Comparative Efficacy of Subcutaneous and Intravenous Infliximab and Vedolizumab for Maintenance Treatment of TNF-naive Adult Patients with Inflammatory Bowel Disease: A Systematic Literature Review and Network Meta-analysis.

BACKGROUND: Infliximab and vedolizumab are widely used to treat Crohn's disease (CD) and ulcerative colitis (UC). AIMS: This systematic review and network meta-analysis evaluated comparative efficacy of various regimens for intravenous or subcutaneous infliximab and vedolizumab during maintenance treatment in CD and UC. METHODS: Parallel-group randomized controlled trials (RCTs) were identified by a systematic literature review (CRD42022383401) and included if they evaluated therapeutics of interest for maintenance treatment of adults with moderate-to-severe luminal CD or UC and assessed clinical remission between Weeks 30 and 60. Clinical remission rates in CD or UC and mucosal healing rates in UC were analyzed in a Bayesian network meta-analysis model. Endoscopic outcomes in CD were synthesized by proportional meta-analysis. RESULTS: Overall, 13 RCTs were included in the analyses. All vedolizumab studies randomized induction responders to maintenance treatment; infliximab studies used a treat-through design. Subcutaneous infliximab 120 mg every 2 weeks had the highest odds ratio (OR) [95% credible interval] versus placebo for clinical remission during the maintenance phase (CD: 5.90 [1.90-18.2]; UC: 5.45 [1.94-15.3]), with surface under the cumulative ranking curve (SUCRA) values of 0.91 and 0.82, respectively. For mucosal healing in UC, subcutaneous infliximab 120 mg every 2 weeks showed the highest OR (4.90 [1.63-14.1]), with SUCRA value of 0.73, followed by intravenous vedolizumab 300 mg every 4 weeks (SUCRA value, 0.70). Endoscopic outcomes in CD were better with subcutaneous infliximab 120 mg every 2 weeks than intravenous infliximab 5 mg/kg every 8 weeks. CONCLUSIONS: Subcutaneous infliximab showed a favorable efficacy profile for achieving clinical remission and endoscopic outcomes during maintenance treatment in CD or UC.

Clinical predictors of polyps recurring in patients with chronic rhinosinusitis and nasal polyps: a systematic review and meta-analysis.

BACKGROUND: Identification of perioperative risk factors for recurrent nasal polyps (RNPs) is important for selection of further treatment and determination of appropriate follow-up period. However, the relative prognostic significance of these risk factors has not been investigated. METHODOLOGY: We compared the nasal symptoms, endoscopic polyp and Lund-Mackey computed tomography scores, and the laboratory and pathological findings of RNP and non-RNP patients. The risk of bias was assessed using the Newcastle-Ottawa scale. RESULTS: Patients with poor nasal symptom scores and olfactory dysfunctions and high Lund-Mackey computed tomography scores were at higher risk of postoperative RNPs, as were those with allergic conditions and elevated tissue and serum eosinophil levels. The tissue neutrophil counts/percentages were significantly lower in the RNP than the other group. The tissue eosinophil level was of higher diagnostic utility than the serum eosinophil level. The RNP diagnostic odds ratio afforded by the tissue eosinophil count or percentage was 54.1247. The area under the receiver operating characteristic curve was 0.936. The sensitivity and specificity were 0.8809 and 0.8834, respectively. CONCLUSION: The tissue eosinophil level reliably predicts RNP after endoscopic sinus surgery.

Significance of photodocumentation-associated factors in colonoscopy on the detection rate of colorectal neoplasms.

