Systemic Inflammatory Markers and Clinical Outcomes of Open versus Biportal Endoscopic Transforaminal Lumbar Interbody Fusion.

Purpose: The purpose of this study is to preliminarily assess the change in perioperative systemic inflammatory markers and clinical outcomes between open TLIF and BE-TLIF procedures. Patients and Methods: In total, 38 patients who underwent single-level lumbar fusion surgery (L4-5 or L5-S1) were retrospectively reviewed. 19 patients were treated by the BE-TLIF technique, while the other patients were managed using open TLIF. The perioperative serum C-reactive protein (CRP), neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), and platelet/lymphocyte ratio (PLR) of the two groups were compared to determine if there was a statistical difference. Meanwhile, clinical evaluations were conducted to assess various factors including operative duration, estimated blood loss (EBL), drainage catheter stay, length of hospitalization, visual analogue scale (VAS), and Oswestry disability index (ODI) scores. Results: The perioperative analysis revealed that BE-TLIF cases experienced a longer operative duration than open TLIF cases (open TLIF: 138.63 ± 31.59 min, BE-TLIF: 204.58 ± 49.37 min, p < 0.001). Meanwhile, the EBL showed an increased trend in the BE-TLIF group (260.7 ± 211.9 mL) in comparison with the open TLIF group (200.9 ± 211.9 mL) (p =0.485). In terms of systemic inflammatory markers, the mean postoperative CRP, NLR, LMR, and PLR were lower in the BE-TLIF group than in the open TLIF group, although these differences were not statistically significant (p > 0.05). The VAS and ODI scores in both groups were significantly improved after surgery (p < 0.05). Conclusion: There was no significant difference found between BE-TLIF and open TLIF in terms of systemic inflammatory markers, and clinical outcomes. Overall, BE-TLIF can be considered a viable choice for lumbar canal decompression and interbody fusion for less invasion. It is worth noting that BE-TLIF does have a longer operation time, indicating that there is still potential for further improvement in this technique.

Advanced drive laser system for a high-brightness continuous-wave photocathode electron gun.

In order to enhance the performance of a continuous-wave photocathode electron gun at Peking University, and to achieve electron beams with higher current and brightness, a multifunctional drive laser system named PULSE (Peking University drive Laser System for high-brightness Electron source) has been developed. This innovative system is capable of delivering an average output power of 120 W infrared laser pulse at 81.25 MHz, as well as approximately 13.8 W of green power with reliable stability. The utilization of two stages of photonic crystal fibers plays a crucial role in achieving this output. Additionally, the incorporation of two acousto-optic modulators enables the selection of macro-pulses with varying repetition frequencies and duty cycles, which is essential for effective electron beam diagnosis. Furthermore, the system employs a series of birefringent crystals for temporal pulse shaping, allowing for stacking Gaussian pulses into multiple types of distribution. Overall, the optical schematic and operating performance of PULSE are detailed in this paper.

Synthesis and Anti-Chagas Activity Profile of a Redox-Active Lead 3-Benzylmenadione Revealed by High-Content Imaging.

Chagas disease, or American trypanosomiasis, is a neglected tropical disease which is a top priority target of the World Health Organization. The disease, endemic mainly in Latin America, is caused by the protozoan Trypanosoma cruzi and has spread around the globe due to human migration. There are multiple transmission routes, including vectorial, congenital, oral, and iatrogenic. Less than 1% of patients have access to treatment, relying on two old redox-active drugs that show poor pharmacokinetics and severe adverse effects. Hence, the priorities for the next steps of R&D include (i) the discovery of novel drugs/chemical classes, (ii) filling the pipeline with drug candidates that have new mechanisms of action, and (iii) the pressing need for more research and access to new chemical entities. In the present work, we first identified a hit (4a) with a potent anti-T. cruzi activity from a library of 3-benzylmenadiones. We then designed a synthetic strategy to build a library of 49 3-(4-monoamino)benzylmenadione derivatives via reductive amination to obtain diazacyclic benz(o)ylmenadiones. Among them, we identified by high content imaging an anti-amastigote "early lead" 11b (henceforth called cruzidione) revealing optimized pharmacokinetic properties and enhanced specificity. Studies in a yeast model revealed that a cruzidione metabolite, the 3-benzoylmenadione (cruzidione oxide), enters redox cycling with the NADH-dehydrogenase, generating reactive oxygen species, as hypothesized for the early hit (4a).

