Nano-energy interference: A novel strategy for blunting tumor adaptation and metastasis.

Blunting the tumor's stress-sensing ability is an effective strategy for controlling tumor adaptive survival and metastasis. Here, we have designed a cyclically amplified nano-energy interference device based on lipid nanoparticles (LNP), focused on altering cellular energy metabolism. This innovative nano device efficiently targets and monitors the tumor's status while simultaneously inhibiting mitochondrial respiration, biogenesis and ribosome production. To this end, we first identified azelaic acid (AA), a binary acid capable of disrupting the mitochondrial respiratory chain. Upon encapsulation in LNP and linkage to mitochondrial-targeting molecules, this disruptive effect is further augmented. Consequently, tumors exhibit a substantial upregulation of the glycolytic pathway, intensifying their glucose demand and worsening the tumor's energy-deprived microenvironment. Then, the glucose analog, 2-Deoxy-D-glucose (2-DG), linked to the LNP, efficiently targets tumors and competitively inhibits the tumor's normal glucose uptake. The synergetic results of combining AA with 2-DG induce comprehensive energy deficiency within tumors, blocking the generation of energy-sensitive ribosomes. Ultimately, the disruption of both mitochondria and ribosomes depletes energy supply and new protein-generating capacity, weakening tumor's ability to adapt to environmental stress and thereby inhibiting growth and metastasis. Comprehensively, this nano-energy interference device, by controlling the tumor's stress-sensing ability, provides a novel therapeutic strategy for refractory tumors.

Diagnosis and treatment of biliary mucinous cystic neoplasms: A single-center experience.

BACKGROUND: Biliary mucinous cystic neoplasms (BMCNs) are rare hepatobiliary cystic tumors, which can be divided into noninvasive and invasive types. This study aimed to investigate the diagnosis, treatment, and prognosis of BMCNs in a large single center. METHODS: We analyzed 49 patients with BMCNs confirmed by postoperative pathology at the First Affiliated Hospital, Zhejiang University School of Medicine between January 2007 and December 2021. RESULTS: Among the 49 patients, 37 were female (75.5%), and the average age was 57.04 years. Common symptoms included abdominal discomfort, jaundice and fever, while 22 patients (44.9%) had no symptoms. Serum carbohydrate antigen (CA) 19-9 and CA125 concentrations were elevated in 34.8% and 19.6% of patients, respectively. Forty-eight patients had tumors in the intrahepatic bile ducts and only one had a tumor in the extrahepatic bile duct. Forty-eight patients with noninvasive intrahepatic BMCNs were further analyzed in terms of pathological features: 34 (70.8%) had low-grade intraepithelial neoplasms (LGINs), and 14 (29.2%) had high-grade intraepithelial neoplasms (HGINs). The potential immunohistochemical markers of BMCNs were cytokeratin (CK) 19, CK7, estrogen receptor and progesterone receptor. Follow-up data for 37 patients with intrahepatic BMCNs were obtained. The median overall survival (OS) of BMCNs was not reached. The longest survival time was 137 months.The 5- and 10-year OS rates were 100% and 85.4%, respectively. The 5- and 10-year recurrence-free survival (RFS) rates were 93.9% and 80.2%, respectively. CONCLUSIONS: BMCNs are rare cystic neoplasms that commonly occur in middle-aged females. BMCNs can only be diagnosed and classified by postoperative pathology, as there are no specific clinical presentations, serological indicators or imaging modalities for preoperative diagnosis. Complete surgical resection is necessary for BMCNs, and the postoperative prognosis is favorable.

LncRNA NKX2-1-AS1 promotes tumor progression and angiogenesis via upregulation of SERPINE1 expression and activation of the VEGFR-2 signaling pathway in gastric cancer.

