Mammalian sirtuin 1 (SIRT1) has connected to an ever widening circle of activities that encompass cellular stress resistance, energy metabolism and tumorigenesis. However, underlying mechanisms ...leading to oncogenic SIRT1 overexpression are less understood. In this study, we identified SIRT1 regulatory microRNA (miRNA) and its function in hepatocellular carcinoma (HCC). Aberrant SIRT1 overexpression was demonstrated in a subset of human HCCs. SIRT1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins. This led to hypophosphorylation of pRb, which inactivated E2F/DP1 target gene transcription, and thereby caused significant increase of HCC cells to remain in the G1/S phase. A comprehensive miRNA profiling analysis indentified five putative endogenous miRNAs that are significantly downregulated in HCC. Ectopic expression of miRNA mimics evidenced miR-29c to suppress SIRT1 in HCC cells. Notably, ectopic miR-29c expression repressed cancer cell growth and proliferation, and it recapitulated SIRT1 knockdown effects in HCC cells. In addition, miR-29c expression was downregulated in a large cohort of HCC patients, and low expression of miR-29c was significantly associated with poor prognosis of HCC patients. Taken together, we demonstrated that miR-29c suppresses oncogenic SIRT1 by way of binding to 3'-untranslated region of SIRT1 mRNA causing translational inhibition in liver cancer cells. The loss or suppression of miR-29c may cause aberrant SIRT1 overexpression and promotes liver tumorigenesis. Overall, we suggest that miR-29c functions as a tumor suppressor by regulating abnormal SIRT1 activity in liver.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This phase II study investigated the efficacy and safety of everolimus, an inhibitor of mammalian target of rapamycin (mTOR), in locally advanced or metastatic thyroid cancer.
Patients with thyroid ...cancer of any histology that was resistant or not appropriate for 131I received everolimus 10 mg daily orally until unacceptable toxicity or disease progression. The primary end point was disease control rate partial response (PR) + stable response ≥12 weeks. Secondary end points included response rates, clinical benefit (PD + durable stable disease (SD), progression-free survival (PFS), overall survival, duration of response, and safety.
Thirty-eight of 40 enrolled patients were evaluable for efficacy. The disease control rate was 81% and two (5%) patients achieved objective response; their duration of response was 21+ and 24+ weeks. Stable disease (SD) and progressive disease was reported in 76% and 17% of patients, respectively. Seventeen (45%) patients showed durable SD (≥24 weeks) and clinical benefit was reported in 19 (50%) patients. Median PFS was 47 weeks 95% confidence interval (CI) 14.9–78.5. Calcitonin, CEA, and thyroglobulin concentrations were ≥50% lower than baseline in three (30%) and four (44%) patients with medullary thyroid cancer and five (33%) patients with PTC, respectively. The most common treatment-related adverse events were mucositis (84%), anorexia (44%), and aspartate transaminase/alanine transaminase elevation (26%).
Everolimus had a limited activity with low response rate in locally advanced or metastatic thyroid cancer. Reasonable clinical benefit rate and safety profile may warrant further investigation.
NCT01164176.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Aim We investigated the role of paraaortic lymph node dissection (PALND) in patients with stage IIIC1 endometrial carcinoma after surgery followed by adjuvant radiotherapy (RT) alone or ...chemoradiotherapy (CTRT) Methods We performed a subgroup analysis in 151 patients treated with adjuvant pelvic RT. Paraaortic-recurrence free survival, disease-free survival (DFS) and overall survival (OS) were analyzed. Results In adjuvant RT alone, PALND was significantly related to reduced risk of paraaortic recurrence (0% vs. 17.1%) and distant metastasis (4.5% vs. 19.5%) compared with the no PALND group. PALND affected 5-year DFS (90.2% vs. 58.9%, p=0.016) and OS (100% vs. 83.1%, p=0.022). For the CTRT group, the paraaortic recurrence rate was 19.5% for the no PALND group and 12.8% for the PALND group (p=0.682). Of patients who underwent PALND in the CTRT group, less extensive PALND was significantly related to increased paraaortic recurrence (≤10 vs. >10 dissected LNs, 17.1% vs. 0%). In the no PALND group (n=82), 5-year paraaortic-recurrence free survival was 79.4% for the CTRT group and 76.2% for the RT alone group (p=0.941). In multivariate analysis, PALND was significantly associated with reduced risk of disease-specific death (HR, 0.50; 95%CI, 0.26-0.96; p=0.037). Conclustion PALND provided excellent paraaortic control and improved outcome in stage IIIC1 endometrial cancer with favorable tumor features treated with adjuvant RT alone. Less extensive PALND was associated with significantly increased paraaortic recurrence in patients with advanced tumor features treated with adjuvant CTRT. Combined CTRT did not affect disease control in the paraaortic region compared with RT alone.