OBJECTIVE: It is unclear whether photodocumentation is associated with colorectal neoplasm (CRN) detection at colonoscopy, despite its ability to take more images with the development of affordable digital imaging systems. This study aimed to investigate whether photodocumentation-related factors could affect the detection rate of CRNs in healthy subjects. PATIENTS AND METHODS: A total of 2,637 subjects undergoing screening colonoscopy in routine health check-ups at CHA Bundang Medical from January to September 2016 were enrolled in this study. Only the endoscopic image data for observation purposes during colonoscopy withdrawal was used in this analysis. The number of observation images, observation time and the speed of photodocumentation (SPD) defined as the number of observation images per minute were used as quantity measures of photodocumentation. The presence of documented anatomical landmarks such as appendix orifice (AO), ileocecal valve (ICV), anorectal junction was used as quality measures of photodocumentation. RESULTS: Among subject-related factors, the independent factors for CRN detection in the multivariate analysis were age, male sex, waist circumference, and family history of colorectal cancer. In photo-documentation-related factors, SPD [Odds ratio (OR) 0.800; 95% confidence interval (CI), 0.740 to 0.864], observation time over 6 min (OR 1.671; 95% CI, 1.145 to 2.439), clear documentation of appendix orifice (AO) (OR 5.976; 95% CI, 4.548 to 7.852) and ileocecal valve (ICV) (OR 3.826; 95% CI, 2.985 to 4.904), and endoscopists (p < 0.001) were independently significant factors. However, the number of observation images was not associated with the detection of CRNs. CONCLUSIONS: Lower SPD and clear documentation of cecal landmarks might be associated with an increased detection rate of CRNs.

SAR user guide to the rectal MR synoptic report (primary staging).

Rectal MR is the key diagnostic exam at initial presentation for rectal cancer patients. It is the primary determinant in establishing clinical stage for the patient and greatly impacts the clinical decision-making process. Consequently, structured reporting for MR is critically important to ensure that all required information is provided to the clinical care team. The SAR initial staging reporting template has been constructed to address these important items, including locoregional extent and factors impacting the surgical approach and management of the patient. Potential outputs to each item are defined, requiring the radiologist to commit to a result. This provides essential information to the surgeon or oncologist to make specific treatment deisions for the patient. The SAR Initial Staging MR reporting template has now been officially adopted by the NAPRC (National Accreditation Program for Rectal Cancer) under the American College of Surgery. With the recent revisions to the reporting template, this user guide has been revamped to improve its practicality and support to the radiologist to complete the structured report. Each line item of the report is supplemented with clinical perspectives, images, and illustrations to help the radiologist understand the potential implications for a given finding. Common errors and pitfalls to avoid are highlighted. Ideally, rectal MR interpretation should not occur in a vacuum but in the context of a multi-disciplinary tumor board to ensure that healthcare providers use common terminology and share a solid understanding of the strengths and weaknesses of MR.

Pilot study of fractional microneedling radiofrequency for hidradenitis suppurativa assessed by clinical response and histology.

BACKGROUND: Hidradenitis suppurativa (HS) is a devastating chronic inflammatory skin disease with frequent recurrences. Various systemic treatments and procedures have been used but the efficacy of fractional microneedling radiofrequency (FMR) has not been reported. AIM: To evaluate the clinical and histological efficacy of FMR in the treatment of HS lesions. METHODS: An 8-week, prospective, split-body, unblinded study was conducted, which enrolled 10 adult patients with mild to moderate HS to receive 3 sessions of FMR treatment biweekly. HS severity was assessed using the number and type of lesions, HS Physician Global Assessment (HS-PGA) and the modified Sartorius score (mSS). Skin biopsies were performed on participants to assess change in inflammation before and after FMR. RESULTS: Severity of HS was significantly reduced on the FMR-treated side of the body, but not on the control side. Inflammatory HS lesions were significantly reduced after 4 weeks, while HS-PGA and mSS were significantly decreased after 6 weeks. Immunohistochemistry staining showed decreased expression of inflammatory markers including neutrophil elastases, interleukin (IL)-8 and IL-17, tumour necrosis factor-α, transforming growth factor-ß1 and matrix metalloproteinases. CONCLUSION: FMR may be a viable treatment option for mild to moderate HS.

A SEER analysis of survival and prognostic factors in merkel cell carcinoma of the head and neck region.

