Butyrate's (a short-chain fatty acid) microbial synthesis, absorption, and preventive roles against colorectal and lung cancer.

Butyrate, a short-chain fatty acid (SCFA) produced by bacterial fermentation of fiber in the colon, is a source of energy for colonocytes. Butyrate is essential for improving gastrointestinal (GI) health since it helps colonocyte function, reduces inflammation, preserves the gut barrier, and fosters a balanced microbiome. Human colonic butyrate producers are Gram-positive firmicutes, which are phylogenetically varied. The two most prevalent subgroups are associated with Eubacterium rectale/Roseburia spp. and Faecalibacterium prausnitzii. Now, the mechanism for the production of butyrate from microbes is a very vital topic to know. In the present study, we discuss the genes encoding the core of the butyrate synthesis pathway and also discuss the butyryl-CoA:acetate CoA-transferase, instead of butyrate kinase, which usually appears to be the enzyme that completes the process. Recently, butyrate-producing microbes have been genetically modified by researchers to increase butyrate synthesis from microbes. The activity of butyrate as a histone deacetylase inhibitor (HDACi) has led to several clinical trials to assess its effectiveness as a potential cancer treatment. Among various significant roles, butyrate is the main energy source for intestinal epithelial cells, which helps maintain colonic homeostasis. Moreover, people with non-small-cell lung cancer (NSCLC) have distinct gut microbiota from healthy adults and frequently have dysbiosis of the butyrate-producing bacteria in their guts. So, with an emphasis on colon and lung cancer, this review also discusses how the microbiome is crucial in preventing the progression of certain cancers through butyrate production. Further studies should be performed to investigate the underlying mechanisms of how these specific butyrate-producing bacteria can control both colon and lung cancer progression and prognosis.

The preventative effects of statin on lung cancer development in patients with idiopathic pulmonary fibrosis using the National Health Insurance Service Database in Korea.

Little is known about the effect of statin use in lung cancer development in idiopathic pulmonary fibrosis (IPF). We analyzed the database of the National Health Insurance Service to further investigate the clinical impacts of statin on lung cancer development and overall survival (OS) in IPF patients. The analysis included 9,182 individuals diagnosed with IPF, of which 3,372 (36.7%) were statin users. Compared to statin non-users, the time from diagnosis of IPF to lung cancer development and OS were longer in statin users in IPF patients. In Cox proportional hazard regression models, higher statin compliance, statin use, and being female had an inverse association with lung cancer risk, while older age at diagnosis of IPF and smoking history were associated with higher risk of lung cancer in IPF patients. For OS, statin use, female sex, higher physical activity frequency, and diabetes were associated with longer survival. In contrast, older age at diagnosis of IPF and smoking history were associated with shorter OS in IPF patients. These data from a large population indicate that statin had an independent protective association with lung cancer development and mortality in IPF patients.

Simultaneous Visualization and Depletion of Peroxynitrite by a Simple Aggregation-Induced Emission Nanoprobe for Preventing Breast Cancer Metastasis after Surgery.

Inflammation has been confirmed to be closely related to the development of tumors, while peroxynitrite (ONOO-) is one of the most powerful oxidative pro-inflammatory factors. Although ONOO- can kill bacteria through oxidation, it will activate matrix metalloproteinases (MMPs), accelerate the degradation of the extracellular matrix (ECM), and subsequently lead to the activation and release of other tumor promotion factors existing in the ECM, promoting tumor metastasis and invasion. Herein, we report a simple aggregation-induced emission (AIE) nanoprobe (NP), TPE-4NMB, that can simultaneously visualize and deplete ONOO-. The probe can light up the endogenous and exogenous ONOO- in cells and selectively inhibit the proliferation and migration of 4T1 cells by inducing an intracellular redox homeostasis imbalance through ONOO- depletion. After being modified with DSPE-PEG2000, the TPE-4NMB NPs can be used to image ONOO- induced by various models in vivo; especially, it can monitor the dynamic changes of ONOO- level in the residual tumor after surgery, which can provide evidence for clarifying the association between surgery, ONOO-, and cancer metastasis. Excitingly, inhibited tumor volume growth and decreased counts of lung metastases were observed in the TPE-4NMB NPs group, which can be attributed to the downregulated expression of MMP-9 and transforming growth factor-ß (TGF-ß), increased cell apoptosis, and inhibited epithelial-mesenchymal transition (EMT) mediated by ONOO-. The results will provide new evidence for clarifying the relationship between surgery, ONOO-, and tumor metastasis and serve as a new intervention strategy for preventing tumor metastasis after tumor resection.

