Bluetongue Viruses Act as Novel Oncolytic Viruses to Effectively Inhibit Human Renal Cancer Cell Growth In Vitro and In Vivo.

BACKGROUND The bluetongue virus (BTV) is the prototype virus in the genus Orbivirus within the family Reoviridae. Recent studies indicate that BTVs are capable of infecting and selectively lysing human hepatic carcinoma cells (Hep-3B) and prostate carcinoma cells (pc-3). This study was designed to evaluate the oncolytic potential of BTV in experimental models of human renal cancer in vitro and in vivo. MATERIAL AND METHODS Five human renal cancer cell lines, ACHN, CAKI-1, OS-RC-2, 786-O, and A498, were used in this study to analyze BTV replication. These cells were lysed by oncolysis compared to normal control. Xenograft models were used to assess the efficacy and toxicity of BTVs in vivo. Data were analyzed by one-way ANOVA or two-sided unpaired t tests. RESULTS The results showed HPTEC cells to be relatively resistant to cytotoxic effects of BTVs and exhibited normal growth rate even at high dose of BTVs. Nonetheless, the renal cancer cells showed a remarkably higher sensitivity to BTVs. Moreover, the ultramicroscopic subcellular changes were also detected in the renal cells. The viral particles were observed in all the RCC cell lines, but not in HPTEC cells. Intratumoral injections of BTVs significantly decreased the tumor volume as compared to animals that received no virus treatment. Infection with BTVs significantly increased the percentage of apoptotic renal cancer cells but not the HPTEC cells. Moreover, BTV triggered apoptosis in renal cancer cells via a mitochondria-mediated pathway. CONCLUSIONS This study for the first time demonstrated the oncolytic potential of BTV in experimental models of human renal cancer. BTV exhibits the potential to inhibit human renal cancer cell growth in vitro and in vivo.

Successful treatment of seminal vesicle calculi and prostatic utricle calculi by transurethral seminal vesiculoscopy.

To investigate the outcomes of transurethral seminal vesiculoscopy (TSV) for the treatment of seminal vesicle calculi (SVC), prostatic utricle calculi (PUC) and combination of them, a retrospective review on 27 patients with SVC and/or PUC who complained of intractable haematospermia was conducted. Patient demographics, disease duration, operation time, stone location and complications were recorded. The calculi in the seminal vesicle and/or prostatic utricle were removed by holmium laser lithotripsy and/or basket extraction. The stone composition was determined in 19 of 27 patients using Infrared spectroscopy. The average age and disease duration of patients were 39.4 years and 23.1 months respectively. The mean operative time was 78.5 min. We detected SVC, SVC and PUC, and PUC in 59.3% (16/27), 33.3% (9/27) and 7.4% (2/27) patients respectively. The stones were mainly composed of calcium oxalate dehydrate (COD), carbonate apatite (CA), COD and calcium oxalate monohydrate (COM), CA and magnesium ammonium phosphate, CA and COM, and COD and uric acid in 42.1% (8/19), 21.1% (4/19), 15.8% (3/19), 15.8% (3/19), 5.3% (1/19) and 5.3% (1/19) cases respectively. No intraoperative and post-operative complications were noted. These results suggested that SVC and PUC can be diagnosed and treated using TSVs.

ErbB4 acts as a suppressor in colitis and its associated carcinoma by negatively regulating cholesterol metabolism.

Previously we reported that ErbB4 played a protective role in chronic liver injury and hepatocellular carcinoma. Herein, we examined the role of ErbB4 in the development of colitis-associated cancer (CAC) in ErbB4 knockout mice models, in vitro cell lines and clinical samples. We found that ErbB4 deficiency may lead to more severe inflammation, slower recovery and the development of CAC. Further, loss of ErbB4 could activate Kras by upregulating rate-limiting enzymes in cholesterol metabolism pathway through interacting with the transcription factor Srebf1. In clinic samples, ErbB4 is downregulated in colonic tissues from patients with Crohn's disease. And data from The Cancer Genome Atlas also showed significant negative correlation between ErbB4 and several cholesterol metabolic enzymes. In summary, our study uncovers ErbB4 as a protector in the development of CAC, for its loss could activate Kras by upregulating cholesterol metabolism.

Inflammatory Cytokines and T-Lymphocyte Subsets in Serum and Sputum in Patients with Bronchial Asthma and Chronic Obstructive Pulmonary Disease.

