Detection of SARS-CoV-2-Specific Humoral and Cellular Immunity in COVID-19 Convalescent Individuals.

The World Health Organization has declared SARS-CoV-2 virus outbreak a worldwide pandemic. However, there is very limited understanding on the immune responses, especially adaptive immune responses to SARS-CoV-2 infection. Here, we collected blood from COVID-19 patients who have recently become virus-free, and therefore were discharged, and detected SARS-CoV-2-specific humoral and cellular immunity in eight newly discharged patients. Follow-up analysis on another cohort of six patients 2 weeks post discharge also revealed high titers of immunoglobulin G (IgG) antibodies. In all 14 patients tested, 13 displayed serum-neutralizing activities in a pseudotype entry assay. Notably, there was a strong correlation between neutralization antibody titers and the numbers of virus-specific T cells. Our work provides a basis for further analysis of protective immunity to SARS-CoV-2, and understanding the pathogenesis of COVID-19, especially in the severe cases. It also has implications in developing an effective vaccine to SARS-CoV-2 infection.

Co-inhibitory Molecule B7 Superfamily Member 1 Expressed by Tumor-Infiltrating Myeloid Cells Induces Dysfunction of Anti-tumor CD8+ T Cells.

The molecular mechanisms whereby CD8+ T cells become "exhausted" in the tumor microenvironment remain unclear. Programmed death ligand-1 (PD-L1) is upregulated on tumor cells and PD-1-PD-L1 blockade has significant efficacy in human tumors; however, most patients do not respond, suggesting additional mechanisms underlying T cell exhaustion. B7 superfamily member 1 (B7S1), also called B7-H4, B7x, or VTCN1, negatively regulates T cell activation. Here we show increased B7S1 expression on myeloid cells from human hepatocellular carcinoma correlated with CD8+ T cell dysfunction. B7S1 inhibition suppressed development of murine tumors. Putative B7S1 receptor was co-expressed with PD-1 but not T cell immunoglobulin and mucin-domain containing-3 (Tim-3) at an activated state of early tumor-infiltrating CD8+ T cells, and B7S1 promoted T cell exhaustion, possibly through Eomes overexpression. Combinatorial blockade of B7S1 and PD-1 synergistically enhanced anti-tumor immune responses. Collectively, B7S1 initiates dysfunction of tumor-infiltrating CD8+ T cells and may be targeted for cancer immunotherapy.

Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction.

T cells become dysfunctional when they encounter self antigens or are exposed to chronic infection or to the tumour microenvironment1. The function of T cells is tightly regulated by a combinational co-stimulatory signal, and dominance of negative co-stimulation results in T cell dysfunction2. However, the molecular mechanisms that underlie this dysfunction remain unclear. Here, using an in vitro T cell tolerance induction system in mice, we characterize genome-wide epigenetic and gene expression features in tolerant T cells, and show that they are distinct from effector and regulatory T cells. Notably, the transcription factor NR4A1 is stably expressed at high levels in tolerant T cells. Overexpression of NR4A1 inhibits effector T cell differentiation, whereas deletion of NR4A1 overcomes T cell tolerance and exaggerates effector function, as well as enhancing immunity against tumour and chronic virus. Mechanistically, NR4A1 is preferentially recruited to binding sites of the transcription factor AP-1, where it represses effector-gene expression by inhibiting AP-1 function. NR4A1 binding also promotes acetylation of histone 3 at lysine 27 (H3K27ac), leading to activation of tolerance-related genes. This study thus identifies NR4A1 as a key general regulator in the induction of T cell dysfunction, and a potential target for tumour immunotherapy.

Confine, Defect, and Interface Manipulation of Fe3 Se4 /3D Graphene Targeting Fast and Stable Potassium-Ion Storage.

The fast electrochemical kinetics behavior and long cycling life have been the goals in developing anode materials for potassium ion batteries (PIBs). On account of high electron conductivity and theoretical capacity, transition metal selenides have been deemed as one of the promising anode materials for PIBs. Herein, a systematic structural manipulation strategy, pertaining to the confine of Fe3 Se4 particles by 3D graphene and the dual phosphorus (P) doping to the Fe3 Se4 /3DG (DP-Fe3 Se4 /3DG), has been proposed to fulfill the efficient potassium-ion (K-ion) evolution kinetics and thus boost the K-ion storage performance. The theoretical calculation results demonstrate that the well-designed dual P doping interface can effectively promote K-ion adsorption behavior and provide a low energy barrier for K-ion diffusion. The insertion-conversion and adsorption mechanism for multi potassium storage behavior in DP-Fe3 Se4 /3DG composite has been also deciphered by combining the in situ/ex situ X-ray diffraction and operando Raman spectra evidences. As expected, the DP-Fe3 Se4 /3DG anode exhibits superior rate capability (120.2 mA h g-1 at 10 A g-1 ) and outstanding cycling performance (157.9 mA h g-1 after 1000 cycles at 5 A g-1 ).

