Prostate cancer is now becoming an emerging health priority in East Asia. Most of our current knowledge on Prostate cancer has been generated from studies conducted in Western population; however, ...there is considerable heterogeneity of Prostate cancer between East and West. In this article, we reviewed epidemiologic trends, risk factors, disease characteristics and management of Prostate cancer in East Asian population over the last decade. Growing evidence from East Asia suggests an important role of genetic and environmental risk factors interactions in the carcinogenesis of Prostate cancer. Exposure to westernized diet and life style and improvement in health care in combination contribute substantially to the increasing epidemic in this region. Diagnostic and treatment guidelines in East Asia are largely based on Western knowledge. Although there is a remarkable improvement in the outcome over the last decade, ample evidence suggests an inneglectable difference in diagnostic accuracy, treatment efficacy and adverse events between different populations. The knowledge from western countries should be calibrated in the Asian setting to provide a better race-based treatment approach. In this review, we intend to reveal the evolving trend of Prostate cancer in the last decade, in order to gain evidence to improve Prostate cancer prevention and control in East Asia.
BackgroundTertiary lymphoid structures (TLS) are organized aggregates of immune cells that develop postnatally in non-lymphoid tissues and are associated with pathological conditions. TLS typically ...comprise B-cell follicles containing and are encompassed by T- cell zones and dendritic cells. The prognostic and predictive value of TLS in the tumor microenvironment (TME) as potential mediators of antitumor immunity have gained interest. However, the precise relationship between localization and maturation of TLS and the clinical outcome of their presence in clear cell renal cell carcinoma (ccRCC) is yet to be elucidated.MethodsImmunohistochemistry and multispectral fluorescence were used to evaluate the TLS heterogeneity along with TME cell-infiltrating characterizations. A thorough investigation of the prognostic implications of the TLS heterogeneity in 395 patients with ccRCC from two independent cohorts was conducted. Associations between TLS heterogeneity and immunologic activity were assessed by quantifying the immune cell infiltration.ResultsInfiltrated TLS were identified in 34.2% of the ccRCC samples (N=395). These TLS were found to be tumor-proximal, tumor-distal, or both in 37.8%, 74.1%, and 11.9% of the TLS-positive cases, respectively. A higher proportion of early TLS was found in tumor-distal TLS (p=0.016), while tumor-proximal TLS primarily comprised secondary follicle-like structures (p=0.004). In the main study cohort (Fudan University Shanghai Cancer Center, N=290), Kaplan-Meier analyses revealed a significant correlation between the presence of tumor-proximal TLS and improved progression-free survival (PFS, p<0.001) and overall survival (OS, p=0.002). Conversely, the presence of tumor-distal TLS was associated with poor PFS (p=0.02) and OS (p=0.021). These findings were further validated in an external validation set of 105 patients with ccRCC. Notably, the presence of mature TLS (namely secondary follicle-like TLS, with CD23+ germinal center) was significantly associated with better clinical outcomes in patients with ccRCC. Furthermore, novel nomograms incorporating the presence of tumor-proximal TLS demonstrated remarkable predictability for the 8-year outcomes of resected ccRCC (area under the curve >0.80). Additionally, ccRCC samples with tumor-distal TLS enriched with primary follicle-like TLS exhibited higher programmed death-ligand 1 tumor-associated macrophages levels and regulatory T cells infiltration in the tumor-distal region, indicative of a suppressive TME.ConclusionThis study for the first time elucidates the impact of TLS localization and maturation heterogeneities on the divergent clinical outcomes of ccRCC. The findings reveal that most TLS in ccRCC are located in the tumor-distal area and are associated with immature, immunosuppressive characterizations. Furthermore, our findings corroborate previous research demonstrating that tumor-proximal TLS were associated with favorable clinical outcomes.
Growing evidence has highlighted the immune response as an important feature of carcinogenesis and therapeutic efficacy in clear cell renal cell carcinoma (ccRCC). This study categorized ccRCC cases ...into high and low score groups based on their immune/stromal scores generated by the ESTIMATE algorithm, and identified an association between these scores and prognosis. Differentially expressed tumor environment (TME)-related genes extracted from common upregulated components in immune and stromal scores were described using functional annotations and protein-protein interaction (PPI) networks. Most PPIs were selected for further prognostic investigation. Many additional previously neglected signatures, including
, exhibited significant prognostic potential. In addition, multivariate Cox analysis indicated that
and
were the most significant prognostic signatures, and were closely related to immune infiltration in TCGA cohort. External prognostic validation of
and
was undertaken in 380 ccRCC cases from a real-world cohort. These findings indicate the relevance of monitoring and manipulation of the microenvironment for ccRCC prognosis and precision immunotherapy.
