Enantioselective Nickel-Catalyzed Denitrogenative Transannulation En Route to N-N Atropisomers.

Nickel-catalyzed transannulation reactions triggered by the extrusion of small gaseous molecules have emerged as a powerful strategy for the efficient construction of heterocyclic compounds. However, it's asymmetric synthesis remains challenging because of the difficulty in controlling stereo- and regioselectivity. Herein, we report the first nickel-catalyzed asymmetric synthesis of N-N atropisomers by the denitrogenative transannulation of benzotriazones with internal alkynes. A broad range of N-N atropisomers was obtained with excellent regio- and enantioselectivity under mild conditions. Moreover, density functional theory (DFT) calculations provided insights into the nickel-catalyzed reaction mechanism and enantioselectivity control.

Palladium-catalyzed asymmetric carbene coupling en route to inherently chiral heptagon-containing polyarenes.

Developing facile and direct synthesis routes for enantioselective construction of cyclic π-conjugated molecules is crucial. However, originate chirality from the distorted structure around heptagon-containing polyarenes is largely overlooked, the enantioselective construction of all-carbon heptagon-containing polyarenes remains a challenge. Herein, we present a highly enantioselective synthesis route for fabricating all carbon heptagon-containing polyarenes via palladium-catalyzed carbene-based cross-coupling of benzyl bromides and N-arylsulfonylhydrazones. A wide range of nonplanar, saddle-shaped tribenzocycloheptene derivatives are efficiently prepared in high yields with excellent enantioselectivities using this approach. In addition, stereochemical stability experiments show that these saddle-shaped tribenzocycloheptene derivatives have high inversion barriers.

A New Design for Forearm Skin Flaps for Areas that Do not Require Additional Grafting.

Forearm skin flaps are widely used to reconstruct oral cancer due to their advantages, such as vascular stability, simple preparation, and a high success rate. However, traditional forearm skin flaps have shortcomings: the donor site requires grafting, which increases surgical trauma by creating a second surgical area, and the scarring at the donor site significantly affects the esthetics of the forearm. Therefore, we have designed a new ^-shaped radial forearm skin flap, in which the flap is designed as 2 semi-elliptical subunits. After the flap is harvested, these 2 subunits are joined, and the reserved skin at the donor site is directly sutured to the outer part of the donor site. The area of the ^-shaped radial forearm skin flap can be as large as that prepared with traditional forearm skin flaps, and there is no need for grafting at the donor site. This avoids additional trauma to the donor site after surgery, significantly reduces related complications, and enhances the esthetic outcome. This paper reports a case of a cheek cancer (carcinoma of the buccal mucosa) patient (T3N0M0), where the flap survived postoperatively, and both the surgical site and donor site healed in the first phase. The patient has no sensory or functional impairments; swallowing and speech functions are satisfactory.

Refined preferences of prioritizers improve intelligent diagnosis for Mendelian diseases.

Phenotype-guided gene prioritizers have proved a highly efficient approach to identifying causal genes for Mendelian diseases. In our previous study, we preliminarily evaluated the performance of ten prioritizers. However, all the selected software was run based on default settings and singleton mode. With a large-scale family dataset from Deciphering Developmental Disorders (DDD) project (N = 305) and an in-house trio cohort (N = 152), the four optimal performers in our prior study including Exomiser, PhenIX, AMELIE, and LIRCIAL were further assessed through parameter optimization and/or the utilization of trio mode. The in-depth assessment revealed high diagnostic yields of the four prioritizers with refined preferences, each alone or together: (1) 83.3-91.8% of the causal genes were presented among the first ten candidates in the final ranking lists of the four tools; (2) Over 97.7% of the causal genes were successfully captured within the top 50 by either of the four software. Exomiser did best in directly hitting the target (ranking the causal gene at the very top) while LIRICAL displayed a predominant overall detection capability. Besides, cases affected by low-penetrance and high-frequency pathogenic variants were found misjudged during the automated prioritization process. The discovery of the limitations shed light on the specific directions of future enhancement for causal-gene ranking tools.

