A highly potent small-molecule antagonist of exportin-1 selectively eliminates CD44+CD24- enriched breast cancer stem-like cells.

Breast cancer stem-like cells (BCSCs) have been suggested as the underlying cause of tumor recurrence, metastasis and drug resistance in triple-negative breast cancer (TNBC). Here, we report the discovery and biological evaluation of a highly potent small-molecule antagonist of exportin-1, LFS-1107. We ascertained that exportin-1 (also named as CRM1) is a main cellular target of LFS-1107 by nuclear export functional assay, bio-layer interferometry binding assay and C528S mutant cell line. We found that LFS-1107 significantly inhibited TNBC tumor cells at low-range nanomolar concentration and LFS-1107 can selectively eliminate CD44+CD24- enriched BCSCs. We demonstrated that LFS-1107 can induce the nuclear retention of Survivin and consequent strong suppression of STAT3 transactivation abilities and the expression of downstream stemness regulators. Administration of LFS-1107 can strongly inhibit tumor growth in mouse xenograft model and eradicate BCSCs in residual tumor tissues. Moreover, LFS-1107 can significantly ablate the patient-derived tumor organoids (PDTOs) of TNBC as compared to a few approved cancer drugs. Lastly, we revealed that LFS-1107 can enhance the killing effects of chemotherapy drugs and downregulate multidrug resistance related protein targets. These new findings provide preclinical evidence of defining LFS-1107 as a promising therapeutic agent to deplete BCSCs for the treatment of TNBC.

Discovery and biological evaluation of a small-molecule inhibitor of CRM1 that suppresses the growth of triple-negative breast cancer cells.

Dysregulation of the nuclear export machinery mediated by chromosomal maintenance 1 (CRM1, also known as exportin-1), is closely associated with various human disorders, such as breast cancer. Previously, we identified sulforaphene and its synthetic analogues as covalent inhibitors of CRM1. Herein, we describe the discovery and biological evaluation of another sulforaphene synthetic analogue, LFS-31, as a potential CRM1 inhibitor. In addition, we investigated the reversible binding mechanism of LFS-31 with CRM1 through molecular simulations coupled with bio-layer interferometry (BLI) and found relatively high binding affinity (KD = 43.1 ± 35.3 nM) between the LFS-31 and CRM1 groups. We found that LFS-31 exhibited a stronger growth suppression of triple-negative breast cancer (TNBC) cells than non-TNBC cells, and had minimal effect on normal breast cells. Pharmacological treatment of TNBC cells with LFS-31 at nanomolar concentrations led to the nuclear retention of IkBα resulting in strong suppression of NF-κB transcriptional activity and attenuated cell growth and proliferation, which collectively contributed to the antitumor responses. To the best of our knowledge, this is the first study to demonstrate the use of a sulforaphene analogue as a potent CRM1 inhibitor that targets the NF-κB signaling pathway for the targeted therapy of TNBC.

Covalent Organic Framework Nanosheets for Fluorescence Quantification of Peptide.

Rapid and sensitive quantification of peptides plays an important role in clinical diagnosis. Fluorescence assay is one of the most promising peptide detection tools, but it relies on intrinsic fluorescence or additional derivatization, resulting in poor versatility. Covalent organic frameworks (COFs) have shown a good application prospect in the field of fluorescence detection, but their application scope is limited to heavy metal ions and some small polar organic molecules. Herein, we report the application of COFs nanosheet for fluorescence detection of peptides. Fluorescent sp2 acrylonitrile-linked COFs nanosheets (TTAN-CON) were prepared by water-assisted ultrasonic exfoliation which performed with excellent fluorescence properties with Stokes shifts of 146 nm and fluorescence quantum yield of up to 24.45%. Compared to the bulk fluorescent COFs, exfoliated CONs films performed with better stability of fluorescence signal in solution. We found the fluorescence of TTAN-CON can be effectively quenched by hydrophobic peptides at a very rapid rate (less than 5 min per sample). TTAN-CON presented good sensitivity and selectivity for hydrophobic peptides detection via the static and dynamic joint quenching mechanism. TTAN-CON was further used to detect NLLGLIEAK and ProGRP31-98, two target peptide fragments of lung cancer biomarker ProGRP. The fluorescence intensities of TTAN-CON were negative linearly correlated with the amounts of hydrophobic NLLGLIEAK over the range of 5-1000 ng/mL with the correlation coefficients over 0.99, and the limit of detection was 1.67 ng/mL, displaying higher sensitivity and convenience than traditional optical methods. What's more, the quantification of ProGRP31-98 was achieved by the quantification of hydrophobic peptides in its enzyme hydrolysis products. We anticipate COFs nanosheets to be a universal fluorescence detection work-box for peptides biomarkers with clinical significance.

