Polyphenol nanocomplex modulates lactate metabolic reprogramming and elicits immune responses to enhance cancer therapeutic effect.

Cancer lactate metabolic reprogramming induces an elevated level of extracellular lactate and H+, leading to an acidic immunosuppressive tumor microenvironment (TEM). High lactic acid level may affect the metabolic programs of various cells that comprise an antitumor immune response, therefore, restricting immune-mediated tumor destruction, and leading to therapeutic resistance and unsatisfactory prognosis. Here, we report a metal-phenolic coordination-based nanocomplex loaded with a natural polyphenol galloflavin, which inhibits the function of lactate dehydrogenase, reducing the production of lactic acid, and alleviating the acidic immunosuppressive TME. Besides, the co-entrapped natural polyphenol carnosic acid and the synthetic PEG-Ce6 polyphenol derivative (serving as a photosensitizer) could induce immunogenic cancer cell death upon laser irradiation, which further activates immune system and promotes immune cell recruitment and infiltration in tumor tissues. We demonstrated that this nanocomplex-based combinational therapy could reshape the TME and elicit immune responses in a murine breast cancer model, which provides a promising strategy to enhance the therapeutic efficiency of drug-resistant breast cancer.

Unraveling the Role of Metal Vacancy Sites and Doped Nitrogen in Enhancing Pseudocapacitance Performance of Defective MXene.

Nitrogen-doped titanium carbides (MXene) films exhibit extraordinary volumetric capacitance when high-concentration sulfuric acid electrolyte is utilized owing to the enhancement of pseudocapacitance. However, the energy storage mechanism of nitrogen-doped MXene is unclear due to the complex electrode structure and electrolyte ions' behavior. Here, based on pristine MXene (Ti3C2O2), three different MXene structures are constructed by introducing metal vacancy sites and doped nitrogen atoms, namely, defective MXene (Ti2.9C2O2), nitrogen-doped MXene (Ti3C2O1.9N0.1), and nitrogen-doped MXene with metal vacancy sites (Ti2.9C2O1.9N0.1). Then, the density functional theory (DFT)-based calculations coupled with the effective screening medium reference interaction site method (ESM-RISM) are applied to reveal the electrochemical behavior at the electrode/electrolyte interfacial area. Through analyzing the electronic structure, electrical double-layer capacitance (EDLC), and equilibrium potential of the pseudocapacitance reaction, the specific effect of structural changes on their performance can be clarified: metal vacancy sites can reduce the potential difference of gap layer (Outer Helmholtz plane) at charged state and increase the electronic capacity of Ti, which can be used to explain the high pseudocapacitance, low charge transfer resistance and high-rate capacity properties of nitrogen-doped MXene observed in experiments.

CMTM6 overexpression confers trastuzumab resistance in HER2-positive breast cancer.

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is characterized by invasive growth, rapid metastasis and chemoresistance. Trastuzumab is an effective treatment for HER2+ breast cancer; however, trastuzumab resistance leads to cancer relapse and metastasis. CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) has been considered as a new immune checkpoint for tumor-induced immunosuppression. The role of CMTM6 in trastuzumab resistance remains unknown. Here, we uncover a role of CMTM6 in trastuzumab-resistant HER2+ breast cancer. CMTM6 expression was upregulated in trastuzumab-resistant HER2+ breast cancer cell. Patients with high CMTM6 expressing HER2+ breast cancer had worse overall and progression-free survival than those with low CMTM6 expression. In vitro, CMTM6 knockdown inhibited the proliferation and migration of HER2+ breast cancer cells, and promoted their apoptosis, while CMTM6 overexpression reversed these effects. CMTM6 and HER2 proteins were co-localized on the surface of breast cancer cells, and CMTM6 silencing reduced HER2 protein levels in breast cancer cells. Co-immunoprecipitation revealed that CMTM6 directly interacted with HER2 in HER2+ breast cancer cells, and CMTM6 overexpression inhibited HER2 ubiquitination. Collectively, these findings highlight that CMTM6 stabilizes HER2 protein, contributing to trastuzumab resistance and implicate CMTM6 as a potential prognostic marker and therapeutic target for overcoming trastuzumab resistance in HER2+ breast cancer.

