Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma.

Mutational processes giving rise to lung adenocarcinomas (LADCs) in non-smokers remain elusive. We analyzed 138 LADC whole genomes, including 83 cases with minimal contribution of smoking-associated mutational signature. Genomic rearrangements were not correlated with smoking-associated mutations and frequently served as driver events of smoking-signature-low LADCs. Complex genomic rearrangements, including chromothripsis and chromoplexy, generated 74% of known fusion oncogenes, including EML4-ALK, CD74-ROS1, and KIF5B-RET. Unlike other collateral rearrangements, these fusion-oncogene-associated rearrangements were frequently copy-number-balanced, representing a genomic signature of early oncogenesis. Analysis of mutation timing revealed that fusions and point mutations of canonical oncogenes were often acquired in the early decades of life. During a long latency, cancer-related genes were disrupted or amplified by complex rearrangements. The genomic landscape was different between subgroups-EGFR-mutant LADCs had frequent whole-genome duplications with p53 mutations, whereas fusion-oncogene-driven LADCs had frequent SETD2 mutations. Our study highlights LADC oncogenesis driven by endogenous mutational processes.

Nanosome-Mediated Delivery Of Hdac Inhibitors and Oxygen Molecules for the Transcriptional Reactivation of Latent Hiv-Infected Cd4+ T Cells.

The treatment of human immunodeficiency virus (HIV) infection is notoriously difficult due to the ability of this virus to remain latent in the host's CD4+ T cells. Histone deacetylases (HDACs) interfere with DNA transcription in HIV-infected hosts, resulting in viral latency. Therefore, HDAC inhibitors can be used to activate viral transcription in latently infected cells, after which the virus can be eliminated through a shock-and-kill strategy. Here, a drug delivery system is developed to effectively deliver HDAC inhibitors to latent HIV-infected cells. Given that the efficacy of HDAC inhibitors is reduced under hypoxic conditions, oxygen-containing nanosomes are used as drug carriers. Oxygen-containing nanosomes can improve the efficiency of chemotherapy by delivering essential oxygen to cells. Additionally, their phospholipid bilayer structure makes them uniquely well-suited for drug delivery. In this study, a novel drug delivery system is developed by taking advantage of the oxygen carriers in these oxygen nanosomes, incorporating a multi-drug strategy consisting of HDAC inhibitors and PKA activators, and introducing CXCR4 binding peptides to specifically target CD4+ T cells. Oxygen nanosomes with enhanced targeting capability through the introduction of the CXCR4 binding peptide mitigate drug toxicity and slow down drug release. The observed changes in the expression of p24, a capsid protein of HIV, indirectly confirm that the proposed drug delivery system can effectively induce transcriptional reactivation of HIV in latent HIV-infected cells.

Machine-Learning Algorithms Using Systemic Inflammatory Markers to Predict the Oncologic Outcomes of Colorectal Cancer After Surgery.

BACKGROUND: This study aimed to investigate the clinical significance of machine-learning (ML) algorithms based on serum inflammatory markers to predict survival outcomes for patients with colorectal cancer (CRC). METHODS: The study included 941 patients with stages I to III CRC. Based on random forest algorithms using 15 compositions of inflammatory markers, four different prediction scores (DFS score-1, DFS score-2, DFS score-3, and DFS score-4) were developed for the Yonsei cohort (training set, n = 803) and tested in the Ulsan cohort (test set, n = 138). The Cox proportional hazards model was used to determine correlation between prediction scores and disease-free survival (DFS). Harrell's concordance index (C-index) was used to compare the predictive ability of prediction scores for each composition. RESULTS: The multivariable analysis showed the DFS score-4 to be an independent prognostic factor after adjustment for clinicopathologic factors in both the training and test sets (hazard ratio [HR], 8.98; 95% confidence interval [CI] 6.7-12.04; P < 0.001 for the training set and HR, 2.55; 95% CI 1.1-5.89; P = 0.028 for the test set]. With regard to DFS, the highest C-index among single compositions was observed in the lymphocyte-to-C-reactive protein ratio (LCR) (0.659; 95% CI 0.656-0.662), and the C-index of DFS score-4 (0.727; 95% CI 0.724-0.729) was significantly higher than that of LCR in the test set. The C-index of DFS score-3 (0.725; 95% CI 0.723-0.728) was similar to that of DFS score-4, but higher than that of DFS score-2 (0.680; 95% CI 0.676-0.683). CONCLUSIONS: The ML-based approaches showed prognostic utility in predicting DFS. They could enhance clinical use of inflammatory markers in patients with CRC.