Dietary γ-mangostin triggers immunogenic cell death and activates cGAS signaling in acute myeloid leukemia.

Immunogenic cell death (ICD), one of cell-death types through release of damage-associated molecular patterns from dying tumor cells, activates tumor-specific immune response and elicits anti-tumor immunity by traditional radiotherapy and chemotherapy. However, whether natural products could induce ICD in leukemia is not elucidated. Here, we report dietary γ-mangostin eradicates murine primary leukemic cells and prolongs the survival of leukemic mice. As well, it restrains primary leukemic cells and CD34+ leukemic progenitor cells from leukemia patients. Strikingly, γ-mangostin attenuates leukemic cells by inducing ICD as characterized by expression of HSP90B1, ANXA1 and IL1B. Additionally, γ-mangostin accelerates cytoplasmic chromatin fragments generation, promoting DNA damage response, and enhances cGAS activation, leading to up-regulation of chemokines. Meanwhile, it induces HDAC4 degradation and acetylated histone H3 accumulation, which promotes chemokines transcription. Ultimately, CD8+ T cell is activated and recruited by γ-mangostin-induced chemokines in the microenvironment. Our study identifies γ-mangostin triggers ICD and activates cGAS signaling through DNA damage response and epigenetic modification. Therefore, dietary γ-mangostin would act as a potential agent to provoke anti-tumor immunity in the prevention and treatment of leukemia.

The catalytic mechanism of direction-dependent interactions for 2,3-dihydroxybenzoate decarboxylase.

Benzoic acid decarboxylases offer an elegant alternative to CO2 fixation by reverse reaction-carboxylation, which is named the bio-Kolbe-Schmitt reaction, but they are unfavorable to carboxylation. Enhancing the carboxylation efficiency of reversible benzoic acid decarboxylases is restricted by the unexplained carboxylation mechanisms. The direction of reversible enzyme catalytic reactions depends on whether catalytic residues at the active center of the enzyme are protonated, which is subjected by the pH. Therefore, the forward and reverse reactions could be separated at different pH values. Reversible 2,3-dihydroxybenzoate acid decarboxylase undergoes decarboxylation at pH 5.0 and carboxylation at pH 8.6. However, it is unknown whether the interaction of enzymes with substrates and products in the forward and reverse reactions can be exploited to improve the catalytic activity of reversible enzymes in the unfavorable direction. Here, we identify a V-shaped tunnel of 2,3-dihydroxybenzoic acid decarboxylase from Aspergillus oryzae (2,3-DHBD_Ao) through which the substrate travels in the enzyme, and demonstrate that the side chain conformation of a tyrosine residue controls the entry and exit of substrate/product during reversible reactions. Together with the kinetic studies of the mutants, it is clarified that interactions between substrate/product traveling through the enzyme tunnel in 2,3-DHBD_Ao are direction-dependent. These results enrich the understanding of the interactions of substrates/products with macromolecular reversible enzymes in different reaction directions, thereby demonstrating a possible path for engineering decarboxylases with higher carboxylation efficiency. KEY POINTS: • The residue Trp23 of 2,3-DHBD_Ao served as a switch to control the entry and exit of catechol • A V-shaped tunnel of 2,3-DHBD_Ao for decarboxylation and carboxylation reactions was identified • The results provide a promising strategy for engineering decarboxylases with direction-dependent residues inside the substrate/product traveling tunnel of the enzyme.

Targeting SOST using a small-molecule compound retards breast cancer bone metastasis.