Prognostic Signature in Osteosarcoma Based on Amino Acid Metabolism-Associated Genes.

Background: Osteosarcoma (OS) is undeniably a formidable bone malignancy characterized by a scarcity of effective treatment options. Reprogramming of amino acid (AA) metabolism has been associated with OS development. The present study was designed to identify metabolism-associated genes (MAGs) that are differentially expressed in OS and to construct a MAG-based prognostic risk signature for this disease. Methods: Expression profiles and clinicopathological data were downloaded from Gene Expression Omnibus (GEO) and UCSC Xena databases. A set of AA MAGs was obtained from the MSigDB database. Differentially expressed genes (DEGs) in GEO dataset were identified using "limma." Prognostic MAGs from UCSC Xena database were determined through univariate Cox regression and used in the prognostic signature development. This signature was validated using another dataset from GEO database. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, single sample gene set enrichment analysis, and GDSC2 analyses were performed to explore the biological functions of the MAGs. A MAG-based nomogram was established to predict 1-, 3-, and 5-year survival. Real-time quantitative polymerase chain reaction, Western blot, and immunohistochemical staining confirmed the expression of MAGs in primary OS and paired adjacent normal tissues. Results: A total of 790 DEGs and 62 prognostic MAGs were identified. A MAG-based signature was constructed based on four MAGs: PIPOX, PSMC2, SMOX, and PSAT1. The prognostic value of this signature was successfully validated, with areas under the receiver operating characteristic curves for 1-, 3-, and 5-year survival of 0.714, 0.719, and 0.715, respectively. This MAG-based signature was correlated with the infiltration of CD56dim natural killer cells and resistance to several antiangiogenic agents. The nomogram was accurate in predictions, with a C-index of 0.77. The expression of MAGs verified by experiment was consistent with the trends observed in GEO database. Conclusion: Four AA MAGs were prognostic of survival in OS patients. This MAG-based signature has the potential to offer valuable insights into the development of treatments for OS.

Infected wound repair with an ultrasound-enhanced nanozyme hydrogel scaffold.

Chronic diabetic wounds persistently face the threat of evolving into diabetic foot ulcers owing to severe hypoxia, high levels of reactive oxygen species (ROS), and a complex inflammatory microenvironment. To concurrently surmount these obstacles, we developed an all-round therapeutic strategy based on nanozymes that simultaneously scavenge ROS, generate O2 and regulate the immune system. First, we designed a dynamic covalent bond hybrid of a metal-organic coordination polymer as a synthesis template, obtaining high-density platinum nanoparticle assemblies (PNAs). This compact assembly of platinum nanoparticles not only effectively simulates antioxidant enzymes (CAT, POD) but also, under ultrasound (US), enhances electron polarization through the surface plasmon resonance effect, endowing it with the ability to induce GSH generation by effectively replicating the enzyme function of glutathione reductase (GR). PNAs, by mimicking the activity of CAT and POD, effectively catalyze hydrogen peroxide, alleviate hypoxia, and effectively generate GSH under ultrasound, further enhancing ROS scavenging. Notably, PNAs can regulate macrophage responses in the inflammatory microenvironment, circumventing the use of any additives. It was confirmed that PNAs can enhance cell proliferation and migration, promote neoangiogenesis IN VITRO, and accelerate the healing of infected diabetic wounds IN VIVO. We believe that an all-round therapeutic method based on PNA nanozymes could be a promising strategy for sustained diabetic wound healing.

Cetuximab enhances radiosensitivity of esophageal squamous cell carcinoma cells by G2/M cycle arrest and DNA repair delay through inhibiting p-EGFR and p-ERK.

