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Objective To evaluate the diagnostic performance of short state homeobox 2 (SHOX2) promoter methylation as biomarker for lung cancer identification through aggregating the open published data. Methods We did an electronic search in Pubmed, EMBASE, Ovid, Web of Science, Google Scholar, and the China National Knowledge Infrastructure (CNKI) to identify the publications related to SHOX2 promoter methylation and lung cancer. The diagnostic performance of sensitivity (SEN), specificity (SPE), odds ratio (DOR), and summary receiver operating characteristic (SROC) cure were aggregated by fixed or random effect model. Fagan's nomogram was used to investigate the post‐test diagnostic probability. Deek's funnel plot and line regression test was applied to evaluate the publication bias. Results In total, 18 clinical studies about SHOX2 promoter methylation and lung cancer were included in the meta‐analysis. The combined diagnostic SEN, SPE, DOR were 0.63 (95% CI = 0.54–0.70), 0.91 (95% CI = 0.87–0.94), and 16.84 (95% CI = 11.18–25.36) in random effect model respectively. The pooled area under the curve (AUC) of SROC was 0.88 (95% CI = 0.84–0.90). The post‐test probability of lung cancer was 88% and 29% when SHOX2 methylated and unmethylated in humoral components given a pre‐test probability of 50%. Deek's funnel plot and regression test indicated no publication bias (p = 0.62). Conclusion SHOX2 promoter methylation in humoral components may be a potential biomarker for lung cancer diagnosis with relative high diagnostic specificity., Fagan's nomogram indicated that if SHOX2 methylated in humoral components, the positive post‐test probability of lung cancer was 88%, whereas the negative post‐test probability was 29% when SHOX2 unmethylated in humoral components give a pre‐test probability of 50%.

The treatment of refractory Burkitt’s lymphoma (BL) is still a challenge. Although CAR-T cell therapy has achieved good responses in diffuse large B cell lymphoma, there is no case series report about the efficacy of CAR-T cell therapy in adult Burkitt’s lymphoma. In this study, we evaluate the efficacy and safety of CAR19/22 T cell therapy in six refractory Burkitt’s lymphoma cases with poor genetic prognostic factors. After CAR-T cell therapy, five cases had grade 1 and one had grade 3 cytokine release syndrome. Three patients achieved an objective response (3/6 50%), including two partial remission and one complete remission. One CR patient received allogeneic hematopoietic stem cell transplantation (HSCT) and one PR patient received CAR22/19-T cells following auto-HSCT, and they were still in remission at 37 and 22 months of follow-up, respectively. Interestingly, patients with bulky disease (case 2, 4 and 5) had higher levels of serum IL-2R, which was secreted by regulatory T cells, lower CAR lentiviral amplification and poorer prognosis with shorter survival time than cases with non-bulky disease. It is suggested that high tumor burden, more immune suppressive cells and limited CAR-T cell expansion might affect the efficacy of CAR-T cell therapy. CAR-T cell therapy in adult BL patients whose best response cannot achieve CR may need to bridge to other treatments (such as HSCT) early.

The rapid spread of coronavirus disease 2019 (COVID-19) represented the most serious issue to public health globally. Hematological patients as immunocompromised hosts are vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There is little information available regarding the clinical features of hematological patients concomitant with COVID-19. In this study, 9 concomitant patients were analyzed for their clinical manifestations, laboratory data, radiological findings, and immunologic features. The median age was 50 years (range, 17-68 years) and 6 patients were male. Seven patients were infected through hospital-associated transmission and other 2 through community-associated transmission. Onset of COVID-19 in all patients occurred during routine treatments for their hematological diseases. Eight patients were classified as moderate and 1 patient as critically ill COVID-19. Four patients died, 1 from leukemia progression, 2 from life-threatening secondary infection, and the other from respiratory failure caused by COVID-19. Abruptly elevated levels of cytokines were often correlated with progressive hematological disease or concurrent bacterial infections. Two patients had atypical computed tomography (CT) imaging findings of COVID-19. The median interval from the first CT scan imaging to improvement in survivors was 40 days (range, 14-51 days). Four of 5 survivors had negative serological tests 1 month after symptom onset. Positive viral load in 4 survivors lasted longer than 45 days. Our results indicated concomitant patients formed a distinct subgroup characterized by atypical clinical features, defective viral clearance, and lower level of SARS-CoV-2-specific Abs. Targeted therapies that impair host humoral immunity should be avoided. These findings will be helpful to tailor appropriate management for the concomitant patients.

Gastrointestinal (GI) tract is the most common site of extranodal involvement in non-Hodgkin lymphoma. Life-threatening complications of GI may occur because of tumor or chemotherapy. Chimeric antigen receptor (CAR) T-cell therapy has been successfully used to treat refractory/relapse B-cell lymphoma, however, little is known about the efficacy and safety of CAR-T cell therapy for GI lymphoma. Here, we reported the efficacy and safety of CAR-T cell therapy in 14 patients with relapsed/refractory aggressive B-cell lymphoma involving the GI tract. After a sequential anti-CD22/anti-CD19 CAR-T therapy, 10 patients achieved an objective response, and seven patients achieved a complete response. CAR transgene and B-cell aplasia persisted in the majority of patients irrespective of response status. Six patients with partial response or stable disease developed progressive disease; two patients lost target antigens. Cytokine release syndrome (CRS) and GI adverse events were generally mild and manageable. The most common GI adverse events were diarrhea (4/14), vomiting (3/14) and hemorrhage (2/14). No perforation occurred during follow-up. Infection is a severe complication in GI lymphoma. Two patients were infected with bacteria that are able to colonize at GI; one died of sepsis early after CAR-T cells infusion. In conclusion, our study showed promising efficacy and safety of CAR-T cell therapy in refractory/relapsed B-cell lymphoma involving the GI tract. However, the characteristics of CAR-T-related infection in GI lymphoma should be further clarified to prevent and control infection.

ObjectiveTo investigate whether enhanced recovery after surgery (ERAS) can promote rehabilitation of patients after neurosurgical craniotomy.MethodsThe clinical data of 100 patients with brain tumor undergoing craniotomy in the Department of Neurosurgery, Xiangya Hospital, Central South University, from January 2018 to August 2020 were collected, including 50 patients in the ERAS group and 50 patients in the control group. t-Test, Wilcoxon’s rank sum test, and chi-square analysis were used to compare the clinical characteristics, prognosis, and hospitalization time between the two groups.ResultsThere was no significant difference in gender, age, and other general clinical data between the two groups (p > 0.05). The days of antiemetic drugs applied in the ERAS group were less than those in the control group (1.00 vs. 2.00 days, p = 0.003), and the proportion of patients requiring analgesics was lower than that of the control group (30% vs. 52%, OR = 0.41, 95% CI 0.18–0.93, p = 0.031). The time of urinary catheter removal and that of patients starting ambulation in the ERAS group were shorter than those in the control group (16.00 vs. 24.00 h, and 1.00 vs. 2.00 days, p < 0.001, respectively); and the hospital length of stay (LOS) in the ERAS group was shorter than that in the control group (Total LOS, 13.00 vs. 15.50 days; Postoperative LOS, 7.00 vs. 10.00 days, p < 0.001). By analyzing the prognosis of patients in the ERAS group and control group, we found that there was no significant difference in postoperative complications and Karnofsky Performance Status (KPS) score 1 month after operation between the two groups.ConclusionThe application of ERAS in craniotomy can accelerate the postoperative recovery of patients without increasing the perioperative risk, which is worthy of wide application. However, whether the ERAS measures can reduce the postoperative complications and improve the prognosis of patients still needs more large-scale case validation and multicenter collaborative study.

