SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species.

DNA repair has been hypothesized to be a longevity determinant, but the evidence for it is based largely on accelerated aging phenotypes of DNA repair mutants. Here, using a panel of 18 rodent species with diverse lifespans, we show that more robust DNA double-strand break (DSB) repair, but not nucleotide excision repair (NER), coevolves with longevity. Evolution of NER, unlike DSB, is shaped primarily by sunlight exposure. We further show that the capacity of the SIRT6 protein to promote DSB repair accounts for a major part of the variation in DSB repair efficacy between short- and long-lived species. We dissected the molecular differences between a weak (mouse) and a strong (beaver) SIRT6 protein and identified five amino acid residues that are fully responsible for their differential activities. Our findings demonstrate that DSB repair and SIRT6 have been optimized during the evolution of longevity, which provides new targets for anti-aging interventions.

Escape from breast tumor dormancy: The convergence of obesity and menopause.

Obesity is associated with an increased risk of, and a poor prognosis for, postmenopausal (PM) breast cancer (BC). Our goal was to determine whether diet-induced obesity (DIO) promotes 1) shorter tumor latency, 2) an escape from tumor dormancy, and 3) an acceleration of tumor growth and to elucidate the underlying mechanism(s). We have developed in vitro assays and PM breast tumor models complemented by a noninvasive imaging system to detect vascular invasion of dormant tumors and have used them to determine whether obesity promotes the escape from breast tumor dormancy and tumor growth by facilitating the switch to the vascular phenotype (SVP) in PM BC. Obese mice had significantly higher tumor frequency, higher tumor volume, and lower overall survival compared with lean mice. We demonstrate that DIO exacerbates mammary gland hyperplasia and neoplasia, reduces tumor latency, and increases tumor frequency via an earlier acquisition of the SVP. DIO establishes a local and systemic proangiogenic and inflammatory environment via the up-regulation of lipocalin-2 (LCN2), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) that may promote the escape from tumor dormancy and tumor progression. In addition, we show that targeting neovascularization via a multitargeted receptor tyrosine kinase inhibitor, sunitinib, can delay the acquisition of the SVP, thereby prolonging tumor latency, reducing tumor frequency, and increasing tumor-free survival, suggesting that targeting neovascularization may be a potential therapeutic strategy in obesity-associated PM BC progression. This study establishes the link between obesity and PM BC and, for the first time to our knowledge, bridges the dysfunctional neovascularization of obesity with the earliest stages of tumor development.

Enhanced response over wavelength range of 7-12 µm for quantum wells in asymmetric micro-pillars.

Efficient coupling in broad wavelength range is desirable for wide-spectrum infrared light detection, yet this is a challenge for intersubband transition in semiconductor quantum wells (QWs). High-Q cavities mostly intensify the absorption at peak wavelengths but with shrinking bandwidth. Here, we propose a novel approach to expand the operating spectral range of the Quantum Well Infrared Photodetectors (QWIPs). By processing the QWs into asymmetric micro-pillar array structure, the device demonstrates a substantial enhancement in spectral response across the wavelength from 7.1 µm to 12.3 µm with guided mode resonance (GMR) effects. The blackbody responsivity is then increased by 3 times compared to that of the 45° polished edge-coupled counterpart. Meanwhile, the dark current density remains unchanged after the deep etching process, which will benefit the electrical performance of the detector with reduced volume duty ratio. In contrast to the symmetric micro-pillar array that contains simple resonance mode, the detectivity of QWIP in asymmetric pillar structure is found to be improved by 2-4 times within the range of 9.5 µm to 15 µm.

Controlled Release of Amphoteric Surfactant from Mesoporous Nanosilica To Enhance Natural Gas Production at High Temperatures.

