The role and mechanism of IFITM1 in developing acquired cisplatin resistance in small cell lung cancer.

Platinum-based chemotherapies, historically the cornerstone of first-line treatment for small-cell lung cancer (SCLC), face a major hurdle: the frequent emergence of chemoresistance, notably to cisplatin (CDDP). Current understanding of the mechanisms driving CDDP resistance in SCLC is incomplete. Notably, Interferon inducible transmembrane protein1 (IFITM1) has been identified as a key player in the distant metastasis of SCLC. Analysis of The Cancer Genome Atlas (TCGA) database revealed that IFITM1 expression is markedly elevated in tumor tissues as compared to that from adjacent normal tissues, correlating with a worse prognosis for patients with SCLC. Our research focused on investigating the role of IFITM1 in the acquisition of cisplatin resistance in SCLC. Further clinical sample analysis highlighted a significant increase in IFITM1 levels in SCLC tissues from cisplatin-resistant patients versus those were responsive to CCDP treatment, with similar trends observed in cisplatin-resistant SCLC cells. Crucially, overexpression of IFITM1 reduced the sensitivity of SCLC cells to cisplatin, while silencing IFITM1 enhanced chemosensitivity in cisplatin-resistant strains. Our in vivo studies further confirmed that silencing IFITM1 significantly boosted the efficacy of cisplatin in inhibiting growth of subcutaneous tumors of NCI-H466/CDDP cells (cisplatin-resistant SCLC cells) in a mouse model. Mechanistically, IFITM1 appears to foster cisplatin resistance through activation of the Wnt/ß-catenin pathway. In summary, our findings suggest that targeting IFITM1, alongside cisplatin treatment, could offer a promising therapeutic strategy to overcome resistance and improve outcomes for SCLC patients.

Improved microalgae growth and lipid production in anaerobic digestate with ultraviolet radiation pretreatment.

Inappropriate sterilization strategies inhibit microalgal growth when culturing microalgae with anaerobic digestate. This study aimed to scientifically select a low-cost disinfection pretreatment of anaerobic digestate for large-scale microalgae cultivations. In this work, three different methods, including autoclaving, ultraviolet or NaClO treatments, were employed to sterilize the municipal anaerobic digestate. Scenedesmus quadricauda was then cultured in diluted liquid digestate for the simultaneous lipid production and nutrient removal. The results indicated that the growth of S. quadricauda was inhibited after NaClO treatment due to the residual free chlorine. The 15-min ultraviolet effectively mitigated microbial contamination and increasing nutrient availability, enhancing the electron transport of microalgal photosynthesis. After 6-days cultivation, the microalgal biomass concentration of the ultraviolet group was 1.09 g/L, comparable to that of the autoclaving group (1.15 g/L). High nutrient removal efficiency was observed: COD (93.30 %), NH4+-N (92.56 %), TN (85.82 %) and TP (95.12 %). Moreover, S. quadricauda outcompeted the indigenous microorganisms, contributing to its dominance in the culture system of ultraviolet group. The facultative anaerobe Comamonadaceae and aerobes Moraxellaceae, rather than strict anaerobe Paludibacteraceae and Bacteroidetes_vadinHA17, played vital roles in synergistic removal of contaminants by bacteria and algae. The potential competition for nitrogen and phosphorus by bacteria contributed to the ultraviolet group having the greatest lipid content (48.19 %). Therefore, this work suggested using 15-min ultraviolet treatment for anaerobic digestate in large-scale microalgae cultivation.

A novel process based on powder carriers demonstrates robustness in nitrogen and phosphorus removal from real municipal wastewater.

The development of efficient and low-consumption wastewater upgrading process is currently at the forefront of the wastewater treatment field. In this study, a novel wastewater treatment process based on powder carriers was proposed. Three systems, namely the activated sludge (AS) system, powder carrier (PC) system, and moving bed biofilm reactor (MBBR) system, were established and operated for over 140 days to treat real municipal wastewater. The characteristics and differences between the three systems were comprehensively investigated. The results suggested that the PC system exhibited notable advantages in nitrogen and phosphorus removal, especially under high influent load and low aeration conditions. The PC system, characterized by a higher nitrification rate compared to the MBBR system and a higher denitrification rate compared to the AS system, contributed to the stable nitrogen removal performance. The particle size of the zoogloea increased under the linkage of the powder carriers, and the mean size of micro-granules reached 170.88 µm. Large number of hydrophobic functional groups on sludge surface, coupled with increased protein content in EPS, further promoted sludge aggregation. Micro-granules formation improved settling performance and enhanced the abundance and activity of functional microbes. A significant enrichment in denitrifying bacteria and denitrifying phosphorus accumulating bacteria was observed in PC system. Up-regulation of the napA, narG, and nosZ genes was responsible for efficient nitrogen removal of the PC system. Moreover, a higher abundance in polyphosphate phosphotransferase (2.11 %) was found in PC system compared with AS and MBBR systems. The increase in the enzymes associated with poly-ß-hydroxybutyrate (PHB) synthesis metabolism in PC system provided the energy for denitrification and phosphorus removal processes.

