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Ching-Chun Li,1 Tsung-Kun Chang,1,2 Yen-Cheng Chen,1,3 Hsiang-Lin Tsai,1,2 Ching-Wen Huang,1,2 Wei-Chih Su,1,3 Cheng-Jen Ma,1,3 Tzu-Chieh Yin,1,4,5 Po-Jung Chen,1 Jaw-Yuan Wang1– 3,6– 8 1Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 2Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 5Department of Surgery, Kaohsiung Municipal Tatung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 6Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; 7Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan; 8Department of Surgery, Pingtung Hospital, Ministry of Health and Welfare, Pingtung, TaiwanCorrespondence: Jaw-Yuan Wang, Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou 1st Road, Kaohsiung, 807, Taiwan, Tel +886-7-3122805, Email cy614112@ms14.hinet.net; jawyuanwang@gmail.comBackground: The prognosis of metastatic colorectal cancer (mCRC) depends on the metastatic site and systemic therapy regimen. Peritoneal metastases are associated with a relatively unfavorable prognosis among patients with mCRC. In this article, we present the treatment outcomes of patients with peritoneal carcinomatosis (PC)-only, liver metastasis (LiM)-only, and lung metastasis (LuM)-only CRC.Methods: Overall, 206 mCRC patients with single-site metastasis and who had received treatment from January 2014 to December 2018 were recruited. Among 206 patients with mCRC, 15 had PC-only mCRC, 145 had LiM-only mCRC, and 46 had LuM-only mCRC. They attended regular follow-ups until November 2020, and the median follow-up period was 24.7 months (5.1– 41.3 months). Patients’ characteristics, including clinical data, gene mutation profiles, and clinical outcomes, were evaluated. All patients with PC-only CRC were treated with first-line bevacizumab and FOLFIRI, and the irinotecan dose escalation depended on UGT1A1 polymorphism.Results: Of the 206 patients, no statistical difference was observed between the PC-only, LiM-only, and LuM-only groups in terms of age, primary tumor location, RAS mutation status, BRAF mutation status, and epidermal growth factor receptor overexpression (all P > 0.05). Patients with PC-only CRC had a median progression-free survival (mPFS) of 18.0 months and a median overall survival (mOS) of 24.6 months. Patients with LiM-only or LuM-only CRC had mPFS of 18.2 and 26.6 months and mOS of 25.0 and 44.5 months, respectively. No significant differences regarding PFS and OS (both P > 0.05) between the three groups of patients with mCRC were observed.Conclusion: Our study revealed that in patients with PC-only mCRC treatment of first-line bevacizumab and FOLFIRI through irinotecan dose escalation according to UGT1A1 polymorphism could confer such patients with comparable outcomes to that of patients with LiM-only and LuM-only mCRC.Keywords: prognosis, metastatic colorectal cancer, peritoneal carcinomatosis-only, UGT1A1, irinotecan dose escalation

Background: This study tested the hypothesis that combined ceftriaxone (Cef) and human umbilical cord-derived mesenchymal stem cells (HUCDMSCs) was better than either therapy for alleviating acute septic arthritis (ASA)., Methods and Results: Adult-male C57BL/6 mice were categorized into control group (Clt), group A (ASA only), group B [ASA + Cef (5 mg/kg, IM per day, at days 2 to 16 after ASA induction)], group C [ASA + HUCDMSCs (5 × 105 per mice at days 2, 3, 4 after ASA induction)], and group D (ASA + Cef + HUCDMSCs). Animals were euthanized by day 28. The result demonstrated that the body weight was significantly lower, whereas the ratio of kidney or spleen weight to WB, circulatory WBC count, bacterial colony-formation-unit from circulatory/kidney extraction were significantly higher in group A than in other groups (all P < .001). The proinflammatory cytokines (IL-6/TNF-α) of knee joint fluid were lowest in Clt and significantly and progressively reduced from groups A to D, whereas the circulatory levels of these 2 parameters at the time points of days 3/7/28 exhibited an identical pattern as knee joint fluid among the groups (all P-value < .0001). The scores of vertebral-bone destructions/inflamed synovium were lowest in Clt, highest in group A, significantly higher in group C than in groups B/D, and significantly higher in group C than in group D (all P < .0001)., Conclusion: Combined antibiotics and Cef and HUCDMSCs was superior to just one therapy for suppressing circulatory and tissue levels of inflammation and knee joint destruction in ASA., (© The Author(s) 2024. Published by Oxford University Press.)

Study Design: Retrospective analysis of clinical data from a single institution., Objective: To assess the day of surgery during the week as a possible predictor of length of stay (LOS) following anterior cervical discectomy and fusion (ACDF)., Summary of Background Data: Surgeries later in the week may result in longer LOS and higher costs for joint arthroplasty, yet this is unclear following spine surgery. Procedures performed later in the week may lead to weekend admissions when there are limited services that may contribute to an extended LOS. We attempt to identify associations between day of surgery and LOS, readmission, and complications following single- and multilevel ACDF., Materials and Methods: Patients at a single institution undergoing ACDF by 7 primary surgeons in both orthopedic and neurosurgery spine departments between 2015 and 2019 were retrospectively reviewed. Patients were stratified by surgery day at either the beginning (Monday/Tuesday) or end (Thursday/Friday) of the week and by single- or multilevel ACDF. Surgery for trauma, infections, adjacent level disease, or revision were excluded. Patient demographics, Charlson Comorbidity Index (CCI), LOS, postoperative complications, and readmission rates were assessed., Results: Six hundred fifty-two patients underwent ACDF. For single-level ACDF, 222 were reviewed, with 112 having surgery at the beginning and 110 at the end of the week. For multilevel ACDF, 431 were reviewed, with 192 having surgery at the beginning and 239 at the end of the week. No differences in pre- or postoperative variables were determined for single-level ACDF. Despite no differences in pre-operative variables, CCI, operative duration, or number of levels, late-week multilevel ACDF had longer average LOS (2.8±3.0 days) compared to early-week surgery (2.0±2.0 days) ( P =0.018)., Conclusions: Late-week multilevel ACDF was associated with an increased LOS, as it may prove beneficial to surgical planning. This conflicts with previous reports that day of week was not associated with LOS following ACDF., Level of Evidence: III., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To evaluate the association of serum 25-hydroxyvitamin D (25(OH) D) levels with bone mineral density (BMD), fracture risk, and bone metabolism., Methods: This multicenter cross-sectional study recruited menopausal females and males greater than or equal to 50 year old with osteoporosis/fractures between September 2016 and September 2021. Assessment included clinical data, 25(OH)D, intact parathyroid hormone (iPTH), procollagen type 1 amino-terminal propeptide (P1NP), carboxy-terminal collagen crosslinks (CTX), lateral thoracolumbar spine x-rays, and BMD., Results: A total of 3003 individuals were stratified by 25(OH) D levels: 720 individuals (24%) <20 ng/mL, 1338 individuals (44.5%) 20 to 29 ng/mL, and 945 individuals (31.5%) ≥30 ng/mL. In unadjusted and multivariable models, BMD T-score, except spine, was significantly and positively associated with 25(OH)D levels. 25(OH) D levels were inversely associated with Fracture Risk Assessment Tool scores. Patients with 25(OH)D <20 ng/mL had significantly higher iPTH and bone turnover markers (P1NP and CTX) than patients with 25(OH)D ≧20 ng/mL in all models. When analyzing bone-related markers and BMD, total hip and femoral neck BMD T-scores were positively correlated with 25(OH)D concentrations and BMI but negatively correlated with iPTH, P1NP, CTX, and age. In multivariate models with all bone-related markers, only 25(OH)D levels were significantly associated with total hip and femoral neck BMD., Conclusion: Vitamin D deficiency is significantly associated with decreased total hip and femoral neck BMD and increased fracture risk as assessed by Fracture Risk Assessment Tool. In those with osteoporosis/fractures, vitamin D is implicated in the causal relationship between bone remodeling and BMD. Assessing vitamin D status is imperative for those at risk for osteoporosis/fractures., Competing Interests: Disclosure The authors have no multiplicity of interest to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To investigate the clinicopathological features, immunophenotype, diagnosis and differential diagnosis of SRF-rearranged cellular perivascular myoid tumor. Methods: Two cases of SRF-rearranged cellular perivascular myoid tumor diagnosed in the Department of Pathology, Fudan University Shanghai Cancer Center from October 2021 to March 2022 were collected. Immunohistochemical staining, fluorescence in-situ hybridization (FISH) and next-generation sequencing (NGS) were performed, and the literature was reviewed. Results: Case 1, a 3-month-old boy presented with a painless tumor of the scalp, measuring about 2 cm in diameter. Case 2, a 3-year-old girl complained with a painless tumor of the knee, measuring approximately 1.5 cm in diameter. Microscopically, the tumor had a clear boundary and showed multinodular growth. The tumor was mainly composed of spindle cells arranged in long intersecting fascicles associated with thin, slit-like or branching ectatic vessels, focally forming hemangiopericytoma-like appearance. The tumor cells were abundant, but there was no obvious atypia. Mitotic figures (3-4/10 HPF) were noted. H-caldesmon and SMA were positive in both cases. Case 1 showed diffuse and strong positivity for Desmin, and focally for CKpan. Ki-67 proliferation index was 20% and 30%, respectively. FISH displayed NCOA2 gene translocation in case 1 and the RELA gene translocation in case 2. NGS detected the SRF-NCOA2 gene fusion in case 1 and the SRF-RELA gene fusion in case 2. Both patients underwent local excisions. During the follow-up of 5-14 months, case 1 had no local recurrence, while case 2 developed local recurrence 1 year post operatively. Conclusions: SRF-rearranged cellular perivascular myoid tumor is a novel variant of perivascular cell tumor, which tends to occur in children and adolescents. The tumor forms a broad morphologic spectrum ranging from a pericytic pattern to a myoid pattern, and include hybrid tumors with a mixture of pericytic and myoid patterns. Due to its diffuse hypercellularity and increased mitotic figures and smooth muscle-like immunophenotype, the tumor is easy to be misdiagnosed as myogenic sarcomas. The tumor usually pursues a benign clinical course and rare cases may locally recur.