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Thraustochytrids were first discovered in 1934, and since the 1960's they have been increasingly studied for their beneficial and deleterious effects. This review aims to provide an enhanced ...understanding of these protists with a particular emphasis on their taxonomy, ecology and biotechnology applications. Over the years, thraustochytrid taxonomy has improved with the development of modern molecular techniques and new biochemical markers, resulting in the isolation and description of new strains. In the present work, the taxonomic history of thraustochytrids is reviewed, while providing an up-to-date classification of these organisms. It also describes the various biomarkers that may be taken into consideration to support taxonomic characterization of the thraustochytrids, together with a review of traditional and modern techniques for their isolation and molecular identification. The originality of this review lies in linking taxonomy and ecology of the thraustochytrids and their biotechnological applications as producers of docosahexaenoic acid (DHA), carotenoids, exopolysaccharides and other compounds of interest. The paper provides a summary of these aspects while also highlighting some of the most important recent studies in this field, which include the diversity of polyunsaturated fatty acid metabolism in thraustochytrids, some novel strategies for biomass production and recovery of compounds of interest. Furthermore, a detailed overview is provided of the direct and current applications of thraustochytrid-derived compounds in the food, fuel, cosmetic, pharmaceutical, and aquaculture industries and of some of the commercial products available. This review is intended to be a source of information and references on the thraustochytrids for both experts and those who are new to this field.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Antimicrobial stewardship programmes (ASPs) are suggested as a vital strategy to address antimicrobial resistance.
To examine the current status of ASPs in Korean hospitals, to identify problems and ...challenges for the implementation of proper ASPs, and to provide a reference for developing more effective ASP policies.
A questionnaire based on the ‘Seven Core Elements of Hospital Antibiotic Stewardship Programs’ from the US Centers for Disease Control and Prevention was developed, modified from the previous questionnaire on ASPs in Korea, 2015. ASP-participating physicians such as infectious disease specialists (IDSs), paediatric IDSs, and directors of infection control departments were targeted. Only one ASP-associated physician per hospital participated in the survey.
The survey response rate was 88.4% (84/95). The median number of medical personnel participating in ASPs was 3 (interquartile range (IQR): 1–5), most of whom were IDS (median: 2; IQR: 1–2). Only 6.0% (5/84) of hospitals had full-time workers for ASPs. Whereas restrictive measures for designated antimicrobials were widely implemented among Korean hospitals (88.1%, 74/84), the proportion of hospitals with interventions for inappropriate long-term antimicrobial use and a conversion strategy from parenteral to oral antimicrobial administration was only 9.5% (8/84) and 1.2% (1/84), respectively. Lack of time, personnel, and appropriate compensation was perceived as the major barrier to establishing an ASP in Korean hospitals.
ASPs in Korean hospitals were primarily carried out by one or two IDSs, and programmes mostly comprised restrictive measures for designated antimicrobials. National-level support to implement appropriate ASPs in Korean hospitals is necessary.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Intestinal tuberculosis and Crohn's disease are chronic inflammatory bowel disorders that are difficult to differentiate from one another. This study aimed to evaluate the diagnostic value of various ...colonoscopic findings in the differential diagnosis between intestinal tuberculosis and Crohn's disease.
Colonoscopic findings on initial work-up were prospectively recorded in patients with an initial diagnosis of either intestinal tuberculosis or Crohn's disease. These findings were analyzed after a final diagnosis of intestinal tuberculosis (n = 44) or Crohn's disease (n = 44) had been made after follow-up.
Four parameters (anorectal lesions, longitudinal ulcers, aphthous ulcers, and cobblestone appearance) were significantly more common in patients with Crohn's disease than in patients with intestinal tuberculosis. Four other parameters (involvement of fewer than four segments, a patulous ileocecal valve, transverse ulcers, and scars or pseudopolyps) were observed more frequently in patients with intestinal tuberculosis than in patients with Crohn's disease. We hypothesized that a diagnosis of Crohn's disease could be made when the number of parameters characteristic of Crohn's disease was higher than the number of parameters characteristic of intestinal tuberculosis, and vice versa. Making these assumptions, we calculated that the diagnosis of either intestinal tuberculosis or Crohn's disease would have been made made correctly in 77 of our 88 patients (87.5 %), incorrectly in seven patients (8.0 %), and would not have been made in four patients (4.5 %).