BACKGROUND: Although radiotherapy has improved local control in esophageal squamous cell carcinoma (ESCC), a considerable number of patients still experience relapse due to resistance. In this study, we aimed to evaluate the effects of cetuximab on radiosensitivity in two ESCC cell lines (ECA109 and TE-13) and to investigate their underlying mechanisms. METHODS: Cells were pretreated with or without cetuximab before irradiation. The MTT assay and clonogenic survival assay were performed to evaluate cell viability and radiosensitivity. Flow cytometry was performed to analyze cell cycle distribution and apoptosis. The γH2AX foci were counted to determine cellular DNA-repairing capacity via immunofluorescence assay. The phosphorylation of key molecules involved in the epidermal growth factor receptor (EGFR) signaling pathway and DNA double-strand break (DSB) repair were measured by western blot. RESULTS: Cetuximab alone was not sufficient to suppress cell viability, but significantly enhanced radiation-induced inhibition of clonogenic survival in ECA109 and TE-13. The radiation sensitivity enhancement ratio (SER) was 1.341 and 1.237 for ECA109 and TE-13, respectively. ESCC cells treated with cetuximab were arrested at the G2/M phase in response to radiation. No significant increase in apoptotic rate was observed in irradiated cells that were treated with cetuximab. The average number of γH2AX foci increased in the combination group (cetuximab and radiation). Cetuximab suppressed phosphorylation of EGFR and downstream ERK, but had no significant effect on AKT. CONCLUSIONS: These results indicate the potential for use of cetuximab as an effective radiosensitizer in ESCC. Cetuximab promotes G2/M cycle arrest and reduces DSB repair, as well as inhibiting EGFR and downstream ERK pathways in ESCC.

Establishment and validation of a prognostic nomogram for postoperative patients with gastric cardia adenocarcinoma: A study based on the Surveillance, Epidemiology, and End Results database and a Chinese cohort.

BACKGROUND: Gastric cardia adenocarcinoma (GCA) is a highly fatal form of cancer in humans. The aim of this study was to extract clinicopathological data of postoperative patients with GCA from the Surveillance, Epidemiology, and End Results database, analyze prognostic risk factors, and build a nomogram. METHODS: In this study, the clinical information of 1448 patients with GCA who underwent radical surgery and were diagnosed between 2010 and 2015 was extracted from the SEER database. The patients were then randomly divided into training (n = 1013) and internal validation (n = 435) cohorts at a 7:3 ratio. The study also included an external validation cohort (n = 218) from a Chinese hospital. The study used the Cox and LASSO models to pinpoint the independent risk factors linked to GCA. The prognostic model was constructed according to the results of the multivariate regression analysis. To assess the predictive accuracy of the nomogram, four methods were used: C-index, calibration curve, time-dependent ROC curve, and DCA curve. Kaplan-Meier survival curves were also generated to illustrate the differences in cancer-specific survival (CSS) between the groups. RESULTS: The results of the multivariate Cox regression analysis showed that age, grade, race, marital status, T stage, and log odds of positive lymph nodes (LODDS) were independently associated with cancer-specific survival in the training cohort. Both the C-index and AUC values depicted in the nomogram were greater than 0.71. The calibration curve revealed that the nomogram's CSS prediction was consistent with the actual outcomes. The decision curve analysis suggested moderately positive net benefits. Based on the nomogram risk score, significant differences in survival between the high- and low-risk groups were observed. CONCLUSIONS: Race, age, marital status, differentiation grade, T stage, and LODDS are independent predictors of CSS in patients with GCA after radical surgery. Our predictive nomogram constructed based on these variables demonstrated good predictive ability.

Fano interference between collective modes in cuprate high-Tc superconductors.

Cuprate high-Tc superconductors are known for their intertwined interactions and the coexistence of competing orders. Uncovering experimental signatures of these interactions is often the first step in understanding their complex relations. A typical spectroscopic signature of the interaction between a discrete mode and a continuum of excitations is the Fano resonance/interference, characterized by the asymmetric light-scattering amplitude of the discrete mode as a function of the electromagnetic driving frequency. In this study, we report a new type of Fano resonance manifested by the nonlinear terahertz response of cuprate high-Tc superconductors, where we resolve both the amplitude and phase signatures of the Fano resonance. Our extensive hole-doping and magnetic field dependent investigation suggests that the Fano resonance may arise from an interplay between the superconducting fluctuations and the charge density wave fluctuations, prompting future studies to look more closely into their dynamical interactions.

