Prognostic factors of intravesical recurrence after radical nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: To evaluate predictive factors of increasing intravesical recurrence (IVR) rate in patients with upper tract urothelial carcinoma (UTUC) after receiving radical nephroureterectomy (RNUx) with bladder cuff excision (BCE). MATERIALS AND METHODS: A total of 2114 patients were included from the updated data of the Taiwan UTUC Collaboration Group. It was divided into two groups: IVR-free and IVR after RNUx, with 1527 and 587 patients, respectively. To determine the factors affecting IVR, TNM stage, the usage of pre-operative ureteroscopy, and pathological outcomes were evaluated. The Kaplan-Meier estimator was used to estimate the rates of prognostic outcomes in overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and bladder recurrence-free survival (BRFS), and the survival curves were compared using the stratified log-rank test. RESULTS: Based on our research, ureter tumor, female, smoking history, age (< 70 years old), multifocal tumor, history of bladder cancer were determined to increase the risk of IVR after univariate analysis. The multivariable analysis revealed that female (BRFS for male: HR 0.566, 95% CI 0.469-0.681, p < 0.001), ureter tumor (BRFS: HR 1.359, 95% CI 1.133-1.631, p = 0.001), multifocal (BRFS: HR 1.200, 95% CI 1.001-1.439, p = 0.049), history of bladder cancer (BRFS: HR 1.480, 95% CI 1.118-1.959, p = 0.006) were the prognostic factors for IVR. Patients who ever received ureterorenoscopy (URS) did not increase the risk of IVR. CONCLUSION: Patients with ureter tumor and previous bladder UC history are important factors to increase the risk of IVR after RNUx. Pre-operative URS manipulation is not associated with higher risk of IVR and diagnostic URS is feasible especially for insufficient information of image study. More frequent surveillance regimen may be needed for these patients.

Ultrasensitive and affordable assay for early detection of primary liver cancer using plasma cell-free DNA fragmentomics.

BACKGROUND AND AIMS: Early detection of primary liver cancer (PLC), including HCC, intrahepatic cholangiocarcinoma (ICC), and combined HCC-ICC (cHCC-ICC), is essential for patients' survival. This study aims to develop an accurate and affordable method for PLC early detection and differentiating ICC from HCC using plasma cell-free DNA (cfDNA) fragmentomic profiles. APPROACH AND RESULTS: Whole-genome sequencings (WGS) were performed using plasma cfDNA samples from 192 patients with PLC (159 HCC, 26 ICC, 7 cHCC-ICC) and 170 noncancer controls (including 53 liver cirrhosis [LC] or HBV-positive) enrolled in the training cohort. An ensembled stacked model for PLC detection was constructed using the training cohort. The model performance was assessed in an independent test cohort (189 patients with PLC [157 HCC, 26 ICC, 6 cHCC-ICC], 164 noncancer controls [including 51 LC/HBV]). Our model showed excellent performance for cancer detection in the test cohort (AUC: 0.995, 96.8% sensitivity at 98.8% specificity). It showed excellent sensitivities in detecting early-stage PLC (I: 95.9%, II: 97.9%), small tumors (≤3 cm: 98.2%), and HCC (96.2%) or ICC (100%). The AUC for distinguishing PLC from LC/HBV reached 0.985 (96.8% specificity at 96.1% specificity). Promisingly, our model maintained consistent performances during the downsampling process, even using 1X coverage data (AUC: 0.994, 93.7% sensitivity at 98.8% specificity). A separate model showed potential for distinguishing ICC from HCC (AUC: 0.776). CONCLUSIONS: Our model, outperforming previous reports at a lower cost by solely using low-coverage WGS data, exhibits excellent clinical potential for ultrasensitive and affordable detection of PLC and its subtypes.

Targeting Rev-Erbα to protect against ischemia-reperfusion-induced acute lung injury in rats.

