Efbemalenograstim alfa not inferior to pegfilgrastim in providing neutrophil support in women with breast cancer undergoing myelotoxic chemotherapy: results of a phase 2 randomized, multicenter, open-label trial.

PURPOSE: Evaluate the safety and efficacy of efbemalenograstim alfa for neutrophil support in breast cancer patients undergoing myelosuppressive chemotherapy in a phase 2, dose-finding, open-label study (NCT01648322, ClinicalTrials.gov, 2012-07-19). METHODS: 232 patients received up to 4 cycles of chemotherapy, 141 patients with docetaxel + cyclophosphamide (TC) and 91 patients with docetaxel + doxorubicin + cyclophosphamide (TAC). Patients were randomized to efbemalenograstim alfa (80, 240, or 320 µg/kg [TC]; 240 or 320 µg/kg [TAC]) or pegfilgrastim (6 mg) on Day 2 of each cycle. RESULTS: Efbemalenograstim alfa was non-inferior to pegfilgrastim in duration of moderate and severe neutropenia (absolute neutrophil count [ANC] < 1.0 × 109/L) in TAC Cycle 1 (mean [SD] of 2.1 [1.58] and 2.1 [1.46] days for 240 µg/kg and 320 µg/kg efbemalenograstim alfa, respectively, and 1.8 [1.28] days for pegfilgrastim), with a difference (95% CI) of 0.3 (-0.4, 1.1) days. ANC nadir occurred between Days 7-8 of TAC Cycle 1, with mean [SD] of 0.68 [1.064], 0.86 [1.407] and 0.78[1.283] × 109/L for 240 µg/kg, 320 µg/kg efbemalenograstim alfa and pegfilgrastim, respectively. Time to ANC recovery post nadir (defined as an ANC > 2.0 × 109/L after the expected ANC nadir) was 2.0-2.4 and 1.9 days for TAC patients treated with efbemalenograstim alfa and pegfilgrastim, respectively. No significant difference was found between any dose of efbemalenograstim alfa and pegfilgrastim in TAC Cycle 1 for incidence of moderate to severe neutropenia (76%-77% of patients) or incidence of severe neutropenia (ANC < 0.5 × 109/L; 63%-72%). Efbemalenograstim alfa exhibited similar safety profile to pegfilgrastim. Febrile neutropenia occurred in 4 (1.8%) patients, 2 patients each for 320 µg/kg efbemalenograstim alfa and pegfilgrastim, with no event considered related to study drug. CONCLUSION: Efbemalenograstim alfa was comparable to pegfilgrastim in efficacy and safety. GOV IDENTIFIER: NCT01648322.

TAT-W61 peptide attenuates neuronal injury through blocking the binding of S100b to the V-domain of Rage during ischemic stroke.

Ischemic stroke is a devastative nervous system disease associated with high mortality and morbidity rates. Unfortunately, no clinically effective neuroprotective drugs are available now. In ischemic stroke, S100 calcium-binding protein b (S100b) binds to receptor for advanced glycation end products (Rage), leading to the neurological injury. Therefore, disruption of the interaction between S100B and Rage can rescue neuronal cells. Here, we designed a peptide, termed TAT-W61, derived from the V domain of Rage which can recognize S100b. Intriguingly, TAT-W61 can reduce the inflammatory caused by ischemic stroke through the direct binding to S100b. The further investigation demonstrated that TAT-W61 can improve pathological infarct volume and reduce the apoptotic rate. Particularly, TAT-W61 significantly improved the learning ability, memory, and motor dysfunction of the mouse in the ischemic stroke model. Our study provides a mechanistic insight into the abnormal expression of S100b and Rage in ischemic stroke and yields an invaluable candidate for the development of drugs in tackling ischemic stroke. KEY MESSAGES: S100b expression is higher in ischemic stroke, in association with a high expression of many genes, especially of Rage. S100b is directly bound to the V-domain of Rage. Blocking the binding of S100b to Rage improves the injury after ischemic stroke.

Establishment of prediction models to predict survival among patients with cervical cancer based on socioeconomic factors: a retrospective cohort study based on the SEER Database.

