Metformin induces lactate accumulation and accelerates renal cyst progression in Pkd1-deficient mice.

Metabolic reprogramming is a potential treatment strategy for autosomal dominant polycystic kidney disease (ADPKD). Metformin has been shown to inhibit the early stages of cyst formation in animal models. However, metformin can lead to lactic acidosis in diabetic patients with advanced chronic kidney disease, and its efficacy in ADPKD is still not fully understood. Here, we investigated the effect of metformin in an established hypomorphic mouse model of PKD that presents stable and heritable knockdown of Pkd1. The Pkd1 miRNA transgenic mice of both genders were randomized to receive metformin or saline injections. Metformin was administrated through daily intraperitoneal injection from postnatal day 35 for 4 weeks. Unexpectedly, metformin treatment at a concentration of 150 mg/kg increased disease severity, including kidney-to-body weight ratio, cystic index and plasma BUN levels, and was associated with increased renal tubular cell proliferation and plasma lactate levels. Functional enrichment analysis for cDNA microarrays from kidney samples revealed significant enrichment of several pro-proliferative pathways including ß-catenin, hypoxia-inducible factor-1α, protein kinase Cα and Notch signaling pathways in the metformin-treated mutant mice. The plasma metformin concentrations were still within the recommended therapeutic range for type 2 diabetic patients. Short-term metformin treatment in a second Pkd1 hypomorphic model (Pkd1RC/RC) was however neutral. These results demonstrate that metformin may exacerbate late-stage cyst growth associated with the activation of lactate-related signaling pathways in Pkd1 deficiency. Our findings indicate that using metformin in the later stage of ADPKD might accelerate disease progression and call for the cautious use of metformin in these patients.

Transcriptome landscape reveals the chronic inflammatory response in kidneys affected by the combinatory effect of leptospirosis and nephrotoxic injury.

Leptospirosis can cause chronic kidney damage, putting patients at risk of additional kidney injury due to other factors that can lead to renal failure. To understand the combined effect, the transcriptome profiles of kidneys of mice with adenine-induced and chronically Leptospira-infected kidneys were analysed. Chronic inflammation and T-helper 17 immune responses were activated and a high-level expression of Indoleamine 2,3-dioxygenase 1 protein was found. The results indicate that the combination may predispose patients to chronic inflammation, kidney function disruption, and symptoms seen in progressive chronic kidney disease (CKD). Furthermore, immunometabolic regulation may contribute to renal injury caused by chronic leptospirosis with secondary nephrotoxic injury. This study identified several significantly disrupted genes that could serve as potential targets for the diagnosis or treatment of CKD. Our work provides insight into the combined effect of leptospirosis and secondary kidney damage and the molecular basis for rapid progression of CKD.

Transcriptomic signatures of exacerbated progression in leptospirosis subclinical chronic kidney disease with secondary nephrotoxic injury.

High-incidence regions of leptospirosis caused by Leptospira spp. coincide with chronic kidney disease. This study investigated whether asymptomatic leptospirosis is an emerging culprit that predisposes to progressive chronic kidney disease when superimposed on secondary nephrotoxic injury. Kidney histology/function and whole transcriptomic profiles were evaluated for Leptospira-infected C57/BL6 mice with adenine-induced kidney injury. The extent of tubulointerstitial kidney lesions and expression of inflammation/fibrosis genes in infected mice with low-dose (0.1%) adenine, particularly in high-dose (0.2%) adenine-fed superimposed on Leptospira-infected mice, were significantly increased compared with mice following infection or adenine diet alone, and the findings are consistent with renal transcriptome analysis. Pathway enrichment findings showed that integrin-ß- and fibronectin-encoding genes had distinct expression within the integrin-linked kinase-signaling pathway, which were upregulated in 0.2% adenine-fed Leptospira-infected mice but not in 0.2% adenine-fed mice, indicating that background subclinical Leptospiral infection indeed enhanced subsequent secondary nephrotoxic kidney injury and potential pathogenic molecules associated with secondary nephrotoxic leptospirosis. Comparative analysis of gene expression patterns with unilateral ureteric obstruction-induced mouse renal fibrosis and patients with chronic kidney disease showed that differentially expressed orthologous genes such as hemoglobin-α2, PDZ-binding kinase, and DNA topoisomerase II-α were identified in infected mice fed with low-dose and high-dose adenine, respectively, revealing differentially expressed signatures identical to those found in the datasets and may serve as markers of aggravated kidney progression. This study indicates that background subclinical leptospirosis, when subjected to various degrees of subsequent secondary nephrotoxic injury, may predispose to exacerbated fibrosis, mimicking the pathophysiological process of progressive chronic kidney disease.NEW & NOTEWORTHYLeptospira-infected mice followed by secondary nephrotoxic injury exacerbated immune/inflammatory responses and renal fibrosis. Comparison with the murine model revealed candidates involved in the progression of renal fibrosis in chronic kidney disease (CKD). Comparative transcriptome study suggests that secondary nephrotoxic injury in Leptospira-infected mice recapitulates the gene expression signatures found in CKD patients. This study indicates that secondary nephrotoxic injury may exacerbate CKD in chronic Leptospira infection implicating in the progression of CKD of unknown etiology.

