Causal effect of age first had sexual intercourse and lifetime number of sexual partners on cervical cancer.

Objective: In this study, we aimed to investigate whether age first had sexual intercourse (AFSI) and lifetime number of sexual partners (LNSP) have a direct causal effect on cervical cancer by Mendelian randomization (MR) analysis. Methods: Four approaches were used for MR Analysis, including MR-Egger, weighted method, weighted median, and inverse variance weighted (IVW). MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) as well as MR-Egger regression analysis were conducted to detect whether there was pleiotropy between IVs and outcome, and the outlier SNPs can be detected by MR-PRESSO. The presence or absence of heterogeneity among IVs was suggested according to Cochran's Q statistic. Leave-one-out sensitivity analysis was performed to identify and remove SNPs which could independently change the results. We corrected the results using Bonferroni correction. Results: From the results of IVW, AFSI had a negative effect on cervical cancer (OR = 0.996, 95 % CI: 0.995, 0.998 P = 1.70E-07), which still persisted after Bonferroni correction. However, no causal effect of LNSP on cervical cancer was found according to the IVW results (OR = 1.003, 95 % CI: 1.000, 1.007, P = 0.071). From the results of MR-PRESSO and MR-Egger, no SNP with horizontal pleiotropy between cervical cancer was detected and no SNP was identified as an outlier SNP. Cochran's Q statistic suggested that no heterogeneity existed among IVs of AFSI and LNSP. According to Leave-one-out analysis, the results of MR did not change after excluding any single IV. Conclusion: This MR study reveals that early AFSI has a causal effect on cervical cancer.

Construction of Multi-Mode Photoelectrochemical Immunoassays for Accurate Detection of Cancer Markers: Assisted with MOF-Confined Plasmonic Nanozyme.

In clinical diagnostics, sensitive and accurate biomarker monitoring is greatly challenged by the limitations of false positive/negative errors in single-modal photoelectrochemical analysis. Herein, we propose a multimode immunoassay by integrating photoelectrochemical, colorimetric, and photothermal imaging analysis into one electrode. The immunosensors could simultaneously achieve three detection modes at one electrode, which provided a new pathway for the accurate detection of the target prostate-specific antigen (PSA) and circumvented false-positive or negative errors during the detection process. To this end, an integrated multifunctional chip (TiO2/ZIF-8/Cu(II)) was first constructed via in situ embedding of Cu(II) in the Metal-organic framework growth process. Then, an alkaline phosphatase-labeled magnetic probe was designed to achieve split-type detection for PSA. In a sodium thiophosphate solution, the in situ generated H2S could react with Cu(II) to form small-size CuS due to the nanoconfinement of ZIF-8 and thus result in the formation of p-n heterojunctions (TiO2/ZIF-8/CuS). The TiO2/ZIF-8/CuS could efficiently improve the light-harvesting ability and facilitate the charge separation efficiency, thus finally resulting in an increased photocurrent in the PEC mode. Furthermore, by constructing the portable colorimetric and photothermal sensors based on the Arduino microcontroller and photothermal imager, the TiO2/ZIF-8/CuS also provided point-of-care and visual detection modes, as the in situ-formed CuS exhibited peroxidase-mimicking activity and outstanding photothermal properties. The work had important prospects for establishing multimode immunoassays for the accurate detection of cancer markers in early disease diagnosis.

Atomically Fe-anchored MOF-on-MOF nanozyme with differential signal amplification for ultrasensitive cathodic electrochemiluminescence immunoassay.

