Advanced theoretical design of light-driven molecular rotary motors: enhancing thermal helix inversion and visible-light activation.

In this study, we have advanced the field of light-driven molecular rotary motors (LDMRMs) by achieving two pivotal goals: lowering the thermal helix inversion (THI) barrier and extending the absorption wavelength into the visible spectrum. This study involves the structural reengineering of a second-generation visible LDMRM, resulting in the synthesis of a novel class, specifically, 2-((2S)-5-methoxy-2-methyl-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-yl)-3-oxo-2,3-dihydro-1H-dibenzo[e,g]indole-6,9-dicarbonitrile. This redesigned motor stands out with its two photoisomerization stages and two thermal helix inversions, featuring exceptionally low THI barriers (4.00 and 2.05 kcal mol-1 at the OM2/MRCI level for the EM → EP and ZM → ZP processes, respectively). Moreover, it displays absorption wavelengths in the visible light range (482.98 and 465.76 nm for the EP and ZP isomers, respectively, at the TD-PBE0-D3/6-31G(d,p) level), surpassing its predecessors in efficiency, as indicated by the narrow HOMO-LUMO energy gap. Ultrafast photoisomerization kinetics (approximately 0.8-1.6 ps) and high quantum yields (around 0.3-0.6) were observed through trajectory surface hopping simulations. Additionally, the simulated time-resolved fluorescence emission spectrum indicates a significantly reduced "dark state" duration (0.09-0.26 ps) in these newly designed LDMRMs compared to the original ones, marking a substantial leap forward in the design and efficiency of LDMRMs.

Normalization of Tumor Vessels by Lenvatinib-Based Metallo-Nanodrugs Alleviates Hypoxia and Enhances Calreticulin-Mediated Immune Responses in Orthotopic HCC and Organoids.

Immunocheckpoint inhibitors combined with Lenvatinib is the first line treatment for hepatocellular carcinoma (HCC), but their potency is hampered by the low response rate and adverse events. Herein, a targeted therapeutic strategy through the coassembly of Lenvatinib, Adriamycin, Fe3+ ion, and a natural polyphenol (metallo-nanodrugs) is presented by coordination effect for potentiating tumor vascular normalization and systematic chemo-immunotherapy to effectively inhibit the progression of HCC in both orthotopic model and patients-derived organoids. In mice with orthotopic HCC, the obtained metallo-nanodrugs efficiently increase the drug accumulation in orthotopic tumors and can respond to acidic tumor environment. The promotion of tumor vascular normalization by metallo-nanodrugs is observed, which enhances the infiltrating T lymphocytes in tumor, and reinforces the calreticulin-mediated antitumor immunity through alleviating hypoxia, reducing regulatory T cells, and down-regulating PDL1 expression of tumors. The excellent therapeutic efficiency with complete remission of orthotopic tumors (3/6) and long-term survival of mice (4/6, 42 days) are also achieved. Furthermore, the excellent therapeutic effect of metallo-nanodrugs is also validated in 5 patient-derived organoids, and hence can provide a marvelous systemic chemo-immunotherapy strategy for enhancing HCC treatment.

Simultaneously improving the efficiencies of photo- and thermal isomerization of an oxindole-based light-driven molecular rotary motor by a structural redesign.

We designed a novel highly efficient light-driven molecular rotary motor theoretically by using electronic structure calculations and nonadiabatic dynamics simulations, and it showed excellent performance for both photo- and thermal isomerization processes simultaneously. By the small structural modification based on 3-(2,7-dimethyl-2,3-dihydro-1H-inden-1-ylidene)-1-methylindolin-2-one (DDIYM) synthesized by Feringa et al. recently, an oxindole-based light-driven molecular rotary motor, 3-(1,5-dimethyl-4,5-dihydrocyclopenta[b]pyrrol-6(1H)-ylidene)-1-methylindolin-2-one (DDPYM), is proposed, which displays a significant electronic push-pull character and weak steric hindrance for double-bond isomerization. The newly designed motor DDPYM shows a remarkable improvement of the quantum yield for both EP → ZM and ZP → EM photoisomerization processes, compared to the original motor DDIYM. Furthermore, the rotary motion in photoisomerization processes of DDPYM behaves more like a pure axial rotational motion approximately, while that of DDIYM is an obvious precessional motion. The weakness of the steric hindrance reduces the energy barriers of the thermal helix EM → EP and ZM → ZP inversion steps, and would accelerate two ground-state isomerization steps significantly. Our results confirm the feasibility of simultaneously improving the efficiencies of photo- and thermal isomerization of oxindole-based light-driven molecular rotary motors and this design idea sheds light on the future development of more efficient molecular motors.