Surfactants are widely used as foaming agents to remove liquid accumulation in gas wells, enhancing natural gas production. The surfactant used in traditional foam sticks was dissolved and released as foam in a short period, especially at elevated downhole temperatures. This often requires the addition of foam sticks to maintain foam. To solve this problem, this study studies the utilization of nano silica to incorporate the amphoteric surfactant, cocamidopropyl betaine (CAB), into the mesoporous structure of silica nanocomposite as foam sticks for controlled release of CAB. Mesoporous nano silica was prepared by a sol-gel acid-catalyzed process with a silica precursor. The formation of nanocomposite solid sticks containing the amphoteric surfactant was achieved by aging and drying. The composite was characterized by various techniques: infrared spectroscopy, thermogravimetric analysis, energy-dispersive spectrometry, scanning electron microscopy, transmission electron microscopy, and small-angle X-ray diffraction. Results showed that 49.3% of CAB was encapsulated within the mesoporous structure of 30-50 nm nano silica. CAB release over time in aqueous solution at 130 °C exhibited 10.1% surfactant left in the nanocomposite after 72 h, as determined by thermal analysis. Surfactant release was systematically evaluated through foam performance tests. The study revealed that CAB could be control-released over 168 h via CAB diffusion from mesoporous silica. This study provides a longer-lasting foam method to enhance gas production by utilizing mesoporous silica as a control release medium for gas well deliquification.

Nanochannel Electro-Injection as a Versatile Platform for Efficient RNA/DNA Programming on Dendritic Cells.

The utilization of dendritic cell (DC) vaccines is a promising approach in cancer immunotherapy, and the modification of DCs for the expression of tumor-associated antigens is critical for successful cancer immunotherapy. A safe and efficient method for delivering DNA/RNA into DCs without inducing maturation is beneficial to achieve successful DC transformation for cell vaccine applications, yet remains challenging. This work presents a nanochannel electro-injection (NEI) system for the safe and efficient delivery of a variety of nucleic acid molecules into DCs. The device is based on track-etched nanochannel membrane as key components, where the nano-sized channels localize the electric field on the cell membrane, enabling lower voltage (<30 V) for cell electroporation. The pulse conditions of NEI are examined so that the transfection efficiency (>70%) and biosafety (viability >85%) on delivering fluorescent dyes, plasmid DNA, messenger RNA, and circular RNA (circRNA) into DC2.4 are optimized. Primary mouse bone marrow DC can also be transfected with circRNA with 68.3% efficiency, but without remarkably affecting cellular viability or inducing DC maturation. These results suggest that NEI can be a safe and efficient transfection platform for in vitro transformation of DCs and possesses a promising potential for developing DC vaccines against cancer.

Quantitative quasi-distributed vibration sensing by φ-OFDR for multiple events over spatially consecutive sensing spatial resolutions.

We report on a quantitative quasi-distributed vibration sensing (DVS) system enabled by phase-sensitive optical frequency domain reflectometry (φ-OFDR), which allows for multiple vibration events over consecutive spatial resolutions. To achieve effective crosstalk suppression and mitigation of the instability during the phase extraction, fiber with embedded ultra-weak grating arrays has been adopted as the sensing fiber. It exhibits a particularly customized low spatial duty cycle, that is, high ratio between the size of the gratings and their spacing and the spacing is additionally designed to match the integer multiple of the theoretical spatial resolution. In combination with a rectified frequency-modulated continuous-wave optical probe enabled by the optical phase-locked loop, it allows to achieve quantitative quasi-DVS for multiple events over consecutive sensing spatial resolution as high as ∼2.5 cm along the distance over ∼2200 m. The ability to simultaneously retrieve arbitrary multi-point vibration events over spatially consecutive sensing spatial resolutions with consistently linear response and sensitivity up to a few nano-strain level even at long distances has shown great potentials for the application of φ-OFDR from a practical point of view.

Enhanced absorption of infrared light for quantum wells in coupled pillar-cavity arrays.

Periodic pillars of semiconductor in sub-wavelength size can serve multiple roles as diffracting, trapping and absorbing light for effective photoelectric conversion which has been intensively studied in the visible range. Here, we design and fabricate the micro-pillar arrays of AlGaAs/GaAs multi quantum wells(QWs) for high performance detection of long wavelength infrared light. Compared to its planar counterpart, the array offers 5.1 times intensified absorption at peak wavelength of 8.7 µm with 4 times shrinked electrical area. It's illustrated by simulation that the normal incident light is guided in the pillars by HE11 resonant cavity mode to form strengthened Ez electrical field, which enables the inter-subband transition of n-type QWs. Moreover, the thick active region of dielectric cavity that contains 50 periods of QWs with fairly low doping concentration will be beneficial to the optical and electrical merits of the detectors. This study demonstrates an inclusive scheme to substantially raise the signal to ratio of infrared detection with all-semiconductor photonic structures.

