Acquired gene alterations in patients treated with ribociclib plus endocrine therapy or endocrine therapy alone using baseline and end-of-treatment circulating tumor DNA samples in the MONALEESA-2, -3, and -7 trials.

BACKGROUND: A prior pooled analysis of the MONALEESA-2, -3, and -7 trials identified baseline markers predictive of sensitivity or resistance to ribociclib plus endocrine therapy (ET). We report the results of an analysis of paired baseline and end-of-treatment (EOT) circulating tumor DNA (ctDNA) samples across the MONALEESA trials. PATIENTS AND METHODS: Paired baseline and EOT ctDNA samples from MONALEESA-2, -3, and -7 were sequenced using a targeted next-generation sequencing panel. Genes with an EOT alteration prevalence of >5% were included. A McNemar test was performed on paired samples and adjusted for multiple testing to control the false discovery rate. A Bayesian mixed-effects model was used to adjust for ctDNA fraction at both time points and for study differences. RESULTS: The analysis included 523 paired samples. At EOT, 21 genes had a >5% alteration prevalence. A trend for higher ctDNA fraction at EOT vs baseline (P=0.08) was observed. Prevalence of alterations was higher at EOT vs baseline in RB1, SPEN, TPR, PCDH15, and FGFR2 in the ribociclib arm; PBRM1 in the placebo arm; and ESR1 in both arms. The mixed-effects model demonstrated that the same trends for increased prevalence of these alterations at EOT were observed after adjusting for ctDNA fraction and that the increased rate of RB1 and SPEN alterations at EOT were specific to ribociclib plus ET. Analysis of ESR1 indicated a similar increase at EOT in both arms. The most common acquired ESR1 mutations at EOT included Y537C/N/S/D, D538G, E380Q, and L536H/R/P/LC. The prevalence of PIK3CA hotspot mutations at baseline and EOT was similar. CONCLUSIONS: This analysis identified acquired gene alterations in patients with HR+/HER2- advanced breast cancer treated with ribociclib plus ET or placebo plus ET. These data may support further studies on acquired resistance mechanisms and inform future systemic interventions in the post-CDK4/6 inhibitor setting.

[Application of immune combination therapy in MSS/pMMR-type colorectal cancer: current status and future perspectives].

In recent years, immune checkpoint inhibitors (ICIs) have been widely used in malignant solid tumors with remarkable efficacy. However, in colorectal cancer (CRC), ICIs have shown significant therapeutic effects only in patients with highly microsatellite unstable/mismatch repair-deficient metastatic CRC and these patients are only a minority of all CRC patients. In contrast, the majority of patients, those with microsatellite stable (MSS)/mismatch repair-complete (pMMR)-type metastatic CRC, could hardly benefit from ICI monotherapies, and immune combination therapies have become the key to solveing this clinical challenge. This article introduces the common patterns and possible mechanisms of immune-combination therapies for MSS/pMMR-type CRC, the exploration and progress made in the application of immune-combination therapies, as well as the possible predictive markers of efficacy of immune therapies. The prospects and directions of ICIs in the treatment of MSS/pMMR-type CRC are also discussed.

Pooled ctDNA analysis of MONALEESA phase III advanced breast cancer trials.

BACKGROUND: The phase III MONALEESA trials tested the efficacy and safety of the cyclin-dependent kinase (CDK)4/6 inhibitor ribociclib with different endocrine therapy partners as first- or second-line treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (ABC). Using the largest pooled biomarker dataset of the CDK4/6 inhibitor ribociclib in ABC to date, we identified potential biomarkers of response to ribociclib. PATIENTS AND METHODS: Baseline circulating tumour DNA from patients in the MONALEESA trials was assessed using next-generation sequencing. An analysis of correlation between gene alteration status and progression-free survival (PFS) was carried out to identify potential biomarkers of response to ribociclib. RESULTS: Multiple frequently altered genes were identified. Alterations in ERBB2, FAT3, FRS2, MDM2, SFRP1, and ZNF217 were associated with a greater PFS benefit with ribociclib versus placebo. Patients with high tumour mutational burden (TMB) and with ANO1, CDKN2A/2B/2C, and RB1 alterations exhibited decreased sensitivity to ribociclib versus placebo. CONCLUSIONS: Although exploratory, these results provide insight into alterations associated with the improved response to ribociclib treatment and may inform treatment sequencing in patients with actionable alterations following progression on CDK4/6 inhibitors. Validation of potential biomarkers identified here and development of prospective trials testing their clinical utility are warranted. GOV IDENTIFIERS: NCT01958021, NCT02422615, NCT02278120.

