EML4-ALK fusion protein in Lung cancer cells enhances venous thrombogenicity through the pERK1/2-AP-1-tissue factor axis.

BACKGROUND: Accumulating evidence links the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement to venous thromboembolism (VTE) in non-small cell lung cancer (NSCLC) patients. However, the corresponding mechanisms remain unclear. METHOD: High-throughput sequencing analysis of H3122 human ALK-positive NSCLC cells treated with ALK inhibitor/ dimethyl sulfoxide (DMSO) was performed to identify coagulation-associated differential genes between EML4-ALK fusion protein inhibited cells and control cells. Sequentially, we confirmed its expression in NSCLC patients' tissues and in the plasma of a subcutaneous xenograft mouse model. An inferior vena cava (IVC) ligation model was used to assess clot formation potential. Additionally, pathways involved in tissue factor (TF) regulation were explored in ALK-positive cell lines H3122 and H2228. Statistical significance was determined by Student t-test and one-way ANOVA using SPSS. RESULTS: Sequencing analysis identified a significant downregulation of TF after inhibiting EML4-ALK fusion protein activity in H3122 cells. In clinical NSCLC cases, TF expression was increased especially in ALK-positive NSCLC tissues. Meanwhile, H3122 and H2228 with high TF expression exhibited shorter plasma clotting time and higher TF activity versus ALK-negative H1299 and A549 in cell culture supernatant. Mice bearing H2228 tumor showed a higher concentration of tumor-derived TF and TF activity in plasma and the highest adjusted IVC clot weights. Limiting EML4-ALK protein phosphorylation downregulated extracellular regulated protein kinases 1/2 (ERK1/2)-activating the protein-1(AP-1) signaling pathway and thus attenuated TF expression. CONCLUSION: EML4-ALK fusion protein may enhance venous thrombogenicity by regulating coagulation factor TF expression. There was potential involvement of the pERK1/2-AP-1 pathway in this process.

Identification, characterisation and expression analysis of peanut sugar invertase genes reveal their vital roles in response to abiotic stress.

KEY MESSAGE: Sucrose invertase activity is positively related to osmotic and salt stress resistance in peanut. Sucrose invertases (INVs) have important functions in plant growth and response to environmental stresses. However, their biological roles in peanut are still not fully revealed. In this research, we identified 42 AhINV genes in the peanut genome. They were highly conserved and clustered into three groups with 24 segmental duplication events occurred under purifying selection. Transcriptional expression analysis exhibited that they were all ubiquitously expressed, and most of them were up-regulated by osmotic and salt stresses, with AhINV09, AhINV23 and AhINV19 showed the most significant up-regulation. Further physiochemical analysis showed that the resistance of peanut to osmotic and salt stress was positively related to the high sugar content and sucrose invertase activity. Our results provided fundamental information on the structure and evolutionary relationship of INV gene family in peanut and gave theoretical guideline for further functional study of AhINV genes in response to abiotic stress.

Protective effects of sodium selenite on insulin secretion and diabetic retinopathy in rats with type 1 diabetes mellitus.

The aim of the present study was to determine the effects of sodium selenite on pancreatic ß cells and diabetic retinopathy in type 1 diabetes mellitus (T1DM) rats. Diabetes was induced by administration of streptozotocin (STZ) and both diabetic and control animals were treated with sodium selenite to measure body weight, food and water intake as well as blood glucose level. Additionally, immunohistochemistry was performed to detect the levels of insulin secretion in pancreatic ß cells. Apoptosis level of pancreatic cells in rats was determined by apoptosis kit. Retinal tissues were stained with hematoxylin-eosin and the area of retinal capillary was measured by Image-Pro Plus 6.0 software. Food and water intake coupled with blood glucose level were increased while body weight of rats was decreased in STZ group. After treatment with sodium selenite, High-Sel group and Low-Sel group showed decreased food intake coupled with blood glucose level and concomitantly increased body weight (vs. STZ group). Of note, the insulin secretion in pancreatic ß cells as well as serum insulin levels were strikingly heightened while apoptosis level of pancreatic tissues was lowered in the High-Sel group (vs. STZ and Low-Sel groups). Additionally, both High-Sel and Low-Sel groups showed a small area of retinal capillary (vs. STZ group). Sodium selenite could promote the levels of insulin secretion in pancreatic ß cells of T1DM rats, and concomitantly ameliorate diabetic retinopathy.

The structure, functional evolution, and evolutionary trajectories of the H+-PPase gene family in plants.