Treatments that are perceived to be helpful for non-neuropathic pain after traumatic spinal cord injury: a multicenter cross-sectional survey.

STUDY DESIGN: Cross-sectional survey. OBJECTIVES: The objective of the study was to identify the treatments that people with traumatic spinal cord injury (SCI) used for their non-neuropathic pains (nonNeuPs) and how they subjectively rated the helpfulness of those treatments. SETTING: Six centers from the Spinal Cord Injury Model Systems. METHODS: Three hundred ninety one individuals who were at least 1-year post-traumatic SCI were enrolled. A telephone survey was conducted for pharmacologic and non-pharmacologic treatments utilized in the last 12 months for each participant's three worst pains and the perceived helpfulness of each treatment for each pain. RESULTS: One hundred ninety (49%) participants reported at least one nonNeuP (Spinal Cord Injury Pain Instrument score < 2) in the previous 7 days. NSAIDs/aspirin, acetaminophen, opioids, and cannabinoids were the most commonly used and helpful pharmacologic treatments for overall nonNeuP locations (helpful in 77-89% of treated pains). Body position adjustment, passive exercise, massage, resistive exercise, and heat therapy were reported as the most commonly used non-pharmacological treatments for nonNeuPs. Heat therapy, aerobic exercise, massage, and body position adjustment were the most helpful non-pharmacological treatments for overall nonNeuP locations (helpful in 71-80% of treated pains). Perceived helpfulness of treatments varied by pain locations, which may be due to different mechanisms underlying pains in different locations. CONCLUSIONS: Results of the study may help guide clinicians in selecting pain-specific treatments for nonNeuPs. The self-reported helpfulness of heat therapy, exercise, and massage suggests a possible direction for clinical trials investigating these treatments of nonNeuP while limiting the side effects accompanying pharmacologic treatments.

Crosstalk between E-Cadherin/ß-Catenin and NF-κB Signaling Pathways: The Regulation of Host-Pathogen Interaction during Leptospirosis.

Approximately 1 million cases of leptospirosis, an emerging infectious zoonotic disease, are reported each year. Pathogenic Leptospira species express leucine-rich repeat (LRR) proteins that are rarely expressed in non-pathogenic Leptospira species. The LRR domain-containing protein family is vital for the virulence of pathogenic Leptospira species. In this study, the biological mechanisms of an essential LRR domain protein from pathogenic Leptospira were examined. The effects of Leptospira and recombinant LRR20 (rLRR20) on the expression levels of factors involved in signal transduction were examined using microarray, quantitative real-time polymerase chain reaction, and western blotting. The secreted biomarkers were measured using an enzyme-linked immunosorbent assay. rLRR20 colocalized with E-cadherin on the cell surface and activated the downstream transcription factor ß-catenin, which subsequently promoted the expression of MMP7, a kidney injury biomarker. Additionally, MMP7 inhibitors were used to demonstrate that the secreted MMP7 degrades surface E-cadherin. This feedback inhibition mechanism downregulated surface E-cadherin expression and inhibited the colonization of Leptospira. The degradation of surface E-cadherin activated the NF-κB signal transduction pathway. Leptospirosis-associated acute kidney injury is associated with the secretion of NGAL, a downstream upregulated biomarker of the NF-κB signal transduction pathway. A working model was proposed to illustrate the crosstalk between E-cadherin/ß-catenin and NF-κB signal transduction pathways during Leptospira infection. Thus, rLRR20 of Leptospira induces kidney injury in host cells and inhibits the adhesion and invasion of Leptospira through the upregulation of MMP7 and NGAL.