Impact of smoking reduction on lung cancer risk in patients with COPD who smoked fewer than 30 pack-years: a nationwide population-based cohort study.

BACKGROUND: The effects of smoking reduction on the incidence of lung cancer in patients with chronic obstructive pulmonary disease (COPD) are not well known. This study aimed to investigate the effects of changes in smoking habits after COPD diagnosis on lung cancer development in patients who smoked less than 30 pack-years. METHODS: This nationwide retrospective cohort study included 16,832 patients with COPD who smoked less than 30 pack-years at the time of COPD diagnosis. Based on changes in smoking habits in the health screening examination data, smokers were categorized into three groups: quitters, reducers, and sustainers. The primary outcome was the risk of lung cancer development, which was estimated using the Cox proportional hazards model. We also modelled the amount of smoking reduction as a continuous variable. RESULTS: During a median follow-up of 4 years, the cumulative incidence of lung cancer was the highest among sustainers, followed by reducers and quitters. Compared with sustainers, reducers (adjusted HR 0.74, 95% CI:0.56-0.98) and quitters (adjusted HR 0.78, 95% CI:0.64-0.96) had a significantly lower risk of lung cancer. Incidence of lung cancer showed a decreasing trend with a decreasing amount of smoking (P for linearity < 0.01). CONCLUSIONS: In patients with COPD who smoked less than 30 pack-years, smoking reduction and cessation lowered the risk of lung cancer.

A ketogenic diet rich in fish oil is superior to other fats in preventing NNK-induced lung cancer in A/J mice.

Given that ketogenic diets (KDs) are extremely high in dietary fat, we compared different fats in KDs to determine which was the best for cancer prevention. Specifically, we compared a Western and a 15% carbohydrate diet to seven different KDs, containing either Western fats or fats enriched in medium chain fatty acids (MCTs), milk fat (MF), palm oil (PO), olive oil (OO), corn oil (CO) or fish oil (FO) for their ability to reduce nicotine-derived nitrosamine ketone (NNK)-induced lung cancer in mice. While all the KDs tested were more effective at reducing lung nodules than the Western or 15% carbohydrate diet, the FO-KD was most effective at reducing lung nodules. Correlating with this, mice on the FO-KD had low blood glucose and the highest ß-hydroxybutyrate level, lowest liver fatty acid synthase/carnitine palmitoyl-1a ratio and a dramatic increase in fecal Akkermansia. We found no liver damage induced by the FO-KD, while the ratio of total cholesterol/HDL was unchanged on the different diets. We conclude that a FO-KD is superior to KDs enriched in other fats in reducing NNK-induced lung cancer, perhaps by being the most effective at skewing whole-body metabolism from a dependence on glucose to fats as an energy source.

Cancer Risk Following Smoking Cessation in Korea.

