Pitavastatin sensitizes the EGFR-TKI associated resistance in lung cancer by inhibiting YAP/AKT/BAD-BCL-2 pathway.

BACKGROUND: Despite effective strategies, resistance in EGFR mutated lung cancer remains a challenge. Metabolic reprogramming is one of the main mechanisms of tumor drug resistance. A class of drugs known as "statins" inhibit lipid cholesterol metabolism and are widely used in patients with cardiovascular diseases. Previous studies have also documented its ability to improve the therapeutic impact in lung cancer patients who receive EGFR-TKI therapy. Therefore, the effect of statins on targeted drug resistance to lung cancer remains to be investigated. METHODS: Prolonged exposure to gefitinib resulted in the emergence of a resistant lung cancer cell line (PC9GR) from the parental sensitive cell line (PC9), which exhibited a traditional EGFR mutation. The CCK-8 assay was employed to assess the impact of various concentrations of pitavastatin on cellular proliferation. RNA sequencing was conducted to detect differentially expressed genes and their correlated pathways. For the detection of protein expression, Western blot was performed. The antitumor activity of pitavastatin was evaluated in vivo via a xenograft mouse model. RESULTS: PC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC9 cells, and the YAP expression was inhibited by pitavastatin administration. With YAP RNA interference, pAKT, pBAD and BCL-2 expression was decreased, while BAX expression as increased. Accordingly, YAP down-regulated significantly increased apoptosis and decreased the survival rate of gefitinib-resistant lung cancer cells. After pAKT was increased by SC79, apoptosis of YAP down-regulated cells induced by gefitinib was decreased, and the cell survival rate was increased. Mechanistically, these effects of pitavastatin are associated with the YAP pathway, thereby inhibiting the downstream AKT/BAD-BCL-2 signaling pathway. CONCLUSION: Our study provides a molecular basis for the clinical application of the lipid-lowering drug pitavastatin enhances the susceptibility of lung cancer to EGFR-TKI drugs and alleviates drug resistance.

Air pollution and the burden of long-term care: Evidence from China.

We examine the causal effects of PM2.5 exposure on the burden of long-term care (LTC) by matching a satellite-based PM2.5 (particulate matter smaller than 2.5 micrometers (µm) in diameter) dataset with a nationally representative longitudinal study in China from 2011 to 2018. We find significant adverse effects of PM2.5 exposure-instrumented by thermal inversions-on the LTC burden. A 10 µg/m3 increase in annual PM2.5 exposure increases average monthly hours of LTC and the associated financial costs by 28 h and CNY 452, respectively. The effects are greater for those who had never smoked nor experienced severe PM2.5 pollution (annual average PM2.5 > 35 µg/m3) in the previous 5 years. We also find that as PM2.5 increases, chronic diseases, particularly cardiovascular diseases, could lead to a higher likelihood of LTC dependency but reduce the total hours and costs of LTC provision. Finally, we find that PM2.5 reduces the total years of LTC need, suggesting that PM2.5 increases LTC costs by increasing the severity of LTC dependency, rather than the duration of LTC need. Our findings can assist policymakers in planning for LTC provisions and clean air policies.

Predictive effect of the systemic inflammation response index (SIRI) on the efficacy and prognosis of neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer.

BACKGROUND: Inflammation is a part of tumours, and inflammatory cells can affect the proliferation, invasion, and development of tumour cells. An increasing number of peripheral blood inflammatory markers have been found to play very important roles in the treatment and prognosis of cancer patients. The systemic inflammatory response index (SIRI) is a newer inflammatory marker, and its role in colorectal cancer, especially in locally advanced rectal cancer, is still unclear. METHODS: From 2015 to 2020, 198 patients with locally advanced rectal cancer (LARC) who underwent surgery following neoadjuvant chemoradiotherapy (Neo-CRT) were analysed. Patients were categorized into good- and poor- response groups according to their pathological results, and clinical characteristics and baseline parameters were compared between the two groups. The optimal cutoff values for inflammatory indicators were determined using receiver operating characteristic (ROC) analysis. Univariate and multivariate analyses were performed using the Cox proportional hazard model. Survival analysis was performed via the Kaplan‒Meier method. RESULTS: After patients were grouped into good and poor response groups, indicator differences were found in CEA, neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and SIRI. According to the ROC analysis, the NLR (P = 0.015), SII (P = 0.001), and SIRI (P = 0.029) were significant prognostic factors. After univariate and multivariate analyses of the Cox proportional hazards regression model, only the SIRI was found to be an independent prognostic factor for overall survival (OS) and disease-free survival (DFS). Finally, Kaplan‒Meier survival curves also confirmed the ability of the SIRI to predict survival. CONCLUSION: The preoperative SIRI can be used to predict the response to Neo-CRT in LARC patients and is an independent predictor of OS and DFS in postoperative patients. A high SIRI was associated with poor radiotherapy response and predicted poor OS and DFS.

