The efficacy and safety of Bazi Bushen Capsule in treating premature aging: A randomized, double blind, multicenter, placebo-controlled clinical trial.

PURPOSE: It is unclear whether traditional Chinese patent medicines can resist premature aging. This prospective study investigated the effects of Bazi Bushen Capsule (BZBS) which is a traditional Chinese patent medicine for tonifying the kidney essence on premature senility symptoms and quality of life, telomerase activity and telomere length. STUDY DESIGN AND METHODS: It was a parallel, multicenter, double-blind, randomized, and placebo-controlled trial. Subjects (n = 530) aged 30-78 years were randomized to receive BZBS or placebo capsules 12 weeks. The primary outcome was the clinical feature of change in kidney deficiency for aging evaluation scale (CFCKD-AES) and tilburg frailty indicator (TFI). The secondary outcomes were SF-36, serum sex hormone level, five times sit-to-stand time (FTSST), 6MWT, motor function test-grip strength, balance test, walking speed, muscle mass measurement, telomerase and telomere length. RESULTS: After 12 weeks of treatment, the CFCKD-AES and TFI scores in the BZBS group decreased by 13.79 and 1.50 respectively (6.42 and 0.58 in the placebo group, respectively); The SF-36 in the BZBS group increased by 98.38 (23.79 in the placebo group). The FTSST, motor function test grip strength, balance test, walking speed, and muscle mass in the elderly subgroup were all improved in the BZBS group. The telomerase content in the BZBS group increased by 150.04 ng/ml compared to the placebo group. The fever led one patient in the placebo group to discontinue the trial. One patient in the placebo group withdrew from the trial due to pregnancy. None of the serious AEs led to treatment discontinuation, and 3 AEs (1.14%) were assessed as related to BZBS by the primary investigator. CONCLUSIONS: BZBS can improve premature aging symptoms, frailty scores, and quality of life, as well as improve FTSST, motor function: grip strength, balance test, walking speed, and muscle mass in elderly subgroups of patients, and enhance telomerase activity, but it is not significantly associated with increasing telomere length which is important for healthy aging. TRIAL REGISTRY: https://www.chictr.org.cn/showproj.html?proj=166181.

PromptMagician: Interactive Prompt Engineering for Text-to-Image Creation.

Generative text-to-image models have gained great popularity among the public for their powerful capability to generate high-quality images based on natural language prompts. However, developing effective prompts for desired images can be challenging due to the complexity and ambiguity of natural language. This research proposes PromptMagician, a visual analysis system that helps users explore the image results and refine the input prompts. The backbone of our system is a prompt recommendation model that takes user prompts as input, retrieves similar prompt-image pairs from DiffusionDB, and identifies special (important and relevant) prompt keywords. To facilitate interactive prompt refinement, PromptMagician introduces a multi-level visualization for the cross-modal embedding of the retrieved images and recommended keywords, and supports users in specifying multiple criteria for personalized exploration. Two usage scenarios, a user study, and expert interviews demonstrate the effectiveness and usability of our system, suggesting it facilitates prompt engineering and improves the creativity support of the generative text-to-image model.

Functional Connectivity Networks with Latent Distributions for Mild Cognitive Impairment Identification.

This work presents a novel approach to estimate brain functional connectivity networks via generative learning. Due to the complexity and variability of rs-fMRI signal, we consider it as a random variable, and utilize variational autoencoder networks to encode it as a confidence distribution in the latent space rather than as a fixed vector, so as to establish the relationship between them. First, the mean time series of each brain region of interest is mapped into a multivariate Gaussian distribution. The correlation between two brain regions is measured by the Jensen-Shannon divergence that describes the statistical similarity between two probability distributions, and then the adjacency matrix is created to indicate the functional connectivity strength of pairwise brain regions. Meanwhile, our findings show that the adjacency matrices obtained at VAE latent spaces of different dimensionalities have good complementarity for MCI identification in precision and recall, and the classification performance can be further boosted by an efficient cascade of classifiers. This proposal constructs brain functional networks from a statistical modeling standpoint, improving the statistical ability of population data and the generalization ability of observation data variability. We evaluate the proposed framework over the task of identifying subjects with MCI from normal controls, and the experimental results on the public dataset show that our method significantly outperforms both the baseline and current state-of-the-art methods.

