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Journal of Cell Communication and... Jun 2024Liver fibrosis is a persistent damage repair response triggered by various injury factors, which leads to an abnormal accumulation of extracellular matrix within liver...
Liver fibrosis is a persistent damage repair response triggered by various injury factors, which leads to an abnormal accumulation of extracellular matrix within liver tissue samples. The current clinical treatment of liver fibrosis is currently ineffective; therefore, elucidating the mechanism of liver fibrogenesis is of significant importance. Herein, the function and related mechanisms of lncRNA within hepatic fibrosis were investigated. expression was shown to be increased in mouse hepatic fibrotic tissue samples, and knockdown suppressed hepatic pathological injury and down-regulated the expression levels of fibrosis-associated proteins. Mechanistically, played a role in the early activation of mouse hepatic stellate cells (mHSCs) based on bioinformatics analysis, and was positively correlated with Igfbp3 expression. Further experimental results demonstrated that knockdown impeded mHSCs proliferation and activation and also downregulated the protein expression of Igfbp3. could interact with IGFBP3 and boost its protein stability, and overexpression of partially reversed the inhibition of mHSCsproliferation and activation by the knockdown of . In conclusion, LncRNA mediates liver fibrosis by targeting IGFBP3 and promoting its protein stability, thereby promoting mHSC proliferation and activation. has been identified as an underlying target for treating liver fibrosis.
PubMed: 38946724
DOI: 10.1002/ccs3.12033 -
Annals of Surgery Jul 2024To investigate the clinical relevance of common myeloid progenitor (CMP) cells in breast tumor microenvironment (TME).
Infiltration of Common Myeloid Progenitor (CMP) Cells is Associated With Less Aggressive Tumor Biology, Lower Risk of Brain Metastasis, Better Response to Immunotherapy and Higher Patient Survival in Breast Cancer.
OBJECTIVE
To investigate the clinical relevance of common myeloid progenitor (CMP) cells in breast tumor microenvironment (TME).
BACKGROUND
The role of rare cells in TME is less studied. In Silico transcriptomic analyses of real-world data enable us to detect and quantify rare cells, including CMP cells.
METHODS
Total of 5,176 breast cancer (BC) patients from SCAN-B, METABRIC, and 5 single-cell sequence cohorts were analyzed using xCell algorithm. High group was defined as more than two thirds of CMP score in each cohort.
RESULTS
CMP cells consist of 0.07-0.25% of bulk breast tumor cells, more in Estrogen Receptor-positive (ER+) compared with triple-negative (TN) subtype (0.1-0.75%, 0.18-0.33% of immune cells, respectively). CMP cells did not correlate with any of myeloid lineage nor stem cells in TME. CMP infiltration was higher in smaller tumors, with lower Nottingham grade, and in ER+/HER2- than in TNBC consistently in both SCAN-B and METABRIC cohorts. High CMP was significantly associated with lower risk of brain metastasis and with better survival, particularly in ER+/HER2- . High CMP enriched epithelial-to-mesenchymal transition and angiogenesis pathways, and less cell proliferation and DNA repair gene sets. High CMP ER+/HER2- was associated with less immune cell infiltration, and cytolytic activity (P<0.001). CMP infiltration correlated with neoadjuvant chemoimmunotherapy response for both ER+/HER2- and TNBC in the ISPY-2 cohort (AUC=0.69 and 0.74, respectively).
CONCLUSIONS
CMP in BC is inversely associated with cell-proliferation and brain metastasis, better response to immunotherapy and survival. This is the first to report the clinical relevance of CMP infiltration in BC.
PubMed: 38946549
DOI: 10.1097/SLA.0000000000006428 -
Emerging Microbes & Infections Jul 2024Rift Valley fever (RVF) is a mosquito-borne zoonotic disease caused by RVF virus (RVFV). RVFV infections of humans are usually asymptomatic or associated with mild...
