Compound heterozygous B3GALNT2 mutations in a fetus with encephalocele: A case report.

An encephalocele is a congenital malformation characterized by protrusion of the intracranial contents through a cranial defect. We report that a fetus of a pregnant mother who had two consecutive pregnancies with ultrasound-detected encephalocele carried compound heterozygous variants in B3GALNT2 NM_152490.5:c.[1423C > T (p.Gln475Ter)]; [261-2A > G] of maternal and paternal origins, respectively, as confirmed by exome sequencing followed by Sanger sequencing validation. The present case implies that mutations in B3GALNT2, a well-known dystroglycanopathy causative gene, may result in a phenotype of neural tube defect, providing new insights into the clinical spectrum of B3GALNT2-related disorders. Our study may contribute to prenatal screening/diagnosis and genetic counseling of congenital brain malformations.

Elk1 enhances inflammatory cell infiltration and exacerbates acute lung injury/acute respiratory distress syndrome by suppressing Fcgr2b transcription.

OBJECTIVE: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with significant mortality rates. The role of Fcgr2b in the pathogenesis of ALI/ARDS is not fully elucidated. This study aimed to investigate the functions of Fcgr2b in ALI/ARDS and explore its underlying mechanisms. METHODS: Methods: In this study, rat models of ARDS and pulmonary microvascular endothelial cell (PMVEC) injury models were established through the administration of lipopolysaccharide (LPS). The expression levels of Fcgr2b and Elk1 were quantified in both LPS-induced ARDS rats and PMVECs. Subsequent gain- and loss-of-function experiments were conducted, followed by comprehensive assessments of lung tissue for pathomorphological changes, edema, glycogen storage, fibrosis, and infiltration of inflammatory cells. Additionally, bronchoalveolar lavage fluid was analyzed for T-helper 17 (Th17) cell infiltration, inflammatory response, and microvascular permeability to evaluate lung injury severity in ARDS models. Furthermore, the activity, cytotoxicity, apoptosis, and angiogenic potential of PMVECs were assessed to gauge cell injury. The interaction between Elk1 and Fcgr2b was also examined to confirm their regulatory relationship. RESULTS: In the context of LPS-induced ARDS and PMVEC injury, Fcgr2b expression was markedly reduced, whereas Elk1 expression was elevated. Overexpression of Fcgr2b led to a decrease in Th17 cell infiltration and mitigated lung tissue damage in ARDS models, in addition to reducing LPS-induced injury in PMVECs. Elk1 was found to suppress Fcgr2b transcription through the recruitment of histone 3 lysine 9 trimethylation (H3K9me3). Knockdown of Elk1 diminished Th17 cell infiltration and lung tissue damage in ARDS models, and alleviated LPS-induced injury in PMVECs, effects that were reversed upon Fcgr2b upregulation. CONCLUSION: Elk1 negatively regulates Fcgr2b transcription, thereby augmenting the inflammatory response and exacerbating lung injury in LPS-induced ALI/ARDS.

Impact of preoperative white blood cell count on outcomes in different stage colorectal cancer patients undergoing surgical resection: a single-institution retrospective cohort study.

PURPOSE: To explore the association between preoperative WBC count and the long-term survival outcomes and clinical outcomes in different stage patients who underwent surgical resection for colorectal cancer (CRC). PATIENTS AND METHODS: A cohort of 8121 Chinese patients who underwent surgical resection for CRC from January 1, 2008 to December 31, 2014 were enrolled as part of the retrospective cohort were retrospectively analyzed. Based on that the preoperative WBC optimal cut-off value was 7*109/L (7,000/µL), the high preoperative WBC group and the low preoperative WBC group was defined. Inverse probability of treatment weighting (IPTW) using the propensity score was used to reduce confounding. The impact of preoperative WBC count on overall survival (OS) and disease-free survival (DFS) was investigated using the Kaplan-Meier method and Univariate Cox proportional hazards models in different stage subgroup respectively. RESULTS: After IPTW, the clinical characters in the high preoperative WBC count group and the low preoperative WBC count group were balanced. Kaplan-Meier analysis showed that the 5-year OS rate were significantly lower in the high preoperative WBC count group overall, in stage II and IV. The 5-year DFS rate was significantly lower overall, in stage II and III in the high preoperative WBC count group. High preoperative WBC count was associated with poorer OS overall in stage II and stage IV. CONCLUSIONS: This study suggests that preoperative WBC count is an independent risk factor for survival in patients undergoing colorectal surgery and may need to consider the stage of cancer when applied to predict long-term adverse outcome prognosis.

