LIN28A enhances regenerative capacity of human somatic tissue stem cells via metabolic and mitochondrial reprogramming.

Developing methods to improve the regenerative capacity of somatic stem cells (SSCs) is a major challenge in regenerative medicine. Here, we propose the forced expression of LIN28A as a method to modulate cellular metabolism, which in turn enhances self-renewal, differentiation capacities, and engraftment after transplantation of various human SSCs. Mechanistically, in undifferentiated/proliferating SSCs, LIN28A induced metabolic reprogramming from oxidative phosphorylation (OxPhos) to glycolysis by activating PDK1-mediated glycolysis-TCA/OxPhos uncoupling. Mitochondria were also reprogrammed into healthy/fused mitochondria with improved functional capacity. The reprogramming allows SSCs to undergo cell proliferation more extensively with low levels of oxidative and mitochondrial stress. When the PDK1-mediated uncoupling was untethered upon differentiation, LIN28A-SSCs differentiated more efficiently with an increase of OxPhos by utilizing the reprogrammed mitochondria. This study provides mechanistic and practical approaches of utilizing LIN28A and metabolic reprogramming in order to improve SSCs utility in regenerative medicine.

Inhibition of SIRT6 potentiates the anti-tumor effect of doxorubicin through suppression of the DNA damage repair pathway in osteosarcoma.

BACKGROUND: SIRT6 has diverse roles in cells, and the role of SIRT6 in tumorigenesis is controversial. Considering the role of SIRT6 as an inducer of DNA damage repair, it might be involved in resistance to anti-cancer therapy. METHODS: We evaluated the prognostic significance of SIRT6 in 37 osteosarcomas and investigated the therapeutic efficacy of SIRT6 on the anticancer effects of doxorubicin, olaparib, and ATM inhibitor. RESULTS: Immunohistochemical expression of SIRT6 was significantly associated with shorter overall survival and relapse-free survival of osteosarcoma patients, especially in patients who received adjuvant chemotherapy. In U2OS and KHOS/NP osteosarcoma cells, knock-down of SIRT6 significantly potentiated apoptotic effects of doxorubicin and SIRT6 overexpression induced resistance to doxorubicin. Moreover, SIRT6 induced the DNA damage repair pathway and SIRT6-mediated resistance to doxorubicin was attenuated by blocking the DNA damage repair pathway with olaparib and ATM inhibitor. CONCLUSIONS: This study suggests that suppression of SIRT6 in combination with doxorubicin might be an effective modality in the treatment of osteosarcoma patients, especially for osteosarcomas with shorter survival with high expression of SIRT6.

FAM83H and SCRIB stabilize ß-catenin and stimulate progression of gastric carcinoma.

FAM83H primarily is known for its function in tooth development. Recently, a role for FAM83H in tumorigenesis, conjunction with MYC and ß-catenin, has been suggested. Analysis of public data indicates that FAM83H expression is closely associated with SCRIB expression in human gastric cancers. Therefore, this study investigated the roles of FAM83H and SCRIB in 200 human gastric cancers and gastric cancer cells. In human gastric carcinomas, both the individual and combined expression patterns of the nuclear FAM83H and SCRIB were independent indicators of shorter survival of gastric carcinoma patients. In MKN-45 and NCI-N87 gastric cancer cells, the expression of FAM83H and SCRIB were associated with proliferation and invasiveness of cells. FAM83H-mediated in vivo tumor growth was attenuated with knock-down of SCRIB. Moreover, immunoprecipitation indicates that FAM83H, SCRIB, and ß-catenin, form a complex, and knock-down of either FAM83H or SCRIB accelerated proteasomal degradation of ß-catenin. In conclusion, this study has found that the individual and combined expression patterns of nuclear FAM83H and SCRIB are prognostic indicators of gastric carcinomas and further suggests that FAM83H and SCRIB are involved in the progression of gastric carcinomas by stabilizing ß-catenin.

Prediction of Smoking Abstinence in Women Living With Human Immunodeficiency Virus Infection.