Photonic compressive sampling of wideband sparse radio frequency signals with 1-bit quantization.

Photonic compressive sampling (PCS) is an effective method to recover wideband sparse radio frequency (RF) signals. However, the noisy and high-loss photonic link leads to signal-to-noise ratio (SNR) degradation of the RF signal to be tested, which limits the recovery performance of the PCS system. In this paper, a random demodulator-based PCS system with 1-bit quantization is proposed. The system consists of a photonic mixer, a low-pass filter, a 1-bit analog-to-digital converter (ADC), and a digital signal processor (DSP). The 1-bit quantized result is used to recover the spectra of the wideband sparse RF signal with the binary iterative hard thresholding (BIHT) algorithm, which can alleviate the negative impact of the SNR degradation caused by the photonic link. A full theoretical framework of the PCS system with 1-bit quantization is given. Simulation results show that the PCS system with 1-bit quantization can provide better recovery performance than the traditional PCS system under low SNR and stringent bit budget.

Photonic distributed compressive sampling of multi-node wideband sparse radio frequency signals.

A photonic distributed compressive sampling (PDCS) approach for identifying the spectra of multi-node wideband sparse signals is proposed. The scheme utilizes wavelength division multiplexing (WDM) technology to transmit multi-node signals to a central station, where distributed compressive sampling (DCS) based on the random demodulator (RD) model is employed to simultaneously identify the signal spectrum. By exploiting signal correlations among nodes, DCS achieves a higher compression ratio of the sampling rate than single-node compressive sampling (CS). In a semi-physical simulation experiment, we demonstrate the feasibility of the approach by recovering the spectra of two wideband sparse signals from nodes located 20 km and 10 km away. The spectra of two signals with a mixed support-set sparsity of 2 and 4 are recovered with a compression ratio of 8 and 4, respectively. We further investigate the impact of common parts and the number of nodes on PDCS performance through numerical simulation. The proposed system takes advantage of the ultra-high bandwidth of photonic technology and the low loss of optical fiber transmission, making it suitable for long-distance, multi-node, and large-coverage electromagnetic spectrum identification.

Time to surgery does not affect oncologic outcomes in locally advanced gastric cancer after neoadjuvant chemotherapy: a meta-analysis.

Aim: The authors conducted a meta-analysis to determine the association between time-to-surgery (TTS) after neoadjuvant chemotherapy and patient outcomes in locally advanced gastric cancer. Methods: Electronic databases were searched to identify potential studies, in which the authors compared patient outcomes between those with TTS within 4 (and 6) weeks of completion of neoadjuvant chemotherapy and those after 4 (and 6) weeks. Results: Six studies, including 1238 patients, were eligible for inclusion. Pooled data showed no significant differences in rates of pathological complete response, major pathological response, ypN0, complications, R0 resection and operative time between groups of longer TTS and shorter TTS. Conclusion: There was no statistically advantageous impact of prolonged TTS on pathological and surgical outcomes. Large, population-based studies are warranted.

A 9­gene expression signature to predict stage development in resectable stomach adenocarcinoma.

