Abstract
Objective
To explore the immunohistochemistry-based molecular subtypes of bladder cancer, and their impact on the prognosis and the chemotherapy response between gemcitabine plus cisplatin ...intra-arterial chemotherapy and epirubicin-inducted intravesical chemotherapy, in patients with T1 stage bladder cancer after bladder-preserving treatment.
Methods
One hundred and seventy-six patients with T1 stage bladder cancer were selected for this study. Thirty-three patients underwent radical cystectomy, 43 received gemcitabine plus cisplatin intra-arterial chemotherapy and 100 received intravesical chemotherapy. The markers labeled with luminal (GATA3, Uroplakin II, CK20) and basal (CK5/6, CK14, CD44) phenotypes were chosen as candidate markers.
Results
One hundred and seventy-six patients were divided into 76 patients as basal/squamous (BASQ), 45 as the luminal A and 55 as the luminal B. Compared with the luminal B and BASQ tumors, the luminal A tumors showed a trend for better recurrence-free survival (P = 0.105) and progression-free survival (P = 0.093). The combination of CK20 and GATA3 was practical to identify the molecular phenotypes with total 84.9% accuracy and significantly associated with recurrence-free survival (P = 0.025) and progression-free survival (P = 0.004). The patient with BASQ tumors who received intravesical chemotherapy showed a trend for worse progression-free survival than the patient who received gemcitabine plus cisplatin intra-arterial chemotherapy or radical cystectomy. Furthermore, the patients with BASQ tumors experienced a significant improvement in progression-free survival after gemcitabine plus cisplatin intra-arterial chemotherapy compared with the patients who received intravesical chemotherapy (P = 0.011).
Conclusions
The immunohistochemistry-based molecular subtypes could predict the patient’s prognosis and clinically different chemotherapeutic survival outcomes in patients with T1 stage bladder cancer after bladder-preserving treatment.
The immunohistochemistry-based molecular subtypes were a predictor for prognosis and clinically different chemotherapeutic survival outcomes in patients with T1 stage bladder cancer after bladder-preserving treatment.
Pyruvate kinase isozyme type M2 (PKM2) catalyzes the final step in glycolysis and has been found to be up-regulated in multiple human malignancies. However, whether PKM2 regulates the ...radiosensitivity of human cervical cancer (CC) remains unknown.
The expression of PKM2 in 94 patients with CC in the complete response (CR) and noncomplete response (nCR) groups, was evaluated by immunohistochemistry. The effect of PKM2 inhibition on radiosensitivity, the cell cycle, DNA damage, and apoptosis was evaluated by immunofluorescence analysis, colony formation assay, flow cytometry analysis and Western blotting.
PKM2 expression was more highly expressed in the nCR group than that in CR group and PKM2 expression was enhanced in CC cells after ionizing radiation (IR). In addition, knockdown of PKM2 combined with IR significantly reduced cell growth, promoted apoptosis, and enhanced radiosensitivity. Additionally, knockdown of PKM2 with IR resulted in increased phosphorylation of DNA repair checkpoint proteins (ATM) and phosphorylated-H2AX. Moreover, knockdown of PKM2 combined with IR significantly increased the expression of cleaved caspase 3 and caspase 9, whereas Bcl2 expression was suppressed. Furthermore, knockdown of PKM2 combined with IR markedly reduced the expression of several cancer stem cell biomarkers in vitro, including NANOG, OCT4, SOX2, and Bmi1.
The results of our study suggests that PKM2 might be involved in mediating CC radiosensitivity and is identified as a potentially important target to enhance radiosensitivity in patients with CC.
The tumor immune microenvironment (TIME) plays an important role in penile squamous cell carcinoma (peSCC) pathogenesis. Here, the immunophenotype of the TIME in peSCC was determined by integrating ...the expression patterns of immune checkpoints (programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), cytotoxic T lymphocyte antigen 4 (CTLA-4), and Siglec-15) and the components of tumor-infiltrating lymphocytes, including CD8+ or Granzyme B+ T cells, FOXP3+ regulatory T cells, and CD68+ or CD206+ macrophages, in 178 patients. A high density of Granzyme B, FOXP3, CD68, CD206, PD-1, and CTLA-4 was associated with better disease-specific survival (DSS). The patients with diffuse PD-L1 tumor cell expression had worse prognoses than those with marginal or negative PD-L1 expression. Four immunophenotypes were identified by unsupervised clustering analysis, based on certain immune markers, which were associated with DSS and lymph node metastasis (LNM) in peSCC. There was no significant relationship between the immunophenotypes and high-risk human papillomavirus (hrHPV) infection. However, the hrHPV–positive peSCC exhibited a higher density of stromal Granzyme B and intratumoral PD-1 than the hrHPV–negative tumors (p = 0.049 and 0.002, respectively). In conclusion, the immunophenotypes of peSCC were of great value in predicting LNM and prognosis, and may provide support for clinical stratification management and immunotherapy intervention.