BACKGROUND: This study examined whether baseline negative emotional states (depression and anxiety) would predict craving for cigarettes and other nicotine withdrawal symptoms in early abstinence and whether those emotional states and withdrawal symptoms would predict failure in quitting smoking at 3 months postquit among U.S. women living with the human immunodeficiency virus (HIV). METHOD: The study is a secondary analysis of data from two smoking cessation studies of women living with HIV. Craving for cigarettes and other withdrawal symptoms were assessed weekly with a total of 229 observations during the first 4 weeks following quit day. Descriptive statistics were used to examine baseline characteristics of the participants. A random growth curve model was used to estimate between-person differences in a within-person trend of changes in the withdrawal symptoms. A binary logistic regression analysis was performed to identify predictors of short-term smoking abstinence. RESULTS: Baseline anxiety was a predictor of postquit nicotine withdrawal symptoms but baseline depression was not. Neither baseline anxiety nor depression predicted postquit craving for cigarettes. Participants who received an HIV-tailored smoking cessation intervention showed a greater decline in craving symptom than those who received an attention-controlled intervention. HIV-tailored intervention and less craving predicted smoking abstinence at 3-month follow-up. DISCUSSION: Compared to an attention-controlled intervention, an HIV-tailored intervention effectively decreased craving for cigarette smoking after quitting-which effectively increased the rate of short-term smoking abstinence in women living with HIV.

The role of age in determining the effects of lipo-PGE1 infusion on immediate arterial maximal flow velocity in patients with diabetes undergoing free flap surgery for lower extremity reconstruction: A prospective observational study.

BACKGROUND: Diabetes mellitus may have a negative effect on free flap perfusion in patients undergoing reconstructive surgery. Little is known of the effects of lipo-prostaglandin E1 (lipo-PGE1) on flap blood flow in diabetes. This study investigated the effects of lipo-PGE1 on maximal blood flow velocity of the free flap arterial pedicle in patients with diabetes. METHODS: This prospective observational study assessed maximal blood flow velocity in the arterial pedicle before and 30 min after infusion of 0.4 µg/h lipo-PGE1 in 40 patients with diabetes who received a free flap for lower extremity reconstruction. Multivariate logistic regression analysis was performed to determine whether age, hemoglobin A1c concentration, duration of diabetes, and flap type were significantly associated with increased maximal blood flow velocity after lipo-PGE1 infusion or not. RESULTS: The maximal blood flow velocity of the free flap did not differ significantly before and 30 min after lipo-PGE1 infusion. Multivariate logistic regression analysis showed that age <65 years was the only independent factor associated with increased maximal blood flow velocity after lipo-PGE1 infusion (odds ratio = 5.344; p = 0.022). CONCLUSION: Assessments of all patients with diabetes undergoing free flap surgery, when age was not taken into consideration, found that lipo-PGE1 did not significantly increase the maximal blood flow velocity of the free flap arterial pedicle. However, when age was taken into consideration, lipo-PGE1 increased blood flow velocity in patients <65 years old, suggesting that age influences the effect of lipo-PGE1 on the blood flow velocity.

Extent of Pedigree Required to Screen for and Diagnose Hereditary Nonpolyposis Colorectal Cancer: Comparison of Simplified and Extended Pedigrees.