Background The aim of this study was to quantitatively analysis the diagnostic performance of adenomatous polyposis coli (APC) gene promoter methylation in serum or sputum/bronchoalveolar lavage fluid (BLAF) as a biomarker for lung cancer identification through pooling of open published data. Methods The relevant electronic MEDLINE, EMBASE, Ovid, web of science and CNKI databases were systematically searched to identify the studies related to APC gene promoter methylation for lung cancer diagnosis. Data of true positive (tp), false positive (fp), false negative (fn) and true negative (tn) were extracted from the publications included in the study. The pooled diagnostic sensitivity, specificity and area under summary receiver operating characteristic (SROC) curve (AUC‐SROC) of APC gene promoter methylation were calculated. Publication bias was evaluated by Begg's funnel plot and Egger's line regression test. Results Fourteen studies associated with APC gene promoter methylation and lung cancer were identified in the databases and finally included in the meta‐analysis. The data was pooled using a random effect model due to significant statistical heterogeneity across the 14 studies (p, The summary receiver operating characteristic (SROC) curve of APC gene promoter methylation for lung cancer diagnosis were 0.7 with the diagnostic sensitivity specificity of 0.43 (95% CI: 0.40–0.45) and 0.92 (95% CI: 0.90–0.95) respectively.

High-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) is the standard of care for chemosensitive relapsed or refractory (R/R) aggressive B cell lymphoma. Patients with a positive positron emission tomography (PET) scan before ASCT have a poor prognosis, and those who fail to achieve a therapeutic response better than partial remission after salvage treatment are ineligible candidates for ASCT. We conducted this open-label single-arm prospective clinical study to evaluate the safety and efficacy of sequential infusion of CD19/22 chimeric antigen receptor (CAR) T cells following HDT-ASCT. Eligibility for this study included patients with R/R aggressive B cell non-Hodgkin lymphoma (B-NHL) with 18F-fluorodeoxyglucose-PET positivity and patients with stable or progressive disease after salvage chemotherapy. Between November 14, 2016, and August 15, 2019, 42 patients underwent HDT-ASCT followed by CD19/22 CAR T cell infusion. Grade 3 cytokine release syndrome (CRS) occurred in only 2 patients. Twenty-one percent of patients experienced any grade of neurotoxicity, 5% with severe grade 3. All cases of CRS and neurotoxicity were reversible. The overall response rate was 90.5% (95% confidence interval [CI], 77.4% to 97.3%). At a median follow-up of 24.3 months, the median progression-free survival (PFS) and overall survival were not reached. The 2-year PFS rate was 83.3 % (95% CI, 68.2% to 91.7%). No patients were found to be CD19- and CD22-negative at the time of progression; 97.1% and 68.6% of patients with ongoing complete remission (CR) had consistently detectable levels of CD19 and CD22 CAR transgene, respectively, at 3 months. The median time to onset of sustained B cell recovery was 8.2 months. The high durable CR rates and favorable safety profiles support the strong potential of the HDT-ASCT plus CD19/CD22 CAR T cell cocktail therapy for the suboptimal group of patients with R/R aggressive B-NHL who are less sensitive or fail salvage chemotherapy. These early data are encouraging and informative for future trials to further test the efficacy and safety of HDT-ASCT plus CAR T cell therapy in a larger population. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Background Relapsed/refractory (R/R) multiple myeloma (MM) patients and primary plasma cell leukemia (PCL) have an unfavorable prognosis and no effective treatment. This study was designed to assess the safety and preliminary efficacy of a novel anti‐B‐cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell in R/R MM and PCL. Methods Between February 22, 2017, and June 25, 2018, 28 R/R and two R/R primary PCL patients received a median dose of 11.2 × 106 CAR+ cells/kg. The subjects were refractory to a proteasome inhibitor and/or an immunomodulatory agent. Fludarabine and cyclophosphamide were given as lymphodepletion chemotherapy. Results Results for these 30 consecutive patients who received an anti‐BCMA CAR T cell infusion are reported. The patients had received a median of four prior lines of therapy. A total of 44 different types of adverse events were recorded, and hematologic toxic effects were the most common events of any grade during treatment. Hematologic toxic effects were also the most common events of grade 3 or higher. A total of 29 patients (96.7%) had cytokine release syndrome, which was of grade 1 or 2 in 24 patients (80%) and grade 3 in five patients (16.7%). Neurologic toxic effects only occurred in one patient (3.3%) and were of grade 1. The objective response rate was 90%, and the complete response rate was 43.3%. With a median follow‐up of 12.6 months, the median progression‐free survival (PFS) and overall survival were 5.2 months and 14.0 months. One of the two primary PCL achieved a complete response with a PFS of 307 days. The other patients achieved a very good partial response with a PFS of 117 days. Conclusions Anti‐BCMA CAR T cell treatment is safe and highly active in R/R multiple myeloma., We report the efficacy and safety of the infusion of anti‐BCMA CAR T cell treatment in with relapsed/refractory malignant plasma cell disease.Anti‐BCMA CAR T cell therapy exerted better safety and preliminary efficacy in relapsed/refractory multiple myeloma.Relapsed/refractory primary plasma cell leukemia may benefit from CAR T Cell treatment, although the duration of response is short.

B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapies have shown efficacy in relapsed/refractory multiple myeloma (RRMM). Because the non-human originated antigen-targeting domain may limit clinical efficacy, we developed a fully human BCMA-specific CAR, CT103A, and report its safety and efficacy in a phase 1 trial. Eighteen consecutive patients with RRMM, including 4 with prior murine BCMA CAR exposures, were enrolled. CT103A was administered at 1, 3, and 6 × 106 CAR-positive T cells/kg in the dose-escalation phase, and 1 × 106 CAR-positive T cells/kg in the expansion cohort. The overall response rate was 100%, with 72.2% of the patients achieving complete response or stringent complete response. For the 4 murine BCMA CAR-exposed patients, 3 achieved stringent complete response, and 1 achieved a very good partial response. At 1 year, the progression-free survival rate was 58.3% for all cohorts and 79.1% for the patients without extramedullary myeloma. Hematologic toxicities were the most common adverse events; 70.6% of the patients experienced grade 1 or 2 cytokine release syndromes. No immune effector cell-associated neurotoxicity syndrome was observed. To the cutoff date, CAR transgenes were detectable in 77.8% of the patients. The median CAR transgene persistence was 307.5 days. Only 1 patient was positive for the anti-drug antibody. Altogether, CT103A is safe and highly active in patients with RRMM and can be developed as a promising therapy for RRMM. Patients who relapsed from prior murine BCMA CAR T-cell therapy may still benefit from CT103A. This trial was registered at http://www.chictr.org.cn as #ChiCTR1800018137.

