Lung cancer is strongly associated with malnutrition and detrimental changes in muscle mass (MM), which can lead to reduced quality of life and reduced tolerance to and efficacy of antineoplastic treatment. The loss of MM and myosteatosis (fat infiltration into muscle) have been linked to inflammation in cancer, and n-3 polyunsaturated fatty acids (PUFA) found in fish oil are known to modulate inflammatory response, lean mass, microbiota, and epigenetic mechanisms.

Colorectal cancer (CRC) with hepatic metastasis is associated with poor prognosis. Stereotactic body radiotherapy (SBRT) can provide local control for unresectable hepatic metastases of patients with CRC. However, the mechanisms of responsiveness to SBRT in metastatic CRC (mCRC) remain unclear. We aimed to identify a strategy to enhance the efficacy of SBRT in patients with CRC liver metastases and its mechanisms. Transcriptomic sequencing of CRC cells exposed to SBRT revealed that SBRT inhibited SLC7A11 expression. Downregulation of SLC7A11 enhanced the sensitivity of CRC cells to SBRT via ferroptosis. SBRT diminished the ability of tumor cells to sustain oxidative stress by impeding the phosphorylation of JNK and c-Jun and the transcription of NRF2. Furthermore, sorafenib, which targets SLC7A11, exerted inhibitory effects on tumor growth when used in combination with SBRT. A phase II clinical trial confirmed that sorafenib combined with SBRT overcame the resistance of liver mCRC with high SLC7A11 expression by inducing ferroptosis. The combination of SBRT and sorafenib demonstrated favorable clinical effects and safety, making it a good option for patients with CRC liver metastasis. STATEMENT OF SIGNIFICANCE: A novel strategy using the combination of SBRT and sorafenib for the treatment of patients with CRC hepatic metastasis was investigated. This strategy overcomes the radiation therapy resistance of mCRC by inhibiting SLC7A11 expression and promoting ferroptosis.

Metformin reduces the incidence of breast cancer in patients with obesity and type 2 diabetes. However, our knowledge of the effects of metformin on breast cancer recurrence is limited. Within the randomized double-blind placebo-controlled phase II trial MetBreCS, we examined changes in breast tissue from breast cancer survivors with BMI > 25 kg/m2 after treatment with metformin. To identify metformin-regulated signaling pathways, we integrated the transcriptomic, metabolomic and steroid hormone profiles using bivariate and functional analyses. We identified MS4A1, HBA2, MT-RNR1, MT-RNR2, EGFL6 and FDCSP expression to be differentially expressed in breast tissues from metformin-treated postmenopausal women. The integration of transcriptomic and metabolomic profiles revealed down-regulation of immune response genes associated with reduced levels of arginine and citrulline in the metformin-treated group. The integration of transcriptomic and steroid hormone profiles showed an enrichment of steroid hormone biosynthesis and metabolism pathways with highly negatively correlated CYP11A1 and CYP1B1 expression in breast tissue from postmenopausal metformin-treated women. Our results indicate that postmenopausal breast cancer survivors treated with metformin have specific changes in breast tissue gene expression that may prevent the development of new tumors.Trial registration: MetBreCs trial is registered at European Union Clinical Trials Register (EudraCT Protocol # 2015-001001-14) on 07/10/2015.

Hypomethylating agents are frontline therapies for myelodysplastic neoplasms (MDS), yet clinical responses remain unpredictable. We conducted a phase 2 trial comparing injectable and oral azacitidine (AZA) administered over one or three weeks per four-week cycle, with the primary objective of investigating whether response is linked to in vivo drug incorporation or DNA hypomethylation. Our findings show that injection results in higher drug incorporation, but lower DNA demethylation per cycle, while global DNA methylation levels in mononuclear cells are comparable between responders and non-responders. However, hematopoietic stem and progenitor cells (HSPCs) from responders exhibit distinct baseline and early treatment-induced CpG methylation changes at regulatory regions linked to tissue patterning, cell migration, and myeloid differentiation. By cycle six-when clinical responses typically emerge-further differential hypomethylation in responder HSPCs suggests marrow adaptation as a driver of improved hematopoiesis. These findings indicate that intrinsic baseline and early drug-induced epigenetic differences in HSPCs may underlie the variable clinical response to AZA in MDS.