Immune-enhancing activity of polysaccharides and flavonoids derived from Phellinus igniarius YASH1.

Introduction: Phellinus igniarius (P. igniarius) (Sanghuang) is a widely used traditional Chinese medicine fungus, and its natural products have great potential for clinical application in immune enhancement. This study aimed to explore the immune-enhancing activity and underlying mechanisms of the polysaccharides and flavonoids derived from Phellinus igniarius (P. igniarius) and to provide a theoretical and experimental basis for the development of novel drugs. Methods: Wild P. igniarius YASH1 from the Loess Plateau in Yan'an region was collected, and polysaccharides and total flavonoids were extracted, isolated and identified from mycelium and sporophore. In vitro antioxidant activity was detected through the scavenging activity of hydroxyl radicals and total antioxidant capacity. Cell Counting Kit-8 and trypan blue detection kit were used to detect the effect of extract polysaccharides and flavonoids on the proliferation and phagocytosis ability of immune cells. To assess the effect of the drugs on cytokine secretion by immune cells and immune recovery in immunocompromised mice, the expression of interleukin (IL)-2, IL-6, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were examined at the cellular and animal levels. The species composition, abundance of gut microbiota and the altered content of short-chain fatty acids in the feces were analyzed to elucidate the possible mechanisms of drugs by 16S ribosomal RNA (rRNA) amplifiers sequencing and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Both polysaccharides and flavonoids derived from mycelium or sporophore had antioxidant activity and may stimulate the expression and secretion of IL-2, IL-6, and IFN-γ in immune cells while inhibiting TNF-α expression and secretion and increasing IL-2, IL-6, and IFN- γ expression levels in mice. Furthermore, polysaccharides and flavonoids from mycelium and sporophore showed different effects on the metabolic response of intestinal short-chain fatty acids (SCFAs) in mice, and the use of these drugs remarkably changed the species composition and abundance of intestinal flora in mice. Discussion: Polysaccharides and flavonoids from P. igniarius YASH1 mycelium and sporophore have in vitro antioxidant activity, and they affect the promotion of cell proliferation, stimulation of IL-2, IL-6, and IFN-γ secretion, and inhibition of TNF-α expression in immune cells. Polysaccharides and flavonoids from P. igniarius YASH1 may enhance immunity in immunocompromised mice and remarkably affect the intestinal flora and content of SCFAs.

E2EFP-MIL: End-to-end and high-generalizability weakly supervised deep convolutional network for lung cancer classification from whole slide image.

Efficient and accurate distinction of histopathological subtype of lung cancer is quite critical for the individualized treatment. So far, artificial intelligence techniques have been developed, whose performance yet remained debatable on more heterogenous data, hindering their clinical deployment. Here, we propose an end-to-end, well-generalized and data-efficient weakly supervised deep learning-based method. The method, end-to-end feature pyramid deep multi-instance learning model (E2EFP-MIL), contains an iterative sampling module, a trainable feature pyramid module and a robust feature aggregation module. E2EFP-MIL uses end-to-end learning to extract generalized morphological features automatically and identify discriminative histomorphological patterns. This method is trained with 1007 whole slide images (WSIs) of lung cancer from TCGA, with AUCs of 0.95-0.97 in test sets. We validated E2EFP-MIL in 5 real-world external heterogenous cohorts including nearly 1600 WSIs from both United States and China with AUCs of 0.94-0.97, and found that 100-200 training images are enough to achieve an AUC of >0.9. E2EFP-MIL overperforms multiple state-of-the-art MIL-based methods with high accuracy and low hardware requirements. Excellent and robust results prove generalizability and effectiveness of E2EFP-MIL in clinical practice. Our code is available at https://github.com/raycaohmu/E2EFP-MIL.