Bioorthogonal "Click and Release" Reaction-Triggered Aggregation of Gold Nanoparticles Combined with Released Lonidamine for Enhanced Cancer Photothermal Therapy.

Cancer has been the most deadly disease, and 13 million cancer casualties are estimated to occur each year by 2030. Gold nanoparticles (AuNPs)-based photothermal therapy (PTT) has attracted great interest due to its high spatiotemporal controllability and noninvasiveness. Due to the trade-off between particle size and photothermal efficiency of AuNPs, rational design is needed to realize aggregation of AuNPs into larger particles with desirable NIR adsorption in tumor site. Exploiting the bioorthogonal "Click and Release" (BCR) reaction between iminosydnone and cycloalkyne, aggregation of AuNPs can be achieved and attractively accompanied by the release of chemotherapeutic drug purposed to photothermal synergizing. We synthesize iminosydnone-lonidamine (ImLND) as a prodrug and choose dibenzocyclooctyne (DBCO) as the trigger of BCR reaction. A PEGylated AuNPs-based two-component nanoplatform consisting of prodrug-loaded AuNPs-ImLND and tumor-targeting peptide RGD-conjugated AuNPs-DBCO-RGD is designed. In the therapeutic regimen, AuNPs-DBCO-RGD are intravenously injected first for tumor-specific enrichment and retention. Once the arrival of AuNPs-ImLND injected later at tumor site, highly photothermally active nanoaggregates of AuNPs are formed via the BCR reaction between ImLND and DBCO. The simultaneous release of lonidamine further enhanced the therapeutic performance by sensitizing cancer cells to PTT.

Chinese expert consensus on imaging diagnosis of drug-resistant pulmonary tuberculosis.

Tuberculosis (TB) remains one of the major infectious diseases in the world with a high incidence rate. Drug-resistant tuberculosis (DR-TB) is a key and difficult challenge in the prevention and treatment of TB. Early, rapid, and accurate diagnosis of DR-TB is essential for selecting appropriate and personalized treatment and is an important means of reducing disease transmission and mortality. In recent years, imaging diagnosis of DR-TB has developed rapidly, but there is a lack of consistent understanding. To this end, the Infectious Disease Imaging Group, Infectious Disease Branch, Chinese Research Hospital Association; Infectious Diseases Group of Chinese Medical Association of Radiology; Digital Health Committee of China Association for the Promotion of Science and Technology Industrialization, and other organizations, formed a group of TB experts across China. The conglomerate then considered the Chinese and international diagnosis and treatment status of DR-TB, China's clinical practice, and evidence-based medicine on the methodological requirements of guidelines and standards. After repeated discussion, the expert consensus of imaging diagnosis of DR-PB was proposed. This consensus includes clinical diagnosis and classification of DR-TB, selection of etiology and imaging examination [mainly X-ray and computed tomography (CT)], imaging manifestations, diagnosis, and differential diagnosis. This expert consensus is expected to improve the understanding of the imaging changes of DR-TB, as a starting point for timely detection of suspected DR-TB patients, and can effectively improve the efficiency of clinical diagnosis and achieve the purpose of early diagnosis and treatment of DR-TB.

Evaluating the clinical performance of SDC2/NDRG4 methylation for colorectal cancer detection.

Purpose: The performance and clinical accuracy of combined SDC2/NDRG4 methylation were evaluated in diagnosing colorectal cancer (CRC) and advanced adenoma. Methods: A total of 2333 participants were enrolled to assess the sensitivity and specificity of biomarkers in diagnosing CRC in a multicenter clinical trial through feces DNA methylation tests. Results: SDC2/NDRG4 methylation showed excellent performance for CRC detection in biomarker research and the real world. Its sensitivity for detecting CRC, early CRC and advanced adenoma were 92.06%, 91.45% and 62.61%, respectively. Its specificity was 94.29%, with a total coincidence rate of 88.28%. When interference samples were included, the specificity was still good (82.61%). Therefore, the SDC2/NDRG4 methylation test showed excellent performance in detecting CRC and advanced adenoma under clinical application.