Cholangiocarcinoma (CCA) is one of the most aggressive cancers with a poor prognosis. Current treatment strategies involve hepatobiliary surgery, chemotherapy, radiotherapy, and supportive care; however, the success of these treatments remains limited. Therefore, this study investigated the potential of Atractylodes lancea (Thunb) D.C. (AL) in limiting the progress of CCA by targeting the expression of cancer-related genes involved in immune responses and circulating tumor cells. The study was part of Phase 2A clinical trial in advanced-stage intrahepatic iCCA (iCCA) patients: Group 1 (n = 16) received low-dose AL (capsule formulation of the standardized extract of AL: CMC-AL) with standard supportive care, Group 2 (n = 16) received high-dose AL with standard supportive care, and Group 3 (n = 16) received standard supportive care alone. Venous whole blood samples (EDTA, 5 ml) were collected from each patient on Day 1 and Day 90 and the non-CCA subjects (n = 16) on Day 1. Fifty-nine samples (48 and 11 samples for Day 1 and Day 90, respectively) were processed for total RNA isolation. Gene expression was evaluated using reverse transcription followed by a PCR array. Regardless of dosage, gene expression patterns in the AL-treated groups closely resembled those of the healthy subjects. Specifically, cancer-associated genes, including VEGF-A, NR4A3, Ki-67, and EpCAM, were significantly down-regulated. Additionally, the expression levels of immune-related genes were modulated in AL-treated patients. The treatment groups exhibited lower levels of the pro-inflammatory cytokine IL-6, increased expression of the anti-inflammatory cytokine IL-10, and cell-mediated immune-related molecules such as CTLA4 and PFR1. These findings suggest the potential of AL for iCCA treatment. However, additional studies are required to confirm the correlation between gene and protein expression profiles, as well as CTCs profile.

Coronavirus disease 2019 (COVID-19) has been associated with impaired endothelial and vascular function. We investigated whether intervention with glycocalyx dietary supplement (GDS), containing glucosamine sulfate and fucoidan, improves endothelial glycocalyx and vascular function after COVID-19 infection.

CDK4/6 inhibitors (CDK4/6i) combined with hormone therapies have demonstrated clinical benefit in HR+, HER2- breast cancer patients. However, the onset of resistance remains a concern and highlights a need for therapeutic strategies to improve outcomes. The objective of this study was to develop an in vitro model to better understand the mechanisms of resistance to CDK4/6i + hormone therapies and identify therapeutic strategies with potential to overcome this resistance.

Aging interventions have progressed in recent years due to the growing curiosity about how lifestyle impacts longevity. This study assessed the effects of SRW Laboratories' Cel System nutraceutical range on epigenetic methylation patterns, inflammation, physical performance, body composition, and epigenetic biomarkers of aging. A 1-year study was conducted with 51 individuals, collecting data at baseline, 3 months, 6 months, and 12 months. Participants were encouraged to walk 10 minutes and practice 5 minutes of mindfulness daily. Significant improvements in muscle strength, body function, and body composition metrics were observed. Epigenetic clock analysis showed a decrease in biological age with significant reductions in stem cell division rates. Immune cell subset analysis indicated significant changes, with increases in eosinophils and CD8T cells and decreases in B memory, CD4T memory, and T-regulatory cells. Predicted epigenetic biomarker proxies (EBPs) showed significant changes in retinol/TTHY, a regulator of cell growth, proliferation, and differentiation, and deoxycholic acid glucuronide levels, a metabolite of deoxycholic acid generated in the liver. Gene ontology analysis revealed significant CpG methylation changes in genes involved in critical biological processes related to aging, such as oxidative stress-induced premature senescence, pyrimidine deoxyribonucleotide metabolic process, TRAIL binding, hyaluronan biosynthetic process, neurotransmitter loading into synaptic vesicles, pore complex assembly, collagen biosynthetic process, protein phosphatase 2A binding activity, and activation of transcription factor binding. Our findings suggest that the Cel System supplement range may effectively reduce biological age and improve health metrics, warranting further investigation into its mechanistic pathways and long-term efficacy.

BACKGROUNDImmune checkpoint blockade (ICB) is an effective treatment in a subset of patients diagnosed with head and neck squamous cell carcinoma (HNSCC); however, the majority of patients are refractory.METHODSIn a nonrandomized, open-label Phase 1b clinical trial, participants with recurrent and/or metastatic (R/M) HNSCC were treated with low-dose 5-azacytidine (5-aza) daily for either 5 or 10 days in combination with durvalumab and tremelimumab after progression on ICB. The primary objective was to assess the biologically effective dose of 5-aza as determined by molecular changes in paired baseline and on-treatment tumor biopsies; the secondary objective was safety.RESULTSThirty-eight percent (3 of 8) of participants with evaluable paired tissue samples had a greater-than 2-fold increase from baseline in IFN-γ signature and CD274 (programmed cell death protein 1 ligand, PD-L1) expression within the tumor microenvironment (TME), which was associated with increased CD8+ T cell infiltration and decreased infiltration of CD4+ T regulatory cells. The mean neutrophil-to-lymphocyte ratio (NLR) decreased by greater than 50%, from 14.2 (SD 22.6) to 6.9 (SD 5.2). Median overall survival (OS) was 16.3 months (95% CI 1.9, NA), 2-year OS rate was 24.7% (95% CI: 4.5%, 53.2%), and 58% (7 of 12) of treated participants demonstrated prolonged OS of greater than 12 months.CONCLUSIONOur findings suggest that low-dose 5-aza can reprogram systemic host immune responses and the local TME to increase IFN-γ and PD-L1 expression. The increased expression of these established biomarkers correlated with prolonged OS upon ICB rechallenge.TRIAL REGISTRATIONClinicalTrials.gov NCT03019003.FUNDINGNIH/NCI P01 CA240239.