The successful application of electrochemiluminescence (ECL) in immunoassays for clinical diagnosis requires stable electrodes and high-efficient ECL signal amplification strategies. Herein, the authors discovered a new class of atomically dispersed peroxidase-like nanozymes with multiple active sites (CoNi-MOF@PCN-224/Fe), which significantly improved the catalytic performance and uncovered the underlying mechanism. Experimental studies and theoretical calculation results revealed that the nanozyme introduced a Fenton-like reaction into the catalytic system and the crucial synergistic effects of definite active moieties endow CoNi-MOF@PCN-224/Fe strong electron-withdrawing effect and low thermodynamic activation energy toward H2O2. Benefiting from the high peroxidase-like activity of the hybrid system, the resultant ECL electrode exhibited superior catalytic activity in the luminol-H2O2 system and resulted in an ≈17-fold increase in the ECL intensity. In addition, plasmonic Ag/Au core-satellite nanocubes (Ag/AuNCs) were designed as high-efficient co-reactant quenchers to improve the performance of the ECL immunoassay. On the basis of the differential signal amplification strategy (DSAS) proposed, the immunoassay displayed superior detection ability, with a low limit of detection (LOD) of 0.13 pg mL-1 for prostate-specific antigen (PSA). The designed atomically anchored MOF-on-MOF nanozyme and DSAS strategy provides more possibilities for the ultrasensitive detection of disease markers in clinical diagnosis.

Fabrication and nano-engineering of non-/noble metal-coupled plasmonic heterostructures for ultrasensitive photoelectrochemical immunoassays.

To achieve reliable and ultrasensitive detection for disease markers in PEC bioanalysis, constructing and nano-engineering of ideal photoelectrodes and signal transduction strategies are of vital importance. Herein, a non-/noble metal coupled plasmonic nanostructure (TiO2/r-STO/Au) was tactically designed with high-efficient PEC performance. Evidenced by the DFT and FDTD calculations, the reduced SrTiO3 (r-STO) was found to support the localized surface plasmon resonance due to the sufficiently increased and delocalized local charge in r-STO. Under the synergistic coupling of plasmonic r-STO and AuNPs, the PEC performance of TiO2/r-STO/Au was found remarkably promoted with reduced onset potential. This merit supported TiO2/r-STO/Au as a self-powered immunoassay via a proposed oxygen-evolution-reaction mediated signal transduction strategy. With the increase of the target biomolecules (PSA), the catalytic active sites of TiO2/r-STO/Au would be blocked and result in the decrease of the oxygen evaluation reaction. Under optimal conditions, the immunoassays exhibited an excellent detection performance with a LOD as low as 1.1 fg/mL. This work proposed a new type of plasmonic nanomaterial for ultrasensitive PEC bioanalysis.

Ion-Exchange Reaction-Mediated Hierarchical Dual Z-Scheme Heterojunction for Split-Type Photoelectrochemical Immunoassays.

Photoelectrochemical (PEC) immunoassays with ultrasensitive detection abilities are highly desirable for in vitro PEC diagnosis and biological detection. In this paper, dual Z-scheme PEC immunoassays with hierarchical nanostructures (TiO2@NH2-MIL-125@CdS) are synthesized through epitaxial growth of MOF-on-MOF and further in situ derivatization. The dual Z-scheme configuration not only extends the light absorption range but also increases the redox ability due to the interface structure nanoengineering, which synergistically suppresses bulk carrier recombination and promotes the charge transfer efficiency at the electron level. Furthermore, a smart MOF-derived labeling probe (CuO@ZnO nanocube) is designed to develop a split-type PEC biosensor by using prostate-specific antigen (PSA) as a target biomarker. In the presence of PSA, the Ab2-labeled CuO@ZnO would specifically bond to the dual Z-scheme electrode. Then, the MOF-derived CuO@ZnO is dissolved by hydrochloric acid to release Cu2+, which could replace Cd2+ via an ion-exchange reaction, thus leading to the decrease of the photocurrent due to the destruction of the dual Z-scheme configuration. In typical applications, the split-type PEC immunoassay exhibits an excellent detection performance for PSA with a LOD as low as 0.025 pg·mL-1.

Do reverse total shoulder replacements have better clinical and functional outcomes than hemiarthroplasty for patients undergoing proximal humeral tumor resection using devitalized autograft composite reconstruction: a case-control study.

