A HIF-1α inhibitor combined with palmitic acid and L-carnitine treatment can prevent the fat metabolic reprogramming under hypoxia and induce apoptosis in hepatocellular carcinoma cells.

BACKGROUND: A hypoxic environment often persists within solid tumors, including hepatocellular carcinoma (HCC). Hypoxia-inducible factor-1α (HIF-1α) can accelerate cancer malignancy by inducing hypoxia-dependent expression of various genes. Tumor hypoxia can also induce metabolic reprogramming of fatty acid (FA) metabolism, through which HIF-1α plays an essential role in diminishing fatty acid ß-oxidation (FAO) in hypoxic cancer cells. METHODS: We aimed to investigate potential new drug therapy options for targeting hypoxic cancer cells within HCC tumors, specifically through combining HIF-1α inhibition with palmitic acid (PA) + L-carnitine (LC) treatment to effectively induce apoptosis in hypoxic HCC cells. To test this hypothesis, in vitro and in vivo studies were performed. RESULTS: We first demonstrated that hypoxia-dependent apoptosis was induced by an overload of PA in two HCC cell lines (HepG2 and Hep3B) via excessive production of reactive oxygen species (ROS). Moreover, this observed PA-induced apoptosis was enhanced by HIF-1α knockdown (KD) in these cells under hypoxia. In addition, the combination of PA with FAO activator LC increased FAO activity and led to stronger cell death than PA alone in hypoxic HIF-1α KD cells, specifically through further ROS generation. To clarify the mechanism of hypoxia-induced FA metabolism reprogramming, expression levels of the genes encoding FAO enzymes CPT1A, ACSL1, MCAD, and LCAD, FA transporter CD36, and FA esterification enzymes DGAT and APGAT were analyzed using HIF-1α KD and scramble control (SC) cells. The results suggested that HIF-1α could repress mRNA expression of the FAO-related enzymes and CD36, while it upregulated FA esterification gene expression. This suggested a central role for HIF-1α in hypoxia-induced reprogramming of FA metabolism in HCC cells. Using a nude mouse model, PA administration was found to induce apoptosis from ROS overproduction in HIF-1α KD tumors compared with SC tumors. Additional LC treatment synergistically enhanced the PA-induced apoptosis in HIF-1α KD tumors. Finally, in vivo therapy composed of HIF-1α inhibitor YC-1 with PA + LC could induce ROS-mediated apoptosis in HepG2 tumors without significant toxicity. CONCLUSIONS: A combination therapy of YC-1 with PA + LC may be a unique anti-tumor therapy for targeting hypoxic HCC cells, specifically by ROS overproduction leading to forced FAO activation.

Clinical parameter-guided initial resuscitation in adult patients with septic shock: A systematic review and network meta-analysis.

Aim: To identify the most useful tissue perfusion parameter for initial resuscitation in sepsis/septic shock adults using a network meta-analysis. Methods: We searched major databases until December 2022 for randomized trials comparing four tissue perfusion parameters or against usual care. The primary outcome was short-term mortality up to 90 days. The Confidence in Network Meta-Analysis web application was used to assess the quality of evidence. Results: Seventeen trials were identified. Lactate-guided therapy (risk ratios, 0.59; 95% confidence intervals [0.45-0.76]; high certainty) and capillary refill time-guided therapy (risk ratios, 0.53; 95% confidence intervals [0.33-0.86]; high certainty) were significantly associated with lower short-term mortality compared with usual care, whereas central venous oxygen saturation-guided therapy (risk ratio, 1.50; 95% confidence intervals [1.16-1.94]; moderate certainty) increased the risk of short-term mortality compared with lactate-guided therapy. Conclusions: Lactate or capillary refill time-guided initial resuscitation for sepsis/septic shock patients may decrease short-term mortality. More research is essential to personalize and optimize treatment strategies for septic shock resuscitation.

Hematopoietic cell-derived IL-15 supports NK cell development in scattered and clustered localization within the bone marrow.

