A universal approach for integrating super large-scale single-cell transcriptomes by exploring gene rankings.

Advancement in single-cell RNA sequencing leads to exponential accumulation of single-cell expression data. However, there is still lack of tools that could integrate these unlimited accumulations of single-cell expression data. Here, we presented a universal approach iSEEEK for integrating super large-scale single-cell expression via exploring expression rankings of top-expressing genes. We developed iSEEEK with 11.9 million single cells. We demonstrated the efficiency of iSEEEK with canonical single-cell downstream tasks on five heterogenous datasets encompassing human and mouse samples. iSEEEK achieved good clustering performance benchmarked against well-annotated cell labels. In addition, iSEEEK could transfer its knowledge learned from large-scale expression data on new dataset that was not involved in its development. iSEEEK enables identification of gene-gene interaction networks that are characteristic of specific cell types. Our study presents a simple and yet effective method to integrate super large-scale single-cell transcriptomes and would facilitate translational single-cell research from bench to bedside.

Comparison of short­term outcomes and 3-year overall survival between robotic and laparoscopic gastrectomy for gastric cancer: a propensity score matching analysis.

BACKGROUND: Despite the increasing use of robotic gastrectomy (RG) as an alternative to laparoscopic gastrectomy (LG) in treating gastric cancer, controversy remains over the advantages of RG compared to LG and there is a paucity of studies comparing the two techniques regarding patient survival. METHODS: In this retrospective cohort study, 675 patients undergoing minimally invasive gastrectomy were recruited from January 2016 to January 2018 (LG: n = 567; RG: n = 108). A one-to-one propensity score matching (PSM) analysis was applied to minimize the selection bias due to confounding factors, yielding 104 patients in each of the RG and LG groups. After matching, the short-term outcomes and 3-year overall survival were compared in the two groups. RESULTS: The PSM cohort analysis showed a similar 3-year overall survival between RG and LG groups (p = .249). Concerning the short-term outcomes, the RG compared to LG resulted in lower blood loss (p = .01), lower postoperative complications (p = .001), lower postoperative pain (p = .016), earlier initiation of soft diet (p = .011), shorter hospital stay |(p = .012), but higher hospitalization expenses (p = .001). CONCLUSION: Our findings suggest that RG may offer advantages in terms of blood loss, surgical complications, recovery time, and pain management compared to LG while maintaining similar overall survival rates. However, RG is associated with higher hospital costs, potentially limiting its wider adoption. Further research, including large, multi-center randomized controlled trials with longer patient follow-up, particularly for advanced gastric cancer, is needed to confirm these findings.

Efficacy of salvage therapies after failure of adjuvant anti-PD-1 monotherapy for melanoma in the Chinese population: a multi-institutional cohort study.

The majority of melanoma patients experience relapse during adjuvant therapy or after the end of therapy. Sixty-one patients from 3 melanoma centres who experienced recurrence and received adjuvant pembrolizumab for resected stage III/IV melanoma were enrolled. Disease characteristics, recurrence characteristics, subsequent management and outcomes were retrospectively analysed. Sixty-one patients were enrolled in this study. The median time to first relapse from the commencement of adjuvant pembrolizumab was 8 months (1-22 months). The first recurrences were locoregional alone in 25 patients (41%), distant alone in 29 (47.5%) and concurrent locoregional and distant relapse in 7 (11.5%). At the first recurrence, 4 patients (80%) who underwent resection alone experienced further relapse of disease. Three (60%) patients who were treated with adjuvant pembrolizumab following surgery, 2 (100%) patients who were treated with adjuvant chemotherapy, 2 (66.7%) patients who were treated with adjuvant chemotherapy and pembrolizumab combined and 3 (100%) patients who were treated with adjuvant radiotherapy and pembrolizumab combined had further recurrence. Of the three patients treated with adjuvant BRAF/MEKi following the first relapse, none had yet recurred. Of the 8 patients treated with pembrolizumab alone, only one patient (12.5%) who recurred after ceasing adjuvant PD1 had a partial response. The overall response rate to BRAF/MEKi was 75%, 3/4; to pembrolizumab in combination with an oral multitargeted receptor tyrosine kinase inhibitor, it was 22.2%, 2/9; to chemotherapeutic agents alone, it was 33.3%, 1/3; and to chemotherapeutic agents combined with pembrolizumab, it was 37.5%, 3/8. The patient treated with imatinib had progressive disease after 3 months of treatment. Of the 6 patients who received temozolomide combined with pembrolizumab, 3 (3/6, 50%) had a partial response. The median OS of the patients who relapsed locoregionally only was longer than that of the patients who relapsed distally at the first recurrence (35 months and 14 months, respectively; P < 0.01). The outcomes of the patients with disease recurrence during or after the completion of 1 year of adjuvant anti-PD1 therapy were poor despite multimodality treatment.