Nanoengineered Red Blood Cells Loaded with TMPRSS2 and Cathepsin L Inhibitors Block SARS-CoV-2 Pseudovirus Entry into Lung ACE2+ Cells.

The enzymatic activities of Furin, Transmembrane serine proteinase 2 (TMPRSS2), Cathepsin L (CTSL), and Angiotensin-converting enzyme 2 (ACE2) receptor binding are necessary for the entry of coronaviruses into host cells. Precise inhibition of these key proteases in ACE2+ lung cells during a viral infection cycle shall prevent viral Spike (S) protein activation and its fusion with a host cell membrane, consequently averting virus entry to the cells. In this study, dual-drug-combined (TMPRSS2 inhibitor Camostat and CTSL inhibitor E-64d) nanocarriers (NCs) are constructed conjugated with an anti-human ACE2 (hACE2) antibody and employ Red Blood Cell (RBC)-hitchhiking, termed "Nanoengineered RBCs," for targeting lung cells. The significant therapeutic efficacy of the dual-drug-loaded nanoengineered RBCs in pseudovirus-infected K18-hACE2 transgenic mice is reported. Notably, the modular nanoengineered RBCs (anti-receptor antibody+NCs+RBCs) precisely target key proteases of host cells in the lungs to block the entry of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), regardless of virus variations. These findings are anticipated to benefit the development of a series of novel and safe host-cell-protecting antiviral therapies.

Cancer cell membrane-coated bacterial ghosts for highly efficient paclitaxel delivery against metastatic lung cancer.

Chemotherapy is one of the major approaches for the treatment of metastatic lung cancer, although it is limited by the low tumor delivery efficacy of anticancer drugs. Bacterial therapy is emerging for cancer treatment due to its high immune stimulation effect; however, excessively generated immunogenicity will cause serious inflammatory response syndrome. Here, we prepared cancer cell membrane-coated liposomal paclitaxel-loaded bacterial ghosts (LP@BG@CCM) by layer-by-layer encapsulation for the treatment of metastatic lung cancer. The preparation processes were simple, only involving film formation, electroporation, and pore extrusion. LP@BG@CCM owned much higher 4T1 cancer cell toxicity than LP@BG due to its faster fusion with cancer cells. In the 4T1 breast cancer metastatic lung cancer mouse models, the remarkably higher lung targeting of intravenously injected LP@BG@CCM was observed with the almost normalized lung appearance, the reduced lung weight, the clear lung tissue structure, and the enhanced cancer cell apoptosis compared to its precursors. Moreover, several major immune factors were improved after administration of LP@BG@CCM, including the CD4+/CD8a+ T cells in the spleen and the TNF-α, IFN-γ, and IL-4 in the lung. LP@BG@CCM exhibits the optimal synergistic chemo-immunotherapy, which is a promising medication for the treatment of metastatic lung cancer.

Oxygen Vacancy-Enriched Bi2SeO5 Nanosheets with Dual Mechanism for Ammonium-Ion Batteries.