Development and validation of a nomogram for patients with stage II/III gastric adenocarcinoma after radical surgery.

Background: We aimed to construct nomograms based on clinicopathological features and routine preoperative hematological indices to predict cancer-specific survival (CSS) and disease-free survival (DFS) in patients with stage II/III gastric adenocarcinoma (GA) after radical resection. Methods: We retrospectively analyzed 468 patients with stage II/III GA after curative gastrectomy between 2012 and 2018; 70% of the patients were randomly assigned to the training set (n = 327) and the rest were assigned to the validation set (n = 141). The nomogram was constructed from independent predictors derived from the Cox regression in the training set. Using the consistency index, the calibration and the time-dependent receiver operating characteristic curves were used to evaluate the accuracy of the nomogram. Decision curve analysis was used to assess the value of the model in clinical applications. Patients were further divided into low- and high-risk groups based on the nomogram risk score. Results: Multivariate Cox model identified depth of invasion, lymph node invasion, tumor differentiation, adjuvant chemotherapy, CA724, and platelet-albumin ratio as covariates associated with CSS and DFS. CA199 is a risk factor unique to CSS. The nomogram constructed using the results of the multivariate analysis showed high accuracy with a consistency index of 0.771 (CSS) and 0.771 (DFS). Moreover, the area under the curve values for the 3-and 5-year CSS were 0.868 and 0.918, and the corresponding values for DFS were 0.872 and 0.919, respectively. The nomogram had a greater clinical benefit than the TNM staging system. High-risk patients based on the nomogram had a worse prognosis than low-risk patients. Conclusion: The prognostic nomogram for patients with stage II/III GA after radical gastrectomy established in this study has a good predictive ability, which is helpful for doctors to accurately evaluate the prognosis of patients to make more reasonable treatment plans.

Development and validation of an online prognostic nomogram for osteosarcoma after surgery: a retrospective study based on the SEER database and external validation with single-center data.

Background: Osteosarcoma is a severe malignancy with relatively low morbidity and significant variation in patient outcomes. Thus the development of predictive models could help clinicians make better-individualized decisions. The present study established a nomogram to predict postoperative survival of osteosarcoma patients using the large population-based Surveillance, Epidemiology, and End Results (SEER) database and validated it with single-center data from an Asian/Chinese population. Methods: Data from osteosarcoma patients who underwent surgery from 2000 to 2016 in the SEER database were obtained and were randomly divided into a training set (n=1,057) and an internal validation set (n=1,057). Data from osteosarcoma patients who underwent surgery in our hospital from 2013 to 2016 were collected as an external validation set (n=65). Univariate and multivariate Cox proportional hazard models were used in the training set to screen for prognostic factors and a nomogram was established to individually predict 1-, 3- and 5-year cancer-specific survival (CSS) and overall survival (OS). The discrimination and calibration ability of the nomogram were evaluated using the Harrell concordance index (C-index), calibration curves and area under the curve (AUC). The clinical utility was evaluated using decision curve analysis (DCA). Results: Predictive nomograms were generated using characteristics including age, pathological subtype, the American Joint Committee on Cancer (AJCC) group-N, AJCC-M, tumor size, and tumor extension for CSS and OS. The C-indexes for the CSS training set, the internal validation set, and the external validation set were 0.731, 0.713, and 0.721, respectively. The C-indexes of OS C-indices were 0.734, 0.706, and 0.719, respectively. The calibration curve suggested that the nomograms were accurate in their predictions and that DCA showed broad clinical benefits. Moreover, the present nomograms exhibited high accuracy (for CSS: AUC =0.871, 0.772, and 0.759 of 1-, 3-, and 5-year; for OS: AUC =0.869, 0.774, and 0.765 of 1-, 3-, and 5-year) versus AJCC-Stage (for CSS: AUC =0.744, 0.670, and 0.671 of 1-, 3-, and 5-year; for OS: AUC =0.721, 0.665, and 0.662 of 1-, 3-, and 5-year). Conclusions: This study developed and validated a prognostic nomogram integrating clinicopathological characteristics for osteosarcoma patients who underwent surgery. This nomogram can provide individual risk assessment for survival.

