Neurotransmitters: Impressive regulators of tumor progression.

In contemporary times, tumors have emerged as the primary cause of mortality in the global population. Ongoing research has shed light on the significance of neurotransmitters in the regulation of tumors. It has been established that neurotransmitters play a pivotal role in tumor cell angiogenesis by triggering the transformation of stromal cells into tumor cells, modulating receptors on tumor stem cells, and even inducing immunosuppression. These actions ultimately foster the proliferation and metastasis of tumor cells. Several major neurotransmitters have been found to exert modulatory effects on tumor cells, including the ability to restrict emergency hematopoiesis and bind to receptors on the postsynaptic membrane, thereby inhibiting malignant progression. The abnormal secretion of neurotransmitters is closely associated with tumor progression, suggesting that focusing on neurotransmitters may yield unexpected breakthroughs in tumor therapy. This article presents an analysis and outlook on the potential of targeting neurotransmitters in tumor therapy.

Bilateral efforts to improve SERS detection efficiency of exosomes by Au/Na7PMo11O39 Combined with Phospholipid Epitope Imprinting.

Detection of cancer-related exosomes in body fluids has become a revolutionary strategy for early cancer diagnosis and prognosis prediction. We have developed a two-step targeting detection method, termed PS-MIPs-NELISA SERS, for rapid and highly sensitive exosomes detection. In the first step, a phospholipid polar site imprinting strategy was employed using magnetic PS-MIPs (phospholipids-molecularly imprinted polymers) to selectively isolate and enrich all exosomes from urine samples. In the second step, a nanozyme-linked immunosorbent assay (NELISA) technique was utilized. We constructed Au/Na7PMo11O39 nanoparticles (NPs) with both surface-enhanced Raman scattering (SERS) property and peroxidase catalytic activity, followed by the immobilization of CD9 antibodies on the surface of Au/Na7PMo11O39 NPs. The Au/Na7PMo11O39-CD9 antibody complexes were then used to recognize CD9 proteins on the surface of exosomes enriched by magnetic PS-MIPs. Lastly, the high sensitivity detection of exosomes was achieved indirectly via the SERS activity and peroxidase-like activity of Au/Na7PMo11O39 NPs. The quantity of exosomes in urine samples from pancreatic cancer patients obtained by the PS-MIPs-NELISA SERS technique showed a linear relationship with the SERS intensity in the range of 6.21 × 107-2.81 × 108 particles/mL, with a limit of detection (LOD) of 5.82 × 107 particles/mL. The SERS signal intensity of exosomes in urine samples from pancreatic cancer patients was higher than that of healthy volunteers. This bidirectional MIPs-NELISA-SERS approach enables noninvasive, highly sensitive, and rapid detection of cancer, facilitating the monitoring of disease progression during treatment and opening up a new avenue for rapid early cancer screening.

Animal models of brain and spinal cord metastases of NSCLC established using a brain stereotactic instrument.

Objective: Animal models of brain and spinal cord metastases of non-small cell lung cancer were established through the intracranial injection of PC-9 Luc cells with a brain stereotaxic device. This method provides a reliable modeling method for studying brain and spinal cord metastases of non-small cell lung cancer. Methods: PC-9 Luc cells at logarithmic growth stage were injected into the skulls of 5-week-old BALB/c nude mice at different cell volumes (30 × 104, 80 × 104) and different locations (using anterior fontanel as a location point, 1 mm from the coronal suture, and 1.5 mm from the sagittal suture on the right upper and right lower side of the skull). After 1 week of cell inoculation, fluorescence signals of tumor cells in the brain and spinal were detected using the IVIS Xenogen Imaging system. After 4 weeks, brain and spinal tissues from the nude mice were harvested. Following paraffin-embedded sectioning, HE staining was performed on the tissues. Results: The fluorescence signals revealed that both brain and spinal cord metastasis occurred in the mice where the cells were injected at the lower right side of the skull. There was only brain metastasis in the nude mice injected with 30 × 104 cells at the upper right side of the skull. Both brain and spinal cord metastasis occurred in the nude mice injected with 80 × 104 cells. The HE staining revealed that both brain and spinal cord metastasis occurred in the mice injected with different amounts of PC-9 Luc cells, consistent with the results detected using the IVIS Xenogen Imaging system, thereby demonstrating the reliability of detecting fluorescent signals in vivo to determine tumor growth. Conclusion: It is a reliable method to establish the animal model of brain and spinal cord metastases of non-small cell lung cancer by injecting different quantities of cells from different positions with a brain stereotaxic device. The IVIS Xenogen Imaging system has high reliability in detecting the fluorescence signals of brain and spinal cord metastatic tumors.