Long noncoding RNAs (lncRNAs) can compete with endogenous RNAs to modulate the gene expression and contribute to oncogenesis and tumor metastasis. lncRNA NKX2-1-AS1 (NKX2-1 antisense RNA 1) plays a pivotal role in cancer progression and metastasis; however, the contribution of aberrant expression of NKX2-1-AS1 and the mechanism by which it functions as a competing endogenous RNA (ceRNA) in gastric cancer (GC) remains elusive. NKX2-1-AS1 expression was detected in paired tumor and nontumor tissues of 178 GC patients by quantitative reverse transcription PCR (qRT-PCR). Using loss-of-function and gain-of-function experiments, the biological functions of NKX2-1-AS1 were evaluated both in vitro and in vivo. Further, to assess that NKX2-1-AS1 regulates angiogenic processes, tube formation and co-culture assays were performed. RNA binding protein immunoprecipitation (RIP) assay, a dual-luciferase reporter assay, quantitative PCR, Western blot, and fluorescence in situ hybridization (FISH) assays were performed to determine the potential molecular mechanism underlying this ceRNA. The results indicated that NKX2-1-AS1 expression was upregulated in GC cell lines and tumor tissues. Overexpression of NKX2-1-AS1 was significantly associated with tumor progression and enhanced angiogenesis. Functionally, NKX2-1-AS1 overexpression promoted GC cell proliferation, metastasis, invasion, and angiogenesis, while NKX2-1-AS1 knockdown restored these effects, both in vitro and in vivo. RIP and dual-luciferase assays revealed that the microRNA miR-145-5p is a direct target of NKX2-1-AS1 and that NKX2-1-AS1 serves as a ceRNA to sponge miRNA and regulate angiogenesis in GC. Moreover, serpin family E member 1 (SERPINE1) is an explicit target for miR-145-5p; besides, the NKX2-1-AS1/miR-145-5p axis induces the translation of SERPINE1, thus activating the VEGFR-2 signaling pathway to promote tumor progression and angiogenesis. NKX2-1-AS1 overexpression is associated with enhanced tumor cell proliferation, angiogenesis, and poor prognosis in GC. Collectively, NKX2-1-AS1 functions as a ceRNA to miR-145-5p and promotes tumor progression and angiogenesis by activating the VEGFR-2 signaling pathway via SERPINE1.

The Impact of SsPI-1 Deletion on Streptococcus suis Virulence.

(1) Background: Streptococcus suis is an important zoonotic pathogen that infects pigs and can occasionally cause life-threatening systemic infections in humans. Two large-scale outbreaks of streptococcal toxic shock-like syndrome in China suggest that the pathogenicity of S. suis has been changing in recent years. Genetic analysis revealed the presence of a chromosomal pathogenicity island (PAI) designated SsPI-1 in Chinese epidemic S. suis strains. The purpose of this study is to define the role of SsPI-1 in the virulence of S. suis. (2) Methods: A SsPI-1 deletion mutant was compared to the wild-type strain regarding the ability to attach to epithelial cells, to cause host disease and mortality, and to stimulate host immune response in experimental infection of piglets. (3) Results: Deletion of SsPI-1 significantly reduces adherence of S. suis to epithelial cells and abolishes the lethality of the wild-type strain in piglets. The SsPI-1 mutant causes no significant pathological lesions and exhibits an impaired ability to induce proinflammatory cytokine production. (4) Conclusions: Deletion of the SsPI-1 PAI attenuates the virulence of this pathogen. We conclude that SsPI-1 is a critical contributor to the evolution of virulence in epidemic S. suis.

Near-infrared light-activated red-emitting upconverting nanoplatform for T1-weighted magnetic resonance imaging and photodynamic therapy.

Photodynamic therapy (PDT) has increasingly become an efficient and attractive cancer treatment modality based on reactive oxygen species (ROS) that can induce tumor death after irradiation with ultraviolet or visible light. Herein, to overcome the limited tissue penetration in traditional PDT, a novel near-infrared (NIR) light-activated NaScF4: 40% Yb, 2% Er@CaF2 upconversion nanoparticle (rUCNP) is successfully designed and synthesized. Chlorin e6, a photosensitizer and a chelating agent for Mn2+, is loaded into human serum albumin (HSA) that further conjugates onto rUCNPs. To increase the ability to target glioma tumor, an acyclic Arg-Gly-Asp peptide (cRGDyK) is linked to rUCNPs@HSA(Ce6-Mn). This nanoplatform enables efficient adsorption and conversion of NIR light (980 nm) into bright red emission (660 nm), which can trigger the photosensitizer Ce6-Mn complex for PDT and T1-weighted magnetic resonance imaging (T1-weighted MRI) for glioma diagnosis. Our in vitro and in vivo experiments demonstrate that NIR light-activated and glioma tumor-targeted PDT can generate large amounts of intracellular ROS that induce U87 cell apoptosis and suppress glioma tumor growth owing to the deep tissue penetration of irradiated light and excellent tumor-targeting ability. Thus, this nanoplatform holds potential for applications in T1-weighted MRI diagnosis and PDT of glioma for antitumor therapy. STATEMENT OF SIGNIFICANCE: A near-infrared (NIR) light-activated nanoplatform for photodynamic therapy (PDT) was designed and synthesized. The Red-to-Green (R/G) ratio of NaScF4: 40% Yb, 2% Er almost reached 9, a value that was much higher than that of a traditional Yb/Er-codoped upconversion nanoparticle (rUCNP). By depositing a CaF2 shell, the red-emission intensities of the rUCNPs were seven times strong as that of NaScF4: 40% Yb, 2% Er. The enhanced red-emitting rUCNPs could be applied in many fields such as bioimaging, controlled release, and real-time diagnosis. The nanoplatform had a strong active glioma-targeting ability, and all results achieved on subcutaneous glioma demonstrated that our NIR light-activated red-emitting upconverting nanoplatform was efficient for PDT. By loading Ce6-Mn complex into rUCNPs@HSA-RGD, the nanoplatform could be used as a T1-weighted magnetic resonance imaging agent for tumor diagnosis.