BACKGROUND: Breast cancer metastasis to the bone can be exacerbated by osteoporosis, is associated with poor long-term survival, and has limited therapeutic options. Sclerostin (SOST) is an endogenous inhibitor of bone formation, and an attractive target for treatment of osteoporosis. However, it is unclear whether SOST can be used as a therapeutic target for bone metastases of breast cancer, and whether small molecule compounds that target SOST in breast cancer cells can inhibit breast cancer bone metastasis. METHODS: SOST expression in 442 breast cancer tissues was characterized by immunohistochemistry and statistically analyzed for the association with breast cancer bone metastases. Bone metastatic breast cancer SCP2 cells were induced for SOST silencing or overexpression and their bone metastatic behaviors were tested in vitro and in vivo. To identify potential therapeutics, we screened inhibitors of the interaction of SOST with STAT3 from a small chemical molecule library and tested the inhibitory effects of one inhibitor on breast cancer growth and bone metastasis in vitro and in vivo. RESULTS: We found that up-regulated SOST expression was associated with breast cancer bone metastases and worse survival of breast cancer patients. SOST silencing significantly reduced the bone metastatic capacity of SCP2 cells. SOST interacted with STAT3 to enhance the TGF-ß/KRAS signaling, increasing both tumor growth and bone metastasis. Treatment with one lead candidate, S6, significantly inhibited the growth of breast-cancer organoids and bone metastasis in mice. CONCLUSIONS: Our findings highlight a new class of potential therapeutics for treatment of bone metastasis in breast cancer.

Kinesiophobia could affect shoulder function after repair of rotator cuff tears.

PURPOSE: Kinesiophobia (fear of movement) is a major limiting factor in the return to pre-injury sport level after surgery of rotator cuff tears. The study aims to gain insights into how kinesiophobia affects shoulder pain and function after the repair of full-thickness rotator cuff tears. METHODS: A prospective study was conducted to evaluate patients who underwent rotator cuff repair between January 2019 and December 2019 in our institution. The patients were divided into a trial group with a high kinesiophobia (Tampa Scale for Kinesiophobia [TSK], TSK > 37) and a control group with a low kinesiophobia (TSK ≤ 37). The indicators of interest included the Constant-Murley scores, numerical rating scale (NRS), visual analogue scale (VAS), Oxford Shoulder Score (OSS), and the American shoulder and elbow score (ASES), shoulder function and strength, and range of motion (ROM) at 3 days, 6 weeks, and 12 months after repair of full-thickness rotator cuff tears. RESULTS: In total, 49 patients who underwent repair of full-thickness rotator cuff tears were enrolled, which was divided into a trial group involving 26 patients (mean TSK 52.54) and a control group involving 23 patients (mean TSK 33.43). There were no statistically significant differences in basic information such as age, gender, and length of stay in the two groups. The preoperative and early postoperative functional scores and the Tampa Scale for Kinesiophobia were statistically significant differences between the two groups. However, long-term postoperative follow-up showed no statistically significant difference in ASES, and Constant-Murley scores, OSS, and VAS scores between the two groups as the kinesiophobia changed from positive to negative. CONCLUSION: Degree of kinesiophobia reduced during post-operative rehabilitation of rotator cuff repair patients, but high kinesiophobia is still present in a large portion of the patients after rotator cuff repair. Patients after rotator cuff repair will benefit from early recognition and prevention of kinesiophobia.

A modified single-endobutton technique combined with nice knot for treatment of Rockwood type III or V acromioclavicular joint dislocation.