Low prognostic nutritional index is associated with poor outcome in middle-aged and elderly patients with non-metastatic nasopharyngeal carcinoma: a retrospective cohort study.

BACKGROUND: Prognostic nutritional index (PNI) and age are effective prognostic factors for patients with non-metastatic nasopharyngeal carcinoma (NPC), and an interaction between them may exist. However, the age cutoff value is generally set at 45 years in current studies. The clinical implications of PNI in middle-aged and elderly patients are unclear. Therefore, we aimed to uncover this issue. PATIENTS AND METHODS: We retrospectively collected data from 132 middle-aged and elderly (≥ 45 years old) patients with non-metastatic NPC. The association between covariates and the PNI was analyzed using 2 or t-test. The effect of PNI on the prognosis was evaluated using univariate and multivariate Cox regression analyses. Unadjusted and multivariate-adjusted models were applied. Stratified and interactive analyses were performed to investigate the potential source of heterogeneity. RESULTS: Median age (61.0 years versus 59.5 years) and the proportion of patients aged ≥ 60 years (57.6% versus 50.0%) in the low-PNI group were higher than those in the high-PNI group (P > 0.05). The patients with a low PNI had shorter overall survival (OS) (hazard ratio (HR) = 0.86, 95% confidence interval (CI) = 0.80-0.93; P < 0.001) and progression-free survival (PFS) (HR = 0.93, 95% CI = 0.87-0.99; P = 0.034). The results remained stable after three adjusted models of covariates, including age (P < 0.05). No significant interactions were observed in middle-aged (45-59 years) and elderly (≥ 60 years) subgroups for OS and PFS (P for interaction > 0.05). CONCLUSION: Although there is an interaction between PNI and age, PNI is an independent prognostic factor in middle-aged and elderly patients with non-metastatic NPC.

Lower Cerebrovascular Reactivity Contributed to White Matter Hyperintensity-Related Cognitive Impairment: A Resting-State Functional MRI Study.

BACKGROUND: Impaired cerebrovascular reactivity (CVR) plays an important role in the pathophysiology of white matter hyperintensities (WMHs). The pathogenesis of CVR in the development of WMH-related cognitive impairment (CI) remains poorly understood. PURPOSE: To detect the CVR status in WMH subjects with/without CI by using a resting-state blood oxygenation level-dependent (BOLD) approach and to explore the mediating relationships among CVR, WMH, and cognitive level. STUDY TYPE: Prospective. SUBJECTS: Subjects with moderate to severe WMH (with CI [WMH-CI], n = 68; without CI [WMH-no-CI, n = 63) as well as normal controls (NCs, n = 87). FIELD STRENGTH/SEQUENCE: 3.0T with gradient-recalled echoplanar imaging and 3D fluid-attenuated inversion recovery. ASSESSMENT: The CVR, WMH volume, and cognitive level were assessed. The CVR map was derived using BOLD signal obtained from resting-state functional MRI data. STATISTICAL TESTS: CVR maps were compared among the three groups. Partial correlation analyses were performed to correlate impaired CVR with WMH volume and cognitive test scores. Mediation analysis was conducted to determine whether WMH acted as a mediating factor between CVR and cognitive function. RESULTS: Compared with the NC group, both WMH groups showed reduced CVR in the left hemisphere (P < 0.05). The WMH-CI group showed further decreased CVR in the left frontal area, when compared with the WMH-no-CI group (P < 0.05). In the WMH-CI group, the lower CVR in left frontal area was a strong indicator of poor performance on general cognition (r = 0.311), executive function (r = 0.362), and information processing speed (r = 0.399) (all P < 0.05). Periventricular WMH (PWMH) volume mediated these correlations, the ß and 95% bootstrap confidence intervals were (0.5097, [0.1498,1.1385]), (-0.4081, [-1.0256,-0.1363]), and (-0.5576, [-1.4666,-0.1538]), respectively. DATA CONCLUSION: WMH-CI subjects showed a greater reduction of CVR derived from a resting-state BOLD approach in the left frontal area than WMH-no-CI subjects. Cognition was highly dependent on the integrity of cerebrovascular reactivity and mediated by PWMH burden. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.