A systematic analysis of colonoscopic findings is very useful in the differential diagnosis between intestinal tuberculosis and Crohn's disease.
There have been limited data on the risk of onward transmission from individuals with Omicron variant infections who return to work after a 5-day isolation.
To evaluate the risk of transmission from ...healthcare workers (HCWs) with Omicron variant who returned to work after a 5-day isolation and the viable-virus shedding kinetics.
This investigation was performed in a tertiary care hospital, Seoul, South Korea. In a secondary transmission study, we retrospectively reviewed the data of HCWs confirmed as COVID-19 from March 14th to April 3rd, 2022 in units with five or more COVID-19-infected HCWs per week. In the viral shedding kinetics study, HCWs with Omicron variant infection who agreed with daily saliva sampling were enrolled between February and March, 2022.
Of the 248 HCWs who were diagnosed with COVID-19 within 5 days of the return of an infected HCW, 18 (7%) had contact with the returned HCW within 1–5 days after their return. Of these, nine (4%) had an epidemiologic link other than with the returning HCW, and nine (4%) had contact with the returning HCW, without any other epidemiologic link. In the study of the kinetics of virus shedding (N = 32), the median time from symptom onset to negative conversion of viable virus was four days (95% confidence interval: 3–5).
Our data suggest that the residual risk of virus transmission after 5 days of isolation following diagnosis or symptom onset is low.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
Background
Oltipraz is a synthetic dithiolethione with an antisteatotic effect by inhibiting the activity of liver X receptor alpha (LXR‐α). Recent studies demonstrated the disruptive role of ...oltipraz on LXR‐α‐dependent lipogenesis in hepatocytes and a high‐fat diet mouse model.
Aim
To evaluate the efficacy and safety of oltipraz for reducing liver fat in subjects with non‐alcoholic fatty liver disease (NAFLD).
Methods
We performed a multicentre, double‐blind, placebo‐controlled, phase II study. Subjects with a liver fat >20% and hypertransaminasemia were randomised to the three groups: placebo (n = 22), 30 mg of oltipraz (n = 22) or 60 mg of oltipraz (n = 24) twice daily for 24 weeks. Changes in the liver fat from baseline to 24 weeks quantified using magnetic resonance spectroscopy were the primary outcome.
Results
Compared with the placebo group (−3.2 ± 11.1%), absolute changes in the liver fat content increased in a dose‐dependent manner: −7.7 ± 7.0% and −13.9 ± 10.7% for the low‐dose and high‐dose groups (P = 0.13 and P < 0.01). Per cent reduction in the liver fat content was also significantly greater in the high‐dose group than in the placebo group (−34.6 ± 29.4% vs. −0.6 ± 62.9%, P = 0.046). Body mass indices (−1.0 ± 0.9% vs. −0.5 ± 1.4%, P = 0.04) significantly decreased in the high‐dose group compared to the placebo group. However, absolute changes in insulin resistance, liver enzymes, lipids and cytokines were not significantly different among groups. The incidence of adverse events was comparable among groups.
Conclusions
Twenty‐four‐week oltipraz treatment significantly reduced the liver fat content in patients with NAFLD. Clinicaltrials.gov (NCT01373554).
Linked ContentThis article is linked to Ajmera and Loomba, Wang and Lin, and Kim and Kim papers. To view this article visit https://doi.org/10.1111/apt.14081, https://doi.org/10.1111/apt.14122 and https://doi.org/10.1111/apt.14146.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
This study was performed to characterize selected rhodanine derivatives as potential preclinical disease-modifying drugs for experimental osteoarthritis (OA) in mice.
Three rhodanine derivatives, ...designated rhodanine (R)-501, R-502, and R-503, were selected as candidate OA disease-modifying drugs. Their effects were evaluated by intra-articular (IA) injection in OA mouse models induced by DMM (destabilization of the medial meniscus) or adenoviral overexpression in joint tissues of hypoxia-inducible factor (HIF)-2α or zinc importer ZIP8. The regulatory mechanisms impacted by the rhodanine derivatives were examined in primary-culture chondrocytes and fibroblast-like synoviocytes (FLS).