BACKGROUND It can be difficult to distinguish between bronchial asthma and chronic obstructive pulmonary disease (COPD) clinically, although these conditions are associated with different profiles of inflammatory cytokines and immune cells. This study aimed to compare T-lymphocyte subsets and inflammatory cytokines in the serum and sputum of patients with bronchial asthma and COPD who had respiratory function testing. MATERIAL AND METHODS The study included 42 patients with bronchial asthma, 48 patients with COPD, and 45 patients with bronchial asthma complicated with COPD. The percentage predicted values of the forced expiratory volume in one second (FEV1), the forced vital capacity (FVC), and the peak expiratory flow (PEF) rate were measured. Serum and sputum levels of interleukin (IL)-4, IL-5, IL-9, IL-13, IL-1ß, IL-6 and tumor necrosis factor-alpha (TNF-alpha) were measured using an enzyme-linked immunosorbent assay (ELISA). Flow cytometry measured the CD4 and CD8 T-lymphocyte subsets, and the CD4: CD8 ratio was calculated. RESULTS The FEV1, FVC, and PEF were significantly lower in patients with COPD compared with the other two patient groups. Serum and sputum levels of IL-4, IL-5, IL-9 and IL-13 were significantly increased in the COPD patient group, and levels of TNF-alpha, IL-1ß and IL-6 were significantly increased in the bronchial asthma patient group. The CD4: CD8 ratio in sputum was lowest in bronchial asthma patient group and highest in COPD patient group. CONCLUSIONS The detection of serum and sputum inflammatory cytokines and T-lymphocyte subsets may distinguish between bronchial asthma and COPD.

The long-term efficacy of one-shot neoadjuvant intra-arterial chemotherapy combined with radical cystectomy versus radical cystectomy alone for bladder cancer: a propensity-score matching study.

BACKGROUND: Bladder cancer is a complex disease associated with high morbidity and mortality. Management of bladder cancer before radical cystectomy continues to be controversial. We compared the long-term efficacy of one-shot neoadjuvant intra-arterial chemotherapy (IAC) versus no IAC (NIAC) before radical cystectomy (RC) for bladder cancer. METHODS: We performed a retrospective review of patients who underwent either one-shot IAC or NIAC before RC between October 2006 and November 2015. A propensity-score matching (1:3) was performed based on key characters. The Kaplan-Meier method was utilized to estimate survival probabilities, and the log-rank test was used to compare survival outcomes between different groups. A multivariable Cox proportional hazard model was used to estimate survival outcomes. RESULTS: Twenty-six patients were treated using IAC before RC, and 123 NIAC patients also underwent RC. After matching, there was no significant difference between groups in baseline characteristics, perioperative variables, complication outcomes or tumor characteristics. Compared with clinical tumor stages, pathological tumor stages demonstrated a significant decrease (P = 0.002) in the IAC group. There was no significant difference in overall survival (OS, p = 0.354) or cancer-specific survival (CSS, p = 0.439) between the groups. Among all patients, BMI significantly affected OS (p = 0.004), and positive lymph nodes (PLN) significantly affected both OS (p<0.001) and CSS (p = 0.010). CONCLUSIONS: One-shot neoadjuvant IAC before RC shows safety and tolerability and provides a significant advantage in pathological downstaging but not in OS or CSS. Further study of neoadjuvant combination therapeutic strategies with RC is needed.

Comparison of intracorporeal and extracorporeal urinary diversions after laparoscopic radical cystectomy in females with bladder cancer.