Prevalence of osteoporosis among patients after stem cell transplantation: a systematic review and meta-analysis.

The prevalence of osteoporosis in post stem cell transplantation (SCT) is poorly defined. We performed a systematic review and meta-analysis to determine the prevalence of osteoporosis in patients with hematologic diseases who underwent SCT. PubMed, EMBASE, and Web of Science were searched (from inception to 30th April 2023) using Medical Subject Headlines to find studies that assessed the prevalence of osteoporosis among post SCT. Thirteen articles meeting the inclusion criteria were included in the analysis. The pooled prevalence rates of osteoporosis, osteopenia, and decreased bone mineral density (BMD) were determined to be 14.2% (95% CI 9.7-18.8), 36.0% (95% CI 23.8-48.2), and 47.8% (95% CI 36.6-58.9), respectively. Substantial heterogeneity was observed among the included studies (I² values ranged from 81% to 99%). Subgroup analyses revealed variations in prevalence based on gender, follow-up duration, age, region, sample size, and study quality. These findings suggest a high prevalence of osteoporosis in post-SCT patients. Given the negative impact of osteoporosis on prognosis and recipient survival, clinicians should prioritize preventive measures, early diagnosis, and effective treatments to minimize its impact.

Interaction between Mesenchymal Stem Cells and Immune Cells during Bone Injury Repair.

Fractures are the most common large organ trauma in humans. The initial inflammatory response promotes bone healing during the initial post-fracture phase, but chronic and persistent inflammation due to infection or other factors does not contribute to the healing process. The precise mechanisms by which immune cells and their cytokines are regulated in bone healing remain unclear. The use of mesenchymal stem cells (MSCs) for cellular therapy of bone injuries is a novel clinical treatment approach. Bone progenitor MSCs not only differentiate into bone, but also interact with the immune system to promote the healing process. We review in vitro and in vivo studies on the role of the immune system and bone marrow MSCs in bone healing and their interactions. A deeper understanding of this paradigm may provide clues to potential therapeutic targets in the healing process, thereby improving the reliability and safety of clinical applications of MSCs to promote bone healing.

Perturbations in gut microbiota composition in patients with polycystic ovary syndrome: a systematic review and meta-analysis.

BACKGROUND: The results of human observational studies on the correlation between gut microbiota perturbations and polycystic ovary syndrome (PCOS) have been contradictory. This study aimed to perform the first systematic review and meta-analysis to evaluate the specificity of the gut microbiota in PCOS patients compared to healthy women. METHODS: Literature through May 22, 2023, was searched on PubMed, Web of Science, Medline, Embase, Cochrane Library, and Wiley Online Library databases. Unreported data in diversity indices were filled by downloading and processing raw sequencing data. Systematic review inclusion: original studies were eligible if they applied an observational case-control design, performed gut microbiota analysis and reported diversity or abundance measures, sampled general pre-menopausal women with PCOS, and are longitudinal studies with baseline comparison between PCOS patients and healthy females. Systematic review exclusion: studies that conducted interventional or longitudinal comparisons in the absence of a control group. Two researchers made abstract, full-text, and data extraction decisions, independently. The Joanna Briggs Institute Critical Appraisal Checklist was used to assess the methodologic quality. Hedge's g standardized mean difference (SMD), confidence intervals (CIs), and heterogeneity (I2) for alpha diversity were calculated. Qualitative syntheses of beta-diversity and microbe alterations were performed. RESULTS: Twenty-eight studies (n = 1022 patients, n = 928 control) that investigated gut microbiota by collecting stool samples were included, with 26 and 27 studies having provided alpha-diversity and beta-diversity results respectively. A significant decrease in microbial evenness and phylogenetic diversity was observed in PCOS patients when compared with control participants (Shannon index: SMD = - 0.27; 95% CI, - 0.37 to - 0.16; phylogenetic diversity: SMD = - 0.39; 95% CI, -- 0.74 to - 0.03). We also found that reported beta-diversity was inconsistent between studies. Despite heterogeneity in bacterial relative abundance, we observed depletion of Lachnospira and Prevotella and enrichment of Bacteroides, Parabacteroides, Lactobacillus, Fusobacterium, and Escherichia/Shigella in PCOS. Gut dysbiosis in PCOS, which might be characterized by the reduction of short-chain fatty acid (SCFA)-producing and bile-acid-metabolizing bacteria, suggests a shift in balance to favor pro-inflammatory rather than anti-inflammatory bacteria. CONCLUSIONS: Gut dysbiosis in PCOS is associated with decreased diversity and alterations in bacteria involved in microbiota-host crosstalk. TRIAL REGISTRATION: PROSPERO registration: CRD42021285206, May 22, 2023.