Colorectal cancer (CRC) is one of the most malignant tumors of the digestive system and second only to breast cancer and lung cancer in terms of global incidence. Early CRCs are challenging to determine given their atypical nature. In contrast, late CRC symptoms are affected by the type, location and range of the lesion and complications. Therefore, CRC patients are generally diagnosed late, present with a high degree of malignancy, and have poor prognosis and 5-year survival rates. The current study therefore evaluated whether SDC2 and NDRG4 methylation could be used for diagnosis CRCs at an early stage and whether it has the potential to detect asymptomatic patients with adenomas. The findings presented herein will certainly help support the early diagnosis of CRC and precancerous lesions in clinical practice.

The integrated analysis and underlying mechanisms of FNDC5 on diabetic induced cognitive deficits.

OBJECTIVES: Chronic hyperglycemia is considered as an important factor to promote the neurodegenerative process of brain, and the synaptic plasticity as well as heterogeneity of hippocampal cells are thought to be associated with cognitive dysfunction in the early process of neurodegeneration. To date, fibronectin type III domain-containing protein 5 (FNDC5) has been highlighted its protective role in multiple neurodegenerative diseases. However, the potential molecular and cellular mechanisms of FNDC5 on synaptic plasticity regulation in cognitive impairment (CI) induced by diabetics are still need to known. METHODS/DESIGN: To investigate the heterogeneity and synaptic plasticity of hippocampus in animals with CI state induced by hyperglycemia, and explore the potential role of FNDC5 involved in this process. Firstly, the single cell sequencing was performed based on the hippocampal tissue from db diabetic mice induced CI and normal health control mice by ex vivo experiments; and then the integrated analysis and observations validation using Quantitative Real-time PCR, western blot as well as other in vitro studies. RESULTS: We observed and clarified the sub-cluster of type IC spiral ganglion neurons expressed marker genes as Trmp3 and sub-cluster of astrocytes with marker gene as Atp1a2 in hippocampal cells from diabetic animals induced CI and the effect of those on neuron-glial communication. We also found that FNDC5\BDNF-Trk axis was involved in the synaptic plasticity regulation of hippocampus. In high glucose induced brain injury model in vitro, we investigated that FNDC5 significantly regulates BDNF expression and that over-expression of FNDC5 up-regulated BDNF expression (p < 0.05) and can also significantly increase the expression of synapsin-1 (p < 0.05), which is related to synaptic plasticity, In addition, the unbalanced methylation level between H3K4 and H3K9 in Fndc5 gene promoter correlated with significantly down-regulated expression of FNDC5 (p < 0.05) in the hyperglycemia state. CONCLUSION: The current study revealed that the synaptic plasticity of hippocampal cells in hyperglycemia might be regulated by FNDC5\BDNF-Trk axis, playing the protective role in the process of CI induced by hyperglycemia and providing a target for the early treatment of hyperglycemia induced cognitive dysfunction in clinic.

Organocatalytic Enantioselective Synthesis of Seven-Membered Ring with Inherent Chirality.

Inherent chirality is used to describe chiral cyclic molecules devoid of central, axial, planar, or helical chirality and has tremendous applications in chiral recognition and enantioselective synthesis. Catalytic and divergent syntheses of inherently chiral molecules have attracted increasing interest from chemists. Herein, we report the enantioselective synthesis of inherently chiral tribenzocycloheptene derivatives via chiral phosphoric acid (CPA)-catalyzed condensation of cyclic ketones and hydroxylamines. This chemistry paves the way to accessing the less stable derivatives of 7-membered rings with inherent chirality. A series of chiral tribenzocycloheptene oxime ethers was synthesized in good yields (up to 97 %) with excellent enantioselectivities (up to 99 % ee).

A PD-L1-targeting Regulator for Metabolic Reprogramming to Enhance Glutamine Inhibition-Mediated Synergistic Antitumor Metabolic and Immune Therapy.

