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Biochemical Society Transactions Jun 2024Neurons are highly specialised cells that need to relay information over long distances and integrate signals from thousands of synaptic inputs. The complexity of...
Neurons are highly specialised cells that need to relay information over long distances and integrate signals from thousands of synaptic inputs. The complexity of neuronal function is evident in the morphology of their plasma membrane (PM), by far the most intricate of all cell types. Yet, within the neuron lies an organelle whose architecture adds another level to this morphological sophistication - the endoplasmic reticulum (ER). Neuronal ER is abundant in the cell body and extends to distant axonal terminals and postsynaptic dendritic spines. It also adopts specialised structures like the spine apparatus in the postsynapse and the cisternal organelle in the axon initial segment. At membrane contact sites (MCSs) between the ER and the PM, the two membranes come in close proximity to create hubs of lipid exchange and Ca2+ signalling called ER-PM junctions. The development of electron and light microscopy techniques extended our knowledge on the physiological relevance of ER-PM MCSs. Equally important was the identification of ER and PM partners that interact in these junctions, most notably the STIM-ORAI and VAP-Kv2.1 pairs. The physiological functions of ER-PM junctions in neurons are being increasingly explored, but their molecular composition and the role in the dynamics of Ca2+ signalling are less clear. This review aims to outline the current state of research on the topic of neuronal ER-PM contacts. Specifically, we will summarise the involvement of different classes of Ca2+ channels in these junctions, discuss their role in neuronal development and neuropathology and propose directions for further research.
PubMed: 38934485
DOI: 10.1042/BST20230819 -
The American Journal of Surgical... Jun 2024The World Health Organization (WHO) diagnostic criteria for malignant phyllodes tumor (MPT) may miss a significant number of MPTs with metastatic potential. New refined...
The World Health Organization (WHO) diagnostic criteria for malignant phyllodes tumor (MPT) may miss a significant number of MPTs with metastatic potential. New refined diagnostic criteria (Refined Criteria) for MPT were recently proposed. The aim of this study is to validate the Refined Criteria. This validation study included 136 borderline (borderline phyllodes tumor [BoPT]) and MPT cases that were not included in the initial study. We evaluated tumor classifications based on both the Refined Criteria and the WHO criteria. The Refined Criteria defines MPT when these criteria are met (1) stromal overgrowth with ≥ 1 feature(s) of marked stromal cellularity, marked stromal cytologic atypia, or ≥10 mitoses per 10 high-power fields (10 mitoses/10 HPFs) or (2) marked stromal cellularity with ≥1 feature(s) of marked stromal cytologic atypia, ≥10 mitoses/10 HPFs or permeative border. The WHO criteria require all 5 morphologic features (stromal overgrowth, permeative border, marked stromal cellularity, marked stromal cytologic atypia, and ≥10 mitoses/10 HPFs) for an MPT diagnosis. Using the Refined Criteria, none of the 61 BoPTs developed metastasis and 40.0% of the 75 MPTs developed metastases; local recurrence was seen in 11.5% BoPTs and 25.3% MPTs. Using the WHO criteria, 9.6% of the 94 BoPTs developed metastases and 50.0% of the 42 MPTs developed metastases; 14.9% of the BoPTs had local recurrence and 28.6% of the MPTs had local recurrence. Nine (30.0%) of the 30 tumors that developed distant metastases were diagnosed as BoPTs by the WHO criteria. When we combined the 75 MPTs from this validation cohort with the 65 MPT cases from the published data using the Refined Criteria, 50 (35.7%) of the 140 MPTs developed metastases, whereas 8 cases with metastases were <5 cm. In the univariate analysis with log-rank test, stromal overgrowth, marked stromal cellularity, marked stromal cytologic atypia, ≥10 mitoses/10 HPFs, presence of heterologous components other than liposarcomatous component, and presence of stromal necrosis were significantly associated with the risk of metastasis (all with P < 0.05). In multivariate analysis with Cox proportional hazard regression, stromal overgrowth and marked stromal cellularity were significantly associated with metastasis (both with P < 0.001). The Refined Criteria are superior to the WHO criteria in predicting the clinical outcomes of BoPTs and MPTs. Using the Refined Criteria, 35.7% of 140 patients with MPT developed metastases, whereas none (0%) of the patients with BoPT developed metastases. Patients with MPT have a high metastatic rate; these patients may benefit from systemic chemotherapy or targeted therapies. In contrast, patients with BoPT may be managed with complete local excision alone without chemotherapy.
