Chemotherapy-Enabled Colorectal Cancer Immunotherapy of Self-Delivery Nano-PROTACs by Inhibiting Tumor Glycolysis and Avoiding Adaptive Immune Resistance.

The chemo-regulation abilities of chemotherapeutic medications are appealing to address the low immunogenicity, immunosuppressive lactate microenvironment, and adaptive immune resistance of colorectal cancer. In this work, the proteolysis targeting chimera (PROTAC) of BRD4 (dBET57) is found to downregulate colorectal cancer glycolysis through the transcription inhibition of c-Myc, which also inhibits the expression of programmed death ligand 1 (PD-L1) to reverse immune evasion and avoid adaptive immune resistance. Based on this, self-delivery nano-PROTACs (designated as DdLD NPs) are further fabricated by the self-assembly of doxorubicin (DOX) and dBET57 with the assistance of DSPE-PEG2000. DdLD NPs can improve the stability, intracellular delivery, and tumor targeting accumulation of DOX and dBET57. Meanwhile, the chemotherapeutic effect of DdLD NPs can efficiently destroy colorectal cancer cells to trigger a robust immunogenic cell death (ICD). More importantly, the chemo-regulation effects of DdLD NPs can inhibit colorectal cancer glycolysis to reduce the lactate production, and downregulate the PD-L1 expression through BRD4 degradation. Taking advantages of the chemotherapy and chemo-regulation ability, DdLD NPs systemically activated the antitumor immunity to suppress the primary and metastatic colorectal cancer progression without inducing any systemic side effects. Such self-delivery nano-PROTACs may provide a new insight for chemotherapy-enabled tumor immunotherapy.

The m6A methylome of SARS-CoV-2 in host cells.

The newly identified Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has resulted in a global health emergency because of its rapid spread and high mortality. The molecular mechanism of interaction between host and viral genomic RNA is yet unclear. We demonstrate herein that SARS-CoV-2 genomic RNA, as well as the negative-sense RNA, is dynamically N6-methyladenosine (m6A)-modified in human and monkey cells. Combined RIP-seq and miCLIP analyses identified a total of 8 m6A sites at single-base resolution in the genome. Especially, epidemic strains with mutations at these identified m6A sites have emerged worldwide, and formed a unique cluster in the US as indicated by phylogenetic analysis. Further functional experiments showed that m6A methylation negatively regulates SARS-CoV-2 infection. SARS-CoV-2 infection also triggered a global increase in host m6A methylome, exhibiting altered localization and motifs of m6A methylation in mRNAs. Altogether, our results identify m6A as a dynamic epitranscriptomic mark mediating the virus-host interaction.

[Application of a modified paramedian lower lip-submandibular approach in maxillary (subtotal) total resection].

OBJECTIVE: To investigate the clinical efficacy of a modified paramedian lower lip-submandibular approach for maxillary (subtotal) total resection. METHODS: Eleven patients of maxillary tumors underwent maxillary (subtotal) total resection through the modified paramedian lower lip-submandibular approach. Clinical follow-up visits were conducted to evaluate appearance restoration, facial nerve functional status, parotid gland functional status, and orbital region complication. RESULTS: During the follow-up period of 6-36 months, the appearance of all 11 patients recovered well. All cases presented hidden scars. No facial nerve and parotid duct injury, lower eyelid edema, lower eyelid ectropion, or epiphora in all cases was observed. CONCLUSIONS: Applying modified paramedian lower lip-submandibular approach to maxillary (subtotal) total resection effectively reduces incidence of orbital region complications including lower eyelid edema, lower eyelid ectropion, and epiphora, which often occur to traditional approach. The modified approach produces more subtle scars than other methods and should be applied to treatment of maxillary (subtotal) total resection.

Low-intensity pulsed ultrasound repair in mandibular condylar cartilage injury rabbit model.

OBJECTIVES: Beneficial effects of low-intensity pulsed ultrasound(US) have been reported for knee articular cartilage injury. It is unclear whether the same effect could be observed on mandibular condylar cartilage. This study was designed to explore the efficacy of ultrasound cartilage repair via autophagy regulation. METHODS: A total of 18 adult rabbits were divided into a sham operation group (exposure to condylar articular surface only), operation without US group (only cartilage surgery), and operation with US group (received ultrasonic therapy daily on day 4 after cartilage surgery). The rabbits were then sacrificed to construct a temporomandibular joint (TMJ) cartilage injury model and HE staining was conducted to observe pathological changes of cartilage in each group. Expression of FGF18, FGFR4, beclin1, ATG3 and ATG7 in rabbit TMJ cartilage were detected using RT-PCR and western blotting. Finally, protein-protein interaction (PPI) analysis was used to observe the interaction among the network of important biomarkers in this injury model. RESULTS: Compared to the operation without US group, the severity of cartilage injury was decreased in the operation with US group according to HE staining. The expression of autophagy biomarkers, beclin1, ATG3, ATG7, FGF18 and FGFR4, in operation with US group were up-regulated compared with those in sham operation group and operation without US group p < 0.05). In PPI analysis, ATG3, ATG7, PIK3C3, PIK3R4, BECN1 were identified as hub nodes connecting with most proteins network. CONCLUSIONS: Our results suggest US has therapeutic potential for the treatment of mandibular condylar cartilage injury, and may affect chondrocyte autophagy.