Advanced central nervous system (CNS) lymphoma is an exclusion criterion for most chimeric antigen receptor (CAR) T-cell studies due to the associated levels of neurotoxicity. In this study, we described five patients with chemorefractory B-cell CNS lymphoma who received CAR19 and CAR22 T-cell “Cocktail” therapy and follow-up for 6–16 months. All patients experienced cytokine release syndrome (CRS). Two patients experienced CAR T-cell-related encephalopathy syndrome (CRES), which was controllable. The best response was observed in two patients, who successfully achieved complete remissions (CR), and the other three patients achieved partial remissions (PR). Four patients had progressive disease (PD) after remission. In addition, one CR patient and one PD patient accepted CAR T-cell infusion following hematopoietic stem cell transplantation therapy in the 3rd month and were in ongoing remission for 14 and 6 months of follow-up, respectively. The targeted antigens in two patients were still positive, and CAR T-cells were reboosted in the cerebrospinal fluid (CSF) after PD, but a small number of CD3-positive T-cells were observed to infiltrate into the tumor. Our study indicates the efficacy of CAR T-cell therapy for CNS lymphoma with an acceptable safety profile; however, the remission did not last long, perhaps due to the tumor immunosuppressive microenvironment (TME) of the CNS. CAR T-cell therapy should be combined with other treatments to help improve the TME of cerebral lymphoma.

Background Accumulating evidence proposed JAK inhibitors as therapeutic targets warranting rapid investigation. Objective This study evaluated the efficacy and safety of ruxolitinib, a Janus-associated kinase (JAK1/2) inhibitor, for COVID-19. Methods We conducted a prospective, multicenter, single-blind, randomized controlled phase II trial involving patients with severe COVID-19. Results Forty-three patients were randomly assigned (1:1) to receive ruxolitinib plus SoC treatment (22 patients) or placebo based on SoC treatment (21 patients). After exclusion of 2 patients (1 ineligible, 1 consent withdrawn) from the ruxolitinib group, 20 patients in intervention group and 21 patients in control group were included in the study. Treatment with ruxolitinib plus SoC was not associated with significantly accelerated clinical improvement in severe patients with COVID-19, although ruxolitinib recipients had a numerically faster clinical improvement. Eighteen (90%) patients from the ruxolitinib group showed CT improvement at D14 compared with 13 (61.9%) patients from the control group (P = 0.0495). Three patients in the control group died of respiratory failure, with 14.3% overall mortality at D28; no patients died in the ruxolitinib group. Ruxolitinib was well tolerated with low toxicities and no new safety signals. Levels of 7 cytokines were significantly decreased in the ruxolitinib group in comparison to the control group. Conclusions Although no statistical difference was observed, ruxolitinib recipients had a numerically faster clinical improvement. Significant chest CT improvement, a faster recovery from lymphopenia and favorable side-effect profile in ruxolitinib group were encouraging and informative to future trials to test efficacy of ruxolitinib in a larger population. This trial is registered at www.chictr.org.cn as ChiCTR-OPN-2000029580., The results of the present study showed that ruxolitinib plus SoC was well tolerated in the treatment of severe COVID-19. It significantly mitigated exuberant cytokine storm featured in severe COVID-19, with significant chest CT improvement.

Background Hemophagocytic lymphohistiocytosis (HLH) associated with B-cell lymphoma is a highly aggressive disease with unclear clinical features and has no standard treatment. Patients and Methods We analyzed the clinical characteristics of 31 patients from two individual centers. Results The median overall survival was only 1.5 months. Both univariate and multivariate analyses, based on lymphoma or HLH-related characteristics, revealed that patients with high Epstein-Barr virus (EBV) DNA load and ≥ 2 extranodal lesions, or hypofibrinogenemia, respectively, showed significantly poorer overall survival. Interestingly, some patients with high EBV DNA load had EBV-positive natural killer (NK) and/or T cells, which may be related to the coexistence of immunodeficiency and/or chronic active EBV infection. Molecular genetics examination confirmed that 47.4% (9/19) of patients had complex karyotypes, 37.5% (3/8) of patients had TP53 deletions, and 21.34% (3/14) of patients had TP53 mutation or alteration of malignancy-related pathways, including BCR/NF-κB, JAK-STAT, and epigenetic regulatory pathways, which may provide clues to choose targets for therapy. Treatment regimens containing etoposide, anti-CD20 monoclonal antibodies, or anthracyclines improved patient prognosis (P = .0183, .025, and .0436, respectively). Patients with infections had significantly shorter survival than those without infections (P = .00019). Conclusion The patients’ performance status, number of extranodal lesions, high EBV DNA load, and hypofibrinogenemia are poor prognostic factors for HLH associated with B-cell lymphoma. Molecular genetic high-risk factors are of particular importance because these factors can provide information for prognosis prediction, treatment decisions, and disease surveillance.

Liquid biopsy is a promising technique for tumor genetic profiling and evaluating disease progression. Recent advances in circulating tumor DNA (ctDNA) research highlight its utility in solid tumors and hematological diseases. Extramedullary multiple myeloma (EMM) is an advanced type of multiple myeloma, defined by the presence of clonal plasma cells outside of the bone marrow. The potential of ctDNA to reveal the holistic genomic landscape of EMM is of great interest. Moreover, the mutational concordance between ctDNA and extramedullary plasmacytoma biopsies requires further investigation. In this study, using time-matched extramedullary plasmacytoma biopsies, bone marrow aspirates, and plasma samples from eight EMM patients, we conducted deep sequencing targeting the coding regions of 22 multiple myeloma-related genes. Sequencing results were further verified using droplet digital PCR. Gene mutations in mitogen-activated protein kinase pathways were identified in all 8 tissue biopsies and 7/8 (87.5%) time-matched plasma samples. The ctDNA to tissue biopsy concordance and bone marrow aspirate to tissue biopsy concordance were 0.873 (P = 8.66e−7) and 0.621 (P = 0.109), respectively. In conclusion, our results suggest that ctDNA can be a reliable surrogate for extramedullary plasmacytoma biopsy to characterize the genomic landscape and track disease progression, particularly when extramedullary plasmacytomas are inaccessible. Funding Statement: This work was supported in part by the National Science Foundation for Young Scientists of China (No. 81700160), National Natural Science Foundation of China (General Program, No. 81873452), National Natural Science Foundation of China (Key Program, No. 81630006). Declaration of Interests: The authors stated: "No relevant conflicts of interest to declare." Ethics Approval Statement: This study was approved by Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. The approval file number is TJ-IRB20180813.

Background The rapid spread of coronavirus disease 2019 (COVID-19) was declared as an emerging public health threat by the World Health Organization. As various measures have been taken successfully to combat the epidemic caused by SARS-CoV-2, a growing number of fully recovered patients have been discharged from hospitals. However, some of them have relapsed. Little is known about the causes that triggered the relapse. Case presentation We report a case of a 40 years old man who suffered from recurrent pulmonary infection with progression of lesions on chest computed tomography (CT), elevated levels of ferritin and IL2R, reduced lymphocyte count and positive oropharyngeal swab test for SARS-CoV-2 again after 5 days discharge from hospital. The anti-SARS-CoV-2 antibody level of this patient was very low at the time of relapse, suggesting a weak humoral immune response to the virus. Total exon sequencing revealed mutations in TRNT1 gene, which may be responsible for B cell immunodeficiency. Therefore, uncleared SARS-CoV-2 at his first discharge was likely to lead to his recurrence. However, viral superinfection and non-infectious organizing pneumonia could not be completely excluded. Conclusion COVID-19 relapse may occur in a part of discharged patients with low titers of anti-SARS-CoV-2 antibodies. These patients should be maintained in isolation for longer time even after discharge. A more sensitive method to detect SARS-CoV-2 needs to be established and serological testing for specific antibodies may be used as a reference to determine the duration of isolation.

