Clear Cell Research Articles

A Rare Diagnostic Challenge of Retroperitoneal Unicentric Castleman Disease.

1. Brief medical history. 48-year-old lady post-menopausal lady, medically free, presented to the hospital with fatigue over the last 8 months, she recently felt a mass in her abdomen. An ultrasound of the abdomen was performed and showed a soft tissue mass in the left hemiabdomen 2. Diagnostic hypothesis. When formulating a differential diagnosis for a soft tissue mass in the retroperitoneal space, it is often helpful to determine first, by radiographic examination, whether the enlargement originates primarily in retroperitoneal, organ, lymph node or vascular. Hence, an enhanced computed tomography (CT) scan was ordered. 3. Radiological findings with clinical outcome. A CT performed after the administration of intravenous contrast material showed a large heterogenous left retroperitoneal soft tissue mass with central area of low attenuation in keeping with necrosis and a few punctate calcifications. Borderline enlarged mesenteric, and para-aortic lymph nodes reaching up to 1 cm in short axis are also noted. 4. Differential diagnosis. The differential diagnosis of a retroperitoneal lesion is broad and can include benign and neoplastic causes. Benign causes such as infection lymphadenopathy or abscess or benign neoplasm such as ganglioneuroma, angiomyolipoma, retroperitoneal fibrosis and hemangioma. Malignant neoplasm such as liposarcoma, leiomyosarcoma and lymphoma. Uncommon tumors of the retroperitoneal space include castleman disease, malignant peripheral nerve sheath tumor, clear cell sarcoma and ewing sarcoma among others. Distinguishing these processes is essentially impossible with imaging criteria alone, and ultimately a diagnosis based on histopathologic findings is essential. 5. Outcome, with definitive pathological diagnosis. Based on radiology finding the pathway was leading toward retroperitoneal liposarcoma. The patient subsequently underwent surgical excision of the mass and the surgical specimen was sent to the pathology department. Retroperitoneal microscopic mass examination showed Atretic germinal centers traversed by sclerotic penetrating vessels and hyalinization - lollipop follicles On the basis of the histopathologic features castleman diseases was diagnosed.

Infiltration of CD8+ cytotoxic T-cells and expression of PD-1 and PD-L1 in ovarian clear cell carcinoma

Ovarian clear cell carcinoma (OCCC) is resistant to chemotherapy, with limited treatment options for advanced and recurrent disease. The prevalence of OCCC differs by region. Assessing the expression of programmed cell death ligand 1 (PD-L1), PD-1, and CD8+T cell infiltration in OCCC is crucial, as their correlation with patient survival may provide valuable prognostic insights. We collected data from 36 samples from 18 OCCC patients, including 18 pairs of tumors and adjacent nonneoplastic samples. The optimized multiplex immunofluorescence technique was used to stain paraffin sections for immune factors related to the immune microenvironment of OCCC and clinical prognosis. The expression of PDL1 and PD1 in the tumor cells and tumor stromal cells was not significantly correlated with prognosis. Professional quantitative pathological analysis software was used to count the CD8+ cytotoxic T-cells in tumor regions and adjacent nonneoplastic regions in postoperative specimens. There were more CD8+ cytotoxic T-cells in the adjacent nonneoplastic areas than in the tumor tissue samples (p < 0.001). Further analysis revealed that a difference in cell density between CD8+ non-tumor-infiltrating lymphocytes (NTILs) and CD8+ tumor-infiltrating lymphocytes (TILs) exceeding 70 cells/mm2 was associated with poorer progression-free survival (PFS) (p = 0.042). In adjacent nonneoplastic regions, worse PFS was significantly observed in patients with high CD8+ T-cell expression in both total and stromal cells than those with low expression (p = 0.012 vs p = 0.007). The presence of CD8+ T-cells had significant potential for predicting the prognosis of patients with OCCC, which lays a foundation for the development of biomarkers for immune checkpoint blockade treatment response in OCCC patients.