ISG15 is associated with cervical cancer development.

Cervical cancer (CC) is a complex disease. Numerous factors contribute to the tumourigenesis and progression of CC neoplasms. The present study analysed transcriptomic differences and simulated tumour progression to explore the pathogenesis of CC. RNA sequencing was performed to analyse the transcriptomic differences among normal tissue (NC), paracarcinoma tissue (TP), and primary tumour tissue (TT). Pseudo-time analysis was performed to simulate tumour progression. Reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemistry (IHC) were used to analyse the expression levels of ISG15 ubiquitin-like modifier (ISG15). Cell proliferation wound healing and Transwell assays were used to examine the effect of ISG15 inhibition and overexpression on HeLa cells. The RT-qPCR and IHC results indicated that ISG15 expression was significantly upregulated in TT. An increasing trend of ISG15 expression from NC to TP to TT was observed, which suggested that elevated ISG15 expression was closely associated with malignant evolution in CC tissues. HeLa cell experiments revealed that ISG15-small interfering RNA inhibited cell proliferation and invasion. The present study demonstrated that ISG15 was upregulated in CC and positively associated with the development of CC. ISG15 may act as an oncogene in the tumourigenesis of CC.

A novel nomogram for decision-making assistance on exemption of axillary lymph node dissection in T1-2 breast cancer with only one sentinel lymph node metastasis.

Background: T1-2 breast cancer patients with only one sentinel lymph node (SLN) metastasis have an extremely low non-SLN (NSLN) metastatic rate and are favorable for axillary lymph node dissection (ALND) exemption. This study aimed to construct a nomogram-based preoperative prediction model of NSLN metastasis for such patients, thereby assisting in preoperatively selecting proper surgical procedures. Methods: A total of 729 T1-2 breast cancer patients with only one SLN metastasis undergoing sentinel lymph node biopsy and ALND were retrospectively selected from Harbin Medical University Cancer Hospital between January 2013 and December 2020, followed by random assignment into training (n=467) and validation cohorts (n=262). A nomogram-based prediction model for NSLN metastasis risk was constructed by incorporating the independent predictors of NSLN metastasis identified from multivariate logistic regression analysis in the training cohort. The performance of the nomogram was evaluated by the calibration curve and the receiver operating characteristic (ROC) curve. Finally, decision curve analysis (DCA) was used to determine the clinical utility of the nomogram. Results: Overall, 160 (21.9%) patients had NSLN metastases. Multivariate analysis in the training cohort revealed that the number of negative SLNs (OR: 0.98), location of primary tumor (OR: 2.34), tumor size (OR: 3.15), and lymph-vascular invasion (OR: 1.61) were independent predictors of NSLN metastasis. The incorporation of four independent predictors into a nomogram-based preoperative estimation of NSLN metastasis demonstrated a satisfactory discriminative capacity, with a C-index and area under the ROC curve of 0.740 and 0.689 in the training and validation cohorts, respectively. The calibration curve showed good agreement between actual and predicted NSLN metastasis risks. Finally, DCA revealed the clinical utility of the nomogram. Conclusion: The nomogram showed a satisfactory discriminative capacity of NSLN metastasis risk in T1-2 breast cancer patients with only one SLN metastasis, and it could be used to preoperatively estimate NSLN metastasis risk, thereby facilitating in precise clinical decision-making on the selective exemption of ALND in such patients.