PURPOSE: To compare the peri-operative outcomes of females undergoing laparoscopic intracorporeal urinary diversions (ICUD) and extracorporeal urinary diversions (ECUD) after laparoscopic radical cystectomies (LRC). PATIENTS AND METHODS: Thirty-eight females who underwent LRCs and urinary diversions from February 2008 to October 2018 were divided into two groups: the ECUD group (19 patients) and the ICUD group (19 patients). We retrospectively analysed the patients in terms of patients' demographics, peri-operative outcomes, and oncological follow-ups. RESULTS: There were significant differences in the mean operative times between ECUDs and ICUDs (364.6 vs. 297.1 min, p = 0.007), transfusion rates (37% vs. 5%, p = 0.042), time to flatus (5 vs. 3 days, p = 0.020), time to ambulation (2 vs. 1 days, p = 0.022), and duration of postoperative hospital stays (22 vs. 13 days, p = 0.002). The mean lymph node yield was 12.9 in the ECUD group and 18.6 in the ICUD group (p = 0.140). Seven out of 19 patients (37%) in the ECUD group and 6 out of 19 patients (32%) in the ICUD group had positive lymph nodes (p > 0.9). Two out of 19 ECUD patients (11%) and 4 of 19 ICUD patients (21%) had positive surgical margins (p = 0.660). Although there were no differences in major complications at 30 days and in all complications at 90 days, the Clavien grade II complications were significantly different at 30 days (ECUD 8, ICUD 2; p = 0.026). The mean follow-up times were 48.7 months (ECUD group) and 26.4 months (ICUD group). There were no statistically significant differences in estimated glomerular filtration rates postoperatively (p = 0.516). Seven patients had disease metastases (ECUD 2 out of 19, ICUD 5 out of 19; p = 0.405) and 5 died (ECUD 3 out of 19, ICUD 2 out of 19; p > 0.9). CONCLUSIONS: ICUDs benefit females by having smaller incisions, faster recoveries, and decreased complication rates.

Simultaneous treatment of parapelvic renal cysts and stones by flexible ureterorenoscopy with a novel four-step cyst localization strategy.

OBJECTIVE: To assess the safety, feasibility, and efficacy of simultaneous treatment of parapelvic renal cysts and stones by flexible ureterorenoscopy with a novel four-step cyst localization strategy in selected patients. PATIENTS AND METHODS: We retrospectively reviewed 11 consecutive cases of parapelvic renal cysts with concomitant calculi treated by flexible ureterorenoscopy and laser lithotripsy (FURSL). Marsupialization was performed subsequently with holmium: YAG laser in our institution. Fragmentation was used to manage renal stones and a novel four-step cyst localization strategy was applied in each case for marsupialization. RESULTS: There were no intraoperative complications. Two cases of cystitis were reported postoperatively. The mean operative times of FURSL and marsupialization were 23.6 ± 3.9 minutes and 29.1 ± 9.7 minutes, respectively. During marsupialization, seven patients underwent the first two steps of the new strategy, two patients underwent three steps and two patients underwent all four steps. The mean reduction in hemoglobin level was 4.7 ± 1.7 g / L (range 3-8 g / L). The mean length of hospital stay was 1.2 ± 0.4 days. During a mean follow-up duration of 18 months, all cases remained stonefree and there was no stone recurrence. Parapelvic cysts became undetectable in eight cases and decreased in size by at least half in three cases. CONCLUSION: With appropriate patient selection, FURSL and marsupialization with a four-step cyst localization strategy is feasible, safe, and effective in treating parapelvic renal cysts with concomitant calculi.

ERBB4 acts as a suppressor in the development of hepatocellular carcinoma.

ERBB4, one member of the epidermal growth factor receptor (EGFR) family, plays a key role in physiological and pathological processes. Recently, we identified that ERBB4 played a protective role from chronic hepatitis B virus infection. However, the role of ERBB4 in hepatocellular carcinoma (HCC) is still unclear. Here, we explore the role of ERBB4 in the development of HCC using in vitro models, in vivo animal models and clinical samples of HCC. Liver-specific ERBB4 knockout alleles and full ERBB4 except heart knockout mice were used in this study. Liver inflammation and tumor models of mice were produced by carbon tetrachloride (CCl4) and diethylnitrosamine (DEN) administration, respectively. Commercial tissue arrays of 90 HCC patients with paired counterparts were used to evaluate the expression and the prognostic value of ERBB4. Genes altered in the setting of ERBB4 loss was studied by microarray analysis and further validated by real-time PCR. We have found that depletion of ERBB4 in mice leads to more severe injury and liver tumor formation and loss of ERBB4 contributes to the development of hepatocellular tumor. In clinic samples of HCC, ERBB4 is down-regulated and exhibit prognostic value of HCC patients. Mechanistically, loss of ERBB4 suppressed p53 expression by inhibiting the expression of the tumor suppressor tp53inp1. Our study uncovers ERBB4 as a suppressor in the development of HCC and implies an ERBB4-TP53INP1-P53 axis in HCC.

Erbin interacts with c-Cbl and promotes tumourigenesis and tumour growth in colorectal cancer by preventing c-Cbl-mediated ubiquitination and down-regulation of EGFR.