Establishing content validity for a composite activities-specific risk of falls scale:linkage between fear of falling and physical activity.

BACKGROUND: Fear of falling (FoF) and physical activity (PA) are important psychological and behavioral factors associated with falls. No instrument quantifies the link between these two factors to evaluate the risk of falls. We aimed to design a scale linking FoF with PA (Composite Activities-specific Risk of Falls Scale, CARFS) for people with various disability levels. METHODS: First, we designed a questionnaire comprising 40 balance-related activities from the International Classification of Functioning, Disability, and Health (ICF) for a pilot survey. Second, participants were interviewed about their activities-specific FoF degree and PA frequency. The participants comprised 30 community-dwelling older adults, hospitalized patients with strokes, and those with spinal cord injuries, each with different disability levels. Third, the content validity of the items was evaluated twice by 12 experienced rehabilitation professionals: one based on experience and the other on the survey responses. Items with a higher than moderate relevance in both evaluations were included in the CARFS. The panel of professionals discussed and voted on the contribution of FoF and PA on the CARF score. Finally, the scale sensitivity in distinguishing disability levels was analyzed to evaluate the population suitability to the CARFS. RESULTS: The CARFS included 14 activities. A five-point Likert scale was used to quantify degree of FoF (A) and frequency of PA (B). The CARF score (C), which was determined using the eq. C = A+(4-B) + A × B/2, reflected sensitivity to disability levels in most items. CONCLUSIONS: The CARFS has strong content validity for measuring risk of falls in relation to the FoF and PA of people with various disability levels. It has a potential to provide a guide for designing individualized exercise- and behavior-focused fall prevention programs and enable the precise trtrun 0acking of program effectiveness as a multidimensional outcome measure.

New checkpoints in cancer immunotherapy.

Immune responses must be fine-tuned to allow effective clearance of invading pathogens, while maintain tolerance to self-antigens. T cells are the major effector cells for fighting and killing tumor cells. Immune checkpoints play a pivotal role in T cell activation, and determine the functional outcome of T cell receptor (TCR) signaling. The blockade of immune checkpoints CTLA-4 and PD-1 has already been one of the most successful cancer immunotherapies. In this review, we will focus on three novel inhibitory B7 family checkpoint molecules, B7-H3, B7S1 and VISTA. The aim of this article is to summarize their expressions in tumors as well as their roles in controlling and suppressing T cell immune responses and anti-tumor immunity. These pathways may be explored in future cancer immunotherapy.

Tetranitrile-anthracene as a probe for fluorescence detection of viscosity in fluid drinks via aggregation-induced emission.

Viscosity is an important quality parameter for fluid drinks, which can serve as an indicator for the extent of food spoilage, since the viscosity of fluid drinks varies during the spoilage process. In this study, a near-infrared fluorophore based on tetranitrile-anthracene (TPAEQ) was designed for viscosity determination via aggregation-induced emission (AIE). With increased viscosity, TPAEQ showed enhanced emission at around 759 nm with a large Stokes shift of 195 nm in water. The probe TPAEQ was successfully used to monitor the viscosity changes during the food spoilage process for fluid drinks. Moreover, the probe TPAEQ has effectively been utilized to determine the mass concentrations of food thickeners added in the real fruit drinks. The approach for the viscosity determination could enable the on-site direct detection with convenient operation in food safety inspection applications.

Relationship between the laminectomy extension and spinal cord injury caused by acute spinal shortening: goat in vivo experiment.