Comparison of Rhomboid Intercostal Block, Erector Spinae Plane Block, and Serratus Plane Block on Analgesia for Video-Assisted Thoracic Surgery: A Prospective, Randomized, Controlled Trial.

Background: Thoracic surgery is one of the most painful surgical steps. An important tool for managing postoperative pain is effective postoperative analgesia. This research aimed at comparing the analgesic roles of three new fascial block techniques in the postoperative period after video-helped thoracoscopic operation (VATS). Methods: We randomly allocated ninety patients into three teams experiencing ultrasound-directed serratus plane block, erector spinae plane block, and the rhomboid intercostal block, respectively. 0.4% ropivacaine of 20 mL was received by all groups. Outcomes. At 0-12 hours, sufentanil consumption was significantly lower in the RIB (35.2 ± 3.3 mg) and ESP (35.4 ± 2.8 mg) groups than that in the SAB (43.3 ± 2.7 mg) group (P < 0.001), and no obvious diversity in sufentanil consumption was shown between the RIB and ESP groups (P=0.813). At 12-24 hours, sufentanil consumption was greatly lower in the RIB and ESP groups than that in the SAB group (P < 0.001), and no great diversity in sufentanil consumption was found between the RIB and ESP groups (P=0.589). No great diversity in sufentanil consumption was shown between the RIB (50.4 ± 1.4 mg), ESP (50.4 ± 1.5 mg), and SAB (51.0 ± 1.7 mg) groups at 24-48 hours (P=0.192). At 6, 12, 18, and 24 hours, the postoperative dynamic NRS scores were significantly lower in the RIB and ESP groups than in the SAB group ((P < 0.05) for all contrasts). Nevertheless, no great diversity was observed in postoperative pain marks at 0.5, 1, 3, 6, 12, 18, 24, 36, and 48 hours after the surgery across the three groups. No statistical diversity was found in the postoperative NRS mark between groups RIB and ESP within 48 hours after surgery in case of active patients ((P < 0.05) for all contrasts). At 24 hours after surgery, a significant difference in IL-1ß and IL-6 inflammatory factor concentrations was found between RIB and ESP compared with SAB block ((P < 0.05) for all contrasts). However, no great diversities were observed in IL-1ß, and IL-6 inflammatory factor concentrations between RIB, ESP, and SAB at 24 hours preoperatively and at 48 hours postoperatively ((P < 0.05) for all comparisons). Conclusion: The dosage of sufentanil can be effectively reduced by ultrasound-directed rhomboid intercostal block and erector spinae plane block within 24 hours after VATS surgery, and pain can be relieved effectively within 24 hours by comparing with serratus plane block.

Design and Nonadiabatic Photoisomerization Dynamics Study of a Three-Stroke Light-Driven Molecular Rotary Motor.

Working cycle of conventional light-driven molecular rotary motors (LDMRMs), especially Feringa-type motors, usually have four steps, two photoisomerization steps, and two thermal helix inversion (THI) steps. THI steps hinder the ability of the motor to operate at lower temperatures and limit the rotation speed of LDMRMs. A three-stroke LDMRM, 2-(2,7-dimethyl-2,3-dihydro-1H-inden-1-ylidene)-1,2-dihydro-3H-pyrrol-3-one (DDIY), is proposed, which is capable of completing an unidirectional rotation by two photoisomerization steps and one thermal helix inversion step at room temperature. On the basis of trajectory surface-hopping simulation at the semi-empirical OM2/MRCI level, the EP→ZP and ZP→EM nonadiabatic photoisomerization dynamics of DDIY were systematically analyzed. Quantum yields of EP→ZP and ZP→EM photoisomerization of DDIY are ca. 34% and 18%, respectively. Both EP→ZP and ZP→EM photoisomerization processes occur on an ultrafast time scale (ca. 100-300 fs). This three-stroke LDMRM may stimulate further research for the development of new families of more efficient LDMRMs.

Effect of Temperature on Photoisomerization Dynamics of a Newly Designed Two-Stroke Light-Driven Molecular Rotary Motor.

