Virulence genes and antimicrobial resistance in Enterococcus strains isolated from dogs and cats in Northeast China.

This study aimed to characterize the antimicrobial resistance and virulence of Enterococcus from dogs and cats in Northeast China and evaluate its zoonotic risk based on a total of 469 enterococci strains from 610 samples, including 238 strains of E. faecium and 128 strains of E. faecalis. The isolation rate from police dog samples was 93.79%, pet dog samples was 69.90% and pet cat samples was 76.67%. The differences in the prevalence of E. faecalis among different hosts were statistically significant (P<0.05). The assays showed that most of the virulence genes detected were existed in E. faecalis and police dogs carried the least number of virulence genes. The correlation between enterococcal surface protein (esp) and aggregation substance (asa1) was determined. Enterococci are most resistant to tetracycline and erythromycin, 68.92% of the isolates were classified as multiple drug resistant. Significant differences (P<0.01) were found between E. faecium and E. faecalis in the resistance rates of nine antimicrobials. Four positive and four negative correlations were found between virulence genes and antimicrobial resistance. The results show that Enterococcus colonization and excretion in dogs and cats were related to animal species and living environments. Some correlation between virulence factors and antimicrobial resistance was obtained. This study confirmed the presence of strains carrying multiple virulence factors and antimicrobial resistance at the same time, suggesting a public health risk for dogs and cats as reservoirs of enterococci.

Interstitial pneumonitis associated with combined regimen of immunotherapy and conventional therapies-pharmacovigilance database analysis with real-world data validation.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy combined with conventional therapies is being broadly applied in non-small cell lung cancer (NSCLC) patients. However, the risk of interstitial pneumonitis (IP) following a combined regimen is incompletely characterized. METHODS: A total of 46,127 NSCLC patients were extracted for disproportionality analyses of IP from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database. A total of 1108 NSCLC patients who received ICI treatment at Nanfang Hospital of Southern Medical University were collected and utilized for real-world validation. RESULTS: Of the 46,127 patients with NSCLC, 3830 cases (8.3%; 95% confidence interval [CI], 8.05-8.56) developed IP. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with radiation (RT) was the highest (121.69; 95% CI, 83.60-184.96; P < 0.0001) among all therapies, while that of ICI combined with chemotherapy (CHEMO) or targeted therapy (TARGET) was 0.90 (95% CI, 0.78-1.04; P = 0.160) and 1.49 (95% CI, 0.95-2.23; P = 0.065), respectively, using ICI monotherapy as reference. Furthermore, analyses from our validation cohort of 1108 cases showed that the adjusted odds ratio of ICI combined with RT was the highest (12.25; 95% CI, 3.34-50.22; P < 0.01) among all the therapies, while that of ICI combined with CHEMO or TARGET was 2.32 (95% CI, 0.89-7.92; P = 0.12) and 0.66 (95% CI, 0.03-4.55; P = 0.71), respectively, using ICI monotherapy as reference. CONCLUSIONS: Compared with ICI monotherapy, ICI combined with RT, rather than with CHEMO or TARGET, is associated with a higher risk of IP in NSCLC patients. Hence, patients receiving these treatments should be carefully monitored for IP.

PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer.

Contradictory characteristics of elevated mutational burden and a "cold" tumor microenvironment (TME) coexist in liver kinase B1 (LKB1)-mutant non-small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult to treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1-driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1-driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation-mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically "hot" TME. Accordingly, PARP1 inhibition restored the disrupted IFNγ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC. SIGNIFICANCE: Targeting PARP exerts dual effects to overcome LKB1 loss-driven immunotherapy resistance through triggering DNA damage and adaptive immunity, providing a rationale for dual PARP and PD-1 inhibition in treating LKB1-mutant lung cancers.

Rare massive hepatic hemangioblastoma: A case report.