Comprehensive analysis of the immune pattern of T cell subsets in chronic myeloid leukemia before and after TKI treatment.

Background: Immunological phenotypes and differentiation statuses commonly decide the T cell function and anti-tumor ability. However, little is known about these alterations in CML patients. Method: Here, we investigated the immunologic phenotypes (CD38/CD69/HLA-DR/CD28/CD57/BTLA/TIGIT/PD-1) of T subsets (TN, TCM, TEM, and TEMRA) in peripheral blood (PB) and bone marrow (BM) from de novo CML patients (DN-CML), patients who achieved a molecular response (MR) and those who failed to achieve an MR (TKI-F) after tyrosine kinase inhibitor (TKI) treatment using multicolor flow cytometry. Results: CD38 or HLA-DR positive PB CD8+TN and TCM cells decreased in the DN-CML patients and this was further decreased in TKI-F patients. Meanwhile, the level of PD-1 elevated in CD8+ TEM and TEMRA cells from PB in all groups. Among BM sample, the level of HLA-DR+CD8+TCM cells significantly decreased in all groups and CD8+TEMRA cells from TKI-F patients exhibited increased level of TIGIT and CD8+ tissue-residual T cells (TRM) from DN-CML patients expressed a higher level of PD-1 and TIGIT. Lastly, we found a significantly decreased proportion of CD86+ dendritic cells (DCs) and an imbalanced CD80/CD86 in the PB and BM of DN-CML patients, which may impair the activation of T cells. Conclusion: In summary, early differentiated TN and TCM cells from CML patients may remain in an inadequate activation state, particularly for TKI-F patients. And effector T cells (TEM, TEMRA and TRM) may be dysfunctional due to the expression of PD-1 and TIGIT in CML patients. Meanwhile, DCs cells exhibited the impairment of costimulatory molecule expression in DN-CML patients. Those factors may jointly contribute to the immune escape in CML patients.

The gut microbiota: A new perspective for tertiary prevention of hepatobiliary and gallbladder diseases.

The gut microbiota is a complex ecosystem that has coevolved with the human body for hundreds of millions of years. In the past 30 years, with the progress of gene sequencing and omics technology, the research related to gut microbiota has developed rapidly especially in the field of digestive system diseases and systemic metabolic diseases. Mechanical, biological, immune, and other factors make the intestinal flora form a close bidirectional connection with the liver and gallbladder, which can be called the "gut-liver-biliary axis." Liver and gallbladder, as internal organs of the peritoneum, suffer from insidious onset, which are not easy to detect. The diagnosis is often made through laboratory chemical tests and imaging methods, and intervention measures are usually taken only when organic lesions have occurred. At this time, some people may have entered the irreversible stage of disease development. We reviewed the literature describing the role of intestinal flora in the pathogenesis and biotherapy of hepatobiliary diseases in the past 3-5 years, including the dynamic changes of intestinal flora at different stages of the disease, as well as the signaling pathways involved in intestinal flora and its metabolites, etc. After summarizing the above contents, we hope to highlight the potential of intestinal flora as a new clinical target for early prevention, early diagnosis, timely treatment and prognosis of hepatobiliary diseases. GRAPHICAL ABSTRACT.

Zunyimycin C enhances immunity and improves cognitive impairment and its mechanism.