The working mechanism of conventional light-driven molecular rotary motors, especially Feringa-type motors, contains two photoisomerization steps and two thermal helix inversion steps. Due to the existence of a thermal helix inversion step, both the ability to work at lower temperatures and the rotation speed are limited. In this work, a two-stroke light-driven molecular rotary motor, 2-(1,5-dimethyl-4,5-dihydrocyclopenta[b]pyrrol-6(1H)-ylidene)-1,2-dihydro-3H-pyrrol-3-one (DDPY), is proposed, which is capable of performing unidirectional and repetitive rotation by only two photoisomerization (EP→ZP and ZP→EP) steps. With trajectory surface-hopping simulation at the semi-empirical OM2/MRCI level, the EP→ZP and ZP→EP nonadiabatic dynamics of DDPY were systematically studied at different temperatures. Both EP→ZP and ZP→EP photoisomerizations are on an ultrafast timescale (ca. 200-300 fs). The decay mode of EP→ZP photoisomerization is approximately bi-exponential, while that of ZP→EP photoisomerization is found to be periodic. For EP and ZP isomers of DDPY, after the S0→S1 excitation, the dynamical processes of nonadiabatic decay are both followed by twisting about the central C=C double bond and the pyramidalization of the C atom at the stator-axle linkage. The effect of temperature on the nonadiabatic dynamics of EP→ZP and ZP→EP photoisomerizations of DDPY has been systematically investigated. The average lifetimes of the S1 excited state and quantum yields for both EP→ZP and ZP→EP photoisomerization are almost temperature-independent, while the corresponding unidirectionality of rotation is significantly increased (e.g., 74% for EP→ZP and 72% for ZP→EP at 300 K vs 100% for EP→ZP and 94% for ZP→EP at 50 K) with lowering the temperature.

The low-complexity domains of the KMT2D protein regulate histone monomethylation transcription to facilitate pancreatic cancer progression.

BACKGROUND: Liquid-liquid phase separation (LLPS) within the nucleus is directly linked to driving gene expression through transcriptional complexes. Histone lysine methyltransferase 2D (KMT2D) is widely present in many cancers. It is known to epigenetically stimulate the expression of genes associated with tumorigenesis and metastasis. Our analyses show that KMT2D possesses two distinct low-complexity domains (LCDs) capable of driving the assembly of membrane-less condensates. The dependence of the mechanisms underlying monomethylation of H3K4 on the LLPS microenvironment derived from KMT2D LCDs is unclear in tumor. METHODS: KMT2D LCD-depletion cells were used to investigate tumor cell proliferation, apoptosis, and migration. We identified some core proteins, including WDR5, RBBP5, and ASH2L, which are involved in the KMT2D-associated catalytic complex in KMT2D LCD-deficient cells to further elucidate the mechanism that decreases monomethylation of H3K4. We also evaluated the viability of KMT2D LCD-deficient cells in vivo. Finally, using 1,6-hexanediol (HD), an inhibitor of LLPS, we determined cell activities associated with KMT2D function in wild-type PANC-1 cells. RESULTS: Without the LLPS microenvironment in KMT2D LCD-deficient cells or wild-type PANC-1 cells treated with HD, the WDR5 protein was significantly less stable and the protein-protein interactions between the components of the KMT2D-enzyme complex were attenuated, impairing the formation of the complex. Moreover, with the decrease in H3K4me1 level at enhancers, transcription factors such as LIFR and KLF4 were markedly downregulated, effectively inhibiting tumor progression. In xenograft tumor models, PANC-1 cells lacking the KMT2D LCDs showed effectively suppressed tumor growth compared to normal cells. CONCLUSIONS: Our data indicate that the two low-complexity domains of the KMT2D protein could form a stable LLPS microenvironment, promoting the KMT2D catalysis of H3K4 monomethylation through stabilization of the WDR5 protein and KMT2D-enzyme complex. Therefore, finding ways to regulate the LLPS microenvironment will be benefitial for new cancer treatment strategies.

Comparison of rhomboid intercostal nerve block, erector spinae plane block and serratus plane block on analgesia for modified radical mastectomy: A prospective randomised controlled trial.