Exoskeletal-Assisted Walking During Acute Inpatient Rehabilitation Leads to Motor and Functional Improvement in Persons With Spinal Cord Injury: A Pilot Study.

OBJECTIVE: To explore the potential effects of incorporating exoskeletal-assisted walking (EAW) into spinal cord injury (SCI) acute inpatient rehabilitation (AIR) on facilitating functional and motor recovery when compared with standard of care AIR. DESIGN: A quasi-experimental design with a prospective intervention group (AIR with EAW) and a retrospective control group (AIR only). SETTING: SCI AIR facility. PARTICIPANTS: Ten acute inpatient participants with SCI who were eligible for locomotor training were recruited in the intervention group. Twenty inpatients with SCI were identified as matched controls by reviewing an AIR database, Uniform Data System for Medical Rehabilitation, by an individual blinded to the study. Both groups (N=30) were matched based on etiology, paraplegia/tetraplegia, completeness of injury, age, and sex. INTERVENTION: EAW incorporated into SCI AIR. MAIN OUTCOME MEASURES: FIM score, International Standards for Neurological Classification of Spinal Cord Injury Upper Extremity Motor Score and Lower Extremity Motor Scores (LEMS), and EAW session results, including adverse events, walking time, and steps. RESULTS: Changes from admission to discharge LEMS and FIM scores were significantly greater in the intervention group (LEMS change: 14.3±10.1; FIM change: 37.8±10.8) compared with the control group (LEMS change: 4.6±6.1; FIM change: 26.5±14.3; Mann-Whitney U tests: LEMS, P<.01 and FIM, P<.05). One adverse event (minor skin abrasion) occurred during 42 walking sessions. Participants on average achieved 31.5 minutes of up time and 18.2 minutes of walk time with 456 steps in one EAW session. CONCLUSIONS: Incorporation of EAW into standard of care AIR is possible. AIR with incorporated EAW has the potential to facilitate functional and motor recovery compared with AIR without EAW.

An interview based approach to the anorectal portion of the International Standards of Neurological Classification of Spinal Cord Injury Exam (I-A-ISNCSCI): a pilot study.

STUDY DESIGN: Prospective, single-blinded study. OBJECTIVE: To design and evaluate the use of an interview based version of the anorectal portion of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) exam in the acute inpatient rehabilitation (AIR) setting. SETTING: AIR unit. METHODS: Participants admitted to AIR underwent standard ISNCSCI exams (S-ISNCSCI) as part of routine inpatient care within 3 days of being administered an interview version of the anorectal portion of the ISNCSCI (I-A-ISNCSCI). Agreement between the anorectal portion of the S-ISNCSCI (S-A-ISNCSCI) and the I-A-ISNCSCI was evaluated. RESULTS: Forty of forty-five enrolled participants completed the assessments. Agreement between the I-A-ISNCSCI and S-A-ISNCSCI was substantial for anorectal sensation to light touch (k = 0.71, 95% CI 0.52-0.90, N = 36), pin prick (k = 0.68, 95% CI 0.48-0.87, N = 38), deep anal pressure (k = 0.77, 95% CI 0.53-1.00, N = 37), and completeness of injury based on combined sacral sensory criteria (k = 0.72, 95% CI 0.47-0.97, N = 40); and fair for voluntary anal contraction (k = 0.29, 95% CI -0.01 to 0.59, N = 36). Responses of "I don't know" were excluded from agreement analyses. CONCLUSIONS: This pilot study was a first step in developing interview based tools such as the I-A-ISNCSCI in an AIR setting providing convenient access to individuals with SCI and their direct feedback. The study design introduces potential recall bias and may not match true clinical situations such as remote follow-up of neurological changes for chronic patients. The use of interview based tools for assessing individuals with SCI remains worthy of further study.

