Germline MLH1 and MSH6 mutations from two Lynch syndrome families identified in a patient with early-onset of endometrial cancer: A case report.

Introduction: Lynch syndrome is caused by a germline mutation in mismatch repair (MMR) genes, leading to the loss of expression of MMR heterodimers, either MLH1/PMS2 or MSH2/MSH6, or isolated loss of PMS2 or MSH6. Concurrent loss of both heterodimers is uncommon, and patients carrying pathogenic variants affecting different MMR genes are rare, leading to the lack of cancer screening recommendation for these patients.Case presentation:Here, we reported a female with a family history of Lynch syndrome with MLH1 c.676C > T mutation. She developed endometrial cancer at 37 years old, with loss of MLH1/PMS2 expression. Immunohistochemical staining on tumor samples incidentally detected the additional loss of MSH6 expression. Whole exome sequencing on genomic DNA from peripheral blood revealed MSH6 c.2731C > T mutation, which was confirmed to be inherited from her mother, who had an early-onset ascending colon cancer without cancer family history. Conclusion: This is a rare case of the Lynch syndrome harboring germline mutations simultaneously in two different MMR genes inherited from two families with Lynch syndrome. The diagnosis of endometrial cancer at the age less than 40 years is uncommon for Lynch syndrome-related endometrial cancer. This suggests an earlier cancer screening for patients carrying two MMR mutations.

Preoperative Vaginal Microbiome as a Predictor of Postoperative Urinary Tract Infection.

This is a single Institute, prospective cohort study. We collected twenty- two postmenopausal women with pelvic organ prolapse planning to undergo vaginal hysterectomy with transvaginal pelvic reconstructive surgery, with or without a concomitant anti-incontinence procedure. Vaginal swabs and urine samples were longitudinally collected at five time points: preoperative consult visit (T1), day of surgery prior to surgical scrub (T2), immediately postoperative (T3), day of hospital discharge (T4), and at the postoperative exam visit (T5). Women experiencing urinary tract infection symptoms provided a sample set prior to antibiotic administration (T6). Microbiome analysis on vaginal and urinary specimens at each time point. Region V3-V5 of the 16S ribosomal RNA gene was amplified and sequenced. Sample DNA was analyzed with visit T1, T2, T5 and T6. Six (27.3%) participants developed postoperative urinary tract infection whose vaginal sample at first clinical visit (T1) revealed beta-diversity analysis with significant differences in microbiome structure and composition. Women diagnosed with a postoperative urinary tract infection had a vaginal microbiome characterized by low abundance of Lactobacillus and high prevalence of Prevotella and Gardnerella species. In our cohort, preoperative vaginal swabs can predict who will develop a urinary tract infection following transvaginal surgery for pelvic organ prolapse.

Tissue Inhibitor of Metalloproteinase 3: Unravelling Its Biological Function and Significance in Oncology.

Tissue inhibitor of metalloproteinases-3 (TIMP3) is vital in regulating several biological processes. TIMP3 exerts antitumour effects via matrix metalloproteinase (MMP)-dependent and MMP-independent pathways. Due to promoter methylation and miRNA binding, TIMP3 expression has been observed to decrease in various cancers. Consequently, the migration and invasion of cancer cells increases. Conflicting results have reported that expression levels of TIMP3 in primary and advanced cancers are higher than those in healthy tissues. Therefore, the role of TIMP3 in cancer biology and progression needs to be elucidated. This review provides an overview of TIMP3, from its biological function to its effects on various cancers. Moreover, gynaecological cancers are discussed in detail. TIMP3 has been associated with cervical adenocarcinoma as well as cancer development in serous ovarian cancer and breast cancer metastasis. However, the relationship between TIMP3 and endometrial cancers remains unclear. TIMP3 may be a useful biomarker for gynaecological cancers and is a potential target for future cancer therapy.

Effectiveness and evolution of anti-SARS-CoV-2 spike protein titers after three doses of COVID-19 vaccination in people with HIV.