BACKGROUND: Stomach adenocarcinoma (STAD) is a highly heterogeneous disease and is among the leading causes of cancer-related death worldwide. At present, TNM stage remains the most effective prognostic factor for STAD. Exploring the changes in gene expression levels associated with TNM stage development may help oncologists to better understand the commonalities in the progression of STAD and may provide a new way of identifying early-stage STAD so that optimal treatment approaches can be provided. METHODS: The RNA profile retrieving strategy was utilized and RNA expression profiling was performed using two large STAD microarray databases (GSE62254, n = 300; GSE15459, n = 192) from the Gene Expression Omnibus (GEO) and the RNA-seq database within the Cancer Genome Atlas (TCGA, n = 375). All sample expression information was obtained from STAD tissues after radical resection. After excluding data with insufficient staging information and lymph node number, samples were grouped into earlier-stage and later-stage. Samples in GSE62254 were randomly divided into a training group (n = 172) and a validation group (n = 86). Differentially expressed genes (DEGs) were selected based on the expression of mRNAs in the training group and the TCGA group (n = 156), and hub genes were further screened by least absolute shrinkage and selection operator (LASSO) logistic regression. Receiver operating characteristic (ROC) curves were used to evaluate the performance of the hub genes in distinguishing STAD stage in the validation group and the GSE15459 dataset. Univariate and multivariate Cox regressions were performed sequentially. RESULTS: 22 DEGs were commonly upregulated (n = 19) or downregulated (n = 3) in the training and TCGA datasets. Nine genes, including MYOCD, GHRL, SCRG1, TYRP1, LYPD6B, THBS4, TNFRSF17, SERPINB2, and NEBL were identified as hub genes by LASSO-logistic regression. The model achieved discrimination in the validation group (AUC = 0.704), training-validation group (AUC = 0.743), and GSE15459 dataset (AUC = 0.658), respectively. Gene Set Enrichment Analysis (GSEA) was used to identify the potential stage-development pathways, including the PI3K-Akt and Calcium signaling pathways. Univariate Cox regression indicated that the nine-gene score was a significant risk factor for overall survival (HR = 1.28, 95% CI 1.08-1.50, P = 0.003). In the multivariate Cox regression, only SCRG1 was an independent prognostic predictor of overall survival after backward stepwise elimination (HR = 1.21, 95% CI 1.11-1.32, P < 0.001). CONCLUSION: Through a series of bioinformatics and validation processes, a nine-gene signature that can distinguish STAD stage was identified. This gene signature has potential clinical application and may provide a novel approach to understanding the progression of STAD.

Optimized tools and timing of response reassessment after neoadjuvant chemoradiation in rectal cancer.

PURPOSE: Reassessment tools of response to long-course neoadjuvant chemoradiation treatment (nCRT) in patients with locally advanced rectal cancer (LARC) are important in predicting complete response (CR) and thus deciding whether a wait-and-watch strategy can be implemented in these patients. Choosing which routine reassessment tools are optimal and when to use them is still unclear and will be researched in the study. METHODS: Altogether, 250 patients with LARC who received nCRT from 2013 to 2021 and were followed up were retrospectively reviewed. Common reassessment tools of response included digital rectal examination (DRE), clinical examination and symptoms, endoscopy, biopsy, magnetic resonance imaging (MRI), and blood biomarkers. RESULTS: Overall, 27.20% (68/250) patients had a complete response and 72.80% (182/250) did not. The combination of MRI, endoscopy, and biopsy showed the best performance in terms of accuracy of 74% and area under the curve (AUC, 0.714, 95% CI 0.546-0.882). Reassessing through DRE and presence of symptoms failed to improve the efficacy of response reassessment. After 100 days, biopsy as an assessment tool would obtain a substantial rise in accuracy from 51.28 to 100% (p = 0.003). CONCLUSION: The combination of MRI, endoscopy, and biopsy is suitable as the reassessment tool of response for applying a wait-and-watch strategy after long-course nCRT in patients with LARC. The accuracy of biopsy as reassessment tools would be improved if they were used over 100 days after nCRT in patients with rectal cancer.

Altered cardiac structure and function is related to seizure frequency in a rat model of chronic acquired temporal lobe epilepsy.

OBJECTIVE: This study aimed to prospectively examine cardiac structure and function in the kainic acid-induced post-status epilepticus (post-KA SE) model of chronic acquired temporal lobe epilepsy (TLE), specifically to examine for changes between the pre-epileptic, early epileptogenesis and the chronic epilepsy stages. We also aimed to examine whether any changes related to the seizure frequency in individual animals. METHODS: Four hours of SE was induced in 9 male Wistar rats at 10 weeks of age, with 8 saline treated matched control rats. Echocardiography was performed prior to the induction of SE, two- and 10-weeks post-SE. Two weeks of continuous video-EEG and simultaneous ECG recordings were acquired for two weeks from 11 weeks post-KA SE. The video-EEG recordings were analyzed blindly to quantify the number and severity of spontaneous seizures, and the ECG recordings analyzed for measures of heart rate variability (HRV). PicroSirius red histology was performed to assess cardiac fibrosis, and intracellular Ca2+ levels and cell contractility were measured by microfluorimetry. RESULTS: All 9 post-KA SE rats were demonstrated to have spontaneous recurrent seizures on the two-week video-EEG recording acquired from 11 weeks SE (seizure frequency ranging from 0.3 to 10.6 seizures/day with the seizure durations from 11 to 62 s), and none of the 8 control rats. Left ventricular wall thickness was thinner, left ventricular internal dimension was shorter, and ejection fraction was significantly decreased in chronically epileptic rats, and was negatively correlated to seizure frequency in individual rats. Diastolic dysfunction was evident in chronically epileptic rats by a decrease in mitral valve deceleration time and an increase in E/E` ratio. Measures of HRV were reduced in the chronically epileptic rats, indicating abnormalities of cardiac autonomic function. Cardiac fibrosis was significantly increased in epileptic rats, positively correlated to seizure frequency, and negatively correlated to ejection fraction. The cardiac fibrosis was not a consequence of direct effect of KA toxicity, as it was not seen in the 6/10 rats from separate cohort that received similar doses of KA but did not go into SE. Cardiomyocyte length, width, volume, and rate of cell lengthening and shortening were significantly reduced in epileptic rats. SIGNIFICANCE: The results from this study demonstrate that chronic epilepsy in the post-KA SE rat model of TLE is associated with a progressive deterioration in cardiac structure and function, with a restrictive cardiomyopathy associated with myocardial fibrosis. Positive correlations between seizure frequency and the severity of the cardiac changes were identified. These results provide new insights into the pathophysiology of cardiac disease in chronic epilepsy, and may have relevance for the heterogeneous mechanisms that place these people at risk of sudden unexplained death.