pH-Responsive Magnetic Mesoporous Silica-Based Nanoplatform for Synergistic Photodynamic Therapy/Chemotherapy.

By overcoming drug resistance and subsequently enhancing the treatment, the combination therapy of photodynamic therapy (PDT) and chemotherapy has promising potential for cancer treatment. However, the major challenge is how to establish an advanced nanoplatform that can be efficiently guided to tumor sites and can then stably release both chemotherapy drugs and a photosensitizer simultaneously and precisely. In this study, which considered the possibility and targeting efficiency of a magnetic targeting strategy, a novel Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoplatform was successfully built; this platform could be employed as an efficient synergistic antitumor nanoplatform with magnetic guidance for highly specific targeting and retention. Doxorubicin (DOX) molecules were loaded into mesoporous silica with high loading capability, and the mesoporous channels were blocked by a polydopamine coating. Human serum albumin (HSA) was conjugated to the outer surface to increase the biocompatibility and blood circulation time, as well as to provide a vehicle for loading photosensitizer chlorin e6 (Ce6). The sustained release of DOX under acidic conditions and the PDT induced by red light exerted a synergistic inhibitory effect on glioma cells. Our experiments demonstrated that the pH-responsive Fe3O4@mSiO2(DOX)@HSA(Ce6) nanoplatform was guided to the tumor region by magnetic targeting and that the nanoplatform suppressed glioma tumor growth efficiently, implying that the system is a highly promising photodynamic therapy/chemotherapy combination nanoplatform with synergistic effects for cancer treatment.

The efficacy of pregabalin for acute pain control in herpetic neuralgia patients: A meta-analysis.

OBJECTIVE: This meta-analysis aimed to illustrate the efficacy and safety of preganalin for pain management in patients with postherpetic neuralgia (PHN). METHODS: In July 2017, a systematic computer-based search was conducted in PubMed, EMBASE, Web of Science, Cochrane Database of Systematic Reviews, and Google database. Data on patients with PHN that compared pregabalin versus placebo were retrieved. The endpoints were the visual analog scale (VAS) at 8 weeks, the percentage of 30% and 50% pain responders; sleep interference score and improvement in patient global impression of change (PGIC). After testing for publication bias and heterogeneity between studies, data were aggregated for random-effects models when necessary. RESULTS: Seven clinical studies with 2192 patients (pregabalin group = 1381, control group = 811) were finally included in the meta-analysis. Pregabalin was associated with reduced pain scores at 8 weeks, corresponding to a reduction of 11.23 points (95% CI, -14.33, -8.13, P = .000) on a 100-point VAS. Pregabalin was also associated with a more percentage of 30% and 50% pain responders than controls (P < .05). Meanwhile, pregabalin can decrease sleep interference score and improvement in PGIC than control groups (P < .05). CONCLUSIONS: Pregabalin was efficacious in the reduction of postoperative pain and improvement the sleep quality in patients with PHN.

Synthesis and electrochemical evolution of mesoporous LiFeSO4F0.56(OH)0.44 with high power and long cyclability.