While Merkel cell carcinoma (MCC) of the head and neck is highly malignant, it remains poorly characterized due to its rarity. The purpose of this study was to examine prognostic factors for overall survival (OS) and disease-specific survival (DSS) in patients with MCC of the head and neck region. The Surveillance, Epidemiology and End Results registry was reviewed for patients diagnosed between 1984 and 2016 with histologically confirmed, primary MCC of the head and neck region. A total of 2818 patients met the inclusion criteria, with a median age at diagnosis of 77 years. At five and 10 years, respectively, the OS was 42.4% and 25.1% and the DSS was 67.9% and 64.1%. Multivariate Cox analysis indicated that predictors of decreased DSS included age at diagnosis ≥75 years, white race, increasing tumor spread, lymph node involvement and either the lip or the scalp/neck as a primary site. When adjusting for the aforementioned factors, tumor depth was not found to be a prognostic factor for DSS. We anticipate these results will help clinicians to counsel patients regarding expectations and potential prognosis.

Lacticaseibacillus paracasei NK112 mitigates Escherichia coli-induced depression and cognitive impairment in mice by regulating IL-6 expression and gut microbiota.

The gut microbiota communicates with the brain through microbiota-gut-brain (MGB) and hypothalamus-pituitary-adrenal (HPA) axes and other pathways. Excessive expression of interleukin (IL)-6 is closely associated with the occurrence of the psychiatric disorders depression and dementia. Therefore, to understand whether IL-6 expression-suppressing probiotics could alleviate psychiatric disorders, we isolated IL-6 expression-inhibiting Lacticaseibacillus paracasei (formerly Lactobacillus paracasei) NK112 from the human faecal bacteria strain collection (Neurobiota Research Center, Seoul, Korea) and examined its therapeutic effect for the depression and cognitive impairment in mice. C57 BL/6J mice with depression and cognitive impairment were prepared by exposure to Escherichia coli K1. Oral gavage of NK112 significantly alleviated K1-induced anxious, depressive, and memory-impaired behaviours in the elevated plus maze, tail-suspension and Y-maze tasks, IL-1ß, IL-6, and tumour necrosis factor (TNF)-α expression, and nuclear factor kappa beta (NF-κB) activation in the hippocampus, while K1-suppressed brain-derived neurotrophic factor (BDNF) expression increased. Treatment with NK112 also improved K1-induced myeloperoxidase activity, IL-6 and TNF-α expression, and NF-κB activation in the colon and reduced K1-induced Proteobacteria population in the gut microbiota. Heat-killed NK112 and its lysate supernatant, and precipitate fractions also improved anxiety/depression, cognitive impairment, and colitis in mice. In conclusion, NK112, even if heat-killed or lysed, alleviated K1 stress-induced colitis, anxiety/depression, and cognitive impairment by suppressing IL-6, TNF-α, and BDNF expression through the regulation of gut microbiota and NF-κB activation.

[Effects of SGI-1027 on Formation and Elimination of PrP

Recently, SGI-1027, a well-known inhibitor of DNA-methyl transferases (DNMTs), was reported to effectively reduce formation of pathogenic PrP^(Sc) in prion-infected cells. Herein, we confirm the elimination of PrP^(Sc) in chronic wasting disease (CWD) prion-infected neurons by SGI-1027, and pinpoint the binding region of human prion protein to SGI-1027. SGI-1027 is broadly functional against various prion disease types, including human prions. Previously, the inhibitory effects of SGI-1027 on DNMT function is well tested in various cell culture models. While neither treatment with a DNMTs enhancer S-adenosyl-L-methionine (SAM), nor with their inhibitor, 5-azacytidine, prevented PrP^(Sc) propagation, SGI-1027 did. Our study suggest that the anti-prion effects of SGI-1027 are a result of its direct interaction with PrP^(C), which effectively interferes with the pathogenic conformational change of PrP^(C) to PrP^(Sc). We conclude that SGI-1027 driven suppression of pathogenic PrP^(Sc) is independent of DNMT.