The epidermal growth factor receptor (EGFR) is implicated in many types of cancer, including colorectal cancer (CRC), and has become one of the most common candidates for targeted therapy. Here, we found that Erbin, a member of the leucine-rich repeat and PDZ domain (LAP) family, plays a key role in EGFR signalling. Erbin inhibited EGFR ubiquitination and stabilized the EGFR protein by interacting with c-Cbl. Moreover, the PDZ domain of Erbin was critical for the interaction between Erbin and c-Cbl and EGFR ubiquitination. Interestingly, Erbin expression was elevated in tumour samples from CRC patients, increased in advanced clinical stage disease and correlated with EGFR expression. In vivo studies using mouse xenograft models of CRC showed that Erbin promotes tumour growth, and that the effects of Erbin on tumour growth are mainly related to the regulatory effects of Erbin on EGFR. The azoxymethane (AOM)-induced colon carcinogenesis model in Erbin(ΔC) (/) (ΔC) mice, with the PDZ domain of Erbin deleted, demonstrated that the PDZ domain of Erbin and its regulation of EGFR signalling are necessary for the tumourigenesis and tumour growth of CRC. We found that Erbin promotes tumourigenesis and tumour growth in CRC by stabilizing EGFR. Our study sheds light on developing Erbin, especially its PDZ domain, as a potential target for CRC treatment.

The Clinical Application of Fluorescence in Situ Hybridization in Diagnosing Urothelial Carcinoma.

BACKGROUND: Chromosomal aberrations in exfoliated urothelial cells have been associated with the development of urothelial carcinoma. This study aimed to evaluate the efficacy of two kinds of fluorescence in situ hybridization (FISH) kit probes in diagnosing urothelial carcinoma (UC). METHODS: From February 2009 through September 2014, urine specimens from 89 consecutive patients with urothelial carcinoma and 11 controls with benign disease were collected and analyzed by means of GP FISH and cytology. Urine samples from 50 consecutive patients with urothelial carcinoma and 68 patients with non-urothelial carcinoma with hematuria were also collected and analyzed by UroVysion FISH and cytology. The sensitivity and specificity of two kinds of FISH and cytology in different stages and grades of urothelial carcinoma were statistically analyzed via SPSS 17.0 and compared. RESULTS: The overall sensitivity of GP FISH and cytology were 88.8% (79/89) and 55.1% (49/89), respectively (p < 0.001), and the overall specificity was 90.9% (10/11) and 100.0% (11/11), respectively (p > 0.05). The overall sensitivity of UroVysion FISH and cytology was 68.0% and 18.0%, respectively (p < 0.05), and the overall specificity was 91.2% and 98.5%, respectively (p > 0.05). The sensitivity of FISH and cytology in diagnosing UUT-UC were 88.9% (16/18) and 44.4%(8/18),respectively. The sensitivity of GP FISH and UroVysion FISH in diagnosing UUT-UC were 100% (10/10) and 75.0% (6/8) respectively. CONCLUSIONS: FISH is a non-invasive technique with higher sensitivity and similar specificity compared with urine exfoliated cell cytology in diagnosing urothelial carcinoma by detecting the aberrations of chromosome 3, 7, 17, and 9p21. FISH is significantly superior to cytology in diagnosing low stage and low grade urothelial carcinomas. FISH is a very valuable and promising technique in diagnosing urothelial carcinomas.

[Research on Adaptive Balance Adjustment of Lower Limb Joints and Muscles in the Process of Unexpected Slip].

Aiming at the gait instability phenomenon under disturbed conditions,domestic and foreign scholars have done some research works,but the relationship between the independent balancing act with the surface electromyographic and gait parameters in the process of instability has yet rarely been involved.In this study,using the gait analysis combined with electromyographic signal analysis,we investigated balance adjustment mechanism of joints and muscles of the human lower limb under the condition of walking on the level trail and after foot heel touching the ground and unexpected sliding.Studying 10 healthy subjects with the unified shoes,we acquired and analyzed the changing rule of the lower limb joint torque,joint angle,and the surface electromyographic of the main muscle groups involved in situations of dry or oid trails.Studies showed that when accident sliding happened,the body would increase ankle dorsiflexion torque moment,knee unbend torque and straight angle,and meanwhile increase the torque of hip extension,and timely adjust muscle activation time(Followed by activation of Tibialis anterior muscle→Rectus femoris→Gastrocnemius→Femoral biceps)to adjust the center of gravity,to maintain balance of the body,and to avoid falling down.The results of the research could be used to explore new ideas and to provide a certain reference value for preventing slip damage,rehabilitation training and development of lower limb walker.