BACKGROUND: The dysregulation of local circadian clock has been implicated in the pathogenesis of a broad spectrum of diseases. However, the pathophysiological role of intrinsic circadian clocks Rev-Erbα in ischemia-reperfusion (IR)-induced acute lung injury (ALI) remains unclear. METHODS: The IR-ALI model was established by subjecting isolated perfused rat lungs to 40 min of ischemia followed by 60 min of reperfusion. Rats were randomly assigned to one of six groups: control, control + SR9009 (Rev-Erbα agonist, 50 mg/kg), IR, and IR + SR9009 at one of three dosages (12.5, 25, 50 mg/kg). Bronchoalveolar lavage fluids (BALF) and lung tissues were obtained and analyzed. In vitro experiments utilized mouse lung epithelial cells (MLE-12) exposed to hypoxia-reoxygenation (HR) and pretreated with SR9009 (10 µM/L) and Rev-Erbα siRNA. RESULTS: SR9009 exhibited a dose-dependent reduction in lung edema in IR-ALI. It significantly inhibited the production of TNF-α, IL-6, and CINC-1 in BALF. Moreover, SR9009 treatment restored suppressed IκB-α levels and reduced nuclear NF-κB p65 levels in lung tissues. In addition, a SR9009 mitigated IR-induced apoptosis and mitogen-activated protein kinase (MAPK) activation in injured lung tissue. Finally, treatment with Rev-Erbα antagonist SR8278 abolished the protective action of SR9009. In vitro analyses showed that SR9009 attenuated NF-κB activation and KC/CXCL-1 levels in MLE-12 cells exposed to HR, and these effects were significantly abrogated by Rev-Erbα siRNA. CONCLUSIONS: The findings suggest that SR9009 exerts protective effects against IR-ALI in a Rev-Erbα-dependent manner. SR9009 may provide a novel adjuvant therapeutic approach for IR-ALI.

Large retroperitoneal extraskeletal Ewing's sarcoma with renal pedicle invasion: a case report.

BACKGROUND: Extraskeletal Ewing's sarcoma (EES) is a rare malignant tumor primarily found in children and young adults. Localized disease can present with nonspecific symptoms such as local mass, regional pain, and increased skin temperature. More severe cases may present with systemic symptoms such as malaise, weakness, fever, anemia, and weight loss. Among these lesions, retroperitoneal sarcomas are relatively uncommon and difficult to diagnose. Since they are usually asymptomatic until large enough to compress or invade the surrounding tissues, most are already advanced at first detection. Traditionally, the treatment of choice is complete surgical resection, sometimes combined with postoperative radiotherapy and chemotherapy. We report a case of EES with left renal artery invasion in the left retroperitoneal cavity successfully treated with transarterial embolization and surgery. CASE PRESENTATION: A 57-year-old woman with a negative family history of cancer presented at our Urology Department with a large left retroperitoneal tumor found by magnetic resonance imaging during the health exam. Physical examination showed a soft abdomen and no palpable mass or tenderness. Imaging studies showed that the tumor covered the entire left renal pedicle, but the left kidney, left adrenal gland, and pancreas appeared tumor free. Since the tumor tightly covered the entire renal pedicle, tumor excision with radical nephrectomy was advised. The patient underwent transarterial embolization of the left renal artery with 10 mg of Gelfoam pieces daily before surgical excision. Tumor excision and left radical nephrectomy were uneventful the day after embolization. Post-operatively, the patient recovered well and was discharged on day 10. The final histopathological analysis showed a round blue cell tumor consistent with an Ewing sarcoma, and the surgical margins were tumor free. CONCLUSIONS: Retroperitoneal malignancies are rare but usually severe conditions. Our case report showed that retroperitoneal EES with renal artery invasion could be treated safely with transarterial embolization and surgery.

A rare case of a combination of ectopic kidney and medial arcuate ligament syndrome: a case report.

