Stretchable pumps for soft machines.

Machines made of soft materials bridge life sciences and engineering1. Advances in soft materials have led to skin-like sensors and muscle-like actuators for soft robots and wearable devices1-3. Flexible or stretchable counterparts of most key mechatronic components have been developed4,5, principally using fluidically driven systems6-8; other reported mechanisms include electrostatic9-12, stimuli-responsive gels13,14 and thermally responsive materials such as liquid metals15-17 and shape-memory polymers18. Despite the widespread use of fluidic actuation, there have been few soft counterparts of pumps or compressors, limiting the portability and autonomy of soft machines4,8. Here we describe a class of soft-matter bidirectional pumps based on charge-injection electrohydrodynamics19. These solid-state pumps are flexible, stretchable, modular, scalable, quiet and rapid. By integrating the pump into a glove, we demonstrate wearable active thermal management. Embedding the pump in an inflatable structure produces a self-contained fluidic 'muscle'. The stretchable pumps have potential uses in wearable laboratory-on-a-chip and microfluidic sensors, thermally active clothing and autonomous soft robots.

Simple model for synchronization of two Belousov-Zhabotinsky gels interacting mechanically.

A Belousov-Zhabotinsky (BZ) gel is a unique biomimetic system that undergoes autonomous volume oscillations induced by the redox oscillation of the BZ reaction. In a previous study, researchers reported that the oscillations of two BZ gels coupled by compression were synchronized by a mechanical interaction. They mathematically explained the synchronization behavior using a phase oscillator model. As a different approach to the previous study, a physicochemical investigation of the phenomenon will lead to a better understanding of the functional biological rhythms essential for life. In this study, we construct a simple phenomenological model to understand the synchronization of BZ gels. The model consists of two parts. One is the dynamics of the chemical reactions in the BZ gels. We use a phenomenological model based on the Oregonator for the BZ reaction. The other is the dynamics of the mechanical deformation of the BZ gel. Using approximations, we extract the parameters essential for the synchronization of a mechanical interaction. Thus, we can derive a novel equation for the deformation dynamics of mechanically coupled BZ gels. By combining these two parts, we perform numerical calculations. This allows us to find that the synchronization of the two BZ gels is less likely to occur under stronger compression. We explain this trend through one physicochemical parameter in our model: the volume fraction of the BZ gel in the reduced state.

Risk factors affecting delay of initiating adjuvant chemotherapy for stage III colorectal cancer.

PURPOSE: Delay in initiating adjuvant chemotherapy (AC) after curative resection of colorectal cancer (CRC) has been reported to lead to poor prognosis, but few studies have looked at associated factors. This study aimed to identify risk factors for delay in initiating AC. METHODS: Data from 200 consecutive patients who underwent curative resection and AC for stage III CRC between 2013 and 2018 were retrospectively collected and analyzed. RESULTS: AC was initiated more than 8 weeks after surgery in 12.5% of patients (the delay group). Compared to those with no delay (the non-delay group), patients in the delay group had significantly higher rates of synchronous double cancers (2.3% vs. 16.0%, p = 0.001), preoperative bowel obstruction (10.3% vs. 32.0%, p = 0.003), laparotomy (56.0% vs. 80.0%, p = 0.02), concomitant resection (2.9% vs. 24.0%, p < 0.001), and postoperative complications (32.0% vs. 56.0%, p = 0.02), and a significantly longer length of hospital stay (median 12 vs. 30 days, p < 0.001). In multivariate analysis, synchronous double cancers (odds ratio 10.2, p = 0.008), preoperative bowel obstruction (odds ratio 4.6, p = 0.01), concomitant resection (odds ratio 5.2, p = 0.03), and postoperative complications of Clavien-Dindo grade ≥ IIIa (odds ratio 4.0, p = 0.03) were identified as independent risk factors for delay in initiating AC. CONCLUSION: Careful preoperative treatment planning for CRC patients with synchronous double cancers, preoperative bowel obstruction, and concomitant resection, and management for postoperative complication are necessary to avoid delay in initiating AC.

[Tips and Outcomes of Safe Laparoscopic Rectal Resection with Adequate Lymph Node Dissection in Patients with Obesity].

