NIR-II-Absorbing TMB Derivative for 1064 nm-Excited Photothermal Immunoassay.

Materials exhibiting strong absorption in the NIR-II region are appealing for photothermal conversion-based imaging, diagnosis, and therapy, due to better thermal effect and decreased absorption of water in such a region. 3,3',5,5'-Tetramethylbenzidine (TMB), the typical substrate in ELISA, has been explored in photothermal immunoassay, since its oxidation product (oxTMB) is photothermally active in the NIR region. However, its absorption at 1064 nm (the most often used laser wavelength in photothermal studies) is not appreciable, thus limiting the assay sensitivity. Here, we proposed a derivative of TMB (3,3'-dimethoxy-5,5'-dimethylbenzidine, 2-OCH3) bearing higher NIR-II absorption for 1064 nm-excited photothermal immunoassay. Since electron-donating groups can help decrease the energy gap of molecules (here -CH3 → -OCH3), the oxidation product of 2-OCH3 exhibited substantially red-shifted absorption as compared with oxTMB, leading to a more than twofold higher absorption coefficient at 1064 nm. As a result, 2-OCH3 showed enhanced sensitivity over TMB in a photothermal immunoassay (PTIA), yielding a limit of detection (LOD) of 0.1 ng/mL for prostate-specific antigen (PSA). The feasibility of 2-OCH3-based PTIA for diagnosis was further validated by analyzing PSA in 61 serum samples. Considering its superior photothermal performance, 2-OCH3 can be explored for a broad range of photothermal applications.

Integrating Recombinase Polymerase Amplification and Photosensitization Colorimetric Detection in One Tube for Fast Screening of C. sakazakii in Formula Milk Powder.

Cronobacter sakazakii (C. sakazakii) is a widely existing opportunistic pathogen and thus threatens people with low immunity, especially infants. To prevent the outbreak, a rapid and accurate on-site testing method is required. The current standard culture-based method is time-consuming (3-4 days), while the nucleic acid amplification (PCR)-based detection is mostly carried out in central laboratories. Herein, isothermal recombinase polymerase amplification (RPA) coupled with a photosensitization colorimetric assay (PCA) was adopted for the on-site detection of C. sakazakii in powdered infant formulas (PIFs). The lowest visual detection concentration of C. sakazakii is 800 cfu/mL and 2 cfu/g after 8 h bacteria pre-enrichment. Furthermore, to avoid typical cap opening-resulted aerosol pollution, the PCA reagents were lyophilized onto the cap of the RPA tube (containing lyophilized RPA reagents). After amplification, the tube was subjected to simple shaking to mix the PCA reagents with the amplification products for light-driven color development. Such a one-tube assay offered a lowest concentration of 1000 copies of genomic DNA of C. sakazakii within 1 h. After 8 h of bacterial enrichment, the lowest detecting concentration could be pushed down to 5 cfu/g bacteria in PIF. To facilitate on-site monitoring, a portable, battery-powered PCA device was designed to mount the typical RPA 8-tube strip, and a color analysis cellphone APP was further employed for facile readout.

Analysis of the efficacy of upfront brain radiotherapy versus deferred radiotherapy for EGFR/ALK-positive non-small cell lung cancer with brain metastases: a retrospective study.

BACKGROUND: For brain metastases (BMs) from EGFR/ALK-positive non-small cell lung cancer (NSCLC), the best time to administer tyrosine kinase inhibitors (TKIs) and brain radiotherapy (RT) has not been identified. This analysis was an attempt to solve this problem in part. METHODS: A total of 163 patients with EGFR/ALK-positive NSCLC and brain metastasis (BM) who were diagnosed between January 2017 and July 2022 were included in this study. Ninety-one patients underwent upfront RT, and 72 patients received deferred RT. Comparing the clinical efficacy and safety in these two patient cohorts was the main goal of the study. RESULTS: The average follow-up period was 20.5 months (range 2.0 to 91.9 months). The median overall survival (OS) was 26.5 months, and the median intracranial progression-free survival (iPFS) was 23.6 months. Upfront RT considerably increased the iPFS (26.9 vs. 20.2 months, hazard ratio [HR] = 5.408, P = 0.020) and OS (31.2 vs. 22.3 months, HR = 4.667, P = 0.031) compared to deferred RT. According to multivariate analysis, upfront RT was an independent risk factor for predicting iPFS (HR = 1.670, P = 0.021). Upfront RT (HR = 1.531, P = 0.044), TKI therapy (HR = 0.423, P < 0.001), and oligometastases (HR = 2.052, P = 0.021) were found to be independent risk factors for OS. CONCLUSION: This study showed that upfront RT combined with TKI treatment can significantly improve intracranial disease management and prolong survival in patients with EGFR/ALK mutations in BMs from NSCLC.