Natural killer (NK) cells are innate immune cells critical for protective immune responses against infection and cancer. Although NK cells differentiate in the bone marrow (BM) in an interleukin-15 (IL-15)-dependent manner, the cellular source of IL-15 remains elusive. Using NK cell reporter mice, we show that NK cells are localized in the BM in scattered and clustered manners. NK cell clusters overlap with monocyte and dendritic cell accumulations, whereas scattered NK cells require CXCR4 signaling. Using cell-specific IL-15-deficient mice, we show that hematopoietic cells, but not stromal cells, support NK cell development in the BM through IL-15. In particular, IL-15 produced by monocytes and dendritic cells appears to contribute to NK cell development. These results demonstrate that hematopoietic cells are the IL-15 niche for NK cell development in the BM and that BM NK cells are present in scattered and clustered compartments by different mechanisms, suggesting their distinct functions in the immune response.

Suppression of NASH-Related HCC by Farnesyltransferase Inhibitor through Inhibition of Inflammation and Hypoxia-Inducible Factor-1α Expression.

Inflammatory processes play major roles in carcinogenesis and the progression of hepatocellular carcinoma (HCC) derived from non-alcoholic steatohepatitis (NASH). But, there are no therapies for NASH-related HCC, especially focusing on these critical steps. Previous studies have reported that farnesyltransferase inhibitors (FTIs) have anti-inflammatory and anti-tumor effects. However, the influence of FTIs on NASH-related HCC has not been elucidated. In hepatoblastoma and HCC cell lines, HepG2, Hep3B, and Huh-7, we confirmed the expression of hypoxia-inducible factor (HIF)-1α, an accelerator of tumor aggressiveness and the inflammatory response. We established NASH-related HCC models under inflammation and free fatty acid burden and confirmed that HIF-1α expression was increased under both conditions. Tipifarnib, which is an FTI, strongly suppressed increased HIF-1α, inhibited cell proliferation, and induced apoptosis. Simultaneously, intracellular interleukin-6 as an inflammation marker was increased under both conditions and significantly suppressed by tipifarnib. Additionally, tipifarnib suppressed the expression of phosphorylated nuclear factor-κB and transforming growth factor-ß. Finally, in a NASH-related HCC mouse model burdened with diethylnitrosamine and a high-fat diet, tipifarnib significantly reduced tumor nodule formation in association with decreased serum interleukin-6. In conclusion, tipifarnib has anti-tumor and anti-inflammatory effects in a NASH-related HCC model and may be a promising new agent to treat this disease.

Diagnostic accuracy of pelvic imaging for acute pelvic inflammatory disease in an emergency care setting: a systematic review and meta-analysis.

The aim of this review is to investigate the diagnostic accuracy or performance of contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) for acute pelvic inflammatory disease (PID) in an emergency care setting. We searched for studies on the diagnostic test accuracy of contrast-enhanced CT or MRI for women of reproductive age with acute abdominal pain using MEDLINE, Embase, Cochrane Central Register of Controlled Trials, International Clinical Trials Registry Platform, and ClinicalTrials.gov. The reference standard was gynecological examinations by gynecologists using standard diagnostic criteria with or without laparoscopy or transcervical endometrial biopsy. Two reviewers undertook screening of records, data extraction, and assessment of the risk of bias in each included study using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. A bivariate model was used for the meta-analysis. Of 2,619 screened studies, three studies investigating contrast-enhanced CT and one study investigating MRI were eligible, including a total 635 patients and with a median prevalence of acute PID of 29%. All of the included studies had a high risk of bias for a reference standard and had some applicability concerns. Contrast-enhanced CT had a pooled sensitivity of 0.79 (95% confidence interval [CI], 0.52-0.93) and specificity of 0.99 (95% CI, 0.94-1.00). Magnetic resonance imaging had a sensitivity of 0.95 (95% CI, 0.76-1.00) and specificity of 0.89 (95% CI, 0.52-1.00). Contrast-enhanced CT might serve as a practical alternative to gynecological examination in the diagnosis of acute PID in an emergency care setting, however, the evidence was uncertain. The evidence on MRI was also very uncertain.

Japanese rapid/living recommendations on drug management for COVID-19: updated guidelines (July 2022).