BACKGROUND: This study aimed to describe the surgical procedures involved in laparoscopic rectal resection in patients with obesity and report the short-term outcomes. MATERIALS AND METHODS: A total of 194 consecutive patients who underwent laparoscopic rectal resection in our department from 2013 to 2018 were divided into non-obese(body mass index[BMI] <25 kg/m2; n=161)and obese groups(BMI≥25 kg/m2; n=33)and subsequently analyzed. RESULTS: The operative time was significantly longer in the obese group(225 vs 266 min; p=0.003)than in the non-obese group. No conversions to laparotomy occurred in either group, and no discernible differences in blood loss(1 vs 5 mL; p=0.582), number of harvested lymph nodes(20 vs 17; p=0.356), and postoperative complication rates(9.3 vs 6.1%; p=0.547)were observed. CONCLUSION: Establishing an appropriate operative field, clarifying landmarks, and standardizing the procedure are important to assure safe laparoscopic rectal resection with adequate lymph node dissection in patients with obesity.

CDC5L promotes early chondrocyte differentiation and proliferation by modulating pre-mRNA splicing of SOX9, COL2A1, and WEE1.

Ossification of the posterior longitudinal ligament (OPLL) of the spine is a common pathological condition that causes intractable myelopathy and radiculopathy, mainly the result of an endochondral ossification-like process. Our previous genome-wide association study identified six susceptibility loci for OPLL, including the cell division cycle 5-like (CDC5L) gene region. Here, we found CDC5L to be expressed in type II collagen-producing chondrocyte-like fibroblasts in human OPLL specimens, as well as in differentiating ATDC5 chondrocytes. Cdc5l siRNA transfection in murine chondrocytes decreased the expression of the early chondrogenic genes Sox9 and Col2a1, diminished the cartilage matrix production, and enhanced the expression of parathyroid-hormone-related protein (a resting chondrocyte marker). We also showed that Cdc5l shRNA suppressed the growth of cultured murine embryonal metatarsal cartilage rudiments and that Cdc5l knockdown suppressed the growth of ATDC5 cells. Fluorescence-activated cell sorting analysis revealed that the G2/M cell cycle transition was blocked; our data showed that Cdc5l siRNA transfection enhanced expression of Wee1, an inhibitor of the G2/M transition. Cdc5l siRNA also decreased the pre-mRNA splicing efficiency of Sox9 and Col2a1 genes in both ATDC5 cells and primary chondrocytes; conversely, loss of Cdc5l resulted in enhanced splicing of Wee1 pre-mRNA. Finally, an RNA-binding protein immunoprecipitation assay revealed that Cdc5l bound directly to these target gene transcripts. Overall, we conclude that Cdc5l promotes both early chondrogenesis and cartilage growth and may play a role in the etiology of OPLL, at least in part by fine-tuning the pre-mRNA splicing of chondrogenic genes and Wee1, thus initiating the endochondral ossification process.

Prognostic Value of Nonischemic Ringlike Left Ventricular Scar in Patients With Apparently Idiopathic Nonsustained Ventricular Arrhythmias.

BACKGROUND: Left ventricular (LV) scar on late gadolinium enhancement (LGE) cardiac magnetic resonance has been correlated with life-threatening arrhythmic events in patients with apparently idiopathic ventricular arrhythmias (VAs). We investigated the prognostic significance of a specific LV-LGE phenotype characterized by a ringlike pattern of fibrosis. METHODS: A total of 686 patients with apparently idiopathic nonsustained VA underwent contrast-enhanced cardiac magnetic resonance. A ringlike pattern of LV scar was defined as LV subepicardial/midmyocardial LGE involving at least 3 contiguous segments in the same short-axis slice. The end point of the study was time to the composite outcome of all-cause death, resuscitated cardiac arrest because of ventricular fibrillation or hemodynamically unstable ventricular tachycardia and appropriate implantable cardioverter defibrillator therapy. RESULTS: A total of 28 patients (4%) had a ringlike pattern of scar (group A), 78 (11%) had a non-ringlike pattern (group B), and 580 (85%) had normal cardiac magnetic resonance with no LGE (group C). Group A patients were younger compared with groups B and C (median age, 40 vs 52 vs 45 years; P<0.01), more frequently men (96% vs 82% vs 55%; P<0.01), with a higher prevalence of family history of sudden cardiac death or cardiomyopathy (39% vs 14% vs 6%; P<0.01) and more frequent history of unexplained syncope (18% vs 9% vs 3%; P<0.01). All patients in group A showed VA with a right bundle-branch block morphology versus 69% in group B and 21% in group C (P<0.01). Multifocal VAs were observed in 46% of group A patients compared with 26% of group B and 4% of group C (P<0.01). After a median follow-up of 61 months (range, 34-84 months), the composite outcome occurred in 14 patients (50.0%) in group A versus 15 (19.0%) in group B and 2 (0.3%) in group C (P<0.01). After multivariable adjustment, the presence of LGE with ringlike pattern remained independently associated with increased risk of the composite end point (hazard ratio, 68.98 [95% CI, 14.67-324.39], P<0.01). CONCLUSIONS: In patients with apparently idiopathic nonsustained VA, nonischemic LV scar with a ringlike pattern is associated with malignant arrhythmic events.