The study was conducted to test the hypothesis that oxidative stress leads to the release of proinflammatory cytokines by activating the Nod-like receptor protein (NLRP)3 inflammasome in patients with obstructive sleep apnoea (OSA). The study recruited 247 participants who were divided into cases and healthy control groups. OSA patients were subdivided into four subgroups according to sex, blood pressure, body mass index (BMI), and severity of disease. No significant differences were found between cases and controls with respect to age or sex. Peripheral blood samples were collected for analysis after examination, and the serum concentrations of oxidative stress (8-isoprostane), inflammation (interleukin (IL)-18, IL-1β, IL-6, tumour necrosis factor (TNF)-α), and NLRP3 inflammasome components (NLRP3, caspase-1, and ASC) were detected by enzyme-linked immunosorbent assay. The serum concentrations of both oxidative stress and proinflammatory factors were higher in OSA patients than healthy controls. Subgroup analysis also revealed significant differences according to the apnoea–hypopnea index and BMI. Additionally, correlations were identified between 8-isoprostane and proinflammatory factors (IL-1β, IL-18, and TNF-α). Multiple regression analysis suggested that sleep parameters and BMI affected inflammation. However, no differences were observed in the serum level of NLRP3 inflammasome components between patients and controls. Furthermore, stratified analysis revealed no additional differences. The current study suggests that oxidative stress leads to inflammation by mechanisms other than activation of the NLRP3 inflammasome in OSA patients. Furthermore, both sleep apnoea and BMI influenced the serum concentration of inflammatory mediators.

Background The purpose of this study was to evaluate the correlation between calcium-binding protein S100A8 and S100A9 expression in non-small cell lung cancer (NSCLC) and patients' clinical features. Methods Fifty-two NSCLC patients who underwent surgery at Zhejiang Hospital from February 2014 to January 2016 were included in this study. Calcium-binding protein S100A8 and S100A9 expression patterns in cancer and para-cancer tissues were examined by immunohistochemistry assay. The correlation between calcium-binding protein S100A8 and S100A9 expression patterns and NSCLC patients' clinical characteristics, including age, gender, tumor node metastasis stage, and pathology type, were evaluated. Results S100A8 and S100A9 were generally expressed on the cytoplasm and nucleus of NSCLC cells, mainly located in the cytoplasm, stained with brown particles, and distributed evenly. The positive expression rates of S100A8 and S100A9 in cancer tissues were 71.2% and 76.9%, respectively, which were significantly higher than in para-cancer tissues at 11.5% and 19.2%, respectively, with statistical significance (P 0.05). Conclusion S100A8 and S100A9 positive expression in cancer tissues was significantly higher than in para-cancer tissues and was correlated with tumor differentiation, which may be a potential marker for poor prognosis.

The lemon essential oil (LEO), extracted from the fruit of lemon, has been used to treat multiple pathological diseases, such as diabetes, inflammation, cardiovascular diseases, depression and hepatobiliary dysfunction. The study was designed to study the effects of LEO on cognitive dysfunction induced by Alzheimer's disease (AD). We used APP/PS1 double transgene (APP/PS1) AD mice in the experiment; these mice exhibit significant deficits in synaptic density and hippocampal-dependent spatial related memory. The effects of LEO on learning and memory were examined using the Morris Water Maze (MWM) test, Novel object recognition test, and correlative indicators, including a neurotransmitter (acetylcholinesterase, AChE), a nerve growth factor (brain-derived neurotrophic factor, BDNF), a postsynaptic marker (PSD95), and presynaptic markers (synapsin-1, and synaptophysin), in APP/PS1 mice. Histopathology was performed to estimate the effects of LEO on AD mice. A significantly lowered brain AChE depression in APP/PS1 and wild-type C57BL/6L (WT) mice. PSD95/ Synaptophysin, the index of synaptic density, was noticeably improved in histopathologic changes. Hence, it can be summarized that memory-enhancing activity might be associated with a reduction in the AChE levels and is elevated by BDNF, PSD95, and synaptophysin through enhancing synaptic plasticity.

Background Chimeric antigen receptor-modified (CAR) T-cell immunotherapy is a novel promising therapy for treatment of B-cell malignancy. Cytokine release syndrome (CRS) and infection are the most common adverse events during CAR T-cell therapy. Similar clinical presentation of concurrent CRS and infection makes it difficult to differentially diagnose and timely treat the condition. Methods We analyzed the features of infection events during the first 30 days after CAR T-cell infusion (CTI) in 109 patients from three clinical trials (ChiCTR-OPN-16008526, ChiCTR-OPC-16009113, ChiCTR-OPN-16009847). Based on the dynamic changes of interleukin (IL)-6 and ferritin, we proposed the “double peaks of IL-6” pattern as a feature of life-threatening infection during the first 30 days after CTI. Meanwhile, we screened candidate biomarkers from 70-biomarker panel to establish a prediction model for life-threatening infection. Results In this study, 19 patients (17.4%) experienced a total of 19 infection events during the first 30 days after CAR T-cell infusion. Eleven patients (10.1%) had grade 4–5 infection, which were all bacterial infection and predominantly sepsis (N = 9). “Double peaks of IL-6” appeared in 9 out of 11 patients with life-threatening infection. The prediction model of three-cytokines (IL-8, IL-1β and interferon-γ) could predict life-threatening infection with high sensitivity (training: 100.0%; validation: 100.0%) and specificity (training: 97.6%; validation: 82.8%). On base of the aforementioned methods, we proposed a workflow for quick identification of life-threatening infection during CAR T-cell therapy. Conclusions In this study, we worked out two diagnostic methods for life-threatening infection during CAR T-cell therapy by analyzing inflammatory signatures, which contributed to reducing risks of infection-induced death.

Antigen-escape relapse has emerged as a major challenge for long-term disease control after CD19-directed therapies, to which dual-targeting of CD19 and CD22 has been proposed as a potential solution. From March 2016 through January 2018, we conducted a pilot study in 89 patients who had refractory/relapsed B-cell malignancies, to evaluate the efficacy and safety of sequential infusion of anti-CD19 and anti-CD22, a cocktail of 2 single-specific, third-generation chimeric antigen receptor-engineered (CAR19/22) T cells. Among the 51 patients with acute lymphoblastic leukemia, the minimal residual disease-negative response rate was 96.0% (95% confidence interval [CI], 86.3-99.5). With a median follow-up of 16.7 months (range, 1.3-33.3), the median progression-free survival (PFS) was 13.6 months (95% CI, 6.5 to not reached [NR]), and the median overall survival (OS) was 31.0 months (95% CI, 10.6-NR). Among the 38 patients with non-Hodgkin lymphoma, the overall response rate was 72.2% (95% CI, 54.8-85.8), with a complete response rate of 50.0% (95% CI, 32.9-67.1). With a median follow-up of 14.4 months (range, 0.4-27.4), the median PFS was 9.9 months (95% CI, 3.3-NR), and the median OS was 18.0 months (95% CI, 6.1-NR). Antigen-loss relapse occurred in 1 patient during follow-up. High-grade cytokine release syndrome and neurotoxicity occurred in 22.4% and 1.12% patients, respectively. In all except 1, these effects were reversible. Our results indicated that sequential infusion of CAR19/22 T cell was safe and efficacious and may have reduced the rate of antigen-escape relapse in B-cell malignancies. This trial was registered at www.chictr.org.cn as #ChiCTR-OPN-16008526.