DNA methylation-mediated repression of exosomal miR-652-5p expression promotes oesophageal squamous cell carcinoma aggressiveness by targeting PARG and VEGF pathways.

Exosomal microRNAs (miRNAs) have been recently shown to play vital regulatory and communication roles in cancers. In this study, we showed that the expression levels of miR-652-5p in tumour tissues and serum samples of oesophageal squamous cell carcinoma (OSCC) patients were lower compared to non-tumorous tissues and serum samples from healthy subjects, respectively. Decreased expression of miR-652-5p was correlated with TNM stages, lymph node metastasis, and short overall survival (OS). More frequent CpG sites hypermethylation in the upstream of miR-652-5p was found in OSCC tissues compared to adjacent normal tissues. Subsequently, miR-652-5p downregulation promoted the proliferation and metastasis of OSCC, and regulated cell cycle both in cells and in vivo. The dual-luciferase reporter assay confirmed that poly (ADP-ribose) glycohydrolase (PARG) and vascular endothelial growth factor A (VEGFA) were the direct targets of miR-652-5p. Moreover, the delivery of miR-652-5p agomir suppressed tumour growth and metastasis, and inhibited the protein expressions of PARG and VEGFA in nude mice. Taken together, our findings provide novel insight into the molecular mechanism underlying OSCC pathogenesis.

Distribution, source investigation, and risk assessment of topsoil heavy metals in areas with intensive anthropogenic activities using the positive matrix factorization (PMF) model coupled with self-organizing map (SOM).

Over the past decade, heavy metal (HMs) contamination in soil environments has become severe worldwide. However, their resulting ecological and health risks remained elusive across a variety of soil ecosystems due to the complicated distributions and sources. This study investigated the HMs (Cr, As, Cu, Pb, Zn, Ni, Cd, and Hg) in areas with multi-mineral resources and intensive agricultural activities to study their distribution and source apportionment using a positive matrix factorization (PMF) model coupled with self-organizing map (SOM). The potential ecological and health risks were assessed in terms of distinct sources of HMs. The results disclosed that the spatial distribution of HM contaminations in the topsoil was region-dependent, primarily located in areas with high population intensity. The geo­accumulation index (Igeo) and enrichment factor (EF) values collectively displayed that the topsoils were severely contaminated by Hg, Cu, and Pb, particularly in residential farmland areas. The comprehensive analysis combined with PMF and SOM identified both geogenic and anthropogenic sources of HMs including natural, agricultural, mining, and mixed sources (caused by multi-anthropogenic factors), accounting for 24.9%, 22.6%, 45.9%, and 6.6% contribution rates, respectively. The potential ecological risk was predominantly due to the enrichment of Hg, followed by Cd. The non-carcinogenic risks were mostly below the acceptable risk level, while the potential carcinogenic health risks caused by As and Cr should be paid prime attention to, particularly for children. In addition to the 40% geogenic sources, agricultural activities contributed to 30% of the non-carcinogenic risk, whereas mining activities contributed to nearly half of the carcinogenic health risks.

Deformation of the aquifer system under groundwater level fluctuations and its implication for land subsidence control in the Tianjin coastal region.

