Prognostic Value of Immune Cells Subsets Within the Tumor Microenvironment in Patients With Rectal Adenocarcinoma.

BACKGROUND/AIM: One-third of newly diagnosed colorectal cancer cases are rectal cancers. Multimodal treatment regimens including surgery, radiotherapy, and chemotherapy improve local control and survival outcome and decrease tumor relapse for patients with rectal adenocarcinoma (READ). However, stratification of patients to predict their responses is urgently needed to improve therapeutic responses. PATIENTS AND METHODS: Immunostainings of CD3+, CD8+, and CD45RO+ immune cell subsets within the tumor microenvironment were evaluated using immunohistochemistry in two hundred seventy-nine READ patients. RESULTS: In this study, we found that examination of the adaptive immune response by quantifying CD3+, CD8+, and CD45RO+ immune cell subsets, provides improved and independent prognostic value for patients with READ. Regardless of conventional clinical and pathologic parameters, the densities of T cell subsets were strongly related to a better prognosis in patients with READ. High density of intratumoral immune cells is associated with absence of nodal metastasis, lymphovascular invasion, and perineural invasion. Moreover, high tumor-infiltrating lymphocyte (TIL) subsets were associated with favorable survival outcome in patients with READ, especially high-risk patients with advanced READ. CONCLUSION: Immune cell subsets including CD3, CD8, and CD45RO within the tumor microenvironment were independent prognostic factors for patients with READ.

Dual Inhibition of B7-H3 and EGFR Overcomes Acquired Chemoresistance in Colon Adenocarcinoma.

Despite advances in therapeutic strategies for colorectal cancer (CRC), CRC has a high disease incidence with significant morbidity and mortality worldwide. Notably, immunotherapy has shown limited efficacy in treating metastatic CRC, underscoring the need for alternative immunotherapeutic targets for the management of metastatic colorectal cancer (mCRC). In the present study, we evaluated the levels of the immune checkpoint proteins PD-L1, PD-L2 and B7-H3 in a large cohort retrospective study. We found that tumor B7-H3 (52.7%) was highly expressed in primary tumors compared to that in PD-L1 (33.6%) or PD-L2 (34.0%). Elevated B7-H3 expression was associated with advanced stage and the risk of distant metastasis and correlated with poor disease-free survival (DFS), suggesting that tumor B7-H3 was an independent prognostic factor associated with worse DFS in colon adenocarcinoma patients (COAD), especially high-risk COAD patients who received adjuvant chemotherapy. Furthermore, we found that B7-H3 significantly promoted cell proliferation and tumor growth in CRC. B7-H3 may stabilize EGFR to activate its downstream pathway for cancer cell proliferation and resistance to oxaliplatin (OXP). Dual targeting of B7-H3 and EGFR markedly rescued the susceptibility to chemotherapy in colorectal cancer cells in vitro and in vivo. Overall, these results showed that B7-H3 exhibited a high prevalence in COAD patients and was significantly associated with worse prognosis in COAD patients. Dual targeting of B7-H3 and EGFR signaling might be a potential therapeutic strategy for high-risk COAD patients.

Dysfunctional TLR1 reduces the therapeutic efficacy of chemotherapy by attenuating HMGB1-mediated antitumor immunity in locally advanced colorectal cancer.

Regional lymph node metastasis is an important predictor for survival outcome and an indicator for postoperative adjuvant chemotherapy in patients with colorectal cancer. Even with advances in adjuvant chemotherapeutic regimens, 5-year distant metastasis and survival rates are still unsatisfactory. Here, we evaluate the clinical significance of polymorphisms in receptors for HMGB1, which is the hallmark of chemotherapy-induced immunogenic cell death, in patients with stage II-III colon carcinoma (COAD). We found that high cytosolic HMGB1 is elicited in stage III COAD patients who received adjuvant chemotherapy. Patients with the TLR1-N248S polymorphism (rs4833095), which causes loss-of-function in HMGB1-mediated TLR1-TLR2 signaling, may influence the therapeutic efficacy of adjuvant chemotherapy, leading to a high risk of distant metastasis within 5 years [HR = 1.694, 95% CI = 1.063-2.698, p = 0.027], suggesting that TLR1-N248S is an independent prognostic factor for locally advanced colon carcinoma patients. We found that defective TLR1 impaired TLR1/2 signaling during dendritic cell (DC) maturation for the antitumor immune response under immunogenic chemotherapy oxaliplatin (OXP) treatment. Defective TLR1 on DCs impaired their maturation ability by HMGB1 and reduced the secretion of IFNγ from T cells to eradicate tumor cells in vitro. Moreover, systemic inhibition of TLR1/2 dramatically reduced the tumor-infiltrating immune cells by OXP treatment, leading to poor therapeutic response to OXP. In contrast, administration of a TLR1/2 agonist synergistically increased the benefit of OXP treatment and triggered a high density of tumor-infiltrating immune cells. We also observed that fewer tumor-infiltrating cytotoxic T lymphocytes were located within the tumor microenvironment in patients bearing the TLR1-N248S polymorphism. Overall, our results suggest that dysfunctional TLR1 may reduce the therapeutic response to adjuvant chemotherapy by impairing HMGB1-mediated DC maturation and attenuating the antitumor immune response in locally advanced colon carcinoma patients.