Short communication: Effects of moringa extract on adhesion and invasion of Escherichia coli O55 in bovine mammary epithelial cells.

The objective of this study was to evaluate the antibacterial activities of extract derived from moringa leaves. In particular, the effect of moringa extract (Mor) on adhesion and invasion of Escherichia coli O55, Enterococcus faecalis, Staphylococcus simulans, and Serratia liquefaciens was evaluated in bovine mammary epithelial cells (MAC-T). Broth microdilution method, minimum inhibitory concentration and minimum bactericidal concentration assays, adhesion and invasion assays, and real-time PCR were performed. The minimum inhibitory concentration and minimum bactericidal concentration of Mor ranged from 12.5 to 50 mg/mL on 18 out of 27 tested isolates. Treatment of E. coli O55 with Mor (100 and 200 µg/mL) inhibited the adhesion and invasion on MAC-T cells via downregulation of adhesion factors (i.e., papC, f17c-A, and eaeA). Also, when MAC-T cells were pretreated with Mor (200 µg/mL, 12 h) and incubated with E. coli O55, Enterococcus faecalis, Staphylococcus simulans, or Serratia liquefaciens, both E. coli O55 and Enterococcus faecalis showed a significant decrease in adhesion and invasion. Staphylococcus simulans exhibited decreased adhesion and increased invasion. Serratia liquefaciens showed increased adhesion and decreased invasion. In addition, Mor increased mRNA expression of antioxidant enzymes (e.g., heme oxygenase-1, NAD(P)H:quinone oxidoreductase-1, and thioredoxin reductase 1) in MAC-T cells. In conclusion, 12.5 to 50 mg/mL of Mor exhibited antibacterial activity against 18 out of 27 tested isolates. Also, pretreatment of 200 µg/mL of Mor to MAC-T cells modulated adhesion and invasion of E. coli O55 and other mastitis-associated pathogens. Furthermore, Mor increased antioxidant capacities in MAC-T cells, but further in vivo studies are needed.

Parkinson's disease and skin cancer risk: a nationwide population-based cohort study in Korea.

BACKGROUND: Previous studies have reported that patients with Parkinson's disease (PD) have a significantly lower risk of cancer. Studies reporting prevalence of skin cancers in Parkinson's disease mostly involve Caucasians. OBJECTIVE: A nationwide population-based study was conducted to determine the risk of skin cancer in patients diagnosed with PD in Korea. METHODS: Data obtained from National Health Insurance Claims records were used to retrieve information about 70 780 patients with newly diagnosed PD between January 2010 and December 2015. The control group included 353 900 sex- and age-matched patients without PD. In this nationwide population-based cohort study, we investigated the association between PD and skin cancer. RESULTS: The overall hazard ratio (HR) of skin cancers in patients with PD was 1.169 (95% CI, 1.005-1.359) compared with non-PD group. Among patients with PD, males aged above 65 had a 2.8-fold increase in the risk for melanoma development than the non-PD group (HR, 2.825; 95% CI, 1.395-5.721). In addition, female PD patients aged above 65 years showed a 1.3-fold increase in non-melanoma skin cancer risk than the non-PD group (HR, 1.305; 95% 1.073-1.589). CONCLUSION: Compared with the general population, Korean patients diagnosed with PD had a greater risk of skin cancer. Especially, male patients aged 65 years and above, and diagnosed with PD had a significant risk of melanoma development compared with control.

Short communication: Effects of a physiologically relevant concentration of aflatoxin B1 with or without sequestering agents on in vitro rumen fermentation of a dairy cow diet.