Importance: Tobacco smoking is associated with increased risk of various cancers, and smoking cessation has been associated with reduced cancer risks, but it is still unclear how many years of smoking cessation are required to significantly reduce the cancer risk. Therefore, investigating the association of smoking cessation with cancer is essential. Objective: To investigate the time course of cancer risk according to the time elapsed since smoking cessation and the benefits of smoking cessation according to the age at quitting. Design, Setting, and Participants: This population-based, retrospective cohort study included Korean participants aged 30 years and older who underwent 2 or more consecutive health examinations under the National Health Insurance Service since 2002 and were followed-up until 2019. Data analysis was performed from April to September 2023. Exposures: Exposures included (1) time-updated smoking status based on biennial changes in smoking status, defined as complete quitters, transient quitters, relapsed quitters, continuous smokers, and never smokers; (2) duration of smoking cessation, defined as years since quitting; and (3) categorical variable for age at quitting. Main Outcomes and Measures: The primary cancer was ascertained using the cancer registry data: all-site cancer (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] codes C00-43, C45-96, or D45-D47), lung cancer (ICD-10 code C34), liver cancer (ICD-10 code C22), stomach cancer (ICD-10 code C16), and colorectal cancer (ICD-10 codes C18-20). Hazard ratios (HRs) and 95% CIs were estimated using a Cox proportional hazards regression model with follow-up years as the timescale. Results: Of the 2 974 820 participants, 1 727 340 (58.1%) were men (mean [SD] age, 43.1 [10.0] years), and 1 247 480 (41.9%) were women (mean [SD] age, 48.5 [9.9] years). Over a mean (SD) follow-up of 13.4 (0.1) years, 196 829 cancer cases were confirmed. Compared with continuous smokers, complete quitters had a lower risk of cancer, with HRs of 0.83 (95% CI, 0.80-0.86) for all cancer sites, 0.58 (95% CI, 0.53-0.62) for lung, 0.73 (95% CI, 0.64-0.82) for liver, 0.86 (95% CI, 0.79-0.93) for stomach, and 0.80 (95% CI, 0.72-0.89) for colorectum. The cancer risk exhibited a slightly higher value for 10 years after quitting compared with continued smoking and then it decreased over time, reaching 50% of the risk associated with continued smoking after 15 or more years. Lung cancer risk decreased 3 years earlier than that of other cancer types, with a larger relative reduction. Regardless of quitting age, a significant reduction in the cancer risk was observed. Quitting before the age of 50 years was associated with a greater reduction in lung cancer risk (HR, 0.43; 95% CI, 0.35-0.53) compared with quitting at age 50 years or later (HR, 0.61; 95% CI, 0.56-0.66). Conclusions and Relevance: In this population-based retrospective cohort study, sustained smoking cessation was associated with significantly reduced risk of cancer after 10 years since quitting. Quitting at any age helped reduce the cancer risk, and especially for lung cancer, early cessation before middle age exhibited a substantial risk reduction.

Study rationale and design of the PEOPLHE trial.

PURPOSE: Lung cancer screening (LCS) by low-dose computed tomography (LDCT) demonstrated a 20-40% reduction in lung cancer mortality. National stakeholders and international scientific societies are increasingly endorsing LCS programs, but translating their benefits into practice is rather challenging. The "Model for Optimized Implementation of Early Lung Cancer Detection: Prospective Evaluation Of Preventive Lung HEalth" (PEOPLHE) is an Italian multicentric LCS program aiming at testing LCS feasibility and implementation within the national healthcare system. PEOPLHE is intended to assess (i) strategies to optimize LCS workflow, (ii) radiological quality assurance, and (iii) the need for dedicated resources, including smoking cessation facilities. METHODS: PEOPLHE aims to recruit 1.500 high-risk individuals across three tertiary general hospitals in three different Italian regions that provide comprehensive services to large populations to explore geographic, demographic, and socioeconomic diversities. Screening by LDCT will target current or former (quitting < 10 years) smokers (> 15 cigarettes/day for > 25 years, or > 10 cigarettes/day for > 30 years) aged 50-75 years. Lung nodules will be volumetric measured and classified by a modified PEOPLHE Lung-RADS 1.1 system. Current smokers will be offered smoking cessation support. CONCLUSION: The PEOPLHE program will provide information on strategies for screening enrollment and smoking cessation interventions; administrative, organizational, and radiological needs for performing a state-of-the-art LCS; collateral and incidental findings (both pulmonary and extrapulmonary), contributing to the LCS implementation within national healthcare systems.

Genetic overlap and causal inferences between diet-derived antioxidants and small-cell lung cancer.

Several studies have reported that antioxidants exert both preventive and inhibitory effects against tumors. However, their causal effects on small-cell lung cancer (SCLC) remain controversial. Herein, we explored the causal effects of 6 antioxidants on SCLC by combining a genome-wide association study database and the Mendelian randomization (MR) approach. We obtained antioxidant genetic variance data for 6 exposure factors: carotene, vitamin A (retinol), selenium, zinc, vitamin C, and vitamin E, from the genome-wide association study database. The instrumental variables for exposure factors and SCLC outcomes were integrated by screening instrumental variables and merging data. Two-sample MR was used to analyze the causal relationship between exposure and outcomes. Finally, we examined the heterogeneity and horizontal pleiotropy of the MR analysis by performing multiple sensitivity analyses. We found a causal relationship between carotene and SCLC using two-sample MR analysis and sensitivity analysis (P = .02; odds ratio = 0.73; 95% confidence interval: 0.55-0.95). In contrast, there was no causal relationship between other examined antioxidants and SCLC. We found that diet-derived circulating antioxidants could afford protection against SCLC, and carotene is the causal protective factor against SCLC.