Background: Coronavirus disease (COVID-19), an infectious disease caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide since early 2020, and there are still no signs of resolution. The Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (J-SSCG) 2020 Special Committee created the Japanese Rapid/Living recommendations on drug management for COVID-19 using the experience of creating the J-SSCG. Methods: The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to determine the certainty of the evidence and strength of recommendations. The first edition of this guideline was released on September 9, 2020, and this is the revised edition (version 5.0; released on July 15, 2022). Clinical questions (CQs) were set for the following 10 drugs: favipiravir (CQ1), remdesivir (CQ2), corticosteroids (CQ4), tocilizumab (CQ5), anticoagulants (CQ7), baricitinib (CQ8), casirivimab/imdevimab (CQ9-1), sotrovimab (CQ9-2), molnupiravir (CQ10), and nirmatrelvir/ritonavir (CQ11). Recommendations: Favipiravir is not suggested for all patients with COVID-19 (GRADE 2C). Remdesivir is suggested for patients with mild COVID-19 who do not require oxygen, and patients with moderate COVID-19 requiring supplemental oxygen/hospitalization (both GRADE 2B). Corticosteroids are recommended for moderate and severe COVID-19 (GRADE 1B, 1A). However, their administration is not recommended for mild COVID-19 (GRADE 1B). Tocilizumab is suggested for moderate and severe COVID-19 (GRADE 2B, 2C). Anticoagulant administration is recommended for moderate and severe COVID-19 (Good Practice Statement). Baricitinib is suggested for moderate and severe COVID-19 (both GRADE 2C). Casirivimab/imdevimab and sotrovimab are recommended for mild COVID-19 (both GRADE 2C). Molnupiravir and nirmatrelvir/ritonavir are recommended for mild COVID-19 (both GRADE 2C). SARS-CoV-2 mutant strains emerge occasionally, and each time, the treatment policy at clinics is forced to change drastically. We ask health-care professionals in the field to refer to the recommendations in these guidelines and use these to keep up to date with COVID-19 epidemiological information.

Bosutinib-induced lung injury: a report of two cases and literature review.

The prognosis of patients with chronic myeloid leukemia (CML) has improved dramatically since the development of tyrosine kinase inhibitors (TKIs). Three second-generation TKIs, including bosutinib, are currently approved for treatment of CML, and show a faster and deeper clinical response than imatinib. Common adverse events (AEs) of bosutinib are diarrhea and hepatic toxicity; however, lung complications are rare. Here, we report two cases of bosutinib-induced severe lung injury, along with a literature review. The events of these cases occurred at early time points and severity was extremely high, requiring high-flow oxygen and steroid treatments. Compared to previously reported cases, the prevalence and severity of the damage may vary among different ethnicities. However, bosutinib-induced lung injury can cause life-threatening complications. In conclusion, patients treated with bosutinib should be monitored carefully to mitigate serious drug-induced lung injury.

Intraperitoneal administration of synthetic microRNA-214 elicits tumor suppression in an intraperitoneal dissemination mouse model of canine hemangiosarcoma.

Canine hemangiosarcoma (HSA) has an extremely poor prognosis, making it necessary to develop new systemic treatment methods. MicroRNA-214 (miR-214) is one of many microRNAs (miRNA) that can induce apoptosis in HSA cell lines. Synthetic miR-214 (miR-214/5AE), which showed higher cytotoxicity and greater nuclease resistance than mature miR-214, has been developed for clinical application. In this study, we evaluated the effects of miR-214/5AE on stage 2 HSA in a mouse model. Mice intraperitoneally administered with miR-214/5AE (5AE group) had significantly fewer intraperitoneal dissemination tumor foci (median number: 72.5 vs. 237.5; p < 0.05) and a lower median foci weight (0.26 g vs. 0.61 g; p < 0.05). Mice in the 5AE group had increased expression of p53 and cleaved caspase-3, and a significantly lower proportion of Ki-67-positive cells, than those in the non-specific miR group. Notably, no significant side effects were observed. These results indicate that intraperitoneal administration of miR-214/5AE exhibits antitumor effects in an intraperitoneal dissemination mouse model of HSA by inducing apoptosis and suppressing cell proliferation. These results provide a basis for future studies on the antitumor effect of miR-214/5AE for HSA.

The impact of COVID-19 on surgical volume and surgical training at a high-volume pelvic oncology centre.