Treatment Switch in Poor Responders with Locally Advanced Gastric Cancer After Neoadjuvant Chemotherapy.

BACKGROUND: Among locally advanced gastric cancer (LAGC) patients, poor response to initial neoadjuvant chemotherapy (NAC) is associated with unfavorable outcomes; however, changing the postoperative therapy regimen in this group of patients is unclear. We compared the poor responders who continued the original protocols with that of patients who switched treatment after NAC plus D2 gastrectomy. METHODS: Our study included LAGC patients who achieved tumor regression grade 3 according to the American Joint Committee on Cancer/College of American Pathologists system, after NAC, between December 2006 and December 2017 at our institution. Outcomes were overall survival (OS), progression-free survival (PFS), and adverse events during postoperative treatment. The propensity score matching method was used to match patients. RESULTS: Overall, 160 patients were enrolled in the final analysis set, including 21 switched cases and 139 non-switched cases. A 1:2 matched cohort (21 switching vs. 42 non-switching) was generated to eliminate all confounding factors. No statistical differences were observed in OS and PFS, either in the whole patients (OS: log-rank p = 0.804; PFS: log-rank p = 0.943) or in the matched cohort (OS: log-rank p = 0.907; PFS: log-rank p = 0.670) between the two groups. Patients with changed regimens had a significantly higher rate of peripheral neurotoxicity (p = 0.045). Contrarily, a lower rate of overall adverse events was observed in the non-switching group with marginal significance (p = 0.069). CONCLUSION: Adjusting to a non-cross-resistant regimen only by post-NAC pathological evaluation may not be sufficient for designing an effective treatment route for LAGC poor responders. Treatment change required a more scrutinized clinical track, which involved a multifaceted assessment.

Short-term outcomes after totally laparoscopic total gastrectomy with esophagojejunostomy constructed by π-shaped method versus overlap method.

BACKGROUND: Regarding the overlap anastomosis and recently introduced π-shaped anastomosis, there is no consensus on which intracorporeal esophagojejunostomy (EJS) methods are preferred using linear stapler in totally laparoscopic total gastrectomy (TLTG). This study aims to evaluate the short-term outcomes using two methods. METHODS: Patients with upper gastric cancer underwent TLTG with either π-shaped (n = 48) or the modified overlap method using knotless barbed sutures (MOBS) (n = 37) were included in our study. Intraoperative and perioperative outcomes were compared. RESULTS: All patients achieved R0 resection margin. The overall esophagojejunal (E-J)-related complications rate was 7.06%. There was no significant difference between the two groups in terms of postoperative complications, margin distance, numbers of lymph nodes (LNs), length of stay. In the π-shaped group, anastomosis time (19.61 ± 7.17 min vs. 27.09 ± 3.59 min, p < 0.001) was significantly lower. The consumable costs for surgery were similar (44 507.74¥ [42 933.03-46 937.29] vs. 43 718.36¥ [42 743.25-47 256.06], p = 0.825). The first defection time was significantly longer in π-shaped group (131.00 h [93.75-171.25] vs. 100.00 h [85.00-120.00], p = 0.026), whereas the other postoperative recovery parameters were similar. No mortality was observed. CONCLUSIONS: Both methods showed similar short-term postoperative outcomes. The π-shaped technique was faster than the MOBS method without significantly increasing the supplies costs. Large prospective studies are warranted.