BACKGROUND: Obtaining an accurate pedigree is the first step in recognizing a patient with hereditary nonpolyposis colorectal cancer, or Lynch syndrome. However, lack of standardization of the degree of relationship included in the pedigrees generally limits obtaining a complete and/or accurate pedigree. DESIGN: This study analyzed the extent of pedigree required to screen for colorectal cancer and to diagnose Lynch syndrome. SETTINGS: The study was conducted at 2 tertiary care centers. PATIENTS: A detailed family history was obtained from patients undergoing surgery for colorectal cancer from 2003 to 2016. A simplified pedigree that included only first-degree relatives was obtained and compared with the extended pedigree. MAIN OUTCOME MEASURES: The eligibility of the 2 pedigrees was assessed for each proband. The proportion of patients who would be missed using a simplified rather than an extended pedigree was calculated based on the American Cancer Society guidelines for recommending screening for colorectal cancer, on the revised Bethesda guidelines and the revised suspected hereditary nonpolyposis colorectal cancer criteria for screening for hereditary colorectal cancer, and on the Amsterdam II criteria for diagnosis of Lynch syndrome. RESULTS: The study examined 2015 families, including 41,826 individuals. Use of simplified and extended pedigrees was comparable in screening for colorectal cancer, with ratios of 183 of 185 (98.9%) for American Cancer Society guidelines, 295 of 295 (100%) for revised Bethesda guidelines, and 60 of 60 (100%) for revised suspected hereditary nonpolyposis colorectal cancer criteria. However, the use of simplified pedigrees missed a definitive diagnosis of Lynch syndrome in 6 of 10 patients fulfilling Amsterdam II criteria based on extended pedigrees. The mean ages at diagnosis of the 4 probands included and the 6 missed using simplified pedigrees differed significantly (60.8 vs 38.2 y). LIMITATIONS: The study was limited by its recall bias, cross-sectional nature, lack of germline testing, and potential inapplicability to the general population. CONCLUSIONS: A simplified pedigree is acceptable for selecting candidates to screen for hereditary colorectal cancer, whereas an extended pedigree is still required for a more precise diagnosis of Lynch syndrome, especially in younger patients. See Video Abstract at http://links.lww.com/DCR/B97. EXTENSIÓN DE PEDIGREE REQUERIDO EN LA DETECCIÓN Y DIAGNÓSTICO DE CÁNCER COLORRECTAL HEREDITARIO SIN POLIPOSIS: COMPARACIÓN DE LOS PEDIGREES SIMPLIFICADO Y EL EXTENDIDO: La obtención de un Pedigree exacto es el primer paso para reconocer un paciente con cáncer colorrectal hereditario sin poliposis o síndrome de Lynch. Sin embargo, la falta de estandarización del grado de relación incluido en los Pedigrees generalmente limita la obtención de un Pedigree completo y / o preciso.Este estudio analizó el grado de Pedigree requerido para detectar el cáncer colorrectal y diagnosticar el síndrome de Lynch.Se obtuvo una historia familiar detallada de pacientes sometidos a cirugía por cáncer colorrectal desde 2003 hasta 2016. Se obtuvo también un Pedigree simplificado que incluía solo familiares de primer grado y se comparó con el Pedigree extendido.La elegibilidad de los dos Pedigrees se evaluó para cada sujeto de prueba (proband). La proporción de pacientes que se perderían usando un Pedigree simplificado en lugar de extendido se calculó en base a las guías de la Sociedad Americana del Cáncer y sus recomendaciones en la detección de cáncer colorrectal, en las pautas revisadas de Bethesda y en los criterios revisados de cáncer colorrectal hereditario sin poliposis para la detección hereditaria de cáncer colorrectal y según las normas de Amsterdam II para el diagnóstico del síndrome de Lynch.El estudio examinó a 2.015 familias, incluidas 41.826 personas. El uso de Pedigree simplificado y extendido fue comparable en la detección del cáncer colorrectal, con proporciones de 183/185 (98,9%) comparadas con las recomendaciones de la American Cancer Society, 295/295 (100%) para las pautas revisadas de Bethesda y 60/60 (100%) para los criterios revisados de sospecha de cáncer colorrectal hereditario sin poliposis. Sin embargo, el uso de Pedigree simplificado omitió un diagnóstico definitivo del síndrome de Lynch en 6 de diez pacientes que cumplían las normas de Amsterdam II basados en Pedigrees extendidos. Las edades medias al diagnóstico de los cuatro sujetos de prueba incluidos y los seis perdidos usando el Pedigree simplificado diferían significativamente (60.8 vs. 38.2 años).Un Pedigre simplificado es aceptable en la selección de candidatos para la detección de cáncer colorrectal hereditario, mientras que aún se requiere un Pedigree extendido para un diagnóstico más preciso de síndrome de Lynch, especialmente en pacientes más jóvenes. Consulte Video Resumen en http://links.lww.com/DCR/B97. (Traducción-Dr. Edgar Xavier Delgadillo).

Pilot Randomized Controlled Trial of a Digital Storytelling Intervention for Smoking Cessation in Women Living With HIV.

