Mussel inspired sequential protein delivery based on self-healing injectable nanocomposite hydrogel.

Polysaccharide based self-healing and injectable hydrogels with reversible characteristics have widespread potential in protein drug delivery. However, it is a challenge to design the dynamic hydrogel for sequential release of protein drugs. Herein, we developed a novel mussel inspired sequential protein delivery dynamic polysaccharide hydrogel. The nanocomposite hydrogel can be fabricated through doping polydopamine nanoparticles (PDA NPs) into reversible covalent bond (imine bonds) crosslinked polymer networks of oxidized hyaluronic acid (OHA) and carboxymethyl chitosan (CEC), named PDA NPs@OHA-l-CEC. Besides multiple capabilities (i.e., injection, self-healing, and biodegradability), the nanocomposite hydrogel can achieve sustained and sequential protein delivery of vascular endothelial growth factor (VEGF) and bovine serum albumin (BSA). PDA NPs doped in hydrogel matrix serve dual roles, acting as secondary protein release structures and form dynamic non-covalent interactions (i.e., hydrogen bonds) with polysaccharides. Moreover, by adjusting the oxidation degree of OHA, the hydrogels with different crosslinking density could control overall protein release rate. Analysis of different release kinetic models revealed that Fickian diffusion drove rapid VEGF release, while the slower BSA release followed a Super Case II transport mechanism. The novel biocompatible system achieved sequential release of protein drugs has potentials in multi-stage synergistic drug deliver based on dynamic hydrogel.

Diagnostic performance of serum galactomannan and ß-D-glucan for invasive aspergillosis in suspected patients: A meta-analysis.

BACKGROUND: Serum galactomannan (GM) and ß-D-glucan (BG) are known markers of invasive aspergillosis (IA). The aim of this meta-analysis was to evaluate the efficiency of serum GM and BG as diagnostic markers of symptomatic IA infection and compare the performance of the combined tests with that of either test individually. METHODS: A literature search was carried out using PubMed, Web of Science, and EMBASE databases to include relevant studies published in English up to May 2023. The quality assessment was performed using Review Manager 5.3 software. A bivariate model was applied to pool diagnostic parameters using Stata 14.0 software. We used Cochrane I2 index to assess heterogeneity and identify the potential source of heterogeneity by meta-regression. Paired t tests were used to compare the value of GM and BG for IA diagnosis when used in combination or alone. RESULTS: Sixteen studies were eligible for inclusion in the meta-analysis. For proven or probable IA, serum GM and BG yielded a pooled sensitivity of 0.53 (95% CI 0.40-0.66) vs 0.72 (95% CI 0.61-0.81) and a pooled specificity of 0.94 (95% CI 0.91-0.97) vs 0.82 (95% CI 0.73-0.88). The area under the curve (AUC) of ROC was 0.90 (95% CI 0.87-0.92) vs 0.83 (95% CI 0.80-0.86) for all studies. The pooled sensitivity and specificity for IA diagnosis by combined GM and BG assays (GM/BG) were 0.84 (95% CI 0.69-0.86) and 0.76 (95% CI 0.69-0.81), respectively. The sensitivity of the combined GM/BG test to diagnose IA was higher than of the GM or BG test alone. CONCLUSION: Serum GM and BG tests had a relatively high accuracy for IA diagnosis in suspected patients. The diagnostic accuracy of both assays is comparable, and the diagnostic sensitivity is further improved by the combined detection of the 2 markers.

Quantifying the energy landscape in weakly and strongly disordered frictional media.