[Determination of methylmercury in urine by direct mercury analyzer].

Objective: To develop asolvent extraction-direct mercury analyzer method for determination of methylmercury in urine. Methods: After the urinehydrolyzesd by hydrobromic acid, methylmercury was extracted by tolueneand reverse-extracted from L-cysteine solution, it was then detectedbydirect mercuryanalyzer. Results: The linear range was 0.2-50.0 µg/L, and the related coefficient was 0.9999. The relative standard deviations (RSD) within the group were 5.04%-6.64%, and the RSD between the group were 5.65%-8.11 %. The average recovery efficiencies were 85.4%-95.5%. The detection limitation was 0.0482 µg/L and the quantification concentrations was 0.1607 µg/L. Conclusion: The method, which has low detection limit, high sensitivity, easy to operate, is stability for the determination of methylmercury in urine.

A case of drug-induced myopathy in alcoholic cirrhosis caused by voriconazole.

BACKGROUND: Voriconazole is a new generation of broad-spectrum antifungal agents commonly used in the treatment of invasive aspergillus infections. CASE REPORT: We reported a rare case of myopathy induced by voriconazole, which showed severe muscle pain and significantly elevated myocardial enzymes. Enzymes eventually achieved good efficacy by switching voriconazole to micafungin and the use of L-carnitine. CONCLUSIONS: This reminded us it was necessary to be vigilant for rare adverse reactions of voriconazole in the population with liver dysfunction, the elderly population, and people with multiple underlying diseases in clinical practice. During medication of voriconazole, close attention should be paid to the occurrence of adverse reactions to avoid life-threatening complications.

Preliminary Extracellular Vesicle Profiling in Drainage Fluid After Neck Dissection in OSCC.

Lymph node metastasis is related to poor prognosis in oral squamous cell carcinoma (OSCC), and few studies have explored the relevance of postoperative drainage fluid (PDF) in metastasis. Extracellular vesicles (EVs) are nanosized vesicles that can transfer oncogenic molecules to regulate tumorigenesis. However, the proteomic profile of postoperative drainage fluid-derived EVs (PDF-EVs) in OSCC has not been elucidated. Herein, we collected drainage fluid from OSCC patients after neck dissection to investigate the difference in PDF-EVs between patients with metastatic lymph nodes (the LN+ group) and nonmetastatic lymph nodes (the LN- group). The proteomic profile of PDF-EVs from the LN+ and LN- groups was compared using label-free liquid chromatography tandem-mass spectrometry-based protein quantification. The results revealed that PDF-EVs were mainly derived from epithelial cells and immune cells. A total of 2,134 proteins in the PDF-EVs were identified, and 313 were differentially expressed between the LN+ and LN- groups. Metabolic proteins, such as EHD2 and CAVIN1, were expressed at higher levels in the LN+ group than in the LN- group, and the levels of EHD2 and CAVIN1 in the postoperative drainage fluid were positively correlated with lymph node metastasis. Our study revealed previously undocumented postoperative drainage fluid-associated proteins in patients with metastatic OSCC, providing a starting point for understanding their role in metastatic and nonmetastatic OSCC.

Probing Operator Spreading via Floquet Engineering in a Superconducting Circuit.

