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Tumor cells form immune escape and subsequently obtain unlimited proliferation ability due to the abnormal immune surveillance mediated by immune checkpoints. Among this class of immune checkpoints, PD-1/PD-L1 was recognized as an anticancer drug target for many years, and so far, several monoclonal antibodies have achieved encouraging outcome in cancer treatment by targeting the PD-1/PD-L1 signaling pathway. Due to the inherent limitations of antibodies, the development of small molecule inhibitors based on PD-1/PD-L1 signaling pathway is gradually reviving in decades. In this review, we summarized a number of small molecule inhibitors based on three different therapeutic approaches interfering PD-1/PD-L1 signaling pathway: (1) blocking direct interaction between PD-1 and PD-L1; (2) inhibiting transcription and translation of PD-L1; and (3) promoting degradation of PD-L1 protein. The development of these small molecule inhibitors opens a new avenue for tumor immunotherapy based on PD-1/PD-L1 signaling pathway.

Since multidrug-resistant tuberculosis (MDR-TB) is a significant public health problem worldwide, identifying associated risk factors is critical for developing appropriate control strategies. A systematic review and meta-analysis was conducted for identifying factors independently predicting MDR-TB. The random-effects model was used to determine pooled odds ratios (ORs) and respective 95% confidence intervals (CIs) for the related factors. Of the 2301 retrieved reports, 28 studies were analyzed, assessing 3152 MDR-TB and 52715 DS-TB cases. Totally 22 related factors were analyzed. The pooled ORs were 1.478 (95%CI 1.077-2.028) for positive sputum AFB smear, 1.716 (95%CI 1.149-2.564) for lung cavity, 6.078 (95%CI 2.903-12.725) for previous TB disease and 5.427 (95%CI 3.469-8.490) for a history of anti-TB therapy. All Z test p values were below 0.05, indicating these parameters were significantly associated with MDR-TB. Positive sputum AFB smear, lung cavity, previously diagnosed TB and a history of anti-TB therapy are significant risk factors for MDR-TB, which are independent of the clinical setting worldwide. Increased attention should be paid to cases with such parameters to achieve more effective TB control and avoid MDR-TB through the development of a global policy.

Cisplatin is a clinically advanced and highly effective anticancer drug used in the treatment of a wide variety of malignancies, such as head and neck, lung, testis, ovary, breast cancer, etc. However, it has only a limited use in clinical practice due to its severe adverse effects, particularly nephrotoxicity; 20%–35% of patients develop acute kidney injury (AKI) after cisplatin administration. The nephrotoxic effect of cisplatin is cumulative and dose dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI result in impaired renal tubular function and acute renal failure, chronic kidney disease, uremia, and hypertensive nephropathy. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, apoptosis, oxidative stress, inflammation, and vascular injury in the kidneys. At present, there are no effective drugs or methods for cisplatin-induced kidney injury. Recent in vitro and in vivo studies show that numerous natural products (flavonoids, saponins, alkaloids, polysaccharide, phenylpropanoids, etc.) have specific antioxidant, anti-inflammatory, and anti-apoptotic properties that regulate the pathways associated with cisplatin-induced kidney damage. In this review we describe the molecular mechanisms of cisplatin-induced nephrotoxicity and summarize recent findings in the field of natural products that undermine these mechanisms to protect against cisplatin-induced kidney damage and provide potential strategies for AKI treatment.