We investigate the "roughness" of the energy landscape of a system that diffuses in a heterogeneous medium with a random position-dependent friction coefficient α(x). This random friction acting on the system stems from spatial inhomogeneity in the surrounding medium and is modeled using the generalized Caldira-Leggett model. For a weakly disordered medium exhibiting a Gaussian random diffusivity D(x) = kBT/α(x) characterized by its average value ⟨D(x)⟩ and a pair-correlation function ⟨D(x1)D(x2)⟩, we find that the renormalized intrinsic diffusion coefficient is lower than the average one due to the fluctuations in diffusivity. The induced weak internal friction leads to increased roughness in the energy landscape. When applying this idea to diffusive motion in liquid water, the dissociation energy for a hydrogen bond gradually approaches experimental findings as fluctuation parameters increase. Conversely, for a strongly disordered medium (i.e., ultrafast-folding proteins), the energy landscape ranges from a few to a few kcal/mol, depending on the strength of the disorder. By fitting protein folding dynamics to the escape process from a metastable potential, the decreased escape rate conceptualizes the role of strong internal friction. Studying the energy landscape in complex systems is helpful because it has implications for the dynamics of biological, soft, and active matter systems.

Transcutaneous electrical acupoint stimulation for postoperative nausea and vomiting in patients undergoing craniotomy: A randomized controlled trial.

BACKGROUND: The incidence of nausea and vomiting following craniotomy is high, and pericardium 6 (P6; Neiguan) acupoint stimulation is an important strategy for treating postoperative nausea and vomiting (PONV). Here, we aimed to evaluate the efficacy of transcutaneous electrical acupoint stimulation (TEAS) at P6 as an adjunct to antiemetic drugs to prevent PONV after craniotomy. MATERIALS AND METHODS: This randomized placebo-controlled trial enrolled 120 patients scheduled for craniotomy. The enrolled patients were randomly assigned to a TEAS or sham TEAS group. The incidence of PONV, pain score, and postoperative remedial treatment with antiemetics and analgesics at 0-2, 2-6, and 6-24 h after craniotomy were assessed. RESULTS: The patient characteristics did not significantly differ between the two groups (P > 0.05). During 0-2 and 6-24 h after craniotomy, the incidence of vomiting was not significantly different between the two groups (P > 0.05). During 2-6 h, the incidence of vomiting was higher in the sham TEAS group than in the TEAS group (29.3 % vs. 14.0 %, P = 0.047). During 0-2 and 2-6 h, the pain scores did not differ significantly between the two groups (P > 0.05). During 6-24 h after craniotomy, the pain score was significantly higher in the sham TEAS group than in the TEAS group (P = 0.001). The degree of nausea and proportion of patients requiring antiemetic drugs were not significantly different between the two groups in each period (P > 0.05). CONCLUSION: TEAS at P6 may reduce vomiting incidence and pain scores following craniotomy.

Ovarian Tumor Domain-Containing 7B Attenuates Pathological Cardiac Hypertrophy by Inhibiting Ubiquitination and Degradation of Krüppel-Like Factor 4.

BACKGROUND: Cardiac hypertrophy (CH) is a well-established risk factor for many cardiovascular diseases and a primary cause of mortality and morbidity among older adults. Currently, no pharmacological interventions have been specifically tailored to treat CH. OTUD7B (ovarian tumor domain-containing 7B) is a member of the ovarian tumor-related protease (OTU) family that regulates many important cell signaling pathways. However, the role of OTUD7B in the development of CH is unclear. Therefore, we investigated the role of OTUD7B in CH. METHODS AND RESULTS: OTUD7B knockout mice were used to assay the role of OTUD7B in CH after transverse aortic coarctation surgery. We further assayed the specific functions of OTUD7B in isolated neonatal rat cardiomyocytes. We found that OTUD7B expression decreased in hypertrophic mice hearts and phenylephrine-stimulated neonatal rat cardiomyocytes. Furthermore, OTUD7B deficiency exacerbated transverse aortic coarctation surgery-induced myocardial hypertrophy, abnormal cardiac function, and fibrosis. In cardiac myocytes, OTUD7B knockdown promoted phenylephrine stimulation-induced myocardial hypertrophy, whereas OTUD7B overexpression had the opposite effect. An immunoprecipitation-mass spectrometry analysis showed that OTUD7B directly binds to KLF4 (Krüppel-like factor 4). Additional molecular experiments showed that OTUD7B impedes KLF4 degradation by inhibiting lysine residue at 48 site-linked ubiquitination and suppressing myocardial hypertrophy by activating the serine/threonine kinase pathway. CONCLUSIONS: These results demonstrate that the OTUD7B-KLF4 axis is a novel molecular target for CH treatment.