Background: We examined the impact of adipose-derived mesenchymal stem cell (ADMSC)-facilitated empagliflozin (EMPA) therapy for alleviating hyperglycemic induced neuropathy [i.e., diabetic neuropathy (DN)]., Methods: Study constituted N2a cell culture and rats to be classified into groups 1 (sham-operated-control)/2 (DN)/3 (DN + empagliflozin/20 mg/kg/daily orally for 6 weeks since post-day-7 DN induction)/4 (DN + ADMSCs/1.2 × 10 6 cells by vein transfusion at time intervals of 1/3/5 weeks after DN induction)/5 (DN + empagliflozin + ADMSCs) and sacrificed by day-42 after DN induction., Results: In vitro results showed that, compared to N2a cells, the cellular levels of senescence/DNA-damage and protein expressions of oxidative-stress (OS), apoptotic, autophagic and inflammatory biomarkers were significantly higher in N2a + glucose (25 mM) but were significantly reversed in N2a + glucose + ADMSCs, whereas the cellular levels of mitochondrial cytochrome C and protein levels of anti-oxidants displayed an opposite pattern of OS (all P<0.001). The above-mentioned parameters (i.e., OS/apoptosis/fibrosis/autophagy/DNA-damage) were lowest in N2a cells, highest in N2a + glucose and significantly higher in N2a + glucose + EMPA (50 μM) than in N2a + glucose + EMPA (150 μM) (all P<0.001). By days 7/14/21/28/35/42 after DN induction, the values of thermal paw-withdrawal-latency (TPWL)/mechanical-paw-withdrawal-threshold were highest in group 1 and significantly progressively increased from groups 2/4/3/5 (all P<0.0001). The cellular levels of unmyelinated C- and myelinated A-δ fibers, and protein levels of OS/apoptotic/DNA-damaged/fibrotic/autophagic/inflammatory/pain-facilitated/voltage-gated sodium channel biomarkers in L4-L5 levels of dorsal-root-ganglia exhibited an contradictory manner of TPWL among the groups (all P<0.0001)., Conclusions: Combination of EMPA and ADMSC therapy was superior to either alone for improving outcomes of DN., Competing Interests: None., (AJTR Copyright © 2023.)

This study investigated the cost-effectiveness and quality of life (QoL) within 1 year of receiving mFOLOFX6 with or without a targeted drug (bevacizumab or ramucirumab) as second-line treatment among patients with metastatic colorectal cancer (mCRC) following the failure of FOLFIRI + bevacizumab as first-line treatment. This prospective cohort study included patients who received a diagnosis of mCRC between March 2015 and May 2020. QoL was evaluated before treatment and at 6 months and 1 year posttreatment. All related variables were controlled using the inverse probability of treatment weighting method. Generalized estimating equations with the difference-in-difference method was used to explore changes in QoL. The incremental cost-utility ratio (ICUR) of the two groups was simulated using the annual-cycle Markov decision tree model. Finally, 39 and 76 patients were included in the targeted and nontargeted agent groups, respectively. At 6 months after treatment, QoL of the two groups improved significantly, but the targeted agent group had significantly better QoL than did the nontargeted agent group at 1 year posttreatment (P < 0.05). When the time frame was set to 20 years, the ICUR of the targeted agent group compared with the nontargeted agent group was US$32,052 per quality-adjusted life years. Addition of a targeted drug to the second-line mFOLOFX6 regimen not only improved the patients' QoL but was also more cost effective when the willingness-to-pay threshold was set at US$33,004 (the per capita gross domestic product of Taiwan). These patients should be reimbursed for these targeted agents by the National Health Insurance scheme in Taiwan., Competing Interests: None., (AJCR Copyright © 2023.)

Insulin resistance (IR) is the root cause of type II diabetes, yet no safe treatment is available to address it. Using a high throughput compatible assay that measures real-time translocation of the glucose transporter glucose transporter 4 (GLUT4), we identified small molecules that potentiate insulin action. In vivo, these insulin sensitizers improve insulin-stimulated GLUT4 translocation, glucose tolerance, and glucose uptake in a model of IR. Using proteomic and CRISPR-based approaches, we identified the targets of those compounds as Unc119 proteins and solved the structure of Unc119 bound to the insulin sensitizer. This study identifies compounds that have the potential to be developed into diabetes treatment and establishes Unc119 proteins as targets for improving insulin sensitivity., Competing Interests: Declaration of interests J.A.S., T.C.Y., and R.J.K. are inventors on a patent related to this work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Multiple rods are utilized in adult spinal deformity (ASD) surgery to increase construct stiffness. However, the impact of multiple rods on proximal junctional kyphosis (PJK) is not well established. This study aimed to investigate the impact of multiple rods on PJK incidence in ASD patients., Methods: ASD patients from a prospective multicenter database with a minimum follow-up of 1 year were retrospectively reviewed. Clinical and radiographic data were collected preoperatively, at 6 weeks postoperatively, at 6 months postoperatively, at 1 year postoperatively, and at every subsequent year postoperatively. PJK was defined as a kyphotic increase of > 10° in the Cobb angle from the upper instrumented vertebra (UIV) to UIV+2 as compared with preoperative values. Demographic data, radiographic parameters, and PJK incidence were compared between the multirod and dual-rod patient cohorts. PJK-free survival analysis was performed using Cox regression to control for demographic characteristics, comorbidities, level of fusion, and radiographic parameters., Results: Overall, 307/1300 (23.62%) cases utilized multiple rods. Cases with multiple rods were more likely to be revisions (68.4% vs 46.5%, p < 0.001), to be posterior only (80.7% vs 61.5%, p < 0.001), involve more levels of fusion (mean 11.73 vs 10.60, p < 0.001), and include 3-column osteotomy (42.9% vs 17.1%, p < 0.001). Patients with multiple rods also had greater preoperative pelvic retroversion (mean pelvic tilt 27.95° vs 23.58°, p < 0.001), greater thoracolumbar junction kyphosis (-15.9° vs -11.9°, p = 0.001), and more severe sagittal malalignment (C7-S1 sagittal vertical axis 99.76 mm vs 62.23 mm, p < 0.001), all of which corrected postoperatively. Patients with multiple rods had similar incidence rates of PJK (58.6% vs 58.1%) and revision surgery (13.0% vs 17.7%). The PJK-free survival analysis demonstrated equivalent PJK-free survival durations among the patients with multiple rods (HR 0.889, 95% CI 0.745-1.062, p = 0.195) after controlling for demographic and radiographic parameters. Further stratification based on implant metal type demonstrated noninferior PJK incidence rates with multiple rods in the titanium (57.1% vs 54.6%, p = 0.858), cobalt chrome (60.5% vs 58.7%, p = 0.646), and stainless steel (20% vs 63.7%, p = 0.008) cohorts., Conclusions: Multirod constructs for ASD are most frequently utilized in revision, long-level reconstructions with 3-column osteotomy. The use of multiple rods in ASD surgery does not result in an increased incidence of PJK and is not affected by rod metal type.

Background: Neoadjuvant chemoradiotherapy followed by total mesorectal excision is the standard treatment for patients with nonmetastatic locally advanced rectal cancer (LARC). However, for patients with LARC and synchronous metastasis, the optimal treatment strategy and sequence remain inconclusive. In the present study, we evaluated the efficacy and safety of concurrent radiotherapy in patients with de novo metastatic rectal cancer who received chemotherapy and targeted therapy., Methods: We retrospectively reviewed the data of 63 patients with LARC and synchronous metastasis who received intensive therapy at the study hospital between April 2015 and November 2018. The included patients were divided into two groups: RT-CT, those who received systemic chemotherapy with targeted therapy and concurrent radiotherapy (for primary rectal cancer), and CT, those who received only systemic chemotherapy with targeted therapy., Results: Treatment response was better in the RT-CT group than in the CT group. The rate of primary tumor resection (PTR) was higher in the RT-CT group than in the CT group (71.4% and 42.9%, respectively; P = .0286). The RT-CT group exhibited considerably longer local recurrence-free survival ( P = .0453) and progression-free survival (PFS; from 13.3 to 22.5 months) than did the CT group ( P = .0091); however, the groups did not differ in terms of overall survival (OS; P = .49). Adverse events were almost similar between the groups, except frequent diarrhea, the prevalence of which was higher in the RT-CT group than in the CT group (59.5% and 23.8%, respectively; P = .0075)., Conclusions: In the era of biologics, radiotherapy may increase the resectability of primary rectal tumors, reducing the risk of locoregional failure and prolonging PFS. Concurrent pelvic radiotherapy may not substantially improve OS, which is indicated by metastasis. Hence, the resection of the distant metastases may be essential for improving long-term OS. To further determine the efficacy of concurrent radiotherapy, additional prospective, randomized studies must combine preoperative pelvic radiotherapy with PTR and metastectomy to treat patients with stage IV LARC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yin, Chen, Yeh, Li, Chen, Su, Chang, Huang, Huang, Tsai and Wang.)