Adipose-derived mesenchymal stem cells combined with platinum nanoparticles accelerate fracture healing in a rat tibial fracture model.

Background: At present, bone union delay or failure remains challenging for clinicians. It has been reported that adipose-derived mesenchymal stem cells (ADMSCs) offer a promising way to promote bone fracture healing. In recent years, nanomaterials have been applied in regenerative medicine. This study aimed to investigate whether ADMSCs combined with platinum nanoparticles (PtNPs) could further improve fracture healing on the basis of ADMSCs. Methods: ADMSCs were co-cultured with PtNPs in vitro to investigate the effect of PtNPs on the differentiation of ADMSCs. Twenty Sprague-Dawley (SD) rats were randomly divided into four groups (with five rats in each group). The left tibias of all rats were fractured. Phosphate-buffered saline (PBS), PtNPs, ADMSC, and ADMSC mixed with PtNPs were then injected into the fracture sites based on the group classifications. The fracture was monitored by X-ray immediately after the fracture and on days 14 and 28 post-fracture. The tibias of the rats were subsequently harvested after the last X-ray and evaluated by micro computed tomography (micro-CT), histological analysis, and immunohistochemical detection. Results: PtNPs significantly enhanced the osteogenic differentiation of ADMSCs in vitro. On days 14 and 28 post-fracture, the radiographic score of the ADMSC + PtNPs group was higher than that of the ADMSC group, the score of the ADMSC group was higher than that of the PtNPs and control groups, and there was no significant difference between the PtNPs and control groups. Micro-CT confirmed that combined ADMSCs with PtNPs were more effective than using ADMSCs alone in promoting fracture healing. The histological and immunohistochemical results further supported this conclusion. Conclusions: Our findings demonstrated that PtNPs could promote osteogenic differentiation of ADMSC in vitro. ADMSCs combined with PtNPs could accelerate fracture healing further in vivo and are a promising a potential method for the treatment of fracture healing.

Stereotactic body radiotherapy for lung metastases in a patient with giant cell tumor of bone: a case report and literature review.

Giant cell tumor of bone (GCTB) is a rare borderline tumor which can develop lung metastasis. Guidelines for patients with multiple pulmonary metastases recommend systemic therapies, such as denosumab and interferons (IFNs). However, when both of these treatment approaches fail, no satisfactory options are available. Thus, additional treatments for GCTB after failure of standard treatment would be beneficial. Here we present a patient with GCTB and multiple pulmonary metastases who was treated with stereotactic body radiotherapy (SBRT) after failure of surgery, denosumab, and bisphosphonates (BPs). This is the first well-documented report of a patient with metastatic GCTB who received lung SBRT after the failure of systemic therapy and achieved a favorable response. Some of the patient's pulmonary metastases were treated using SBRT (44 Gy/4 F). The long diameters of the irradiated nodules decreased 58.2% from baseline in the 30 months after SBRT. Moreover, the peritumoral volume of another nodule also shrank by 29.1% after receiving a low-scatter dose of 7.6 Gy/4 F, which was too small to have induced tumor regression. No obvious adverse events were observed during SBRT or in the follow-up period. Our case provides clinical evidence that SBRT may be a safe and effective method to treat metastatic GCTB and can produce a low-dose radiation-induced abscopal response, suggesting that immune responses can contribute to GCTB regression. In addition, we reviewed publications regarding treatment recommendations, the prospects for SBRT application, and possible effects of abscopal responses on GCTB.

