Discovery of a major QTL for resistance to the guava root-knot nematode (Meloidogyne enterolobii) in 'Tanzania', an African landrace sweetpotato (Ipomoea batatas).

Sweetpotato, Ipomoea batatas (L.) Lam. (2n = 6x = 90), is among the world's most important food crops and is North Carolina's most important vegetable crop. The recent introduction of Meloidogyne enterolobii poses a significant economic threat to North Carolina's sweetpotato industry and breeding resistance into new varieties has become a high priority for the US sweetpotato industry. Previous studies have shown that 'Tanzania', a released African landrace, is resistant to M. enterolobii. We screened the biparental sweetpotato mapping population, 'Tanzania' x 'Beauregard', for resistance to M. enterolobii by inoculating 246 full-sibs with 10,000 eggs each under greenhouse conditions. 'Tanzania', the female parent, was highly resistant, while 'Beauregard' was highly susceptible. Our bioassays exhibited strong skewing toward resistance for three measures of resistance: reproductive factor, eggs per gram of root tissue, and root gall severity ratings. A 1:1 segregation for resistance suggested a major gene conferred M. enterolobii resistance. Using a random-effect multiple interval mapping model, we identified a single major QTL, herein designated as qIbMe-4.1, on linkage group 4 that explained 70% of variation in resistance to M. enterolobii. This study provides a new understanding of the genetic basis of M. enterolobii resistance in sweetpotato and represents a major step towards the identification of selectable markers for nematode resistance breeding.

The efficacy and safety of anti-vascular endothelial growth factor combined with Ahmed glaucoma valve implantation in the treatment of neovascular glaucoma: a systematic review and meta-analysis.

Background: The intraocular injections of anti-vascular endothelial growth factor (anti-VEGF) demonstrates significant efficacy in inhibiting the formation of ocular neovascularization in neovascular glaucoma (NVG). Ahmed glaucoma valve implantation (AGVI) is extensively employed for the management of diverse glaucoma types. Objective: To further evaluate the efficacy and safety of anti-VEGF combined with AGVI in the treatment of neovascular glaucoma. Methods: A thorough search for randomized controlled trials (RCTs) was conducted across eight databases: PubMed, EMBASE, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang, SinoMed, and VIP. The search period was set from the inception of each database until March 2, 2024, to identify RCTs investigating the effectiveness and safety of combining AGVI with anti-VEGF therapy for NVG. We used the Cochrane Risk of Bias Assessment Tool to evaluate the quality of the literature and performed statistical analysis using Stata 15.0 software. Results: Fourteen RCTs were included in this study. Compared with AGVI alone, the combination of anti-VEGF drugs and AGVI can reduce postoperative intraocular pressure (IOP) at 1 week [WMD = -4.03, 95% CI (-5.73, -2.34), p < 0.001], 1 month [WMD = -5.39, 95% CI (-7.05, -3.74), p < 0.001], 3 months [WMD = -6.59, 95% CI (-7.85, -5.32), p < 0.001], 6 months [WMD = -4.99, 95% CI (-9.56, -0.43), p = 0.032], and more than 12 months [WMD = -3.86, 95% CI (-6.82, -0.90), p = 0.011], with a higher Effective rate [RR = 1.27, 95% CI (1.18, 1.37), p < 0.001], decreased incidence of postoperative hyphema [RR = 0.24, 95% CI (0.15, 0.39), p < 0.001], reduced use of postoperative antiglaucoma medications [WMD = -0.48, 95% CI (-0.61, -0.35), p < 0.001], and decreased aqueous humor VEGF levels [SMD = -2.84, 95% CI (-4.37, -1.31), p < 0.001]. Conclusion: In comparison to AGVI alone, the combination of AGVI with anti-VEGF therapy has better effects in reducing IOP at various time intervals, diminishing postoperative antiglaucoma medication requirements and reducing aqueous humor VEGF levels. Furthermore, it effectively minimizes the incidence of postoperative hyphema. Nevertheless, due to the variability in the quality of the trials included, further high-quality experiments will be required in the future to substantiate this conclusion. Systematic review registration: PROSPERO, identifier CRD42024519862, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024519862.

