A Novel Sushi-IL15-PD1 CAR-NK92 Cell Line With Enhanced and PD-L1 Targeted Cytotoxicity Against Pancreatic Cancer Cells.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy with a limited response to current therapies. Novel and effective treatment is urgently needed. Herein, a chimeric antigen receptor (CAR)-NK92 cell line, with an interleukin (IL)-15Rα-sushi/IL-15 complex and a Programmed cell death-1(PD1) signal inverter was constructed and named SP ( S ushi-IL15- P D1). We showed that CAR expression enabled SP cells to proliferate independently of IL-2 and became more resistant to nutrition starvation-induced apoptosis. Meanwhile, SP cells were more effective than NK92 in PDAC cell killing assays in vitro and in vivo, and there was a positive correlation between the killing capability of SP cells and PD-L1 expression in pancreatic cancer cells. Based on the synergistic and comprehensive effects of the special CAR structure, the adhesion, responsiveness, degranulation efficiency, targeted delivery of cytotoxic granule content, and cytotoxicity of SP cells were significantly stronger than those of NK92. In conclusion, the SP cell line is a promising adoptive immunotherapy cell line and has potential value as an adjuvant treatment for pancreatic cancer, especially in patients with high PD-L1 expression.

Clinical analysis of skin lesions in 796 Chinese HIV- positive patients.

Skin lesions are often associated with human immunodeficiency virus (HIV) infection, reflecting the immunocompromised status of the individual. We investigated the relationship between skin lesions and immune function in a retrospective study of 796 Chinese HIV patients with and without highly active antiretroviral therapy (HAART). Of the 651 patients who had not received HAART, we found that 531 (81.6%) had apparent skin lesions. The incidence of infectious skin diseases (fungi, viruses, bacteria, spirochetes and parasites) and non-infectious skin diseases (excluding skin cancer) was 68.8% and 34.9%, respectively. Mean CD4(+) T-cell counts and CD4(+)/CD8(+) ratios were lower in patients with skin lesions than in patients without lesions (178 ± 96/µl vs. 306 ± 189/µl (p < 0.05) and 0.22 vs. 0.34 (p < 0.01), respectively). Candidiasis (25.8%), eczema (19.2%), nodular prurigo (13.8%), dermatophyte infections (10.6%) and herpes zoster (9.4%) were most common in Chinese patients with HIV. Among the 145 patients who had started HAART, there was a significantly lower prevalence of skin diseases (29.0%), although drug eruptions (12.4%) were more commonly observed. These findings indicate that HAART often reduces the incidence of infectious and non-infectious skin lesions in patients with HIV, but can itself be the cause of drug eruptions.

Efficacy and Safety of Tenofovir and Lamivudine in Combination with Efavirenz in Patients Co-infected with Human Immunodeficiency Virus and Hepatitis B Virus in China.

BACKGROUND: The prevalence of hepatitis B virus (HBV) infection is high among individuals infected with human immunodeficiency virus (HIV) in China. Both HIV and HBV can be treated with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC), so we evaluated the safety and efficacy of combination antiretroviral therapy (ART) that included TDF, 3TC, and efavirenz (EFV) among ART-naive individuals who were co-infected with HIV and HBV. METHODS: One hundred HIV/HBV co-infected ARV-naive individuals were started on the regimen of TDF, 3TC, and EFV, and the levels of plasma HBV DNA, HIV RNA, and biochemical evaluation related to the function of liver and kidney were analyzed. RESULTS: Concerning efficacy, this study found that by week 48, the vast majority co-infected participants receiving this ART regimen had undetectable HBV DNA levels (71%) and/or HIV RNA levels (90%). Concerning safety, this study found that the median estimated glomerular filtration rate of participants decreased from baseline (109 ml·min-1·1.73 m-2) to week 12 (104 ml·min-1·1.73 m-2) but was almost back to baseline at week 48 (111 ml·min-1·1.73 m-2). CONCLUSION: This combination ART regimen is safe and effective for patients with HIV/HBV co-infection. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01751555; https://clinicaltrials.gov/ct2/show/NCT01751555.

[Study on HIV-1 drug resistance profile of 257 AIDS patients with failure on the first-line antiretroviral treatment in Henan].

OBJECTIVE: To understand the current situation related to genotypic resistance in patients receiving the first-line antiretroviral treatment, but with with virologic failure, in Henan province and to compare the patterns of drug resistance in patients from different areas. METHODS: 276 patients with virologic failure on first-line antiretroviral treatment were selected in three different areas of Henan, in 2010. CD4(+)T cells, virus load and genotypic resistance were measured and tested. Prevalence and mutations related to drug-resistant were analyzed. RESULTS: The overall prevalence of drug-resistance was 68.48% in 257 patients, with non-nucleoside reverse transcriptase inhibitor (NNRTIs) as 67.70%. Rate of nucleoside reverse transcriptase inhibitor (NRTIs) was 54.09%, and protease inhibitors (PIs) was 1.18%. The prevalence rates of drug-resistance in A, B and C groups were 82.35%, 97.47% and 52.80%, respectively, and withs significant differences (χ2=50.624, P=0.000). The Prevalence rates related to resistance of NNRTIs and NRTIs were also significantly different (χ2=48.771, P=0.000 and χ2=33.912, P=0.000). 26.46% of the samples had M184V/I mutation which was the highest NRTIs mutation among the 257 patients. The prevalence rates on resistance of A and B were 47.06% and 49.37%, higher than that of C (13.04%, χ2=39.905, P=0.000) followed by TAMs, TAMs-1 and TAMs-2 which were 8.56% and 4.28%. C had the lower prevalence of TAMs-1 than A and B (χ2=13.499, P=0.001). 40.47% of the samples harbored≥1 TAM, with T215Y/F having the most, as 33.85%. 31.13% of 257 patients appeared most NNRTIs mutation K103N in this study, with the prevalence rates also significant different (χ2=14.213, P=0.001) in the three areas. Two PIs mutations were detected in 257 patients: M46I/L, (1.17%) and V82F (0.39%). However, none was detected in area A. CONCLUSION: Different patterns of drug resistance were found in different areas of Henan province and should be treated differently. The work related to AIDS second-line antiretroviral therapy in Henan should be more opportune, rigorous and standardized.

