Therapeutic progress in relapsed/refractory multiple myeloma.

Improvement in the therapeutics for multiple myeloma (MM) has been continuously developed owing to the application of novel drugs and technologies in the last 20 years. The standard first-line therapy for MM consists of a three-drug induction regimen based on immunomodulatory drugs and proteasome inhibitors combined with autologous stem cell transplantation. However, MM remains incurable; therefore, therapies for relapsed/refractory MM (RRMM) are emerging and evolving rapidly. This study aimed to summarize and review the results of RRMM trials over the past 5 years to provide a holistic overview and insights for practitioners in related fields and to provide additional ideas for clinical trialists. This study shows that daratumumab and isatuximab continue to significantly advance as treatment options. Additionally, novel antibody drugs, such as elotuzumab and selinexor, as well as bispecific antibodies, teclistamab and talquetamab, are currently undergoing clinical research with promising outcomes. However, chimeric antigen receptor-T cell therapy targeting B-cell maturation antigen remains the optimal approach for MM treatment.

Different Preharvest Diseases in Garlic and Their Eco-Friendly Management Strategies.

BACKGROUND: garlic reproduces mainly through clove planting, as sexual reproduction via seeds is uncommon. Growers encounter challenges with pathogens due to the larger size and vegetative nature of seed cloves, as well as the storage conditions conducive to fungal growth. Some Phyto-pathogenic fungi, previously unrecognized as garlic infections, can remain latent within bulb tissues long after harvest. Although outwardly healthy, these infected bulbs may develop rot under specific conditions. AIM OF REVIEW: planting diseased seed cloves can contaminate field soil, with some fungal and bacterial infections persisting for extended periods. The substantial size of seed cloves makes complete eradication of deeply ingrained infections difficult, despite the use of systemic fungicides during the preplanting and postharvest phases. Additionally, viruses, resistant to fungicides, persist in vegetative material. They are prevalent in much of the garlic used for planting, and their host vectors are difficult to eliminate. To address these challenges, tissue-culture techniques are increasingly employed to produce disease-free planting stock. Key scientific concepts of the review: garlic faces a concealed spectrum of diseases that pose a global challenge, encompassing fungal threats like Fusarium's vascular wilt and Alternaria's moldy rot, bacterial blights, and the elusive garlic yellow stripe virus. The struggle to eliminate deeply ingrained infections is exacerbated by the substantial size of seed cloves. Moreover, viruses persist in garlic seeds, spreading through carrier vectors, and remain unaffected by fungicides. This review emphasizes eco-friendly strategies to address these challenges, focusing on preventive measures, biocontrol agents, and plant extracts. Tissue-culture techniques emerge as a promising solution for generating disease-free garlic planting material. The review advocates for ongoing research to ensure sustainable garlic cultivation, recognizing the imperative of safeguarding this culinary staple from an array of fungal and viral threats.

The influence of first desaturase subfamily genes on fatty acid synthesis, desiccation tolerance and inter-caste nutrient transfer in the termite Coptotermes formosanus.

Desaturase enzymes play an essential role in the biosynthesis of unsaturated fatty acids (UFAs). In this study, we identified seven "first desaturase" subfamily genes (Cfor-desatA1, Cfor-desatA2-a, Cfor-desatA2-b, Cfor-desatB-a, Cfor-desatB-b, Cfor-desatD and Cfor-desatE) from the Formosan subterranean termite Coptotermes formosanus. These desaturases were highly expressed in the cuticle and fat body of C. formosanus. Inhibition of either the Cfor-desatA2-a or Cfor-desatA2-b gene resulted in a significant decrease in the contents of fatty acids (C16:0, C18:0, C18:1 and C18:2) in worker castes. Moreover, we observed that inhibition of most of desaturase genes identified in this study had a negative impact on the survival rate and desiccation tolerance of workers. Interestingly, when normal soldiers were reared together with dsCfor-desatA2-b-treated workers, they exhibited higher mortality, suggesting that desaturase had an impact on trophallaxis among C. formosanus castes. Our findings shed light on the novel roles of desaturase family genes in the eusocial termite C. formosanus.

PTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling.