All three rhodanine derivatives inhibited OA development caused by DMM or overexpression of HIF-2α or ZIP8. Compared to vehicle-treated group, for example, IA injection of R-501 in DMM-operated mice reduced median OARSI grade from 3.78 (IQR 3.00–5.00) to 1.89 (IQR 0.94–2.00, P = 0.0001). R-502 and R-503 also reduced from 3.67 (IQR 2.11–4.56) to 2.00 (IQR 1.00–2.00, P = 0.0030) and 2.00 (IQR 1.83–2.67, P = 0.0378), respectively. Mechanistically, the rhodanine derivatives inhibited the nuclear localization and transcriptional activity of HIF-2α in chondrocytes and FLS. They did not bind to Zn2+ or modulate Zn2+ homeostasis in chondrocytes or FLS; instead, they inhibited the nuclear localization and transcriptional activity of the Zn2+-dependent transcription factor, MTF1. HIF-2α, ZIP8, and interleukin-1β could upregulate matrix-degrading enzymes in chondrocytes and FLS, and the rhodanine derivatives inhibited these effects.
IA administration of rhodanine derivatives significantly reduced OA pathogenesis in various mouse models, demonstrating that these derivatives have disease-modifying therapeutic potential against OA pathogenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Background The safety and short-term efficacy of laparoscopic surgery for rectal cancer after preoperative chemoradiotherapy has not been demonstrated. The aim of the randomised Comparison of ...Open versus laparoscopic surgery for mid and low REctal cancer After Neoadjuvant chemoradiotherapy (COREAN) trial was to compare open surgery with laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy. Methods Between April 4, 2006, and Aug 26, 2009, patients with cT3N0–2 mid or low rectal cancer without distant metastasis after preoperative chemoradiotherapy were enrolled at three tertiary-referral hospitals. Patients were randomised 1:1 to receive either open surgery (n=170) or laparoscopic surgery (n=170), stratified according to sex and preoperative chemotherapy regimen. Short-term outcomes assessed were involvement of the circumferential resection margin, macroscopic quality of the total mesorectal excision specimen, number of harvested lymph nodes, recovery of bowel function, perioperative morbidity, postoperative pain, and quality of life. Analyses were based on the intention-to-treat population. Patients continue to be followed up for the primary outcome (3-year disease-free survival). This study is registered with ClinicalTrials.gov , number NCT00470951. Findings Two patients (1·2%) in the laparoscopic group were converted to open surgery, but were included in the laparoscopic group for analyses. Estimated blood loss was less in the laparoscopic group than in the open group (median 217·5 mL 150·0–400·0 in the open group vs 200·0 mL 100·0–300·0 in the laparoscopic group, p=0·006), although surgery time was longer in the laparoscopic group (mean 244·9 min SD 75·4 vs 197·0 min 62·9, p<0·0001). Involvement of the circumferential resection margin, macroscopic quality of the total mesorectal excision specimen, number of harvested lymph nodes, and perioperative morbidity did not differ between the two groups. The laparoscopic surgery group showed earlier recovery of bowel function than the open surgery group (time to pass first flatus, median 38·5 h 23·0–53·0 vs 60·0 h 43·0–73·0, p<0·0001; time to resume a normal diet, 85·0 h 66·0–95·0 vs 93·0 h 86·0–121·0, p<0·0001; time to first defecation, 96·5 h 70·0–125·0 vs 123 h 94·0–156·0, p<0·0001). The total amount of morphine used was less in the laparoscopic group than in the open group (median 107·2 mg 80·0–150·0 vs 156·9 mg 117·0–185·2, p<0·0001). 3 months after proctectomy or ileostomy takedown, the laparoscopic group showed better physical functioning score than the open group (0·501 n=122 vs −4·970 n=128, p=0·0073), less fatigue (−5·659 n=122 vs 0·098 n=129, p=0·0206), and fewer micturition (−2·583 n=122 vs 4·725 n=129, p=0·0002), gastrointestinal (−0·400 n=122 vs 4·331 n=129, p=0·0102), and defecation problems (0·535 n=103 vs 5·327 n=99, p=0·0184) in repeated measures analysis of covariance, adjusted for baseline values. Interpretation Laparoscopic surgery after preoperative chemoradiotherapy for mid or low rectal cancer is safe and has short-term benefits compared with open surgery; the quality of oncological resection was equivalent. Funding The National Cancer Center, South Korea.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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