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Experimental Hematology May 2024Key studies in pre-leukemic disorders have linked increases in pro-inflammatory cytokines with accelerated phases of disease, but the precise role of the cellular...
Key studies in pre-leukemic disorders have linked increases in pro-inflammatory cytokines with accelerated phases of disease, but the precise role of the cellular microenvironment in disease initiation and evolution remains poorly understood. In myeloproliferative neoplasms (MPNs), higher levels of specific cytokines have been previously correlated with increased disease severity (TNF-α, IP-10) and decreased survival (IL-8). Whereas TNF-α and IL-8 have been studied by numerous groups, there is a relative paucity of studies on IP-10 (CXCL10). Here we explore the relationship of IP-10 levels with detailed genomic and clinical data and undertake a complementary cytokine screen alongside functional assays in a wide range of MPN mouse models. Similar to patients, levels of IP-10 were increased in mice with more severe disease phenotypes (e.g., JAK2 TET2 double mutant mice) compared to those with less severe phenotypes (e.g., CALR or JAK2 mice) and WT littermate controls. While exposure to IP-10 did not directly alter proliferation or survival in single hematopoietic stem cells (HSCs) in vitro, IP-10 mice transplanted with disease initiating HSCs developed an MPN phenotype more slowly, suggesting that the effect of IP-10 loss was non-cell autonomous. To explore the broader effects of IP-10 loss, we crossed IP-10 mice into a series of MPN mouse models and show that its loss reduces the erythrocytosis observed in mice with the most severe phenotype. Together these data point to a potential role for blocking IP-10 activity in the management of MPNs.
PubMed: 38763471
DOI: 10.1016/j.exphem.2024.104246 -
The Journal of Biological Chemistry May 2024ASCT2 (alanine serine cysteine transporter 2), a member of the SLC1 (solute carrier 1) family, mediates Na-dependent exchange of small neutral amino acids across cell...
ASCT2 (alanine serine cysteine transporter 2), a member of the SLC1 (solute carrier 1) family, mediates Na-dependent exchange of small neutral amino acids across cell membranes. ASCT2 was shown to be highly expressed in tumor cells, making it a promising target for anti-cancer therapies. In this study, we explored the binding mechanism of the high-affinity competitive inhibitor Lc-BPE with ASCT2, using electrophysiological and rapid kinetic methods. Our investigations reveal that Lc-BPE binding requires one or two Na ions initially bound to the apo-transporter with high affinity, with Na1 site occupancy being more critical for inhibitor binding. In contrast to the amino acid substrate bound form, the final, third Na ion cannot bind, due to distortion of its binding site (Na2), thus preventing the formation of a translocation-competent complex. Based on the rapid kinetic analysis, the application of Lc-BPE generated outward transient currents, indicating that, despite its net neutral nature, the binding of Lc-BPE in ASCT2 is weakly electrogenic, most likely because of asymmetric charge distribution within the amino acid moiety of the inhibitor. The pre-incubation with Lc-BPE also led to a decrease of the turnover rate of substrate exchange and a delay in the activation of substrate-induced anion current, indicating relatively slow Lc-BPE dissociation kinetics. Overall, our results provide new insight into the mechanism of binding of a prototypical competitive inhibitor to the ASCT transporters.
PubMed: 38763337
DOI: 10.1016/j.jbc.2024.107382 -
NeuroImage. Clinical May 2024The main objective was to characterize the tracer uptake kinetics of [F]fluoromethylcholine ([F]F-CHO) in high-grade gliomas (HGG) through a full PET kinetic modeling...
PURPOSE
The main objective was to characterize the tracer uptake kinetics of [F]fluoromethylcholine ([F]F-CHO) in high-grade gliomas (HGG) through a full PET kinetic modeling approach. Secondarily, we aimed to explore the relationship between the PET uptake measures and the HGG molecular features.
MATERIALS AND METHODS
Twenty-four patients with a suspected diagnosis of HGG were prospectively included. They underwent a dynamic brain [F]F-CHO-PET/CT, from which a tumoral time-activity curve was extracted. The plasma input function was obtained through arterial blood sampling with metabolite correction. These data were fitted to 1- and 2-tissue-compartment models, the best of which was selected through the Akaike information criterion. We assessed the correlation between the kinetic parameters and the conventional static PET metrics (SUV, SUV and tumor-to-background ratio TBR). We explored the association between the [F]F-CHO-PET quantitative parameters and relevant molecular biomarkers in HGG.
RESULTS
Tumoral time-activity curves in all patients showed a rapid rise of [F]F-CHO uptake followed by a plateau-like shape. Best fits were obtained with near-irreversible 2-tissue-compartment models. The perfusion-transport constant K and the net influx rate K showed strong correlation with SUV (r = 0.808-0.861), SUV (r = 0.794-0.851) and TBR (r = 0.643-0.784), p < 0.002. HGG was confirmed in 21 patients, of which those with methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter showed higher mean K (p = 0.020), K (p = 0.025) and TBR (p = 0.001) than the unmethylated ones.