Neutral pH photoenzymatic activity of Au-doped g-C3N4 nanosheet for colorimetric detection of total antioxidant capacity in food samples.

Total antioxidant capacity (TAC) is vital for food quality evaluation. The emergence of various nanozymes with TMB as substrate offered a new avenue for TAC detection due to simple operation and fast response, but a long-standing challenge is its low activity at physiological pH, which may account for the discrepancy between the measured TAC and the actual antioxidant capacity in vivo. Herein, Au doping was explored to break the pH limitation of g-C3N4 nanosheets (CNNS) photozyme. The catalytic activities of Au@CNNS at pH 4.0 and 7.4 were 14.9- and 6.2-fold higher than that of CNNS at pH 4. The neutral pH photozymatic activity (photosensitized oxidation of TMB, oxidase mimic) of Au@CNNS was explored for sensitivity TAC detection (LOD: 1.0 µM TE), which featured more convenient operations and higher sensitivity over the DPPH assay. The proposed Au@CNNS-based photozymatic colorimetric method was explored for accurate detection of TAC in drinks and juices.

Transcriptional factor CCAAT enhancer binding protein beta inhibits epithelial-mesenchymal transition in cervical cancer via regulating attractin-like 1.

Cervical cancer (CC) is a malignancy seriously endangering women's life and health worldwide. GEPIA demonstrated that attractin-like 1 (ATRNL1) presents downregulation in CC tissue. Transcription factor CCAAT enhancer binding protein beta (CEBPB) was previously revealed to present depletion in CC tissue. We attempted to clarify molecular mechanism between ATRNL1 and CEBPB underlying CC progression. Bioinformatics, RT-qPCR and western blotting revealed expression characteristics of ATRNL1 in CC. RT-qPCR measured ATRNL1 and CEBPB levels in CC cell lines. Gain-of-function assays clarified role of ATRNL1 in CC cell behaviors. Bioinformatics, Pearson correlation, ChIP and luciferase reporter experiments assessed association of ATRNL1 and CEBPB in CC cells. Rescue assays assessed regulatory function of CEBPB-ATRNL1 in CC cellular processes. ATRNL1 showed depletion in CC tissue and cells at mRNA and protein levels. ATRNL1 upregulation repressed CC cell viability, migration and EMT. CEBPB bound to ATRNL1 promoter to transcriptionally upregulate ATRNL1 in CC cells. The impact of CEBPB elevation on CC cell viability, migration and EMT were countervailed by ATRNL1 depletion. ATRNL1 and CEBPB present depletion and serve as tumor suppressors in CC cells. ATRNL1 suppresses CC cell malignancy through CEBPB activation, which may provide a potential new direction for seeking therapeutic plans for CC.

Active Breathing Coordinator reduces radiation dose to the stomach in patients with left breast cancer.