BACKGROUND: Hepatic hemangioblastoma is an extremely rare disease; only three cases have been reported in the literature, and its magnetic resonance imaging (MRI) findings are unreported. CASE SUMMARY: We report a case of incidental hepatic hemangioblastoma. The patient had no history of von Hippel-Lindau disease or associated clinical signs. Computed tomography and MRI showed a large tumor occupying almost half of the right side of the liver with expansive growth, well-defined borders, heterogeneous mildly progressive enhancement, and visibly enlarged blood supply vessels. Flow voids were observed on T2-weighted imaging. Both diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) map findings of the mass were predominantly inhomogeneous. Postoperative pathology indicated a diagnosis of hemangioblastoma. CONCLUSION: Enlarged peripheral blood-supplying vessels and progressive enhancement seem to be typical imaging features of hepatic hemangioblastoma. However, a solid significantly enhanced mass with a low signal on DWI and a high signal on ADC may also be helpful for the diagnosis of hepatic hemangioblastoma.

Thromboelastography in guiding preventive platelet transfusion in patients with haematologic diseases.

OBJECTIVE: This study analysed the relationships between the main thromboelastography (TEG) parameters, the platelet (PLT) count and clinical bleeding in patients with blood diseases. We explored the threshold of the relevant parameters in the pathological condition of bleeding, aiming to scientifically guide clinical prophylactic PLT transfusion. METHODS: In total, 268 patients with clear diagnoses of blood diseases and thrombocytopenia were enrolled and divided into five groups, A, B, C, D and E, corresponding to PLT counts of 0-10 × 109 /L, 11-20 × 109 /L, 21-30 × 109 /L, 31-50 × 109 /L and 51-100 × 109 /L, respectively. TEG and routine blood testing were performed simultaneously, the main TEG parameters and the PLT count were analysed, and the thresholds of the main TEG parameters in each group when the patient had bleeding were obtained. RESULTS: The maximum amplitude (MA) in groups A, B and C increased gradually, with a significant difference between each pair of these groups (P < 0.05). In groups A, B, C, D and E, the corresponding MA at the time of bleeding was 43.5 mm, 39.6 mm, 38.0 mm, 35.2 mm and 50.5 mm, respectively, with statistically significant differences (P < 0.05). CONCLUSIONS: The MA can be used as a reference indicator for preventive PLT transfusion to a certain extent. When the PLT count is within different ranges, the MA threshold for preventive PLT transfusion also differs. It is recommended that different PLT counts be correlated with different MA thresholds to guide clinical prophylactic PLT transfusion.

Organ-specific metastatic landscape dissects PD-(L)1 blockade efficacy in advanced non-small cell lung cancer: applicability from clinical trials to real-world practice.

BACKGROUND: Organ-specific metastatic context has not been incorporated into the clinical practice of guiding programmed death-(ligand) 1 [PD-(L)1] blockade, due to a lack of understanding of its predictive versus prognostic value. We aim at delineating and then incorporating both the predictive and prognostic effects of the metastatic-organ landscape to dissect PD-(L)1 blockade efficacy in non-small cell lung cancer (NSCLC). METHODS: A total of 2062 NSCLC patients from a double-arm randomized trial (OAK), two immunotherapy trials (FIR, BIRCH), and a real-world cohort (NFyy) were included. The metastatic organs were stratified into two categories based on their treatment-dependent predictive significance versus treatment-independent prognosis. A metastasis-based scoring system (METscore) was developed and validated for guiding PD-(L)1 blockade in clinical trials and real-world practice. RESULTS: Patients harboring various organ-specific metastases presented significantly different responses to immunotherapy, and those with brain and adrenal gland metastases survived longer than others [overall survival (OS), p = 0.0105; progression-free survival (PFS), p = 0.0167]. In contrast, survival outcomes were similar in chemotherapy-treated patients regardless of metastatic sites (OS, p = 0.3742; PFS, p = 0.8242). Intriguingly, the immunotherapeutic predictive significance of the metastatic-organ landscape was specifically presented in PD-L1-positive populations (PD-L1 > 1%). Among them, a paradoxical coexistence of a favorable predictive effect coupled with an unfavorable prognostic effect was observed in metastases to adrenal glands, brain, and liver (category I organs), whereas metastases to bone, pleura, pleural effusion, and mediastinum yielded consistent unfavorable predictive and prognostic effects (category II organs). METscore was capable of integrating both predictive and prognostic effects of the entire landscape and dissected OS outcome of NSCLC patients received PD-(L)1 blockade (p < 0.0001) but not chemotherapy (p = 0.0805) in the OAK training cohort. Meanwhile, general performance of METscore was first validated in FIR (p = 0.0350) and BIRCH (p < 0.0001), and then in the real-world NFyy cohort (p = 0.0181). Notably, METscore was also applicable to patients received PD-(L)1 blockade as first-line treatment both in the clinical trials (OS, p = 0.0087; PFS, p = 0.0290) and in the real-world practice (OS, p = 0.0182; PFS, p = 0.0045). CONCLUSIONS: Organ-specific metastatic landscape served as a potential predictor of immunotherapy, and METscore might enable noninvasive forecast of PD-(L)1 blockade efficacy using baseline radiologic assessments in advanced NSCLC.