Pathological features and immunohistochemical characteristics of clear cell (glycogen-rich) urothelial carcinoma: a case report and systematic review of the literature

Clear cell (glycogen-rich) urothelial carcinoma is an exceedingly rare variant of invasive urothelial carcinoma, distinguished by the presence of abundant cytoplasmic glycogen, which imparts a clear appearance to the tumor cells under histological examination. In this case report, the diagnosis was established through histopathological evaluation with hematoxylin and eosin (HE) staining, immunohistochemical analysis, and the identification of significant cytoplasmic glycogen accumulation. The patient, an 89-year-old male, was admitted on July 24, 2024, presenting with painless gross hematuria persisting for one week. Abdominal ultrasound and CT urography revealed a soft tissue mass on the right side of the bladder wall, measuring 30 × 30 mm, with a broad base connected to the bladder wall. The mass exhibited significant enhancement on contrast-enhanced scans, raising suspicion for malignancy. Microscopic examination revealed two distinct tumor cell morphologies: the conventional urothelial carcinoma pattern and a clear nest-like morphology, with the latter comprising over 70% of the tumor. Immunohistochemical staining for GATA-3, CK7, PAS, PAS-D, CAIX, PAX8, and RCC confirmed the diagnosis of clear cell (glycogen-rich) urothelial carcinoma. This rare variant of invasive urothelial carcinoma underscores the need for detailed diagnostic analysis to inform prognosis and treatment strategies. There have been similar cases reported before, involving a 57-year-old male-patient (Sahetia et al. in Ind J Cancer 60:575–577, 2023).

Paediatric Renal Tumors: A State-of-the-Art Review.

Pediatric renal tumors comprise a wide range of conditions, both malignant and benign, that affect children and require a multidisciplinary approach for optimal diagnosis and treatment. This review offers an in-depth analysis of the epidemiology, diagnosis, treatment options, outcomes, and survival of major pediatric renal tumors. Wilms tumor, or nephroblastoma, is the most common form of renal tumor in children, characterized by growth from primitive renal cells. Standard treatment involves a combination of surgery, chemotherapy and, in some cases, radiation therapy, with the aim of removing the tumor, preventing recurrence and maximizing the chances of long-term recovery. Less common pediatric renal tumors, such as renal clear cell sarcoma, renal cell carcinoma, mesoblastic nephroma, and malignant rhabdoid tumor, require similarly careful and individualized management. Therapeutic strategies, which depend on the characteristics of the tumor, the stage of the disease and the individual response to therapy, may include surgery, chemotherapy, radiotherapy and, in some cases, molecular targeted therapies, immunotherapies and genetic and epigenetic therapies. The management of pediatric kidney tumors requires the involvement of a multidisciplinary team of specialists to ensure accurate evaluation, optimal treatments and long-term follow-up. The aim is to maximize the prospects for recovery and improve the quality of life of patients and their families. Advances in innovative, personalized therapies represent an important opportunity to further improve clinical outcomes in these patients.

Clear-cell meningioma: An uncommon aggressive variant of meningioma.

Clear-cell meningioma is a rare subtype, representing 0.2-0.8% of all meningiomas. It is classified as grade 2 according to World Health Organization (WHO) classification due to its aggressive clinical course. Morphologically, it can mimic other clear-cell tumors arising in the central nervous system, each having different clinical behavior, therapeutic protocol, and prognostic outcome. This study aims to describe clinicopathological characteristics of clear-cell meningioma and to discuss the histomorphological features and differential diagnosis. The demographic, clinical, radiological, histopathological features, and follow-up of the patients were recorded and analyzed. Clear-cell meningioma constituted 1.3% of all meningiomas. The age of the patients ranged from 16-46 years (mean age - 27 years), with a slight female predominance. Follow-up varied from six months to six years. Recurrence was noted in four patients while three patients died. Histopathology revealed sheets of clear cells with prominent blocky interstitial and perivascular collagen deposition. Focal vague whorl formation and occasional intranuclear inclusions could be identified on careful search. Conventional meningothelial areas or typical psammoma bodies were not seen. Clear-cell meningioma is a rare subtype of meningioma with aggressive behavior. The presence of blocky collagen, a careful search for whorl formation, and intranuclear inclusions are helpful in approaching the correct diagnosis. An interdisciplinary approach by correlating the clinical, radiological, and histological features can enhance the accuracy of diagnosis.

