KMT2D mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-induced regulatory T cell trafficking via FBXW7-NOTCH-MYC/TGF-ß1 axis.

Histone methyltransferase KMT2D is one of the most frequently mutated genes in diffuse large B-cell lymphoma (DLBCL) and has been identified as an important pathogenic factor and prognostic marker. However, the biological relevance of KMT2D mutations on tumor microenvironment remains to be determined. KMT2D mutations were assessed by whole-genome/exome sequencing (WGS/WES) in 334 patients and by targeted sequencing in 427 patients with newly diagnosed DLBCL. Among all 761 DLBCL patients, somatic mutations in KMT2D were observed in 143 (18.79%) patients and significantly associated with advanced Ann Arbor stage and MYC expression ≥ 40%, as well as inferior progression-free survival and overall survival. In B-lymphoma cells, the mutation or knockdown of KMT2D inhibited methylation of lysine 4 on histone H3 (H3K4), downregulated FBXW7 expression, activated NOTCH signaling pathway and downstream MYC/TGF-ß1, resulting in alterations of tumor-induced regulatory T cell trafficking. In B-lymphoma murine models established with subcutaneous injection of SU-DHL-4 cells, xenografted tumors bearing KMT2D mutation presented lower H3K4 methylation, higher regulatory T cell recruitment, thereby provoking rapid tumor growth compared with wild-type KMT2D via FBXW7-NOTCH-MYC/TGF-ß1 axis.

Characteristics and Differences in Mpox Patients with and without HIV Infection: A Retrospective Cross-Sectional Study in Chengdu, China.

Purpose: To date, there are few reports about mpox case series in China, and scarce information is available about the in-vivo kinetics of T-cell responses in the early stage of mpox infection. This study aims to investigate the clinical difference among mpox patients with and without human immunodeficiency virus (HIV) infection. Patients and Methods: A total of 56 patients diagnosed with mpox by Chengdu Center for Disease Control and Prevention (CDC) and hospitalized in Public Health Clinical Center of Chengdu were retrospectively included and divided into an HIV-infected group (n=23) and a non-HIV-infected group (n=33). Clinical characteristics and serum chemistry findings of mpox patients were collected in order to analyze the differences between the HIV-infected group and the non-HIV-infected group. Results: Multiple laboratory abnormalities, including elevated C-reactive protein (69.1%), hypocalcemia (50.9%), elevated CD3+CD8+T counts (47.0%) and inverted ratio of CD3+CD4+T to CD3+CD8+T (64.7%) were common in mpox cases. There were statistically significant differences (all P < 0.05) in age, serum calcium levels, CD3+CD4+T counts, the ratio of CD3+CD4+T to CD3+CD8+T, proportion with >10 rashes, incidence of proctitis anus and time from rash growth to rash scab shedding between HIV-infected group and non-HIV-infected group. In the early stage of mpox infection, the median of CD3+CD8+T counts in the non-HIV-infected group was significantly higher than that in healthy donors (P<0.001), and the median of CD3+CD4+T/CD3+CD8+T ratio was significantly lower (P<0.001). The median of CD3+CD4+T counts in mpox patients co-infected with HIV significantly decreased compared to the pre-infection level (p =0.033). Conclusion: Our study indicates that mpox co-infected with HIV patients have longer lasting rash lesions and a higher incidence of proctitis anus. T-cell responses may be different between HIV-infected and non-HIV-infected individuals in the early stage of mpox infection.

A case report of abdominal metastatic dermatofibrosarcoma protuberans misdiagnosed as gastrointestinal stromal tumor.

Dermatofibrosarcoma protuberans (DFSP) is a low-grade malignant soft-tissue tumor that originates from the skin. It has a slow onset in the early stages, non-specific clinical symptoms, low specificity, and can easily be overlooked, missed, or misdiagnosed by clinicians and pathologists. In addition, DFSP is prone to recurrence after local surgical treatment; however, distant metastasis, especially abdominal metastasis, is rare, which is also a challenge for the accurate diagnosis of DFSP when it progresses distantly. Now a case of abdominal metastasis of DFSP is reported. The patient has been treated with imatinib for ten years, and the lesion has shrunk, but because the patient has been receiving imatinib treatment, his abdominal lesion was once misdiagnosed as gastrointestinal stromal tumor. Therefore, we report on this case to enhance the understanding of the diagnosis and treatment of DFSP, and to provide reference for the pathological diagnosis and precise treatment of such patients.