BACKGROUND: The H+-PPase (pyrophosphatase) gene family is an important class of proton transporters that play key roles in plant development and stress resistance. Although the physiological and biochemical functions of H+-PPases are well characterized, the structural evolution and functional differentiation of this gene family remain unclear. RESULTS: We identified 124 H+-PPase members from 27 plant species using complete genomic data obtained from algae to angiosperms. We found that all analyzed plants carried H+-PPase genes, and members were not limited to the two main types (type I and II). Differentiation of this gene family occurred early in evolutionary history, probably prior to the emergence of algae. The type I and II H+-PPase genes were retained during the subsequent evolution of higher plants, and their copy numbers increased rapidly in some angiosperms following whole-genome duplication (WGD) events, with obvious expression pattern differentiation among the new copies. We found significant functional divergence between type I and II H+-PPase genes, with both showing evidence for positive selection pressure. We classified angiosperm type I H+-PPases into subtypes Ia and non-Ia, which probably differentiated at an early stage of angiosperm evolution. Compared with non-Ia subtype, the Ia subtype appears to confer some advantage in angiosperms, as it is highly conserved and abundantly expressed, but shows no evidence for positive selection. CONCLUSIONS: We hypothesized that there were many types of H+-PPase genes in the plant ancestral genome, and that different plant groups retained different types of these genes. In the early stages of angiosperm evolution, the type I H+-PPase genes differentiated into various subtypes. In addition, the expression pattern varied not only among genes of different types or subtypes, but also among copies of the same subtype. Based on the expression patterns and copy numbers of H+-PPase genes in higher plants, we propose two possible evolutionary trajectories for this gene family.

Formulation and Pharmacokinetic Evaluation of a Drug-in-Adhesive Patch for Transdermal Delivery of Koumine.

The aim of this study was to develop a suitable drug-in-adhesive patch for transdermal delivery of koumine. Acrylic polymer Duro-Tak® 87-4287, which contains hydroxyl groups, may significantly enhance the skin permeation of koumine from transdermal patches containing 0.93-3.72% koumine. Among permeation enhancers, 10% azone showed the greatest potential and increased the flux of koumine to 1.48-fold that of the control. Therefore, an optimized patch formulation containing 3.72% koumine and 10% azone in Duro-Tak® 87-4287 that offers good physical properties was selected for an in vivo pharmacokinetic study using rats. The maximal plasma drug concentration (Cmax) of koumine after transdermal administration (4 mg/patch) was 25.80 ± 1.51 ng/mL, which was in the range of those after oral administration (3 mg/kg and 15 mg/kg). The time to the maximal concentration (Tmax) and the half-life (t1/2) of the drug with transdermal administration were 3.96 ± 0.46 h and 21.10 ± 1.36 h, respectively, which were longer than those with oral administration. Furthermore, the area under the concentration-time curve (AUC0-72 h) of 898.20 ± 45.57 ng·h/mL for the transdermal patch was much higher than that for oral administration (15 mg/kg). In conclusion, the drug-in-adhesive patch containing koumine provides a steady plasma koumine level and sustained release in vivo and can be an effective means of transdermal delivery for koumine.

Active Biomonitoring of Metals with Cultured Anodonta woodiana: A Case Study in the Taihu Lake, China.

Freshwater bivalves (Anodonta woodiana), cultured in the Nanquan Aquaculture Base, were translocated to the water source area of Xidong Waterworks in the Taihu Lake for 18-months to biomonitor 13 metals, and determine the suitability of using these cultures as an indicator of long-term metal contamination. Mussel and water samples were analyzed every 6 months, with the Nanquan Aquaculture Base serving as control. Metal concentrations in water and mussels from both sites were generally within the Chinese permissible levels. Metal pollution indexes between the two sites were similar. However, the metal loads of mussels in the water source area of Xidong Waterworks were 57.3, 1.7, and 295.5-fold higher after 6-, 12-, and 18-months relative to the control mussels from the Nanquan Aquaculture Base, respectively. Moreover, the water area in Taihu Lake was moderately, considerably, and highly contaminated by Cd, Al, and Cu, respectively.

Effects of Koumine on Adjuvant- and Collagen-Induced Arthritis in Rats.