Ammonium ions feature a light molar mass and small hydrated radius, and the interesting interaction between NH4+ and host materials has attracted widespread attention in aqueous energy storage, while few studies focus on high-performance NH4+ storage anodes. Herein, we present a high-performance inset-type anode for aqueous ammonium-ion batteries (AIBs) based on Bi2SeO5 nanosheets. A reversible NH4+/H+ co-intercalation/deintercalation accompanied by hydrogen bond formation/breaking and a conversion reaction mechanism in layered Bi2SeO5 is proposed according to ex situ characterizations. Accordingly, the optimized Bi2SeO5 anode has a high reversible capacity of 341.03 mAh g-1 at 0.3 A g-1 in 1 M NH4Cl electrolyte and an impressive capacity retention of 86.7% after 7000 cycles at 3 A g-1, which is related to the existence of oxygen vacancies that enhance ion/electron transfer and promote the formation of hydrogen bonds between NH4+ and the host material. When the rocking-chair ammonium-ion battery is assembled using a MnO2 cathode, the device delivers an ultrahigh capacity of 140.73 mAh g-1 at 0.15 A g-1 and energy density of 207.13 Wh kg-1 at the power density of 2985.07 W kg-1. This work provides a promising strategy for designing high-performance anodes for next-generation AIBs.

Irf7 regulates the expression of Srg3 and ferroptosis axis aggravated sepsis-induced acute lung injury.

OBJECTIVE: To investigate the mechanism of action of Srg3 in acute lung injury caused by sepsis. METHODS: First, a sepsis-induced acute lung injury rat model was established using cecal ligation and puncture (CLP). RNA sequencing (RNA-seq) was used to screen for highly expressed genes in sepsis-induced acute lung injury (ALI), and the results showed that Srg3 was significantly upregulated. Then, SWI3-related gene 3 (Srg3) was knocked down using AAV9 vector in vivo, and changes in ALI symptoms in rats were analyzed. In vitro experiments were conducted by establishing a cell model using lipopolysaccharide (LPS)-induced BEAS-2B cells and coculturing them with phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells to analyze macrophage polarization. Next, downstream signaling pathways regulated by Srg3 and transcription factors involved in regulating Srg3 expression were analyzed using the KEGG database. Finally, gain-of-loss functional validation experiments were performed to analyze the role of downstream signaling pathways regulated by Srg3 and transcription factors involved in regulating Srg3 expression in sepsis-induced acute lung injury. RESULTS: Srg3 was significantly upregulated in sepsis-induced acute lung injury, and knocking down Srg3 significantly improved the symptoms of ALI in rats. Furthermore, in vitro experiments showed that knocking down Srg3 significantly weakened the inhibitory effect of LPS on the viability of BEAS-2B cells and promoted alternative activation phenotype (M2) macrophage polarization. Subsequent experiments showed that Srg3 can regulate the activation of the NF-κB signaling pathway and promote ferroptosis. Specific activation of the NF-κB signaling pathway or ferroptosis significantly weakened the effect of Srg3 knockdown. It was then found that Srg3 can be transcriptionally activated by interferon regulatory factor 7 (Irf7), and specific inhibition of Irf7 significantly improved the symptoms of ALI. CONCLUSIONS: Irf7 transcriptionally activates the expression of Srg3, which can promote ferroptosis and activate classical activation phenotype (M1) macrophage polarization by regulating the NF-κB signaling pathway, thereby exacerbating the symptoms of septic lung injury.

Ovariectomy induces hyperalgesia accompanied by upregulated estrogen receptor α and protein kinase B in the rat spinal cord.

Hormone supplementation is one of the common therapies for menopause-related disorders. Among different tools, the ovariectomy (OVX) rodents are widely accepted as an appropriate menopausal pain model. Our previous study has showed that OVX produces a significant pain facilitation in both acute pain and tonic pain, however, the underlying mechanisms remain unclear. In this study, we examined the effects of OVX treatment and estradiol (E2) supplementation on formalin-induced nociceptive responses, and explored the associated spinal mechanisms. Female Sprague-Dawley rats underwent bilateral OVX, and E2 supplementation was given subcutaneously from the 5th week after surgery (30 µg/day for 7 days). Our results showed that formalin-induced nociceptive behaviors did not differ between diestrus and proestrus stages of the estrous in intact rats. However, OVX exacerbated formalin-evoked inflammatory pain, especially in the late phase at 4-5 weeks but not 2 weeks post-surgery. E2 supplementation significantly reversed the OVX-triggered hyperalgesia. Double immunofluorescence staining revealed that both ERα and ERß in the spinal dorsal horn were co-labeled with the neuronal markers, but not with markers of astrocytes or microglia. The spinal ERα (but not ERß) expression significantly increased in the OVX group, which was reversed by E2 supplementation. Moreover, the OVX individuals showed an increased protein kinase B (AKT) level in lumbar spinal cord, and E2 supplementation diminished the AKT expression in OVX rats. Finally, intrathecal injection Wortmannin, an inhibitor for AKT signaling, effectively reduced the nociceptive behaviors in the late phase and the number of c-fos positive cells. Together, our findings indicate that E2 supplementation alleviates the OVX-induced hyperalgesia, which might be involved in spinal ERα and AKT mechanisms.