Inhibition of glutamine metabolism in tumor cells can cause metabolic compensation-mediated glycolysis enhancement and PD-L1 upregulation-induced immune evasion, significantly limiting the therapeutic efficacy of glutamine inhibitors. Here, inspired by the specific binding of receptor and ligand, a PD-L1-targeting metabolism and immune regulator (PMIR) are constructed by decorating the glutaminase inhibitor (BPTES)-loading zeolitic imidazolate framework (ZIF) with PD-L1-targeting peptides for regulating the metabolism within the tumor microenvironment (TME) to improve immunotherapy. At tumor sites, PMIR inhibits glutamine metabolism of tumor cells for elevating glutamine levels within the TME to improve the function of immune cells. Ingeniously, the accompanying PD-L1 upregulation on tumor cells causes self-amplifying accumulation of PMIR through PD-L1 targeting, while also blocking PD-L1, which has the effects of converting enemies into friends. Meanwhile, PMIR exactly offsets the compensatory glycolysis, while disrupting the redox homeostasis in tumor cells via the cooperation of components of the ZIF and BPTES. These together cause immunogenic cell death of tumor cells and relieve PD-L1-mediated immune evasion, further reshaping the immunosuppressive TME and evoking robust immune responses to effectively suppress bilateral tumor progression and metastasis. This work proposes a rational strategy to surmount the obstacles in glutamine inhibition for boosting existing clinical treatments.

Coupling capillary electrophoresis with mass spectrometry for the analysis of oxidized phospholipids in human high-density lipoproteins.

The oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (ox-PAPC) products in human high-density lipoproteins (HDLs) were investigated by low-flow capillary electrophoresis-mass spectrometry (low-flow CE-MS). To accelerate the optimization, native PAPC (n-PAPC) standard was first analyzed by a commercial CE instrument with a photodiode array detector. The optimal separation buffer contained 60% (v/v) acetonitrile, 40% (v/v) methanol, 20 mM ammonium acetate, 0.5% (v/v) formic acid, and 0.1% (v/v) water. The selected separation voltage and capillary temperature were 20 kV and 23°C. The optimal CE separation buffer was then used for the low-flow CE-MS analysis. The selected MS conditions contained heated capillary temperature (250°C), capillary voltage (10 V), and injection time (1 s). No sheath gas was used for MS. The linear range for n-PAPC was 2.5-100.0 µg/mL. The coefficient of determination (R2 ) was 0.9918. The concentration limit of detection was 1.52 µg/mL, and the concentration limit of quantitation was 4.60 µg/mL. The optimal low-flow CE-MS method showed good repeatability and sensitivity. The ox-PAPC products in human HDLs were determined based on the in vitro ox-PAPC products of n-PAPC standard. Twenty-one ox-PAPC products have been analyzed in human HDLs. Uremic patients showed significantly higher levels of 15 ox-PAPC products than healthy subjects.

Drynaria Naringin alleviated mechanical stress deficiency-caused bone loss deterioration via Rspo1/Lgr4-mediated Wnt/ß-catenin signalling pathway.

Osteoporosis is a metabolic condition distinguished by the degradation of bone microstructure and mechanical characteristics. Traditional Chinese medicine (TCM) has been employed in China for the treatment of various illnesses. Naringin, an ingredient found in Drynariae TCM, is known to have a significant impact on bone metabolism. For this research, we studied the precise potential effect of Drynaria Naringin on protecting against bone loss caused by stress deficiency. In this study, a tail-suspension (TS) test was performed to establish a mouse model with hind leg bone loss. Some mice received subcutaneous injections of Drynaria Naringin for 30 d. Trabecular bone microarchitecture was evaluated using micro-computed tomography analysis and bone histological analysis. Bone formation and resorption markers were quantified in blood samples from mice or in the supernatant of MC3T3-E1 cells by ELISA analysis, Western blotting, and PCR. Immunofluorescence was utilized to visualize the location of ß-catenin. Additionally, siRNA was employed to knockdown-specific genes in the cells. Our findings highlight the efficacy of Drynaria Naringin in protecting against the deterioration of bone loss and promoting bone formation and Rspo1 expression in a mouse model following the TS test. Specifically, in vitro experiments also indicated that Drynaria Naringin may promote osteogenesis through the Wnt/ß-catenin signalling pathway. Moreover, our results suggest that Drynaria Naringin upregulates the expression of Rspo1/Lgr4, leading to the promotion of osteogenesis via the Wnt/ß-catenin signalling pathway. Therefore, Drynaria Naringin holds potential as a therapeutic medication for osteoporosis. Drynaria Naringin alleviates bone loss deterioration caused by mechanical stress deficiency through the Rspo1/Lgr4-mediated Wnt/ß-catenin signalling pathway.

