Spinal cord injury (SCI) is a devastating medical condition affecting 1.2 million people in the United States. Central neuropathic pain is one of the most common medical complications of SCI. Current treatment options include opioids, antiepileptic agents such as gabapentin, antispastic agents such as baclofen or tizanidine, and tricyclic acid. Other options include complementary, nonpharmacological treatment such as exercise or acupuncture, interventional treatments, and psychological approaches. Although these treatment options exist, central neuropathic pain in patients with SCI is still extremely difficult to treat because of its complexity. To develop and provide more effective treatment options to these patients, proper assessment of and classification tools for central neuropathic pain, as well as a better understanding of the pathophysiology, are needed. A combination of approaches, from standard general pain assessments to medically specific questions unique to SCI pathophysiology, is essential for this population. A multidisciplinary approach to patient care, in addition with a better understanding of pathophysiology and diagnosis, will lead to improved management and treatment of patients with SCI displaying central neuropathic pain. Here we summarize the most recent classification tools, pathophysiology, and current treatment options for patients with SCI with central neuropathic pain.
Little is known about the clinical value of peripheral blood immune profiling. Here, we aimed to identify colorectal cancer (CRC)-related peripheral blood immune cells and develop liquid biopsy-based immune profiling models for CRC diagnosis.Peripheral blood from 131 preoperative patients with CRC and 174 healthy controls was analyzed by flow cytometry and automated hematology. CRC-related immune factors were identified by comparing the mean values of immune cell percentages and counts. Subsequently, CRC diagnostic algorithms were constructed using binary logistic regression.Significant differences were observed in percentages and counts of white blood cells, lymphocytes, neutrophils, regulatory T cells, and myeloid-derived suppressor cells (MDSCs) of patients and controls. The neutrophil/lymphocyte and Th1/Th2 ratios were also significantly different. Likewise, the percentages and counts of peripheral blood programed death 1, cytotoxic T lymphocyte antigen 4, B-and T-lymphocyte attenuator, and lymphocyte activation gene-3 were higher in patients with CRC. The binary logistic regression model included 12 variables, age, CD3+%, NK%, CD4+CD279+%, CD4+CD25+%, CD4+CD152+%, CD3+CD366+%, CD3+CD272+%, CD3+CD223+%, CD158b-CD314+CD3-CD56+%, Th2%, and MDSCs cells/µL, for the prediction of cancer. Results of retrospective and prospective evaluation of the area under the curve, sensitivity, and specificity were 0.980 and 0.940, 91.53% and 85.80%, and 93.50% and 86.20%, respectively.Peripheral blood immune profiling may be valuable in evaluating the immunity of CRC patients. Our liquid biopsy-based immune diagnostic method and its algorithms may serve as a novel tool for CRC diagnosis. Future largescale studies are needed for better characterization of its diagnostic value and potential for clinical application.
Claudin-11(CLDN11) is a component of tight junction, and important for normal CNS functions. The function of CLDN11 is well elucidated in oligodendrocytes and CNS system, but its expression pattern according to human vascular bed such as intracranial and extracranial, role in the vascular smooth muscles (vSMCs) plasticity and atherosclerosis is still unknown. Human left anterior descending coronary artery (LAD) and middle cerebral artery (MCA) vascular smooth muscle layer was dissected from the dead body. CLDN11 expression is identified in LAD and MCA vascular smooth muscle cell layer, and the CLDN11 expression is higher in MCA than in LAD (p<0.01). Interestingly, the CLDN11 expression is decreased in vSMCs around the atherosclerotic lesions compare to non-atheromatous lesions by immunohistochemistry. To determine the functional role of CLDN11 in vSMCs, microarray analysis was performed following siCLDN11 knockdown. Compared to normal HASMC (human aortic vascular smooth muscle cells), siCLDN11-HASMC was showed increased gene expression such as RSPO3, CXCL8, EGR3, CYP1B1, TNFAIP2, PTGS2, HEY1, BMPER and these set was related to cell migration, proliferation and angiogenesis. CLDN11 knockdown vSMCs showed increased the cell migration of HASMC measured by wound healing, tube formation, and cell cycle assay, and reduced cas-3 cleavage. Finally, CLDN11 expression was inversely correlated with the progression of coronary atherosclerosis and the sudden cardiac death with complicated coronary atherosclerosis. This study shows that CLDN11 play a role in the initiation and propagation of atherosclerosis by regulating the plasticity of vSMCs, suggesting the possibility of biological marker for atherosclerosis in clinical diagnosis (This work was supported by NRF-2019R1A2C1089108, NRF-2019M3E5D1A02068082, COMPA-2022C100, and BK21 Program, Center for Glocal Future Biomedical Scientists at Chonnam National University).