Identification of Immune Infiltration and Effective Immune Biomarkers in Acute Lung Injury by Bioinformatics Analysis.

Acute lung injury (ALI) is a serious complication in clinical settings. This study aimed to elucidate the immune molecular mechanisms underlying ALI by bioinformatics analysis. Human ALI and six ALI mouse model datasets were collected. Immune cell infiltration between the ALI samples and non-ALI controls was estimated using the ssGSEA algorithm. Least absolute shrinkage and selection operator (LASSO) regression analysis and Wilcoxon test were performed to obtain the significantly different immune cell infiltration types. Immune feature genes were screened by differential analysis and the weighted correlation network analysis (WGCNA) algorithm. Functional enrichment was then performed and candidate hub biomarkers were identified. Finally, the receiver operator characteristic curve (ROC) analysis was used to predict their diagnostic performances. Three significantly different immune cell types (B cells, CD4 T cells, and CD8 T cells) were identified between the ALI samples and controls. A total of 13 immune feature genes were obtained by WGCNA and differential analysis and found to be significantly associated with immune functions and lung diseases. Four hub genes, including CD180, CD4, CD74, and MCL1 were identified using cytoHubba and were shown to have good specificity and sensitivity for the diagnosis of ALI. Correlation analysis suggested that CD4 was positively associated with T cells, whereas MCL1 was negatively correlated with B and T cells. We found that CD180, CD4, CD74, and MCL1 can serve as specific immune biomarkers for ALI. MCL1-B cell, MCL1-T cell, and CD4-T cell axes may be involved in the progression of ALI.

Rational development of a combined mRNA vaccine against COVID-19 and influenza.

As the world continues to experience the COVID-19 pandemic, seasonal influenza remain a cause of severe morbidity and mortality globally. Worse yet, coinfection with SARS-CoV-2 and influenza A virus (IAV) leads to more severe clinical outcomes. The development of a combined vaccine against both COVID-19 and influenza is thus of high priority. Based on our established lipid nanoparticle (LNP)-encapsulated mRNA vaccine platform, we developed and characterized a novel mRNA vaccine encoding the HA antigen of influenza A (H1N1) virus, termed ARIAV. Then, ARIAV was combined with our COVID-19 mRNA vaccine ARCoV, which encodes the receptor-binding domain (RBD) of the SARS-CoV-2 S protein, to formulate the final combined vaccine, AR-CoV/IAV. Further characterization demonstrated that immunization with two doses of AR-CoV/IAV elicited robust protective antibodies as well as antigen-specific cellular immune responses against SARS-CoV-2 and IAV. More importantly, AR-CoV/IAV immunization protected mice from coinfection with IAV and the SARS-CoV-2 Alpha and Delta variants. Our results highlight the potential of the LNP-mRNA vaccine platform in preventing COVID-19 and influenza, as well as other respiratory diseases.

Gestational high-fat diet impaired demethylation of Pparα and induced obesity of offspring.