Black phosphorus-Au-thiosugar nanosheets mediated photothermal induced anti-tumor effect enhancement by promoting infiltration of NK cells in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a heterogeneous cancer required combination therapy, such as photothermal therapy and chemotherapy. In recent years, cancer immunotherapies are rapidly evolving and are some of the most promising avenues to approach malignancies. Thus, the combination of the traditional therapies and immunotherapy in one platform may improve the efficacy for HCC treatment. RESULTS: In this work, we have prepared a black phosphorus (BP)-Au-thiosugar nanosheets (BATNS), in which Au-thiosugar coating and functionalization improved the stability of both black phosphorus nanosheets (BPNS) and gold ions in different simulated physiological environments. The compression of the BATNS band gap can convert more photon energy to heat generation compared with BPNS, resulting in higher photothermal conversion efficiency. The in vitro and in vivo results also revealed a stronger reduction on the hepatocellular carcinoma of mice and prolonged survival of disease models compared with BPNS. More importantly, BATNS showed an additional immune effect by increasing local NK cell infiltration but not T cell on the liver cancer treatment, and this immune effect was caused by the thermal effect of BATNS photothermal treatment. CONCLUSIONS: The novel BATNS could improve the stability of BPNS and simultaneously combine the cancer thermotherapy and immunotherapy leaded by local NK cell infiltration, resulting in a better therapeutic efficacy on hepatocellular carcinoma. This work also provided a new path to design BP-based materials for biomedical applications.

Complement factor H deficiency combined with smoking promotes retinal degeneration in a novel mouse model.

Age-related macular degeneration is the leading cause of blindness in the elderly. The Y402H polymorphism in complement factor H promotes disease-like pathogenesis, and a Cfh+/- murine model can replicate this phenotype, but only after two years. We reasoned that by combining CFH deficiency with cigarette smoke exposure, we might be able to accelerate disease progression to facilitate preclinical research in this disease. Wild-type and Cfh+/- mice were exposed to nose-only cigarette smoke for three months. Retinal tissue morphology and visual function were evaluated by optical coherence tomography, fundus photography and autofluorescence, and electroretinogram. Retinal pigment epithelial cell phenotype and ultrastructure were evaluated by immunofluorescence staining and transmission electron microscopy. Cfh+/- smoking mice showed a dome-like protruding lesion at the ellipsoid zone (drusen-like deposition), many retinal hyper-autofluorescence spots, and a marked decrease in A- and B-wave amplitudes. Compared with non-smoking mice, wild-type and Cfh+/- smoking mice showed sub-retinal pigment epithelium complement protein 3 deposition, activation of microglia, metabolic waste accumulation, and impairment of tight junctions. Microglia cells migrated into the photoreceptor outer segment layer in Cfh+/- smoking mice showed increased activation. Our results suggest that exposing Cfh+/- mice to smoking leads to earlier onset of age-related macular degeneration than in other animal models, which may facilitate preclinical research into the pathophysiology and treatment of this disease.

Tuberous sclerosis complex misdiagnosed as multiple metastases in a cervical cancer patient: case report and literature review.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organs and is caused by inactive mutations in the TSC1 or TSC2 genes. The main symptoms of TSC are neurocutaneous syndrome and benign hamartoma formation. Notably, malignancy is not an indication of TSC. In this article, we present the case of a 48-year-old female with cervical cancer (CC) combined with TSC, who was misdiagnosed with multiple metastases. Toe masses, pelvic nodules, and multiple osteogenic lesions were initially observed. Multi-site puncture biopsies and a toe amputation were performed; the pathology results did not indicate malignancy. Subsequently, hypomelanotic macules on the back, subependymal nodules (SENs), ungual fibromas, multiple renal cysts, and sclerotic-bone-lesions (SBLs) of the skull, and vertebrae were observed, leading to a diagnosis of TSC. Given that TSC is a benign disease and has not yet caused any organ disfunction, no special treatment was provided to this patient. After a follow-up period of almost 65 months, the patient's quality of life remained good without therapy. Oncologists should pay attention to benign diseases in the face of multiple lesions to reduce misdiagnosis and overtreatment. In addition, TSC may interact with CC through molecular mechanisms, such as the mammalian target of rapamycin (mTOR) pathway.

High power drive laser system for photocathode at IHEP.