TANK-binding kinase 1 (TBK1) is a key kinase in regulating antiviral innate immune responses. While the oligomerization of TBK1 is critical for its full activation, the molecular mechanism of how TBK1 forms oligomers remains unclear. Here, we show that protein tyrosine kinase 2 beta (PTK2B) acts as a TBK1-interacting protein and regulates TBK1 oligomerization. Functional assays reveal that PTK2B depletion reduces antiviral signaling in mouse embryonic fibroblasts, macrophages and dendritic cells, and genetic experiments show that Ptk2b-deficient mice are more susceptible to viral infection than control mice. Mechanistically, we demonstrate that PTK2B directly phosphorylates residue Tyr591 of TBK1, which increases TBK1 oligomerization and activation. In addition, we find that PTK2B also interacts with the stimulator of interferon genes (STING) and can promote its oligomerization in a kinase-independent manner. Collectively, PTK2B enhances the oligomerization of TBK1 and STING via different mechanisms, subsequently regulating STING-TBK1 activation to ensure efficient antiviral innate immune responses.

Protocol for altering connexin hemichannel function in primary chicken lens fiber cells using high-titer retroviral RCAS(A) infection.

Connexins (Cxs) play a crucial role in maintaining lens transparency. Here, we present a protocol for altering Cx hemichannel (HC) function in primary chicken lens fiber cells using high-titer retroviral replication competent avian sarcoma-leukosis virus long terminal repeat with splice acceptor (A) infection. We describe steps for incubating eggs, isolating lenses, culturing cells, preparing reagents, and infecting cells. We then detail cell treatment and detection of apoptosis and death. This protocol can assess protein kinase A, HC activity, and increased glutathione transport for protecting lens fiber cells against oxidative stress. For complete details on the use and execution of this protocol, please refer to Liu et al.,1 Riquelme et al.,2 Shi et al.,3 Jiang,4 and Rath et al.5.

FN1 mRNA 3'-UTR supersedes traditional fibronectin 1 in facilitating the invasion and metastasis of gastric cancer through the FN1 3'-UTR-let-7i-5p-THBS1 axis.

Background: Current clinical treatments for gastric cancer (GC), particularly advanced GC, lack infallible therapeutic targets. The 3'-untranslated region (3'-UTR) has attracted increasing attention as a drug target. Methods: In vitro and in vivo experiments were conducted to determine the function of FN1 3'-UTR and FN1 protein in invasion and metastasis. RNA pull-down assay and high-throughput sequencing were used to screen the factors regulated by FN1 3'-UTR and construct the regulatory network. Western blotting and polymerase chain reaction were used to examine the correlation of intermolecular expression levels. RNA-binding protein immunoprecipitation was used to verify the correlation between FN1 3'-UTR and target mRNAs. Results: The FN1 3'-UTR may have stronger prognostic implications than the FN1 protein in GC patients. Upregulation of FN1 3'-UTR significantly promoted the invasive and metastatic abilities of GC cells to a greater extent than FN1 protein in vitro and in vivo. A novel regulatory network was constructed based on the FN1 3'-UTR-let-7i-5p-THBS1 axis, wherein FN1 3'-UTR displayed stronger oncogenic effects than the FN1 protein. Conclusions: FN1 3'-UTR may be a better therapeutic target for constructing targeted drugs in GC than the FN1 protein.

Effects of hydrolyzed gallotannin on intestinal physical barrier, immune function, and microbiota structure of yellow-feather broilers.