Evidence summary on the non-pharmacological management of sleep disorders in shift workers.

PURPOSE: This study aimed to evaluate, and integrate the relevant evidence on the non-pharmacological management of sleep disorders in shift workers to provide a reference for improving sleep of shift workers. METHODS: According to the "6S" pyramid model of evidence, a comprehensive search was conducted in evidence-based databases, including BMJ-Best Practice, UpToDate, DynaMed, Cochrane Library, and Joanna Briggs Institute (JBI); clinical practice guideline websites, such as the Guidelines International Network; professional association websites, such as the World Sleep Society; and literature databases, including PubMed, Embase, CINAHL, China National Knowledge Infrastructure (CNKI), Wanfang Database, and Chinese Biology Medicine disc (CBM) from inception to November 30, 2022. Two researchers independently evaluated the literature in accordance with the evaluation standards; conducted the extraction, classification, and synthesis of the evidence; and evaluated its grade and recommendation grade. RESULTS: A total of 18 studies were included, including 2 clinical decisions, 2 guidelines, 3 expert consensuses, and 11 systematic reviews. In total, 25 pieces of evidence were summarized from 6 aspects: sleep assessment, sleep scheduling, sleep hygiene, light therapy, workplace intervention, and other managements. CONCLUSION: This study summarized the best evidence for the non-pharmacological management of sleep disorders in shift workers. Shift workers should reasonably arrange their sleep time and develop good sleep hygiene. Additionally, work organizations should jointly promote sleep to improve the sleep conditions of shift workers and promote their physical and mental health.

Detection of Antibiotic Resistance in Feline-Origin ESBL Escherichia coli from Different Areas of China and the Resistance Elimination of Garlic Oil to Cefquinome on ESBL E. coli.

The development of drug-resistance in the opportunistic pathogen Escherichia coli has become a global public health concern. Due to the share of similar flora between pets and their owners, the detection of pet-origin antibiotic-resistant E. coli is necessary. This study aimed to detect the prevalence of feline-origin ESBL E. coli in China and to explore the resistance elimination effect of garlic oil to cefquinome on ESBL E. coli. Cat fecal samples were collected from animal hospitals. The E. coli isolates were separated and purified by indicator media and polymerase chain reaction (PCR). ESBL genes were detected by PCR and Sanger sequencing. The MICs were determined. The synergistic effect of garlic oil and cefquinome against ESBL E. coli was investigated by checkerboard assays, time-kill and growth curves, drug-resistance curves, PI and NPN staining, and a scanning electronic microscope. A total of 80 E. coli strains were isolated from 101 fecal samples. The rate of ESBL E. coli was 52.5% (42/80). The prevailing ESBL genotypes in China were CTX-M-1, CTX-M-14, and TEM-116. In ESBL E. coli, garlic oil increased the susceptibility to cefquinome with FICIs from 0.2 to 0.7 and enhanced the killing effect of cefquinome with membrane destruction. Resistance to cefquinome decreased with treatment of garlic oil after 15 generations. Our study indicates that ESBL E. coli has been detected in cats kept as pets. The sensitivity of ESBL E. coli to cefquinome was enhanced by garlic oil, indicating that garlic oil may be a potential antibiotic enhancer.

Detection of antibiotic-resistant canine origin Escherichia coli and the synergistic effect of magnolol in reducing the resistance of multidrug-resistant Escherichia coli.

