Chidamide plus envafolimab as subsequent treatment in advanced non-small cell lung cancer patients resistant to anti-PD-1 therapy: A multicohort, open-label, phase II trial with biomarker analysis.

BACKGROUND: Combination of chidamide and anti-PD-L1 inhibitor produce synergistic anti-tumor effect in advanced NSCLC patients resistant to anti-PD-1 treatment. However, the effect of chidamide plus envafolimab has not been reported. AIMS: This study aimed to evaluate the efficacy of chidamide plus envafolimab in advanced NSCLC patients resistant toanti-PD-1 treatment. MATERIALS AND METHODS: Eligible advanced NSCLC patients after resistant to anti-PD-1 therapy received chidamide and envafolimab. The primary endpoint was objective response rate (ORR). The secondary end points included disease control rate (DCR), progression-free survival (PFS), and safety. The expression of histone deacetylase 2 (HDAC2), PD-L1, and blood TMB (bTMB) was also analyzed. RESULTS: After a median follow-up of 8.1 (range: 7.6-9.2) months, only two patients achieved partial response. The ORR was 6.7% (2/30), DCR was 50% (15/30), and median PFS (mPFS) was 3.5 (95% confidence interval: 1.9-5.5) months. Biomarker analysis revealed that patients with high-level HDAC2 expression had numerically superior ORR (4.3% vs. 0), DCR (52.2% vs. 0) and mPFS (3.7 vs. 1.4m). Patients with negative PD-L1 had numerically superior DCR (52.2% vs. 33.3%) and mPFS (3.7m vs. 1.8m), so were those with low-level bTMB (DCR: 59.1% vs. 16.7%, mPFS: 3.8 vs.1.9m). Overall safety was controllable. DISCUSSION: High HDAC2patients showed better ORR, DCR, and PFS. In addition, patient with negative PD-L1 and low-level bTMB had better DCR and PFS. This may be related to the epigenetic function of chidamide. However, the sample size was not big enough, so it is necessary to increase sample size to confirm the conclusion. CONCLUSION: Combination of chidamide and envafolimab showed efficacy signals in certain NSCLC patients. But further identification of beneficial population is necessary for precision treatment.

Development and internal validation of a nomogram based on peripheral blood inflammatory markers for predicting prognosis in nasopharyngeal carcinoma.

BACKGROUND: Inflammatory markers, including the product of neutrophil count, platelet count, and monocyte count divided by lymphocyte count (PIV) and the platelet-to-white blood cell ratio (PWR), have not been previously reported as prognostic factors in nasopharyngeal carcinoma (NPC) patients. In order to predict overall survival (OS) in NPC patients, our goal was to create and internally evaluate a nomogram based on inflammatory markers (PIV, PWR). METHODS: A retrospective study was done on patients who received an NPC diagnosis between January 2015 and December 2018. After identifying independent prognostic indicators linked to OS using Cox proportional hazards regression analysis, we created a nomogram with the factors we had chosen. RESULTS: A total of 630 NPC patients in all were split into training (n = 441) and validation sets (n = 189) after being enrolled in a population-based study in 2015-2018 and monitored for a median of 5.9 years. In the training set, the age, PIV, and PWR, selected as independent predictors for OS via multivariate Cox's regression model, were chosen to develop a nomogram. Both training and validation cohorts had C-indices of 0.850 (95% confidence interval [CI]: 0.768-0.849) and 0.851 (95% CI: 0.765-0.877). Furthermore, compared with traditional TNM staging, our nomogram demonstrated greater accuracy in predicting patient outcomes. The risk stratification model derived from our prediction model may facilitate personalized treatment strategies for NPC patients. CONCLUSION: Our findings confirmed the prognostic significance of the PWR and PIV in NPC. High PIV levels (>363.47) and low PWR (≤36.42) values are associated with worse OS in NPC patients.

Mitochondrial ATP generation is more proteome efficient than glycolysis.