BACKGROUND: Ectopic kidney and median arcuate ligament syndrome are both rare conditions. The clinical presentation and diagnosis of these conditions are not well studied. There are no reports on the combination of these two rare conditions. CASE PRESENTATION: We report a 24-year-old woman with fever, dysuria, urinary frequency and left flank pain for two days. The primary diagnoses in the clinic were left acute pyelonephritis and left hydronephrosis due to throbbing pain in the left costovertebral angle and pyuria. However, further computed tomography showed right ectopic pelvic kidney, left renal pelvis dilatation without definite ureteral lesion, good bilateral renal contrast enhancement, and compression of the celiac axis due to obstruction by the median arcuate ligament. Chronic abdominal symptoms were reported by the patient after repeat history taking. The patient's condition was fully explained and discussed with her and her family, but they refused further therapy. After the acute pyelonephritis began improving, the patient was discharged for follow-up at our outpatient clinic. CONCLUSION: We present an extremely rare case of a combination of two rare conditions: ectopic kidney and median arcuate ligament syndrome. No study to date has reported on the relationship between the two diseases. Given the rarity of the two conditions, no evidence or even a hypothesis exists to explain the possible etiology of their combination. More reports are required to enhance the understanding of these rare conditions.

Associations of genome-wide cell-free DNA fragmentation profiles with blood biochemical and hematological parameters in healthy individuals.

Cell-free DNA (cfDNA), as a non-invasive approach, has been introduced in a wide range of applications, including cancer diagnosis/ monitoring, prenatal testing, and transplantation monitoring. Yet, studies of cfDNA fragmentomics in physiological conditions are lacking. In this study, we aim to explore the correlation of fragmentation patterns of cfDNA with blood biochemical and hematological parameters in healthy individuals. We addressed the impact of physiological variables and abnormal blood biochemical and hematological parameters on cfDNA fragment size distribution. We also figured and validated that hematological inflammation markers, including leukocyte, lymphocyte, neutrophil, and platelet distribution width as well as aspartate transaminase levels were significantly correlated with the genome-wide cfDNA fragmentation pattern. Our findings suggest that cfDNA fragmentation profiles were associated with physiological parameters related to cardiovascular risk factors, inflammatory response and hepatocyte injury, which may provide insights for further research on the potential role of cfDNA fragmentation in diagnosis and monitor of several disease.

Impact of pathological response on oncological outcomes in patients with upper tract urothelial cancer receiving neo-adjuvant chemotherapy.

PURPOSE: The purpose of this study is to evaluate the rates of pathological complete response (ypT0N0/X) and pathological response (ypT1N0/X or less) in patients with upper tract urothelial cancer who were treated with neo-adjuvant chemotherapy and to examine their impact on oncological outcomes. METHODS: This study is a multi-institutional retrospective analysis of patients with high-risk upper tract urothelial cancer who underwent neoadjuvant chemotherapy and radical nephroureterectomy between 2002 and 2021. Logistic regression analyses were used to investigate all clinical parameters for response after neoadjuvant chemotherapy. Cox proportional hazard models were performed to assess the effect of the response on the oncological outcomes. RESULTS: A total of 84 patients with UTUC who received neo-adjuvant chemotherapy were identified. Among them, 44 (52.4%) patients received cisplatin-based chemotherapy, and 22 (26.2%) patients had a carboplatin-based regimen. The pathological complete response rate was 11.6% (n = 10), and the pathological response rate was 42.9% (n = 36). Multifocal tumors or tumors larger than 3 cm significantly reduced the odds of pathological response. In the multivariable Cox proportional hazard model, pathological response was independently associated with better overall survival (HR 0.38, p = 0.024), cancer-specific survival (HR 0.24, p = 0.033), and recurrence-free survival (HR 0.17, p = 0.001), but it was not associated with bladder recurrence-free survival (HR 0.84, p = 0.69). CONCLUSION: Pathological response after neo-adjuvant chemotherapy and radical nephroureterectomy is strongly associated with patient survival and recurrence, and it might be a good surrogate for evaluating the efficacy of neo-adjuvant chemotherapy in the future.