Comprehensive analysis of α2,3-sialyltransferases as prognostic biomarkers and immunotherapy targets in kidney renal clear cell carcinoma

Kidney renal clear cell carcinoma (KIRC), a therapy-resistant aggressive kidney cancer, exhibits resistance to immune checkpoint inhibitors. Altered sialylation is involved in tumor development, affecting immune microenvironment dynamics. In the study, through systematic bioinformatics analysis and experimental verification, we demonstrated that ST3Gal5 expression was elevated in tumor tissues of KIRC patients, correlating with poor prognosis, and ST3Gal1 was downregulated and associated with a better prognosis. Immunohistochemistry analysis confirmed the expression patterns of ST3Gal1 and ST3Gal5 in 30 KIRC patients. Furthermore, KIRC patients were stratified into two clusters based on ST3Gal1 and ST3Gal5 levels using consensus clustering to investigate their roles in KIRC tumorigenesis, immune characteristics and treatment sensitivity. KIRC patients in Cluster 2, characterized by increased ST3Gal5 and downregulated ST3Gal1 expression, exhibited increased expression of immune checkpoints, immune cell infiltration, immune escape scores, and worse prognosis. Knockdown of ST3Gal5 in KIRC cell lines (786-O and 769-P) resulted in reduced tumor proliferation, migration, and invasion in vivo and in vitro. Together, the dysregulation of sialyltransferases (ST3Gal1 and ST3Gal5) in KIRC influences tumorigenesis and immune responses. These findings underscore the potential of ST3Gal1 and ST3Gal5 as prognostic factors and immunotherapy targets for KIRC.

Senolytic Treatment Alleviates Corneal Allograft Rejection Through Upregulation of Angiotensin-Converting Enzyme 2 (ACE2).

Allograft rejection remains a major cause of failure in high-risk corneal transplants, but the underlying mechanisms are not fully understood. This study aimed to investigate the contribution of transplantation stress-induced cellular senescence to corneal allograft rejection and to elucidate the associated molecular mechanisms. Age-matched murine corneal transplantation models were established. Cellular senescence was evaluated using senescence-associated β-galactosidase (SA-β-Gal) staining, western blot, and immunofluorescence staining. The role of cellular senescence in corneal allograft rejection was analyzed using p16 knockout mice and adoptive transfer experiments. Senolytic treatment with ABT-263 was administered intraperitoneally to evaluate its effects on corneal allograft rejection. RNA sequencing and pharmacological approaches were employed to identify the underlying mechanisms. Surgical injury induced a senescence-like phenotype in both donor corneas and recipient corneal beds, characterized by an increased accumulation of SA-β-Gal-positive cells in the corneal endothelium and stroma and elevated expression of senescence markers p16 and p21. Using genetic and adoptive transfer models, transplantation stress-induced senescence was shown to exacerbate corneal allograft rejection. Importantly, clearance of senescent cells by ABT-263 significantly suppressed ocular alloresponses and immune rejection. Mechanistically, RNA sequencing and loss-of-function experiments demonstrated that the anti-rejection effects of senolytic treatment were closely dependent on angiotensin-converting enzyme 2 (ACE2). These findings highlight transplantation stress-induced senescence as a pivotal pathogenic factor in corneal allograft rejection. Senolytic therapy emerges as a potential novel strategy to mitigate transplant rejection and improve corneal allograft survival.

Associations between parity, history of breastfeeding, and T cell profile of ovarian tumors.

Parity and breastfeeding are associated with systemic changes in maternal inflammation and reduced risk of ovarian cancer, but little is known about their impact on the ovarian tumor immune microenvironment. We evaluated the associations of self-reported parity and history of breastfeeding with tumor-infiltrating T cells among 1,706 ovarian carcinoma cases with tumor tissue collected across four studies. The abundance of tumor-infiltrating T cells was measured by multiplex immunofluorescence in tumor tissue microarrays. Odds ratios (OR) and 95% confidence intervals (CIs) for the positivity of tumor immune cells were calculated using beta-binomial models and stratified by histotype. Compared to ovarian tumors in nulliparous women, there was no association between parity and ovarian tumor T cell abundance among all histotypes combined, but suggestion of increased cytotoxic T cells and T cell exhaustion among parous women with clear cell tumors. When restricted to parous women, history of breastfeeding was associated with increased odds for all T cell types (i.e., total, cytotoxic, helper, regulatory, and exhausted T cells), with ORs ranging from 1.11-1.42. For every 6 months of breastfeeding, we observed increased odds of activated helper T cell infiltration (CD3+CD4+CD69+, OR:1.13, 95% CI: 0.99-1.29), with a similar association for high-grade serous tumors, but lower odds in clear cell tumors (OR:0.43, 95% CI:0.21-0.87). History of breastfeeding may alter the ovarian tumor immune microenvironment by modulating the abundance of tumor-infiltrating T cells. While replication is required, history of breastfeeding may play a role in activation of the ovarian tumor immune response.

