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Since the beginning of the 21st century, major epidemics and pandemics such as SARS, H1N1pdm09, Ebola, and COVID-19 have repeatedly challenged global systems of disease diagnostics and control. These crises exposed the weaknesses of traditional diagnostic models, including long turnaround times, uneven resource distribution, and supply chain bottlenecks. As a result, there is an urgent need for more advanced diagnostic technologies and integrated diagnostics strategies. Our review summarizes key lessons learned from four recent major outbreaks and highlights advances in diagnostic technologies. Among these, molecular techniques such as loop-mediated isothermal amplification (LAMP), transcription-mediated amplification (TMA), recombinase polymerase amplification (RPA), and droplet digital polymerase chain reaction (ddPCR) have demonstrated significant advantages and are increasingly becoming core components of the detection framework. Antigen testing plays a critical role in rapid screening, particularly in settings such as schools, workplaces, and communities. Serological assays provide unique value for retrospective outbreak analysis and assessing population immunity. Next-generation sequencing (NGS) has become a powerful tool for identifying novel pathogens and monitoring viral mutations. Furthermore, point-of-care testing (POCT), enhanced by miniaturization, biosensing, and artificial intelligence (AI), has extended diagnostic capacity to the front lines of epidemic control. In summary, the future of epidemic and pandemic response will not depend on a single technology, but rather on a multi-layered and complementary system. By combining laboratory diagnostics, distributed screening, and real-time monitoring, this system will form a global diagnostic network capable of rapid response, ensuring preparedness for the next global health crisis.

People living with HIV/AIDS on antiretroviral therapy have increased risk of non-AIDS-defining cancers (NADCs). However, the underlying mechanism for development and progression of certain NADCs remains obscure. Here we show that exosomes released from HIV-infected T cells and those purified from blood of HIV-positive patients stimulate proliferation, migration and invasion of oral/oropharyngeal and lung cancer cells. The HIV transactivation response (TAR) element RNA in HIV-infected T-cell exosomes is responsible for promoting cancer cell proliferation and inducing expression of proto-oncogenes and Toll-like receptor 3 (TLR3)-inducible genes. These effects depend on the loop/bulge region of the molecule. HIV-infected T-cell exosomes rapidly enter recipient cells through epidermal growth factor receptor (EGFR) and stimulate ERK1/2 phosphorylation via the EGFR/TLR3 axis. Thus, our findings indicate that TAR RNA-containing exosomes from HIV-infected T cells promote growth and progression of particular NADCs through activation of the ERK cascade in an EGFR/TLR3-dependent manner. HIV patients have an increased risk of developing non-AIDS-defining cancers but the molecular mechanisms underlying this predisposition are unclear. Here the authors show that exosomes secreted by HIV-infected T cells or isolated from the blood of HIV-positive patients, stimulate oncogenic properties of cancer cells through the activation of ERK1/2 signaling pathway.

Elevated serum cytokine production in COVID-19 patients is associated with disease progression and severity. However, the stimuli that initiate cytokine production in patients remain to be fully revealed. Virus-infected cells release virus-associated exosomes, extracellular vesicles of endocytic origin, into the blood to deliver viral cargoes able to regulate immune responses. Here, we report that plasma exosomes of COVID-19 patients contain SARS-CoV-2 double stranded RNA (dsRNA) and stimulate robust production of interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α), and other inflammatory cytokines and chemokines by human peripheral mononuclear cells. Exosome depletion abolished these stimulated responses. COVID-19 plasma exosomes induced proinflammatory responses in CD4 + T cells, CD8 + T cells, and CD14 + monocytes but not significantly in regulatory T cells, Th17 T cells, or central memory T cells. COVID-19 plasma exosomes protect the SARS-CoV-2 dsRNA cargo from RNase and deliver the dsRNA into recipient cells. These exosomes significantly increase expression of endosomal toll-like receptor 3 (TLR3), TLR7, TLR8, and TLR9 in peripheral T cells and monocytes. A pharmacological inhibitor of TLR3 considerably reduced cytokine and chemokine production by CD4 + and CD8 + T cells but not by CD14 + monocytes, highlighting divergent signaling pathways of immune cells in response to COVID-19 plasma exosomes. Our results identify a novel model of intercellular crosstalk following SARS-CoV-2 infection that evoke immune responses positioned to contribute to elevated cytokine production associated with COVID-19 progression, severity, and long-haul symptoms.