OBJECTIVE: To compare the efficacy and prognosis of reverse total shoulder arthroplasty (rTSA) with shoulder hemiarthroplasty (SHA) using devitalized autograft or allograft composite reconstruction after proximal humeral tumor resection. METHODS: We retrospectively reviewed patients who underwent SHA (32) and rTSA (20) for tumor resections of the proximal humerus from January 2014 to July 2020. The clinical results included duration of the operation, intraoperative blood loss, bone union, visual analog scale (VAS) score, shoulder range of motion (ROM), American Shoulder and Elbow Surgeons (ASES) shoulder score, recurrence, and overall survival. RESULTS: Fifty-two patients were followed up for a mean of 30 months. Thirty-two patients were SHA with allograft-prosthetic composite (APC) reconstructions, while other 20 were rTSA with devitalized autograft-prosthetic composite reconstructions. At the end of the follow-up, 2 recurrence, 3 postoperative infections, and 4 subluxations occurred among the SHA patients. Two patients in the rTSA group had postoperative anterior dislocation and underwent revision surgery with surgical mesh, and 2 (2/20) had grade II scapular notching. The mean VAS score of the shoulder was 1.5 ± 0.8 in the rTSA group and 2.3 ± 1.2 in the SHA group (p < 0.05). The mean active forward flexion of the shoulder joint was 50.6 ± 6.0 in the SHA group and 100 ± 7.6 in the rTSA group (p < 0.05). The ASES shoulder score was 78 ± 3.0 in the rTSA group and 52 ± 5.6 in the SHA group (p < 0.05). The overall 3-year survival rate of all patients was 60.0%, and patients in the rTSA group showed better survival in terms of the mean 3-year OS than patients in the SHA group (p = 0.04). CONCLUSION: rTSA with devitalized autograft-prosthetic composite can offer a reasonable reconstruction of the shoulder joint after Malawer type I tumor resection. Compared with patients who underwent SHA, patients who underwent rTSA present good outcomes, a better range of motion, better bone union, and no increase in instability rate in the mid-term.

Effects of Qingshen Granules on Immune Function in Patients with Comorbid Chronic Renal Failure and Damp-Heat Syndrome: A Multicenter, Randomized, Controlled Trial.

OBJECTIVE: The current study sought to compare the effects of the addition of Qingshen granules to conventional Western medicine on immune function in patients with comorbid chronic renal failure and damp-heat syndrome and to explore the possible mechanisms responsible for any differences observed. METHODS: Through a multicenter, randomized, controlled study, a total of 282 eligible patients were divided into experimental (n = 136) and control groups (n = 146). All of the patients were treated with conventional Western medical therapy. The experimental group also received Qingshen granules three times daily for 12 weeks. Clinical efficacy was observed in the two groups. Peripheral blood levels of CD4+ T cells, CD8+ T cells, Th17 cells, nuclear factor-κB p65 (NF-κB p65) activity, serum interleukin-17 (IL-17), serum interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), tumor necrosis factor receptor-associated factor 6 (TRAF6), fibronectin (FN), and type IV collagen (Col-IV) were detected in both groups. RESULTS: The total clinical curative effective rate was significantly higher (p < 0.05) in the experimental group (79.41%) than in the control group (67.12%). Before treatment, there were no significant differences in CD4+/CD8+ T cell ratio, Th17 cell level, NF-κB p65 activity, serum IL-17, IL-6, TNF-α, TRAF6, FN, and Col-IV between the experimental and control groups (p > 0.05); however, all of the measures were significantly higher than those observed in a healthy comparison group (p < 0.05 or p < 0.01). After treatment, the above indexes in the experimental group were significantly lower than those before treatment (p < 0.05 or p < 0.01). Similarly, NF-κB p65 activity, serum IL-17, TNF-α, TRAF6, FN, and Col-IV in the control group were significantly lower than the levels observed prior to treatment (p < 0.05 or p < 0.01); however, while all of the other indexes were lower than those observed before treatment, the differences were not statistically significant (p > 0.05). CONCLUSION: Qingshen granules adjust immune dysfunction, improve immunity mediated inflammatory response, and attenuate renal fibrosis in patients with comorbid chronic renal failure and damp-heat syndrome.

Plasmonic SERS Au Nanosunflowers for Sensitive and Label-Free Diagnosis of DNA Base Damage in Stimulus-Induced Cell Apoptosis.