BACKGROUND: People living with HIV in the USA smoke at a rate nearly three times that of the general population, and Black women are disproportionately affected by HIV infection. PURPOSE: This study was conducted to test the preliminary efficacy of a digital storytelling intervention for smoking cessation in U.S. women living with HIV. METHODS: Participants in the treatment arm viewed a film in which women living with HIV talk about quitting smoking, and those in the control arm viewed an attention-control film in which women talk about living with HIV infection. Participants in both arms received eight weekly video-call counseling sessions focused on smoking cessation and nicotine patches or gum during the same period. Participants were followed on a monthly basis from quit day for 3 months. RESULTS: Of the 53 participants randomized, four withdrew before receiving any intervention, one dropped out during the intervention, and 48 (90.6%) completed the study. No difference was found in the baseline characteristics between the two arms with the exception that the treatment arm had higher nicotine dependence scores [t(1.51) = 2.30, p = .03] than the control arm. Seven day point-prevalence abstinence rates at 3 month follow-up were not found to differ between the two arms. However, the odds of achieving 3 month prolonged abstinence were four times greater (odds ratio = 4.23, 95% confidence interval = 1.10, 16.23) in the treatment arm than the control arm when the analysis was performed with those (n = 49, 92.5%) who received any part of the allotted intervention. CONCLUSIONS: A digital storytelling intervention seems to be a valuable strategy to enhance the effect of conventional tobacco dependence treatment for women living with HIV. However, the underlying mechanism of the effect of digital storytelling necessitates further investigations in a large RCT.Clinical Trials Registration No. NCT03289676.

Intravenous Lidocaine for the Prevention of Postoperative Catheter-Related Bladder Discomfort in Male Patients Undergoing Transurethral Resection of Bladder Tumors: A Randomized, Double-Blind, Controlled Trial.

BACKGROUND: Male patients undergoing transurethral resection of bladder tumors (TURBT) are prone to suffer from catheter-related bladder discomfort (CRBD). Lidocaine administration has been widely performed to reduce postoperative pain. Here, the effect of intravenous lidocaine administration on moderate-to-severe CRBD was evaluated in male patients undergoing TURBT. METHODS: Patients were randomly allocated to receive intravenous lidocaine (1.5 mg/kg bolus dose followed by a 2 mg/kg/h continuous infusion during the intraoperative period, which was continued for 1 hour postsurgery; group L) or placebo (normal saline; group C). The primary outcome was moderate-to-severe CRBD at 0 hour postsurgery (on admission to the postanesthetic care unit), analyzed using the χ test. The secondary outcome was opioid requirement during the 24-hour postoperative period. None, mild, and moderate-to-severe CRBD at 1, 2, and 6 hours postsurgery, postoperative pain, patient satisfaction, side effects of lidocaine and rescue medications (tramadol and fentanyl), and surgical complications were also assessed. RESULTS: A total of 132 patients were included in the study (66 patients in each group). The incidence of moderate-to-severe CRBD at 0 hour postsurgery was significantly lower in group L than in group C (25.8% vs 66.7%, P < .001, relative risk: 0.386, 95% confidence interval: 0.248-0.602). Opioid requirements during the 24-hour postoperative period were significantly lower in group L than in group C (10.0 mg [interquartile range (IQR), 5.0-15.0 mg] vs 13.8 mg [IQR, 10.0-20.0 mg], P = .005). At 1 and 2 hours postsurgery (but not at 6 hours), the incidence of moderate-to-severe CRBD was significantly lower in group L than in group C (1 hour: 10.6% vs 27.3%, P = .026; 2 hours: 0.0% vs 15.2%, P = .003). Patient satisfaction was significantly greater in group L than in group C (5.0 [IQR, 4.8-6.0] vs 4.0 [IQR, 4.0-5.0], P < .001). No lidocaine-related side effects were reported. Rescue medication-related side effects and surgical complications did not differ significantly between the 2 groups. CONCLUSIONS: Intravenous lidocaine administration resulted in lower incidence of moderate-to-severe CRBD, lower opioid requirement, and higher patient satisfaction in male patients undergoing TURBT without evidence of significant side effects.

A randomized controlled pilot trial of a smoking cessation intervention for US women living with HIV: telephone-based video call vs voice call.