Background: Extramedullary myeloma (EMM) and primary plasma cell leukemia (pPCL) remains a treatment challenge even in the era of new drugs. The prognosis of EMM is inferior, and the median overall survival of patients who experience an extramedullary relapse is < 6 months. Chimeric antigen receptor (CAR)- B-cell maturation antigen (BCMA) has the potential for the treatment of EMM and PCL. Methods: Between February 22, 2017 and June 25, 2018, twenty-eight R/R MM patients (including fourteen EMM patients) and 2 pPCL patients received median dose of 11.2 × 106 CAR+ cells/kg (range, 5.4 – 25.0 × 106 CAR+ cells/kg). Patients had a median of 4 (range, 3 – 11) prior lines of therapy, including a proteasome inhibitor and/or an immunomodulatory agent. A lymphodepleting chemotherapy with cyclophosphamide 20mg/kg and fludarabine 25 mg/m2 daily on days -4 to -2 was administered before infusion of CAR-BCMA T cells on day 0. Findings: Hematologic toxic effects were the most common events of grade 3 or higher, including neutropenia (in 96.7% of the patients), lymphopenia (in 100%), anemia (in 76.7%), and thrombocytopenia (in 80.0%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 16.7% and 3.3% of the patients, respectively. The objective response rate (ORR) was 90%, and the complete response (CR) rate was 43.3%. One of 2 primary Plasma cell leukemia achieved CR, and another achieved a very good partial response (VGPR). With a median follow-up of 385 days, relapse occurred in nine of the 13 patients who had a CR. The median progression-free survival (PFS) and overall survivals (OS) were 158 days and 427 days. The median OS of patients with EMM/PCL was 243 days. Interpretation: CAR-BCMA T cell treatment is safe and effective in heavily treated R/R Multiple Myeloma with Extramedullary disease. Trial Registration: Chinese Clinical Trial Registry (http://www.chictr.org.cn. Number, ChiCTR OPC16009113). Funding Statement: This work is supported by the funding from the Key Program of the National Natural Science Foundation of China (81830008 and 81630006, to Dr. J.Z.), the Clinical research program of Huazhong University of Science and Technology affiliated Tongji Hospital (2019YBKY016, to Dr. J.Z.), the National Natural Science Foundation of China (81873452, to Dr. C.L.;81670152, to Dr. L.H.; 81600120, to Dr. N.W.). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: This study was conducted in compliance with the Declaration of Helsinki. The study protocol was approved by the institutional review board of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.

Aim Successful catheter implantation is highly essential for delivering effective peritoneal dialysis (PD). The aim of the present study was to describe a newly developed, minimally invasive percutaneous technique for providing safe, timely, and effective peritoneal catheter insertion and assess the long-term outcome. Materials and methods 100 PD catheters were placed in 100 consecutive patients by a nephrologist using the modified percutaneous technique with a special trocar, from August 1, 2010 to December 31, 2011. The patients were followed up until October 31, 2015. Demographic and clinical features of study subjects, duration of hospital stay, follow-up time, complications, and catheter survival were assessed in all patients. Results The patient study group included 47 men and 53 women, with a mean age of 55.3 ± 13.7 years. The mean hospitalization time was 17.1 ± 8.6 days, and the mean duration of follow-up was 44.7 ± 15.1 months. 71 patients were still on continuous ambulatory peritoneal dialysis at the time of study completion. Peritonitis was the most common complication observed, with an incidence of 28%. None of the patients experienced surgical complications such as bleeding or incisional hernia. The mean catheter survival time was 57.0 ± 1.5 months. Conclusion Peritoneal catheter placement using our modified percutaneous technique is simple, safe, minimally invasive, and efficient. It carried less morbidity with respect to bowel perforation, catheter-related infection, and exit-site leak. .

High-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or refractory(R/R) B-cell lymphoma. Eligibility for HDT-ASCT is based upon the presence of chemo-sensitive disease to salvage therapy. Patients with a positive PET scan prior to ASCT have a substantially inferior suvival. Furthermore, the outcomes of patients who have progressive disease after salvage treatment is extremely dismal. We hypothesized that, following HSCT, the immunosuppressive microenvironment would be diminished as a result of myeloablative conditioning and that administering CAR-T cell therapy during the hematopoietic reconstitution could eradicate posttransplant residual disease, leading to lower relapse rates after HSCT. Based on our previous work that a dual-targeting CAR T cell cocktail of sequential cell infusions targeting CD19 and CD22 may help overcome antigen escape relapse in B-cell malignancies, we therefore conducted an open-label, single-center, and single-arm pilot study of a treatment comprising the sequential infusion of CD22 and CD19 CAR-T cells following autologous hematopoietic stem cell transplantation (HSCT). We aimed to evaluate the safety and efficacy of the treatment in R/R B cell lymphoma patients with residual or progression disease after salvage treatment. Between November 14, 2016 and August 15, 2019, 42 patients underwent BEAM conditioned HDT-ASCT and followed by CAR 19 /22 T cells infusion. The overall response rate was 90.5% (95% CI, 77.4-97.3). At a median follow-up of 13.8 months, the median progression-free survival (PFS) and overall survival (OS) were not reached. The 12-month PFS rate was 85.7 % (95% CI, 70.9 to 93.3). Grade 3 cytokine release syndrome (CRS) occurred in only 2 (5%) patients. 21% patients experienced any grade of neurotoxicity, 5% was severe Grade 3. All CRS and neurotoxicity were reversible. Beyond its extremely high complete response rates, the durability of remission and low toxicity of the autologous HSCT plus CD19/CD22 CAR-T cell cocktail therapy examined in this study emphasize strong potential of such myeloablative conditioning and dual-targeting approaches for R/R B-cell lymphomas. Disclosures No relevant conflicts of interest to declare.

