Nab-paclitaxel plus S-1 versus oxaliplatin plus S-1 as first-line treatment in advanced gastric cancer: results of a multicenter, randomized, phase III trial (GAPSO study).

Background: This study aimed to investigate the superiority of nab-paclitaxel plus S-1 (AS) over oxaliplatin plus S-1 (SOX) in patients with advanced gastric cancer (AGC). Methods: In this multicenter, randomized, phase III superiority trial, eligible patients with unresectable, locally advanced gastric adenocarcinoma were recruited and randomly assigned (1:1) to receive AS (nab-paclitaxel 260 mg/m2 on day 1 or 130 mg/m2 on days 1 and 8; oral S-1 40-60 mg twice daily for 14 days) or SOX (130 mg/m2 oxaliplatin on day 1; oral S-1 40-60 mg twice daily for 14 days) every 3 weeks for up to six cycles. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival, objective response rate, and safety. Results: Owing to slow enrolment, an unplanned interim analysis was performed, resulting in the early termination of the study on 31 December 2021 (data cutoff). Between March 2019 and March 2021, 97 patients (AS, n = 48; SOX, n = 49) were treated and evaluated for efficacy and safety of AS and SOX. As of the data cutoff, the median follow-up was 23.13 months [95% confidence interval (CI), 13.39-32.87]. The median PFS was 9.03 months (95% CI, 6.50-11.56) in the AS group and 5.07 months (95% CI, 4.33-5.81) in the SOX group, demonstrating a better PFS tendency following AS treatment than SOX treatment (hazard ratio = 0.59; 95% CI, 0.37-0.94; p = 0.03). The most common grade 3 or worse adverse events were anemia, neutropenia, and leukopenia in both groups, with a higher incidence of thrombocytopenia in the SOX group. Conclusion: Although this study was terminated early, the results demonstrated a better PFS tendency in patients with AGC who were treated with AS than in those treated with SOX, with controllable toxicities. Trial registration: Clinical Trials.gov identifiers: NCT03801668. Registered January 11, 2019.

Dexmedetomidine inhibits the growth and metastasis of esophageal cancer cells by down-regulation of lncRNA MALAT1.

This study aims to evaluate the effect of dexmedetomidine (DEX)-on esophageal cancer (EC) via regulating long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). The effect of DEX on MALAT1 expression and EC cell viability was detected. EC cells were divided into Blank, DEX, scrambled/MALAT1 siRNA, and DEX + control/MALAT1 groups, followed by a series of experiments including quantitative reverse-transcription polymerase chain reaction (qRT-PCR), western blotting, 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT), Annexin V-FITC/PI staining, wound healing, and Transwell assays. Additionally, mice were subjected to the subcutaneous injection of Eca109 cells transfected by control/MALAT1 activation lentiviral vector to construct EC models with the DEX treatment, and then the tumor volume and the expression of Ki-67 and active caspase-3 were determined. DEX reduced the expression of MALAT1 in EC cells in a dose-dependent manner. DEX inhibited the viability of EC cells, but increased the cell apoptosis, which, however, was reversed by MALAT1 overexpression. Moreover, MALAT1 overexpression abolished the inhibitory effect of DEX on the epithelial-mesenchymal transition (EMT) of EC cells, with enhanced migration and invasion. Furthermore, DEX succeeded in decreasing the tumor volume with the down-regulation of MALAT1. In comparison with the DEX group, mice in the DEX + MALAT1 group had larger tumors, with the up-regulation of Ki-67 and the down-regulation of active caspase-3. DEX can reduce the expression of MALAT1 in EC cells, thereby inhibiting the proliferation, invasion and migration, as well as EMT, and promoting the apoptosis of EC cells.

High C-Reactive Protein to Albumin Ratio Predicts Inferior Clinical Outcomes in Extranodal Natural Killer T-Cell Lymphoma.

OBJECTIVE: The prognostic value of C-reactive protein to albumin ratio (CAR) has been identified in several cancers but not in extranodal natural killer T-cell lymphoma (ENKTL) as yet. We aimed to evaluate the prognostic value of CAR in ENKTL. METHODS: A retrospective study with 246 patients with ENKTL was performed to determine the prognostic value of pretreatment CAR and examine the prognostic performance of CAR incorporating with International Prognostic Index (IPI) or natural killer/T-cell lymphoma prognostic index (NKPI) by nomogram. RESULTS: The Cox regression analyses showed that high CAR (>0.3) independently predicted unfavorable progression-free survival (PFS, P = .011) and overall survival (OS, P = .012). In the stratification analysis, the CAR was able to separate patients into different prognoses regarding both OS and PFS in Ann Arbor stage I+II as well as III+IV, IPI score 0 to 1, and NKPI score 1 to 2 subgroups (all P < .05). Additionally, the predictive accuracy of the IPI-based nomogram incorporating CAR, albumin to globulin ratio (AGR), and IPI for OS and PFS appeared to be lower than the NKPI-based nomogram incorporating CAR, age, AGR, extranodal site, and NKPI. CONCLUSION: Pretreatment CAR is a simple and easily accessible parameter for independently predicting OS and PFS in patients with ENKTL.