Metabolic efficiency profoundly influences organismal fitness. Nonphotosynthetic organisms, from yeast to mammals, derive usable energy primarily through glycolysis and respiration. Although respiration is more energy efficient, some cells favor glycolysis even when oxygen is available (aerobic glycolysis, Warburg effect). A leading explanation is that glycolysis is more efficient in terms of ATP production per unit mass of protein (that is, faster). Through quantitative flux analysis and proteomics, we find, however, that mitochondrial respiration is actually more proteome efficient than aerobic glycolysis. This is shown across yeast strains, T cells, cancer cells, and tissues and tumors in vivo. Instead of aerobic glycolysis being valuable for fast ATP production, it correlates with high glycolytic protein expression, which promotes hypoxic growth. Aerobic glycolytic yeasts do not excel at aerobic growth but outgrow respiratory cells during oxygen limitation. We accordingly propose that aerobic glycolysis emerges from cells maintaining a proteome conducive to both aerobic and hypoxic growth.

One-carbon unit supplementation fuels tumor-infiltrating T cells and augments checkpoint blockade.

Nucleotides perform important metabolic functions, carrying energy and feeding nucleic acid synthesis. Here, we use isotope tracing-mass spectrometry to quantitate the contributions to purine nucleotides of salvage versus de novo synthesis. We further explore the impact of augmenting a key precursor for purine synthesis, one-carbon (1C) units. We show that tumors and tumor-infiltrating T cells (relative to splenic T cells) synthesize purines de novo. Purine synthesis requires two 1C units, which come from serine catabolism and circulating formate. Shortage of 1C units is a potential bottleneck for anti-tumor immunity. Elevating circulating formate drives its usage by tumor-infiltrating T cells. Orally administered methanol functions as a formate pro-drug, with deuteration enabling control of formate-production kinetics. In MC38 tumors, safe doses of methanol raise formate levels and augment anti-PD-1 checkpoint blockade, tripling durable regressions. Thus, 1C deficiency can gate antitumor immunity and this metabolic checkpoint can be overcome with pharmacological 1C supplementation.

Elevation and phylogeny shape herbaceous seed dormancy in a biodiversity hotspot of southwest China.

Seed dormancy contributes greatly to successful establishment and community stability and shows large variation over a continuous status scale in mountain ecosystems. Although empirical studies have shown that seed dormancy status (SDS) is shaped by elevation and phylogenetic history in mountain ecosystems, few studies have quantified their combined effects on SDS. Here, we collected mature seeds from 51 populations of 11 Impatiens species (Balsaminaceae) along an elevational gradient in the Gaoligong Mountains of southwest China and estimated SDS using mean dormancy percentage of fresh seeds germinated at three constant temperatures (15, 20, and 25°C). We downloaded 19 bioclimatic variables from WorldClim v.2.1 for each Impatiens population and used internal transcribed spacer (ITS), atpB-rbcL, and trnL-F molecular sequences from the GenBank nucleotide database to construct a phylogenetic tree of the 11 species of Impatiens. Logistic regression model analysis was performed to quantify the effects of phylogeny and environment on SDS. Results identified a significant phylogenetic SDS signal in the Impatiens species. Furthermore, elevation and phylogeny accounted for 63.629% of the total variation in SDS among the Impatiens populations. The best logistic model indicated that temperature was the main factor influencing variation in SDS among the Impatiens species, and model residuals were significantly correlated with phylogeny, but not with elevation. Our results indicated that seed dormancy is phylogenetically conserved, and climate drives elevational patterns of SDS variation in mountain ecosystems. This study provides new insights into the response of seed plant diversity to climate change.

Durable response of tislelizumab plus cisplatin, nab-paclitaxel followed by concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: A case report.

RATIONALE: Limited patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) have achieved complete response (CR) from induction chemotherapy (IC). Neoadjuvant immunotherapy combined with chemotherapy has marked therapeutic effects in some locoregionally advanced solid tumors. However, its efficacy and safety of NPC have not been reported so far. The rapid response of neoadjuvant tislelizumab combined with chemotherapy on LA-NPC may be associated with long-term survival benefit. PATIENT CONCERNS: A 57-year-old male patient presented with a 2-month history of bloody nasal discharge and right neck mass for 2 weeks. DIAGNOSIS: The patient was eventually diagnosed with nasopharyngeal nonkeratinizing undifferentiated cell carcinoma (stage IVA). INTERVENTIONS: The patient received tislelizumab combined with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) nab-paclitaxel plus cisplatin for 4 cycles, followed by cisplatin-based concurrent chemoradiotherapy (CCRT). OUTCOMES: A partial response (PR) was achieved after 2 cycles of tislelizumab and nab-paclitaxel plus cisplatin, and CR was achieved after 4 cycles of neoadjuvant treatment. The duration of response lasted 24 months, and the patient was still in CR as of November 2022. The patient had no serious adverse event (AEs) during the treatment. LESSONS: This case report showed that tislelizumab combined with cisplatin plus nab-paclitaxel followed CCRT for treatment of patients with LA-NPC may receive a fast and durable response with a manageable safety profile and long-term survival.