INTRODUCTION: The coronavirus (COVID-19) pandemic has overwhelmed most health services. As a result, many surgeries have been deferred and diagnoses delayed. The aim of this study was to assess the effect of the COVID-19 pandemic at a high-volume pelvic oncology centre. METHODS: A retrospective review was performed of clinical activity from 2017 to 2020. We compared caseload for index procedures 2017-2019 (period 1) versus 2020 (period 2) to see the effect of the COVID pandemic. We then compared the activity during the first lockdown (March 23rd) to the rest of the year when we increased our theatre access by utilising a 'clean' site. RESULTS: The average annual number of robotic assisted radical cystectomy (RARC) and robotic assisted radical prostatectomy (RARP) performed during period 1 was 82 and 352 respectively. This reduced to 68 (17.1% reduction) and 262 (25.6% reduction) during period 2. The number of patients who underwent prostate brachytherapy decreased from 308 to 243 (21% reduction). The number of prostate biopsies decreased from 420 to 234 (44.3% reduction). The number of radical orchidectomies decreased from 18 to 11 (39% reduction). The mean number of RARC and RARP per month during period 2 was 5.5 and 22. This decreased to 4 and 9 per month during the first national lockdown but was maintained thereafter despite two further lockdowns. CONCLUSION: There has been a substantial decrease in urological oncology caseload during the COVID pandemic. The use of alternate pathways such as 'clean' sites can ensure continuity of care for cancer surgery and training needs.

Matrix metalloproteinase­1 expression is regulated by HIF­1­dependent and epigenetic mechanisms and serves a tumor­suppressive role in gastric cancer progression.

The matrix metalloproteinase (MMP) family is associated with degradation of the extracellular matrix and is known to promote cancer invasion. The present study aimed to investigate the biological role of MMP­1 in gastric cancer cells and analyze the association between MMP­1 expression and the clinical outcomes of gastric cancer patients. In the present study, hypoxia accelerated invasion, accompanied by elevated MMP­1 expression in the gastric cancer cell line 58As9. Additionally, hypoxia­inducible factor­1α (HIF­1α) knockdown in 58As9 cells reduced MMP­1 expression under hypoxic conditions. Treatment with 5­aza­2­deoxycytidine and trichostatin A restored MMP­1 expression in the MMP­1­deficient cell lines MKN45 and MKN74. These results indicated that MMP­1 expression was controlled by both HIF­1α­dependent and epigenetic mechanisms in gastric cancer cell lines. In addition, MMP­1 knockdown impaired the hypoxia­induced invasiveness of 58As9 cells, implicating MMP­1 in the elevated invasion. By contrast, knockdown enhanced the proliferative ability of 58As9 cells, whereby expression of cell cycle­related genes was subsequently altered. In nude mouse models, the knockdown accelerated the growth of xenograft tumor and the development of peritoneal dissemination. In an immunohistochemical study using 161 surgically resected cancer tissues, the Ki67 score was significantly higher in the group with low MMP­1 expression (P<0.001). Disease­free survival (DFS) and disease­specific survival (DSS) were both significantly reduced in patients with low MMP­1 expression (log­rank test; DFS: P=0.005; DSS: P=0.022). Multivariate analysis demonstrated that MMP­1 expression was an independent prognostic factor for DFS and DSS [DFS: HR=2.11 (1.22­3.92) P=0.005, DSS: HR=2.90 (1.23­8.50) P=0.012]. In conclusion, the present study indicated that MMP­1 may serve as a tumor­suppressive factor that inhibits gastric cancer progression, although it promoted invasion in vitro.

Japanese rapid/living recommendations on drug management for COVID-19: updated guidelines (September 2021).

