Consistency in human papillomavirus type detection between self-collected vaginal specimens and physician-sampled cervical specimens.

With the rising need for accessible cervical cancer screening, self-sampling methods offer a promising alternative to traditional physician-led sampling. This study aims to evaluate the efficacy of the HygeiaTouch Self Sampling Kit for Women in detecting human papillomavirus (HPV) types and predicting cervical lesions. We studied the concordance in identifying high-risk HPV (hrHPV) types between samples collected by physicians and those self-collected by women using a self-sampling kit for validation. Women aged 21-65, fitting into specific categories based on their cervical health history were eligible. Cohen's kappa coefficient to gauge concordance between the two specimen types and relative accuracy metrics in identifying cervical intraepithelial neoplasia (CIN) were also calculated, with physician-sampled specimens serving as a reference. A total of 1210 participants from three institutes were involved. The self-sampling kit closely matched the physician-led method in terms of collecting valid specimens (100% vs. 100%), identifying hrHPV types (kappa: 0.75, 95% confidence interval [95% CI]: 0.72-0.79; agreement: 87.7%, 95% CI: 85.8-89.6) and predicting CIN grade 2 or worse (CIN2+) (relative sensitivity: 0.949, relative accuracy: 0.959). Kappa values varied between 0.71 and 0.83 for different hrHPV types and combinations, with an overall value 0.75 (95% CI: 0.72-0.79) signifying robust compatibility between the two methods. Our study underscores the potential of the HygeiaTouch Self Sampling Kit as a reliable, efficient, and user-friendly alternative to traditional sampling methods. This suggests that self-sampling could be pivotal in expanding cervical cancer screening accessibility and enhancing detection rates.

Modulating DNA damage response in uveal melanoma through embryonic stem cell microenvironment.

BACKGROUND: Uveal melanoma (UVM) is the most common primary intraocular tumor in adults, with a median survival of 4-5 months following metastasis. DNA damage response (DDR) upregulation in UVM, which could be linked to its frequent activation of the PI3K/AKT pathway, contributes to its treatment resistance. We have reported that embryonic stem cell microenvironments (ESCMe) can revert cancer cells to less aggressive states through downregulation of the PI3K signaling, showing promise in modulating the DDR of UVM. METHODS: Since nonhomologous end joining (NHEJ) is the main DNA repair mechanism in UVM, this study utilized gene expression analysis and survival prognosis analysis to investigate the role of NHEJ-related genes in UVM based on public databases. Xenograft mouse models were established to assess the therapeutic potential of ESC transplantation and exposure to ESC-conditioned medium (ESC-CM) on key DNA repair pathways in UVM. Quantitative PCR and immunohistochemistry were used to analyze NHEJ pathway-related gene expression in UVM and surrounding normal tissues. Apoptosis in UVM tissues was evaluated using the TUNEL assay. RESULTS: PRKDC, KU70, XRCC5, LIG4 and PARP1 showed significant correlations with UM progression. High expression of PRKDC and XRCC5 predicted poorer overall survival, while low PARP1 and XRCC6 expression predicted better disease-free survival in UVM patients. ESCMe treatment significantly inhibited the NHEJ pathway transcriptionally and translationally and promoted apoptosis in tumor tissues in mice bearing UVM. Furthermore, ESC transplantation enhanced DDR activities in surrounding normal cells, potentially mitigating the side effects of cancer therapy. Notably, direct cell-to-cell contact with ESCs was more effective than their secreted factors in regulating the NHEJ pathway. CONCLUSIONS: Our results suggest that NHEJ-related genes might serve as prognostic markers and therapeutic targets in UVM. These findings support the therapeutic potential of ESC-based therapy in enhancing UVM sensitivity to radiochemotherapy and improving treatment outcomes while minimizing damage to healthy cells.