Enhanced biological phosphorus removal by high concentration powder carrier bio-fluidized bed (HPB): Phosphorus distribution, cyclone separation, and metagenomics.

This study provides a comparative investigation of phosphorus removal between anaerobic-anoxic-oxic (AAO) and high-concentration powder carrier bio-fluidized bed (HPB) in the same full-scale wastewater treatment plant. The results showed that the total phosphorus removal of HPB was 71.45%-96.71%. Compared with AAO, the total phosphorus removal of HPB can be increased by a maximum of 15.73%. The mechanisms of enhanced phosphorus removal by HPB include the followings. Biological phosphorus removal was significant. The anaerobic phosphorus release capacity of HPB was enhanced and polyphosphate (Poly-P) in the excess sludge of HPB was 1.5 times higher than that of AAO. The relative abundance of Candidatus Accumulibacter was 5 times higher than that of AAO, and oxidative phosphorylation and butanoate metabolism were enhanced. The analysis of phosphorus distribution showed that cyclone separation increased the chemical phosphorus precipitation (Chem-P) in the excess sludge by 16.96% to avoid accumulation in the biochemical tank. The phosphorus adsorbed by extracellular polymeric substance (EPS) in the recycled sludge was stripped, and the EPS bound-P in the excess sludge increased by 1.5 times. This study demonstrated the feasibility of HPB to improve the phosphorus removal efficiency for domestic wastewater.

The dissolution of polysaccharides and amino acids enhanced lactic acid production from household food waste during pretreatment process.

A large amount of household food waste (HFW) is produced yearly, resulting in environmental problems and financial burdens. Bio-production of lactic acid (LA), a high value-added platform chemical, from HFW by anaerobic fermentation is a promising way of resource recovery. However, the LA production yield from HFW is low. This paper compared several pretreatment methods (hydrothermal pretreatment, chemical pretreatment, and combined hydrothermal and chemical pretreatment) to improve LA production from HFW. The result showed that the combined pretreatment (alkali-thermal pretreatment at pH 10 and 120 °C) significantly increased the LA production than single hydrothermal and chemical pretreatment. The pretreatment process promoted the dissolution of organics, especially the polysaccharides and amino acids, and further influenced the LA production by Lactobacillus rhamnosus ATCC 7469. Among the amino acids, aspartic acid (Asp), threonine (Thr), glutamic acid (Glu), glycine (Gly), alanine (Ala), cystine (Cys), valine (Val), isoleucine (Ile), arginine (Arg), and proline (Pro) significantly correlated with LA concentration.

Calorie Restriction Protects against Contrast-Induced Nephropathy via SIRT1/GPX4 Activation.

Calorie restriction (CR) extends lifespan and increases resistance to multiple forms of stress, including renal ischemia-reperfusion (I/R) injury. However, whether CR has protective effects on contrast-induced nephropathy (CIN) remains to be determined. In this study, we evaluated the therapeutic effects of CR on CIN and investigated the potential mechanisms. CIN was induced by the intravenous injection of iodinated contrast medium (CM) iopromide (1.8 g/kg) into Sprague Dawley rats with normal food intake or 40% reduced food intake, 4 weeks prior to iopromide administration. We found that CR was protective of CIN, assessed by renal structure and function. CM increased apoptosis, reactive oxygen species (ROS), and inflammation in the renal outer medulla, which were decreased by CR. The silent information regulator 1 (SIRT1) participated in the protective effect of CR on CIN, by upregulating glutathione peroxidase 4 (GPX4), a regulator of ferroptosis, because this protective effect was reversed by EX527, a specific SIRT1 antagonist. Our study showed that CR protected CIN via SIRT1/GPX4 activation. CR may be used to mitigate CIN.