BACKGROUND: Real-world vaccine effectiveness following the third dose of vaccination against SARS-CoV-2 remains less investigated among people with HIV (PWH). METHODS: PWH receiving the third dose of BNT162b2 and mRNA-1273 (either 50- or 100-µg) were enrolled. Participants were followed for 180 days until the fourth dose of COVID-19 vaccination, SARS-CoV-2 infection, seroconversion of anti-nucleocapsid IgG, death, or loss to follow-up. Anti-spike IgG was determined every 1-3 months. RESULTS: Of 1427 participants undergoing the third-dose COVID-19 vaccination, 632 (44.3%) received 100-µg mRNA-1273, 467 (32.8%) 50-µg mRNA-1273, and 328 (23.0%) BNT162b2 vaccine and the respective rate of SARS-CoV-2 infection or seroconversion of anti-nucleocapsid IgG was 246.1, 280.8 and 245.2 per 1000 person-months of follow-up (log-rank test, p = 0.28). Factors associated with achieving anti-S IgG titers >1047 BAU/mL included CD4 count <200 cells/mm3 (adjusted odds ratio [aOR], 0.11; 95% CI, 0.04-0.31), plasma HIV RNA >200 copies/mL (aOR, 0.27; 95% CI, 0.09-0.80), having achieved anti-spike IgG >141 BAU/mL within 3 months after primary vaccination (aOR, 3.69; 95% CI, 2.68-5.07), receiving BNT162b2 vaccine as the third dose (aOR, 0.20; 95% CI, 0.10-0.41; reference, 100-µg mRNA-1273), and having previously received two doses of mRNA vaccine in primary vaccination (aOR, 2.46; 95% CI, 1,75-3.45; reference, no exposure to mRNA vaccine). CONCLUSIONS: PWH receiving different types of the third dose of COVID-19 vaccine showed similar vaccine effectiveness against SARS-CoV-2 infection. An additional dose with 100-µg mRNA-1273 could generate a higher antibody response than with 50-µg mRNA-1273 and BNT162b2 vaccine.

Production of Bioactive Porcine Lactoferrin through a Novel Glucose-Inducible Expression System in Pichia pastoris: Unveiling Antimicrobial and Anticancer Functionalities.

Lactoferrin (LF) stands as one of the extensively investigated iron-binding glycoproteins within milk, exhibiting diverse biological functionalities. The global demand for LF has experienced consistent growth. Biotechnological strategies aimed at enhancing LF productivity through microbial expression systems offer substantial cost-effective advantages and exhibit fewer constraints compared to traditional animal bioreactor technologies. This study devised a novel recombinant plasmid, wherein the AOX1 promoter was replaced with a glucose-inducible G1 promoter (PG1) to govern the expression of recombinant porcine LF (rpLF) in Pichia pastoris GS115. High-copy-number PG1-rpLF yeast clones were meticulously selected, and subsequent induction with 0.05 g/L glucose demonstrated robust secretion of rpLF. Scaling up production transpired in a 5 L fermenter, yielding an estimated rpLF productivity of approximately 2.8 g/L by the conclusion of glycerol-fed fermentation. A three-step purification process involving tangential-flow ultrafiltration yielded approximately 6.55 g of rpLF crude (approximately 85% purity). Notably, exceptional purity of rpLF was achieved through sequential heparin and size-exclusion column purification. Comparatively, the present glucose-inducible system outperformed our previous methanol-induced system, which yielded a level of 87 mg/L of extracellular rpLF secretion. Furthermore, yeast-produced rpLF demonstrated affinity for ferric ions (Fe3+) and exhibited growth inhibition against various pathogenic microbes (E. coli, S. aureus, and C. albicans) and human cancer cells (A549, MDA-MB-231, and Hep3B), similar to commercial bovine LF (bLF). Intriguingly, the hydrolysate of rpLF (rpLFH) manifested heightened antimicrobial and anticancer effects compared to its intact form. In conclusion, this study presents an efficient glucose-inducible yeast expression system for large-scale production and purification of active rpLF protein with the potential for veterinary or medical applications.

Cooperation between PRMT1 and PRMT6 drives lung cancer health disparities among Black/African American men.

