Immune checkpoint inhibitors: breakthroughs in cancer treatment.

Over the past two decades, immunotherapies have increasingly been considered as first-line treatments for most cancers. One such treatment is immune checkpoint blockade (ICB), which has demonstrated promising results against various solid tumors in clinical trials. Monoclonal antibodies (mAbs) are currently available as immune checkpoint inhibitors (ICIs). These ICIs target specific immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Clinical trial results strongly support the feasibility of this immunotherapeutic approach. However, a substantial proportion of patients with cancer develop resistance or tolerance to treatment, owing to tumor immune evasion mechanisms that counteract the host immune response. Consequently, substantial research focus has been aimed at identifying additional ICIs or synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1, anti-programmed cell death ligand 1 (anti-PD-L1), and anti-CTLA-4 treatments. Recently, several immune checkpoint molecular targets have been identified, such as T cell immunoreceptor with Ig and ITIM domains (TIGIT), mucin domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B and T lymphocyte attenuator (BTLA), and signal-regulatory protein α (SIRPα). Functional mAbs targeting these molecules are under development. CTLA-4, PD-1/PD-L1, and other recently discovered immune checkpoint proteins with distinct structures are at the forefront of research. This review discusses these structures, as well as clinical progress in mAbs targeting these immune checkpoint molecules and their potential applications.

Phytochemical Profiling and Biological Activities of Pericarps and Seeds Reveal the Controversy on "Enucleation" or "Nucleus-Retaining" of Cornus officinalis Fruits.

The fruits of Cornus officinalis are used not only as a popular health food to tonify the liver and kidney, but also as staple materials to treat dementia and other age-related diseases. The pharmacological function of C. officinalis fruits with or without seeds is controversial for treating some symptoms in a few herbal prescriptions. However, the related metabolite and pharmacological information between its pericarps and seeds are largely deficient. Here, comparative metabolomics analysis between C. officinalis pericarps and seeds were conducted using an ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry, and therapeutic effects were also evaluated using several in vitro bioactivity arrays (antioxidant activity, α-glucosidase and cholinesterase inhibitory activities, and cell inhibitory properties). A total of 499 secondary metabolites were identified. Thereinto, 77 metabolites were determined as key differential metabolites between C. officinalis pericarps and seeds, and the flavonoid biosynthesis pathway was identified as the most significantly different pathway. Further, 47 metabolites were determined as potential bioactive constituents. In summary, C. officinalis seeds, which demonstrated higher contents in total phenolics, stronger in vitro antioxidant activities, better α-glucosidase and butyrylcholinesterase inhibitory activities, and stronger anticancer activities, exhibited considerable potential for food and health fields. This work provided insight into the metabolites and bioactivities of C. officinalis pericarps and seeds, contributing to their precise development and utilization.

Safety and feasibility of anti-CD19 CAR T cells expressing inducible IL-7 and CCL19 in patients with relapsed or refractory large B-cell lymphoma.

Although CD19-specific chimeric antigen receptor (CAR) T cells are curative for patients with relapsed or refractory large B-cell lymphoma (R/R LBCL), disease relapse with tumor antigen-positive remains a challenge. Cytokine/chemokine-expressing CAR-T cells could overcome a suppressive milieu, but the clinical safety and efficacy of this CAR-T therapy remain unclear. Here we report the preclinical development of CD19-specific CAR-T cells capable of expressing interleukin (IL)-7 and chemokine (C-C motif) ligand (CCL)-19 upon CD19 engagement (referred to as 7 × 19 CAR-T cells) and results from a phase 1 and expansion phase trial of 7 × 19 CAR-T cell therapy in patients with R/R LBCL (NCT03258047). In dose-escalation phase, there were no dose-limiting toxicities observed. 39 patients with R/R LBCL received 7 × 19 CAR-T with doses ranged from 0.5 × 106-4.0 × 106 cells per kg body weight. Grade 3 cytokine release syndrome occurred in 5 (12.8%) patients and ≥ grade 3 neurotoxicity in 4 (10.3%) patients. The overall response rate at 3 months post-single infusion was 79.5% (complete remission, 56.4%; partial response, 23.1%). With a median follow-up of 32 months, the median progression-free survival was 13 months, and median overall survival was not reached, with an estimated rate of 53.8% (95% CI, 40.3% to 72.0%) at two years. Together, these long-term follow-up data from the multicenter clinical study suggest that 7 × 19 CAR-T cells can induce durable responses with a median overall survival of greater than 2 years, and have a manageable safety profile in patients with R/R LBCL.