Interval-locked dual-frequency φ-OFDR with an enhanced strain dynamic range and a long-term stability.

We report on an interval-locked dual-frequency phase-sensitive optical frequency-domain reflectometry relying on a common-reference optical phase-locked loop. With a shared unbalanced interferometry, this design allows for synchronizing the frequency drift of two lasers, leading to a steadily stabilized dual frequency with an arbitrary interval. Equivalently to a longer synthetic wavelength, their phase difference is utilized to demodulate the ambient changes of interest with an enhanced dynamic range and long-term stability. With a stabilized interval of 1 THz, it allows for an enhancement in a strain measurement range of up to 193-fold in theory. Demonstration in terms of distributed strain sensing covering a distance of 500 m with a 10 cm spatial resolution has been verified, showing a significant extension in the achievable strain dynamic range with a preserved sensitivity over 1 h.

Clinical characteristics and prognostic characterization of endometrial carcinoma: a comparative analysis of molecular typing protocols.

BACKGROUND: Endometrial carcinoma (EC) is one of the most common gynecological malignancies in China and globally, accounting for the fourth-prevalent cancer in women. Although numerous studies have confirmed prognostic value of The Cancer Genome Atlas (TCGA) molecular subgroups, it is unclear how they are combined with histological features. The main objective of this study was to compare ProMisE and TCGA classification for the rapid and accurate prediction of prognosis within EC patients, together with the provision of a revised strategy for individualized diagnosis and treatment of patients. METHODS: Within this study, 70 patients with EC from Beijing Tsinghua Changgeng Hospital (affiliated to Tsinghua University) were retrospectively examined between July 2015 and December 2021. Samples were processed for determination of clinical markers, together with ProMisE and TCGA classification. RESULTS: Comparative analysis across four TCGA types (POLE, Low-CN, High-CN, and MSI-H) and age, was statistically significant (χ²= 7.000, p = 0.029). There was no significant difference observed among the four TCGA types and FIGO stage, vascular invasion and depth of invasion, or lymph node metastasis and tumor area. There was no significant association between the expression of Vimentin, Ki-67, PTEN, MSH2, PAX-8, ß-catenin, CD10, ER, PR, P16, MLH1, and PMS2 with the four TCGA types. In addition, p63 expression (χ²= 11.09, p = 0.029) and p53 expression (χ²= 11.585, p = 0.005) were statistically significant. Numerous models demonstrated that patients with POLE mutations and low-CN had higher progression free survival (PFS) and overall survival (OS), whereas those with high-CN had lowest values. The log-rank test revealed that the survival rate of PR-positive and ER-positive patients was significantly higher (p < 0.001). CONCLUSION: Overall, these results can be of additional benefit for clinical applications, in comparison to the ProMisE classification method. In addition, PR, ER, vascular infiltration, hyperlipidemia and atherosclerosis were found to be the key factors affecting EC prognosis.

Purvalanol A induces apoptosis and reverses cisplatin resistance in ovarian cancer.

Cisplatin (DDP) resistance limits therapeutic efficacy in patients diagnosed with ovarian cancer. Purvalanol A (Pur) is a novel cyclin-dependent kinase (CDK) inhibitor that has been demonstrated to induce apoptosis in various cancer cells. The present study investigated the effect of the combination treatment of Pur and DDP, and the potential anticancer mechanisms in epithelial ovarian cancer (EOC) cells in vitro and in vivo . We found that Pur enhanced the anti-tumor efficacy of cisplatin in EOC cells. The combination of Pur and DDP had more significant effects on apoptosis induction in EOC cells compared with the individual-treatment groups and the control group. We further demonstrated that the combination of Pur and DDP may trigger apoptosis and autophagy in EOC cells by inducing reactive oxygen species (ROS). And the ROS/Akt/mammalian target of rapamycin signaling pathway as a potential mechanism for the initiation of autophagy induced by combination therapy. Similar results were observed in vivo . These results demonstrated that Pur sensitized the response of EOC cells to cisplatin in vitro and in vivo , reversing the resistance to cisplatin in ovarian cancer.