Lung cancer is the third most common cancer with Black/AA men showing higher risk and poorer outcomes than NHW men. Lung cancer disparities are multifactorial, driven by tobacco exposure, inequities in care access, upstream health determinants, and molecular determinants including biological and genetic factors. Elevated expressions of protein arginine methyltransferases (PRMTs) correlating with poorer prognosis have been observed in many cancers. Most importantly, our study shows that PRMT6 displays higher expression in lung cancer tissues of Black/AA men compared to NHW men. In this study, we investigated the underlying mechanism of PRMT6 and its cooperation with PRMT1 to form a heteromer as a driver of lung cancer. Disrupting PRMT1/PRMT6 heteromer by a competitive peptide reduced proliferation in non-small cell lung cancer cell lines and patient-derived organoids, therefore, giving rise to a more strategic approach in the treatment of Black/AA men with lung cancer and to eliminate cancer health disparities.

Tight junction protein cingulin variant is associated with cancer susceptibility by overexpressed IQGAP1 and Rac1-dependent epithelial-mesenchymal transition.

BACKGROUND: Cingulin (CGN) is a pivotal cytoskeletal adaptor protein located at tight junctions. This study investigates the link between CGN mutation and increased cancer susceptibility through genetic and mechanistic analyses and proposes a potential targeted therapeutic approach. METHODS: In a high-cancer-density family without known pathogenic variants, we performed tumor-targeted and germline whole-genome sequencing to identify novel cancer-associated variants. Subsequently, these variants were validated in a 222 cancer patient cohort, and CGN c.3560C > T was identified as a potential cancer-risk allele. Both wild-type (WT) (c.3560C > C) and variant (c.3560C > T) were transfected into cancer cell lines and incorporated into orthotopic xenograft mice model for evaluating their effects on cancer progression. Western blot, immunofluorescence analysis, migration and invasion assays, two-dimensional gel electrophoresis with mass spectrometry, immunoprecipitation assays, and siRNA applications were used to explore the biological consequence of CGN c.3560C > T. RESULTS: In cancer cell lines and orthotopic animal models, CGN c.3560C > T enhanced tumor progression with reduced sensitivity to oxaliplatin compared to the CGN WT. The variant induced downregulation of epithelial marker, upregulation of mesenchymal marker and transcription factor, which converged to initiate epithelial-mesenchymal transition (EMT). Proteomic analysis was conducted to investigate the elements driving EMT in CGN c.3560C > T. This exploration unveiled overexpression of IQGAP1 induced by the variant, contrasting the levels observed in CGN WT. Immunoprecipitation assay confirmed a direct interaction between CGN and IQGAP1. IQGAP1 functions as a regulator of multiple GTPases, particularly the Rho family. This overexpressed IQGAP1 was consistently associated with the activation of Rac1, as evidenced by the analysis of the cancer cell line and clinical sample harboring CGN c.3560C > T. Notably, activated Rac1 was suppressed following the downregulation of IQGAP1 by siRNA. Treatment with NSC23766, a selective inhibitor for Rac1-GEF interaction, resulted in the inactivation of Rac1. This intervention mitigated the EMT program in cancer cells carrying CGN c.3560C > T. Consistently, xenograft tumors with WT CGN showed no sensitivity to NSC23766 treatment, but NSC23766 demonstrated the capacity to attenuate tumor growth harboring c.3560C > T. CONCLUSIONS: CGN c.3560C > T leads to IQGAP1 overexpression, subsequently triggering Rac1-dependent EMT. Targeting activated Rac1 is a strategy to impede the advancement of cancers carrying this specific variant.

Under-utilization of statins among people with HIV who were aged 40 years or older.

From June 2022 to April 2023, 1629 HIV-positive participants were assessed for the risk of atherosclerotic cardiovascular disease (ASCVD). The 10-year ASCVD risk of <5 %, 5 % to <7.5 %, ≥7.5 % to <20 % and ≥20 % were 59.9 %, 14.4 %, 20.7 % and 5.0 %, respectively; 440 (27.0 %) participants met the criteria for statin therapy, but only 171 (38.8 %) were prescribed statins.

Polypharmacy and potential drug-drug interactions among people living with HIV in the era of integrase strand transfer inhibitor-based antiretroviral therapy.