Management of Intraocular Pressure Elevation After CO2 Laser-Assisted Sclerectomy Surgery in Patients With Primary Open-Angle Glaucoma.

Purpose: To report the safety and efficiency of carbon dioxide (CO2) laser-assisted sclerectomy surgery (CLASS) in Chinese patients with primary open-angle glaucoma (POAG) and the management of unexpected postoperative intraocular pressure (IOP) elevation. Methods: This was a prospective case series study. A total of 23 eyes from 23 patients with POAG who underwent CLASS were involved and followed-up for 12 months. The primary outcomes included the changes in best corrected visual acuity (BCVA), IOP, and medications before and after CLASS. The secondary outcomes were success rate and postoperative laser interventions. Results: The mean age of the patient was 42.6 ± 16.0 years. There was no significant change in BCVA and visual field at baseline and 12 months after CLASS. The number of medications was significantly reduced after CLASS. The IOP was also significantly decreased and remained well controlled during the follow-up period, except for a transient elevation at 1 month postoperatively, due to the occurrence of peripheral anterior synechiae (PAS). Generally, 17 patients (73.9%) were treated with neodymium-doped yttrium aluminum garnet (Nd:YAG) laser synechiolysis to remove iris obstruction in the filtration site and seven patients (30.4%) underwent Nd:YAG laser goniopuncture to deal with scleral reservoir reduction. Only one patient (4.3%) received surgical repositioning due to iris incarceration. The complete success rate and total success rate at 12 months were 69.6 and 95.7%, respectively. Conclusion: CLASS was a safe and effective approach for Chinese patients with POAG. Peripheral anterior synechiae (PAS), iris incarceration, and scleral reservoir reduction were common causes of unexpected postoperative IOP elevation. Individualized Nd:YAG laser intervention helps to improve the long-term outcomes after CLASS.

Patient Preferences For Specialty Pharmacy Services: A Stated Preference Discrete-Choice Experiment in China.

Objectives: To survey, analyze, and ascertain the preferences for specialty pharmacy services among patients requiring complex care and to provide evidence to support specialty pharmacy service decision-making in China. Methods: To identify essential service attributes and levels, a review of the literature, discussions with specialty pharmacy managers and a pilot questionnaire were conducted. A D-efficient fractional factorial design was used to generate the discrete-choice experiment (DCE) questionnaire. A face-to-face survey of patients with chronic illness and their families or friends was conducted at three specialty pharmacies in Chengdu and Qingdao, China. A mixed logit model was used for estimation. Results: Six relevant attributes were identified and incorporated into the DCE questionnaire. A total of 417 participants completed the survey (mean age 43 years, 45.1% males), and 32.1% had lung cancer. The conditional relative importance showed that the most critical attribute was "frequency of telephone follow-up to monitor adverse drug reactions (ADRs), "followed by "mode of drug delivery," "provider of medication guidance services," and "availability of medical insurance consultation"; the least important attribute was "business hours." A 1 min increase in time spent led to a 0.73% decrease in the probability that a service profile would be chosen. Negative preferences were noted for ADR monitoring by telephone follow-up once a year (ß = -0.23, p < 0.001) and business hours [8:30-20:00 (Monday to Friday), 8:30-17:30 (weekend)] (ß = -0.12, p < 0.001). Compared with women, men had a higher preference for service monitoring ADRs once every 3 months. Conclusions: Preference measurements showed that "frequency of telephone follow-up to monitor ADRs" had the most critical impact on decisions, followed by "mode of drug delivery." Specialty pharmacies in China need to take these findings into account to improve their design to increase uptake and patient loyalty.

Retrospective analysis of CT-guided percutaneous cryoablation for treatment of painful osteolytic bone metastasis.