CT-defined visual emphysema in smokers with normal spirometry: association with prolonged air leak and other respiratory complications after lobectomy for lung cancer.

OBJECTIVES: To evaluate the association of visual emphysema on preoperative CT with respiratory complications and prolonged air leak (PAL) in smokers with normal spirometry who underwent lobectomy for lung cancer. METHODS: Among patients who underwent lobectomy for lung cancer between 2018 and 2019 at a single center, ever-smokers with normal spirometry were identified retrospectively. Visual emphysema was graded for centrilobular emphysema (CLE) and paraseptal emphysema (PSE), respectively, by two thoracic radiologists. The associations of visual emphysema with PAL and respiratory complications (except PAL) were investigated. RESULTS: In total, 282 patients were evaluated (257 men; mean age, 64.6 ± 9.8 years). Visual emphysema was present in 126 patients (44.7%) (CLE, 26; PSE, 40; combined CLE and PSE, 60). PAL and respiratory complications occurred in 34 (12.1%) and 26 patients (26.9%), respectively. Greater frequency of PAL and respiratory complications were observed in patients with higher grades of CLE (p = 0.002 for PAL; p = 0.039 for respiratory complications) and PSE (p < 0.001 for PAL; p < 0.001 for respiratory complications). For reader 1 evaluation, the presence of both CLE and PSE was associated with PAL (adjusted odds ratio [OR], 4.94; 95% confidence interval [CI], 1.75-13.95; p = 0.003). For reader 2 evaluation, PSE (adjusted OR, 4.26; 95% CI, 1.22-14.97; p = 0.024) and combined CLE and PSE (adjusted OR, 3.49; 95% CI, 12.1-10.06; p = 0.020) were associated with PAL. The presence of solely CLE was not associated with any adverse outcome (all p > 0.05) for both readers. CONCLUSIONS: Visual assessment of PSE in smokers with normal spirometry may help identify those who develop PAL after lobectomy. KEY POINTS: • Visual emphysema was highly prevalent (44.7%) in smokers with normal lung function who underwent lobectomy for lung cancer. • Increasing tendency of postoperative complications was observed as the grade of visual emphysema increased. • The presence of paraseptal emphysema was associated with prolonged air leak.

Inflammation-sensing catalase-mimicking nanozymes alleviate acute kidney injury via reversing local oxidative stress.

BACKGROUND: The reactive oxygen species (ROS) and inflammation, a critical contributor to tissue damage, is well-known to be associated with various disease. The kidney is susceptible to hypoxia and vulnerable to ROS. Thus, the vicious cycle between oxidative stress and renal hypoxia critically contributes to the progression of chronic kidney disease and finally, end-stage renal disease. Thus, delivering therapeutic agents to the ROS-rich inflammation site and releasing the therapeutic agents is a feasible solution. RESULTS: We developed a longer-circulating, inflammation-sensing, ROS-scavenging versatile nanoplatform by stably loading catalase-mimicking 1-dodecanethiol stabilized Mn3O4 (dMn3O4) nanoparticles inside ROS-sensitive nanomicelles (PTC), resulting in an ROS-sensitive nanozyme (PTC-M). Hydrophobic dMn3O4 nanoparticles were loaded inside PTC micelles to prevent premature release during circulation and act as a therapeutic agent by ROS-responsive release of loaded dMn3O4 once it reached the inflammation site. CONCLUSIONS: The findings of our study demonstrated the successful attenuation of inflammation and apoptosis in the IRI mice kidneys, suggesting that PTC-M nanozyme could possess promising potential in AKI therapy. This study paves the way for high-performance ROS depletion in treating various inflammation-related diseases.

Association of Adipopenia at Preoperative PET/CT with Mortality in Stage I Non-Small Cell Lung Cancer.