Traumatic spinal cord injury (SCI) is a highly destructive disease in human neurological functions. Adipose-derived mesenchymal stem cells (ADMSCs) have tissue regenerations and anti-inflammations, especially with prion protein overexpression (PrPc OE ). Therefore, this study tested whether PrPc OE -ADMSCs therapy offered benefits in improving outcomes via regulating nod-like-receptor-protein-3 (NLRP3) inflammasome/DAMP signalling after acute SCI in rats. Compared with ADMSCs only, the capabilities of PrPc OE -ADMSCs were significantly enhanced in cellular viability, anti-oxidative stress and migration against H 2 O 2 and lipopolysaccharide damages. Similarly, PrPc OE -ADMSCs significantly inhibited the inflammatory patterns of Raw264.7 cells. The SD rats (n = 32) were categorized into group 1 (Sham-operated-control), group 2 (SCI), group 3 (SCI + ADMSCs) and group 4 (SCI + PrPc OE -ADMSCs). Compared with SCI group 2, both ADMSCs and PrPc OE -ADMSCs significantly improved neurological functions. Additionally, the circulatory inflammatory cytokines levels (TNF-α/IL-6) and inflammatory cells (CD11b/c+/MPO+/Ly6G+) were highest in group 2, lowest in group 1, and significantly higher in group 3 than in group 4. By Day 3 after SCI induction, the protein expressions of inflammasome signalling (HGMB1/TLR4/MyD88/TRIF/c-caspase8/FADD/p-NF-κB/NEK7/NRLP3/ASC/c-caspase1/IL-ß) and by Day 42 the protein expressions of DAMP-inflammatory signalling (HGMB1/TLR-4/MyD88/TRIF/TRAF6/p-NF-κB/TNF-α/IL-1ß) in spinal cord tissues displayed an identical pattern as the inflammatory patterns. In conclusion, PrPc OE -ADMSCs significantly attenuated SCI in rodents that could be through suppressing the inflammatory signalling., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Aims: An adjuvant oxaliplatin-based regimen is the standard of care for patients with stage III colorectal cancer (CRC). Few reports have compared the clinicopathological features and oncological outcomes of such treatment between patients with early (≤1 year) and late recurrence (>1 year)., Methods: Between January 2012 and December 2019, CRC recurred in 128 (24.1%) of 531 patients with consecutive stage III CRC after they received curative resection and an adjuvant oxaliplatin-based regimen. The clinicopathological features and oncological outcomes of the 128 patients were analyzed retrospectively., Results: The median follow-up period after the first chemotherapy cycle was 35.0 months (range, 7-100.9), and the median recurrence time was 16.1 months. Forty-seven patients (36.7%) had an early recurrence and eighty-one patients (63.3%) had a late recurrence. Compared with patients with late recurrence, those with early recurrence were mostly younger (median: 58 vs. 64 years, p =0.009), had less oxaliplatin-based therapy cycles (median: 8 vs. 12 cycles, p < 0.001), and had a shorter overall survival time (median: 23.3 vs. 39.7 months, p < 0.001). The area under the curve of patient age and chemotherapy cycles for predicting early recurrence was 0.629 and 0.705 ( p =0.015 and p < 0.001), respectively. The receiver operating characteristic curve analysis demonstrated that the cutoff level for patient age was 57 years and the number of chemotherapy cycles was 8. A multivariate analysis revealed that patient age ≤57 years and oxaliplatin-based therapy ≤8 cycles were independent risk factors for early recurrence (odds ratio (OR) = 3.049, p =0.022; OR = 4.995, p =0.002). These factors were associated with an approximately 77.8% risk of recurrence within 1 year, compared with the 21.5% risk associated with patient age >57 years and oxaliplatin-based therapy >8 cycles ( p  = 0.003)., Conclusion: Patients with early recurrence had poorer survival than those with late recurrence. If >8 cycles of oxaliplatin-based therapy can be administered without disease progression, then patients with stage III CRC would have a lower risk of early recurrence., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Yu-Tang Chang et al.)

Energy homeostasis is a complex system involving multiple hormones, neuropeptides, and receptors. Prokineticins (PK1 and PK2) are agonists to two G protein-coupled receptors, prokineticin receptor 1 and 2 (PKR1 and PKR2), which decrease food intake when injected in rodents. The relative contribution of PKR1 and PKR2 to the anorexigenic effect of PK2 and their site of action in the brain have not yet been elucidated. While PKR1 and PKR2 are both expressed in the hypothalamus, a central region involved in the control of energy homeostasis, PKR2 is also present in the amygdala, which has recently been shown to regulate food intake in response to several anorexigenic signals. PKR trafficking and signaling are inhibited by the melanocortin receptor accessory protein 2 (MRAP2), thus suggesting that MRAP2 has the potential to alter the anorexigenic activity of PK2 in vivo. In this study, we investigated the importance of PKR1 and PKR2 for PK2-mediated inhibition of food intake, the brain region involved in this function, and the effect of MRAP2 on PK2 action in vivo. Using targeted silencing of PKR2 and chemogenetic manipulation of PKR2 neurons, we show that the anorexigenic effect of PK2 is mediated by PKR2 in the amygdala and that altering MRAP2 expression in PKR2 neurons modulates the activity of PK2. Collectively, our results provide evidence that inhibition of food intake by PKs is not mediated through activation of hypothalamic neurons but rather amygdala PKR2 neurons and further establishes the importance of MRAP2 in the regulation of energy homeostasis., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to validate the Global Alignment and Proportion (GAP) score as a predictor of health-related quality of life (HRQOL) outcomes for patients undergoing adult spinal deformity (ASD) surgery., Methods: This was a retrospective cohort study of patients with ASD undergoing long-segment spine fusions (≥ 5 vertebrae fused) at a single institution over a 2-year period (n = 85). Radiographic parameters were measured at preoperative, 6-week postoperative, 1-year postoperative, and 2-year postoperative visits. GAP scores were calculated using 4 sagittal parameters: relative pelvic version, relative lumbar lordosis, lordosis distribution index, and relative spinopelvic alignment. Patients were stratified into 3 GAP categories at each time point: proportioned (score 0-2), moderately disproportioned (score 3-6), and severely disproportioned (score ≥ 7). HRQOL outcomes were collected at preoperative, 1-year postoperative, and 2-year postoperative visits; these measures included patient self-reported outcome measures (i.e., PROMIS), Scoliosis Research Society-22 spinal deformity questionnaire (SRS-22), and Oswestry Disability Index (ODI) scores., Results: Overall, 42% of cases were revision surgeries and 96.5% of patients underwent fusion to the sacrum. The mean preoperative GAP score significantly improved from preoperative (7.84) to immediate postoperative (3.31) assessment (p < 0.001). Similarly, the percentage of patients categorized as proportioned improved from 9.4% at preoperative to 45.9% at immediate postoperative evaluation. The preoperative GAP score or category was not significantly associated with any preoperative HRQOL outcome metrics. The immediate postoperative GAP score was not correlated with any 1-year HRQOL outcomes. However, the immediate postoperative GAP score was significantly associated with 2-year SRS-22 outcomes, including SRS-22 function (r = -0.35, p < 0.01), self-image (r = -0.27, p = 0.044), and subtotal (r = -0.35, p < 0.01) scores. As compared to severely disproportioned patients, proportioned patients had better SRS-22 pain (4.08 vs 3.17, p = 0.04), satisfaction (4.40 vs 3.50, p = 0.02), and subtotal (4.01 vs 3.27, p = 0.036) scores. The immediate postoperative GAP score was also significantly associated with 2-year PROMIS outcomes, including PROMIS pain (r = 0.31, p = 0.023) and physical function (r = -0.35, p < 0.01) scores. As compared to severely disproportioned patients, proportioned patients had better PROMIS pain (53.18 vs 63.60, p = 0.025) and physical function (41.66 vs 34.18, p = 0.017) scores. Postoperative GAP score or category did not predict any ODI outcomes., Conclusions: The postoperative GAP score is a predictor of long-term HRQOL outcomes following ASD surgery, and proportioned patients are more likely to have less pain and be satisfied with their surgery. However, the postoperative GAP score does not predict outcomes as measured by ODI.

This study investigated the hypothesis that probiotics enhanced the therapeutic effect of adipose-derived mesenchymal stem cells (ADMSCs) on alleviating neuropathic pain (NP) due to chronic constriction injury (CCI) mainly through regulating the microbiota in rats. SD rats (n = 50) were categorized into group 1 (sham-control), group 2 (NP), group 3 (NP + probiotics (i.e., 1.5 billion C.F.U./day/rat, orally 3 h after NP procedure, followed by QOD 30 times)), group 4 (NP + ADMSCs (3.0 × 105 cells) 3 h after CCI procedure, followed by QOD six times (i.e., seven times in total, i.e., mimic a clinical setting of drug use) and group 5 (NP + probiotics + ADMSCs (3.0 × 105 cells)) and euthanized by day 60 after NP induction. By day 28 after NP induction, flow-cytometric analysis showed circulating levels of early (AN-V+/PI−) and late (AN-V+/PI+) apoptotic, and three inflammatory (CD11b-c+, Ly6G+ and MPO+) cells were lowest in group 1 and significantly progressively reduced in groups 2 to 5 (all p < 0.0001). By days 7, 14, 21, 28, and 60 after CCI, the thresholds of thermal paw withdrawal latency (PWL) and mechanical paw withdrawal threshold (PWT) were highest in group 1 and significantly progressively increased in groups 2 to 5 (all p < 0.0001). Numbers of pain-connived cells (Nav1.8+/peripherin+, p-ERK+/peripherin+, p-p38+/peripherin+ and p-p38+/NF200+) and protein expressions of inflammatory (p-NF-κB, IL-1ß, TNF-α and MMP-9), apoptotic (cleaved-caspase-3, cleaved-PARP), oxidative-stress (NOX-1, NOX-2), DNA-damaged (γ-H2AX) and MAPK-family (p-P38, p-JNK, p-ERK1/2) biomarkers as well as the protein levels of Nav.1.3, Nav.1.8, and Nav.1.9 in L4-L5 in dorsal root ganglia displayed an opposite pattern of mechanical PWT among the groups (all p < 0.0001). In conclusion, combined probiotic and ADMSC therapy was superior to merely one for alleviating CCI-induced NP mainly through suppressing inflammation and oxidative stress.