BACKGROUND: The coronavirus disease 2019 (COVID-19) has spread worldwide since early 2020, and there are still no signs of resolution. The Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (J-SSCG) 2020 Special Committee created the Japanese rapid/living recommendations on drug management for COVID-19 using the experience of creating the J-SSCG. METHODS: The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to determine the certainty of the evidence and strength of the recommendations. The first edition of this guideline was released on September 9, 2020, and this document is the revised edition (version 4.0; released on September 9, 2021). Clinical questions (CQs) were set for the following seven drugs: favipiravir (CQ1), remdesivir (CQ2), corticosteroids (CQ4), tocilizumab (CQ5), anticoagulants (CQ7), baricitinib (CQ8), and casirivimab/imdevimab (CQ9). Two CQs (hydroxychloroquine [CQ3] and ciclesonide [CQ6]) were retrieved in this updated version. RECOMMENDATIONS: Favipiravir is not suggested for all patients with COVID-19 (GRADE 2C). Remdesivir is suggested for patients with moderate COVID-19 requiring supplemental oxygen/hospitalization (GRADE 2B). Corticosteroids are recommended for patients with moderate COVID-19 requiring supplemental oxygen/hospitalization (GRADE 1B) and for patients with severe COVID-19 requiring mechanical ventilation/intensive care (GRADE 1A); however, their administration is not recommended for patients with mild COVID-19 not requiring supplemental oxygen (GRADE 1B). Tocilizumab is suggested for patients with moderate COVID-19 requiring supplemental oxygen/hospitalization (GRADE 2B). Anticoagulant administration is recommended for patients with moderate COVID-19 requiring supplemental oxygen/hospitalization and patients with severe COVID-19 requiring mechanical ventilation/intensive care (good practice statement). Baricitinib is suggested for patients with moderate COVID-19 requiring supplemental oxygen/hospitalization (GRADE 2C). Casirivimab/imdevimab is recommended for patients with mild COVID-19 not requiring supplemental oxygen (GRADE 1B). We hope that these updated clinical practice guidelines will help medical professionals involved in the care of patients with COVID-19.

Japanese rapid/living recommendations on drug management for COVID-19.

The coronavirus disease (COVID-19) has spread worldwide since early 2020, and there are still no signs of resolution. The Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (J-SSCG) 2020 Special Committee created the Japanese rapid/living recommendations on drug management for COVID-19 using the experience of creating the J-SSCGs. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to determine the certainty of the evidence and strength of the recommendations. The first edition of this guideline was released on 9 September, 2020, and this document is the revised edition (version 3.1) (released 30 March, 2021). Clinical questions (CQs) were set for the following seven drugs: favipiravir (CQ1), remdesivir (CQ2), hydroxychloroquine (CQ3), corticosteroids (CQ4), tocilizumab (CQ5), ciclesonide (CQ6), and anticoagulants (CQ7). Favipiravir is recommended for patients with mild COVID-19 not requiring supplemental oxygen (GRADE 2C); remdesivir for moderate COVID-19 patients requiring supplemental oxygen/hospitalization (GRADE 2B). Hydroxychloroquine is not recommended for all COVID-19 patients (GRADE 1B). Corticosteroids are recommended for moderate COVID-19 patients requiring supplemental oxygen/hospitalization (GRADE 1B) and severe COVID-19 patients requiring ventilator management/intensive care (GRADE 1A); however, their use is not recommended for mild COVID-19 patients not requiring supplemental oxygen (GRADE 1B). Tocilizumab is recommended for moderate COVID-19 patients requiring supplemental oxygen/hospitalization (GRADE 2B). Anticoagulant therapy is recommended for moderate COVID-19 patients requiring supplemental oxygen/hospitalization and severe COVID-19 patients requiring ventilator management/intensive care (GRADE 2C). We hope that these clinical practice guidelines will aid medical professionals involved in the care of COVID-19 patients.

Antitumor effects of low-dose tipifarnib on the mTOR signaling pathway and reactive oxygen species production in HIF-1α-expressing gastric cancer cells.

Farnesyltransferase inhibitors (FTIs) suppress tumor aggressiveness in several malignancies by inhibiting Ras signaling. However, treatment of cells with a low dose of the FTI tipifarnib suppresses the expression of hypoxia-inducible factor-1α (HIF-1α) and results in antitumor effects without inhibiting the Ras pathway. Although we previously reported that elevated HIF-1α expression is associated with an aggressive phenotype in gastric cancer (GC), little is known about the antitumor effects of FTIs on GC. In this study, we examined the relationship between the antitumor effects of low-dose tipifarnib and HIF-1α expression in GC cells. Under normoxic conditions, HIF-1α was expressed only in MKN45 and KATOIII cells. The inhibitory effect of tipifarnib on HIF-1α was observed in HIF-1α-positive cells. Low-dose tipifarnib had antitumor effects only on HIF-1α-positive cells both in vitro and in vivo. Furthermore, low-dose tipifarnib inactivated ras homolog enriched in brain (Rheb)/mammalian target of rapamycin (mTOR) signaling and decreased intracellular reactive oxygen species (ROS) levels in HIF-1α-positive GC cells. Our results that the antitumor effects of low-dose tipifarnib are at least partially mediated through suppression of mTOR signaling and HIF-1α expression via inhibition of Rheb farnesylation and reduction in ROS levels. These findings suggest that low-dose tipifarnib may be capable of exerting an antitumor effect that is dependent on HIF-1α expression in GC cells. Tipifarnib may have potential as a novel therapeutic agent for HIF-1α-expressing GC exhibiting an aggressive phenotype.