Ferroptosis is a newly characterized iron-dependent form of nonapoptotic regulated cell death triggered by lipid reactive oxygen species (LOOH). The dysregulation of ferroptosis is highly related to cancer, and the induction of ferroptosis is also proposed as a potential strategy for cancer therapy. Although several key regulators have been identified that are involved in ferroptosis, the molecular mechanism underlying this process remains largely unknown. Here, we report that Peroxiredoxin-6 (PRDX6) is a bona fide negative regulator of ferroptotic cell death. The knockdown of intracellular PRDX6 significantly enhances LOOH and ferroptotic cell death triggered by ferroptosis inducers (Erastin and RSL-3), which is correlated with the transcriptional activation of heme oxygenase-1. Moreover, overexpression of heme oxygenase-1 enhances both Erastin- and RSL-3-triggered LOOH, suggesting that heme oxygenase-1 mediates PRDX6 silencing-enhanced ferroptosis. More importantly, the application of a specific PRDX6 phospholipase A2 (iPLA2) inhibitor, MJ-33, synergistically enhances the ferroptosis induced by Erastin, suggesting that PRDX6 removes LOOH through its iPLA2 activity. Thus, our findings reveal an essential role of PRDX6 in protecting cells against ferroptosis and provide a potential target to improve the antitumor activity of ferroptosis-based chemotherapy.

The moist processes of the Madden‐Julian Oscillation (MJO) in the Coupled Model Intercomparison Project Phase 6 models are assessed using moisture mode theory‐based diagnostics over the Indian Ocean (10°S–10°N, 75°E–100°E). Results show that no model can capture all the moisture mode properties relative to the reanalysis. Most models satisfy weak temperature gradient balance but have unrealistically fast MJO propagation and a lower moisture‐precipitation correlation. Models that satisfy the most moisture mode criteria reliably simulate a stronger MJO. The background moist static energy (MSE) and low‐level zonal winds are more realistic in the models that satisfy the most criteria. The MSE budget associated with the MJO is also well‐represented in the good models. Capturing the MJO's moisture mode properties over the Indian Ocean is associated with a more realistic representation of the MJO and thus can be employed to diagnose MJO performance. Plain Language Summary The Madden‐Julian Oscillation (MJO) is arguably the most important tropical phenomenon that drives weather at the intraseasonal time scale. Although the MJO has been analyzed for the past decades, its simulation in climate models can still be improved. Previous studies have emphasized that the MJO evolution is tightly modulated by moisture fluctuations and posited the moisture mode theory to explain its behavior. Here, we show that no climate model can realistically reproduce the moist thermodynamics of the MJO, particularly its sensitivity to humidity anomalies. The models that most reproduce the MJO's moist thermodynamics simulate a stronger MJO, and are generally more realistic. Key Points Madden‐Julian Oscillation (MJO) simulation skill in 25 Coupled Model Intercomparison Project Phase 6 models is assessed using moisture mode theory No model can realistically reproduce all the moisture mode properties of the MJO over the Indian Ocean Models that best capture the MJO's moisture mode features exhibit more realistic mean states and MJO structure and propagation features

A recent theory–originally proposed for tropical depression (TD)‐type waves–is extended to the Madden‐Julian Oscillation (MJO) and convectively‐coupled equatorial Rossby (ER) waves across the Indo‐Western Pacific region using reanalysis and Coupled Model Intercomparison Project Phase 6 (CMIP6) data. This framework posits that waves grow from a Hadley Cell‐linked instability, quantified by a metric tied to the product of the meridional gradient of background vertical velocity and planetary vorticity. Results show that wave activity, diagnosed via wave‐filtered moisture variance and poleward eddy moisture fluxes, is strongest in MJO and ER waves when the instability metric peaks. CMIP6 models with a higher instability metric exhibit stronger Southern Hemisphere MJO and ER waves. While significant in both, the correlations are stronger for ER waves. These results suggest that ER waves are driven by the same mechanisms as TD‐type waves, whereas other processes not accounted for in this framework are also important for the MJO.