Angiogenesis and antiapoptosis effects are the major factors influencing malignancy progression. Hypoxia induces multiple mechanisms involving microRNA (miRNA) activity. Vascular endothelial growth factor (VEGF) is correlated with angiogenesis. An antiapoptotic factor, myeloid leukemia 1 (Mcl-1) is the main regulator of cell death. This study examined the role of miR-148a in inhibiting VEGF and Mcl-1 secretion by directly targeting ROCK1/c-Met by downregulating HIF-1α under hypoxia. The protein expression of ROCK1 or Met/HIF-1α/Mcl-1 in HCT116 and HT29 cells (all P < 0.05) was significantly reduced by miR-148a . The tube-formation assay revealed that miR-148a significantly suppressed angiogenesis and synergistically enhanced the effects of bevacizumab (both P < 0.05). The MTT assay revealed the inhibitory ability of miR-148a in HCT116 and HT29 cells (both P < 0.05). miR-148a and bevacizumab exerted synergistic antitumorigenic effects ( P < 0.05) in an animal model. Serum miR-148a expression of metastatic colorectal cancer (mCRC) patients with a partial response was higher than that of mCRC patients with disease progression ( P = 0.026). This result revealed that miR-148a downregulated HIF-1α/VEGF and Mcl-1 by directly targeting ROCK1/c-Met to decrease angiogenesis and increase the apoptosis of colon cancer cells. Furthermore, serum miR-148a levels have prognostic/predictive value in patients with mCRC receiving bevacizumab.

Objective: The UGT1A1*28 polymorphism reduces UGT1A1 enzymatic activity, which may increase the risk of severe toxicity in patients who receive standard-dose irinotecan, such as severe neutropenia and diarrhea. This real-world study assessed the optimal irinotecan dose in terms of efficacy and toxicity in metastatic colorectal cancer (mCRC) patients homozygous for the UGT1A1*28 polymorphism and receiving FOLFIRI plus bevacizumab or cetuximab as first-line therapy., Methods: We analyzed toxicity and treatment outcomes in seven mCRC patients who were homozygous for UGT1A1*28 and received FOLFIRI plus bevacizumab or cetuximab, with an initial irinotecan dose of 120 mg/m 2 ., Results: Six of the seven patients tolerated 120 mg/m 2 irinotecan without requiring dose reductions in subsequent cycles. The overall response and disease control rates were 43.0% (3/7) and 71.4% (5/7), respectively. The median progression-free survival and overall survival were 11.0 and 33.0 months, respectively. Only one severe adverse event, grade III neutropenia (2.5%), was observed., Conclusions: mCRC patients homozygous for the UGT1A1*28 allele can tolerate irinotecan at an initial dose of 120 mg/m 2 with favorable oncological outcomes and toxicity profiles. Further prospective studies are warranted to optimize irinotecan-based chemotherapy in these patients.

Uridine diphosphate glucuronosyltransferase 1A1 ( UGT1A1 ) polymorphism plays a crucial role in the increased susceptibility and toxicity of patients to irinotecan. This retrospective, observational study compared the clinical outcomes and adverse events (AEs) in RAS wild-type metastatic colorectal cancer (mCRC) patients treated with cetuximab or bevacizumab plus FOLFIRI with UGT1A1 genotyping and irinotecan dose escalation as the first-line therapy. In total, 173 patients with mCRC with RAS wild-type were enrolled. Among them, 98 patients were treated with cetuximab, whereas 75 patients were treated with bevacizumab. All patients received irinotecan dose escalation based on UGT1A1 genotyping. We compared the progression-free survival (PFS), overall survival (OS), objective response rates (ORRs), disease control rates (DCRs), metastatectomy, and severe adverse events (SAEs) between the two groups. The clinical effects of primary tumor sidedness and target therapy crossover were further analyzed. Over a median follow-up of 23.0 months [interquartile range (IQR), 15.032.5 months], no significant differences were observed between the cetuximab and bevacizumab groups in PFS [18.0 months vs. 14.0 months; 95% confidence interval (CI), 0.5171.027; hazard ratio (HR), 0.729; p =0.071], OS (40.0 months vs. 30.0 months; 95% CI, 0.4101.008; HR, 0.643; p =0.054), ORR (65.3% vs. 62.7%; p =0.720), DCR (92.8% vs. 86.7%; p =0.175), metastatectomy (36.7% vs. 29.3%; p =0.307), and SAEs ( p =0.685). Regardless of primary tumor sidedness and target therapy crossover, no significant differences were noted in efficacy and safety between the two groups (all p >0.05). Our results revealed that patients with wild-type RAS mCRC, regardless of biologics, with UGT1A1 genotyping can tolerate escalated doses of irinotecan and potentially achieve a more favorable clinical outcome without significantly increased toxicity.

Personalized treatments based on the genetic profiles of tumors can simultaneously optimize efficacy and minimize toxicity, which is beneficial for improving patient outcomes. This study aimed to integrate gene alterations associated with predictive and prognostic outcomes in patients with metastatic colorectal cancer (mCRC) with polymerase chain reaction (PCR) and in-house next-generation sequencing (NGS) to detect KRAS , NRAS , and BRAF mutations. In the present study, 41 patients with mCRC were assessed between August 2017 and June 2019 at a single institution. The overall concordance between NGS and PCR results for detecting KRAS , NRAS, and BRAF mutations was considerably high (87.8-92.7%), with only 15 discrepant results between PCR and NGS. Our companion diagnostic test analyzes KRAS , NRAS, and BRAF as a panel of CRC molecular targets; therefore, it has the advantages of requiring fewer specimens and being more time and cost efficient than conventional testing for separate analyses, allowing for the simultaneous analysis of multiple genes.

Background: The safety and efficacy of gastrectomy for locally advanced gastric cancer (LAGC) following neoadjuvant therapy have gained increasing attention. In this article, we present our preliminary treatment results and compare the surgical safety and outcomes of neoadjuvant concurrent chemoradiotherapy (CCRT) with those of chemotherapy in patients with LAGC. Patients and Methods . Sixty-three patients with a diagnosis of LAGC (clinical staging cT3N2+, cT4aN+, or cT4b) who had received neoadjuvant therapy at any period from January 2014 to December 2020 were enrolled. Among 63 patients who received neoadjuvant therapy, 38 were treated with CCRT and 25 were treated with chemotherapy. They regularly received follow-up until July 2021. The patients' characteristics, including their clinical data, perioperative results, and pathologic outcomes, were analyzed., Results: The CCRT and chemotherapy groups did not significantly differ with respect to age, sex, or clinical stage (all p > 0.05). Finally, radical gastrectomy was performed in 15 (39.5%) patients with neoadjuvant CCRT and 10 (40.0%) patients with neoadjuvant chemotherapy. Both groups did not significantly differ with respect to operation time, blood loss, operative morbidities, or postoperative length of stay (both p > 0.05). The patients in the CCRT group exhibited favorable pathologic responses after treatment: three patients exhibited a pathologic complete response (pCR) and four, seven, and one patients exhibited a response at pathologic stages I, II, and III, respectively. By contrast, among the patients in the chemotherapy group after treatment, one patient exhibited a pCR and one, four, and four patients exhibited a response at pathologic stages I, II, and III, respectively., Conclusions: Radical resection in patients with LAGC is challenging. This study reports that neoadjuvant CCRT is associated with better pathologic response with no increase in serious postoperative complications. However, further prospective randomized trials involving patients with LAGC receiving neoadjuvant CCRT should be conducted to verify the findings of this retrospective study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ching-Chun Li et al.)

Objective: Patients with metastatic colorectal cancer (mCRC) had oncological benefits with irinotecan dose escalation of FOLFIRI regimen combined with bevacizumab according to UGT1A1 genotypes in our previous study. In the current study, we performed a quality of life (QOL) outcome evaluation and cost-utility analysis of different irinotecan dose regimens in patients with mCRC., Materials and Methods: With inverse probability-of-treatment weighting (IPTW) matching on all covariates, 75 patients with dose escalation of irinotecan (study group) and 121 patients with the recommended dose of irinotecan (control group) were recruited between October 2015 and December 2019. The QOL outcome measures were Functional Assessment of Cancer Therapy-Colorectal, Beck Anxiety Inventory, Beck Depression Inventory, and SF-36; cost-utility outcome measures were medical direct costs, quality-adjusted life-years (QALYs), and incremental cost-utility ratios (ICURs)., Results: All mCRC patients exhibited a significant decrease in both emotional wellbeing and depression from pretherapeutic period to posttherapeutic 6th month ( P < 0.05); however, from the posttherapeutic 1st year to the 2nd year, improvement in most QOL measures was significantly better in the study group than in the control group ( P < 0.05). Over a 2-year time period, the study group had higher total medical direct costs than the control group (US$ 54,742 ± 14,013 vs. US$ 54,608 ± 9,673) and higher average QALYs gained (1.88 vs. 1.65), with an ICUR of US$ 583 per QALY gained., Conclusion: For patients with mCRC, irinotecan dose escalation appeared cost-effective with considerable QOL improvements during the study period. Further randomized, multi-institutional controlled trials are warranted to corroborate these results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shi, Chen, Huang, Li, Su, Chang, Chen, Yin, Tsai and Wang.)