The present study was performed to explore the effects of dietary supplementation of hydrolyzed gallotannin (HGT) on intestinal physical barrier, immune function and microbiota structure in yellow-feather broilers. A total of 288 male yellow-feather broilers were randomly allocated to 4 diet treatments: the basal diet (CON) and 3 diets supplemented with 150, 300, and 450 mg/kg HGT for 63 d, respectively, with 6 replicates per treatment and 12 birds per replicate. The findings demonstrated that 300 or 450 mg/kg HGT addition enhanced the expression of duodenal occludin (OCLN) and tight junction protein1 (TJP-1) genes of birds at 21 d of age, and the expression of duodenal and ileal OCLN gene in 63-day-old broilers was upregulated due to 450 mg/kg HGT treatment (P < 0.05). The dietary supplementation of 150 mg/kg HGT strengthened the expression of duodenal IL-6 and IL-4 genes and ileal IL-4 gene of 21-day-old broilers, whereas the expression of jejunal IL1B and IL-6 genes in birds at 63 d of age weakened because of 300 or 450 mg/kg HGT addition (P < 0.05). As for microbial community, the HGT addition altered the cecal microbiota structure of birds at 21 d of age based on analysis of similarities (ANOSIM) test and 450 mg/kg HGT treatment increased the relative abundance of norank Eubacterium coprostanoligenes group at 21 d of age and unclassified Lachnospiraceae at 63 d of age (P < 0.05). In short, diet supplemented with 300 to 450 mg/kg HGT may be the optimal for yellow-feather broilers to enhance intestinal barrier function. Altogether, our study clarified the regulatory role of HGT in broiler intestinal health in earnest, but the underlying mechanism is still unclear. Hence, more research is needed to carry out until the application of HGT as a new functional additive in broiler production.

The PLOD2/succinate axis regulates the epithelial-mesenchymal plasticity and cancer cell stemness.

Aberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in cancer progression is not completely understood. Using stable isotope-resolved metabolomics analysis, we showed that the epithelial mesenchymal transition (EMT) was associated with profound changes in metabolites, including elevation of cytoplasmic succinate levels. The treatment with cell-permeable succinate induced mesenchymal phenotypes in mammary epithelial cells and enhanced cancer cell stemness. Chromatin immunoprecipitation and sequence analysis showed that elevated cytoplasmic succinate levels were sufficient to reduce global 5-hydroxymethylcytosinene (5hmC) accumulation and induce transcriptional repression of EMT-related genes. We showed that expression of procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) was associated with elevation of cytoplasmic succinate during the EMT process. Silencing of PLOD2 expression in breast cancer cells reduced succinate levels and inhibited cancer cell mesenchymal phenotypes and stemness, which was accompanied by elevated 5hmC levels in chromatin. Importantly, exogenous succinate rescued cancer cell stemness and 5hmC levels in PLOD2-silenced cells, suggesting that PLOD2 promotes cancer progression at least partially through succinate. These results reveal the previously unidentified function of succinate in enhancing cancer cell plasticity and stemness.

The integrated analysis of digestive physiology and gastrointestinal microbiota structure in Changle goose.

Changle goose in Fujian, China is a rare genetic resource and in urgent need to be protected. Understanding the characteristics of digestive physiology and spatial variation of gastrointestinal microbiota is crucial for developing nutritional intervention strategies to improve intestinal health and production performance of goose. Hence, histomorphological assay was used for observing development status of proventriculus, jejunum, and cecum in 70-day-old Changle geese, whereas digesta from 6 alimentary canal locations (crop, proventriculus, gizzard, jejunum, cecum, and rectum) were collected for 16S rRNA gene sequencing and short chain fatty acids (SCFAs) quantitative analysis. The histomorphological observation indicated that the jejunum and cecum of Changle goose were well developed. The alpha diversity analysis revealed that, except rectum, microbiota in other noncecum sections were in high diversity as cecum. The Nonmetric MultiDimensional Scaling (NMDS) analysis showed that microbial community of proventriculus, gizzard, and jejunum formed a cluster, which distinctly discrete with the microbiota of the other gastrointestinal locations. Additionally, the proportions of Proteobacteria, Bacteroidota, and Campilobacterota at the phylum level and Lactobacillus, Streptococcus, Helicobacter, and Subdoligranulum at the genus level exhibited tremendous alternations among different gastrointestinal locations. The characteristic bacterial composition in each section was further disclosed by analyzing the core and feature Amplicon Sequence Variants (ASVs) and SCFAs pattern. Importantly, 7 body-weight-associated ASVs and 2 cecum-development-related ASVs were identified via correlation analysis. In a whole, our findings provided the first insights into the specialized digestive physiology of Changle geese and distinctive regional distribution of gastrointestinal microbiota, which laid the important foundation for improving growth performance through microbiota manipulation in geese.

Protein kinase A activation alleviates cataract formation via increased gap junction intercellular communication.