Expansion of China's free antiretroviral treatment program.

BACKGROUND: In 2003, China's National Free Antiretroviral Treatment Program (NFATP) was initiated as a pilot, which covered only 100 HIV/AIDS patients. By 2011, the pilot had evolved into a nationwide program and had provided free treatment for over 150 000 patients. The objective of this study was to report and evaluate the progress of China's free antiretroviral treatment program. METHODS: The NFATP Database was systematically reviewed and a total of 150 692 HIV/AIDS patients were included in this study. Program progress indicators including the number of treated HIV/AIDS patients, follow-up visit rate, CD4 test rate, and viral load test rate were summarized and examined over a calendar year to evaluate the progress of NFATP quantitatively and qualitatively. RESULTS: By the end of 2011, a total of 150 692 HIV/AIDS patients had been treated through the NFATP and 122 613 of them were still on treatment. Of all patients, about 72% were enrolled during the past four years. The dominant transmission route was blood related in the early phase of the NFATP, but gradually changed to sexual contact. Besides quantitative improvements, progress indicators also demonstrated significant qualitative improvements that the program had made during the past 9 years. CONCLUSIONS: Great achievement has been made by China's NFATP. China's experience indicates the importance of a comprehensive response to the success of its treatment program. However, to ensure the quality and sustainability of treatment in the long term, more attention and resources should be paid towards program management.

[Env gene sequencing and HIV-1 subtyping of infected MSM from Beijing].

OBJECTIVE: To comprehend the latest HIV-I epidemic tendency and the character of V3 loop in MSM population of Beijing. METHODS; The C2-V3 regions of the HIV envelop gene were amplified by nest-PCR and sequenced from 11 HIV-l-infected MSM in Beijing in 2007. The subtype and sequences of V3 loop was analyzed. RESULTS There are 4 subtype B strains, 5 CRF AE, 1 CRFO7BC and 1 CRF15-01B strains within all 11 strains. There are five types of central motifs of the 11 samples, in which GPGR and GPGQ are most common. CONCLUSION: Recombination subtype of HIV-1 are spread extensively in MSM population of Beijing.

[Sequence polymorphisms of mitochondrial DNA hypervariable 1 of peripheral blood cells from 47 HIV/AIDS patients of Han nationality].

OBJECTIVE: To investigate alterations of hyper variable region 1 (HR 1) of mitochondrial DNA Blood cells were (mtDNA) in white blood cells of Chinese Han nationality HIV/AIDS patients. METHODS: obtained from 47 cases of therapy-naïve HIV/AIDS patients without opportunity infection and DNA were extracted using blood DNA extracted kit. About 600 bp fragments which contain HR 1 were amplified by PCR. Alterations were determined by directed DNA sequencing. RESULTS: There were 124 polymorphism sites in mtDNA HR 1 (nb16024-16383) in 47 HIV/AIDS patients. The alteration rate was 0 to 20.47% (median 5.33%). 36 cases experienced C to T nucleotide change at nt 16 223, and the alteration rate was 70.97%. At nt 16 362, 26 individuals showed T to C nucleotide change and 3 individuals showed T to G alteration, alteration rate was 55.32% (26/47) and 6.38% (3/47) individually. CONCLUSION: HIV infection may cause more alterations in HR 1 regions.

[Expression of K18, Ser-33 and Ser-52 phosphorylated K18 in HBV infected human liver disease and its significance].

OBJECTIVE: To investigate the expression of K18, Ser-33 and Ser-52 phosphorylated K18 in HBV infected human liver disease and its significance. METHODS: The expression and localization of K18 and Ser-33, Ser-52 phosphorylated K18 in healthy liver tissue, in liver tissues of patients with post-HBV infection cirrhosis and severe chronic hepatitis were detected by histochemistry. RESULTS: K18, Ser-33 and Ser-52 phosphorylated K18 were expressed in normal liver cells, in liver tissues of cirrhosis patients and severe chronic hepatitis cases. The expression of K18 in the liver cells from the 3 different sources had no significant difference in levels. Ser-33 and Ser-52 phosphorylated K18 were expressed in normal liver cells, in liver tissues of cirrhosis patients chronicity HBV hepatitis and severe chronic hepatitis cases. Ser-33 and Ser-52 located around cytoplasmic membrane, diffused into cytoplasm and expressed at a higher levels in cirrhosis and severe chronic hepatitis. CONCLUSION: The expression levels of Ser-33 and Ser-52 phosphorylated K18 increased along with the progression of HBV infected human liver disease. The phosphorylation of K18 could be a marker of progression of HBV infected human liver disease.