BACKGROUND AND OBJECTIVES: Breast cancer is one of the most common malignant tumours among women. In this study, we compared the analgesic efficacy of ultrasound (US)-guided rhomboid intercostal nerve block, erector spinae plane (ESP) block and serratus plane block (SAB) after modified radical mastectomy (MRM) of unilateral breast cancer. METHODS: This study involved a double-blind clinical trial that was carried out in the Affiliated Hospital of Jiaxing University on 23 September 2020. The inclusion criteria were the following: The American Society of Anesthesiologists (ASA) grade needed to be 1-2, the patients needed to be between 18 and 80 years old, and MRM needed to be proposed in our hospital. The exclusion criteria were patients with contraindications related to nerve block. Ninety patients were randomly divided into three groups receiving US-guided SAB, ESP block and rhomboid intercostal block (RIB). All groups received 20 mL 0.5% ropivacaine. Within 24 hours after the operation, the patients received an intravenous injection of tramadol 1-2 mg/kg in the surgical ward for pain relief. RESULTS: The dosage of tramadol 24 hours after the operation in the RIB (269.67 ± 48.75 mg) and ESP block groups (273.67 ± 36.90 mg) was significantly lower than that in the SAB group (314.33 ± 18.88 mg) (P < .001). There was no statistical difference in tramadol consumption between the ESP block and RIB groups within 24 hours (P = .676). The numerical rating scale (NRS) scores in the ESP block and RIB groups at 0.5, 1, 3, 6, 12, 18 and 24 hours after the operation once patients were active were significantly lower than that in the SAB group (P < .05 for all comparisons); however, the NRS scores of the RIB and ESP block groups did not differ significantly within 24 hours after surgery when patients were active. CONCLUSIONS: US-guided rhomboid intercostal block (US-RIB) and ESP block can effectively reduce the dosage of tramadol within 24 hours after MRM, and they can effectively relieve pain within 24 hours after MRM compared with SAB.

Photoinduced electron-driven proton transfer from water to an N-heterocyclic chromophore: nonadiabatic dynamics studies for pyridine-water clusters.

It has been found in recent molecular beam experiments that pyridine molecules photoexcited at 255 nm can abstract hydrogen atoms from hydrogen-bonded water molecules in pyridine-water clusters, resulting in pyridinyl-hydroxyl radical pairs. The reaction could only be detected for clusters containing at least four water molecules. To provide insight into the mechanisms of this reaction, we performed ab initio excited-state trajectory surface-hopping dynamics simulations for two pyridine-water complexes, containing one and four water molecules, respectively, using the second-order algebraic-diagrammatic-construction (ADC(2)) electronic-structure method. A computationally efficient surface-hopping algorithm based on the Landau-Zener formula has been used to evaluate the transition probability between electronic states. The formation of the pyridinyl radical via an electron-driven proton transfer (EDPT) process from water to pyridine is confirmed by the simulations. The analysis of the competing excited-state reaction mechanisms up to 500 fs reveals that adiabatic relaxation to local minima of the S1(nπ*) potential-energy surface is the dominant channel in both clusters, followed by internal conversion to the electronic ground state via so-called ring-puckering conical intersections. The efficiency of the latter contribution is weakly dependent of the size of the clusters. The EDPT reaction occurs on the fastest time scales (faster than 200 fs) with a branching ratio of several percent. It is found to be four times more efficient in the pyridine-(H2O)4 cluster than in the pyridine-H2O cluster, which is qualitatively consistent with the experimental observations. A detailed understanding of the photoinduced reaction mechanisms in complexes of N-heterocyclic chromophores with water molecules is of relevance for future systematic knowledge-based developments of optimized materials for photocatalytic water splitting with sunlight.

Ultrafast unidirectional chiral rotation in the Z-E photoisomerization of two azoheteroarene photoswitches.

Unidirectional rotation represents a very important functional feature in photochemistry, such as in the design of light-driven molecular rotary motors. Great attention has recently been devoted to the unidirectional preference of the torsional motion of azobenzene and other molecules. Azoheteroarenes offer functional advantages over their more conventional azobenzene counterparts due to the introduction of heteroaromatic rings. In this paper, the Z-E photoisomerization dynamics of two azoheteroarenes, 1,2-bis(1-methyl-1H-imidazol-2-yl)diazene and 1,2-bis(1H-imidazol-2-yl)diazene, are investigated with trajectory surface-hopping molecular dynamics at the semi-empirical OM2/MRCI level. Starting from the S1 excited state of the M-helical Z-isomer of both azoheteroarenes, more than 99% of the trajectories decay to their ground states through the M-helical conical intersections by twisting about the central N[double bond, length as m-dash]N double bond. This chiral path preference can be well understood by the energy profiles generated by the linear interpolation between the Franck-Condon geometry of the M-helical Z-isomer and the relevant S1/S0 conical intersections. The Z-E photoisomerization mechanisms of these two azoheteroarenes display a higher preference for unidirectional rotary dynamics under a chiral path than their counterpart azobenzene.