Pembrolizumab in Patients With Advanced Clear Cell Gynecological Cancer

Advanced clear cell gynecological cancers (CCGCs) have a poor prognosis, with response rates to second-line chemotherapy less than 8%. Preliminary clinical activity with programmed cell death 1 protein (PD-1) inhibitors reported in CCGC merits further investigation. To assess the clinical benefit of pembrolizumab in patients with previously treated advanced CCGC. The PEACOCC trial is a single-arm multicenter phase 2 trial conducted at 5 UK centers investigating the clinical benefit and safety of pembrolizumab. PD-1 inhibitor-naive patients with histologically confirmed advanced CCGC, radiological disease progression following 1 or more prior courses of chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 to 1 were included. Patients were enrolled from March 2019 to October 2021, with data collected until July 2024. Pembrolizumab, 200 mg, intravenously every 21 days up to 2 years until progression, discontinuation due to toxic effects, or patient/clinician decision. Up to 1 year of retreatment on diseases progression, if stable disease, partial response, or complete response at 2 years. The primary end point was progression-free survival (PFS) rate at 12 weeks using Response Evaluation Criteria in Solid Tumors version 1.1 to detect a 12-week PFS rate of 33% or greater and exclude a PFS rate of less than 15%, with 90% power and 1-sided 5% significance level. Secondary end points included objective response rate, duration of response, PFS, overall survival, safety, and quality of life. A total of 48 patients were eligible. The median (range) age was 58.5 (32-77) years, and 26 (54%) had an ECOG PS score of 0 and 22 (46%) had an ECOG PS score of 1; 41 (85%) had ovarian, 6 (13%) had endometrial, and 1 (2%) had cervical advanced CCGC. The median (range) courses prior therapy was 3 (1-6); 19 patients (40%) received prior anti-angiogenic therapy, and 19 (40%) had a platinum-free interval of more than 12 months. Grade 3 treatment-related adverse events were observed in 9 patients (19%), and no patients had grade 4 or 5 adverse events. A total of 45 of 46 patients (98%) had mismatch repair-proficient tumors. The 12-week PFS rate was 42% (95% CI, 28-57), and the best objective response rate was 25% (95% CI, 14-40), with 12 partial responses. After a median follow-up of 46.9 months (95% CI, 43.4-55.0), the median PFS was 2.7 months (95% CI, 1.3-5.4), and the median overall survival was 14.8 months (95% CI, 6.7-28.2). The PEACOCC trial showed clinical benefit with pembrolizumab in patients with previously treated advanced CCGC, of whom all except 1 had MMR-proficient disease. Clinical outcomes were durable with an overall tolerable safety profile, justifying further evaluation of pembrolizumab monotherapy for advanced CCGC in a randomized clinical trial. ClinicalTrials.gov Identifier: NCT03425565.

Percutaneous microwave ablation of cT1b renal cell carcinoma: safety and oncologic efficacy in a large, single-center elderly and comorbid cohort.