Detection of Two Copies of a bla NDM-1-Encoding Plasmid in Escherichia coli Isolates from a Pediatric Patient with Diarrhea.

PURPOSE: To elucidate the contribution of a transferable plasmid harboring the bla NDM-1 gene in an Escherichia coli clinical isolate to the spread of resistance determinants. METHODS: Nine extended-spectrum ß-lactamase-producing E. coli were collected from diarrhea samples from a pediatric patient and genetic linkage was investigated through enterobacteriaceae repetitive intragenic consensus polymerase chain reaction (PCR). Bacterial species were identified by 16s rRNA sequencing, susceptibility testing with the use of a BD PhoenixTM-100 Automated Microbiology System, and assessment of virulence genes by PCR. The transferability of bla NDM-1 in E. coli strain TCM3e1 was confirmed by conjugation experiments. Complete sequencing of E. coli strain TCM3e1 was determined with the PacBio and Illumina NovaSeq platforms and the characteristics were analyzed with bioinformatics software. RESULTS: The results showed that all nine E. coli strains were the same clone. E. coli strain TCM3e1 was resistant to 12 antimicrobial agents and carried the virulence gene EAST-1. Conjugation transfer analysis showed that bla NDM-1 was carried on a self-transmissible plasmid. Two copies of the bla NDM-1 gene were present on an IncC plasmid and some resistance genes with two or three copies were located downstream of the bla NDM-1 gene and formed a tandem repeat fragment (bla DNM-1-bleo-sul1- aadA17- dfrA12). CONCLUSION: A transmissible plasmid harboring two copies of the bla NDM-1 gene, including clonal dispersions of the bla NDM-1 gene, was identified in clinical isolates. These findings emphasized the necessity of surveillance of the plasmid-borne bla NDM-1 to prevent dissemination.

Assessment of anti-PD-(L)1 for patients with coexisting malignant tumor and tuberculosis classified by active, latent, and obsolete stage.

BACKGROUND: It is not a rare clinical scenario to have patients presenting with coexisting malignant tumor and tuberculosis. Whether it is feasible to conduct programmed death-(ligand) 1 [PD-(L)1] inhibitors to these patients, especially those with active tuberculosis treated with concurrent anti-tuberculosis, is still unknown. METHODS: This study enrolled patients with coexisting malignancy and tuberculosis and treated with anti-PD-(L)1 from Jan 2018 to July 2021 in 2 institutions. The progression-free survival (PFS), objective response rate (ORR), and safety of anti-PD-(L)1 therapy, as well as response to anti-tuberculosis treatment, were evaluated. RESULTS: A total of 98 patients were screened from this cohort study, with 45 (45.9%), 21 (21.4%), and 32 (32.7%) patients diagnosed with active, latent, and obsolete tuberculosis, respectively. The overall ORR was 36.0% for anti-PD-(L)1 therapy, with 34.2%, 35.5%, and 41.2% for each subgroup. Median PFS was 8.0 vs 6.0 vs 6.0 months (P=0.685) for each subgroup at the time of this analysis. For patients with active tuberculosis treated with concurrent anti-tuberculosis, median duration of anti-tuberculosis therapy was 10.0 (95% CI, 8.01-11.99) months. There were 83.3% (20/24) and 93.3% (42/45) patients showing sputum conversion and radiographic response, respectively, after anti-tuberculosis therapy, and two patients experienced tuberculosis relapse. Notably, none of the patients in latent and only one patient in obsolete subgroups showed tuberculosis induction or relapse after anti-PD-(L)1 therapy. Treatment-related adverse events (TRAEs) occurred in 33 patients (73.3%) when treated with concurrent anti-PD-(L)1 and anti-tuberculosis. Grade 3 or higher TRAEs were hematotoxicity (n = 5, 11.1%), and one patient suffered grade 3 pneumonitis leading to the discontinuation of immunotherapy. CONCLUSIONS: This study demonstrated that patients with coexisting malignant tumor and tuberculosis benefited equally from anti-PD-(L)1 therapy, and anti-tuberculosis response was unimpaired for those with active tuberculosis. Notably, the combination of anti-PD-(L)1 and anti-tuberculosis therapy was well-tolerated without significant unexpected toxic effects.