Spasticity is a velocity-dependent increase in muscle tone and uncontrolled, repetitive, involuntary contractions of skeletal muscles. Spasticity presents as upper motor neuron symptoms in patients with central nervous system pathology such as stroke, spinal cord injury, brain injury, or multiple sclerosis. As a result, a patient can have significant pain and limited mobility, which can lead to decreased quality of life and difficulty maintaining personal care. In this article we discuss mechanisms, indications, efficacy, and side effects of the most accepted current treatments. Currently available treatment options include oral medications and interventional procedures. Oral medications comprise centrally acting agents, such as baclofen, clonidine, and tizanidine, as well as anticonvulsants such as benzodiazepines and gabapentin and peripherally acting dantrolene. Interventional procedures include focal injections of botulinum toxin, phenol or alcohol, and an intrathecal baclofen pump. Surgical treatments include selective dorsal rhizotomy and neurectomy. We found that there are several treatments available with data to support their use, but many still need further research to prove their efficacy and develop optimal utilization.
362 Background: Although chemotherapy is widely recommended to the patients with metastatic biliary tract cancer, the natural course of those group, especially with good PS who are indicated for chemotherapy was rarely known. Methods: We retrospectively reviewed metastatic or distant relapsed BTC patients seen between January 2005 and August 2011 at four cancer centers. Patients were eligible if they had good PS (ECOG 0-2), no history of surgery, chemotherapy, radiotherapy or any treatment for cancer. Results: A total of 1302 patient cohort was identified for metastatic or distantly relapsed BTC and 959 patients were categorized for non-treatment group, 343 patients for treatment group. Of 959 patients, 131 patients were eligible for inclusion criteria and 737 patients were excluded for referral to other hospitals or lost followup, 89 patients for poor PS. The patient demographics were median age of 71 (range:39-89) and male predominant (n=81, 61.8%). Extrahepatic cholangiocarcinoma (n=55, 42.0%) was the most common site of eligible BTC followed by intrahepatic cholangiocarcinoma (n=42,32.1%). Median overall survival was 6.0 months (95% confidence interval [CI];4.9-7.1 months). Univariate analysis showed significant difference of survival depending on the serum level of CA19-9 (CA19-9≥100; 8.2 months vs CA19-9<100;4.4 months, log-rank p-value<0.001). Another potential prognostic factors including age, sex, PS, leucocytosis, serum albumin, CEA level and bile drainage did not have statistical difference in survival. Multivariate analysis showed that elevated 19-9 level was an independent poor prognostic factor(p<0.001, odd ratio, 2.8; 95% CI;1.8-4.8). Conclusions: Metastatic BTC patients with good PS had modest survival. However, patients with normal CA19-9 level showed favorable survival. Further studies comparing chemotherapeutic effect with best supportive care in those group are warranted.