Pelvic Neoadjuvant Radiotherapy for Stage M1a Rectal Adenocarcinoma Patients Treated With Systemic Therapy Followed by Proctectomy and Metastasectomy: A Nationwide Retrospective Cohort Study.

BACKGROUND/AIM: The effect of pelvic neoadjuvant radiotherapy (nRT) for stage M1a rectal adenocarcinoma patients treated with systemic therapy followed by proctectomy and metastasectomy was scarcely investigated in the literatures. PATIENTS AND METHODS: The eligible rectal cancer patients diagnosed between 2011-2019 were identified via the Taiwan Cancer Registry. In the primary analysis, we used propensity score weighting to balance observable potential confounders and compared the hazard ratio (HR) of death for the nRT group vs. without RT group. We also compared the incidence of rectal cancer mortality (IRCM) and performed various supplementary analyses. RESULTS: Our primary analyses included 145 patients. nRT was associated with improved OS (HR=0.51, p=0.01). The numerical trends remained similar for IRCM and in supplementary analyses. CONCLUSION: nRT was associated with improved OS in our study population.

LongPhase: an ultra-fast chromosome-scale phasing algorithm for small and large variants.

MOTIVATION: Long-read phasing has been used for reconstructing diploid genomes, improving variant calling and resolving microbial strains in metagenomics. However, the phasing blocks of existing methods are broken by large Structural Variations (SVs), and the efficiency is unsatisfactory for population-scale phasing. RESULTS: This article presents a novel algorithm, LongPhase, which can simultaneously phase single nucleotide polymorphisms (SNPs) and SVs of a human genome in 10-20 min, 10× faster than the state-of-the-art WhatsHap, HapCUT2 and Margin. In particular, co-phasing SNPs and SVs produces much larger haplotype blocks (N50 = 25 Mbp) than those of existing methods (N50 = 10-15 Mbp). We show that LongPhase combined with Nanopore ultra-long reads is a cost-effective and highly contiguous solution, which can produce between one and 26 blocks per chromosome arm without the need for additional trios, chromosome-conformation and strand-seq data. AVAILABILITYAND IMPLEMENTATION: LongPhase is freely available at https://github.com/twolinin/LongPhase/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Effects of task prioritization on a postural-motor task in early-stage Parkinson's disease: EEG connectivity and clinical implication.

Appropriate attentional resource allocation could minimize exaggerated dual-task interference due to basal ganglia dysfunction in Parkinson's disease (PD). Here, we assessed the electroencephalography (EEG) functional connectivity to investigate how task prioritization affected posture-motor dual-tasks in PD. Sixteen early-stage PD patients and 16 healthy controls maintained balance in narrow stance alone (single-posture task) or while separating two interlocking rings (postural dual-task). The participants applied a posture-focus or supraposture-focus strategy in the postural dual-task. Postural sway dynamics, ring-touching time, and scalp EEG were analyzed. Both groups exhibited smaller postural sway size, postural determinism, and ring-touching time with the supraposture-focus versus posture-focus strategy. PD patients exhibited higher mean inter-regional connectivity strength than control subjects in both single and dual-task postural conditions. To cope with dual-task interference, PD patients increased inter-regional connectivity (especially with the posture-focus strategy), while control subjects reduced inter-regional connectivity. The difference in mean connectivity strength between the dual-task condition with supraposture-focus and single-posture condition was negatively correlated to the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III total scores and hand-related sub-scores. Our findings suggest differential task prioritization effects on dual-task performance and cortical reorganization between early-stage PD and healthy individuals. Early-stage PD patients are advocated to use a supraposture-focus strategy during a postural dual-task. In addition, with a supraposture-focus strategy, PD patients with mild motor severity could increase compensatory inter-regional connectivity to cope with dual-task interference.

The Effects of Task Prioritization on Dual-Tasking Postural Control in Patients With Parkinson Disease Who Have Different Postural Impairments.