Migratory wild birds carrying multidrug-resistant Escherichia coli as potential transmitters of antimicrobial resistance in China.

Migratory birds play an important role in the spread of multidrug-resistant (MDR) bacteria. To investigate the prevalence of MDR Escherichia coli in migratory birds in China and potential relationships with the environment, a total of 1387 samples (fecal samples, cloacal swabs, or throat swabs) were collected from migratory birds from three different river basins in China. The collected samples were processed and subjected to bacteriological examinations. Antimicrobial susceptibility testing of the recovered isolates was performed using the E-test for the detection of minimum inhibitory concentrations (MICs). Some antibiotic resistance genes were detected and the PCR products were confirmed by sequencing. In total, 478 (34.7%) E. coli isolates were recovered. The results showed that the drug-resistant E. coli isolates were highly resistant to ß-lactams (43.7%) and tetracycline (22.6%), and 73 (15.3%) were MDR, including eight that were extended spectrum ß-lactamase-positive. The retrieved strains harbored the blaCTX-M, blaTEM-1, tet(A), tet(B), tet(M), sul1, sul2, sul3, cmlA, floR, and intI1 genes with a prevalence of 5.9%, 36.4%, 80.5%, 11.9%, 6.8%, 6.8%, 47.5%, 12.7%, 50.8%, 37.3%, and 61.0%, respectively. The drug resistance rate of the isolates from southern China was higher than those from northern China. The E. coli samples collected for migratory birds in the Pearl River Basin had the highest proportion (46.7%) MDR isolates. Furthermore, MDR bacteria carried by migratory birds were closely related to the antibiotic content in the basin, which confirms that MDR bacteria carried by migratory birds are likely acquired from the environment. This study also confirmed that migratory birds are potential transmitters of MDR bacteria, demonstrating the need to reduce the use and emission of antibiotics and further in-depth studies on the mechanisms underlying drug resistance of bacteria.

Investigation and Analysis of Iron-Deficiency Anemia Complicated by Splenomegaly.

OBJECTIVE: This study aimed to determine the incidence of iron-deficiency anemia (IDA) complicated by splenomegaly in our hospital over the past 6 years and to analyze the possible causes of this result. METHODS: This is a retrospective study. In total, 668 patients with IDA who were hospitalized in the hematology department of our hospital from 2013 to 2019 were selected as the research subjects and included in the IDA group, and 3201 patients who underwent outpatient physical examinations in our hospital during the same period were included in the control group. The incidences of splenomegaly in the IDA and control groups were calculated, and the difference was analyzed by means of statistical methods. RESULTS: Among the 668 IDA patients, 46 (6.9%) had splenomegaly, and among the 3201 patients in the control group, 21 had splenomegaly (0.7%). The incidence of splenomegaly was significantly higher in the IDA group than in the control group, and the severity of anemia in the IDA group was associated with the occurrence of splenomegaly. Specifically, the incidence of splenomegaly was 12.4% among patients with severe anemia and as high as 50% among patients with extremely severe anemia. CONCLUSION: IDA is correlated with the incidence of splenomegaly, and the incidence of splenomegaly significantly increases as the severity of IDA increases. This is considered to be caused by extramedullary hematopoiesis.