CONCLUSION
[F]F-CHO uptake kinetics in HGG is best explained by a 2-tissue-compartment model. The conventional static [F]F-CHO-PET measures have been validated against the perfusion-transport constant (K) and the net influx rate (K) derived from kinetic modeling. A relationship between [F]F-CHO uptake rate and MGMT methylation is suggested but needs further confirmation.
PubMed: 38763039
DOI: 10.1016/j.nicl.2024.103616 -
International Journal of Surgery Case... May 2024Multiple Primary Malignant Neoplasms (MPMNs) are rare and refer to the occurrence of two or more distinct primary cancers with unrelated histopathological features in...
INTRODUCTION AND IMPORTANCE
Multiple Primary Malignant Neoplasms (MPMNs) are rare and refer to the occurrence of two or more distinct primary cancers with unrelated histopathological features in one patient. MPMNs can be classified as synchronous when tumors appear simultaneously or within six months of each other, and as metachronous when identified six months or more after the initial cancer diagnosis. While breast cancer often co-occurs with other primary cancers such as colorectal, endometrial, and ovarian cancers, the simultaneous presence of invasive lobular breast carcinoma and clear cell renal cancer is rare.
CASE PRESENTATION
Here, we present the case of a 59-year-old postmenopausal woman who initially presented with breast carcinoma. Further investigation revealed a mass in the left kidney. The patient underwent a radical mastectomy and axillary dissection, followed by a left nephrectomy. After 8 months follow up, the patient is doing well and disease-free.
CLINICAL DISCUSSION
Based on our case and literature review, the co-occurrence of breast carcinoma with renal cell carcinoma (RCC) is uncommon. Most reported cases involve metastatic tumors or metachronous breast malignancy with RCC. The etiology of synchronous malignancy is complex, and treatment options usually include a combination of surgery and/or adjuvant therapy.
CONCLUSION
This case report contributes valuable insights to the limited literature on synchronous breast cancer with renal cell carcinoma. The rarity of this simultaneous occurrence underscores the importance of considering such cases. Documenting these cases is crucial for increasing awareness and reducing the resulting morbidity and mortality.
PubMed: 38762959
DOI: 10.1016/j.ijscr.2024.109778 -
World Journal of Surgical Oncology May 2024Human endogenous retrovirus subfamily H long terminal repeat associating protein 2, (HHLA2), a member of B7 family, exhibits heightened expression in various malignant...
BACKGROUND
Human endogenous retrovirus subfamily H long terminal repeat associating protein 2, (HHLA2), a member of B7 family, exhibits heightened expression in various malignant tumors. However, the exact functions of HHLA2 in pancreatic cancer (PC) remain incompletely elucidated.
METHODS
We initially conducted an analysis of the B7 family members' expression pattern in pancreatic tumor samples and adjacent normal tissues using The Cancer Genome Atlas (TCGA) database. Subsequently, immunohistochemistry, RT-qPCR and western blot methods were used to assess HHLA2 expression levels in PC tissues and cell lines. Furthermore, after silencing HHLA2 in PC cell lines, cell migration and proliferation of PC cells were detected by wound healing and CCK-8 assays, and cell invasion of PC cells was detected by transwell assays. We also investigated the regulation of epithelial-mesenchymal transition (EMT) markers and levels of EGFR, MEK, ERK1/2, mTOR and AKT via western blot analysis. Finally, the correlation between HHLA2 expression and immune infiltration was further explored.
RESULTS
Silencing of HHLA2 resulted in the inhibition of PC cell proliferation, migration and invasion, potentially through the suppression of the EGFR/MAPK/ERK and mTOR/AKT signaling pathway. Additionally, silencing HHLA2 led to the inhibition of M2-type polarization of tumor associated macrophages (TAMs).
CONCLUSION
The knockdown of HHLA2 was observed to inhibit the migration and invasion of PC cells through the regulation of the EMT process and EGFR/MAPK/ERK and mTOR/AKT pathway. Furthermore, silencing HHLA2 was found to modulate M2 polarization of TAMs. These finding suggest that HHLA2 could be a promising therapeutic target for Pancreatic cancer.
Topics: Humans; Pancreatic Neoplasms; TOR Serine-Threonine Kinases; ErbB Receptors; Cell Proliferation; Proto-Oncogene Proteins c-akt; Cell Movement; Epithelial-Mesenchymal Transition; Disease Progression; Prognosis; Macrophages; Tumor Cells, Cultured; Signal Transduction; Male; Biomarkers, Tumor; MAP Kinase Signaling System; Apoptosis; THP-1 Cells; Gene Expression Regulation, Neoplastic; Female; Immunoglobulins
PubMed: 38762741
DOI: 10.1186/s12957-024-03409-2 -
Nature Communications May 2024Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by invasive behavior and a compromised immune response, presenting treatment challenges....
Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by invasive behavior and a compromised immune response, presenting treatment challenges. Surgical debulking of GBM fails to address its highly infiltrative nature, leaving neoplastic satellites in an environment characterized by impaired immune surveillance, ultimately paving the way for tumor recurrence. Tracking and eradicating residual GBM cells by boosting antitumor immunity is critical for preventing postoperative relapse, but effective immunotherapeutic strategies remain elusive. Here, we report a cavity-injectable bacterium-hydrogel superstructure that targets GBM satellites around the cavity, triggers GBM pyroptosis, and initiates innate and adaptive immune responses, which prevent postoperative GBM relapse in male mice. The immunostimulatory Salmonella delivery vehicles (SDVs) engineered from attenuated Salmonella typhimurium (VNP20009) seek and attack GBM cells. Salmonella lysis-inducing nanocapsules (SLINs), designed to trigger autolysis, are tethered to the SDVs, eliciting antitumor immune response through the intracellular release of bacterial components. Furthermore, SDVs and SLINs administration via intracavitary injection of the ATP-responsive hydrogel can recruit phagocytes and promote antigen presentation, initiating an adaptive immune response. Therefore, our work offers a local bacteriotherapy for stimulating anti-GBM immunity, with potential applicability for patients facing malignancies at a high risk of recurrence.
Topics: Glioblastoma; Animals; Mice; Salmonella typhimurium; Male; Neoplasm Recurrence, Local; Brain Neoplasms; Humans; Cell Line, Tumor; Mice, Inbred C57BL; Pyroptosis; Adaptive Immunity; Immunity, Innate; Hydrogels; Immunotherapy
PubMed: 38762500
DOI: 10.1038/s41467-024-48606-5 -
Acta Neuropathologica Communications May 2024Glioblastoma (GBM) is the most common malignant brain tumor in adults, which remains incurable and often recurs rapidly after initial therapy. While large efforts have...
A longer time to relapse is associated with a larger increase in differences between paired primary and recurrent IDH wild-type glioblastomas at both the transcriptomic and genomic levels.
Glioblastoma (GBM) is the most common malignant brain tumor in adults, which remains incurable and often recurs rapidly after initial therapy. While large efforts have been dedicated to uncover genomic/transcriptomic alternations associated with the recurrence of GBMs, the evolutionary trajectories of matched pairs of primary and recurrent (P-R) GBMs remain largely elusive. It remains challenging to identify genes associated with time to relapse (TTR) and construct a stable and effective prognostic model for predicting TTR of primary GBM patients. By integrating RNA-sequencing and genomic data from multiple datasets of patient-matched longitudinal GBMs of isocitrate dehydrogenase wild-type (IDH-wt), here we examined the associations of TTR with heterogeneities between paired P-R GBMs in gene expression profiles, tumor mutation burden (TMB), and microenvironment. Our results revealed a positive correlation between TTR and transcriptomic/genomic differences between paired P-R GBMs, higher percentages of non-mesenchymal-to-mesenchymal transition and mesenchymal subtype for patients with a short TTR than for those with a long TTR, a high correlation between paired P-R GBMs in gene expression profiles and TMB, and a negative correlation between the fitting level of such a paired P-R GBM correlation and TTR. According to these observations, we identified 55 TTR-associated genes and thereby constructed a seven-gene (ZSCAN10, SIGLEC14, GHRHR, TBX15, TAS2R1, CDKL1, and CD101) prognostic model for predicting TTR of primary IDH-wt GBM patients using univariate/multivariate Cox regression analyses. The risk scores estimated by the model were significantly negatively correlated with TTR in the training set and two independent testing sets. The model also segregated IDH-wt GBM patients into two groups with significantly divergent progression-free survival outcomes and showed promising performance for predicting 1-, 2-, and 3-year progression-free survival rates in all training and testing sets. Our findings provide new insights into the molecular understanding of GBM progression at recurrence and potential targets for therapeutic treatments.
Topics: Humans; Glioblastoma; Isocitrate Dehydrogenase; Brain Neoplasms; Transcriptome; Neoplasm Recurrence, Local; Male; Female; Genomics; Mutation; Middle Aged; Time Factors
PubMed: 38762464
DOI: 10.1186/s40478-024-01790-3 -
International Journal of Surgery Case... May 2024A pituitary abscess (PA) is an extremely rare disease. It is characterized by the presence of an infected purulent collection within the Sella turcica. PAs are...