To examine the effect of koumine, a Gelsemium alkaloid, on two experimental models of rheumatoid arthritis (RA), rats with adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) were administered koumine (0.6, 3, or 15 mg/kg/day) or vehicle through gastric gavage (i.g.). Clinical evaluation was performed via measurements of hind paw volume, arthritis index (AI) score, mechanical withdrawal threshold, organ weight, and by radiographic and histological examinations. Levels of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and antitype II collagen (CII) antibody were also examined. In rats with AIA, koumine reduced the AI score and mechanical allodynia of the injected hind paw in a dose-dependent manner and significantly inhibited increase in thymus and liver weights. In rats with CIA, koumine inhibited increase in hind paw volume, AI score, and mechanical allodynia in a dose-dependent manner and reduced joint space narrowing. Furthermore, koumine also attenuated the increase in the expression of IL-1ß and TNF-α, as well as the robust increase of serum anti-CII antibodies in response to immunization. These results suggested that koumine effectively attenuated arthritis progression in two rat models of RA and that this therapeutic effect may be associated with its immunoregulatory action.

Effects of Calcium and Magnesium Ions on Acute Copper Toxicity to Glochidia and Early Juveniles of the Chinese Pond Mussel Anodonta woodiana.

We evaluated the effects of calcium (Ca(2+)) and magnesium (Mg(2+)) ions on copper (Cu) toxicity to glochidia and newly-transformed juvenile mussels (age 1-2 days) of the Chinese pond mussel (Anodonta woodiana). Acute Cu toxicity tests were performed with glochidia for 24 h and juveniles for 96 h with measured Ca(2+) concentrations of 1.1, 14, 26, 51, and 99 mg L(-1), or measured Mg(2+) concentrations of 2.6, 11, 21, and 39 mg L(-1). The Ca(2+) and Mg(2+) cations provided no statistically significant protection against Cu toxicity to glochidia or juveniles. The 24-h EC50 value for glochidia was 82 µg L(-1) Cu, and contrastly, 96-h EC50 value for newly-transformed juvenile mussels was as low as 12 µg L(-1) Cu, implying that the juveniles of A. woodiana are more vulnerable to Cu contamination at concentrations close to currently-accepted levels.

Development and Validation of a Dual-Energy CT-Based Model for Predicting the Number of Central Lymph Node Metastases in Clinically Node-Negative Papillary Thyroid Carcinoma.

RATIONALE AND OBJECTIVES: This study aimed to develop and validate a dual-energy CT (DECT)-based model for preoperative prediction of the number of central lymph node metastases (CLNMs) in clinically node-negative (cN0) papillary thyroid carcinoma (PTC) patients. MATERIALS AND METHODS: Between January 2016 and January 2021, 490 patients who underwent lobectomy or thyroidectomy, CLN dissection, and preoperative DECT examinations were enrolled and randomly allocated into the training (N = 345) and validation cohorts (N = 145). The patients' clinical characteristics and quantitative DECT parameters obtained on primary tumors were collected. Independent predictors of> 5 CLNMs were identified and integrated to construct a DECT-based prediction model, for which the area under the curve (AUC), calibration, and clinical usefulness were assessed. Risk group stratification was performed to distinguish patients with different recurrence risks. RESULTS: More than 5 CLNMs were found in 75 (15.3%) cN0 PTC patients. Age, tumor size, normalized iodine concentration (NIC), normalized effective atomic number (nZeff) and the slope of the spectral Hounsfield unit curve (λHu) in the arterial phase were independently associated with> 5 CLNMs. The DECT-based nomogram that incorporated predictors demonstrated favorable performance in both cohorts (AUC: 0.842 and 0.848) and significantly outperformed the clinical model (AUC: 0.688 and 0.694). The nomogram showed good calibration and added clinical benefit for predicting> 5 CLNMs. The KaplanMeier curves for recurrence-free survival showed that the high- and low-risk groups stratified by the nomogram were significantly different. CONCLUSION: The nomogram based on DECT parameters and clinical factors could facilitate preoperative prediction of the number of CLNMs in cN0 PTC patients.

Establishment and optimization of an in vitro guinea pig oocyte maturation system.

Guinea pigs are a valuable animal model for studying various diseases, including reproductive diseases. However, techniques for generating embryos via embryo engineering in guinea pigs are limited; for instance, in vitro maturation (IVM) technique is preliminary for guinea pig oocytes. In this study, we aimed to establish and optimize an IVM method for guinea pig oocytes by investigating various factors, such as superovulation induced by different hormones, culture supplementation (e.g., amino acids, hormone, and inhibitors), culture conditions (e.g., oocyte type, culture medium type, and treatment time), and in vivo hCG stimulation. We found that oocytes collected from guinea pigs with superovulation induced by hMG have a higher IVM rate compared to those collected from natural cycling individuals. Moreover, we found that addition of L-cysteine, cystine, and ROS in the culture medium can increase the IVM rate. In addition, we demonstrated that in vivo stimulation with hCG for 3-8 h can further increase the IVM rate. As a result, the overall IVM rate of guinea pig oocytes under our optimized conditions can reach ~69%, and the mature oocytes have high GSH levels and normal morphology. In summary, we established an effective IVM method for guinea pig oocytes by optimizing various factors and conditions, which provides a basis for embryo engineering using guinea pigs as a model.

