Current Progress in CAR-T Cell Therapy for Solid Tumors

Cancer immunotherapy by chimeric antigen receptor-modified T (CAR-T) cells has shown exhilarative clinical efficacy for hematological malignancies. Recently two CAR-T cell based therapeutics, Kymriah (Tisagenlecleucel) and Yescarta (Axicabtagene ciloleucel) approved by US FDA (US Food and Drug Administration) are now used for treatment of B cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) respectively in the US. Despite the progresses made in treating hematological malignancies, challenges still remain for use of CAR-T cell therapy to treat solid tumors. In this landscape, most studies have primarily focused on improving CAR-T cells and overcoming the unfavorable effects of tumor microenvironment on solid tumors. To further understand the current status and trend for developing CAR-T cell based therapies for various solid tumors, this review emphasizes on CAR-T techniques, current obstacles, and strategies for application, as well as necessary companion diagnostics for treatment of solid tumors with CAR-T cells

No evidence of a causal relationship between ankylosing spondylitis and cardiovascular disease: a two-sample Mendelian randomization study

ObjectiveObservational studies have suggested an increased risk of cardiovascular disease in individuals with ankylosing spondylitis. However, these studies are prone to confounding factors and reverse causality. To address these limitations, we conducted a Mendelian randomization study to assess the causal relationship between AS and CVD.MethodsThe study population comprises 9,069 individuals with ankylosing spondylitis and 509,093 individuals with either of six common cardiovascular diseases and a related indicator. Causal analysis using summary effect estimates and inverse variance weighting were employed as the main methods.ResultsThe CAUSE analysis showed no evidence of a causal relationship between AS and CVD. The odds ratios for total CVD, heart failure, myocardial infarction, valvular heart disease, ischemic heart disease, and venous thromboembolism, Arterial stiffness index, were as follows: OR, 1.01; 95% confidence interval, 0.96–1.05; P = 0.91; OR, 1.03; 95% CI, 0.99–1.08; P = 0.50; OR, 0.94; 95% CI, 0.86–1.03; P = 0.53; OR, 0.99; 95% CI, 0.94–1.04; P = 0.99; OR, 0.98; 95% CI, 0.91–1.04; P = 0.94; OR, 0.98; 95% CI, 0.91–1.04; P = 0.99; β, −0.0019; 95% CI, 0.97–1.01; P = 0.99. The IVW and weighted median methods also yielded consistent results, and no heterogeneity or pleiotropy was found. Likewise, a reverse Mendelian randomization analysis did not uncover a heritable causal relationship between AS and CVD.ConclusionThis Mendelian randomization study does not support a causal relationship between AS and CVD. Further research is needed to confirm this association

Detecting and phenotyping of aneuploid circulating tumor cells in patients with various malignancies

Circulating tumor cells (CTCs) have been exclusively studied and served to assess the clinical outcomes of treatments and progression of cancer. Most CTC data have mainly been derived from distinct cohorts or selected tumor types. In the present study, a total of 594 blood samples from 479 cases with 19 different carcinomas and 30 healthy samples were collected and analyzed by Subtraction enrichment method combined with immunostaining-fluorescence in situ hybridization (iFISH). Non-hematopoietic cells with aneuploid chromosome 8 (more than 2 copies) were regarded as positive CTCs. The results showed that none of CTCs was found in all 30 healthy samples. The overall positive rate of CTCs was 89.0% in diagnosed cancer patients (ranging from 75.0% to 100.0%). Average number of 11, 5, 8 and 4 CTCs per 7.5 mL was observed in lung cancer, liver cancer, renal cancer and colorectal cancer, respectively. Among 19 different carcinomas, the total number of CTCs, tetraploid chromosome 8, polyploid chromosome 8, CTM (Circulating tumor microemboli) and large CTCs in patients with stage Ⅲ and Ⅳ were statistically higher than patients with stage Ⅰ and Ⅱ (P < 0.05). Furthermore, EpCAM expression was more frequently found in most CTCs than vimentin expression, confirming that these CTCs were of epithelial origin. In addition, small and large CTCs were also classified, and the expression of vimentin was mostly observed in small CTCs and CTM. Our results revealed that there are higher numbers of CTCs, tetraploid, polyploid and large CTCs in patients with stage Ⅲ and Ⅳ, indicating that the quantification of chromosome ploidy performed by SE-iFISH for CTCs might be a useful tool to predict and evaluate therapeutic efficacy as well as to monitoring disease progression

Respiratory Syncytial Virus Exacerbates Kidney Damages in IgA Nephropathy Mice via the C5a-C5aR1 Axis Orchestrating Th17 Cell Responses

Respiratory viral infections can directly lead to kidney damage such as IgA nephropathy (IgAN), partly due to mucosal immune system dysfunction. Although the activated C5a-C5aR1 axis results in increased Th1 and Th17 frequencies but reduced Treg frequencies in Respiratory syncytial virus (RSV) infection, how this axis affects Th cell disorders in RSV-induced IgAN exacerbation remains unknown. Here, we used a mouse model to dissect the activation of C5a-C5aR1 by RSV and the consequences on the regulation of Th1, Th17, and Treg immune responses in IgA nephropathy. RSV fusion protein was clearly deposited not only in the pulmonary interstitium but also in the glomerulus in RSV-IgAN mice, and RSV infection led to more severe pathological changes in the kidneys in IgAN mice. Blocking the C5a-C5aR1 axis resulted in a decrease in the albumin-to-creatinine ratio, and the attenuation of kidney damage in IgAN and RSV-IgAN mice might be partly attributed to the inhibition of Th cell and cytokine dysfunction. Th1, Th17 and Treg immune responses and their corelative cytokines were disrupted by RSV infection and rescued by C5aR1 inhibition. Moreover, we constructed a coculture system of human mesangial cells and CD4+ T cells and found that RSV infection might lead to CD4+ T cell production via human mesangial cells-enhanced CD4+ T cell proliferation, consequently increasing IL-17 levels. These pathological behaviors were augmented by C5a stimulation and decreased by C5aR1 inhibition. Thus, C5aR1 inhibition alters both kidney damage and Th1, Th17, and Treg cell dysfunction in RSV-induced IgAN exacerbation and locally regulates HMC antigen presentation function in the kidney. Taken together, our data offer profound evidence that blocking the C5a-C5aR1 axis might be a potential therapy for RSV-induced IgAN