De Novo Mutation in Non-Tyrosine Kinase Domain of ROS1 as a Potential Predictor of Immune Checkpoint Inhibitors in Melanoma.

PURPOSE: Despite the success of targeted therapy in c-ros oncogene 1 (ROS1)-rearranged cancers, especially non-small cell lung cancer (NSCLC), the clinical significance of ROS1 de novo mutation has not yet been understood. We sought to elucidate the predictive effect of ROS1 mutation for immune checkpoint inhibitor (ICI) therapy in melanoma. METHODS: The Cancer Genome Atlas [TCGA (n = 10967)] and Memorial Sloan Kettering Cancer Center [MSK (n = 10,945)] datasets, as well as two clinical cohorts of melanoma received ICI [CA209-038 (n = 73) and MEL-IPI (n = 110)], were included to explore the prevalence, prognostic effect, and immunotherapeutic predictive effect of ROS1 mutation in melanoma. Overall survival (OS) was defined as the primary outcome. RESULTS: Overall, melanoma accounted for the highest proportion of ROS1 mutation (~20%) which made up the majority (~95%) of the ROS1-alterated cases. Remarkably, ROS1 mutation yielded longer OS from ICI than the wild-type counterpart in the MSK melanoma population [hazard ratio (HR) 0.47, 95% confidence interval (CI) 0.30-0.74], and two external melanoma cohorts (CA209-038: HR 0.42, 95% CI 0.20-0.89; MEL-IPI: HR 0.55, 95% CI 0.34-0.91), without affecting the prognosis of patients. Elevated tumor mutational burden and enrichment of DNA damage repair was observed in ROS1 mutated patients, providing an explanation for the favorable responses to ICI therapy. Precisely, ROS1 mutation in non-protein tyrosine kinase (PTK) domain but not PTK mutation was responsible for the immunotherapy-specific responses of the ROS1 mutated patients in melanoma. CONCLUSIONS: Collectively, ROS1 mutation, specifically the non-PTK mutation, is a potential predictor of ICI therapy in melanoma, which is distinct from the well-established role of ROS1 rearrangement for targeted therapy in NSCLC.

Pan-Genome Analysis of Vibrio cholerae and Vibrio metschnikovii Strains Isolated From Migratory Birds at Dali Nouer Lake in Chifeng, China.

Migratory birds are recently recognized as Vibrio disease vectors, but may be widespread transporters of Vibrio strains. We isolated Vibrio cholerae (V. cholerae) and Vibrio metschnikovii (V. metschnikovii) strains from migratory bird epidemic samples from 2017 to 2018 and isolated V. metschnikovii from migratory bird feces in 2019 from bird samples taken from the Inner Mongolia autonomous region of China. To investigate the evolution of these two Vibrio species, we sequenced the genomes of 40 V. cholerae strains and 34 V. metschnikovii strains isolated from the bird samples and compared these genomes with reference strain genomes. The pan-genome of all V. cholerae and V. metschnikovii genomes was large, with strains exhibiting considerable individual differences. A total of 2,130 and 1,352 core genes were identified in the V. cholerae and V. metschnikovii genomes, respectively, while dispensable genes accounted for 16,180 and 9,178 of all genes for the two strains, respectively. All V. cholerae strains isolated from the migratory birds that encoded T6SS and hlyA were non-O1/O139 serotypes without the ability to produce CTX. These strains also lacked the ability to produce the TCP fimbriae nor the extracellular matrix protein RbmA and could not metabolize trimetlylamine oxide (TMAO). Thus, these characteristics render them unlikely to be pandemic-inducing strains. However, a V. metschnikovii isolate encoding the complete T6SS system was isolated for the first time. These data provide new molecular insights into the diversity of V. cholerae and V. metschnikovii isolates recovered from migratory birds.

Integrative evaluation of primary and metastatic lesion spectrum to guide anti-PD-L1 therapy of non-small cell lung cancer: results from two randomized studies.