BACKGROUND: People living with HIV smoke at a rate three times that of the general population. This randomized controlled pilot trial tested the feasibility and acceptability of a video-call smoking cessation intervention in women living with HIV and its preliminary efficacy compared with a voice-call smoking cessation intervention. The study focused on women due to a paucity of studies among this population, and women are less likely than men to quit smoking when provided with conventional treatment. METHODS: Participants in both arms received an HIV-tailored smoking cessation intervention comprising eight 30-minute weekly counseling sessions in conjunction with active nicotine patches for 8 weeks. The only difference between the two arms was the delivery mode of the intervention: via either telephone-based video or voice call. Survival analysis and a Cox proportional hazard regression model were performed to identify factors predicting 6-month prolonged abstinence from smoking. RESULTS: A video-call intervention was almost 30% less feasible than a voice-call intervention because women in their 50s and 60s or poorer women living in some southern states did not have access to video-call equipment. However, those who received the video-call intervention were more likely to complete the study than those who had the voice-call intervention. There was no difference in the acceptability of the two interventions. A survival analysis revealed that those in the video arm were significantly more likely to maintain smoking abstinence over the 6-month follow-up period than those in the voice arm (log rank χ 2=4.02, P<0.05). CONCLUSION: Although a video-call intervention is less feasible than a voice-call intervention, the former seems to outperform the latter in achieving long-term smoking abstinence for women living with HIV, which may offer an advantage over establishing therapeutic alliance and visually monitoring their adherence to nicotine patches. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02898597.

Combined Treatment for Lung Metastasis from Hepatocellular Carcinoma: A Case Report.

The survival rate of patients with hepatocellular carcinoma and extrahepatic metastases is very poor. Sorafenib, a targeted chemotherapy agent, has been shown effective for patients with advanced hepatocellular carcinoma (HCC), but it is associated with serious side effects. In addition, although surgery has been regarded as effective for lung metastases from HCC, its use in these patients is limited. Complementary and alternative medicine, including traditional Korean medicine (TKM), is increasingly used in cancer treatment, as it has been found to improve patient quality of life and maintain tumor size. This report describes a 62-year-old Korean woman with lung metastases from HCC. She first underwent surgery (stage IV) and six cycles of adjuvant chemotherapy. She was subsequently treated with sorafenib, but computed tomography showed progressive disease and she experienced the side effects of sorafenib. The patient started treatment with TKM, including pharmacopuncture and herbal medicine, in addition to sorafenib. After 8 weeks of TKM treatment, the size of the metastatic nodules decreased and the sorafenib-associated side effect symptoms improved. These findings suggest that treatment with a combination of TKM and sorafenib may be a promising method for patients with HCC and extrahepatic metastases.

Antagonism of PPAR-γ signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis.

Hematopoietic stem cells (HSCs) quiescently reside in bone marrow niches and have the capacity to self-renew or differentiate to form all of the blood cells throughout the lifespan of an animal. Allogeneic HSC transplantation is a life-saving treatment for malignant and nonmalignant disorders. HSCs isolated from umbilical cord blood (CB) are used for hematopoietic cell transplantation (HCT), but due to the limited numbers of HSCs in single units of umbilical CB, a number of methods have been proposed for ex vivo expansion of human HSCs. We show here that antagonism of peroxisome proliferator-activated receptor (PPAR)-γ promotes ex vivo expansion of phenotypically and functionally defined subsets of human CB HSCs and hematopoietic progenitor cells (HSPCs). PPAR-γ antagonism in CB HSPCs strongly downregulated expression of several differentiation-associated genes, as well as fructose-bisphosphatase 1 (FBP1; which encodes a negative regulator of glycolysis), and enhanced glycolysis without compromising mitochondrial metabolism. The expansion of CB HSPCs by PPAR-γ antagonism was completely suppressed by removal of glucose or inhibition of glycolysis. Moreover, knockdown of FBP1 expression promoted glycolysis and ex vivo expansion of long-term repopulating CB HSPCs, whereas overexpression of FBP1 suppressed the expansion of CB HSPCs that was induced by PPAR-γ antagonism. Our study suggests the possibility for a new and simple means for metabolic reprogramming of CB HSPCs to improve the efficacy of HCT.

An All-Organic Composite System for Resistive Change Memory via the Self-Assembly of Plastic-Crystalline Molecules.