PURPOSE: Double-endobutton technique, as a widely accepted strategy for the treatment of acromioclavicular joint dislocation, is undergoing constant improvement. This study aims to assess the clinical effect of a modified single-endobutton combined with the nice knot in the fixation of Rockwood type III or V acromioclavicular joint dislocation. METHODS: From January 2016 to June 2019, 16 adult patients (13 males and 3 females) with Rockwood type III or V acromioclavicular joint dislocation were treated with a modified single-endobutton technique combined with the nice knot in our department. The age ranged from 18 to 64 years old with an average of 32.8 years old. Operative time, intraoperative blood loss, post-operative clinical outcomes and radiographic results were recorded and analyzed. Preoperative and last follow-up scores in the Constant-Murley Scale, Neer score, Rating Scale of the American Shoulder and Elbow Surgeons and VAS scale and complications such as infection, re-dislocation, implant loosening, medical origin fracture and hardware pain were recorded and evaluated. RESULTS: Sixteen patients were followed up for 6 to 18 months with an average of 10.3 months. The operative time was 50-90 min with an average of (62.5 ± 3.10) min. The intraoperative blood loss was 30-100 ml, with an average of (55.0 ± 4.28) ml. The complications, such as wound infection, internal fixation failure and fractures, were not found in these cases. According to Karlsson criteria, there were excellent in 14 cases, good in 2 cases at the final follow-up. The mean VAS score of the patients was 5.88 ± 0.26 preoperatively, compared with 0.19 ± 0.14 at the final follow-up evaluation. The difference was statistically significant (P < 0.05). The mean Constant score was 45.5 ± 2.0 preoperatively, compared to 94.0 ± 0.73 at the final follow-up evaluation. The difference was statistically significant (P < 0.05). Patients had statistically significant preoperative and postoperative AC (acromioclavicular distance) and CC (coracoclavicular distance) distances (P < 0.05); 6 months postoperatively the AC(P = 0.412) and CC(P = 0.324) distances were not statistically significant compared to the healthy side. CONCLUSION: Nice knot provides a reliable fixation for the single-endobutton technique in the treatment of acromioclavicular dislocations. The modified single-endobutton technique combined with the nice knot can achieve good clinical outcomes in the treatment of Rockwood type III or V acromioclavicular joint dislocation.

Prognosis assessment of CD44+/CD24- in breast cancer patients: a systematic review and meta-analysis.

PURPOSE: This meta-analysis investigated the relationships between the CD44+/CD24- phenotype and tumor size, lymph node metastasis, distant metastasis, disease-free survival (DFS), and overall survival (OS) in 8036 postoperative breast cancer patients enrolled in 23 studies. METHODS: A literature search of PubMed, Medline, Cochrane, Embase, and PMC was conducted to identify eligible studies. The combined odds ratios (ORs) and 95% confidence intervals (95% CIs) were analyzed to evaluate the relationships between the CD44+/CD24- phenotype and the pathological and biological characteristics of breast cancer patients, and the combined hazard ratios (HRs) and 95% CIs were calculated to evaluate the relationships between CD44+/CD24- and DFS and OS of breast cancer patients using Stata12.0 software. RESULTS: The CD44+/CD24- phenotype were not related to the tumor size (tumor size > 2.0 vs ≤ 2.0 cm, combined OR = 0.98, 95% CI 0.68-1.34, p = 0.792) and did not promote lymph node metastasis (lymph node metastasis vs. no lymph node metastasis, OR = 0.92, 95% CI 0.67-1.27, p = 0.626) and distant metastasis (distant metastasis vs no distant metastasis, combined OR = 3.88, 95% CI 0.93-16.24, p = 0.064). The CD44+/CD24- phenotype was negatively correlated with postoperative DFS (HR = 1.67, 95% CI 1.35-2.07, p < 0.00001) and OS (combined HR = 1.52, 95% CI 1.21-1.91, p = 0.0004). CONCLUSION: These results suggested expression of the CD44+/CD24- phenotype cannot be used as a reliable indicator of the tumor size, lymph node metastasis, and distant metastasis, however, it can be used be a potential therapeutic targets of DFS, OS in breast cancer patients.

One-pot molten salt method for constructing CdS/C3N4 nanojunctions with highly enhanced photocatalytic performance for hydrogen evolution reaction.

The construction of heterojunction photocatalysts for efficiently utilizing solar energy has attracted considerable attention to solve the energy crisis and reduce environmental pollution. In this study, we use the energy released from an easily-occurred exothermic chemical reaction to serve as the drive force to trigger the formation of CdS and C3N4 nanocomposites which are successfully fabricated with cadmium nitrate and thiourea without addition of any solvents and protection of inert gas at initial temperature, a little higher than the melting point of thiourea. The as-prepared CdS/C3N4 materials exhibit high efficiency for photocatalytic hydrogen evolution reaction (HER) with the HER rate as high as 15,866 µmol/(g∙hr) under visible light irradiation (λ > 420 nm), which is 89 and 9 times those of pristine C3N4 and CdS, respectively. Also, the apparent quantum efficiency (AQE) of CdS/C3N4-1:2-200-2 (CdS/C3N4-1:2-200-2 means the ratio of Cd to S is 1:2 and the reaction temperature is set at 200°C for two hours) reaches 3.25% at λ = 420 ± 15 nm. After irradiated for more than 24 hr, the HER efficiencies of CdS/C3N4 do not exhibit any attenuation. The DFT calculation suggests that the charge difference causes an internal electric field from C3N4 pointing to CdS, which can more effectively promote the transfer of photogenerated electrons from CdS to C3N4. Therefore, most HER should occur on C3N4 surface where photogenerated electrons accumulate, which largely protects CdS from photo-corrosion.