To evaluate the roles of climate and hydrology in continental-scale silicate weathering, we applied Li isotopes to the Yellow River and systematically investigated seasonal Li flux, Li isotopic ...compositions and potential sources. We collected samples from the middle reaches of the Yellow River weekly over the full hydrological year of 2013. We find that the dissolved Li is mainly derived from silicates and evaporites in the arid to semi-arid Yellow River basin. Silicate weathering of loess during the monsoonal season dominates the Li flux in the middle reaches of the Yellow River, with a positive relationship between dissolved Li flux and physical erosion rate. Evaporite contribution for riverine Li was relatively constant in the middle reaches of the Yellow River but slightly increased after the storm event, with an average proportion of ∼25%, which might represent the proportion of evaporite contribution to global oceans. Seasonal variations in the riverine Li isotopic compositions are dominantly controlled by temperature with a fractionation gradient as −0.182‰ per °C over the full year with deviations likely driven by re-dissolution of suspended particulate matter, extreme hydrological events, and groundwater contribution. Temperature dependent δ7Li value variation of river water inputted into oceans indicates that Cenozoic climate cooling itself may be able to explain ∼2‰ of the 9‰ rise of Cenozoic seawater δ7Li value (Misra and Froelich, 2012). The seasonal variation in riverine Li isotopes highlights that erosion and weathering of loess may provide valuable clues on secular chemical weathering and seawater δ7Li variation spanning a range of time scales.
PYCARD is a protein engaged in inflammation, pyroptosis, and apoptosis. However, the function of PYCARD in human cancers remains unclear. The objective of our study was to explore PYCARD expression ...and prognostic value in human cancers. Public databases were used to assess PYCARD expression and prognostic value. The TISIDB database was used to explore the associations between PYCARD expression and different immune subtypes. The correlations between PYCARD expression and ICP genes, MMR genes, MSI, and TMB were also investigated. The immunotherapy response was assessed using the TIDE database. Single-cell RNA databases evaluated the PYCARD expression of immune cells. External datasets and immunohistochemical staining were conducted to validate PYCARD expression and prognostic value. The results showed that PYCARD expression varied in several cancers and was associated with prognosis, immune-related genes, published biomarkers, and immunotherapy response. Of note, PYCARD expression was upregulated in renal cancers with high diagnostic ability. Upregulation of PYCARD was correlated with worse prognosis in KIRC and external validation cohorts. In conclusion, PYCARD demonstrated strong correlations with prognosis, immune response, and disease progression in pan-cancer analysis. In ccRCC, PYCARD might serve as a biomarker for diagnosis and therapeutic target-boosting immunotherapy response.
This study aims to identify potential prognostic and therapeutic biomarkers in papillary renal cell carcinoma (pRCC).
Two microarray datasets were downloaded from the Gene Expression Omnibus (GEO) ...database and differentially expressed genes (DEGs) were identified. The protein-protein interaction (PPI) networks and functional annotations of DEGs were established. Survival analysis was utilized to evaluate the prognostic significance of the DEGs and the association between the expression level of candidate biomarkers and various tumour-infiltrating immune cells was explored. The role of PTTG1 in tumour microenvironments (TME) was further explored using Single-cell RNA-seq and its prognostic and therapeutic significance was validated in Fudan University Shanghai Cancer Centre (FUSCC) cohort.
Eight genes, including BUB1B, CCNB1, CCNB2, MAD2L1, TTK, CDC20, PTTG1, and MCM were found to be negatively associated with patients' prognosis. The expression level of PTTG1 was found to be significantly associated with lymphocytes, immunomodulators, and chemokine in the TCGA cohort. Single-cell RNA-seq information indicated that PTTG1 was strongly associated with the proliferation of T cells. In the FUSCC cohort, the expression level of PTTG1 was also statistically significant for both progression-free survival (PFS) and overall survival (OS) prediction (HR = 2.683, p < .001; HR = 2.673, p = .001). And higher expression level of PTTG1 was significantly associated with immune checkpoint blockade (ICB) response in the FUSCC cohort (χ
2
=3.99, p
< .05).
Eight genes were identified as a prognostic biomarker and the expression level of PTTG1 was also found to serve as a potential predictor for ICB response in pRCC patients.
Key messages:
Eight genes, including BUB1B, CCNB1, CCNB2, MAD2L1, TTK, CDC20, PTTG1, and MCM were found to be negatively associated with pRCC patients' prognosis.
Expression level of PTTG1 was significantly associated with tumour microenvironment including lymphocytes, immunomodulators, and chemokines.
Higher expression level of PTTG1 was significantly associated with immune checkpoint blockade (ICB) response in FUSCC cohort
Nimotuzumab is a humanized IgG1 monoclonal antibody specifically targeting EGFR. In this study, we aimed to investigate the molecular mechanisms of nimotuzumab in its effects of enhancing cancer cell ...radiosensitivity.