Taurine up-regulated gene 1 functions as a master regulator to coordinate glycolysis and metastasis in hepatocellular carcinoma.

Cancer cells display altered glucose metabolism characterized by a preference for aerobic glycolysis. The aerobic glycolytic phenotype of hepatocellular carcinoma (HCC) is often correlated with tumor progression and poorer clinical outcomes. However, the issue of whether glycolytic metabolism influences metastasis in HCC remains unclear. In the current study, we showed that knockdown of taurine up-regulated gene 1 (TUG1) induces marked inhibition of cell migration, invasion, and glycolysis through suppression of microRNA (miR)-455-3p. MiR-455-3p, which is transcriptionally repressed by p21, directly targets the 3' untranslated region of adenosine monophosphate-activated protein kinase subunit beta 2 (AMPKß2). The TUG1/miR-455-3p/AMPKß2 axis regulates cell growth, metastasis, and glycolysis through regulation of hexokinase 2 (HK2). TUG1 is clearly associated with HK2 overexpression and unfavorable prognosis in HCC patients. CONCLUSION: Our data collectively highlight that novel regulatory associations among TUG1, miR-455-3p, AMPKß2, and HK2 are an important determinant of glycolytic metabolism and metastasis in HCC cells and support the potential utility of targeting TUG1/HK2 as a therapeutic strategy for HCC. (Hepatology 2018;67:188-203).

Argininosuccinate synthetase 1 contributes to gastric cancer invasion and progression by modulating autophagy.

Argininosuccinate synthetase 1 (ASS1) is a rate-limited enzyme in arginine biosynthesis. The oncogenic potential of ASS1 in terms of prognosis and cancer metastasis in arginine prototrophic gastric cancer (GC) remains unclear at present. We identify differentially expressed proteins in microdissected GC tumor cells relative to adjacent nontumor epithelia by isobaric mass tag for relative and absolute quantitation proteomics analysis. GC cells with stable expression or depletion of ASS1 were further analyzed to identify downstream molecules. We investigated their effects on chemoresistance and cell invasion in the presence or absence of arginine. ASS1 was highly expressed in GC and positively correlated with GC aggressiveness and poor outcome. Depletion of ASS1 led to inhibition of tumor growth and decreased cell invasion via induction of autophagy-lysosome machinery, resulting in degradation of active ß-catenin, Snail, and Twist. Ectopic expression of ASS1 in GC cells reversed these effects and protected cancer cells from chemotherapy drug-induced apoptosis via activation of the AKT-mammalian target of rapamycin signaling pathway. ASS1 contributes to GC progression by enhancing aggressive potential resulting from active ß-catenin, Snail, and Twist accumulation. Our results propose that ASS1 might contribute to GC metastasis and support its utility as a prognostic predictor of GC.-Tsai, C.-Y., Chi, H.-C., Chi, L.-M., Yang, H.-Y., Tsai, M.-M., Lee, K.-F., Huang, H.-W., Chou, L.-F., Cheng, A.-J., Yang, C.-W., Wang, C.-S., Lin, K.-H. Argininosuccinate synthetase 1 contributes to gastric cancer invasion and progression by modulating autophagy.

Molecular functions and clinical impact of thyroid hormone-triggered autophagy in liver-related diseases.

The liver is controlled by several metabolic hormones, including thyroid hormone, and characteristically displays high lysosomal activity as well as metabolic stress-triggered autophagy, which is stringently regulated by the levels of hormones and metabolites. Hepatic autophagy provides energy through catabolism of glucose, amino acids and free fatty acids for starved cells, facilitating the generation of new macromolecules and maintenance of the quantity and quality of cellular organelles, such as mitochondria. Dysregulation of autophagy and defective mitochondrial homeostasis contribute to hepatocyte injury and liver-related diseases, such as non-alcoholic fatty liver disease (NAFLD) and liver cancer.Thyroid hormones (TH) mediate several critical physiological processes including organ development, cell differentiation, metabolism and cell growth and maintenance. Accumulating evidence has revealed dysregulation of cellular TH activity as the underlying cause of several liver-related diseases, including alcoholic or non-alcoholic fatty liver disease and liver cancer. Data from epidemiologic, animal and clinical studies collectively support preventive functions of THs in liver-related diseases, highlighting the therapeutic potential of TH analogs. Elucidation of the molecular mechanisms and downstream targets of TH should thus facilitate the development of therapeutic strategies for a number of major public health issues.Here, we have reviewed recent studies focusing on the involvement of THs in hepatic homeostasis through induction of autophagy and their implications in liver-related diseases. Additionally, the potential underlying molecular pathways and therapeutic applications of THs in NAFLD and HCC are discussed.