Guideline on treating community-acquired pneumonia with Chinese patent medicines.

Community-acquired pneumonia (CAP) is one of the most common infectious diseases, and its morbidity and mortality increase with age. Resistance and mutations development make the use of anti-infective therapy challenging. Chinese patent medicines (CPMs) are often used to treat CAP in China and well tolerable. However, currently there are no evidence-based guideline for the treatment of CAP with CPMs, and the misuse of CPMs is common. Therefore, we established a guideline panel to develop this guideline. We identified six clinical questions through two rounds of survey, and we then systematically searched relevant evidence and performed meta-analyses, evidence summaries and GRADE decision tables to draft recommendations, which were then voted on by a consensus panel using the Delphi method. Finally, we developed ten recommendations based on evidence synthesis and expert consensus. For the treatment of severe CAP in adults, we recommend Tanreqing injection, Reduning injection, Xuebijing injection, Shenfu injection, and Shenmai injection respectively. For the treatment of non-severe CAP in adults, we recommend Tanreqing injection, Reduning injection, Lianhua Qingwen capsule/granule, Qingfei Xiaoyan Pill and Shufeng Jiedu capsule respectively. CPMs have great potential to help in the fight against CAP worldwide, but more high-quality studies are still needed to strengthen the evidence.

The association between mortality and door-to-antibiotic time: a systematic review and meta-analysis.

PURPOSE: Previous studies evaluating the impact of antibiotic timing on mortality in sepsis have shown conflicting results. We performed a meta-analysis to evaluate the association between door-to-antibiotic time (each hour of delay) and mortality in sepsis. METHODS: We searched PubMed and Embase through 10 November 2022 to identity cohort studies that evaluated the adjusted association between door-to-antibiotic time (each hour of delay) and mortality in adult patients with sepsis. The primary outcome was mortality. Analysis was based on inverse-variance weighting using a fixed-effects model. The variances were derived from the logarithms of the reported confidence intervals (CIs) for associations. We estimated the odds ratio, 95% CI, and number needed to treat for the pooled data. RESULTS: Fifteen cohort studies involving 106 845 patients were included in the meta-analysis. Door-to-antibiotic time (each hour of delay) was associated with increased risk of mortality (odds ratio: 1.07; 95% CI: 1.06-1.08; P < 0.0001; number needed to treat = 91), with high heterogeneity (I2 = 82.2%). The association was robust in sensitivity analyses and consistent in subgroup analyses. No publication bias was found. CONCLUSION: In adult patients with sepsis, each hour of delay in antibiotic administration is associated with increased odds of mortality. Key messages What is already known on this topic Sepsis is a common and lethal syndrome that affects millions of people worldwide. The updated 2018 Surviving Sepsis Campaign guidelines recommended initiating empirical broad-spectrum antibiotic coverage within 1 hour of identification of sepsis and septic shock. Delay in antibiotic administration may increase the risk of mortality in patients with sepsis. What this study adds This meta-analysis evaluates and quantifies the association between door-to-antibiotic time (each hour of delay) and mortality in patients with sepsis. Each hour of delay in antibiotic administration is associated with increased odds of mortality in sepsis. The number needed to treat (NNT) with delayed antibiotic administration for one additional death was 91. How this study might affect research, practice, or policy: More efforts should be made to speed up the diagnosis of sepsis or sepsis shock.

Quantitative Detection of Tank Floor Defects by Pseudo-Color Imaging of Three-Dimensional Magnetic Flux Leakage Signals.

Highly integrated three-dimensional magnetic sensors have just been developed and have been used in some fields, such as angle measurement of moving objects. The sensor used in this paper is a three-dimensional magnetic sensor with three Hall probes highly integrated inside; 15 sensors are used to design the sensor array and then measure the magnetic field leakage of the steel plate; the three-dimensional component characteristics of the magnetic field leakage are used to determine the defect area. Pseudo-color imaging is the most widely used in the imaging field. In this paper, color imaging is used to process magnetic field data. Compared with analyzing the three-dimensional magnetic field information obtained directly, this paper converts the magnetic field information into color image information through pseudo-color imaging and then obtains the color moment characteristic values of the color image in the defect area. Moreover, the least-square support-vector machine and particle swarm optimization (PSO-LSSVM) algorithm are used to quantitatively identify the defects. The results show that the three-dimensional component of the magnetic field leakage can effectively determine the area range of defects, and it is feasible to use the color image characteristic value of the three-dimensional magnetic field leakage signal to identify defects quantitatively. Compared with a single component, the three-dimensional component can effectively improve the identification rate of defects.