Lung cancer A549 cells and breast cancer MCF-7 cells were pretreated with or without nimotuzumab for 24 h before radiation to perform the clonogenic survival assay and to analyze the cell apoptosis by flow ctyometry. γ-H2AX foci were detected by confocal microscopy to assess the effect of nimotuzumab on radiation induced DNA repair. EGFR activation was examined and the levels of DNA damage repair related proteins in A549 cells at different time point and at varying doses exposure after nimotuzumab and radiation treatment were examined by Western blot. Pretreatment with nimotuzumab reduced clonogenic survival after radiation, inhibited radiation-induced EGFR activation and increased the radiation-induced apoptosis in both A549 cells and MCF-7 cells. The foci of γ-H2AX 24 h after radiation significantly increased in nimotuzumab pretreated cells with different doses. The phosphorylation of AKT and DNA-PKcs were remarkably inhibited in the combination group at each dose point as well as time point.
Our results revealed that the possible mechanism of nimotuzumab enhancing the cancer radiosensitivity is that nimotuzumab inhibited the radiation-induced activation of DNA-PKcs through blocking the PI3K/AKT pathway, which ultimately affected the DNA DSBs repair.
Abstract
Speed and enhancement are the two most important metrics for anti-scattering light focusing by wavefront shaping (WS), which requires a spatial light modulator with a large number of ...modulation modes and a fast speed of response. Among the commercial modulators, the digital-micromirror device (DMD) is the sole solution providing millions of modulation modes and a pattern rate higher than 20 kHz. Thus, it has the potential to accelerate the process of anti-scattering light focusing with a high enhancement. Nevertheless, modulating light in a binary mode by the DMD restricts both the speed and enhancement seriously. Here, we propose a multi-pixel encoded DMD-based WS method by combining multiple micromirrors into a single modulation unit to overcome the drawbacks of binary modulation. In addition, to efficiently optimize the wavefront, we adopted separable natural evolution strategies (SNES), which could carry out a global search against a noisy environment. Compared with the state-of-the-art DMD-based WS method, the proposed method increased the speed of optimization and enhancement of focus by a factor of 179 and 16, respectively. In our demonstration, we achieved 10 foci with homogeneous brightness at a high speed and formed W- and S-shape patterns against the scattering medium. The experimental results suggest that the proposed method will pave a new avenue for WS in the applications of biomedical imaging, photon therapy, optogenetics, dynamic holographic display, etc.
Abstract
Background
To identify the malignant potential and prognostic indicators of renal epithelioid angiomyolipoma (eAML), clinicopathological and molecular features as well as the drug efficacy ...of 67 eAML cases were analyzed.
Materials and methods
Sixty-seven renal eAML patients were enrolled and the immunohistochemical features of these patients were examined. FFPE slides of all patients were re-examined. 21 patients with metastasis received Everolimus 10 mg orally once daily. Responses were evaluated with RECIST criteria by three authors. A risk stratification model was constructed using the following factors: pT3 and pT4, presence of necrosis, mitotic count ≥ 2; the presence of atypical mitoses; severe nuclear atypia, SMA negative, Ki-67 ≥ 10%.
Results
The average percentage of the epithelioid component was 85.6% (range 80–95%). Immunohistochemically, Ki-67 ≥ 10% and negative SMA staining were significantly correlated with malignant characteristics (Ki-67:
p
< 0.001; SMA:
p
= 0.001). Survival analysis suggested that pT3-pT4 stage, presence of necrosis, severe nuclear atypia, presence of atypical mitoses, mitotic count ≥ 2, Ki-67 ≥ 10% and negative SMA expression were significantly associated with poorer PFS and OS (
p
< 0.05). The risk model sufficiently discriminated recurrence/metastasis (AUC = 0.897) and cancer-specific mortality (AUC = 0.932) of renal eAML patients in different risk groups. 21 patients had received Everolimus targeted therapy after recurrence/metastasis. The best response for Everolimus treatment was 8/21 (38.1%) partial responses (PR), 9/21 (42.9%) stable disease (SD) and 4/21 (19.0%) progressive disease (PD).
Conclusion
The risk stratification model could well distinguish eAML patients at high risk of recurrence/metastasis. Everolimus targeted treatment showed good efficacy in patients with recurrence/metastasis.
In vitro models of the blood-brain barrier (BBB) are critical tools for the study of BBB transport and the development of drugs that can reach the CNS. Brain endothelial cells grown in culture are ...often used to model the BBB; however, it is challenging to maintain reproducible BBB properties and function. 'BBB organoids' are obtained following coculture of endothelial cells, pericytes and astrocytes under low-adhesion conditions. These organoids reproduce many features of the BBB, including the expression of tight junctions, molecular transporters and drug efflux pumps, and hence can be used to model drug transport across the BBB. This protocol provides a comprehensive description of the techniques required to culture and maintain BBB organoids. We also describe two separate detection approaches that can be used to analyze drug penetration into the organoids: confocal fluorescence microscopy and mass spectrometry imaging. Using our protocol, BBB organoids can be established within 2-3 d. An additional day is required to analyze drug permeability. The BBB organoid platform represents an accurate, versatile and cost-effective in vitro tool. It can easily be scaled to a high-throughput format, offering a tool for BBB modeling that could accelerate therapeutic discovery for the treatment of various neuropathologies.
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