2D TiS2-Nanosheet-Coated Concave Gold Arrays with Triple-Coupled Resonances as Sensitive SERS Substrates.

Herein, a hybrid substrate for surface-enhanced Raman scattering (SERS) is fabricated, which couples localized surface plasmon resonance (LSPR), charge transfer (CT) resonance, and molecular resonance. Exfoliated 2D TiS2 nanosheets with semimetallic properties accelerate the CT with the tested analytes, inducing a remarkable chemical mechanism enhancement. In addition, the LSPR effect is coupled with a concave gold array located underneath the thin TiS2 nanosheet, providing a strong electromagnetic enhancement. The concave gold array is prepared by etching silicone nanospheres assembled on larger polystyrene nanospheres, followed by depositing a gold layer. The LSPR intensity near the gold layer can be adjusted by changing the layer thickness to couple the molecular and CT resonances, in order to maximize the SERS enhancement. The best SERS performance is recorded on TiS2-nanosheet-coated plasmonic substrates, with a detectable methylene blue concentration down to 10-13 m and an enhancement factor of 2.1 × 109 and this concentration is several orders of magnitude lower than that of the TiS2 nanosheet (10-11 m) and plasmonic substrates (10-9 m). The present hybrid substrate with triple-coupled resonance further shows significant advantages in the label-free monitoring of curcumin (a widely applied drug for treating multiple cancers and inflammations) in serum and urine.

Mycobacterium tuberculosis Mce2D protein blocks M1 polarization in macrophages by inhibiting the ERK signaling pathway.

Macrophages play a pivotal role in controlling Mycobacterium infection, and the pathogen thrives in the event of immune evasion and immunosuppression of macrophages. Mammalian cell entry proteins (Mce) are required for Mycobacterium tuberculosis (M. tb) growth and the host cell's initial phagocytosis and cytokine response. Mce2D protein is one of a family of proteins that infect M. tb; however, the function and mechanism of action remain unclear. In this study, we constructed the Mce2D knockout strain using Mycobacterium smegmatis to study the function of Mce2D in the infection of macrophages. The results indicated that compared to the knockout strain, the release of proinflammatory cytokines (TNF-α and IL-1ß) reduced when WT strain infected the macrophages. Moreover, Mce2D boosted the metabolism of oxidized fatty acids, increased the energy supply of TCA, and lowered the glycolysis of glucose in macrophages after bacterial infection, all of which prevented the polarization of macrophages to M1, which was driven by the fact that Mce2D blocked ERK2 phosphorylation by interacting with ERK2 through its DEF motif. This, in turn, promoted nuclear translocation of HIF-1α, allowing signal accumulation, which increased the HIF-1α transcription levels. Finally, the mouse infection experiment showed that Mce2D caused blockage of M1 polarization of alveolar macrophages, resulting in reduced bactericidal activity and antigen presentation, weakening Th1 cell-mediated immune response and helping bacteria escape the immune system. Our results reveal that Mce2D causes immune escape by blocking M1 polarization in macrophages, providing potential targets for the rational design of therapies against M. tb infection.

Structural insight into the constitutive activity of human orphan receptor GPR12.

G protein-coupled receptor 12 (GPR12) is an orphan G protein-coupled receptor that is highly expressed in the thalamus of the brain and plays a vital role in driving thalamocortical functions in short-term memory. GPR12 performs high constitutive activity and couples with Gs, increasing the intracellular cyclic adenosine monophosphate (cAMP) level when it is expressed. However, exploitation for drug development is limited since it is unclear how GPR12 initiates self-activation and signal transduction, and whether it can be modulated by endogenous or synthetic ligands. Here, we report the cryo-electron microscopy structure of the GPR12-Gs complex in the absence of agonists. Our structure reveals the key determinants for the intrinsically high basal activity of GPR12, including extracellular loop 2 partially occupying the orthosteric binding pocket, a tight-packed TM1 and TM7, and unique activation-related residues in TM6 and TM7. Together with mutagenesis data, this study will improve our understanding of the function and self-activation of the orphan receptor GPR12, enable the identification of endogenous ligands, and guide drug discovery efforts that target GPR12.