This study demonstrates characteristics and mechanisms of deformation of an aquifer system in response to seasonal fluctuations of groundwater level when groundwater pumping has been strictly regulated after experiencing longtime land subsidence. Two boreholes with depth of 1226 m (G2 site) and 905 m (G3 site) were drilled at the Tianjin coastal region where severe land subsidence had occurred since the 1950s. Extensometer/piezometer groups installed at the G2 site illustrate synchronized variations of compaction and groundwater level since 2010 in the aquifer system between depth of 100-400 m which contributes most groundwater pumpage. Monitored land subsidence demonstrates that the shallow aquifer has become the main contributor to the land subsidence, and inelastic compaction still occurred in the aquifers where groundwater level has recovered. Pre-consolidation stresses show that clayey soils in depth < 100 m are under-consolidated, and deep clayey soils show the state of normal- to over-consolidation. The effects of the cyclic groundwater level oscillation on deformation were investigated using repeated loading and unloading tests. Void ratio changes in loading/unloading cycles illustrate that inelastic deformation rate decreases gradually and elastic deformation rate remains almost unchanged with increases of cyclic numbers. The deformation of soil samples from 100 to 400 m is mostly elastic for loading stress in the over-consolidation stress range. These findings suggest that groundwater dewatering in the shallow (depth < 100 m) aquifer will be the primary target to control land subsidence. Groundwater level fluctuations higher than pre-consolidation value in 100-400 m only lead to elastic and recoverable deformation even small residual permanent deformation may continue for a long time. The results improve the understanding of deformation in complex urban aquifers affected by groundwater level fluctuations and highlight the importance of city planning management for controlling land subsidence in coastal cities.

High-density linkage map construction and QTL analysis for earliness-related traits in Gossypium hirsutum L.

BACKGROUND: Gossypium hirsutum L., or upland cotton, is an important renewable resource for textile fiber. To enhance understanding of the genetic basis of cotton earliness, we constructed an intra-specific recombinant inbred line population (RIL) containing 137 lines, and performed linkage map construction and quantitative trait locus (QTL) mapping. RESULTS: Using restriction-site associated DNA sequencing, a genetic map composed of 6,434 loci, including 6,295 single nucleotide polymorphisms and 139 simple sequence repeat loci, was developed from RIL population. This map spanned 4,071.98 cM, with an average distance of 0.63 cM between adjacent markers. A total of 247 QTLs for six earliness-related traits were detected in 6 consecutive years. In addition, 55 QTL coincidence regions representing more than 60 % of total QTLs were found on 22 chromosomes, which indicated that several earliness-related traits might be simultaneously improved. Fine-mapping of a 2-Mb region on chromosome D3 associated with five stable QTLs between Marker25958 and Marker25963 revealed that lines containing alleles derived from CCRI36 in this region exhibited smaller phenotypes and earlier maturity. One candidate gene (EMF2) was predicted and validated by quantitative real-time PCR in early-, medium- and late-maturing cultivars from 3- to 6-leaf stages, with highest expression level in early-maturing cultivar, CCRI74, lowest expression level in late-maturing cultivar, Bomian1. CONCLUSIONS: We developed an SNP-based genetic map, and this map is the first high-density genetic map for short-season cotton and has the potential to provide deeper insights into earliness. Cotton earliness-related QTLs and QTL coincidence regions will provide useful materials for QTL fine mapping, gene positional cloning and MAS. And the gene, EMF2, is promising for further study.

Clinical characteristics and prognostic indicators for metastatic melanoma: data from 446 patients in north China.

Melanoma is an extremely rare tumor in Asia. This retrospective study aimed to identify the clinical characteristics and prognostic factors of metastatic melanoma patients at Tianjin Medical University Cancer Hospital over the last 30 years. Survival analysis was performed with Kaplan-Meier, log-rank test, and multivariate Cox regression method using SPSS 19.0 software. The 1-, 2-, and 5-year survival rates of metastatic melanoma patients were 52, 32, and 16 %, respectively. Median overall survival (OS) was 13.5 months, median progression-free survival (PFS) 9.0 months, and median disease-free survival 20.3 months. Furthermore, patients with a single metastatic site achieved better OS and PFS than those with two or more metastatic lesions (OS 21.6 vs. 8.9 months, P < 0.001; PFS 11.3 vs. 7.1 months, P < 0.001). Survival times of patients with visceral metastases were the shortest (OS 8.5 months; PFS 7.5 months). Specifically, patients with primary mucosal lesions had a worse OS (9.7 months) and PFS (6.8 months) than those with acral (19.2 and 15.6 months, respectively) or non-acral primary lesions (11.8 and 11.1 months, respectively). The treatment of advanced melanoma was unitary, and prognoses of patients with metastatic melanoma in China were poor. Visceral metastasis, multiple metastatic sites, and primary mucosal lesions were significant predictors of survival of patients with metastatic melanoma. Those with primary mucosal lesions had significantly worse survivals than those with primary cutaneous lesions. More active involvement in clinical studies and more feedback on various treatment options are required.