OBJECTIVE: To construct and validate predictive models based on socioeconomic factors for predicting overall survival (OS) in cervical cancer and compare them with the American Joint Council on Cancer (AJCC) staging system. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: We extracted data from 5954 patients who were diagnosed with cervical cancer between 2007 and 2011 from the Surveillance, Epidemiology, and End Results Database. This database holds data related to cancer incidence from 18 population-based cancer registries in the USA. OUTCOME MEASURES: 1-year and 5-year OS. RESULTS: Of the total 5954 patients, 5820 patients had 1-year mortality and 5460 patients had 5-year mortality. Lower local education level [Hazard ratios (HR): 1.15, 95% confidence interval (CI): 1.04 to 1.27, p= 0.005] and being widowed (HR 1.28, 95% CI 1.06 to 1.55, p=0.009) were associated with a worse OS for patients with cervical cancer. Having insurance (HR 0.75, 95% CI 0.62 to 0.90, p=0.002), earning a local median annual income of ≥US$56 270 (HR 0.83, 95% CI 0.75 to 0.92, p<0.001) and being married (HR 0.79, 95% CI 0.69 to 0.89, p<0.001) were related to better OS in patients with cervical cancer. The predictive models based on socioeconomic factors and the AJCC staging system had a favourable performance for predicting OS in cervical cancer compared with the AJCC staging system alone. CONCLUSION: Our proposed predictive models exhibit superior predictive performance, which may highlight the potential clinical application of incorporating socioeconomic factors in predicting OS in cervical cancer.

The influence of comorbidities on outcomes for older people with back pain: BACE-D cohort study.

BACKGROUND: Comorbidities are common in older people with back pain but little is known about the influence of comorbidities on outcomes. OBJECTIVES: To explore the influence of the most prevalent comorbidities, and the number of comorbidities, on short (at 3 months) and long-term (at 12 months) outcomes of back pain in older people. METHODS: We analyzed data from the 'Back Complaints in the Elders' Dutch study cohort (BACE-D) and included participants aged >55 years. We used the modified Self-Administered Comorbidities Questionnaire (SCQ), the Numeric Rating Scale (NRS) and the Roland-Morris Disability Questionnaire (RMDQ) to assess the number of comorbidities, pain intensity and back-related physical functioning, respectively. We conducted separate linear regression models to analyze the association between comorbidities and outcomes including potential confounders of age, sex, body mass index, smoking and alcoholic drinking status, back pain history, and baseline NRS and RMDQ scores. RESULTS: Our study included 669 participants with a mean age of 66.5 (SD 7.7) years of whom 394 were female. More comorbidities were positively associated with higher pain intensity (3-month regression coefficient (ß) =0.27, 95% CI 0.14-0.39; 12-month ß = 0.31, 95% CI 0.17-0.45) and worse physical functioning (3-month ß = 0.54, 95% CI 0.31-0.77; 12-month ß = 0.64, 95% CI 0.37-0.92). Four of the 5 commonest comorbidities were musculoskeletal problems. Older participants with musculoskeletal comorbidities had higher pain intensity (3-month ß = 0.89 95% CI 0.41-1.37; 12-month ß = 1.17, 95% CI 0.65-1.69), and worse physical functioning (3-month ß = 1.61, 95% CI 0.71-2.52; 12-month ß = 1.85, 95% CI 0.82-2.89, P-value < 0.001) compared to participants without musculoskeletal comorbidities. CONCLUSIONS: More comorbidities are associated with worse back pain outcomes in older adults. Participants with musculoskeletal comorbidities had worse back pain outcomes than those without.

Knockdown of LINC00511 enhances radiosensitivity of lung adenocarcinoma via regulating miR-497-5p/SMAD3.

As the most common histological subtype of primary lung cancer, lung adenocarcinoma (LUAD) causes enormous cancer deaths worldwide. Radiotherapy has been frequently used in LUAD cases, and radiosensitivity is vital for LUAD therapy. This research sought to explore the genetic factors affecting radiosensitivity in LUAD and inner mechanisms. LINC00511, miR-497-5p, and SMAD3 expression in LUAD cells were detected via qRT-PCR and western blot. CCK-8 assays, colony formation, and flow cytometry assays were employed to explore the cell viability, apoptosis, and radiosensitivity in PC-9 and A549 cells. The targeting relationship between LINC00511, miR-497-5p, and SMAD3 was verified by dual luciferase reporter assay. Furthermore, xenograft experiments were performed for the in vivo verification. In conclusion, LINC00511 was overexpressed in LUAD cells, which downregulated downstream miR-497-5p expression and mediately led to SMAD3 activation. LINC00511 downregulation suppressed cell viability while enhanced apoptosis rate in LUAD cells. Also, LINC00511 and SMAD3 were overexpressed, while miR-497-5p was downregulated in LUAD cells exposed to 4Gy irradiation treatment. Moreover, LINC00511 inhibition could block SMAD3 expression and promoted the radiosensitivity both in vitro and in vivo. These findings uncover LINC00511 knockdown promoted miR-497-5p expression and subsequently led to lower SMAD3 level, which enhanced radiosensitivity in LUAD cells. LINC00511/miR-497-5p/SMAD3 axis could be of considerable potential to enhance radiosensitivity in LUAD.

