Baseline extracellular vesicle TGF-ß is a predictive biomarker for response to immune checkpoint inhibitors and survival in non-small cell lung cancer.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) are an effective therapeutic strategy, improving the survival of patients with lung cancer compared with conventional treatments. However, novel predictive biomarkers are needed to stratify which patients derive clinical benefit because the currently used and highly heterogenic histological PD-L1 has shown low accuracy. Liquid biopsy is the analysis of biomarkers in body fluids and represents a minimally invasive tool that can be used to monitor tumor evolution and treatment effects, potentially reducing biases associated with tumor heterogeneity associated with tissue biopsies. In this context, cytokines, such as transforming growth factor-ß (TGF-ß), can be found free in circulation in the blood and packaged into extracellular vesicles (EVs), which have a specific delivery tropism and can affect in tumor/immune system interaction. TGF-ß is an immunosuppressive cytokine that plays a crucial role in tumor immune escape, treatment resistance, and metastasis. Thus, we aimed to evaluate the predictive value of circulating and EV TGF-ß in patients with non-small-cell lung cancer receiving ICIs. METHODS: Plasma samples were collected in 33 patients with advanced non-small-cell lung cancer before and during treatment with ICIs. EV were isolated from plasma by serial ultracentrifugation methods and circulating and EV TGF-ß expression levels were evaluated by enzyme-linked immunosorbent assay. RESULTS: Baseline high expression of TGF-ß in EVs was associated with nonresponse to ICIs as well as shorter progression-free survival and overall survival, outperforming circulating TGF-ß levels and tissue PD-L1 as a predictive biomarker. CONCLUSION: If validated, EV TGF-ß could be used to improve patient stratification, increasing the effectiveness of treatment with ICIs and potentially informing combinatory treatments with TGF-ß blockade. PLAIN LANGUAGE SUMMARY: Treatment with immune-checkpoint inhibitors (ICIs) has improved the survival of some patients with lung cancer. However, the majority of patients do not benefit from this treatment, making it essential to develop more reliable biomarkers to identify patients most likely to benefit. In this pilot study, the expression of transforming growth factor-ß (TGF-ß) in blood circulation and in extracellular vesicles was analyzed. The levels of extracellular vesicle TGF-ß before treatment were able to determine which patients would benefit from treatment with ICIs and have a longer survival with higher accuracy than circulating TGF-ß and tissue PD-L1, which is the currently used biomarker in clinical practice.

Association of cardiac calcium burden with overall survival after radiotherapy for non-small cell lung cancer.

Background and purpose: Coronary calcifications are associated with coronary artery disease in patients undergoing radiotherapy (RT) for non-small cell lung cancer (NSCLC). We quantified calcifications in the coronary arteries and aorta and investigated their relationship with overall survival (OS) in patients treated with definitive RT (Def-RT) or post-operative RT (PORT). Materials and methods: We analyzed 263 NSCLC patients treated from 2004 to 2017. Calcium burden was ascertained with a Hounsfield unit (HU) cutoff of > 130 in addition to a deep learning (DL) plaque estimator. The HU cutoff volumes were defined for coronary arteries (PlaqueCoro) and coronary arteries and aorta combined (PlaqueCoro+Ao), while the DL estimator ranged from 0 (no plaque) to 3 (high plaque). Patient and treatment characteristics were explored for association with OS. Results: The median PlaqueCoro and PlaqueCoro+Ao was 0.75 cm3 and 0.87 cm3 in the Def-RT group and 0.03 cm3 and 0.52 cm3 in the PORT group. The median DL estimator was 2 in both cohorts. In Def-RT, large PlaqueCoro (HR:1.11 (95%CI:1.04-1.19); p = 0.008), and PlaqueCoro+Ao (HR:1.06 (95%CI:1.02-1.11); p = 0.03), and poor Karnofsky Performance Status (HR: 0.97 (95%CI: 0.94-0.99); p = 0.03) were associated with worse OS. No relationship was identified between the plaque volumes and OS in PORT, or between the DL plaque estimator and OS in either Def-RT or PORT. Conclusions: Coronary artery calcification assessed from RT planning CT scans was significantly associated with OS in patients who underwent Def-RT for NSCLC. This HU thresholding method can be straightforwardly implemented such that the role of calcifications can be further explored.

Emerging noncoding RNAs contained in extracellular vesicles: rising stars as biomarkers in lung cancer liquid biopsy.

Lung cancer has a high morbidity and mortality rate, and affected patients have a poor prognosis and low survival. The therapeutic approaches for lung cancer treatment, including surgery, radiotherapy, and chemotherapy, are not completely effective, due to late diagnosis. Although the identification of genetic drivers has contributed to the improvement of lung cancer clinical management, the discovery of new diagnostic and prognostic tools remains a critical issue. Liquid biopsy (LB) represents a minimally invasive approach and practical alternative source to investigate tumor-derived alterations and to facilitate the selection of targeted therapies. LB allows for the testing of different analytes such as circulating tumor cells, extracellular vesicles (EVs), tumor-educated platelets, and cell-free nucleic acids including DNAs, RNAs, and noncoding RNAs (ncRNAs). Several regulatory factors control the key cellular oncogenic pathways involved in cancers. ncRNAs have a wide range of regulatory effects in lung cancers. This review focuses on emerging regulatory ncRNAs, freely circulating in body fluids or shuttled by EVs, such as circular-RNAs, small nucleolar-RNAs, small nuclear-RNAs, and piwi-RNAs, as new biomarkers for early detection, prognosis, and monitoring of therapeutic strategy of lung cancer treatment.

A trinuclear Fe-Fe-Ni complex formed by ligand reshuffling.