Coexpression of CXCR4 and MMP9 predicts lung metastasis and poor prognosis in resected osteosarcoma.

Osteosarcoma is a highly aggressive bone disease with a tendency to metastasize to the lung. The 5-year survival of patients with metastatic osteosarcoma is only 20 %. Many studies have demonstrated SDF-1/CXCR4 and MMP9 play important roles in the metastasis of malignant tumors, including osteosarcoma. The aim of this study was to investigate the association of CXCR4 and MMP9 expression with clinicopathological features and pulmonary metastasis in osteosarcoma. Using tumor tissue microarrays, we analyzed the expression of CXCR4 and MMP9 among 34 primary osteosarcomas with pulmonary metastasis and 62 primary osteosarcomas without metastasis. A median time of 57.5 months (range: 6 to 171 months) follow-up was performed to evaluate tumor metastasis and the patient survival. The prognostic values were determined by univariate Kaplan-Meier survival analysis and multivariate Cox proportional hazard model analysis. The accuracy of oncologic outcome prediction was evaluated by receiver-operating characteristics (ROC) curves (AUC). The expression of CXCR4 and MMP9 was significantly correlated in tumor tissues (P = 0.026). Both CXCR4 and MMP9 were independent predictors for overall survival and metastasis-free survival by Cox multivariate analysis, and high expression for both CXCR4 and MMP9 were even more significant and better biomarkers for osteosarcoma metastasis and survival. The combination of CXCR4 and MMP9 high expression is very likely to be a valuable independent predictor of lung metastasis and survival in osteosarcoma patients.

The genetic basis for inactivation of Wnt pathway in human osteosarcoma.

BACKGROUND: Osteosarcoma is a highly genetically unstable tumor with poor prognosis. We performed microarray-based comparative genomic hybridization (aCGH), transcriptome sequencing (RNA-seq), and pathway analysis to gain a systemic view of the pathway alterations of osteosarcoma. METHODS: aCGH experiments were carried out on 10 fresh osteosarcoma samples. The output data (Gene Expression Omnibus Series accession number GSE19180) were pooled with published aCGH raw data (GSE9654) to determine recurrent copy number changes. These were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to identify altered pathways in osteosarcoma. Transcriptome sequencing of six osteosarcomas was performed to detect the expression profile of Wnt signaling pathway genes. Protein expression of WNT1, ß-catenin, c-myc, and cyclin D1 in the Wnt pathway was detected by immunohistochemistry (IHC) in an independent group of 46 osteosarcoma samples. RESULTS: KEGG pathway analysis identified frequent deletions of Wnt and other Wnt signaling pathway genes. At the mRNA level, transcriptome sequencing found reduced levels of mRNA expression of Wnt signaling pathway transcripts. While WNT1 protein expression was detected by IHC in 69.6% (32/46) of the osteosarcomas, no ß-catenin protein was detected in the nucleus. ß-catenin protein expression was, however, detected in the membrane and cytoplasm of 69.6% (32/46) of the osteosarcomas. c-myc protein expression was detected in only 47.8% (22/46) and cyclin D1 protein expression in 52.2% (24/46) of osteosarcoma samples. Kaplan-Meier survival analysis showed that WNT1-negative patients had a trend towards longer disease free survival than WNT1-positive patients. Interestingly, in WNT1-negative patients, those who were also cyclin D1-negative had significantly longer disease free survival than cyclin D1-positive patients. However, there was no significant association between any of the investigated proteins and overall survival of human osteosarcoma patients. CONCLUSIONS: Frequent deletions of Wnt and other Wnt signaling pathway genes suggest that the Wnt signaling pathway is genetically inactivated in human osteosarcoma.

Investigation of osteosarcoma genomics and its impact on targeted therapy: an international collaboration to conquer human osteosarcoma.

