Investigation of the role of nutrients for protection against acute kidney injury

Ischaemia reperfusion injury and nephrotoxicity are the common insults of acute kidney injury. Drug induced nephrotoxicity can also lead to an ischaemic phenomenon. The key mediator to both insults is oxidative injury caused by reactive oxygen species, and prolonged injury can result in irreversible kidney fibrosis and chronic kidney disease. This thesis developed a simulated ischaemia reperfusion injury in an in-vitro model to investigate whether amino acid supplementation may facilitate human proximal tubule cell recovery and protect from H2O2 damage following starvation and whether this was mediated by pH. The findings showed that resupply of amino acids at pH 7.5 under H2O2 injury after starvation exacerbated cell death. The mammalian target of rapamycin was also activated in response to amino acids in a concentration dependent manner even if under H2O2 damage, but the link between mammalian target of rapamycin activation and endoplasmic reticulum stress leading to cell death was not yet identified in this thesis. The constant expression of chaperone protein Grp78 may suggest the persistent cellular stress caused by starvation. While amino acids at pH 6.4 failed to activate the mammalian target of rapamycin and potentially reduced protein synthesis, it still exacerbated cell death under H2O2 damage. It also inhibited Grp78 expression, but the link between Grp78 inhibition and cell death was unclear. Moreover, this thesis established an aristolochic acid induced nephrotoxicity in mice and investigated whether another putative nutrient, sodium nitrite, could be renoprotective. However, the therapeutic effects of sodium nitrite remain to be confirmed, as aristolochic acid did not induce any injury in this animal model. Overall, this thesis implicated that the return of circulating amino acids may be detrimental for ischaemia reperfusion injury and that antioxidant therapy may be the priority for acute kidney injury

Reassessment of Progression-Free Survival as a Surrogate End Point of Overall Survival

Progression-free survival (PFS) has been increasingly used as a surrogate endpoint for overall survival (OS) by FDA in cancer drug approval. However, whether PFS can fully represent OS has remained uncertain. Breast cancer is the most prevalent cancer among females, and PFS has been the most common endpoint in drug approval trials for decades. Nevertheless, studies have shown conflicting results on whether PFS correlates with OS among subtypes of breast cancer and across different treatments. This study aims to reassess the correlation between PFS and OS in breast cancer, and evaluate under what circumstances can we consider using PFS as a surrogate of OS.Doctor of Pharmac

Purification and Characterization of Hemagglutinating Proteins from Poker-Chip Venus (Meretrix lusoria) and Corbicula Clam (Corbicula fluminea)

Hemagglutinating proteins (HAPs) were purified from Poker-chip Venus (Meretrix lusoria) and Corbicula clam (Corbicula fluminea) using gel-filtration chromatography on a Sephacryl S-300 column. The molecular weights of the HAPs obtained from Poker-chip Venus and Corbicula clam were 358 kDa and 380 kDa, respectively. Purified HAP from Poker-chip Venus yielded two subunits with molecular weights of 26 kDa and 29 kDa. However, only one HAP subunit was purified from Corbicula clam, and its molecular weight was 32 kDa. The two Poker-chip Venus HAPs possessed hemagglutinating ability (HAA) for erythrocytes of some vertebrate animal species, especially tilapia. Moreover, HAA of the HAP purified from Poker-chip Venus was higher than that of the HAP of Corbicula clam. Furthermore, Poker-chip Venus HAPs possessed better HAA at a pH higher than 7.0. When the temperature was at 4°C–10°C or the salinity was less than 0.5‰, the two Poker-chip Venus HAPs possessed better HAA compared with that of Corbicula clam

Integrated analysis of the prostate cancer small-nucleolar transcriptome reveals <i>SNORA55</i> as a driver of prostate cancer progression

Metastasis is the primary cause of death in prostate cancer (PCa) patients. Small nucleolar RNAs (snoRNAs) have long been considered "housekeeping" genes with no relevance for cancer biology. Emerging evidence has challenged this assumption, suggesting that snoRNA expression is frequently modulated during cancer progression. Despite this, no study has systematically addressed the prognostic and functional significance of snoRNAs in PCa. We performed RNA Sequencing on paired metastatic/non-metastatic PCa xenografts derived from clinical specimens. The clinical significance of differentially expressed snoRNAs was further investigated in two independent primary PCa cohorts (131 and 43 patients, respectively). The snoRNA demonstrating the strongest association with clinical outcome was quantified in PCa patient-derived serum samples and its functional relevance was investigated in PCa cells via gene expression profiling, pathway analysis and gene silencing. Our comparison revealed 21 differentially expressed snoRNAs in the metastatic vs. non-metastatic xenografts. Of those, 12 were represented in clinical databases and were further analyzed. SNORA55 emerged as a predictor of shorter relapse-free survival (results confirmed in two independent databases). SNORA55 was reproducibly detectable in serum samples from PCa patients. SNORA55 silencing in PCa cell lines significantly inhibited cell proliferation and migration. Pathway analysis revealed that SNORA55 expression is significantly associated with growth factor signaling and pro-inflammatory cytokine expression in PCa. Our results demonstrate that SNORA55 up-regulation predicts PCa progression and that silencing this non-coding gene affects PCa cell proliferation and metastatic potential, thus positioning it as both a novel biomarker and therapeutic target

Hazard-based risk grouping effectively stratifying breast cancer patients in post-irradiation long-term heart diseases: a population-based cohort study