It is reported that the level of serum adiponectin is closely associated with status of obstructive sleep apnea (OSA). However, the effect of continuous positive airway pressure (CPAP) on adiponectin concentration remains controversial. Therefore, the aim of study is to testify the hypothesis that there is a systematic elevation in serum adiponectin with CPAP. We reviewed relevant studies by searching Medline, Pubmed, Embase, and the Cochrane library from 2006 to 2014. Eligible studies which focused on effects of CPAP on adiponectin levels in OSA patients, were identified by two independent reviewers. RevMan and STATA software were utilized for data synthesis and analysis. Association between CPAP and adiponectin was evaluated by polled analysis, and subgroup analysis, basing on detection method, duration of CPAP, sample size, body mass index (BMI), apnea hypopnea index and regional distribution. In total 10 articles were enrolled into the meta-analysis. The results demonstrated that standardised mean difference of the adiponectin levels pre- and post-CPAP therapy was −0.04 (95 % CI −0.21 to 0.12), test for overall effect z = 0.49 (P = 0.62). Subgroup analysis showed that differences in detection method, duration of CPAP, sample size, BMI, OSA severity and regional distribution did not affect the results of polled analysis. The study demonstrated that there was no systematic change in serum adiponectin with CPAP in OSA patients.

Objective: To investigate genotype-phenotype changes between rs29230 in γ-aminobutyric acid B receptor (GABBR1), rs1801278 in insulin receptor substrate-1 (IRS-1), and rs9902709 in hypocretin neuropeptide precursor (HCRT) and obstructive sleep apnea hypopnea syndrome (OSAHS) in Chinese Han individuals. Materials and Methods: A total of 130 patients with OSAHS and 136 age- and gender-matched healthy controls were enrolled in this study. A brief description of DNA extraction and genotyping is given. Multivariate unconditional logistic regression analysis adjusted for gender and age was used to estimate the associations of single nucleotide polymorphisms (SNPs) rs29230 (GABBR1), rs1801278 (IRS-1), and rs9902709 (HCRT) with OSAHS risk. Subgroup analysis was performed to evaluate differences in these SNPs among subgroups according to gender, body mass index (BMI), and severity of disease. Results: Genotype and allele frequencies of rs29230 were significantly different between cases and controls (p = 0.0205 and p = 0.0191, respectively; odds ratio = 0.493, 95% confidence interval = 0.271-0.896), especially for male patients (p = 0.0259 and p = 0.0202, respectively). Subgroup analysis according to BMI also revealed a significant allele difference for rs29230 between cases and controls in the overweight subgroup (p = 0.0333). Furthermore, allele and genotype frequencies of rs1801278 showed significant differences between cases and controls (p = 0.0488 and p = 0.0471, respectively). However, no association was observed between rs9902709 and OSAHS risk (p = 0.2762), and no differences were identified in other subgroups. Conclusion: In this study, there was an association between variants of rs29230 and rs1801278 and OSAHS risk in the Chinese Han population but not for rs9902709.

Background: Previous studies indicate that patients with relapsed/refractory multiple myeloma (RRMM) who receive BCMA-targeting CAR-T cells may achieve better remission but have a higher relapse rate. Persistence of CAR T cells post-infusion may be one determinant of the duration of response. Moreover, once the disease progresses again, the re-infusion of CAR-T cells is not effective. To solve this dilemma, we have developed a novel BCMA-targeting CAR-T (CT103A) with a lentiviral vector containing a CAR structure with a fully human scFv, CD8a hinger, and transmembrane, 4-1BB co-stimulatory and CD3z activation domains. Methods: ChiCTR1800018137 is a single-center and single-arm trial of CT103A in patients with RRMM (≥ 3 prior lines, including a proteasome inhibitor and an IMiD, or double refractory). The primary objectives are the incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). The secondary objectives are the duration of clinical response, evaluation of minimal residual disease (MRD), progression-free and overall survival, and CAR-T cell persistence in blood. Between September 21, 2018, and August 1st, 2019, sixteen patients (including 4 patients having relapsed after being given a murine BCMA CAR-T and 5 patients having extramedullary disease and/or plasma cell leukemia) received CT103A in 3+3 dose-escalation trial (four doses at 1, 3, 6, 8 ×106/kg) after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. Median follow-up after CT103A infusion was 195 days (23 to 314 days) and all 16 patients were evaluable for initial (14 days) clinical response. Results: As of August 1st, 2019, the objective response rate was 100%, 6/16 patients achieved CR/sCR within two weeks post-infusion and all 8 patients surpassing 6 months achieved VGPR/CR/sCR. CR/sCR was 75%, and VGPR was 25% for these 8 patients, according to the IMWG Uniform Response Criteria for MM. In 4 patients who have participated in a prior CAR-T trial, three have achieved sCR, and 1 achieved VGPR. All 15 patients who could be evaluated for minimal residual disease (MRD) had MRD-negative status (≤10-4 nucleated cells by flow). The circulating CT103A cells were detected in the blood by flow and digital polymerase chain reaction, peaking at 14 days (ranging from 9 to 25), and remaining detectable in 12/16 patients, at the time of their last evaluation. Patient #1 (the first patient treated) has now exceeded 314 days of CART persistence, post-infusion. All sixteen patients developed cytokine release syndrome (according to ASBMT Consensus Grading for Cytokine Release Syndrome and Neurological Toxicity Associated with Immune Effector Cells: 10 Grade 1-2, 5 Grade 3,1 Grade 4). A grade 4 CRS appeared at the 6×106 /kg dose level and was considered as a dose-limiting toxicity DLT. No neurotoxicity was observed in all dose groups. One patient died of a lung infection 19 days post-infusion. Conclusions: Data from this early-stage clinical study showed the unparalleled safety and efficacy of CT103A in heavily pretreated R/R multiple myeloma patients. Highly active (ORR 100%) and rapid response within two weeks, suggests CT103A could be developed as a competitive therapy to treat patients with RRMM. Disclosures Hu: Nanjing Iaso Biotherapeutics Co. Ltd..: Employment. Yang:Nanjing Iaso Biotherapeutics Co.: Employment. Zhou:Nanjing Iaso Biotherapeutics Co. Ltd.: Other: Chairman of Advisory Committee of Science and Medicine .

8013 Background: Previous studies indicate patients with relapsed/refractory multiple myeloma (RRMM) who receive high-dose BCMA-targeting CAR-T cells may achieve better remission but have worse adverse events. Moreover, once the disease progresses again, the re-infusion of CAR-T cells is not effective. To solve this dilemma, we have developed a novel BCMA-targeting CAR-T (CT103A) with a lentiviral vector containing a CAR structure with a fully human scFv, CD8a hinger and transmembrane, 4-1BB co-stimulatory and CD3z activation domains. Methods: ChiCTR1800018137 is a single-center and single-arm trial of CT103A in patients with RRMM. The primary objectives are to characterize the safety and tolerability in patients with R/R MM. The secondary objectives include evaluation of anti-myeloma activity, cytokines, CAR-T cell persistence, and pharmacokinetics. Between September 21, 2018, and January 21, 2019, nine patients (including 3 patients having relapsed after being given a murine BCMA CAR-T) received CT103A in 3+3 dose-escalation trial (three doses at 1, 3, 6 ×106/kg) after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. All Patients had received a median of 4 prior lines (range 3 - 5) of MM therapy. Results: At the time of the February 4, 2019 data analysis, the overall response rate was 100% (Table), and all patients had a rapid response within 14 days, with 67% (2/3) reaching CR/sCR at the lowest dose. The pharmacokinetics of CT103A were assessed by a digital polymerase chain reaction. Robust expansions were seen even at the lowest dosage level. In addition, Cmax and AUC0-28 reached levels comparable to reported CD19 CAR-T. In the first two dose groups, the grade of cytokine release syndrome (CRS) was 0 - 2. In the 6 ×106 /kg dose group, DLT had been observed in one patient. Conclusions: Data from this early-stage clinical study showed the unparalleled safety and efficacy of CT103A. Major AEs were transient, manageable, and reversible. three patients who relapsed the murine BCMA CAR-T were treated with CT103A, two patients achieved CR, and one patient achieved VGPR. 100% ORR and a rapid response within 2 weeks, suggests CT103A could be developed as a competitive therapeutic to treat patients with RRMM. Treatment Response (Case 1,5 and 7 are patients who relapsed the murine BCMA CAR-T). Clinical trial information: ChiCTR1800018137. [Table: see text]