Cataract is the leading cause of blindness worldwide. Here, we reported a potential, effective therapeutic mean for cataract prevention and treatment. Gap junction communication, an important mechanism in maintaining lens transparency, is increased by protein kinase A (PKA). We found that PKA activation reduced cataracts induced by oxidative stress, increased gap junctions/hemichannels in connexin (Cx) 50, Cx46 or Cx50 and Cx46 co-expressing cells, and decreased reactive oxygen species (ROS) levels. However, ROS reduction was shown in wild-type, Cx46 and Cx50 knockout, but not in Cx46/Cx50 double KO lens. In addition, PKA activation protects lens fiber cell death induced by oxidative stress via hemichannel-mediated glutathione transport. Connexin deletion increased lens opacity induced by oxidative stress associated with reduction of anti-oxidative stress gene expression. Together, our results suggest that PKA activation through increased connexin channels in lens fiber cell decreases ROS levels and cell death, leading to alleviated cataracts.

Effect of Hydrolyzed Gallotannin on Growth Performance, Immune Function, and Antioxidant Capacity of Yellow-Feather Broilers.

Tannins were traditionally considered as anti-nutritional factors in poultry production. Recent studies found that the addition of hydrolyzed gallotannin (HGT) could improve animal health; however, the proper dosage of HGT in chickens' diet is still unknown. Hence, our study aims to recommend its optimal dose by exploring the effects of HGT from Chinese gallnuts on the growth performance, immune function, and antioxidant capacity of yellow-feather broilers. A total of 288 male yellow-feather broilers (34.10 ± 0.08 g) were randomly allocated to four diet treatments, the basal diet with 0 (CON), 150, 300, and 450 mg/kg HGT for 63 days, respectively, with six replications per treatment and 12 birds per replication. The growth performance, slaughter performance, immune organ index, liver antioxidant-related indicators, and serum immune-related factors were evaluated. Results show that HGT supplementation did not influence the growth performance of broilers, but the diets supplemented with 300 and 450 mg/kg HGT increased the semi-eviscerated rate. Furthermore, HGT increased the content of liver T-AOC and the ratio of GSH/GSSG, which can protect against oxidative damage of birds. Additionally, supplementing HGT raised the contents of serum IL-10, IL-4, IL-6, IgA, and IgM. In conclusion, diet supplemented with 450 mg/kg HGT may be the optimal to the health of yellow-feather broilers on the whole.

Advances in the previous two decades in our understanding of the post-translational modifications, functions, and drug perspectives of ArgBP2 and its family members.

Arginine kinase-binding protein 2 (ArgBP2) is an adapter protein that belongs to the sorbin homology (SoHo) family. The SoHo family also includes c-Cbl-associated protein (CAP) and vinexin, both of which share structural and functional similarities to ArgBP2. However, the role of SoHo family proteins in cell signaling, drug resistance, metabolism, and diseases, especially cancer, is not fully understood. Herein, we summarize the structure of SoHo family proteins, their post-translational modifications and the comprehensive network of cellular pathways regulated by these proteins, with an emphasis on ArgBP2. We also discuss the relevance of the SoHo family proteins in lipid raft distribution, extracellular matrix-associated microenvironments, and drug discovery. This review provides insights into the possibility of targeting ArgBP2 and other SoHo family proteins as drugs for use in preclinical trials.

Effects of lutein on jejunal mucosal barrier function and inflammatory responses in lipopolysaccharide-challenged yellow-feather broilers.

