Neutrophil left shift and white blood cell (WBC) count are routine laboratory tests used to assess neutrophil state, which depends on supply from the bone marrow and consumption in the tissues. If ...WBC count is constant, the presence of left shift indicates an increase of neutrophil consumption that is equal to an increase of production. A decrease in WBC count indicates that neutrophil consumption surpasses supply. During a bacterial infection, large numbers of neutrophils are consumed. Thus, from onset of infection to recovery, dynamic changes occur in WBC count and left shift data, reflecting the mild to serious condition of the bacterial infection. Although various stimuli in healthy and pathological conditions also cause left shift, a change as sudden and significant is only seen in bacterial infection. Left shift does not occur in the extremely early or late phases of infection; therefore, assessing data from a single time point is unsuitable for diagnosing a bacterial infection. We argue that time-series data of left shift and WBC count reflect real-time neutrophil consumption during the course of a bacterial infection, allowing more accurate evaluation of patient condition.
•A larger left shift indicates a larger neutrophil consumption in the blood.•A larger left shift represents a more severe bacterial infection.•Left shift reflects the severity of a bacterial infection consuming neutrophils.•High WBC count in the blood shows sufficient neutrophil supply to the infected site.•WBC (or neutrophil) count in the blood depends on neutrophil supply and consumption.
Biliary tract cancer (BTC) is typically lethal due to the difficulty of early stage diagnosis. Thus, novel biomarkers of BTC precursors are necessary. Biliary intraepithelial neoplasia (BilIN) is a ...major precursor of BTC and is classified as low or high grade based on cell atypia. In normal gastric mucosa, gastric gland mucin‐specific O‐glycans are unique in having α1,4‐linked N‐acetylglucosamine (αGlcNAc) attached to MUC6. Previously, we reported that αGlcNAc functions as a tumor suppressor of differentiated‐type gastric adenocarcinoma and that decreased αGlcNAc glycosylation on MUC6 in gastric, pancreatic, and uterine cervical neoplasms occurs in cancer as well as in their precursor lesions. However, αGlcNAc and MUC6 expression patterns in biliary tract neoplasms have remained unclear. Here, we analyzed MUC5AC, MUC6, and αGlcNAc expression status in 51 BTC cases and compared the expression of each with progression from low‐grade BilIN to invasive adenocarcinoma (IAC). The frequency of αGlcNAc‐positive and MUC6‐positive lesions decreased with tumor progression. When we compared each marker’s expression level with tumor progression, we found that the MUC6 expression score in IAC was significantly lower than in low‐grade or high‐grade BilIN (P < 0.001 or P < 0.01, respectively). However, the αGlcNAc expression score was low irrespective of histological grade, and also lower than that of MUC6 across all histological grades (P < 0.001 for low‐grade and high‐grade BilIN, and P < 0.01 for IAC). These results suggest that decreased expression of αGlcNAc relative to MUC6 marks the initiation of BTC progression.
Alpha‐1,4‐linked N‐acetylglucosamine glycosylation on MUC6 is already decreased in biliary intraepithelial neoplasia.
We attempted to examine the factors contributing to the difficulty in performance of colorectal ESD, with the aim of constructing a scoring system that could help in prediction of the difficulty ...level of the procedure.
The data were analyzed from two viewpoints: to determine the factors contributing to 1) non-en bloc resection and the factors contributing to 2) a slow resection speed. Factors falling under these two categories contributing to difficulty in performance of ESD were extracted and used to construct a scoring system. The validity of this scoring system was evaluated by calculating the correlation between the score and the resection speed in a different dataset.
Based on the results of our analysis, we assigned scores for various factors as follows: 4 points for EMR of a scarred lesion, 1 point for tumors with a diameter of ≥ 30 mm, 2 points for lesions located in the liver/splenic flexure, 1 point for lesions located in the transverse colon, 3 points for LST-NG-PD/depressed lesions, 1 point for protruded lesions and LST-NG-F lesions (range 0-10). In the validation study, the rank correlation coefficient between the score according to the scoring system and the resection speed was -0.130, representing a weak and negative correlation (P = 0.03). We defined the difficulty level depending on the sum of the scores: 0-2, low difficulty level; 3-5, intermediate difficulty level; ≥ 6, high difficulty level. The average resection speed was 12.6 mm2/min in the group with scores of 0-2, 8.1 mm2/min in the group with scores of 3-5, and 5.5 mm2/min in the group with scores of ≥ 6 (11.2 mm2/min in all lesions).
Our colorectal ESD scoring system would be useful for selection of operators with the appropriate skill level in the procedure for colorectal ESD cases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Improved prognosis for triple-negative breast cancer (TNBC) has plateaued and the development of novel therapeutic strategies is required. This study aimed to explore the anti-tumor effect of ...combined eribulin and HDAC inhibitor (vorinostat: VOR, pan-HDAC inhibitor and ricolinostat: RICO, selective HDAC6 inhibitor) treatment for TNBC.