The U-shaped association between hospitalization time and fall incidence in inpatients using publicly available data: A cross-sectional study in Japan.

AIM: To examine the association between the hospitalization time and fall incidence. DESIGN: A secondary analysis using the Dryad Digital Repository public database. METHODS: Data were extracted from the Fukushima Medical University Hospital cohort study between August 2008 and September 2009. The final analytic sample included 8,598 participants, 156 of who fell. The risk of fall incidents according to hospitalization time was estimated using logistic proportional hazards models, and restricted cubic splines with four knots model were developed. RESULTS: The median hospitalization time was 9.00 (4.00, 17.00) days. The incidence of falls was 1.81% (N = 156). A U-shaped association between the hospitalization time and fall incidence, with an inflextion point of 8 days. We found a decreasing fall incidence as the hospitalization time increased from 0 to 8 days (OR 0.72 [0.62 ~ 0.83], p < .001); beyond 8 days, the fall incidence increased as the hospitalization time increased (OR 1.06 [1.04 ~ 1.09]).

Clinical Effect of Apatinib Mesylate Tablets Combined with Paclitaxel Concurrent Radiotherapy and Chemotherapy in the First-Line Treatment of Locally Advanced Nasopharyngeal Carcinoma.

Objective: To explore the clinical efficacy and safety of apatinib combined with paclitaxel in the first-line treatment of locally advanced nasopharyngeal carcinoma. Methods: From March 2016 to June 2018, 114 patients with locally advanced nasopharyngeal carcinoma who received first-line treatment in our hospital were selected as the patient group, and those who received apatinib combined with paclitaxel concurrent radiotherapy and chemotherapy were selected as the research group (n = 54), while those who received paclitaxel concurrent radiotherapy and chemotherapy were selected as the control group (n = 60). Sixty healthy individuals in our hospital were recruited in the same period as the healthy group. The clinical effective rate, adverse reactions, 2-year overall survival rate (OS), 2-year progression-free survival rate (PFS), and quality of life were compared between the two groups, and the expression of miR-655 in the serum of each group was tested by RT-qPCR. Results: The total clinical effective rate of the research group was higher than that of the control group, and the 2-year OS and PFS of the research group were also higher than those of the control group (P < 0.05). Both groups of patients could tolerate the treatment, but the incidence of hypertension and proteinuria in the research group was higher than that in the control group (P < 0.05). The expression of miR-655 in the serum of patients was lower than that of the healthy group (P < 0.05). After treatment, miR-655 in serum increased in both the groups and miR-655 in the research group was higher than that in the control group (P < 0.05). The 2-year survival rate of OS and PFS in patients with low expression of miR-655 was significantly lower than that in patients with high expression of miR-655 (P < 0.05). Conclusion: Apatinib combined with paclitaxel concurrent radiotherapy and chemotherapy is effective and well-tolerated in the treatment of locally advanced nasopharyngeal carcinoma, which improves the quality of life of patients and can be popularized in clinical practice. In addition, the increase of miR-655 may be a target for treating nasopharyngeal carcinoma.

Oxy-fuel co-combustion dynamics of phytoremediation biomass and textile dyeing sludge: Gas-to-ash pollution abatement.

The environmental pressures of major wastes in the circular economies can be abated leveraging the complementarity and optimal conditions of their co-combustion. The oxy-fuel co-combustion of phytoremediation biomass of Sedum alfredii Hance (SAH) and textile dyeing sludge (TDS) may be a promising choice for sustainable CO2 capture and a waste-to-energy conversion. This study characterized and quantified their co-combustion performances, kinetics, and interactions as a function of blend ratio, atmosphere type, and temperature. With a focus on the characteristic elements of SAH (Ca, K, Zn, and Cd) and TDS (Al and S), changes in the mineral phases and ash melting and slagging trends of K2O-Al2O3-SiO2 and CaO-Al2O3-SiO2 systems were quantified. The Zn and Cd residual rates of the co-combustion of 75% SAH and 25% TDS rose by 58.52% and 5.93%, respectively, in the oxy-fuel atmosphere at the 30% oxygen concentration, relative to the mono-combustion of SAH in the air atmosphere. The co-combustion in the oxy-fuel atmosphere at the 20% oxygen concentration delayed the release peaks of SO2, C2S, and H2S, while the Ca-rich SAH captured S in TDS through the formation of CaSO4. Our findings provide new and practical insights into the oxy-fuel co-combustion toward the enhanced co-circularity.