Newly diagnosed non-small cell lung cancer with interstitial lung abnormality: Prevalence, characteristics, and prognosis.

BACKGROUND: Along with the improvement of lung cancer screening implementation, the identification of interstitial lung abnormality (ILA) is increasing. Currently, there is a limited description of the oncogenic status and ILA subtypes among newly diagnosed non-small cell lung cancer (NSCLC) patients with ILA in the Chinese population. This study aimed to investigate the prevalence, characteristics, oncogenic status and factors associated with overall survival (OS) among NSCLC patients with ILA. METHODS: A total of 765 newly diagnosed NSCLC cases at our hospital were reviewed and ILA was diagnosed according to the criteria of the Fleischner Society. The characteristics, clinical pathological features and OS of NSCLC patients with ILA were retrospectively analyzed. RESULTS: Of the 765 patients included in the study, 101 (13.2%) cases experienced ILA at the time of NSCLC diagnosis. Multivariate analysis revealed that ILA was more likely to be detected in NSCLC patients who were age ≥60 (OR 2.404, p = 0.001), male gender (OR 2.476, p = 0.004), and EGFR wild-type (OR 2.035, p = 0.007). Additionally, according to the multivariate Cox model, the presence of ILA in NSCLC patients was significantly associated with a shorter OS period than those without ILA (751 days vs. 445 days, HR 0.6, p = 0.001). Following analysis, it was determined that OS in patients with usual interstitial pneumonia (UIP) was shorter than in those without UIP (HR 1.82, p = 0.037). CONCLUSION: ILA is a common comorbidity among newly diagnosed NSCLC patients. We found that patients with EGFR wild-type NSCLC were more likely to develop ILA. The presence of ILA, especially UIP, was significantly associated with poor NSCLC prognosis.

The association of chest computed tomography-defined visual emphysema and prognosis in patients with nonsmall cell lung cancer.

Background: Although computed tomography (CT)-defined emphysema is considered a predictor of lung cancer risk, it is not fully clear whether CT-defined emphysema is associated with the prognosis of lung cancer. We aimed to assess the clinical impact of CT-defined emphysema on the survival of lung cancer. Methods: In the prospective cohort study of nonsmall cell lung cancer (NSCLC), the correlation between CT-defined emphysema and clinical variables was analysed. A multivariable Cox regression model was built to assess the association between CT-defined emphysema and overall survival (OS) for up to 8.8 years. The differences in survival analyses were derived by Kaplan-Meier analysis and log-rank testing. Low attenuation area (LAA%) was defined as the per cent of voxels below -950 HU. Results: 854 patients were included and CT-defined emphysema was present in 300 (35.1%) at diagnosis. Epidermal growth factor receptor (EGFR) wild-type (OR 1.998; p<0.001) and anaplastic lymphoma kinase (ALK) wild-type (OR 2.277; p=0.004) were associated with CT-defined emphysema. CT-defined emphysema remained a significant predictor of prognosis adjusting for age, sex, smoking history, tumour histology and Eastern Cooperative Oncology Group Performance Status (ECOG PS), whether in I-IIIA stage (adjusted hazard ratio (HR) 1.745; p=0.017) or in IIIB-IV stage (adjusted HR 1.291; p=0.022). Stratified analyses showed that OS rate among the driver oncogene groups with different CT-defined emphysema status differed significantly (log-rank p<0.001). Furthermore, patients with centrilobular emphysema (CLE) with LAA% >17% displayed poorer survival than those with LAA% ≤17% (median 432 versus 670 days; HR 1.564; p=0.020). Conclusions: CT-defined emphysema, especially CLE with LAA%>17%, is an independent predictor of NSCLC prognosis. Moreover, prospective studies are needed to further explore this association.

Precise prediction of the sensitivity of platinum chemotherapy in SCLC: Establishing and verifying the feasibility of a CT-based radiomics nomogram.