Coalescence, Partial Coalescence, and Noncoalescence of Two Free Droplets Suspended in Low-Viscosity Oil under a DC Electric Field.

Enhancing the electric field strength can facilitate the approach of droplets and the drainage of liquid film. However, two droplets do not coalesce but bounce off after contact under an excessively high electric field strength. To reveal the underlying mechanism, the dynamic behaviors of two free droplets suspended in low-viscosity silicone oil under a DC electric field were investigated herein. Three distinct behavior modes were successively observed by a high-speed camera with the increase in electric field strength: coalescence, partial coalescence, and noncoalescence. The mechanisms and key criteria of partial coalescence and noncoalescence were explored by studying the competition between electric force and interfacial force. The theoretical formula of critical electric field strength for droplet coalescence was derived and validated by experiments. The results indicated that the electric capillary number Ca can be used as the criterion to identify the behavior modes of two free droplets. The droplets undergo partial coalescence or noncoalescence when Ca > 0.11; otherwise, the droplets experience coalescence.

Effects of PHA-665752 and vemurafenib combination treatment on in vitro and murine xenograft growth of human colorectal cancer cells with BRAFV600E mutations.

It remains unknown whether blockade of B-Raf proto-oncogene, serine/threonine kinase (BRAF)V600E signaling and MET proto-oncogene, receptor tyrosine kinase (c-Met) signaling is effective in suppressing the growth of human colorectal cancer (CRC) cells. The present study investigated the effects of the vemurafenib alone and in combination with c-Met inhibitor PHA-665752 on the growth of human CRC cells in vitro and in mouse xenografts. HT-29 and RKO CRC cell lines with BRAFV600E mutations and mice bearing HT-29 xenografts were treated with vemurafenib in the absence or presence of PHA-665752. Cell viability and cycle phase were respectively examined by using the MTT and flow cytometry assay. Immunohistochemistry was conducted to detect the protein expression levels of hepatocyte growth factor (HGF), phosphorylated (p)-c-Met, p-AKT serine/threonine kinase (AKT) and p-extracellular signal-regulated kinase (p-ERK). The MTT assay demonstrated that the growth of RKO and HT-29 cells was inhibited by PHA-665752 in a time- and dose-dependent manner (P<0.05), however no significant suppressive effects were observed with vemurafenib. Relative to the PHA-665752 or vemurafenib stand-alone treatment groups, the combination of PHA-665752 and vemurafenib had a significant inhibitory effect on the proliferation of CRC cell lines (P<0.05). The mean tumor volume in mice treated with vemurafenib in combination with PHA-665752 was significantly smaller compared with those treated with only vemurafenib or PHA-665752 (P<0.05). Flow cytometry assay revealed that the G0/G1 phase frequency was significantly increased in the combination group compared with any other treatment groups (P<0.05). Immunohistochemistry demonstrated that vemurafenib in combination with PHA-665752 effectively induced the expression of p-c-Met, p-AKT and p-ERK, however had no effect on HGF.

Effects of PHA-665752 and Cetuximab Combination Treatment on In Vitro and Murine Xenograft Growth of Human Colorectal Cancer Cells with KRAS or BRAF Mutations.

BACKGROUND: It remains unknown whether blockade of c-Met signaling and epidermal growth factor receptor signaling is effective in suppressing the growth of human colorectal cancer (CRC) cells. In this study, we investigated the effects of the c-Met inhibitor PHA-665752 alone and in combination with cetuximab on the growth of human CRC cells in vitro and in mouse xenografts. METHODS: Human CRC cell lines (Caco2, HCT-116, and HT-29) and mice bearing HCT-116 xenografts were treated with cetuximab in the absence or presence of PHA-665752. Cell viability and apoptosis were examined using the MTT and TUNEL assays, respectively. Vimentin was measured by immunohistochemistry as a marker for epithelial-to-mesenchymal transition. Western blotting was used to determine signaling protein expression levels. RESULTS: The MTT assay showed that the growth of Caco2, HCT-116, and HT-29 cells was inhibited by PHA-665752 in a dose-dependent manner, but only Caco2 cell growth was suppressed by cetuximab. Combination treatment with PHA-665752 and cetuximab inhibited the proliferation of Caco2 cells and RAS mutant CRC cell lines. However, relative to the PHA-665752-alone treatment group, HT-29 cells with a BRAF mutation showed no noticeable effect. The mean tumor volume in mice treated with cetuximab in combination with PHA-665752 was significantly smaller than that in the mice treated with only cetuximab (P = 0.033) or PHA-665752 (P < 0.01). Similarly, the expression of vimentin in the mice treated with PHA-665752 in combination with cetuximab was significantly lower than that in the mice treated with cetuximab or PHA-665752 alone (P < 0.05 in each case). TUNEL assays revealed that treatment with PHA-665752 in combination with cetuximab markedly increased CRC cell apoptosis. Western blotting analysis of signaling protein expression showed that PHA- 665752 inhibited Met phosphorylation (P < 0.05). In addition, treatment with cetuximab alone or in combination with PHA-665752 effectively inhibited EGFR phosphorylation (P < 0.05). CONCLUSION: Combination treatment with PHA-665752 and cetuximab suppressed in vitro and in vivo CRC cell growth more than treatment with either agent alone did.