The Motion Paradigm of Pre-Dock Zearalenone Hydrolase Predictions with Molecular Dynamics and the Docking Phase with Umbrella Sampling.

Zearalenone (ZEN) is one of the most prevalent estrogenic mycotoxins, is produced mainly by the Fusarium family of fungi, and poses a risk to the health of animals. Zearalenone hydrolase (ZHD) is an important enzyme capable of degrading ZEN into a non-toxic compound. Although previous research has investigated the catalytic mechanism of ZHD, information on its dynamic interaction with ZEN remains unknown. This study aimed to develop a pipeline for identifying the allosteric pathway of ZHD. Using an identity analysis, we identified hub genes whose sequences can generalize a set of sequences in a protein family. We then utilized a neural relational inference (NRI) model to identify the allosteric pathway of the protein throughout the entire molecular dynamics simulation. The production run lasted 1 microsecond, and we analyzed residues 139-222 for the allosteric pathway using the NRI model. We found that the cap domain of the protein opened up during catalysis, resembling a hemostatic tape. We used umbrella sampling to simulate the dynamic docking phase of the ligand-protein complex and found that the protein took on a square sandwich shape. Our energy analysis, using both molecular mechanics/Poisson-Boltzmann (Generalized-Born) surface area (MMPBSA) and Potential Mean Force (PMF) analysis, showed discrepancies, with scores of -8.45 kcal/mol and -1.95 kcal/mol, respectively. MMPBSA, however, obtained a similar score to that of a previous report.

Enhanced frequency-modulated continuous-wave generation by injection-locking period-one oscillation in a semiconductor laser with an intensity modulated comb.

We report on an enhanced photonic generation of frequency-modulated continuous-wave (FMCW) signals by injection-locking a semiconductor laser operating in period-one (P1) nonlinear dynamic with an intensity modulated electro-optic frequency comb. When the cavity mode is injection-locked with respect to any of the comb modes, through linearly sweeping the frequency of the injected comb mode while synchronously modulating the injected intensity, the center wavelength of the cavity mode can be tuned following the injected comb mode. This way, it allows maintaining the phase-locking between the cavity mode and comb mode even if beyond the original locking bandwidth of the cavity mode, since it is tuned accordingly. It thus leads to the generation of FMCW signal with efficient phase noise suppression and improved achievable sweep range compared with the limited original injection-locking bandwidth. Such injection enhanced phase-locking is investigated and a demonstration with the injection of -4th order comb mode has realized photonic FMCW generation with enhanced sweep range and suppressed phase noise. Thanks to the flexibility in sweep parameters, this method can also be readily applied for the generation of arbitrary waveforms.

Modeling and optimization of an unbalanced delay interferometer based OPLL system.

We present and establish a versatile analytical model that allows overall analysis and optimization for the phase noise performance of the delay interferometer based optical phase-locked loop (OPLL). It allows considering any type of lasers with arbitrary frequency noise properties while taking into account the contributions from various practical noise sources, thus enabling comprehensive investigation for the complicated interaction among underlying limiting factors. The quantitative analysis for their evolution along with the change of the delay of the interferometer unveils the resulting impact on the fundamental limit and dynamics of the output phase noise, leading to a well-balanced loop bandwidth and sensitivity thus enabling the overall optimization in terms of closed-loop noise performance. The tendencies observed and the results predicted in terms of coherence metrics in numerical verification with different lasers have testified to the precision and effectiveness of the proposed model, which is quite capable of acting as a design tool for the insightful analysis and overall optimization with guiding significance for practical applications.

Use of acid-suppressive drugs and risk of fracture in children and young adults: a meta-analysis of observational studies.