Background Body mass index (BMI) and sarcopenia status are well-established prognostic factors in patients with lung cancer. However, the relationship between the amount of adipose tissue and survival remains unclear. Purpose To investigate the association between baseline adipopenia and outcomes in patients with early-stage non-small cell lung cancer (NSCLC). Materials and Methods Consecutive patients who underwent surgical resection for stage I NSCLC between 2011 and 2015 at a single tertiary care center were retrospectively identified. The primary outcome was the 5-year overall survival (OS) rate, and secondary outcomes were the 5-year disease-free survival (DFS) rate and the major postoperative complication rate. The abdominal total fat volume at the waist and the skeletal muscle area at the L3 level were obtained from preoperative PET/CT data and were normalized by the height squared to calculate the fat volume index (FVI) and skeletal muscle index. Adipopenia was defined as the sex-specific lowest quartile of the FVI for the study sample, and sarcopenia was determined using the skeletal muscle index reference value (men, <55 cm2/m2; women, <39 cm2/m2). The association between body composition and outcomes was evaluated using Cox regression analysis. Results A total of 440 patients (median age, 65 years [interquartile range, 58-72 years]; 243 men) were evaluated. Most underweight patients (<20 kg/m2) had adipopenia (97%, 36 of 37 patients), but overweight patients (25-30 kg/m2, n = 138) and obese patients (>30 kg/m2, n = 14) did not have adipopenia (3%, four of 152 patients). In the group with a normal BMI (20-25 kg/m2), 28% (70 of 251 patients) had adipopenia and 67% (168 of 251 patients) had sarcopenia. After adjusting for age, sex, smoking history, surgical procedure, stage, histologic type, BMI, and sarcopenia, adipopenia was associated with reduced 5-year OS (hazard ratio [HR] = 2.2; 95% CI: 1.1, 3.8; P = .02) and 5-year non-cancer-specific OS rates (HR = 3.2; 95% CI: 1.2, 8.7; P = .02). There was no association between adipopenia and postoperative complications (P = .45) or between adipopenia and the 5-year DFS rate (P = .18). Conclusion Baseline adipopenia was associated with a reduced 5-year overall survival rate in patients with early-stage non-small cell lung cancer and may indicate risk for non-cancer-related death. © RSNA, 2021 Online supplemental material is available for this article.

Glycol chitosan-based tacrolimus-loaded nanomicelle therapy ameliorates lupus nephritis.

BACKGROUND: Recently, we developed hydrophobically modified glycol chitosan (HGC) nanomicelles loaded with tacrolimus (TAC) (HGC-TAC) for the targeted renal delivery of TAC. Herein, we determined whether the administration of the HGC-TAC nanomicelles decreases kidney injury in a model of lupus nephritis. Lupus-prone female MRL/lpr mice were randomly assigned into three groups that received intravenous administration of either vehicle control, an equivalent dose of TAC, or HGC-TAC (0.5 mg/kg TAC) weekly for 8 weeks. Age-matched MRL/MpJ mice without Faslpr mutation were also treated with HGC vehicle and used as healthy controls. RESULTS: Weekly intravenous treatment with HGC-TAC significantly reduced genetically attributable lupus activity in lupus nephritis-positive mice. In addition, HGC-TAC treatment mitigated renal dysfunction, proteinuria, and histological injury, including glomerular proliferative lesions and tubulointerstitial infiltration. Furthermore, HGC-TAC treatment reduced renal inflammation and inflammatory gene expression and ameliorated increased apoptosis and glomerular fibrosis. Moreover, HGC-TAC administration regulated renal injury via the TGF-ß1/MAPK/NF-κB signaling pathway. These renoprotective effects of HGC-TAC treatment were more potent in lupus mice compared to those of TAC treatment alone. CONCLUSION: Our study indicates that weekly treatment with the HGC-TAC nanomicelles reduces kidney injury resulting from lupus nephritis by preventing inflammation, fibrosis, and apoptosis. This advantage of a new therapeutic modality using kidney-targeted HGC-TAC nanocarriers may improve drug adherence and provide treatment efficacy in lupus nephritis mice.

Outcomes of adjunctive surgery for nontuberculous mycobacterial pulmonary disease.

BACKGROUND: Owing to the unsatisfactory results of antibiotic treatment alone, surgical resection is currently considered as adjunctive therapy in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD). However, reports regarding the outcomes of surgery vary considerably by institution. Here, we investigated the surgical outcomes and risk factors associated with unfavorable outcomes after surgery. METHODS: We analyzed patients with NTM-PD who underwent pulmonary resection at Seoul National University Hospital between January 1, 2006, and December 31, 2020, and assessed the types of surgical procedures, complications, and long-term outcomes. Multivariate logistic regression analysis was used to identify the risk factors associated with treatment refractoriness or recurrence after surgery. RESULTS: Among 67 patients who underwent surgery during the study period, the most common indication for surgery was persistent culture positivity despite rigorous medical treatment (80.6%), followed by longstanding cavitary lesions or radiographic aggravation (10.4%) and massive hemoptysis (4.5%). Among 53 patients with positive mycobacterial cultures at the time of surgery, 38 (71.7%) achieved initial negative culture conversion, 9 (17.0%) of whom experienced recurrence. Nine (13.4%) patients experienced postoperative complications, which were managed without lasting morbidity and mortality. Female sex (adjusted odds ratio [aOR] 6.63; 95% confidence interval [CI] 1.04-42.4; P = .046), preoperative positive mycobacterial culture (aOR 5.87; 95 %CI 1.04-33.08; P = .045), and residual lesions (aOR 6.86; 95 %CI 1.49-31.56; P = .013) were associated with refractoriness or recurrence. CONCLUSIONS: Pulmonary resection is a reasonable treatment modality for patients with refractory NTM-PD or major complications such as massive hemoptysis. The potential risk factors associated with unfavorable outcomes included female sex, preoperative positive mycobacterial culture, and residual lesions after surgery.