Objectives: Clinical benefits of immune-checkpoint blockade (ICB) versus standard chemotherapy have been established in unselected non-small cell lung cancer (NSCLC). However, the response to ICB therapy among patients is heterogeneous in clinical practice. Materials and Methods: We retrospectively assessed the predicitive effect of the primary and metastatic lesion spectrum (baseline sum of the longest diameters [SLD], number of metastatic sites and specific organ metastases) on the efficacy of atezolizumab over docetaxel in OAK and POPLAR trial cohorts. A decision model, termed DSO (Diameter-Site-Organ), based on the spectrum was developed and validated for guiding ICB. Results: Higher SLD (>38 mm) and more metastatic sites (≥2) were characterized with pronounced overall survival (OS) benefits from atezolizumab versus docetaxel. Specifically, adrenal gland and brain metastases were identified as favorable predictors of atezolizumab treatment. The DSO model was developed in the discovery cohort to integrate the directive effect of the primary and metastatic lesion spectrum. Remarkably, a general pattern of enhanced efficacy of atezolizumab versus docetaxel was observed along with the increase of the DSO score. For patients with DSO score > 0, atezolizumab yielded a significantly prolonged OS than docetaxel, whereas OS was generally similar between two treatments in patients with DSO score ≤ 0. Equivalent findings were also seen in the internal and external validation cohorts. Conclusions: The response to anti-PD-L1 therapy among patients varied with the primary and metastatic lesion spectrum. The DSO-based system might provide promising medication guidance for ICB treatment in NSCLC patients.

Development and interpretation of a pathomics-based model for the prediction of microsatellite instability in Colorectal Cancer.

Microsatellite instability (MSI) has been approved as a pan-cancer biomarker for immune checkpoint blockade (ICB) therapy. However, current MSI identification methods are not available for all patients. We proposed an ensemble multiple instance deep learning model to predict microsatellite status based on histopathology images, and interpreted the pathomics-based model with multi-omics correlation. Methods: Two cohorts of patients were collected, including 429 from The Cancer Genome Atlas (TCGA-COAD) and 785 from an Asian colorectal cancer (CRC) cohort (Asian-CRC). We established the pathomics model, named Ensembled Patch Likelihood Aggregation (EPLA), based on two consecutive stages: patch-level prediction and WSI-level prediction. The initial model was developed and validated in TCGA-COAD, and then generalized in Asian-CRC through transfer learning. The pathological signatures extracted from the model were analyzed with genomic and transcriptomic profiles for model interpretation. Results: The EPLA model achieved an area-under-the-curve (AUC) of 0.8848 (95% CI: 0.8185-0.9512) in the TCGA-COAD test set and an AUC of 0.8504 (95% CI: 0.7591-0.9323) in the external validation set Asian-CRC after transfer learning. Notably, EPLA captured the relationship between pathological phenotype of poor differentiation and MSI (P < 0.001). Furthermore, the five pathological imaging signatures identified from the EPLA model were associated with mutation burden and DNA damage repair related genotype in the genomic profiles, and antitumor immunity activated pathway in the transcriptomic profiles. Conclusions: Our pathomics-based deep learning model can effectively predict MSI from histopathology images and is transferable to a new patient cohort. The interpretability of our model by association with pathological, genomic and transcriptomic phenotypes lays the foundation for prospective clinical trials of the application of this artificial intelligence (AI) platform in ICB therapy.

Regional Injection of CAR-T Cells for the Treatment of Refractory and Recurrent Diffuse Large B Cell Lymphoma: A Case Report.

BACKGROUND: Lymphoma is a common hematological malignancy with many subtypes and considerable heterogeneity. Traditional treatments include chemotherapy, radiotherapy, and surgery. Patients with relapsed, refractory or advanced stage lymphoma have a dismal prognosis. In recent years, chimeric antigen receptors (CARs) have been recognized as powerful tools that redirect antigen-specific T cells independent of human lymphocyte antigen (HLA) restriction and specifically kill tumor cells. Satisfactory results with CAR-based treatments have been achieved in relapsed/refractory B cell leukemia/lymphoma. Our center explored the strategy of subcutaneous injections combined with intravenous drip to overcome certain issues. CASE PRESENTATION: A patient with stage IV refractory and relapsed diffuse large B cell lymphoma was treated with regional and intravenous CAR-T cells. During the observation period, the temperature of the skin at the abdominal wall mass was slightly elevated, and tolerable pain in the injection area was reported. Imaging showed regional liquefactive necrosis. After the sequential administration of ibrutinib and venetoclax, the abdominal wall mass significantly decreased in size. CONCLUSION: The regional injection of CAR-T cells might be safe and feasible for the treatment of regional lesions in patients with refractory and relapsed advanced lymphoma.