A novel intranasal peptide vaccine inhibits non-small cell lung cancer with KRAS mutation.

KRAS mutations occur commonly in the lung and can lead to the development of non-small cell lung cancer (NSCLC). While the mutated KRAS protein is a neoantigen, it usually does not generate an effective anti-tumor immune response on mucosal/epithelial surfaces. Despite this, mutated KRAS remains a potential target for immunotherapy since immune targeting of this protein in animal models has been effective at eliminating tumor cells. We attempted to develop a KRAS vaccine using mutated and wild-type KRAS peptides in combination with a nanoemulsion (NE) adjuvant. The efficacy of this approach was tested in an inducible mutant KRAS-mouse lung tumor model. Animals were immunized intranasally using NE with KRAS peptides. These animals had decreased CD4+FoxP3+ T cells in both lymph nodes and spleen. Immunized animals also showed higher IFN-γ and IL-17a levels to mutated KRAS that were produced by CD8+ T cells and enhancement in KRAS-specific Th1 and Th17 responses that persisted for 3 months after the last vaccination. Importantly, the immunized animals had significantly decreased tumor incidence compared to control animals. In conclusion, a mucosal approach to KRAS vaccination demonstrated the ability to induce local KRAS-specific immune responses in the lung and resulted in reduced tumor incidence.

Blocking tumor-platelet crosstalk to prevent tumor metastasis via reprograming glycolysis using biomimetic membrane-hybridized liposomes.

Activated platelets promote tumor progression and metastasis through active interactions with cancer cells, especially in promoting epithelial-mesenchymal transition (EMT) of tumor cells and shedding tumor cells into the blood. Blocking platelet-tumor cell interactions can be a potential strategy to inhibit tumor metastasis. Platelet activation requires energy produced from aerobic glycolysis. Based on this, we propose a platelet suppression strategy by reprogramming glucose metabolism of platelets, which has an advantage over conventional antiplatelet treatment that has a risk of serious hemorrhage. We develop a biomimetic delivery system using platelet membrane-hybridized liposomes (PM-Lipo) for codelivery of quercetin and shikonin to simultaneously inhibit lactate transporter MCT-4 and a glycolytic enzyme PKM2 for achieving metabolic reprogramming of platelets and suppressing platelet activation. Notably, PM-Lipo can also inhibit glycolysis in cancer cells, which actually takes "two-birds-one-stone" action. Consequently, the platelet-tumor cell interactions are inhibited. Moreover, PM-Lipo can bind with circulating tumor cells and reduce their seeding in the premetastatic microenvironment. The in vivo studies further demonstrated that PM-Lipo can effectively suppress primary tumor growth and reduce lung metastasis without affecting inherited functions of platelets. Reprogramming glycolysis of platelets can remodel the tumor immune microenvironment, including suppression of Treg and stimulation of CTLs.

Lung Cancer Screening in Head and Neck Cancer Patients: An Untapped Opportunity.

BACKGROUND: Despite evidence demonstrating that lung cancer screening (LCS) decreases mortality, widespread implementation is lagging. Efforts to identify and recruit patients for LCS are in need. Candidacy for LCS is based on identifiable risk factors, many of which overlap with those of head and neck malignancies. Thus, we aimed to evaluate the prevalence of candidacy for LCS in the head and neck cancer patient population. METHODS: We performed a review of anonymous surveys collected from patients who presented to a head and neck cancer clinic. Variables collected from these surveys included age, biologic sex, smoking history, and head and neck cancer history. Patients' candidacy for screening was determined, and descriptive analyses were performed. RESULTS: A total of 321 patient surveys were reviewed. Mean age was 63.7 years, and 195 (60.7%) were men. In this sample, 19 (5.91%) were current smokers, and 112 (34.9%) were former smokers, having quit an average of 19.4 years prior to completing the survey. Average pack-years was 29.3. Of the 321 patients surveyed, 60 (18.7%) would qualify for LCS using current guidelines. However, among those 60 patients who qualified for LCS, only 15 (25%) patients had been offered screening and only 14 (23.3%) had been screened. CONCLUSIONS: We have importantly demonstrated both a substantial prevalence of candidacy for LCS in the head and neck cancer population as well as disappointingly low levels of screening utilization in this group of patients. We have identified this setting as a key patient population that ought to be targeted for information about and access to LCS.