A feasible and scalable two-step method is developed to synthesize LiFeSO4F(y)(OH)(1-y) which could deliver 92 and 80 mA h g(-1) when cycled at 1 C and 15 C, respectively. Moreover, with 80% of capacity retention after 2800 cycles at 1 C, this material should be of great interest as a contender to LiFePO4 for use in high power Li-ion batteries.

Synthesis of superior fast charging-discharging nano-LiFePO4/C from nano-FePO4 generated using a confined area impinging jet reactor approach.

LiFePO4/C nanocomposites with excellent electrochemical performance is synthesized from nano-FePO4, generated by a novel method using a confined area impinging jet reactor (CIJR). When discharged at 80 C (13.6 Ag(-1)), the LiFePO4/C delivers a discharge capacity of 95 mA h g(-1), an energy density of 227 W h kg(-1) and a power density of 34 kW kg(-1).

Application of nanosized Fe3O4 in anticancer drug carriers with target-orientation and sustained-release properties.

The purpose of this study was to prepare human serum albumin (HSA) microspheres with Fe(3)O(4) magnetic nanoparticles for tumor target therapy. Fe(3)O(4) was obtained by liquid-phase coprecipitation; HSA-coated magnetic particles were attained by solidification at high temperature. The result was that nanosized Fe(3)O(4) is a cubic crystal by XRD and the average size is 18.7 nm; the average size of HSA-coated magnetic particles is 341 nm. Fe(3)O(4) magnetic nanoparticles coated with HSA can be used for targeted-drug carriers with target-orientation and sustained-release properties.

[Physiological and biochemical effects of intermittent fasting combined with hunger-resistant food on mice].

OBJECTIVE: To observe the physiological and biochemical effects of intermittent fasting combined with hunger-resistant food on mice, and to evaluate the safety and beneficial effects of this regimen. METHODS: One hundred and forty-four adult ICR mice were divided into 4 groups: standard feed AL group (ad libitum intake of standard feed), hunger-resistant food AL group (ad libitum intake of hunger-resistant food), standard feed IF group (feeding standard feed and fasting on alternate days), and hunger-resistant food IF group (feeding hunger-resistant food and fasting on alternate days). The experiment lasted for 4-8 weeks and all mice drank water freely. The quality of life, body weight, fasting blood glucose, serum lipid, blood routine test, liver and kidney functions as well as the viscera indexes were examined. RESULTS: Compared to the standard feed AL group, the caloric taking and the increment of body-weight were reduced (P<0.01), and the viscera indexes of the liver and kidney were elevated (P<0.05) in the hunger-resistant food AL group and the hunger-resistant food IF group, the values of fasting blood glucose were reduced in standard feed IF group and hunger-resistant food IF group (P<0.01), the value of triglycerides was reduced in hunger-resistant food IF group (P<0.05), while the quality of life, blood routine test as well as the liver and kidney functions were not obviously affected in the hunger-resistant food AL group, standard feed IF group and hunger-resistant food IF group. CONCLUSION: The regimen of intermittent fasting combined with hunger-resistant food is safe and beneficial to metabolic regulation, such as controlling body-weight and adjusting blood glucose and serum lipid. It is expected that development of this regimen will be helpful to the control of obesity and diabetes, etc.

Adhesion of different cell cycle human hepatoma cells to endothelial cells and roles of integrin beta1.

AIM: To investigate the adhesive mechanical properties of different cell cycle human hepatoma cells (SMMC-7721) to human umbilical vein endothelial cells (ECV-304), expression of adhesive molecule integrinbeta1 in SMMC-7721 cells and its contribution to this adhesive course. METHODS: Adhesive force of SMMC-7721 cells to endothelial cells was measured using micropipette aspiration technique. Synchronous G1 and S phase SMMC-7721 cells were achieved by thymine-2-deoxyriboside and colchicines sequential blockage method and double thymine-2-deoxyriboside blockage method, respectively. Synchronous rates of SMMC-7721 cells and expression of integrinbeta1 in SMMC-7721 cells were detected by flow cytometer. RESULTS: The percentage of cell cycle phases of general SMMC-7721 cells was 11.01% in G2/M phases, 53.51% in G0/G1 phase, and 35.48% in S phase. The synchronous rates of G1 and S phase SMMC-7721 cells amounted to 74.09% and 98.29%, respectively. The adhesive force of SMMC-7721 cells to endothelial cells changed with the variations of adhesive time and presented behavior characteristics of adhesion and de-adhesion. S phase SMMC-7721 cells had higher adhesive forces than G1 phase cells ((307.65+/-92.10) x 10(-10) N vs (195.42+/-60.72) x 10(-10) N, P<0.01). The expressive fluorescent intensity of integrinbeta(1) in G(1) phase SMMC-7721 cells was depressed more significantly than the values of S phase and general SMMC-7721 cells. The contribution of adhesive integrinbeta1 was about 53% in this adhesive course. CONCLUSION: SMMC-7721 cells can be synchronized preferably in G1 and S phases with thymine-2-deoxyriboside and colchicines. The adhesive molecule integrinbeta1 expresses a high level in SMMC-7721 cells and shows differences in various cell cycles, suggesting integrin beta1 plays an important role in adhesion to endothelial cells. The change of adhesive forces in different cell cycle SMMC-7721 cells indicates that S phase cells play predominant roles possibly while they interact with endothelial cells.