This study aimed to explore the efficacy of zunyimycin C in the immunological enhancement of hypoimmune mice and improvement of cognitive impairment in a mice model of Alzheimer's disease (AD). Zunyimycin C was administered intranasally to interfere with AD mouse models or gavage to hypoimmune animals. Results of the Morris water maze (MWM) showed that zunyimycin may improve the learning and memory abilities of the AD mice model. The results of differential expression analysis of mRNA levels of inflammatory factors and pathways in brain tissues of the AD mouse model suggested that differential expression was more obvious under Zun-Int L. Western blot revealed that the relative expression of glial fibrillary acidic protein in the brain tissue of the AD mouse model in the Zun-Pre group was significantly higher than that in the other groups, and the difference was statistically significant. The relative expression of interleukin (IL)-6 protein in the brain tissue of mice in the low-dose intervention group was significantly lower than that in the other groups, and the difference was statistically significant. As for hypoimmune animals, short chain fatty acids (SCFAs) assay and intestinal flora assay results showed that zunyimycin C may change intestinal flora diversity and SCFA biosynthesis. The prophylactic administration of zunyimycin C could not inhibit acute neuroinflammation in AD mice. Zunyimycin C may participate in the immune response by activating the Ras-Raf-MEK-ERK signaling pathway to stimulate microglia to produce more inflammatory factors. Zunyimycin C may inhibit autophagy by activating the PI3K-AKT-mTOR signaling pathway, promote cell survival, mediate neuroprotective effects of reactive microglia and reactive astrocytes, and reduce IL-1ß in brain tissue and IL-6 secretion, thereby attenuating neuroinflammation in AD mice and achieving the effect of improving learning and memory impairment. Zunyimycin C may play a role in immunological enhancement by changing intestinal flora diversity and SCFAs.

Development and research progress of anti-drug resistant fungal drugs.

With the widespread use of immunosuppressive agents and the increase in patients with severe infections, the incidence of fungal infections worldwide has increased year by year. The fungal pathogens Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus cause a total of more than 1 million deaths each year. Long-term use of antifungal drugs can easily lead to fungal resistance, and the prevalence of drug-resistant fungi is a major global health challenge. In order to effectively control global fungal infections, there is an urgent need for new drugs that can exert effective antifungal activity and overcome drug resistance. We must promote the discovery of new antifungal targets and drugs, and find effective ways to control drug-resistant fungi through different ways, so as to reduce the threat of drug-resistant fungi to human life, health and safety. In the past few years, certain progress has been made in the research and development of antifungal drugs. In addition to summarizing some of the antifungal drugs currently approved by the FDA, this review also focuses on potential antifungal drugs, the repositioned drugs, and drugs that can treat drug-resistant bacteria and fungal infections, and provide new ideas for the development of antifungal drugs in the future.

BET bromodomain inhibition rescues PD-1-mediated T-cell exhaustion in acute myeloid leukemia.

Sustained expression of programmed cell death receptor-1 (PD-1) is correlated with the exhaustion of T cells, and blockade of the PD-1 pathway is an effective immunotherapeutic strategy for treating various cancers. However, response rates are limited, and many patients do not achieve durable responses. Thus, it is important to seek additional strategies that can improve anticancer immunity. Here, we report that the bromodomain and extraterminal domain (BET) inhibitor JQ1 inhibits PD-1 expression in Jurkat T cells, primary T cells, and T-cell exhaustion models. Furthermore, JQ1 dramatically impaired the expression of PD-1 and T-cell immunoglobulin mucin-domain-containing-3 (Tim-3) and promoted the secretion of cytokines in T cells from patients with acute myeloid leukemia (AML). In line with that, BET inhibitor-treated CD19-CAR T and CD123-CAR T cells have enhanced anti-leukemia potency and resistant to exhaustion. Mechanistically, BRD4 binds to the NFAT2 and PDCD1 (encoding PD-1) promoters, and NFAT2 binds to the PDCD1 and HAVCR2 (encoding Tim-3) promoters. JQ1-treated T cells showed downregulated NFAT2, PD-1, and Tim-3 expression. In addition, BET inhibitor suppressed programmed death-ligand 1 (PD-L1) expression and cell growth in AML cell lines and in primary AML cells. We also demonstrated that JQ1 treatment led to inhibition of leukemia progression, reduced T-cell PD-1/Tim-3 expression, and prolonged survival in MLL-AF9 AML mouse model and Nalm6 (B-cell acute lymphoblastic leukemia cell)-bearing mouse leukemia model. Taken together, BET inhibition improved anti-leukemia immunity by regulating PD-1/PD-L1 expression, and also directly suppressed AML cells, which provides novel insights on the multiple effects of BET inhibition for cancer therapy.