BACKGROUND: Biliary tract cancers (BTCs) are known to have a dismal prognosis. A number of chemokines play important roles in the progress of BTCs. However, the serum levels of chemokines in BTCs have not yet been explored. METHODS: The sera of healthy donors (n = 8) and patients with BTCs who were enrolled in second line sunitinib trials (n = 27) were collected. The concentrations of three kinds of chemokines (CXCL5, CXCL8 and CXCL12) were measured using ELISA assay. The median concentrations of chemokines were compared between healthy donors and BTC patients and the role of chemokines as a prognostic biomarker was examined. RESULTS: BTC patients generally had higher serum levels of CXCL5 and CXCL12 compared to healthy donors. Patients with cholangiocarcinoma showed significantly higher levels of serum CXCL12 than patients with gallbladder cancer. In survival analysis, only CXCL12 level showed a prognostic impact on overall survival (median OS: 6.9 vs. 0.9 months in low CXCL12 vs. high CXCL12, respectively; P = .008). High CXCL5 levels were also correlated with poor survival without statistical insignificance (median OS: 6.2 vs. 2.0 months in low CXCL5 vs. high CXCL5, respectively; P = .070). CONCLUSIONS: There was a significant difference in OS according to the level of CXCL12, suggesting that serum CXCL12 levels may be a useful surrogate marker for clinical outcome in advanced BTCs.
The uterus is dynamically regulated in response to various signaling triggered by hormones during the estrous cycle. The Hippo signaling pathway is known as an important signaling for regulating cellular processes during development by balancing between cell growth and apoptosis. Serine/threonine protein kinase 3/4 (STK3/4) is a key component of the Hippo signaling network. However, the regulation of STK3/4-Hippo signaling in the uterus is little known. In this study, we investigated the regulation and expression of STK3/4 in the uterine endometrium during the estrous cycle. STK3/4 expression was dynamically regulated in the uterus during the estrous cycle. STK3/4 protein expression was gradually increased from the diestrus stage and reached the highest in the estrus stage. STK3/4 was exclusively localized in the luminal and glandular epithelial cells of the uterus, and phosphorylated STK3/4 was also increased at the estrus stage. Moreover, the increase of STK3/4 expression in uteri was induced by administration of estradiol, but not by progesterone injection in ovariectomized mice. Pretreatment with an estrogen receptor antagonist ICI 182,780 reduced estrogen-induced STK3/4 expression and its phosphorylation. The estrogen-induced STK3/4 expression was related to the increase in phosphorylation of downstream targets including LATS1/2 and YAP. These findings suggest that STK3/4-Hippo signaling acts a novel signaling pathway in the uterine epithelium and STK3/4-Hippo is one of key molecules for connecting between the estrogen downstream signaling pathway and the Hippo signaling pathway leading to regulate dynamic uterine epithelium during the estrous cycle.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death globally. Mechanistic target of rapamycin (mTOR) is frequently up-regulated in HCC and plays an important role in HCC tumorigenesis. Tumors with loss of tuberous sclerosis complex 2 (TSC2), a negative regulator of mTOR signaling, tend to respond well to mTOR inhibitors. We analyzed TSC2 expression status in Korean patients with HCC and evaluated the correlation between TSC2 loss and response to the mTOR inhibitor, everolimus.We retrospectively assessed 36 patients with advanced HCC who had received sorafenib at a single center in Korea between 2008 and 2014, and for whom tumor specimens were available for TSC2 immunohistochemical analysis (IHC). Three patient-derived tumor cell lines (PDCs) were analyzed by western blotting to determine TSC2 expression and drug sensitivity to mTOR.Twelve of 36 patients (33.3%) showed low to undetectable levels of TSC2 expression. No significant differences were observed in progression-free survival (PFS) or overall survival with sorafenib treatment based on TSC2 expression status. Two patients were treated with everolimus after sorafenib failure; one patient, with moderate TSC2 expression, experienced stable disease with a PFS of 5.8 months; the other, with high TSC2 expression, experienced rapid progression. PDC models demonstrated that the TSC2-low HCC PDC line was significantly more sensitive to everolimus than the TSC2-high HCC PDC lines.Loss of TSC2 may predict improved response to everolimus in HCC patients, but further studies are needed to confirm the predictive role of TSC2 expression for everolimus treatment.
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