Aflatoxin is a potent carcinogen commonly found in animal feeds that can impair rumen fermentation at high concentrations; however, its effects at physiologically relevant concentrations are unknown. This study examined the effects of aflatoxin B1 (AFB1), with or without bentonite clay (CL) and Saccharomyces cerevisiae fermentation product (SCFP)-based sequestering agents on in vitro rumen fermentation and digestibility of a dairy cow TMR. Corn silage-based TMR (0.5 g, 17.3% crude protein and 1.67 Mcal/kg of net energy for lactation) was incubated in a rumen fluid-buffer inoculum (1:2 ratio; 50 mL) with the following treatments: (1) no additives (control); (2) control + 0.75 µg/L AFB1 (T); (3) T + 80 mg/L sodium bentonite clay (CL; Astra-Ben-20, Prince Agri Products Inc., Quincy, IL); or (4) CL + 14 mg/L SCFP (CL+SCFP; Diamond V, Cedar Rapids, IA). Ruminal fluid was collected 3 h after the morning feeding from 3 cannulated cows fed the same TMR, and rumen fluid from individual cows was used to prepare separate inocula. Each treatment was incubated in duplicate at 39°C for 0, 4, 8, 16, and 24 h in each of 3 runs. Adding T reduced total volatile fatty acid (VFA) concentration after 4 and 8 h and molar proportion of propionate after 4 and 24 h of incubation relative to control. Adding sequestering agents (CL and CL+SCFP) with T did not affect total VFA concentration after 4 or 8 h, but increased total VFA after 16 h and tended to increase molar proportion of propionate after 24 h compared with T. At 24 h, T had lower DM digestibility and higher NH3-N concentration compared with the control. Thus, AFB1, even at very low concentration (0.75 µg/L), had detrimental effects on rumen fermentation and subsequently DM digestibility of the TMR. Adding sequestering agents did not prevent negative effects of T on rumen fermentation within 8 h of incubation; however, sequestering agents were effective after 16 h of incubation.

Volumetric growth rates of sessile serrated adenomas/polyps observed in situ at longitudinal CT colonography.

OBJECTIVE: Sessile serrated adenomas/polyps (SSA/Ps) are now recognized as potential cancer precursors, but little is known about their natural history. We assessed the in vivo growth rates of histologically proven SSA/Ps at longitudinal CT colonography (CTC) and compared results with non-advanced tubular adenomas (TAs). METHODS: We identified a cohort of 53 patients (mean age, 54.8 ± 5.5 years; M:F, 26:27) from one center with a total of 58 SSA/Ps followed longitudinally at CTC (mean follow-up interval, 5.3 ± 1.9 years). Initial and final size measurements were determined using dedicated CTC software. Findings were compared with 141 non-advanced TAs followed at CTC (mean, 4.1 ± 2.3 years) in 113 patients (mean age, 56.8 ± 6.9 years). RESULTS: SSA/Ps were more often flat (62% [36/58] vs. 14% [20/141], p < 0.0001) and right-sided (98% [57/58] vs. 46% [65/141], p < 0.0001) compared with TAs. Initial average diameter was greater for SSA/Ps (9.3 mm vs. 6.3 mm; p < 0.0001). Mean annual volumetric growth was + 12.7%/year for SSA/Ps vs. + 36.4%/year for TAs (p = 0.028). Using a previously defined threshold of + 20% increase in volume/year to define progression, 22% (13/58) of SSA/Ps and 41% (58/141) of TAs progressed (p = 0.014). None of the SSA/Ps had dysplasia or invasive cancer at histopathology. CONCLUSIONS: Sessile serrated adenoma/polyps demonstrate slower growth compared with conventional non-advanced tubular adenomas, despite larger initial linear size. This less aggressive behavior may help explain the more advanced patient age for serrated pathway cancers. Furthermore, these findings could help inform future colonoscopic surveillance strategies, as current guidelines are largely restricted to expert opinion related to the absence of natural history data. KEY POINTS: • Sessile serrated adenoma/polyps (SSA/Ps) tend to be flat, right-sided, and demonstrate slower growth compared with conventional non-advanced tubular adenomas. • This less aggressive behavior of SSA/Ps may help explain the more advanced patient age for serrated pathway cancers.

Long-term follow-up of intradermal injection of methylene blue for intractable, idiopathic pruritus ani.