Identification of gene signatures associated with ulcerative colitis and the association with immune infiltrates in colon cancer.

Background: Inflammatory bowel diseases, including ulcerative colitis (UC) and Crohn's disease, are some of the most common inflammatory disorders of the gastrointestinal tract. The dysfunction of the immune system in the intestines is suggested to be the underlying cause of the pathogenesis of UC. However, the mechanisms regulating these dysfunctional immune cells and inflammatory phenotypes are still unclear. Methods: The differential expression analysis on microarray datasets were performed including GSE24287, GSE87466, GSE102133, and GSE107499, including 376 samples. "Gene Ontology" and "Kyoto Encyclopedia of Genes and Genomes" pathway enrichment analyses were conducted to identify the common differentially expressed genes (DEGs) in these datasets and explore their underlying biological mechanisms. Further algorithms like "Cell-type Identification by Estimating Relative Subsets of RNA Transcripts" were used to determine the infiltration status of immune cells in patients with UC. "Cytoscape" and "Gene Set Enrichment Analysis" were used to screen for hub genes and to investigate their biological mechanisms. The Tumor Immune Estimation Resource database was used to study the correlation between hub genes and infiltrating immune cells in patients with UC. A total of three hub genes, CCL3, MMP3, and TIMP1, were identified using Cytoscape. Results: A positive correlation was observed between these hub genes and patients with active UC. These genes served as a biomarker for active UC. Moreover, a decrease in CCL3, MMP3, and TIMP1 expression was observed in the mucosa of the intestine of patients with active UC who responded to Golimumab therapy. In addition, results show a significant positive correlation between CCL3, MMP3, and TIMP1 expression and different immune cell types including dendritic cells, macrophages, CD8+ T cells, and neutrophils in patients with colon cancer. Moreover, CCL3, MMP3, and TIMP1 expression were strongly correlated with different immune cell markers. Conclusion: Study results show the involvement of hub genes like CCL3, MMP3, and TIMP1 in the pathogenesis of UC. These genes could serve as a novel pharmacological regulator of UC. These could be used as a therapeutic target for treating patients with UC and may serve as biomarkers for immune cell infiltration in colon cancer.

Changes of the effective optical zone after small-incision lenticule extraction and a correlation analysis.

The objective of the study is to observe the changes in the effective optical zone (EOZ) after small incision lenticule extraction (SMILE) and explore possible correlations with some influencing factors. In total, 133 eyes after SMILE were divided into the mild to moderate myopia group (- 1.75 D to - 5.75 D, 70 eyes) and the high myopia group (- 6.00 D to - 9.50 D, 63 eyes). The postoperative EOZ was calculated by utilizing the corneal tangential curvature map. Changes in EOZ (△-OZ) were monitored and compared between the two groups. Pearson correlation analysis was conducted to determine the correlation between △-OZ and corneal high-order wavefront aberrations. Multicollinearity analysis and ridge regression analysis were performed to assess the correlation between △-OZ and some corneal parameters. After SMILE, the horizontal EOZ (H-EOZ), vertical EOZ (V-EOZ), and average EOZ (A-EOZ) were significantly smaller than the programmed optical zone (POZ) in both groups (p < 0.05). The difference between V-EOZ and POZ (△V-OZ) and the difference between A-EOZ and POZ (△A-OZ) showed more significant changes in the high myopia group than in the mild to moderate myopia group, and △V-OZ was significantly larger than the difference between H-EOZ and POZ (△H-OZ) in the high myopia group. In both groups, the total high-order aberration (T-HOA) and spherical aberration (SA) both increased after SMILE, and they had a similar significant negative correlation with A-EOZ. Moreover, there was a significant negative correlation between △-OZ and Km (X1), Q-value (X2), spherical equivalent (SE, X3), ablating depth (AD, X4) and △e (X6), and a significant positive correlation between △-OZ and △Q (X5). △H-OZ was expressed as Y1, △V-OZ as Y2, and △A-OZ as Y3. The multiple linear regression equations were as follows: Y1 = 3.683 - 0.065X1, Y2 = 1.549 - 0.469X2 - 0.059X3, Y3 = 4.015 - 0.07X1 - 0.03X3, Y1 = 1.337 - 0.005X4 + 0.413X5, Y2 = 1.265 + 0.469X5, and Y3 = 0.852 - 0.002X4 - 0.398X6. The correlation degree with △A-OZ was ranked as Km > △Q > Q-value > AD > e-value > △e > SE > △Km, as represented by the ridge regression analysis. The EOZ was irregularly reduced after SMILE, which should be taken into consideration in the design of POZ, especially for high myopia. Consideration of the refractive diopter and corneal topography is advised for the design of POZ, the latter of which has greater reference significance.