Mechanism of Social Stress-Related Erectile Dysfunction in Mice: Impaired Parasympathetic Neurotransmission and Ketamine.

This study aimed to investigate the mechanism underlying social stress (SS)-induced erectile dysfunction (ED) and evaluate the effects of a single subanesthetic dose of ketamine on SS-related ED. Male FVB mice were exposed to retired male C57BL/6 mice for 60 min daily over a 4-week period. In the third week, these FVB mice received intraperitoneal injections of either saline (SSS group) or ketamine (SSK group). Erectile function was assessed by measuring the intracavernosal pressure (ICP) during electrical stimulation of the major pelvic ganglia. Corpus cavernosum (CC) strips were utilized for wire myography to assess their reactivity. Both SSS and SSK mice exhibited significantly lower ICP in response to electrical stimulation than control mice. SS mice showed increased contractility of the CC induced by phenylephrine. Acetylcholine-induced relaxation was significantly reduced in SSS and SSK mice. Sodium nitroprusside-induced relaxation was higher in SSS mice compared to control and SSK mice. Nicotine-induced neurogenic and nitric oxide-dependent relaxation was significantly impaired in both SSS and SSK mice. An immunohistochemical analysis revealed co-localization of tyrosine hydroxylase and neuronal nitric oxide synthase-immunoreactive fibers in the CC. These findings highlight the complex nature of SS-related ED and suggest the limited efficacy of ketamine as a therapeutic intervention.

Letter to the Editor: An ultra-sensitive assay using cell-free DNA fragmentomics for multi-cancer early detection.

Early detection can benefit cancer patients with more effective treatments and better prognosis, but existing early screening tests are limited, especially for multi-cancer detection. This study investigated the most prevalent and lethal cancer types, including primary liver cancer (PLC), colorectal adenocarcinoma (CRC), and lung adenocarcinoma (LUAD). Leveraging the emerging cell-free DNA (cfDNA) fragmentomics, we developed a robust machine learning model for multi-cancer early detection. 1,214 participants, including 381 PLC, 298 CRC, 292 LUAD patients, and 243 healthy volunteers, were enrolled. The majority of patients (N = 971) were at early stages (stage 0, N = 34; stage I, N = 799). The participants were randomly divided into a training cohort and a test cohort in a 1:1 ratio while maintaining the ratio for the major histology subtypes. An ensemble stacked machine learning approach was developed using multiple plasma cfDNA fragmentomic features. The model was trained solely in the training cohort and then evaluated in the test cohort. Our model showed an Area Under the Curve (AUC) of 0.983 for differentiating cancer patients from healthy individuals. At 95.0% specificity, the sensitivity of detecting all cancer reached 95.5%, while 100%, 94.6%, and 90.4% for PLC, CRC, and LUAD, individually. The cancer origin model demonstrated an overall 93.1% accuracy for predicting cancer origin in the test cohort (97.4%, 94.3%, and 85.6% for PLC, CRC, and LUAD, respectively). Our model sensitivity is consistently high for early-stage and small-size tumors. Furthermore, its detection and origin classification power remained superior when reducing sequencing depth to 1× (cancer detection: ≥ 91.5% sensitivity at 95.0% specificity; cancer origin: ≥ 91.6% accuracy). In conclusion, we have incorporated plasma cfDNA fragmentomics into the ensemble stacked model and established an ultrasensitive assay for multi-cancer early detection, shedding light on developing cancer early screening in clinical practice.

An Artificial Intelligence Model Based on ACR TI-RADS Characteristics for US Diagnosis of Thyroid Nodules.