PubMed: 38934254
DOI: 10.1097/PAS.0000000000002264 -
Oncology Research and Treatment Jun 2024Anal mucinous adenocarcinoma (AMAC) is an extremely rare form of anal cancer. Our objective was to examine the incidence, management, and prognostic factors of AMAC.
BACKGROUND
Anal mucinous adenocarcinoma (AMAC) is an extremely rare form of anal cancer. Our objective was to examine the incidence, management, and prognostic factors of AMAC.
MATERIALS AND METHODS
We analyzed age-adjusted incidence rates (AAI) over time and compared the prognosis of AMAC with anal squamous cell carcinoma (ASCC) and adenocarcinoma (AAC) using propensity score matching (PSM) and Kaplan-Meier analysis. Patients were classified based on summary stage and treatments to determine cancer-specific survival (CSS).
RESULTS
AAI of AMAC fluctuated within a narrow range (0.082-0.237 per million person-years) from 2000 to 2018. AMAC had a slight non-significant trend of worse prognosis than ASCC (p=0.348) and a better prognosis than AAC (p<0.01). Females made up a larger proportion of patients diagnosed with the distant disease (p<0.05) and unmarried (p<0.05), and somewhat less probably to need surgical removal (p<0.01) and radiotherapy (p<0.01). Elderly patients, with regional stage, distant-stage disease, no surgery tended to have lower rates of survival (all p<0.05). Localized stage was associated with better prognosis (p<0.05). Surgery was associated with a tendency towards better survival (p=0.095).
CONCLUSIONS
The incidence of AMAC is consistently low. AMAC demonstrates a more favorable prognosis compared to typical AAC and a slightly worse prognosis compared to ASCC. Females with AMAC were less likely to undergo surgical removal or receive radiotherapy. AMAC exhibits a low incidence yet favorable prognosis compared to typical AAC and slightly worse compared to ASCC. Elderly age is associated with poorer prognosis, while localized stage indicates better prognosis. Surgery demonstrates a trend towards improved survival.
PubMed: 38934176
DOI: 10.1159/000539930 -
Frontiers in Oncology 2024Thyroid-like follicular renal cell carcinoma (TLFRCC), also known as thyroid-like follicular carcinoma of the kidney or thyroid follicular carcinoma like renal tumor, is...
Thyroid-like follicular renal cell carcinoma (TLFRCC), also known as thyroid-like follicular carcinoma of the kidney or thyroid follicular carcinoma like renal tumor, is an exceedingly rare variant of renal cell carcinoma that has only recently been acknowledged. This neoplasm exhibits a distinct follicular morphology resembling that of the thyroid gland. Immunohistochemical analysis reveals positive expression of PAX8, Vimentin, and EMA, while thyroid-specific markers TG and TTF1 are consistently absent. Furthermore, there is a notable absence of any concurrent thyroid pathology on clinical evaluation. Previous reports have suggested that TLFRCC is an indolent, slow-growing malignancy with infrequent metastatic potential. In this report, we present a case of TLFRCC characterized by remarkable ossification and widespread metastasis, including multifocal pulmonary lesions, involvement of the abdominal wall, and infiltration into the psoas muscle. To our knowledge, this represents only the third documented instance of distant metastasis in thyroid follicular renal carcinoma. The current case demonstrates a therapeutic approach that combines radiotherapy with the utilization of toripalimab, a programmed cell death 1 (PD-1) receptor inhibitor, and pazopanib. This treatment regimen was tailored based on comprehensive genomic profiling, which identified mutations in the POLE (catalytic subunit of DNA polymerase epsilon) and ATM (ataxia-telangiectasia mutated) genes, both of which have been implicated in the pathogenesis of various malignant tumors. These findings represent a novel discovery, as such mutations have never been reported in association with TLFRCC. Thus far, this therapeutic approach has proven to be the most efficacious option for treating metastatic TLFRCC among previously reported, and it also marks the first mention of the potential benefits of radiotherapy in managing this particular subtype of renal cell carcinoma.