Combination of tumor markers predicts progression and pathological response in patients with locally advanced gastric cancer after neoadjuvant chemotherapy treatment.

BACKGROUND: The prognostic values of preoperative tumor markers (TMs) remain elusive in patients with locally advanced gastric cancer (LAGC) after neoadjuvant chemotherapy treatment (NACT). This study aimed to assess and establish a novel scoring system incorporating carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 72-4 (CA72-4) to enhance prognostic accuracy for progression-free survival (PFS) and pathological response (pCR). METHODS: Patients' data were retrospectively analyzed from December 2006 to December 2017 in our center. The cutoff value of TMs was determined using the time-dependent receiver operating test characteristics method. These three TMs were allocated 1 point each for the post neoadjuvant chemotherapy combination of tumor markers (post-NACT CTM) scores. The training group comprised 533 patients, responsible for full analysis, and the validation group comprised 137 patients based on the selection protocol. RESULTS: Of 533 enrolled patients, 138, 233, 117, and 45 patients scored 0, 1, 2, 3 respectively. The 3-year PFS rate Multivariate analysis revealed that post-NACT CTM score was an independent predictor of PFS (0 vs. 1, HR: 1.34, 95% CI: 0.92-1.96, P = 0.128; 0 vs. 2, HR: 2.03, 95% CI: 1.35-3.05, P = 0.001; 0 vs. 3, HR: 2.98, 95% CI: 1.83-4.86, P < 0.001). The time-dependent area under curve (AUC) revealed a consistent highest level for post-NACT CTM than other three single TMs. Lower post-NACT CTM score significantly correlated with higher pCR rate based on multivariate logistic regression (2/3 vs. 1, OR: 2.77, 95% CI: 0.90-8.53, P = 0.077; 2/3 vs. 0, OR: 4.33, 95% CI: 1.38-13.61, P = 0.012). A nomogram was formed with both internal and external validation. CONCLUSIONS: The post-NACT CTM score system served as a strong independent predictor for PFS and pCR in LAGC patients who received NACT. Further population-based studies are required to confirm our results.

Membranous Nephropathy in Pregnancy.

BACKGROUND: Primary membranous nephropathy (pMN) is less common in women of child-bearing age. The kidney risk factors to adverse maternal-fetal outcomes and the effects of pregnancy on pMN process need to be investigated. METHODS: We retrospectively screened all the patients with biopsy-proven pMN from 2008 to 2018. Any cases of pregnancy that occurred at the time of pMN diagnosis or during follow-up were included in the study. Clinical and pathological data were collected from all patients at the time of kidney biopsy and their gestational results were recorded. RESULTS: Of the 27 pregnancies with gestational time of 35.9 ± 4.5 weeks, 10 adverse maternal-fetal events occurred, including fetal loss (11%), preterm delivery (26%), and severe preeclampsia (15%). The kidney parameters were relatively stable with all preserved kidney function. Time-averaged urinary protein (p < 0.001) and serum albumin (p < 0.001), maximum urinary protein (p = 0.001) and minimum serum albumin (p = 0.01) before week 20, anti-phospholipase A2 receptor (PLA2R) positivity (p = 0.03), and no remission during pregnancy (p = 0.004) were risk factors to adverse maternal-fetal outcomes. Time-averaged urinary protein and serum albumin correlated with the birth weight percentile of neonates. CONCLUSIONS: Pregnancy in pMN patients showed risks to adverse maternal-fetal events. Heavy proteinuria, especially before week 20 of gestation, severe hypoalbuminemia, positive anti-PLA2R, and no remission were risk factors to worse outcomes.

Copper-Catalyzed Coupling of Sulfonamides with Alkylamines: Synthesis of (E)-N-Sulfonylformamidines.

Herein, we describe an efficient copper-catalyzed coupling of sulfonamides with alkylamines to synthesize (E)-N-sulfonylformamidines. The reaction is accomplished under mild conditions without the use of a corrosive acid or base as an additive. It tolerates a broad scope of substrates and generates the products with exclusive (E)-stereoselectivity.

Which obesity-associated parameters can better reflect the risk of the occurrence of the anastomotic leakage?

