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The effects of sodium thiosulfate (STS) were studied in patients who received a combination therapy of cis-dichlorodiammineplatinum (CDDP) and vindesine. In this study, 61 patients with non-small-cell lung carcinoma were randomized to receive either CDDP and vindesine (both given i.v.) with i.v. STS [30 patients, STS(+) group] or CDDP and vindesine without STS [31 patients, STS(-) group]. In the STS(+) group, 16 patients who showed an improvement (reduction in tumor size or relief of symptoms) after the first course received the second STS(+) treatment, and 15 patients in the STS(-) group who showed an improvement after the first course received the second STS(-) treatment. Urinary levels of beta 2-microglobulin (BMG) and N-acetyl-beta-D-glucosaminidase (NAG) were measured as an index of proximal tubular function. Analysis of both levels indicated that STS suppressed CDDP nephrotoxicity to a minimal level. Serum BMG, blood urea nitrogen (BUN), and total as well as 24-h creatinine clearance levels were measured as an index of glomerular function. There were no significant differences in these levels between the STS(+) and STS(-) groups. The urinary recoveries of total platinum 24 h after CDDP administration were 29% and 21% in the STS(+) and STS(-) groups, respectively. The mean plasma concentrations of total platinum at 24 h after CDDP administration were 2.24 and 2.70 micrograms/ml in the STS(+) and STS(-) groups, respectively. There were no significant differences in the response rates of the STS(+) and STS(-) groups at a fixed dose of 100 mg/m2 CDDP. Therefore, the present study clearly demonstrates that systemic administration of STS reduces the side effects of CDDP to a minimal level without impairing its antitumor activity and that STS treatment is applicable in a repeated chemotherapy using CDDP alone or in combination with other antitumor agents. [ABSTRACT FROM AUTHOR]

Background: Between November 2021 and February 2022, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta and Omicron variants co-circulated in the United States, allowing for co-infections and possible recombination events., Methods: We sequenced 29,719 positive samples during this period and analyzed the presence and fraction of reads supporting mutations specific to either the Delta or Omicron variant., Findings: We identified 18 co-infections, one of which displayed evidence of a low Delta-Omicron recombinant viral population. We also identified two independent cases of infection by a Delta-Omicron recombinant virus, where 100% of the viral RNA came from one clonal recombinant. In the three cases, the 5' end of the viral genome was from the Delta genome and the 3' end from Omicron, including the majority of the spike protein gene, though the breakpoints were different., Conclusions: Delta-Omicron recombinant viruses were rare, and there is currently no evidence that Delta-Omicron recombinant viruses are more transmissible between hosts compared with the circulating Omicron lineages., Funding: This research was supported by the NIH RADx initiative and by the Centers for Disease Control Contract 75D30121C12730 (Helix)., Competing Interests: Declarations of interests A.B., T.B., S.W., A.D.R., D.W., H.D., J.T.M., E.K., T.C., K.T., J.N., J.R., S.C., E.T.C., K.S.B., N.L.W., P.B.-F., S.J., E.S., D.B., J.T.L., M.I., W.L., and S.L. are all employees of Helix., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The rapid emergence of SARS-CoV-2 variants raised public health questions concerning the capability of diagnostic tests to detect new strains, the efficacy of vaccines, and how to map the geographical distribution of variants to understand transmission patterns and loads on healthcare resources. Next-generation sequencing (NGS) is the primary method for detecting and tracing new variants, but it is expensive, and it can take weeks before sequence data are available in public repositories. This article describes a customizable reverse transcription PCR (RT-PCR)-based genotyping approach which is significantly less expensive, accelerates reporting, and can be implemented in any lab that performs RT-PCR. Specific single-nucleotide polymorphisms (SNPs) and indels were identified which had high positive-percent agreement (PPA) and negative-percent agreement (NPA) compared to NGS for the major genotypes that circulated through September 11, 2021. Using a 48-marker panel, testing on 1,031 retrospective SARS-CoV-2 positive samples yielded a PPA and NPA ranging from 96.3 to 100% and 99.2 to 100%, respectively, for the top 10 most prevalent World Health Organization (WHO) lineages during that time. The effect of reducing the quantity of panel markers was explored, and a 16-marker panel was determined to be nearly as effective as the 48-marker panel at lineage assignment. Responding to the emergence of Omicron, a genotyping panel was developed which distinguishes Delta and Omicron using four highly specific SNPs. The results demonstrate the utility of the condensed panel to rapidly track the growing prevalence of Omicron across the US in December 2021 and January 2022.