BACKGROUND: While various medical treatments such as topical steroid ointment, antihistamine agent, and sedatives have been used for treating idiopathic intractable pruritus ani, they are not long-term solutions, due to the high recurrence rate. The aim of this study was to determine the effect of methylene-blue intradermal-injection therapy for treating patients with idiopathic intractable pruritus ani. Symptom improvement and recurrence rates were determined with a long-term follow-up. METHODS: A retrospective study was conducted from January 2011 to October 2013 on consecutive patients with intractable pruritus ani treated with methylene-blue intradermal injection. The therapy included 5 ml of 1% methylene blue and 15 ml of 1% lidocaine. Follow-up included a physical exam and satisfaction-score survey (1 = much worse, 2 = worse, 3 = no improvement, 4 = much better, 5 = gone completely) before treatment, 6 weeks after treatment, and 3 years after treatment to check patient status and recurrence rate. RESULTS: Of 103 treated patients, 96 were able to attend the 6-week follow-up visit. There were 58 (60.4%) males and 38 (39.6%) females with a mean age of 48.34 ± 10.21 years. Their mean satisfaction score at 6 weeks was 4.23 ± 0.86. Of the total of 96 patients, 9 (9.4%) patients scored 3 or less in their satisfactions score at 6 weeks. 62 (64.6%) patients were evaluated 3-year post-treatment. The satisfaction score at 3 years after treatment was 4.74 ± 0.57. Besides the 9 patients who initially failed treatment, 4 of the remaining 53 patients scored 3 or less in their satisfaction score surveys. Thus, the recurrence rate at 3 years was 7.5% (4/53). CONCLUSIONS: Methylene-blue intradermal injection can result in a high symptom improvement rate with low recurrence rate for patients with idiopathic pruritus ani.

Initial Experience With Hand-Assisted Laparoscopic Living Donor Nephrectomy: Training and Clinical Practice as a General Surgeon.

BACKGROUND: To analyze our initial results of hand-assisted laparoscopic living donor nephrectomy, executed by a skilled gastrointestinal surgeon. METHODS: A total of 22 consecutive patients underwent the hand-assisted laparoscopic living donor nephrectomy between December 2014 and January 2017. We retrospectively analyze the patient's perioperative clinical data, which were collected prospectively. RESULTS: The right kidney was harvested in 12 patients. The mean operative time and intraoperative blood loss was 241.0 ± 43.4 minutes (range, 140-310 min) and 293.2 ± 203.1 mL (range, 50-700 mL), respectively. The mean warm ischemic time was 288.4 ± 103.4 seconds (range, 179-610 s). Postoperative complications included chyle leakage in 2 patients who were left kidney donors and oliguria in 1 patient who was a right kidney donor. All patients recovered with conservative care, and the mean hospital stay was 7.5 ± 1.7 days. The mean creatinine level was 0.7 ± 0.2 mg/dL before surgery, 1.1 ± 0.3 mg/dL at postoperative day (POD) 1, and 1.0 ± 0.2 mg/dL after discharge. The mean glomerular filtration rate was 97.9 ± 18.2 mL/min/1.73 m2 before surgery, 60.7 ± 10.4 at POD 1, and 67.3 ± 11.1 after discharge. Operation time was not associated with patient body mass index and case number. No significant differences, other than postoperative complications, were found in the perioperative data for the side of kidney donation. CONCLUSION: A skilled surgeon with experience in laparoscopic abdominal surgery (such as gastrectomy or colectomy) might safely perform hand-assisted donor nephrectomy. However, we could not identify a clear case number to complete the learning curve.

Carotid ultrasound measurements for assessing fluid responsiveness in spontaneously breathing patients: corrected flow time and respirophasic variation in blood flow peak velocity.