We assessed the prevalence of HPV DNA in a large series of Chinese penile cancer and examine its association with the histological subtype, p16
INK4a
expression, and prognosis. We pathologically ...categorized 226 invasive penile squamous cell carcinomas and assessed HPV genotyping by real-time PCR and p16
INK4a
immunohistochemistry. The results were correlated with histopathological and clinical parameters and disease-specific survival (DSS). HPV DNA was detected in 32.7% (74/226) of penile cancer cases. The most frequent genotype was HPV 16 (64/74, 86.5%), followed by HPV 18 (6/74, 8.1%). Fifty-nine (26.1%) cases were positive for the p16
INK4a
expression, and p16
INK4a
expression had a sensitivity of 56.8% (95% CI, 45.2–68.3%) and a specificity of 88.8% (95% CI, 83.8–93.9%) for defining HPV status. HPV DNA (
P
= 0.019), p16
INK4a
(
P
= 0.038), age (
P
= 0.018), grade of differentiation (
P
= 0.001), lymph nodes (
P
< 0.001), T stage (
P
< 0.001), M stage (
P
< 0.001), and lymphovascular invasion (LVI,
P
= 0.001) were prognostic factors for DSS. HPV-positivity (HR 0.334; 95% CI, 0.158–0.705,
P
= 0.004) was still a significant prognostic factor for DSS in the multivariate Cox regression model. HPV DNA was observed in one third of Chinese penile carcinoma cases. The p16INK4a expression can indicate high-risk human papillomavirus (HR-HPV). HPV-positive penile tumors confer a survival benefit over HPV-negative tumors.
UPK2 exhibits excellent specificity for urothelial carcinoma (UC). UPK2 evaluation can be useful in making the correct diagnosis of UC. However, UPK2 detection by immunohistochemistry (IHC) has ...relatively low sensitivity. This paper aimed to compare the diagnostic sensitivity of RNAscope and IHC for evaluation of the UPK2 status in UC.
Tissue blocks from 127 conventional bladder UCs, 45 variant bladder UCs, 24 upper tract UCs and 23 metastatic UCs were selected for this study. IHC and RNAscope were used to detect the UPK2 status in UCs. Then, comparisons of the two methods were undertaken.
There was no significant difference between RNAscope and IHC for the evaluation of the UPK2 positivity rate in UC (68.0% vs. 62.6%, P = 0.141). Correlation analysis revealed a moderate positive correlation for detection of UPK2: RNAscope vs. IHC (P < 0.001, R = 0.441). Our results showed a trend toward a higher positive UPK2 rate detected by RNAscope (53.3%) than by IHC (35.6%) in variant bladder UCs. Disappointingly, the P value did not indicate a significant difference (P = 0.057).
RNAscope for UPK2 appeared to perform similarly to IHC, with a marginally higher positive rate, suggesting it could be used as an alternative or adjunct to UPK2 IHC.
Introduction:
The use of antibodies against programmed death receptor-1 (PD-1) and its ligand (PD-L1) has improved survival in metastatic urothelial carcinoma (mUC) patients. However, reliable and ...convenient biomarkers of early responses and outcomes are still lacking.
Materials and Methods:
We retrospectively screened mUC patients who received anti–PD-1/PD-L1–based therapy at our institute. A modified urothelium immune prognostic index (mUIPI) based on the neutrophil-to-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) was developed to characterize the three groups as good, intermediate, and poor mUIPI. Major observations were progression-free survival (PFS), overall survival (OS), and disease control rate (DCR).
Results:
We identified 52 mUC patients with a median follow-up time of 29.8 months (95% CI, 26.3–53.2). Low NLR was with improved PFS and OS (hazard ratio HR, 0.40, 95% CI, 0.18–0.92; HR, 0.27, 95% CI, 0.11–0.69, respectively). Normal LDH was associated with improved PFS but not OS (HR, 0.22, 95% CI, 0.10–0.52; HR, 0.86, 95% CI, 0.34–2.13, respectively). The median PFS for the poor, intermediate, and good mUIPI groups was 1.97 months (95% CI, 1.15 to NR), 3.48 months (95% CI, 1.58 to NR), and 14.52 months (95% CI, 5.75 to NR), respectively (
p
< 0.001). The median OS for the poor, intermediate, and good mUIPI was 12.82, 18.11, and 34.87 months, respectively (
p
= 0.28). A good mUIPI was associated with a higher DCR compared to intermediate and poor mUIPI (odds ratio OR 7.58, 95% CI, 1.73–43.69; OR, 6.49, 95% CI, 0.14–295.42, respectively). In the subgroup analysis, a good mUIPI was associated with improved PFS in the subgroups of male patients and patients with low urinary tract primary tumors, liver metastases, non–first-line treatment, and monotherapy.