Circulating glycated albumin levels and gestational diabetes mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) is characterized by glucose intolerance that is first diagnosed during pregnancy, making it the most common complication associated with this period. Early detection and targeted treatment of GDM can minimize foetal exposure to maternal hyperglycaemia and subsequently reduce the associated adverse pregnancy outcomes. Previous studies have inconsistently suggested that the level of glycated albumin (GA) might predict GDM. AIM: To review and synthesize existing evidence to evaluate the relationship between GA levels and the development of GDM. METHODS: We sought to compare GA levels between GDM and control groups in this meta-analysis by systematically searching the Web of Science, PubMed, Cochrane Library, and Embase databases for articles published up to June 2023. The analysis utilized the weighted mean difference (WMD) as the primary metric. The data were meticulously extracted, and the quality of the included studies was assessed. Additionally, we conducted a subgroup analysis based on study region and sample size. We assessed heterogeneity using I 2 statistics and evaluated publication bias through funnel plots. Additionally, trim-and-fill analysis was employed to detect and address any potential publication bias. RESULTS: The meta-analysis included a total of 11 studies involving 5477 participants, comprising 1900 patients with GDM and 3577 control individuals. The synthesized results revealed a notable correlation between elevated GA levels and increased susceptibility to GDM. The calculated WMD was 0.42, with a 95% confidence interval (95%CI) ranging from 0.11 to 0.74, yielding a P value less than 0.001. Concerning specific GA levels, the mean GA level in the GDM group was 12.6, while for the control group, it was lower, at 11.6. This discrepancy underscores the potential of GA as a biomarker for assessing GDM risk. Moreover, we explored the levels of glycated haemoglobin (HbA1c) in both cohorts. The WMD for HbA1c was 0.19, with a 95%CI ranging from 0.15 to 0.22 and a P value less than 0.001. This observation suggested that both GA and HbA1c levels were elevated in individuals in the GDM group compared to those in the control group. CONCLUSION: Our meta-analysis revealed a substantial correlation between elevated GA levels and increased GDM risk. Furthermore, our findings revealed elevated levels of HbA1c in GDM patients, emphasizing the significance of monitoring both GA and HbA1c levels for early GDM detection and effective management.

Antibiotic-induced gut microbiota disruption promotes vascular calcification by reducing short-chain fatty acid acetate.

BACKGROUND: Vascular calcification is a common vascular lesion associated with high morbidity and mortality from cardiovascular events. Antibiotics can disrupt the gut microbiota (GM) and have been shown to exacerbate or attenuate several human diseases. However, whether antibiotic-induced GM disruption affects vascular calcification remains unclear. METHODS: Antibiotic cocktail (ABX) treatment was utilized to test the potential effects of antibiotics on vascular calcification. The effects of antibiotics on GM and serum short-chain fatty acids (SCFAs) in vascular calcification mice were analyzed using 16 S rRNA gene sequencing and targeted metabolomics, respectively. Further, the effects of acetate, propionate and butyrate on vascular calcification were evaluated. Finally, the potential mechanism by which acetate inhibits osteogenic transformation of VSMCs was explored by proteomics. RESULTS: ABX and vancomycin exacerbated vascular calcification. 16 S rRNA gene sequencing and targeted metabolomics analyses showed that ABX and vancomycin treatments resulted in decreased abundance of Bacteroidetes in the fecal microbiota of the mice and decreased serum levels of SCFAs. In addition, supplementation with acetate was found to reduce calcium salt deposition in the aorta of mice and inhibit osteogenic transformation in VSMCs. Finally, using proteomics, we found that the inhibition of osteogenic transformation of VSMCs by acetate may be related to glutathione metabolism and ubiquitin-mediated proteolysis. After adding the glutathione inhibitor Buthionine sulfoximine (BSO) and the ubiquitination inhibitor MG132, we found that the inhibitory effect of acetate on VSMC osteogenic differentiation was weakened by the intervention of BSO, but MG132 had no effect. CONCLUSION: ABX exacerbates vascular calcification, possibly by depleting the abundance of Bacteroidetes and SCFAs in the intestine. Supplementation with acetate has the potential to alleviate vascular calcification, which may be an important target for future treatment of vascular calcification.