Long non-coding RNA small nucleolar RNA host gene 1 alleviates the progression of recurrent spontaneous abortion via the microRNA-183-5p/ZEB2 axis.

Long non-coding RNAs (lncRNAs) have been elucidated to play vital roles in the phenotype of trophoblast cells. Nevertheless, the effect of SNHG1 has not been investigated on trophoblast cells in recurrent spontaneous abortion (RSA). We aim to investigate the effect of SNHG1 on the phenotype of trophoblast cells during RSA. The RSA mice were established by mating female CBA/J mice with male DBA/2 mice. Microarray analysis was applied in RSA mice, and SNHG1 was identified as a significantly downregulated lncRNA. SNHG1 improved pregnancy outcome and reduced embryo resorption in RSA mice. Trophoblast cell proliferation, apoptosis, migration, and invasion were investigated by CCK8, EdU, TUNEL, wound healing, and Transwell assays. SNHG1 promoted proliferation, migration, and invasion of trophoblast cells, and reduced apoptosis. Mechanistically, SNHG1 bound to miR-183-5p in trophoblast cells. Moreover, miR-183-5p directly targeted ZEB2. Rescue experiment showed that ZEB2 silencing reversed the ameliorative effect of SNHG1 on pregnancy outcome and the promotion of trophoblast activity in RSA mice by impaired the Wnt/ß-catenin pathway. In conclusion, we found that SNHG1 plays a critical role in the progression of RSA via miR-183-5p/ZEB2 and Wnt/ß-catenin signaling. It has potential to be a therapeutic marker of RSA.

Research on Chest Disease Recognition Based on Deep Hierarchical Learning Algorithm.

Chest X-ray has become one of the most common ways in diagnostic radiology exams, and this technology assists expert radiologists with finding the patients at potential risk of cardiopathy and lung diseases. However, it is still a challenge for expert radiologists to assess thousands of cases in a short period so that deep learning methods are introduced to tackle this problem. Since the diseases have correlations with each other and have hierarchical features, the traditional classification scheme could not achieve a good performance. In order to extract the correlation features among the diseases, some GCN-based models are introduced to combine the features extracted from the images to make prediction. This scheme can work well with the high quality of image features, so backbone with high computation cost plays a vital role in this scheme. However, a fast prediction in diagnostic radiology is also needed especially in case of emergency or region with low computation facilities, so we proposed an efficient convolutional neural network with GCN, which is named SGGCN, to meet the need of efficient computation and considerable accuracy. SGGCN used SGNet-101 as backbone, which is built by ShuffleGhost Block (Huang et al., 2021) to extract features with a low computation cost. In order to make sufficient usage of the information in GCN, a new GCN architecture is designed to combine information from different layers together in GCNM module so that we can utilize various hierarchical features and meanwhile make the GCN scheme faster. The experiment on CheXPert datasets illustrated that SGGCN achieves a considerable performance. Compared with GCN and ResNet-101 (He et al., 2015) backbone (test AUC 0.8080, parameters 4.7M and FLOPs 16.0B), the SGGCN achieves 0.7831 (-3.08%) test AUC with parameters 1.2M (-73.73%) and FLOPs 3.1B (-80.82%), where GCN with MobileNet (Sandler and Howard, 2018) backbone achieves 0.7531 (-6.79%) test AUC with parameters 0.5M (-88.46%) and FLOPs 0.66B (-95.88%).

Co-combustion, life-cycle circularity, and artificial intelligence-based multi-objective optimization of two plastics and textile dyeing sludge.