Operator spreading, often characterized by out-of-time-order correlators (OTOCs), is one of the central concepts in quantum many-body physics. However, measuring OTOCs is experimentally challenging due to the requirement of reversing the time evolution of systems. Here we apply Floquet engineering to investigate operator spreading in a superconducting 10-qubit chain. Floquet engineering provides an effective way to tune the coupling strength between nearby qubits, which is used to demonstrate quantum walks with tunable couplings, reversed time evolution, and the measurement of OTOCs. A clear light-cone-like operator propagation is observed in the system with multiple excitations, and has a nearly equal velocity as the single-particle quantum walk. For the butterfly operator that is nonlocal (local) under the Jordan-Wigner transformation, the OTOCs show distinct behaviors with (without) a signature of information scrambling in the near integrable system.

[Establishment and clinical validation of an artificial intelligence YOLOv51 model for the detection of precancerous lesions and superficial esophageal cancer in endoscopic procedure].

Objective: To construct the diagnostic model of superficial esophageal squamous cell carcinoma (ESCC) and precancerous lesions in endoscopic images based on the YOLOv5l model by using deep learning method of artificial intelligence to improve the diagnosis of early ESCC and precancerous lesions under endoscopy. Methods: 13, 009 endoscopic esophageal images of white light imaging (WLI), narrow band imaging (NBI) and lugol chromoendoscopy (LCE) were collected from June 2019 to July 2021 from 1, 126 patients at the Cancer Hospital, Chinese Academy of Medical Sciences, including low-grade intraepithelial neoplasia, high-grade intraepithelial neoplasia, ESCC limited to the mucosal layer, benign esophageal lesions and normal esophagus. By computerized random function method, the images were divided into a training set (11, 547 images from 1, 025 patients) and a validation set (1, 462 images from 101 patients). The YOLOv5l model was trained and constructed with the training set, and the model was validated with the validation set, while the validation set was diagnosed by two senior and two junior endoscopists, respectively, to compare the diagnostic results of YOLOv5l model and those of the endoscopists. Results: In the validation set, the accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the YOLOv5l model in diagnosing early ESCC and precancerous lesions in the WLI, NBI and LCE modes were 96.9%, 87.9%, 98.3%, 88.8%, 98.1%, and 98.6%, 89.3%, 99.5%, 94.4%, 98.2%, and 93.0%, 77.5%, 98.0%, 92.6%, 93.1%, respectively. The accuracy in the NBI model was higher than that in the WLI model (P<0.05) and lower than that in the LCE model (P<0.05). The diagnostic accuracies of YOLOv5l model in the WLI, NBI and LCE modes for the early ESCC and precancerous lesions were similar to those of the 2 senior endoscopists (96.9%, 98.8%, 94.3%, and 97.5%, 99.6%, 91.9%, respectively; P>0.05), but significantly higher than those of the 2 junior endoscopists (84.7%, 92.9%, 81.6% and 88.3%, 91.9%, 81.2%, respectively; P<0.05). Conclusion: The constructed YOLOv5l model has high accuracy in diagnosing early ESCC and precancerous lesions in endoscopic WLI, NBI and LCE modes, which can assist junior endoscopists to improve diagnosis and reduce missed diagnoses.

[A case report of orbital epithelioid hemangioendothelioma].

A 70-year-old male patient, who had a right upper eyelid tumor excision 4 years ago, complained of eyelid swelling and ptosis for 3 months. Orbital CT and MRI showed an orbital cystic lesion with hemorrhage in the right eye. The tumor was resected under general anesthesia. The pathological diagnosis was epithelioid hemangioendothelioma. (Chin J Ophthalmol, 2021, 57:696-698).

Microbially induced carbonate precipitation via methanogenesis pathway by a microbial consortium enriched from activated anaerobic sludge.