PubMed: 38933440
DOI: 10.3389/fonc.2024.1352865 -
World Journal of Nuclear Medicine Jun 2024Differentiated thyroid carcinoma (DTC) usually is slow growing and carries a good prognosis. It most commonly tends to spread locally to regional lymph nodes in 20 to...
Unusual Metastatic Sites and Radioiodine Uptake in Patients of Differentiated Thyroid Carcinoma with Atypical Clinical Presentations: Utilization of I-Whole-Body Scintigraphy with Regional SPECT/CT.
Differentiated thyroid carcinoma (DTC) usually is slow growing and carries a good prognosis. It most commonly tends to spread locally to regional lymph nodes in 20 to 60% of patients. The presence of distant metastasis impacts overall survival and prognosis. The lungs, bones, and the brain are typically involved in distant sites with less common metastatic sites that include the liver, kidney, skeletal muscle, adrenal glands, bladder, and skin. These unusual sites are rare and pose a diagnostic challenge and impact clinical decision-making to a great extent. The radioiodine I whole-body scintigraphy with single-photon emission computed tomography/computed tomography can provide a thorough investigation of unusual sites of uptake leading to diagnosis of these metastases. We present a case series of DTC showing unusual sites of metastasis and/or radioiodine uptake in urinary bladder, in the third metacarpal bone of left hand and lastly in the forearm at postoperative hypertrophic scar area.
PubMed: 38933072
DOI: 10.1055/s-0044-1779750 -
Journal of Diabetes and Metabolic... Jun 2024Thyroid cancer is recognized as the predominant form of endocrine cancer. The likelihood of cancer recurrence and the development of distant metastases varies depending...
PURPOSE
Thyroid cancer is recognized as the predominant form of endocrine cancer. The likelihood of cancer recurrence and the development of distant metastases varies depending on the cancer's pathology and stage. Iran currently lacks country-specific data on thyroid cancer, which can potentially result in clinicians deviating from the optimal treatment. The primary objectives of establishing such a registry are to determine the incidence, identify risk factors, and evaluate treatment outcomes for thyroid cancer within the Iranian population. Ultimately, the overarching goal of this protocol study is to reduce mortality and morbidity rates among thyroid cancer patients by implementing appropriate interventions based on the findings derived from this registration system.
METHODS
The study will enroll all individuals aged 18 years and older who have received a diagnosis of primary thyroid carcinoma based on pathology criteria. Data will be collected from various thyroid clinic centers. The participating centers include the Endocrinology Clinic at Shariati Hospital, the Thyroid Clinic in the Nuclear Medicine Center at Shariati Hospital, as well as pathology and nuclear medicine centers in Kerman and Bushehr. Patient records comprise information on outpatient visits to the clinic.
CONCLUSION
The registry aims to enhance treatment approaches and follow-up protocols while serving as a foundation for conducting clinical, epidemiological, and basic science studies based on robust evidence-based data.
PubMed: 38932868
DOI: 10.1007/s40200-023-01320-3 -
Vaccines Jun 2024Oligodeoxynucleotides (ODNs) containing unmethylated cytosine-phosphate-guanosine (CpG) motifs are readily recognized by Toll-like receptor 9 on immune cells, trigger an...