Methods
The effect of eribulin in combination with an HDAC inhibitor was tested in three TNBC cell lines (MDA-MB-231, Hs578T, and MDA-MB-157) and their eribulin-resistant derivatives. The expression of acetylated α-tubulin was analyzed by Western blotting for TNBC cells and immunohistochemical analyses for clinical specimens obtained from breast cancer patients who were treated with eribulin.
Results
The simultaneous administration of low concentrations (0.2 μM) of VOR or RICO enhanced the anti-tumor effect of eribulin in MDA-MB-231 and Hs578T cells but not in MDA-MB-157 cells. Meanwhile, pretreatment with 5 μM of VOR or RICO enhanced eribulin sensitivity in all three cell lines. Low concentration of VOR or RICO increased acetylated α-tubulin expression in MDA-MB-231 and Hs578T cells. In contrast, whereas 5 μM of VOR or RICO increased the expression of acetylated α-tubulin in MDA-MB-157 cells, low concentrations did not. Eribulin increased the expression of acetylated α-tubulin in MDA-MB-231 and Hs578T cells but not in MDA-MB-157 cells. These phenomena were also observed in eribulin-resistant cells. Immunohistochemical analyses revealed that the expression of acetylated α-tubulin was increased after eribulin treatment in TNBC.
Conclusions
HDAC6 inhibition enhances the anti-tumor effect of eribulin through the acetylation of α-tubulin. This combination therapy could represent a novel therapeutic strategy for TNBC.
Autophagy is a lysosome-dependent degradative process that protects cancer cells from multiple stresses. In preclinical models, autophagy inhibition with chloroquine (CQ) derivatives augments the ...efficacy of many anticancer therapies, but CQ has limited activity as a single agent. Clinical trials are underway combining anticancer agents with hydroxychloroquine (HCQ), but concentrations of HCQ required to inhibit autophagy are not consistently achievable in the clinic. We report the synthesis and characterization of bisaminoquinoline autophagy inhibitors that potently inhibit autophagy and impair tumor growth in vivo. The structural motifs that are necessary for improved autophagy inhibition compared with CQ include the presence of two aminoquinoline rings and a triamine linker and C-7 chlorine. The lead compound, Lys01, is a 10-fold more potent autophagy inhibitor than HCQ. Compared with HCQ, Lys05, a water-soluble salt of Lys01, more potently accumulates within and deacidifies the lysosome, resulting in impaired autophagy and tumor growth. At the highest dose administered, some mice develop Paneth cell dysfunction that resembles the intestinal phenotype of mice and humans with genetic defects in the autophagy gene ATG16L1, providing in vivo evidence that Lys05 targets autophagy. Unlike HCQ, significant single-agent antitumor activity is observed without toxicity in mice treated with lower doses of Lys05, establishing the therapeutic potential of this compound in cancer.
IgG4, which plays a pivotal role in the progression of phenotypically diverse tumors, serves as a prognostic marker because of its influence on cancer immunity. Nevertheless, the functions of IgG4 in ...tongue squamous cell carcinoma (TSCC) remained to be identified.
To evaluate the significance of IgG4 expression in TSCC, we performed immunohistochemical analysis of patients with TSCC (n = 50) to evaluate the correlation of IgG4 expression with patients' clinicopathological features and prognoses.
Higher IgG4 expression detected in TSCC tissues was associated with the less advanced mode of invasion (Yamamoto-Kohama YK 1-3) (P = 0.031) and with well-differentiated TSCC (P = 0.077). Kaplan-Meier analyses revealed that the higher IgG4 expression group exhibited better prognosis indicated by overall survival (OS) (P = 0.04) and recurrence-free survival (RFS) (P = 0.016). Univariate analysis of OS indicated that IgG4 expression was associated with longer OS (P = 0.061), and multivariate analysis of RFS revealed that IgG4 expression served as an independent prognostic factor for longer RFS (P = 0.005).
These results indicate that relatively higher IgG4 levels serve as a favorable prognostic factor for TSCC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Immunochromatographic antigen tests have been widely used for detection of influenza virus; however its low sensitivity restricts the use of clinical materials other than nasopharyngeal swabs. Saliva ...is obtained non-invasively and has utility for diagnosis of influenza. Polymerase chain reaction (PCR) is not typically used for rapid testing because it is time consuming. We evaluated the utility of saliva as diagnostic materials for influenza virus infection by PCR-based assays.
Nasopharyngeal swabs and saliva were simultaneously collected from 144 patients and investigated by reverse transcription-quantitative PCR (RT-qPCR) and droplet-RT-PCR.
Overall concordance of results from nasopharyngeal swabs and saliva were 95.8%. Influenza gene was detectable in less than 12min in saliva by the droplet-RT-PCR. Saliva as well as nasopharyngeal swabs contained more than 1×102 copies/μl of the influenza gene. About half of the patients provided positive results in nasopharyngeal swabs and saliva within 24h from the onset of the symptoms.
