Yin Yang 1 expression predicts a favourable survival in diffuse large B-cell lymphoma.

Aims: Yin Yang 1 (YY1) is a multifunctional transcription factor that plays an important role in tumour development and progression, while its clinical significance in diffuse large B-cell lymphoma (DLBCL) remains largely unexplored. This study aimed to investigate the expression and clinical implications of YY1 in DLBCL. Methods: YY1 expression in 198 cases of DLBCL was determined using immunohistochemistry. The correlation between YY1 expression and clinicopathological parameters as well as the overall survival (OS) and progression-free survival (PFS) of patients was analyzed. Results: YY1 protein expression was observed in 121 out of 198 (61.1 %) DLBCL cases. YY1 expression was significantly more frequent in cases of the GCB subgroup than in the non-GCB subgroup (P = 0.005). YY1 was positively correlated with the expression of MUM1, BCL6, pAKT and MYC/BCL2 but was negatively associated with the expression of CXCR4. No significant relationships were identified between YY1 and clinical characteristics, including age, sex, stage, localization, and B symptoms. Univariate analysis showed that the OS (P = 0.003) and PFS (P = 0.005) of patients in the YY1-negative group were significantly worse than those in the YY1-positive group. Multivariate analysis indicated that negative YY1 was a risk factor for inferior OS (P < 0.001) and PFS (P = 0.017) independent of the international prognostic index (IPI) score, treatment and Ann Arbor stage. Furthermore, YY1 is more powerful for stratifying DLBCL patients into different risk groups when combined with MYC/BCL2 double-expression (DE) status. Conclusions: YY1 was frequently expressed in DLBCL, especially in those of GCB phenotype and with MYC/BCL2-DE. As an independent prognostic factor, YY1 expression could predict a favourable outcome in DLBCL. In addition, a complex regulatory mechanism might be involved in the interactions between YY1 and MYC, pAKT as well as CXCR4 in DLBCL, which warrants further investigation.

Light modulates glucose metabolism by a retina-hypothalamus-brown adipose tissue axis.

Public health studies indicate that artificial light is a high-risk factor for metabolic disorders. However, the neural mechanism underlying metabolic modulation by light remains elusive. Here, we found that light can acutely decrease glucose tolerance (GT) in mice by activation of intrinsically photosensitive retinal ganglion cells (ipRGCs) innervating the hypothalamic supraoptic nucleus (SON). Vasopressin neurons in the SON project to the paraventricular nucleus, then to the GABAergic neurons in the solitary tract nucleus, and eventually to brown adipose tissue (BAT). Light activation of this neural circuit directly blocks adaptive thermogenesis in BAT, thereby decreasing GT. In humans, light also modulates GT at the temperature where BAT is active. Thus, our work unveils a retina-SON-BAT axis that mediates the effect of light on glucose metabolism, which may explain the connection between artificial light and metabolic dysregulation, suggesting a potential prevention and treatment strategy for managing glucose metabolic disorders.

Effects of SLCO1B1 on elimination and toxicities of high-dose methotrexate in pediatric acute lymphoblastic leukemia.

Aim: To evaluate the association between SLCO1B1 polymorphisms and elimination/toxicities of high-dose methotrexate (MTX). Methods: SLCO1B1 rs11045879 and rs4149056 polymorphisms were retrospectively genotyped in 301 children with newly diagnosed acute lymphoblastic leukemia. MTX concentration, doses of leucovorin rescue and toxicities were recorded. Results: SLCO1B1 rs11045879C carriers (CC + CT) had higher plasma MTX levels at 96 hr, and longer MTX elimination time. The number of leucovorin rescue doses in rs4149056C carriers (CC + CT) was more than those in TT ones. Moreover, SLCO1B1 polymorphisms were associated with HDMTX toxicities including thrombocytopenia, renal toxicity and anal mucositis, but not associated with MTX level at other time points or delayed elimination. Conclusions: Our data demonstrate that genotyping of SLCO1B1 might be useful to optimize MTX therapy.

