ResearchPad - articles https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Improved reperfusion following alternative surgical approach for experimental stroke in mice]]> https://www.researchpad.co/article/elastic_article_13798 Background: Following ischemic stroke, recanalisation and restoration of blood flow to the affected area of the brain is critical and directly correlates with patient recovery.  In vivo models of ischemic stroke show high variability in outcomes, which may be due to variability in reperfusion.  We previously reported that a surgical refinement in the middle cerebral artery occlusion (MCAO) model of stroke, via repair of the common carotid artery (CCA), removes the reliance on the Circle of Willis for reperfusion and reduced infarct variability.  Here we further assess this refined surgical approach on reperfusion characteristics following transient MCAO in mice.

Methods: Mice underwent 60 min of MCAO, followed by either CCA repair or ligation at reperfusion.  All mice underwent laser speckle contrast imaging at baseline, 24 h and 48 h post-MCAO.

Results: CCA ligation reduced cerebral perfusion in the ipsilateral hemisphere compared to baseline (102.3 ± 4.57%) at 24 h (85.13 ± 16.09%; P < 0.01) and 48 h (75.04 ± 12.954%; P < 0.001) post-MCAO. Repair of the CCA returned perfusion to baseline (94.152 ± 2.44%) levels and perfusion was significantly improved compared to CCA ligation at both 24 h (102.83 ± 8.41%; P < 0.05) and 48 h (102.13 ± 9.34%; P < 0.001) post-MCAO.

Conclusions: Our findings show CCA repair, an alternative surgical approach for MCAO, results in improved ischemic hemisphere perfusion during the acute phase.

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<![CDATA[The Neural Origin of Nociceptive-Induced Gamma-Band Oscillations]]> https://www.researchpad.co/article/elastic_article_13787 Gamma-band oscillations (GBOs) elicited by transient nociceptive stimuli are one of the most promising biomarkers of pain across species. Still, whether these GBOs reflect stimulus encoding in the primary somatosensory cortex (S1) or nocifensive behavior in the primary motor cortex (M1) is debated. Here we recorded neural activity simultaneously from the brain surface as well as at different depths of the bilateral S1/M1 in freely-moving male rats receiving nociceptive stimulation. GBOs measured from superficial layers of S1 contralateral to the stimulated paw not only had the largest magnitude, but also showed the strongest temporal and phase coupling with epidural GBOs. Also, spiking of superficial S1 interneurons had the strongest phase coherence with epidural GBOs. These results provide the first direct demonstration that scalp GBOs, one of the most promising pain biomarkers, reflect neural activity strongly coupled with the fast spiking of interneurons in the superficial layers of the S1 contralateral to the stimulated side.

SIGNIFICANCE STATEMENT Nociceptive-induced gamma-band oscillations (GBOs) measured at population level are one of the most promising biomarkers of pain perception. Our results provide the direct demonstration that these GBOs reflect neural activity coupled with the spike firing of interneurons in the superficial layers of the primary somatosensory cortex (S1) contralateral to the side of nociceptive stimulation. These results address the ongoing debate about whether nociceptive-induced GBOs recorded with scalp EEG or epidurally reflect stimulus encoding in the S1 or nocifensive behavior in the primary motor cortex (M1), and will therefore influence how experiments in pain neuroscience will be designed and interpreted.