Gestational and postpartum high-fat diets (HFDs) have been implicated as causes of obesity in offspring in later life. The present study aimed to investigate the effects of gestational and/or postpartum HFD on obesity in offspring. We established a mouse model of HFD exposure that included gestation, lactation and post-weaning periods. We found that gestation was the most sensitive period, as the administration of a HFD impaired lipid metabolism, especially fatty acid oxidation in both foetal and adult mice, and caused obesity in offspring. Mechanistically, the DNA hypermethylation level of the nuclear receptor, peroxisome proliferator-activated receptor-α (Pparα), and the decreased mRNA levels of ten-eleven translocation 1 (Tet1) and/or ten-eleven translocation 2 (Tet2) were detected in the livers of foetal and adult offspring from mothers given a HFD during gestation, which was also associated with low Pparα expression in hepatic cells. We speculated that the hypermethylation of Pparα resulted from the decreased Tet1/2 expression in mothers given a HFD during gestation, thereby causing lipid metabolism disorders and obesity. In conclusion, this study demonstrates that a HFD during gestation exerts long-term effects on the health of offspring via the DNA demethylation of Pparα, thereby highlighting the importance of the gestational period in regulating epigenetic mechanisms involved in metabolism.

Mean effective volume of local anesthetics by nerve conduction technique.

BACKGROUND: This study aimed to investigate whether nerve conduction could be used to objectively evaluate mean effective volume of 1.5% lidocaine after subparaneural or extraparaneural injection. METHODS: Twenty patients undergoing unilateral foot or ankle surgery were randomized into either subparaneural or extraparaneural injection group, and ultrasound-guided continuous popliteal sciatic nerve block was performed. The action potential amplitude of the distal gastrocnemius muscle was monitored. The time of anesthesia onset and dosage of lidocaine were recorded when amplitude declined to 0.5 mV. The operative analgesic effect, score of numeric rating scales, patient's satisfaction, and movement or sensation were recorded during or after surgery. RESULTS: Preoperative dose of local anesthetics (10.7±1.6 vs. 16.2±1.2 mL) and the time of onset (19.4±3.3 vs. 30.4±2.5 min) reduced significantly in the subparaneural group (P<0.05). The intra-operative analgesic effect (1.2±0.422 vs. 1.3±0.483) and the score of resting numeric rating scales (0.6±1.0 vs. 1.9±2.1 and 0.4±0.7 vs. 1.2±1.1) 24 and 48 h after surgery were comparable between groups, but the subparaneural group had markedly lower scores of activity numeric rating scales (0.3±0.6 vs. 2.1±2.0, 0.7±1.2 vs. 2.2±1.9 and 0.5±0.8 vs. 1.5±1.2) at 6, 24 and 48 h, and significantly higher satisfaction (9.7±0.5 vs. 8.8±0.8) (P<0.05). There were no obvious symptoms of movement or sensation within 3 days in two groups. CONCLUSIONS: The nerve conduction can be used to objectively evaluate the mean effective volume of 1.5% lidocaine in different injection groups, and subparaneural injection has more advantages as compared to extraparaneural injection for continuous popliteal sciatic nerve block.

Factors Associated With Minimum Effective Volume of Lidocaine 1.5% for Sciatic Nerve Blocks.