BackgroundEven though advanced radiotherapy techniques provide a better protective effect on surrounding normal tissues, the late sequelae from radiation exposure to the heart are still considerable in breast cancer patients. The present population-based study explored the role of cox-regression-based hazard risk grouping and intended to stratify patients with post-irradiation long-term heart diseases.Materials and methodsThe present study investigated the Taiwan National Health Insurance (TNHI) database. From 2000 to 2017, we identified 158,798 breast cancer patients. Using a propensity score match of 1:1, we included 21,123 patients in each left and right breast irradiation cohort. Heart diseases, including heart failure (HF), ischemic heart disease (IHD), and other heart diseases (OHD), and anticancer agents, including epirubicin, doxorubicin, and trastuzumab, were included for analysis.ResultsPatients received left breast irradiation demonstrated increased risks on IHD (aHR, 1.16; 95% CI, 1.06–1.26; p &lt; 0.01) and OHD (aHR, 1.08; 95% CI, 1.01–1.15; p &lt; 0.05), but not HF (aHR, 1.11; 95% CI, 0.96–1.28; p = 0.14), when compared with patients received right breast irradiation. In patients who received left breast irradiation dose of &gt;6,040 cGy, subsequent epirubicin might have a trend to increase the risk of heart failure (aHR, 1.53; 95% CI, 0.98–2.39; p = 0.058), while doxorubicin (aHR, 0.59; 95% CI, 0.26–1.32; p = 0.19) and trastuzumab (aHR, 0.93; 95% CI, 0.33–2.62; p = 0.89) did not. Older age was the highest independent risk factor for post-irradiation long-term heart diseases.ConclusionGenerally, systemic anticancer agents are safe in conjunction with radiotherapy for managing post-operative breast cancer patients. Hazard-based risk grouping may help stratify breast cancer patients associated with post-irradiation long-term heart diseases. Notably, radiotherapy should be performed cautiously for elderly left breast cancer patients who received epirubicin. Limited irradiation dose to the heart should be critically considered. Regular monitoring of potential signs of heart failure may be conducted

Porcine circovirus type 2 (PCV2) induces cell proliferation, fusion, and chemokine expression in swine monocytic cells in vitro

Granulomatous lymphadenitis is one of the pathognomonic lesions in post-weaning multisystemic wasting syndrome (PMWS)-affected pigs. This unique lesion has not been reported in direct association with viral infection in pigs. The objective of the present study was to evaluate whether porcine circovirus type 2 (PCV2) alone is able to induce functional modulation in porcine monocytic cells in vitro to elucidate its possible role in the development of granulomatous inflammation. It was found that the proliferation activity of blood monocytes (Mo) and monocyte-derived macrophages (MDM) was significantly enhanced by PCV2. During monocyte-macrophage differentiation, the PCV2 antigen-containing rate and formation of multinucleated giant cells (MGC) were significantly increased in MDM when compared to those in Mo. The MDM-derived MGC displayed a significantly higher PCV2 antigen-containing rate than did the mono-nucleated MDM. Supernatants from PCV2-inoculated MDM at 24 h post-inoculation induced an increased tendency of chemotactic activity for blood Mo. At the same inoculation time period, levels of mRNA expression of the monocytic chemokines, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1, also significantly increased in PCV2-inoculated MDM. The results suggest that PCV2 alone may induce cell proliferation, fusion, and chemokine expression in swine monocytic cells. Thus, PCV2 itself may play a significant role in the induction of granulomatous inflammation in PMWS-affected pigs

Comparative outcomes of SARS-CoV-2 primary and reinfection in older adult patients

BackgroundThe outcomes of older adult people acquiring SARS-CoV-2 reinfection was unclear. This study aimed to compare the outcomes of older adult patients with COVID-19 reinfection and those with primary infection.MethodsThis retrospective cohort study used electronic medical records from the TriNetX Research Network. Older adult patients (aged ≥65 years) with COVID-19 between January 1, 2022, and December 31, 2022, were included in the study. The patients were subsequently categorized into reinfection or primary infection groups, according to whether they manifested two distinct COVID-19 episodes with an intervening period of more than 90 days. Propensity score matching was performed for covariate adjustment between the reinfection and primary infection groups. The primary outcome was a composite outcome, including emergency department visits, hospitalization, intensive care unit admission, mechanical ventilation use, and mortality, following primary infection and reinfection.ResultsAfter matching, 31,899 patients were identified in both the reinfection and primary infection groups. The risk of primary composite outcomes was 7.15% (n = 2,281) in the reinfection group and 7.53% (n = 2,403) in the primary infection group. No significant difference in the primary outcome was observed between groups (HR, 0.96; 95% CI, 0.91 to 1.02, p = 0.17). In addition, there was no significant differences between the reinfection and primary infection groups in terms of emergency department visit (HR, 1.03; 95% CI, 0.95 to 1.11, p = 0.49), all-cause hospitalization (HR, 0.94; 95% CI, 0.86 to 1.02, p = 0.14), intensive care unit admission (HR, 0.92; 95% CI, 0.67 to 1.28, p = 0.62), mechanical ventilation use (HR,1.35 95% CI, 0.69 to 2.64 p = 0.38), and all-cause mortality (HR, 0.94; 95% CI, 0.74 to 1.20, p = 0.62).ConclusionThere were no significant differences in clinical outcomes between older adult patients with COVID-19 reinfection and those with primary infection