Targeting SOST using a small-molecule compound retards breast cancer bone metastasis.

BACKGROUND: Breast cancer metastasis to the bone can be exacerbated by osteoporosis, is associated with poor long-term survival, and has limited therapeutic options. Sclerostin (SOST) is an endogenous inhibitor of bone formation, and an attractive target for treatment of osteoporosis. However, it is unclear whether SOST can be used as a therapeutic target for bone metastases of breast cancer, and whether small molecule compounds that target SOST in breast cancer cells can inhibit breast cancer bone metastasis. METHODS: SOST expression in 442 breast cancer tissues was characterized by immunohistochemistry and statistically analyzed for the association with breast cancer bone metastases. Bone metastatic breast cancer SCP2 cells were induced for SOST silencing or overexpression and their bone metastatic behaviors were tested in vitro and in vivo. To identify potential therapeutics, we screened inhibitors of the interaction of SOST with STAT3 from a small chemical molecule library and tested the inhibitory effects of one inhibitor on breast cancer growth and bone metastasis in vitro and in vivo. RESULTS: We found that up-regulated SOST expression was associated with breast cancer bone metastases and worse survival of breast cancer patients. SOST silencing significantly reduced the bone metastatic capacity of SCP2 cells. SOST interacted with STAT3 to enhance the TGF-ß/KRAS signaling, increasing both tumor growth and bone metastasis. Treatment with one lead candidate, S6, significantly inhibited the growth of breast-cancer organoids and bone metastasis in mice. CONCLUSIONS: Our findings highlight a new class of potential therapeutics for treatment of bone metastasis in breast cancer.

HCK can serve as novel prognostic biomarker and therapeutic target for Breast Cancer patients.

The role of HCK expression in the prognosis of breast cancer patients is unclear. Thus, this study aimed to explore the clinical implications of HCK expression in breast cancer. We assessed HCK expression and genetic variations in breast cancer using Oncomine, GEPIA, UALCAN, and cBioPortal databases. Then, immunochemistry was used to analyze HCK expression in breast cancer specimens, non-cancer tissues and metastatic cancer tissues. Consequently, we evaluated the effect of HCK expression on survival outcomes set as disease-free survival (DFS) and overall survival (OS). Finally, STRING, Coexpedia, and TISIDB database were explored to identify the molecular functions and regulation pathways of HCK. We found that breast cancer tissues have more HCK mRNA transcripts than non-cancer tissues. Patients with HCK expression had significantly shorter DFS and OS. The ratio of HCK expression was higher in cancer tissues than in non-cancer tissues. These results from STRING database, FunRich software, and TISIDB database showed that HCK was involved in mediating multiple biological processes including immune response-regulating signaling pathway, cell growth and maintenance through multiple signaling pathways including epithelial to mesenchymal transition, PI3K/AKT signaling pathway, and focal adhesion. Overall, HCK may be an oncogene in the development of breast cancer and thus may as a novel biomarker and therapeutic target for breast cancer.

Pre-column derivatization method for determining phenylephrine in human plasma and its application in a pharmacokinetic study.

In the present study, a rapid derivatization liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to evaluate phenylephrine in human plasma. The plasma samples were processed to precipitate the proteins, followed by derivatization of the phenylephrine in the plasma with dansyl-chloride solution and extraction with methyl tert-butyl ether-n-hexane (2:1, v/v). The treated samples were analyzed on a Gemini C18 column with 3 min gradient elution, and sensitive detection was achieved with a Waters TQ-s. The method gave linear results over a concentration range from 0.020 to 10.0 ng/ml. The lower limit of quantification was 0.020 ng/ml. Intra- and inter-day precision was <15%, and accuracy was 95.0-105.3%. The validated LC-MS/MS method was successfully applied in the pharmacokinetic analysis of phenylephrine in Chinese subjects with common cold after a single-dose administration of 5, 10 or 20 mg phenylephrine. This pre-column derivatization method may also be applied for the analysis of endogenous hormones such as norepinephrine and adrenaline in a biological matrix.