An all-organic composite system was introduced as an active component for organic resistive memory applications. The active layer was prepared by mixing a highly polar plastic-crystalline organic molecule (succinonitrile, SN) into an insulating polymer (poly(methyl methacrylate), PMMA). As increasing concentrations of SN from 0 to 3.0 wt % were added to solutions of different concentrations of PMMA, we observed distinguishable microscopic surface structures on blended films of SN and PMMA at certain concentrations after the spin-casting process. The structures were organic dormant volcanos composed of micron-scale PMMA craters and disk type SN lava. Atomic force microscopy (AFM), cross-sectional transmission electron microscopy (TEM), scanning electron microscopy (SEM), and energy dispersive X-ray spectrometer (EDX) analysis showed that these structures were located in the middle of the film. Self-assembly of the plastic-crystalline molecules resulted in the phase separation of the SN:PMMA mixture during solvent evaporation. The organic craters remained at the surface after the spin-casting process, indicative of the formation of an all-organic composite film. Because one organic crater contains one SN disk, our system has a coplanar monolayer disk composite system, indicative of the simplest composite type of organic memory system. Current-voltage (I-V) characteristics of the composite films with organic craters revealed that our all-organic composite system showed unipolar type resistive switching behavior. From logarithmic I-V characteristics, we found that the current flow was governed by space charge limited current (SCLC). From these results, we believe that a plastic-crystalline molecule-polymer composite system is one of the most reliable ways to develop organic composite systems as potential candidates for the active components of organic resistive memory applications.

Regulation of c-Myc Expression by Ahnak Promotes Induced Pluripotent Stem Cell Generation.

We have previously reported that Ahnak-mediated TGFß signaling leads to down-regulation of c-Myc expression. Here, we show that inhibition of Ahnak can promote generation of induced pluripotent stem cells (iPSC) via up-regulation of endogenous c-Myc. Consistent with the c-Myc inhibitory role of Ahnak, mouse embryonic fibroblasts from Ahnak-deficient mouse (Ahnak(-/-) MEF) show an increased level of c-Myc expression compared with wild type MEF. Generation of iPSC with just three of the four Yamanaka factors, Oct4, Sox2, and Klf4 (hereafter 3F), was significantly enhanced in Ahnak(-/-) MEF. Similar results were obtained when Ahnak-specific shRNA was applied to wild type MEF. Of note, expressionof Ahnak was significantly induced during the formation of embryoid bodies from embryonic stem cells, suggesting that Ahnak-mediated c-Myc inhibition is involved in embryoid body formation and the initial differentiation of pluripotent stem cells. The iPSC from 3F-infected Ahnak(-/-) MEF cells (Ahnak(-/-)-iPSC-3F) showed expression of all stem cell markers examined and the capability to form three primary germ layers. Moreover, injection of Ahnak(-/-)-iPSC-3F into athymic nude mice led to development of teratoma containing tissues from all three primary germ layers, indicating that iPSC from Ahnak(-/-) MEF are bona fide pluripotent stem cells. Taken together, these data provide evidence for a new role for Ahnak in cell fate determination during development and suggest that manipulation of Ahnak and the associated signaling pathway may provide a means to regulate iPSC generation.

Involvement of iron depletion in palmitate-induced lipotoxicity of beta cells.

High levels of plasma free fatty acid are thought to contribute to the loss of pancreatic beta-cells in type 2 diabetes. In particular, saturated fatty acid such as palmitate or stearate can induce apoptosis in cultured beta cells (lipotoxicity). Endoplasmic reticulum stress is a critical mediator of free fatty acid-induced lipotoxicity. Recently, disorders in mitochondrial respiratory metabolism have been linked to lipotoxicity. Since iron is a critical component of respiratory metabolism, this study is initiated to determine whether abnormal iron metabolism is involved in palmitate-induced beta cell death. Immunoblotting analysis showed that treatment of INS-1 beta cells with palmitate reduced the level of transferrin receptor 1 (TfR1), but increased the level of heavy chain ferritin (FTH). In addition, palmitate reduced intracellular labile iron pool. Whereas iron depletion through treatment with iron-chelators deferoxamine or deferasirox augmented palmitate-induced cell death, iron supplementation with ferric chloride, ferrous sulfate, or holo-transferrin significantly protected cells against palmitate-induced death. Furthermore, overexpression of TfR1 reduced palmitate-induced cell death, whereas knockdown of TfR1 augmented cell death. In particular, treatment with deferoxamine increased the level of endoplasmic reticulum (ER) stress markers phospho-PERK, phospho-eIF2α, CHOP and phospho-c-Jun N-terminal kinase. Treatment with chemical chaperone significantly protected cells against deferoxamine-induced apoptosis. Iron supplementation also protected cells against palmitate-induced primary islet death. These data suggest that iron depletion plays an important role in palmitate-induced beta cell death through inducing ER stress. Therefore, attempts to block iron depletion might be able to prevent beta cell loss in type 2 diabetes.