Description of three new Boulenophrys species from eastern Guangdong, China, emphasizing the urgency of ecological conservation in this region (Anura, Megophryidae).

The hilly region in eastern Guangdong, China lacks comprehensive scientific investigations for decades, especially in terms of herpetofauna. In recent years, several highly threatened amphibians have been gradually discovered from this region. In this work, three new species of the genus Boulenophrys are described, which are endemic from only one or two known localities in eastern Guangdong. These discoveries enrich the diversity of Boulenophrys in eastern Guangdong. With the large number of threatened urodeles and anuran species occurring in this densely populated area, the unique herpetological diversity in eastern Guangdong is facing the impacts of habitat degradation and fragmentation, and conservation actions are urgently required.

Increased TOX expression concurrent with PD-1, Tim-3, and CD244 in T cells from patients with non-Hodgkin lymphoma.

AIM: To characterize immune suppression in lymphoma, thymocyte selection-associated high mobility group box protein (TOX) expression and co-expression with programmed cell death receptor-1 (PD-1), T cell immunoglobulin mucin-domain-containing-3 (Tim-3), and CD244 in CD3+, CD4+, CD8+, and regulatory T (Treg) cells from patients with lymphomas were analyzed. METHODS: TOX expression and co-expression with PD-1, Tim-3, and CD244 in CD3+, CD4+, Treg, and CD8+ T cells were analyzed by multi-color fluorescent flow cytometry using peripheral blood (PB) from 13 newly diagnosed, untreated lymphoma patients, and 11 healthy individuals. RESULTS: An increased percentage of TOX+ CD3+, CD4+, and CD8+ T cells was found in PB from patients with B cell non-Hodgkin's lymphoma (B-NHL) in comparison with healthy controls. Moreover, TOX+PD-1+ and TOX+Tim-3+ double-positive T cells increased among the CD3+, CD4+, and CD8+T cell populations in the B-NHL group. There was apparent heterogeneity in TOX expression and co-expression with PD-1, Tim-3, and CD244 in CD3+, CD4+, and CD8+ T cells in different lymphoma patients. In addition, the percentage of CD4+CD25+FoxP3+ T cells (Treg) among the CD3+ and CD4+ T cells significantly increased, and the number of TOX+ and TOX+PD-1+ Treg cells also significantly increased in the B-NHL group. CONCLUSIONS: Higher expression of TOX concurrent with PD-1, Tim-3, and CD244 in T cells from patients with B-NHL may contribute to T cell exhaustion and impair their special anti-tumor T cell activity. TOX may be considered a potential target for reversing T cell exhaustion and improving T cell function in hematological malignancies.

Terminal differentiation of bone marrow NK cells and increased circulation of TIGIT+ NK cells may be related to poor outcome in acute myeloid leukemia.

AIM: In order to further understand the feature of natural killer cell (NK) dysfunction in acute myeloid leukemia (AML), The distribution of NK cell subset the expression of the inhibitory receptors immunoglobulin and ITIM domain (TIGIT), killer cell lectin-like receptor (KLRG1), and the expression of maturation marker CD57 in NK cell subsets and their correlation with patient outcomes were analyzed in this study. METHODS: We collected peripheral blood (PB) and bone marrow (BM) samples from de novo AML (AML-DN) patients, patients who achieved complete remission after chemotherapy (AML-CR), and healthy individuals. An eight-color flow cytometry panel was used to identify different NK subsets and their expression of TIGIT, CD57 and KLRG1. RESULTS: Decreased percentage of CD56dim CD16+ NK cells was found only in the PB of AML-DN and AML-CR patients but not in the BM. The expression frequency of TIGIT and KLRG1 was elevated on NK cells from the PB of AML-DN patients, while it was recovered in AML-CR patients. Moreover, a higher percentage of CD57+ CD56dim CD16+ NK cells, representing a terminally differentiated NK subset with strong cytotoxic capacity but defective replication potential, was detected in the BM of AML-DN patients and predicted sub-optimal survival for patients. CONCLUSION: The results indicated that the NK cell subsets in the PB of AML patients had an exhaustion phenotype, while the BM NK cells had a terminally differentiated phenotype, which correlated with short survival for AML patients.