Background US-based diagnosis of thyroid nodules is subjective and influenced by radiologists' experience levels. Purpose To develop an artificial intelligence model based on American College of Radiology Thyroid Imaging Reporting and Data System characteristics for diagnosing thyroid nodules and identifying nodule characteristics (hereafter, MTI-RADS) and to compare the performance of MTI-RADS, radiologists, and a model trained on benign and malignant status based on surgical histopathologic analysis (hereafter, MDiag). Materials and Methods In this retrospective study, 1588 surgically proven nodules from 636 consecutive patients (mean age, 49 years ± 14 [SD]; 485 women) were included. MTI-RADS and MDiag were trained on US images of 1345 nodules (January 2018 to December 2019). The performance of MTI-RADS was compared with that of MDiag and radiologists with different experience levels on the test data set (243 nodules, January 2019 to December 2019) with the DeLong method and McNemar test. Results The area under the receiver operating characteristic curve (AUC) and sensitivity of MTI-RADS were 0.91 and 83% (55 of 66 nodules), respectively, which were not significantly different from those of experienced radiologists (0.93 [P = .45] and 92% [61 of 66 nodules; P = .07]) and exceeded those of junior radiologists (0.78 [P < .001] and 70% [46 of 66 nodules; P = .04]). The specificity of MTI-RADS (87% [154 of 177 nodules]) was higher than that of both experienced and junior radiologists (80% [141 of 177 nodules; P = .02] and 75% [133 of 177 nodules; P = .001], respectively). The AUC of MTI-RADS was higher than that of MDiag (0.91 vs 0.84, respectively; P = .001). In the test set of 243 nodules, the consistency rates between MTI-RADS and the experienced group were higher than those between MTI-RADS and the junior group for composition (79% [n = 193] vs 73% [n = 178], respectively; P = .02), echogenicity (75% [n = 183] vs 68% [n = 166]; P = .04), shape (93% [n = 227] vs 88% [n = 215]; P = .04), and smooth or ill-defined margin (72% [n = 174] vs 63% [n = 152]; P = .002). Conclusion The area under the receiver operating characteristic curve (AUC) of an artificial intelligence model based on the American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) was higher than that of a model trained on benign and malignant status based on surgical histopathologic analysis. The AUC and sensitivity of the model based on TI-RADS exceeded those of junior radiologists; the specificity of the model was higher than that of both experienced and junior radiologists. © RSNA, 2022.

Wheat heat tolerance is impaired by heightened deletions in the distal end of 4AL chromosomal arm.

Heat stress (HS) causes substantial damages to worldwide crop production. As a cool season crop, wheat (Triticum aestivum) is sensitive to HS-induced damages. To support the genetic improvement of wheat HS tolerance (HST), we conducted fine mapping of TaHST1, a locus required for maintaining wheat vegetative and reproductive growth under elevated temperatures. TaHST1 was mapped to the distal terminus of 4AL chromosome arm using genetic populations derived from two BC6 F6 breeding lines showing tolerance (E6015-4T) or sensitivity (E6015-3S) to HS. The 4AL region carrying TaHST1 locus was approximately 0.949 Mbp and contained the last 19 high confidence genes of 4AL according to wheat reference genome sequence. Resequencing of E6015-3S and E6015-4T and haplotype analysis of 3087 worldwide wheat accessions revealed heightened deletion polymorphisms in the distal 0.949 Mbp region of 4AL, which was confirmed by the finding of frequent gene losses in this region in eight genome-sequenced hexaploid wheat cultivars. The great majority (86.36%) of the 3087 lines displayed different degrees of nucleotide sequence deletions, with only 13.64% of them resembling E6015-4T in this region. These deletions can impair the presence and/or function of TaHST1 and surrounding genes, thus rendering global wheat germplasm vulnerable to HS or other environmental adversities. Therefore, conscientious and urgent efforts are needed in global wheat breeding programmes to optimize the structure and function of 4AL distal terminus by ensuring the presence of TaHST1 and surrounding genes. The new information reported here will help to accelerate the ongoing global efforts in improving wheat HST.

Norovirus Outbreak Surveillance, China, 2016-2018.