Background: The development of antimicrobial resistance in the opportunistic pathogen Escherichia coli has become a global public health concern. Due to daily close contact, dogs kept as pets share the same E. coli with their owners. Therefore, the detection of antimicrobial resistance in canine E. coli is important, as the results could provide guidance for the future use of antibiotics. This study aimed to detect the prevalence of antibiotic-resistance of canine origin E. coli in Shaanxi province and to explore the inhibition effect of magnolol combined with cefquinome on MDR E. coli, so as to provide evidence for the use of antibiotics. Methods: Canine fecal samples were collected from animal hospitals. The E. coli isolates were separated and purified using various indicator media and polymerase chain reaction (PCR). Drug-resistance genes [aacC2, ant(3')-I, aph(3')-II, aac(6')-Ib-cr, aac(3')-IIe, bla KPC , bla IMP-4 , bla OXA , bla CMY , bla TEM-1 , bla SHV , bla CTX-M-1 , bla CTX-M-9 , Qnra, Qnrb, Qnrs, TetA, TetB, TetM, Ermb] were also detected by PCR. The minimum inhibitory concentration (MIC) was determined for 10 antibiotics using the broth-microdilution method. Synergistic activity of magnolol and cefquinome against multidrug-resistant (MDR) E. coli strains was investigated using checkerboard assays, time-kill curves, and drug-resistance curves. Results: A total of 101 E. coli strains were isolated from 158 fecal samples collected from animal hospitals. MIC determinations showed that 75.25% (76/101) of the E. coli strains were MDR. A total of 22 drug-resistance genes were detected among the 101 strains. The bla TEM-1gene exhibited the highest detection rate (89.77%). The TetA and Sul gene also exhibited high detection rate (66.34 and 53.47%, respectively). Carbapenem-resistant E. coli strains were found in Shangluo and Yan'an. Additionally, in MDR E. coli initially resistant to cefquinome, magnolol increased the susceptibility to cefquinome, with an FICI (Fractional Inhibitory Concentration Index) between 0.125 and 0.5, indicating stable synergy. Furthermore, magnolol enhanced the killing effect of cefquinome against MDR E. coli. Resistance of MDR E. coli to cefquinome decreased markedly after treatment with magnolol for 15 generations. Conclusion: Our study indicates that antibiotic-resistance E. coli has been found in domestic dogs. After treatment with magnolol extracted from the Chinese herb Houpo (Magnolia officinalis), the sensitivity of MDR E. coli to cefquinome was enhanced, indicating that magnolol reverses the resistance of MDR E. coli. The results of this study thus provide reference for the control of E. coli resistance.

The platelet pannexin 1-IL-1ß axis orchestrates pancreatic ductal adenocarcinoma invasion and metastasis.

We aimed to investigate the protumor mechanisms of platelets in pancreatic ductal adenocarcinoma (PDAC). Serum samples were collected from 656 PDAC patients and 3105 healthy people, and a Panx1 knockout tumor model and an adoptive platelet transfusion mouse model were established. We showed that the blood platelet counts were not significantly different between stage III/IV and stage I/II patients, while the number of the CD41+/CD62P+ platelets was significantly elevated in stage III/IV patients, indicating that CD41+/CD62P+ platelets are associated with a poor prognosis. Further analysis showed that a high level of CD41+/CD62P+ platelets was significantly correlated with microvascular invasion (P = 0.002), advanced 8th edition AJCC stage (P < 0.001), and a high CA19-9 level (P = 0.027) and independently predicted a poor prognosis for resectable I/II PDAC. Furthermore, we found significantly higher Panx1 expression in CD41+/CD62P+ platelets than in CD41+/CD62P- platelets in PDAC patients. Mechanistically, Panx1 was able to enhance IL-1ß secretion in CD41+/CD62P+ platelets by phosphorylating p38 MAPK and consequently promoted the invasion and metastasis of PDAC cells. Finally, we synthesized a novel compound named PC63435 by the ligation of carbenoxolone (a Panx1 inhibitor) and PSGL-1 (a CD62P ligand). PC63435 specifically bound to CD41+/CD62P+ platelets, then blocked the Panx1/IL-1ß pathway and reduced the proportion of CD41+/CD62P+ platelets, which suppressed PDAC tumor invasion and metastasis in vivo. These results demonstrated that the Panx1/IL-1ß axis in CD41+/CD62P+ platelets enhanced PDAC cell malignancy and that this axis may be a promising target for PDAC therapy.

Carrier-envelope-phase-dependent below-threshold harmonic generation in few-cycle mid-infrared laser fields.