Oligodeoxynucleotides (ODNs) containing unmethylated cytosine-phosphate-guanosine (CpG) motifs are readily recognized by Toll-like receptor 9 on immune cells, trigger an immunomodulatory cascade, induce a Th1 -biased immune milieu, and have great potential as an adjuvant in cancer vaccines. In this study, a green one-step synthesis process was adopted to prepare an amino-rich metal-organic nanoplatform (FN). The synthesized FN nanoplatform can simultaneously and effectively load model tumor antigens (OVA)/autologous tumor antigens (dLLC) and immunostimulatory CpG ODNs with an unmodified PD backbone and a guanine quadruplex structure to obtain various cancer vaccines. The FN nanoplatform and immunostimulatory CpG ODNs generate synergistic effects to enhance the immunogenicity of different antigens and inhibit the growth of established and distant tumors in both the murine E.G7-OVA lymphoma model and the murine Lewis lung carcinoma model. In the E.G7-OVA lymphoma model, vaccination efficiently increases the CD4, CD8, and tetramerCD8 T cell populations in the spleens. In the Lewis lung carcinoma model, vaccination efficiently increases the CD3CD4 and CD3CD8 T cell populations in the spleens and CD3CD8, CD3CD8, and CD11bCD80 cell populations in the tumors, suggesting the alteration of tumor microenvironments from cold to hot tumors.
PubMed: 38932378
DOI: 10.3390/vaccines12060649 -
Pharmaceutics Jun 2024The inhibition of the immune response in the tumor microenvironment by therapy regimens can impede the eradication of tumors, potentially resulting in tumor metastasis....
The inhibition of the immune response in the tumor microenvironment by therapy regimens can impede the eradication of tumors, potentially resulting in tumor metastasis. As a non-invasive therapeutic method, radiotherapy is utilized for tumor ablation. In this study, we aimed to improve the therapeutic impact of radiotherapy and trigger an immune response by formulating a benzothiazole sulfinate (BTS)-loaded fusion liposome (BFL) nanoplatform, which was then combined with radiotherapy for anti-cancer treatment. The platelet cell membrane, equipped with distinctive surface receptors, enables BFL to effectively target tumors while evading the immune system and adhering to tumor cells. This facilitates BFL's engulfment by cancer cells, subsequently releasing BTS within them. Following the release, the BTS produces sulfur dioxide (SO) for gas therapy, initiating the oxidation of intracellular glutathione (GSH). This process demonstrates efficacy in repairing damage post-radiotherapy, thereby achieving effective radiosensitization. It was revealed that an immune response was triggered following the enhanced radiosensitization facilitated by BFL. This approach facilitated the maturation of dendritic cell (DC) within lymph nodes, leading to an increase in the proportion of T cells in distant tumors. This resulted in significant eradication of primary tumors and inhibition of growth in distant tumors. In summary, the integration of personalized BFL with radiotherapy shows potential in enhancing both tumor immune response and the elimination of tumors, including metastasis.
PubMed: 38931953
DOI: 10.3390/pharmaceutics16060833 -
Plants (Basel, Switzerland) Jun 2024Long-distance transfer of genetic material and metabolites between rootstock and scions is well documented in homo-grafted hybrids but has rarely been reported in...
Long-distance transfer of genetic material and metabolites between rootstock and scions is well documented in homo-grafted hybrids but has rarely been reported in genetically-distant grafts where the rootstock and scion belong to different families. In this study, we grafted scions onto stocks and obtained 20 vegetative hybrids, / (Vs). After 25 years of growth, we found that the phenotypes of the leaves, internodes, and fruits of the Vs hybrids above the graft union resembled an intermediate phenotype between and and the new traits were stable when propagated vegetatively. We further analyzed genetic differences between Vv plants and Vs hybrids using high-throughput sequencing, while metabolomes were analyzed by liquid chromatography-mass spectrometry (LC-MS). We found a total of 2113 differentially expressed genes (DEGs). GO annotation and KEGG pathway enrichment analysis showed that these DEGs enriched mainly in oxidation-reduction and metabolic processes. Seventy-nine differentially expressed miRNAs (DEMs) containing 27 known miRNAs and 52 novel miRNAs were identified. A degradation analysis detected 840 target genes corresponding to 252 miRNAs, of which 12 DEMs and their corresponding target gene expression levels were mostly negatively correlated. Furthermore, 1188 differential metabolic compounds were identified. In particular, in Vs hybrids, the abundance of the metabolites schizandrin and gomisin as the main medicinal ingredients in were down-regulated and up-regulated, respectively. Our data demonstrated the effects of interfamily grafts on the phenotype, transcript profile and metabolites of the scion, and also provided new insight into the genetic, phenotypic, and metabolic plasticity associated with genetically distant grafted hybrids.