Osteosarcoma is a genetically unstable malignancy that most frequently occurs in children and young adults. The lack of progress in managing this devastating disease in the clinic has prompted international researchers to collaborate to profile key genomic alterations that define osteosarcoma. A team of researchers and clinicians from China, Finland, and the United States investigated human osteosarcoma by integrating transcriptome sequencing (RNA-seq), high-density genome-wide array comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH), reverse transcription-polymerase chain reaction (RT-PCR), Sanger sequencing, cell culture, and molecular biological approaches. Systematic analysis of genetic/genomic alterations and further functional studies have led to several important findings, including novel rearrangement hotspots, osteosarcoma-specific LRP1-SNRNP25 and KCNMB4-CCND3 fusion genes, VEGF and Wnt signaling pathway alterations, deletion of the WWOX gene, and amplification of the APEX1 and RUNX2 genes. Importantly, these genetic events associate significantly with pathogenesis, prognosis, progression, and therapeutic activity in osteosarcoma, suggesting their potential impact on improved managements of human osteosarcoma. This international initiative provides opportunities for developing new treatment modalities to conquer osteosarcoma.

Novel anti-melanoma treatment: focus on immunotherapy.

Melanoma is an intractable cancer that is aggressive, lethal, and metastatic. The prognosis of advanced melanoma is very poor because it is insensitive to chemotherapy and radiotherapy. The incidence of melanoma has been ascending stably for years worldwide, accompanied by increasing mortality. New approaches to managing this deadly disease are much anticipated to enhance the cure rate and to extend clinical benefits to patients with metastatic melanoma. Due to its high degree of immunogenicity, melanoma could be a good target for immunotherapy, which has been developed for decades and has achieved certain progress. This article provides an overview of immunotherapy for melanoma.

The fusion gene LRP1-SNRNP25 drives invasion and migration by activating the pJNK/37LRP/MMP2 signaling pathway in osteosarcoma.

Through transcriptome sequencing, we previously identified a new osteosarcoma-specific, frequent fusion gene, LRP1-SNRNP25, and found that it played an important role in tumor cell invasion and migration. However, the specific mechanism remains unclear. In this article, whole-genome sequencing further confirmed that the LRP1-SNRNP25 fusion gene is formed by fusion of LRP1 exon 8 and SNRNP25 exon 2. In vitro, scratch and Transwell assays demonstrated that the migration and invasion abilities of LRP1-SNRNP25-overexpressing osteosarcoma cells were significantly increased. To explore the molecular mechanism of the LRP1-SNRNP25 fusion in affecting osteosarcoma cell migration and invasion, we evaluated the migration and invasion-related molecular signaling pathways by western blotting. Some migration- and invasion-related genes, including pJNK and MMP2, were upregulated. Coimmunoprecipitation-mass spectrometry showed that 37LRP can interact with pJNK. Western blotting confirmed that LRP1-SNRNP25 overexpression upregulates 37LRP protein expression. Immunofluorescence staining showed the intracellular colocalization of LRP1-SNRNP25 with pJNK and 37LRP proteins and that LRP1-SNRNP25 expression increased the pJNK and 37LRP levels. Coimmunoprecipitation (co-IP) confirmed that LRP1-SNRNP25 interacted with pJNK and 37LRP proteins. The pJNK inhibitor SP600125 dose-dependently decreased the pJNK/37LRP/MMP2 levels. After siRNA-mediated 37LRP knockdown, the MMP2 protein level decreased. These two experiments proved the upstream/downstream relationship among pJNK, 37LRP, and MMP2, with pJNK the farthest upstream and MMP2 the farthest downstream. These results proved that the LRP1-SNRNP25 fusion gene exerts biological effects through the pJNK/37LRP/MMP2 signaling pathway. In vivo, LRP1-SNRNP25 promoted osteosarcoma cell growth. Tumor growth was significantly inhibited after SP600125 treatment. Immunohistochemical analysis showed that the pJNK, MMP2, and Ki-67 protein levels were significantly increased in tumor tissues of LRP1-SNRNP25-overexpressing cell-injected nude mice. Furthermore, lung and liver metastasis were more prevalent in these mice. In a word, LRP1-SNRNP25 promotes invasion, migration, and metastasis via pJNK/37LRP/MMP2 pathway. LRP1-SNRNP25 is a potential therapeutic target for LRP1-SNRNP25-positive osteosarcoma.

Tumoral C2 Regulates the Tumor Microenvironment by Increasing the Ratio of M1/M2 Macrophages and Tertiary Lymphoid Structures to Improve Prognosis in Melanoma.