The title complex, dicarbonyl-3κ(2)C-(µ(3)-3,6-dimethyl-3,6-diaza-octane-1,8-dithiol-ato-1:2:3κ(7)S:S,N,N',S':S,S')(µ(2)-3,6-di-methyl-3,6-diaza-octane-1,8-dithiol-ato-1:2κ(5)S,N,N',S':S)-1,2-diiron(II)-3-nickel(0) [Fe(2)Ni(C(8)H(18)N(2)S(2))(2)(CO)(2)], is the second example showing M(µ-SR)(2)Ni(0)(CO)(2) coordination (M = any metal atom). Both Fe(II) ions are five-coordinated in distorted trigonal-bipyramidal geometries by two N atoms and three S atoms. The Ni atom is four-coordinated in a distorted tetra-hedral geometry by two S atoms and two carbonyl ligands. One of the 3,6-dimethyl-3,6-diaza-octane-1,8-dithiol-ate ligands is disordered, the major component having a refined occupancy of 0.873 (2). The Fe⋯Fe distance is 3.0945 (3)Å and the Ni⋯Fe distance is 2.8505 (3) Å.

Relation of Body Mass Index to Development of Atrial Fibrillation in Hispanics, Blacks, and Non-Hispanic Whites.

No previous studies have examined the interaction between body mass index (BMI) and race/ethnicity with the risk of atrial fibrillation (AF). We retrospectively followed 48,323 persons free of AF (43% Hispanic, 37% black, and 20% white; median age 60 years) for subsequent incident AF (ascertained from electrocardiograms). BMI categories included very severely underweight (BMI <15 kg/m2), severely underweight (BMI 15.1 to 15.9 kg/m2), underweight (BMI 16 to 18.4 kg/m2), normal (BMI 18.5 to 24.9 kg/m2), overweight (BMI 25.0 to 29.9 kg/m2), moderately obese (BMI 30 to 34.9 kg/m2), severely obese (BMI 35 to 39.9 kg/m2), and very severely obese (BMI >40 kg/m2). Cox regression analysis controlled for baseline covariates: heart failure, gender, age, treatment for hypertension, diabetes, PR length, systolic blood pressure, left ventricular hypertrophy, socioeconomic status, use of ß blockers, calcium channel blockers, and digoxin. Over a follow-up of 13 years, 4,744 AF cases occurred. BMI in units of 10 was associated with the development of AF (adjusted hazard ratio 1.088, 95% confidence interval 1.048 to 1.130, p <0.01). When stratified by race/ethnicity, non-Hispanic whites compared with blacks and Hispanics had a higher risk of developing AF, noted in those whom BMI classes were overweight to severely obese. In conclusion, our study demonstrates that there exists a relation between obesity and race/ethnicity for the development of AF. Non-Hispanic whites had a higher risk of developing AF compared with blacks and Hispanics.

Histologic findings of femoral heads from patients with Gaucher disease treated with enzyme replacement.

OBJECTIVES: To assess correlations of patient demographics, including enzyme replacement therapy (ERT) with bone histology, to facilitate decisions of whether and when to perform hip replacement surgery in patients with Gaucher disease. METHODS: We examined the histology of surgically removed femoral heads and categorized findings by the presence or extent of osteonecrosis, Gaucher cell (GC) infiltration, and bone regeneration qualifiers using a tripartite histology-based scoring system. RESULTS: Twenty-two patients with 26 bone specimens were evaluated. Seventeen patients (77%) were splenectomized, 16 (73%) received ERT, and 12 (55%) had the putatively milder genotype (N370S/N370S), with the rest putatively at increased risk for skeletal disease (N370S/other). The 3 histology subscores were applicable to all specimens. Osteonecrotic bone was seen in 19 of 26 (73%); osteoarthritis was seen in all cartilage specimens. Gaucher cell infiltration was not correlated with demographics or disease severity. A trend was noted between reduced GC infiltration and ERT (ρ = 0.407), but regeneration qualifiers were not correlated with ERT or other features. CONCLUSIONS: Histologic findings of GC infiltration and bone regeneration qualifiers did not correlate with demographics or with exposure to ERT. Most specimens unexpectedly showed good regenerative responses to osteonecrosis despite heavy GC infiltration.

Alleviation of gut inflammation by Cdx2/Pxr pathway in a mouse model of chemical colitis.

Pregnane X Receptor (PXR), a master regulator of drug metabolism and inflammation, is abundantly expressed in the gastrointestinal tract. Baicalein and its O-glucuronide baicalin are potent anti-inflammatory and anti-cancer herbal flavonoids that undergo a complex cycle of interconversion in the liver and gut. We sought to investigate the role these flavonoids play in inhibiting gut inflammation by an axis involving PXR and other potential factors. The consequences of PXR regulation and activation by the herbal flavonoids, baicalein and baicalin were evaluated in vitro in human colon carcinoma cells and in vivo using wild-type, Pxr-null, and humanized (hPXR) PXR mice. Baicalein, but not its glucuronidated metabolite baicalin, activates PXR in a Cdx2-dependent manner in vitro, in human colon carcinoma LS174T cells, and in the murine colon in vivo. While both flavonoids abrogate dextran sodium sulfate (DSS)-mediated colon inflammation in vivo, oral delivery of a potent bacterial ß-glucuronidase inhibitor eliminates baicalin's effect on gastrointestinal inflammation by preventing the microbial conversion of baicalin to baicalien. Finally, reduction of gastrointestinal inflammation requires the binding of Cdx2 to a specific proximal site on the PXR promoter. Pharmacological targeting of intestinal PXR using natural metabolically labile ligands could serve as effective and potent therapeutics for gut inflammation that avert systemic drug interactions.