[Analysis of Risk Factors Affecting the Chemotherapy-related Infections in Patients with ALL].

OBJECTIVE: To analyze the risk factors affecting the chemotherapy-related infections in patients with acute lympho-blastic leukemia (ALL). METHODS: The clinical data of 102 patients with ALL from January 2014 to December 2018 were collected and retrospectively studies. The risk factors of chemotherapy-related infections were analyzed by univa-riate and multivariate logistic regression. RESULTS: A total of 386 courses of chemotherapy were completed, out of which the infection occurred in 201 course, with the infection rate of 52.07%, identified infection number was 215 case-times, including perianal infection of 13.95% (30/215), oral infection of 13.49% (29/215), blood flow infection of 1721% (37/215), lower respiratory tract infection of 37.21% (80/215), urinary infection of 3.26% (7/215), skin infection of 3.72% (8/215), digestive and intra abdominal infection of 9.30% (20/215), and other infections of 1.86 (4/215). Totally 88 strains of pathogenic bacteria were detected, including 29 Gram-positive bacteria (32.95%), 52 Gram-negative bacteria (59.09%) and 7 fungi (7.95%). Gram-positive bacteria mainly were Staphylococcus haemolyticus and Enterococcus faecium, susceptible to tegacycline, vancomycin and linezolid; Gram-negative bacteria mainly were Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae, susceptible to tegacycline, amikacin, piperacillin/tazobactam and imipenem; Candida was the dominant fungus. Living in an ordinart ward, neutrophil defi-ciency for more than 7 days after chemotherapy and incomplete remission were independent risk factors of related infections during the induction chemotherapy in ALL inpatients, and hospitalization time also closely related with chemo-therapy-related infections in ALL inpatients (P<0.05). Neutrophil deficiency for more than 7 days after chemotherapy was an independent risk factor of chemotherapy-related infections in ALL inpatients in the consolidation chemotherapy (P<0.05). CONCLUSION: Patients with ALL are prone to chemotherapeutic-related infections, and those who lack neutrophils for more than 7 days after chemotherapy and who do not reach complete remission are more prone to infection. Living in laminar flow ward and reducing hospitalization stay can help reduce the incidence of infection.

Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer.

PURPOSE: Although tumor mutation burden (TMB) has been well known to predict the response to immune checkpoint inhibitors (ICI), lack of randomized clinical trial data has restricted its clinical application. This study aimed to explore the significance and feasibility of biomarker combination based on TMB and copy-number alteration (CNA) for the prognosis of each tumor and prediction for ICI therapy in metastatic pan-cancer milieu. EXPERIMENTAL DESIGN: Non-ICI-treated MSK pan-cancer cohort was used for prognosis analysis. Three independent immunotherapy cohorts, including non-small cell lung cancer (n = 240), skin cutaneous melanoma (n = 174), and mixed cancer (Dana-Farber, n = 98) patients from previous studies, were analyzed for efficacy of ICI therapy. RESULTS: TMB and CNA showed optimized combination for the prognosis of most metastatic cancer types, and patients with TMBlowCNAlow showed better survival. In the predictive analysis, both TMB and CNA were independent predictive factors for ICI therapy. Remarkably, when TMB and CNA were jointly analyzed, those with TMBhighCNAlow showed favorable responses to ICI therapy. Meanwhile, TMBhighCNAlow as a new biomarker showed better prediction for ICI efficacy compared with either TMB-high or CNA-low alone. Furthermore, analysis of the non-ICI-treated MSK pan-cancer cohort supported that the joint stratification of TMB and CNA can be used to categorize tumors into distinct sensitivity to ICI therapy across pan-tumors. CONCLUSIONS: The combination of TMB and CNA can jointly stratify multiple metastatic tumors into groups with different prognosis and heterogeneous clinical responses to ICI treatment. Patients with TMBhighCNAlow cancer can be an optimal subgroup for ICI therapy.

