Progression signature underlies clonal evolution and dissemination of multiple myeloma.

Clonal evolution drives tumor progression, dissemination, and relapse in multiple myeloma (MM), with most patients dying of relapsed disease. This multistage process requires tumor cells to enter the circulation, extravasate, and colonize distant bone marrow (BM) sites. Here, we developed a fluorescent or DNA-barcode clone-tracking system on MM PrEDiCT (progression through evolution and dissemination of clonal tumor cells) xenograft mouse model to study clonal behavior within the BM microenvironment. We showed that only the few clones that successfully adapt to the BM microenvironment can enter the circulation and colonize distant BM sites. RNA sequencing of primary and distant-site MM tumor cells revealed a progression signature sequentially activated along human MM progression and significantly associated with overall survival when evaluated against patient data sets. A total of 28 genes were then computationally predicted to be master regulators (MRs) of MM progression. HMGA1 and PA2G4 were validated in vivo using CRISPR-Cas9 in the PrEDiCT model and were shown to be significantly depleted in distant BM sites, indicating their role in MM progression and dissemination. Loss of HMGA1 and PA2G4 also compromised the proliferation, migration, and adhesion abilities of MM cells in vitro. Overall, our model successfully recapitulates key characteristics of human MM disease progression and identified potential new therapeutic targets for MM.

Who benefit from adjuvant chemotherapy in stage I lung adenocarcinoma? A multi-dimensional model for candidate selection.

BACKGROUND: Despite promising overall survival of stage I lung adenocarcinoma (LUAD) patients, 10-25 % of them still went through recurrence after surgery. [1] While it is still disputable whether adjuvant chemotherapy is necessary for stage I patients. [2] IASLC grading system for non-mucinous LUAD shows that minor high-grade patterns are significant indicator of poor prognosis. [3] Other risk factors, such as, pleura invasion, lympho-vascular invasion, STAS, etc. are also related to poor prognosis. [4-6] There still lack evidence whether IASLC grade itself or together with other risk factors can guide the use of adjuvant therapy in stage I patients. In this article, we tried to establish a multi-variable recurrence prediction model for stage I LUAD patients that is able to identify candidates of adjuvant chemotherapy. METHODS: We retrospectively collected patients who underwent lung surgery from 2018.8.1 to 2018.12.31 at our institution and diagnosed with lung adenocarcinoma pT1-2aN0M0 (stage I). Clinical data, manifestation on CT scan, pathologic features, driver gene mutations and follow-up information were collected. Cox proportional hazards regression analyses were performed utilizing the non-adjuvant cohort to predict disease free survival (DFS) and a nomogram was constructed and applied to the total cohort. Kaplan-Meier method was used to compare DFS between groups. Statistical analysis was conducted by R version 3.6.3. FINDINGS: A total of 913 stage I LUAD patients were included in this study. Median follow-up time is 48.1 months.4-year and 5-year DFS are 92.9 % and 89.6 % for the total cohort. 65 patient experienced recurrence or death. 4-year DFS are 97.0 %,94.6 % and 76.2 %, and 5-year DFS are 95.5 %, 90.0 % and 74.1 % in IASLC Grade1, 2 and 3, respectively(p < 0.0001). High-risk patients defined by single risk factors, such as, IASLC grade 3, pleura invasion, STAS, less LN resected could not benefit from adjuvant therapy. A LASSO-COX regression model was built and patients are divided into high-risk and low-risk groups. In the high-risk group, patients underwent adjuvant chemotherapy have longer DFS than those who did not (p = 0.024), while in the low-risk group, patients underwent adjuvant chemotherapy have inferior DFS than those who did not (p < 0.001). INTERPRETATION: IASLC grading is a significant indicator of DFS, however it could not guide adjuvant therapy in our stage I LUAD cohort. Growth patterns and T indicators together with other risk factors could identify high-risk patients that are potential candidate of adjuvant therapy, including some stage IA LUAD patients.

Long-term music adjuvant therapy enhances the efficacy of sub-dose antiepileptic drugs in temporal lobe epilepsy.

AIMS: Noninvasive music adjuvant therapy shows great potential in improving seizure control when combined with routine antiepileptic drugs. However, the diversity of previous music protocols has resulted in disparate outcomes. The optimized protocol and features for music adjuvant therapy are still not fully understood which limits its feasibility. METHODS: By applying different regimens of music therapy in various temporal lobe epilepsy models, we evaluated the effect of music in combination with sub-dose drugs on epileptic seizures to determine the optimized protocol. RESULTS: A subgroup of kindled mice that were responsive to music adjuvant therapy was screened. In those mice, sub-dose drugs which were noneffective on kindled seizures, alleviated seizure severity after 12 h/day Mozart K.448 for 14 days. Shorter durations of music therapy (2 and 6 h/day) were ineffective. Furthermore, only full-length Mozart K.448, not its episodes or other music varieties, was capable of enhancing the efficacy of sub-dose drugs. This music therapeutic effect was not due to increasing cerebral drug concentration, but instead was related with the modulation of seizure electroencephalogram (EEG) spectral powers in the hippocampus. CONCLUSION: These results indicate that long-term full-length Mozart K.448 could enhance the anti-seizure efficacy of sub-dose drugs and may be a promising noninvasive adjuvant therapy for temporal lobe epilepsy.