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<![CDATA[EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks]]> https://www.researchpad.co/article/elastic_article_13744 Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long‐term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients.Approach and ResultsEXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0‐52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0‐37.0]). Elevated levels of hepatic δ‐aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ‐aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization.ConclusionsPatients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day‐to‐day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. ]]> <![CDATA[Assessing risk factors for SARS-CoV-2 infection in patients presenting with symptoms in Shanghai, China: a multicentre, observational cohort study]]> https://www.researchpad.co/article/elastic_article_13653 The outbreak of COVID-19 has led to international concern. We aimed to establish an effective screening strategy in Shanghai, China, to aid early identification of patients with COVID-19.MethodsWe did a multicentre, observational cohort study in fever clinics of 25 hospitals in 16 districts of Shanghai. All patients visiting the clinics within the study period were included. A strategy for COVID-19 screening was presented and then suspected cases were monitored and analysed until they were confirmed as cases or excluded. Logistic regression was used to determine the risk factors of COVID-19.FindingsWe enrolled patients visiting fever clinics from Jan 17 to Feb 16, 2020. Among 53 617 patients visiting fever clinics, 1004 (1·9%) were considered as suspected cases, with 188 (0·4% of all patients, 18·7% of suspected cases) eventually diagnosed as confirmed cases. 154 patients with missing data were excluded from the analysis. Exposure history (odds ratio [OR] 4·16, 95% CI 2·74–6·33; p<0·0001), fatigue (OR 1·56, 1·01–2·41; p=0·043), white blood cell count less than 4 × 109 per L (OR 2·44, 1·28–4·64; p=0·0066), lymphocyte count less than 0·8 × 109 per L (OR 1·82, 1·00–3·31; p=0·049), ground glass opacity (OR 1·95, 1·32–2·89; p=0·0009), and having both lungs affected (OR 1·54, 1·04–2·28; p=0·032) were independent risk factors for confirmed COVID-19.InterpretationThe screening strategy was effective for confirming or excluding COVID-19 during the spread of this contagious disease. Relevant independent risk factors identified in this study might be helpful for early recognition of the disease.FundingNational Natural Science Foundation of China. ]]> <![CDATA[Palliative Care Utilization Among Patients With COVID-19 in an Underserved Population: A Single-Center Retrospective Study]]> https://www.researchpad.co/article/elastic_article_13615 As health-care institutions mobilize resources to address the coronavirus disease 2019 (COVID-19) pandemic, palliative care may potentially be underutilized. It is important to assess the use of palliative care in response to the COVID-19 pandemic.MethodsThis is a retrospective single-center study of patients with COVID-19 diagnosed via reverse transcriptase-polymerase chain reaction assay admitted between March 1, 2020, and April 24, 2020. An analysis of the utilization of palliative care in accordance with patient comorbidities and other characteristics was performed while considering clinical outcomes. Chi-square test was used to determine associations between categorical variables while t-tests were used to compare continuous variables.ResultsThe overall mortality rate was 21.5% (n = 52), and in 48% (n = 25) of these patients, palliative care was not involved. Fifty-nine percent (n = 24) of those who had palliative consults eventually elected for comfort measures and transitioned to hospice care. Among those classified as having severe COVID-19, only 40% (n = 31) had palliative care involvement. Of these patients with severe COVID-19, 68% (n = 52) died. Patients who got palliative care consults were of older age, had higher rates of intubation, a need for vasopressors, and were dead.ConclusionThere was a low utilization rate of palliative care in patients with COVID-19. Conscious utilization of palliative care is needed at the time of COVID-19. ]]> <![CDATA[Development of a Palliative Care Toolkit for the COVID-19 Pandemic]]> https://www.researchpad.co/article/elastic_article_13585 The Coronavirus disease 2019 (COVID-19) pandemic has led to high numbers of critically ill and dying patients in need of expert management of dyspnea, delirium, and serious illness communication. The rapid spread of severe acute respiratory syndrome-Coronavirus-2 creates surges of infected patients requiring hospitalization and puts palliative care programs at risk of being overwhelmed by patients, families, and clinicians seeking help. In response to this unprecedented need for palliative care, our program sought to create a collection of palliative care resources for nonpalliative care clinicians. A workgroup of interdisciplinary palliative care clinicians developed the Palliative Care Toolkit, consisting of a detailed chapter in a COVID-19 online resource, a mobile and desktop Web application, one-page guides, pocket cards, and communication skills training videos. The suite of resources provides expert and evidence-based guidance on symptom management including dyspnea, pain, and delirium, as well as on serious illness communication, including conversations about goals of care, code status, and end of life. We also created a nurse resource hotline staffed by palliative care nurse practitioners and virtual office hours staffed by a palliative care attending physician. Since its development, the Toolkit has helped us disseminate best practices to nonpalliative care clinicians delivering primary palliative care, allowing our team to focus on the highest-need consults and increasing acceptance of palliative care across hospital settings.