OBJECTIVES: The objectives of this study were to investigate the correlations between the minimum effective volume (MEV) of lidocaine 1.5% for an ultrasound-guided popliteal sciatic nerve block and individual factors including the cross-sectional nerve area, sex, age, body mass index, and the depth of the sciatic nerve and to evaluate the safety of combined femoral and sciatic nerve blocks by monitoring the plasma concentration of local anesthetics. METHODS: Forty patients received combined single-shot femoral and continuous sciatic nerve blocks. The femoral nerve block was performed with an in-plane technique and 15 mL of lidocaine 1.5%. A continuous peripheral nerve block annular tube was positioned between the tibial and peroneal nerves inside the paraneural sheath. Thirty minutes after the femoral nerve block, a loading dose of 5 mL of lidocaine 1.5% was given to block the sciatic nerve after obtaining the maximum compound muscle action potential (CMAP) amplitude using nerve conduction studies. Additional lidocaine 1.5% was pumped at a rate of 30 mL/h through the indwelling annular tube if, after 8 minutes, the CMAP amplitude was still present. The CMAP amplitude monitored by the nerve conduction studies and pinprick tests were recorded every 2 minutes after the administration of lidocaine 1.5%. When the CMAP amplitude decreased to nearly 0 mV, this MEV was recorded. The influences of the cross-sectional area of the sciatic nerve, sex, age, body mass index, and the depth of the sciatic nerve on the MEV were analyzed using stepwise multiple linear regression. Blood samples were collected from 10 patients to evaluate the safety of combined femoral and sciatic nerve blocks by ultra-performance liquid chromatography-tandem mass spectrometry. Blood was drawn at 0 minutes before femoral nerve injection; 0 minutes before sciatic nerve injection; 8 minutes after sciatic nerve injection; and 0, 10, 20, 30, 45, 60, 75, 90, and 120 minutes after the pumping of lidocaine 1.5% stopped. RESULTS: A significant correlation was found between the MEV of lidocaine 1.5% and the cross-sectional area of the sciatic nerve (r=0.459), with a regression equation of the MEV (mL)=5.969+0.095×(the cross-sectional area of the sciatic nerve). The coefficient of determination was 0.211 (P<0.05). The MEV of lidocaine 1.5% for complete sciatic nerve blocks ranged from 7 to 15 mL. The maximum concentrations of lidocaine, monoethylglycinexylidide, and glycinexylidide were 1672.9 (227.6), 265.7 (32.7), and 42.2 (22.4) ng/mL, respectively. CONCLUSIONS: There is a positive correlation between the cross-sectional area of the sciatic nerve and the MEV. The regression equation can help to predict the MEV of lidocaine 1.5% for popliteal sciatic nerve blocks. The maximum concentrations of lidocaine and its metabolites did not approach toxic threshold limits in this study.

Kilohertz high-frequency alternating current blocks nerve conduction without causing nerve damage in rats.

BACKGROUND: In recent years, 2-50 kHz high-frequency alternating current has been shown to block nerve conduction mostly based on simulation models or experiments in vitro. This study aimed to assess the nerve block effects and related parameters of kilohertz alternating current in a rat model. METHODS: High-frequency biphasic rectangular stimulus pulse was applied to rat's sciatic nerve in vivo, and its blockade frequency and intensity was studied by recording the changes of compound muscle action potential (CMAP) amplitude and muscle states before and after stimulation. Secondly, diameter and circumference of sciatic nerve was measured at stimulating point by ultrasound. The correlation between stimulus' frequency and the nerve's diameter and circumference was studied. Lastly, we assessed nerve damage causing by high-frequency electrical stimulation by measuring CMAP and nerve conduction velocity (NCV) in the following day and sciatic nerve hematoxylin-eosin staining, both blocked side and contralateral side. RESULTS: When the current intensity was fixed, the blockade only occurred in a specific frequency range, above or below might have partial block effect. Preliminary statistical results showed that the blocking frequency of high-frequency alternating current was negatively linearly correlated with the circumference of sciatic nerve (P<0.05); HE staining of the sciatic nerve showed no axon and myelin sheath damage on blocked or opposite side, and the CMAP and NCV of the sciatic nerve remeasured in the next day were normal, indicating high-frequency electrical stimulation produced no nerve injury. CONCLUSIONS: High-frequency alternating current stimulation can block nerve conduction without causing nerve damage, and the complete block frequency is negatively linearly correlated with the circumference of sciatic nerve.

A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing.

The development of clinically viable delivery methods presents one of the greatest challenges in the therapeutic application of CRISPR/Cas9 mediated genome editing. Here, we report the development of a lipid nanoparticle (LNP)-mediated delivery system that, with a single administration, enabled significant editing of the mouse transthyretin (Ttr) gene in the liver, with a >97% reduction in serum protein levels that persisted for at least 12 months. These results were achieved with an LNP delivery system that was biodegradable and well tolerated. The LNP delivery system was combined with a sgRNA having a chemical modification pattern that was important for high levels of in vivo activity. The formulation was similarly effective in a rat model. Our work demonstrates that this LNP system can deliver CRISPR/Cas9 components to achieve clinically relevant levels of in vivo genome editing with a concomitant reduction of TTR serum protein, highlighting the potential of this system as an effective genome editing platform.