Immunotherapy is an essential therapy for individuals with advanced melanoma. However, not all patients respond to such treatment due to individual differences. We conducted a multidimensional analysis using transcriptome data from our center, as well as publicly available databases. We found that effective nivolumab treatment led to an upregulation of C2 levels, and higher levels following treatment are indicative of a good outcome. Through bioinformatics analyses and immunofluorescence, we identified a correlation between C2 and M1 macrophages. To further investigate the role of C2 in melanoma, we constructed subcutaneous tumorigenic models in C57BL/6 mice. The tumors in the C2 overexpression group exhibited significantly smaller sizes. Flow cytometric analysis of the mouse tumors demonstrated enhanced recruitment of macrophages, particularly of the M1 subtype, in the overexpression group. Moreover, single-cell RNA sequencing analysis revealed that C2-positive tumor cells exhibited enhanced communication with immune cells. We co-cultured tumor cell supernatants with macrophages in vitro and observed the induction of M1 subtype polarization. In addition, we discovered a close correlation between C2 and tertiary lymphoid structures. C2 has been demonstrated to exert a protective effect, mediated by its ability to modulate the tumor microenvironment. C2 serves as a prognostic marker for melanoma and can be employed to monitor the efficacy of immunotherapy.

Evaluation of the efficacy and safety of immunotherapy in sarcoma: a two-center study.

Background: Sarcoma is a highly heterogeneous malignancy with a poor prognosis. Although chemotherapy and targeted therapy have improved the prognosis to some extent, the efficacy remains unsatisfactory in some patients. The efficacy and safety of immunotherapy in sarcoma need further evaluation. Methods: We conducted a two-center study of sarcoma patients receiving PD-1 immunotherapy at Tianjin Medical University Cancer Institute and Hospital and Henan Provincial Cancer Hospital. The treatment regimens included PD-1 inhibitor monotherapy and combination therapy based on PD-1 inhibitors. The observed primary endpoints were median progression-free survival (mPFS) and median overall survival (mOS). Survival curves were compared using the Kaplan-Meier method. Results: A total of 43 patients were included from the two centers. The median follow-up time for all patients was 13 months (range, 1-48 months). In the group of 37 patients with advanced or unresectable sarcoma, the mPFS was 6 months (95%CI: 5-12 months), and the mOS was 16 months (95%CI: 10-28 months). The ORR was 10.8% (4/37), and the DCR was 18.9% (7/37). Subgroup analysis showed no significant differences in mPFS (p=0.11) and mOS (p=0.88) between patients with PD-L1 negative/positive expression. There were also no significant differences in mPFS (p=0.13) or mOS (p=0.72) between PD-1 inhibitor monotherapy and combination therapy. Additionally, there were no significant differences in mPFS (p=0.52) or mOS (p=0.49) between osteogenic sarcoma and soft tissue sarcoma. Furthermore, the results showed no significant differences in mPFS (p=0.66) or mOS (p=0.96) between PD-1 inhibitors combined with targeted therapy and PD-1 inhibitors combined with AI chemotherapy. Among the 6 patients receiving adjuvant therapy after surgery, the mPFS was 15 months (95%CI: 6-NA months), and the mOS was not reached. In terms of safety, most adverse events were mild (grade 1-2) and manageable. The most severe grade 4 adverse events were bone marrow suppression, which occurred in 4 patients but resolved after treatment. There was also one case of a grade 4 adverse event related to hypertension. Conclusion: Immunotherapy is an effective treatment modality for sarcoma with manageable safety. Further inclusion of more patients or prospective clinical trials is needed to validate these findings.

New molecular insights into osteosarcoma targeted therapy.