Background: Perforated appendicitis without an associated abscess necessitates emergency surgery. However, it is difficult to predict the presence of perforation before surgery, and the predictive factors are still unclarified. Our purposes were to characterize a patient population with perforated appendicitis without an associated abscess to identify the preoperative predictive factors of appendiceal perforation., Methods: We retrospectively identified 150 patients who underwent appendectomy for acute appendicitis at our institution from June 2018 to November 2020. Logistic regression analysis was performed to analyze the concurrent effects of various factors on the prevalence of perforated appendicitis., Results: Forty (29%) of 150 patients had appendiceal perforation detected intraoperatively. Of these 40 patients, only 19 had appendiceal perforation detected on preoperative computed tomography. Multivariable analysis found that a higher C-reactive protein level, higher total bilirubin level, and the presence of an appendiceal fecalith were independent predictive factors for appendicitis with perforation., Conclusion: Our analysis suggests that the presence of an appendiceal fecalith, a total bilirubin level of more than 21.38 μmol/L, and a C-reactive protein level of more than 3.0 × 10 4  μg/L are predictive factors of perforated appendicitis., (© 2021 The Authors.)

BACKGROUND Protein-losing enteropathy as a complication of superior mesenteric artery occlusion is extremely rare and severe, and sometimes requires intestinal resection. However, the ideal treatment strategy has not yet been determined. CASE REPORT A 77-year-old man with underlying hypertension and diabetes was admitted to the Emergency Department with acute abdominal pain after eating. Contrast-enhanced computed tomography revealed complete occlusion of the superior mesenteric artery with thrombosis, and superior mesenteric artery occlusion was diagnosed. It was successfully treated with interventional therapy, followed by continuous intra-arterial prostaglandin E1 infusion and continuous intravenous heparin infusion. However, the patient developed hypoproteinemia and diarrhea about 10 days after the interventional therapy. Colonoscopy and X-ray studies did not reveal any abnormal findings; however, technetium-99m-labeled human serum albumin scintigraphy indicated protein-losing enteropathy. With total parenteral nutrition and protein-rich oral nutrition, with protein intake at twice the amount in a standard diet, serum albumin improved from 15 g/L to 32 g/L after treatment. Additionally, we administered diuretics to avoiding edema related to the hypoproteinemia. The patient recovered from the hypoproteinemia and diarrhea without complications. CONCLUSIONS Protein-losing enteropathy is an extremely rare but critical complication of superior mesenteric artery occlusion. Treating the underlying pathology is the mainstay of protein-losing enteropathy and dietary modifications also play a critical role. Our patient was successfully treated with strict nutritional therapy, combined oral protein-rich nutrition and total parenteral nutrition, which avoided surgery.

Our previous report demonstrated that epigallocatechin gallate (EGCg) promotes translocation of glucose transporter 4 (GLUT4) in skeletal muscle. In this study, we investigated the molecular mechanism of GLUT4 translocation by EGCg at the physiological concentration range. In L6 cells, EGCg induced phosphorylation of phosphatidylinositide 3'-kinase (PI3K) and downstream protein kinase C (PKC) λ/ξ without affecting the phosphorylation of insulin receptor and Akt. EGCg-induced GLUT4 translocation was suppressed by RNA interference-mediated knockdown of PI3K and treatment with PKC inhibitor Go6983. Moreover, EGCg increased Rac1 activity and actin remodelling as downstream events of PKCλ/ξ. These results indicate that EGCg induced GLUT4 translocation through a PI3K-dependent pathway, but its mode of action differed from that of insulin. EGCg also induced GLUT4 translocation through a 5'-adenosine monophosphate-activated protein kinase (AMPK)-dependent pathway. 67 kDa laminin receptor, which is a target molecule of EGCg, was not involved in EGCg-induced glucose uptake in L6 cells. The oral administration of EGCg suppressed postprandial hyperglycaemia accompanied by GLUT4 translocation through both PI3K- and AMPK-dependent pathways, and promoted glycogen accumulation in skeletal muscle of ICR mice. EGCg promotes GLUT4 translocation through both PI3K- and AMPK-dependent pathways and glycogen accumulation in skeletal muscle.