Mechanism of immune activation mediated by genomic instability and its implication in radiotherapy combined with immune checkpoint inhibitors.

Various genetic and epigenetic changes associated with genomic instability (GI), including DNA damage repair defects, chromosomal instability, and mitochondrial GI, contribute to development and progression of cancer. These alterations not only result in DNA leakage into the cytoplasm, either directly or through micronuclei, but also trigger downstream inflammatory signals, such as the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. Apart from directly inducing DNA damage to eliminate cancer cells, radiotherapy (RT) exerts its antitumor effects through intracellular DNA damage sensing mechanisms, leading to the activation of downstream inflammatory signaling pathways. This not only enables local tumor control but also reshapes the immune microenvironment, triggering systemic immune responses. The combination of RT and immunotherapy has emerged as a promising approach to increase the probability of abscopal effects, where distant tumors respond to treatment due to the systemic immunomodulatory effects. This review emphasizes the importance of GI in cancer biology and elucidates the mechanisms by which RT induces GI remodeling of the immune microenvironment. By elucidating the mechanisms of GI and RT-induced immune responses, we aim to emphasize the crucial importance of this approach in modern oncology. Understanding the impact of GI on tumor biological behavior and therapeutic response, as well as the possibility of activating systemic anti-tumor immunity through RT, will pave the way for the development of new treatment strategies and improve prognosis for patients.

M6A-modified lncRNA FAM83H-AS1 promotes colorectal cancer progression through PTBP1.

LncRNA plays a crucial role in cancer progression and targeting, but it has been difficult to identify the critical lncRNAs involved in colorectal cancer (CRC) progression. We identified FAM83H-AS1 as a tumor-promoting associated lncRNA using 21 pairs of stage IV CRC tissues and adjacent normal tissues. In vitro and in vivo experiments revealed that knockdown of FAM83H-AS1 in CRC cells inhibited tumor proliferation and metastasis, and vice versa. M6A modification is critical for FAM83H-AS1 RNA stability through the writer METTL3 and the readers IGF2BP2/IGFBP3. PTBP1-an RNA binding protein-is responsible for the FAM83H-AS1 function in CRC. T4 (1770-2440 nt) and T5 (2440-2743 nt) on exon 4 of FAM83H-AS1 provide a platform for PTBP1 RRM2 interactions. Our results demonstrated that m6A modification dysregulated the FAM83H-AS1 oncogenic role by phosphorylated PTBP1 on its RNA splicing effect. In patient-derived xenograft models, ASO-FAM83H-AS1 significantly suppressed the growth of gastrointestinal (GI) tumors, not only CRC but also GC and ESCC. The combination of ASO-FAM83H-AS1 and oxaliplatin/cisplatin significantly suppressed tumor growth compared with treatment with either agent alone. Notably, there was pathological complete response in all these three GI cancers. Our findings suggest that FAM83H-AS1 targeted therapy would benefit patients primarily receiving platinum-based therapy in GI cancers.

Distinct effects of phyllosphere and rhizosphere microbes on invader Ageratina adenophora during its early life stages.

Microbes strongly affect invasive plant growth. However, how phyllosphere and rhizosphere soil microbes distinctively affect seedling mortality and growth of invaders across ontogeny under varying soil nutrient levels remains unclear. In this study, we used the invader Ageratina adenophora to evaluate these effects. We found that higher proportions of potential pathogens were detected in core microbial taxa in leaf litter than rhizosphere soil and thus leaf inoculation had more adverse effects on seed germination and seedling survival than soil inoculation. Microbial inoculation at different growth stages altered the microbial community and functions of seedlings, and earlier inoculation had a more adverse effect on seedling survival and growth. The soil nutrient level did not affect microbe-mediated seedling growth and the relative abundance of the microbial community and functions involved in seedling growth. The effects of some microbial genera on seedling survival are distinct from those on growth. Moreover, the A. adenophora seedling-killing effects of fungal strains isolated from dead seedlings by non-sterile leaf inoculation exhibited significant phylogenetic signals, by which strains of Allophoma and Alternaria generally caused high seedling mortality. Our study stresses the essential role of A. adenophora litter microbes in population establishment by regulating seedling density and growth.