Fatty acids metabolism affects the therapeutic effect of anti-PD-1/PD-L1 in tumor immune microenvironment in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a highly invasive and metastatic subtype of kidney malignancy and is correlated with metabolic reprogramming for adaptation to the tumor microenvironment comprising infiltrated immune cells and immunomodulatory molecules. The role of immune cells in the tumor microenvironment (TME) and their association with abnormal fatty acids metabolism in ccRCC remains poorly understood. METHOD: RNA-seq and clinical data of KIRC from The Cancer Genome Atlas (TCGA) and E-MTAB-1980 from the ArrayExpress dataset. The Nivolumab group and Everolimus group of the CheckMate 025 study, the Atezolizumab arm of IMmotion150 and the Atezolizumab plus Bevacizumab group of IMmotion151 cohort were obtained for subsequent analysis. After differential expression genes identification, the signature was constructed through univariate Cox proportional hazard regression and simultaneously the least absolute shrinkage and selection operator (Lasso) analysis and the predictive performance of our signature was assessed by using receiver operating characteristic (ROC), Kaplan-Meier (KM) survival analysis, nomogram, drug sensitivity analysis, immunotherapeutic effect analysis and enrichment analysis. Immunohistochemistry (IHC), qPCR and western blot were performed to measure related mRNA or protein expression. Biological features were evaluated by wound healing, cell migration and invasion assays and colony formation test and analyzed using coculture assay and flow cytometry. RESULTS: Twenty fatty acids metabolism-related mRNA signatures were constructed in TCGA and possessed a strong predictive performance demonstrated through time-dependent ROC and KM survival analysis. Notably, the high-risk group exhibited an impaired response to anti-PD-1/PD-L1 (Programmed death-1 receptor/Programmed death-1 receptor-ligand) therapy compared to the low-risk group. The overall levels of the immune score were higher in the high-risk group. Additionally, drug sensitivity analysis observed that the model could effectively predict efficacy and sensitivity to chemotherapy. Enrichment analysis revealed that the IL6-JAK-STAT3 signaling pathway was a major pathway. IL4I1 could promote ccRCC cells' malignant features through JAK1/STAT3 signaling pathway and M2-like macrophage polarization. CONCLUSION: The study elucidates that targeting fatty acids metabolism can affect the therapeutic effect of PD-1/PD-L1 in TME and related signal pathways. The model can effectively predict the response to several treatment options, underscoring its potential clinical utility.

Macular Vascular Complexity Analysis of Diabetes Mellitus by Swept-Source Optical Coherence Tomographic Angiography.

PURPOSE: This study was designed to evaluate the associations between retinal vascular complexity features, including fractal dimension (FD) and blood vessel tortuosity (BVT), and the severity of diabetic retinopathy (DR) by using optical coherence tomographic angiography (OCTA). METHODS: In this prospective cross-sectional study, 1,282 ocular-treatment-naive patients with type 2 diabetes mellitus (DM) (1,059 without DR and 223 with DR) registered in the community of Guangzhou, China, were enrolled. OCTA was used to measure FD and BVT in the superficial capillary plexus (SCP) and the deep capillary plexus (DCP). Univariate and multivariate linear regression analyses were performed to analyze the correlation of FD and BVT in different layers with DR severity. RESULTS: In this study, 1,282 patients with DM (1,282 eyes), with a mean age of 64.2 ± 7.8 years, were included. FD in the DCP decreased and BVT in the DCP increased in patients with DR compared with those in patients without DR, even after adjusting for confounding factors (p < 0.05). Trend analysis showed a significant decrease in the FD values as the DR progressed, whereas the BVT progressively increased with worsening DR severity (p < 0.01). The FD in DCP had a statistically significant positive correlation with FD in SCP and a negative correlation with BVT in SCP and BVT in DCP in all of the participants, including the non-DR group, moderate DR group, and severe DR group (p < 0.01). CONCLUSIONS: FD and BVT determined using OCTA might be useful parameters for objectively distinguishing DR from non-DR and indicating DR progression.

Role of human papillomavirus status after conization for high-grade cervical intraepithelial neoplasia.