BACKGROUND/PURPOSE: Gastric dose parameters comparison for deep inspiration breath-hold (DIBH) or free breathing (FB) mode during radiotherapy (RT) for left-sided breast cancer patients (LSBCPs) has not been investigated before. This study aimed to analyze the impact of Active Breath Coordinator (ABC)-DIBH technique on the dose received by the stomach during RT for LSBCPs and to provide organ-specific dosimetric parameters. MATERIALS AND METHODS: The study included 73 LSBCPs. The dosimetric parameters of the stomach were compared between FB and DIBH mode. The correlation between the stomach volume and dosimetric parameters was analyzed. RESULTS: Compared to FB mode, statistically significant reductions were observed in gastric dose parameters in ABC-DIBH mode, including Dmax (46.60 vs 17.25, p < 0.001), D1cc (38.42 vs 9.60, p < 0.001), Dmean (4.10 vs 0.80, p < 0.001), V40Gy (0.50 vs 0.00, p < 0.001), V30Gy (6.30 vs 0.00, p < 0.001), V20Gy (20.80 vs 0.00, p < 0.001), V10Gy (51.10 vs 0.77, p < 0.001), and V5Gy (93.20 vs 9.60, p < 0.001). ABC-DIBH increased the distance between the stomach and the breast PTV when compared to FB, from 1.3 cm to 2.8 cm (p < 0.001). Physiologic decrease in stomach volume was not found from FB to ABC-DIBH (415.54 cm3 vs 411.61 cm3, p = 0.260). The stomach volume showed a positive correlation with V40Gy (r2 = 0.289; p < 0.05), V30Gy (r2 = 0.287; p < 0.05), V20Gy (r2 = 0.343; p < 0.05), V10Gy (r2 = 0.039; p < 0.001), V5Gy (r2 = 0.439; p < 0.001), Dmax (r2 = 0.269; p < 0.05) and D1cc (r2 = 0.278; p < 0.05) in FB mode. While in ABC-DIBH mode, most stomach dosimetric parameters were not correlated with gastric volume. CONCLUSIONS: The implementation of ABC-DIBH in LSBCPs radiotherapy resulted in lower irradiation of the stomach. Larger stomach volume was associated with statistically significantly higher dose irradiation in FB mode. To reduce radiotherapy related side effects in FB mode, patients should be fast for at least 2 hours before the CT simulation and treatment.

An injectable hydrogel based on Bi2Se3 nanosheets and hyaluronic acid for chemo-photothermal synergistic therapy.

To resolve poor accumulation caused by systemic administration, injectable and responsive hydrogels are the prospective drug delivery systems for localized tumor treatment, owning to negligible invasiveness and accurate administration. Herein, an injectable hydrogel, based on dopamine (DA) crosslinked hyaluronic acid and Bi2Se3 nanosheets (NSs) loading with doxorubicin (DOX) coated with polydopamine (Bi2Se3-DOX@PDA), was developed for synergistic chem-photothermal cancer therapy. The ultrathin functional Bi2Se3-DOX@PDA NSs could be responsive to the weak acidic condition and photothermal effect under NIR laser irradiation, achieving controlled release of DOX. Moreover, nanocomposite hydrogel based on hyaluronic acid matrix could be precisely administrated through intratumoral injection since its injectability and self-healing capacity, remaining at injected sites for at least 12 days. Furthermore, the excellent therapeutics effect of Bi2Se3-DOX@PDA nanocomposite hydrogel was demonstrated on 4 T1 xenograft tumor with outstanding injectability and negligible systemic side-effect. In short, the construction of Bi2Se3-DOX@PDA nanocomposite hydrogel paves a prospective path for local treatment of cancers.

Isotoxic dose escalated radiotherapy for glioblastoma based on diffusion-weighted MRI and tumor control probability-an in-silico study.

OBJECTIVES: Glioblastoma (GBM) is the most common malignant primary brain tumor with local recurrence after radiotherapy (RT), the most common mode of failure. Standard RT practice applies the prescription dose uniformly across tumor volume disregarding radiological tumor heterogeneity. We present a novel strategy using diffusion-weighted (DW-) MRI to calculate the cellular density within the gross tumor volume (GTV) in order to facilitate dose escalation to a biological target volume (BTV) to improve tumor control probability (TCP). METHODS: The pre-treatment apparent diffusion coefficient (ADC) maps derived from DW-MRI of ten GBM patients treated with radical chemoradiotherapy were used to calculate the local cellular density based on published data. Then, a TCP model was used to calculate TCP maps from the derived cell density values. The dose was escalated using a simultaneous integrated boost (SIB) to the BTV, defined as the voxels for which the expected pre-boost TCP was in the lowest quartile of the TCP range for each patient. The SIB dose was chosen so that the TCP in the BTV increased to match the average TCP of the whole tumor. RESULTS: By applying a SIB of between 3.60 Gy and 16.80 Gy isotoxically to the BTV, the cohort's calculated TCP increased by a mean of 8.44% (ranging from 7.19 to 16.84%). The radiation dose to organ at risk is still under their tolerance. CONCLUSIONS: Our findings indicate that TCPs of GBM patients could be increased by escalating radiation doses to intratumoral locations guided by the patient's biology (i.e., cellularity), moreover offering the possibility for personalized RT GBM treatments. ADVANCES IN KNOWLEDGE: A personalized and voxel level SIB radiotherapy method for GBM is proposed using DW-MRI, which can increase the tumor control probability and maintain organ at risk dose constraints.