OBJECTIVE: To investigate the relationship between different types of laminectomy extension and spinal cord injury subsequent to acute spinal shorting after 3-column osteotomy in living goat model. METHODS: A total of 18 healthy goats were selected, and a procedure of bivertebral column resections and total laminectomy of T13 and L1 was completed followed by different laminectomy extensions under the somatosensory evoked potential (SSEP) monitoring. The samples were divided into three groups according to types of subsequent laminectomy extension. In the first group (enlarged resection of upper lamina group), laminectomy extension was performed on 10 mm caudal to T12; in the second group (equidistant enlarged resection of upper and lower lamina group), laminectomy extension was performed on 5 mm caudal to T12 and 5 mm cranial to L2 simultaneously; and in the third group (enlarged resection of lower lamina group), laminectomy extension was performed on 10 mm cranial to L2. The SSEP measured after vertebral resection was set as the baseline, and the SSEP decreased by 50% from the baseline amplitude and/or delayed by 10% relative to the baseline peak latency was set as positive results, which indicated spinal cord injury. Spinal column was gradually shortened until the SSEP monitoring just did not show a positive result. The shortened distance (ΔH) and the changed angle of the spinal cord buckling (Δα) were measured in each group. Neurologic function was recorded by the Tarlov scores at 2 days after the surgery. RESULTS: The safe shortening distances of three groups were 38.6 ± 1.2 mm, 41.5 ± 0.7 mm, 43.7 ± 0.8 mm, respectively; the corresponding changed angles of the spinal cord buckling were 62.8 ± 6.9°, 82.8 ± 7.5°, and 98.5 ± 7.0°. Significant differences of ΔH and Δα were found among the three groups by LSD multiple comparison test (P < 0.05). Strong correlation between ΔH and Δα was shown in each group by Pearson's correlation test. CONCLUSIONS: Different laminectomy extensions after 3-column osteotomy have different effects on the prevention of SCI caused by acute spinal shortening. The enlarged resection of lower lamina is superior to equidistant enlarged resection of upper and lower laminas which is superior to enlarged resection of upper lamina in preventing SCI. These slides can be retrieved under Electronic Supplementary Material.

Transoral intraarticular cage distraction and C-JAWS fixation for revision of basilar invagination with irreducible atlantoaxial dislocation.

BACKGROUND: The revision surgery of basilar invagination (BI) with irreducible atlantoaxial dislocation (IAAD) after a previous occipitocervical fusion (OCF) is challenging. Transoral revision surgery has more advantages than a combined anterior and posterior approach in addressing this pathology. The C-JAWS is a cervical compressive staple that has been used in the lower cervical spine with many advantages. Up to now, there is no report on the application of C-JAWS in the atlantoaxial joint. We therefore present this report to investigate the clinical outcomes of transoral intraarticular cage distraction and C-JAWS fixation for revision of BI with IAAD. METHODS: From June 2011 to June 2015, 9 patients with BI and IAAD were revised by this technique after previous posterior OCF in our department. Plain cervical radiographs, computed tomographic scans and magnetic resonance imaging were obtained pre- and postoperatively to assess the degree of atlantoaxial dislocation and compression of the cervical cord. The Japanese Orthopedic Association (JOA) score was used to evaluate the neurological function. RESULTS: The revision surgeries were successfully performed in all patients. The average follow-up duration was 18.9 ± 7.3 months (range 9-30 months). The postoperative atlas-dens interval (ADI), cervicomedullary angle (CMA), distance between the top of the odontoid process and the Chamberlain line (CL) and JOA score were significantly improved in all patients (P < 0.05). Bony fusion was achieved after 3-9 months in all cases. No patients developed recurrent atlantoaxial instability. CONCLUSIONS: Transoral revision surgery by intraarticular cage distraction and C-JAWS fixation could provide a satisfactory outcome for BI with IAAD after a previous unsuccessful posterior operation.

Motion-preserving treatment of unstable atlas fracture: transoral anterior C1-ring osteosynthesis using a laminoplasty plate.

BACKGROUND: C1-ring osteosynthesis is a valid alternative to posterior C1-C2 or C0-C2 fusion to preserve important C1-C2 motion in the treatment of unstable atlas fractures. Nevertheless, the fixation instruments used in current studies for transoral anterior C1-ring osteosynthesis were not suitable for anterior anatomy of the atlas or did not have reduction mechanism. We therefore present this report to investigate preliminary clinical effects of transoral anterior C1-ring osteosynthesis using a laminoplasty plate in unstable atlas fractures. METHODS: From January 2014 to December 2017, 13 patients with unstable atlas fractures were retrospectively reviewed. All patients were treated with transoral anterior C1-ring osteosynthesis using a laminoplasty plate. Pre- and postoperative images were obtained to assess reduction of the fracture, internal fixation placement, and bone union. Neurological function, range of motion, and pain levels were evaluated clinically on follow-up. RESULTS: The surgeries were successfully performed in all cases. The average follow-up duration was 16.6 ± 4.4 months (range 12-24 months). One patient suffered screw loosening after operation and underwent replacement operation subsequently. Satisfactory clinical outcomes were achieved in all patients with ideal fracture reduction, reliable plate placement, well-preserved range of motion, and neck pain alleviation. All patients achieved bone union of fractures without loss of reduction or implant failure or C1-C2 instability during the follow-up. No vascular or neurological complication was noted during the operation and follow-up. CONCLUSIONS: Transoral anterior C1-ring osteosynthesis using a laminoplasty plate is a effective surgical treatment for unstable atlas fractures. This technique has a ingenious reduction mechanism, and can provide satisfactory bone union and preservation of C1-C2 motion.