Objectives: To develop and validate a CT-based radiomics nomogram that can provide individualized pretreatment prediction of the response to platinum treatment in small cell lung cancer (SCLC). Materials: A total of 134 SCLC patients who were treated with platinum as a first-line therapy were eligible for this study, including 51 patients with platinum resistance (PR) and 83 patients with platinum sensitivity (PS). The variance threshold, SelectKBest, and least absolute shrinkage and selection operator (LASSO) were applied for feature selection and model construction. The selected texture features were calculated to obtain the radiomics score (Rad-score), and the predictive nomogram model was composed of the Rad-score and the clinical features selected by multivariate analysis. Receiver operating characteristic (ROC) curves, calibration curves, and decision curves were used to assess the performance of the nomogram. Results: The Rad-score was calculated using 10 radiomic features, and the resulting radiomics signature demonstrated good discrimination in both the training set (area under the curve [AUC], 0.727; 95% confidence interval [CI], 0.627-0.809) and the validation set (AUC, 0.723; 95% CI, 0.562-0.799). To improve diagnostic effectiveness, the Rad-score created a novel prediction nomogram by combining CA125 and CA72-4. The radiomics nomogram showed good calibration and discrimination in the training set (AUC, 0.900; 95% CI, 0.844-0.947) and the validation set (AUC, 0.838; 95% CI, 0.534-0.735). The radiomics nomogram proved to be clinically beneficial based on decision curve analysis. Conclusion: We developed and validated a radiomics nomogram model for predicting the response to platinum in SCLC patients. The outcomes of this model can provide useful suggestions for the development of tailored and customized second-line chemotherapy regimens.

Inactivation of KDM5A suppresses growth and enhances chemosensitivity in liver cancer by modulating ROCK1/PTEN/AKT pathway.

Liver cancer is a kind of malignant tumor with poor sensitivity to chemotherapy. It is urgent to investigate approaches to improve the outcome of chemotherapy. KDM5A has been reported to be an oncogene in various cancers and is associated with drug resistance. However, the functions of KDM5A in chemotherapeutic sensitivity of liver cancer not been well illustrated. In this study, we found that KDM5A was upregulated in liver cancer tissue and cell lines. KDM5A knockdown using a gene interference strategy suppressed the growth of liver cancer in vitro and in vivo. CPI-455, a pharmacological inactivation of KDM5A enhanced the cytotoxicity of cisplatin (CDDP) in liver cells. CPI-455 and CDDP cotreatment resulted in apoptosis and mitochondrial dysfunction. We also found that knockdown or inactivation of KDM5A resulted in the downregulation of ROCK1, an oncogene regulating the activation of the PTEN/AKT signaling pathway. In particular, overexpression of ROCK1 or SF1670, a pharmacological inhibitor of PTEN, alleviated the cytotoxicity of CPI-455 and CDDP cotreatment. In HCCLM3 xenografts, CPI-455 and CDDP cotreatment dramatically inhibited the growth of xenograft tumor compared to CPI-455 or CDDP treatment alone. In conclusion, this study suggested that targeting the inactivation of KDM5A is an efficient strategy to enhance the chemosensitivity of liver cancer cells to CDDP by modulating the ROCK1/PTEN/AKT signaling pathway.

An Arabidopsis gene encoding a C2H2-domain protein with alternatively spliced transcripts is essential for endosperm development.

The endosperm is an essential part of the seed which sustains embryo development and contains storage reserves. Endosperm development involves a series of nuclear divisions in the absence of cytokinesis. In this study, it is shown that a mutant Arabidopsis plant carrying the disrupted At4g24900 gene exhibits severe defects during seed development. At4g24900 encodes a nuclear-localized C2H2-containing protein and the transcripts of this gene are alternatively spliced, consequently producing at least nine differentially spliced isoforms. The heterozygous T-DNA insertion mutation in this gene resulted in abortion of 25% of seeds, and the homozygous mutant allele displayed embryo lethality. Differential interfernce contrast (DIC) analyses revealed that the mutant has endosperm nuclei with more than one nucleolus and an embryo arrested at the globular to heart stage transition. Because this mutant exhibits a titan-like phenotype, it was designated ttl. The TTL gene is preferentially expressed in tissues with quickly dividing cells as revealed in P(TTL)::GUS (ß-glucuronidase) transgenic plants. It is proposed that TTL is likely to function as a key regulator of endosperm nuclear division.

Metals and metalloids in the water-bloom-forming cyanobacteria and ambient water from Nanquan coast of Taihu Lake, China.