Various lipids and lipid metabolites are bound to and modify the proteins in eukaryotic cells, which are known as ‘protein lipidation’. There are four major types of the protein lipidation, i.e. myristoylation, palmitoylation, prenylation, and glycosylphosphatidylinositol anchor. N-myristoylation refers to the attachment of 14-carbon fatty acid myristates to the N-terminal glycine of proteins by N-myristoyltransferases (NMT) and affects their physiology such as plasma targeting, subcellular tracking and localization, thereby influencing the function of proteins. With more novel pathogenic N-myristoylated proteins are identified, the N-myristoylation will attract great attentions in various human diseases including infectious diseases, parasitic diseases, and cancers. In this review, we summarize the current understanding of N-myristoylation in physiological processes and discuss the hitherto implication of crosstalk between N-myristoylation and other protein modification. Furthermore, we mention several well-studied NMT inhibitors mainly in infectious diseases and cancers and generalize the relation of NMT and cancer progression by browsing the clinic database. This review also aims to highlight the further investigation into the dynamic crosstalk of N-myristoylation in physiological processes as well as the potential application of protein N-myristoylation in translational medicine.

Emerging evidence indicates that M2-polarized tumor-associated macrophages (TAMs) directly participate in tumor initiation, progression and metastasis. However, to date, few studies have investigated novel strategies for inhibiting TAMs in order to overcome osteosarcoma. In this study, we reported that M2 macrophages were enriched in osteosarcoma tissues from patients, and M2-polarized TAMs enhanced cancer initiation and stemness of osteosarcoma cells, thereby establishing M2-polarized TAMs as a therapeutic target for blocking osteosarcoma formation. We also found that all- trans retinoic acid (ATRA) weakened TAM-induced osteosarcoma tumor formation by inhibiting M2 polarization of TAMs in vivo, and inhibited the colony formation, as well as sphere-formation capacity of osteosarcoma cells promoted by M2-type macrophages in vitro. Furthermore, M2-type macrophages enhanced cancer stem cells (CSCs) properties as assessed by increasing the numbers of CD117 + Stro-1 + cells accompanied by the upregulation of CSC markers (CD133, CXCR4, Nanog, and Oct4), which could clearly be reduced by ATRA. Taken together, the results of this study demonstrated the role of M2-polarized TAMs in osteosarcoma initiation and stemness by activating CSCs, and indicated that ATRA treatment is a promising approach for treating osteosarcoma by preventing M2 polarization of TAMs.

An efficient stereoselective strategy for the synthesis of chiral bisspiro barbituric acid–oxindole derivatives was developed. The asymmetric Michael addition/cyclization tandem reaction between benzylidene barbituric acids and oxindolylmalonitriles was catalyzed by squaramide catalyst, and the corresponding spirocyclic products were obtained in good-to-high yields (up to 97%) with excellent stereoselectivities (up to >99% ee, >20:1 dr). At the same time, the practicality of the reaction was verified by the gram-scale preparation reaction.

Despite more effective chemotherapy combined with limb-salvage surgery for the osteosarcoma treatment, survival rates for osteosarcoma patients have stagnated over the past three decades due to the poor prognosis. Osteosarcoma cancer stem cells (OSCs) are responsible for the growth and metastasis of osteosarcoma. The existence of OSCs offers a theoretical explanation for therapeutic failures including tumor recurrence, metastasis, and drug resistance. Understanding the pathways that regulate properties of OSCs may shed light on mechanisms that lead to osteosarcoma and suggest better modes of treatment. In this study, we showed that the expression level of Kruppel-like factor 4 (KLF4) is highly associated with human osteosarcoma cancer stemness. KLF4-overexpressed osteosarcoma cells displayed characteristics of OSCs: increased sphere-forming potential, enhanced levels of stemness-associated genes, great chemoresistance to adriamycin and CDDP, as well as more metastasis potential. Inversely, KLF4 knockdown could reduce colony formation in vitro and inhibit tumorigenesis in vivo, supporting an oncogenic role for KLF4 in osteosarcoma pathogenesis. Furthermore, KLF4 was shown to activate the p38 MAPK signaling pathway to promote cancer stemness. Altogether, our studies uncover an essential role for KLF4 in regulation of OSCs and identify KLF4–p38 MAPK axis as a potential therapeutic target for osteosarcoma treatment.