BACKGROUND: This study evaluated the ability of two Doppler ultrasound-derived parameters, the carotid corrected flow time (FTc) and respirophasic variation in carotid artery blood flow peak velocity (ΔVpeak), to predict fluid responsiveness in spontaneously breathing patients. METHODS: A total of 53 spontaneously breathing patients were studied before anaesthetic induction for neurosurgery. Carotid FTc, ΔVpeak, and haemodynamic data were measured before and after administration of 6 ml kg-1 colloid. Fluid responsiveness was defined as a 15% or more increase in stroke volume index as assessed by transthoracic echocardiography after the fluid challenge. RESULTS: Twenty-two (42%) patients were fluid responders. The areas under the receiver operating characteristic curves for FTc and ΔVpeak were 0.842 [95% confidence interval (CI) 0.735-0.948, P<0.001] and 0.818 (95% CI: 0.701-0.935, P<0.001), respectively. The optimal cut-off values of FTc and ΔVpeak for fluid responsiveness were 349.4 ms (sensitivity of 72.7%; specificity of 83.9%) and 9.1% (sensitivity of 72.7%; specificity of 87.1%), respectively. The grey zone for FTc was 346.9-361.0 ms and included 28% of the patients, and the grey zone for ΔVpeak was 6.5-10.2% and included 50% of the patients. CONCLUSIONS: Using Doppler ultrasound-derived parameters measured at the carotid artery, FTc predicted fluid responsiveness in spontaneously breathing patients better than ΔVpeak. However, further studies are warranted before these parameters are recommended for clinical use. CLINICAL TRIAL REGISTRATION: NCT 02843477.

The Processing Time for Recanalization and Size of Ischemic Lesions on DWI is Related With Complete Reperfusion After Mechanical Thrombectomy.

Recent studies demonstrated that modified thrombolysis in cerebral infarction (TICI) 3 reperfusion have better functional outcomes than modified TICI 2b after mechanical thrombectomy in acute ischemic stroke with large vessel occlusion. The purpose of this study was to determine significant factors to forecast the presence of complete reperfusion after mechanical thrombectomy based on multimodal magnetic resonance imaging (MRI). We investigated 96 consecutive patients with acute large intracranial artery occlusion of anterior circulation who based on multimodal MRI. Also, we compared clinical and radiologic parameters between patients with modified TICI 3 and those with modified TICI 0-2b. Among 96 eligible subjects received mechanical thrombectomy, 39 patients (40.6%) showed complete reperfusion and 57 partial or nonreperfusion (mTICI 2b-26, mTICI 2a-9, mTICI 1-8, and mTICI 0-14) after mechanical thrombectomy. Patients with mTICI 3 had significantly smaller initial Diffusion weighted images (DWI) lesion volume (P < .01) and much shorter time interval from onset to reperfusion (P < .01) than those patients with mTICI (0-2b). In multivariate analysis, smaller initial DWI volume (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.23-2.57; P < .01) and faster reperfusion time (OR, 1.07; 95% CI 1.01-1.14; P = .015) had an independence significance for complete reperfusion after mechanical thrombectomy. In this study, the ischemic lesion volume on DWI and faster processing time are critical factor to predict the state of complete reperfusion after mechanical thrombectomy.

Stemmed DNA nanostructure for the selective delivery of therapeutics.

DNA has emerged as a biocompatible biomaterial that may be considered for various applications. Here, we report tumor cell-specific aptamer-modified DNA nanostructures for the specific recognition and delivery of therapeutic chemicals to cancer cells. Protein tyrosine kinase (PTK)7-specific DNA aptamer sequences were linked to 15 consecutive guanines. The resulting aptamer-modified product, AptG15, self-assembled into a Y-shaped structure. The presence of a G-quadruplex at AptG15 was confirmed by circular dichroism and Raman spectroscopy. The utility of AptG15 as a nanocarrier of therapeutics was tested by loading the photosensitizer, methylene blue (MB), to the G-quadruplex as a model drug. The generated MB-loaded AptG15 (MB/AptG15) showed specific and enhanced uptake to CCRF-CEM cells, which overexpress PTK7, compared with Ramos cells, which lack PTK7, or CCRF-CEM cells treated with a PTK7-specific siRNA. The therapeutic activity of MB/AptG15 was tested by triggering its photodynamic effects. Upon 660 nm light irradiation, MB/AptG15 showed greater reactive oxygen species generation and anticancer activity in PTK7-overexpressing cells compared to cells treated with MB alone, those treated with AptG15, and other comparison groups. AptG15 stemmed DNA nanostructures have significant potential for the cell-type-specific delivery of therapeutics, and possibly for the molecular imaging of target cells.

