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The growth of a tumor depends to a certain extent on an increase in mitotic events. Key steps during mitosis are the regulated assembly of the spindle apparatus and the separation of the sister chromatids. The microtubule-associated protein Aurora kinase A phosphorylates DLGAP5 in order to correctly segregate the chromatids. Its activity and recruitment to the spindle apparatus is regulated by TPX2. KIF11 and CKAP5 control the correct arrangement of the microtubules and prevent their degradation. In the present study, we investigated the role of these five molecules in non-small cell lung cancer (NSCLC). We analyzed the expression of the five genes in a large cohort of NSCLC patients (n=362) by quantitative real-time PCR. Each of the genes was highly overexpressed in the tumor tissues compared to corresponding normal lung tissue. The correlation of the expression of the individual genes depended on the histology. An increased expression of AURKA, DLGAP5, TPX2, KIF11 and CKAP5 was associated with poor overall survival (P=0.001-0.065). AURKA was a significant prognostic marker using multivariate analyses (P=0.006). Immunofluorescence studies demonstrated that the five mitosis-associated proteins co-localized with the spindle apparatus during cell division. Taken together, our data demonstrate that the expression of the mitosis-associated genes AURKA, DLGAP5, TPX2, KIF11 and CKAP5 is associated with the prognosis of NSCLC patients.

Background: Triple-negative breast cancer (TNBC) has a poor prognosis because of frequent recurrence. Androgen receptor (AR) is involved in the pathogenesis of breast cancer, but its role is not clearly defined. The aim of this study was to explore the expression of AR and its relationship with clinicopathologic features in TNBC. Methods: This study investigated 1036 cases of sporadic invasive breast carcinoma. Immunohistochemical assays were performed to determine the expression of AR in 190 TNBC samples. The relationships between AR expression and clinicopathologic data and prognosis were analyzed. Results: In 190 TNBC cases, the prognosis of AR-positive patients was significantly better (p = 0.019, log-rank) than AR-negative patients, and in multivariate analysis, AR expression was an independent indicator of good prognosis (p = 0.039, hazard ratio = 0.36). In patients with disease relapse, AR positivity was significantly correlated with better prognosis (p = 0.034, log-rank). Conclusions: AR expression may be useful as a subclassification marker for prognosis in TNBC.

Activation of the NRF2 pathway through gain-of-function mutations or loss-of-function of its suppressor KEAP1 is a frequent finding in lung cancer. NRF2 activation has been reported to alter the tumor microenvironment. Here, we demonstrated that NRF2 alters tryptophan metabolism through the kynurenine pathway that is associated with a tumor-promoting, immune suppressed microenvironment. Specifically, proteomic profiles of 47 lung adenocarcinoma (LUAD) cell lines (11 KEAP1 mutant and 36 KEAP1 wild-type) revealed the tryptophan-kynurenine enzyme kynureninase (KYNU) as a top overexpressed protein associated with activated NRF2. The siRNA-mediated knockdown of NFE2L2, the gene encoding for NRF2, or activation of the NRF2 pathway through siRNA-mediated knockdown of KEAP1 or via chemical induction with the NRF2-activator CDDO-Me confirmed that NRF2 is a regulator of KYNU expression in LUAD. Metabolomic analyses confirmed KYNU to be enzymatically functional. Analysis of multiple independent gene expression datasets of LUAD, as well as a LUAD tumor microarray demonstrated that elevated KYNU was associated with immunosuppression, including potent induction of T-regulatory cells, increased levels of PD1 and PD-L1, and resulted in poorer survival. Our findings indicate a novel mechanism of NRF2 tumoral immunosuppression through upregulation of KYNU.