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<![CDATA[Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans]]> https://www.researchpad.co/article/elastic_article_13544 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly across the USA, causing extensive morbidity and mortality, particularly in the African American community. Autopsy can considerably contribute to our understanding of many disease processes and could provide crucial information to guide management of patients with coronavirus disease 2019 (COVID-19). We report on the relevant cardiopulmonary findings in, to our knowledge, the first autopsy series of ten African American decedents, with the cause of death attributed to COVID-19.MethodsAutopsies were performed on ten African American decedents aged 44–78 years with cause of death attributed to COVID-19, reflective of the dominant demographic of deaths following COVID-19 diagnosis in New Orleans. Autopsies were done with consent of the decedents' next of kin. Pulmonary and cardiac features were examined, with relevant immunostains to characterise the inflammatory response, and RNA labelling and electron microscopy on representative sections.FindingsImportant findings include the presence of thrombosis and microangiopathy in the small vessels and capillaries of the lungs, with associated haemorrhage, that significantly contributed to death. Features of diffuse alveolar damage, including hyaline membranes, were present, even in patients who had not been ventilated. Cardiac findings included individual cell necrosis without lymphocytic myocarditis. There was no evidence of secondary pulmonary infection by microorganisms.InterpretationWe identify key pathological states, including thrombotic and microangiopathic pathology in the lungs, that contributed to death in patients with severe COVID-19 and decompensation in this demographic. Management of these patients should include treatment to target these pathological mechanisms.FundingNone. ]]> <![CDATA[Comprehensive analysis of long non-coding RNA using an associated competitive endogenous RNA network in Wilms tumor]]> https://www.researchpad.co/article/elastic_article_13238 Wilms tumor (WT) is the most common malignant renal neoplasm in children; however, the underlying molecular mechanisms are not well understood. According to the competing endogenous RNA (ceRNA) theory, long non-coding RNAs (lncRNAs) can regulate the expression of target genes by adsorbing microRNAs (miRNAs/miRs). However, the role of lncRNAs in WT has not been fully elucidated. The aim of the present study was to construct a ceRNA network to identify the potential lncRNAs involved in WT. The expression profiles of lncRNAs, miRNAs and mRNAs in 120 WT and six normal tissues were obtained from the Therapeutically Applicable Research to Generate Effective Treatments database. A total of 442 lncRNAs, 214 miRNAs and 4,912 mRNAs were identified as differentially expressed in WT and were enriched in 472 Gene Ontology terms (355 biological processes, 89 cellular components and 29 molecular functions) and 18 Kyoto Encyclopedia of Genes and Genomes pathways. A lncRNA-miRNA-mRNA ceRNA network of WT consisting of with 32 lncRNAs, 14 miRNAs and 158 mRNAs was constructed, based on the bioinformatics analysis of the miR target prediction database and the miRNAcode, miRTarBase and TargetScan databases. Subsequently, three lncRNAs, three miRNAs and 17 mRNAs, which had a significant effect on the overall survival rate of patients with WT, were identified based on the survival analysis. The three lncRNAs were also differentially expressed in the late and early stages of WT and were validated using the GSE66405 dataset obtained from the Gene Expression Omnibus database. In conclusion, the present study generated a specific lncRNA-related ceRNA network of WT, which may provide a novel perspective on the molecular mechanisms underlying the progression and prognosis of the disease.