Coating and Corruption of Human Neutrophils by Bacterial Outer Membrane Vesicles.

Porphyromonas gingivalis is a keystone oral pathogen that successfully manipulates the human innate immune defenses, resulting in a chronic proinflammatory state of periodontal tissues and beyond. Here, we demonstrate that secreted outer membrane vesicles (OMVs) are deployed by P. gingivalis to selectively coat and activate human neutrophils, thereby provoking degranulation without neutrophil killing. Secreted granule components with antibacterial activity, especially LL-37 and myeloperoxidase (MPO), are subsequently degraded by potent OMV-bound proteases known as gingipains, thereby ensuring bacterial survival. In contrast to neutrophils, the P. gingivalis OMVs are efficiently internalized by macrophages and epithelial cells. Importantly, we show that neutrophil coating is a conserved feature displayed by OMVs of at least one other oral pathogen, namely, Aggregatibacter actinomycetemcomitans. We conclude that P. gingivalis deploys its OMVs for a neutrophil-deceptive strategy to create a favorable inflammatory niche and escape killing. IMPORTANCE Severe periodontitis is a dysbiotic inflammatory disease that affects about 15% of the adult population, making it one of the most prevalent diseases worldwide. Importantly, periodontitis has been associated with the development of nonoral diseases, such as rheumatoid arthritis, pancreatic cancer, and Alzheimer's disease. Periodontal pathogens implicated in periodontitis can survive in the oral cavity only by avoiding the insults of neutrophils while at the same time promoting an inflamed environment where they successfully thrive. Our present findings show that outer membrane vesicles secreted by the keystone pathogen Porphyromonas gingivalis provide an effective delivery tool of virulence factors that protect the bacterium from being killed while simultaneously activating human neutrophils.

Efficacy, safety and prognostic factors of camrelizumab plus carboplatin and pemetrexed chemotherapy in advanced lung adenocarcinoma patients.

WHAT IS KNOWN AND OBJECTIVE: Camrelizumab is a recently developed PD-1 inhibitor in China applied in treating different cancers including lung cancer. This study is designed to evaluate the efficacy, safety and prognostic factors for camrelizumab plus carboplatin and pemetrexed (CP) chemotherapy in treating patients with advanced lung adenocarcinoma. METHODS: Of 51 advanced lung adenocarcinoma patients with negative driver genes who received camrelizumab plus CP chemotherapy were recruited. These patients received four cycles of camrelizumab plus CP chemotherapy in a 21-day cycle. Then, camrelizumab, pemetrexed or camrelizumab plus pemetrexed was administered as maintenance therapy. RESULTS AND DISCUSSION: The rates of complete response, partial response, stable disease and progressive disease were 2.0%, 56.8%, 19.6% and 5.9%, respectively; while treatment response of 15.7% of patients was missing or not evaluable. The objective response and disease control rates were 58.8% and 78.4%, respectively. With a median follow-up period of 14.9 months (the follow-up duration ranged from 3.9 months to 24.3 months), 41 (83.4%) cases of disease progression and 22 (43.1%) cases of death were recorded. The median progression-free survival (PFS) was 10.5 months (95% confidence interval (CI): 8.4-12.6 months) with a 1-year PFS rate of 36.3% and a 2-year PFS rate of 7.5%. In addition, the median overall survival (OS) was 18.7 months (95% CI: 16.4-21.0 months) with a 1-year OS rate of 79.1% and a 2-year OS rate of 30.4%. In consideration of safety, the most frequent adverse events were peripheral neuropathy (37.3%), neutropenia (37.3%), alopecia (35.3%), etc. and most of them were grade 1-2 and could be controlled. WHAT IS NEW AND CONCLUSION: Camrelizumab plus CP chemotherapy achieves favourable efficacy and tolerable adverse events in advanced lung adenocarcinoma patients.