Vimentin Targeted Nano-gene Carrier for Treatment of Renal Diseases.

BACKGROUND: Chronic kidney disease (CKD) is a global health problem, and there is no permanent treatment for reversing kidney failure; thus, early diagnosis and effective treatment are required. Gene therapy has outstanding potential; however, the lack of safe gene delivery vectors, a reasonable transfection rate, and kidney targeting ability limit its application. Nanoparticles can offer innovative ways to diagnose and treat kidney diseases as they facilitate targetability and therapeutic efficacy. METHODS: Herein, we developed a proximal renal tubule-targeting gene delivery system based on alternative copolymer (PS) of sorbitol and polyethyleneimine (PEI), modified with vimentin-specific chitobionic acid (CA), producing PS-conjugated CA (PSC) for targeting toward vimentin-expressing cells in the kidneys. In vitro studies were used to determine cell viability, transfection efficiency, serum influence, and specific uptake in the human proximal renal tubular epithelial cell line (HK-2). Finally, the targeting efficiency of the prepared PSC gene carriers was checked in a murine model of Alport syndrome. RESULTS: Our results suggested that the prepared polyplex showed low cytotoxicity, enhanced transfection efficiency, specific uptake toward HK-2 cells, and excellent targeting efficiency toward the kidneys. CONCLUSION: Collectively, from these results it can be inferred that the PSC can be further evaluated as a potential gene carrier for the kidney-targeted delivery of therapeutic genes for treating diseases.

Indocyanine Green Fluorescence Imaging-Guided Laparoscopic Surgery Could Achieve Radical D3 Dissection in Patients With Advanced Right-Sided Colon Cancer.

BACKGROUND: The optimal lymph node dissection with central vascular ligation is an important part for oncological outcomes after laparoscopic right-sided colon cancer surgery. Few studies have examined the clinical value of indocyanine green fluorescence imaging-guided D3 dissection for right-sided colon cancer. OBJECTIVES: We assessed the clinical value of indocyanine green fluorescence imaging-guided laparoscopic surgery in improving the radicality of lymph node dissection for right-sided colon cancer by comparing the outcomes of conventional laparoscopic surgery. DESIGN: The data were retrospectively reviewed and analyzed. SETTING: This study was conducted at a single university hospital. PATIENTS: A 1:2 matched case-control study included 25 patients undergoing fluorescence imaging-guided laparoscopic surgery and 50 patients undergoing conventional laparoscopic surgery for clinical T3 or T4 right-sided colon cancer between June 2016 and December 2017. MAIN OUTCOME MEASURES: The extent of D3 dissection and pathological results (tumor stage, lymph node yield, and number of metastatic lymph nodes) were analyzed. RESULTS: The 2 groups were similar in baseline characteristics. The numbers of harvested pericolic and intermediate lymph nodes were not different between the 2 groups. The numbers of central lymph nodes (14 vs 7, p < 0.001) and total harvested lymph nodes (39 vs 30, p = 0.003) were significantly higher in the fluorescence group than in the conventional group. In the multivariate analysis, the use of indocyanine green fluorescence imaging was an independently related factor for the retrieval of higher numbers of overall and central lymph nodes. The number of metastatic lymph nodes was not significantly different between the 2 groups. LIMITATIONS: The results of this study were limited by its small patient numbers and retrospective nature. CONCLUSIONS: Real-time indocyanine green fluorescence imaging of lymph nodes may improve the performance of more radical D3 lymph node dissection during laparoscopic right hemicolectomy for advanced right-sided colon cancer. See Video Abstract at http://links.lww.com/DCR/B150. LA CIRUGÍA LAPAROSCÓPICA GUIADA POR IMÁGENES DE FLUORESCENCIA VERDE INDOCIANINA PODRÍA LOGRAR UNA DISECCIÓN RADICAL D3 EN PACIENTES CON CÁNCER DE COLON AVANZADO DEL LADO DERECHO: La disección óptima de los ganglios linfáticos con ligadura vascular central es una parte importante para los resultados oncológicos después de la cirugía laparoscópica de cáncer de colon del lado derecho. Pocos estudios han examinado el valor clínico de la disección D3 guiada por imágenes de fluorescencia verde indocianina para el cáncer de colon del lado derecho.Evaluamos el valor clínico de la cirugía laparoscópica guiada por imagen de fluorescencia verde indocianina para mejorar la radicalidad de la disección de ganglios linfáticos para el cáncer de colon del lado derecho mediante la comparación de los resultados de la cirugía laparoscópica convencional.Los datos se revisaron y analizaron retrospectivamente.Este estudio se realizó en un solo hospital universitario.Un estudio de casos y controles emparejado 1:2 incluyó a 25 pacientes sometidos a cirugía laparoscópica guiada por imágenes de fluorescencia y 50 pacientes sometidos a cirugía laparoscópica convencional para cáncer de colon derecho clínico T3 o T4 entre Junio de 2016 y Diciembre de 2017.Se analizó el alcance de la disección D3 y los resultados patológicos (estadio tumoral, rendimiento de los ganglios linfáticos y número de ganglios linfáticos metastásicos).Los dos grupos fueron similares en las características basicas. El número de ganglios linfáticos pericólicos e intermedios recolectados no fue diferente entre los dos grupos. El número de ganglios linfáticos centrales (14 vs 7, p < 0.001) y el total de ganglios linfáticos recolectados (39 vs 30, p = 0.003) fueron significativamente mayores en el grupo de fluorescencia que en el grupo convencional. En el análisis multivariante, el uso de imágenes de fluorescencia verde indocianina fue un factor independiente relacionado para la recuperación de un mayor número de ganglios linfáticos centrales y globales. El número de ganglios linfáticos metastásicos no fue significativamente diferente entre los dos grupos.Los resultados de este estudio fueron limitados por su pequeño número de pacientes y su naturaleza retrospectiva.Las imágenes de fluorescencia verde indocianina en tiempo real de los ganglios linfáticos pueden mejorar el rendimiento de la disección más radical de los ganglios linfáticos D3 durante la hemicolectomía derecha laparoscópica para el cáncer de colon avanzado del lado derecho. Consulte Video Resumen en http://links.lww.com/DCR/B150.