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<![CDATA[Cyclovirobuxine D inhibits colorectal cancer tumorigenesis via the CTHRC1-AKT/ERK-Snail signaling pathway]]> https://www.researchpad.co/article/elastic_article_13166 Cyclovirobuxine D (CVB-D) is an alkaloid, which is mainly derived from Buxus microphylla. It has been reported that CVB-D has positive effects on breast cancer, gastric cancer and other malignant tumors. However, to the best of our knowledge, there are no reports regarding the effects of CVB-D on colorectal cancer (CRC). The purpose of the present study was to determine the anticancer effects of CVB-D and further elucidate its molecular mechanism(s). DLD-1 and LoVo cell lines were selected to evaluate the antitumor effect of CVB-D. Cytotoxicity, viability and proliferation were evaluated by the MTT and colony formation assays. Flow cytometry was used to detect the effects on apoptosis and the cell cycle in CVB-D-treated CRC cells. The migration and invasion abilities of CRC cells were examined by wound healing and Transwell assays. In addition, RNA sequencing, bioinformatics analysis and western blotting were performed to investigate the target of drug action and clarify the molecular mechanisms. A xenograft model was established using nude mice, and ultrasound was employed to assess the preclinical therapeutic effects of CVB-D in vivo. It was identified that CVB-D inhibited the proliferation, migration, stemness, angiogenesis and epithelial-mesenchymal transition of CRC cells, and induced apoptosis and S-phase arrest. In addition, CVB-D significantly inhibited the growth of xenografts. It is notable that CVB-D exerted anticancer effects in CRC cells partly by targeting collagen triple helix repeat containing 1 (CTHRC1), which may be upstream of the AKT and ERK pathways. CVB-D exerted anticancer effects through the CTHRC1-AKT/ERK-Snail signaling pathway. Targeted therapy combining CTHRC1 with CVB-D may offer a promising novel therapeutic approach for CRC treatment.

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<![CDATA[Effects of selected deubiquitinating enzyme inhibitors on the proliferation and motility of lung cancer and mesothelioma cell lines]]> https://www.researchpad.co/article/elastic_article_13165 The post-translational modification of proteins by ubiquitinating enzymes plays a central role in a number of cellular functions, such as cell proteolysis, DNA repair, and cell signaling and communication. Deubiquitinating enzymes (DUBs) disassemble ubiquitin chains and remove ubiquitin moieties from proteins. Targeting DUBs in cancer models has revealed an important role for these enzymes in tumorigenesis, and they therefore have emerged as attractive therapeutic targets. In the present study, the effects of three DUB inhibitors, PR-619, RA-9 and LDN-91946, on a non-small cell lung cancer cell line (A549) and a mesothelioma cell line (H2373) were investigated. PR-619 significantly inhibited cell adhesion and the proliferation of both cell lines. RA-9 exerted an inhibitory effect on the adhesion and proliferation of H2373 cells, whereas it had no effect on A549 cells. Notably, however, while PR-619 attenuated the proliferation of both cell lines, it exerted an opposite effect on cell motility; in the case of A549 cells, there was a significant increase in cell motility, while for the H2373 cells, there was a significant decrease. Furthermore, protein phosphorylation kinetic analyses revealed that the effects were cell line-specific. In H2373 cells, the phosphorylation of only one peptide corresponding to the P85A protein was significantly affected, and while LDN-91946 treatment increased phosphorylation, treatment with RA-9 or PR-619 decreased its phosphorylation compared to the DMSO control. By contrast, in the case of A549 cells, the phosphorylation of 21 peptides was significantly affected by the same compounds. In light of the potential for the negative side-effects of DUB inhibition, such as increased cancer cell motility, the data presented herein underscore the dire need for the development of specific DUB inhibitors and to elucidate the individual role of DUB family members in cancer biology before they can be specifically pharmacologically targeted.

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<![CDATA[miR-508-3p suppresses the development of ovarian carcinoma by targeting CCNA2 and MMP7]]> https://www.researchpad.co/article/elastic_article_13164 Ovarian cancer is the most lethal gynecological tumor, and the 5-year survival rate is only ~40%. The poor survival rate is due to cancer diagnosis at an advanced stage, when the tumor has metastasized. A better understanding of the molecular pathogenesis of tumor growth and metastasis is needed to improve patient prognosis. MicroRNAs (miRs) regulate carcinogenesis and development of cancers. However, the role of miR-508-3p in ovarian cancer remains largely unknown. Thus, the present study aimed to investigate the possible functions of miR-508-3p in the modulation of development of ovarian cancer. The results of the present study demonstrated that miR-508-3p mimics inhibited ovarian cancer cell proliferation, migration and invasion. Reporter gene assay results demonstrated that miR-508-3p suppressed cancer cell proliferation by directly targeting the 3′-untranslated region (UTR) of cyclin A2 (CCNA2) and suppressed migration and invasion by directly targeting the 3′-UTR of matrix metallo-proteinase 7 (MMP7). In addition, high CCNA2 and MMP7 expression levels were associated with low miR-508-3p expression in ovarian cancer tissues. Furthermore, miR-508-3p and CCNA2 were independent predictors for overall survival in patients with ovarian cancer. To the best of our knowledge, this is the first study to demonstrated that miR-508-3p suppressed ovarian cancer development by directly targeting CCNA2 and MMP7. The results of this study suggested the potential value of miR-508-3p and CCNA2 as prognostic indicators and therapeutics for ovarian cancer.