PD-1 and TIGIT Are Highly Co-Expressed on CD8+ T Cells in AML Patient Bone Marrow.

Despite the great success of immune-checkpoint inhibitor (ICI) treatment for multiple cancers, evidence for the clinical use of ICIs in acute myeloid leukemia (AML) remains inadequate. Further exploration of the causes of immune evasion in the bone marrow (BM) environment, the primary leukemia site, and peripheral blood (PB) and understanding how T cells are affected by AML induction chemotherapy or the influence of age may help to select patients who may benefit from ICI treatment. In this study, we comprehensively compared the distribution of PD-1 and TIGIT, two of the most well-studied IC proteins, in PB and BM T cells from AML patients at the stages of initial diagnosis, complete remission (CR), and relapse-refractory (R/R) disease after chemotherapy. Our results show that PD-1 was generally expressed higher in PB and BM T cells from de novo (DN) and R/R patients, while it was partially recovered in CR patients. The expression of TIGIT was increased in the BM of CD8+ T cells from DN and R/R patients, but it did not recover with CR. In addition, according to age correlation analysis, we found that elderly AML patients possess an even higher percentage of PD-1 and TIGIT single-positive CD8+ T cells in PB and BM, which indicate greater impairment of T cell function in elderly patients. In addition, we found that both DN and R/R patients accumulate a higher frequency of PD-1+ and TIGIT+ CD8+ T cells in BM than in corresponding PB, indicating that a more immunosuppressive microenvironment in leukemia BM may promote disease progression. Collectively, our study may help guide the combined use of anti-PD-1 and anti-TIGIT antibodies for treating elderly AML patients and pave the way for the exploration of strategies for reviving the immunosuppressive BM microenvironment to improve the survival of AML patients.

Single-Cell RNA-Seq of T Cells in B-ALL Patients Reveals an Exhausted Subset with Remarkable Heterogeneity.

Characterization of functional T cell clusters is key to developing strategies for immunotherapy and predicting clinical responses in leukemia. Here, single-cell RNA sequencing is performed with T cells sorted from the peripheral blood of healthy individuals and patients with B cell-acute lymphoblastic leukemia (B-ALL). Unbiased bioinformatics analysis enabled the authors to identify 13 T cell clusters in the patients based on their molecular properties. All 11 major T cell subsets in healthy individuals are found in the patients with B-ALL, with the counterparts in the patients universally showing more activated characteristics. Two exhausted T cell populations, characterized by up-regulation of TIGIT, PDCD1, HLADRA, LAG3, and CTLA4 are specifically discovered in B-ALL patients. Of note, these exhausted T cells possess remarkable heterogeneity, and ten sub-clusters are further identified, which are characterized by different cell cycle phases, naïve states, and GNLY (coding granulysin) expression. Coupled with single-cell T cell receptor repertoire profiling, diverse originations of the exhausted T cells in B-ALL are suggested, and clonally expanded exhausted T cells are likely to originate from CD8+ effector memory/terminal effector cells. Together, these data provide for the first-time valuable insights for understanding exhausted T cell populations in leukemia.

ChaiQi Decoction Alleviates Vascular Endothelial Injury by Downregulating the Inflammatory Response in ApoE-Model Mice.