To evaluate safety and oncologic efficacy of percutaneous microwave ablation (MWA) for treating clinically localized T1b (cT1b) renal cell carcinoma (RCC). This single-center retrospective study was performed under a waiver of informed consent. Seventy-four consecutive patients (49M/25F) with 76 cT1b RCC (median tumor diameter 4.5cm) were treated with percutaneous MWA between 5/2012 and 8/2020. Patients were stratified into two groups by technique, depending on whether antennas were repositioned for additional ablation or not. Primary efficacy, complications, and local tumor progression (LTP) were compared using the Wilcoxon rank sum and Fisher's exact tests. The Kaplan Meier method was used for survival analysis. Patients were elderly (median age 69.5), obese (median BMI 34.5), and comorbid (Charlson Comorbidity Index=4). Most tumors were low-grade (grade 1-2) (67/89, 88%) and clear cell RCC was the most common histology (62/76, 82%). A median of three MWA antennas were powered at 65W for 7min for treatment. Renal masses were larger (4.6 vs 4.5cm, p=0.01) and procedure times longer (100min vs 80.5min, p=0.04) for the antenna reposition cohort (n=34, 45%). Primary efficacy and high-grade complication rates were 93% and 8%, respectively. The local tumor progression rate (LTP), at a median follow-up was 28.2 months, was 16%. Primary efficacy, low and high-grade complications, change in estimated glomerular filtration rate and LTP were similar between cohorts (p=0.20-0.55). Percutaneous MWA for cT1b RCC is safe in elderly and comorbid patients with acceptable oncologic efficacy. Repeat ablation is well-tolerated and can improve oncologic efficacy.

Dimethyl fumarate promotes the degradation of HNF1B and suppresses the progression of clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is the most lethal subtype of renal cancer, and its treatment options remain limited. Therefore, there is an urgent need to discover therapeutic agents for ccRCC treatment. Here, we demonstrate that dimethyl fumarate (DMF), an approved medication for multiple sclerosis [1] and psoriasis, can inhibit the proliferation of ccRCC cells. Mechanistically, hepatocyte nuclear factor 1β (HNF1B), a transcription factor highly expressed in ccRCC, is succinated by DMF at cysteine residues, leading to its proteasomal degradation. Furthermore, HNF1B interacts with and stabilizes Yes-associated protein (YAP), thus DMF-mediated HNF1B degradation decreases YAP protein level and the expression of its target genes, resulting in the suppression of ccRCC cell proliferation. Importantly, oral administration of DMF sensitizes ccRCC to sunitinib treatment and enhances its efficacy in mice. In summary, we provide evidences supporting DMF as a potential drug for clinical treatment of ccRCC by targeting HNF1B and reveal a previously unrecognized role of HNF1B in regulating YAP in ccRCC.

Value of [68Ga]Ga-PSMA-11 PET/CT in Reflecting the Intra- and Intertumor Heterogeneity of Neovascularization in Clear Cell Renal Cell Carcinoma.

Prostate-specific membrane antigen (PSMA) is a potential target for the diagnosis and treatment of angiogenesis in clear cell renal cell carcinoma (ccRCC). We aimed to investigate the degree of PSMA signal variability in ccRCC and assess its correlation with neovascularization in the tumor microenvironment. We included 120 patients with suspected renal tumors who underwent [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) scan before surgery in this retrospective study, including 98 ccRCC, 17 non-ccRCC, and 5 benign diseases. We compared the maximum standard uptake value (SUVmax) and tumor-to-liver ratio (TLR) of primary lesions in different groups and analyzed the diagnostic efficacy of PSMA imaging for ccRCC. The coefficient of variation (CV) of SUVmax, which reflects intertumor heterogeneity, and volume ratio (VR), which reflects intratumor heterogeneity, were obtained from PET imaging. We analyzed the correlation between SUVmax, PSMA immunohistiochemical (IHC) staining, microvessel density (MVD), and serum vascular endothelial growth factor (VEGF) and compared the inter- and intratumor heterogeneity of primary lesions and metastases. In our study, ccRCC showed significantly higher SUVmax and TLR compared to non-ccRCC and benign diseases (F = 14.48, p < 0.001; F = 14.49, p < 0.001). PSMA IHC staining exhibited moderate correlation with SUVmax (r = 0.421, p = 0.021) and MVD (r = 0.518, p = 0.003), but it was not correlated with serum VEGF (r = -0.003, p = 0.989). SUVmax had a moderate correlation with MVD (r = 0.448, p = 0.013) and serum VEGF (r = 0.345, p = 0.020). Serum VEGF exhibited a weak correlation with MVD (r = 0.338, p = 0.145). Based on the correlation, the SUVmax-to-angiogenesis model was validated. The mean SUVmax values of primary lesions, bone metastases, and tumor thrombi were 16.13, 18.69, and 6.02, respectively. The CV of the mean SUVmax was 58.5%, 55.9%, and 80.6%. The mean VR values of primary lesions, bone metastases, and tumor thrombi were 0.33, 0.46, and 0.75, respectively. The CV of the mean VR was 81.8%, 41.3%, and 26.7%. The SUVmax of primary lesions was significantly correlated with corresponding bone metastases and tumor thrombi (r = 0.52, p = 0.011; r = 0.87, p = 0.024). The SUVmax of primary lesion in localized ccRCC and advanced ccRCC showed no significant difference (p = 0.251), while the VR was significantly different (p = 0.049). In conclusion, [68Ga]Ga-PSMA-11 PET/CT is an effective molecular imaging tool for assessing angiogenesis and its heterogeneity and differentiating ccRCC. The SUVmax of primary lesions was significantly correlated with PSMA IHC staining, MVD, and serum VEGF. The intertumor heterogeneity of tumor thrombi was significantly higher than that of primary lesions and bone metastases. Primary lesions exhibited the highest intratumor heterogeneity, and lesions with high intratumor heterogeneity showed invasive behavior. PSMA uptake by primary lesions has a positive effect on metastasis.