BACKGROUND: Acid-suppressive drugs (ASDs) are being used by increasing number of children and young adults. However, evidence for a relationship between ASD use and the risk of fracture in these groups of patients is conflicting. We conducted a meta-analysis to evaluate the risk of fracture in children and young adults exposed to ASDs. METHODS: A literature search was performed using the PUBMED, EMBASE, and Cochrane Library databases from inception to November 2020. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated to determine the relationship of ASD use with fracture risk in children and young adults. RESULTS: Six studies reporting the outcomes of more than 900,000 children and young adults with ASD use were included in the meta-analysis. The pooled RR for fracture with the use of proton pump inhibitors (PPIs) versus non-use of these medications was 1.17 (95% CI = 1.1-1.25; P < 0.001) in children and 1.2 (95% CI = 0.87-1.65; P = 0.272) in young adults. By contrast, the use of histamine H2-receptor antagonists (H2RAs) was not significantly associated with fracture risk in children (RR, 1.08, 95% CI = 0.99-1.17; P = 0. 083) or young adults (RR, 1.08, 95% CI = 0.82-1.42; P = 0.589). Significant statistical and clinical heterogeneity among studies were determined for the main analysis and most of the subgroup analyses. CONCLUSIONS: Our study provides evidence linking PPI use to an increased risk of fracture in children. Thus, the use of PPIs in these patients should be carefully considered. However, randomized controlled studies are needed to determine causality and the role of unmeasured/residual confounding factors in this association.

Monosaccharide-mediated rational synthesis of a universal plasmonic platform with broad spectral fluorescence enhancement for high-sensitivity cancer biomarker analysis.

BACKGROUND: Effective and accurate screening of oncological biomarkers in peripheral blood circulation plays an increasingly vital role in diagnosis and prognosis. High-sensitivity assays can effectively aid clinical decision-making and intervene in cancer in a localized status before they metastasize and become unmanageable. Meanwhile, it is equally pivotal to prevent overdiagnosis of non-life-threatening cancer by eliminating unnecessary treatment and repeated blood draws. Unfortunately, current clinical screening methodologies can hardly simultaneously attain sufficient sensitivity and specificity, especially under resource-restrained circumstances. To circumvent such limitations, particularly for cancer biomarkers from early-onset and recurrence, we aim to develop a universal plasmonic platform for clinical applications, which macroscopically amplifies multiplexed fluorescence signals in a broad spectral window and readily adapts to current assay setups without sophisticated accessories or expertise at low cost. METHODS: The plasmonic substrate was chemically synthesized in situ at the solid-liquid interface by rationally screening a panel of reducing monosaccharides and tuning the redox reactions at various catalyst densities and precursor concentrations. The redox properties were studied by Benedict's assay and electrochemistry. We systemically characterized the morphologies and optical properties of the engineered plasmonic Ag structures by scanning electron microscopy (SEM) and spectroscopy. The structure-fluorescence enhancement correlation was explicitly explained by the finite-difference time-domain (FDTD) simulation and a computational model for gap distribution. Next, we established an enhanced fluoroimmunoassay (eFIA) using a model biomarker for prostate cancer (PCa) and validated it in healthy and PCa cohorts. Prognosis was explored in patients subject to surgical and hormonal interventions following recommended PCa guidelines. RESULTS: The monosaccharide-mediated redox reaction yielded a broad category of Ag structures, including sparsely dispersed nanoparticles (NPs) of various sizes, semi-continuous nanoislands, and crackless continuous films. Optimal broad-spectral fluorescence enhancement from green to far-red was observed for the inhomogeneous, irregularly-shaped semi-continuous Ag nanoisland substrate (AgNIS), synthesized from a well-balanced redox reaction at a stable rate mediated by mannose. In addition, different local electric field intensity distributions in response to various incident excitations were observed at the nanoscale, elucidating the need for irregular and inhomogeneous structures. AgNIS enabled a maximized 54.7-fold macroscopically amplified fluorescence and long-lasting photostability. Point-of-care availability was fulfilled using a customized smartphone prototype with well-paired optics. The eFIA effectively detected the PCa marker in cell lines, xenograft tumors, and patient sera. The plasmonic platform rendered a diagnostic sensitivity of 86.0% and a specificity of 94.7% and capably staged high-grade PCa that the clinical gold standard test failed to stratify. Patient prognosis of robotic-assisted surgeries and hormone therapies was non-invasively monitored following efficient medical interventions. The assay time was significantly curtailed on the plasmonic platform upon microwave irradiation. CONCLUSIONS: By investigating the effects of reducing monosaccharides on the seed-mediated chemical synthesis of plasmonic Ag structures, we deduced that potent multiplexed fluorescence enhancement originated from both an adequate reducing power and a steady reduction rate. Furthermore, the inhomogeneous structure with adequate medium gap distances afforded optimal multiwavelength fluorescence enhancement, thus empowering an effective eFIA for PCa. The clinically validated diagnostic and prognostic features, along with the low sample volume, point-of-care feasibility with a smartphone, and microwave-shortened assay time, warrant its potential clinical translation for widespread cancer biomarker analysis.