AIMS: Various applications of microbially induced carbonate precipitation (MICP) has been proposed. However, most studies use cultured pure strains to obtain MICP, ignoring advantages of microbial consortia. The aims of this study were to: (i) test the feasibility of a microbial consortium to produce MICP; (ii) identify functional micro-organisms and their relationship; (iii) explain the MICP mechanism; (iv) propose a way of applying the MICP technique to soil media. METHODS AND RESULTS: Anaerobic sludge was used as the source of the microbial consortium. A laboratory anaerobic sequencing batch reactor and beaker were used to perform precipitation experiment. The microbial consortium produced MICP with an efficiency of 96·6%. XRD and SEM analysis showed that the precipitation composed of different-size calcite crystals. According to high-throughput 16S rRNA gene sequencing, the functional micro-organisms included acetogenic bacteria, acetate-oxidizing bacteria and archaea Methanosaeta and Methanobacterium beijingense. The methanogenesis acetate degradation provides dissolved inorganic carbon and increases pH for MICP. A series of reactions catalysed by many enzymes and cofactors of methanogens and acetate-oxidizers are involved in the acetate degradation. CONCLUSION: This work demonstrates the feasibility of using the microbial consortium to achieve MICP from an experimental and theoretical perspective. SIGNIFICANCE AND IMPACT OF THE STUDY: A method of applying the microbial-consortium MICP to soil media is proposed. It has the advantages of low cost, low environmental impact, treatment uniformity and less limitations from natural soils. This method could be used to improve mechanical properties, plug pores and fix harmful elements of soil media, etc.

Effect of a training course on the diagnosis of vocal fold leukoplakia by narrow-band imaging.

OBJECTIVE: To investigate the value of narrow-band imaging training for differentiating between benign and malignant vocal fold leukoplakia. METHOD: Thirty cases of vocal fold leukoplakia were selected. RESULTS: Narrow-band imaging endoscopy training had a significant positive effect on the specificity of the differential diagnosis of vocal fold leukoplakia. In addition, the consistency of diagnostic typing of vocal fold leukoplakia by narrow-band imaging improved to 'moderate agreement' following the combination of types I and II and the combination of types IV, V and VI in the typing of vocal fold leukoplakia. CONCLUSION: The narrow-band imaging training course may improve the ability of laryngologists to diagnose vocal fold leukoplakia. The new endoscopic diagnostic classification by narrow-band imaging needs to be further simplified to facilitate clinical application.

[Association between parental socioeconomic status and preschoolers' consumption of sugar-sweetened beverages].

Objective: To explore the association between parental socioeconomic status (SES) and preschoolers' consumption of sugar-sweetened beverages (SSB). Methods: In June 2018, all preschoolers from 15 kindergartens were selected from the jurisdiction of Education Commission in Dongcheng District of Beijing by using an equal-proportion stratified cluster sampling method in the study. A self-designed questionnaire was used to investigate the parents of preschoolers to obtain the basic information of preschoolers and parents, the consumption situation of preschoolers' sugar-sweetened beverages and the perception of parents to SSB. A tatol of 3 217 preschoolers were finally included in the analysis. A generalized structural equation model was used to analyze the relationship between preschoolers' consumption of sugar-sweetened beverages and their parents' socioeconomic status and the mediating effect of their cognition of sugar-sweetened beverages. The size of mediating effect was estimated by using deviation correction non-parameter percentile Bootstrap method. Results: The age of 3 217 preschoolers was (4.23±0.67) years, of which 52.6% (n=1 692) were boys, and 77.62% (n=2 497) were SSB consumers. Among the parents of 3 217 preschoolers, fathers and mothers accounted for 24.90% (n=801) and 75.10% (n=2 416), and the M (P25, P75) scores of SES were 66.7 (62.5, 69.5) and 69.5 (64.6, 71.4), respectively. The proportion of parents who took the initiative to learn about their children's consumption of SSB, lacked confidence in restricting preschooler's consumption of SSB and read nutrition labels before purchasing food was 74.08% (n=2 383), 82.90% (n=2 667) and 36.24% (n=1 166), respectively. The generalized structural equation model showed that after adjusting for preschoolers' gender, age, body mass index (BMI) of preschoolers and their parents, preschoolers' consumption of SSB was negatively associated with their parents' SES score [path coefficient (95%CI):-4.69×10-2 (-6.56×10-2,-2.69×10-2) ]. The mediating effect of parents' perception of SSB consumption could explain 48.71% of the total effect [path coefficient (95%CI):-2.28×10-2 (-3.54×10-2, -1.10×10-2)]. Conclusion: The consumption of SSB in preschoolers is negatively associated with their parent's SES, and this relationship is partially mediated by parent's perception of SSB consumption.