Hsa_circ_0007460 affects the survival of intracellular Mycobacterium tuberculosis by regulating autophagy and apoptosis of macrophages.

Circular RNA (circRNA) is a category of non-coding RNAs characterized by the absence of a 5'-cap and 3'-poly(A) tail, and participates in the physiological processes of various human diseases. Nonetheless, the diagnostic and functional significance of circRNAs in active pulmonary tuberculosis (ATB) remains uncertain. Consequently, the purpose of this study is to investigate whether hsa_circ_0007460 can be employed as a potential diagnostic biomarker in ATB patients and explore its function. The result of real-time quantitative fluorescent PCR (RT-qPCR) validated a notable increase in the expression of hsa_circ_0007460 in the peripheral blood of 32 ATB patients, as well as in THP-1 human macrophages infected with Bacillus Calmette Guerin (BCG) which is an attenuated strain of Mycobacterium bovis. Additionally, the receiver operating curve (ROC) illustrated that the area under the ROC curve (AUC), sensitivity and specificity were 0.7474, 76.67%, and 78.13% respectively. RNase R, Actinomycin D and other experiments confirmed that hsa_circ_0007460 was stabler than its linear mRNA, indicating that hsa_circ_0007460 has potential as a diagnostic biomarker of ATB. Furthermore, Western blot (WB), Cell Counting Kit-8 (CCK-8), plate counting, and immunofluorescence experiments revealed that hsa_circ_0007460 could regulate apoptosis and autophagy of macrophages. The downstream miRNAs and mRNAs were subsequently predicted using bioinformatics, and the hsa circ 0007460/hsa-miR-3127-5p/PATZ1 axis was built. These above results suggest that hsa_circ_0007460 is substantially up-regulated in the peripheral blood of patients with ATB and can be utilized as a potential diagnostic biomarker. In addition, hsa_circ_0007460 can promote apoptosis of macrophages and inhibit autophagy of macrophages, thereby promoting the survival of BCG.

Cryo-EM structure of the human adenosine A2B receptor-Gs signaling complex.

The human adenosine A2B receptor (A2BR) is a class A G protein-coupled receptor that is involved in several major physiological and pathological processes throughout the body. A2BR recognizes its ligands adenosine and NECA with relatively low affinity, but the detailed mechanism for its ligand recognition and signaling is still elusive. Here, we present two structures determined by cryo-electron microscopy of A2BR bound to its agonists NECA and BAY60-6583, each coupled to an engineered Gs protein. The structures reveal conserved orthosteric binding pockets with subtle differences, whereas the selectivity or specificity can mainly be attributed to regions extended from the orthosteric pocket. We also found that BAY60-6583 occupies a secondary pocket, where residues V2506.51 and N2737.36 were two key determinants for its selectivity against A2BR. This study offers a better understanding of ligand selectivity for the adenosine receptor family and provides a structural template for further development of A2BR ligands for related diseases.

Mussel-Inspired Clickable Antibacterial Peptide Coating on Ureteral Stents for Encrustation Prevention.

Long-term indwelling catheters or stents often cause complications like infection, encrustation, hematuria, pain, and so on. The source of these problems is bacteria, which can form biofilms on the stents to reduce antibiotic sensitivity and produce urease to form encrustation by increasing the urine pH. Urinary tract infection (UTI) can aggravate the body damage and even seriously endanger lives, and the encrustation will block the stents, which can cause hydronephrosis and renal function damage. Therefore, the prevention of UTI and encrustation represents a great challenge in clinical ureteral stent uses. In this work, a clickable mussel-inspired peptide and antimicrobial peptide (AMP) were used to functionalize the commercial stents' surfaces to inhibit long-term infection and encrustation caused by bacteria. Copper (Cu) ions were used to coordinate the mussel-inspired peptide to improve the stability. The AMP with an azido group was clicked to the mussel-inspired Cu-coordinated peptide coating through click chemistry. The bio-inspired antibacterial coating was constructed with excellent stability, bactericidal properties, and improved biological compatibility. In in vitro and in vivo experiments, it was further found that the coating showed bactericidal and encrustation reduction abilities. This study thus developed an effective, safe, and stable AMP coating on urinary stents/catheters capable of long-term antibacterial and encrustation inhibition.