A Brainstem reticulotegmental neural ensemble drives acoustic startle reflexes.

The reticulotegmental nucleus (RtTg) has long been recognized as a crucial component of brainstem reticular formation (RF). However, the function of RtTg and its related circuits remain elusive. Here, we report a role of the RtTg in startle reflex, a highly conserved innate defensive behaviour. Optogenetic activation of RtTg neurons evokes robust startle responses in mice. The glutamatergic neurons in the RtTg are significantly activated during acoustic startle reflexes (ASR). Chemogenetic inhibition of the RtTg glutamatergic neurons decreases the ASR amplitudes. Viral tracing reveals an ASR neural circuit that the cochlear nucleus carrying auditory information sends direct excitatory innervations to the RtTg glutamatergic neurons, which in turn project to spinal motor neurons. Together, our findings describe a functional role of RtTg and its related neural circuit in startle reflexes, and demonstrate how the RF connects auditory system with motor functions.

Distinct thalamocortical circuits underlie allodynia induced by tissue injury and by depression-like states.

In humans, tissue injury and depression can both cause pain hypersensitivity, but whether this involves distinct circuits remains unknown. Here, we identify two discrete glutamatergic neuronal circuits in male mice: a projection from the posterior thalamic nucleus (POGlu) to primary somatosensory cortex glutamatergic neurons (S1Glu) mediates allodynia from tissue injury, whereas a pathway from the parafascicular thalamic nucleus (PFGlu) to anterior cingulate cortex GABA-containing neurons to glutamatergic neurons (ACCGABA→Glu) mediates allodynia associated with a depression-like state. In vivo calcium imaging and multi-tetrode electrophysiological recordings reveal that POGlu and PFGlu populations undergo different adaptations in the two conditions. Artificial manipulation of each circuit affects allodynia resulting from either tissue injury or depression-like states, but not both. Our study demonstrates that the distinct thalamocortical circuits POGlu→S1Glu and PFGlu→ACCGABA→Glu subserve allodynia associated with tissue injury and depression-like states, respectively, thus providing insights into the circuit basis of pathological pain resulting from different etiologies.

A circadian rhythm-gated subcortical pathway for nighttime-light-induced depressive-like behaviors in mice.

Besides generating vision, light modulates various physiological functions, including mood. While light therapy applied in the daytime is known to have anti-depressive properties, excessive light exposure at night has been reportedly associated with depressive symptoms. The neural mechanisms underlying this day-night difference in the effects of light are unknown. Using a light-at-night (LAN) paradigm in mice, we showed that LAN induced depressive-like behaviors without disturbing the circadian rhythm. This effect was mediated by a neural pathway from retinal melanopsin-expressing ganglion cells to the dorsal perihabenular nucleus (dpHb) to the nucleus accumbens (NAc). Importantly, the dpHb was gated by the circadian rhythm, being more excitable at night than during the day. This indicates that the ipRGC→dpHb→NAc pathway preferentially conducts light signals at night, thereby mediating LAN-induced depressive-like behaviors. These findings may be relevant when considering the mental health effects of the prevalent nighttime illumination in the industrial world.

A Visual Circuit Related to Habenula Underlies the Antidepressive Effects of Light Therapy.

Light plays a pivotal role in the regulation of affective behaviors. However, the precise circuits that mediate the impact of light on depressive-like behaviors are not well understood. Here, we show that light influences depressive-like behaviors through a disynaptic circuit linking the retina and the lateral habenula (LHb). Specifically, M4-type melanopsin-expressing retinal ganglion cells (RGCs) innervate GABA neurons in the thalamic ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL), which in turn inhibit CaMKIIα neurons in the LHb. Specific activation of vLGN/IGL-projecting RGCs, activation of LHb-projecting vLGN/IGL neurons, or inhibition of postsynaptic LHb neurons is sufficient to decrease the depressive-like behaviors evoked by long-term exposure to aversive stimuli or chronic social defeat stress. Furthermore, we demonstrate that the antidepressive effects of light therapy require activation of the retina-vLGN/IGL-LHb pathway. These results reveal a dedicated retina-vLGN/IGL-LHb circuit that regulates depressive-like behaviors and provide a potential mechanistic explanation for light treatment of depression.