OBJECTIVE: To investigate the effect of task prioritization on dual-task control in Parkinson disease (PD) associated with different postural impairments. DESIGN: Cross-sectional study. Participants were instructed to keep 2 interlocking rings apart and maintain balance in a tandem stance. Attention was focused on either stance stability (posture-focus strategy) or the interlocking rings (supraposture-focus strategy). SETTING: University research laboratory. PARTICIPANTS: Fifteen patients with PD and less postural impairment and 15 patients with PD and more postural impairment (N=30). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Postural sway, postural determinism (%DET), ankle co-contraction, and ring-touching time. RESULTS: In the less-impairment group, the supraposture-focus strategy provided smaller postural sway and postural %DET compared with the posture-focus strategy. In the more-impairment group, task prioritization showed lower effect on both postural sway and postural %DET. The supraposture-focus strategy led to less ankle co-contraction than the posture-focus strategy in the more-impairment group, but task prioritization did not affect ankle co-contraction in the less-impairment group. In both groups, the supraposture-focus strategy led to less ring-touching time than the posture-focus strategy. CONCLUSIONS: The supraposture-focus strategy provided better dual-task control than the posture-focus strategy in both PD groups. In the less-impairment group, the supraposture-focus strategy enhanced postural automaticity and postural stability. In the more-impairment group, the supraposture-focus strategy reduced ankle stiffness, owing to reduced muscle co-contraction.

Phenylphenol-Derived Carbon and Antimony-Coated Carbon Nanotubes as the Electroactive Materials of Lithium-Ion Hybrid Capacitors.

Energy storage of the lithium-ion hybrid capacitor can be upgraded through adjusting the mismatched rate qualities between the positive and negative electrodes because the positive electrode of the electrical double layer (EDL) stores and releases electricity in a smaller quantity, yet much faster than the negative battery electrode. To increase the EDL capacity, nitrogen-doped carbon (KPN900) with a hollow-onion structure is prepared with phenylphenol, achieving a surface area above 3000 m2 g-1. The capacitance of KPN900 displays a diffusive component of 57 F g-1, exceeding its capacitive counterpart at 10 mV s-1. Moreover, its total capacitance reaches 168 F g-1 at 1 mV s-1 with a diffusive component of 112 F g-1. On the other hand, the power of the negative electrode is improved through electrodeposition of metallic antimony on carbon nanotubes, Sb/CNTs, evidenced by the capacity of ∼250 mA h g-1 at 1.0 A g-1. Hence, the capacitor, with a 2:1 mass ratio of KPN900 to Sb/CNT, exhibits an effective trade-off between energy and power, distinct from the one-sided dependence on the carbon electrode of most hybrid capacitors. This capacitor stores 97 W h kg-1 at a power level 0.12 kW kg-1 and 17.4 W h kg-1 at power 7.90 kW kg-1.

ERK1/2 mediates the lipopolysaccharide-induced upregulation of FGF-2, uPA, MMP-2, MMP-9 and cellular migration in cardiac fibroblasts.

Myocardial fibrosis is a critical event during septic shock. Upregulation in the fibrosis signaling cascade proteins such as fibroblast growth factor (FGF), urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA) and activation of matrix metalloproteinases (MMPs) are widely associated with the development of myocardial infarction, dilated cardiomyopathy, cardiac fibrosis and heart failure. However, evidences suggest that the common upstream mediators of fibrosis cascade play little role in cardiac fibrosis induced by LPS; further, it is unknown if LPS directly triggers the expressions and/or activity of FGF-2, uPA, tPA, MMP-2 and MMP-9 in cardiac fibroblasts. In the present study, we treated primary cultures of cardiac fibroblasts with LPS to explore whether LPS upregulates FGF-2, uPA, tPA, MMP-2, MMP-9 and enhance cellular migration. Further the precise molecular and cellular mechanisms behind these LPS induced responses were identified. Inhibition assays on MAPKs using U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor), CsA (calcineurin inhibitor) and QNZ (NFκB inhibitor) show that LPS-induced upregulation of FGF-2, uPA, MMP-2 and MMP-9 in cardiac fibroblasts was mediated through ERK1/2 signaling. Collectively, our results provide a link between LPS-induced cardiac dysfunction and ERK1/2 signaling pathway and thereby implies ERK1/2 as a possible target to regulate LPS induced upregulation of FGF-2, uPA, MMP-2, MMP-9 and cellular migration in cardiac fibroblasts.

Vertebral Compression Fracture Related to Pancreatic Cancer With Osteoblastic Metastasis: A Case Report and Literature Review.