The photocathode drive laser system in the Institute of High Energy Physics (IHEP) has been upgraded. An all-fiber drive laser system has been developed using photonic crystal fibers and photonic crystal rods as the main gain medium. This system has been operated stably. The output infrared (IR) power reaches 116.2 W. The pulse width and maximum output power of the green laser generated by the second harmonic generation (SHG) are less than 2 ps and about 39.4 W, respectively. The SHG efficiency exceeds 60%. This paper introduces the development of the drive laser system and reports the measurement results of the performance test.

Construction and Validation of a Nomogram to Predict Overall Survival in Very Young Female Patients with Curatively Resected Breast Cancer.

PURPOSE: Young age is an independent negative predictor of breast cancer (BC) survival and correlates with the risk of local recurrence and contralateral BC. We aimed to design an effective and comprehensive nomogram to predict prognosis in very young patients with curatively resected BC. METHODS: Female patients with a diagnosis of BC aged ≤35 years at presentation were identified from the SEER database as a training cohort. The validation cohort consisted of 1002 consecutive women with BC aged ≤35 years that had received curative resection for BC at the Sun Yat-sen University Cancer Center. A nomogram was built based on the identified variables in multivariate Cox proportional hazards model. The performance of the nomogram was quantified using Harrell's concordance index (C-index) and calibration curves. RESULTS: Overall, 10,872 young female patients who underwent surgery for BC were enrolled in the training cohort, while 1002 very young female BC patients were identified as independent validation cohort. Eight covariables (age, race, grade; ER, PR, and HER2 status; T, and N stages) were identified and incorporated to construct a nomogram. The C-index values of the nomogram were 0.727 (95% CI: 0.714-0.740) and 0.722 (95% CI: 0.666-0.778) for OS in the training and validation cohorts, respectively. The calibration curves showed a high degree of agreement between the predicted and actual observed survival rates in both training and validation cohorts. The nomogram displayed good calibration and acceptable discrimination. Based on the TPS of the nomogram model for OS with the X-tile program, patients were divided into 3 risk groups, which were easily discriminated on survival analyses for OS. CONCLUSION: We have successfully constructed an effective nomogram to predict survival outcomes for young female patients with curatively resected BC, which may provide individual survival prediction to benefit prognosis evaluation and individualized therapy.

Plasmodium falciparum Ferredoxin-NADP+ Reductase-Catalyzed Redox Cycling of Plasmodione Generates Both Predicted Key Drug Metabolites: Implication for Antimalarial Drug Development.

Plasmodione (PD) is a potent antimalarial redox-active 3-benzyl-menadione acting at low nanomolar range concentrations on different malaria parasite stages. The specific bioactivation of PD was proposed to occur via a cascade of redox reactions starting from one-electron reduction and then benzylic oxidation, leading to the generation of several key metabolites including corresponding benzylic alcohol (PD-bzol, for PD benzhydrol) and 3-benzoylmenadione (PDO, for PD oxide). In this study, we showed that the benzylic oxidation of PD is closely related to the formation of a benzylic semiquinone radical, which can be produced under two conditions: UV photoirradiation or catalysis by Plasmodium falciparum apicoplast ferredoxin-NADP+ reductase (PfFNR) redox cycling in the presence of oxygen and the parent PD. Electrochemical properties of both PD metabolites were investigated in DMSO and in water. The single-electron reduction potential values of PD, PD-bzol, PDO, and a series of 3-benzoylmenadiones were determined according to ascorbate oxidation kinetics. These compounds possess enhanced reactivity toward PfFNR as compared with model quinones. Optimal conditions were set up to obtain the best conversion of the starting PD to the corresponding metabolites. UV irradiation of PD in isopropanol under positive oxygen pressure led to an isolated yield of 31% PDO through the transient semiquinone species formed in a cascade of reactions. In the presence of PfFNR, PDO and PD-bzol could be observed during long lasting redox cycling of PD continuously fueled by NADPH regenerated by an enzymatic system. Finally, we observed and quantified the effect of PD on the production of oxidative stress in the apicoplast of transgenic 3D7[Api-roGFP2-hGrx1]P. falciparum parasites by using the described genetically encoded glutathione redox sensor hGrx1-roGFP2 methodology. The observed fast reactive oxygen species (ROS) pulse released in the apicoplast is proposed to be mediated by PD redox cycling catalyzed by PfFNR.