Transformation of spatiotemporal dynamics in the macaque vestibular system from otolith afferents to cortex.

Sensory signals undergo substantial recoding when neural activity is relayed from sensors through pre-thalamic and thalamic nuclei to cortex. To explore how temporal dynamics and directional tuning are sculpted in hierarchical vestibular circuits, we compared responses of macaque otolith afferents with neurons in the vestibular and cerebellar nuclei, as well as five cortical areas, to identical three-dimensional translational motion. We demonstrate a remarkable spatio-temporal transformation: otolith afferents carry spatially aligned cosine-tuned translational acceleration and jerk signals. In contrast, brainstem and cerebellar neurons exhibit non-linear, mixed selectivity for translational velocity, acceleration, jerk and position. Furthermore, these components often show dissimilar spatial tuning. Moderate further transformation of translation signals occurs in the cortex, such that similar spatio-temporal properties are found in multiple cortical areas. These results suggest that the first synapse represents a key processing element in vestibular pathways, robustly shaping how self-motion is represented in central vestibular circuits and cortical areas.

Elevated red cell distribution width contributes to a poor prognosis in patients with esophageal carcinoma.

BACKGROUND: The red cell distribution width (RDW) has also been reported to reliably reflect the inflammation and nutrition status and predict the prognosis across several types of cancer, however, the prognostic value of RDW in esophageal carcinoma has seldom been studied. METHODS: A retrospective study was performed to assess the prognostic value of RDW in patients with esophageal carcinoma by the Kaplan-Meier analysis and multivariate Cox regression proportional hazard model. All enrolled patients were divided into high RDW group (≧15%) and low RDW group (<15%) according to the detected RDW values. RESULTS: Clinical and laboratory data from a total of 179 patients with esophageal carcinoma were retrieved. With a median follow-up of 21months, the high RDW group exhibited a shorter disease-free survival (DFS) (p<0.001) and an unfavorable overall survival (OS) (p<0.001) in the univariate analysis. The multivariate analysis revealed that elevated RDW at diagnosis was an independent prognostic factor for shorter PFS (p=0.043, HR=1.907, 95% CI=1.020-3.565) and poor OS (p=0.042, HR=1.895, 95% CI=1.023-3.508) after adjustment with other cancer-related prognostic factors. CONCLUSION: The present study suggests that elevated preoperative RDW(≧15%) at the diagnosis may independently predict poorer disease-free and overall survival among patients with esophageal carcinoma.

Cyclooxygenase-2 polymorphisms and bladder cancer risk: a meta-analysis based on case-control studies.

The current meta-analysis incorporating 15 case-control studies involving 4,138 cases and 4,269 controls was performed on the basis of a systematical search in electronic databases for a more precise estimation on the associations of three common polymorphisms -765 G>C (rs20417), -1195G>A (rs689466) and +8473 C>T (rs5275) in Cyclooxygenase-2 (Cox-2) gene with the susceptibility to bladder cancer. The results showed that there was a significant association between rs5275 polymorphism and bladder cancer risk (C vs. T; OR=0.84; CC vs. TT: OR=0.76), especially among Chinese (CC vs. TC+TT: OR=0.48) and American (C vs. T; OR=0.83; TC vs. TT: OR=0.73; CC+TC vs. TT: OR=0.73). and the rs20417 polymorphism was significantly associated with an increased risk of bladder cancer among Chinese (C vs. G: OR=1.46; GC vs. GG: OR=1.49; CC+GC vs. GG: OR=1.51) and Indian (GC vs. GG: OR=1.63; CC+GC vs. GG: OR=1.46), but a reduced risk among American (C vs. G: OR=0.81; GC vs. GG: OR=0.76; CC+GC vs. GG: OR=0.76). Additionally, we found that the rs689466 polymorphism was associated with a decreased risk of bladder cancer in Indian (GA vs. GG: OR=0.68; AA vs. GG: OR=0.39).The present meta-analysis suggests that Cox-2 rs5275 polymorphism may contribute to the risk of bladder cancer, particularly among Chinese and American. The rs20417 polymorphism may play a protective role in the development of bladder cancer in Indian and Chinese but act as a risk factor among American, while the rs689466 polymorphism was more likely to be associated with a decreased risk of bladder cancer in Indian.

Neuronal thresholds and choice-related activity of otolith afferent fibers during heading perception.

How activity of sensory neurons leads to perceptual decisions remains a challenge to understand. Correlations between choices and single neuron firing rates have been found early in vestibular processing, in the brainstem and cerebellum. To investigate the origins of choice-related activity, we have recorded from otolith afferent fibers while animals performed a fine heading discrimination task. We find that afferent fibers have similar discrimination thresholds as central cells, and the most sensitive fibers have thresholds that are only twofold or threefold greater than perceptual thresholds. Unlike brainstem and cerebellar nuclei neurons, spike counts from afferent fibers do not exhibit trial-by-trial correlations with perceptual decisions. This finding may reflect the fact that otolith afferent responses are poorly suited for driving heading perception because they fail to discriminate self-motion from changes in orientation relative to gravity. Alternatively, if choice probabilities reflect top-down inference signals, they are not relayed to the vestibular periphery.