The study demonstrates that saliva can be used as an alternative specimen source to nasopharyngeal swabs. When rapid PCR assay including RNA extraction to be full-automation in a miniaturized machine, point-of-care test based on PCR may be realized using saliva without restriction of materials.
•High degree of result concordance was obtained from nasopharyngeal swabs and saliva.•The droplet-RT-PCR assay could amplify influenza gene in the saliva within 14min.•Saliva contained influenza gene more than 1×102 copies/μl of influenza gene.•About 50% of saliva was positive within 24h after the onset of symptoms.
Elevated serum IgG4 is a useful marker of IgG4-related disease (IgG4-RD) activity. However, there is no uniformity in the cut-off values of IgG4 among the various reagents. The aim of this study was ...to compare the measured and cut-off values of IgG4 assessed using three different reagents. This study enrolled 466 IgG4-RD and non-IgG4-RD patients who required measurement of serum IgG4 levels to diagnose or treat IgG4-RD. Serum IgG4 was measured using three reagents: N-assay LA IgG4 Nittobo (Nittobo), BS-NIA IgG4 (TBS), and N Latex IgG4 (Siemens). The values obtained using the three reagents were compared, and cut-off values were calculated for each. Although there was good correlation among the results with the three reagents, the measured and cut-off values were all different. The Nittobo values were 1.4 times the TBS values and the TBS values were almost half those of the Siemens values. ROC curve analysis showed cut-off values for the Nittobo, TBS, and Siemens reagents of 1.42, 1.31, and 2.38 g/L, respectively. The measured and cut-off values of serum IgG4 vary depending on the reagents used for the assay, although there is good correlation among the values measured by the three reagents.
Idiopathic pulmonary fibrosis (IPF), a fibrosing interstitial lung disease, predominantly affects the elderly and is associated with a high mortality risk. Nintedanib, a tyrosine kinase inhibitor, ...significantly reduces IPF progression. However, data on the tolerability and efficacy of nintedanib in the elderly with IPF are limited. Therefore, this study aimed to examine the tolerability and efficacy of nintedanib in the elderly with IPF in a real-world setting. Medical records of 19 elderly IPF patients (≥ 75 years) and 46 non-elderly IPF patients (< 75 years) newly administered nintedanib were retrospectively analyzed. We compared the forced vital capacity (FVC) level, incidence and severity of adverse events, and continuation rates of nintedanib between the two groups. FVC and percent predicted diffusing capacity of the lung for carbon monoxide (DLco) were lower in the elderly IPF group at baseline. Although the elderly IPF patients had a significantly higher incidence of adverse events, such as diarrhea, nausea, and elevation of hepatic enzymes, the rate of discontinuation of nintedanib owing to adverse events was not different between the groups. The continuation rates of nintedanib treatment at 6 months and 1 year in the elderly IPF group were equivalent. Furthermore, there was a similar trend in the reduction of the annual FVC decline after nintedanib initiation between the groups. Our study demonstrated that nintedanib was tolerable in both the IPF patient groups in a real-world setting. Proper management of adverse events in the elderly with IPF would lead to a better clinical outcome.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Emergency endoscopic hemostasis for colonic diverticular bleeding is effective in preventing serious consequences. However, the low identification rate of the bleeding source makes the procedure ...burdensome for both patients and providers. We aimed to establish an efficient and safe emergency endoscopy system. We prospectively evaluated the usefulness of a scoring system (Jichi Medical University diverticular hemorrhage score: JD score) based on our experiences with past cases. The JD score was determined using four criteria: CT evidence of contrast agent extravasation, 3 points; oral anticoagulant (any type) use, 2 points; C-reactive protein greater than or equal to1 mg/dL, 1 point; and comorbidity index greater than or equal to3, 1 point. Based on the JD score, patients with acute diverticular bleeding who underwent emergency or elective endoscopy were grouped into JD greater than or equal to3 or JD <3 groups, respectively. The primary and secondary endpoints were the bleeding source identification rate and clinical outcomes. The JD greater than or equal to3 and JD <3 groups included 35 and 47 patients, respectively. The rate of bleeding source identification, followed by the hemostatic procedure, was significantly higher in the JD greater than or equal to3 group than in the JD <3 group (77% vs. 23%, p <0.001), with a higher JD score associated with a higher bleeding source identification rate. No significant difference was observed between the groups in terms of clinical outcomes, except for a higher incidence of rebleeding at one-month post-discharge and a higher number of patients requiring interventional radiology in the JD greater than or equal to3 group than in the JD <3 group. Subgroup analysis showed that successful identification of the bleeding source and hemostasis contributed to a shorter hospital stay. We established a safe and efficient endoscopic scoring system for treating colonic diverticular bleeding. The higher the JD score, the higher the bleeding source identification, leading to a successful hemostatic procedure. Elective endoscopy was possible in the JD <3 group when vital signs were stable.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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