Molecular diagnosis and accurate damage analysis of complex genomic DNAs in tumor cells are crucial to the theranostics of cancers but still a huge challenge. Herein, by designed preparation of a uniform plasmonic sunflower-like assembly gold (Au) nanostructure that is capable of efficient DNA capture and providing high-density gap-plasmon "hot spots" for adequate surface-enhanced Raman spectroscopy (SERS) enhancement, we succeeded in sensitive and reliable label-free SERS detection of DNA damage in electrostimulus-induced apoptotic cancer cells at the DNA base level for the first time. The SERS results showed that the external electrostimulus (at 1.2 V, for 5 min) was almost harmless to normal healthy cells, but it caused pronounced double strand break and adenine base damage in cancer cell DNAs, which effectively destroyed the reproduction and transcription of DNAs and ultimately induced cell apoptosis. The developed sensing platform and method are promising for cell study of genetically related diseases.

Nanoengineered Metasurface Immunosensor with over 1000-Fold Electrochemiluminescence Enhancement for Ultra-sensitive Bioassay.

Enhancing electrochemiluminescence (ECL) with plasmonic materials is promising but still a long-standing barrier to improve its sensitivity for ultrasensitive bioassays, due to the lack of comprehensive understanding and effective strategies to fully utilize plasmonic effects for ECL enhancement. Herein, by insulating gold nanoparticles with silica shells (Au@SiO2 NPs), and finely tuning their core/shell sizes and controlling interparticle spacing via assembling them into a dense nanomembrane, we develop a novel 2D metasurface. Due to well-controlled high density "hot spots" and 2D ordered arrangement of the unit NPs in the nanomembrane, the metasurfaced ECL electrode shows over 1,000-fold plasmonic ECL enhancement for the classical Ru(bpy)32+-tripropylamine system, which is two orders of magnitude higher than ever reported (<30-fold). Such fabricated ECL biosensor demonstrates superior detection performance for prostate-specific antigen with a detection limit of 3 fg mL-1. Our results provide understanding of plasmonic effects for ECL enhancement and will benefit for biosensor construction for ultrasensitive bioassays.

Living-Cell Imaging of Mitochondrial Membrane Potential Oscillation and Phenylalanine Metabolism Modulation during Periodic Electrostimulus.

Special electrosensory cells are sensitive to electric fields and give responses upon stimulation, but little is known about normal regular cells and cancerous cells. Herein, by designing nucleus- and mitochondria-targeting SERS nanoprobes combined with fluorescent monitoring of the mitochondrial membrane potential (MMP) variations, we found an interesting electrosensory and self-healing response in MMP within cancerous and normal cells during periodic impulse electrostimulation (IES). More importantly, the key regulator role of phenylalanine (phe) was revealed by cell fluorescent imaging and SERS detection, whose expression level was increased in response to IES to induce cell apoptosis. During IES off-state, the self-repair function of cells was activated to reduce phe release. We also found that cancerous cells (MCF-7 and HeLa cells) demonstrated a response more remarkable than that of normal cells (L929 and H8 cells) to periodic IES. Our finding revealed a common electrosensory and self-repair biofunction of cells and its related phe metabolism response. Understanding the difference of biophysical/electrophysiological responses between cancerous and normal cells may broaden the view for cancer therapy in the future.

Smart Plasmonic Nanorobot for Real-Time Monitoring Cytochrome c Release and Cell Acidification in Apoptosis during Electrostimulation.

Cytochrome c (Cyt c) release and cellular pH change are two important mediators of apoptosis. Effective methods to regulate or monitor such two events are therefore highly desired for apoptosis research and cancer cell therapy. Herein, we exploited electrostimulation to regulate cellular Cyt c release and apoptosis process, and by designing and preparing a smart and efficient plasmonic nanorobot (with surface-modified Cyt c-specific aptamer and 4-mercaptobenzoic acid) that is capable of Cyt c capture and self-sensing, we achieved real-time SERS monitoring of dynamic Cyt c release and simultaneous cell acidification in apoptosis during electrostimulation. Distinctly different molecular stress responses in the two events for cancerous MCF-7 and HeLa cells and normal L929 cells were identified and revealed. The method and results are valuable and promising for apoptosis and Cyt c-mediated biology studies.