Progesterone supplementation reverses 83% of transcript changes in the secretory endometrium induced by postovulatory mifepristone, potentially mitigating its antiprogestogenic effects.

CALGB 40903 (Alliance) was a phase II single arm multicenter trial conducted in postmenopausal patients diagnosed with estrogen-receptor (ER) positive breast ductal carcinoma in situ (DCIS) without invasion. Patients were treated with the aromatase inhibitor (AI) letrozole for 6 months prior to surgery with change in magnetic resonance imaging (MRI) enhancement volume compared to baseline as the primary endpoint. In the current study, we performed sequence analysis of pre- and post-treatment specimens to determine gene expression and DNA copy number parameters associated with treatment and response.

Protein carbonyl (PC) content, a stable marker of oxidative stress, is increased in chronic obstructive pulmonary disease (COPD) and shows association with cardiovascular events. We investigated prothrombotic effects of increased PC content and its modulation by statin use in COPD.

Osteoarthritis (OA) is among the most prevalent articular disorders, whose incidence is directly related to aging. Due to the antiinflammatory potential of curcumin as the active component of turmeric, the present study evaluated the effects of curcumin on the expression of genes related to T helper 17 (Th17), including forkhead box p3 (FOXP3), forkhead box o1 (FOXO1), transforming growth factor-β (TGFB1) and microRNA-873, human (HSA-MIR-873), in OA patients. Female patients with knee OA (n=30) were randomly categorized into 2 groups, including the intervention group who received curcumin (n=15) and the placebo (n=15) in a double-blind clinical trial for 3 months. The expression of FOXO1, FOXP3, TGFB1, and HSA-MIR-873 genes was evaluated by SYBR Green real-time reverse transcription polymerase chain reaction. In the curcumin group, FOXO1 gene expression was significantly increased, while the increase in FOXP3 gene expression was not significant. Moreover, the expression level of the HSA-MIR-873 gene showed a significant increase in the curcumin group. The modulatory effects of curcumin on Th17 function might be associated with the expression of FOXO1 and HSA-MIR-873 genes.

Therapy-induced molecular adaptation of triple-negative breast cancer is crucial for immunotherapy response and resistance. We analyze tumor biopsies from three different time points in the randomized neoadjuvant GeparNuevo trial (NCT02685059), evaluating the combination of durvalumab with chemotherapy, for longitudinal alterations of gene expression. Durvalumab induces an activation of immune and stromal gene expression as well as a reduction of proliferation-related gene expression. Immune genes are positive prognostic factors irrespective of treatment, while proliferation genes are positive prognostic factors only in the durvalumab arm. We identify stromal-related gene expression as a contributor to immunotherapy resistance and poor therapy response. The results provide evidence from clinical trial cohorts suggesting a role for stromal reorganization in therapy resistance to immunotherapy and in the generation of an immune-suppressive microenvironment, which might be relevant for future therapy approaches targeting the tumor stroma parallel to immunotherapy, such as combinations of immunotherapy with anti-angiogenic therapy.

Elevated numbers of atherogenic lipoproteins (apoB) predict the incidence of type 2 diabetes (T2D). We reported that this may be mediated via the activation of the NLRP3 inflammasome, as low-density lipoproteins (LDL) induce interleukin-1 beta (IL-1β) secretion from human white adipose tissue (WAT) and macrophages. However, mitigating nutritional approaches remained unknown. We tested whether omega-3 eicosapentaenoic and docosahexaenoic acids (EPA and DHA) treat LDL-induced upregulation of WAT IL-1β-secretion and its relation to T2D risk factors. Twelve-week intervention with EPA and DHA (2.7 g/day, Webber Naturals) abolished baseline group-differences in WAT IL-1β-secretion between subjects with high-apoB (N = 17) and low-apoB (N = 16) separated around median plasma apoB. Post-intervention LDL failed to trigger IL-1β-secretion and inhibited it in lipopolysaccharide-stimulated WAT. Omega-3 supplementation also improved β-cell function and postprandial fat metabolism in association with higher blood EPA and mostly DHA. It also blunted the association of WAT NLRP3 and IL1B expression and IL-1β-secretion with multiple cardiometabolic risk factors including adiposity. Ex vivo, EPA and DHA inhibited WAT IL-1β-secretion in a dose-dependent manner. In conclusion, EPA and DHA treat LDL-induced upregulation of WAT NLRP3 inflammasome/IL-1β pathway and related T2D risk factors. This may aid in the prevention of T2D and related morbidities in subjects with high-apoB.Clinical Trail Registration ClinicalTrials.gov (NCT04496154): Omega-3 to Reduce Diabetes Risk in Subjects with High Number of Particles That Carry "Bad Cholesterol" in the Blood - Full Text View - ClinicalTrials.gov.