"Watching" the Dark State in Ultrafast Nonadiabatic Photoisomerization Process of a Light-Driven Molecular Rotary Motor.

Photoisomerization dynamics of a light-driven molecular rotary motor, 9-(2-methyl-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-ylidene)-9H-fluorene, is investigated with trajectory surface-hopping dynamics at the semiempirical OM2/MRCI level. The rapid population decay of the S1 excited state for the M isomer is observed, with two different decay time scales (500 fs and 1.0 ps). By weighting the contributions of fast and slow decay trajectories, the averaged lifetime of the S1 excited state is about 710 fs. The calculated quantum yield of the M-to-P photoisomerization of this molecular rotary motor is about 59.9%. After the S0 → S1 excitation, the dynamical process of electronic decay is followed by twisting about the central C═C double bond and the motion of pyramidalization at the carbon atom of the stator-axle linkage. Although two S0/S1 minimum-energy conical intersections are obtained at the OM2/MRCI level, only one conical intersection is found to be responsible for the nonadiabatic dynamics. The existence of "dark state" in the molecular rotary motor is confirmed through the simulated time-resolved fluorescence emission spectrum. Both quenching and red shift of fluorescence emission spectrum observed by Conyard et al. [ Conyard, J.; Addison, K.; Heisler, I. A.; Cnossen, A.; Browne, W. R.; Feringa, B. L.; Meech, S. R. Nat. Chem. 2012 , 4 , 547 - 551 ; Conyard, J.; Conssen, A.; Browne, W. R.; Feringa, B. L.; Meech, S. R. J. Am. Chem. Soc. 2014 , 136 , 9692 - 9700 ] are well understood. We find that this "dark state" in the molecular rotary motor is not a new electronic state, but the "dark region" with low oscillator strength on the initial S1 state.

Electronic and structural response of nanomaterials to ultrafast and ultraintense laser pulses.

The interaction of materials with ultrafast and ultraintense laser pulses is a current frontier of science both experimentally and theoretically. In this review, we briefly discuss some recent theoretical studies by the present authors with our method of semiclassical electron-radiation-ion dynamics (SERID). In particular, Zhou et al. and Jiang et al. respectively, determined the optimal duration and optimal timing for a series of femtosecond scale laser pulses to excite a specific vibrational mode in a general chemical system. A set of such modes can be used as a "fingerprint" for characterizing a particular molecule or a complex in a solid. One can therefore envision many applications, ranging from fundamental studies to detection of chemical or biological agents. Allen et al. proved that dimers are preferentially emitted during photofragmentation of C60 under an ultrafast and ultraintense laser pulse. For interactions between laser pulses and semiconductors, e.g., GaAs, Si and InSb, besides experimentally accessible optical properties--epsilon(omega) and chi(2)-Allen et al. offered many other indicators to confirm the nonthermal nature of structural changes driven by electronic excitations and occurring during the first few hundred femtoseconds. Lin et al. found that, after the application of a femtosecond laser pulse, excited electrons in materials automatically equilibrate to a Fermi-Dirac distribution within roughly 100 fs, solely because of their coupling to the nuclear motion, even though the resulting electronic temperature is one to two orders of magnitude higher than the kinetic temperature defined by the nuclear motion.

Advances in local drug delivery technologies for improved rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by an inflammatory microenvironment and cartilage erosion within the joint cavity. Currently, antirheumatic agents yield significant outcomes in RA treatment. However, their systemic administration is limited by inadequate drug retention in lesion areas and non-specific tissue distribution, reducing efficacy and increasing risks such as infection due to systemic immunosuppression. Development in local drug delivery technologies, such as nanostructure-based and scaffold-assisted delivery platforms, facilitate enhanced drug accumulation at the target site, controlled drug release, extended duration of the drug action, reduced both dosage and administration frequency, and ultimately improve therapeutic outcomes with minimized damage to healthy tissues. In this review, we introduced pathogenesis and clinically used therapeutic agents for RA, comprehensively summarized locally administered nanostructure-based and scaffold-assisted drug delivery systems, aiming at improving the therapeutic efficiency of RA by alleviating the inflammatory response, preventing bone erosion and promoting cartilage regeneration. In addition, the challenges and future prospects of local delivery for clinical translation in RA are discussed.