Polymicrobial keratitis after accelerated corneal collagen cross-linking in keratoconus: Case reports and literature review.

PURPOSE: To report two cases of polymicrobial keratitis following corneal collagen cross-linking for keratoconus and to review the literature. METHODS: Retrospective case note and literature review. RESULTS: The first case involved a 27-year-old male who presented with amebic corneal ulcers 3 days after the collagen cross-linking procedure. Some gram-negative (gram-ve) cocci were found upon staining, and cysts were observed by confocal microscopy at 7 days after surgery. Acanthamoeba infection mixed with gram-ve organisms was diagnosed. In the second case, a 14-year male developed Staphylococcus aureus corneal infection with anterior chamber empyema 3 days after the collagen cross-linking procedure for keratoconus. Occasional gram-positive (gram + ve) cocci and gram-ve bacilli were observed under a microscope. The mixed keratitis in the two patients resolved after systemic and topical antibiotic therapy, but the infection ultimately resulted in corneal scarring. Follow-up keratoplasty was needed to improve vision acuity in both patients. CONCLUSION: Although ultraviolet irradiation and the reactive oxygen released by riboflavin during collagen cross-linking have bactericidal effects, a lack of a corneal epithelial barrier, bandage contact lens usage, perioperative hygiene, and an abnormal immune state are risk factors for infectious keratitis after collagen cross-linking. Perioperative management of collagen cross-linking is important to prevent infection.

Comparison of the optical quality after SMILE and FS-LASIK for high myopia by OQAS and iTrace analyzer: a one-year retrospective study.

BACKGROUND: To compare the correction effect and optical quality after small-incision lenticule extraction (SMILE) and femtosecond laser assisted laser in situ keratomileusis (FS-LASIK) for high myopia. METHODS: 51 high myopia eyes after SMILE and 49 high myopia eyes after FS-LASIK were enrolled and divided into two groups retrospectively. The OQAS and iTrace analyzer were used for optical quality inspection. Between the two groups the spherical equivalent (SE), astigmatism, uncorrected distant visual acuity (UDVA), strehl ratio (SR), modulation transfer function cutoff frequency (MTF cutoff), objective scatter index (OSI) and wavefront aberrations were analyzed and compared before surgery and at 1, 6 and 12 months after surgery. RESULTS: After the operation: (1) SE and astigmatism declined and UDVA increased significantly in both groups, and UDVA was better after SMILE than FS-LASIK. (2) SR and MTF cutoff reduced and OSI increased significantly after SMILE and FS-LASIK. SR and MTF cutoff were significantly higher after SMILE than FS-LASIK. OSI was significantly lower after SMILE than FS-LASIK. (3) The total wavefront aberration, total low-order wavefront aberration, defocus and astigmatism aberration as well as trefoil aberration reduced significantly in both groups. The total high-order wavefront aberration increased significantly after FS-LASIK. The spherical and coma aberration increased significantly in both groups. The total high-order wavefront aberration and coma aberration at 1 month were higher after FS-LASIK than SMILE. CONCLUSION: The optical quality descended after SMILE and FS-LASIK. SMILE was superior to FS-LASIK at the correction effect and optical quality for high myopia. The combination of OQAS and iTrace analyzer is a valuable complementary measurement in evaluating the optical quality after the refractive surgery. TRIAL REGISTRATION: This is a retrospective study. This research was approved by the ethics committee of Xiangya Hospital and the IRB approval number is 201612074.

Detection of Static and Dynamic Stereopsis after Femtosecond Laser Small Incision Lenticule Extraction for High Myopia.