(1) This study tests hypothesis whether extracorporeal shock wave (ECSW) therapy effectively salvages mouse critical limb ischemia (CLI). In vitro result demonstrated that the angiogenesis parameters (i.e., tubular length/cluster/network formation) and protein expressions of EGFR/VEGFR2/RAS/c-Raf/MEK/ERK/VEGF/p-PI3K/p-Akt/p-m-TOR were significantly and progressively increased with stepwise augmentation of ECSW energy (0.1/0.14/0.20 mJ/mm 2 /140 impulses). On the other hand, they were suppressed by administration of Avastin (20 μM). Adult male B6 mice ( n = 24) were equally categorized into group 1 (sham-operated control), group 2 (CLI), group 3 [CLI + ECSW (0.12 mJ/mm 2 /120 impulses/at days 1/3/7 after CLI induction)] and group 4 [CLI + ECSW (0.12 mJ/mm 2 /120 impulses) + Avastin (1 mg/intramuscular-injection)] at days 1/3/7 after CLI induction] and quadriceps were harvested by day 14. The laser Doppler result showed that the ratio of left (ischemia) to right (normal) limb blood flow was highest in group 1, lowest in group 2, and significantly higher in group 3 than in group 4 by days 7/14 after the CLI procedure ( p < 0.0001). The protein expressions of cell proliferation/migration/angiogenesis receptors (EGFR/VEGFR2), angiogenesis biomarkers (VEGF/CXCR4/SDF-1) and cell proliferation/growth/survival (Ras/c-Raf/MEK/ERK)/(PI3K/Akt/m-TOR) and cell motility/proliferation (p-FAK/p-Scr) signaling biomarkers were significantly higher in group 3 than in groups 1/2/4, and significantly lower in group 1 than in groups 2/4, but they did not show a difference between groups 2 and 4 (all p < 0.001). The small vessel density and cellular levels of endothelial cell surface marker (CD31+) exhibited an identical pattern of blood flow, whereas the angiogenesis (CXCR4+/VEGF+) displayed an identical pattern of VEGFR2 among the groups (all p < 0.0001). The in vitro and in vivo studies found ECSW salvaged the CLI mainly through upregulating Ras-Raf-MEK/ERK/cell motility, cell proliferation/growth pathways and angiogenesis.

This study tested whether combined hyperbaric oxygen (HBO) and allogenic adipose-derived mesenchymal stem cells (ADMSCs) would be superior to either one for improving the locomotor recovery in rat after acute traumatic spinal cord injury (TSCI) in rat. Adult-male Sprague-Dawley rats were equally categorized into group 1 (sham-operated control), group 2 (TSCI), group 3 (TSCI + HBO for 1.5 h/day for 14 consecutive days after TSCI), group 4 (TSCI + ADMSCs/1.2 × 10 6 cells by intravenous injection at 3 h and days 1/2 after TSCI), and group 5 (TSCI + HBO + ADMSCs), euthanized, and spinal cord tissue was harvested by day 49 after TSCI. The protein expressions of oxidative-stress (NOX-1/NOX-2), inflammatory-signaling (TLR-4/MyD88/IL-1β/TNF-α/substance-p), cell-stress signaling (PI3K/p-AKT/p-mTOR), and the voltage-gated sodium channel (Nav1.3/1.8/1.9) biomarkers were highest in group 2, lowest in group 1, and significantly lower in group 5 than in groups 3/4 (all P <0.0001), but they did not differ between groups 3 and 4. The spinal cord damaged area, the cellular levels of inflammatory/DNA-damaged biomarkers (CD68+/GFAP+/γ-H2AX+ cells), mitogen-activated protein kinase family biomarkers (p-P38/p-JNK/p-ERK1/2), and cellular expressions of voltage-gated sodium channel (Nav.1.3, Nav.1.8, and Nav.1.9 in NF200+ cells) as well as the pain-facilitated cellular expressions (p-P38+/peripherin+ cells, p-JNK+/peripherin+ cells, p-ERK/NF200+ cells) exhibited an identical pattern of inflammation, whereas the locomotor recovery displayed an opposite pattern of inflammation among the groups (all P < 0.0001). Combined HBO-ADMSCs therapy offered additional benefits for preserving the neurological architecture and facilitated the locomotor recovery against acute TSCI.

Background: Locally advanced colon cancer (LACC) is associated with surgical challenges during R0 resection, increased postoperative complications, and unfavorable treatment outcomes. Neoadjuvant concurrent chemoradiotherapy followed by surgical resection is an effective treatment strategy that can increase the complete surgical resection rate and improve the patient survival rate. This study investigated the efficacy and toxicity of concurrent chemoradiotherapy in patients with LACC as well as the prognosis and long-term clinical outcomes of these patients., Materials: From January 2012 to July 2020, we retrospectively reviewed the real-world data of 75 patients with LACC who received neoadjuvant concurrent chemoradiotherapy. The chemotherapy regimen consisted of folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX). The following data were obtained from medical records: patients' characteristics, pathologic results, toxicity, and long-term oncologic outcome., Results: Of the 75 patients, 13 (17.3%) had pathologic complete responses. Hematologic adverse effects were the most common (grade 1 anemia: 80.0% and leukopenia: 82.7%). Conversely, grade 2 or 3 adverse effects were relatively uncommon (<10%). Pathologic N downstaging, ypT0, and pathologic complete responses were significant prognostic factors for patient survival. Multivariate analysis revealed that pathologic N downstaging was an independent predictor of patients' overall survival (P = 0.019). The estimated 5-year overall and disease-free survival rates were 68.6% and 50.6%, and the medians of overall and disease-free survival periods were 72.3 and 58.7 months, respectively. Moreover, patients with pathologic complete responses had improved overall survival (P = 0.039) and an improved local recurrence control rate (P = 0.042) but an unfavorable distant metastasis control rate (P = 0.666) in the long-term follow-up., Conclusion: The long-term oncologic outcome of patients with LACC following concurrent chemoradiotherapy is acceptable, and the adverse effects seem to be tolerable. Pathologic N downstaging was an independent prognostic factor for patients' overall survival. However, a large prospective, randomized control study is required to confirm the current results., Competing Interests: The authors have declared that no competing interests exist.

Irinotecan, a topoisomerase inhibitor, is a common cytotoxic agent prescribed for metastatic colorectal cancer (mCRC) patients. Diarrhea is the most common adverse event (AE). The underlying mechanism of irinotecan-induced diarrhea is intestinal mucosal damage caused by SN-38 (active metabolite of irinotecan) hydrolyzed from SN-38G (inactive metabolite) by bacterial -glucuronidase (G). According to an animal study, silymarin reduces the activity of bacterial G without impairing antitumor efficacy. We conducted a prospective open-label pilot study to evaluate the effect of silymarin as supplementation in reducing toxicities of mCRC patients undergoing irinotecan-based chemotherapy. We enrolled and randomized 70 mCRC patients receiving first-line FOLFIRI (5-fluorouracil/leucovorin/irinotecan) plus bevacizumab. In each treatment cycle, the study group was administered silymarin capsules (150 mg) three times daily for 7 days. The study group experienced less AEs in diarrhea (5.7% vs. 14.6%, p =0.002) and nausea (27.0% vs. 40.2%, p =0.005) in comparison with the control group, but no significant differences in hepatic toxicities were observed. In conclusion, simultaneous administration of silymarin is a potential effective supplementation for reducing toxicities in mCRC patients undergoing first-line FOLFIRI plus bevacizumab, especially in diarrhea and nausea.

This study investigated the roles of low-molecular-weight fucoidan (LMWF) in enhancing the anti-cancer effects of fluoropyrimidine-based chemotherapy. HCT116 and Caco-2 cells were treated with LMWF and 5-FU. Cell viability, cell cycle, apoptosis, and migration were analyzed in both cell types. Potential mechanisms underlying how LMWF enhances the anti-cancer effects of fluoropyrimidine-based chemotherapy were also explored. The cell viability of HCT116 and Caco-2 cells was significantly reduced after treatment with a LMWF--5FU combination. In HCT116 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through the (1) induction of cell cycle arrest in the S phase and (2) late apoptosis mediated by the Jun-N-terminal kinase (JNK) signaling pathway. In Caco-2 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through both the c-mesenchymal-epithelial transition (MET)/Kirsten rat sarcoma virus (KRAS)/extracellular signal-regulated kinase (ERK) and the c-MET/phosphatidyl-inositol 3-kinases (PI3K)/protein kinase B (AKT) signaling pathways. Moreover, LMWF enhanced the suppressive effects of 5-FU on tumor cell migration through the c-MET/matrix metalloproteinase (MMP)-2 signaling pathway in both HCT116 and Caco-2 cells. Our results demonstrated that LMWF is a potential complementary therapy for enhancing the efficacies of fluoropyrimidine-based chemotherapy in colorectal cancers (CRCs) with the wild-type or mutated KRAS gene through different mechanisms. However, in vivo studies and in clinical trials are required in order to validate the results of the present study.