STING Agonist-Loaded Nanoparticles Promotes Positive Regulation of Type I Interferon-Dependent Radioimmunotherapy in Rectal Cancer.

Hypoxia-associated radioresistance in rectal cancer (RC) has severely hampered the response to radioimmunotherapy (iRT), necessitating innovative strategies to enhance RC radiosensitivity and improve iRT efficacy. Here, a catalytic radiosensitizer, DMPtNPS, and a STING agonist, cGAMP, are integrated to overcome RC radioresistance and enhance iRT. DMPtNPS promotes efficient X-ray energy transfer to generate reactive oxygen species, while alleviating hypoxia within tumors, thereby increasing radiosensitivity. Mechanistically, the transcriptomic and immunoassay analysis reveal that the combination of DMPtNPS and RT provokes bidirectional regulatory effects on the immune response, which may potentially reduce the antitumor efficacy. To mitigate this, cGAMP is loaded into DMPtNPS to reverse the negative impact of DMPtNPS and RT on the tumor immune microenvironment (TiME) through the type I interferon-dependent pathway, which promotes cancer immunotherapy. In a bilateral tumor model, the combination treatment of RT, DMPtNPS@cGAMP, and αPD-1 demonstrates a durable complete response at the primary site and enhanced abscopal effect at the distant site. This study highlights the critical role of incorporating catalytic radiosensitizers and STING agonists into the iRT approach for RC.

Systemic delivery of glycosylated-PEG-masked oncolytic virus enhances targeting of antitumor immuno-virotherapy and modulates T and NK cell infiltration.

Rationale: Immuno-virotherapy has emerged as a promising approach for cancer treatment, as it directly and cytotoxically eliminates tumors with systemic immune stimulation. However, the clinical efficacy of this approach remains limited by inappropriate delivery routes, robust antiviral responses, and the tumor immunosuppressive microenvironment. Methods: To address these challenges, we propose a surface engineering strategy that masks oncolytic herpes simplex virus (oHSV) with a galactose-polyethylene-glycol (PEG) polymer chain to minimize host antiviral responses and selectively targets tumors by limiting exposure to circulation upon systemic administration. We evaluated the antitumor efficacy of glycosylated-PEG-oHSV by examining tumor growth in animal models and analyzing tumor-infiltrating CD8+T cells and NK cells in the tumor microenvironment (TME). To assess the neutralizing antibody levels after systemic administration of glycosylated-PEG-oHSV, we utilized a mouse model and measured oHSV-specific IgG. Results: We demonstrate that the glycosylated-PEG modified oHSV does not affect the replication of oHSV yet exhibits high specificity to the asialoglycoprotein receptor (ASGPR) overexpressed in hepatocellular carcinoma cells. This results in selectively targeting cancer cells and deep penetration into tumors while avoiding spreading into the brain. Our approach also effectively reduces oHSV-specific neutralizing antibody levels to mitigate host antiviral immune response. Notably, our glycosylated-PEG-oHSV alleviates the immunosuppressive microenvironment within tumors by reducing regulatory T cells, augmenting the infiltration of activated CD8+T cells and NK cells with increasing release of anti-tumor cytokines, to impede tumor progression. Conclusion: Our findings offer a widely applicable and universal strategy to enhance cancer immuno-virotherapy through systemic administration of non-genetically engineered oncolytic viruses. This approach has the potential to overcome the limitations of current immune-virotherapy strategies and may improve clinical outcomes for cancer patients.

Methylglyoxal from gut microbes boosts radiosensitivity and radioimmunotherapy in rectal cancer by triggering endoplasmic reticulum stress and cGAS-STING activation.