PURPOSE: The purpose of this study is to test binocular visual function after femtosecond laser small incision lenticule extraction (SMILE) for high myopia. The traditional Titmus stereotest and dynamic stereotest based on the visual perception biological model were used for comparative analysis. METHODS: A total of 43 patients were enrolled in this prospective study. At Week 1, Month 1, and Month 3 after surgery, the Titmus stereotest and dynamic stereotest generated by MATLAB were conducted. Dynamic stereopsis consists of randomly flickering Gabor spots and is divided into two models of high energy and low energy according to flicker frequency. RESULTS: The preoperative manifest refraction spherical equivalent was -7.21 ± 0.70 D. The preoperative anisometropia was 0.52 ± 0.54D. The quartiles of static stereoacuity in preoperation and 3 follow-ups were as follows: 50.00 (25.00, 100.00) in preoperation, 63.00 (40.00, 63.00) at Week 1, 40.00 (32.00, 63.00) at Month 1, and 40.00 (25.00, 50.00) at Month 3. Static stereopsis improved at Month 1 and Month 3 compared with preoperation and Week 1 (P < 0.05). There were statistically significant differences in high energy dynamic stereopsis at Week 1 and Month 1 compared to preoperation (P < 0.05). In addition, significant differences in low energy dynamic stereopsis were detected between Month 1 and preoperation and also at Month 3 compared to Month 1 (P < 0.05). CONCLUSION: Most high myopia patients have a dynamic stereopsis deficiency before refractive correction. SMILE surgery can improve both static and dynamic stereopsis early in the postoperation period. However, in the long term, there is no significant difference or even a decrease in dynamic stereopsis.

A microscopic study of the corneal stromal lenticules extracted during femtosecond laser-assisted small incision lenticule extraction.

The aim of the present study was to investigate the histological and morphological characteristics of corneal stromal lenticules extracted during femtosecond laser-assisted small incision lenticule extraction (SMILE) surgery by light and electron microscopy. A total of 20 human corneal stromal lenticules extracted during SMILE surgery were sent for microscopic examination immediately after surgery. Of these, six were observed under a light microscope and 14 were observed under an electron microscope. The smoothness of the front and rear surface of the lenticules observed under an electron microscope was rated on a scale of 0 to 4 according to unified evaluation criteria and the scores were statistically compared. Under the light microscope, the edge of the cross section of the corneal stromal lenticules was deeply stained and certain burrs and broken collagen fibers were observed. The swollen corneal stromal fibers were distributed irregularly, with a few bubbles of different sizes. Under the electron microscope, the surface of the lenticules ablated using a femtosecond laser was not perfectly smooth and the front surface was smoother than the rear surface. The side edge of the lenticules ablated using a femtosecond laser was not as regular as the edge cut using microscissors. Necrosis and dissolution of collagen fibers were observed near the surface of the lenticules. In conclusion, the surface quality of corneal stromal lenticules ablated using a femtosecond laser was not optimal when observed under a microscope. Increased attention should be paid to the histology and morphology of the corneal surface following laser ablation.

Persistent luminescent metal-organic frameworks with long-lasting near infrared emission for tumor site activated imaging and drug delivery.

Luminescent porous materials have been widely used in biosensing, bioimaging and drug delivery by virtue of the special porous structure and luminescent property. The main obstacle for the application in biosensing and bioimaging is the background interference of external irradiation. Herein, we report a background interference-free persistent luminescent metal-organic framework (PLMOF) with persistent luminescent near infrared (NIR) luminescence for tumor site activated persistent luminescence imaging. The PLMOF (PLNPs@ZIF-8) was prepared by in-situ growth of MOF on the persistent luminescent nanoparticles (PLNPs) via a surface adsorption induced self-assembly method. The PLMOF possessed NIR persistent luminescence and renewable NIR luminescence and thus enabled deep-tissue and long-term imaging without external excitation. Specifically, the PLMOF showed acidic tumor site activated persistent luminescence for in vitro and in vivo tumor imaging, which was also help to reduce the background interference. The mechanism of acidic activation was attributed to the protonation of imidazole that induces disassembly of ZIF-8. In addition, the PLMOF presented a high anti-cancer drug loading capacity, acidity-responsive drug release behavior, and significant anti-tumor effect. All these results indicate that our PLMOF can serve as a promising theranostic platform for precision medicine.

Identification of novel mutations in preaxial polydactyly patients through whole-exome sequencing.