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<![CDATA[ADAM17-regulated CX3CL1 expression produced by bone marrow endothelial cells promotes spinal metastasis from hepatocellular carcinoma]]> https://www.researchpad.co/article/elastic_article_13163 Spinal metastasis occurs in 50-75% of bone metastases caused by hepatocellular carcinoma (HCC), and HCC-derived spinal metastasis can lead to a less favorable prognosis. Recently, several studies have demonstrated that C-X3-C motif chemokine ligand 1 (CX3CL1) is closely associated with cancer metastasis, and its secretion is modulated by a disintegrin and metalloproteinase 17 (ADAM17). Bone marrow endothelial cells (BMECs) are an essential component of bone marrow. However, little is known about the roles in and effects of BMECs on HCC spinal metastasis. The present study demonstrated that CX3CL1 and C-X-C motif chemokine receptor 3 (CXCR3) expression was upregulated in HCC spinal metastases, and that CX3CL1 promoted the migration and invasion of HCC cells to the spine. Western blot analysis revealed that the Src/protein tyrosine kinase 2 (PTK2) axis participated in CX3CL1-induced HCC cell invasion and migration. CX3CL1 also increased the expression of M2 macrophage markers in THP-1 monocytes. BMECs promoted the migration and invasion of Hep3B and MHCC97H cells by secreting soluble CX3CL1, whereas the neutralization of CX3CL1 inhibited this enhancement. CX3CL1 enhanced the activation of the phosphatidylinositol-4,5-bisphos-phate 3-kinase catalytic subunit alpha (PIK3CA)/AKT serine/threonine kinase 1 (AKT1) and Ras homolog family member A (RHOA)/Rho associated coiled-coil containing protein kinase 2 (ROCK2) signaling pathways through the Src/PTK2 signaling pathway. Furthermore, ADAM17 was activated by mitogen-activated protein kinase (MAPK) z14 in BMECs and significantly promoted the secretion of CX3CL1. HCC cells enhanced the recruitment and proliferation of BMECs. The overexpression of CX3CR1 facilitated the spinal metastasis of HCC in a mouse model in vivo. In addition, in vivo experiments revealed that BMECs promoted the growth of HCC in the spine. The present study demonstrated that CX3CL1 participates in HCC spinal metastasis, and that BMECs play an important role in the regulation of CX3CL1 in the spinal metastatic environment.

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<![CDATA[G6PD facilitates clear cell renal cell carcinoma invasion by enhancing MMP2 expression through ROS-MAPK axis pathway]]> https://www.researchpad.co/article/elastic_article_13162 Glucose-6-phosphate dehydrogenase (G6PD) is crucial rate-limiting enzyme of the pentose phosphate pathway (PPP). G6PD dysregulation has been reported in various types of human cancer, and the role of G6PD in cancer progression was demonstrated in numerous studies. A previous study from our laboratory described the prognostic significance of G6PD in clear cell renal cell carcinoma (ccRCC), and demonstrated its proliferative role through positive feedback regulation of the phosphorylated form of signal transducer and activator of transcription 3. However, the role of G6PD in ccRCC invasion remains unclear. In the present study, reverse transcription-quantitative (RT-q) PCR, western blotting, enzyme activity assay, transwell assay and immunohistochemistry analysis in cell model, xenograft mice model and human specimen studies were performed to evaluate the role of G6PD in ccRCC invasion. The results from the present study demonstrated that G6PD may promote ccRCC cell invasive ability by increasing matrix metalloproteinase 2 (MMP2) mRNA and protein expression both in vitro and in vivo. In addition, a positive correlation between G6PD and MMP2 expression was demonstrated by RT-qPCR and western blotting in twenty pairs of ccRCC tumor specimens and matched adjacent normal tissues. Furthermore, G6PD promoted reactive oxygen species (ROS) generation and activated the MAPK signaling pathway in ccRCC cells. In addition, ROS significantly promoted the MAPK signaling pathway activation, which in turn contributed to MMP2 overexpression in ccRCC cells. In conclusion, the present study demonstrated that G6PD may facilitate ccRCC cell invasive ability by enhancing MMP2 expression through ROS-MAPK axis pathway.