BACKGROUND: Preoperative radiation therapy (preRT) is a fundamental aspect of neoadjuvant treatment for rectal cancer (RC), but the response to this treatment remains unsatisfactory. The combination of radiation therapy (RT) and immunotherapy (iRT) presents a promising approach to cancer treatment, though the underlying mechanisms are not yet fully understood. The gut microbiota may influence the response to RT and immunotherapy. Therefore, we aimed to identify the metabolism of gut microbiota to reverse radioresistance and enhance the efficacy of iRT. METHODS: Fecal and serum samples were prospectively collected from patients with locally advanced rectal cancer (LARC) who had undergone pre-RT treatment. Candidate gut microbiome-derived metabolites linked with radiosensitization were screened using 16s rRNA gene sequencing and ultrahigh-performance liquid chromatography-mass coupled with mass spectrometry. In vitro and in vivo studies were conducted to assess the radiosensitizing effects of the metabolites including the syngeneic CT26 tumor model and HCT116 xenograft tumor model, transcriptomics and immunofluorescence. The CT26 abscopal effect modeling was employed to evaluate the combined effects of metabolites on iRT. RESULTS: We initially discovered the gut microbiota-associated metabolite, methylglyoxal (MG), which accurately predicts the response to preRT (Area Under Curve (AUC) value of 0.856) among patients with LARC. Subsequently, we observed that MG amplifies the RT response in RC by stimulating intracellular reactive oxygen species (ROS) and reducing hypoxia in the tumor in vitro and in vivo. Additionally, our study demonstrated that MG amplifies the RT-induced activation of the cyclic guanosine monophosphate AMP synthase-stimulator of interferon genes pathway by elevating DNA double-strand breaks. Moreover, it facilitates immunogenic cell death generated by ROS-mediated endoplasmic reticulum stress, consequently leading to an increase in CD8+ T and natural killer cells infiltrated in the tumor immune microenvironment. Lastly, we discovered that the combination of anti-programmed cell death protein 1 (anti-PD1) therapy produced long-lasting complete responses in all irradiated tumor sites and half of the non-irradiated ones. CONCLUSIONS: Our research indicates that MG shows promise as a radiosensitizer and immunomodulator for RC. Furthermore, we propose that combining MG with iRT has great potential for clinical practice.

Caveolin-mediated cytosolic delivery of spike nanoparticle enhances antitumor immunity of neoantigen vaccine for hepatocellular carcinoma.

Rationale: Although neoantigen-based cancer vaccines have shown promise in various solid tumors, limited immune responses and clinical outcomes have been reported in patients with advanced disease. Cytosolic transport of neoantigen and adjuvant is required for the activation of intracellular Toll-like receptors (TLRs) and cross-presentation to prime neoantigen-specific CD8+T cells but remains a significant challenge. Methods: In this study, we aimed to develop a virus-like silicon vaccine (V-scVLPs) with a unique spike topological structure, capable of efficiently co-delivering a hepatocellular carcinoma (HCC)-specific neoantigen and a TLR9 agonist to dendritic cells (DCs) to induce a robust CD8+T cell response to prevent orthotopic tumor growth. We evaluated the antitumor efficacy of V-scVLPs by examining tumor growth and survival time in animal models, as well as analyzing tumor-infiltrating CD8+T cells and cytokine responses in the tumor microenvironment (TME). To evaluate the synergistic efficacy of V-scVLPs in combination with α-TIM-3 in HCC, we used an orthotopic HCC mouse model, a lung metastasis model, and a tumor rechallenge model after hepatectomy. Results: We found that V-scVLPs can efficiently co-deliver the hepatocellular carcinoma (HCC)-specific neoantigen and the TLR9 agonist to DCs via caveolin-mediated endocytosis. This advanced delivery strategy results in efficient lymph node draining of V-scVLPs to activate lymphoid DC maturation for promoting robust CD8+T cells and central memory T cells responses, which effectively prevents orthotopic HCC tumor growth. However, in the established orthotopic liver tumor models, the inhibitory receptor of TIM-3 was significantly upregulated in tumor-infiltrating CD8+T cells after immunization with V-scVLPs. Blocking the TIM-3 signaling further restored the antitumor activity of V-scVLPs-induced CD8+T cells, reduced the proportion of regulatory T cells, and increased the levels of cytokines to alter the tumor microenvironment to efficiently suppress established orthotopic HCC tumor growth, and inhibit lung metastasis as well as recurrence after hepatectomy. Conclusion: Overall, the developed novel spike nanoparticles with efficient neoantigen and adjuvant intracellular delivery capability holds great promise for future clinical translation to improve HCC immunotherapy.