Can multiparametric MRI clear cell likelihood scores differentiate fat-Poor AML from CcRCC in subcentimeter lesions?

To investigate the potential of multiparametric MRI clear cell likelihood scores (ccLS) for differentiating between fat-poor angiomyolipoma (AML) and clear cell renal cell carcinoma (ccRCC) in subcentimeter Lesions (1cm or smaller). This retrospective study included consecutive patients with subcentimeter renal masses who underwent multiparametric MRI between September 2009 and September 2022 across three hospitals. Clinical and MRI findings were analyzed to differentiate between fat-poor AML and ccRCC. Lesions were categorized using the ccLS and receiver operating characteristic curve analysis was performed to assess ccLS performance. Thirty-eight patients (mean age: 52 years ± 12; 19 women) with 39 lesions were included. Of the 39 lesions [mean size: 9.1mm ± 1.0 (range, 6.0-10.0mm)], 20 (51%) were ccRCC and 19 (49%) were fat-poor AML. Compared to the ccRCC, subcentimeter fat-poor AMLs were more likely to show hypointensity on T2WI (P < 0.001), homogeneous enhancement (P = 0.010), the presence of microscopic fat (P = 0.036), and the absence of a pseudocapsule (P = 0.020). The diagnostic percentage of fat-poor AML was 47% for a ccLS of 1 or 2, and ccRCC accounted for 75% in the ccLS 4 or 5 category. The AUC for discrimination was 0.846 (95% CI: 0.695-0.941, P < 0.001), with a sensitivity of 75.00% (95% CI: 50.9-91.3) and a specificity of 89.47% (95% CI: 66.9-98.7). Multiparametric MRI clear cell likelihood scores can potentially be used to differentiate between fat-poor AML and ccRCC in lesions 1cm or smaller.

The Role of Senescence in Experimental Periodontitis at the Causal Level: An in Vivo Study

The occurrence and severity of periodontitis (PD) tend to increase with age, and yet the underlying mechanisms remain unclear. Immune senescence is known to be triggered in mice and humans as they age. Experimental PD in mice has been shown to induce senescence biomarkers p16 INK4a and p21, dysfunction of antigen-presenting cells (APCs), and activation of the senescence-associated secretory phenotype (SASP). However, the causal links of senescence to experimental PD are not yet established. This study aims to elucidate the role of senescence in experimental PD at a causal level. The P16-3MR mouse model harbors the p16INK4a (Cdkn2a) promoter, driving in vivo expression of synthetic Renilla luciferase, monomeric red fluorescent protein (mRFP), and herpes simplex virus-1 thymidine kinase (HSV-TK). This facilitates in vivo identification of p16 INK4a activation at the cellular level and the consequences of selective elimination of p16INK4a-positive cells by ganciclovir (GCV) treatment. Mice were treated with/without GCV for two weeks during ligature-induced PD. In vivo bioluminescence imaging quantified p16INK4a activation, while Western blot and immunofluorescence analyses assessed key senescence and inflammatory markers (p16, p21, p53, Cyclin D1, p-H2A.X, IL17, and IL1β). Alveolar bone volume was analyzed by micro-CT and histomorphometry. Our findings demonstrate that clearance of senescent cells in mice subjected to experimental PD alleviates inflammation and mitigates bone loss. These results suggest a causal role for senescence in PD pathology, raising the future prospect of senolytic agents for therapeutic intervention in PD.