Rift Valley fever (RVF) is a mosquito-borne zoonotic disease caused by RVF virus (RVFV). RVFV infections of humans are usually asymptomatic or associated with mild febrile illness, although more severe cases of haemorrhagic disease and encephalitis with high mortality also occur. Currently, there are no licensed human vaccines available. Safety and efficacy of a genetically engineered four-segmented RVFV variant (hRVFV-4s) as a potential live-attenuated human vaccine has been tested successfully in mice, ruminants, and marmosets though the correlates of protection of this vaccine are still largely unknown. In the present study we have assessed hRVFV-4s induced humoral and cellular immunity in a mouse model of RVFV infection. Our results confirm that a single dose of hRVFV-4s is highly efficient in protecting naïve mice from developing severe disease following intraperitoneal challenge with a highly virulent RVFV strain and data show that virus neutralizing (VN) serum antibody titers in a prime-boost regimen are significantly higher compared to the single dose. Subsequently, VN antibodies from prime-boost-vaccinated recipients were shown to be protective when transferred to naïve mice. In addition, hRVFV-4s vaccination induced a significant virus-specific T cell response as shown by IFN-γ ELISpot assay, though these T cells did not provide significant protection upon passive transfer to naïve recipient mice. Collectively, this study highlights hRVFV-4s-induced VN antibodies as a major correlate of protection against lethal RVFV infection.
PubMed: 38946528
DOI: 10.1080/22221751.2024.2373313 -
International Immunology Jul 2024Chronic inflammation is implicated in many types of diseases, including cardiovascular, neurodegenerative, metabolic, and immune disorders. The search for therapeutic...
Chronic inflammation is implicated in many types of diseases, including cardiovascular, neurodegenerative, metabolic, and immune disorders. The search for therapeutic targets to control chronic inflammation often involves narrowing down the various molecules associated with pathology that have been discovered by various omics analyses. Herein, a different approach to identify therapeutic targets against chronic inflammation is proposed and one such target is discussed as an example. In chronically inflamed tissues, a large number of cells receive diverse proinflammatory signals, the intracellular signals are intricately integrated, and complicated intercellular interactions are orchestrated. This review focuses on effectively blocking this chaotic inflammatory signaling network via the endolysosomal system, which acts as a cellular signaling hub. In endolysosomes, the inflammatory signals mediated by pathogen sensors, such as Toll-like receptors, and the signals from nutrient and metabolic pathways are integrally regulated. Disruption of endolysosome signaling results in a strong anti-inflammatory effect by disrupting various signaling pathways, including pathogen sensor-mediated signals, in multiple immune cells. The endolysosome-resident amino acid transporter, solute carrier family 15 member 4 (SLC15A4), which plays an important role in the regulation of endolysosome-mediated signals, is a promising therapeutic target for several inflammatory diseases, including autoimmune diseases. The mechanisms by which SLC15A4 regulates inflammatory responses may provide a proof of concept for the efficacy of therapeutic strategies targeting immune cell endolysosomes.
PubMed: 38946351
DOI: 10.1093/intimm/dxae041 -
Journal of Surgical Oncology Jul 2024Tumor-infiltrating lymphocytes (TILs) represent a host-tumor interaction, frequently signifying an augmented immunological response. Nonetheless, implications with...
BACKGROUND AND OBJECTIVES
Tumor-infiltrating lymphocytes (TILs) represent a host-tumor interaction, frequently signifying an augmented immunological response. Nonetheless, implications with survival outcomes in patients with colorectal carcinoma liver metastasis (CRLM) warrant rigorous validation. The objective was to demonstrate the association between TILs and survival in patients with CRLM.
METHOD
In a retrospective evaluation conducted in a single institution, we assessed all patients who underwent hepatectomy due to CRLM between 2014 and 2018. Comprehensive medical documentation reviews were executed. TILs were assessed by a liver pathologist, blinded to the clinical information, in all surgical slides.
RESULTS
This retrospective cohort included 112 patients. Median overall survival (OS) was 58 months and disease-free survival (DFS) was 12 months for the entire cohort. Comparison between groups showed a median OS of 81 months in the dense TILs group and 40 months in the weak/absent group (p = 0.001), and DFS was 14 months versus 9 months (p = 0.041). Multivariable analysis showed that TILs were an independent predictor of OS (HR 1.95; p = 0.031).
CONCLUSIONS
Dense TILs are a pivotal prognostic indicator, correlating with enhanced OS. Including TILs information in histopathological evaluations should refine the clinical decision-making process for this group of patients.
PubMed: 38946284
DOI: 10.1002/jso.27759 -
Journal of Cellular Physiology Jun 2024The small Rho GTP-binding proteins are important cell morphology, function, and apoptosis regulators. Unlike other Rho proteins, RhoB can be subjected to either...