Implications of Persistent HPV52 and HPV58 Positivity for the Management of Cervical Lesions.

Objective: This study aimed to compare the variability of HPV16/18/52/58 subtype infections in patients with different cervical lesions, to explore the guiding significance of persistent positive HPV subtypes 52 and 58 in the stratified management of cervical lesions, and to determine the appropriate management model. Method: This study was conducted through a retrospective analysis of 244,218 patients who underwent HPV testing at the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University from September 2014 to December 2020 to examine the distribution of different types of HPV infection. From March 2015 to September 2017, 3,014 patients with known HPV underwent colposcopy to analyze high-risk HPV infection for different cervical lesions. Meanwhile, from September 2014 to December 2020, 1,616 patients positive for HPV16/18/52/58 alone with normal TCT who underwent colposcopy in our hospital were retrospectively analyzed for the occurrence of cervical and vulvovaginal lesions, with colposcopic biopsy pathology results serving as the gold standard for statistical analysis. Result: Analysis of 244,218 patients who had HPV tested revealed that the top 3 high-risk HPV types were HPV52, HPV58, and HPV16. Further analysis of 3,014 patients showed that 78.04% of patients referred for colposcopy had HPV16/18/52/58 alone. Among high-grade squamous intraepithelial lesions (HSIL) and cervical cancer, the most common is HPV16, followed by HPV58 and then HPV52 (p < 0.05). A total of 1,616 patients with normal TCT who were referred for colposcopy due to HPV16/18/52/58 infection were further analyzed. Based on pathological findings in lesions of HSIL and CC, HPV16 is the most common, followed by HPV58 and then HPV18 (p < 0.05). In the 1,616 patients analyzed, high-grade vulvovaginal lesions were detected, with HPV58 being the most common, followed by HPV16 and then HPV52 (p < 0.05). Conclusion: 1. In patients with positive HPV58 alone and normal TCT, the indications for colposcopy may be relaxed, with particular attention paid to the possibility of vulvar and vaginal lesions.2. Patients with a positive HPV type 52 alone and normal TCT may be considered for a follow-up review and, if necessary, a colposcopy.3. The development of a more suitable HPV vaccine for the Asian population, such as HPV16/18/52/58, may better protect women's health.

A Facile Temperature-Controlled "Green" Method to Prepare Multi-kinds of High-Quality Alumina Hydrates via a Ga-In-Sn-Alloyed Aluminum-Water Interface Reaction.

The Al sheets alloyed by Ga-In-Sn are generally utilized to react with water for H2 production, while the valuable byproducts, i.e., alumina hydrates, have not been fully studied. In this work, through controlling the reaction temperature, three types of alumina hydrates, bayerite (40 °C), pseudo-boehmite (PB) (70-120 °C), and boehmite (130-160 °C), were successfully prepared based on a series of interface reactions and structural transformations. These alumina hydrates and their calcined products (alumina) possess high purity with a total impurity element content of <450 ppm, especially an extremely low sodium content (<21 ppm) and iron content (<52 ppm). Significantly, the obtained pseudo-boehmite displays excellent surface properties (specific surface area: 332.7 m2 g-1, pore volume: 0.3 cm3 g-1, and pore diameter: 3.6 nm), competitive to the current commercial SB powder by Sasol. This work not only deepens the understanding of the byproducts in a Ga-In-Sn-alloyed Al-water reaction but also establishes a facile "green" method oriented to industrial applications, which is promising for the linkage benefits of the hydrogen production industry.

Realization of an ideal Weyl semimetal band in a quantum gas with 3D spin-orbit coupling.