A case of idiopathic myointimal hyperplasia of the mesenteric veins presenting with small bowel obstruction.

BACKGROUND: Idiopathic myointimal hyperplasia of the mesenteric veins (IMHMV) is a rare ischemic bowel disease with venous occlusion resulting from the proliferation of smooth muscles in the venous intima. In most patients, the disease affects rectosigmoid colon and causes persistent abdominal pain and hematochezia, which is similar to inflammatory bowel disease (IBD). In addition, it is difficult to make a precise diagnosis of IMHMV without surgery. CASE PRESENTATION: An 81-year-old woman was admitted to our hospital with mild abdominal pain, nausea and vomiting. Repeated adhesive ileus was suspected due to the previous open and laparoscopic surgeries. Surgery was planned to treat small bowel obstruction. Intraoperatively no adhesive lesions were observed. However, a mass lesion was seen at the terminal ileum, which was suspected to have caused her bowel obstruction. Partial resection of the small intestine was performed. Macroscopic and histopathological examinations of the excised specimen showed circumferential ulceration with scarring, a thickened venous wall with active inflammation, and fibrotic changes that consequently produced stenosis and obstruction of the venous lumen in the subserosa. Additionally, Elastica van Gieson staining demonstrated thickening of the venous intima. The final diagnosis was IMHMV. At two years and 8 months after the operation, the patient was well without any additional medication. CONCLUSION: IMHMV of the small intestine is rare. We described a case of IMHMV that was associated with ileus.

Humidity-Resistive Optical NO Gas Sensor Devices Based on Cobalt Tetraphenylporphyrin Dispersed in Hydrophobic Polymer Matrix.

We report on an optical nitrogen oxide (NO) gas sensor device using cobalt tetraphenylporphyrin (CoTPP) dispersed in three kinds of hydrophobic polymer film matrix (polystyrene (PSt), ethylcellulose (EC), and polycyclohexyl methacrylate (PCHMA)) to improve humidity resistance. Our approach is very effective because it allows us to achieve not only high humidity resistance, but also a more than sixfold increase in sensitivity compared with CoTPP film due to the high dispersion of CoTPP in the polymer film. The limit of detection was calculated as 33 ppb for the CoTPP-dispersed EC film, which is lower than that of CoTPP film (92 ppb).

7-Deaza-7-fluoro modification confers on 4'-cyano-nucleosides potent activity against entecavir/adefovir-resistant HBV variants and favorable safety.

We designed, synthesized and identified a novel nucleoside derivative, 4'-C-cyano-7-deaza-7-fluoro-2'-deoxyadenosine (CdFA), which exerts potent anti-HBV activity (IC50 ~26 nM) with favorable hepatocytotoxicity (CC50 ~56 µM). Southern blot analysis using wild-type HBV (HBVWT)-encoding-plasmid-transfected HepG2 cells revealed that CdFA efficiently suppresses the production of HBVWT (IC50 = 153.7 nM), entecavir (ETV)-resistant HBV carrying L180M/S202G/M204V substitutions (HBVETVR; IC50 = 373.2 nM), and adefovir dipivoxil (ADV)-resistant HBV carrying A181T/N236T substitutions (HBVADVR; IC50=192.6 nM), whereas ETV and ADV were less potent against HBVETVR and HBVADVR (IC50: >1,000 and 4,022.5 nM, respectively). Once-daily peroral administration of CdFA to human-liver-chimeric mice over 14 days (1 mg/kg/day) comparably blocked HBVWT and HBVETVR viremia by 0.7 and 1.2 logs, respectively, without significant changes in body-weight or serum human-albumin levels, although ETV only slightly suppressed HBVETVR viremia (CdFA vs ETV; p = 0.032). Molecular modeling suggested that ETV-TP has good nonpolar interactions with HBVWT reverse transcriptase (RTWT)'s Met204 and Asp205, while CdFA-TP fails to interact with Met204, in line with the relatively inferior activity against HBVWT of CdFA compared to ETV (IC50: 0.026 versus 0.003 nM). In contrast, the 4'-cyano of CdFA-TP forms good nonpolar contacts with RTWT's Leu180 and RTETVR's Met180, while ETV-TP loses interactions with RTETVR's Met180, explaining in part why ETV is less potent against HBVETVR than CdFA. The present results show that CdFA exerts potent activity against HBVWT, HBVETVR and HBVADVR with enhanced safety and that 7-deaza-7-fluoro modification confers potent activity against drug-resistant HBV variants and favorable safety, shedding light to further design more potent and safer anti-HBV nucleoside analogs.