High hyperdiploid karyotype with ≥ 49 chromosomes represents a heterogeneous subgroup of acute myeloid leukemia with differential TP53 mutation status and prognosis: a single-center study from China.

High hyperdiploid karyotype with ≥ 49 chromosomes (which will be referred to as HHK) is rare in acute myeloid leukemia (AML). The European leukemia network (ELN) excluded those harboring only numerical changes (with ≥ 3 chromosome gains) from CK and listed them in the intermediate risk group, while the UK National Cancer Research Institute Adult Leukaemia Working Group classification defined ≥ 4 unrelated chromosome abnormalities as the cutoff for a poorer prognosis. Controversies occurred among studies on the clinical outcome of HHK AML, and their molecular characteristics remained unstudied. We identified 1.31% (133/10,131) HHK cases within our center, among which 48 cases only had numerical changes (NUM), 42 had ELN defined adverse abnormalities (ADV) and 43 had other structural abnormalities (STR). Our study demonstrated that: (1) No statistical significance for overall survival (OS) was observed among three cytogenetic subgroups (NUM, STR and ADV) and HHK AML should be assigned to the adverse cytogenetic risk group. (2) The OS was significantly worse in HHK AML with ≥ 51 chromosomes compared with those with 49-50 chromosomes. (3) The clinical characteristics were similar between NUM and STR group compared to ADV group. The former two groups had higher white blood cell counts and blasts, lower platelet counts, and mutations associated with signaling, while the ADV group exhibited older age, higher chromosome counts, higher percentage of myelodysplastic syndrome (MDS) history, and a dominant TP53 mutation.

Contrasting nidification behaviors facilitate diversification and colonization of the Music frogs under a changing paleoclimate.

In order to cope with the complexity and variability of the terrestrial environment, amphibians have developed a wide range of reproductive and parental behaviors. Nest building occurs in some anuran species as parental care. Species of the Music frog genus Nidirana are known for their unique courtship behavior and mud nesting in several congeners. However, the evolution of these frogs and their nidification behavior has yet to be studied. With phylogenomic and phylogeographic analyses based on a wide sampling of the genus, we find that Nidirana originated from central-southwestern China and the nidification behavior initially evolved at ca 19.3 Ma but subsequently lost in several descendants. Further population genomic analyses suggest that the nidification species have an older diversification and colonization history, while N. adenopleura complex congeners that do not exhibit nidification behavior have experienced a recent rapid radiation. The presence and loss of the nidification behavior in the Music frogs may be associated with paleoclimatic factors such as temperature and precipitation. This study highlights the nidification behavior as a key evolutionary innovation that has contributed to the diversification of an amphibian group under past climate changes.

The association of depressive symptoms with adverse clinical outcomes in hypertension: Data from SPRINT randomized trail.

OBJECTIVE: This study intends to explore the effect of depressive symptoms on adverse clinical outcomes in middle-aged and elderly hypertensive patients. METHODS: This post hoc analysis was conducted using data from the Systolic Blood Pressure Intervention Trial (SPRINT), and we used cox proportional risk regression to examine the relationship between depressive symptoms and adverse clinical outcomes (primary outcome, all-cause mortality, cardiovascular disease(CVD) mortality, heart failure(HF), myocardial infarction(MI), non-myocardial infarction acute coronary syndrome(non-MI ACS)). RESULTS: In a follow-up study of 9259 participants, we found that depression symptoms was significantly and positively associated with the primary outcome (HR 1.03, 95%CI 1.01-1.05; p for trend = 0.0038), all-cause mortality (HR 1.03, 95%CI 1.01-1.05; p for trend = 0.0308), HF(HR 1.05, 95%CI 1.01-1.08; p for trend = 0.0107), and non-MI ACS(HR 1.06, 95%CI 1.01-1.10; p for trend = 0.0120). Kaplan-Meier survival curves for depression symptoms severity (none, mild, moderate, and above) and adverse clinical outcomes suggested that for all but primary clinical outcomes, the cumulative risk of adverse clinical outcomes increased with increasing depression symptoms severity. CONCLUSION: For middle-aged and elderly hypertensive patients, depression symptoms exacerbates the risk of adverse clinical outcomes (primary outcome, all-cause mortality, CVD death, MI, HF, and non-MI ACS), and the risk increases with the severity of depression symptoms.