This study aimed to evaluate the safety and effectiveness of CT-guided percutaneous cryoablation for treatment of painful osteolytic bone metastases. A total of 26 patients (36 bone metastases) treated with CT-guided percutaneous cryoablation between May 2012 and June 2016 were enrolled in this retrospective study. All procedures were performed under local anesthesia. A visual analog scale (VAS) was used to evaluate pain before the procedure and at 1 day, 1 month, 3 months, and 6 months after the procedure. Complications during and after the procedure were recorded and graded by the Clavien-Dindo classification. The mean VAS pain score was 7.1 ± 1.1 (range, 4-10) before cryoablation. It was significantly lower at all timepoints after treatment: 2.1 ± 1.7 (P < 0.0001) at 1 day after treatment, 1.3 ± 1.8 (P < 0.0001) at 1 month, 1.6 ± 1.7 (P < 0.0001) at 3 months, and 1.8 ± 1.3 (P < 0.0001) at 6 months. The response rates were 91.7%, 94.4%, 91.7%, and 94.4%, respectively, at 1 day, 1 month, 3 months, and 6 months after cryoablation; the complete response rates were 22.2%, 41.7%, 36.1%, and 22.2%, respectively. Adverse events (skin frostbite, nerve injury, pathologic fracture) occurred in 3 patients. CT-guided percutaneous cryoablation under local anesthesia appears to be a safe and effective treatment for painful osteolytic bone metastases. Prospective clinical trials on large samples needed to confirm this conclusion.

Efficacy and Safety of Percutaneous Argon-Helium Cryoablation for Hepatocellular Carcinoma Abutting the Diaphragm.

PURPOSE: To evaluate the efficacy and safety of percutaneous argon-helium cryoablation (CA) for hepatocellular carcinoma (HCC) abutting the diaphragm (<5 mm). MATERIALS AND METHODS: A total of 61 consecutive patients (50 men, 11 women; mean age, 56.3 ± 12.1 years old; range, 32-83 years) with 74 HCC tumors (mean size, 3.3 ± 1.7 cm; range, 0.8-7 cm) who were treated with percutaneous argon-helium CA were enrolled in this retrospective study. Adverse events were evaluated according to Common Terminology Criteria for Adverse Events, version 5.0. Local tumor progression (LTP) and overall survival (OS) were analyzed using the Kaplan-Meier method and the log-rank test. The risk factors associated with OS and LTP were evaluated using univariate and multivariate Cox regression analysis. RESULTS: No periprocedural (30-day) deaths occurred. A total of 29 intrathoracic adverse events occurred in 24 of the 61 patients. Major adverse events were reported in 5 patients (pleural effusion requiring catheter drainage in 4 patients and pneumothorax requiring catheter placement in 1 patient). Median follow-up was 18.7 months (range, 2.3-60.0 months). Median time to LTP after CA was 20.9 months (interquartile range [IQR], 14.1-30.6 months). Median times of OS after CA and diagnosis were 27.3 months (IQR, 15.1-45.1 months) and 40.9 months (interquartile range, 24.8-68.6 months), respectively. Independent prognostic factors for OS included tumor location (left lobe vs right lobe; hazard ratio [HR], 2.031; 95% confidence interval [CI], 1.062-3.885; P = .032) and number of intrahepatic tumors (solitary vs multifocal; HR, 2.684; 95% CI, 1.322-5.447; P = .006). Independent prognostic factors for LTP included age (HR, 0.931; 95% CI, 0.900-0.963; P  < .001), guidance modality (ultrasound vs computed tomography and US; HR, 6.156 95% CI, 1.862-20.348; P  =   .003) and origin of liver disease. CONCLUSIONS: Percutaneous argon-helium CA is safe for the treatment of HCC abutting the diaphragm, with acceptable LTP and OS.

Safety and Short-Term Efficacy of Irreversible Electroporation and Allogenic Natural Killer Cell Immunotherapy Combination in the Treatment of Patients with Unresectable Primary Liver Cancer.