BACKGROUND: Polydactyly is one of the most common hereditary limb malformation characterized by additional digits in hands and/or feet. With extra fingers/toes, which could be very problematic, polydactyly patients are usually treated in early childhood by removing of extra digits with surgery. Genetically, polydactyly is caused by mutations of genes that involve in digit formation. METHODS: In the current report, we performed genetic analysis for polydactyly using DNA samples from a cohort of 20 Chinese patients. All patients show preaxial polydactyly in one of their hands. RESULTS: With whole-exome sequencing (WES), we have identified two novel heterozygous mutations c.G2844A in GLI3 gene (OMIM 165240) and c.1409_1410del in EVC gene (OMIM 604831). Compound heterozygous mutations that affect KIAA0586 gene (OMIM 610178) are also detected. Proteins encoded by the genes have important roles in primary cilia and regulate sonic hedgehog signaling pathway. CONCLUSION: Our study highlights the important roles of primary cilia in limb development, and helps to further understand the molecular mechanisms for polydactyly formation.

Mass production of poly(ethylene glycol) monooleate-modified core-shell structured upconversion nanoparticles for bio-imaging and photodynamic therapy.

Developing robust and high-efficient synthesis approaches has significant importance for the expanded applications of upconversion nanoparticles (UCNPs). Here, we report a high-throughput synthesis strategy to fabricate water-dispersible core-shell structured UCNPs. Firstly, we successfully obtain more than 10 grams core UCNPs with high quality from one-pot reaction using liquid rare-earth precursors. Afterwards, different core-shell structured UCNPs are fabricated by successive layer-by-layer strategy to get enhanced fluorescence property. Finally, the hydrophobic UCNPs are modified with poly(ethylene glycol) monooleate (PEG-OA) though a novel physical grinding method. On the basis of mass-production, we use the as-prepared PEG-UCNPs to construct an 808-nm stimuli photodynamic therapy agent, and apply them in cancer therapy and bio-imaging.

The potential role of HO-1 in regulating the MLK3-MKK7-JNK3 module scaffolded by JIP1 during cerebral ischemia/reperfusion in rats.

Heme oxygenase (HO-1), which may be induced by Cobaltic protoporphyrin IX chloride (CoPPIX) or Rosiglitazone (Ros), is a neuroprotective agent that effectively reduces ischemic stroke. Previous studies have shown that the neuroprotective mechanisms of HO-1 are related to JNK signaling. The expression of HO-1 protects cells from death through the JNK signaling pathway. This study aimed to ascertain whether the neuroprotective effect of HO-1 depends on the assembly of the MLK3-MKK7-JNK3 signaling module scaffolded by JIP1 and further influences the JNK signal transmission through HO-1. Prior to the ischemia-reperfusion experiment, CoPPIX was injected through the lateral ventricle for 5 consecutive days or Ros was administered via intraperitoneal administration in the week prior to transient ischemia. Our results demonstrated that HO-1 could inhibit the assembly of the MLK3-MKK7-JNK3 signaling module scaffolded by JIP1 and could ultimately diminish the phosphorylation of JNK3. Furthermore, the inhibition of JNK3 phosphorylation downregulated the level of p-c-Jun and elevated neuronal cell death in the CA1 of the hippocampus. Taken together, these findings suggested that HO-1 could ameliorate brain injury by regulating the MLK3-MKK7-JNK3 signaling module, which was scaffolded by JIP1 and JNK signaling during cerebral ischemia/reperfusion.

Recent advances of stimuli-responsive systems based on transition metal dichalcogenides for smart cancer therapy.

Stimuli-responsive systems, which can be used for temporally and spatially controllable therapeutic platforms, have been widely investigated in cancer therapy. Among a wide range of stimuli-responsive nanomaterials, transition metal dichalcogenides (TMDCs) have recently attracted great attention due to their large surface-to-volume ratio, atomic thickness, and other unique physicochemical properties. Thus, TMDCs are able to be responsive to various endogenous (e.g. acidic pH and overexpressed enzymes) or exogenous stimuli (e.g. light and magnetic). The majority of TMDC-based therapeutic platforms are triggered by near-infrared (NIR) light. However, due to the limited penetration of NIR light, novel strategies that are able to ablate deep-seated tumor tissues have emerged in recent years and have been applied to design multi-stimuli-responsive nano-systems. A comprehensive overview of the development of stimuli-responsive TMDC-based nanoplatforms for "smart" cancer therapy is presented to demonstrate a more intelligent and better controllable therapeutic strategy. Furthermore, the versatile properties of TMDCs and the typical responsive principles of certain stimuli-responsive platforms are discussed for a better understanding of selected examples in this review.