ERK-dependent IL-6 autocrine signaling mediates adaptive resistance to pan-PI3K inhibitor BKM120 in head and neck squamous cell carcinoma.

Hyperactivation of phosphatidylinositol 3-kinase (PI3K) pathway occurs frequently in head and neck squamous cell carcinoma (HNSCC). However, clinical outcomes of targeting the PI3K pathway have been underwhelming. In present study, we investigated the resistant mechanisms and potential combination therapeutic strategy to overcome adaptive resistance to PI3K inhibitor in HNSCC. Treatment of NVP-BKM120, a pan-PI3K inhibitor, led to upregulation of interleukin-6 (IL-6) and subsequent activation of either extracellular signal-regulated kinase (ERK) or signal transducers and activators of transcription 3 (STAT3), causing modest antitumor effects on the growth of HNSCC cells. Blockade of autocrine IL-6 signaling with siRNA or neutralizing antibody for IL-6 receptor (IL-6R) completely abolished NVP-BKM120-induced activation of ERK and STAT3 as well as expression of c-Myc oncogene, which resulted in enhanced sensitivity to NVP-BKM120. Moreover, when compared with a pharmacologic inhibitor or silencing of STAT3, trametinib, a MEK inhibitor, in combination with NVP-BKM120 yielded more potent anti-proliferative effects by inhibiting S phase transition, arresting cells at G0/G1 phase, and downregulating IL-6 and c-Myc expression. Furthermore, as compared with either agent alone, combination of NVP-BKM120 with trametinib or tocilizumab, a humanized anti-IL-6R antibody, significantly suppressed tumor growth in NVP-BKM120-resistant patient-derived tumor xenograft (PDTX) models, which was also confirmed in PDTX-derived cell lines. Collectively, these results suggested that IL-6/ERK signaling is closely involved in adaptive resistance of NVP-BKM120 in HNSCC cells, providing a rationale for a novel combination therapy to overcome resistance to PI3K inhibitors.

Gastrointestinal inflammation by gut microbiota disturbance induces memory impairment in mice.

In this study, we tested our hypothesis regarding mechanistic cross-talk between gastrointestinal inflammation and memory loss in a mouse model. Intrarectal injection of the colitis inducer 2,4,6-trinitrobenzenesulfonic acid (TNBS) in mice caused colitis via activation of nuclear factor (NF)-κB and increase in membrane permeability. TNBS treatment increased fecal and blood levels of lipopolysaccharide (LPS) and the number of Enterobacteriaceae, particularly Escherichia coli (EC), in the gut microbiota composition, but significantly reduced the number of Lactobacillus johnsonii (LJ). Indeed, we observed that the mice treated with TNBS displayed impaired memory, as assessed using the Y-maze and passive avoidance tasks. Furthermore, treatment with EC, which was isolated from the feces of mice with TNBS-induced colitis, caused memory impairment and colitis, and increased the absorption of orally administered LPS into the blood. Treatment with TNBS or EC induced NF-κB activation and tumor necrosis factor-α expression in the hippocampus of mice, as well as suppressed brain-derived neurotrophic factor expression. However, treatment with LJ restored the disturbed gut microbiota composition, lowered gut microbiota, and blood LPS levels, and attenuated both TNBS- and EC-induced memory impairment and colitis. These results suggest that the gut microbiota disturbance by extrinsic stresses can cause gastrointestinal inflammation, resulting in memory impairment.