DEK Is a Potential Biomarker Associated with Malignant Phenotype in Gastric Cancer Tissues and Plasma.

Gastric cancer (GC) is the second most widespread cause of cancer-related mortality worldwide. The discovery of novel biomarkers of oncoproteins can facilitate the development of therapeutic strategies for GC treatment. In this study, we identified novel biomarkers by integrating isobaric tags for relative and absolute quantitation (iTRAQ), a human plasma proteome database, and public Oncomine datasets to search for aberrantly expressed oncogene-associated proteins in GC tissues and plasma. One of the most significantly upregulated biomarkers, DEK, was selected and its expression validated. Our immunohistochemistry (IHC) (n = 92) and quantitative real-time polymerase chain reaction (qRT-PCR) (n = 72) analyses disclosed a marked increase in DEK expression in tumor tissue, compared with paired nontumor mucosa. Importantly, significantly higher preoperative plasma DEK levels were detected in GC patients than in healthy controls via enzyme-linked immunosorbent assay (ELISA). In clinicopathological analysis, higher expression of DEK in both tissue and plasma was significantly associated with advanced stage and poorer survival outcomes of GC patients. Data from receiver operating characteristic (ROC) curve analysis disclosed a better diagnostic accuracy of plasma DEK than carcinoembryonic antigen (CEA), carbohydrate antigen 19.9 (CA 19.9), and C-reactive protein (CRP), highlighting its potential as an effective plasma biomarker for GC. Plasma DEK is also more sensitive in tumor detection than the other three biomarkers. Knockdown of DEK resulted in inhibition of GC cell migration via a mechanism involving modulation of matrix metalloproteinase MMP-2/MMP-9 level and vice versa. Our results collectively support plasma DEK as a useful biomarker for making diagnosis and prognosis of GC patients.

Murine Renal Transcriptome Profiles Upon Leptospiral Infection: Implications for Chronic Kidney Diseases.

Background: Leptospirosis caused by pathogenic Leptospira spp leads to kidney damage that may progress to chronic kidney disease. However, how leptospiral infections induced renal damage is unclear. Methods: We apply microarray and next-generation sequencing technologies to investigate the first murine transcriptome-wide, leptospires-mediated changes in renal gene expression to identify biological pathways associated with kidney damage. Results: Leptospiral genes were detected in renal transcriptomes of mice infected with Leptospira interrogans at day 28 postinfection, suggesting colonization of leptospires within the kidney with propensity of chronicity. Comparative differential gene expression and pathway analysis were investigated in renal transcriptomes of mice infected with pathogens and nonpathogens. Pathways analysis showed that Toll-like receptor signaling, complements activation, T-helper 1 type immune response, and T cell-mediated immunity/chemotaxis/proliferation were strongly associated with progressive tubulointerstitial damage caused by pathogenic leptospiral infection. In addition, 26 genes related with complement system, immune function, and cell-cell interactions were found to be significantly up-regulated in the L interrogans-infected renal transcriptome. Conclusions: Our results provided comprehensive knowledge regarding the host transcriptional response to leptospiral infection in murine kidneys, particularly the involvement of cell-to-cell interaction in the immune response. It would provide valuable resources to explore functional studies of chronic renal damage caused by leptospiral infection.

Impact of DNA and RNA Methylation on Radiobiology and Cancer Progression.