Longitudinal changes in the transcriptionally active and intact HIV reservoir after starting ART during acute infection.

Even in antiretroviral therapy (ART)-suppressed human immunodeficiency virus (HIV)-infected individuals, there are heterogeneous populations of HIV-expressing cells exhibiting variable degrees of progression through blocks to HIV transcriptional initiation, elongation, completion, and splicing. These HIV-transcribing cells likely contribute to HIV-associated immune activation and inflammation as well as the viral rebound that occurs after stopping ART. However, it is unclear whether the blocks to HIV transcription are present before ART and how the timing and duration of ART may affect the clearance of cells expressing HIV transcripts that differ in their processivity and/or presence of mutations. To investigate these questions, we quantified different types of HIV transcripts and the corresponding HIV DNA regions/proviruses in longitudinal blood samples obtained before ART initiation (T1) and after 6 months (T2) and 1 year (T3) of ART in 16 individuals who initiated ART during acute HIV infection. Before ART, the pattern of HIV transcripts suggested blocks to elongation and splicing, and only ~10% of intact proviruses were transcribing intact HIV RNA. During the first 6 months of ART, we detected progressively greater reductions in initiated, 5'-elongated, mid-transcribed, completed, and multiply spliced HIV transcripts. Completed HIV RNA decayed faster than initiated or 5'-elongated HIV RNA, and intact HIV RNA tended to decay faster than defective HIV RNA. HIV DNA and RNA levels at T1-T3 correlated inversely with baseline CD4+ T-cell counts. Our findings suggest the existence of immune responses that act selectively to reduce HIV transcriptional completion and/or preferentially kill cells making completed or intact HIV RNA.IMPORTANCEEven in virologically suppressed HIV-infected individuals, expression of viral products from both intact and defective proviruses may contribute to HIV-associated immune activation and inflammation, which are thought to underlie the organ damage that persists despite suppressive ART. We investigated how the timing of ART initiation and the duration of ART affect the heterogeneous populations of HIV-transcribing cells, including a detailed characterization of the different HIV transcripts produced before ART and the rate at which they decay after ART initiation during acute HIV infection. Even during untreated infection, most cells (~90%) have blocks at some stage of transcription. Furthermore, different HIV transcripts decline at different rates on ART, with the fastest decay of cells making completed and intact HIV RNA. Our results suggest that intrinsic or extrinsic immune responses act selectively to either reduce particular stages of HIV transcription or cause selective killing of cells making particular HIV transcripts.

Impact of contrast enhancement phase on CT-based radiomics analysis for predicting post-surgical recurrence in renal cell carcinoma.

To investigate the effect of CT enhancement phase on radiomics features for predicting post-surgical recurrence of clear cell renal cell carcinoma (ccRCC). This retrospective study included 144 patients who underwent radical or partial nephrectomy for ccRCC. Preoperative multiphase abdominal CT scans (non-contrast, corticomedullary, and nephrographic phases) were obtained for each patient. Automated segmentation of renal masses was performed using the nnU-Net framework. Radiomics signatures (RS) were developed for each phase using ensembles of machine learning-based models (Random Survival Forests [RSF], Survival Support Vector Machines [S-SVM], and Extreme Gradient Boosting [XGBoost]) with and without feature selection. Feature selection was performed using Affinity Propagation Clustering. The primary endpoint was disease-free survival, assessed by concordance index (C-index). The study included 144 patients. Radical and partial nephrectomies were performed in 81% and 19% of patients, respectively, with 81% of tumors classified as high grade. Disease recurrence occurred in 74 patients (51%). A total of 1,316 radiomics features were extracted per phase per patient. Without feature selection, C-index values for RSF, S-SVM, XGBoost, and Penalized Cox models ranged from 0.43 to 0.61 across phases. With Affinity Propagation feature selection, C-index values improved to 0.51-0.74, with the corticomedullary phase achieving the highest performance (C-index up to 0.74). The results of our study indicate that radiomics analysis of corticomedullary phase contrast-enhanced CT images may provide valuable predictive insight into recurrence risk for non-metastatic ccRCC following surgical resection. However, the lack of external validation is a limitation, and further studies are needed to confirm these findings in independent cohorts.