6-Shogaol prevents benzo (A) pyrene-exposed lung carcinogenesis via modulating PRDX1-associated oxidative stress, inflammation, and proliferation in mouse models.

In this study, we have investigated the chemopreventive role of 6-shogaol (6-SGL) on benzopyrene (BaP) exposed lung carcinogenesis by modulating PRDX1-associated oxidative stress, inflammation, and proliferation in Swiss albino mouse models. Mice were exposed to BaP (50 mg/kg b.wt) orally twice a week for four consecutive weeks and maintained for 16 weeks, respectively. 6-SGL (30 mg/kg b.wt) were orally administered to mouse 1 h before BaP exposure for 16 weeks. After the experiment's termination, 6-SGL (30 mg/kg b.wt) prevented the loss in body weight, increased lung weight, and the total number of tumors in the mice. Moreover, we observed that 6-SGL treatment reverted the activity of BaP-induced lipid peroxidation and antioxidants in mice. Also, 6-SGL impeded the phosphorylation of MAPK family proteins such as Erk1, p38, and Jnk1 in BaP-exposed mice. PRDX1 is an essential antioxidant protein that scavenges toxic radicals and enhances several antioxidant proteins. Overexpression of PRDX1 substantially inhibits MAPKs, proliferation, and inflammation signaling axis. Hence, PRDX1 is thought to be a novel targeting protein for preventing BaP-induced lung cancer. In this study, we have obtained the 6-SGL treatment in a mouse model that reverted BaP-induced depletion of PRDX1 expression. Moreover, pretreatment of 6-SGL (30 mg/kg b.wt) significantly inhibited enhanced proinflammatory cytokines (TNF-α, IL-6, IL-ß1, IL-10) and proliferative markers (Cyclin-D1, Cyclin-D2, and PCNA) in BaP-exposed mice. The histopathological studies also confirmed that 6-SGL effectively protected the cells with less damage. Thus, the study demonstrated that 6-SGL could be a potential phytochemical and act as a chemopreventive agent in BaP-induced lung cancer by enhancing PRDX1 expression.

Increasing Lung Cancer Screening for High-Risk Smokers in a Frontier Population.

Northern Plains American Indians (AIs) have some of the highest smoking and lung cancer mortality rates in the USA. They are a high-risk population in which many are eligible for low-dose computed tomography (LDCT) screening, but such screening is rarely used. This study investigated methods to increase LDCT utilization through both a provider and community intervention to lower lung cancer mortality rates. This study used the Precaution Adoption Model for provider and community interventions implemented in four study regions in western South Dakota. The goal was to increase LDCT screening for eligible participants. Intake surveys and LDCT screenings were compared at baseline and 6 months following the education programs for both interventions. A total of 131 providers participated in the provider intervention. At the 6-month follow-up survey, 31 (63%) referred at least one patient for LDCT (p < 0.05). Forty (32.3%) community participants reported their provider recommended an LDCT and of those, 30(75%) reported getting an LDCT (p < 0.05). A total of 2829 patient surveys were completed at the imaging sites and most (88%, n = 962) cited provider recommendation as their reason for obtaining an LDCT. Almost half (46%; n = 131) of the referring providers attended a provider education workshop, and 73% of the providers worked at a clinic that hosted at least one community education session. Over the study period, LDCT utilization increased from 640 to 1706, a 90.9% increase. The provider intervention had the strongest impact on LDCT utilization. This study demonstrated increased LDCT utilization through the provider intervention but increases also were documented for the other intervention combinations. The community-based education program increased both community and provider awareness on the value of LDCTs to lower lung cancer mortality rates.