We theoretically study the dependence of below-threshold harmonic generation (BTHG) of atoms on the carrier-envelope phase (CEP) driven by few-cycle mid-infrared laser pulses. The BTHG spectra can be accurately and efficiently calculated by solving the three-dimensional time-dependent Schrödinger equation using the time-dependent generalized pseudospectral method. We present the BTHG spectra as a function of the laser-field CEP. CEP-dependent enhancement or suppression occurred at low laser field intensities owing to the changes in the resonant effects associated with multiple quantum trajectories. However, the BTHG of atoms driven by high laser intensities is insensitive to the CEP. The synchrosqueezing time-frequency transform of the BTHG and extended semiclassical analysis are performed to elucidate the underlying physical mechanism.

Improving the diagnostic performance of computed tomography angiography for intracranial large arterial stenosis by a novel super-resolution algorithm based on multi-scale residual denoising generative adversarial network.

BACKGROUND: Computed tomography angiography (CTA) is very popular because it is characterized by rapidity and accessibility. However, CTA is inferior to digital subtraction angiography (DSA) in the diagnosis of intracranial artery stenosis or occlusion. DSA is an invasive examination, so we optimized the quality of cephalic CTA images. METHODS: We used 5000 CTA images to train multi-scale residual denoising generative adversarial network (MRDGAN). And then 71 CTA images with intracranial large arterial stenosis were treated by Super-Resolution based on Generative Adversarial Network (SRGAN), Enhanced Super-Resolution based on Generative Adversarial Network (ESRGAN) and post-trained MRDGAN, respectively. Peak signal-to-noise ratio (PSNR) and structural similarity index measurement (SSIM) of the SRGAN, ESRGAN, MRDGAN and original CTA images were measured respectively. The qualities of MRDGAN and original images were visually assessed using a 4-point scale. The diagnostic coherence of digital subtraction angiography (DSA) with MRDGAN and original images was analyzed. RESULTS: The PSNR was significantly higher in the MRDGAN CTA images (35.96 ± 1.51) than in the original (31.51 ± 1.43), SRGAN (25.75 ± 1.18) and ESRGAN (30.36 ± 1.05) CTA images (all P < 0.001). The SSIM was significantly higher in the MRDGAN CTA images (0.95 ± 0.02) than in the SRGAN (0.88 ± 0.03) and ESRGAN (0.90 ± 0.02) CTA images (all P < 0.01). The visual assessment was significantly higher in the MRDGAN CTA images (3.52 ± 0.58) than in the original CTA images (2.39 ± 0.69) (P < 0.05). The diagnostic coherence between MRDGAN and DSA (κ = 0.89) was superior to that between original images and DSA (κ = 0.62). CONCLUSION: Our MRDGAN can effectively optimize original CTA images and improve its clinical diagnostic value for intracranial large artery stenosis.

A Primer on Home Infusion Administration Methods.

Home infusion therapy is a rapidly growing field in healthcare, allowing patients to receive postacute care at home at a fraction of the cost of an inpatient stay. Understanding the various drug delivery systems can facilitate a more seamless discharge to home with improved patient outcomes. Herein we review several home infusion methods of administration utilized to transition patients from hospital to home care for a variety of therapies.

Efficacy of Xiyanping in the Treatment of Elderly Patients with Chronic Obstructive Pulmonary Disease and Its Effect on the Expression of GDF-15 and HIF-1α in Serum.