Molecular characterization and functional analysis of a novel candidate of cuticle carboxylesterase in Spodoptera exigua degradating sex pheromones and plant volatile esters.

Odorant-degrading enzymes (ODEs) are considered to play key roles in odorant inactivation to maintain the odorant receptor sensitivity of insects. Some members of carboxylesterase (CXE) is a major sub-family of ODEs. However, only a few CXEs have been functionally characterized so far. In the present study, we cloned the antennal esterase SexiCXE11 cDNA full-length sequences from the male antennae of a notorious crop pest, Spodoptera exigua, and its encoded 538 amino acids. It was similar to other insect esterases and had the characteristics of a carboxylesterase. We expressed recombinant enzyme in High-Five insect cells and obtained the high level purified recombinant protein by affinity column. Furthermore we test enzyme activity toward its two acetate sex pheromone components (Z9,E12-Tetradecadienyl acetate, Z9E12-14:Ac and Z9-Tetradecenyl acetate, Z9-14:Ac) and other 18 ester plant volatiles. Our results demonstrated that SexiCXE11 degraded acetate sex pheromone components with similar degradation activities (about 15.75% with Z9E12-14:Ac and 19.28% with Z9-14:Ac) and plant volatiles with a relatively high activity such as pentyl acetate and (Z)-3-hexenyl caproate. SexiCXE11 had high hydrolytic activity with these two ester odorants (>50% degradation), which is characterized that although a ubiquitous expression esterase SexiCXE11 may be partly involved with olfaction. This study may facilitate a better understanding of moth ODE differentiation and suggest strategies for the development of new pest behavior inhibitors.

Overexpression of rice aquaporin OsPIP1;2 improves yield by enhancing mesophyll CO2 conductance and phloem sucrose transport.

Aquaporins are involved in CO2 transport from the leaf intercellular air space to the chloroplast, which contributes to CO2 assimilation. However, the mechanism of CO2 transport by rice (Oryza sativa L.) aquaporins is unknown. Here, we investigated the function of the aquaporin OsPIP1;2 in CO2 diffusion-associated photosynthesis and phloem sucrose transport. Moreover, the grain yield of rice lines overexpressing OsPIP1;2 was determined. OsPIP1;2 was localized to the plasma membrane and the relative expression of OsPIP1;2 was approximately 5-fold higher in leaves in the presence of an elevated CO2 concentration. Overexpression of OsPIP1;2 increased mesophyll conductance by approximately 150% compared with wild-type (WT) rice. The OsPIP1;2-overexpressing lines had higher biomass than the WT, possibly due to increased phloem sucrose transport. In addition, the grain yield of OsPIP1;2-overexpressing lines was approximately 25% higher than that of the WT in three-season field experiments, due to the increased numbers of effective tillers and spikelets per panicle. Our results suggest that OsPIP1;2 modulates rice growth and grain yield by facilitating leaf CO2 diffusion, which increases both the net CO2 assimilation rate and sucrose transport.

In Situ Transmission Electron Microscope Liquid Cell 3D Profile Reconstruction and Analysis of Nanoscale Liquid Water Contact Line Movements.

Static nanodroplets and dynamic contact line (CL) movements were visualized by an in situ transmission electron microscope (TEM) liquid cell technique at nanometer spatial resolution. Crawling and sliding movements of nanoscale CL were observed. The crawling happened at a capillary number (Ca) range of ∼10-9 to ∼10-8, and the sliding happened at a Ca range of ∼10-8 to ∼10-7. Three dimensional (3D) image construction had been employed to study static and dynamic contact angles (CAs) at nanoscale. CA hysteresis at nanoscale was observed in the sliding but not in the crawling. The energies associated with sliding were analyzed to investigate the CA hysteresis. An empirical model of the relationship between nanoscale CAs and Ca was developed. Both the experimental observation and the empirical analysis suggested that the competition among substrate defect, CL elastic, and molecular activation energies dictated different CL movements at nanoscale.