Two different placement paths in popliteal fossa with a novel nerve block needle for postoperative analgesia after foot and ankle surgery.

BACKGROUND: Previous studies have documented that single injection nearby the sciatic nerve bifurcation would influence the anesthesia and analgesia effect. But this is uncertain for preoperative continuous popliteal sciatic nerve block. This trial was conducted to compare two paths (proximal to the bifurcation and at the bifurcation) of ultrasound-guided continuous popliteal sciatic nerve block in foot and ankle surgery. METHODS: Forty recruited objects were randomly assigned to receive ultrasound-guided continuous popliteal sciatic nerve block at the puncture path proximal to the nerve bifurcation either at the nerve bifurcation. Subjects received an injection using a novel nerve block needle with external indwelling cannula guided by ultrasound invented by the corresponding author. The external indwelling cannula was inserted for postoperative analgesia. The primary outcome was NRS scores (at rest and during movement) times at 24 hours after surgery. The secondary outcomes included the measurements related to the performance of the nerve block and efficacy of analgesia, such as anesthesia effect grade, grade of nausea and vomiting, case number of patients with cannula leaking, occlusion or slipping, patient satisfaction, etc. RESULTS: During the surgery, six subjects in the proximal group needed additional analgesic, significantly different from one in the at bifurcation group (P<0.05). There was significant difference on anesthesia effect rating, 1.6±0.8 in the proximal group and 1.1±0.4 in another (P<0.05). The proximal group got 2.1±1.6 of NRS on rest at 24 hours and 1.7±1.5 at 48 hours, and the at bifurcation group got 0.9±1.4 at 24 hours and 0.7±1.1 at 48 hours (P<0.05). The proximal group got more PCA times during 6-24 hours and 24-48 hours and lower satisfaction scores. CONCLUSIONS: Continuous popliteal sciatic nerve block at nerve bifurcation could receive better analgesia effect and more patients' satisfaction, rather than proximal to the bifurcation.

Enhanced Anti-Tumor Efficacy of Lipid-Modified Platinum Derivatives in Combination with Survivin Silencing siRNA in Resistant Non-Small Cell Lung Cancer.

PURPOSE: Cisplatin, is recognized as a first line therapeutic for the treatment of non-small cell lung cancer (NSCLC). Cisplatin resistance is identified as the most detrimental complication during treatment and has been associated with upregulation of several genes, such as the anti-apoptotic gene survivin. In this study, we have evaluated the cytotoxic activity of lipid (C6 and C8)-modified platinum compounds in combination with a survivin-silencing siRNA against cisplatin resistant tumors. METHODS: We synthesized and characterized several lipid-modified platinum compounds and evaluated their cytotoxic activity alone or in combination with survivin-silencing siRNA in vitro and in vivo against A549DDP cells and in vivo in tumor xenograft model. RESULTS: The lipid-modified compounds exhibited significantly stronger cytotoxic activity in vitro compared to cisplatin, with CDDP-C6 and CDDP-C8 producing the most pronounced effect, in both A549 and A549DDP cells. Pre-treatment of the A549DDP cells with survivin-silencing siRNA enhanced the cytotoxic activity of these compounds. In vivo, the co-treatment of the survivin-silencing siRNA and CDDP-C8 produced the strongest tumor growth inhibition effect (64.5%, p < 0.05) on a cancer mouse model of chemoresistant lung cancer. In contrast, cisplatin treatment exhibited no significant tumor growth inhibition (4.5%, no p). CONCLUSIONS: Co-treatment of lipid-modified compounds and survivin-silencing siRNA can constitute a reliable alternative to cisplatin treatment for cisplatin-resistant lung tumors that merit further evaluation.