Wnt/β-catenin and Hippo pathways play essential roles in the tumorigenesis and development of colorectal cancer. We found that Celastrol, isolated from Tripterygium wilfordii plant, exerted a significant inhibitory effect on colorectal cancer cell growth in vitro and in vivo, and further unraveled the molecular mechanisms. Celastrol induced β-catenin degradation through phosphorylation of Yes-associated protein (YAP), a major downstream effector of Hippo pathway, and also Celastrol-induced β-catenin degradation was dependent on liver kinase B1 (LKB1). Celastrol increased the transcriptional activation of LKB1, partially through the heat shock factor 1 (HSF1). Moreover, LKB1 activated AMP-activated protein kinase α (AMPKα) and further phosphorylated YAP, which eventually promoted the degradation of β-catenin. In addition, LKB1 deficiency promoted colorectal cancer cell growth and attenuated the inhibitory effect of Celastrol on colorectal cancer growth both in vitro and in vivo. Taken together, Celastrol inhibited colorectal cancer cell growth by promoting β-catenin degradation via the HSF1–LKB1–AMPKα–YAP pathway. These results suggested that Celastrol may potentially serve as a future drug for colorectal cancer treatment.

Oesophageal squamous cell carcinoma (ESCC) occurs at a very high rates in certain regions of China. There are increasing evidences demonstrating that selenium could act as a potential anti-oesophageal cancer agent, but the precise mechanisms involved are still not completely understood. Methylseleninic acid (MSA), as a potent second-generation selenium compound, is a promising chemopreventive agent. Previous studies demonstrated that the kelch-like ECH-associated protein 1 (Keap1)/nuclear factor E2-related factor 2 (Nrf2) system plays a critical role in cancer prevention, but little is known about its association with MSA in ESCC cells. In the present study, we observed that MSA treatment significantly down-regulated Keap1, induced nuclear accumulation of Nrf2 and enhance the antioxidant response element (ARE) promoter activity in ESCC cells. MSA could also significantly induce miR-200a expression and inhibit Keap1 directly. Antagomir-200a could attenuate MSA treatment-induced Keap1 down-regulation in ESCC cells. Moreover, MSA-induced miR-200a expression was dependent on the mediation of Krüpple-like factor 4 (KLF4). These results reaffirm the potential role of MSA as a chemopreventive agent via the regulation of KLF4/miR-200a/Keap1/Nrf2 axis in ESCC cells.

Abstract Background Multiple myeloma (MM) is a plasma cell disorder in which anion gap and sodium measurement are critically influenced by the presence of abnormal protein concentrations. This study investigates the relationship between anion gap, pseudohyponatremia, and monoclonal immunoglobulin levels (IgG, IgA, IgM), particularly the common IgG. Focusing on the clinical implications of these laboratory results. Methods We retrospectively analyzed data from 136 patients diagnosed with MM, focusing on anion gap values, monoclonal immunoglobulin levels, and sodium levels. The patients were categorized based on their anion gap values (<8) into five groups (anion gap=3, 4, 5, 6, and 7). Monoclonal immunoglobulin levels were standardized to the same units as the anion gap for direct comparison. Additionally, we investigated the pseudohyponatremia by examining sodium levels in these patients. Results Among the 136 MM patients, 70 patients’ anion gap were lower than 8. A negative correlation between MM monoclonal immunoglobulins and anion gap values were observed. The anion gap decreased from 7 to 3 as the IgG average levels ranged increasing from 1755 mg/dL to 2655 mg/dL (RI 610-1616 mg/dL). Similarly, the anion gap decreased from 6 to 3 as the IgM average levels ranged increasing from 1170 mg/dL to 2880 mg/dL (RI 35-242 mg/dL). Additionally, a number of low sodium levels (<136 mmol/L) was observed in each group. Conclusion Our study highlights the negative impact of MM monoclonal immunoglobulins, particularly IgG and IgM, on the anion gap. Both laboratory and clinical personnel should be aware of these phenomena, might prevent unnecessary diagnosis, streamlining patient management and avoiding potential mismanagement.

Abstract Background Prostate Cancer remains a significant global public health concern. It is the most common cancer and the second leading cause of cancer death among men in the United States. Current guidelines, including those by the USPSTF, ACS and ASCO offer varying recommendations on PSA screening. Present clinical practice, primarily targeting men aged 50-69. Our study aimed to assess the feasibility and validity of using PSA for targeted screening in men under 50 who are at high risk, enhancing early detection of prostate cancer. Methods This retrospective analysis utilized data from our hospital’s prostate cancer screening program collected from 2022 to 2023, including104 individuals under 50. Participants were categorized based on PSA levels 4-10 ng/mL (n=71) and over10 ng/mL (n=33). We analyzed the number of cases diagnosed with prostate cancer and the correlation with PSA levels, Gleason Scores (GS), family history, and ethnicity/race. Results In the104 participants, 88 of them were diagnosed with prostate cancer, highlighting an 84.6% detection rate. Among PSA levels 4-10 ng/mL group, 36 out of 43 White or Caucasian and 13 out of 13 Black or African American men were identified as GS 6-10. In the group PSA over 10 ng/mL, 18 White or Caucasian and 6 Black or African American individuals with more aggressive disease (GS 6-10). Importantly, a substantial fraction of these cases had a first-degree relative with prostate cancer, emphasizing the influence of family history on PSA screening decision. Conclusion Our findings suggest that PSA-guided screening in men under 50 at high risk can enhance the early detection of prostate cancer. The significant presence of intermediate-risk prostate cancer (GS 6 or 7) in populations at higher risk due to ethnicity/race and family history. Our study highlights the potential benefits of revisiting current screening guidelines to lower the age threshold for high-risk populations.

Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related death in China and has limited effective therapeutic options except for early surgery, since the underlying molecular mechanism driving its precursor lesions towards invasive ESCC is not fully understood. Cellular senescence is the state of the permanent growth arrest of a cell, and is considered as the initial barrier of tumor development. Human differentiated embryo chondrocyte expressed gene 1 (Dec1) is an important transcription factor that related to senescence. In this study, DEC1 immunohistochemical analysis was performed on tissue microarray blocks constructed from ESCC combined with adjacent precursor tissues of 241 patients. Compared with normal epithelia, DEC1 expression was significantly increased in intraepithelial neoplasia and DEC1 expression was significantly decreased in ESCC in comparison with intraepithelial neoplasia. In vitro, DEC1 overexpression induced cellular senescence, and it inhibited cell growth and colony formation in ESCC cell line EC9706. Fresh esophagectomy tissue sections from five ESCC patients were detected by immunohistochemistry of DEC1 and senescence-associated β-galactosidase (SA-β-Gal) activity, and strongly positive expression of DEC1 was correlated to more senescent cells in these fresh tissue sections. Kaplan-Meier method analysis of the 241 patients revealed that DEC1 expression levels were significantly correlated with the survival of ESCC patients after surgery. The expression levels of DEC1 were also correlated with age, tumor embolus, depth of invasion of ESCC, lymph metastasis status and pTNMs. These results suggest that DEC1 overexpression in precursor lesions of ESCC is a protective mechanism by inducing cellular senescence in ESCC initiation, and DEC1 may be a potential prognostic marker of ESCC.

Aurora-A overexpression is common in various types of cancers and has been shown to be involved in tumorigenesis through different signaling pathways, yet how the deregulation affects cancer therapeutics remains elusive. Here we showed that overexpression of Aurora-A rendered esophageal cancer cells resistance to cisplatin (CDDP) by inhibiting apoptosis. By using an apoptosis array, we identified a downstream gene, p21-activated kinase 7 (PAK7). PAK7 was upregulated by Aurora-A overexpression at both mRNA and protein levels. Importantly, the expression levels of Aurora-A and PAK7 were correlated in ESCC primary samples. Chromatin immunoprecipitation (ChIP) assay revealed that binding of E2F1 to the promoter of PAK7 was significantly enhanced upon Aurora-A activation, and knockdown of transcription factor E2F1 decreased PAK7 expression, suggesting that Aurora-A regulated PAK7 through E2F1. Furthermore, we demonstrated that PAK7 knockdown led to increased apoptosis, and Aurora-A-induced resistance to CDDP was reversed by downregulation of PAK7, suggesting PAK7 was a downstream player of Aurora-A that mediated chemoresistance of ESCC cells to CDDP. Our data suggest that PAK7 may serve as an attractive candidate for therapeutics in ESCC patients with Aurora-A abnormality.

Abstract Background The accuracy of clinical laboratory measurements can be compromised by laboratory test interferences. PV-10 (Rose Bengal), a chemotherapy medication used in the treatment of metastatic melanoma, was observed to cause a cherry-red discoloration in plasma. This plasma color change, resembling hemolysis, raises serious concerns about potential interference in clinical laboratory tests. Our study focused on understanding the potential interference of PV-10, particularly the impact on the hemolysis index (H index) and various chemistry assays to ensure result accuracy in cancer treatment. Methods To investigate the potential interference of PV-10, pooled normal and high baseline bilirubin plasma samples were spiked with a gradient of PV-10 concentrations (0 to 22 µg/100µL). Samples were analyzed on Roche Cobas 8000 analyzer with H index and all the chemistry assays measured. Results The presence of PV-10 in plasma significantly increased the H index, in a dose-dependent manner. Specifically, the H index increased from 14 (control plasma) to 2643 at the highest PV-10 concentration (22 µg/100µL) in pooled plasma. Among all chemistry assays, most of them were not affected by PV-10. However, certain assays like IRON have dose dependent increase with PV-10 concentration. CHO2A (Total Cholesterol), TP (Total Protein), and TRIG (Triglycerides) have shown a consistent increase trend. In contrast, the DBILI values decreased with increasing PV-10 concentrations, from 6.7 mg/dL to 0.2 mg/dL. TBIL levels also demonstrated a gradual decline from 9.6 mg/dL to 8.4 mg/dL as PV-10 concentration increased in pooled high baseline bilirubin plasma. Conclusion This study provides insights into the potential interference of PV-10 in clinical chemistry assays. The elevated H index by PV-10 is not attributed to hemolysis. It is imperative for both laboratory professionals and care providers to recognize the implications of PV-10-induced plasma discoloration and its potential interference in laboratory tests.