Preoperative embolization for bone metastasis from hepatocellular carcinoma.

Preoperative transcatheter arterial embolization for hypervascular bone tumors is now widely accepted as a safe and effective procedure for reducing intraoperative blood loss and surgical morbidity. However, few studies have reported the use of preoperative transcatheter arterial embolization for nonspine bone metastases from hepatocellular carcinoma. The goal of this study was to assess the effect of preoperative embolization on blood loss and clinical outcomes in surgery for nonspine bone metastasis from hepatocellular carcinoma. Seventy-five patients with metastases from hepatocellular carcinoma to the pelvis and extremities were reviewed retrospectively. The study population consisted of 62 men and 13 women, with a mean age of 64.6 years (range, 40.0-80.1). The average follow-up period was 8.2 months (range, 0.3-66.1). Twenty-two patients underwent transcatheter arterial embolization for preoperative devascularization (group A), and 53 patients underwent operative treatment only (group B). The proportion of pelvis metastases was significantly higher (P<.001) and operative time was longer (P=.006) in group A than in group B. However, a significantly smaller decrease in hemoglobin level before and after surgery was seen in group A (P=.017). No significant differences were seen in intraoperative estimated blood loss, perioperative hemoglobin level, number of allogeneic transfusions, or length of hospitalization between the 2 groups. Preoperative transcatheter arterial embolization is an effective means to reduce bleeding during surgery for nonspine metastases from hepatocellular carcinoma. In general, surgical procedures that included transcatheter arterial embolization took longer and were more extensive.

Adjunctive biomarkers for improving diagnosis of tuberculosis and monitoring therapeutic effects.

OBJECTIVES: To identify host biomarkers associated with latent tuberculosis infection (LTBI), active tuberculosis (TB), and nontuberculous mycobacteria (NTM) diseases to improve diagnosis and effective anti-TB treatment. METHODS: Active TB and NTM patients at diagnosis, recent TB contacts, and normal healthy subjects were recruited. Tuberculin skin tests, QuantiFERON-TB Gold In-Tube tests, and multiplex bead arrays with 17 analytes were performed. TB patients were re-evaluated after 2 and 6 months of treatment. RESULTS: Mycobacterium tuberculosis (M. tb) antigen-specific IFN-γ, IL-2, and CXCL10 responses were significantly higher in active TB and LTBI compared with controls (P < 0.01). Only serum VEGF levels varied between the active TB and LTBI groups (AUC = 0.7576, P < 0.001). Active TB and NTM diseases were differentiated by serum IL-2, IL-9, IL-13, IL-17, TNF-α and sCD40L levels (P < 0.05). Increased sCD40L and decreased M. tb antigen-specific IFN-γ levels correlated with sputum clearance of M. tb after 2 months of treatment (P < 0.001). CONCLUSIONS: Serum IL-2, IL-9, IL-13, IL-17, TNF-α, sCD40L and VEGF-A levels may be adjunctive biomarkers for differential diagnosis of active TB, LTBI, and NTM disease. Assessment of serum sCD40L and M. tb antigen-specific IFN-γ, TNF-α, and IL-2 levels could help predict successful anti-TB treatment in conjunction with M. tb clearance.

Non-spine bone metastasis as an initial manifestation of cancer in Korea.

Non-spine bone metastasis accounts for approximately 20% of all skeletal metastases, but little data have been published that focused on bone metastasis to the pelvis and extremities as an initial manifestation of cancer. We determined 1) clinicopathologic characteristics of patients who presented with non-spine bone metastasis of unknown primary malignancy, and 2) process by which the diagnosis of primary cancer was made. We retrospectively reviewed 84 patients with bone metastasis of unknown primary cancer site at the time of presentation. The study population consisted of 56 men and 28 women, with a mean age of 59.1 yr (17.5-85.6 yr). The average follow-up period was 20.8 months (1-120 mo). Primary cancer site was identified in 79 patients (94.0%), and was determined to be the lung (46.4%), kidney (13.1%), liver (9.5%), thyroid (8.3%), and prostate (4.8%). Five-year overall survival rate was 28.0%. Multiple bone metastases, distant organ metastasis, and multiple bone with organ metastases were the significant prognostic factors in univariate analysis. Multiple bone metastases remained significant after multivariate analysis (P = 0.008). Lung cancer is the most common site of primary cancer, and patients with multiple bone metastases have a poor prognosis, possibly due to disseminated cancer and a greater tumor burden.