Radiotherapy is a well-established regimen for nearly half the cancer patients worldwide. However, not all cancer patients respond to irradiation treatment, and radioresistance is highly associated with poor prognosis and risk of recurrence. Elucidation of the biological characteristics of radioresistance and development of effective prognostic markers to guide clinical decision making clearly remain an urgent medical requirement. In tumorigenic and radioresistant cancer cell populations, phenotypic switch is observed during the course of irradiation treatment, which is associated with both stable genetic and epigenetic changes. While the importance of epigenetic changes is widely accepted, the irradiation-triggered specific epigenetic alterations at the molecular level are incompletely defined. The present review provides a summary of current studies on the molecular functions of DNA and RNA m6A methylation, the key epigenetic mechanisms involved in regulating the expression of genetic information, in resistance to irradiation and cancer progression. We additionally discuss the effects of DNA methylation and RNA N6-methyladenosine (m6A) of specific genes in cancer progression, recurrence, and radioresistance. As epigenetic alterations could be reversed by drug treatment or inhibition of specific genes, they are also considered potential targets for anticancer therapy and/or radiotherapy sensitizers. The mechanisms of irradiation-induced alterations in DNA and RNA m6A methylation, and ways in which this understanding can be applied clinically, including utilization of methylation patterns as prognostic markers for cancer radiotherapy and their manipulation for anticancer therapy or use as radiotherapy sensitizers, have been further discussed.

Hepatoma cell functions modulated by NEK2 are associated with liver cancer progression.

NEK2 (NIMA-related expressed kinase 2) is a serine/threonine centrosomal kinase that acts as a critical regulator of centrosome structure and function. Aberrant NEK2 activities lead to failure in regulating centrosome duplication. NEK2 overexpression promotes tumorigenesis and is associated with poor prognosis in several cancers. Increased NEK2 expression during the late pathological stage has been detected in the Oncomine liver dataset and hepatocellular carcinoma (HCC) specimens. Elevated NEK2 protein is associated with poor overall survival in patients with HCC. However, the precise roles and mechanisms of NEK2 in liver cancer progression remain largely unknown. An earlier functional study revealed that NEK2 mediates drug resistance (cisplatin or lipo-doxorubicin) via expression of an ABCC10 transporter. Active angiogenesis and metastasis underlie the rapid recurrence and poor survival of HCC. Results from the current study showed that NEK2 mediates tumor growth, metastasis and angiogenesis in vivo. NEK2-mediated drug resistance was blocked by a specific PI3K or AKT inhibitor. Moreover, NEK2 mediated liver cancer cell migration via pAKT/NF-κB signaling and matrix metalloproteinase (MMP) activation. Angiogenesis was induced via the same signaling pathway and IL-8 stimulation. Our findings collectively indicate that NEK2 modulates hepatoma cell functions, including growth, drug resistance, metastasis and angiogenesis via downstream genes activation.

Roles of Long Noncoding RNAs in Recurrence and Metastasis of Radiotherapy-Resistant Cancer Stem Cells.

Radiotherapy is a well-established therapeutic regimen applied to treat at least half of all cancer patients worldwide. Radioresistance of cancers or failure to treat certain tumor types with radiation is associated with enhanced local invasion, metastasis and poor prognosis. Elucidation of the biological characteristics underlying radioresistance is therefore critical to ensure the development of effective strategies to resolve this issue, which remains an urgent medical problem. Cancer stem cells (CSCs) comprise a small population of tumor cells that constitute the origin of most cancer cell types. CSCs are virtually resistant to radiotherapy, and consequently contribute to recurrence and disease progression. Metastasis is an increasing problem in resistance to cancer radiotherapy and closely associated with the morbidity and mortality rates of several cancer types. Accumulating evidence has demonstrated that radiation induces epithelial-mesenchymal transition (EMT) accompanied by increased cancer recurrence, metastasis and CSC generation. CSCs are believed to serve as the basis of metastasis. Previous studies indicate that CSCs contribute to the generation of metastasis, either in a direct or indirect manner. Moreover, the heterogeneity of CSCs may be responsible for organ specificity and considerable complexity of metastases. Long noncoding RNAs (lncRNAs) are a class of noncoding molecules over 200 nucleotides in length involved in the initiation and progression of several cancer types. Recently, lncRNAs have attracted considerable attention as novel critical regulators of cancer progression and metastasis. In the current review, we have discussed lncRNA-mediated regulation of CSCs following radiotherapy, their association with tumor metastasis and significance in radioresistance of cancer.

Immediate Biomechanical Implications of Transfer Component Skills Training on Independent Wheelchair Transfers.