Increases in serum carbonylated protein levels of dogs with hypercortisolism.

Protein carbonylation is an irreversible and degenerative modification that can be used to evaluate oxidative stress caused by glucocorticoids. In this study, we focused on protein carbonylation in dogs with hypercortisolism (HC). Sera samples were collected from 14 dogs diagnosed with HC and treated with trilostane, 12 dogs with inflammatory diseases (disease control group), and eight clinically healthy dogs. When the carbonylated protein levels were detected by the immunoblot analysis, one band of approximately 40 kDa was predominantly increased in the dogs with HC. The band was identified as haptoglobin using the liquid chromatography tandem mass spectrometry method. Furthermore, haptoglobin immune reactivity was higher in the dogs with HC. Although the average protein carbonylation level of the HC group was not significantly different from that of the other groups, the carbonylation level was significantly higher for the poorly controlled HC cases than for the well-controlled HC group. Additionally, the primary culture of canine hepatocytes was used to clarify the direct effect of glucocorticoids on protein carbonylation in dog livers. Both the carbonylated protein and haptoglobin clearly increased after 72 h. These findings suggest that haptoglobin and its carbonylated form are increased with canine HC, and that the protein carbonylation ratio and/or haptoglobin level could be related to disease management. These factors could be useful as biomarkers for an oxidative stress reaction, at least in the liver, and for treatment monitoring of HC.

Fecalith in the Proximal Area of the Appendix is a Predictor of Failure of Nonoperative Treatment for Complicated Appendicitis in Adults.

BACKGROUND: The management of complicated appendicitis remains controversial, since this disease has various clinical presentations and is associated with high rates of adverse events. Although initial nonoperative treatment is generally employed for complicated appendicitis, its clinical presentation and the predictors of nonoperative treatment failure are unclear. METHODS: Patients diagnosed with complicated appendicitis in our hospital between April 2015 and March 2020 were enrolled. In total, 113 patients were classified into three categories: emergency appendectomy, failure of nonoperative treatment and successful nonoperative treatment. The primary outcome was the rate of failure of nonoperative treatment, as assessed by logistic regression analysis. The secondary outcomes were the operative procedures and postoperative courses of the three groups. RESULTS: Of 113 patients, 45 (40%) underwent emergency appendectomy, 25 (22%) failed nonoperative treatment, and 43 (38%) had successful nonoperative treatment. Among these successful cases, 38 patients (88%) underwent interval appendectomy. In multivariate analyses, the presence of a fecalith in the proximal area of the appendix was an independent risk factor for failure of nonoperative treatment (odds ratio, 20.5; 95% confidence interval, 4.37-95.7, P < 0.001). Postoperative outcomes were more unfavorable in cases of failed nonoperative treatment than in cases of emergency and interval appendectomy. CONCLUSIONS: The presence of a fecalith in the proximal area of the appendix is an independent predictor for failure of nonoperative treatment for complicated appendicitis in adults. Patients with this risk factor should be considered candidates for surgical treatment.

Mobile health applications for the detection of atrial fibrillation: a systematic review.

AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia and an important risk factor for stroke and heart failure. We aimed to conduct a systematic review of the literature and summarize the performance of mobile health (mHealth) devices in diagnosing and screening for AF. METHODS AND RESULTS: We conducted a systematic search of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. Forty-three studies met the inclusion criteria and were divided into two groups: 28 studies aimed at validating smart devices for AF diagnosis, and 15 studies used smart devices to screen for AF. Evaluated technologies included smartphones, with photoplethysmographic (PPG) pulse waveform measurement or accelerometer sensors, smartbands, external electrodes that can provide a smartphone single-lead electrocardiogram (iECG), such as AliveCor, Zenicor and MyDiagnostick, and earlobe monitor. The accuracy of these devices depended on the technology and the population, AliveCor and smartphone PPG sensors being the most frequent systems analysed. The iECG provided by AliveCor demonstrated a sensitivity and specificity between 66.7% and 98.5% and 99.4% and 99.0%, respectively. The PPG sensors detected AF with a sensitivity of 85.0-100% and a specificity of 93.5-99.0%. The incidence of newly diagnosed arrhythmia ranged from 0.12% in a healthy population to 8% among hospitalized patients. CONCLUSION: Although the evidence for clinical effectiveness is limited, these devices may be useful in detecting AF. While mHealth is growing in popularity, its clinical, economic, and policy implications merit further investigation. More head-to-head comparisons between mHealth and medical devices are needed to establish their comparative effectiveness.

Exercise-induced ventricular tachycardia in a case with hypertrophic cardiomyopathy taking cibenzoline.

We report a 17-year-old woman with hypertrophic cardiomyopathy (HCM) successfully resuscitated from ventricular fibrillation while taking cibenzoline. During exercise-stress testing before implanting an implantable cardioverter-defibrillator, ventricular tachycardia was induced and thought to be a proarrhythmia due to the use-dependent effect of the Na channel blockade with cibenzoline. In patients with arrhythmogenic substrates such as HCM, it is critical to pay attention to the proarrhythmic effects of class I antiarrhythmic drugs while increasing heart rate.

Torsade de pointes induced by intravenous amiodarone therapy accompanied by marked augmentation of the transmural dispersion of repolarization in a patient with tachycardia-induced-cardiomyopathy.

We report a 77-year-old human on renal dialysis for end-stage renal disease with heart failure and atrial fibrillation (AF) complicated by a high ventricular frequency. The underlying disease was thought as tachycardia-induced-cardiomyopathy. Intravenous infusion of amiodarone was initiated, and direct current cardioversion succeeded in converting AF to sinus rhythm. Then, excessive increases in the QT and Tpeak-Tend (Tp-e) intervals were seen and hypokalemia induced by hemodialysis led to the development of numerous episodes of torsades de pointes (TdP). Magnesium repletion was effective in preventing TdP, while Tp-e intervals returned to the previous values 2 days after the discontinuation of amiodarone.

Aggressive and frequent resection of recurrences in retroperitoneal sarcoma contributes to long-term survival.

PURPOSE: Retroperitoneal sarcoma (RPS) is a rare tumor with a poor prognosis and is often undetected until it is significantly enlarged. While surgical resection remains the primary treatment, there is little research on its benefits, especially that concerning the reoperation of recurrent disease. This study investigated the impact of surgical procedures, especially reoperation of recurrent RPS, on prognosis. METHODS: This retrospective study included 51 patients who underwent radical resection surgery (R0 status) for primary or recurrent RPS without distant metastasis. Patient outcomes and prognosis were defined in terms of the clinicopathologic factors and surgical techniques performed. RESULTS: In all cases, the 5-year disease-free survival (DFS) rate was 28.2%, 5-year overall survival rate was 89.9%, and 5-year no residual liposarcoma rate was 54.3% after operation and re-reoperation. There was a statistically significant difference between the 5-year DFS rate and 5-year no residual liposarcoma rate due to frequent re-reoperation (p = 0.011). On univariate analysis of primary and recurrent lesions, the histological type and the number of organs involved were identified as statistically significant prognostic factors. Patients with well-differentiated liposarcomas had a statistically better prognosis than those with other cancer types (primary RPS, p = 0.028; recurrence, p = 0.024). CONCLUSIONS: Aggressive and frequent resection of recurrent RPS with combined resection of adjacent organs contributes to long-term survival. The establishment of a surgical strategy for RPS will require a prospective study.