Surgical treatment for basilar invagination with irreducible atlantoaxial dislocation: transoral atlantoaxial reduction plate fixation vs occipitocervical fixation.

BACKGROUND: Transoral atlantoaxial reduction plate (TARP) fixation or occipitocervical fixation (OF) is an effective treatment for basilar invagination (BI) with irreducible atlantoaxial dislocation (IAAD). But, all current clinical studies involved a single surgical procedure. The clinical effects of TARP and OF operation for BI with IAAD have yet to be compared. We therefore present this report to compare the treatment of TARP and OF procedure for BI with IAAD. METHODS: Fifty-six patients with BI with IAAD who underwent TARP or OF operation from June 2011 to June 2017 were retrospectively analyzed. Among these, 35 patients underwent TARP operation (TARP group), and 21 patients underwent OF operation (OF group). We compared the difference of clinical, radiological, and surgical outcomes between the TARP and OF groups postoperatively. RESULTS: Compared with OF group, the operative time and blood loss in TARP group were lower. There was no statistical difference in the atlantodental interval (ADI), clivus canal angle (CCA), cervicomedullary angle (CMA), distance between the top of the odontoid process and the Chamberlain line (CL) and Japanese Orthopaedic Association (JOA) score between the TARP and OF groups preoperatively, but the improvements of these parameters in the TARP group were superior to those in the OF group postoperatively. The fusion rates were higher in the TARP group than those in the OF group at the early stage postoperatively. CONCLUSIONS: TARP and OF operations are effective surgical treatment for BI with IAAD, but the performance of reduction and decompression and earlier bone fusion rates of TARP procedure are superior to those of OF.

One-step analysis of brain perfusion and function for acute stroke patients after reperfusion: A resting-state fMRI study.

BACKGROUND: Resting-state functional magnetic resonance imaging (rs-fMRI) can noninvasively estimate the perfusion and function of the brain. PURPOSE: To investigate the perfusion and functional status using rs-fMRI in acute ischemic stroke (AIS) patients after reperfusion therapy. STUDY TYPE: Prospective. SUBJECTS: Twenty-five AIS patients who underwent dynamic susceptibility contrast (DSC) upon hospital admission and both rs-fMRI and DSC scans at 24 hours after reperfusion therapy. FIELD STRENGTH/SEQUENCE: 3T; DSC, rs-fMRI. ASSESSMENT: The time delay of the blood oxygenation level-dependent (BOLD) signal was calculated using time-shift-analysis (TSA) and compared with the time to peak (TTP) derived from the DSC. For patients who exhibited partial or complete reperfusion in the supratentorial hemisphere, we quantified the function of different regions (healthy tissue, reperfused tissue, not reperfused tissue) by using three rs-fMRI measurements (functional connectivity, the amplitude of low-frequency fluctuation [ALFF] and regional homogeneity [ReHo]). Correlations between the functional measurements and modified Rankin Scale (mRS) scores were calculated. STATISTICAL TESTS: Dice coefficient (DC) analysis, two-sample t-tests, Pearson correlation coefficient. RESULTS: Twelve patients who exhibited complete reperfusion on their TTP maps showed no time-delayed areas on the TSA maps. For the remaining 13 patients with partial reperfusion (5/13) or no reperfusion (8/13) on the TTP maps, the TSA detected comparable time-delayed areas. Eleven out of 13 patients showed moderate to good overlap (mean DC, 0.58 ± 0.1) between the TTP and TSA results. Fourteen patients were chosen for functional analyses and most patients (12/14) showed abnormal functional connectivity in the reperfused regions. The reperfused and not reperfused tissues had lower mean ReHo values than those of the healthy tissue (both P < 0.001). The mRS scores showed negative correlation with mean ReHo values of reperfused region (R = -0.523, P = 0.027). DATA CONCLUSION: rs-fMRI might be a useful way to estimate both the perfusion and functional status for AIS patients after reperfusion therapy. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:221-229.