The small Rho GTP-binding proteins are important cell morphology, function, and apoptosis regulators. Unlike other Rho proteins, RhoB can be subjected to either geranylgeranylation (RhoB-GG) or farnesylation (RhoB-F), making that the only target of the farnesyltransferase inhibitor (FTI). Fluorescence resonance energy transfer experiments revealed that RhoB is activated by hyperosmolarity. By contrast, hyposmolarity did not affect RhoB activity. Interestingly, treatment with farnesyltransferase inhibitor-277 (FTI-277) decreased the cell size. To evaluate whether RhoB plays a role in volume reduction, renal collecting duct MCD4 cells and Human Kidney, HK-2 were transiently transfected with RhoB-wildtype-Enhance Green Fluorescence Protein (RhoB-wt-EGFP) and RhoB-CLLL-EGFP which cannot undergo farnesylation. A calcein-based fluorescent assay revealed that hyperosmolarity caused a significant reduction of cell volume in mock and RhoB-wt-EGFP-expressing cells. By contrast, cells treated with FTI-277 or expressing the RhoB-CLLL-EGFP mutant did not properly respond to hyperosmolarity with respect to mock and RhoB-wt-EGFP expressing cells. These findings were further confirmed by 3D-LSCM showing that RhoB-CLLL-EGFP cells displayed a significant reduction in cell size compared to cells expressing RhoB-wt-EGFP. Moreover, flow cytometry analysis revealed that RhoB-CLLL-EGFP expressing cells as well as FTI-277-treated cells showed a significant increase in cell apoptosis. Together, these data suggested that: (i) RhoB is sensitive to hyperosmolarity and not to hyposmolarity; (ii) inhibition of RhoB farnesylation associates with an increase in cell apoptosis, likely suggesting that RhoB might be a paramount player controlling apoptosis by interfering with responses to cell volume change.
PubMed: 38946197
DOI: 10.1002/jcp.31343 -
Acta Dermatovenerologica Croatica : ADC Mar 2024Mutation of the BRAF oncogene is one of the most common mutations detected in human neoplasia, occurring in 40-60% of all cutaneous melanoma. BRAF is a serine/threonine...
Mutation of the BRAF oncogene is one of the most common mutations detected in human neoplasia, occurring in 40-60% of all cutaneous melanoma. BRAF is a serine/threonine protein kinase which is an essential part of the mitogen-activated protein kinase (MAPK) pathway. It is physiologically activated by RAS, but in mutated form, due to molecular conformational change, BRAF becomes constitutively active with subsequent persistent activation of downstream cytoplasmic and nuclear proteins (MEK, ERK, ETS), which finally leads to gene expression that promotes cell growth and survival. Inhibition of the altered MAPK pathway by BRAF inhibitors and combined BRAF/MEK inhibitors in BRAF mutated melanoma has become a standard therapeutic approach (1,2). We recently reported the frequency and clinicopathological features of BRAF V600E mutated melanomas in the Dalmatian region of Croatia. This report included 80 cutaneous melanomas with BRAF analyses performed at our institution until the second half of 2017, using a kit which detected only BRAF V600E mutation (3). From the second half of 2017, we started using a kit which detects several types of BRAF mutations along with NRAS mutation. The aim of this report was to determine the spectrum and frequency of different BRAF mutations in a group of skin melanomas in the Dalmatian region of Croatia and to comment on the relationship between type of BRAF mutation and therapeutic response to MAPK pathway inhibition. The analysis included 179 patients with stage 3 and stage 4 cutaneous melanoma with known BRAF/NRAS mutational status. The paraffin blocks were forwarded from four Dalmatian hospitals (Split: 139 cases, Zadar: 17 cases, Šibenik: 13 cases, Dubrovnik: 10 cases). BRAF/NRAS mutation analysis was performed at the Institute of Pathology, Clinical Hospital Center Split, Croatia, in the period from the second half of 2017 to the end of 2022. For DNA extraction analysis, hematoxylin and eosin stained slides from each submitted sample were reviewed by a pathologist, and tumor tissue was identified for analysis. For all tissue specimens, DNA was extracted from sections (10 mm thick) using