Breakup characteristics of aqueous droplet with surfactant in oil under direct current electric field.

The breakup process of aqueous droplet with surfactant suspended in oil under direct current (DC) electric field is investigated in this paper. The characteristics of the breakup process, stretching, necking and breakup, are discussed quantitatively with the electric capillary number Ca and the dimensionless surfactant concentration C∗ which is the ratio of surfactant concentration to the critical micelle concentration. The results show that the presence of surfactant reduces the steady deformation of droplet and significantly decelerates the stretching process, resulting from the redistribution of surfactant molecules within the oil/water interface. The law of droplet stretching process when C∗≥1 indicates that the exchange of surfactant molecules between the bulk phase and the interface could not catch up with the increase of oil/water interfacial area. Ca and C∗ count a great deal to the necking position and the daughter droplet size. The daughter droplet size decreases with the increase of surfactant concentration. These results provide a mechanistic framework to promote the electrocoalescence efficiency of oil/water emulsion and to the application of electric emulsification.

Significance of decoy receptor 3 (Dcr3) and external-signal regulated kinase 1/2 (Erk1/2) in gastric cancer.

BACKGROUND: Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor (TNFR) superfamily, is associated with anti-tumor immunity suppression. It is highly expressed in many tumors, and its expression can be regulated by the MAPK/MEK/ERK signaling pathway. The MAPK/MEK/ERK pathway has been reported to be a regulator in tumor occurrence, development and clonal expansion. External-signal regulated kinase (ERK) is a vital member of this pathway. RESULTS: The expression of DcR3 and ERK1/2 in tumor tissues of gastric cancer patients was significantly higher than the non-cancerous group (P < 0.05). There was no statistical difference among tumor tissues from patients with different ages or gender, and even of different differentiation (P > 0.05). However, in patients with stage I gastric cancer, the DcR3 and ERK1/2 levels were significantly lower than patients with more advanced stages. CONCLUSIONS: DcR3 and ERK1/2 play a vital role in the development of gastric cancer, and they may be new markers for indicating the efficiency of gastric cancer treatment in the future.

Abdominal hernia repair with a decellularized dermal scaffold seeded with autologous bone marrow-derived mesenchymal stem cells.

Surgeons usually use synthetic polymer meshes for abdominal wall hernia repair. However, synthetic polymer meshes exhibit a lack of growth and related complications. In this study, we produced a tissue-engineered patch for abdominal hernia repair. Autologous bone-marrow-derived mesenchymal stem cells (BMSCs) were isolated and proliferated in vitro; decellularized dermal scaffolds (DSs) were prepared using enzymatic process; and then BMSCs were seeded onto the DSs for the construction of tissue-engineered patches. Under general anesthesia, rabbits underwent creation of abdominal wall defects and which were repaired with BMSC-seeded DSs, acellular DSs, and skin sutures only, respectively. Animals were sacrificed after 2 months for assessing the histological and gross examination. Abdominal hernias were absent in animals repaired with cell-seeded group, and abdominal hernias or bulges appeared in all animals repaired with acellular group. All the animals that were not repaired died within 10 days. The cell-seeded implants were thicker and indicated good angiogenesis compared with that of the acellular implants, both in histological and gross examination. The tissue-engineered patches prepared with BMSCs seeding on DSs can be used for abdominal wall hernia repair.