Atroposelective Synthesis of C-N Vinylindole Atropisomers by Palladium-Catalyzed Asymmetric Hydroarylation of 1-Alkynylindoles.

Transition-metal-catalyzed hydroarylation of unsymmetrical internal alkynes remains challenging because of the difficulty in controlling regioselectivity and stereoselectivity. Moreover, the enantioselective hydroarylation of alkynes using organoboron reagents has not been reported. Herein, we report for the first time that palladium compounds can catalyze the hydroarylation of 1-alkynylindoles with organoborons for the synthesis of chiral C-N atropisomers. A series of rarely reported vinylindole atropisomers was synthesized with excellent regio-, stereo- (Z-selectivity), and enantioselectivity under mild reaction conditions. The ready availability of organoborons and alkynes and the simplicity, high stereoselectivity, and good functional group tolerance of this catalytic system make it highly attractive.

Catalytic Asymmetric Synthesis of Atropisomers Featuring an Aza Axis.

ConspectusAtropisomers bearing a rotation-restricted axis are common structural units in natural products, chiral ligands, and drugs; thus, the prevalence of asymmetric synthesis has increased in recent decades. Research into atropisomers featuring an N-containing axis (N-X atropisomers) remains in its infancy compared with the well-developed C-C atropisomer analogue. Notably, N-X atropisomers could offer divergent scaffolds, which are extremely important in bioactive molecules. The asymmetric synthesis of N-X atropisomers is recognized as both appealing and challenging. Recently, we devoted our efforts to the catalytic asymmetric synthesis of N-X atropisomers, benzimidazole-aryl N-C atropisomers, indole-aryl N-C atropisomers, hydrogen-bond-assisted N-C atropisomers, pyrrole-pyrrole N-N atropisomers, pyrrole-indole N-N atropisomers, and indole-indole N-N atropisomers. To obtain the N-C atropisomers, an asymmetric Buchwald-Hartwig reaction of amidines or enamines was employed. Using a Pd(OAc)2/(S)-BINAP or Pd(OAc)2/(S)-Xyl-BINAP catalyst system, benzimidazole-aryl N-C atropisomers and indole-aryl N-C atropisomers were readily obtained. To address the issue of the reduced stability of the diarylamine axis, a six-membered intramolecular N-H-O hydrogen bond was introduced into the N-C atropisomer scaffold. A tandem N-arylation/oxidation process was used for the chiral phosphoric acid (CPA)-catalyzed asymmetric synthesis of N-aryl quinone atropisomers. For N-N atropisomers, a copper-mediated asymmetric Friedel-Crafts alkylation/arylation reaction was developed. The desymmetrization process was completed successfully via a Cu(OTf)2/chiral bisoxazoline or (CuOTf)·Tol/bis(phosphine) dioxide system, thereby achieving the first catalytic asymmetric synthesis of N/N bipyrrole atropisomers. Asymmetric Buchwald-Hartwig amination of enamines was utilized to provide N-N bisindole atropisomers with excellent stereogenic control. This was the first asymmetric synthesis of N-N atropisomers featuring a bisindole structural scaffold using the de novo indole construction strategy. The asymmetric N-N heterobiaryl atropisomer synthesis was substantially facilitated using palladium-catalyzed transient directing group (TDG)-mediated C-H functionalization. Atropisomeric alkenylation, allylation, or alkynylation was accomplished using the Pd(OAc)2/l-tert-leucine system. Herein, we summarize our work on the palladium-, copper-, and CPA-catalyzed asymmetric syntheses of N-C and N-N atropisomers. Furthermore, the application of our work in the synthesis of bioactive molecule analogues and axially chiral ligands is demonstrated. Subsequently, the stability of the chiral N-containing axis is briefly discussed in terms of single crystals and obtained rotational barriers. Finally, an outlook on the asymmetric N-X atropisomer synthesis is provided.