Retrospective Risk Analysis for Anastomotic Leakage Following Laparoscopic Rectal Cancer Surgery in a Single Institute.

PURPOSE: Anastomotic leakage (AL) is one of the most serious complications after laparoscopic low anterior resection (LALAR) for rectal cancer. The aim of the present study was to investigate the risk factors for AL after LALAR. METHODS: A retrospective study was conducted of 103 patients who underwent LALAR in a single institute between October 2008 and January 2018. Univariate and multivariate analyses were performed to determine the clinicopathological factors associated with AL. RESULTS: The overall incidence of AL was 9.7% (10/103). After anastomosis using the double-stapling technique, a transanal tube was placed in 88 patients (85.4%). A diverting stoma was created in 26 patients (25.2%). The univariate analysis showed that a younger age (P = 0.014), higher stage (P = 0.048), deeper depth of tumor invasion (P = 0.028), larger tumor circumference (P = 0.024), longer operation time (P = 0.015), and early postoperative diarrhea (P = 0.002) were associated with AL. The multivariate logistic regression analysis revealed early postoperative diarrhea (odds ratio [OR] 16.513, 95% confidence interval [CI] 2.393-113.971, P = 0.004) a younger age (10-year increments; OR 0.351, 95% CI 0.147-0.839, P = 0.019), operative time (10-min increments; OR 1.089, 95% CI 1.012-1.172, P = 0.022), and higher stage (OR 10.605, 95% CI 1.279-87.919, P = 0.029) were independent risk factors for AL CONCLUSION: Our findings suggest that tumor progression accompanied by a high stage, long operative time, and insufficient bowel preparation and early postoperative diarrhea due to a large tumor circumference may be risk factors of AL after LALAR for rectal cancer.

Development of radioiodine labeled acetaminophen for specific, high-contrast imaging of malignant melanoma.

INTRODUCTION: Due to its poor prognosis, specific imaging for early detection of malignant melanoma is strongly desired. Although radioiodine labeled 4-hydroxyphenylcysteamine, which we previously developed, has good affinity for tyrosinase, an enzyme in the melanin metabolic pathway, image contrast of the melanoma:organ ratios is not sufficiently high for detection of primary melanoma and metastases at early injection times. In this study, we developed radioiodine labeled acetaminophen (I-AP) for specific, high-contrast imaging of malignant melanoma. METHODS: Radioiodine-125-labeled AP (125I-AP) was prepared using the chloramine-T method under no carrier-added conditions. Accumulation of radioactivity and the mechanism were evaluated in vitro using B16 melanoma cells incubated with 125I-AP or 14C(U)-labeled AP (14C-AP) with and without l-tyrosine as a substrate of tyrosinase, phenylthiourea as an inhibitor of tyrosinase, and thymidine as an inhibitor of DNA polymerase. The biological distribution of radioactivity in B16 melanoma-bearing mice was evaluated to determine the accumulation of 125I-AP. The stability of 125I-AP over time was evaluated in mice. RESULTS: The labeling efficiency and radiochemical purity of 125I-AP were >80% and 95%, respectively. Accumulation of 125I-AP was higher than that of 14C-AP at 60 min of incubation in vitro. The affinity of 14C-AP for tyrosinase and DNA polymerase was higher than that of 125I-AP, whereas the Vmax of 125I-AP was higher than that of 14C-AP. 125I-AP showed the highest accumulation in the gall bladder, and clearance from the blood and kidney was rapid. Melanoma:muscle and melanoma:normal skin ratios of 125I-AP for imaging contrast were the highest at 15 min after injection, whereas the melanoma:blood and melanoma:bone ratios gradually increased over time. 125I-AP remained stable for 60 min after injection in mice. CONCLUSIONS: 125I-AP has affinity for tyrosinase and high image contrast at early time points after injection. Therefore, 123I-AP imaging has great potential for specific, high-contrast detection of malignant melanoma. ADVANCES IN KNOWLEDGE: 123I-AP will provide specific, high-contrast imaging for malignant melanoma at early injection times. IMPLICATIONS FOR PATIENT CARE: 123I-AP has good potential for the diagnosis of malignant melanoma compared with 123I-labeled 4-hydroxyphenylcysteamine, which we previously developed.