Retroperitoneal Laparoscopic Nephroureterectomy for Tuberculous Nonfunctioning Kidneys: a single-center experience.

PURPOSE: To present our surgical techniques and experiences of retroperitoneal laparoscopic nephroureterectomy for the treatment of tuberculous nonfunctioning kidneys. MATERIALS AND METHODS: From March 2005 to March 2013, a total of 51 patients with tuberculous nonfunctioning kidney underwent retroperitoneal laparoscopic nephroureterectomy at our medical center. The techniques included early control of renal vessels and dissection of the diseased kidney along the underlying layer outside the Gerato's fascia. The distal ureter was dissected through a Gibson incision and the entire specimen was removed en bloc from the incision. Patient demographics, perioperative characteristics and laboratory parameters as well as postoperative outcome were retrospectively reviewed. RESULTS: Retroperitoneal laparoscopic nephroureterectomy was successfully performed in 50 patients, whereas one case required conversion to open surgery due to non-progression of dissection. The mean operating time was 123.0 minutes (107-160 minutes) and the mean estimated blood loss was 134 mL (80-650 mL).The mean postoperative hospital stay was 3.6 days (3-5 days) and the mean return to normal activity was 11.6 days (10-14 days). Most intra-operative and post-operative complications were minor complications and can be managed conservatively. After 68 months (12-96 months) follow-up, the outcome was satisfactory, and ureteral stump syndrome did not occur. CONCLUSIONS: Retroperitoneal laparoscopic nephroureterectomy as a minimally invasive treatment option is feasible for treatment of tuberculous nonfunctioning kidneys.

[Mid-long-term follow-up of radical cystectomy with orthotopic ileal neobladder in women patients with bladder carcinoma].

OBJECTIVE: To assess the mid-long-term efficacies of orthotopic urinary diversion in women. METHODS: From February 2003 to August 2012, 28 female patients with bladder cancer underwent radical cystectomy and orthotopic ileal neobladder.Open (n = 18) and laparoscopic (n = 9) procedures were performed.Ileal neobladder included 17 T-pouch and 11 modified Studer pouch reconstruction. The continence status, urodynamics, serum electrolyte and renal function were followed up. RESULTS: The mean follow-up period was 55 (8-114) months.Excellent continence was achieved during day-time in 82.1%, 92.3% and 90.5% cases at 6, 12 and 24 months postoperatively and in 53.6%, 88.5% and 90.5% cases at night respectively. The mean capacity of pouch was 282 ± 87, 345 ± 72 and 357 ± 75 ml at 6, 12 and 24 months postoperatively respectively. The mean filling pressure of pouch was 10.8 ± 3.2, 6.7 ± 2.6 and 6.2 ± 2.1 cmH2O postoperatively respectively.One case of neobladder-vaginal fistula was cured by surgical repair. Another case of urethral stenosis responded well after regular dilation for 6 months.Renal function and electrolyte metabolism were stable in all cases. There was no instance of tumor recurrence or metastasis. CONCLUSION: Orthotopic urinary diversion in females has excellent long-term results with fewer complications so that it is highly recommended.

Comparison between CFR-PEEK and titanium plate for proximal humeral fracture: A meta-analysis.

OBJECTIVES: The aim of the present meta-analysis was to compare the efficacy and safety of the carbon fiber-reinforced polyetheretherketone (CFR-PEEK) and titanium plate for the treatment of proximal humeral fractures (PHFs) from clinical comparative trials. MATERIALS AND METHODS: A comprehensive search of English databases was carried out, such as PubMed, Web of Science, ScienceDirect, Springer and Cochrane Library databases. The RevMan version 5.1 software was applied for statistical analysis, and the mean difference (MD) and risk difference (RD) as the combined variables, and "95%" as the confidence interval (CIs). RESULTS: One randomized-controlled trial and five retrospective controlled studies including 282 PHFs were considered eligible and finally included. Meta-analysis demonstrated that there were significant differences in Constant score (CS) (MD=9.23; 95% CI: 5.02, 13.44; p<0.0001), anterior elevation (MD=18.83; 95% CI: 6.27, 31.38; p=0.003), lateral elevation (MD=18.42; 95% CI: 3.64, 33.19; p=0.01) and adduction (MD=3.53; 95% CI: 0.22, 6.84; p=0.04). No significant differences were observed regarding Constant score compared to the contralateral shoulder, Oxford Shoulder Score, internal rotation, external rotation, screw perforation and cutout, varus/valgus malalignment, humeral head collapse/necrosis, implant removal, and revision surgery between the two groups. CONCLUSION: Compared to titanium plate, CFR-PEEK plate showed better Constant score, anterior elevation, lateral elevation and adduction in treating PHFs. The complications are comparable to those achieved with conventional titanium plates.