Background: COPD is a chronic respiratory disease with a long course and recurrent characteristics. According to relevant statistics, the global incidence of COPD is more than 30%, which seriously affects the life of patients and endangers their health. Objective: To observe the curative effect of Xiyanping in elderly patients with COPD and its influence on the expressions of growth differentiation GDF-15 and HIF-1α in serum. Methods: From August 2019 to December 2021, 86 elderly patients with acute exacerbation of COPD were admitted to our hospital. As the research objects, they were divided into the control group (n = 43) and the observation group (n = 43) randomly. The control group received the conventional treatment, while the observation group got Xiyanping on the basis of the control group. The differences in the duration of antibiotic use, expectoration, hospital stays, adverse reactions and serum-related factors, blood routine, pulmonary function, airway hyperreactivity index, COPD assessment test (CAT) score, and Borg score were made a comparison between them. Results: On the 3rd and 7th days after being treated, the sputum excretion in them was higher than before, but on the 3rd day of treatment, the sputum excretion in the observation group was higher than that in the control group, while on the 7th day of treatment, the sputum excretion was lower than that in the control group with statistically significant differences (P < 0.05). Before treatment, the serum-related factors and blood routine indexes between them were similar (P > 0.05). After treatment, GDF-15, HIF-1α, CXCL12, TNF-α, IL-8, TGF-ß, WBC, and NEU in them were significantly lower than before, and the values in the observation group were significantly lower than those in the control group with statistically significant differences (P < 0.05). There was no difference in the related indexes of pulmonary function and airway hyperreactivity between them before treatment. After being treated, FEV1, FVC, and FEV1/FVC in them were significantly higher than those before treatment. The airway resistance and lung compliance of the two groups at exhalation and inspiration were significantly lower than before, and the values in the observation group were significantly lower than those in the control group (P < 0.05). There was no difference in CAT and Borg scores between them before treatment. After treatment, the CAT score and Borg score of these patients were significantly lower than those before treatment, and the value of the observation group was significantly lower than that of the control group (P < 0.05). The duration of antibiotic use and length of stay in the observation group were significantly shorter than those of the control group, while the incidence of adverse reactions was not statistically significantly different compared with the control group (P > 0.05). Conclusion: Xiyanping can improve pulmonary function of elderly patients with acute exacerbation of COPD, reduce the response of airway hyperreactivity, and promote the excretion of sputum.

Myotubularin-Related Protein14 Prevents Neointima Formation and Vascular Smooth Muscle Cell Proliferation by Inhibiting Polo-Like Kinase1.

Background Restenosis is one of the main bottlenecks in restricting the further development of cardiovascular interventional therapy. New signaling molecules involved in the progress have continuously been discovered; however, the specific molecular mechanisms remain unclear. MTMR14 (myotubularin-related protein 14) is a novel phosphoinositide phosphatase that has a variety of biological functions and is involved in diverse biological processes. However, the role of MTMR14 in vascular biology remains unclear. Herein, we addressed the role of MTMR14 in neointima formation and vascular smooth muscle cell (VSMC) proliferation after vessel injury. Methods and Results Vessel injury models were established using SMC-specific conditional MTMR14-knockout and -transgenic mice. Neointima formation was assessed by histopathological methods, and VSMC proliferation and migration were assessed using fluorescence ubiquitination-based cell cycle indicator, transwell, and scratch wound assay. Neointima formation and the expression of MTMR14 was increased after injury. MTMR14 deficiency accelerated neointima formation and promoted VSMC proliferation after injury, whereas MTMR14 overexpression remarkably attenuated this process. Mechanistically, we demonstrated that MTMR14 suppressed the activation of PLK1 (polo-like kinase 1) by interacting with it, which further leads to the inhibition of the activation of MEK/ERK/AKT (mitogen-activated protein kinase kinase/extracellular-signal-regulated kinase/protein kinase B), thereby inhibiting the proliferation of VSMC from the medial to the intima and thus preventing neointima formation. Conclusions MTMR14 prevents neointima formation and VSMC proliferation by inhibiting PLK1. Our findings reveal that MTMR14 serves as an inhibitor of VSMC proliferation and establish a link between MTMR14 and PLK1 in regulating VSMC proliferation. MTMR14 may become a novel potential therapeutic target in the treatment of restenosis.

An effective method to reduce lymphatic drainage post-lateral cervical lymph node dissection of differentiated thyroid cancer: a retrospective analysis.