Human papillomavirus (HPV) is the well-established etiologic factor for cervical neoplasia. Cervical conization constitutes an effective treatment for high-grade cervical intraepithelial neoplasia (HG-CIN). We conducted an observational study for long-term outcomes and HPV genotype changes after conization for HG-CIN. Between 2008 and 2014, patients with newly diagnosed HG-CIN before conization (surveillance new [SN] group) and those who had undergone conization without hysterectomy (surveillance previous [SP] group) were enrolled. HPV testing and Pap smear were performed periodically for the SN and SP (collectively S) groups. All other patients receiving conization for HG-CIN during the study period were identified from our hospital database. Those eligible but not enrolled into our study were assigned to the non-surveillance (non-S) group. For the S group (n = 493), the median follow-up period was 74.3 months. Eighty-four cases had recurrent CIN Grade 2 or worse (CIN2+) (5-year cumulative rate: 14.8%), of which six had invasive cancer. Among the 84 patients, 65 (77.4%) exhibited type-specific persistence in the paired HPV results, whereas only 7 (8.3%) harbored new HPV types that belonged to the 9-valent vaccine types. Among the 7397 non-S patients, 789 demonstrated recurrent CIN2+, of which 57 had invasive cancer. The stages distribution of those progressed to invasive cancer in the non-S group were more advanced than the S group (P = .033). Active surveillance might reduce the severity of those progressed to cancer. Because a majority of the patients with recurrent CIN2+ had persistent type-specific HPV infections, effective therapeutic vaccines are an unmet medical need.

Management and clinical outcomes of patients with recurrent/progressive ovarian clear cell carcinoma.

BACKGROUND/PURPOSE: Ovarian clear cell carcinoma (OCCC) with recurrence/progression after treatment has dismal prognosis. We aimed to investigate the management and outcomes of such patients. METHODS: OCCC patients who were treated between 2000 and 2013 with cancer recurrence or progression after primary treatment were analyzed. Univariate and multivariate analyses were used to identify the independent predictors of survival after recurrence (SAR) and cancer-specific survival (CSS). RESULTS: A total of 64 patients experienced treatment failure (49 recurred after remission and 15 progressed without remission). The 5-year CSS rates of recurrent/progressive OCCC patients were 22.9% (progression group: median CSS 5.9 months [range, 0.8-25.2] vs recurrence group: 43.6 months [range, 7.1-217.8]; p < 0.001). Patients with solitary recurrence had significantly better SAR than those with disseminated relapse (median: not reached vs 10.4 months, p < 0.001). On multivariate analysis, six models each for SAR and CSS were formulated alternatively including highly correlated variables for the recurrence group. Of these models, solitary relapse pattern (HR: 0.07, p < 0.001), progression-free interval (PFI) > 12 months (HR: 0.22-0.40, p = 0.001 and p = 0.023), CA125 < 35 U/mL at initial recurrence (HR: 0.32, p = 0.007), and overall salvage treatment including radiotherapy (HR: 0.19, p = 0.001) were significant predictors of favorable SAR. The same significant predictors were selected for CSS. CONCLUSION: Recurrent OCCC can be treated with curative intent if the relapse is solitary and can be completely resected or encompassed with radiotherapy, whereas novel therapies are needed for disseminated relapse or progression during primary treatment.

Multifunctional Organic Emitters for High-Performance and Low-Cost Organic Light-Emitting Didoes.

Organic light-emitting diodes (OLEDs) have great potential applications in display and solid-state lighting. Stability, cost and high operational efficiency are key issues governing the future commercial application of OLEDs. In this context, searching for multifunctional emitting materials with acceptable light-emitting and charge-transporting characteristics has gained increasing attention. For achieving high-performance and low-cost OLEDs, the suitable molecular design featured with different electronic and optical nature should be incorporated by combining the advantages of both functional units into the same molecules. This review highlights recent and current advances in developing bifunctional or multifunctional molecules, with the focus on structures, properties, and applications in OLEDs and organic laser.

Signal/noise ratio of orbital angular momentum modes for a partially coherent modified Bessel-correlated beam in a biological tissue.

The random fluctuation of the refractive index is an important factor that affects the light transmission in a biological tissue. Here we have derived an expression of signal/noise ratio or equivalent intensity of the orbital angular momentum (OAM) mode for the partially coherent modified Bessel-correlated beam in a turbulent biological tissue. Effects of specific parameters of the biological tissue on it have been studied, such as the outer scale of the tissue index inhomogeneities, the fractal dimension of the particle size distribution, temperature fluctuation strength, and the cutoff correlation length. We argue that selecting a small quantum number of OAM modes is an effective means to improve signal transmission quality. We can adjust the propagation distance, the wavelength of the light source, and the diameter of the receiving aperture to obtain the optimum signal detection results. Also, nondiffracting vortex light can increase the communication channel capacity. Our findings will provide an important theoretical basis for the design and research of medical devices.