Structural or/and functional MRI-based machine learning techniques for attention-deficit/hyperactivity disorder diagnosis: A systematic review and meta-analysis.

BACKGROUND: The aim of this study was to investigate the diagnostic value of ML techniques based on sMRI or/and fMRI for ADHD. METHODS: We conducted a comprehensive search (from database creation date to March 2024) for relevant English articles on sMRI or/and fMRI-based ML techniques for diagnosing ADHD. The pooled sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), summary receiver operating characteristic (SROC) curve and area under the curve (AUC) were calculated to assess the diagnostic value of sMRI or/and fMRI-based ML techniques. The I2 test was used to assess heterogeneity and the source of heterogeneity was investigated by performing a meta-regression analysis. Publication bias was assessed using the Deeks funnel plot asymmetry test. RESULTS: Forty-three studies were included in the systematic review, 27 of which were included in our meta-analysis. The pooled sensitivity and specificity of sMRI or/and fMRI-based ML techniques for the diagnosis of ADHD were 0.74 (95 % CI 0.65-0.81) and 0.75 (95 % CI 0.67-0.81), respectively. SROC curve showed that AUC was 0.81 (95 % CI 0.77-0.84). Based on these findings, the sMRI or/and fMRI-based ML techniques have relatively good diagnostic value for ADHD. LIMITATIONS: Our meta-analysis specifically focused on ML techniques based on sMRI or/and fMRI studies. Since EEG-based ML techniques are also used for diagnosing ADHD, further systematic analyses are necessary to explore ML methods based on multimodal medical data. CONCLUSION: sMRI or/and fMRI-based ML technique is a promising objective diagnostic method for ADHD.

Serum Lactate Is an Indicator for Short-Term and Long-Term Mortality in Patients with Acute Pancreatitis.

BACKGROUND: Serum lactate, as a single and an easily available biomarker, has been applied in various diseases. AIMS: In this study, we aimed to explore the predictive value of serum lactate for short-term and long-term prognosis in acute pancreatitis (AP) admitted in intensive care unit (ICU) based on a large-scale database. METHODS: AP patients admitted in ICU in the MIMIC-IV database were included. We constructed three different models to investigate the relationships between serum lactate and clinical outcomes, including 30-day, 180-day and 1-year mortality in AP. Smooth fitting curves were performed for intuitively demonstrating the relationship between serum lactate and different outcomes in AP by the generalized additive model. RESULTS: A total of 895 AP patients admitted in ICU were included. The mortalities of 30 days, 180 days, and 1 year were 12.63% (n = 113), 16.87% (n = 151), and 17.54% (n = 157). In model B, with 1-mmol/L increment in serum lactate, the values of OR in 30-day, 180-day and 1-year mortality were 1.20 (95%CI 1.04-1.37, P = 0.0094), 1.21 (95%CI 1.06-1.37, P = 0.0039), and 1.21 (95%CI 1.07-1.38, P = 0.0035). The AUCs of serum lactate for predicting 30-day, 180-day, and 1-year mortality in AP were 0.688 (95%CI 0.633-0.743), 0.655 (95%CI 0.605-0.705), and 0.653 (95%CI 0.603-0.701), respectively. The cut-off value of serum lactate predicting 30-day, 180-day and 1-year mortality in AP was 2.4 mmol/L. CONCLUSION: Serum lactate could be an indicator for short-term and long-term mortality in patients with AP admitted in ICU.

Stereotactic body radiation therapy in patients with centrally located hepatocellular carcinoma: A retrospective, single-arm, multi-center study.