It is known that catechins interact with the tryptophan (Trp) residue at the drug-binding site of serum albumin. In this study, we used catechin derivatives to investigate which position of the catechin structure strongly influences the binding affinity against bovine serum albumin (BSA) and human serum albumin (HSA). A docking simulation showed that (-)-epigallocatechin gallate (EGCg) interacted with both Trp residues of BSA (one at drug-binding site I and the other on the molecular surface), mainly by π-π stacking. Fluorescence analysis showed that EGCg and substituted EGCg caused a red shift of the peak wavelength of Trp similarly to warfarin (a drug-binding site I-specific compound), while 3- O -acyl-catechins caused a blue shift. To evaluate the binding affinities, the quenching constants were determined by the Stern-Volmer equation. A gallate ester at the C-3 position increased the quenching constants of the catechins. Against BSA, acyl substitution increased the quenching constant proportionally to the carbon chain lengths of the acyl group, whereas methyl substitution decreased the quenching constant. Against HSA, neither acyl nor methyl substitution affected the quenching constant. In conclusion, substitution at the C-3 position of catechins has an important influence on the binding affinity against serum albumin.

It is well known that propolis has the ability to prevent hyperglycemia. However, the underlying mechanism is not yet fully understood. We therefore investigated whether a Brazilian propolis ethanol extract affects glucose uptake and translocation of insulin-sensitive glucose transporter (GLUT) 4 in skeletal muscle cells. In L6 myotubes, the extract at 1 μg/mL significantly promoted GLUT4 translocation and glucose uptake activity. Regarding the mechanism of GLUT4 translocation, propolis extract induced both PI3K and AMPK phosphorylation in a dose-dependent manner in L6 myotubes. However, we could not define which pathway was preferentially associated with GLUT4 translocation, because both PI3K and AMPK inhibitors revealed off-target effects to each other. The main polyphenols found in the propolis extract, artepillin C, coumaric acid, and kaempferide, promoted GLUT4 translocation in L6 myotubes. Additionally, these compounds activated both PI3K- and AMPK-dependent dual-signaling pathways. However, only kaempferide increased glucose uptake activity under our experimental conditions. Single oral administrations of propolis extract, at 250 mg/kg body weight, lowered postprandial blood glucose levels in ICR mice. The extract promoted GLUT4 translocation in skeletal muscle of rats and mice, but did not inhibit α-glucosidase activity in the small intestine under our experimental conditions. It was confirmed that propolis extract promoted phosphorylation of both PI3K and AMPK in rat skeletal muscle. In conclusion, we show that Brazilian propolis has the potential to prevent hyperglycemia through the promotion of GLUT4 translocation in skeletal muscle and that kaempferide is one of the candidates for active compound in propolis., (Copyright © 2013 International Union of Biochemistry and Molecular Biology, Inc.)

For the past 10 years (2000-2009), 50 patients of pulmonary mycobacteriosis underwent surgical treatment at Ibarakihigashi National Hospital. Three MDR-TB cases received lobectomy and one case of MDR-TB received intracavity aspiration and thoracoplasty. One bronchial tuberculosis received sleeve lobectomy. Two cases with hemoptysis due to M. avium pulmonary disease underwent pulmonary resection (lobectomy and completion pneumonectomy). One nontuberculous mycobacteriosis case accompanied by lung cancer received lobectomy. In one case because cavity lesion remained after chemotherapy she received lobectomy. All of patients were discharged without complication after operation. For the purpose of definite diagnosis 41 cases (38 cases with a solitary pulmonary nodule and 3 cases with multiple pulmonary nodules) were received surgical procedures. Results of culture examination for the resected lesion were 4 M. tuberculosis complex, 8 M. avium and 4 M. intracellulare. There was only one case with M. avium who needed additional lobectomy because scattered lesions became worse after the previous pulmonary partial resection. The remaining patients were discharged without complication.