Surgical Outcomes of Implant-based Breast Reconstruction Using TiLoop Bra Mesh Combined With Pectoralis Major Disconnection.

OBJECTIVE: This study aimed to compare breast symmetry and patient satisfaction with breast appearance between implant-based breast reconstruction using TiLoop Bra mesh combined with pectoralis major disconnection (IMR) and conventional implant reconstruction (IR), and to analyze differences in complications. METHODS: This retrospective study included 59 patients administered IMR or IR in 2016 to 2018. Three-dimensional scanning was performed to objectively evaluate breast symmetry. The BREAST-Q scale was used to survey satisfaction with breast appearance, social psychosocial health, physical health, and sexual well-being. RESULTS: There were no significant differences in age, TNM stage, and chemotherapy between the 2 groups (all P > 0.05). In 3-dimensional scanning data, patients who underwent IMR had better bilateral breast symmetry compared with those administered IR (all P < 0.001). Based on the BREAST-Q survey, the satisfaction rate was significantly higher for IMR compared with IR (P = 0.0368), whereas psychosocial health, physical health, and sexual well-being showed no significant differences between the 2 groups (all P > 0.05). The IMR model showed no obvious advantages in common complications, including hematoma, incision site infection, skin flap necrosis, and prosthesis exposure and rupture compared with IR; loss of skin and nipple sensations was evident in both groups. The IMR model was associated with reduced incidence of fibrous capsule contracture compared with IR (0% vs 18.75%, P = 0.0267). The incidence rates of pectoralis major disconnection syndrome after IMR and IR were 18.50% and 0%, respectively (P = 0.0161). CONCLUSIONS: Patients administered IMR have better breast symmetry and greater satisfaction with breast appearance compared with those treated by IR; however, IMR has unique complications, including pectoralis major disconnection syndrome.

Binding affinity characterization of an antennae-enriched chemosensory protein from the white-backed planthopper, Sogatella furcifera (Horváth), with host plant volatiles.

The white-backed planthopper (WBPH) Sogatella furcifera is a notorious rice pest in Asia. Olfaction is crucial for the WBPH to seek and locate rice plants. However, its mechanism is still not fully understood. Chemosensory proteins (CSPs) are some of the important olfactory-related proteins. In this study, we first used a bacterial system to successfully express the recombinant, antennae-enriched protein SfurCSP5. Further, competitive fluorescence binding assays with 86 candidate ligands, including some known rice plant volatiles, showed that SfurCSP5 has high affinities for 2-tridecanone, 2-pentadecanone, and ß-ionone, which are known to be present in volatile mixtures that can attract rice planthoppers, and produced Ki values of 4.89, 4.09, and 1.39 µmol/L, respectively. Additionally, homology modeling of the protein structure of SfurCSP5 showed that it possesses five α-helixes (α-1, α-2, α-3, α-4, and α-5), which is a non-typical feature of the insect CSPs. Finally, ligand docking results revealed that Leu-44, Ile-64, Phe-90, Trp-98, and Phe-101 are five hydrophobic residues that interact with all of the ligands, indicating their key involvement in the binding of SfurCSP5. Our study lays the foundation for an understanding of the olfaction mechanism of rice planthoppers.

Reduced graphene oxide wrapped on microfiber and its light-control-light characteristics.

Reduced graphene oxide (rGO) sheet wrapped on the tapered region of microfiber is demonstrated to enhance the interaction between rGO and strong evanescent field of optical fiber. The 405 nm and 980 nm lasers are employed to illuminate the rGO to investigate the response characteristics of the optical transmitted power (λ = 1550 nm) in the MF. The transmitted optical power of the MF with rGO changes with ~1.7 dB relative variation when the violet light is ranging from 0 mW to 12 mW (~0.21dB/mW) in the outside-pumped experiment. And in the inside-pumped experiment, the change of the 980 nm laser power from 0 mW to 156.5 mW makes ~6 dB relative variation power of the transmitted optical powers of the MF with rGO. These results indicate the optical transmitted power of the MF with wrapped rGO can be manipulated by the 405 and 980 nm light (order of mW), which signifies the device can potentially be applied as all optically and versatilely controllable devices.