Centrally located hepatocellular carcinoma (HCC) is difficult to be radically resected due to its special location close to major hepatic vessels. Thus, we aimed to assess whether stereotactic body radiation therapy (SBRT) can be an effective and safe approach for centrally located HCC. This retrospective study included 172 patients with centrally located HCC who were treated with SBRT. Overall survival (OS) was analyzed as the primary endpoint. Rates of progression-free survival (PFS), local control, intrahepatic relapse, extrahepatic metastasis and toxicities were analyzed as secondary endpoints. The OS rates of 1-, 3-, and 5-year were 97.7%, 86.7%, and 76.3%, respectively. The PFS/local control rates of 1-, 3-, and 5-year were 94.1%/98.2%, 76.8%/94.9%, and 59.3%/92.3%, respectively. The cumulative incidence of intrahepatic relapse/extrahepatic metastases of 1-, 3-, and 5-year were 3.7%/2.9%, 25.0%/7.4%, and 33.3%/9.8%, respectively. Both univariate and multivariate analyses revealed that patients received BED10 at 100 Gy or more had better OS. Radiation-related adverse events were mild to moderate according to Common Terminology Criteria for Adverse Events, and no toxicities over grade 3 were observed. Patients with centrally located HCC in our cohort who received SBRT had similar OS and PFS rates compared to those reported in literatures who received surgery with neoadjuvant or adjuvant intensity-modulated radiation therapy. These results indicate that SBRT is an effective and well-tolerated method for patients with centrally located HCC, suggesting that it may serve as a reasonable alternative treatment for these kind of patients.

The novel TERF2::PDGFRB fusion gene enhances tumorigenesis via PDGFRB/STAT5 signalling pathways and sensitivity to TKI in ph-like ALL.

Patients with Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like ALL) often face a grim prognosis, with PDGFRB gene fusions being commonly detected in this subgroup. Our study has unveiled a newfound fusion gene, TERF2::PDGFRB, and we have found that patients carrying this fusion gene exhibit sensitivity to dasatinib. Ba/F3 cells harbouring the TERF2::PDGFRB fusion display IL-3-independent cell proliferation through activation of the p-PDGFRB and p-STAT5 signalling pathways. These cells exhibit reduced apoptosis and demonstrate sensitivity to imatinib in vitro. When transfused into mice, Ba/F3 cells with the TERF2::PDGFRB fusion gene induce tumorigenesis and a shortened lifespan in cell-derived graft models, but this outcome can be improved with imatinib treatment. In summary, we have identified the novel TERF2::PDGFRB fusion gene, which exhibits oncogenic potential both in vitro and in vivo, making it a potential therapeutic target for tyrosine kinase inhibitors (TKIs).

Machine learning-based extrachromosomal DNA identification in large-scale cohorts reveals its clinical implications in cancer.

The clinical implications of extrachromosomal DNA (ecDNA) in cancer therapy remain largely elusive. Here, we present a comprehensive analysis of ecDNA amplification spectra and their association with clinical and molecular features in multiple cohorts comprising over 13,000 pan-cancer patients. Using our developed computational framework, GCAP, and validating it with multifaceted approaches, we reveal a consistent pan-cancer pattern of mutual exclusivity between ecDNA amplification and microsatellite instability (MSI). In addition, we establish the role of ecDNA amplification as a risk factor and refine genomic subtypes in a cohort from 1015 colorectal cancer patients. Importantly, our investigation incorporates data from four clinical trials focused on anti-PD-1 immunotherapy, demonstrating the pivotal role of ecDNA amplification as a biomarker for guiding checkpoint blockade immunotherapy in gastrointestinal cancer. This finding represents clinical evidence linking ecDNA amplification to the effectiveness of immunotherapeutic interventions. Overall, our study provides a proof-of-concept of identifying ecDNA amplification from cancer whole-exome sequencing (WES) data, highlighting the potential of ecDNA amplification as a valuable biomarker for facilitating personalized cancer treatment.

Risk factors and survival analysis of human leukocyte antigen loss in relapsed acute myeloid leukaemia/myelodysplastic syndrome patients after allogeneic haematopoietic stem cell transplantation.