PubMed: 38931108
DOI: 10.3390/plants13121676 -
Journal of Clinical Medicine Jun 2024: Although the role of PET/CT imaging is well established in oncology, its diagnostic value in routine monitoring for recurrent colorectal cancer (CRC) is still...
: Although the role of PET/CT imaging is well established in oncology, its diagnostic value in routine monitoring for recurrent colorectal cancer (CRC) is still controversial. The aim was to evaluate the diagnostic value of F-18 FDG PET/CT in detecting recurrent CRC in correlation with CEA, CA 19-9 levels, and conventional imaging modalities (CIM). Between 2009 and 2023, a retrospective study was performed including 134 CRC patients referred for PET/CT imaging on the suspicion of recurrence, based on elevated CEA and/or CA 19-9 and/or equivocal CIM findings. According to our institution's Tumor Board CRC protocol, after the initial treatment, which was dependent on the TNM stage (neoadjuvant therapy, primary resection, or adjuvant treatment), patients underwent a standard 5-year surveillance including CEA and CA 19-9 measurements, CIM, and colonoscopy, every six months. The statistics, including univariate and multivariate analyses were conducted using the IBM SPSS 20.0 statistical software. -values < 0.05 were considered statistically significant. Recurrent CRC was confirmed in 54/134 (40.3%) patients with elevated tumor markers. PET/CT showed high diagnostic performance in detecting recurrent CRC with sensitivity, specificity, PPV, NPV, and accuracy of 94.4%, 82.5%, 78.5%, 95.7%, and 87.3%, respectively. The CEA showed a high sensitivity of 98.1% but both low specificity and accuracy of 15% and 48.5%, respectively. The sensitivity, specificity, and accuracy for CA 19-9 and CIM for diagnosis of CRC recurrence were 44.4%, 67.5%, 58.2%, and 51.9%, 98.8%, 79.9%, respectively. The AUC for PET/CT, elevated CEA levels, CIM, and elevated CA 19-9 levels was 0.885 (95% CI: 0.824-0.946; < 0.001), 0.844 (95% CI: 0.772-0.916; < 0.001), 0.753 (95% CI: 0.612-0.844; < 0.001), and 0.547 (95% CI: 0.442-0.652; = 0.358), respectively. Univariate analysis showed that both PET/CT and CIM positive results were highly associated with CRC recurrence ( < 0.001 and < 0.001, respectively). At the same time, gender, mucinous tumor type, presence of initial lymph node metastasis (N+), and presence of initial distant metastasis (M+) had no significance ( = 0.211, = 0.158, = 0.583, and = 0.201, respectively). Our multivariate analysis showed that independent predictors for CRC recurrence are positive PET/CT scans ( < 0.001), positive CIM results ( = 0.001), and elevated CA 19-9 levels ( = 0.023). Although CA 19-9 was not detected as a statistically significant predictor in the univariate analysis ( = 0.358), in a multivariate analysis it was recognized as a significant predicting factor in detecting the CRC recurrence ( = 0.023). F-18 FDG PET/CT showed high diagnostic efficacy in CRC recurrence detection, in correlation with CEA levels, CA 19-9 levels, and CIM. This imaging modality should be routinely integrated into the post-operative follow-op in patients with elevated tumor markers.
PubMed: 38930131
DOI: 10.3390/jcm13123602