Sodium chloride (NaCl) potentiates digoxin-induced anti-tumor activity in small cell lung cancer.

Small cell lung cancer (SCLC) is a malignant neuroendocrine tumor with very high mortality. Effective new therapy for advanced SCLC patients is urgently needed. By screening a FDA-approved drug library, we identified a cardiac glycoside (CG), namely digoxin (an inhibitor of cellular Na+/K+ ATPase pump), which was highly effective in inhibiting SCLC cell growth. Intriguing findings showed that NaCl supplement markedly enhanced the anti-tumor activities of digoxin in both in vitro and in vivo models of SCLC. Subsequent analysis revealed that this novel combination of digoxin/NaCl caused an up-regulation of intracellular Na+ and Ca2+ levels with an induction of higher resting membrane potential of SCLC cells. We also found that this combination lead to morphological shrinking of SCLC cells, together with high levels of cytochrome C release. Lastly, our data revealed that NaCl supplement was able to induce the expression of ATP1A1 (a Na+/K+ ATPase subunit), in which contributes directly to the increased sensitivity of SCLC cells to digoxin. Thus, this is the first demonstration that NaCl is a potent supplement necessitating superior anti-cancer effects of digoxin for SCLC. Further, our study suggests that digoxin treatment could need to be combined with NaCl supplement in future clinical trial of SCLC, particularly where low Na+ is often present in SCLC patients.

Effects of Acupuncture on the Level of Inflammatory Cytokines and Toll-like Receptor 4 in Hypothalamic Paraventricular Nucleus of Spontaneously Hypertensive Rats / 中国中医药信息杂志

Objective To observe the effects of acupuncture on the level of inflammatory cytokines and toll-like receptor 4 in hypothalamic paraventricular nucleus (PVN) of SHR; To investigate the mechanisms of acupuncture in reduction of mean arterial blood pressure (MAP) in SHR. Methods Thirty 10-week old SHR were randomly divided into SHR group, acupuncture group and non-acupoint group, with 10 rats in each group. 10 WKY rats were set as control group. Acupuncture group received bilateral acupuncture in "Taichong" acupoint, and twisting and diarrhea method was used to stimulate; non-acupoint group received acupuncture at the back of feet, and soothing and diarrhea with twisting method was used to stimulate. Materials were taken two weeks later. The mean arterial pressure of rats was detected every day; the expression of TLR4 mRNA in PVN was detected by RT-PCR; The expression of TLR4 protein in PVN was detected by Western blot; The levels of TNF-αa nd IL-6 were detected. Results Compared with control group, the mean arterial pressure of SHR group increased; TLR4 mRNA and protein expression in PVN increased significantly; the level of TNF-α and IL-6 increased significantly (P<0.05). Compared with SHR group, the mean arterial pressure of acupuncture group decreased significantly;TLR4 mRNA and protein expression in PVN decreased significantly; the level of TNF-α and IL-6 decreased significantly (P<0.05). There was no significant change in non-acupoint group. Conclusion Acupuncture in"Taichong" acupoint can attenuate blood pressure of SHR by inhibiting expression of TLR4 in PVN and reducing the levels of TNF-α and IL-6.

Clinical Observation of Scalp Acupuncture Combined with Swallowing and Speech Therapeutic Instrument for Treatment of Post-stroke Dysphagia / 广州中医药大学学报