To investigate the clinical characteristics and risk factors of specific human leukocyte antigen loss (HLA loss) in relapsed acute myeloid leukaemia (AML)/myelodysplastic syndrome (MDS) patients after allogeneic haematopoietic stem cell transplantation (allo-HSCT), and compare the responses of patients with HLA loss relapse with those without HLA loss (non-HLA loss) to different treatment regimens. Clinical data of traceable patients with AML/MDS after myeloablative allo-HSCT in our centre between January 2010 and June 2021, who experienced disease relapse after the transplantation, were collected. The patients were divided into the HLA loss relapse group and the non-HLA loss relapsed group based on HLA loss gene test findings by next-generation sequencing. The patients' median overall survival (OS) after the relapse were compared, and univariate and multivariate analyses were performed using the Kaplan-Meier survival curve and Cox proportional hazard model to explore the responses to different treatments after relapse. A total of 2359 patients were selected. Retrospective HLA gene loss gene detection was performed for the deoxyribonucleic acid in 179 relapsed patients, including 47 patients in the HLA loss group (27.2%), 126 patients in the non-HLA loss group (72.8%) and 6 patients were excluded due to a lack of confirmed results. There was no significant statistical difference in the baseline characteristics of patients between the two groups, but as to transplantation-related characteristics, the donor-recipient relationship and HLA mismatched loci were statistically different between the two groups (both p < 0.001). Multivariate Cox analysis showed that more HLA mismatched loci ≥3 (HR = 3.66; 95% CI: 1.61-8.31; p = 0.002), time (≤6 months) from HSCT to relapse (HR = 7.92; 95% CI: 3.35-18.74; p < 0.001) and donor chimerism (CD3) in bone marrow at relapse (HR = 1.02; 95% CI: 1.00-1.03; p = 0.036) were independent factors affecting HLA loss relapse. The ratio of negative conversion of FLT3-ITD or CEBPA mutation was significantly lower in patients with post-transplantation HLA loss relapse than in the non-HLA loss group (0.0% vs. 45.5%, p = 0.003; 0.0% vs. 80.0%, p = 0.035), with none of the patients with FLT3-ITD or CEBPA mutation turned negative in the HLA loss group. The number of gene mutations turned negative when relapse in the non-HLA loss group was remarkably higher than that in the HLA loss group (p = 0.001). Using donor lymphocyte infusion (DLI) could not prolong OS for the HLA loss group (p = 0.42). Nevertheless, second transplantation had a significant positive impact on OS in the HLA loss group (p = 0.017), although only five patients in the HLA loss group underwent second transplantation. However, patients in the non-HLA loss group using DLI had a relatively longer OS time than those without DLI (p = 0.017). Second transplantation could also prolong OS in the non-HLA loss group, but the effect was not as significant as in the HLA loss group (p = 0.053). In summary, HLA loss detection is essential for patients with recurrence after transplantation, especially for those with more HLA mismatched loci and non-sibling donor. Furthermore, the detection of HLA loss has a guiding role in choosing subsequent therapy when relapsed, as secondary transplantation is more suitable than DLI for those with HLA loss.

HIPK3 maintains sensitivity to platinum drugs and prevents disease progression in gastric cancer.

In the realm of cancer therapeutics and resistance, kinases play a crucial role, particularly in gastric cancer (GC). Our study focused on platinum-based chemotherapy resistance in GC, revealing a significant reduction in homeodomain-interacting protein kinase 3 (HIPK3) expression in platinum-resistant tumors through meticulous analysis of transcriptome datasets. In vitro and in vivo experiments demonstrated that HIPK3 knockdown enhanced tumor proliferation and metastasis, while upregulation had the opposite effect. We identified the myocyte enhancer factor 2C (MEF2C) as a transcriptional regulator of HIPK3 and uncovered HIPK3's role in downregulating the morphogenesis regulator microtubule-associated protein (MAP7) through ubiquitination. Phosphoproteome profiling revealed HIPK3's inhibitory effects on mTOR and Wnt pathways crucial in cell proliferation and movement. A combined treatment strategy involving oxaliplatin, rapamycin, and IWR1-1-endo effectively overcame platinum resistance induced by reduced HIPK3 expression. Monitoring HIPK3 levels could serve as a GC malignancy and platinum resistance indicator, with our proposed treatment strategy offering novel avenues for reversing resistance in gastric cancer.