Maternal smoking during pregnancy (MSDP), driven by nicotine crossing the placenta, causes lifelong decreases in offspring pulmonary function and vitamin C supplementation during pregnancy prevents some of those changes. We have also shown in animal models of prenatal nicotine exposure that vitamin C supplementation during pregnancy improves placental function. In this study we examined whether vitamin C supplementation mitigates the effects of MSDP on placental structure, function, and gene expression in pregnant human smokers. Doppler ultrasound was performed in a subset of 55 pregnant smokers participating in the "Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function" (VCSIP) randomized clinical trial (NCT01723696) and in 33 pregnant nonsmokers. Doppler ultrasound measurements showed decreased umbilical vein Doppler velocity (Vmax) in placebo-treated smokers that was significantly improved in smokers randomized to vitamin C, restoring to levels comparable to nonsmokers. RNA-sequencing demonstrated that vitamin C supplementation to pregnant smokers was associated with changes in mRNA expression in genes highly relevant to vascular and cardiac development, suggesting a potential mechanism for vitamin C supplementation in pregnant smokers to improve some aspects of offspring health.

Recently, we showed that three months of resistance exercise significantly alters 18 canonical pathways related to chronic inflammation in PBMCs of older adults. In this exploratory sub-study, the aim is to explore whether resistance exercise enhances the PBMCs stress response by mimicking an acute infection through in vitro LPS stimulation. Women (≥65 years) were randomly divided into intensive strength training (IST), strength endurance training (SET), or flexibility training (as control group, CON) groups. PBMCs were isolated and cultured with and without LPS for 24 h. Their RNA was analyzed via targeted RNA sequencing of 407 inflammation-related genes, with relevant fold-changes defined as ≤0.67 or ≥1.5 (3 months vs. baseline). A pathway analysis using ingenuity pathway analyses identified significant pathways among 407 genes with p < 0.05 and z-scores of ≤-2 or ≥2. Fourteen women were included in the analyses. A total of 151 genes with a significant fold-change were identified. In the CON group, a less-pronounced effect was observed. Strength training altered 23 pathways in the LPS-stimulated PBMCs, none of which overlapped between the IST and SET groups. A balanced exercise program that includes both IST and SET could beneficially adapt the immune responses in older adults by inducing alterations in the inflammatory stress response of PBMCs through different genes and pathways.

Periodontal disease results in oral dysbiosis, increasing plaque virulence and oxidative stress. Stannous fluoride (SnF2) binds lipopolysaccharides to reduce plaque virulence. This study prospectively assessed SnF2 effects on oxidative stress in adults with gingivitis.

PTC518 is an orally administered, centrally and peripherally distributed huntingtin (HTT) pre-mRNA splicing modifier being developed for the treatment of Huntington's disease (HD) for which there is a high unmet medical need as there are currently no approved disease-modifying treatments. This first-in-human study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PTC518 in healthy volunteers.

Beta glucans are found in many natural sources, however, only Baker's Yeast Beta Glucan (BYBG) has been well documented to have structure-function effects that are associated with improved innate immune response to stressors (e.g., exercise, infection, etc.). The purpose was to identify a BYBG-associated mRNA expression pattern following exercise. Participants gave IRB-approved consent and were randomized to BYBG (Wellmune®; N=9) or Placebo (maltodextrin; N=10) for 6-weeks prior to performing 90 min of whole-body exercise. Paxgene blood samples were collected prior to exercise (PRE), after exercise (POST), two hours after exercise (2H), and four hours after exercise (4H). Total RNA was isolated and analyzed for the expression of 770 innate immune response mRNA (730 mRNA targets; 40 housekeepers/controls; Nanostring nCounter). The raw data were normalized against housekeeping controls and expressed as Log2 fold change from PRE for a given condition. Significance was set at p < 0.05 with adjustments for multiple comparisons and false discovery rate. We identified 47 mRNA whose expression was changed after exercise with BYBG and classified them to four functional pathways: 1) Immune Cell Maturation (8 mRNA), 2) Immune Response and Function (5 mRNA), 3) Pattern Recognition Receptors and DAMP or PAMP Detection (25 mRNA), and 4) Detection and Resolution of Tissue Damage (9 mRNA). The identified mRNA whose expression was altered after exercise with BYBG may represent an innate immune response pattern and supports previous conclusions that BYBG improves immune response to a future sterile inflammation or infection.