Aims: This study analyzed the oncological outcomes of robotic-assisted total mesorectal excision (TME) in patients with rectal cancer after neoadjuvant concurrent chemoradiotherapy (CCRT)., Methods: We enrolled 109 consecutive patients with stage II-III rectal cancer who underwent robotic-assisted TME after neoadjuvant CCRT at one hospital between July 2013 and June 2018., Results: All 109 patients underwent preoperative CCRT. Of them, 37 (33.9%) achieved a pathologic complete response, and 29 (26.6%) experienced relapse, with local recurrence in 9 (8.3%) and distant metastasis in 20 (18.3%). R0 resection was performed in 104 (95.7%) patients; however, 7 (6.7%) of them developed local recurrence and 17 (16.3%) developed distant metastasis. Over a median follow-up of 42 months, the 3-year disease-free survival and overall survival rates were 73.4% and 87.2%, respectively., Conclusions: Robotic-assisted TME after neoadjuvant CCRT is safe and effective for treating patients with stage II-III rectal cancer in one institution with acceptable short-term oncological outcomes. It may be a therapeutic alternative to salvage surgery for T4 tumors invading adjacent organs, such as the bladder, prostate, and uterus., Competing Interests: Declaration of competing interest None., (Copyright © 2021. Published by Elsevier Taiwan LLC.)

Colorectal cancer (CRC) is the third leading cause of cancer death in Taiwan. A recent study suggested a link between exposure to endocrine-disrupting chemicals (EDCs) and increased susceptibility to pathology. Exposure to di-(2-ethylhexyl) phthalate (DEHP), an EDC and plasticizer widely used in consumer products, has been reported to be significantly positively correlated with increased risks of various cancers. We explored this connection of DEHP exposure with the development of CRC through the detection of urinary monoethylhexyl phthalate (MEHP), a potent metabolite of DEHP. Participants comprised 221 individuals recruited between October 2016 and November 2019 from a single institution. Overall, urinary MEHP concentrations were significantly higher in patients with CRC than in the patients with adenoma or healthy participants (both P < 0.001). Higher exposure to DEHP may contribute to the occurrence of CRC. Urinary MEHP detection may serve as a beneficial noninvasive indicator of increased CRC risk.

This study tested the hypothesis that combined therapy with human umbilical cord-derived mesenchymal stem cells (HUCDMSCs) and hyperbaric oxygen (HBO) was superior to either one on preserving neurological function and reducing brain haemorrhagic volume (BHV) in rat after acute intracerebral haemorrhage (ICH) induced by intracranial injection of collagenase. Adult male SD rats (n = 30) were equally divided into group 1 (sham-operated control), group 2 (ICH), group 3 (ICH +HUCDMSCs/1.2 × 10 6 cells/intravenous injection at 3h and days 1 and 2 after ICH), group 4 (ICH +HBO/at 3 hours and days 1 and 2 after ICH) and group 5 (ICH +HUCDMSCs-HBO), and killed by day 28 after ICH. By day 1, the neurological function was significantly impaired in groups 2-5 than in group 1 (P < .001), but it did not differ among groups 2 to 5. By days 7, 14 and 28, the integrity of neurological function was highest in group 1, lowest in group 2 and significantly progressively improved from groups 3 to 5 (all P < .001). By day 28, the BHV was lowest in group 1, highest in group 2 and significantly lower in group 5 than in groups 3/4 (all P < .0001). The protein expressions of inflammation (HMGB1/TLR-2/TLR-4/MyD88/TRAF6/p-NF-κB/IFN-γ/IL-1ß/TNF-α), oxidative stress/autophagy (NOX-1/NOX-2/oxidized protein/ratio of LC3B-II/LC3B-I) and apoptosis (cleaved-capspase3/PARP), and cellular expressions of inflammation (CD14+, F4/80+) in brain tissues exhibited an identical pattern, whereas cellular levels of angiogenesis (CD31+/vWF+/small-vessel number) and number of neurons (NeuN+) exhibited an opposite pattern of BHV among the groups (all P < .0001). These results indicate that combined HUCDMSC-HBO therapy offered better outcomes after rat ICH., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background : Disorders of the hip and lumbar spine can create similar patterns of pain and dysfunction. It is unknown whether all surgeons, regardless of orthopedic or neurosurgery training, investigate and diagnose concurrent hip and spine pathology at the same rate. Methods : Data were retrieved from Taiwan's National Health Insurance Research Database (NHIRD). Enrolled patients were stratified into hip and spine surgery at the same admission (Both), hip surgery before spine surgery (HS), or spine surgery before hip surgery (SH). The SH group was further subdivided based on whether spine surgery was performed by an orthopedic surgeon (OS) or neurosurgeon (NS), and differences in preoperative radiographic examinations and diagnoses were collected and analyzed. Results : In total, 1824 patients received lumbar spine surgery within 1 year before or after hip replacement surgery. Of these, 103 patients had spine and hip surgery in the same admission (Both), 1290 patients had spine surgery before hip surgery (SH), and 431 patients had hip surgery before spine surgery (HS). In the SH group, patients were categorized into spine surgery by orthopedic surgeons (OS) ( n = 679) or neurosurgeons (NS) ( n = 522). In the SH group, orthopedic surgeons investigated hip pathology with X-rays more often (52.6% vs. 38.1%, p < 0.001) and diagnosed more cases of hip disease (43.6% vs. 28.9%, p < 0.001) than neurosurgeons. Conclusions : Of patients in Taiwan's NHIRD who had concurrent surgical degenerative hip and lumbar spine disorders who had spine surgery before hip surgery, orthopedic surgeons obtained hip images and made hip-related diagnoses more frequently than did neurosurgeons.

Background: Patients with metastatic colorectal cancer (mCRC) and BRAF V600E mutation have a poor prognosis, with a median progression-free survival (PFS) of only 5-7 months after initial therapy. The current standard first-line chemotherapy for these patients includes FOLFOX or FOLFIRI plus bevacizumab. In this study, we explored the effects and oncological outcomes of UGT1A1 polymorphism for irinotecan escalation in patients with BRAF- mutated mCRC. Patients and Methods . This retrospective study included 17 patients with BRAF- mutated mCRC between April 2016 and December 2019. UGT1A1 genotyping was performed on all patients prior to initiating bevacizumab plus FOLFIRI chemotherapy. The primary endpoint was PFS, and the secondary endpoints were toxicity, response rate, disease control rate, and overall survival (OS)., Results: Fifteen and two patients had UGT1A1 1∗/1∗ and 1∗/28∗, respectively. Eight underwent irinotecan dose escalation with tolerable adverse effects (AEs), and nine maintained an irinotecan dose of 180 mg/m 2 or required deescalation to 150 mg/m 2 due to intolerable AEs. After a median follow-up period of 15.7 (range, 3-54) months, the median PFS and OS were 9.4 and 15.7 months, respectively. Grade 3/4 AEs were observed in three (6%) patients. The disease control and partial response rates were 64.7% and 11.8%, respectively, indicating that most patients (14, 82.3%) could maintain this as a first-line line therapy with stable disease or proceed to second-line therapy if disease progression occurred, thereby maintaining acceptable performance status., Conclusions: The oncological outcomes of patients with BRAF- mutated mCRC treated using FOLFIRI plus bevacizumab with irinotecan dose escalation as a first-line therapy are acceptable with tolerable AEs; this may be a feasible treatment option in such patients. Pretherapeutic UGT1A1 genotyping-guided dose adjustment can achieve favorable outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2021 Yi-Chien Hsieh et al.)

Background: Enhanced recovery after surgery (ERAS) is valuable in perioperative care for its ability to improve short-term surgical outcomes and facilitate patient recuperation after major surgery. Early postoperative mobilization is a vital component of the integrated care pathway and is a factor strongly associated with successful outcomes. However, early mobilization still has various definitions and lacks specific strategies. Methods: Patients who underwent minimally invasive surgery for colorectal cancer followed our perioperative ERAS program, including mobilization from the first postoperative day. After perioperative care skills were improved in our well-established program, compliance, inpatient surgical outcomes, and complications associated with adding smartband use were evaluated and compared with the outcomes for standard protocol. Quality of recovery was evaluated using patient-rated QoR-40 questionnaires the day before surgery, on postoperative days 1 and 3, and on the day of discharge. Results: Smartband use after minimally invasive colorectal surgery failed to increase compliance with early mobilization or reduce the occurrence of postoperative complications significantly compared with standard ERAS protocol. However, when smartbands were utilized, quality of recovery was optimized and patients returned to their preoperative status earlier, at postoperative day 3. The length of hospital stay, as defined by discharge criteria, and hospital stay of patients without complications was reduced by 1.1 and 0.9 days, respectively ( P = 0.009 and 0.049, respectively). Conclusions: Smartbands enable enhanced communication between patients and surgical teams and strengthen self-management in patients undergoing minimally invasive colorectal resection surgery. Accelerated recovery to preoperative functional status can be facilitated by integrating smartbands into the process of early mobilization during ERAS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yin, Huang, Tsai, Su, Ma, Chang and Wang.)

Background: The purpose of this work was to evaluate orthopedic surgeons' exposure to occupational radiation doses from scattering using a mobile flat panel C-arm X-ray machine at different standing positions during an intraoperative pedicle screw implantation., Objective: Evaluate the radiation dose received by medical staff, by applying flat X-ray machine in surgical room during an intraoperative pedicle screw implantation., Methods: A mobile flat-panel C-arm X-ray machine at a dedicated orthopedic operating room was used to image an anthropomorphic female phantom which was set in a prone position on the operating table. The X-ray was projected horizontally, and 1 minute continuous fluoroscopy was used for lumbar spine and thoracolumbar spine during pedicle screw implantation. Scattering radiation doses to orthopedic surgeons were measured at different standing positions and body heights (50, 100, 150 cm above the ground) with and without limited collimations., Results: The dose area product (DAP) in this experiment is normalized as 343 μGy⋅m2. In the four areas, the lowest scattered radiation measured by DF is 11.2 vs. 0.7 μSv, outside and inside the lead suit, respectively, with or without restricted field, 150 cm above the ground, and the lowest scattered radiation dose inside the lead suit. It is 1.3 vs. 0.5 μSv. Comparing the highest dose of the TF at with the lowest dose of the DF, the average result is 73.7 vs. 11.1 μSv, P< 0.05., Conclusions: Using a mobile flat-panel C-arm X-ray machine during a pedicle screw implantation, the minimum scattering radiation to surgeons was found to be at the terminal DF area based on the analysis of the scattering doses orthopedic surgeons were exposed to.