USP28 Serves as a Key Suppressor of Mitochondrial Morphofunctional Defects and Cardiac Dysfunction in the Diabetic Heart.

BACKGROUND: The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct diabetic cardiomyopathy progression. Herein, we assessed the potential role and therapeutic value of USP28 (ubiquitin-specific protease 28) on the metabolic vulnerability of diabetic cardiomyopathy. METHODS: The type 2 diabetes mouse model was established using db/db leptin receptor-deficient mice and high-fat diet/streptozotocin-induced mice. Cardiac-specific knockout of USP28 in the db/db background mice was generated by crossbreeding db/m and Myh6-Cre+/USP28fl/fl mice. Recombinant adeno-associated virus serotype 9 carrying USP28 under cardiac troponin T promoter was injected into db/db mice. High glucose plus palmitic acid-incubated neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing, immunoprecipitation and mass spectrometry analysis, protein pull-down, chromatin immunoprecipitation sequencing, and chromatin immunoprecipitation assay. RESULTS: Microarray profiling of the UPS (ubiquitin-proteasome system) on the basis of db/db mouse hearts and diabetic patients' hearts demonstrated that the diabetic ventricle presented a significant reduction in USP28 expression. Diabetic Myh6-Cre+/USP28fl/fl mice exhibited more severe progressive cardiac dysfunction, lipid accumulation, and mitochondrial disarrangement, compared with their controls. On the other hand, USP28 overexpression improved systolic and diastolic dysfunction and ameliorated cardiac hypertrophy and fibrosis in the diabetic heart. Adeno-associated virus serotype 9-USP28 diabetic mice also exhibited less lipid storage, reduced reactive oxygen species formation, and mitochondrial impairment in heart tissues than adeno-associated virus serotype 9-null diabetic mice. As a result, USP28 overexpression attenuated cardiac remodeling and dysfunction, lipid accumulation, and mitochondrial impairment in high-fat diet/streptozotocin-induced type 2 diabetes mice. These results were also confirmed in neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes. RNA sequencing, immunoprecipitation and mass spectrometry analysis, chromatin immunoprecipitation assays, chromatin immunoprecipitation sequencing, and protein pull-down assay mechanistically revealed that USP28 directly interacted with PPARα (peroxisome proliferator-activated receptor α), deubiquitinating and stabilizing PPARα (Lys152) to promote Mfn2 (mitofusin 2) transcription, thereby impeding mitochondrial morphofunctional defects. However, such cardioprotective benefits of USP28 were largely abrogated in db/db mice with PPARα deletion and conditional loss-of-function of Mfn2. CONCLUSIONS: Our findings provide a USP28-modulated mitochondria homeostasis mechanism that involves the PPARα-Mfn2 axis in diabetic hearts, suggesting that USP28 activation or adeno-associated virus therapy targeting USP28 represents a potential therapeutic strategy for diabetic cardiomyopathy.

How does economic inequality shape conspiracy theories? Empirical evidence from China.

Conspiracy theories tend to be prevalent, particularly in societies with high economic inequality. However, few studies have examined the relationship between economic inequality and belief in conspiracy theories. We propose that economic inequality leads people to believe conspiracy theories about economically advantaged groups (i.e., upwards conspiracy theories) and that moral evaluations of those groups mediate this relationship. Study 1 (N = 300) found support for these ideas in a survey among Chinese residents. Study 2 (N = 160) manipulated participants' perceptions of economic inequality in a virtual society. The manipulation shaped moral evaluations of economically advantaged groups, and conspiracy beliefs, in the predicted manner. In Study 3 (N = 191) and Study 4 (N = 210), we experimentally manipulated participants' perceptions of economic inequality in real Chinese society and replicated the results of Study 2. In addition, in Study 4, we find that economic inequality predicts belief in conspiracy theories about economically disadvantaged groups (i.e., downward conspiracy theories), which was mediated by anomie. We conclude that perceived economic inequality predicts conspiracy theories about economically advantaged groups and that moral evaluations account for this effect. Also, upward and downward conspiracy theory beliefs are associated with different psychological processes.