Protease-Activated Receptor-2 Is Associated With Adverse Outcomes in Canine Mammary Carcinoma.

Protease-activated receptor-2 (PAR2) is a G protein-coupled receptor that is activated by serine proteases. In humans, PAR2 is highly expressed in various cancers, including breast cancer, and is associated with cancer progression and metastasis. However, the expression and roles of PAR2 in canine mammary carcinoma remain unclear. The purpose of this study was to examine the expression of PAR2 in canine mammary carcinoma, the association between PAR2 expression and clinical characteristics, and the role of PAR2 in the metastatic phenotypes of tumor cells. Mammary carcinoma from 31 dogs and 10 normal mammary glands were included in this study, and used for immunohistochemical analysis of PAR2 expression. Normal mammary glands did not express PAR2. In contrast, mammary carcinomas showed PAR2 immunoreactivity in the cytoplasm, and its expression level varied between specimens from negative to strongly positive. The overall survival of dogs with high PAR2 expression was shorter than that of dogs with low PAR2 expression. Moreover, PAR2 expression level was associated with the presence of lymph node involvement, advanced clinical stage, and high histopathological grade. In vitro analyses revealed that a PAR2 agonist accelerated cell migration and invasion in a canine mammary carcinoma cell line. In addition, the PAR2 agonist induced epithelial-mesenchymal transition and actin polymerization. These results suggest that PAR2 expression plays a role in tumor progression and clinical outcomes in canine mammary carcinoma.

BRAFV595E Mutation Associates CCL17 Expression and Regulatory T Cell Recruitment in Urothelial Carcinoma of Dogs.

Regulatory T cells may serve as targets in cancer immunotherapy. A previous study showed that the chemokine CCL17 and the receptor CCR4 play roles in regulatory T cell recruitment in canine urothelial carcinoma. In this article, we show that the BRAFV595E mutation is associated with tumor-produced CCL17 and regulatory T cell infiltration in dogs with urothelial carcinoma. In comparison with healthy dogs, dogs with urothelial carcinoma showed increased CCL17 mRNA expression in the bladder and elevated CCL17 protein concentration in urine. Immunohistochemistry showed increased levels of Foxp3+ regulatory T cells in the tumor tissues of urothelial carcinoma. The density of Foxp3+ regulatory T cells was positively correlated with CCL17 concentration in urine, indicating that CCL17 is involved in regulatory T cell recruitment. Moreover, tumor-infiltrating regulatory T cells and urine CCL17 concentration were associated with poor prognosis in dogs with urothelial carcinoma. The number of tumor-infiltrating regulatory T cells, CCL17 mRNA expression, and urine CCL17 concentration in cases with BRAFV595E mutation were higher than those in cases with wild-type BRAF. In vitro, high CCL17 production was detected in a canine urothelial carcinoma cell line with BRAFV595E mutation but not in an urothelial carcinoma cell line with wild-type BRAF. Dabrafenib, a BRAF inhibitor, decreased CCL17 production in the cell line with BRAFV595E mutation. These results suggest that BRAFV595E mutation induced CCL17 production and contributed to regulatory T cell recruitment in canine urothelial carcinoma.

Risk factors for peristomal skin disorders associated with temporary ileostomy construction.

PURPOSE: Skin disorders are the most common stoma-related complications after temporary diverting loop ileostomy with proctectomy. The aim of the present study was to investigate risk factors for skin disorders associated with temporary ileostomy construction. METHODS: A total of 185 consecutive patients who underwent curative proctectomy with temporary diverting loop ileostomy for rectal malignancies at a single comprehensive cancer center between 2013 and 2018 were collected and analyzed. RESULTS: The most frequent stoma-related complications were skin disorders (n = 62, 33.5%), followed by mucocutaneous separation (n = 38, 20.5%) and high-output stoma (n = 34, 18.4%). Patients with skin disorders had a higher median body mass index (BMI; 22.4 vs. 21.3 kg/m2, P = 0.002) and lower stoma height (16 vs. 20 mm, P < 0.001) than those without skin disorders. According to a multivariable logistic regression analysis, independent predictors of skin disorders included overweight (median BMI ≥ 25 kg/m2 [odds ratio = 3.6, 95% confidence interval: 1.5-8.6], P = 0.004) and lower stomal height (median stoma height < 20 mm [odds ratio = 3.2, 95% confidence interval: 1.6-6.3], P < 0.001). CONCLUSION: Overweight and lower stoma height are correlated with the presence of skin disorders. Construction of a well-elevated stoma can reduce skin disorders associated with temporary ileostomy construction.