A naturally occurring FXR agonist, alisol B 23-acetate, protects against renal ischemia-reperfusion injury.

The ligand-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating renal function. Activation of FXR by its specific agonists exerts renoprotective action in animals with acute kidney injury (AKI). In the present study, we aimed to identify naturally occurring agonists of FXR with potential as therapeutic agents in renal ischemia-reperfusion injury. In vitro and in vivo FXR activation was determined by a dual-luciferase assay, docking analysis, site-directed mutagenesis, and whole kidney transcriptome analysis. Wild-type (WT) and FXR knockout (FXR-/-) mice were used to determine the effect of potential FXR agonist on renal ischemia-reperfusion injury (IRI). We found that alisol B 23-acetate (ABA), a major active triterpenoid extracted from Alismatis rhizoma, a well-known traditional Chinese medicine, can activate renal FXR and induce FXR downstream gene expression in mouse kidney. ABA treatment significantly attenuated renal ischemia-reperfusion-induced AKI in WT mice but not in FXR-/- mice. Our results demonstrate that ABA can activate renal FXR to exert renoprotection against ischemia-reperfusion injury-induced AKI. Therefore, ABA may represent a potential therapeutic agent in the treatment of ischemic AKI.NEW & NOTEWORTHY In the present study, we found that alisol B 23-acetate (ABA), an identified natural farnesoid X receptor (FXR) agonist from the well-known traditional Chinese medicine Alismatis rhizoma, protects against ischemic acute kidney injury (AKI) in an FXR-dependent manner, as reflected by improved renal function, reduced renal tubular apoptosis, ameliorated oxidative stress, and suppressed inflammatory factor expression. Therefore, ABA may have great potential as a novel therapeutic agent in the treatment of AKI in the future.

Intraoperative Nice knots assistance for reduction in displaced comminuted clavicle fractures.

PURPOSE: The Nice knots have been widely used in orthopedic surgeries to fix torn soft tissue and fracture in recent years. The study aims to investigate the clinical efficacy and prognosis of intraoperative and postoperative Nice Knots-assisted reduction in the treatment of displaced comminuted clavicle fracture. METHODS: From Jan 2014 to Dec 2019, 75 patients diagnosed with unilateral closed displaced comminuted clavicle fracture were treated with open reduction and internal fixation (ORIF) in this study. Nice knot group (the NK group) included 38 patients and the other 37 patients were in the traditional group (the TK group). The time of operation and the amount of bleeding during operation were recorded. Post-operative clinical outcomes and radiographic results were recorded and compared between these two groups. The Visual Analogue Scale (VAS), Neer score, Rating Scale of the American Shoulder and Elbow Surgeons, Constant-Murley score and complications such as infection, nonunion, implant loosening, fragment displacement and hardware pain were observed in the two groups. RESULTS: In the comparison between the two groups, there was no significant difference in age, sex, the cause of displaced clavicle fracture, and other basic information between the two groups. The operation time, intraoperative fluoroscopy time, and intraoperative blood loss were significantly reduced in the NK group (P < 0.01). There were 2 cases of plate fracture in the TK group. The follow-up results showed that there was no significant difference in VAS, Neer score, ASES, and Constant-Murley scores between the two groups. CONCLUSION: The use of Nice knot, in comminuted and displaced clavicle fractures can reduce intraoperative blood loss, shorten operation time, facilitate intraoperative reduction, and achieve satisfactory postoperative clinical results. This study demonstrates that Nice knot is a simple, safe, practical and effective auxiliary reduction method.

FSIP1 regulates autophagy in breast cancer.