Positron emission tomography in the management of documented or suspected recurrent ovarian cancer.

BACKGROUND: To prospectively evaluate the value of positron emission tomography (PET) or integrated computed tomography (CT) and PET (PET/CT) in the management of documented or suspected recurrent ovarian cancer. METHODS: Patients with ovarian cancer who had completed primary cytoreductive surgery and standard adjuvant chemotherapy were studied to evaluate the following indications: (1) CA125 elevation after complete remission with negative CT or magnetic resonance imaging (MRI) result; (2) post-therapy surveillance CT/MRI-detected suspicious lesions that guided biopsy was not feasible; (3) documented relapse for restaging prior to or after curative salvage therapy. The clinical impact of PET, as compared with those of CT/MRI, was determined on a per scan basis. RESULTS: From 2002 to 2009, 73 patients were recruited, and 92 PET scans were performed. Up to June 2015, 53 patients had died of disease, four were alive with disease, and the remaining 16 were alive without disease. Among the 92 scans, PET had positive impacts in 72.8%, no clinical impacts in 21.7%, and negative impacts in 5.4%. For indication 1, the sensitivity and positive predictive value of PET in detecting recurrence were 80.0% and 92.3%, respectively. For indication 2, the sensitivity, specificity, positive predictive value, and negative predictive value of PET were 91.2%, 62.5%, 91.2%, and 62.5%, respectively. For indication 3, PET provided positive impact in 85.3% and negative impact in 2.9% of the 34 scans. CONCLUSION: PET has value in the management of suspected or documented recurrent ovarian cancer, with positive impacts on confirming recurrent status and offering a better treatment plan.

(18)F-FDG PET in small-cell cervical cancer: a prospective study with long-term follow-up.

PURPOSE: Small-cell cervical cancer (SCCC) is rare and prone to metastasize. We conducted a prospective study to evaluate the role of (18)F-FDG PET in the management of this aggressive malignancy. METHODS: Patients with untreated primary, histologically confirmed SCCC were enrolled. (18)F-FDG PET (or PET/CT) was performed immediately after MRI or CT, for primary staging, monitoring response to treatment or restaging when there was suspicion of recurrence. The clinical impact of PET was determined on a scan basis. RESULTS: A total of 25 patients were recruited and 43 PET scans were performed. The PET images were obtained for primary staging (25 patients), monitoring response (10 patients) and restaging when there was suspicion of recurrence (8 patients). The median follow-up time in event-free patients was 109.3 months (range 97.5 - 157.7 months). A positive impact of PET was found in 8 (18.6 %) of the 43 scans, which included detection of additional regions of distal lymph node (LN) metastasis (one primary staging scan, two restaging scans), bone metastasis (two primary staging scans, one monitoring response scan), and exclusion of false-positive lesions on MRI (one primary staging scan, one restaging scan). On the other hand, one negative impact was recorded as one false-positive lesion on a restaging PET scan. One positive impact was noted for monitoring response (bone metastasis). The impact of three scans was indeterminate. The positive impact of down-staging in avoiding overtreatment but finding additional distal LN (except one on restaging) or bone metastases had no beneficial effect on long-term survival. CONCLUSION: The results of this preliminary study suggest that PET is useful in the management of SCCC. PET could have more value in detecting occult metastases if future novel therapies are able to offer better control of extensive SCCC.

Propagation of the OAM mode carried by partially coherent modified Bessel-Gaussian beams in an anisotropic non-Kolmogorov marine atmosphere.

This study investigates the effect of the anisotropic non-Kolmogorov turbulence of the marine atmosphere on propagation of orbital angular momentum (OAM) modes carried by partially coherent modified Bessel-Gaussian (PCMBG) beams. The analytic formula of the probability density of OAM modes is derived and used to explore the evolution of the received power of the OAM mode. PCMBG beams with long wavelength, low quantum number of the OAM mode, and a high spectral degree of coherence of the source are robust for the OAM mode propagation in turbulence. The influences of the source characteristics and turbulent properties on the received power of the OAM mode are also analyzed in depth.