Weyl semimetals are three-dimensional (3D) gapless topological phases with Weyl cones in the bulk band. According to lattice theory, Weyl cones must come in pairs, with the minimum number of cones being two. A semimetal with only two Weyl cones is an ideal Weyl semimetal (IWSM). Here we report the experimental realization of an IWSM band by engineering 3D spin-orbit coupling for ultracold atoms. The topological Weyl points are clearly measured via the virtual slicing imaging technique in equilibrium and are further resolved in the quench dynamics. The realization of an IWSM band opens an avenue to investigate various exotic phenomena that are difficult to access in solids.

WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity.

Cytoskeletal regulatory protein dysfunction has been etiologically linked to inherited diseases associated with immunodeficiency and autoimmunity, but the mechanisms involved are incompletely understood. Here, we show that conditional Wave2 ablation in T cells causes severe autoimmunity associated with increased mammalian target of rapamycin (mTOR) activation and metabolic reprogramming that engender spontaneous activation and accelerated differentiation of peripheral T cells. These mice also manifest diminished antigen-specific T cell responses associated with increased inhibitory receptor expression, dysregulated mitochondrial function, and reduced cell survival upon activation. Mechanistically, WAVE2 directly bound mTOR and inhibited its activation by impeding mTOR interactions with RAPTOR (regulatory-associated protein of mTOR) and RICTOR (rapamycin-insensitive companion of mTOR). Both the T cell defects and immunodysregulatory disease were ameliorated by pharmacological mTOR inhibitors. Thus, WAVE2 restraint of mTOR activation is an absolute requirement for maintaining the T cell homeostasis supporting adaptive immune responses and preventing autoimmunity.

Nucleoside-based fluorescent carbon dots for discrimination of metal ions.

Carbon dots (Cdots) play an important role in many biological and chemical applications. To prepare strongly fluorescent Cdots, the starting material should contain nitrogen in addition to carbon. Nucleobases are nitrogen rich with interesting metal binding properties. In this work, we prepared a series of Cdots with citrate as the carbon source, and ethylenediamine, adenosine, cytidine, thymidine or guanosine as the respective nitrogen sources. The resulting Cdots were all fluorescent with the ethylenediamine sample being the most strongly emissive. These Cdots were then tested for their metal sensitivity and all tested metal ions can quench their fluorescence. The fluorescence of the G-Cdots prepared with guanosine was quenched most efficiently by Cu2+, while the Cdots prepared with ethylenediamine were more sensitive to Hg2+. With the differential quenching by different metal ions, we prepared a sensor array to discriminate multiple metal ions, and quantified Cu2+ and Hg2+ at the same time. Our work has expanded the range of starting materials for preparing Cdots and showed that by tuning the precursor composition, Cdots with different optical and metal binding properties can be obtained, which is useful in constructing a sensing platform for a large number of metal ions.

Preparation of a new high-efficiency resin deodorant from coal gasification fine slag and its application in the removal of volatile organic compounds in polypropylene composites.

Deodorizing materials are often restricted from large-scale industrial production due to the high preparation cost. By utilizing the simple acid leaching technology, this study made use of the coal gasification fine slag (FS) as raw material to prepare a cost effective FS-based deodorant (FSD) with a specific surface area of 393 m2 g-1 and a pore volume of 0.405 cm3 g-1. The propane adsorption test on FSD showed the maximum adsorption capacity to be as high as 121.61 mg g-1 at 273 K. The partition coefficient values at 10% and 100% breakthrough (BT) for FSD to adsorb propane were 1.5 × 10-3 and 3.2 × 10-4 mol kg-1 Pa-1, respectively. Furthermore, the FSD was applied in the removal of volatile organic compounds (VOCs) pollutants from polypropylene resin (PP). It showed that the deodorizing effect of the FSD was nearly three times as good as the commonly used zeolite deodorants, which was able to decrease 50 percent of the VOCs volatilization amount in PP resin. Moreover, the FSD can better strengthen the mechanical properties of PP resin. This work provides a new method for the industrial production of deodorants as well as a new direction for the recycle of coal gasification wastes.