Fibrous sheath interacting protein 1 (FSIP1) is a cancer antigen expressed in the majority of breast cancer tissues and is associated with poor prognosis. However, the role of FSIP1 in the progression and drug sensitivity of triple-negative breast cancer (TNBC) has not been explored. Here, we show that FSIP1 deficiency by shRNA-mediated knockdown or CRISPR-Cas9-mediated knockout significantly inhibits the proliferation and invasion of TNBC cells and impairs chemotherapy-induced growth inhibition in vivo. Computational modeling predicted that FSIP1 binds to ULK1, and this was established by coimmunoprecipitation. FSIP1 deficiency promoted autophagy, enhanced AMP-activated protein kinase (AMPK) signaling, and decreased mechanistic target of rapamycin (mTOR) and Wnt/ß-catenin activity. In contrast, knockdown of AMPK or inhibition of autophagy restored the sensitivity to chemotherapy drugs in TNBC cells. Our findings uncover a role of FSIP1 as well as mechanisms underlying FSIP1 action in drug sensitivity and may, therefore, aid in design of TNBC therapies.

Blood pressure changes PVAT function and transcriptome: use of the mid-thoracic aorta coarcted rat.

Perivascular adipose tissue (PVAT) modifies the contractile function of the vessel it surrounds (outside-in signaling). Little work points to the vessel actively affecting its surrounding PVAT. We hypothesized that inside-out arterial signaling to PVAT would be evidenced by the response of PVAT to changes in tangential vascular wall stress. Rats coarcted in the mid-thoracic aorta created PVAT tissues that would exemplify pressure-dependent changes (above vs. below coarctation); a sham rat was used as a control. Radiotelemetry revealed a ∼20 mmHg systolic pressure gradient across the coarctation 4 wk after surgery. Four measures (histochemical, adipocyte progenitor proliferation and differentiation, isometric tone, and bulk mRNA sequencing) were used to compare PVAT above versus below the ligature in sham and coarcted rats. Neither aortic collagen deposition in PVAT nor arterial media/radius ratio above coarctation was increased versus below segments. However, differentiated adipocytes derived from PVAT above the coarctation accumulated substantially less triglycerides versus those below; their relative proliferation rate as adipogenic precursors was not different. Functionally, the ability of PVAT to assist stress relaxation of isolated aorta was reduced in rings above versus below the coarctation. Transcriptomic analyses revealed that the coarctation resulted in more differentially expressed genes (DEGs) between PVAT above versus below when compared with sham samples from the same locations. A majority of DEGs were in PVAT below the coarctation and were enriched in neuronal/synaptic terms. These findings provide initial evidence that signaling from the vascular wall, as stimulated by a pressure change, influences the function and transcriptional profile of its PVAT.NEW & NOTEWORTHY A mid-thoracic aorta coarcted rat was created to generate a stable pressure difference above versus below the coarctation ligature. This study determined that the PVAT around the thoracic aorta exposed to a higher pressure has a significantly reduced ability to assist stress relaxation versus that below the ligature and appears to retain the ability to be anticontractile. At the same time, the PVAT around the thoracic aorta exposed to higher pressure had a reduced adipogenic potential versus that below the ligature. Transcriptomics analyses indicated that PVAT below the coarctation showed the greatest number of DEGs with an increased profile of the synaptic neurotransmitter gene network.

Comparative efficacy and safety of PD-1/PD-L1 Inhibitors versus platinum-based chemotherapy for the first-line treatment of advanced non-small cell lung cancer: a meta analysis of randomized controlled trials.