PURPOSE OF REVIEW: Recent translational studies in osteosarcoma are discussed with the purpose to shed light on the new molecular therapeutic targets. RECENT FINDINGS: The genetic aberrations of vascular endothelial growth factor (VEGF), mammalian target of rapamycin, Wnt signaling pathway, the inactivation of p53, Rb, WWOX genes, and amplification of APEX1, c-myc, RECQL4, RPL8, MDM2, VEGFA might be involved in the pathogenesis of osteosarcoma. The promising therapeutic targets for osteosarcoma patients include: integrin, ezrin, statin, NOTCH/HES1, matrix metalloproteinases (MMPs), m-calpain, and Src, which are involved in tumor cell invasion and metastasis; aldolase A, fructose-bisphosphate, sulfotransferase family 3A, member 1, BCL2-associated athanogene 3, heat shock protein 70 (HSP70), B-cell lymphoma 2-interacting mediator (BIM), polo-like kinase 1, hypoxia inducible factor 1, alpha subunit, minibrain-related kinase, Bcl-xl, caspase-3, midkine, high mobility group box 1 protein (HMGB1), and Beclin1, which are involved in tumor proliferation and apoptosis; met proto-oncogene (hepatocyte growth factor receptor), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, insulin-like growth factor (IGF)-1R, fms-related tyrosine kinase 4, platelet-derived growth factor receptor, beta polypeptide, IGF-I/II, and c-kit, which are involved in tumor growth; endosialin, VEGF, thrombin, and MMPs, which are involved in tumor angiogenesis; transforming growth factor-α/ß, parathyroid hormone-like hormone, interleukin-6, interleukin-11, receptor activator of nuclear factor-κB ligand, nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1, and cathepsin, which are involved in osteoclast function; Myc, HSP90, p-Met, p-Akt, p-STAT3, and cyclin D1, which are transcriptional factors; p-GP, hydroxysteroid (17-beta) dehydrogenase 10, HMGB1, BIM, inorganic phosphate, Bcl-2, PARP, mdm2, p21, Bax, and mitogen-activated protein kinase 1, which are involved in drug sensitivity. Furthermore, microRNAs such as miR-215 are also therapeutic targets. SUMMARY: These translational studies in osteosarcoma have identified new molecular targets for osteosarcoma.

The prognostic role of PRUNE2 in leiomyosarcoma.

PRUNE2 plays an important role in regulating tumor cell differentiation, proliferation, and invasiveness in neuroblastoma. Our previous study revealed that PRUNE2/OBSCN two-gene relative expression classifer accurately differentiated leiomyosarcoma from gastrointestinal stromal tumor. However, the association between PRUNE2 expression and prognosis in leiomyosarcoma is poorly understood. In this study, we evaluated the prognostic role of PRUNE2 in leiomyosarcoma. PRUNE2 expression was detected using immunohistochemistry in 30 formalin-fixed, paraffin-embedded leiomyosarcoma tissues from MD Anderson Cancer Center, and high expression was detected in 36.7% (11/30) of the samples. To validate these results, immunohistochemistry was performed on another cohort of 45 formalin-fixed, paraffin-embedded leiomyosarcoma tissues from Tianjin Medical University Cancer Institute & Hospital, and high PRUNE2 protein expression was detected in 37.8% (17/45) of the samples. Moreover, elevated PRUNE2 expression was significantly associated with tumor size (P = 0.03) and hemorrhage/cyst (P = 0.014), and was an independent favorable prognostic factor for overall survival in leiomyosarcoma patients from Tianjin Medical University Cancer Institute & Hospital (P < 0.05). These data suggest that increased PRUNE2 protein expression may serve as a favorable prognostic marker in human leiomyosarcoma.

[Effects of feeding patterns after hospital discharge on increase rates of growth indices in preterm and low-birth-weight infants within 3 months after birth].

OBJECTIVE: To study the effects of post-discharge formula (PDF) for preterm infants, breast milk (BM) and term infant formula (TF) on increase rates of body weight, length and head circumference in preterm and low-birth-weight infants (PLBWIs) from discharge to 3 months after birth, and to provide a reference for the choice of feeding pattern for PLBWIs. METHODS: A total of 407 PLBWIs discharged from the newborn departments of ten hospitals in Guangzhou City and Foshan City in Guangdong Province, China were chosen for this study. According to feeding pattern, they were assigned to three groups: PDF-fed (n=258), BM-fed (n=58) and TF-fed (n=91). Their body weight, length and head circumference were measured at 3 months after birth, and the increase rates of growth indices relative to baseline values (at birth) were calculated and compared. RESULTS: At 3 months after birth, the PDF-fed group had significantly greater body weight, length and head circumference than the BM-fed and TF-fed groups (P<0.05). The increase rates of body weight and length were significantly higher in the PDF-fed group than in the BM-fed and TF-fed groups (P<0.05). CONCLUSIONS: Compared with those fed with BM and TF after discharge, the PDF-fed PLBWIs have higher increase rates of body weight and length and show greater body weight and length at 3 months after birth. However, further study is needed to investigate the long-term effects.