Concentrations of 12 metal(oid)s were investigated in the bloom-forming cyanobacteria and ambient water samples collected monthly between March 2009 and February 2010 at the Nanquan coast of Taihu Lake, China. The metal(oid) concentrations in ambient water decreased in the order Fe > Zn > Ni ≈ As ≈ Cu > Mn > Ag > Cr > Se > Cd > Co > Tl, while those in cyanobacteria followed a sequence Fe > Mn > Zn > Cu ≈ Ni > Co > Ag > Cr ≈ As > Cd > Tl > Se. The metal(loid) burdens removed by cyanobacteria were estimated as 164 t Fe, 12.4 t Mn, 3.6 t Zn, 2.0 t Ni, 2.0 t Cu, 0.5 t As, 0.5 t Cr, 0.4 t Cd, 0.9 t Ag, 1.1 t Co, 0.2 t Tl, and 0.09 t Se during the 2008-2010 bloom seasons.

Lox as the Potential Key Gene of Clear Cell Renal Carcinoma.

Clear cell renal carcinoma (CCRC) is the most common type of renal carcinoma. We hope to find out the potential key genes playing important roles in CCRC genesis and progression by analysing the recent expression profiling by array from 2014 to 2016. In order to find out the differentially expressed genes (DEGs) between CCRC and normal renal tissue. Gene Ontology (GO) and Kyoto Encyclopedia of Genes, and Genomes (KEGG) pathway enrichment were carried out by the Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8. Protein-Protein Interaction (PPI) Networks Functional Enrichment Analysis of these DEGs was analyzed using the Search Tool for Recurring Instances of Neighbouring Genes (STRING). The results were then visualized by the software Cytoscape. The authors also used the online tool of Kaplan-Meier plotter survival analysis to assess the significance of the top ten genes in the prognosis of CCRC. A total of 192 DEGs were identified and the top ten key genes were picked out by the software Cytoscape. FN1, CXCR4, LOX, and PLG were then further screened out based on the overall survival analysis; SLC12A1 and LOX were screened out after the recurrence-free survival analysis. LOX was finally believed to be the most reliable prognostic factor since it has prognostic value for both overall survival and recurrence-free survival analysis. Our analysis suggests that LOX is the most reliable prognostic factor for CCRC patients. Key Words: Renal clear cell carcinoma, Microarray datasets, Bioinformatics approach, Prognostic factor, LOX.

MicroRNAs/LncRNAs Modulate MDSCs in Tumor Microenvironment.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature cells derived from bone marrow that play critical immunosuppressive functions in the tumor microenvironment (TME), promoting cancer progression. According to base length, Non-coding RNAs (ncRNAs) are mainly divided into: microRNAs (miRNAs), lncRNAs, snRNAs and CircRNAs. Both miRNA and lncRNA are transcribed by RNA polymerase II, and they play an important role in gene expression under both physiological and pathological conditions. The increasing data have shown that MiRNAs/LncRNAs regulate MDSCs within TME, becoming one of potential breakthrough points at the investigation and treatment of cancer. Therefore, we summarize how miRNAs/lncRNAs mediate the differentiation, expansion and immunosuppressive function of tumor MDSCs in TME. We will then focus on the regulatory mechanisms of exosomal MicroRNAs/LncRNAs on tumor MDSCs. Finally, we will discuss how the interaction of miRNAs/lncRNAs modulates tumor MDSCs.

Solid-State Forms of Koumine Hydrochloride: Phase Transformations and the Crystal Structure and Properties of the Stable Form.

To investigate the solid-state forms of koumine hydrochloride (KMY), solid form screening was performed, and one amorphous form and five crystalline forms (forms A, B, C, D, and E) were identified by powder X-ray diffraction. Form A was the dominant crystal product, and its crystal structure and packing pattern were determined by single-crystal X-ray diffraction. The crystals displayed an orthorhombic crystal system and symmetry of space group P212121 with Z' = 1. The amorphous form transformed to form A at 105-120 °C or 75% RH, while forms B, C, D, and E could only be intermediate phases and readily transformed to form A at room temperature. Therefore, the phase transformations of KMY solid-state forms were established. The properties of the amorphous form and form A were further elucidated by applying vibrational spectroscopy, moisture sorption analysis, and thermal analysis. Accordingly, form A, the KMY anhydrate, was found to be the thermodynamically stable form with low hygroscopicity under ambient conditions. These characteristics are crucial in the manufacture and storage of active pharmaceutical ingredients.