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<![CDATA[Immunological potential of tertiary lymphoid structures surrounding the primary tumor in gastric cancer]]> https://www.researchpad.co/article/elastic_article_13161 Tertiary lymphoid structures (TLSs), which consist of B cells, T cells, follicular dendritic cells and high endothelial venules, have recently been found to be associated with effective antitumor immune responses in patients with cancer. Tumor-infiltrating T cells and B cells have each been demonstrated to be associated with survival in patients with cancer. We hypothesized that TLSs, an assembly of immune cells, may be important for the initiation and/or maintenance of T cell and B cell responses against tumors. The aim of the present study was to examine the cellular mechanism of B cells in TLSs within gastric cancer and to understand the antitumor immune response of TLSs. Each B cell subset in a tumor was examined using flow cytometry to evaluate B cell differentiation and the functional status of B cells. In addition, B cell clonality was investigated by analyzing the B cell antigen receptor gene using PCR, and the function and formation/maintenance of TLSs were evaluated using reverse transcription-quantitative PCR. Tumor-infiltrating B cells were more differentiated compared with that in distant non-tumor tissues and tumor-draining lymph nodes. The PCR results revealed specific BCR gene expression in tumor-infiltrating B cells. The expression of co-stimulatory factors, CD80 and CD86, was observed, in addition to the constantly expressed major histocompatibility complex molecules (HLA-ABC and HLA-DR). CD70 was expressed in addition to CD27 in both CD20+ B cells and CD8+ T cells, indicating that these factors are activated together through their interaction. The mRNA expression levels of CCL21, CXCL13, PD-L1, perforin and granzyme B in TLSs was significantly higher compared with that in non-TLSs. The majority of tumor-infiltrating B cells in gastric cancer exist in the form of TLSs around the tumor and have been antigen-sensitized and differentiated, and proliferated in TLSs but not in the lymph nodes. In addition, B cells in TLSs might primarily function as antigen-presenting cells and be associated with the induction of cytotoxic T cells.

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<![CDATA[Gli2 mediates the development of castration-resistant prostate cancer]]> https://www.researchpad.co/article/elastic_article_13160 Glioma-associated oncogene family zinc finger 2 (Gli2), a key component of the hedgehog signaling pathway, has been previously demonstrated to promote the malignant properties of prostate cancer in vitro. However, the role of Gli2 in the development of castration-resistant prostate cancer (CRPC) has yet to be fully elucidated. In the present study, Gli2 expression was knocked down in androgen-responsive prostate cancer cells using an inducible Gli2 short hairpin RNA. Suppression of Gli2 expression resulted in significant reduction of cell viability, increased the proportion of cells in the G0/G1 phases of the cell cycle and reduced the expression of genes associated with cell cycle progression. Gli2 knockdown sensitized both androgen-dependent and -independent prostate cancer cells to the antiandrogen drug Casodex and prevented the outgrowth of LNCaP prostate cancer cells. In addition, Gli2 knockdown significantly suppressed the development of CRPC in a LNCaP xenograft mouse model, which was reversed by the re-expression of Gli2. In conclusion, to the best of our knowledge, the present study was the first occasion in which the essential role of Gli2 in the development of CRPC was demonstrated, providing a potential therapeutic target for the intervention of CRPC.