Prognostic value of Controlling Nutritional Status score for postoperative complications and biochemical recurrence in prostate cancer patients undergoing laparoscopic radical prostatectomy.

Background: Controlling Nutritional Status (CONUT) score was used for screening the preoperative nutritional status. The correlation between the CONUT score and the prognosis of patients with prostate cancer (PCa) has yet to be elucidated. Herein, we analyzed the prognostic value of CONUT scores in patients with PCa who underwent laparoscopic radical prostatectomy. Materials and methods: Data of 244 patients were retrospectively evaluated. Perioperative variables and follow-up data were analyzed. The patients were categorized into 2 groups according to their preoperative CONUT scores. Postoperative complication and incontinence rates were also compared. The Kaplan-Meier method was used to estimate the median biochemical recurrence-free survival (BCRFS) between the 2 groups. Univariate and multivariate Cox regression analyses were performed to identify the potential prognostic factors for BCRFS. Results: Patients were categorized into the low-CONUT group (CONUT score <3, n = 207) and high-CONUT group (CONUT score ≥3, n = 37). The high-CONUT group had a higher overall complication rate (40.5% vs.19.3%, p = 0.004), a higher major complication rate (10.8% vs. 3.9%, p = 0.013), and longer postoperative length of stay (8 days vs. 7 days, p = 0.017). More fever, urinary infection, abdominal infection, scrotal edema, rash, and hemorrhagic events (all p values < 0.05) were observed in the high-CONUT group. A higher rate of urinary incontinence was observed in the high-CONUT group at 1 (34.4% vs. 13.2%, p = 0.030) and 3 months (24.1% vs. 8.2%, p = 0.023) postoperatively. The high-CONUT group had shorter medium BCRFS (23.8 months vs. 54.6 months, p = 0.029), and a CONUT score ≥3 was an independent risk factor for a shorter BCRFS (hazards ratio, 1.842; p = 0.026). Conclusions: The CONUT score is a useful predictive tool for higher postoperative complication rates and shorter BCRFS in patients with PCa who undergo laparoscopic radical prostatectomy.

USP24 promotes autophagy-dependent ferroptosis in hepatocellular carcinoma by reducing the K48-linked ubiquitination of Beclin1.

Ubiquitination is a post-translational modification (PTM), which is critical to maintain cell homeostasis. Ubiquitin-specific protease 24 (USP24) plays roles in various diseases, the mechanisms by which USP24 regulates hepatocellular carcinoma (HCC) remain poorly understood. In this study, USP24 is found to be significantly downregulated in HCC. Knocking down USP24 promotes HCC proliferation and migration, whereas USP24 overexpression inhibits HCC in vitro and in vivo. The endogenous interaction between USP24 and Beclin1 is confirmed. Mechanically, USP24 delays Beclin1 degradation by reducing its K48-linked ubiquitination, the effects of overexpressing USP24 on HCC proliferation can be partially reversed by silencing Beclin1. We find that increased autophagy is accompanied by ferroptosis in USP24 overexpressed HCC cells and USP24 increases the susceptibility of HCC to sorafenib. Collectively, this study highlights the critical role of USP24 in regulating autophagy-dependent ferroptosis by decreasing Beclin1 ubiquitination, suggesting that targeting USP24 may be a strategy for treating HCC.

Non-contrasted computed tomography (NCCT) based chronic thromboembolic pulmonary hypertension (CTEPH) automatic diagnosis using cascaded network with multiple instance learning.