PURPOSE: This study aimed to investigate the safety and short-term efficacy of irreversible electroporation (IRE) combined with allogenic natural killer (NK) cell immunotherapy in the treatment of patients with unresectable primary liver cancer. MATERIALS AND METHODS: Between October 2015 and December 2016, 40 patients were enrolled and randomly allocated to either the IRE group (n = 22) or the IRE-NK group (n = 18). All adverse events experienced by the patients were recorded; the changes in tumor biomarkers [AFP, CA 19-9, circulating tumor cells (CTCs)], lymphocyte number and function, quality of life, clinical response, progression-free survival (PFS) and overall survival (OS) were assessed. RESULTS: Patients who received combination therapy exhibited significantly longer median PFS and OS than who just received IRE (PFS 15.1 vs. 10.6 months, P < 0.05, OS 17.9 vs. 23.2 months, P < 0.05). The combination therapy of IRE and NK cell immunotherapy significantly reduced CTCs and increased immune function and Karnofsky performance status. CONCLUSION: Our data suggest a novel, promising combination therapy using IRE and allogenic NK cell immunotherapy. Larger clinical trials are required to confirm these conclusions.

Integrated analysis of tobacco miRNA and mRNA expression profiles under PVY infection provids insight into tobacco-PVY interactions.

Potato virus Y (PVY) is a globally and economically important pathogen of potato, tobacco, tomato and other staple crops and caused significant yield losses and reductions in quality.To explore the molecular PVY-host interactions, we analysed changes in the miRNA and mRNA profiles of tobacco in response to PVY infection. A total of 81 differentially expressed miRNAs belonging to 29 families and 8133 mRNAs were identified. The Gene Ontology (GO) enrichment analyses showed that genes encoding the DNA/RNA binding, catalytic activity and signalling molecules were all significantly enriched. Moreover, 88 miRNA-mRNA interaction pairs were identified through a combined analysis of the two datasets. We also found evidence showing that the virus-derived siRNAs (vsiRNAs) from the PVY genome target tobacco translationally controlled tumor protein (NtTCTP) mRNA and mediate plant resistance to PVY. Together, our findings revealed that both miRNA and mRNA expression patterns can be changed in response to PVY infection and novel vsiRNA-plant interactions that may regulate plant resistance to PVY. Both provide fresh insights into the virus-plant interactions.

Liver-Specific Overexpression of Gamma-Glutamyltransferase Ameliorates Insulin Sensitivity of Male C57BL/6 Mice.

In the current study, we developed a liver-specific GGT-overexpressing mice model by rapid injection pLIVE-GGT vector through tail vein and investigated the effects of GGT elevation on glucose metabolism and insulin sensitivity. The serum GGT activity was significantly increased after 7 days of pLIVE-GGT1 vector delivery and lasted for about 3 weeks. GGT overexpression reduced the levels of GSSG and GSH in the liver and serum and had no effects on total antioxidative capacity in the liver, kidney, and skeletal muscle except for the pancreas. Increased GGT activity had no effect on the glucose tolerance but could facilitate blood glucose lowering after intraperitoneal insulin administration. The results of Western blotting showed that increased GGT activity enhanced insulin-induced AKT phosphorylation at Ser473. Furthermore, GGT inhibitor could attenuate the changes of insulin-induced blood glucose uptake and AKT phosphorylation in the liver. In summary, the present study developed a liver-specific GGT-overexpressing mice model and found that GGT elevation in short term had no effects on glucose metabolism but could increase insulin sensitivity through enhancing the activity of insulin signaling pathway.

Molecular Cloning, Expression Analysis, and Functional Characterization of the H(+)-Pyrophosphatase from Jatropha curcas.

H(+)-pyrophosphatase (H(+)-PPase) is a primary pyrophosphate (PPi)-energized proton pump to generate electrochemical H(+) gradient for ATP production and substance translocations across membranes. It plays an important role in stress adaptation that was intensively substantiated by numerous transgenic plants overexpressing H(+)-PPases yet devoid of any correlated studies pointing to the elite energy plant, Jatropha curcas. Herein, we cloned the full length of J. curcas H(+)-PPase (JcVP1) complementary DNA (cDNA) by reverse transcription PCR, based on the assembled sequence of its ESTs highly matched to Hevea brasiliensis H(+)-PPase. This gene encodes a polypeptide of 765 amino acids that was predicted as a K(+)-dependent H(+)-PPase evolutionarily closest to those of other Euphorbiaceae plants. Many cis-regulatory elements relevant to environmental stresses, molecular signals, or tissue-specificity were identified by promoter prediction within the 1.5-kb region upstream of JcVP1 coding sequence. Meanwhile, the responses of JcVP1 expression to several common abiotic stresses (salt, drought, heat, cold) were characterized with a considerable accordance with the inherent stress tolerance of J. curcas. Moreover, we found that the heterologous expression of JcVP1 could significantly improve the salt tolerance in both recombinant Escherichia coli and Saccharomyces cerevisiae, and this effect could be further fortified in yeast by N-terminal addition of a vacuole-targeting signal peptide from the H(+)-PPase of Trypanosoma cruzi.