Enhanced optical sensitivity of molybdenum diselenide (MoSe2) coated side polished fiber for humidity sensing.

In this paper, a side-polished fiber (SPF) coated with molybdenum diselenide (MoSe2) is proposed, and its characteristic of relative humidity (RH) sensing is investigated. It is found in the experiment that an enhancement in RH sensitivity (0.321 dB/%RH) can be achieved in a very wide RH range of 32%RH to 73%RH for the proposed MoSe2 coated SPF (MoSe2CSPF). It is also shown that the MoSe2CSPF has a rapid response of 1s and recovery time of 4s, which makes the sensor capable of monitoring human breath. The experimental results suggest MoSe2 has a promising potential in photonics applications such as all-fiber optic humidity sensing networks.

Higher viral load and genetic diversity of HIV-1 in seminal compartments than in blood of seven Chinese men who have sex with men and have early HIV-1 infection.

To date, there have been no reports characterizing HIV-1 in the semen of Chinese men who have sex with men (MSM) with early infection. In this study, genetic diversity and viral load of HIV-1 in the seminal compartments and blood of Chinese MSM with early HIV-1 infection were examined. Viral load and genetic diversity of HIV-1 in paired samples of semen and blood were analyzed in seven MSM with early HIV-1 infection. HIV-1 RNA and DNA were quantitated by real-time PCR assays. Through sequencing the C2-V5 region of the HIV-1 env gene, the HIV-1 genotype and genetic diversity based on V3 loop amino acid sequences were determined by using Geno2pheno and PSSM programs co-receptor usage. It was found that there was more HIV-1 RNA in seminal plasma than in blood plasma and total, and more 2-LTR circular and integrated HIV-1 DNA in seminal cells than in peripheral blood mononuclear cells from all seven patients with early HIV-infection. There was also greater HIV-1 genetic diversity in seminal than in blood compartments. HIV-1 in plasma displayed higher genetic diversity than in cells from the blood and semen. In addition, V3 loop central motifs, which present some key neutralizing antibody epitopes, varied between blood and semen. Thus, virological characteristics in semen may be more representative when evaluating risk of transmission in persons with early HIV infection.

Clinical significance of SPRR1A expression in progesterone receptor-positive breast cancer.

Small proline-rich repeat protein 1A (SPRR1A) is a marker for terminal squamous cell differentiation. Previous studies showed that SPRR1A expression increases in squamous cell carcinoma of the skin, but decreases in esophageal squamous cell carcinoma. This study focuses on the expression of SPRR1A protein in breast cancers (BCs) in China. A total of 111 patients with histologically confirmed BC, who underwent radical surgery between January 2006 and September 2007 in China Medical University, were enrolled. The relationship between SPRR1A expression and clinicopathological factors as well as BC prognoses was also determined. Overall, SPRR1A expression was detected in more than half of the BC specimens by immunohistochemistry (56/111, 53.8%), but there was no significant difference between age groups (≥50 vs. <50 years) in terms of SPRR1A expression (P = 0.915), as well as no differences between SPRR1A expression and the clinical stage (0-I vs. II-III) or nodal status (P = 0.234 and 0.632, respectively). Moreover, human epidermal growth factor receptor 2 overexpression was not correlated with SPRR1A expression, whereas Ki67 was associated with SPRR1A expression (P = 0.155 and 0.028, respectively). Interestingly, SPRR1A expression was significantly associated with progesterone receptor-positive (P = 0.010) rather than estrogen receptor-positive (0.778) BCs. The 5-year survival rate in patients did not differ with the presence or absence of SPRR1A expression (P = 0.753), whereas the combination of SPRR1A expression, progesterone receptor status, and menopausal status allowed identification of a subgroup of BC patients with a good long-term prognosis. Thus, the SPRR1A status might play an important role in the prognosis of postmenopausal breast carcinoma patients, especially that of progesterone receptor-positive subgroups.