Compression fracture of the vertebral body is common in the older patients. The possible etiology like osteoporosis or cancer metastasis should be included as a possibility in the differential diagnosis for severe back pain, to prevent delays in diagnosis and treatment. More severe fractures can cause significant pain, leading to inability to perform activities of daily living, and life-threatening in the older patient.We report a rare case of a 61-year-old man suffering from severe lower back pain and intermittent abdominal fullness. He came to our clinic, where muscle power was normal, but could not stand up or change posture because of severe back pain. Plain film and magnetic resonance imaging of lumbar spine both revealed osteoblastic lesion at L2 spine. Abdomen computed tomography showed a mass at the pancreatic body. The pancreatic cancer with osteoblastic metastasis was diagnosed. After receiving multimodality therapy such as percutaneous vertebroplasty and pain controlling, we provided effective palliation of symptoms, aggressive rehabilitation program, and better quality of life.Our case highlights the benefits of multidisciplinary cancer treatment for such patient, preventing the complications such as immobilization accompanied with adverse effects like musculoskeletal, respiratory, and cardiovascular systems. All clinicians should be informed of the clinical findings to provide patients with suitable therapies and surveys.

Ligand-independent androgen receptors promote ovarian teratocarcinoma cell growth by stimulating self-renewal of cancer stem/progenitor cells.

BACKGROUND: Ovarian teratocarcinoma (OVTC) arises from germ cells and contains a high percentage of cancer stem/progenitor cells (CSPCs), which promote cancer development through their ability to self-renew. Androgen and androgen receptor (androgen/AR) signaling has been reported to participate in cancer stemness in some types of cancer; however, this phenomenon has never been studied in OVTC. METHODS: Ovarian teratocarcinoma cell line PA1 was manipulated to overexpress or knockdown AR by lentiviral deliver system. After analyzing of AR expression in PA1 cells, cell growth assay was assessed at every given time point. In order to determine ligand effect on AR actions, luciferase assay was performed to evaluate endogenous and exogenous AR function in PA1 cells. CD133 stem cell marker antibody was used to identify CSPCs in PA1 cells, and AR expression level in enriched CSPCs was determined. To assess AR effects on CD133+ population progression, stem cell functional assays (side population, sphere formation assay, CD133 expression) were used to analyze role of AR in PA1 CSPCs. In tissue specimen, immunohistochemistry staining was used to carry out AR and CD133 staining in normal and tumor tissue. RESULTS: We examined androgen/AR signaling in OVTC PA1 cells, a CSPCs-rich cell line, and found that AR, but not androgen, promoted cell growth. We also examined the effects of AR on CSPCs characteristics and found that AR expression was more abundant in CD133+ cells, a well-defined ovarian cancer stem/progenitor marker, than in CD133- populations. Moreover, results of the sphere formation assay revealed that AR expression was required to maintain CSPCs populations. Interestingly, this AR-governed self-renewal capacity of CSPCs was only observed in CD133+ cells. In addition, we found that AR-mediated CSPCs enrichment was accompanied by down-regulation of p53 and p16. Finally, co-expression of AR and CD133 was more abundant in OVTC lesions than in normal ovarian tissue. CONCLUSION: The results of this study suggest that AR itself might play a ligand-independent role in the development of OVTC.

Non-genomic estrogen/estrogen receptor α promotes cellular malignancy of immature ovarian teratoma in vitro.

Malignant immature ovarian teratomas (IOTs) most often occur in women of reproductive age. It is unclear, however, what roles estrogenic signaling plays in the development of IOT. In this study, we examined whether estrogen receptors (ERα and ß) promote the cellular malignancy of IOT. Estradiol (E2), PPT (propylpyrazole), and DPN (diarylpropionitrile) (ERα- and ß-specific agonists, respectively), as well as ERα- or ERß-specific short hairpin (sh)RNA were applied to PA-1 cells, a well-characterized IOT cell line. Cellular tumorigenic characteristics, for example, cell migration/invasion, expression of the cancer stem/progenitor cell marker CD133, and evidence for epithelial-mesenchymal transition (EMT) were examined. In PA-1 cells that expressed ERα and ERß, we found that ERα promoted cell migration and invasion. We also found that E2/ERα signaling altered cell behavior through non-classical transactivation function. Our data show non-genomic E2/ERα activations of focal adhesion kinase-Ras homolog gene family member A (FAK-RhoA) and ERK governed cell mobility capacity. Moreover, E2/ERα signaling induces EMT and overexpression of CD133 through upregulation micro-RNA 21 (miR21; IOT stem/progenitor promoter), and ERK phosphorylations. Furthermore, E2/ERα signaling triggers a positive feedback regulatory loop within miR21 and ERK. At last, expression levels of ERα, CD133, and EMT markers in IOT tissue samples were examined by immunohistochemistry. We found that cytosolic ERα was co-expressed with CD133 and mesenchymal cell markers but not epithelial cell markers. In conclusion, estrogenic signals exert malignant transformation capacity of cancer cells, exclusively through non-genomic regulation in female germ cell tumors.