LINC00511 can promote the proliferation, migration and invasion of esophageal cancer cells through regulating microRNA-150-5p.

OBJECTIVE: The aim of this study was to investigate the potential role of LINC00511 in esophageal cancer (ECa), and to explore its underlying mechanism through in vitro cell experiments. PATIENTS AND METHODS: LINC00511 expression in ECa was analyzed by GEPIA database and verified by real-time fluorescence quantitative polymerase chain reaction (qPCR). The bioinformatics website was used to analyze the miRNAs that can bind to LINC00511, and the regulatory relationship between them was verified through Luciferase assay, qPCR as well as Western blotting analysis. Then, the impacts of LINC00511 and microRNA-150-5p on the proliferation or invasiveness of ECa cell lines Kyse30 and ECA109 were investigated by cell counting kit-8 (CCK-8) test and transwell experiment, respectively. Meanwhile, cell cycle and apoptosis were detected by flow cytometry. RESULTS: Analysis results of the GEPIA database revealed that LINC00511 had a significant high expression in ECa tissue samples in comparison with normal control ones, which is consistent with qPCR results. Meanwhile, a significant negative correlation was found between LINC00511 and microRNA-150-5p. In brief, LINC00511 was able to bind to microRNA-150-5p and inhibited its expression. Besides, overexpression of LINC00511 enhanced ECa cell proliferation and migration, accelerated cell cycle, and suppressed cell apoptosis, while transfection with microRNA-150-5p mimics caused the opposite effects. CONCLUSIONS: This study shows for the first time that LINC00511 modulates the progression of ECa by binding to microRNA-150-5p.

Evaluation of emissions and exposures at workplaces using desktop 3-dimensional printer.

There is a paucity of data on additive manufacturing process emissions and personal exposures in real-world workplaces. Hence, we evaluated atmospheres in four workplaces utilizing desktop "3-dimensional" (3-d) printers [fused filament fabrication (FFF) and sheer] for production, prototyping, or research. Airborne particle diameter and number concentration and total volatile organic compound concentrations were measured using real-time instruments. Airborne particles and volatile organic compounds were collected using time-integrated sampling techniques for off-line analysis. Personal exposures for metals and volatile organic compounds were measured in the breathing zone of operators. All 3-d printers that were monitored released ultrafine and fine particles and organic vapors into workplace air. Particle number-based emission rates (#/min) ranged from 9.4 × 109 to 4.4 × 1011 (n = 9samples) for FFF3-d printers and from 1.9 to 3.8 × 109 (n = 2 samples) for a sheer 3-d printer. The large variability in emission rate values reflected variability from the printers as well as differences in printer design, operating conditions, and feedstock materials among printers. A custom-built ventilated enclosure evaluated at one facility was capable of reducing particle number and total organic chemical concentrations by 99.7% and 53.2%, respectively. Carbonyl compounds were detected in room air; however, none were specifically attributed to the 3-d printing process. Personal exposure to metals (aluminum, iron) and 12 different organic chemicals were all below applicable NIOSH Recommended Exposure Limit values, but results are not reflective of all possible exposure scenarios. More research is needed to understand 3-d printer emissions, exposures, and efficacy of engineering controls in occupational settings.

Particle and vapor emissions from vat polymerization desktop-scale 3-dimensional printers.