COVID-19 in Japan: What could happen in the future? (Recent developments on inverse problems for partial differential equations and their applications)

This paper was finished in February, 2020 and posted in MedRxiv on Feb. 28th, 2020.COVID-19 has been impacting on the whole world critically and constantly Since December 2019. We have independently developed a novel statistical time delay dynamic model on the basis of the distribution models from CCDC. Based only on the numbers of confirmed cases in different regions in China, the model can clearly reveal that the containment of the epidemic highly depends on early and effective isolation. We apply the model on the epidemic in Japan and conclude that there could be a rapid outbreak in Japan if no effective quarantine measures are carried out immediately

TELEX HEBDOMADAIRE NR 95 DU 17.09.82 DESTINE A L'ENSEMBLE DES DELEGATIONS EXTERIEURES ET BUREAUX DE PRESS ET D'INFORMATION INDEPENDANTS DANS LES PAYS TIERS = WEEKLY MEMO NO. 95 FOR 17.09.82 TO FOREIGN DELEGATIONS AND PRESS BUREAUS OF THIRD COUNTRIES

<p>High-performance liquid chromatography (HPLC) results of (A) commercial surfactin sample, and (B) our extract surfactin of <i>B</i>. <i>subtilis</i> HH2 in LB medium. There were three main peaks (Peak A-C) of the extract and the surfactin standard in the same location.</p

To compare the efficacy of two kinds of Zhizhu pills in the treatment of functional dyspepsia of spleen-deficiency and qi-stagnation syndrome:a randomized group sequential comparative trial

<p>Abstract</p> <p>Background</p> <p>In Traditional Chinese Medicine (TCM) theory, functional dyspepsia (FD) can be divided into different syndromes according to different clinical symptoms and signs, and the most common one is spleen-deficiency and qi-stagnation syndrome that can be treated by Chinese traditional patent medicine ---- two kinds of Zhizhu pills, between which the primary difference in ingredients is that one contains immature orange fruit of Citrus aurantium L.(IFCA) and the other contains that of Citrus sinensis Osbeck (IFCS). The trial's objective was to compare the efficacy of two kinds of Zhizhu pills on symptom changes in patients with FD of spleen-deficiency and qi-stagnation syndrome.</p> <p>Methods</p> <p>A randomized, group sequential, double-blinded, multicenter trial was conducted in patients with FD of spleen-deficiency and qi-stagnation syndrome at 3 hospitals in Beijing between June 2003 and May 2005. Participants were randomly allocated into two groups (IFCA group and IFCS group) in a 1:1 ratio, and respectively took one of the two kinds of Zhizhu pills orally, 6 g each time, 3 times a day, for 4 weeks. Statistical analysis was performed with use of a group sequential method, the triangular test (TT).</p> <p>Results</p> <p>A total of 163 patients were randomized, and 3 patients were excluded from analysis because of early dropouts, leaving 160 patients (IFCA group: n = 82; IFCS group: n = 78) for statistical analysis. Three interim analyses were done after 62, 116, and 160 patients had completed their 4-week treatment, respectively. At the third interim analysis, the sample path crossed the upper boundary and the trial was stopped, the cure-markedly effective rates were 45% for IFCS group and 67% for IFCA group, respectively, the one-sided <it>p</it>-value was 0.0036, the median unbiased estimate of the odds ratio (OR) for the benefit of IFCA relative to IFCS was 2.91 with 95%CI: 1.40 to 6.06.</p> <p>No adverse events were observed in the two groups.</p> <p>Conclusions</p> <p>Zhizhu pills containing IFCA was superior to Zhizhu pills containing IFCS in the treatment of FD of spleen-deficiency and qi-stagnation syndrome. The application of group sequential analysis in clinical trials of TCM may offer some financial and ethical benefits.</p> <p>Trial Registration</p> <p>Chinese Clinical Trial Registry (ChiCTR): ChiCTR-TRC-00000485</p

Climate change : strategies for mitigation and adaptation

The sustainability of life on Earth is under increasing threat due to humaninduced climate change. This perilous change in the Earth's climate is caused by increases in carbon dioxide and other greenhouse gases in the atmosphere, primarily due to emissions associated with burning fossil fuels. Over the next two to three decades, the effects of climate change, such as heatwaves, wildfires, droughts, storms, and floods, are expected to worsen, posing greater risks to human health and global stability. These trends call for the implementation of mitigation and adaptation strategies. Pollution and environmental degradation exacerbate existing problems and make people and nature more susceptible to the effects of climate change. In this review, we examine the current state of global climate change from different perspectives. We summarize evidence of climate change in Earth’s spheres, discuss emission pathways and drivers of climate change, and analyze the impact of climate change on environmental and human health. We also explore strategies for climate change mitigation and adaptation and highlight key challenges for reversing and adapting to global climate change