Metabolic syndrome (MetS) is a pathological state of metabolic disorders that primarily occur in human proteins, fats, and carbohydrates. It is a complex cluster of core metabolic disorder syndromes including obesity, hyperglycemia, dyslipidemia, and hypertension, and vascular endothelial injury, occurring over time. The currently available treatment options cannot effectively manage MetS. In our previous research, we revealed ChaiQi decoction (CQD) as an effective prescription for improving MetS; however, the specific mechanism remains unclear. Herein, we assessed the efficacy and mechanism of CQD in ApoE gene knockout (ApoE-) mice. Mice were administered with CQD daily for 12 weeks, and the measurement of their body weight was taken monthly. To evaluate the metabolic levels of mice, we determined the fasting blood glucose (FBG), fasting serum insulin (FINS), insulin resistance index (IRI), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels. Furthermore, immunohistochemical analysis was adopted to determine the expression of ICAM-1 and VCAM-1 in vascular endothelium, while an optical microscope was adopted to observe the pathological morphology of abdominal aorta in mice. Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) levels were determined using the ELISA method, whereas Western blotting was used to determine nuclear factor- (NF-) κB p65. Of note, intragastric CQD administration ameliorated ApoE-model mice, as evidenced by reduced levels of FBG, FINS, IRI, TG, TC, and LDL-C. Furthermore, CQD alleviated vascular endothelial injury and regularized the structure of the abdominal aorta by downregulating the expressions of proinflammatory cytokines TNF-α, IL-6, ICAM-1, VCAM-1, and NF-κB p65. Overall, these findings advocated that CQD ameliorates metabolic levels and vascular endothelial injury in mice by downregulating the inflammatory response and thus may be utilized as a novel MetS therapy.

Development and Research Progress of Anti-Drug Resistant Bacteria Drugs.

Bacterial resistance has become increasingly serious because of the widespread use and abuse of antibiotics. In particular, the emergence of multidrug-resistant bacteria has posed a serious threat to human public health and attracted the attention of the World Health Organization (WHO) and the governments of various countries. Therefore, the establishment of measures against bacterial resistance and the discovery of new antibacterial drugs are increasingly urgent to better contain the emergence of bacterial resistance and provide a reference for the development of new antibacterial drugs. In this review, we discuss some antibiotic drugs that have been approved for clinical use and a partial summary of the meaningful research results of anti-drug resistant bacterial drugs in different fields, including the antibiotic drugs approved by the FDA from 2015 to 2020, the potential drugs against drug-resistant bacteria, the new molecules synthesized by chemical modification, combination therapy, drug repurposing, immunotherapy and other therapies.

Increased Expression of TIGIT/CD57 in Peripheral Blood/Bone Marrow NK Cells in Patients with Chronic Myeloid Leukemia.

The antitumor activity of NK cells in patients with chronic myeloid leukemia (CML) is inhibited by the leukemia microenvironment. Recent studies have identified that the expression of TIGIT, CD57, and KLRG1 is related to the function, maturation, and antitumor capabilities of NK cells. However, the characteristics of the expression of these genes in the peripheral blood (PB) and bone marrow (BM) from patients with CML remain unknown. In this study, we used multicolor flow cytometry to assay the quantity and phenotypic changes of NK cells in PB and BM from de novo CML (DN-CML) and CML patients acquiring molecular response (MR-CML). We found that the expression of TIGIT, which inhibits NK cell function, is increased on CD56+ and CD56dim NK cells in DN-CML PB compared with those in healthy individuals (HIs), and it is restored to normal in patients who achieve MR. We also found that the expression of CD57 on NK cells was approximately the same level in PB and BM from DN-CML patients, while decreased CD57 expression was found on CD56+ and CD56dim NK cells in HI BM compared with PB. Additionally, those two subsets were significantly increased in DN-CML BM compared to HI BM. The expression of CD57 correlates with replicative senescence and maturity for human NK cells; therefore, the increase in TIGIT on PB NK cells together with an increase in CD57 on BM NK cells may explain the subdued NK cell antileukemia capacity and proliferative ability in DN-CML patients. These results indicate that reversing the immune suppression of PB NK cells by blocking TIGIT while improving the proliferation of BM NK cells via targeting CD57 may be more effective in removing tumor cells.