Long-term deficits in motion detection thresholds and spike count variability after unilateral vestibular lesion.

The vestibular system operates in a push-pull fashion using signals from both labyrinths and an intricate bilateral organization. Unilateral vestibular lesions cause well-characterized motor deficits that are partially compensated over time and whose neural correlates have been traced in the mean response modulation of vestibular nuclei cells. Here we compare both response gains and neural detection thresholds of vestibular nuclei and semicircular canal afferent neurons in intact vs. unilateral-lesioned macaques using three-dimensional rotation and translation stimuli. We found increased stimulus-driven spike count variability and detection thresholds in semicircular canal afferents, although mean responses were unchanged, after contralateral labyrinth lesion. Analysis of trial-by-trial spike count correlations of a limited number of simultaneously recorded pairs of canal afferents suggests increased noise correlations after lesion. In addition, we also found persistent, chronic deficits in rotation detection thresholds of vestibular nuclei neurons, which were larger in the ipsilesional than the contralesional brain stem. These deficits, which persisted several months after lesion, were due to lower rotational response gains, whereas spike count variability was similar in intact and lesioned animals. In contrast to persistent deficits in rotation threshold, translation detection thresholds were not different from those in intact animals. These findings suggest that, after compensation, a single labyrinth is sufficient to recover motion sensitivity and normal thresholds for the otolith, but not the semicircular canal, system.

Detection thresholds of macaque otolith afferents.

The vestibular system is our sixth sense and is important for spatial perception functions, yet the sensory detection and discrimination properties of vestibular neurons remain relatively unexplored. Here we have used signal detection theory to measure detection thresholds of otolith afferents using 1 Hz linear accelerations delivered along three cardinal axes. Direction detection thresholds were measured by comparing mean firing rates centered on response peak and trough (full-cycle thresholds) or by comparing peak/trough firing rates with spontaneous activity (half-cycle thresholds). Thresholds were similar for utricular and saccular afferents, as well as for lateral, fore/aft, and vertical motion directions. When computed along the preferred direction, full-cycle direction detection thresholds were 7.54 and 3.01 cm/s(2) for regular and irregular firing otolith afferents, respectively. Half-cycle thresholds were approximately double, with excitatory thresholds being half as large as inhibitory thresholds. The variability in threshold among afferents was directly related to neuronal gain and did not depend on spike count variance. The exact threshold values depended on both the time window used for spike count analysis and the filtering method used to calculate mean firing rate, although differences between regular and irregular afferent thresholds were independent of analysis parameters. The fact that minimum thresholds measured in macaque otolith afferents are of the same order of magnitude as human behavioral thresholds suggests that the vestibular periphery might determine the limit on our ability to detect or discriminate small differences in head movement, with little noise added during downstream processing.

Change detection by thalamic reticular neurons.

The thalamic reticular nucleus (TRN) is thought to function in the attentional searchlight. We analyzed the detection of deviant acoustic stimuli by TRN neurons and the consequences of deviance detection on the TRN target, the medial geniculate body (MGB) of the rat. TRN neurons responded more strongly to pure-tone stimuli presented as deviant stimuli (low appearance probability) than those presented as standard stimuli (high probability) (deviance-detection index = 0.321). MGB neurons also showed deviance detection in this procedure, albeit to a smaller extent (deviance-detection index = 0.154). TRN neuron deviance detection either enhanced (14 neurons) or suppressed (27 neurons) MGB neuronal responses to a probe stimulus. Both effects were neutralized by inactivation of the auditory TRN. Deviance modulation effects were cross-modal. Deviance detection probably causes TRN neurons to transiently deactivate surrounding TRN neurons in response to a fresh stimulus, altering auditory thalamus responses and inducing attention shift.

Slow recovery from excitation of thalamic reticular nucleus neurons.

Responses to repeated auditory stimuli were examined in 103 neurons in the auditory region of the thalamic reticular nucleus (TRN) and in 20 medial geniculate (MGB) neurons of anesthetized rats. A further six TRN neurons were recorded from awake rats. The TRN neurons showed strong responses to the first trial and weak responses to the subsequent trials of repeated auditory stimuli and electrical stimulation of the MGB and auditory cortex when the interstimulus interval (ISI) was short (<3 s). They responded to the second trial when the interstimulus interval was lengthened to >or=3 s. These responses contrasted to those of MGB neurons, which responded to repeated auditory stimuli of different ISIs. The TRN neurons showed a significant increase in the onset auditory response from 9.5 to 76.5 Hz when the ISI was increased from 200 ms to 10 s (P<0.001, ANOVA). The duration of the auditory-evoked oscillation was longer when the ISI was lengthened. The slow recovery of the TRN neurons after oscillation of burst firings to fast repetitive stimulus was a reflection of a different role than that of the thalamocortical relay neurons. Supposedly the TRN is involved in the process of attention such as attention shift; the slow recovery of TRN neurons probably limits the frequent change of the attention in a fast rhythm.