Non-steroidal anti-inflammatory drug-induced enteropathy as a major risk factor for small bowel bleeding: a retrospective study.

BACKGROUND: Small bowel (SB) bleeding accounts for 5% of all gastrointestinal (GI) bleeding cases and 80% of obscure GI bleeding cases. Although angioectasia is the common etiology of SB bleeding, nonsteroidal anti-inflammatory drug (NSAID)-induced SB lesions are also reported as a major cause in studies from Eastern countries. Herein, we assessed the frequency of occurrence of NSAID-induced SB lesions in Korean patients with obscure GI bleeding. METHODS: We retrospectively analyzed medical records of all consecutive patients aged ≥18 years who underwent capsule endoscopy from March 2018 to February 2019 at Ulsan University Hospital and Kosin University Gospel Hospital. RESULTS: Of the 83 subjects (all Korean; mean age ± standard deviation: 59 ± 18 years; age range: 18-84 years; men: n = 52; women: n = 31), 55 (66.2%) had stool with clear blood and 28 (33.8%) had normal stool with iron deficiency anemia. The detection rate of SB bleeding and lesions using capsule endoscopy was 72.3% (60 of 83 patients). A significantly higher frequency (40 of 51) of ulcerative/erosive lesions than other causes was observed in patients with inactive bleeding but visible SB lesions. As a result, NSAID-induced enteropathy accounted for 30.1% of 83 patients with obscure GI bleeding (25 of the all 60 SB bleeding cases). CONCLUSIONS: Contrary to what is reported for patients in Western countries, this study in Korean patients showed an improved diagnostic yield of capsule endoscopy for obscure GI bleeding and that NSAID-induced enteropathy was the most common etiology of SB bleeding. Aggressive small intestine examination is required for patients with unexplained GI bleeding.

Efficacy and Cost-effectiveness of Surgical Biopsy for Histologic Diagnosis of Indeterminate Nodules Suspected for Early Stage Lung Cancer: Comparison with Percutaneous Needle Biopsy.