OBJECTIVE: To evaluate the immediate effects of transfer training based on the Transfer Assessment Instrument (TAI) on the upper limb biomechanics during transfers. DESIGN: Pre-post intervention. SETTING: Biomechanics laboratory. PARTICIPANTS: Full-time manual wheelchair users (N=24) performed 5 transfers to a level height bench, while their natural transfer skills were scored using the TAI, and their biomechanical data were recorded. INTERVENTION: Participants with 2 or more component skill deficits were invited to return to receive personalized transfer training. MAIN OUTCOME MEASURES: TAI part 1 summary scores and biomechanical variables calculated at the shoulder, elbow, and wrist joints were compared before and immediately after transfer training. RESULTS: Sixteen of the 24 manual wheelchair users met the criteria for training, and 11 manual wheelchair users came back for the revisit. Their TAI part 1 summary scores improved from 6.31±.98 to 9.92±.25. They had significantly smaller elbow range of motion, shoulder resultant moment, and rates of rise of elbow and wrist resultant forces on their trailing side during transfers after training (P<.05). On the leading side, shoulder maximum internal rotation and elevation angles, and shoulder resultant moments and rates of rise of shoulder resultant force and moment decreased after training (P<.04). CONCLUSIONS: The TAI-based training showed short-term beneficial biomechanical effects on wheelchair users' upper limbs, such as better shoulder positioning and lower joint loadings. If the skills are practiced longer-term, they may help protect the upper limbs from developing pain and injuries.

Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer.

Human gastric cancer (GC) is characterized by a high incidence and mortality rate, largely because it is normally not identified until a relatively advanced stage owing to a lack of early diagnostic biomarkers. Gastroscopy with biopsy is the routine method for screening, and gastrectomy is the major therapeutic strategy for GC. However, in more than 30% of GC surgical patients, cancer has progressed too far for effective medical resection. Thus, useful biomarkers for early screening or detection of GC are essential for improving patients' survival rate. MicroRNAs (miRNAs) play an important role in tumorigenesis. They contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors. Because of their stability in tissues, serum/plasma and other body fluids, miRNAs have been suggested as novel tumor biomarkers with suitable clinical potential. Recently, aberrantly expressed miRNAs have been identified and tested for clinical application in the management of GC. Aberrant miRNA expression profiles determined with miRNA microarrays, quantitative reverse transcription-polymerase chain reaction and next-generation sequencing approaches could be used to establish sample specificity and to identify tumor type. Here, we provide an up-to-date summary of tissue-based GC-associated miRNAs, describing their involvement and that of their downstream targets in tumorigenic and biological processes. We examine correlations among significant clinical parameters and prognostic indicators, and discuss recurrence monitoring and therapeutic options in GC. We also review plasma/serum-based, GC-associated, circulating miRNAs and their clinical applications, focusing especially on early diagnosis. By providing insights into the mechanisms of miRNA-related tumor progression, this review will hopefully aid in the identification of novel potential therapeutic targets.

Negative modulation of the epigenetic regulator, UHRF1, by thyroid hormone receptors suppresses liver cancer cell growth.

The thyroid hormone, 3,3',5-triiodo-l-thyronine (T3 ), mediates several physiological processes, including embryonic development, cellular differentiation, metabolism and regulation of cell proliferation. Thyroid hormone (T3 ) and its receptor (TR) are involved in metabolism and growth. In addition to their developmental and metabolic functions, TRs play a tumor suppressor role, and therefore, their aberrant expression can lead to tumor transformation. Aberrant epigenetic silencing of tumor suppressor genes promotes cancer progression. The epigenetic regulator, Ubiquitin-like with PHD and ring finger domains 1 (UHRF1), is overexpressed in various cancers. In our study, we demonstrated that T3 negatively regulates UHRF1 expression, both in vitro and in vivo. Our results further indicate that UHRF1 regulation by T3 is indirect and mediated by Sp1. Sp1-binding elements of UHRF1 were identified at positions -664/-505 of the promoter region using the luciferase and chromatin immunoprecipitation assays. Notably, UHRF1 and Sp1 levels were elevated in subgroups of hepatocellular carcinoma patients and inversely correlated with TRα1 expression. Knockdown of UHRF1 expression should therefore provide a means to inhibit hepatoma cell proliferation. Expression of UHRF1 was downregulated by TRs, in turn, relieving silencing of the UHRF1 target gene, p21. Based on the collective findings, we propose that T3 /TR signaling induces hepatoma cell growth inhibition via UHRF1 repression.