A fluorescent probe based on aggregation-induced emission for hydrogen sulfide-specific assaying in food and biological systems.

A fluorescent probe based on a triphenylamine benzopyridine platform for hydrogen sulfide (H2S) assaying has been designed and synthesized. As a result of the H2S-triggered cleavage reaction, the disappearance of the quenching effect of dinitrophenyl and the increased hydrophobicity in a poor solvent lead to the aggregation-induced emission (AIE) effect; consequently an obvious 'turn-on' fluorescence signal can be observed in this process. The probe TPANF features high selectivity towards H2S, low detection limit (0.17 µM), and good photostability and biocompatibility. Moreover, it has been successfully utilized to monitor H2S in food samples to distinguish the extent of food deterioration and to identify the H2S concentration variation in living cells. In addition, endogenous H2S in HCT-116 xenograft tumor tissues was imaged by using this probe. The approach could provide useful insight for the development of other activatable AIE-based probes that are potentially helpful for specific assaying in food chemistry and biological systems.

Restless legs syndrome in end stage renal disease patients undergoing hemodialysis.

BACKGROUND: The prevalence of Restless legs syndrome (RLS) in End Stage Renal Disease (ESRD) patients is higher than that in the general population. However, the associations of RLS within the ESRD population are inconsistent and RLS is usually neglected in dialysis centers, although it impairs the life quality among ESRD patients. We aim to investigate the prevalence of RLS in patients with ESRD undergoing maintenance hemodialysis and evaluate the risk factors of developing RLS and the effect of RLS on quality of life among ESRD patients. METHODS: ESRD patients undergoing maintenance hemodialysis in Shanghai General Hospital dialysis unit from July 2016 to October 2016 were enrolled in the study. RLS was diagnosed according to the criteria of the International Restless Legs Syndrome Study Group (IRLSSG). IRLSSG Severity Scale was used to evaluate the severity of RLS. Pittsburgh Sleep Quality Index (PSQI) was used to evaluate sleep quality, and Hospital Anxiety and Depression Scale (HADS) was used to estimate anxiety and depression. Serologic and historic variables were analyzed to determine predictors of RLS in the ESRD population. RESULTS: A total of 137 ESRD patients were enrolled. The prevalence of RLS among the ESRD patients was 20.44%. The risk of RLS was increased significantly in females (OR = 2.729, p = 0.032) and daily alcohol drinkers (OR = 4.716, p = 0.022). RLS increased the risks of sleep disorders (25/28, 89.3% vs 73/109, 67.0%, p = 0.02) and sedative hypnotics intake (7/28, 25.0% vs 10/109, 9.2%, p = 0.047) and impaired the sleep quality (7/109 vs 11/28, p = 0.001) according to PSQI sum scores. CONCLUSION: A high RLS prevalence among the ESRD patients undergoing hemodialysis was confirmed. ESRD patients who are women and drinking alcohol have a higher risk of RLS. The sleep quality was significantly impaired and sleeping medication use was more common among the ESRD patients with RLS.

Expression of the inhibitory B7 family molecule VISTA in human colorectal carcinoma tumors.

Colorectal carcinoma (CRC) is one of the most common malignancies in the world. PD-1/PD-L1 inhibitors have benefited cancer patients with multiple tumor types. However, their efficacy for CRC is low and this treatment in melanoma patients results in adaptive resistance through upregulation of VISTA, another checkpoint inhibitory pathway. Thus, there is an urgent need to explore additional co-inhibitory molecular pathways such as VISTA for CRC treatment. In this study, C10orf54 (encoding VISTA) expression was analyzed by RNA-seq data from 367 CRC patients in human cancer datasets. Moreover, 28 clinical CRC specimens were used to assess VISTA protein expression. Human cancer datasets showed that CRC tumors expressed higher levels of C10orf54 than CD274 (encoding PD-L1). Moreover, C10orf54 mRNA expression was significantly correlated with genes responsible for tumor immune evasion. VISTA protein expression was high in tumors compared with para-tumors and normal tissues, which is similar to PD-L1 expression. However, in contrast to PD-L1, VISTA was mainly expressed by tumor-infiltrating lymphocytes. This study is the first investigation of VISTA expression in human resected CRC tumors, and the results justify the need for future studies on the role of VISTA in anti-CRC immunity in clinical samples.