Nucleus and Mitochondria Targeting Theranostic Plasmonic Surface-Enhanced Raman Spectroscopy Nanoprobes as a Means for Revealing Molecular Stress Response Differences in Hyperthermia Cell Death between Cancerous and Normal Cells.

Metallic plasmonic nanoparticles have been intensively exploited as theranostic nanoprobes for plasmonic photothermal therapy (PPT) and surface-enhanced Raman spectroscopy (SERS) applications. But the underlying molecular mechanisms associated with PPT-induced apoptosis between cancerous and normal cells have remained largely unknown or disputed. In this study, we designed an organelle-targeting theranostic plasmonic SERS nanoprobe (CDs-Ag/Au NS) composed of porous Ag/Au nanoshell (p-Ag/Au NSs) and carbon dots (CDs) for nucleus and mitochondria targeted PPT of cells. The differences in molecular stress response in the PPT-induced hyperthermia cell death between cancerous HeLa and normal L929 and H8 cells have been revealed by site-specific single-cell SERS detection. The contents of tryptophan (Trp), phenylalanine (Phe), and tyrosine (Tyr) in HeLa cells were found more evidently increased than L929 and H8 cells during the PPT-induced cell-death process. And from the mitochondria point of view, we found that the PPT-induced cell apoptosis for HeLa cells mainly stems from (or is regulated through) cellular thermal stress-responsive proteins, while for L929 and H8 cells it seems more related to DNA. Understanding molecular stress response difference of the PPT-induced cell apoptosis between cancerous and normal cells is helpful for diagnosis and treatment of cancer, and the method will open an avenue for single-cell studies.

Controlled Decoration of Divalent Nickel onto CdS/CdSe Core/Shell Quantum Dots to Boost Visible-Light-Induced Hydrogen Generation in Water.

The search for a low-cost, noble-metal-free cocatalyst to replace expensive Pt for hydrogen (H2 ) photogeneration in water has become a hot research topic, and among these, Ni-based cocatalysts are promising and highly desired. Developing new strategies and protocols to obtain Ni-based cocatalysts with high activity is therefore vitally important. Herein, we develop a new method to efficiently decorate divalent Ni onto pre-synthesized CdS/CdSe core/shell quantum dots (QDs). The concentration of Ni on the QDs can be easily tuned by varying the amount of the Ni precursor introduced during the synthesis. Further analyses reveal that Ni2+ can be strongly decorated onto QDs. Impressively, the Ni-decorated QDs displayed a significantly enhanced H2 photogeneration performance as compared to the two components prepared separately. Through the optimization of the Ni concentration on the QDs, the turnover frequency (TOF) with respect to Ni and quantum yield ( Φ H 2 ) at 520 nm for H2 evolution from water could reach 322 h-1 and 12.3 %, respectively. A possible mechanism has also been proposed and discussed in detail.

Single-cell pH imaging and detection for pH profiling and label-free rapid identification of cancer-cells.

Single-cell pH-sensing and accurate detection and label-free fast identification of cancer-cells are two long-standing pursuits in cell and life science, as intracellular pH plays a crucial role in many cellular events and fates, while the latter is vital for early cancer theranostics. Numerous methods based on functionalized nanoparticles and fluorescence probes have been developed for cell pH-sensing, but are often hindered for single-cell studies by their main drawbacks of complicated probe preparation and labeling, low sensitivity and poor reproducibility. Here we report a simple and reliable method for single-cell pH imaging and sensing by innovative combined use of UV-Vis microspectroscopy and common pH indicators. Accurate and sensitive pH detection on single-cell or sub-cell level with good reproducibility is achieved by the method, which enables facile single-cell pH profiling and label-free rapid identification of cancer-cells (due to distinguishable intracellular pH levels) for early cancer diagnosis, and may open a new avenue for pH-related single-cell studies.