Synthetic dissipation and cascade fluxes in a turbulent quantum gas.

Scale-invariant fluxes are the defining property of turbulent cascades, but their direct measurement is a challenging experimental problem. Here we perform such a measurement for a direct energy cascade in a turbulent quantum gas. Using a time-periodic force, we inject energy at a large length scale and generate a cascade in a uniformly trapped three-dimensional Bose gas. The adjustable trap depth provides a high-momentum cutoff k D, which realizes a synthetic dissipation scale. This gives us direct access to the particle flux across a momentum shell of radius k D, and the tunability of k D allows for a clear demonstration of the zeroth law of turbulence. Moreover, our time-resolved measurements give unique access to the pre-steady-state dynamics, when the cascade front propagates in momentum space.

Design, Synthesis, and Structure-Activity Relationship of 7-Propanamide Benzoxaboroles as Potent Anticancer Agents.

Benzoxaboroles, as a novel class of bioactive molecules with unique physicochemical properties, have been shown to possess excellent antimicrobial activities with tavaborole approved in 2014 as an antifungal drug. Although urgently needed, the investigation of benzoxaboroles as anticancer agents has been lacking so far. In this study, we report the design, synthesis, and anticancer structure-activity relationship of a series of 7-propanamide benzoxaboroles. Compounds 103 and 115 showed potent activity against ovarian cancer cells with IC50 values of 33 and 21 nM, respectively. Apoptosis was induced by these compounds and colony formation was effectively inhibited. Furthermore, they also showed excellent efficacy in ovarian tumor xenograft mouse model.

Synergistic Efficacy of the Demethylation Agent Decitabine in Combination With the Protease Inhibitor Bortezomib for Treating Multiple Myeloma Through the Wnt/ß-Catenin Pathway.

Multiple myeloma (MM) is a hematopoietic malignancy characterized by the clonal proliferation of antibody-secreting plasma cells. Bortezomib (BZM), the first FDA-approved proteasome inhibitor, has significant antimyeloma activity and prolongs the median survival of MM patients. However, MM remains incurable predominantly due to acquired drug resistance and disease relapse. ß-Catenin, a key effector protein in the canonical Wnt signaling pathway, has been implicated in regulating myeloma cell sensitivity to BZM. Decitabine (DAC) is an epigenetic modulating agent that induces tumor suppressor gene reexpression based on its gene-specific DNA hypomethylation. DAC has been implicated in modulating Wnt/ß-catenin signaling by promoting the demethylation of the Wnt/ß-catenin antagonists sFRP and DKK. In this study, we report the effects of single reagent DAC therapy and DAC combined with BZM on ß-catenin accumulation, myeloma cell survival, apoptosis, and treatment sensitivity. Our study proved that DAC demethylated and induced the reexpression of the Wnt antagonists sFRP3 and DKK1. DAC also reduced GSK3ß (Ser9) phosphorylation and decreased ß-catenin accumulation in the nucleus, which were induced by BZM. Thus, the transcription of cyclin D1, c-Myc, and LEF/TCF was reduced, which synergistically inhibited cell proliferation, enhanced BZM-induced apoptosis, and promoted BZM-induced cell cycle arrest in myeloma cells. In summary, these results indicated that DAC could synergistically enhance myeloma cell sensitivity to BZM at least partly by regulating Wnt/ß-catenin signaling. Our results can be used to optimize therapeutic regimens for MM.

A Novel Vehicle Detection Method Based on the Fusion of Radio Received Signal Strength and Geomagnetism.

A geomagnetic signal blind zone exists between the front and rear axle of high-chassis vehicle such as trucks and buses, which leads to multiple-detection problem in detecting those vehicles running at low speed on roads or error-detection problem in the case of the stopping position of the vehicle is not standard when waiting for the traffic light to change. In order to improve the detection accuracy of any type of vehicle running at any speed, a novel two-sensors data fusion vehicle detection method through combining received signal strength from radio stations with geomagnetism around vehicles is designed and verified in the paper. Experimental results show that the accuracy of our proposed method can reach 95.4% and traditional single magnetism-based detection method was only 83.4% in the detection of high-chassis vehicles.