Eosinophilic funiculitis initially diagnosed as irreducible inguinal hernia: A case report.

BACKGROUND: Most groin masses are first suspected to be groin hernias. More than 80% of bulging groin lesions are reportedly diagnosed as hernias by ultrasonography. Establishment of the correct diagnosis of hernia among all differential diagnoses is not easy. We herein describe a very rare case of groin eosinophilic funiculitis that presented as an irreducible groin hernia. CASE PRESENTATION: A 59-year-old man presented to our hospital with suspicion of a right groin hernia. He had a 1-week history of a painful right groin tumor. The tumor was about 4 cm without skin redness or warmth, irreducible even in the supine position, and associated with mild tenderness. Enhanced computed tomography showed that the mass seemed to be connected to the intra-abdominal structures. With time, the patient's pain did not increase, the inflammatory response did not worsen, and no ischemic signs were observed by enhanced computed tomography. Therefore, we diagnosed the tumor as an irreducible but not incarcerated hernia and performed elective surgery. Intraoperative examination revealed no hernia sac, and a 4-×3-cm tumor was observed around the spermatic cord. A malignant tumor was not completely ruled out. High orchiectomy was performed after consultation with the urologists. Pathological examination of the tumor showed no malignant features, and the final diagnosis was eosinophilic funiculitis with massive inflammatory changes and eosinophil invasion. CONCLUSION: Eosinophilic funiculitis is very rare; only three cases have been reported to date. We should always consider unusual causes of groin masses during a surgical approach to hernia-like lesions.

Gas phase ultraviolet and infrared spectroscopy on a partial peptide of ß2-adrenoceptor SIVSF-NH2 by a laser desorption supersonic jet technique.

Laser desorption supersonic jet laser spectroscopy has been applied to a penta-peptide, Ser-Ile-Val-Ser-Phe-NH2 (SIVSF-NH2), which is a partial sequence of a binding site in a ß2-adrenaline receptor protein. By comparing the resonance enhanced multiphoton ionization spectrum with the ultraviolet-ultraviolet hole burning (HB) spectrum, it is concluded that only a single conformer exists. The infrared (IR) spectrum of the X-H stretching region, measured by IR dip spectroscopy, shows that all of the OH and NH groups form hydrogen bonds. The structure of SIVSF-NH2 is assigned by the combination of a force field calculation (CONFLEX) and quantum chemical calculations both in S0 and S1. Over 20 000 stable conformations, given by CONFLEX, are classified into 6987 groups and 1068 groups in which all of the NH and OH bonds are hydrogen-bonded are selected. The most stable structure in each group was geometrically optimized by density functional theory (DFT) calculations, and theoretical IR spectra were calculated for the conformers for which the energies are within 10 kJ mol(-1) of the most stable one. It has been found that the most stable and the secondmost stable conformers well-reproduce the observed IR spectrum. The vibrational frequencies in S1 were also calculated for these two conformers. According to the reproduction of the vibrational frequencies in the HB spectrum, the structure of SIVSF-NH2 is assigned to the most stable conformer, which forms a hydrogen-bonded structure corresponding to a compact, distorted version of the beta hairpin of peptides and proteins.