Endocardial contact mapping of the left atrial appendage in persistent atrial fibrillation.

INTRODUCTION: Isolation of the left atrial appendage (LAA) is often performed in persistent atrial fibrillation (AF). Propagation patterns in the LAA during AF remain to be elucidated. We sought to characterize propagation patterns in the LAA during AF in persistent AF. METHODS: Persistent AF patients undergoing catheter ablation were studied. Pulmonary vein isolation (PVI) was performed during continuous AF. If AF was not terminated by PVI, bi-atrial mapping was performed using a multi-electrode catheter during AF. Maps were collected at each site for 30 seconds and analyzed offline with a novel software, CARTOFINDER. This software made automatic determinations of whether activation was focal or rotational. The left atrium (LA) was divided into five regions, of which the LAA was one, and the right atrium (RA) into three. RESULTS: Eighty patients were studied (62 ± 10 years, 65 males). On average, 9.6 ± 2.2 and 4.1 ± 1.2 maps were created in the LA and RA, respectively. The LAA was mapped in 70 patients, resulting in 85 maps. In the LAA, activation was identified as focal more often than rotational (64 [91%] vs 10 [14%] patients, P < .001), seven patients displayed both. The number of focal activation events was greatest in the LAA (28.5 events/30 seconds [interquartile range, 15-54]) of the eight atrial regions. During focal activation, sites designated as earliest activation frequently covered a wide area, rather than being localized to a discrete site (5.4 ± 3.1 electrodes). CONCLUSIONS: The results of this study suggest that focal activation is a major mechanism underlying the arrhythmogenicity of the LAA in persistent AF.

Epithelial cell-derived prostaglandin D2 inhibits chronic allergic lung inflammation in mice.

The precise role of prostaglandin D (PGD)2 in allergic lung inflammation remains controversial. Here, we aimed to clarify the role of PGD2 in chronic allergic lung inflammation using hematopoietic PGD synthase (H-PGDS)-deficient mice. Repeated intranasal administration of ovalbumin (OVA) resulted in eosinophilic infiltration and mucin production in the lungs of wild type (WT) mice, leading to respiratory dysfunction. H-PGDS deficiency exacerbated these effects, which were accompanied by increased mRNA expression of TNF-α and eosinophil chemoattractants. The bronchial epithelium expressed both H-PGDS and TNF-α in the inflamed WT lung, and H-PGDS deficiency increased TNF-α expression further. In cultured bronchial tissue of WT mice, treatment with LPS elevated mRNA expression of TNF-α and eosinophil chemoattractants. H-PGDS deficiency promoted the expression of these factors, which was inhibited by treatment with PGD2 receptor, D prostanoid (DP) receptor agonist, or PGD2 metabolite 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2). Treatment with TNF-α receptor antibody inhibited eosinophil chemoattractant expression. In vivo, administration of DP agonist or 15d-PGJ2 inhibited OVA-induced allergic lung inflammation. Bronchial epithelial cell-derived PGD2 attenuated lung eosinophilic infiltration with chronic allergic inflammation; these phenomena are at least partly attributed to the inhibition of TNF-α production via DP activation or 15-deoxy-Δ12,14-PGJ2 signaling.-Maehara, T., Nakamura, T., Maeda, S., Aritake, K., Nakamura, M., Murata, T. Epithelial cell-derived prostaglandin D2 inhibits chronic allergic lung inflammation in mice.

Foxp3+ Regulatory T Cells Associated With CCL17/CCR4 Expression in Carcinomas of Dogs.