Therapeutic genome editing of triple-negative breast tumors using a noncationic and deformable nanolipogel.

Triple-negative breast cancer (TNBC), which has the highest mortality rate of all breast cancer, is in urgent need of a therapeutic that hinders the spread and growth of cancer cells. CRISPR genome editing holds the promise of a potential cure for many genetic diseases, including TNBC; however, its clinical translation is being challenged by the lack of safe and effective nonviral delivery systems for in vivo therapeutic genome editing. Here we report the synthesis and application of a noncationic, deformable, and tumor-targeted nanolipogel system (tNLG) for CRISPR genome editing in TNBC tumors. We have demonstrated that tNLGs mediate a potent CRISPR knockout of Lipocalin 2 (Lcn2), a known breast cancer oncogene, in human TNBC cells in vitro and in vivo. The loss of Lcn2 significantly inhibits the migration and the mesenchymal phenotype of human TNBC cells and subsequently attenuates TNBC aggressiveness. In an orthotopic TNBC model, we have shown that systemically administered tNLGs mediated >81% CRISPR knockout of Lcn2 in TNBC tumor tissues, resulting in significant tumor growth suppression (>77%). Our proof-of-principle results provide experimental evidence that tNLGs can be used as a safe, precise, and effective delivery approach for in vivo CRISPR genome editing in TNBC.

A risk prediction model for acute kidney injury in patients with pulmonary tuberculosis during anti-tuberculosis treatment.

BACKGROUND: Acute kidney injury (AKI) is not a rare complication during anti-tuberculosis treatment in some patients with pulmonary tuberculosis (PTB). We aimed to develop a risk prediction model for early recognition of patients with PTB at high risk for AKI during anti-TB treatment. METHODS: This retrospective cohort study assessed the clinical baseline, and laboratory test data of 315 inpatients with active PTB who were screened for predictive factors from January 2019 to June 2020. The elements were analyzed by logistic regression analysis. A nomogram was established by the results of the logistic regression analysis. The prediction model discrimination and calibration were evaluated by the concordance index (C-index), ROC curve, and Hosmer-Lemeshow analysis. RESULTS: A total of 315 patients with PTB were enrolled (67 patients with AKI and 248 patients without AKI). Seven factors, including microalbuminuria, hematuria, cystatin-C (CYS-C), albumin (ALB), creatinine-based estimated glomerular filtration rates (eGFRs), body mass index (BMI), and CA-125 were acquired to develop the predictive model. According to the logistic regression, microalbuminuria (OR = 3.038, 95%CI 1.168-7.904), hematuria (OR = 3.656, 95%CI 1.325-10.083), CYS-C (OR = 4.416, 95%CI 2.296-8.491), and CA-125 (OR = 3.93, 95%CI 1.436-10.756) were risk parameter, while ALB (OR = 0.741, 95%CI 0.650-0.844) was protective parameter. The nomogram demonstrated good prediction in estimating AKI (C-index= 0.967, AUC = 0.967, 95%CI (0.941-0.984), sensitivity = 91.04%, specificity = 93.95%, Hosmer-Lemeshow analysis SD = 0.00054, and quantile of absolute error = 0.049). CONCLUSIONS: Microalbuminuria, hematuria, ALB reduction, elevated CYS-C, and CA-125 are predictive factors for the development of AKI in patients with PTB during anti-TB treatments. The predictive nomogram based on five predictive factors is achieved good risk prediction for AKI during anti-TB treatments.