Effects of anisotropic turbulence on average polarizability of Gaussian Schell-model quantized beams through ocean link.

Based on the spatial power spectrum of the refractive index of anisotropic turbulence, the average polarizability of the Gaussian Schell-model quantized beams and lateral coherence length of the spherical wave propagating through the ocean water channel are derived. Numerical results show that, in strong temperature fluctuation, the depolarization effects of anisotropic turbulence are inferior to isotropic turbulence, as the other parameters of two links are the same. The depolarization effects of salinity fluctuation are less than the effects of the temperature fluctuation; the average polarizability of beams increases when increasing the inner scale of turbulence and the source's transverse size; and the larger rate of dissipation of kinetic energy per unit mass of fluid enhances the average polarizability of beams. The region of the receiving radius is smaller than the characteristic radius and the average polarizability of beams in isotropy turbulence is smaller than that of beams in anisotropy turbulence. However, the receiving radius region is larger than a characteristic radius and the average polarizability of beams in isotropy turbulence is larger than that of beams in anisotropy turbulence.

Self-sampling HPV test in women not undergoing Pap smear for more than 5 years and factors associated with under-screening in Taiwan.

BACKGROUND/PURPOSE: Under-utilization of Papanicolaou (Pap) smear causes a gap in the prevention of cervical neoplasms. A prospective population-based study was conducted investigating whether a self-sampling human papillomavirus (HPV) test was feasible for under-users of Pap smear and factors associated with under-screening in Taiwan. METHODS: Women not having Pap smear screening for > 5 years were invited to participate in this study. Invitation letters and educational brochures were mailed to 4% of randomly selected eligible women from Taoyuan City, Taiwan, and responders received an HPV self-sampling kit. Those with HPV-positive results were recalled for a Pap smear and colposcopy. RESULTS: Between March 2010 and June 2012, 10,693 women were invited, 354 responded (3.3%), and 282 (2.6%) gave valid informed consent, answered the questionnaire, and submitted HPV samples. The median age of enrolled women was 48.1 years. Forty-seven women (16.7%) had a positive HPV test, and 14 women accepted further survey to find two CIN2+. Another two cases of CIN2+ were identified from a national registry database. The cost of direct mailing self-samplers was less than that done on request (from NT$434,866 to NT$164,229, response rate of 5% to 15%, respectively, versus NT$683,957 for detecting 1 CIN2+). Reasons for not attending screening included lack of time, embarrassment, assumed low risk, fear of positive results, and perceived potential pain. Among the responders, 90.8% found the method acceptable. CONCLUSION: Our study indicated that different approaches (e.g., direct mailing self-samplers to under-users and/or various educational interventions) must be explored to improve coverage in populations with culture characteristics similar to Taiwan.

Serum concentrations of anthraquinones after intake of Folium Sennae and potential modulation on P-glycoprotein.

Folium Sennae (leaves of Cassia angustifolia or senna) is a laxative and a component in diets for weight control. It contains a variety of anthranoids such as sennosides, aloe-emodin, and rhein. In order to measure the serum concentrations of senna anthranoids, Sprague-Dawley rats were orally administered with single dose and multiple doses of Folium Sennae. The concentrations of anthranoids in serum were determined by HPLC method before and after hydrolysis with sulfatase and ß-glucuronidase. The results showed that in the serum, aloe-emodin glucuronides and rhein glucuronides were the major metabolites. Traces of rhein free form were present transiently during the early phase, whereas the free form of aloe-emodin was not detected. We also evaluated the modulation effect of Folium Sennae on P-glycoprotein by using the LS 180 cell model which showed that it significantly inhibited P-glycoprotein by 16-46 %. In conclusion, senna anthranoids were rapidly and extensively metabolized to rhein glucuronides and aloe-emodin glucuronides in rats. Folium Sennae ingestion inhibited the efflux function of P-glycoprotein in the intestine.

Site-specific immobilization of Cysteinyl leukotriene receptor 1 through enzymatic DNA-protein conjugation strategy for lead screening.