Background: The Japan-Multinational Trial Organization (JMTO) lung cancer (LC) 0003 was a prospective randomized phase III trial investigating advanced non-small cell lung cancer comparing paclitaxel (P) plus carboplatin (C) versus vinorelbine (V), gemcitabine (G) followed by docetaxel (D). This trial was conducted with Southwest Oncology Group (SWOG) 0003 using a common arm of PC. An analysis of SWOG 0003 samples showed that low osteopontin (OPN) plasma levels were highly prognostic for a better outcome. We performed an independent investigation to validate these results using samples from Japanese patients enrolled in the JMTO LC 0004, a correlative study associated with JMTO LC 0003., Methods: A total of 20 ml of blood was collected before treatment from patients enrolled in JMTO LC 0003. Serum concentrations of OPN and basic fibroblast growth factor (bFGF) were measured by enzyme-linked immunosorbent assay. Effects of OPN and bFGF levels on tumor response, progression-free survival (PFS), and overall survival (OS) were examined., Results: Seventy-one samples were obtained, including 32 specimens from the PC arm and 39 from the VGD arm. There were no significant relationships between either OPN or bFGF levels with patient characteristics. In an analysis of clinical outcome, low OPN levels correlated with better OS and progression-free survival (hazard ratio [HR] = 0.57; 95% confidence interval [CI], 0.33-0.97; p = 0.037, HR = 0.42; 95% CI, 0.25-0.70; p = 0.001, respectively) and high bFGF levels correlated with better OS (HR = 0.53; 95% CI, 0.31-0.90; p = 0.018)., Conclusion: Consistent with the findings from SWOG 0003, low OPN serum levels were significantly associated with a favorable prognosis in the JMTO LC 0004. Additionally, high bFGF levels were associated with improved survival.

A 67-year-old woman was admitted to our hospital because of progressive dyspnea, cough, bloody sputum, and backache. Chest radiography and CT scans showed bilateral diffuse interstitial shadows, bilateral pleural effusion and dilatation of the pulmonary artery. Echocardiography indicated pulmonary hypertension, and the serum tumor marker levels were elevated. We performed right cardiac catheterization, and withdrew some blood from a pulmonary artery catheter in the wedge position. We confirmed moderate pulmonary hypertension, and adenocarcinoma-like malignant cells were seen in the aspirated blood. The patient died of progressive respiratory failure despite supportive care. In addition to PTTM and lymphangiosis carcinomatosa, autopsy of the right lung revealed interstitial pneumonia and lipoid pneumonia, both of which were not reported before to be associated with PTTM.

A 58-year-old man presented with right backache and bloody sputum. Chest X-ray revealed a nodular opacity in the right lung. Since could not obtain a diagnosis by bronchoscopy, we performed a lower lobectomy. Histopathologically, there were irregularly shaped necrotizing granulomas and an area of acute hemorrhagic, eosinophilic abscess. We suspected paragonimiasis. The diagnosis of paragonimiasis miyazakii was confirmed by ELISA. This is a valuable case of suspected paragonimiasis confirmed pathologically.

Survival data for non-small cell lung cancer is typically reported from clinical trials that include patients fit enough to meet treatment criteria. The denominator of all patients from which the gefitinib-treated population is derived has rarely been reported and the impact of gefitinib on population-based outcomes is difficult to measure. We have retrospectively reviewed data of 626 patients who received gefitinib in Ibaraki Prefecture (with a population of 3 million) in Japan from July 2002 until September 2007. Overall response rate was found to 30.8%, and the median survival time was 8.0 months (95% confidence interval: 7.0-9.0 months). Female gender, good PS, and adenocarcinoma were significantly associated with prolonged survival. Adverse events were generally mild and were mostly skin reactions and diarrhea. Our population-based study has generated similar results to those previously reported in published clinical trials, which had restrictive criteria for eligible patients.

Deletion of any one of three subunits of the yeast Mediator of transcriptional regulation, Med2, Pgd1 (Hrs1), and Sin4, abolished activation by Gal4-VP16 in vitro. By contrast, other Mediator functions, stimulation of basal transcription and of TFIIH kinase activity, were unaffected. A different but overlapping Mediator subunit dependence was found for activation by Gcn4. The genetic requirements for activation in vivo were closely coincident with those in vitro. A whole genome expression profile of a Deltamed2 strain showed diminished transcription of a subset of inducible genes but only minor effects on "basal" transcription. These findings make an important connection between transcriptional activation in vitro and in vivo, and identify Mediator as a "global" transcriptional coactivator.