BACKGROUND: Lymph or chyle leak (LL/CL) is severe complications after lateral cervical lymph node dissection (LLND), mainly due to iatrogenic injury of the lymphatic duct. Efficient and well-operated methods to reduce postoperative drainage are still lacking. This was a feasibility study to evaluate a new method of preventing LL/CL compared to conventional treatment. METHOD: We retrospectively analyzed 20 consecutive patients who used the "pedicled omohyoid flap covering (POFC)" method during LLND from January 2019 to December 2021 in our center as an observation group. Another 20 consecutive patients used the conventional method during LLND in this period as a control group. The clinical and pathological features of the two groups were compared, and the related factors that affected postoperative lymphatic drainage were analyzed with Cox proportional hazards models. RESULTS: The drainage volume per 24 h and the incidence of LL/CL in the control group were both higher than that in the observation group (all P < 0.05), and the number of lymph nodes dissected in the IV region > 10 and the use of the POFC method were the independent risk factors that significantly affected the incidence of LL/CL post LLND (all P < 0.05). CONCLUSIONS: POFC is a safe and useful method for reducing drainage and preventing LL/CL post-LLND, especially for patients with heavy metastasis of the lymph nodes in the IV region.

Neoadjuvant chemotherapy endows CD9 with prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer.

BACKGROUND: The selective pressure imposed by chemotherapy creates a barrier to tumor eradication and an opportunity for metastasis and recurrence. As a newly discovered stemness marker of pancreatic ductal adenocarcinoma (PDAC), the impact of CD9 on tumor progression and patient's prognosis remain controversial. METHODS: A total of 179 and 211 PDAC patients who underwent surgical resection with or without neoadjuvant chemotherapy, respectively, were recruited for immunohistochemical analyses of CD9 expression in both tumor and stromal areas prior to statistical analyses to determine the prognostic impact and predictive accuracy of CD9. RESULTS: The relationship between CD9 and prognostic indicators was not significant in the non-neoadjuvant group. Nevertheless, CD9 expression in both tumor (T-CD9) and stromal areas (S-CD9) was significantly correlated with the clinicopathological features in the neoadjuvant group. High levels of T-CD9 were significantly associated with worse OS (p = 0.005) and RFS (p = 0.007), while positive S-CD9 showed the opposite results (OS: p = 0.024; RFS: p = 0.008). Cox regression analyses identified CD9 in both areas as an independent prognostic factor. The T&S-CD9 risk-level system was used to stratify patients with different survival levels. The combination of T&S-CD9 risk level and TNM stage were accurate predictors of OS (C-index: 0.676; AIC: 512.51) and RFS (C-index: 0.680; AIC: 519.53). The calibration curve of the nomogram composed of the combined parameters showed excellent predictive consistency for 1-year RFS. These results were verified using a validation cohort. CONCLUSION: Neoadjuvant chemotherapy endows CD9 with a significant prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer.

Evolution of the frequency-comb structure and coherence from a Keldysh multiphoton into a tunneling regime.

We present a theoretical study of the characteristics of the frequency-comb structure and coherence via high-order harmonic generation (HHG) driven by the laser pulse trains when the ionization process is pushed from Keldysh multiphoton into tunneling regime. HHG is obtained by solving accurately the time-dependent Schrödinger equation by means of the time-dependent generalized pseudospectral method. We find that the nested comb structures are formed from each harmonic order in the Keldysh multiphoton ionization regime. But it is severely suppressed or even disappeared in the Keldysh tunneling ionization regime. It implies that the temporal coherence of the emitted frequency comb modes is very sensitive to the Keldysh ionization regime. To understand the evolution of frequency-comb structure and coherence, we perform the calculation of the time-dependent ionization probability and the spectral phase of frequency-comb HHG. We find that the frequency-comb HHG driven by the laser pulse trains in the Keldysh multiphoton regime has a good coherence because the ionization probability of the atom driven by each laser pulse is stable, leading to a phase-coherent frequency-comb structure rather than those cases in the Keldysh tunneling regime with high laser intensity. Our results shed light on current interest and significance to the experimental realization of controllable and frequency-comb vacuum-ultraviolet light sources.

SOX2 knockdown with siRNA reverses cisplatin resistance in NSCLC by regulating APE1 signaling.