Establishment and characterization of ovarian clear cell carcinoma patient-derived xenografts

Establishment and characterization of ovarian clear cell carcinoma patient-derived xenografts

A rare case of hyalinizing clear cell carcinoma of the tongue root: A case report and literature review

A rare case of hyalinizing clear cell carcinoma of the tongue root: A case report and literature review

Hemangioma-Like Clear Cell Renal Cell Carcinoma Exhibiting Aggressive Behavior and High Stage: A Case Report.

Clear cell renal cell carcinoma (CCRCC) displays a variety of architectural patterns, which are often intermingled. However, a predominant or purely multicystic growth with diffuse intracystic hemorrhage leading to hemangioma-like histomorphology, is extremely rare in CCRCC. In this article, we describe a CCRCC exhibiting a pure hemangioma-like architecture and aggressive behavior. The patient was a 73-year-old man with a tumor of the left kidney measuring 70 mm in the largest dimension. Histological examination of the nephrectomy specimen revealed a tumor composed entirely of blood filled spaces lined by a single layer of flattened or low cuboidal cells lacking high-grade features or voluminous clear cytoplasm. These cells showed diffuse immunohistochemical positivity for keratin AE1/AE3 and carbonic anhydrase 9 and focal positivity for PAX8, CD10, and alpha-methylacyl-CoA racemase. The tumor invaded the renal vein; no lymph nodes or extension of the tumor into the soft tissues of the hilum were detected (stage pT3a pNx). Using the Illumina TruSight Oncology 500 kit, a clinically significant c.3481dup, p.(Arg1161LysfsTer13) and c.2050del, p.(Gln684Asnfs4) mutations of the tet methylcytosine dioxygenase 2 (TET2) gene and c.296, p.(Pro99GlnfsTer60) mutation of the von Hippel-Lindau (VHL) gene were identified. The immunophenotype and molecular genetics of our tumor were consistent with CCRCC, suggesting that the unusual hemangioma-like growth pattern is most likely the result of extensive regressive changes. In contrast to all previously published reports, our study demonstrated that, despite the bland histological appearance, renal cell carcinomas with hemangioma-like features can invade the renal vein and follow an aggressive clinical course.

Deciphering the Role of PEGylation on the Lipid Nanoparticle-Mediated mRNA Delivery to the Liver.

Organ- and cell-specific delivery of mRNA via modular lipid nanoparticles (LNPs) is promising in treating various diseases, but targeted cargo delivery is still very challenging. Most previous work focuses on screening ionizable and helper lipids to address the above issues. Here, we report the multifacial role of PEGylated lipids in manipulating LNP-mediated delivery of mRNA to the liver. We employed the typical excipients in LNP products, including DLin-MC3-DMA, DPSC, and cholesterol. Five types of PEGylated lipids were selected, and their molar ratio was fixed at 1.5% with a constant PEG molecular weight of 2000 Da. The architecture of steric lipids dramatically affected the in vitro gene transfection, in vivo blood clearance, liver deposition, and targeting of specific cells, all of which were closely linked to the de-PEGylation rate. The fast de-PEGylation resulted in short blood circulation and high accumulation in the liver. However, the ultrafast de-PEGylation enabled the deposition of more LNPs in Kupffer cells other than hepatocytes. Surprisingly, simply changing the terminal groups of PEGylated lipids from methoxyl to carboxyl or amine could dramatically increase the liver delivery of LNPs, which might be associated with the accelerated de-PEGylation rate and enhanced LNP-cell interaction. The current work highlights the importance of manipulating steric lipids in promoting mRNA delivery, offering an alternative approach for formulating and optimizing mRNA LNPs.