[The therapeutic efficacy of tumor-derived heat shock protein70 combining interleukin-2 on tumor-bearing mice].

AIM: To investigate the therapeutic efficacy of the combination of tumor-derived HSP70 and IL-2 on tumor-bearing mice. METHODS: HSP70 was purified from the murine tumor cell line by liquid chromatography. And then identified by SDS-PAGE and Western blot,the purity of purified product was analyzed by capillary electrophoresis. The anti-tumor efficacies of mono-administration of HSP70 or IL-2 and their combination were observed by zoopery. RESULTS: Combination of HSP70 and IL-2 was more effective than either of the two therapeutic agents alone in treating tumor-bearing mice. 10 microg HSP70 displayed obviously therapeutic effect no matter applied alone or combined with IL-2. The averaged life span of the mice treated with IL-2 was only 36.6+/-13.0 days, while 40% of the mice treated with 10 microg HSP70, tumors disappeared eventually and their survival time was more than 90 days, and the averaged life span of this group was over 59.2+/-29.6 days. HSP70 plus IL-2 could get tumors disappeared completely in 60% of mice, averaged life time of this group was over 70.8+/-26.5 days. CONCLUSION: The Combination of HSP70 and IL-2 demonstrated apparently therapeutic effect on tumor-bearing mice. The results will be of greater value to the study on the immunotherapy of human malignant tumors.

Efficacy of intraperitoneal thermochemotherapy and immunotherapy in intraperitoneal recurrence after gastrointestinal cancer resection.

AIM: To investigate the prophylactic and therapeutic efficacy of intraperitoneal IL-2 immunotherapy following intraperitoneal thermochemotherapy in the metastasis and recurrence of gastric and colorectal cancer after operation. METHODS: Forty-two gastric cancer patients at T(3)II-T(4)III( B) stages and 96 patients with colorectal cancer at B to D stages admitted from January 1996 to October 1998 were randomly divided into control group (group I, 65 cases) receiving intraperitoneal thermochemotherapy, and group II (73 cases) receiving both intraperitoneal thermochemotherapy and intraperitoneal IL-2 immunotherapy. Distilled water at 43-45 degrees containing 5-Fu 0.5 g/L and MMC 8 mg/L was perfused into peritoneal cavity before closure at the end of operation for 1 h, and from the third day, IL-2 10 million IU in 500 ml 0.9 % sodium chloride was intraperitoneally administrated daily for 10 times. One month after operation, all the patients underwent regular intravenous chemotherapy. Before and after the IL-2 immunotherapy, some Th1 type cytokines in the peripheral blood of the patients in the two groups were detected by ELISA, and the intraperitoneal recurrence and liver metastasis rates and the 3-year survival rate were statistically evaluated after intensive follow-up. RESULTS: IL-2 intraperitoneal immunotherapy significantly elevated the level of some Th1 type cytokines (P<0.01 compared with that of control group), and the 3-year survival rate of group II was 18.1 % higher and the rates of intraperitoneal recurrence and liver metastasis were 16.9 % and 6.0 % lower than those of group I significantly (P<0.05-0.01). CONCLUSION: The combination of intraperitoneal IL-2 immunotherapy and thermochemotherapy could promote Th1 immune paradigm and enforce anti-tumor activity of bodies, which plays a positive role in preventing gastric and colorectal cancer from intraperitoneal recurrence and development.