CaliciNet China, a network of provincial, county, and city laboratories coordinated by the Chinese Centers for Disease Control and Prevention, was launched in October 2016 to monitor the epidemiology and genotype distribution of norovirus outbreaks in China. During October 2016-September 2018, a total of 556 norovirus outbreaks were reported, and positive fecal samples from 470 (84.5%) outbreaks were genotyped. Most of these outbreaks were associated with person-to-person transmission (95.1%), occurred in childcare centers or schools (78.2%), and were reported during November-March of each year (63.5%). During the 2-year study period, 81.2% of all norovirus outbreaks were typed as GII.2[P16]. In China, most norovirus outbreaks are reported by childcare centers or schools; GII.2[P16] is the predominant genotype. Ongoing surveillance by CaliciNet China will provide information about the evolving norovirus genotype distribution and outbreak characteristics important for the development of effective interventions, including vaccines.

Loss of αB-crystallin function in zebrafish reveals critical roles in the development of the lens and stress resistance of the heart.

Genetic mutations in the human small heat shock protein αB-crystallin have been implicated in autosomal cataracts and skeletal myopathies, including heart muscle diseases (cardiomyopathy). Although these mutations lead to modulation of their chaperone activity in vitro, the in vivo functions of αB-crystallin in the maintenance of both lens transparency and muscle integrity remain unclear. This lack of information has hindered a mechanistic understanding of these diseases. To better define the functional roles of αB-crystallin, we generated loss-of-function zebrafish mutant lines by utilizing the CRISPR/Cas9 system to specifically disrupt the two αB-crystallin genes, αBa and αBb We observed lens abnormalities in the mutant lines of both genes, and the penetrance of the lens phenotype was higher in αBa than αBb mutants. This finding is in contrast with the lack of a phenotype previously reported in αB-crystallin knock-out mice and suggests that the elevated chaperone activity of the two zebrafish orthologs is critical for lens development. Besides its key role in the lens, we uncovered another critical role for αB-crystallin in providing stress tolerance to the heart. The αB-crystallin mutants exhibited hypersusceptibility to develop pericardial edema when challenged by crowding stress or exposed to elevated cortisol stress, both of which activate glucocorticoid receptor signaling. Our work illuminates the involvement of αB-crystallin in stress tolerance of the heart presumably through the proteostasis network and reinforces the critical role of the chaperone activity of αB-crystallin in the maintenance of lens transparency.

Phytoplankton decline in the eastern North Pacific transition zone associated with atmospheric blocking.

Global climate change can significantly influence oceanic phytoplankton dynamics, and thus biogeochemical cycles and marine food webs. However, associative explanations based on the correlation between chlorophyll-a concentration (Chl-a) and climatic indices is inadequate to describe the mechanism of the connection between climate change, large-scale atmospheric dynamics, and phytoplankton variability. Here, by analyzing multiple satellite observations of Chl-a and atmospheric conditions from National Center for Environmental Prediction/National Center for Atmospheric Research reanalysis datasets, we show that high-latitude atmospheric blocking events over Alaska are the primary drivers of the recent decline of Chl-a in the eastern North Pacific transition zone. These blocking events were associated with the persistence of large-scale atmosphere pressure fields that decreased westerly winds and southward Ekman transport over the subarctic ocean gyre. Reduced southward Ekman transport leads to reductions in nutrient availability to phytoplankton in the transition zone. The findings describe a previously unidentified climatic factor that contributed to the recent decline of phytoplankton in this region and propose a mechanism of the top-down teleconnection between the high-latitude atmospheric circulation anomalies and the subtropical oceanic primary productivity. The results also highlight the importance of understanding teleconnection among atmosphere-ocean interactions as a means to anticipate future climate change impacts on oceanic primary production.

Long-term outcomes of anti-incontinence surgery and subsequent transvaginal sling incision for urethral obstruction.