Given the globally abundant availability of waste plastics and the negative environmental impacts of textile dyeing sludge (TDS), their co-combustion can effectively enhance the circular economies, energy recovery, and environmental pollution control. The (co-)combustion performances, gas emissions, and ashes of TDS and two plastics of polypropylene (PP) and polyethylene (PE) were quantified and characterized. The increased blend ratio of PP and PE improved the ignition, burnout, and comprehensive combustion indices. The two plastics interacted with TDS significantly in the range of 200-600 â„ƒ. TDS pre-ignited the combustion of the plastics which in turn promoted the combustion of TDS. The co-combustions released more CO2 but less CH4, C-H, and CO as CO2 was less persistent than the others in the atmosphere. The Ca-based minerals in the plastics enhanced S-fixation and reduced SO2 emission. The activation energy of the co-combustion fell from 126.78 to 111.85 kJ/mol and 133.71-79.91 kJ/mol when the PE and PP additions rose from 10% to 50%, respectively. The co-combustion reaction mechanism was best described by the model of f(α) = (1-α)n. The reaction order was reduced with the additions of the plastics. The co-combustion operation interactions were optimized via an artificial neural network so as to jointly meet the multiple objectives of maximum energy production and minimum emissions.

Activation of the NRF2 antioxidant program sensitizes tumors to G6PD inhibition.

The KEAP1/NRF2 pathway promotes metabolic rewiring to support redox homeostasis. Activation of NRF2 occurs in many cancers, often due to KEAP1 mutations, and is associated with more aggressive disease and treatment resistance. To identify metabolic dependencies in cancers with NRF2 activation, we performed a metabolism-focused CRISPR screen. Glucose-6-phosphate dehydrogenase (G6PD), which was recently shown to be dispensable in Ras-driven tumors, was a top dependency. G6PD catalyzes the committed step of the oxidative pentose phosphate pathway that produces NADPH and nucleotide precursors, but neither antioxidants nor nucleosides rescued. Instead, G6PD loss triggered tricarboxylic acid (TCA) intermediate depletion because of up-regulation of the alternative NADPH-producing enzymes malic enzyme and isocitrate dehydrogenase. In vivo, G6PD impairment markedly suppressed KEAP1 mutant tumor growth, and this suppression was further augmented by TCA depletion by glutaminase inhibition. Thus, G6PD inhibition­induced TCA depletion is a therapeutic vulnerability of NRF2-activated cancer.

Emission-to-ash detoxification mechanisms of co-combustion of spent pot lining and pulverized coal.

In response to the global initiative for greenhouse gas emission reduction, the co-combustion of coal and spent pot lining (SPL) may cost-effectively minimize waste streams and environmental risks. This study aimed to quantify the emission-to-ash detoxification mechanisms of the co-combustion of SPL and pulverized coal (PC) and their kinetics, gas emission, fluorine-leaching toxicity, mineral phases, and migrations. The main reaction covered the ranges of 335-540 °C and 540-870 °C while the interactions occurred at 360-780 °C. The apparent activation energy minimized (66.99 kJ/mol) with 90% PC addition. The rising PC fraction weakened the peak intensity of NaF and strengthened that of Ca2F, NaAlSiO4, and NaAlSi2O6. The addition of PC enhanced the combustion efficiency of SPL and raised the melting temperature by capturing Na. PC exhibited a positive effect on solidifying water-soluble fluorine and stabilizing alkali and alkaline earth metals. The leaching fluorine concentrations of the co-combustion ashes were lower than did SPL mono-combustion. The main gases emitted were HF, NH3, NOx, CO, and CO2. HF was largely released at above 800 °C. Multivariate Gaussian process model-based optimization of the operational conditions also verified the gas emissions results. Our study synchronizes the utilization and detoxification of SPL though co-combustion and provides insights into an eco-friendlier life-cycle control on the waste-to-energy conversion.

A specific selenium-chelating peptide isolated from the protein hydrolysate of Grifola frondosa.