Construction of silver-coated high translucent zirconia implanting abutment material and its property of antibacterial.

High translucent zirconia (HTZ) has excellent mechanical properties, biocompatibility, and good semi-translucency making it an ideal material for aesthetic anterior dental implant abutments without antibacterial properties. In the oral environment, the surface of the abutment material is susceptible to microbial adhesion and biofilm formation, which can lead to infection or peri-implantitis and even implant failure. This study aims to promote the formation of a biological seal at the implant-soft tissue interface by modifying the HTZ surface, using the load-bearing capacity of the aluminosilicate porous structure and the broad-spectrum antibacterial effect of silver nanoparticles to prevent peri-implant bacterial infection and inflammation and to improve the success rate and prolong the use of the implant. FE-SEM (field emission scanning electron microscopes), EDS (energy dispersive spectroscopy), and XPS (X-ray photoelectron spectroscopy) results showed that aluminosilicate non-vacuum sintering can form open micro- and nanoporous structures on HTZ surfaces, and that porous aluminosilicate coatings obtain a larger number, smaller size, and more uniformly shaped silver nanoparticles than smooth aluminosilicate coatings, and could be deposited deeper in the coating. The ICP-AES (inductively coupled plasma-atomic emission spectroscopy) results showed that the early silver ion release of both the smooth silver coating and the porous silver coating was obvious, the silver ion concentration released by the former was higher than that of the latter. However, the silver ion concentration released by the porous silver coating was higher than that of the smooth coating when the release slowed down. Both smooth and porous silver coatings both inhibited E. coli (Escherichia coli), S. aureus (Staphylococcus aureus), and L. acidophilus (L. acidophilus), and porous silver coatings had stronger antibacterial properties. The silver coating was successfully constructed on the surface of HTZ, through aluminium silicate sintering and silver nitrate solution impregnation. It was found that the high concentration environment of silver nitrate solution was more advantageous for nano-Ag deposition, and the non-vacuum sintered porous surface was able to obtain a larger number of nano-Ag particles with smaller sizes. The porous Ag coating exhibited superior antibacterial properties. It was suggested that the HTZ with silver coating had clinical application, and good antibacterial properties that can improve the survival rate and service life of implants.

A retrospective cohort study evaluating the improvement of medical records management based on whole-process control.

BACKGROUND: Whole-process management is a novel approach widely applied in industry and commerce; however, it is not widely used in the management of medical records in hospitals. OBJECTIVE: The purpose of this study is to investigate the application of whole-process control in the administration of a hospital's medical records department to achieve refined management of medical records. METHODS: Whole-process control is a management measure that begins with process conception and implementation and includes control over all processes. The control group included medical records that were created prior to the implementation of whole-process control, i.e., those created between June 1 and December 31, 2020. The observation group included medical records that were created after the implementation of whole-process control. The behavior of the medical records staff (in terms of medical record collection, sorting, entry, inquiry, and supply) and the final quality of the medical records (the number of grade-A medical records and their front-page quality) were compared between the two groups, and subjective judgments related to staff satisfaction were reviewed. RESULTS: The implementation of whole-process control improved the behavior of the medical records staff. The final quality of the medical records was also improved, as was the job satisfaction of the medical records staff. CONCLUSION: Implementing whole-process control improved the management of medical records and quality of medical records.

Palladium-Catalyzed Double N-Arylation to Access Unsymmetric N,N'-Bicarbazole Scaffolds.