CD19 CAR T-cell (CAR-19) therapy have elicited great clinical responses in B-cell malignancies. However, CD19-negative relapse has emerged as a major challenge for the long-term disease control post CAR-19 therapy and conferred a dismal outcome to these pts. Recently, co-targeting of CD19/CD20, CD19/CD22 or CD19/CD123 has been proposed as a strategic approach to overcome antigen loss relapse after CAR-19 therapy. However, the infusion scheme has not yet been defined, the efficacy to avoid antigen escape has not been tested, and its toxicity remains to be assessed. Furthermore, the impact of genetic abnormalities on the outcome post CAR T-cell therapy has not been fully elucidated. We conducted an open-label, single-center and single-arm pilot study of sequential infusion of third generation CAR T-cell "cocktail" comprising both anti-CD22 and anti-CD19 CAR T-cells, which was registered with Chinese Clinical Trial Registry (ChiCTR, number ChiCTR-OPN-16008526). Between March 2016 and January 2018, a total of 89 eligibility pts completed CAR-22/19 "cocktail" infusion and were included for analysis. Of 89 pts (median age 36 years; range, 9-71), 51 had refractory/relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and 38 had R/R B-cell non-Hodgkin lymphoma (B-NHL). The cutoff date for data collection was April 30, 2018, with a median follow-up of 7.6 months (mos) for B-ALL and 5.4 mos for B-NHL. CAR-22 and CAR-19 cells were given separately in 2 divided doses (range, 1 to 4 for CAR-22, and 1 to 5 for CAR-19) with a dose-escalation infusion. Eighty-one pts firstly received CAR-22 infusion, and then CAR-19 infusion, while 8 pts received CAR-19 first and CAR-22 later. B-ALL pts received 2.73±1.19×106/kg CAR-22 and 2.61±1.45×106/kg CAR-19; B-NHL pts received instead higher doses, i.e. 5.28±2.44 ×106/kg CAR-22 and 5.14±2.06 ×106/kg CAR-19. Of the 50 evaluable B-ALL pts, 48 (96.0%) achieved complete remission (CR)/or CR with incomplete count recovery (CRi) at the day 30 assessment. By sensitive multi-parameter flow cytometry (MFC) assay, 47 (94.0%) achieved MRD-negative CR/CRi. At a median follow-up of 7.6 mos (range, 1.3 to 22.2), the progression-free survival (PFS) of all B-ALL pts was 12.0 mos and the overall survival (OS) was not reached. Of the 13 pts with Ph+ B-ALL, 6 of whom had T315I mutation, 11 (84.6%) achieved MRD-negative CR/CRi. The PFS was 15.4 months, and the OS was not reached at a median follow-up of 13.5 months (range, 3 to 22.5). Of the 6 pts with MLL translocations (mainly MLL-AF6), 66.7% were progression-free and the median PFS was not reached. However, among pts with Ph-like ALL, the PFS was only 4.6 months. A total of 23 pts relapsed, however, antigen loss of CD19 and CD22 was not detected by MFC. Forty-Seven pts (92.2%) experienced cytokine release syndrome (CRS) and 11 (21.6%) had severe CRS (≥ grade 3). Except for 1 pt, all the severe cases were reversible. Seven pts (13.7%) developed neurotoxicity. At a minimum follow-up of 3 months, the overall response rate (ORR) and CR rate in 36 evaluable B-NHL pts was 72.2% and 50%, respectively. At the cutoff date for data collection, 50.5% of all pts remained progression-free. A total of 8 pts (26.7%) had relapsed with a median PFS of 2.6 months. Re-biopsy and immunophenotyping was performed in 3 relapsed pts and antigen loss of CD19 or CD22 was not detected. At a median follow-up of 5.4 months (range, 3.0 to 16.2), both PFS and OS of all pts were not reached. Of the 9 pts with MYC translocation, 8 had a response and 7 maintained their responses with a median follow-up of 10.1 months, including all the 4 pts with "double-hit" lymphoma (concurrently carrying MYC and BCL2 or BCL6 translocations). Of the 10 pts with del(17p) or TP53 mutation, 8 (80.0%) had a clinical response. With a median follow-up of 5.3 months, the PFS was 3.3 months, and 45.0% of these pts were progression-free. All the B-NHL pts experienced CRS, but only 21.1% had severe (grade 3 or 4), but reversible CRS and 13.2% developed reversible neurotoxicity. In summary, our results indicated that infusion of third generation CD22/19 CAR T-cell "cocktail" is feasible and safe for pts with B-cell malignancies. Co-targeting to CD19/CD22 is a promising approach for overcoming antigen escape relapse of CAR-19 therapy, but this remain to be fully tested. The treatment response predictive value of distinct genetic subtypes for CAR T-cell therapy should be considered for selection of pts for personalized immunotherapy. Disclosures No relevant conflicts of interest to declare.

This study aimed to test the hypothesis that erectile dysfunction (ED) is common in men with obstructive sleep apnea (OSA). We also assessed the efficacy of continuous positive airway pressure (CPAP) treatment for ED and sex hormone levels in patients with severe OSA and ED.A total of 153 OSA patients and 60 healthy controls were enrolled in this study. The International Index of Erectile Dysfunction-5 (IIEF-5) score was obtained, and blood samples were collected for analysis of sex hormones after polysomnography. The IIEF-5 score, sex hormone levels, and polysomnographic parameters were re-evaluated in 32 patients with severe OSA and ED after 1 month of CPAP treatment.The present study showed that the prevalence of ED was 47.1% in all cases and only 13.3% in controls, and a lower sex hormone levels was presented in OSA patients. OSA patients with ED had greater severity of disease, and lower serum levels of follicle stimulating hormone (FSH) and testosterone than OSA patients without ED (p 0.05). After CPAP therapy, there was a significant increase in the IIEF-5 score, and serum levels of FSH, luteinizing hormone, and testosterone, were elevated compared with baseline levels (p 0.05). Multivariate regression analysis indicated the serum level of testosterone had impact on the ED.OSA patients had lower sex hormone levels and a higher occurrence of ED than controls, and serum level of testosterone had effect on ED. CPAP treatment ameliorated the symptoms of ED and elevated serum levels of FSH, luteinizing hormone, and testosterone.

The authors would like to correct Fig 5, as errors were introduced in the preparation of this figure for publication. In Fig 5D, the assay image for ADV-GFP is derived from the same microscopic image as the assay of PBS. The authors have provided a corrected version of Fig 5 here. Fig 5 Effect of Tim-3 inhibition on Hela cell migration and invasion in vitro. The authors confirm that these changes do not alter their findings. The authors have provided the underlying images for all figures in the original article as Supporting Information.