Purpose: We investigated which obesity-associated parameters can better predict the risk of anastomotic leakage (AL) in rectal cancer patients that underwent anterior resection of the rectum.Method: Patients (n = 589) who underwent anterior resection of the rectum with a primary anastomosis were included in this study, including 44 patients with AL and 545 without AL. Univariate analysis was used to compare demographic characteristics and to select risk factors that were used in one-to-one propensity score matching (PSM). Obesity-associated parameters, including preoperative body mass index (BMI), visceral fat area (VFA), subcutaneous fat area (SFA), total fat area (TFA), VFA/TFA ratio, serum cholesterol, and triglycerides, were compared between the two groups after PSM.Results: Sex, neoadjuvant chemotherapy, operation time, and anastomosis level from the anal verge were risk factors for AL (p < .05). After the PSM, BMI, VFA, SFA, TFA, VFA/TFA, and serum cholesterol showed no significant difference between the two group (p > .05). However, the level of serum triglycerides was an independent risk factor for AL (p = .024, odds ratio = 2.95).Conclusions: Serum triglycerides have potential as a predictive indicator for AL, which may improve the treatment and outcomes of patients with AL.

A Novel Ruthenium(II) Polypyridyl Complex Bearing 1,8-Naphthyridine as a High Selectivity and Sensitivity Fluorescent Chemosensor for Cu2+ and Fe3+ Ions.

A novel ruthenium(II) polypyridyl complex bearing 1,8-naphthyridine was successfully designed and synthesized. This complex was fully characterized by EI-HRMS, NMR, and elemental analyses. The recognition properties of the complex for various metal ions were investigated. The results suggested that the complex displayed high selectivity and sensitivity for Cu2+ and Fe3+ ions with good anti-interference in the CH3CN/H2O (1:1, v/v) solution. The fluorescent chemosensor showed obvious fluorescence quenching when the Cu2+ and Fe3+ ions were added. The detection limits of Cu2+ and Fe3+ were 39.9 nmol/L and 6.68 nmol/L, respectively. This study suggested that this Ru(II) polypyridyl complex can be used as a high selectivity and sensitivity fluorescent chemosensor for Cu2+ and Fe3+ ions.

A d-Peptide Ligand of Integrins for Simultaneously Targeting Angiogenic Blood Vasculature and Glioma Cells.

The current prognosis of glioma patients remains poor after intensive multimodal treatments, which is partially due to the existence of the blood-brain tumor barrier (BBTB). In the present study, a novel "bifunctional ligand" (termed DVS) was developed by retro-inverso isomerization. DVS is a ligand of integrins highly expressed on glioma cells and tumor neovasculature. DVS exhibited exceptional stability in serum and demonstrated significantly higher targeting efficiency for glioma and HUVEC cells compared with the parent L-peptide. As a result, DVS modified micelles (DVS-MS) exhibited high encapsulation efficiency of doxorubicin, ideal size distribution, and sustained release behavior of the payload. In vivo studies showed that DVS-MS could target and efficiently deliver fluorescence to tumor cells and tumor vasculature not only in the mice bearing subcutaneous tumors but also in those bearing intracranial tumors. Moreover, doxorubicin loaded DVS modified micelles exerted potent tumor growth inhibitory activity against subcutaneous and intracranial human glioma in comparison to drug loaded plain micelles and LVS modified micelles. Therefore, DVS appears to be a suitable targeting ligand with potential applications for glioma targeted drug delivery.

Intermolecular Amination of Unactivated C(sp3 )-H Bonds with Cyclic Alkylamines: Formation of C(sp3 )-N Bonds through Copper/Oxygen-Mediated C(sp3 )-H/N-H Activation.

The first example of intermolecular amination of unactivated C(sp3 )-H bonds by cyclic alkylamines mediated by Cu(OAc)2 /O2 is reported. This method avoids the use of benzoyloxyamines as the aminating reagent, which are normally prepared from alkylamines in extra steps. A variety of unnatural ß2, 2 -amino acid analogues are synthesized by this simple and efficient procedure. This approach offers a solution to the previous unmet challenge of C(sp3 )-H/N-H activation for the formation of C(sp3 )-N bonds.

Pd(II) -Catalyzed Intermolecular Amination of Unactivated C(sp(3) )-H Bonds.

Pd(II) -catalyzed intermolecular amination of unactivated C(sp(3) )-H bonds has been successfully developed for the first time. This method provides a new way to achieve the challenging intermolecular amination of unactivated C(sp(3) )-H bonds, producing a variety of unnatural ß(2) -amino carboxylic acid analogues. This C(sp(3) )-H amination protocol is demonstrated with a broad substrate scope, good functional-group tolerance, and chemoselectivity. It is operated without use of phosphine ligand or external oxidant.