OBJECTIVES: To investigate the prevalence of polypharmacy and potential drug-drug interactions (DDIs), and the factors associated with DDIs among people living with human immunodeficiency virus (HIV; PLWH) in the modern era of antiretroviral therapy (ART). METHODS: This cross-sectional study included PLWH who had been on ART for ≥3 months at two designated HIV hospitals in Taiwan. All ART and non-ART prescriptions were collected from the NHI-MediCloud System and screened for DDIs using the University of Liverpool HIV drug interactions database. A case-control analysis was conducted to investigate the factors associated with DDIs. RESULTS: In total, 1007 PLWH were included in this study from June 2021 to August 2022. The median age was 40 (interquartile range 33-49) years, and 96.2% were taking integrase strand transfer inhibitor (INSTI)-based ART. The proportions of PLWH with at least one non-communicable disease and polypharmacy were 50.0% and 18.7%, respectively. Seven (0.7%) PLWH had red-flagged DDIs, and 159 (15.8%) had amber-flagged DDIs. In multi-variable models, the prevalence of DDIs was associated with older age [adjusted odds ratio (aOR) per 1-year increase 1.022), number of co-medications (aOR 1.097), use of boosted INSTI-based ART (vs unboosted INSTI, aOR 8.653), and concomitant medications in the alimentary tract and metabolism category (aOR 11.058) and anti-neoplastic and immunomodulating agents (aOR 14.733). CONCLUSIONS: In the INSTI era, the prevalence of potential DDIs is lower than noted previously, but remains substantial. Clinicians should monitor DDIs routinely, especially in older PLWH, those taking a higher number of co-medications, and those who are taking booster-containing ART or medications from specific categories.

Setting up a specialized maternity unit in a tertiary hospital: An oasis for pregnant women with COVID-19 during the pandemic.

OBJECTIVE: The COVID-19 pandemic has had an enormous impact on society and the medical environment in Taiwan in 2022. As pregnant women with COVID-19 are at higher risk for multiple complications, Taiwan needs a COVID-19 specialized maternity unit to improve the quality of maternal and neonatal care. MATERIALS AND METHODS: We share our experience with specialized maternity unit for pregnant women with COVID-19 at the National Cheng Kung University Hospital, where we can have careful evaluation, safe birth, and comprehensive postpartum care. RESULTS: Our COVID-19 specialized maternity unit enrolled 253 pregnant women with COVID-19, 90 (35.6%) pregnant women were admitted to the specialized maternity unit, and 71 (28.1%) pregnant women gave birth during hospitalization in two months. All pregnant women recovery well and real-time polymerase chain reaction tests on all infants were negative for COVID-19. CONCLUSION: A specialized maternity unit can provide pregnant women with a safe birth environment, immediate maternity care, and high medical quality. It can also help health workers in non-specialized maternity units deal with COVID-19-related psychological stress. Therefore, setting up one specialized maternity unit in the city during the pandemic should be guardedly considered.

The downregulation of miR-509-3p expression by collagen type XI alpha 1-regulated hypermethylation facilitates cancer progression and chemoresistance via the DNA methyltransferase 1/Small ubiquitin-like modifier-3 axis in ovarian cancer cells.

BACKGROUND: MicroRNAs are a group of small non-coding RNAs that are involved in development and diseases such as cancer. Previously, we demonstrated that miR-335 is crucial for preventing collagen type XI alpha 1 (COL11A1)-mediated epithelial ovarian cancer (EOC) progression and chemoresistance. Here, we examined the role of miR-509-3p in EOC. METHODS: The patients with EOC who underwent primary cytoreductive surgery and postoperative platinum-based chemotherapy were recruited. Their clinic-pathologic characteristics were collected, and disease-related survivals were determined. The COL11A1 and miR-509-3p mRNA expression levels of 161 ovarian tumors were determined by real-time reverse transcription-polymerase chain reaction. Additionally, miR-509-3p hypermethylation was evaluated by sequencing in these tumors. The A2780CP70 and OVCAR-8 cells transfected with miR-509-3p mimic, while the A2780 and OVCAR-3 cells transfected with miR-509-3p inhibitor. The A2780CP70 cells transfected with a small interference RNA of COL11A1, and the A2780 cells transfected with a COL11A1 expression plasmid. Site-directed mutagenesis, luciferase, and chromatin immunoprecipitation assays were performed in this study. RESULTS: Low miR-509-3p levels were correlated with disease progression, a poor survival, and high COL11A1 expression levels. In vivo studies reinforced these findings and indicated that the occurrence of invasive EOC cell phenotypes and resistance to cisplatin are decreased by miR-509-3p. The miR-509-3p promoter region (p278) is important for miR-509-3p transcription regulation via methylation. The miR-509-3p hypermethylation frequency was significantly higher in EOC tumors with a low miR-509-3p expression than in those with a high miR-509-3p expression. The patients with miR-509-3p hypermethylation had a significantly shorter overall survival (OS) than those without miR-509-3p hypermethylation. Mechanistic studies further indicated that miR-509-3p transcription was downregulated by COL11A1 through a DNA methyltransferase 1 (DNMT1) stability increase. Moreover, miR-509-3p targets small ubiquitin-like modifier (SUMO)-3 to regulate EOC cell growth, invasiveness, and chemosensitivity. CONCLUSION: The miR-509-3p/DNMT1/SUMO-3 axis may be an ovarian cancer treatment target.