Understanding heavy metal distribution in timberline vegetations: A case from the Gongga Mountain, eastern Tibetan Plateau.

To quantify impacts of vegetation and topographic factors on heavy metal accumulation in montane forests, we assessed the spatial distribution and determined the sources of mercury (Hg), cadmium (Cd), lead (Pb), chromium (Cr), copper (Cu) and zinc (Zn) in timberline forests of Gongga Mountain. Our results show that vegetation type has little impact on the soil Hg, Cd and Pb concentrations. The soil concentrations of Cr, Cu and Zn are controlled by litter return, moss and lichen biomass, and canopy interception, with the highest concentrations in shrub forest. In contrast to other forests, the soil Hg pool in coniferous forest is significantly high due to the elevated Hg concentration and greater biomass production in litter. However, the soil pool sizes of Cd, Cr, Cu and Zn show a distinct increase along the elevation, which are attributed to the elevated heavy metal inputs from litter and moss, as well as the greater cloud water-induced atmospheric heavy metal depositions. The highest Hg concentrations of the aboveground parts of plant are in the foliage and bark, while the concentrations of Cd, Pb, Cr, Cu and Zn in the branch and bark are the highest. The decreased biomass density leads to a downward trend in the total vegetation pool sizes of Hg, Cd, Pb, Cr, Cu and Zn by 0.4-4.4 times with increasing elevation. The statistical analysis finally suggests that Hg, Cd and Pb mainly originate from anthropogenic atmospheric deposition, whereas Cr, Cu and Zn are mainly from natural sources. Our results highlight the importance of vegetation types and terrain conditions on distribution patterns of heavy metal in alpine forests.

Dual-Gene Isothermal Amplification Coupled with Lateral Flow Strip for On-Site Accurate Detection of E. coli O157:H7 in Food Samples.

On-site field detection of E. coli O157:H7 in food samples is of utmost importance, since it causes a series of foodborne diseases due to infections-associated ready-to-eat foods. Due to the instrument-free nature, recombinase polymerase amplification (RPA) coupled with lateral flow assay (LFA) is well-suited for such goal. However, the high genomic similarity of different E. coli serotypes adds difficulty to accurate differentiation of E. coli O157:H7 from others. Dual-gene analysis could significantly improve the serotype selectivity, but will further aggravate the RPA artifacts. To address such issue, here we proposed a protocol of dual-gene RPA-LFA, in which the target amplicons were selectively recognized by peptide nucleic acid (PNA) and T7 exonuclease (TeaPNA), thus eliminating false-positives in LFA readout. Adapting rfbEO157 and fliCH7 genes as the targets, dual-gene RPA-TeaPNA-LFA was demonstrated to be selective for E. coli O157:H7 over other E. coli serotypes and common foodborne bacteria. The minimum detection concentration was 10 copies/µL for the genomic DNA (∼300 cfu/mL E. coli O157:H7), and 0.24 cfu/mL E. coli O157:H7 in food samples after 5 h bacterial preculture. For lettuce samples contaminated with E. coli O157:H7 (single-blind), the sensitivity and specificity of the proposed method were 85% and 100%, respectively. Using DNA releaser for fast genomic DNA extraction, the assay time could be reduced to ∼1 h, which is appealing for on-site food monitoring.

Noncancerous disease-targeting AIEgens.