Immobilization of functional protein, especially G protein-coupled receptors (GPCRs), is particularly significant in various fields such as the development of assays for diagnosis, lead compound screening, as well as drug-protein interaction analysis. However, there are still some challenges with the immobilized proteins such as undefined loads, orientations, and the loss of activity. Herein, we introduced a DNA conjugation strategy into the immobilization of Cysteinyl leukotriene receptor 1(CysLTR1) which enables exquisite molecular control and higher activity of the receptor. We used the bacterial relaxases VirD2 as an immobilized tag fused at the C terminus of CysLTR1. Tyrosine residue(Y29) at the core binding site of the VirD2 tag can react with the single-strand piece of DNA(T-DNA) in the form of a covalent bond. Inspired by this strategy, we developed a new immobilization method by mixing the T-DNA-modified silica gel with the cell lysate containing the expressed VirD2-tagged CysLTR1 for 1 hour. We found that the successful formation of DNA-protein conjugate enables the immobilization of CysLTR1 fast, site-specific, and with minimal loss of activity. The feasibility of the immobilized CysLTR1 was evaluated in drug-protein binding interaction by frontal analysis and adsorption energy distribution analysis. The binding of pranlukast, zafirlukast, and MK571 to the immobilized CysLTR1 was realized, and the association constants presented good agreement between the two methods. Rosmarinic acid was retained in the immobilized CysLTR1 column, and the in-vitro test revealed that the compound binds to the receptor in one type of binding site mode. Despite these results, we concluded that the DNA-protein conjugate strategy will probably open up the possibilities for capturing other functional proteins in covalent and site-specific modes from the complex matrices and the immobilized receptor preserves the potential in fishing out lead compounds from natural products.

Potential Function of 3,5-Dihydroxy-4-Methoxybenzyl Alcohol from Pacific Oyster (Crassostrea gigas) in Brain of Old Mice.

SCOPE: 3,5-Dihydroxy-4-methoxybenzyl alcohol (DHMBA) is found in oyster extracts in recent years and is reported to have antioxidant activity. Although it has been reported to be protective in various models of oxidative stress, the therapeutic effect of DHMBA on neurological damage caused by aging remains to be demonstrated. METHODS AND RESULTS: The present study investigates the potential functions of DHMBA in brain of old C57BL/6J mice and aging cell model. Administration of DHMBA improves working memory, reduces anxiety behavior, decreases the expression levels of cell cycle proteins, cycin-dependent kinase inhibitor 1(P21) and peptidase inhibitor 16(P16)  and inhibits neuronal loss in old mice. The data obtained from the aging cell model are consistent with those from the old mice. The interaction between DHMBA and Kelch-like ECH-associated protein 1 (Keap1) is predicted by molecular docking assay, and then it is verified by co-immunopricipitation (CoIP) that factor red lineage 2-related factor 2 (Nrf2)-Keap1 protein-protein interaction is inhibited by DHMBA. Protein levels of Nrf2 and its target genes, such as glutathione peroxidase 4(GPX4) and heme oxygenase 1 (HO-1), are detected in old mice and aging cell model. CONCLUSION: This study provides new evidence that explores the antioxidant mechanism of DHMBA and implies a potential role of DHMBA on antiaging in brain.

Steric Effects on the Photovoltaic Performance of Panchromatic Ruthenium Sensitizers for Dye-Sensitized Solar Cells.

Three new heteroleptic Ru complexes, CYC-B22, CYC-B23C, and CYC-B23T, were prepared as sensitizers for coadsorbent-free, panchromatic, and efficient dye-sensitized solar cells. They are simultaneously functionalized with highly conjugated anchoring and ancillary ligands to explore the electronic and steric effects on their photovoltaic characteristics. The coadsorbent-free device based on CYC-B22 achieved the best power conversion efficiency (PCE) of 8.63% and a panchromatic response extending to 850 nm. The two stereoisomers, CYC-B23C and CYC-B23T coordinated with an unsymmetrical anchoring ligand, display similar absorption properties and the same driving forces for electron injection as well as dye regeneration. Nevertheless, the devices show not only the remarkably distinct PCE (6.64% vs 8.38%) but also discernible stability. The molecular simulation for the two stereoisomers adsorbed on TiO2 clarifies the distinguishable distances (16.9 Å vs 19.0 Å) between the sulfur atoms in the NCS ligands and the surface of the TiO2, dominating the charge recombination dynamics and iodine binding and therefore the PCE and stability of the devices. This study on the steric effects caused by the highly conjugated and unsymmetrical anchoring ligand on the adsorption geometry and photovoltaic performance of the dyes paves a new way for advancing the molecular design of polypyridyl metal complex sensitizers.