The identity of alanine tRNAs is dependent on a G:U base pair at the 3:70 position of the acceptor helix. This system of molecular recognition is widely distributed from bacteria to human-cell cytoplasm. In contrast, some mitochondrial alanine acceptor helices are markedly different and contain nucleotides known to block aminoacylation by a nonmitochondrial enzyme. Thus, acceptor helix recognition may differ in these systems and may not depend on G:U. Here we report an example of a Caenorhabditis elegans mitochondrial system where the G:U pair is preserved but where proximal nucleotides known to block charging by a nonmitochondrial enzyme are also present. We show that, as expected, the mitochondrial substrate is not charged by the bacterial enzyme. In contrast, the cloned mitochondrial enzyme charged both mitochondrial and bacterial microhelices. Strikingly, charging of each required the G:U pair. Thus, G:U recognition persists even with an acceptor helix context that inactivates nonmitochondrial systems. The results suggest strong selective pressure to use G:U in a variety of contexts to mark an acceptor stem for alanine. Separate experiments also demonstrate that, at least for the mitochondrial enzyme, helix instability or irregularity is not important for recognition of G:U.

An early phase II study of MST-16 for breast cancer was conducted with the participation of 9 hospitals. MST-16 was administered at three doses; 1) 1,600 mg/body for 5 consecutive days repeating every 4 weeks, 2) 1,200 mg/body for 10-14 consecutive days every 5 weeks, and 3) 1,200 mg/body daily for at least 4 weeks. A total of 28 patients were entered, and 27 cases were eligible. Twenty-five cases were evaluated for efficacy and 27 cases for safety. One patient achieved complete response, 2 patients attained partial response, and the response rate thus obtained was 12.0%. Major side effects observed were myelosuppression represented by leukopenia (69.2%) followed by gastrointestinal disorders. These symptoms, however, were reversible by the cessation of administration.

In the template-directed interference (TDI) footprinting method (Hayashibara & Verdine, 1990), analogs of the naturally occurring DNA bases are incorporated into DNA enzymatically and assayed for interference of sequence-specific binding by a protein. Here we extend this method to include analysis of contacts of amino acid residues to the major groove surface of cytosine residues (TDI-C footprinting). The base analog 5-aza-2'-deoxycytidine, in which the hydrophobic 5-CH of cytosine is replaced by a hydrophilic aza nitrogen, was incorporated into DNA via the corresponding 5'-triphosphate. The analog was found to base pair with guanine during polymerization, resulting in substitution of 2'-deoxycytidine residues. TDI-C footprints of the lambda repressor-OL1 operator complex revealed apparent contacts to the cytosines at operator positions 7 and 8. Inspection of the high-resolution X-ray crystal structure of the lambda-OL1 complex (Clarke et al., 1992; Beamer & Pabo, 1992) revealed that C8 makes a hydrogen binding contact with the Lys3; C7, on the other hand, makes a previously unnoticed hydrophobic contact with the alkane side chain of Lys3. In only the consensus operator half-site was cytosine interference observed, suggesting that the nonconsensus arm binds DNA very differently if at all. The N-terminal arm represents the archetypal case of a sequence-specific peptide-DNA complex characterized at high resolution; thus, the present studies suggest strategies for design and screening of DNA binding peptides. The finding that 5-aza-2'-deoxycytidine inhibits sequence-specific DNA binding proteins may suggest an alternative rationale for the biological activities of this and related azapyrimidine nucleosides.

Forty-five patients with lung carcinoma were randomized to receive CDDP alone (STS (-) group) or combination of sodium thiosulfate (STS (+) group). Among the 45 patients, 42 had primary lung carcinoma and four had metastatic lung carcinoma. The combination of CDDP and STS infusion was performed in twenty-three patients and CDDP alone in 22 patients. The patients given STS were evaluated for renal function and pharmacokinetics. Urinary excretion of beta 2 microglobulin (BMG) and urinary concentration of N-acetyl-beta-D-glucosaminide (NAG), which reflect the function of the proximal tubules, were almost normal in the STS (+) group, but abnormally high in the STS (-) group. For serum BMG, BUN, creatinine, and 24-h creatinine clearance, which reflect glomerular function, no significant differences were found between the two groups. Urinary platinum excretion over 24 h was 29% in the STS (+) group and 21% in the STS (-) group. Total concentration of serum platinum after 24-h administration of CDDP was 2.1 micrograms/ml in the STS (+) group and 2.4 micrograms/ml in the STS (-) group. This study indicated that the combination of CDDP and STS promotes urinary excretion of CDDP, and rescues the dysfunction of the proximal tubules.