HPV-positive status associated with inflamed immune microenvironment and improved response to anti-PD-1 therapy in head and neck squamous cell carcinoma.

Chemotherapy and radiotherapy predominantly improve the clinical outcomes of patients with human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC). Whether this superiority goes on when treated with immune checkpoint inhibitors is still unclear. This study sought to determine the predictive value and potential mechanisms of HPV status for the treatment of programmed cell death 1 (PD-1)/ligand 1(PD-L1) inhibitors. We conducted an integrated analysis of the relationships between HPV status and PD-L1, tumor mutation burden (TMB) and inflammation-related immune cells and molecules, based on the analysis of repository databases and resected HNSCC specimens. The pooled analysis of overall survival (OS) and objective response rate (ORR) suggested that HPV-positive patients benefited more from PD-1/PD-L1 inhibitors than HPV-negative patients (OS: hazard ratio (HR) = 0.71, p = 0.02; ORR: 21.9% vs 14.1%, odds ratio (OR) = 1.79, p = 0.01). Analysis of public databases and resected HNSCC specimens revealed that HPV status was independent of PD-L1 expression and TMB in HNSCC. However, HPV infection significantly increased T-cell infiltration, immune effector cell activation and the diversity of T-cell receptors. Notably, HPV-positivity correlated with increased immune cytolytic activity and a T-cell-inflamed gene expression profile. This work provides evidence that HPV status can be used to predict the effectiveness of PD-1 inhibitors in HNSCC, independently of PD-L1 expression and TMB, and probably results from an inflamed immune microenvironment induced by HPV infection.

Epigenetics recording varied environment and complex cell events represents the origin of cellular aging.

Although a relationship between epigenetics and aging phenotypic changes has been established, a theoretical explanation of the intrinsic connection between the epigenetics and aging is lacking. In this essay, we propose that epigenetic recording of varied cell environment and complex history could be an origin of cellular aging. Through epigenetic modifications, the environment and historical events can induce the chromatin template into an activated or repressive accessible structure, thereby shaping the DNA template into a spectrum of chromatin states. The inner nature of diversity and conflicts born by the cell environment and its historical events are hence recorded into the chromatin template. This could result in a dissipated spectrum of the chromatin state and chaos in overall gene expression. An unavoidable degradation of epigenome entropy, similar to Shannon entropy, would be consequently induced. The resultant disorder in epigenome, characterized by corrosion of epigenome entropy as reflected in chromatin template, can be stably memorized and propagated through cell division. Furthermore, the hysteretic nature of epigenetics responding to the emerging environment could exacerbate the degradation of epigenome entropy. As well as stochastic errors, we propose that outside entropy (or chaos) derived from the varied environment and complex cell history, gradually input and imprinted into the chromatin via epigenetic modifications, would lead inevitably to cellular aging, the extent of which could be aggravated by hysteresis of epigenetics without error erasing and correction.

TNF-TNFR2 Signaling Inhibits Th2 and Th17 Polarization and Alleviates Allergic Airway Inflammation.

BACKGROUND: TNF-TNFR2 signaling has been indicated to be involved in CD4+ T lymphocyte differentiation. However, its role in allergic airway inflammation is not well understood. OBJECTIVES: The aim of this study was to investigate the role of TNF-TNFR2 signaling in allergic airway inflammation. METHODS AND RESULTS: In this study, we used an allergen-induced asthma model to show that TNF-TNFR2 signaling alleviated allergic airway inflammation by reducing the airway infiltration of eosinophils and neutrophils. Activated TNF-TNFR2 signaling decreased the expression of Th2 and Th17 cytokines in serum and bronchoalveolar lavage fluid. Furthermore, TNF-TNFR2 signaling inhibited Th2 and Th17 polarization but promoted Th1 and CD4+CD25+ T cell differentiation in vivo. CONCLUSIONS: Our study indicates that TNF-TNFR2 signaling alleviates allergic airway inflammation through inhibition of Th2 and Th17 cell differentiation.