Repression of microRNA-130b by thyroid hormone enhances cell motility.

BACKGROUND & AIMS: Thyroid hormone (T3) and its receptor (TR) are involved in cell growth and cancer progression. Although deregulation of microRNA (miRNA) expression has been detected in many tumor types, the mechanisms underlying functional impairment and specific involvement of miRNAs in tumor metastasis remain unclear. In the current study, we aimed to elucidate the involvement of deregulated miRNA-130b (miR-130b) and its target genes mediated by T3/TR in cancer progression. METHODS: Quantitative reverse transcription-PCR, luciferase and chromatin immunoprecipitation assays were performed to identify the miR-130b transcript and the mechanisms implicated in its regulation. The effects of miR-130b on hepatocellular carcinoma (HCC) invasion were further examined in vitro and in vivo. Clinical correlations among miR-130b, TRs and interferon regulatory factor 1 (IRF1) were examined in HCC samples using Spearman correlation analysis. RESULTS: Our experiments disclosed negative regulation of miR-130b expression by T3/TR. Overexpression of miR-130b led to marked inhibition of cell migration and invasion, which was mediated via suppression of IRF1. Cell migration ability was promoted by T3, but partially suppressed upon miR-130b overexpression. Furthermore, miR-130b suppressed expression of epithelial-mesenchymal transition (EMT)-related genes, matrix metalloproteinase-9, phosphorylated mammalian target of rapamycin (mTOR), p-ERK1/2, p-AKT and p-signal transducer and activator of transcription (STAT)-3. Notably, miR-130b was downregulated in hepatoma samples and its expression patterns were inversely correlated with those of TRα1 and IRF1. CONCLUSIONS: Our data collectively highlight a novel pathway interlinking T3/TR, miR-130b, IRF1, the EMT-related genes, p-mTOR, p-STAT3 and the p-AKT cascade, which regulates the motility and invasion of hepatoma cells.

Thyroid hormone enhanced human hepatoma cell motility involves brain-specific serine protease 4 activation via ERK signaling.

BACKGROUND: The thyroid hormone, 3, 3', 5-triiodo-L-thyronine (T3), has been shown to modulate cellular processes via interactions with thyroid hormone receptors (TRs), but the secretory proteins that are regulated to exert these effects remain to be characterized. Brain-specific serine protease 4 (BSSP4), a member of the human serine protease family, participates in extracellular matrix remodeling. However, the physiological role and underlying mechanism of T3-mediated regulation of BSSP4 in hepatocellular carcinogenesis are yet to be established. METHODS: The thyroid hormone response element was identified by reporter and chromatin immunoprecipitation assays. The cell motility was analyzed via transwell and SCID mice. The BSSP4 expression in clinical specimens was examined by Western blot and quantitative reverse transcription polymerase chain reaction. RESULTS: Upregulation of BSSP4 at mRNA and protein levels after T3 stimulation is a time- and dose-dependent manner in hepatoma cell lines. Additionally, the regulatory region of the BSSP4 promoter stimulated by T3 was identified at positions -609/-594. BSSP4 overexpression enhanced tumor cell migration and invasion, both in vitro and in vivo. Subsequently, BSSP4-induced migration occurs through the ERK 1/2-C/EBPß-VEGF cascade, similar to that observed in HepG2-TRα1 and J7-TRα1 cells. BSSP4 was overexpressed in clinical hepatocellular carcinoma (HCC) patients, compared with normal subjects, and positively associated with TRα1 and VEGF to a significant extent. Importantly, a mild association between BSSP4 expression and distant metastasis was observed. CONCLUSIONS: Our findings collectively support a potential role of T3 in cancer cell progression through regulation of the BSSP4 protease via the ERK 1/2-C/EBPß-VEGF cascade. BSSP4 may thus be effectively utilized as a novel marker and anti-cancer therapeutic target in HCC.