Objective.The diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) is challenging due to nonspecific early symptoms, complex diagnostic processes, and small lesion sizes. This study aims to develop an automatic diagnosis method for CTEPH using non-contrasted computed tomography (NCCT) scans, enabling automated diagnosis without precise lesion annotation.Approach.A novel cascade network (CN) with multiple instance learning (CNMIL) framework was developed to improve the diagnosis of CTEPH. This method uses a CN architecture combining two Resnet-18 CNN networks to progressively distinguish between normal and CTEPH cases. Multiple instance learning (MIL) is employed to treat each 3D CT case as a 'bag' of image slices, using attention scoring to identify the most important slices. An attention module helps the model focus on diagnostically relevant regions within each slice. The dataset comprised NCCT scans from 300 subjects, including 117 males and 183 females, with an average age of 52.5 ± 20.9 years, consisting of 132 normal cases and 168 cases of lung diseases, including 88 cases of CTEPH. The CNMIL framework was evaluated using sensitivity, specificity, and the area under the curve (AUC) metrics, and compared with common 3D supervised classification networks and existing CTEPH automatic diagnosis networks.Main results. The CNMIL framework demonstrated high diagnostic performance, achieving an AUC of 0.807, accuracy of 0.833, sensitivity of 0.795, and specificity of 0.849 in distinguishing CTEPH cases. Ablation studies revealed that integrating MIL and the CN significantly enhanced performance, with the model achieving an AUC of 0.978 and perfect sensitivity (1.000) in normal classification. Comparisons with other 3D network architectures confirmed that the integrated model outperformed others, achieving the highest AUC of 0.8419.Significance. The CNMIL network requires no additional scans or annotations, relying solely on NCCT. This approach can improve timely and accurate CTEPH detection, resulting in better patient outcomes.

Cell-cycle dependent nuclear gene delivery enhances the effects of E-cadherin against tumor invasion and metastasis.

Gene delivery is the process by which foreign DNA is transferred to host cells, released from intracellular vesicles, and transported to the nuclei for transcription. This process is frequently inefficient and difficult to control spatiotemporally. We developed a gene delivery strategy that uses ultrasound to directly deliver plasmid DNA into nuclei via gas vesicles (GVs)-based intracellular cavitation. pDNA-binding GVs can be taken up by cells and cause intracellular cavitation when exposed to acoustic irradiation and delivering their pDNA payloads into nuclei. Importantly, GVs can remain stable in the cytoplasm in the absence of acoustic irradiation, allowing for temporally controlled nuclear gene delivery. We were able to achieve spatiotemporal control of E-cadherin nuclear gene delivery in this manner, demonstrating its efficacy in tumor invasion and metastasis inhibition. Interestingly, we discovered that nuclear gene delivery of E-cadherin during the G2/M phase of the cell cycle in C6 tumor cells inhibited tumor invasion and metastasis more effectively than during the G1 and S phases. The gene delivery of E-cadherin at the G2/M phase resulted in significantly lower expression of Fam50a, which reduced Fam50a/Runx2 interaction and led to reduced transactivation of MMP13, an important factor for epithelial-mesenchymal transition, as observed in a molecular mechanism assay. Thus, using remote acoustic control of intracellular cavitation of pDNA-GVs, we developed a high spatiotemporally controllable gene delivery strategy and achieved stronger tumor invasion and metastasis inhibition effects by delivering the E-cadherin gene at the G2/M phase.

CBCT-to-CT Synthesis for Cervical Cancer Adaptive Radiotherapy via U-Net-Based Model Hierarchically Trained with Hybrid Dataset.

PURPOSE: To develop a deep learning framework based on a hybrid dataset to enhance the quality of CBCT images and obtain accurate HU values. MATERIALS AND METHODS: A total of 228 cervical cancer patients treated in different LINACs were enrolled. We developed an encoder-decoder architecture with residual learning and skip connections. The model was hierarchically trained and validated on 5279 paired CBCT/planning CT images and tested on 1302 paired images. The mean absolute error (MAE), peak signal to noise ratio (PSNR), and structural similarity index (SSIM) were utilized to access the quality of the synthetic CT images generated by our model. RESULTS: The MAE between synthetic CT images generated by our model and planning CT was 10.93 HU, compared to 50.02 HU for the CBCT images. The PSNR increased from 27.79 dB to 33.91 dB, and the SSIM increased from 0.76 to 0.90. Compared with synthetic CT images generated by the convolution neural networks with residual blocks, our model had superior performance both in qualitative and quantitative aspects. CONCLUSIONS: Our model could synthesize CT images with enhanced image quality and accurate HU values. The synthetic CT images preserved the edges of tissues well, which is important for downstream tasks in adaptive radiotherapy.