Background: The application of minimally invasive surgery in patients with colorectal cancer (CRC) and a history of previous abdominal surgery (PAS) remains controversial. This retrospective study with propensity score matching (PSM) investigated the impact of PAS on robotic-assisted rectal surgery outcomes in patients with locally advanced rectal adenocarcinoma undergoing preoperative concurrent chemoradiotherapy (CCRT)., Methods: In total, 203 patients with locally advanced rectal adenocarcinoma who underwent preoperative CCRT and robotic-assisted rectal surgery between May 2013 and December 2019 were enrolled. Patients were categorized into PAS and non-PAS groups based on the PAS history. The PSM caliper matching method with 1-to-3 matches was used to match PAS patients with non-PAS., Results: Of the 203 enrolled patients, 35 were PAS patients and 168 were non-PAS patients. After PSM, 32 PAS patients and 96 non-PAS patients were included for analysis. No significant between-group differences were noted in the perioperative outcomes, including median console time (165 min (PAS) vs. 175 min (non-PAS), P = 0.4542) and median operation time (275 min (PAS) vs. 290 min (non-PAS), P = 0.5943) after PSM. Postoperative recovery and overall complication rates were also similar (all P > 0.05). Moreover, the between-group differences in pathological or short-term oncological outcomes were also nonsignificant (all P > 0.05). No 30-day postoperative deaths were observed in either group., Conclusion: The current results indicate that robotic-assisted surgery is safe and feasible for PAS patients with locally advanced rectal adenocarcinoma undergoing preoperative CCRT. However, future prospective randomized clinical trials are required to verify these findings.

Chronic neurodegeneration in survivors of traumatic brain injury (TBI) is a major cause of morbidity, with no effective therapies to mitigate this progressive and debilitating form of nerve cell death. Here, we report that pharmacologic restoration of the blood-brain barrier (BBB), 12 mo after murine TBI, is associated with arrested axonal neurodegeneration and cognitive recovery, benefits that persisted for months after treatment cessation. Recovery was achieved by 30 d of once-daily administration of P7C3-A20, a compound that stabilizes cellular energy levels. Four months after P7C3-A20, electron microscopy revealed full repair of TBI-induced breaks in cortical and hippocampal BBB endothelium. Immunohistochemical staining identified additional benefits of P7C3-A20, including restoration of normal BBB endothelium length, increased brain capillary pericyte density, increased expression of BBB tight junction proteins, reduced brain infiltration of immunoglobulin, and attenuated neuroinflammation. These changes were accompanied by cessation of TBI-induced chronic axonal degeneration. Specificity for P7C3-A20 action on the endothelium was confirmed by protection of cultured human brain microvascular endothelial cells from hydrogen peroxide-induced cell death, as well as preservation of BBB integrity in mice after exposure to toxic levels of lipopolysaccharide. P7C3-A20 also protected mice from BBB degradation after acute TBI. Collectively, our results provide insights into the pathophysiologic mechanisms behind chronic neurodegeneration after TBI, along with a putative treatment strategy. Because TBI increases the risks of other forms of neurodegeneration involving BBB deterioration (e.g., Alzheimer's disease, Parkinson's disease, vascular dementia, chronic traumatic encephalopathy), P7C3-A20 may have widespread clinical utility in the setting of neurodegenerative conditions., Competing Interests: Competing interest statement: A.A.P. is an inventor on patents related to P7C3. No other authors declare competing interests., (Copyright © 2020 the Author(s). Published by PNAS.)

Colorectal cancer (CRC) of the clinical tumor stage T4b (cT4b) refers to advanced tumors with direct invasion of adjacent structures and the tumors are considered unresectable. Despite advancements in aggressive surgery and combination chemotherapy, the prognosis of cT4b CRC remains poor. Optimizing the therapeutic sequence administered to patients with cT4b CRC to improve clinical outcomes is crucial. In the present study, patients with unresectable cT4b and nodal stage N1-2 CRC were investigated at a single institution. A total of 20 consecutive patients were treated with pre-operative concurrent chemoradiation by using 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) since February 2015 and were regularly followed up until March 2020. Due to their poor response to concurrent chemoradiation (CCRT) with FOLFOX, the chemotherapy regimen was changed to irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as the second-line neoadjuvant treatment. Genetic alterations, such as microsatellite instability (MSI), were documented, and the expression levels of excision repair cross-complementing group 1 (ERCC1) and ERCC2 were examined. Of the 20 patients, the tumors of 14 patients (70%) became resectable after FOLFIRI administration. The median duration between the last date of radiotherapy and surgery was 32.7 weeks (range, 10.1-59.3 weeks). Of note, 4 of the 14 patients with resectable tumors (28.6%) achieved a pathologic complete response. The median overall survival and progression-free survival were 27.5 months (range, 12-39 months) and 27.5 months (range, 8-39 months), respectively. The cancerous specimens of all of the patients (100%) exhibited ERCC2 overexpression and 18 specimens (90%) had ERCC1 overexpression. Only one tumor (5%) exhibited high MSI. The present study indicated that ERCC overexpression associated with the poor response of FOLFOX-based CCRT and FOLFIRI after FOLFOX-based CCRT failure may have a potential role in conversion to resectable tumors by neoadjuvant treatment in cT4b CRC. However, a further prospective study with more patients is required to improve the precision of the conclusions., (Copyright: © Huang et al.)

Background: Curative resection of sigmoid colon and rectal cancer includes "high tie" of the inferior mesenteric artery (IMA). However, IMA ligation compromises blood flow to the anastomosis, which may increase the complication rate. We present preliminary experiences of operative and oncologic outcomes of patients with rectal or sigmoid colon cancer who underwent robotic surgery employing the high dissection and selective ligation technique. Methods: Over May 2013 to April 2017, 113 stage I-III rectal or sigmoid colon cancer patients underwent robotic surgery with the single-docking technique at one institution. We performed D3 lymph node dissection and low-tie ligation of the IMA (i.e., high dissection and selective ligation technique). Clinicopathological features, perioperative parameters, and postoperative outcomes were retrospectively analyzed. Overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan-Meier method. Results: Sphincter preservation rate was 96.3% in rectal cancer patients. Median number of harvested lymph nodes was 12. Apical nodes were pathologically harvested in 84 (82.4%) patients. R0 resection was performed in 108 (95.6%) patients. Overall complication rate was 17.7%; but most complications were mild and the patients recovered uneventfully. Estimated 5-year OS was 86.1% and 3-year DFS was 79.6% after median follow-up periods of 49.1 months (range, 5.3-85.3). Conclusions: High dissection of the IMA and selective ligation of the major feeding vessel to the sigmoid colon or rectum can be safely performed using da Vinci Surgical System,yielding favorable clinical, and oncologic outcomes in rectal or sigmoid colon cancer treatment., (Copyright © 2020 Yin, Su, Chen, Chang, Chen, Li, Hsieh, Tsai, Huang and Wang.)

Background: This aim of this study was to evaluate the effects of time interval between the completion of radiotherapy and robotic-assisted surgery on the outcomes among patients with rectal cancer undergoing preoperative concurrent chemoradiotherapy (CCRT)., Methods: In total, 116 patients with stage I-III rectal cancer who underwent preoperative CCRT and robotic-assisted surgery between September 2013 and February 2019 were enrolled. Patients were categorized into two groups based on the time interval: group A (10-12 weeks) and group B (≥ 12 weeks)., Results: Among the 116 enrolled patients, 98 (84.5%) had middle and lower rectal cancers. Two (1.7%) patients underwent abdominoperineal resection with a sphincter preservation rate of 98.3%. Thirty-seven (31.9%) patients had a pathologic complete response (pCR). The circumferential resection margin and distal resection margin were positive in 2 (1.7%) and 1 (0.9%) patients, respectively. Therefore, the R0 resection rate was 97.4%. A total of 24 (22.4%) patients experienced postoperative relapse and 12 (10.3%) patients died; these were slightly more common in group B than in group A (28.8% vs 15.8% and 15.3% vs 5.3%, respectively; both P > 0.05); however, this difference was nonsignificant. Three-year disease-free survival (DFS) and overall survival (OS) were 75% and 89%, respectively, among all patients. Non-significant trend of favorable 3-year DFS, 3-year OS, 3-year locoregional control rate and 3-year distant metastasis control rate were observed in group A compared with group B (all P > 0.05)., Conclusion: Robotic-assisted surgery after a longer interval is safe and feasible for patients with rectal cancer undergoing preoperative CCRT. The present study's results suggested that the time interval of 10-12 weeks can be considered because comparable clinical and perioperative outcomes and preferable oncological outcomes were observed for interval of this length. However, future prospective randomized clinical trials are required to verify the present finding., Competing Interests: The authors have declared that no competing interests exist.