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<![CDATA[Artificial intelligence radiogenomics for advancing precision and effectiveness in oncologic care (Review)]]> https://www.researchpad.co/article/elastic_article_13159 The new era of artificial intelligence (AI) has introduced revolutionary data-driven analysis paradigms that have led to significant advancements in information processing techniques in the context of clinical decision-support systems. These advances have created unprecedented momentum in computational medical imaging applications and have given rise to new precision medicine research areas. Radiogenomics is a novel research field focusing on establishing associations between radiological features and genomic or molecular expression in order to shed light on the underlying disease mechanisms and enhance diagnostic procedures towards personalized medicine. The aim of the current review was to elucidate recent advances in radiogenomics research, focusing on deep learning with emphasis on radiology and oncology applications. The main deep learning radiogenomics architectures, together with the clinical questions addressed, and the achieved genetic or molecular correlations are presented, while a performance comparison of the proposed methodologies is conducted. Finally, current limitations, potentially understudied topics and future research directions are discussed.

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<![CDATA[High expression of immune checkpoints is associated with the TIL load, mutation rate and patient survival in colorectal cancer]]> https://www.researchpad.co/article/elastic_article_13158 Adoptive cell therapy with the use of tumor-infiltrating lymphocytes (TILs) is a very promising immunotherapeutic approach for the treatment of patients with colorectal cancer (CRC). However, within the tumor microenvironment, co-inhibitory immune checkpoints can inactivate TILs. The aim of the present study was to examine the association between the TIL load, the mutation rate and the clinical outcome in the immune landscape of patients with CRC. RNA-seq and whole exome seq data of 453 colon adenocarcinomas (COAD) and rectal adenocarcinomas (READ), along with the TIL load and clinicopathological information of each patient, were extracted from the TCGA GDC Data Portal and analyzed computationally. The expression of immune checkpoint molecules was compared between colon cancer and normal tissue. A total of 9 immune-related gene signatures were investigated in CRC. Spearman's correlation analysis was performed to examine the correlation between the TIL load with the expression of each immune checkpoint molecule. Indoleamine 2,3-dioxygenase 1 (IDO1) was found to be significantly overexpressed in CRC, whereas V-domain Ig suppressor of T cell activation (VISTA) and lymphocyte activating 3 (LAG3) were markedly downregulated. A high expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), IDO1, programmed cell death 1 (PD-1) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT), tended to be associated with a better overall survival of the patients. In COAD, the TIL load positively correlated with the expression of adenosine A2A receptor (ADORA2A), CTLA-4, hepatitis A virus cellular receptor 2 (HAVCR2), lymphocyte activating 3 (LAG3), programmed death-ligand PD-L1, PD-L2, TIGIT and VISTA, whereas in READ, such positive correlations were noted only between the TIL load and LAG3 or PD-L2. The 'central memory T-cell' and 'exhausted T-cell' gene signatures were significantly lower among the READ tumors. The expression of PD-1, PD-L1, PD-L2, CTLA-4 and IDO1 was significantly higher among COAD patients with a high mutation rate (>34 mutations/Mb) compared to those with a lower rate. Somatic mutations in PD-1, PD-L1, CTLA-4 and other checkpoint molecules did not seem to affect their expression levels. On the whole, the data of the present study highlight the association of immune checkpoint molecules with the TIL load, patient survival and a high mutation rate in CRC. The data corroborate that patients with colon cancer with higher PD1, PD-L1/2, CTLA-4 and IDO1 expression, and a high mutation rate, are the ones who will benefit more from the respective immune checkpoint inhibition therapies.