the cobas® DNA Sample Preparation Kit (Roche Molecular Diagnostics), following the manufacturer's protocol. The amount of genomic DNA was quantified using the Qubit® 2.0 Fluorometer (Life Technologies) and adjusted to a fixed concentration to be added to the amplification/detection mixture. For mutation analysis, the target DNA was amplified and detected on the cobas z 480 analyzer using the amplification and detection reagents provided in the Roche BRAF/NRAS mutation test (LSR) kit, according to the manufacturer's protocol. The test results were reported as follows: BRAF exon 11 mutation detected, BRAF V600E/E2/D mutation detected, BRAF V600K mutation detected, BRAF V600R mutation detected, BRAF K601E mutation detected, NRAS (G12X, G13X, A18T, Q61X, other NRAS Ex3/4) mutation detected, mutation not detected, or invalid result (no result was obtained on the cobas test). BRAF mutation was observed in 87 patients (48.6%), NRAS mutation was found in 27 patients (15.1%), while 65 patients (36.3%) were without BRAF/NRAS mutation (Table 1). In the group of BRAF mutated melanomas, 61 cases (70.1%) had V600E/E2/D mutation, 20 cases (23%) had V600K mutation, 3 cases (3.4%) had exon 11 mutation, 2 cases (2.3%) had V600R mutation, and 1 case (1.2%) had K601E mutation (Table 2). The observed frequency of BRAF mutated melanomas in this study was similar to the frequency reported in our previous study (48.6% and 47.5%, respectively) (3). The vast majority were BRAF V600 mutations, while BRAF non-V600 mutations were rare (95.4% and 4.6%, respectively). In the group of BRAF V600 mutations, V600E/E2/D mutations predominated, followed by V600K mutations, while V600R mutations were rare. Greaves et al. reported similar frequency of BRAF V600 mutations in a group of 499 BRAF-mutated cutaneous melanomas, with V600E/E2/D mutations observed in 77.2% cases, followed by V600K mutations observed in 17.2% cases, and V600R mutations observed in 2.6% cases (4). BRAF non-V600 mutations (exon 11 and K601E mutations) were rarely observed in this study, confirming the findings of other authors (4,5). A three-class system of BRAF mutations was recently proposed that takes into account the differences in their kinase activity, with class I containing mutants with high kinase activity and high response rate to BRAF and BRAF/MEK inhibitors. Class II BRAF mutations have lower kinase activity than class I mutants, but higher than wild-type BRAF, showing resistance to BRAF inhibitor monotherapy and sensitivity to MEK and BRAF/MEK inhibitors. Finally, class III BRAF mutations are characterized by low kinase activity and low response rate to targeted therapy (6). BRAF V600 mutations belong to class I mutations, which means that the large majority of BRAF-positive melanomas in this study (95.4%) were sensitive to targeted therapy. However, the sensitivity to targeted therapy is different among different class I BRAF mutations. While large randomized controlled trials on combined BRAF/MEK inhibition showed good overall response (63-68%) and improvement of progression-free survival (PFS) and overall survival (OS) for the melanomas with most prevalent V600E and V600K mutations, Menzer et al. showed lower response rate to MAPK pathway inhibition (45%) in the group of metastatic melanomas with BRAF V600 mutations other than V600E/K. The overall response rate to MAPK pathway inhibition in the same group of melanomas with BRAF non-V600 mutations (class II and III mutations) was only 18% (7). In our group of BRAF mutated skin metastatic melanomas, we found only 6 cases (6.9%) with expected lower response rate to MAPK pathway inhibition: 2 cases with V600R mutation (class I non-V600E/K mutation), 1 case with K601E mutation (class II mutation), and 3 cases with exon 11 mutation (class II and III mutations).
Topics: Humans; Proto-Oncogene Proteins B-raf; Melanoma; Skin Neoplasms; Croatia; Mutation; Female; Male; Middle Aged; Aged; Adult; Aged, 80 and over
PubMed: 38946192
DOI: No ID Found -
Journal of Cellular Physiology Jun 2024Schwannomas are benign tumors of the peripheral nervous system arising from the transformation of Schwann cells (SCs). On the whole, these tumors are related to...