Continuous Rhomboid Intercostal Block for Thoracoscopic Postoperative Analgesia.

BACKGROUND: Rhomboid intercostal block is a type of plane block used for postoperative analgesia after video-assisted thoracoscopic surgery. This prospective randomized controlled trial was conducted to investigate the effects of ultrasound-guided continuous rhomboid intercostal block (CRIB) on the global Quality of Recovery (QoR-40) scores and postoperative analgesia after video-assisted thoracoscopic surgery. METHODS: A total of 66 adult patients scheduled for elective unilateral video-assisted thoracoscopic surgery were randomly allocated to group C and group CRIB. In group C, patients were administered patient-controlled intravenous analgesia with sufentanil after operation. Patients in group CRIB received patient-controlled analgesia with ropivacaine CRIB. All patients completed the QoR-40 test during the preoperative evaluation and again 24 hours after the operation. Information on 48-hour postoperative pain and adverse events was recorded. RESULTS: The QoR-40 scores of group C were significantly lower than the scores of group CRIB (155.4 ± 6.1 vs 172.6 ± 6.3; P < .001), with a mean difference of -17.2 (95% CI, -20.4 to -13.9) 24 hours after operation. The postoperative numeric rating scale scores in group CRIB at 6, 12, 18, and 24 hours after the surgical procedure, when patients were at rest, were significantly lower than the scores in group C (all P < .05). The postoperative numeric rating scale scores in group CRIB at 1, 3, 6, 12, 18, 24, and 36 hours after surgical procedure, when patients were moving, were significantly lower than the scores in group C (all P < .05). CONCLUSIONS: In patients who underwent video-assisted thoracoscopic surgery, CRIB led to improved quality of recovery and postoperative analgesia.

Comparative studies of the trans-cis photoisomerizations of azobenzene and a bridged azobenzene.

Using density-functional-based molecular dynamics simulations, we have performed comparative studies of the trans-cis isomerizations of azobenzene and bridged azobenzene (B-Ab) 5,6-dihydrodibenzo[c,g][1,2]diazocine induced by nπ* electronic excitation. The quantum yields found in our calculations, 45% for the bridged azobenzene versus 25% for azobenzene, are consistent with the experiment. Both isomerization processes involve two steps: (1) Starting from the trans structure, each molecule moves on its S(1) excited-state potential energy surface, via rotation around the NN bond, to an avoided crossing near the S(1)/S(0) conical intersection, where de-excitation occurs. (2) Subsequently, in the electronic ground state, there is further rotation around the NN bond, accompanied by twisting of the phenyl rings around their CN bonds, until the cis geometry is achieved. Because of its lower symmetry and smaller initial CNNC dihedral angle, the bridged azobenzene has a much shorter lifetime for the S(1) excited state, about 30 fs, as compared to about 400 fs for azobenzene. However, we find that the complete isomerizations have approximately the same time scales. Although the bridging feature in trans-B-Ab does not hinder rotation around the NN bond in step 1, it makes twisting of the two phenyl rings around the CN bonds much slower in step 2.

Advances in the phase separation-organized membraneless organelles in cells: a narrative review.

Membraneless organelles (MLOs) are micro-compartments that lack delimiting membranes, concentrating several macro-molecules with a high local concentration in eukaryotic cells. Recent studies have shown that MLOs have pivotal roles in multiple biological processes, including gene transcription, RNA metabolism, translation, protein modification, and signal transduction. These biological processes in cells have essential functions in many diseases, such as cancer, neurodegenerative diseases, and virus-related diseases. The liquid-liquid phase separation (LLPS) microenvironment within cells is thought to be the driving force for initiating the formation of micro-compartments with a liquid-like property, becoming an important organizing principle for MLOs to mediate organism responses. In this review, we comprehensively elucidated the formation of these MLOs and the relationship between biological functions and associated diseases. The mechanisms underlying the influence of protein concentration and valency on phase separation in cells are also discussed. MLOs undergoing the LLPS process have diverse functions, including stimulation of some adaptive and reversible responses to alter the transcriptional or translational processes, regulation of the concentrations of biomolecules in living cells, and maintenance of cell morphogenesis. Finally, we highlight that the development of this field could pave the way for developing novel therapeutic strategies for the treatment of LLPS-related diseases based on the understanding of phase separation in the coming years.