Regulatory T cells (Tregs) can be targeted in cancer immunotherapy. A previous study has shown that the chemokine CCL17 and the receptor CCR4 play a role in Treg recruitment in canine urothelial carcinoma. Here, we describe the association of tumor-infiltrating Tregs with CCL17/CCR4 expression in dogs with other carcinomas. In this study, we investigated 23 dogs with mammary carcinoma, 14 dogs with oral squamous cell carcinoma, 16 dogs with pulmonary adenocarcinoma, and 8 healthy control dogs. Immunohistochemistry showed that Foxp3+ Tregs and CCR4+ cells were increased in the tumor tissues of mammary carcinoma, squamous cell carcinoma, and pulmonary adenocarcinoma, when compared with the healthy tissues. The number of CCR4+ cells was associated with that of Foxp3+ Tregs. Double immunofluorescence labeling confirmed that most tumor-infiltrating Foxp3+ Tregs expressed CCR4. In vitro, canine carcinoma cell lines expressed CCL17 mRNA. Quantitative RT-PCR (reverse transcriptase-polymerase chain reaction) showed that CCL17 mRNA expression in canine carcinomas was increased approximately 10- to 25-fold relative to that of healthy tissues. These results suggest that the CCL17/CCR4 axis may drive Treg recruitment in a variety of canine carcinomas. CCR4 blockade may be a potential therapeutic option for tumor eradication through Treg depletion.

ErbB2 Copy Number Aberration in Canine Urothelial Carcinoma Detected by a Digital Polymerase Chain Reaction Assay.

Urothelial carcinoma (UC) is the most common tumor affecting the urinary bladder of dogs. Protein overexpression of ErbB2 (the canine homolog of HER2) has been observed in dogs with UC. However, no study regarding ErbB2 copy number aberration (CNA) is reported in dogs with UC. In this study, a digital PCR assay for detecting CNA of canine ErbB2 was developed. DNA samples were isolated from 83 formalin-fixed, paraffin-embedded urinary bladder tissues (36 UC, 8 polypoid cystitis, and 39 normal) and 94 urinary sediments (54 UC, 30 nonneoplastic, and 10 normal). The copy number of canine chromosome 8 (CFA8) was used as a control. In the urinary bladder tissues, ErbB2 CNA was detected in 12 of 36 (33%) UC, 2 of 8 (25%) polypoid cystitis, and 0 of 39 (0%) normal controls. In the urinary sediments, ErbB2 CNA was also detected in 19 of 54 (35%) UC; however, no ErbB2 CNA was detected in nonneoplastic diseases or normal controls. The sensitivity and specificity of ErbB2 CNA in urinary sediment for the detection of UC were 35% and 100%, respectively. There was a positive correlation between the copy number ratios of ErbB2 to CFA8 in the urinary bladder tissues and urinary sediments. Our findings indicate that the digital PCR assay of urinary sediments may be a useful, noninvasive method for detecting ErbB2 CNA in dogs with UC.

A Survey of Direct Oral Anticoagulant Cessation in General Surgery and Outcomes in Patients with Nonvalvular Atrial Fibrillation.

There is little data on management and outcomes of atrial fibrillation (AF) patients on direct oral anticoagulants (DOAC) undergoing general surgery.We retrospectively assessed 98 surgeries in 85 nonvalvular AF patients aged 73 ± 8 (59 men) receiving DOACs. Cardiac, emergency, and minimally invasive surgeries were excluded.The CHA2DS2-VASc score ranged from 0 to 8. The DOACs being given were: dabigatran, 16; rivaroxaban, 25; apixaban, 28; and edoxaban, 16. While the DOACs were not suspended in 11 cases, they were interrupted for a median of 2.0 days before surgery and restarted at a median of 3.0 days after surgery. There were 9 complications (9.2%), 3 instances of thromboembolism and 6 bleeding. Thromboembolism occurred at a mean of 3.0 postoperative days, all of which occurred before resumption of DOACs, while bleeding events occurred at a mean of 4.0 postoperative days. Two of the 3 patients with thromboembolism went into cardiopulmonary arrest during the event, but were resuscitated. There were significantly more patients with congestive heart failure or combined antiplatelets in the patients with complications. The complication group had a significantly higher HAS-BLED score and lower preoperative hemoglobin level. There were no significant differences in the management of DOAC interruption between those with complications and without.The perioperative complication rate in nonvalvular AF patients undergoing elective surgery treating with DOACs was 9.2%. Patients with congestive heart failure, receiving combined therapy with antiplatelets, a higher HAS-BLED score, or lower preoperative hemoglobin level were at higher risk. Further studies evaluating the ideal perioperative DOAC protocol are warranted.