Autophagy and autophagy dysfunction contribute to apoptosis in HepG2 cells exposed to nanosilica.

Great concerns have led to the evaluation of the potential hazards of nanosilica to human health and the environment. However, there still exists persistent debates on the biological effects and toxic consequences induced by nanosilica. The present study investigated both autophagy and apoptosis in ICR mice and Human hepatocellular carcinoma cells (HepG2), and then explored the interactive mechanism between these two distinct cell death modalities in HepG2 cells. Mice liver injuries seen by hematoxylin and eosin (HE) staining indicated the hepatotoxic effects of nanosilica. The TUNEL assay and immunohistochemistry results confirmed that nanosilica could induce both apoptosis and autophagy in vivo. Flow cytometry analysis demonstrated apoptosis induction in vitro, while autophagic ultrastructures, LC3-II expression and immunofluorescence clarified autophagy activation by nanosilica. Apoptosis suppression by the autophagy inhibitor of 3-methyladenine (3-MA) implied that autophagy was involved in apoptotic cell death. A mechanistic study verified that nanosilica induced autophagy via negative regulation of mammalian target of rapamycin (mTOR) signaling but not the Beclin-1 associated pathway. The enhancement of p62 accumulation and mTOR down-regulation might account for the molecular mechanism in contribution of autophagy to apoptosis. As an emerging new mechanism of nanomaterial toxicity, autophagy might be a more susceptive indicator for toxicological consequence evaluation in nanoparticle toxicity. The present study provides novel evidence to elucidate the toxicity mechanisms and may be beneficial to more rational applications of nanosilica in the future.

Ovarian metastasis from non-small cell lung cancer with ALK and EGFR mutations: A report of two cases.

Ovarian metastasis from non-small cell lung cancer (NSCLC) is a rare condition. The current study presents the cases of 2 female patients aged 38 and 47 years old, respectively, who were initially diagnosed with NSCLC adenocarcinoma on histology. Both patients initially presented with chest pain and a cough, and subsequently developed ovarian metastases following multiple treatments. The 38-year old patient exhibited an epidermal growth factor receptor mutation, confirmed by scorpion/amplified refractory mutation system analysis from a lung biopsy. The 47-year old exhibited an anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement, revealed by fluorescence in situ hybridization analysis of the breast tissue biopsy, confirming a diagnosis of ALK rearrangement-positive NSCLC. These patients developed ovarian metastasis in the course of the disease. The current study reports the diagnostic challenges and clinical management of the disease, and provides a review of the literature.

Membrane-bound pyrophosphatase of human gut microbe Clostridium methylpentosum confers improved salt tolerance in Escherichia coli, Saccharomyces cerevisiae and tobacco.

Membrane-bound pyrophosphatases (PPases) are involved in the adaption of organisms to stress conditions, which was substantiated by numerous plant transgenic studies with H+-PPase yet devoid of any correlated evidences for other two subfamilies, Na+-PPase and Na+,H+-PPase. Herein, we demonstrate the gene cloning and functional evaluation of the membrane-bound PPase (CmPP) of the human gut microbe Clostridium methylpentosum. The CmPP gene encodes a single polypeptide of 699 amino acids that was predicted as a multi-spanning membrane and K+-dependent Na+,H+-PPase. Heterologous expression of CmPP could significantly enhance the salt tolerance of both Escherichia coli and Saccharomyces cerevisiae, and this effect in yeast could be fortified by N-terminal addition of a vacuole-targeting signal peptide from the H+-PPase of Trypanosoma cruzi. Furthermore, introduction of CmPP could remarkably improve the salt tolerance of tobacco, implying its potential use in constructing salt-resistant transgenic crops. Consequently, the possible mechanisms of CmPP to underlie salt tolerance are discussed.