Unless counteracted by appropriate measures, all these effects could seriously compromise clinical PDT efficacy. Here, we will review specific examples of these negative side effects of PDT and how they might be suppressed by adjuvants such as NO scavengers or inhibitors of iNOS activity or expression.