De Novo CD5-positive diffuse large B-cell lymphoma: A genomic profiling study and prognostic analysis of 46 patients.

We reported 46 cases of Diffuse Large B-cell lymphoma which abnormally expressed CD5 protein (De Novo CD5-positive DLBCL), which had attracted researcher's attention for a period of time for its poor prognosis. However, there were few studies on its molecular change. In the present article, we summarized the genetic alterations using a lymphopanel detection method by Next Generation Sequencing(NGS). The most frequently mutated genes were MYD88L265P (20/46, 43.5%), followed by PIMI (19/46, 41.3%), IGLL5 (13/46, 28.3%)and CD79B (11/46, 23.9%). We further investigated the relationship between gene alterations and prognosis using OS(Overall survival) and PFS(Progression-free survival). MYD88, CREBBP, and ACTB mutation were significantly associated with inferior OS (P = 0.032, 0.000, 0.001), PIMI, CREBBP, ACTB and CXCR4 mutation were significantly associated with inferior PFS (P = 0.016, 0.001, 0.045, 0.024). Meanwhile, we found that De Novo CD5-positive DLBCL had BCL-6(9/46,19.6%), C-MYC (4/46, 8.7%) and IRF4 (2/19, 10.5%) rearrangement, but without BCL-2 rearrangement, there were no significantly associations with prognosis. In summary, our research explored the gene alterations of De Novo CD5-positive DLBCL in a relatively large scale for the first time, the most common gene mutation was MYD88L265P which was also a potential prognostic factor, providing a potential therapeutic target for the patients of De Novo CD5-positive DLBCL.

Characteristics of Salmonella From Chinese Native Chicken Breeds Fed on Conventional or Antibiotic-Free Diets.

Salmonella is a common food-borne Gram-negative pathogen with multiple serotypes. Pullorum disease, caused by Salmonella Pullorum, seriously threatens the poultry industry. Many previous studies were focused on the epidemiological characteristics of Salmonella infections in conventional antibiotic use poultry. However, little is known about Salmonella infections in chicken flocks fed on antibiotic-free diets. Herein, we investigated and compared Salmonella infections in three Chinese native breeders fed on antibiotic-free diets, including the Luhua, Langya, and Qingjiaoma chickens, and one conventional breeder, the Bairi chicken, via analyzing 360 dead embryos in 2019. The results showed that the main Salmonella serotypes detected in a total of 155 isolates were S. Pullorum (82.6%) and S. Enteritidis (17.4%). Coinfection with two serotypes of Salmonella was specifically found in Bairi chicken. The sequence type (ST) in S. Pullorum was ST92 (n = 96) and ST2151 (n = 32), whereas only ST11 (n = 27) was found in S. Enteritidis. The Salmonella isolates from three breeder flocks fed on antibiotic-free diets exhibited phenotypic heterogeneity with a great variety of drug resistance spectrum. Most of the isolates among three chicken breeds Luhua (64.9%, 50/77), Langya (60%, 12/20) and Qingjiaoma (58.3%, 7/12) fed on antibiotic-free diets were resistant to only one antibiotic (erythromycin), whereas the rate of resistance to one antibiotic in conventional Bairi chicken isolates was only 4.3% (2/46). The multidrug-resistance rate in Salmonella isolates from layer flocks fed on antibiotic-free diets (20.2%, 22/109) was significantly (P < 0.0001) lower than that from chickens fed on conventional diets (93.5%, 43/46). However, high rate of resistance to erythromycin (97.4%~100%) and streptomycin (26%~41.7%) were also found among three breeder flocks fed on antibiotic-free diets, indicating resistance to these antibiotics likely spread before antibiotic-free feeding in poultry farms. The findings of this study supplement the epidemiological data of salmonellosis and provide an example of the characteristics of Salmonella in the chicken flocks without direct antibiotic selective pressure.

Decreased pulmonary artery distensibility as a marker for severity in acute pulmonary embolism patients undergoing ECG-gated CTPA.