Conclusions:
mUIPI predicts early responses in mUC patients who received anti–PD-1/PD-L1–based therapy.
A universal, fast deformation–fluctuation hybrid approach with the merits of both the direct and fluctuation methods for evaluation of elastic constants is proposed. Deformation is shown to provide ...an inherent connection between the latter two methods. Based on this finding, the hybrid method utilizes group perturbation of atoms by means of six homogeneous deformations for fast evaluation of the Born term in the stress fluctuation method. The hybrid method is tested with three typical and widely used many-body potentials, i.e., for crystalline silicon with a Stillinger–Weber potential, for crystalline copper with second nearest-neighbor modified embedded-atom method and for diamond with a second-generation reactive empirical bond order potential. The calculated elastic constants agree well with either the theoretical or experimental results for all three cases. The hybrid method is especially valuable for complicated many-body potentials for which the analytical second derivative of the energy is challenging or impractical to obtain.
To deal with the problem that information shares hardly and data exchanges inefficiently in distribution system, various information systems need multi-source integration. The IEC61968-based ...information exchange platform is an effective means to resolve the integration problem, realizing seamless data exchange and sharing of data between various subsystems. This paper mainly analyzes the Distribution Management System (DMS) information integration architecture and the message structure. Firstly, the paper proposes a design scheme of power Enterprise Service Bus (ESB) based on Service-Oriented Architecture (SOA) which meeting IEC 61970/61968 standards. Meanwhile, by analyzing the message characteristic of IEC61968 standard, introduce a kind of message format which is suitable for the loosely coupled heterogeneous system with application services and integrating and information sharing. The proposed ESB architecture and message format can meet the need of data processing under different business integration scenes, so as to facilitate the information integration of distribution management system.
Retrograde axonal transport of nerve growth factor (NGF) signals is critical for the survival, differentiation, and maintenance of peripheral sympathetic and sensory neurons and basal forebrain ...cholinergic neurons. However, the mechanisms by which the NGF signal is propagated from the axon terminal to the cell body are yet to be fully elucidated. To gain insight into the mechanisms, we used quantum dot-labeled NGF (QD-NGF) to track the movement of NGF in real time in compartmentalized culture of rat dorsal root ganglion (DRG) neurons. Our studies showed that active transport of NGF within the axons was characterized by rapid, unidirectional movements interrupted by frequent pauses. Almost all movements were retrograde, but short-distance anterograde movements were occasionally observed. Surprisingly, quantitative analysis at the single molecule level demonstrated that the majority of NGF-containing endosomes contained only a single NGF dimer. Electron microscopic analysis of axonal vesicles carrying QD-NGF confirmed this finding. The majority of QD-NGF was found to localize in vesicles 50-150 nm in diameter with a single lumen and no visible intralumenal membranous components. Our findings point to the possibility that a single NGF dimer is sufficient to sustain signaling during retrograde axonal transport to the cell body.
Trastuzumab is a humanized mAb used to treat HER2-overexpressing breast cancer; however its mechanisms remain to be fully elucidated. Previous studies suggest a role for immunity in mediating ...trastuzumab-specific antitumor effects. This study evaluated the role(s) of trastuzumab and other antibodies on macrophage activation and Ab-dependent cell-mediated phagocytosis (ADCP) of HER2+ breast cancer cells in vitro and in vivo. We employed orthotopic implantation of HER2+ murine breast cancer (BC) cells in immunocompetent mouse models, a human HER2+ BC xenograft in an immune humanized mouse model, and human PDXs involving adoptive transfer of autologous macrophages to simulate an endogenous mammary tumor-immune microenvironment. Our study demonstrated that trastuzumab greatly and consistently increased macrophage frequency and tumor-cell phagocytosis, and that concurrent knockdown of B7-H4 by a neutralizing antibody increased immune cell infiltration and promoted an antitumor phenotype. Furthermore, neoadjuvant trastuzumab therapy significantly upregulated B7-H4 in the cancer-infiltrating macrophages of HER2+ BC patients, which predicted poor trastuzumab response. We suggest that strategies to specifically enhance ADCP activity might be critical to overcoming resistance to HER2 mAb therapies by inhibiting tumor growth and potentially enhance antigen presentation. Furthermore, these results advance the understanding of macrophage plasticity by uncovering a dual role for ADCP in macrophages involving elimination of tumors by engulfing cancer cells while causing a concomitant undesired effect by upregulating immunosuppressive checkpoints.
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