OBJECTIVE: The main aim of this study was to systematically evaluate the efficacy and safety of inhibitors of programmed cell death receptor 1 (PD-1) and its ligand, programmed cell death ligand-1 (PD-L1), in the treatment of advanced non-small cell lung cancer (NSCLC). METHODS: Randomized controlled trials assessing the efficacy of PD-1/PD-L1 inhibitors relative to platinum-based chemotherapy for advanced NSCLC in PubMed, EMBASE, and Cochrane libraries from 2015 to 2020 were searched, along with review of studies at American Society of Clinical Oncology (ASCO) and European society for Medical Oncology (ESMO). Pooled hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS) and odds ratios (OR) for adverse events (AE) were calculated using STATA and Revman software. RESULTS: PD-1/PD-L1 inhibitors alone or combined with chemotherapy significantly improved OS (HR = 0.82, 95% CI:0.74-0.91, P = 0.01 or HR = 0.74, 95% CI:0.67-0.82, P = 0.001). PD-1/PD-L1 inhibitors alone did not benefit PFS (HR = 0.99, 95% CI: 0.89-1.10, P = 0.892), while combination therapy led to prolonged PFS (HR = 0.61, 95% CI: 0.56-0.67, P < 0.001). Subgroup analysis showed that in NSCLC with PD-L1 ≥ 50%, treatment with PD-1/PD-L1 inhibitors alone significantly improved both PFS and OS. In patients subjected to the combined treatment regimen, we observed significant differences in PFS among groups stratified by PD-L1 expression (p < 0.001), immune drug type (p = 0.029), gender (p = 0.014) and liver metastasis (p = 0.035) and OS among groups stratified by immune drug type (p < 0.001), gender (P = 0.001) and smoking status (P = 0.041). Safety analysis showed that combination therapy increased chemotherapy-induced adverse events (AE), while PD-1/PD-L1 inhibitors alone were associated with a lower incidence of any grade of treatment-related AEs (TRAE). A higher incidence of Grade 3-5 TRAEs and hypothyroidism was observed with PD-1 inhibitors than PD-L1 inhibitors. CONCLUSIONS: First-line treatment of advanced NSCLC with immune monotherapy or immunochemotherapy confers a greater survival benefit than chemotherapy alone. Combination of chemotherapy with PD-1/PD-L1 inhibitors leads to an increase in adverse events, and PD-1 inhibitors offer enhanced survival benefits and fewer adverse events than PD-L1 inhibitors. Remarkably, female patients undergoing combination therapy had longer overall survival than male patients.

FSIP2 can serve as a predictive biomarker for Clear Cell Renal Cell Carcinoma prognosis.

Purpose: To characterize the role of fibrous sheath interacting protein 2 (FSIP2) in the survival outcomes and prognosis of clear cell renal cell carcinoma (ccRCC) patients, which is currently not well understood. Methods: The Oncomine and CCLE databases were used to investigate the differential expression of FSIP2 in ccRCC versus other cancer types. Levels of FSIP2 in 85 ccRCC patients were assessed by immunohistochemical analysis; clinicopathological features related to FSIP2 expression were examined in these patients finally, disease-free survival and overall survival were estimated by survival analysis to elucidate the impact of FSIP2 expression in ccRCC patients. Results: Analysis using the Oncomine database revealed significant upregulation of the FSIP2 gene in papillary RCC, compared to that in normal tissues. Additionally, FSIP2 expression was found to be significantly associated with abnormal platelet count, positive distant metastasis, and death as the incidence of distant metastasis and death were higher in patients with FSIP2 expression compared to those without FSIP2 expression. Survival analysis revealed that FSIP2 expression was significantly related to shorter disease-free survival and overall survival. Meanwhile, patients with FSIP2 expression had worse prognosis than those without FSIP2 expression. Conclusions: FSIP2 expression is associated with poor survival outcomes and poor prognosis in ccRCC patients. FSIP2 may therefore serve as a potential predictive biomarker of ccRCC prognosis.

Source Tracking and Risk Assessment of Pharmaceutical and Personal Care Products in Surface Waters of Qingdao, China, with Emphasis on Influence of Animal Farming in Rural Areas.

The occurrence and potential sources of pharmaceuticals and personal care products (PPCPs) in surface waters from a large coastal city Qingdao, North China, were investigated. Forty-five compounds were analyzed by high-performance liquid chromatography-tandem mass spectrometry. The results showed that 28 compounds of PPCPs were detected. The most frequently detected compounds were atrazine, clarithromycin, nonylphenol, and bisphenol A with the detection rates > 90%. Paracetamol showed the highest concentration up to 4400 ng/L (mean 152.5 ng/L), followed by ampicillin (max. 2980 ng/L) with the highest mean concentration (229.3 ng/L), iopromide (max. 1744 ng/L, mean 74.5 ng/L), atrazine (max. 1612 ng/L, mean 96.1 ng/L), and bisphenol A (max. 1384 ng/L, mean 78.3 ng/L). The contamination levels and composition profiles of PPCPs along the rivers flowing through rural and urban areas and in seawater showed large spatial variability. Typical source markers and principle component analysis were used to track and differentiate the potential PPCP sources. The emphases of the study were the influence of animal farming in rural areas on PPCP composition profiles and the ecological risk. The results indicated that PPCPs in Qingdao surface water mainly came from three potential sources, i.e., treated wastewater (effluents from WWTPs), untreated wastewater, and nonpoint sources in agricultural areas.