Objective To observe the c linical effect of scalp acupuncture combined with swallowing and speech therapeutic instrument for the treatment of post-stroke dysphagia. Methods Sixty-eight patients with post-stroke dysphagia were randomly divided into treatment group (N = 34)and control group (N = 34). Both groups were given the internal medicine treatment for lowering blood lipids,stabilizing plaque,and nourishing nerves,and took rehabilitation training. And additionally,the treatment group was given scalp acupuncture therapy and the treatment with swallowing and speech therapeutic instrument,and the control group was given the treatment with s wallowing speech therapeutic instrument alone. Two weeks constituted one treatment course, and the two groups were treated for 4 weeks. The scores of Standardized Swallowing Assessment(SSA) and Swallowing Quality of Life Instrument (SWAL-QOL) of the two groups were observed before and after treatment, and then the curative effects were evaluated by Saito 7-grade dysphagia assessment method. Results (1)Till the end of the trial,7 cases of the 68 patients were excluded for transferring to other departments or loss to follow-up. Of the 7 excluded cases, 3 cases were from the treatment group and 4 were from the control group. (2) The total effective rate of the treatment group was 90.32%and that of the control group was 66.67%,the difference being significant(P < 0.05).(3)After treatment,SSA scores of the 2 groups were decreased(P < 0.01)and SWAL-QOL scores were increased (P < 0.01),and the effect on improving SSA scores and SWAL-QOL scores in the treatment group was superior to that in the control group (P < 0.01). Conclusion Both groups can relieve dysphagia and improve the quality of life of post-stroke dysphagia patients,and the scalp acupuncture combined with swallowing and speech therapeutic instrument is more effective for the treatment of post-stroke dysphagia.

Intraoperative opioid-sparing effect of different frequency transcutaneous electrical acupoint stimulation in patients undergoing video-assisted thoracoscopic pneumonectomy / 中华麻醉学杂志

Objective To evaluate the intraoperative opioid-sparing effect of different frequency transcutaneous electrical acupoint stimulation (TEAS) in the patients undergoing video-assisted thoracoscopic pneumonectomy.Methods Eighty patients,aged 40-64 yr,weighing 50-90 kg,of ASA physical status Ⅰ-Ⅲ,scheduled for elective thoracoscopic pneumonectomy under general anesthesia,were randomly divided into 4 groups (n =20 each) using a random number table:control group (group Con),stimulation on Lieque (LU7)-Quchi (LI11)-Neiguan (PC6)-Hegu (LI4) at 2/100 Hz group (group 2/100 Hz),stimulation on LU7-LI11-PC6-LI4 at 2 Hz group (group 2 Hz),and stimulation on LU7-LI1 1-PC6-LI4 at 100 Hz group (group 100 Hz).The patients in group Con had the electrodes applied,but received no stimulation.In 2/100 Hz,2 Hz and 100 Hz groups,the patients received 2/100,2 and 100 Hz TEAS on LU7-LI11-PC6-LI4 acupoints ipsilateral to the surgery site,respectively,starting from 30 min before induction of anesthesia until the end of surgery,and the intensity was the maximum current that could be tolerated.Anesthesia was induced with iv midazolam,propofol,sufentanil and cisatracurim,and maintained with target-controlled infusion of remifentanil and propofol,continuous infusion of cisatracurim,and iv boluses of sufentanil when necessary.The target plasma concentration of propofol was adjusted to maintain BIS value at 40-60 during operation.The initial target effect-site concentration of remifentanil was 1 ng/ml,and adjusted to 4 ng/ml at skin incision.The concentration of remifentanil and consumption of sufentanil were adjusted to maintain Analgesia Nociception Index (ANI) at 50-70.When the concentration of remifentanil was increased to 4 ng/ml,ANI was still less than 50,and then 0.1 μg/kg sufentanil was given.The duration of operation and intraoperative consumption of remifentanil and sufentanil (the consumption of sufentanil was converted to the consumption of remifentanil producing the equivalent effect by 1:10) were recorded.Results The intraoperative consumption of remifentanil was significantly reduced in 2/100 Hz group as compared with Con,2 Hz and 100 Hz groups.There was no significant difference in the intraoperative consumption of remifentanil between Con group,2 Hz group and 100 Hz group.Conclusion The use of 2/100 Hz but not 2 and 100 Hz TEAS on LU7-LI11-PC6-LI4 significantly reduces intraoperative opioid consumption in the patients undergoing video-assisted thoracoscopic pneumonectomy.