BACKGROUND: Indeterminate pulmonary nodules (IPN) suspected for early stage lung cancer mandate accurate diagnosis. Both percutaneous needle biopsy (PCNB) and surgical biopsy (SB) are valuable options. The present study aimed to compare the efficacy and cost-effectiveness between PCNB and SB for IPN suspected for early stage lung cancer. METHODS: During January-November 2018, patients who underwent operation for IPN suspected for early stage lung cancer (SB group, n = 245) or operation after PCNB (PCNB group, n = 113) were included. Patient-level cost data were extracted from medical bills from the institution. Propensity score matching was performed between the two groups from a retrospectively-collected database. RESULTS: Fifteen patients (11.5%) had complications after PCNB; thirteen (11.5%) were not confirmed to have lung cancer through PCNB but underwent operation for IPN. In SB group, 172 (70.2%) and 7 (2.9%) patients underwent wedge resection and segmentectomy for SB, respectively; 66 patients (26.9%) underwent direct lobectomy without SB. After propensity score matching, 58 paired samples were produced. Most patients in PCNB group were admitted twice (n = 55, 94.8%). The average hospital stay was longer in PCNB group (12.9 ± 5.3 vs. 7.3 ± 3.0, P < 0.001). Though the cost of the operation was comparable (USD 12,509 ± 2,909 vs. 12,669 ± 3,334; P = 0.782), the total cost was higher for PCNB group (USD 14,403 ± 3,085 vs. 12,669 ± 3,334; P = 0.006). The average subcategory cost, which increases proportional to hospital stay, was higher in PCNB group, whereas the cost of operation and surgical materials were comparable between the two groups. CONCLUSION: Lung cancer operation following SB for IPN was associated with lesser cost, shorter hospital stays, and lesser admission time than lung cancer operation after PCNB. The increased cost and longer hospital stay appear largely related to the admission for PCNB.

The Biological Function and Therapeutic Potential of Exosomes in Cancer: Exosomes as Efficient Nanocommunicators for Cancer Therapy.

Cancer therapeutics must be delivered to their targets for improving efficacy and reducing toxicity, though they encounter physiological barriers in the tumor microenvironment. They also face limitations associated with genetic instability and dynamic changes of surface proteins in cancer cells. Nanosized exosomes generated from the endosomal compartment, however, transfer their cargo to the recipient cells and mediate the intercellular communication, which affects malignancy progression, tumor immunity, and chemoresistance. In this review, we give an overview of exosomes' biological aspects and therapeutic potential as diagnostic biomarkers and drug delivery vehicles for oncotherapy. Furthermore, we discuss whether exosomes could contribute to personalized cancer immunotherapy drug design as efficient nanocommunicators.

Intravitreal Injection of Liposomes Loaded with a Histone Deacetylase Inhibitor Promotes Retinal Ganglion Cell Survival in a Mouse Model of Optic Nerve Crush.

Various neuroprotective agents have been studied for the treatment of retinal ganglion cell (RGC) diseases, but issues concerning the side effects of systemically administered drugs and the short retention time of intravitreally injected drugs limit their clinical applications. The current study aimed to evaluate the neuroprotective effects of intravitreally injected trichostatin A (TSA)-loaded liposomes in a mouse model of optic nerve crush (ONC) and determine whether TSA-loaded liposomes have therapeutic potential in RGC diseases. The histone deacetylase inhibitor, TSA, was incorporated into polyethylene glycolylated liposomes. C57BL/6J mice were treated with an intravitreal injection of TSA-loaded liposomes and liposomes loaded with a lipophilic fluorescent dye for tracking, immediately after ONC injury. The expression of macroglial and microglial cell markers (glial fibrillary acidic protein and ionized calcium binding adaptor molecule-1), RGC survival, and apoptosis were assessed. We found that the liposomes reached the inner retina. Their fluorescence was detected for up to 10 days after the intravitreal injection, with peak intensity at 3 days postinjection. Intravitreally administered TSA-loaded liposomes significantly decreased reactive gliosis and RGC apoptosis and increased RGC survival in a mouse model of ONC. Our results suggest that TSA-loaded liposomes may help in the treatment of various RGC diseases.

Utilization of Polymer-Lipid Hybrid Nanoparticles for Targeted Anti-Cancer Therapy.