A nomogram based on TFE3 IHC results and clinical factors as a preliminary screening scheme for TFE3-rearranged renal cell carcinoma.

BACKGROUND: TFE3 immunohistochemistry (TFE3-IHC) is controversial in the diagnosis of TFE3-rearranged renal cell carcinoma (TFE3-rearranged RCC). This study is to investigate the accuracy and sensitivity of IHC and establish a predictive model to diagnose TFE3-rearranged RCC. METHODS: Retrospective analysis was performed by collecting IHC and fluorescence in situ hybridization (FISH) results from 228 patients. IHC results were evaluated using three scoring systems. Scoring system 1 is graded based on nuclear staining intensity, scoring system 2 is graded based on the percentage of stained tumor cell nuclei, and scoring system 3 is graded based on both the nuclear staining intensity and the percentage. We collected patients' IHC results and clinical information. Important variables were screened based on univariate logistic regression analysis. Then, independent risk factors were established through multivariate logistic regression, and a nomogram model was constructed. The model was validated in internal test set and external validation set. The receiver operating characteristic curve (ROC curve), calibration curve, and decision curve analysis (DCA) were generated to assess discriminative ability of the model. RESULTS: The accuracy of IHC based on three scoring systems were 0.829, 0.772, and 0.807, respectively. The model included four factors including age, gender, lymph node metastasis and IHC results. Area under the curve (AUC) values were 0.935 for the training set, 0.934 for the internal test set, 0.933 for all 228 patients, and 0.916 for the external validation set. CONCLUSIONS: TFE3 IHC has high accuracy in the diagnosis of TFE3-rearranged RCC. Clinical information such as age and lymph node metastasis are independent risk factors, which can be used as a supplement to the results of TFE3 IHC. This study confirms the value of IHC in the diagnosis of TFE3-rearranged RCC. The accuracy of the diagnosis can be improved by incorporating IHC with other clinical risk factors.

PABPC1L Induces IDO1 to Promote Tryptophan Metabolism and Immune Suppression in Renal Cell Carcinoma.

The tumor microenvironment (TME) in renal cell carcinomas (RCC) is marked by substantial immunosuppression and immune resistance despite having extensive T-cell infiltration. Elucidation of the mechanisms underlying immune evasion could help identify therapeutic strategies to boost the efficacy of immune checkpoint blockade (ICB) in RCC. This study uncovered a mechanism wherein the polyadenylate-binding protein PABPC1L modulates indoleamine 2,3-dioxygenase 1 (IDO1), a prospective target for immunotherapy. PABPC1L was markedly upregulated in RCC, and high PABPC1L expression correlated with unfavorable prognosis and resistance to ICB. PABPC1L bolstered tryptophan metabolism by upregulating IDO1, inducing T-cell dysfunction and Treg infiltration. PABPC1L enhanced the stability of JAK2 mRNA, leading to increased JAK2-STAT1 signaling that induced IDO1 expression. Additionally, PABPC1L-induced activation of the JAK2-STAT1 axis created a positive feedback loop to promote PABPC1L transcription. Conversely, loss of PABPC1L diminished IDO1 expression, mitigated cytotoxic T-cell suppression, and enhanced responsiveness to anti-PD-1 therapy in patient-derived xenograft models. These findings reveal the crucial role of PABPC1L in facilitating immune evasion in RCC and indicate that inhibiting PABPC1L could be a potential immunotherapeutic approach in combination with ICB to improve patient outcomes. SIGNIFICANCE: PABPC1L functions as a key factor in renal cell carcinoma immune evasion, enhancing IDO1 and impeding T-cell function, and represents a potential target to enhance the efficacy of immune checkpoint blockade therapy.