Tuning Both Surface Chemistry and Porous Properties of Polymer-Derived Porous Carbons for High-Performance Gas Adsorption.

In this study, we have prepared novel pyrrole-formaldehyde polymers through polymerizing pyrrole and formaldehyde in the mixture solvent of water and ethanol by using hydrochloric acid as a catalyst. The as-synthesized polymers possess a nitrogen content of 6.7 atom % and are composed of spherical particles with the diameter of approximately 1-3 µm. A series of nitrogen-doped porous carbons with high specific surface areas (680-2340 m2 g-1) were successfully obtained through the activation treatment of the polymer spheres. The porous properties and surface chemistry of the as-prepared porous carbons are tuned by choosing different activating agents and changing the activation temperature. The morphology, porous properties, and chemical composition of the obtained nitrogen-doped porous carbons are revealed by various characterization methods, such as scanning electron microscopy, nitrogen sorption measurement, and X-ray photoelectron spectroscopy. The as-prepared nitrogen-doped porous carbons as gas adsorbents display high carbon dioxide uptake capacities of 3.80-5.81 mmol g-1 at 273 K and 1.0 bar. They also show excellent carbon dioxide adsorption capacities (2.40-3.37 mmol g-1 at 1.0 bar) and good gas selectivities (CO2/N2 selectivities of 16.9-70.2) at 298 K.

An Improved Barcoded Oligonucleotide Primers-based Next-generation Sequencing Approach for Direct Identification of Viral Pathogens in Clinical Specimens.

OBJECTIVE: To provide a feasible and cost-effective next-generation sequencing (NGS) method for accurate identification of viral pathogens in clinical specimens, because enormous limitations impede the clinical use of common NGS, such as high cost, complicated procedures, tremendous data analysis, and high background noise in clinical samples. METHODS: Viruses from cell culture materials or clinical specimens were identified following an improved NGS procedure: reduction of background noise by sample preprocessing, viral enrichment by barcoded oligonucleotide (random hexamer or non-ribosomal hexanucleotide) primer-based amplification, fragmentation-free library construction and sequencing of one-tube mixtures, as well as rapid data analysis using an in-house pipeline. RESULTS: NGS data demonstrated that both barcoded primer sets were useful to simultaneously capture multiple viral pathogens in cell culture materials or clinical specimens and verified that hexanucleotide primers captured as many viral sequences as hexamers did. Moreover, direct testing of clinical specimens using this improved hexanucleotide primer-based NGS approach provided further detailed genotypes of enteroviruses causing hand, foot, and mouth disease (HFMD) and identified other potential viruses or differentiated misdiagnosis events. CONCLUSION: The improved barcoded oligonucleotide primer-based NGS approach is simplified, time saving, cost effective, and appropriate for direct identification of viral pathogens in clinical practice.

[Application of anterolateral thigh myocutaneous flap in the reconstruction of tongue and mouth floor defect after tongue carcinoma].

OBJECTIVE: To investigate the application of free anterolateral thigh myocutaneous flap in the reconstruction of tongue and mouth floor defect after radical resection of tongue carcinoma. METHODS: From June 2006 to April 2009, 14 cases with tongue carcinoma underwent radical resection, leaving tongue and mouth floor defects which were reconstructed by anterolateral thigh myocutaneous flaps at the same stage. These 14 cases included tongue carcinoma at lingual margin (n=9), at ventral tongue (n=3) and at mouth floor (n=2). The flap size ranged from 7 cm x 9 cm to 5 cm x 7 cm. RESULTS: All the 14 flaps survived completely with primary healing. There was no functional morbidity in the lower extremities. The patients were followed up for 12-26 months with satisfied esthetic and functional results in reconstructed tongue. Only one case (T4 N1 M0) died of metastasis carcinoma 14 months after operation. No local recurrence happened. CONCLUSIONS: The anterolateral thigh myocutaneous flap has abundant tissue volume to reconstruct the tongue and mouth floor defect, while leaving less morbidity at donor site. Both satisfied esthetic and functional results can be achieved.