Herein, the palladium-catalyzed double C-N coupling of 9H-carbazol-9-amines and 2,2'-dibromo-1,1'-biphenyl is reported. This protocol offers access to N,N'-bicarbazole scaffolds, which have frequently been used as linkers in the construction of functional covalent organic frameworks (COFs). A variety of substituted N,N'-bicarbazoles were synthesized in moderate to high yields based on this chemistry, and the potential application of this method was showcased by the synthesis of COF monomers like tetrabromide 4 and tetraalkynylate 5.

Resistance to Chemotherapeutic 5-Fluorouracil Conferred by Modulation of Heterochromatic Integrity through Ino80 Function in Fission Yeast.

5-Fluorouracil (5-FU) is a conventional chemotherapeutic drug widely used in clinics worldwide, but development of resistance that compromises responsiveness remains a major hurdle to its efficacy. The mechanism underlying 5-FU resistance is conventionally attributed to the disruption of nucleotide synthesis, even though research has implicated other pathways such as RNA processing and chromatin dysregulation. Aiming to clarify resistance mechanisms of 5-FU, we tested the response of a collection of fission yeast (Schizosaccharomyces pombe) null mutants, which confer multiple environmental factor responsiveness (MER). Our screen identified disruption of membrane transport, chromosome segregation and mitochondrial oxidative phosphorylation to increase cellular susceptibility towards 5-FU. Conversely, we revealed several null mutants of Ino80 complex factors exhibited resistance to 5-FU. Furthermore, attenuation of Ino80 function via deleting several subunit genes reversed loss of chromosome-segregation fidelity in 5-FU in the loss-of-function mutant of the Argonaute protein, which regulates RNA interference (RNAi)-dependent maintenance of pericentromeric heterochromatin. Our study thus uncovered a critical role played by chromatin remodeling Ino80 complex factors in 5-FU resistance, which may constitute a possible target to modulate in reversing 5-FU resistance.

Engineering metal-based hydrogel-mediated tertiary lymphoid structure formation via activation of the STING pathway for enhanced immunotherapy.

Tertiary lymphoid structures (TLSs) primarily constructed by multiple immune cells can effectively enhance tumor immune responses, but expediting the formation of TLSs is still an enormous challenge. Herein, a stimulator of interferon gene (STING)-activating hydrogel (ZCCG) was elaborately developed by coordinating Zn2+ with 4,5-imidazole dicarboxylic acid, and simultaneously integrating chitosan (a stimulant of STING pathway activation) and CpG (an agonist of toll-like receptor 9, TLR9) for initiating and activating cGAS-STING and TLR9 pathway-mediated immunotherapy. Moreover, the dual-pathway activation could effectively enhance the infiltration of immune cells and the expression of lymphocyte-recruiting chemokines in the tumor microenvironment (TME), thereby promoting the formation of TLSs and further strengthening tumoricidal immunity. Local administration of the hydrogel could prime systemic immune responses and long-term immune memory and improve the therapeutic effects of programmed death-1 antibody (αPD-1) to inhibit tumor progression, metastasis and recurrence. The engineered hydrogel lays the foundation for tumor immunotherapy strategies based on the enhanced formation of TLSs via the activation of the cGAS-STING and TLR9 pathways.

Evaluation of PAX1/ST6GALNAC5 methylation as a triage test for cervical intraepithelial neoplasia and cervical cancer.

Aim: To identify DNA methylation markers for triage in a cohort of human papillomavirus-positive (HPV+) women. Methods: The methylation markers were identified and evaluated for the detection of cervical high-grade squamous intraepithelial lesions (HSILs) or cervical cancer (collectively referred to as 'HSIL+') in HPV+ women (n = 692). Results: Combined PAX1/ST6GALNAC5 methylation testing yielded HSIL+ sensitivity of 0.838 and 0.818, with a specificity of 0.827 and 0.810, in the training and test sets, respectively. For cervical cancer, the specificity and sensitivity were 0.969 and 1.000 in the training set and 0.967 and 0.875 in the test set. Moreover, the combined marker methylation test (0.86; 77/90) was more sensitive than the cytology (0.31; 28/90) for HSIL+. Conclusion: The combined PAX1/ST6GALNAC5 marker may have clinical application for detecting HSIL+ in HPV+ women undergoing screening.