Broilers are frequently exposed to various immunological stresses, which lead to intestinal damage, weakened immunity, and even growth retardation. Lutein, as a kind of carotenoid, possesses antioxidant and immunomodulatory functions. Therefore, this study was conducted to investigate the effects of lutein on jejunal mucosal barrier function and inflammatory responses of yellow-feather broilers challenged with lipopolysaccharide (LPS). A total of two hundred eight-eight 1-day-old yellow-feather broilers were randomly allocated to 3 groups with 8 replicate cages containing 12 birds each. Birds were fed broken-rice-soybean basal diet containing 0, 20 and 40 mg/kg lutein (CON, LU20 and LU40) for 26 d. On days 21, 23, and 25 of the trial, broilers were intraperitoneally injected with LPS (1 mg/kg body weight). The results showed that, compared with CON group, LU40 supplementations significantly increased the average daily gain (ADG) of broilers at 1 to 21 and 22 to 26 d of age (P < 0.05), significantly decreased the ratio of feed to gain (F/G) of broilers at 22 to 26 d of age (P < 0.05). LU20 and LU40 supplementations increased goblet cell density in jejunum of broilers under LPS challenge, and LU20 supplementation elevated the villus area (P < 0.05). Scanning electron microscopy of jejunal mucosa revealed significant villi damage, while transmission electron microscopy demonstrated severe enterocyte damage and loss of cellular integrity in CON group. In particular, mitochondria were morphologically altered, appearing irregular or swollen. Apical junctional complexes between adjacent enterocytes were obviously shorter and saccular in CON group. LU20 and LU40 supplementations increased the mRNA expressions of Occludin, Claudin-1, and ZO-1 in the jejunal mucosa of broilers under LPS challenge (P < 0.05), restrained TLR4/MyD88/NF-κB pathway activation in the jejunal mucosa, decreased the mRNA expressions of IL-1ß and IL-6, and strengthened the mRNA expressions of IL-4 and IL-10 (P < 0.05). Meanwhile, the protein expressions of p38 and JNK in LU40 group were lower than CON group (P < 0.05). It can be concluded that 40 mg/kg lutein supplementation improved LPS-induced jejunal mucosal barrier function and tamed inflammation of yellow-feather broilers.

Curcumin against gastrointestinal cancer: A review of the pharmacological mechanisms underlying its antitumor activity.

Gastrointestinal cancer (GIC) poses a serious threat to human health globally. Curcumin (CUR), a hydrophobic polyphenol extracted from the rhizome of Curcuma longa, has shown reliable anticancer function and low toxicity, thereby offering broad research prospects. Numerous studies have demonstrated the pharmacological mechanisms underlying the effectiveness of CUR against GIC, including the induction of apoptosis and autophagy, arrest of the cell cycle, inhibition of the epithelial-mesenchymal transition (EMT) processes, inhibition of cell invasion and migration, regulation of multiple signaling pathways, sensitization to chemotherapy and reversal of resistance to such treatments, and regulation of the tumor survival environment. It has been confirmed that CUR exerts its antitumor effects on GIC through these mechanisms in vitro and in vivo. Moreover, treatment with CUR is safe and tolerable. Newly discovered types of regulated cell death (RCD), such as pyroptosis, necroptosis, and ferroptosis, may provide a new direction for research on the efficacy of CUR against GIC. In this review, we discuss the recently found pharmacological mechanisms underlying the effects of CUR against GIC (gastric and colorectal cancers). The objective is to provide a reference for further research on treatments against GIC.

Optical coherence tomography evaluation of retinal nerve fiber layer thickness in non-arteritic anterior ischemic optic neuropathy and primary open angle glaucoma: a systematic review and Meta-analysis.

AIM: To assess the differences in average and sectoral peripapillary retinal nerve fiber layer (pRNFL) thickness using spectral domain optical coherence tomography (SD-OCT) in patients with non-arteritic anterior ischemic neuropathy (NAION) compared with those with primary open angle glaucoma (POAG). METHODS: A comprehensive literature search of the PubMed, Cochrane Library, and Embase databases were performed prior to October, 2021. Studies that compared the pRNFL thickness in NAION eyes with that in POAG eyes with matched mean deviation of the visual fields were included. The weighted mean difference (WMD) with 95% confidence interval (CI) was used to pool continuous outcomes. RESULTS: Ten cross-sectional studies (11 datasets) comprising a total of 625 eyes (278 NAION eyes, 347 POAG eyes) were included in the qualitative and quantitative analyses. The pooled results demonstrated that the superior pRNFL was significantly thinner in NAION eyes than in POAG eyes (WMD=-6.40, 95%CI: -12.22 to -0.58, P=0.031), whereas the inferior pRNFL was significant thinner in POAG eyes than in NAION eyes (WMD=11.10, 95%CI: 7.06 to 15.14, P≤0.001). No difference was noted concerning the average, nasal, and temporal pRNFL thickness (average: WMD=1.45, 95%CI: -0.75 to 3.66, P=0.196; nasal: WMD=-2.12, 95%CI: -4.43 to 0.19, P=0.072; temporal: WMD=-1.24, 95%CI: -3.96 to 1.47, P=0.370). CONCLUSION: SD-OCT based evaluation of inferior and superior pRNFL thickness can be potentially utilized to differentiate NAION from POAG, and help to understand the different pathophysiological mechanisms between these two diseases. Further longitudinal studies and studies using eight-quadrant or clock-hour classification method are required to validate the obtained findings.