Comparison of Characteristics of Benign Prostatic Hyperplasia (BPH) Patients Treated with Finasteride and Alpha Blocker Combination Therapy Versus Alpha Blocker Monotherapy in China: An Analysis of Electronic Medical Record Data.

INTRODUCTION: Benign prostatic hyperplasia (BPH) is commonly treated with 5-alpha-reductase inhibitor/alpha blocker combination therapy or with alpha blocker monotherapy. However, in China, the characteristics of BPH patients receiving 5-alpha-reductase inhibitor/alpha blocker combination therapy or alpha blocker monotherapy remain largely unknown. Therefore, this study compared the characteristics of BPH patients receiving either the 5-alpha-reductase inhibitor finasteride in combination with an alpha blocker or an alpha blocker as monotherapy in clinical practice in China. METHODS: Data were obtained from a large electronic medical record database from four tertiary hospitals in major cities in China (2009-2016). BPH patients aged ≥ 50 years with ≥ 1 alpha blocker fill on/after the first BPH diagnosis were selected. Patients were further classified as receiving combination therapy (≥ 1 overlapping day of supply for finasteride and an alpha blocker) or alpha blocker monotherapy (did not receive any 5-alpha-reductase inhibitor). Patient characteristics, visit type (in- vs. outpatient) at treatment initiation, and comorbidities were evaluated during the 6-month baseline period and compared between the two groups using two sample t tests and chi-square tests/Fisher's exact tests. RESULTS: A total of 2666 and 2738 patients received combination therapy and monotherapy, respectively. The combination group was older (70.3 vs. 67.3 years, p < 0.0001) and had more patients initiated in an inpatient setting (46.0% vs. 26.4%, p < 0.0001). Compared with the monotherapy group, the combination group had more comorbidities, such as hypertension (48.3% vs. 35.6%, p < 0.0001), cardiovascular disease (65.3% vs. 48.0%, p < 0.0001), and diabetes (21.1% vs. 15.7%, p < 0.0001), and a higher Charlson comorbidity index (0.9 vs. 0.7, p < 0.0001). CONCLUSION: Chinese BPH patients using finasteride/alpha blocker combination therapy were older and had a higher comorbidity burden than those using alpha blocker monotherapy. These findings provide Chinese healthcare decision-makers with a better understanding of the patient characteristics generally associated with BPH combination therapy vs. alpha blocker monotherapy. FUNDING: Merck Sharp and Dohme (China) Co., Ltd., Shanghai, China.

Microarray analysis reveals gene and microRNA signatures in diabetic kidney disease.

The current study aimed to identify therapeutic gene and microRNA (miRNA) biomarkers for diabetic kidney disease (DKD). The public expression profile GSE30122 was used. Following data preprocessing, the limma package was used to select differentially-expressed genes (DEGs) in DKD glomeruli samples and tubuli samples and they were compared with corresponding controls. Then overlapping DEGs in glomeruli and tubuli were identified and enriched analysis was performed. In addition, protein­protein interaction (PPI) network analysis as well as sub­network analysis was conducted. miRNAs of the overlapping DEGs were investigated using WebGestal. A total of 139 upregulated and 28 downregulated overlapping DEGs were selected, which were primarily associated with pathways involved in extracellular matrix (ECM)­receptor interactions and cytokine­cytokine receptor interactions. CD44, fibronectin 1, C­C motif chemokine ligand 5 and C­X­C motif chemokine receptor 4 were four primary nodes in the PPI network. miRNA (miR)­17­5p, miR­20a and miR­106a were important and nuclear receptor subfamily 4 group A member 3 (NR4A3), protein tyrosine phosphatase, receptor type O (PTPRO) and Kruppel like factor 9 (KLF9) were all predicted as target genes of the three miRNAs in the integrated miRNA­target network. Several genes were identified in DKD, which may be involved in pathways such as ECM­receptor interaction and cytokine­cytokine receptor interaction. Three miRNAs may also be used as biomarkers for therapy of DKD, including miR­17­5p, miR­20a and miR­106a, with the predicted targets of NR4A3, PTPRO and KLF9.