Febrile response following megaprosthesis replacement for primary bone sarcoma.

The presence of early postoperative fever after megaprosthesis replacement surgery is a concern for orthopedic oncologists due to the possibility of infection. The aims of the current study were to determine the incidences and patterns of fever and factors associated with its development and to determine the clinical significance of fever after megaprosthesis replacement surgery. Seventy-one patients who had undergone megaprosthesis reconstruction for previously unoperated localized lower-extremity osteosarcoma were reviewed. No patient had evidence of infection preoperatively. Mean patient age was 23.72±16.84 years (range, 6.7-74 years), and average follow-up was 59.5 months (range, 4-240 months). Five postoperative surgical wound infections (4 deep, 1 superficial) occurred on postoperative days 5, 13, 14, 20, and 21. Fevers (body temperature of 38 °C or higher) were present in 62 patients (87.3%) at some point during the first 2 postoperative weeks. Peak body temperature was observed on postoperative day 1 in 62% of the febrile patients. Of the 62 febrile patients, 94% were relieved of fever by postoperative day 5. No significant association was observed between the presence of fever and surgical wound infection. Body temperature curves in patients with infection showed that several atypical patterns, such as multiple fever peaks and persistent fever, were accompanied by physical findings within the normalization period. Fever during the first 5 postoperative days is common after megaprosthesis replacement for bone sarcomas and seems to be a normal physiologic response to surgery. However, atypical fever patterns or additional physical findings require investigation.

Unplanned excision of soft tissue sarcoma: the impact of the referring hospital.

BACKGROUND: Unplanned excision of soft tissue sarcoma (STS) remains a common problem performed at various levels of hospitals, where clinical characteristics may differ. However, there is little literature describing the impact of the referring hospital on patient characteristics and/or outcome in unplanned excision of STS. This study examined the possible different patient characteristics and prognoses according to the level of referring hospitals where unplanned excision was performed. METHODS: Patients referred to our institute after unplanned excision of STS on their extremities were reviewed. Referring hospitals were categorized into two groups according to their referral grades; tertiary hospitals (general hospitals with tertiary [highest] referral grade, n = 42) and non-tertiary hospitals (others, n = 79). RESULTS: Patients referred from tertiary hospitals had significantly larger number of high-grade tumors (p = 0.019) but lower chance of finding a residual tumor at re-excision (p = 0.020) than non-tertiary hospitals. For oncological outcomes, referral from tertiary hospital was an independent factor for better local control (hazard ratio, 0.211; 95% confidence interval, 0.061-0.730). However, there was no difference in disease-specific death (p = 0.729) or metastasis (p = 0.978) between the two groups. CONCLUSIONS: Despite having worse clinicopathologic characteristics, patients referred from tertiary hospitals had fewer local recurrences than patients from non-tertiary hospitals. The impact of the referring hospital on patient outcome and disease characteristics needs to be considered in unplanned excision of STS.

Supplementation of pyruvate prevents palmitate-induced impairment of glucose uptake in C2 myotubes.

Elevated fatty acid levels have been thought to contribute to insulin resistance. Repression of the glucose transporter 4 (GLUT4) gene as well as impaired GLUT4 translocation may be a mediator for fatty acid-induced insulin resistance. This study was initiated to determine whether palmitate treatment repressed GLUT4 expression, whether glucose/fatty acid metabolism influenced palmitate-induced GLUT4 gene repression (PIGR), and whether attempts to prevent PIGR restored palmitate-induced impairment of glucose uptake (PIIGU) in C2 myotubes. Not only stimulators of fatty acid oxidation, such as bezafibrate, AICAR, and TOFA, but also TCA cycle substrates, such as pyruvate, leucine/glutamine, and α-ketoisocaproate/monomethyl succinate, significantly prevented PIGR. In particular, supplementing with pyruvate through methyl pyruvate resulted in nearly complete prevention of PIIGU, whereas palmitate treatment reduced the intracellular pyruvate level. These results suggest that pyruvate depletion plays a critical role in PIGR and PIIGU; thus, pyruvate supplementation may help prevent obesity-induced insulin resistance in muscle cells.