Relationships of urinary VEGF/CR and IL-6/CR with glomerular pathological injury in asymptomatic hematuria patients.

BACKGROUND: Interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) have important functions in injury and repair processes of glomerular intrinsic cells. A study was conducted to analyze the urinary VEGF/creatinine (CR) and IL-6/CR levels in simple hematuria patients after excluding the interference of creatinine. We aimed to investigate the function and relationships of the above indices in the glomerular pathological injury process, and to elaborate the values of urinary VEGF and IL-6 changes in the diagnosis of asymptomatic hematuria or hematuria with proteinuria. MATERIAL/METHODS: A total of 121 renal hematuria patients diagnosed by clinical and laboratory tests were included as research subjects. The midstream fresh morning urine was collected on the day renal biopsy was performed. RESULTS: The IL-6/CR value of the group III was significantly greater than in group I (Z=-2.478, P<0.05), with a statistically significant difference between these 2 groups. The VEGF/CR value of group III was significantly greater than in group II (P<0.01). Compared with group I, the VEGF/CR of group III was significantly greater (Z=-4.65, P<0.01), with a statistically significant difference. CONCLUSIONS: The VEGF/CR and IL-6/CR values in simple hematuria patients were positively correlated with glomerular pathological injury scores. VEGF/CR and IL-6/CR might be used as biological diagnostic indicators in determining the extent of simple hematuria glomerular injury.

Clinicopathologic analysis of isolated hematuria in child/adolescent and adult patients.

To our knowledge, no in-depth clinicopathologic study of isolated hematuria (IH) is currently available. To address this gap, we analyzed the clinicopathologic features of IH as it manifests in child/adolescent and adult patients. The clinical data and pathological types of 543 IH patients who underwent renal pathological examinations from January 2005 to June 2010 were retrospectively analyzed. Clinical manifestations differed among the age groups: children/adolescents exhibited the highest percentage of mesangial proliferative glomerulonephritis (41.78%), whereas adults showed the highest percentage of immunoglobulin A nephropathy (IgAN) (52.39%). In addition, the percentage of IH patients who were classified according to clinical pathology differed from that of patients who were classified according to renal pathological type. Patients with IgAN who were found to have minimal proteinuria had more severe IH. For IH patients, especially those with a small amount of proteinuria, renal biopsy should be performed as early as possible in order to develop a long-term treatment plan and prognosis evaluation.

Clinical implications of GRHL3 protein expression in breast cancer.

The objective of this study was to investigate the expression and significance of the GRHL3 protein in breast cancer diagnosis and prognosis. Overall, 111 patients with histologically confirmed breast cancer who had undergone radical surgery were enrolled in this study. The GRHL3 protein expression status in the breast cancers was evaluated by immunohistochemistry. The relationship between GRHL3 protein expression status and clinicopathological factors and the breast cancer prognoses was also determined. In total, 71 (63.96%) out of 111 cases were found to express GRHL3 protein. GRHL3 expression was higher in breast cancers, compared to other pathologic cancer types (χ (2) = 5.68, P < 0.05). Moreover, GRHL3 protein was also observed to correlate with breast cancer clinical stage and histological grade (χ (2) = 7.99, P < 0.05 and χ (2) = 7.907, P < 0.05, respectively). Interestingly, triple-negative breast cancers had lower expression rates than other breast cancers (41.18 vs. 71.28%, P < 0.05). GRHL3 was shown to be an independent prognostic factor of breast cancer in Cox regression analysis. Altogether, our results indicate predominant GRHL3 expression in breast cancers, especially non-triple-negative cancers and early stage cancers. GRHL3 expression appeared to decrease with tumor progression. Survival analysis demonstrated the inhibitory effect of GRHL3 in breast cancer. These results strongly suggest the possible involvement of GRHL3 in tumor suppression.