INTRODUCTION AND HYPOTHESIS: The suburethral sling procedure has been widely used as the first-line treatment for stress urinary incontinence (SUI) in women. Although the success rate is high, difficult urination and urine retention can occur in a small portion of patients. A transvaginal sling incision can solve this problem but recurrent SUI may occur. This study investigated the long-term outcomes of women who underwent the pubovaginal sling (PVS) procedure and subsequent transvaginal sling incision for urethral obstruction. METHODS: We retrospectively reviewed the voiding conditions of women who underwent transvaginal sling incision owing to bladder outlet obstruction after the PVS procedure over the past two decades. Urodynamic study was performed before and after each operation. The patients' Global Impression of Improvement (PGI-I) and quality of life index (QoL-I) due to urinary symptoms were used for outcome evaluation. RESULTS: Among 405 women who underwent PVS procedure, 14 (3.5%) underwent subsequent transvaginal sling incision. The main symptoms were severe dysuria, followed by urinary retention or severe wound discomfort. The average interval between the two operations was 147.6 ± 353.6 days (range 3~1,344). The mean follow-up time after sling incision was 91.1 ± 50.7 months. At follow-up, 12 patients (85.7%) could maintain urinary continence whereas 2 had urgency incontinence. Ten patients (71.4%) were satisfied with their quality of life postoperatively. CONCLUSIONS: Transvaginal sling incision is effective for urethral obstruction after PVS procedure. Voiding dysfunction after PVS could be resolved via sling incision. Most patients could maintain urinary continence and reported good satisfaction.

Pre-Treatment with Ten-Minute Carbon Dioxide Inhalation Prevents Lipopolysaccharide-Induced Lung Injury in Mice via Down-Regulation of Toll-Like Receptor 4 Expression.

Various animal studies have shown beneficial effects of hypercapnia in lung injury. However, in patients with acute respiratory distress syndrome (ARDS), there is controversial information regarding the effect of hypercapnia on outcomes. The duration of carbon dioxide inhalation may be the key to the protective effect of hypercapnia. We investigated the effect of pre-treatment with inhaled carbon dioxide on lipopolysaccharide (LPS)-induced lung injury in mice. C57BL/6 mice were randomly divided into a control group or an LPS group. Each LPS group received intratracheal LPS (2 mg/kg); the LPS groups were exposed to hypercapnia (5% carbon dioxide) for 10 min or 60 min before LPS. Bronchoalveolar lavage fluid (BALF) and lung tissues were collected to evaluate the degree of lung injury. LPS significantly increased the ratio of lung weight to body weight; concentrations of BALF protein, tumor necrosis factor-α, and CXCL2; protein carbonyls; neutrophil infiltration; and lung injury score. LPS induced the degradation of the inhibitor of nuclear factor-κB-α (IκB-α) and nuclear translocation of NF-κB. LPS increased the surface protein expression of toll-like receptor 4 (TLR4). Pre-treatment with inhaled carbon dioxide for 10 min, but not for 60 min, inhibited LPS-induced pulmonary edema, inflammation, oxidative stress, lung injury, and TLR4 surface expression, and, accordingly, reduced NF-κB signaling. In summary, our data demonstrated that pre-treatment with 10-min carbon dioxide inhalation can ameliorate LPS-induced lung injury. The protective effect may be associated with down-regulation of the surface expression of TLR4 in the lungs.

Genetic and clonal dissection of osteosarcoma progression and lung metastasis.

Osteosarcoma is a primary malignant bone tumor that has a high potential to metastasize to lungs. Little is known about the mechanisms underlying the dissemination of OS cancer cells to lungs. We performed whole exome sequencing of 13 OS primary tumors, with matched lung metastases and normal tissues. Phylogenetic analyses revealed that lung metastatic tumors often harbor clones that are nonexistent or rare in the matched primary OS tumors. Spatially and temporally separated lung metastases were from parallel seeding events with a polyphyletic pattern. Loss of TP53 or RB1 is among the early events during OS tumorigenesis, while loss of PTEN is involved at the later stages associated with lung metastases. Finally, KEAP1 was identified as a novel biomarker for increased metastatic risk. Patients whose primary tumors harbored KEAP1 amplification have significantly poorer lung-metastasis free survival. This finding was validated in two independent datasets. Further, in vitro experiments exhibited that KEAP1 depletion suppressed the invasion of OS cells. Our findings uncover the patterns of clonal evolution during OS progression and highlight KEAP1 as a novel candidate associated with the risk of lung metastasis in OS patients.