Prognostic Value of Inflammatory Biomarkers in Patients With Stage I Lung Adenocarcinoma Treated With Surgical Dissection.

OBJECTIVE: Inflammation plays a crucial role in tumorigenesis and progression. Our purpose was to investigate the prognostic value of neutrophil-to-lymphocyte ratio (NLR), systemic inflammation response index (SIRI) and systemic immune-inflammation index (SII), and develop a nomogram to predict the cancer-specific survival (CSS) and disease-free survival (DFS) of stage I lung adenocarcinoma patients. METHODS: 1431 patients undergoing surgical resection with pathologically confirmed stage I lung adenocarcinoma were reviewed. The optimal cut-off values for NLR, SII, and SIRI were defined by the receiver operating characteristic (ROC) curve. Cox proportional hazards regression analyses were performed to recognize factors significantly correlated with CSS and DFS to construct the nomogram. The value of adjuvant chemotherapy on model-defined high-risk and low-risk patients was further explored. RESULTS: The cohort had a median follow-up time of 63 months. Multivariate analysis revealed that higher NLR (≥2.606), higher SIRI (≥0.705), higher SII (≥580.671), later T stage, histological pattern with solid or micropapillary components and radiologic features with solid nodules were significantly associated with worse CSS and DFS. The concordance index (C-index) of the nomogram established by all these factors was higher than that of the TNM staging system both in CSS (validation set 0.778 vs 0.652) and DFS (validation set 0.758 vs 0.695). Furthermore, the value of the established nomogram on risk stratification in stage I lung adenocarcinoma patients was validated. CONCLUSIONS: Higher NLR, SII and SIRI pretreatment were associated with worse survival outcomes. A practical nomogram based on these three inflammatory biomarkers may help clinicians to precisely stratify stage I lung adenocarcinoma patients into high- and low-risk and implement individualized treatment.

Isolation of a methyl parathion-degrading strain Stenotrophomonas sp. SMSP-1 and cloning of the ophc2 gene.

A rod-shaped, gram-negative bacterium Stenotrophomonas sp. SMSP-1 was isolated from the sludge of a wastewater treating system of a pesticide manufacturer. Strain SMSP-1 could hydrolyze methyl parathion to p-nitrophenol (PNP) and dimethyl phosphorothioate but could not degrade PNP further. Strain SMSP-1 was able to hydrolyze other organophosphate pesticides, including fenitrothion, ethyl parathion, fenthion, and phoxim, but not chlorpyrifos. A 4395-bp DNA fragment, including an organophosphorus hydrolase encoding gene ophc2, was cloned from the chromosome of strain SMSP-1 using the shotgun technique. Its sequence analysis showed that ophc2 was associated with a typical mobile element ISPpu12 consisting of tnpA (encoding a transposase), lspA (encoding a lipoprotein signal peptidase), and orf1 (encoding a CDF family heavy metal/H(+) antiporter). The ophc2 gene was effectively expressed in E. coli. This is the second report of cloning the ophc2 gene and the first report of this gene from the genus of Stenotrophomonas.

Genome instability in multiple myeloma.

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by clonal proliferation of plasma cells and a heterogenous genomic landscape. Copy number and structural changes due to chromosomal instability (CIN) are common features of MM. In this review, we describe how primary and secondary genetic events caused by CIN can contribute to increased instability across the genome of malignant plasma cells; with a focus on specific driver genomic events, and how they interfere with cell-cycle checkpoints, to prompt accelerated proliferation. We also provide insight into other forms of CIN, such as chromothripsis and chromoplexy. We evaluate how the tumor microenvironment can contribute to a further increase in chromosomal instability in myeloma cells. Lastly, we highlight the role of certain mutational signatures in leading to high mutation rate and genome instability in certain MM patients. We suggest that assessing CIN in MM and its precursors states may help improve predicting the risk of progression to symptomatic disease and relapse and identifying future therapeutic targets.

Radiotherapy for non-small cell lung cancer in the immunotherapy era: the opportunity and challenge-a narrative review.

Immunotherapy has radically changed the clinical management of patients with cancer in recent years. Immune checkpoint inhibitors (ICIs) reversing the immunosuppressive effects of the tumor microenvironment are one type of immunotherapy, several of which are approved by the US Food and Drug Administration (FDA) as first-line treatments for patients with non-small cell lung cancer (NSCLC). However, response rates to ICIs are around 19-47% among patients with advanced NSCLC. As a result, the development of combined ICI and radiotherapy has begun with the aim of strengthening patients' antitumor immunity. Radiotherapy with substantial technological improvements not only achieves local tumor control through the induction of deoxyribonucleic acid (DNA) damage in irradiated regions, but also has the potential to mediate immunostimulatory effects that could result in tumor regression beyond irradiated regions. At present, numerous preclinical and clinical research are investigating the efficiency and safety of combining ICI with radiotherapy. The PACIFIC trial showed that combining chemoradiotherapy with ICI could improve clinical outcomes. In this review, we summarize the rationale for combining radiotherapy with immunotherapy. We also discuss the opportunities and challenges of combination therapy, including the timing of radiotherapy, optimal dose and fractionations, radiotherapy target and target volume, acquired resistance, patient selection, and radioimmunotherapy toxicity.