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<![CDATA[Knockdown of GSG2 inhibits prostate cancer progression <i>in vitro</i> and <i>in vivo</i>]]> https://www.researchpad.co/article/elastic_article_13157 Prostate cancer (PCa) is the second leading cause of cancer related death among men worldwide. The present study aimed to investigate the role of germ cell-specific gene 2 protein (GSG2), also termed histone H3 phosphorylated by GSG2 at threonine 3, in the development and progression of PCa. GSG2 expression levels in PCa tissues and para carcinoma tissues was detected by immunohistochemistry. The GSG2 knockdown cell model was constructed by lentivirus infec tion, and the knockdown efficiency was verified by qPCR and WB. In addition, the effects of shGSG2 on cell proliferation, colony formation and apoptosis were evaluated by Celigo cell counting assay, Giemsa staining and flow cytometry, respec tively. Tumor development in nude mice was also detected. GSG2 expression was upregulated in PCa tissues and human PCa cell lines PC 3 and DU 145. High expression of GSG2 in tumor samples was associated with progressed tumors. GSG2 knockdown suppressed cell proliferation and colony forma tion, but promoted apoptosis, which was also verified in vivo. The results of the present study revealed that GSG2 upregula tion was associated with PCa progression; GSG2 knockdown inhibited cell proliferation and colony formation and induced apoptosis, and may therefore serve as a potential therapeutic target for PCa therapy.

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<![CDATA[Identification of the <i>cis</i>-molecular neighbours of the immune checkpoint protein B7-H4 in the breast cancer cell-line SK-BR-3 by proteomic proximity labelling]]> https://www.researchpad.co/article/elastic_article_13155 The immune checkpoint protein B7-H4 plays an important role in the positive as well as the negative regulation of immune T-cell responses. When expressed on cancer cells, B7-H4 inhibits T-cell activity, and numerous types of cancer cells use upregulation of B7-H4 as a survival strategy. Thus, B7-H4 is a potential target for anticancer drug therapy. Unfortunately, the cell biology of this molecule has yet to be fully elucidated. Even basic properties, such as the nature of B7-H4 interactors, are controversial. In particular, the cis-inter-actors of B7-H4 on cancer cell plasma membranes have not been investigated to date. The present study used a proteomic proximity-labelling assay to investigate the molecular neighbours of B7-H4 on the surface of the human breast cancer cells SK-BR-3. By comparison to a comprehensive proteome analysis of SK-BR-3 cells, the proximity method detected a relatively small number of low abundance plasma membrane proteins highly enriched for proteins known to modulate cell adhesion and immune recognition. It may be inferred that these molecules contribute to the immunosuppressive behaviour that is characteristic of B7-H4 on cancer cells.

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<![CDATA[HSulf-1 and palbociclib exert synergistic antitumor effects on RB-positive triple-negative breast cancer]]> https://www.researchpad.co/article/elastic_article_13153 Human sulfatase-1 (HSulf-1) is emerging as a novel prognostic biomarker in breast cancer. Previous studies demonstrated HSulf-1 to function as a negative regulator of cyclin D1 in breast cancer. Accumulating preclinical evidence is supporting the efficacy of cyclin-dependent kinase (CDK) 4/6 inhibitors against the luminal androgen receptor sub-type of triple-negative breast cancer (TNBC). It was therefore hypothesized that HSulf-1 may cooperate with CDK4/6 inhibitors to control cell cycle progression in breast cancer cells. HSulf-1 expression was found to be downregulated in TNBC tissues and cell lines compared with that in healthy tissues and non-breast cancer cell lines, respectively. High levels of HSulf-1 expression was also found to be associated with increased progression-free survival and overall survival in patients with TNBC. Functionally, it was demonstrated that HSulf-1 served as tumor suppressor in TNBC by inducing cell cycle arrest and apoptosis whilst inhibiting proliferation, epithelial-mesenchymal transition, migration and invasion. Subsequent overexpression of HSulf-1 coupled with treatment with the CDK4/6 inhibitor palbociclib exhibited a synergistic antitumor effect on retinoblastoma (RB)-positive TNBC. Further studies revealed the mechanism underlying this cooperative antiproliferative effect involved to be due to the prohibitive effects of HSulf-1 on the palbociclib-induced accumulation of cyclin D1 through AKT/STAT3 and ERK1/2/STAT3 signaling. Taken together, findings from the present study not only suggest that HSulf-1 may be a potential therapeutic target for TNBC, but also indicate that combinatorial treatment could be an alternative therapeutic option for RB-positive TNBC, which may open novel perspectives.

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