Noncancerous diseases include a wide plethora of medical conditions beyond cancer and are a major cause of mortality around the world. Despite progresses in clinical research, many puzzles about these diseases remain unanswered, and new therapies are continuously being sought. The evolution of bio-nanomedicine has enabled huge advancements in biosensing, diagnosis, bioimaging, and therapeutics. The recent development of aggregation-induced emission luminogens (AIEgens) has provided an impetus to the field of molecular bionanomaterials. Following aggregation, AIEgens show strong emission, overcoming the problems associated with the aggregation-caused quenching (ACQ) effect. They also have other unique properties, including low background interferences, high signal-to-noise ratios, photostability, and excellent biocompatibility, along with activatable aggregation-enhanced theranostic effects, which help them achieve excellent therapeutic effects as an one-for-all multimodal theranostic platform. This review provides a comprehensive overview of the overall progresses in AIEgen-based nanoplatforms for the detection, diagnosis, bioimaging, and bioimaging-guided treatment of noncancerous diseases. In addition, it details future perspectives and the potential clinical applications of these AIEgens in noncancerous diseases are also proposed. This review hopes to motivate further interest in this topic and promote ideation for the further exploration of more advanced AIEgens in a broad range of biomedical and clinical applications in patients with noncancerous diseases.

Adjuvant Temozolomide Chemotherapy With or Without Interferon Alfa Among Patients With Newly Diagnosed High-grade Gliomas: A Randomized Clinical Trial.

Importance: High-grade gliomas (HGGs) constitute the most common and aggressive primary brain tumor, with 5-year survival rates of 30.9% for grade 3 gliomas and 6.6% for grade 4 gliomas. The add-on efficacy of interferon alfa is unclear for the treatment of HGG. Objectives: To compare the therapeutic efficacy and toxic effects of the combination of temozolomide and interferon alfa and temozolomide alone in patients with newly diagnosed HGG. Design, Setting, and Participants: This multicenter, randomized, phase 3 clinical trial enrolled 199 patients with newly diagnosed HGG from May 1, 2012, to March 30, 2016, at 15 Chinese medical centers. Follow-up was completed July 31, 2021, and data were analyzed from September 13 to November 24, 2021. Eligible patients were aged 18 to 75 years with newly diagnosed and histologically confirmed HGG and had received no prior chemotherapy, radiotherapy, or immunotherapy for their HGG. Interventions: All patients received standard radiotherapy concurrent with temozolomide. After a 4-week break, patients in the temozolomide with interferon alfa group received standard temozolomide combined with interferon alfa every 28 days. Patients in the temozolomide group received standard temozolomide. Main Outcomes and Measures: The primary end point was 2-year overall survival (OS). Secondary end points were 2-year progression-free survival (PFS) and treatment tolerability. Results: A total of 199 patients with HGG were enrolled, with a median follow-up time of 66.0 (95% CI, 59.1-72.9) months. Seventy-nine patients (39.7%) were women and 120 (60.3%) were men, with ages ranging from 18 to 75 years and a median age of 46.9 (95% CI, 45.3-48.7) years. The median OS of patients in the temozolomide plus interferon alfa group (26.7 [95% CI, 21.6-31.7] months) was significantly longer than that in the standard group (18.8 [95% CI, 16.9-20.7] months; hazard ratio [HR], 0.64 [95% CI, 0.47-0.88]; P = .005). Temozolomide plus interferon alfa also significantly improved median OS in patients with O6-methylguanine-DNA methyltransferase (MGMT) unmethylation (24.7 [95% CI, 20.5-28.8] months) compared with temozolomide (17.4 [95% CI, 14.1-20.7] months; HR, 0.57 [95% CI, 0.37-0.87]; P = .008). Seizure and influenzalike symptoms were more common in the temozolomide plus interferon alfa group, with 2 of 100 (2.0%) and 5 of 100 (5.0%) patients with grades 1 and 2 toxic effects, respectively (P = .02). Finally, results suggested that methylation level at the IFNAR1/2 promoter was a marker of sensitivity to temozolomide plus interferon alfa. Conclusions and Relevance: Compared with the standard regimen, temozolomide plus interferon alfa treatment could prolong the survival time of patients with HGG, especially the MGMT promoter unmethylation variant, and the toxic effects remained tolerable. Trial Registration: ClinicalTrials.gov Identifier: NCT01765088.