Herein we reported a case of follicular lymphoma with 50.26% clonal malignant lymphocytes and 50% tumor cells positive for the immunoglobulin heavy chain gene and B-cell lymphoma 2 gene (IGH-BCL2). To determine whether endothelial cells (ECs) within the tumor share the feature of advanced malignancy, we isolated and purified the ECs from the tumor by using the immunomagnetic beads conjugated with a monoclonal antibody against CD34, a surface marker of ECs. Thereafter, we identified ECs according to their morphology and found that ECs presented consistently flat and elongated appearance with a lot of Weibel-Palade bodies in the cytoplasm. Results of flow cytometry confirmed that ECs isolated from the follicular lymphoma expressed high level of both vWF and CD34 and the purity of the ECs fraction was more than 90%. Additionally, we used FISH to check chromosomal aberration in the purified ECs and found that some of the ECs had only one fusion signal for the green IGH probe and the red BCL2 probe in contrast to typical t(14;18)(q32;q21) translocation with two fusion signals. This phenomenon was also observed in the tumor cells. It might be a different breakpoint of IGH in this case, which induced the loss of the fusion signal, indicating t(14;18)(q32;q21) translocation. The positive cells accounted for 18% of the isolated ECs from the tumor, indicating that a proportion of ECs from follicular lymphoma had the same chromosome aberration as the neoplastic cells.

Jinan Shi,1 Yin Duan,2 Lei Pan,2 Xiaoxi Zhou3 1Department of Medical Oncology, Zhejiang Hospital, 2Department of Breast Surgery, Zhejiang Provincial Traditional Chinese Medical Hospital, 3Department of Respiratory Medicine, Zhejiang Hospital, Hangzhou, Zhejiang Province, People’s Republic of China Background: Cluster of differentiation 44 (CD44) is an important surface marker of cancer stem cells in a variety of tumors. A number of previous studies have been conducted to investigate the association between CD44 gene rs13347 C>T polymorphism and cancer risk in humans; nevertheless, the results remain controversial. We therefore performed this meta-analysis to confirm the role of this polymorphism in susceptibility to human cancer.Materials and methods: The studies published up to December 2015 were searched in PubMed, Web of Science, and China National Knowledge Infrastructure databases. Twelve eligible case–control studies were identified, involving a total of 6,982 cases and 7,430 controls. Pooled odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated using a fixed or random-effect model to estimate the strength of the association.Results: The results of the overall analyses indicated that CD44 gene rs13347 polymorphism was significantly associated with cancer risk in Asians (CT vs CC: OR =1.35, 95% CI =1.12–1.62; TT vs CC: OR =1.99, 95% CI =1.52–2.60; TT + CT vs CC: OR =1.41, 95% CI =1.16–1.71; and TT vs CC + CT: OR =1.74, 95% CI =1.41–2.14), especially in Chinese population (CT vs CC: OR =1.42, 95% CI =1.16–1.75; TT vs CC: OR =2.13, 95% CI =1.58–2.86; TT + CT vs CC: OR =1.50, 95% CI =1.21–1.87; and TT vs CC + CT: OR =1.80, 95% CI =1.43–2.26). In stratified analyses by cancer types, there was evidence for an association between this polymorphism and nasopharyngeal cancer and breast cancer, respectively.Conclusion: The results of this meta-analysis suggest that the CD44 gene rs13347 C>T polymorphism is associated with elevated risk of human cancer in Asians, especially in Chinese population. Further well-designed studies on a larger population covering other ethnicities should be carried out to validate our results. Keywords: cancer, CD44, polymorphism, meta-analysis

BackgroundT cell immunoglobulin mucin-3 (Tim-3) has been identified as a negative regulator of anti-tumor immunity. Recent studies highlight the important role of Tim-3 in the CD8(+) T cell exhaustion that takes place in both human and animal cancer models. However, the nature of Tim-3 expression in the tumor cell and the mechanism by which it inhibits anti-tumor immunity are unclear. This present study aims to determine Tim-3 is expressed in cervical cancer cells and to evaluate the role of Tim-3 in cervical cancer progression.MethodologyA total of 85 cervical tissue specimens including 43 human cervical cancer, 22 cervical intraepithelial neoplasia (CIN) and 20 chronic cervicitis were involved. Tim-3 expression in tumor cells was detected and was found to correlate with clinicopathological parameters. Meanwhile, expression of Tim-3 was assessed by RT-PCR, Western Blot and confocal microscopy in cervical cancer cell lines, HeLa and SiHa. The migration and invasion potential of Hela cells was evaluated after inhibiting Tim-3 expression by ADV-antisense Tim-3.ConclusionsWe found that Tim-3 was expressed at a higher level in the clinical cervical cancer cells compared to the CIN and chronic cervicitis controls. We supported this finding by confirming the presence of Tim-3 mRNA and protein in the cervical cell lines. Tim-3 expression in tumor cells correlated with clinicopathological parameters. Patients with high expression of Tim-3 had a significant metastatic potential, advanced cancer grades and shorter overall survival than those with lower expression. Multivariate analysis showed that Tim-3 expression was an independent factor for predicting the prognosis of cervical cancer. Significantly, down-regulating the expression of Tim-3 protein inhibited migration and invasion of Hela cells. Our study suggests that the expression of Tim-3 in tumor cells may be an independent prognostic factor for patients with cervical cancer. Moreover, Tim-3 expression may promote metastatic potential in cervical cancers.

The aim of this study was to evaluate the safety and efficiency of a novel, oncolytic adenovirus mutant M1 administered in conjunction with immunosuppressive agents. Animal models were established by administering purified M1 either intravenously or retroperitoneally. At different time points, blood samples were taken from the mice for testing of liver and renal function. Microscopic examination of the liver was performed to observe pathological changes. Immunohistochemical analyses were used to evaluate the expression of the adenovirus in the liver. Lymphocyte recruitment to the liver and the activation of adenovirus specific T cells were also analyzed. No signs of general toxicity were observed, but transient increases in ALT and Scr were observed following the administration of M1. Microscopic examination revealed a mild inflammatory response in the liver. Compared to intravenous injection, higher expression levels of adenoviral proteins were observed after retroperitoneal injection. Combined treatment with cyclosporine A resolved the liver and kidney dysfunction and increased the concentration of the adenovirus in the liver. The use of the novel oncolytic adenovirus mutant M1 in vivo is safe, and the combined administration of M1 with immunosuppressive agents was able to enhance the effectiveness and safety profile of M1.

SIL-TAL1 rearrangement is common in T-cell acute lymphoblastic leukemia (T-ALL), however its prognostic implication remains controversial. To investigate the clinical characteristics and outcome of this subtype in Chinese population, we systemically reviewed 62 patients with newly diagnosed T-ALL, including 15 patients with SIL-TAL1 rearrangement. We found that SIL-TAL1(+) T-ALL was characterized by higher white blood cell count (P = 0.029) at diagnosis, predominant cortical T-ALL immunophenotype (P = 0.028) of the leukemic blasts, and a higher prevalence of tumor lysis syndrome (TLS, P