ABSTRACT Objective: To investigate the relationship between immature platelet fraction and poor short-term prognosis in dengue fever patients. Study Design: Comparative cross-sectional study. Place and Duration of Study: Pakistan Air Force Hospital, Islamabad Pakistan, from Oct to Dec 2022. Methodology: In this study, a total of 300 cases had a confirmed diagnosis of dengue fever and were admitted to the hospital. An immature platelet fraction was performed on all the patients on the fifth day of febrile illness. All the patients were monitored closely by the treating team at 24, 48, and 72 hours for the presence of thrombocytopenia on the complete blood picture or other clinical complications of dengue fever. Results: In the study, the median age of patients with dengue fever was 36(IQR-42) years. Out of 350 patients, 239(68.2%) were males, while 111(31.8%) were females. 282(80.5%) patients had a good prognosis, while 68(19.5%) did not have a good prognosis and showed clinical or haematological manifestations. On the fifth day of illness, 279(79.7%) had an IPF of >10%, whereas 71(20.3%) had an IPF of <10%. A statistical test revealed that IPF of less than 10% had a statistically significant association with poor prognosis in patients treated for dengue fever (p-value<0.001). Conclusion: The immature platelet fraction was found to be less than 10% in a considerable number of patients. In the first week of illness, a decreased immature platelet fraction was found to be associated with the presence of thrombocytopenia and other clinical complications among patients managed for dengue fever.

Background Breast cancer is a potentially fatal malignancy in females despite the improvement in therapeutic techniques. The identification of novel molecular signatures is needed for earlier detection, monitoring effects of treatment, and predicting prognosis. We have previously used microarray analysis to identify differentially expressed genes in aggressive breast tumors. The purpose of the present study was to investigate the prognostic value of the candidate biomarkers CCNB2 , ASPM , CDCA7 , KIAA0101, and SLC27A2 in breast cancer. Methods The expression levels and subcellular localization of the CCNB2, ASPM, CDCA7, KIAA0101, and SLC27A2 proteins were measured using immunohistochemistry (IHC) on a panel of 80 primary invasive breast tumors. Furthermore, the mRNA levels of CCNB2 , KIAA0101, and SLC27A2 were subsequently examined by qRT-PCR to validate IHC results. Patient disease-specific survival (DSS) was evaluated in correlation to protein levels using the Kaplan-Meier method. Multivariate Cox regression analysis was used to determine the impact of aberrant protein expression of the candidate biomarkers on patient DSS and to estimate the hazard ratio at 8-year follow-up. Results Elevated cytoplasmic CCNB2 protein levels were strongly associated with short-term disease-specific survival of breast cancer patients (≤ 8 years; P <0.001) and with histological tumor type ( P = 0.04). However, no association with other clinicopathological parameters was observed. Multivariate Cox regression analysis specified that CCNB2 protein expression is an independent prognostic marker of DSS in breast cancer. The predictive ability of several classical clinicopathological parameters was improved when used in conjunction with CCNB2 protein expression (C-index = 0.795) in comparison with a model without CCNB2 expression (C-index = 0.698). The protein levels of ASPM, CDCA7, KIAA0101, and SLC27A2 did not correlate with any clinicopathological parameter and had no influence on DSS. However, a significant correlation between the expression of the CCNB2 and ASPM proteins was detected ( P = 0.03). Conclusion These findings suggest that cytoplasmic CCNB2 may function as an oncogene and could serve as a potential biomarker of unfavorable prognosis over short-term follow-up in breast cancer.