To investigate the characteristics of pulmonary artery distensibility (PAD) in patients with acute pulmonary embolism (APE) and to assess whether a relationship exists between PAD and the disease severity. Clinical and radiological data of 30 APE patients who underwent retrospective electrocardiogram (ECG)-gated computed tomography pulmonary angiography (CTPA) with a definite diagnosis of APE were retrospectively reviewed in the present study, including 15 subjects in severe (SPE) group and 15 subjects in non-severe (NSPE) group. PAD and cardiac function parameters were compared between the two groups, their relationships were investigated, and receiver operating characteristic (ROC) curves were used to determine the sensitivity and specificity of the above parameters for the diagnosis of APE severity. The PAD decreased in the following order: NSPE group (6.065 ± 2.114) × 10-3 (%/mmHg), and SPE group (4.334 ± 1.777) × 10-3 (%/mmHg) (P < 0.05). All the cardiac function parameters except RA/LAdiameter showed statistically significant different values between the two groups (P < 0.05). As APE severity increased, the cardiac morphological measurements of RV/LVdiameter, RV/LVarea, RVEDV/LVEDV and RVESV/LVESV increased. There was a weak to moderate negative correlation between PAD and PAmax, PAmin, PA/AAmin, PA/AAmax, RV/LVdiameter, RV/LVarea (r = -0.393 to -0.625), that is, PAD was inversely correlated with cardiac function parameters. There was a moderate negative correlation between PAD and hemoptysis(r = -0.672). The area under the ROC curve (AUC) of PAD was 0.724, the critical value was 4.137 × 10-3  mm/Hg, and the sensitivity and specificity were 60.0% and 93.3%, respectively. PAmin showed the strongest discriminatory power to identify high-risk patients (AUC = 0.827), with the highest sensitivity of 100%, which was also achieved by RA/LAarea. The PAD obtained by retrospective ECG-gated CTPA could be an indicator to be used in the evaluation of the presence and severity of APE.

Altered Functional Connectivity of Alpha Rhythm in Obsessive-Compulsive Disorder During Rest.

Obsessive-compulsive disorder (OCD) is a common inheritable psychiatric disorder characteristic of repetitive thinking, imagination (obsession), and stereotyped behaviors (compulsive). To explore whether there is an alteration of brain functional connectivity (BFC) in patients with OCD during rest, electroencephalogram (EEG) data of healthy controls (HCs) and patients with OCD were collected during rest in both eyes-closed and eyes-open states. Synchronization likelihood and graph theory were applied to construct and analyze brain functional networks of patients with OCD and HCs. Patients with OCD showed abnormal graph-theoretic parameters and impaired small world features in the alpha and beta bands. In addition, the topological analysis consistently showed that the long-range BFC of alpha rhythm was significantly reduced in the bilateral posterior areas in patients with OCD in comparison with HCs, while the BFC in the beta rhythm was significantly increased only in the eyes-open state. The findings suggest that the BFC of patients with OCD show abnormal small-world features and altered topological structure during rest, mainly in alpha and beta bands, which may provide a new insight for the diagnosis and treatment of OCD.

Pathophysiology of refractory obsessive-compulsive disorder: A study of visual search combined with overactive performance monitoring.

Based on both functional and structural studies of excessive activity, fronto-striatal-thalamic-cortical and cortico-striatal circuits have been hypothesized to underlie the pathophysiology of obsessive-compulsive disorder (OCD). However, the neurobiological underpinnings of OCD refractory to medication and therapy remain controversial. This study aimed to evaluate neuroanatomical abnormalities of the whole brain and to evaluate visual processing in patients with refractory OCD.This study was comprised of 2 experiments. The neuroanatomical abnormalities of the whole brain were evaluated using a visual search in combination with overactive performance monitoring (Experiment I), and visual processing was evaluated using event-related potentials recorded from subjects during performance of a visual search task. We also examined the amplitudes and latency of the error-related negativity (ERN) using a modified flanker task (Experiment II). Standard low-resolution electromagnetic tomography analysis was applied to determine the special areas.Patients with refractory OCD had a significantly greater number of saccades and prolonged latencies relative to the healthy controls. Scalp map topography confirmed that visual cognitive and executive dysfunction was localized to the fusiform gyrus. Furthermore, we found that during a modified flanker task, ERNs had a greater amplitude and a prolonged latency relative to those of the healthy controls. Further data analysis suggested that cognitive dysfunction and compulsive behavior in OCD patients were linked to abnormalities within the dorsolateral prefrontal cortex (DLPFC).We identified abnormal activities within the fusiform gyrus and DLPFC that likely play important roles in the pathophysiology of OCD.