Ghrelin regulates both energy intake and glucose homeostasis. In the endocrine pancreas, ghrelin inhibits insulin release to prevent hypoglycemia during fasting. The mechanism through which this is accomplished is unclear, but recent studies suggest that ghrelin acts on δ cells to stimulate somatostatin release, which in turn inhibits insulin release from β cells. Recently, the Melanocortin Receptor Accessory Protein 2 (MRAP2) was identified as an essential partner of the ghrelin receptor (GHSR1a) in mediating the central orexigenic action of ghrelin. In this study we show that MRAP2 is expressed in islet δ cells and is required for ghrelin to elicit a calcium response in those cells. Additionally, we show that both global and δ cell targeted deletion of MRAP2 abrogates the insulinostatic effect of ghrelin. Together, these findings establish that ghrelin signaling within δ cells is essential for the inhibition of insulin release and identify MRAP2 as a regulator of insulin secretion., Competing Interests: Declaration of Interests The authors declare no competing interest., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: This study tested the hypothesis that intramuscular injections of erythropoietin (EPO) and endothelial progenitor cells (EPC) to critical limb ischemia (CLI; primary treatment site) could also improve heart function in rat after acute myocardial infarction (AMI; remote ischemic organ)., Method: Adult-male SD rats (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (CLI-AMI), group 3 [CLI-AMI + EPO (10 mg/kg)], group 4 [CLI-AMI + EPCs (1.2 × 10 6 )] and group 5 (CLI-AMI + EPCs + EPO)., Results: By day 21 (end of study period), 2-D echo and Laser doppler showed that left-ventricular injection fraction (LVEF) and the ratio of ischemic to normal blood flow were highest in group 1, lowest in group 2, significantly higher in group 5 than in groups 3 and 4, but not different in the latter two groups (all p < 0.0001). Flow cytometry and ELISA demonstrated that circulating angiogenesis factors were significantly progressively increased from groups 1 to 5 (all p < 0.001). The number of small vessels and protein (CD31/eNOS)/cellular (vWF) expressions reflecting integrity of endothelium exhibited an identical pattern to LVEF whereas protein (VEGF/SDF-1α)/cellular (VEGF) expressions were significantly progressively increased from groups 1 to 5 in quadriceps and heart tissues (all p < 0.0001). Protein expressions of apoptotic (Bax/caspase-3/PARP)/inflammatory (MMP-9) and microscopic findings of ischemic/fibrotic/collagen-deposition areas and DNA-damage marker (γ-H2AX+) were lowest in group 1 and significantly progressively decreased from groups 2 to 5 in quadriceps and heart tissues (all p < 0.0001)., Conclusions: Direct injection of EPO-EPC into CLI effectively restored blood flow in the CLI area and also preserved remote heart function., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

We tested the hypothesis that hyperbaric oxygen (HBO) (100% oxygen/2.4 atmospheres) facilitated the effect of autologous endothelial progenitor cell (EPC) therapy on restoring the blood flow in rat critical-limb ischemia (CLI). Adult-male-SD rats (n = 8/each group) were categorized into group 1 [sham control (SC)], group 2 (CLI-treated with culture medium), group 3 [CLI-intermittent HBO (3 h/day for 5 consecutive days after CLI), group 4 (CLI-EPC/2.0 × 10 6 cells), and group 5 (CLI-HBO-EPC). By day 5 after CLI, flow cytometry showed that the circulating EPC (Sca-1/CD31+/C-kit/CD31+/CD34+) levels were highest in group 5 and lowest in group 2 (all P < 0.001). By day 14, laser Doppler demonstrated that the ratio of blood flow (i.e., CLI to normal hind-limb) was highest in group 1, lowest in group 2 and significantly higher in group 5 than in groups 3 and 4 (all P < 0.0001). The protein expressions of endothelial-cell biomarkers (CD31/vWF/eNOS), and numbers of endothelial-cell markers (CD31+/vWF+) and small vessels exhibited a similar pattern to blood-flow ratio among five groups, whereas the angiogenesis parameters in protein (CXCR4/SDF-1α/HIF-1α/VEGF) and cellular (HIF-1α/SDF-1α/CXCR4+) levels were progressively increased from groups 1 to 5 (all P < 0.0001). The protein expression of apoptotic (mitochondrial-Bax/cleaved-capspase-3/PARP), fibrotic (p-Smad3/TGF-ß) and mitochondrial-damaged (cytosolic-cytochrome C) exhibited an opposite pattern, whereas the protein expressions of anti-fibrotic (BMP-2/p-Smad1/5) and mitochondrial integrity (mitochondrial-cytochrome C) exhibited an identical pattern of ratio of blood flow among the five groups (all P < 0.0001). Combined HBO-EPC therapy is superior to either one alone in improving ischemia in rodent CLI., Competing Interests: None.

We evaluated the ability of extracorporeal shock wave (ECSW)-assisted melatonin (Mel) therapy to offer an additional benefit for alleviating the neuropathic pain (NP) in rats. Left sciatic nerve was subjected to chronic constriction injury (CCI) to induce NP. Animals (n = 30) were randomized into group 1 (sham-operated control), group 2 (CCI only), group 3 (CCI + ECSW), group 4 (CCI + Mel) and group 5 (CCI + ECSW + Mel). By days 15, 22 and 29 after CCI, the thermal paw withdrawal latency (TPWL) and mechanical paw withdrawal threshold (MPWT) were highest in group 1, lowest in group 2, significantly higher in group 5 than in groups 3 and 4, but they showed no difference between the later two groups (all p < 0.0001). The protein expressions of inflammatory (TNF-α, NF-κB, MMP-9, IL-1ß), oxidative-stress (NOXs-1, -2, -4, oxidized protein), apoptotic (cleaved-caspase3, cleaved-PARP), DNA/mitochondrial-damaged (γ-H2AX/cytosolic-cytochrome C), microglia/astrocyte activation (ox42/GFAP), and MAPKs [phosphorylated (p)-p38, p-JNK, p-ERK] biomarkers in dorsal root ganglia neurons (DRGs) and in spinal dorsal horn were exhibited an opposite pattern of TPWL among the five groups (all p < 0.0001). Additionally, protein expressions of Nav.1.3, Nav.1.8 and Nav.1.9 in sciatic nerve exhibited an identical pattern to inflammation among the five groups (all p < 0.0001). The numbers of cellular expressions of MAPKs (p-ERK1/2+/peripherin + cells, p-ERK1/2+/NF200 + cells and p-JNK+/peripherin + cells, p-JNK+/NF200 + cells) and voltage-gated sodium channels (Nav.1.8+/peripherin + cells, Nav.1.8+/NF200 + cells, Nav.1.9+/peripherin + cells, Nav.1.9+/NF200 + cells) in small and large DRGs displayed an identical pattern to inflammation among the five groups (all p < 0.0001). In conclusion, the synergistic effect of combined ECSW-Mel therapy is superior to either one alone for long-term improvement of mononeuropathic pain-induced by CCI in rats.

Compounds targeting the sigma 2 receptor, which we recently cloned and showed to be identical with transmembrane protein 97 (σ2R/TMEM97), are broadly applicable therapeutic agents currently in clinical trials for imaging in breast cancer and for treatment of Alzheimer's disease and schizophrenia. These promising applications coupled with our previous observation that the σ2R/TMEM97 modulator SAS-0132 has neuroprotective attributes and improves cognition in wild-type mice suggests that modulating σ2R/TMEM97 may also have therapeutic benefits in other neurodegenerative conditions such as traumatic brain injury (TBI). Herein, we report that DKR-1677, a novel derivative of SAS-0132 with increased affinity and selectivity for σ2R/Tmem97 ( K i = 5.1 nM), is neuroprotective after blast-induced and controlled cortical impact (CCI) TBI in mice. Specifically, we discovered that treatment with DKR-1677 decreases axonal degeneration after blast-induced TBI and enhances survival of cortical neurons and oligodendrocytes after CCI injury. Furthermore, treatment with DKR-1677 preserves cognition in the Morris water maze after blast TBI. Our results support an increasingly broad role for σ2R/Tmem97 modulation in neuroprotection and suggest a new approach for treating patients suffering from TBI.

We tested the hypothesis that extracorporeal-shock-wave (ECSW)-assisted adipose-derived stromal vascular fraction (SVF) therapy was better than either one for restoring the blood flow in critical limb ischemia (CLI). Adult male-SD rats were categorized into group 1 (sham-operated-control), group 2 (CLI), group 3 [CLI + ECSW (280 impulses/0.10 mJ/mm 2 ) applied to left inguinal area at 3 h after CLI], group 4 [CLI + SVF (1.2 × 10 6 ) implanted into CLI area at 3 h after CLI], group 5 (CLI + ECSW-SVF). In vitro studies showed that ECSW significantly enhanced angiogenesis in human umbilical-vein endothelial cells and carotid-artery ring, and SVF significantly suppressed inflammation (TNF-α/NF-Κb/IL-1ß/MMP-9) in smooth-muscle cells treated by LPS (all p < .001). By day 14 after CLI, the ratio of ischemic/normal blood flow (INBF) was highest in group 1, lowest in group 2, significantly higher in group 5 than in groups 3 and 4, but no difference was shown between the latter two groups (all p < .001). The fibrotic area in CLI region exhibited an opposite pattern of INBF ratio (all p < .0001). Protein (CD31/vWF/eNOS) and cellular (CD31/vWF) expressions and number of small vessels in CLI area exhibited an identical pattern, whilst protein expressions of apoptotic (caspase3/PARP/mitochondrial-Bax) fibrotic/DNA-damaged (Samd3/TFG-ß/γ-H2AX) biomarkers exhibited an opposite pattern to INBF among five groups (all p < .0001). The numbers of angiogenetic cells in CLI region (SDF-1α/VEGF/CXCR4) and endothelial-progenitor cells (C-kit/CD31+//Sca-1/CD31+//CD34/KDR+/VE-cadherin/CD34+) in circulation significantly and progressively increased from groups 2 to 5 (all p < .0001). In conclusion, ECSW-SVF therapy effectively enhanced angiogenesis and restoration of blood flow in CLI area., (Copyright © 2018. Published by Elsevier Inc.)