Specific lateral flow detection of isothermal nucleic acid amplicons for accurate point-of-care testing.

For point-of-care testing (POCT), coupling isothermal nucleic acid amplification schemes (e.g., recombinase polymerase amplification, RPA) with lateral flow assay (LFA) readout is an ideal platform, since such integration offers both high sensitivity and deployability. However, isothermal schemes typically suffers from non-specific amplification, which is difficult to be differentiated by LFA and thus results in false-positives. Here, we proposed an accurate POCT platform by specific recognition of target amplicons with peptide nucleic acid (PNA, assisted by T7 Exonuclease), which could be directly plugged into the existing RPA kits and commercial LFA test strips. With SARS-CoV-2 as the model, the proposed method (RPA-TeaPNA-LFA) efficiently eliminated the false-positives, exhibiting a lowest detection concentration of 6.7 copies/µL of RNA and 90 copies/µL of virus. Using dual-gene (orf1ab and N genes of SARS-CoV-2) as the targets, RPA-TeaPNA-LFA offered a high specificity (100%) and sensitivity (RT-PCR Ct < 31, 100%; Ct < 40, 71.4%), and is valuable for on-site screening or self-testing during isolation. In addition, the dual test lines in the test strips were successfully explored for simultaneous detection of SARS-CoV-2 and H1N1, showing great potential in response to future pathogen-based pandemics.

Analysis of Immunotherapy Combined with Radiotherapy in Patients with Brain Metastasis of Driver Gene-Negative Non-Small-Cell Lung Cancer.

Purpose: To observe the remission rate and side effects of immunotherapy combined with radiotherapy in patients with brain metastasis of driver gene-negative non-small-cell lung cancer (NSCLC). Methods: 152 patients with NSCLC brain metastasis admitted to our hospital from January 2019 to December 2021 were selected as the research objects. Patients were divided into a single group (85 cases) and a combined group (67 cases) according to treatment methods. The therapeutic effects and side effects of the single group and combined group were compared. In addition, the patients who received immunotherapy combined with radiotherapy were divided into three subgroups: A, B, and C, and the therapeutic effects and side effects of different radiotherapy modes were compared among group A [whole brain radiotherapy (WBRT)], group B (WBRT combined with local radiotherapy) and group C (local radiotherapy). Results: The objective response rate (ORR) and disease control rate (DCR) in the combined group were higher than those in the single group (P < 0.05). The incidence of reactive capillary hyperplasia and immune-related pneumonia in the combined group were higher than that in the single group (P < 0.05). There was no significant difference in the incidence of other side effects between the two groups (P > 0.05). ORR and DCR in group B were higher than those in group A (P < 0.05). There was no significant difference in the incidence of side effects among the three groups (P > 0.05). Conclusion: Immunotherapy combined with radiotherapy is effective in patients with brain metastasis of driver gene-negative NSCLC, which can improve the disease control rate without increasing the side effects. In addition, WBRT combined with local push radiotherapy is effective and safe. Clinical Study Registration Number. The Clinical study registration number is K2019086.

Significance of intratreatment tumor volume change during chemoradiotherapy for potentially resectable thoracic esophageal squamous cell carcinoma.