Little is known about emissions and exposure potential from vat polymerization additive manufacturing, a process that uses light-activated polymerization of a resin to build an object. Five vat polymerization printers (three stereolithography (SLA) and two digital light processing (DLP) were evaluated individually in a 12.85 m3 chamber. Aerosols (number, size) and total volatile organic compounds (TVOC) were measured using real-time monitors. Carbonyl vapors and particulate matter were collected for offline analysis using impingers and filters, respectively. During printing, particle emission yields (#/g printed) ranged from 1.3 ± 0.3 to 2.8 ± 2.6 x 108 (SLA printers) and from 3.3 ± 1.5 to 9.2 ± 3.0 x 108 (DLP printers). Yields for number of particles with sizes 5.6 to 560 nm (#/g printed) were 0.8 ± 0.1 to 2.1 ± 0.9 x 1010 and from 1.1 ± 0.3 to 4.0 ± 1.2 x 1010 for SLA and DLP printers, respectively. TVOC yield values (µg/g printed) ranged from 161 ± 47 to 322 ± 229 (SLA printers) and from 1281 ± 313 to 1931 ± 234 (DLP printers). Geometric mean mobility particle sizes were 41.1-45.1 nm for SLA printers and 15.3-28.8 nm for DLP printers. Mean particle and TVOC yields were statistically significantly higher and mean particle sizes were significantly smaller for DLP printers compared with SLA printers (p < 0.05). Energy dispersive X-ray analysis of individual particles qualitatively identified potential occupational carcinogens (chromium, nickel) as well as reactive metals implicated in generation of reactive oxygen species (iron, zinc). Lung deposition modeling indicates that about 15-37% of emitted particles would deposit in the pulmonary region (alveoli). Benzaldehyde (1.0-2.3 ppb) and acetone (0.7-18.0 ppb) were quantified in emissions from four of the printers and 4-oxopentanal (0.07 ppb) was detectable in the emissions from one printer. Vat polymerization printers emitted nanoscale particles that contained potential carcinogens, sensitizers, and reactive metals as well as carbonyl compound vapors. Differences in emissions between SLA and DLP printers indicate that the underlying technology is an important factor when considering exposure reduction strategies such as engineering controls.

[Association of platelet/lymphocyte ratio and neutrophil/lymphocyte ratio with protein-energy wasting in maintenance hemodialysis patients].

Objective: To explore the association of platelet/lymphocyte ratio (PLR) and neutrophil/lymphocyte ratio (NLR) with protein energy wasting (PEW) in maintenance hemodialysis (MHD) patients. Methods: A multicenter cross-sectional study was conducted in eleven hemodialysis centers of Guizhou province from June to August, 2017. Clinical data, physical parameters, body composition data and laboratory values of MHD patients were collected. PLR and NLR were calculated according to routine blood test. All patients were divided into four groups (Q1-Q4) according to the median and quartile of PLR and NLR. Multivariate logistic regression models were applied to analyze the relationships between PLR, NLR and PEW. The comparison of predictive power of PLR and NLR for PEW was evaluated by receiver operating characteristic curve (ROC). Results: A total of 936 MHD patients were enrolled (519 males, 417 females), with a mean age of (55.6±15.6) years. The prevalence of PEW was 46.2% (432/936). Multivariate logistic regression analysis showed that patients in group PLR Q3 and Q4 were 2.07 (95%CI: 1.03-4.13, P=0.014) and 2.73 (95%CI: 1.58-4.74, P<0.001) times more likely to have PEW, compared with those in group PLR Q1 in unadjusted models. PLR was significantly associated with the development of PEW after adjusting age, sex, history of hypertension, diabetes and hemoglobin. Patients in Group PLR Q3 and Q4 were 2.82 times (95%CI: 1.42-5.60, P=0.003) and 2.93 times (95%CI: 1.50-5.73, P=0.002) times more likely to have PEW than those in Group PLR Q1. The ROC showed that only PLR can predict the development of PEW with a diagnostic threshold of 144.09 [area under curve (AUC)=0.61, 95%CI: 0.56-0.66, P<0.001], with a sensitivity and specificity of 61% and 58%, respectively, while the AUC of NLR is 0.55 (P=0.091). Conclusion: For MHD patients, only PLR could be a relevent factor of PEW and it showed the predictive power of PEW rather than NLR.