A T cell-dependent mechanism for the induction of human mucosal homing immunoglobulin A-secreting plasmablasts.

Mucosal immunoglobulin A (IgA) secreted by local plasma cells (PCs) is a critical component of mucosal immunity. Although IgA class switching can occur at mucosal sites, high-affinity PCs are optimally generated in germinal centers (GCs) in a T cell-dependent fashion. However, how CD4(+) helper T cells induce mucosal-homing IgA-PCs remains unclear. Here, we show that transforming growth factor beta1 (TGFbeta1) and interleukin 21 (IL-21), produced by follicular helper T cells (Tfh), synergized to generate abundant IgA-plasmablasts (PBs). In the presence of IL-21, TGFbeta1 promoted naive B cell proliferation and differentiation and overrode IL-21-induced IgG class switching in favor of IgA. Furthermore, TGFbeta1 and IL-21 downregulated CXCR5 while upregulating CCR10 on plasmablasts, enabling their exit from GCs and migration toward local mucosa. This was supported by the presence of CCR10(+)IgA(+)PBs in tonsil GCs. These findings show that Tfh contribute to mucosal IgA. Thus, mucosal vaccines should aim to induce robust Tfh responses.

Outcome and prognostic factors in cervical cancer patients treated with surgery and concurrent chemoradiotherapy: a retrospective study.

BACKGROUND: The objective of this study is to analyze the treatment outcome and secondary reactions in 98 patients with stage I-III cervical carcinoma who underwent postoperative radiotherapy. METHODS: From 2006 to 2014, 98 patients with stage I-III cervical carcinoma were treated with postoperative radiotherapy. The major histological type, found in 92.86% of the patients (91 cases), was squamous cell carcinoma. Patients were staged according to the 2002 TNM guidelines. The postoperative radiotherapy methods included two-field irradiation (16 patients, 16.32%), four-field box irradiation (16 patients, 16.32%), and intensity-modulated radiotherapy (IMRT; 66 patients, 67.36%). The survival rates were represented using Kaplan-Meier curves, and prognosis analyses were performed using Cox multivariate analyses. RESULTS: The 5-year overall survival and progression-free survival rates were 82.0 and 76.0%, respectively. Only one patient (1.02%) developed a grade 3 acute radiation enteritis, while grade 3 and 4 myelosuppression was noted in 17 patients (17.35%) and one patient (1.02%), respectively. Multivariate analyses showed that anemia before radiotherapy and tumor size were predictors of the OS (P = 0.008, P = 0.045) rates. CONCLUSIONS: Postoperative radiotherapy for patients with risk factors of cervical cancer procured good efficacy levels with mild side effects. Anemia and tumor size were important OS predictors.

Increased Active Tumor Targeting by An αvß3-Targeting and Cell-Penetrating Bifunctional Peptide-Mediated Dendrimer-Based Conjugate.

PURPOSE: A bifunctional RGDTAT peptide-modified PEG-PAMAM dendrimer conjugate RGDTAT-PEG-PAMAM (RTPP) was established for the targeted treatment of αvß3-overexpressing tumor cells. METHODS: The RGDTAT peptide was synthesized and attached to PAMAM using PEG to construct the RTPP conjugate. The methotrexate (MTX) encapsulated RTPPM complex was prepared and characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM) and in vitro release. The targeting ability was then studied in cells and tumor-bearing nude mice using fluorescence microscopy, confocal fluorescence microscopy, flow cytometry, and in vivo imaging. The cytotoxicity and pharmacokinetics of the RTPPM complex was also evaluated in cells and rats. RESULTS: The successful synthesis of the RTPP conjugate was confirmed by 1H-NMR. DLS and TEM measurements revealed that the size was 37 nm and the complex had a spherical shape. RTPP and RTPPM were taken up by αvß3-overexpressing cells more efficiently than by αvß3-lowexpressing cells. The RTPP conjugate localized to the cell nucleus and accumulated in the tumor more efficiently than did the conjugates without RGDTAT. The pharmacokinetic study of the RTPPM complex showed sustained drug release. CONCLUSIONS: The bifunctional peptide-mediated dendrimer-based RTPP conjugate can serve as a promising nanocarrier for targeted drug delivery to improve anti-tumor activity.