A real-world experience with augmentation enterocystoplasty-High patient satisfaction with high complication rates.

AIMS: To investigate the real treatment outcomes after augmentation enterocystoplasty (AE) of patients with refractory neurogenic lower urinary tract dysfunction. METHODS: Retrospective follow-up in a single center. The videourodynamic data, renal function, incontinence grade, voiding pattern and management, clinical outcome, and complications were evaluated. RESULTS: Seventy-nine patients (62 men and 17 women) were included. The mean age at operation was 39.4 ± 11.6 years and the mean follow-up period was 128.4 ± 85.2 months. At follow-up, 5 (6.7%) patients had spontaneous voiding, 60 (80%) had to perform clean intermittent catheterization, and 10 (13.3%) chose to keep the indwelling catheter. The catheter-dependent rate was 93.3% and complete catheter-dependent rate was 76%. Renal function of the patients did not appear to be significantly different after AE. Three patients developed end-stage renal disease. The incontinence grade showed significant improvement (P = 0.000). Among all the patients, 41.8% experienced recurrent urinary tract infections requiring medical treatment and 21.5% suffered from chronic diarrhea. Overall, 45.6% of the patients experienced complications requiring surgical interventions, most of which were stones. Life-threatening complications like bowel obstruction and bladder cancer were also noted. Three patients even expired within one year postoperatively. The majority (86.8%) of patients reported moderate to excellent satisfaction with the outcome of AE. CONCLUSIONS: AE is a procedure with long-term durability and high rates of patient satisfaction. However, several bothersome complications affecting life quality may occur. Both patients and doctors thus need to consider possible outcomes carefully before the operation.

Correction: Wen-I Liao, et al. Ac2-26, an Annexin A1 Peptide, Attenuates Ischemia-Reperfusion-Induced Acute Lung Injury. Int. J. Mol. Sci. 2017, 18, 1771.

The authors would like to make a correction to their published paper [1][...].

Expression of Cataract-linked γ-Crystallin Variants in Zebrafish Reveals a Proteostasis Network That Senses Protein Stability.

The refractivity and transparency of the ocular lens is dependent on the stability and solubility of the crystallins in the fiber cells. A number of mutations of lens crystallins have been associated with dominant cataracts in humans and mice. Of particular interest were γB- and γD-crystallin mutants linked to dominant cataracts in mouse models. Although thermodynamically destabilized and aggregation-prone, these mutants were found to have weak affinity to the resident chaperone α-crystallin in vitro To better understand the mechanism of the cataract phenotype, we transgenically expressed different γD-crystallin mutants in the zebrafish lens and observed a range of lens defects that arise primarily from the aggregation of the mutant proteins. Unlike mouse models, a strong correlation was observed between the severity and penetrance of the phenotype and the level of destabilization of the mutant. We interpret this result to reflect the presence of a proteostasis network that can "sense" protein stability. In the more destabilized mutants, the capacity of this network is overwhelmed, leading to the observed increase in phenotypic penetrance. Overexpression of αA-crystallin had no significant effects on the penetrance of lens defects, suggesting that its chaperone capacity is not limiting. Although consistent with the prevailing hypothesis that a chaperone network is required for lens transparency, our results suggest that αA-crystallin may not be efficient to inhibit aggregation of lens γ-crystallin. Furthermore, our work implicates additional inputs/factors in this underlying proteostasis network and demonstrates the utility of zebrafish as a platform to delineate mechanisms of cataract.