Background: Grifola frondosa is a type of edible medicinal mushroom with abundant proteins. Selenium (Se) is an essential micronutrient for human. Many animal experiments and clinical studies had indicated that Se plays an important role in diverse physiologic actions. Most inorganic selenium compounds are toxic, and the lowest lethal dose is relatively small. Peptide-Se chelate can probably be dietary supplements in functional foods for humans with Se deficiency. Methods: In this study, a specific tripeptide Arg-Leu-Ala (RLA) with strong Se-chelating capacity was purified from Grifola frondosa through ultrafiltration, reversed-phase HPLC and gel filtration chromatography. The UV, SEM, XRD, 1H NMR spectra are shown to provide more information about characterization of RLA-Se chelates. The bioavailability of RLA-Se chelate in Caco-2 cell line was investigated by using human colon cancer Caco-2 cells as model. iTRAQ comparative proteomics approach were used to identify the differentially expressed proteins. Results: The Se binding capacity of RLA was 84.47 ± 1.21 mg g-1. The results of UV, X-ray diffraction (XRD), 1H NMR and SEM structure analysis showed that the binding of selenium in the hydrolysate of Grifola frondosa protein was successful, and the amino and carboxyl groups of RLA were involved in the coordination of Se, which was the main site of chelation. The results of absorption of RLA-Se chelate in Caco-2 cells showed that RLA-Se chelate could be used as selenium supplement source. Using iTRAQ comparative proteomics approach, 40 proteins found significant. RLA-Se treatment had been demonstrated to present a higher accumulation of Se compared with control treatment and show an effective absorption by Caco-2 with the result that E3 protein performed up regulation. RLA-Se may play roles in cell cycle and apoptosis as an essential micronutrient. To sum up, our research results show that Grifola polypeptide-Se chelate is a promising multifunctional organic selenium product, which can be used as a new functional supplement for selenium deficiency.

Dynamic pyrolysis behaviors, products, and mechanisms of waste rubber and polyurethane bicycle tires.

Given their non-biodegradable, space-consuming, and environmentally more benign nature, waste bicycle tires may be pyrolyzed for cleaner energies relative to the waste truck, car, and motorcycle tires. This study combined thermogravimetry (TG), TG-Fourier transform infrared spectroscopy (TG-FTIR), and pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS) analyses to dynamically characterize the pyrolysis behavior, gaseous products, and reaction mechanisms of both waste rubber (RT) and polyurethane tires (PUT) of bicycles. The main devolatilization process included the decompositions of the natural, styrene-butadiene, and butadiene rubbers for RT and of urethane groups in the hard segments, polyols in the soft segments, and regenerated isocyanates for PUT. The main TG-FTIR-detected functional groups included C-H, C=C, C=O, and C-O for both waste tires, and also, N-H and C-O-C for the PUT pyrolysis. The main Py-GC/MS-detected pyrolysis products in the decreasing order were isoprene and D-limonene for RT and 4, 4'-diaminodiphenylmethane and 2-hexene for PUT. The kinetic, thermodynamic, and comprehensive pyrolysis index data verified the easier decomposition of PUT than RT. The pyrolysis mechanism models for three sub-stages of the main devolatilization process were best described by two-dimensional diffusion and two second-order models for RT, and the three consecutive reaction-order (three-halves order, first-order, and second-order) models for PUT.

Mechanisms Regulating Muscle Protein Synthesis in CKD.

BACKGROUND: CKD induces loss of muscle proteins partly by suppressing muscle protein synthesis. Muscles of mice with CKD have increased expression of nucleolar protein 66 (NO66), as do muscle biopsy specimens from patients with CKD or those undergoing hemodialysis. Inflammation stimulates NO66 expression and changes in NF-κB mediate the response. METHODS: Subtotal nephrectomy created a mouse model of CKD with BUN >80 mg/dl. Crossing NO66flox/flox with MCK-Cre mice bred muscle-specific NO66 (MCK-NO66) knockout mice. Experiments assessed the effect of removing NO66. RESULTS: Muscle-specific NO66 knockout in mice blocks CKD-induced loss of muscle mass and improves protein synthesis. NO66 suppression of ribosomal biogenesis via demethylase activity is the mechanism behind these responses. In muscle cells, expression of NO66, but not of demethylase-dead mutant NO66, decreased H3K4me3 and H3K36me3 and suppressed pre-rRNA expression. Knocking out NO66 increased the enrichment of H3K4me3 and H3K36me3 on ribosomal DNA. In primary muscle cells and in muscles of mice without NO66, ribosomal RNA, pre-rRNA, and protein synthesis all increased. CONCLUSIONS: CKD suppresses muscle protein synthesis via epigenetic mechanisms that NO66 mediates. Blocking NO66 could suggest strategies that counter CKD-induced abnormal muscle protein catabolism.

Water-soluble fluorine detoxification mechanisms of spent potlining incineration in response to calcium compounds.