Background: NSCLC (non-small cell lung cancer) has become the malignancy with the highest incidence and mortality rate worldwide. Fructose-6-phosphate 2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is a key regulator of glycolysis with both kinase and phosphatase activities. The Warburg effect, or increased glycolysis in tumors, provides the metabolic basis for cancer cell proliferation and metastasis, and the Warburg pathway enzyme PFKFB4 is a newly identified important kinase. This study aimed to elucidate the poor prognostic relevance of PFKFB4 in non-small cell lung cancer tissues and its relationship with immune cell infiltration, immune cell biomarkers, and immune checkpoints. Methods: In this study, immunohistochemical methods were used to assess PFKFB4 expression levels in 140 surgical specimens from patients with histologically confirmed non-small cell lung cancer and to investigate the relationship between PFKFB4 expression levels and the patients' clinicopathological characteristics. The impact of PFKFB4 expression on prognosis was evaluated using Kaplan--Meier survival analysis and Cox regression analysis. Results: When compared to normal paracrine tissues, PFKFB4 expression was enhanced in lung cancer tissues, and Kaplan--Meier survival analysis revealed that patients with high PFKFB4 expression had a worse prognosis. In NSCLC, PFKFB4 was found to be associated with immune cell infiltration and immunological checkpoints. Conclusion: PFKFB4 expression may be upregulated as a sign of poor prognosis in NSCLC, and PFKFB4 may be implicated not only in the genesis and progression of NSCLC but also in its immunological control. Keywords: PFKFB4, NSCLC, prognostic marker, immune cells

Inflammation-based prognostic markers based on a combination of blood-based parameters, including the modified Glasgow prognostic score (mGPS), have been associated with clinical outcomes in patients with various types of cancer. The present study aimed to evaluate and compare the accuracy of these previously reported markers in patients with metastatic pancreatic cancer receiving first-line chemotherapy. A total of 846 patients were identified between April 2010 and March 2020 as part of a nationwide real-world study from 46 Tokushukai medical group hospitals in Japan. Blood laboratory data collected within 14 days of starting first-line chemotherapy assessed 17 inflammation-based prognostic markers. Information from patients with no missing data was used to compare the accuracy and performance of the inflammation-based prognostic markers. A total of 487 patients were eligible for this supplemental analysis. The 17 inflammation-based markers demonstrated significant prognostic value. Among them, the concordance rate with overall survival (OS) was highest for mGPS. The median OS time of patients with mGPS 0, 1 and 2 was 8.2, 6.0 and 2.9 months, respectively. Compared with mGPS 0, mGPS 1 and 2 showed hazard ratios of 1.39 (95% confidence interval, 1.07-1.81) and 2.63 (2.00-3.45), respectively. The present real-world data analysis showed that various previously reported inflammation-based markers had significant prognostic value in patients with metastatic pancreatic cancer. Among these markers, the mGPS demonstrated the highest level of accuracy. This trial has been registered in the University Hospital Medical Information Network Clinical Trials Registry as UMIN000050590 on April 1, 2023.

Background： Traumatic brain injury （TBI） is a life-threatening disease worldwide. Regulatory T cells （Treg ceils） were involved in the immunological system in central nervous system. It is defined as a subpopulation of CD4＋ cells that express CD25 and transcription lactor forkhead box P3. The level of circulating Treg cells increases in a variety of pathologic conditions. The purpose of this study was to uncover the role of circulating Treg cells in TBI. Methods： A clinical study was conducted in two neurosurgical intensive care units of Tianjin Medical University General Hospital and Second Hospital of Tianjin Medical University （Tianjin, China）. Forty patients and 30 healthy controls were recruited t＇rom August 2013 to November 2013. Circulating Treg cells was detected on the follow-up period of 1,4, 7, 14, and 21 days alter TBI. Blood sample （ 1 ml） was withdrawn in the morning and processed within 2 h. Results： There was no significant difference in the level of circulating Treg cells between TBI patients and normal controls during follow-up. TBI patients exhibited higher circulating Treg level than normal controls on the 1st day after TBI. Treg level was decreased on the 4th day, climbed tip on the 7th day and peaked on 14th day after TBI. Treg cells declined to the normal level on 21th day alter TBI. The level of circulating Treg cells was significantly higher in survival TBI patients when compared to nonsurvival TBI patients. TBI patients with improved conditions exhibited significantly higher circulating Treg level when compared to those with deteriorated conditions. The circulating Treg level was correlated with neurologic recovery after TBI. A better neural recovery and lower hospital mortality were found in TBI patients with circulating Treg cells more than 4.91% in total CD4＋ inononuclear cells as compared to those with circulating Treg cells less than 4.91% in total CD4 mononuclear cells in the first 14 days. Conclusions： The level of circulating Treg cells is positively correlated with clinical outcome of TBI. The level of Treg cells predicts the progress for TBI patients and may be a target in TBI treatment.