Schwannomas are benign tumors of the peripheral nervous system arising from the transformation of Schwann cells (SCs). On the whole, these tumors are related to alterations of the neurofibromin type 2 gene, coding for the oncosuppressor merlin, a cytoskeleton-associated protein belonging to the ezrin-radixin-moesin family. However, the underlying mechanisms of schwannoma onset and progression are not fully elucidated, whereas one of the challenges might be the environment. In this light, the exposure to electromagnetic field (EMF), generated by the use of common electrical devices, has been defiantly suggested as the cause of SCs transformation even if the evidence was mostly epidemiologic. Indeed, insubstantial mechanisms have been so far identified to explain SCs oncotransformation. Recently, some in vitro evidence pointed out alterations in proliferation and migration abilities in SCs exposed to EMF (0.1 T, 50 Hz, 10 min). Here, we used the same experimental paradigma to discuss the involvement of putative epigenetic mechanisms in SCs adaptation to EMF and to explain the occurrence of hypoxic alterations after the exposure. Our findings indicate a set of environmental-induced changes in SCs, toward a less-physiological state, which may be pathologically relevant for the SCs differentiation and the schwannoma development.
PubMed: 38946084
DOI: 10.1002/jcp.31365 -
Radiation Oncology Journal Jun 2024For the treatment of locally advanced rectal cancer (LARC), research on primary lesions with mesorectal fascia (MRF) involvement is lacking. This study analyzed the...
PURPOSE
For the treatment of locally advanced rectal cancer (LARC), research on primary lesions with mesorectal fascia (MRF) involvement is lacking. This study analyzed the clinical outcomes and efficacy of dose-escalated neoadjuvant concurrent chemoradiotherapy (NCRT) to patients with LARC involving MRF.
MATERIALS AND METHODS
We retrospectively reviewed 301 patients who were diagnosed with LARC involving MRF and underwent NCRT followed by total mesorectal excision (TME). Patients who received radiotherapy (RT) doses of ≤50.4 Gy were defined as the non-boost group, while ≥54.0 Gy as the boost group. Pathological tumor response and survival outcomes, including intrapelvic recurrence-free survival (IPRFS), distant metastases-free survival (DMFS) and overall survival (OS), were analyzed.
RESULTS
A total of 269 patients (89.4%) achieved a negative pathological circumferential resection margin and 104 (34.6%) had good pathological tumor regression grades. With a median follow-up of 32.4 months, IPRFS, DMFS, and OS rates at 5-years were 88.6%, 78.0%, and 91.2%, respectively. In the subgroup analysis by RT dose, the boost group included more advanced clinical stages of patients. For the non-boost group and boost group, 5-year IPRFS rates were 90.3% and 87.0% (p = 0.242), 5-year DMFS rates were 82.0% and 71.3% (p = 0.105), and 5-year OS rates were 93.0% and 80.6% (p = 0.439), respectively. Treatment related toxicity was comparable between the two groups (p = 0.211).
CONCLUSION
Although this retrospective study failed to confirm the efficacy of dose-escalated NCRT, favorable IPRFS and pathological complete response was achieved with NCRT followed by TME. Further studies combining patient customized RT dose with systemic therapies are needed.
PubMed: 38946075
DOI: 10.3857/roj.2023.01032 -
Stem Cells Translational Medicine Jun 2024Radiation therapy (RT) is a common treatment for lung cancer. Still, it can lead to irreversible loss of pulmonary function and a significant reduction in quality of...
Enhanced radiation sensitivity, decreased DNA damage repair, and differentiation defects in airway stem cells derived from patients with chronic obstructive pulmonary disease.
Radiation therapy (RT) is a common treatment for lung cancer. Still, it can lead to irreversible loss of pulmonary function and a significant reduction in quality of life for one-third of patients. Preexisting comorbidities, such as chronic obstructive pulmonary disease (COPD), are frequent in patients with lung cancer and further increase the risk of complications. Because lung stem cells are crucial for the regeneration of lung tissue following injury, we hypothesized that airway stem cells from patients with COPD with lung cancer might contribute to increased radiation sensitivity. We used the air-liquid interface model, a three-dimensional (3D) culture system, to compare the radiation response of primary human airway stem cells from healthy and patients with COPD. We found that COPD-derived airway stem cells, compared to healthy airway stem cell cultures, exhibited disproportionate pathological mucociliary differentiation, aberrant cell cycle checkpoints, residual DNA damage, reduced survival of stem cells and self-renewal, and terminally differentiated cells post-irradiation, which could be reversed by blocking the Notch pathway using small-molecule γ-secretase inhibitors. Our findings shed light on the mechanisms underlying the increased radiation sensitivity of COPD and suggest that airway stem cells reflect part of the pathological remodeling seen in lung tissue from patients with lung cancer receiving thoracic RT.
PubMed: 38946043
DOI: 10.1093/stcltm/szae043