In this study, the detoxification mechanisms of water-soluble fluorine in the bottom ash and the distribution of fluorine during the spent potlining (SPL) incineration were characterized in response to four calcium compounds using an experimental tube furnace. CaSiO3, CaO, Ca(OH)2, and CaCO3-assisted SPL incineration converted NaF to low toxicity compounds in the bottom ash yielding a conversion range of 54.24-99.45% relative to the individual SPL incineration. The two main mechanisms of the fluorine transformation were the formations of CaF2 and Ca4Si2O7F2. The fluorine transformation efficiency was greater with CaSiO3 than CaO, Ca(OH)2, and CaCO3. Our simulations demonstrated that SiO2 enhanced the conversion of NaF. The fluorine leaching content of the bottom ash was estimated at 13.71 mg⋅L-1 after the SPL co-incineration with CaSiO3 (Ca:F = 1.2:1). The acid-alkali solutions had no significant effect on the fluorine leaching content of the bottom ash when 3 ≤ pH ≤ 12. Fluorine during the SPL co-incineration with CaSiO3 (Ca:F = 1.2:1) at 850 °C for 60 min was partitioned into 83.37, 13.90, and 2.72% in the bottom ash, fly ash, and flue gas, respectively. The transformation and detoxification mechanisms of water-soluble fluorine provide new insights into controls on fluorine emission from the SPL incineration.

Glucose-6-Phosphate Dehydrogenase Is Not Essential for K-Ras-Driven Tumor Growth or Metastasis.

The enzyme glucose-6-phosphate dehydrogenase (G6PD) is a major contributor to NADPH production and redox homeostasis and its expression is upregulated and correlated with negative patient outcomes in multiple human cancer types. Despite these associations, whether G6PD is essential for tumor initiation, growth, or metastasis remains unclear. Here, we employ modern genetic tools to evaluate the role of G6PD in lung, breast, and colon cancer driven by oncogenic K-Ras. Human HCT116 colorectal cancer cells lacking G6PD exhibited metabolic indicators of oxidative stress, but developed into subcutaneous xenografts with growth comparable with that of wild-type controls. In a genetically engineered mouse model of non-small cell lung cancer driven by K-Ras G12D and p53 deficiency, G6PD knockout did not block formation or proliferation of primary lung tumors. In MDA-MB-231-derived human triple-negative breast cancer cells implanted as orthotopic xenografts, loss of G6PD modestly decreased primary site growth without ablating spontaneous metastasis to the lung and moderately impaired the ability of breast cancer cells to colonize the lung when delivered via tail vein injection. Thus, in the studied K-Ras tumor models, G6PD was not strictly essential for tumorigenesis and at most modestly promoted disease progression. SIGNIFICANCE: K-Ras-driven tumors can grow and metastasize even in the absence of the oxidative pentose pathway, a main NADPH production route.

Pharmacokinetics and pharmacodynamics of TTI-101, a STAT3 inhibitor that blocks muscle proteolysis in rats with chronic kidney disease.

Loss of muscle proteins increases the morbidity and mortality of patients with chronic kidney disease (CKD), and there are no reliable preventive treatments. We uncovered a STAT3/CCAAT-enhancer-binding protein-δ to myostatin signaling pathway that activates muscle protein degradation in mice with CKD or cancer; we also identified a small-molecule inhibitor of STAT3 (TTI-101) that blocks this pathway. To evaluate TTI-101 as a treatment for CKD-induced cachexia, we measured TTI-101 pharmacokinetics and pharmacodynamics in control and CKD rats that were orally administered TTI-101or its diluent. The following two groups of gavage-fed rats were studied: sham-operated control rats and CKD rats. Plasma was collected serially (0, 0.25, 0.5, 1, 2, 4, 8, and 24 h) following TTI-101 administration (at oral doses of 0, 10, 30, or 100 mg/kg). Plasma levels of TTI-101 were measured by LC-MS/MS, and pharmacokinetic results were analyzed with the PKSolver program. Plasma TTI-101 levels increased linearly with doses; the maximum plasma concentrations and time to maximal plasma levels (~1 h) were similar in sham-operated control rats and CKD rats. Notably, gavage treatment of TTI-101 for 3 days produced TTI-101 muscle levels in sham control rats and CKD rats that were not significantly different. CKD rats that received TTI-101 for 7 days had suppression of activated STAT3 and improved muscle grip strength; there also was a trend for increasing body and muscle weights. TTI-101 was tolerated at doses of 100 mg·kg-1·day-1 for 7 days. These results with TTI-101 in rats warrant its development as a treatment for cachexia in humans.