Cancer represents one of the most dangerous diseases, with 1.8 million deaths worldwide. Despite remarkable advances in conventional therapies, these treatments are not effective to completely eradicate cancer. Nanotechnology offers potential cancer treatment based on formulations of several nanoparticles (NPs). Liposomes and polymeric nanoparticle are the most investigated and effective drug delivery systems (DDS) for cancer treatment. Liposomes represent potential DDS due to their distinct properties, including high-drug entrapment efficacy, biocompatibility, low cost, and scalability. However, their use is restricted by susceptibility to lipid peroxidation, instability, burst release of drugs, and the limited surface modification. Similarly, polymeric nanoparticles show several chemical modifications with polymers, good stability, and controlled release, but their drawbacks for biological applications include limited drug loading, polymer toxicity, and difficulties in scaling up. Therefore, polymeric nanoparticles and liposomes are combined to form polymer-lipid hybrid nanoparticles (PLHNPs), with the positive attributes of both components such as high biocompatibility and stability, improved drug payload, controlled drug release, longer circulation time, and superior in vivo efficacy. In this review, we have focused on the prominent strategies used to develop tumor targeting PLHNPs and discuss their advantages and unique properties contributing to an ideal DDS.

Hyaluronan-Stabilized Redox-Sensitive Nanoassembly for Chemo-Gene Therapy and Dual T1/T2 MR Imaging in Drug-Resistant Breast Cancer Cells.

Tailoring combinatorial therapies along with real-time monitoring strategies has been the major focus of overcoming multidrug resistance in cancer. However, attempting to develop a multifunctional nanoplatform in a single construct leads to compromising therapeutic outcomes. Herein, we developed a simple, theranostic nanoassembly containing a hyaluronic acid-stabilized redox-sensitive (HART) polyethylenimine polyplex composed of a doxorubicin (DOX) intercalated Bcl-2 shRNA encoded plasmid along with a green-synthesized hausmannite (Mn3O4) and hematite (Fe3O4) nanoparticle (GMF). The highly stable HART nanoassembly has enhanced CD44-mediated intracellular uptake along with hyaluronidase (hylase) and redox-responsive drug-gene release. With Bcl-2 gene silencing induced by the successful delivery of HART in multidrug-resistant MCF7 breast cancer cells, the synergistic cytotoxic effect of Bcl-2 silencing and DOX was achieved. In addition, the HART nanoassembly containing GMF exhibited excellent dual MRI contrast (T1/T2) by reducing artifact signals. Overall, the HART nanoassembly with its enhanced theranostic properties has the potential to improve the therapeutic efficacy in future preclinical and clinical trials.

Sleeve Lobectomy for Non-Small Cell Lung Cancers: Predictive CT Features for Resectability and Outcome Analysis.

OBJECTIVE. The purpose of this study was to investigate the CT features predictive of resectability in sleeve lobectomy (SL) for patients with non-small cell lung cancers (NSCLCs) and the outcomes of this procedure. MATERIALS AND METHODS. The study included 45 patients with NSCLCs who planned to undergo SL as a first-line surgical option and underwent SL or pneumonectomy between February 2014 and July 2017. The patients were dichotomized according to whether SL was achieved without residual disease. ROC curve and logistic regression analyses were performed to identify CT features predictive of resectability in SL without residual disease. For outcome analysis, postoperative complications and survival were compared between the two patient groups. RESULTS. SL was successfully performed in 25 patients (55.6%), whereas eight patients underwent SL but had a positive resection margin and 12 required pneumonectomy. The AUC value of the tumor-involved length of the salvage bronchus for SL without residual disease was 0.802, with 5 mm considered the optimal cutoff for this tumor-involved length. A tumor-involved length of 5 mm or less for the salvage bronchus representing the distal anastomosis end in SL was the sole significant predictor for resectability in SL without residual disease in logistic regression analysis (odds ratio, 16.0; 95% CI, 3.7-69.6; p < 0.001). The group of patients who underwent SL without residual disease tended to have a more favorable survival outcome than patients who underwent SL but had residual disease or those who underwent pneumonectomy (p = 0.110), but postoperative complication rates were similar between the two patient groups (20.0% vs 25.0%, respectively). CONCLUSION. A tumor-involved salvage bronchus length of 5 mm or less was a CT feature predictive of resectability in SL without residual disease, which may improve the survival of patients with NSCLCs.

Effect of combining a recruitment maneuver with protective ventilation on inflammatory responses in video-assisted thoracoscopic lobectomy: a randomized controlled trial.