Low-Rank Matrix Recovery from Noise via an MDL Framework-Based Atomic Norm.

The recovery of the underlying low-rank structure of clean data corrupted with sparse noise/outliers is attracting increasing interest. However, in many low-level vision problems, the exact target rank of the underlying structure and the particular locations and values of the sparse outliers are not known. Thus, the conventional methods cannot separate the low-rank and sparse components completely, especially in the case of gross outliers or deficient observations. Therefore, in this study, we employ the minimum description length (MDL) principle and atomic norm for low-rank matrix recovery to overcome these limitations. First, we employ the atomic norm to find all the candidate atoms of low-rank and sparse terms, and then we minimize the description length of the model in order to select the appropriate atoms of low-rank and the sparse matrices, respectively. Our experimental analyses show that the proposed approach can obtain a higher success rate than the state-of-the-art methods, even when the number of observations is limited or the corruption ratio is high. Experimental results utilizing synthetic data and real sensing applications (high dynamic range imaging, background modeling, removing noise and shadows) demonstrate the effectiveness, robustness and efficiency of the proposed method.

Crystal structure of a cytocidal protein from lamprey and its mechanism of action in the selective killing of cancer cells.

BACKGROUND: In previous research, we found that lamprey immune protein (LIP) possessed cytocidal activity against tumor cells, but the mechanism of the selective recognition and killing of tumor cells by LIP was not identified. METHODS: Superresolution microscopy, crystallographic structural analysis, glycan chip assay, SPR experiments, FACS assays, computational studies and mass spectrometric analysis firmly establish the mode of action of LIP, which involves dual selective recognition and efficient binding. RESULTS: We determined the overall crystallographic structure of LIP at a resolution of 2.25 Å. LIP exhibits an elongated structure with dimensions of 105 Å × 30 Å × 30 Å containing an N-terminal lectin module and a C-terminal aerolysin module. Moreover, the Phe209-Gly232 region is predicted to insert into the lipid bilayer to form a transmembrane ß-barrel, in which the hydrophobic residues face the lipid bilayer, and the polar residues constitute the hydrophilic lumen of the pore. We found that LIP is able to kill various human cancer cells with minimal effects on normal cells. Notably, by coupling biochemical and computational studies, we propose a hypothetical mechanism that involves dual selective recognition and efficient binding dependent on both N-linked glycans on GPI-anchored proteins (GPI-APs) and sphingomyelin (SM) in lipid rafts. Furthermore, specific binding of the lectin module with biantennary bisialylated nonfucosylated N-glycan or sialyl Lewis X-containing glycan structures on GPI-APs triggers substantial conformational changes in the aerolysin module, which interacts with SM, ultimately resulting in the formation of a membrane-bound oligomer in lipid rafts. CONCLUSIONS: LIP holds great potential for the application of a marine protein towards targeted cancer therapy and early diagnosis in humans.

Optimization of Protein-Protein Interaction Measurements for Drug Discovery Using AFM Force Spectroscopy.

Increasingly targeted in drug discovery, protein-protein interactions challenge current high throughput screening technologies in the pharmaceutical industry. Developing an effective and efficient method for screening small molecules or compounds is critical to accelerate the discovery of ligands for enzymes, receptors and other pharmaceutical targets. Here, we report developments of methods to increase the signal-to-noise ratio (SNR) for screening protein-protein interactions using atomic force microscopy (AFM) force spectroscopy. We have demonstrated the effectiveness of these developments on detecting the binding process between focal adhesion kinases (FAK) with protein kinase B (Akt1), which is a target for potential cancer drugs. These developments include optimized probe and substrate functionalization processes and redesigned probe-substrate contact regimes. Furthermore, a statistical-based data processing method was developed to enhance the contrast of the experimental data. Collectively, these results demonstrate the potential of the AFM force spectroscopy in automating drug screening with high throughput.