INTRODUCTION AND IMPORTANCE
A pituitary abscess (PA) is an extremely rare disease. It is characterized by the presence of an infected purulent collection within the Sella turcica. PAs are categorized in two categories: primary, when the pituitary is normal before the infection, or secondary, when there is a pre-existing sellar pathology (e.g., pituitary adenoma, Rathke's cleft cysts, or craniopharyngioma), meningitis, paranasal sinusitis, or head surgery, which may be indicative of the source of infection.
CASE PRESENTATION
We presented a case of a 52-year-old male with visual disturbances. Both a computerized tomography scan and magnetic resonance imaging revealed a sellar mass lesion, initially suspected to be a pituitary tumor. During transsphenoidal surgery for excision of the pituitary mass, an amount of pus was drained, indicating a pituitary abscess, which was confirmed by positive Staphylococcus aureus colonies in the culture. After surgery, the patient received antibiotic treatment for 12 weeks. After two years of follow-up, the patient remained free of complications and did not require hormone replacement therapy.
CLINICAL DISCUSSION
In previous research, there were a total of 488 patients, of those, 318 were primary pituitary abscess. Preoperative diagnosis is still difficult due to a combination of nonspecific symptoms and imaging findings. Endonasal trans-sphenoidal pus evacuation, culture, and individualized antibiotic therapy are available treatment options.
CONCLUSION
Pituitary abscess is a rare illness, but it should always be considered when evaluating a patient with a fast visual decline. Following the diagnosis, surgery and antibiotics should be started immediately. Proper therapy usually yields a positive effect.
PubMed: 38761689
DOI: 10.1016/j.ijscr.2024.109753 -
Neoplasia (New York, N.Y.) May 2024Colorectal cancer (CRC) stands as a prevalent malignancy globally. A pivotal event in CRC pathogenesis involves the loss-of-function mutation in the APC gene, leading to...
Colorectal cancer (CRC) stands as a prevalent malignancy globally. A pivotal event in CRC pathogenesis involves the loss-of-function mutation in the APC gene, leading to the formation of benign polyps. Despite the well-established role of APC, the contribution of CUL4B to CRC initiation in the pre-tumorous stage remains poorly understood. In this investigation, we generated a murine model by crossing Apc mice with Cul4b mice to achieve specific deletion of Cul4b in the gut epithelium against an Apc background. By employing histological methods, RNA-sequencing (RNA-seq), and flow cytometry, we assessed alterations and characterized the immune microenvironment. Our results unveiled that CUL4B deficiency in gut epithelium expedited Apc adenoma formation. Notably, CUL4B in adenomas restrained the accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). In vivo inhibition of MDSCs significantly delayed the growth of CUL4B deleted Apc adenomas. Furthermore, the addition of MDSCs to in vitro cultured Apc; Cul4b adenoma organoids mitigated their alterations. Mechanistically, CUL4B directly interacted with the promoter of Csf3, the gene encoding granulocyte-colony stimulating factor (G-CSF) by coordinating with PRC2. Inhibiting CUL4B epigenetically activated the expression of G-CSF, promoting the recruitment of MDSCs. These findings offer novel insights into the tumor suppressor-like roles of CUL4B in regulating Apc adenomas, suggesting a potential therapeutic strategy for CRC initiation and progression in the context of activated Wnt signaling.
PubMed: 38761506
DOI: 10.1016/j.neo.2024.101005 -
Journal of Investigative Medicine High... 2024Breast cancers of either ductal or lobular pathology make up the vast majority of breast malignancies. Other cancers occur rarely in the breast. Benign pathology can at... (Review)
Review
Breast cancers of either ductal or lobular pathology make up the vast majority of breast malignancies. Other cancers occur rarely in the breast. Benign pathology can at times mimic breast cancers on imaging and initial needle biopsies. We report a rare breast pathology of cylindroma. Cylindromas are usually benign, rare dermatologic lesions most commonly associated with head or neck locations. They more commonly occur as sporadic and solitary masses. Less commonly is an autosomal-dominant multi-centric form of this disease. Malignant cylindromas are very rare. We present a patient with findings of a cylindroma of the breast after excision. This was initially felt to be concerning for breast cancer on imaging and core biopsy. Treatment of cylindromas of the breast is excision. Sentinel lymph node dissection is not indicated, nor are adjuvant therapies when identified in the breast. This lesion needs to be included in the differential diagnosis for breast cancer. If cylindromas can be accurately diagnosed preoperatively, this would negate the need for consideration of axillary nodal surgery and adjuvant therapies.
Topics: Humans; Female; Breast Neoplasms; Carcinoma, Adenoid Cystic; Diagnosis, Differential; Biopsy, Large-Core Needle; Breast; Middle Aged; Mammography
PubMed: 38761035
DOI: 10.1177/23247096241246627