SOX2 is related to drug resistance in many types of cancer, including lung cancer. Herein, we investigated the role of SOX2 and its regulatory signaling in cisplatin-treated non-small-cell lung cancer (NSCLC). The effects of SOX2 on cell viability, proliferation, and apoptosis were evaluated in vitro. Western blotting, real-time quantitative PCR, immunohistochemistry, and luciferase reporter assays were used to investigate the underlying mechanism. Kaplan-Meier survival analysis and the log-rank test were used to assess the relationship between SOX2 expression and patient survival. A549/CDDP cells had marked resistance to cisplatin and stronger colony formation ability than A549 cells. The expression of SOX2 protein or mRNA in A549/CDDP was higher than that in A549. Knockdown of SOX2 in A549/CDDP-induced apoptosis by inhibiting colony formation and decreasing viability, but overexpression of SOX2 reversed these effects. Interestingly, Genomatix software predicted that the APE1 promoter has some SOX2 binding sites, while the SOX2 promoter has no APE1 binding sites. Furthermore, luciferase reporter assays proved that SOX2 could bind the promoter of APE1 in 293T cells. We further verified that SOX2 expression was not affected by shAPE1 in A549/CDDP. As expected, colony formation was obviously inhibited and apoptosis was strongly enhanced in A549/CDDP treated with SOX2 siSOX2 alone or combined with CDDP compared with control cells. Meaningfully, patients with low expression of SOX2, and even including its regulating APE1, survived longer than those with high expression of SOX2, and APE1. siSOX2 overcomes cisplatin resistance by regulating APE1 signaling, providing a new target for overcoming cisplatin resistance in NSCLC.

SIGLEC15 amplifies immunosuppressive properties of tumor-associated macrophages in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) usually presents infrequent infiltration of T lymphocytes. The known immune-checkpoint inhibitors to date focus on activating T cells and manifest limited effectiveness in PDAC. SIGLEC15 was identified as a novel tumor-associated macrophage (TAM)-related immune-checkpoint in other cancer types, while its immunosuppressive role and clinical significance remained unclear in PDAC. In our study, SIGLEC15 presented immunosuppressive relevance in PDAC via bioinformatic analysis and expressed on TAM and PDAC cells. SIGLEC15+ TAM, rather than SIGLEC15+ PDAC cells or SIGLEC15- TAM, correlated with poor prognosis and immunosuppressive microenvironment in the PDAC microarray cohort. Compared with SIGLEC15- TAM, SIGLEC15+ TAM presented an M2-like phenotype that could be modulated by SIGLEC15 in a tumor cell-dependent manner. In mechanism, SIGLEC15 interacted with PDAC-expressed sialic acid, preferentially α-2, 3 sialic acids, to stimulate SYK phosphorylation in TAM, which further promoted its immunoregulatory cytokines and chemokines production. In vivo, SIGLEC15+ TAM also presented an M2-like phenotype, accelerated tumor growth, and facilitated immunosuppressive microenvironment, which was greatly abolished by SYK inhibitor. Our study highlighted a novel M2-promoting function of SIGLEC15 and strongly suggested SIGLEC15 as a potential immunotherapeutic target for PDAC.

Histone deacetylases: A novel class of therapeutic targets for pancreatic cancer.

Pancreatic cancer is the seventh leading cause of cancer death worldwide, with a low 5-year survival rate. Novel agents are urgently necessary to treat the main pathological type, known as pancreatic ductal carcinoma (PDAC). The dysregulation of histone deacetylases (HDACs) has been identified in association with PDAC, which can be more easily targeted by small molecular inhibitors than gene mutations and may represent a therapeutic breakthrough for PDAC. However, the contributions of HDACs to PDAC remain controversial, and pharmacokinetic challenges have limited the application of HDAC inhibitors (HDACis) in PDAC. This review summarizes the mechanisms associated with success and failure of HDACis in PDAC and discusses the recent progress made in HDACi development and application, such as combination therapies designed to enhance efficacy. More precise strategies involving HDACis might eventually improve the outcomes of PDAC treatment.