OBJECTIVE: The purpose of this study was to investigate the clinical significance of tumor response assessment at a twentieth fraction of radiotherapy when predicting the survival of patients with potentially resectable esophageal squamous cell carcinoma (ESCC). METHODS: A total of 123 ESCC patients with clinical stages II to IVa were enrolled and analyzed. Gross tumor volume (GTV) of the esophagus (GTVe) and GTV of the metastatic lymph node (GTVnd) were manually contoured by at least 2 senior professional radiotherapists on the simulated computed tomography (CT) images in a process that followed the delineating rules for ESCC. RESULTS: The GTVe reduction ratio (RR) and GTVnd RR were calculated based on the evaluation of the tumor volume at a twentieth fraction of radiotherapy. Univariate analysis showed that GTVe and GTVnd before treatment, and GTVe RR and GTVnd RR at the twentieth fraction of radiotherapy were all significantly associated with complete clinical response (cCR) and overall survival (OS). The Kaplan-Meier method was used to estimate OS and locoregional recurrence-free survival (LRRFS). CONCLUSIONS: The GTVe RR ≥27.92% and GTVnd RR ≥21.49% at a twentieth fraction of radiotherapy are positive predictive factors of LRRFS, and according to multivariate analysis, only GTVe RR at the twentieth fraction of radiotherapy ≥27.92% is prognostic for a favorable OS.

Impact of Previous Local Treatment for Brain Metastases on Response to Molecular Targeted Therapy in BRAF-Mutant Melanoma Brain Metastasis: A Systematic Review and Meta-Analysis.

Background: Melanoma brain metastases (BMs) are associated with poor prognosis and are the main cause of mortality in melanoma patients. BRAF inhibitors have shown intracranial activity in both treatment-naïve and previously treated BM patients. We aimed to investigate if there was any difference in response of BRAF inhibitors in these two cohorts. Materials and Methods: Electronic database search included PubMed, Medline, and Cochrane library until March 2021 for studies with desired comparative outcomes. Outcomes of interest that were obtained for meta-analysis included intracranial response rate as the primary outcome and survival and safety outcomes as the secondary outcomes. Review Manager version 5.4 was used for data analysis. Results: Three studies comprising 410 BRAF-mutated melanoma patients with BMs were included according to eligibility criteria. The comparative cohort included patients with treatment-naïve BMs (TN cohort; n = 255) and those who had progressive disease after receiving local brain treatment for BMs (PT cohort; n = 155). Meta-analysis revealed that BRAF inhibitors (vemurafenib and dabrafenib) and BRAF/MEK inhibitor combination (dabrafenib and trametinib) induced significantly higher intracranial disease control (OR 0.58 [95% CI: 0.34, 0.97], p = 0.04) and a trend toward improved progression-free survival (PFS) (HR 1.22 [95% CI: 0.98, 1.52], p = 0.08) in the PT cohort as compared to the TN cohort. Overall survival was not significantly different between the cohorts (HR 1.16 [95% CI: 0.89, 1.51], p = 0.28). Subgroup analysis revealed that PFS was significantly improved (HR 1.67 [95% CI: 1.06, 2.62], p = 0.03), and a trend toward improved OS (HR 1.62 [95% CI: 0.95, 2.75], p = 0.08) was achieved in patients receiving BRAF/MEK inhibitor combination and patients with BRAFv600K mutation receiving dabrafenib alone. No increase in overall adverse events (AEs), grade 3/4 AEs, and severe adverse events (SAEs) was observed between the cohorts. Conclusions: BRAF inhibitors (plus MEK inhibitor) may achieve better intracranial disease stability in BRAF-mutant melanoma patients who have received previous local treatment for BMs. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/), identifier CRD42020185984.

Evaluation of the sequence-dependent relative activity of APE1 for optimal biosensing design.

Apurinic/apyrimidinic endonuclease 1 (APE1) can selectively incise the AP site of DNA, thus is universal for various DNA substrates for flexible endonuclease-assisted signal amplification. However, the substrate preference of APE1 has never been systematically investigated. Therefore in this work, the detailed sequence-dependent relative activity of APE1 was determined. It turned out that the APE1 activity did vary with the change of the adjacent and opposite bases, and over 10-fold relative activity difference was observed for different sequence combinations. Such difference is appreciable enough to induce evident impact on APE1-involved biosensing. With an APE1 probe designed for cycled signal amplification, the sensitivities followed exactly with the above activity order. Compared with Nb.BbvCl, the sensitivity of the APE1 probe varied between higher and lower than the Nb.BbvCl probe (with varied substrates), demonstrating the importance of the sequence-dependent relative activity of APE1 for optimal biosensor development. Moreover, the above APE1 probe design was harvested and engineered for sensitive biosensing of uracil-DNA glycosylase (UDG). Through theoretical analysis of the interaction between APE1 and the substrates, the accuracy of the determined sequence-dependent relative activity of APE1 was partially confirmed.