Prevalence and correlates of depression and anxiety among Chinese international students in US colleges during the COVID-19 pandemic: A cross-sectional study.

BACKGROUND: Previous studies showed that the COVID-19 outbreak increased the levels of depression and anxiety in heterogeneous populations. However, none has explored the prevalence and correlates of depression and anxiety among Chinese international students studying in US colleges during the pandemic. OBJECTIVE: This study examines the prevalence of depression and anxiety among Chinese international students enrolled in US universities during the COVID-19 pandemic and identifies the associated factors, including habits, social and psychological support, sleep quality, and remote learning. METHODS: Between June and July 2020, we conducted a cross-sectional study through Wenjuanxing, a web-based survey platform. Participants were recruited with snowball sampling through 21 Chinese international student associations in US universities. The survey consisted of demographic questions, the Social Support Rating Scale (SSRS), the Insomnia Severity Index (ISI), the Patient Health Questionnaire-9 (PHQ-9), the General Anxiety Disorder-7 (GAD-7), and self-constructed questions on academic performance, financial concerns, use of social media, physical exercise, and psychological support. Cut-off scores of 10 were used for both PHQ-9 and GAD-7 to determine the binary outcomes of depression and anxiety, respectively. Bivariant analyses and multivariable logistic regression analyses were performed to identify the associated factors. RESULTS: Among 1881 participants, we found a prevalence of depression (PHQ-9 score⩾ 10) at 24.5% and that of anxiety (GAD-7 score⩾ 10) at 20.7%. A higher risk of depression was associated with recent exposure to traumatic events, agreement to pandemic's negative impacts on financial status, agreement and strong agreement to the negative impacts of remote learning on personal relationships, and a higher ISI score. A lower risk of depression was associated with disagreement to the negative impacts of remote learning on academic performance and future careers, strong willingness to seek professional help with emotional issues, and a higher SSRS score. In addition, a higher risk of anxiety was associated with recent exposure to traumatic events, a lot of workloads, often staying up for online classes, agreement and strong agreement to the negative impacts of remote learning on personal relationships, and a higher ISI score. A lower risk of anxiety was associated with the willingness and strong willingness to seek professional help with emotional issues, and a higher SSRS score. CONCLUSION: This study showed a high prevalence of depression and anxiety among Chinese international students studying in US colleges during the COVID-19 pandemic. Multiple correlates-including recent exposure to traumatic events, pandemic-related financial concerns, workload, social support, remote learning, willingness to seek professional help, and sleep quality-were identified. It is critical for future studies to further investigate this student population and for universities to provide more flexible learning options and more access to psychological services.

RBPMS2, as a novel biomarker for predicting lymph node metastasis, guides therapeutic regimens in gastric cancer.

RNA-binding protein with multiple splicing 2 (RBPMS2) is a critical gene that encodes a member of the RNA-recognition-motif-containing protein family and is involved in the development and dedifferentiation of digestive smooth muscle cells. However, whether RBPMS2 has an effect on the prognosis of gastric cancer (GC) and its possible mechanism during GC progression remain unknown. Here, we collected 596 GC patients who underwent curative surgical resection to evaluate expression of RBPMS2. RBPMS2 was upregulated in GC tissues, and was associated with lymph node metastasis. We analysis the KEGG pathway and GO biological processes, cellular component and molecular function of RBPMS2 interactive genes, as well as RBPMS2-binding partner ESRP1 interactive genes. We also focus on the correlation analysis between EMT-related genes and RBPMS2/ESRP1. Finally, we analysed the correlation between RBPMS2 expression and chemotherapeutic drugs which may assist in GC therapy and demonstrated that RBPMS2 expression was associated with tumour mutation burden (TMB) and Microsatellite Instability (MSI), as well as immune infiltration level in GC.