The Downregulation of miR-509-3p Expression by Collagen Type XI Alpha 1-Regulated Hypermethylation Facilitates Cancer Progression and Chemoresistance via the DNA Methyltransferase 1/Small Ubiquitin-like Modifier-3 Axis in Ovarian Cancer Cells.

Background MicroRNAs are a group of small non-coding RNAs that are involved in development and diseases such as cancer. Previously, we demonstrated that miR-335 is crucial for preventing collagen type XI alpha 1 (COL11A1)-mediated epithelial ovarian cancer (EOC) progression and chemoresistance. Here, we examined the role of miR-509-3p in EOC. Methods The patients with EOC who underwent primary cytoreductive surgery and postoperative platinum-based chemotherapy were recruited. Their clinic-pathologic characteristics were collected, and disease-related survivals were determined. The COL11A1 and miR-509-3p mRNA expression levels of 161 ovarian tumors were determined by real-time reverse transcription-polymerase chain reaction. Additionally, miR-509-3p hypermethylation was evaluated by sequencing in these tumors. The A2780CP70 and OVCAR-8 cells transfected with miR-509-3p mimic, while the A2780 and OVCAR-3 cells transfected with miR-509-3p inhibitor. The A2780CP70 cells transfected with a small interference RNA of COL11A1, and the A2780 cells transfected with a COL11A1 expression plasmid. Site-directed mutagenesis, luciferase, and chromatin immunoprecipitation assays were performed in this study. Results Low miR-509-3p levels were correlated with disease progression, a poor survival, and high COL11A1 expression levels. In vivo studies reinforced these findings and indicated that the occurrence of invasive EOC cell phenotypes and resistance to cisplatin are decreased by miR-509-3p. The miR-509-3p promoter region (p278) is important for miR-509-3p transcription regulation via methylation. The miR-509-3p hypermethylation frequency was significantly higher in EOC tumors with a low miR-509-3p expression than in those with a high miR-509-3p expression. The patients with miR-509-3p hypermethylation had a significantly shorter overall survival (OS) than those without miR-509-3p hypermethylation. Mechanistic studies further indicated that miR-509-3p transcription was downregulated by COL11A1 through a DNA methyltransferase 1 (DNMT1) phosphorylation and stability increase. Moreover, miR-509-3p targets small ubiquitin-like modifier (SUMO)-3 to regulate EOC cell growth, invasiveness, and chemosensitivity. Conclusion The miR-509-3p/DNMT1/SUMO-3 axis may be an ovarian cancer treatment target.

Patient-reported outcomes among virally suppressed people living with HIV after switching to Co-formulated bictegravir, emtricitabine and tenofovir alafenamide.