BACKGROUND: We hypothesized that the addition of a recruitment maneuver to protective ventilation (PVRM) would result in lower pulmonary and systemic inflammatory responses than traditional ventilation or protective ventilation (PV) alone in patients undergoing lung surgery. METHODS: Sixty patients who underwent scheduled thoracoscopic lobectomy were randomly assigned to three groups: traditional ventilation, PV, or PVRM. Ventilations were performed using a tidal volume of 10 mL/kg for the traditional ventilation group and either 8 mL/kg (two-lung) or 6 mL/kg (one-lung, OLV) with a positive end-expiratory pressure of 5 cm H2O for the PV and PVRM groups. The RM was performed 10 min after the start of OLV. Fiberoptic bronchoalveolar lavage (BAL) was performed twice in dependent and non-dependent lungs: before the start and immediately after the end of OLV. Blood samples were collected at the same time points. The levels of cytokines, including TNF-α, IL-1ß, IL-6, IL-8, and IL-10, were measured. RESULTS: After OLV, the level of TNF-α in the BAL fluid of dependent lungs was significantly higher in the PV than in the PVRM group (P = 0.049), whereas IL-1ß, IL-6, IL-8, and IL-10 levels were not significantly different among the groups. In non-dependent lung BAL fluid, no cytokines were significantly different among the groups. After OLV, IL-10 serum levels were significantly higher in the traditional ventilation than in the PVRM group (P = 0.027). CONCLUSIONS: Lower inflammatory responses in the ventilated lung and serum were observed with PVRM than with traditional ventilation or PV alone. Larger multi-center clinical trials are warranted to confirm the effects of different ventilatory strategies on postoperative outcomes.

Long-term oncologic after robotic versus laparoscopic right colectomy: a prospective randomized study.

OBJECTIVE: The aim of this study was to compare the long-term outcomes of robot-assisted right colectomy (RAC) with those for conventional laparoscopy-assisted right surgery (LAC) for treating right-sided colon cancer. BACKGROUND: The enthusiasm for the robotic techniques has gained increasing interest in colorectal malignancies. However, the role of robotic surgery in the oncologic safety has not yet been defined. METHODS: From September 2009 to July 2011, 71 patients with right-sided colonic cancer were randomized in the study. Adjuvant therapy and postoperative follow-up were similar in both groups. The primary and secondary endpoints of the study were hospital stay and survival, respectively. Data were analyzed by intention-to-treat principle. RESULTS: The RAC and LAC groups did not differ significantly in terms of baseline clinical characteristics. Compared with the LAC group, RAC was associated with longer operation times (195 min vs. 129 min, P < 0.001) and higher cost ($12,235 vs. $10,319, P = 0.013). The median follow-up was 49.23 months (interquartile range 40.63-56.20). The combined 5-year disease-free rate for all tumor stages was 77.4% (95% confidence interval [CI], 60.6-92.1%) in the RAC group and 83.6% (95% CI 72.1-0.97.0%) in the LAC group (P = 0.442). The combined 5-year overall survival rates for all stages were 91.1% (95% CI 78.8-100%) in the RAC group and 91.0% (95% CI 81.3-100%) in the LAC group (P = 0.678). Using multivariate analysis, RAC was not a predictor of recurrence. CONCLUSIONS: RAC appears to similar long-term survival as compared with LAC. However, we did not observe any clinical benefits of RAC which could translate to a decrease in expenditures. TRIAL REGISTRY: http://www.ClinicalTrials.gov , number NCT00470951.

Role of Immunosuppressive Microenvironment in Acquiring Immunotolerance Post-Photothermal Therapy.

BACKGROUND: Nanoparticle-mediated photothermal therapy (PTT) has been well studied as a treatment for cancer. However, the therapeutic outcome of PTT is often hindered by the penetration depth of laser light. In the tumor margin beyond the laser penetration limit, tumor recurrence often occurs, bypassing the immune response of the host. Accumulating evidence suggests the prominent role of tumor microenvironment (TME) and its interactions with the immune components contribute to an immunosuppressive milieu during the post-therapy period. Here, we explored the immunosuppressive cascade generated after PTT, which is responsible for tumor recurrence, and identified the potential targets to achieve an effective PTT period. METHODS: Here, we investigated the immunosuppressive cascade generated after PTT in a CT26 tumor bearing mouse. The liposomal system loaded with the indocyanine green (ICG) was utilized for the generation of PTT with high efficiency. Immunological factors such as cytokines and protein expressions post-therapy were investigated through enzyme-linked immunosorbent assay, flow cytometry and western blot analysis. RESULTS: Our results suggested that PTT with ICG-loaded liposomes (Lipo-ICG) was effective for the first 5 days after treatment, resulting in tumor suppression. However, an immunosuppressive and pro-inflammatory environment developed thereafter, causing the recruitment and upregulation of the immune evasion factors of heat shock protein 70, programmed death ligand 1, indoleamine-dioxygenase, interleukin-6, transforming growth factor-ß, regulatory T-cells, and myeloid-derived suppressor cells, to develop immunotolerance. CONCLUSION: Collectively, these findings have determined potential therapeutic targets to modulate the TME during PTT and achieve tumor ablation without remission.