Serum visceral proteins such as albumin and prealbumin have traditionally been used as markers of the nutritional status of patients. Prealbumin is nowadays often preferred over albumin due to its shorter half live, reflecting more rapid changes of the nutritional state. However, recent focus has been on an appropriate nutrition-focused physical examination and on the patient’s history for diagnosing malnutrition, and the role of inflammation as a risk factor for malnutrition has been more and more recognized. Inflammatory signals are potent inhibitors of visceral protein synthesis, and the use of these proteins as biomarkers of the nutritional status has been debated since they are strongly influenced by inflammation and less so by protein energy stores. The current consensus is that laboratory markers could be used as a complement to a thorough physical examination. Other markers of the nutritional status such as urinary creatinine or 3-methylhistidine as indicators of muscle protein breakdown have not found widespread use. Serum IGF-1 is less influenced by inflammation and falls during malnutrition. However, its concentration changes are not sufficiently specific to be useful clinically as a marker of malnutrition, and serum IGF-1 has less been used in clinical trials. Nevertheless, biomarkers of malnutrition such as prealbumin may be of interest as easily measurable predictors of the prognosis for surgical outcomes and of mortality in severe illnesses.

Background. Pediatric-onset Sjögren’s disease (pSjD) presents distinct clinical and serological features compared with the adult form (SjD). While adults more frequently exhibit sicca symptoms such as xerophthalmia and xerostomia, parotid swelling and cutaneous involvement are the most common clinical manifestations in pSjD. From a serological perspective, pediatric patients less frequently test positive for ANA and anti-SSA/SSB antibodies but tend to show higher levels of rheumatoid factor (RF). The aim of this study was to compare the histopathological characteristics of minor salivary gland (MSG) biopsies between pediatric and adult patients with SjD.   Materials and Methods. The study included 18 consecutive patients with pSjD followed at an Italian pediatric rheumatology center and 54 consecutively evaluated adult SjD patients from an adult rheumatology unit. All biopsy samples were examined by an expert pathologist at each site according to the EULAR recommendations for standardized histopathological assessment of minor salivary gland biopsies.   Results. The surface area of biopsy specimens did not differ significantly between the two groups (p = 0.551). Pediatric patients displayed significantly higher focus scores (p = 0.0227) and a greater prevalence of ectopic germinal centers, as evidenced by increased CD21 (52.94% vs. 16.22%, p = 0.005) and Bcl6 expression (47.06% vs. 8.11%, p = 0.0011). Lymphoepithelial lesions were also more frequent in the pediatric cohort (55.56% vs. 18.92%, p = 0.0065), as was fibrosis (66.67% vs. 29.73%, p = 0.031). No significant differences were observed for glandular atrophy (p = 0.687) or ductal dilation (p = 0.128). When stratified by disease onset relative to menarche, prepubertal-onset patients exhibited a higher frequency of germinal centers and lymphoepithelial lesions than those with postpubertal-onset disease (p < 0.05).   Conclusions. This study represents the first direct histopathological comparison of minor salivary gland biopsies between pediatric and adult patients with Sjögren’s disease. The findings confirm a more pronounced inflammatory pattern in pediatric patients, consistent with the higher clinical activity observed in this population. In particular, the increased frequency of ectopic germinal centers and lymphoepithelial lesions in prepubertal-onset cases suggests the possible involvement of age-dependent immunopathogenic mechanisms underlying early-onset pSjD. These results reinforce the pivotal role of minor salivary gland biopsy not only in diagnosis but also in disease prognostication, emphasizing the importance of early recognition and close clinical monitoring in pediatric patients.