Case Report: Radiotherapy Plus Immunotherapy and Lenvatinib for the Treatment of Recurrent Hepatocellular Carcinoma With a Right Atrium and Inferior Vena Cava Tumor Thrombus.

Background: The treatment of hepatocellular carcinoma (HCC) with right atrium (RA) and inferior vena cava (IVC) tumor thrombi is challenging, with the standard treatment being not well established. Immunotherapy plus antiangiogenic therapy is a potentially effective treatment for patients with advanced HCC. Here, we described the case of a patient with HCC with RA and IVC tumor thrombi who achieved a successful response from radiotherapy and targeted therapy plus immunotherapy. Case Summary: A 62-year-old women presented with severe bilateral lower extremity edema identified as recurrent HCC with RA and IVC tumor thrombi based on past medical history and computed tomography. The patient received palliative radiotherapy plus pembrolizumab and lenvatinib treatment and was relieved of disease symptoms of bilateral lower extremity edema. The HCC with RA and IVC tumor thrombi shrunk, and the progression-free survival of this patient was > seven months. Conclusion: Tumor thrombus-directed radiotherapy plus concurrent immunotherapy and targeted therapy might be a feasible and safe approach for patients with HCC with RA and IVC tumor thrombi.

Activating the neutral pH photozymatic activity of g-C3N4 nanosheets through post-synthetic incorporation of Pt.

The catalytic activity of photozymes can be regulated through light irradiation time and intensity, but they still suffer from low activity in physiologically neutral pH (typically, pH < 5). Herein, through simple post-synthetic incorporation of Pt, the neutral pH activity of the g-C3N4 nanosheet (CNNS) was activated. Most importantly, the catalytic activities of Pt@CNNS at pH 4.0 and 7.0 were ∼19- and 4.7-fold higher than that of CNNS at pH 4 (the optimal pH for CNNS).

Establishment of prognostic nomogram for high-grade parotid gland mucoepidermoid carcinoma based on the SEER database.

Purpose: We aim to investigate the clinical factors that affect the prognosis of overall survival (OS) for patients with high-grade parotid gland mucoepidermoid carcinoma (high-grade pMEC) and construct a nomogram for prognosis prediction. Subjects and method: Totally, 519 patients diagnosed as high-grade pMEC from the surveillance, epidemiology, and end results (SEER) database between 2004 and 2015 were reviewed. Independent prognostic factors for OS were identified by univariate and multivariate Cox regression analyses. Nomogram was generated to predict the individual's 3- and 5- year OS rates by using R software. Prediction ability was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC) and model calibration was evaluated through calibration plots. Decision curve analysis (DCA) was used to assess the clinical usefulness and net benefit. Results: The results of univariate analysis demonstrated that age, AJCC stage, T stage, N stage, M stage, extraparenchymal lesions, regional lymph nodes status, lymph node dissection status, radiotherapy, chemotherapy, and surgery were significantly correlated with the OS (P < 0.05). Multivariate Cox regression analyses showed that older age at diagnosis, advanced AJCC stage, and positive regional lymph nodes were independent risk factors for OS. In addition, the present study revealed that radiotherapy and surgery were independent protective factors for OS (P < 0.05). The nomograms showed accurate prognostic ability that individually predict 3-years and 5-years overall survival (OS) rates based on age, AJCC stage, regional lymph nodes status, radiotherapy, and surgery. The area under the receiver operating characteristic (ROC) curve (AUC) of the nomogram used to predict the 3-year and 5-year overall survival rate were 0.779 and 0.793, indicating that the model had a good predictive power for the overall survival in high-grade pMEC patient. Conclusions: Using the SEER database, we performed univariate and multivariate analyses to determine independent prognostic factors in high-grade pMEC patients. Subsequently, we constructed and validated a prognostic nomogram to predict 3-and 5-year OS rates based on the SEER database and can assist clinicians to intuitively evaluate prognosis of high-grade pMEC patients.