Isolation and characterization of a carbofuran-degrading strain Novosphingobium sp. FND-3.

A gram-negative Novosphingobium sp. strain FND-3 capable of degrading carbofuran was isolated and characterized. The carbofuran-degrading ability of strain FND-3 was investigated under various culture conditions. Strain FND-3 showed a high average carbofuran-degrading rate of 28.6 mg L(-1) h(-1) in mineral salts medium with 100 mg L(-1) carbofuran. GC/MS analysis pointed out the presence of several unknown metabolites. One hydrolyzate was identified as 2-hydroxy-3-(3-methypropan-2-ol) phenol via hydrolysis of carbofuran phenol. The appearance of another metabolite with M(+) of 180 m/z indicated that the hydroxylation of carbofuran occurred at the aromatic ring. One novel degrading product with M(+) of 239 m/z was identified as 2-hydroxy-3-(3-methylpropan-2-ol) benzene-N-methylcarbamate via hydrolyzing at the ether bond of furanyl ring of carbofuran. Strain FND-3 was also able to degrade other N-methylcarbamate pesticides.

Nonautonomous matter waves in a spin-1 Bose-Einstein condensate.

To investigate nonautonomous matter waves with time-dependent modulation in a one-dimensional trapped spin-1 Bose-Einstein condensate, we hereby work on the generalized three-coupled Gross-Pitaevskii equations by means of the Hirota bilinear method. By modulating the external trap potential, atom gain or loss, and coupling coefficients, we can obtain several nonautonomous matter-wave solitons and rogue waves including "bright" and "dark" shapes and arrive at the following conclusions: (i) the external trap potential and atom gain or loss can influence the propagation of matter-wave solitons and the duration and frequency of bound solitonic interaction, but they have little effect on the head-on solitonic interaction; (ii) through numerical simulation, stable evolution of the matter-wave solitons is realized with a perturbation of 5% initial random noise, and the spin-exchange interaction of atoms can be affected by the time-dependent modulation; (iii) under the influence of a periodically modulated trap potential and periodic atom gain or loss, rogue waves can emerge in the superposition of localized character and periodic oscillating properties.

[Effects of (-)-epigallocatechin-3-gallate on interleukin-1beta expression in mouse wound healing].

(-)-Epigallocatechin-3-gallate (EGCG), a main constituent of green tea polyphenols, plays important roles in antioxidative, anti-senescence, anti-tumor, anti-inflammation and bacterail action. In this study, effects of EGCG on the expression of IL-1beta gene and the IL-1beta level at wound sites during cutaneous wound healing were investigated with histological stain, ELISA and RT-PCR technique. The results show that EGCG (50 mg/L) inhibited the expression of IL-1beta gene and reduced the IL-beta level at wound sites at 72 h after cutaneous wound, but not change the expression of IL-1beta gene and the IL-1beta level at early stage (< or =24 h).

[Bioremediation of fenpropathrin-contaminated soil by Sphingomonas sp.JQL4-5].

JQL4-5 (Sphingomonas sp.), a fenpropathrin-degrading strain isolated from soils exposed to repeated pesticides contamination, was used in this work to study factors affecting its degrading capacity of fenpropathrin in soil microcosms. In sterilized soil, the degradation rates of fenpropathrin by JQL4-5 were faster than those in unsterilized soil. Various factors, including soil pH, temperature, initial fenitrothion concentration, and inoculum size influenced its degradation efficiency. The addition of 10(6) CFU x g(-1) was able to degrade varying concentrations (10-200 mg x kg(-1) soil) of fenpropathrin over a temperature range of 20-40 degrees C and pH range (6.5 - 7.5). The results indicated that strain JQL4-5 has potential use in bioremediation of fenpropathrin-contaminated soil.

[Isolation, identification and characteristics of a phoxim-degrading bacterium XSP-1].

A bacteria strain XSP-1 capable of utilizing phoxim as sole carbon source was isolated from sludge collected from a pesticide manufacturer. It was preliminarily identified as Delftia sp. according to its physiological-biochemical analysis and the similarity analysis of its 16S rRNA gene sequence (GenBank Accession No. EF061135). Strain XSP-1 could degrade 100 mg/L phoxim within 7 h completely. The optimal pH and temperature for degradation were 7.0 and 35 degrees C respectively. The degrading rate showed a positive correlation to the initial inoculum size. Strain XSP-1 also showed good degrading performance against methyl parathion, chlorpyrifos and fenitrothion. PCR detection with degenerated primers designed according to the conserved sequences of reported mpd gene did not find target band, but it needs further study to verify whether strain XSP-1 harbors a new mpd gene.