BACKGROUND: While some evidence has suggested the benefits of co-formulated bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) in improving the quality of life of people living with HIV (PLWH), patient-reported outcome studies that focus on Asian population remain scarce. We aimed to determine the changes in HIV-related symptom burden in virally-suppressed PLWH switching to B/F/TAF in a real-world setting. METHODS: PLWH on stable antiretroviral therapy (ART) for ≥6 months with plasma HIV RNA <200 copies/mL who decided to switch to B/F/TAF were eligible for the study. Participants' experience with 20 symptoms were assessed using HIV Symptom Index at baseline and weeks 24 and 48. Responses were dichotomized in two ways: 1) present vs. not present; and 2) bothersome vs. not bothersome, and compared across time points. RESULTS: Six hundred and thirty participants (prior regimen, 94.4% integrase inhibitor-based) who completed week 48 visit were included in the analysis. Forty-eight weeks after switching to B/F/TAF, six symptoms were significantly less prevalent, and seven symptoms were significantly less bothersome. Improvement was more pronounced in participants whose prior regimen was elvitegravir-based versus dolutegravir-based. Logistic regression results showed that prior dolutegravir-based ART and pre-existing diabetes independently predicted improvement in diarrhea/loose bowels and muscle aches/joint pain, respectively. Despite the overall improvement, some symptoms persisted in a substantial proportion of participants. CONCLUSIONS: Virally-suppressed PLWH might benefit from a regimen switch to B/F/TAF to reduce the prevalence and level of bother of HIV-related symptoms. Nevertheless, additional multidisciplinary interventions are warranted to further alleviate the symptom burden of PLWH.

Skin Marks in Critically Endangered Taiwanese Humpback Dolphins (Sousa chinensis taiwanensis).

As long-lived apex predators, Indo-Pacific humpback dolphins (Sousa chinensis) are key indicators of marine coastal environmental health. Skin marks can be observed on dorsal body surfaces that are visible during mark-recapture studies that rely on photo-identification (photo-ID) methods. Skin mark prevalence may be an indicator of environmental or anthropogenic stressors in the ecosystem, which may lead to individual and/or population-level health concerns. The prevalence of marks of anthropogenic origin was assessed in the Critically Endangered S. chinensis taiwanensis population along the coasts of central Taiwan. Fifty, twenty-eight, and thirty-four individuals were identified in 2018, 2019, and 2021, respectively. At least one category of injuries was observed in 47 of 57 distinctive individuals (82%), and adults showed a higher prevalence of deep injuries than the other coloration stages. At least one category of skin lesion was observed in 33 of 57 distinctive individuals (58%), and high prevalence of skin lesions was found in mature individuals. Given the difficulty in taking direct observations, skin mark prevalence is proposed as a proxy for estimating habitat health and anthropogenic stressors upon S. chinensis taiwanensis. The moderate-to-high prevalence of skin marks in this study was designated as a warning of risks. This study provides important updated information for the assessment of the health and survival of this population. More effective management measures are urgently needed to reverse the observed population decline.

Desmoid-type fibromatosis mimicking uterine fibroid invade the urinary bladder: A case report and literature review.

OBJECTIVE: Desmoid fibromatosis (DF) is a rare, locally aggressive soft tissue tumor. Computed tomography (CT) and magnetic resonance imaging (MRI) play a critical role in the diagnosis of DF and in developing treatment plans. Currently, observation is the primary therapeutic option for a biopsy-confirmed DF. Here, we present a case of a DF that was misdiagnosed as uterine fibroid before surgery. CASE REPORT: A 36-year-old woman presented with urinary frequency and a palpable lower abdominal mass, which was suspected as uterine fibroid based on sonography and CT. During surgery, an abdominal wall mass was found to be densely adherent to the bladder. Permanent pathology revealed that the tumor was desmoid-type fibromatosis. CONCLUSION: Desmoid tumors often occur in the abdomen, abdominal wall, extremities, head, and neck. Abdominal wall DF involving the rectus abdominis muscles is most commonly observed. Conversely, desmoid tumors involving the bladder are less described. The review of similar cases reported since 1985 showed that partial cystectomy was primarily performed for complete resection.

KCNF1 promotes lung cancer by modulating ITGB4 expression.

Lung cancer continues to be the leading cause of cancer death in the United States. Despite recent advances, the five-year survival rate for lung cancer compared to other cancers still remains fairly low. The discovery of molecular targets for lung cancer is key to the development of new approaches and therapies. Electrically silent voltage-gated potassium channel (KvS) subfamilies, which are unable to form functional homotetramers, are implicated in cell-cycle progression, cell proliferation and tumorigenesis. Here, we analyzed the expression of KvS subfamilies in human lung tumors and identified that potassium voltage-gated channel subfamily F member 1 (KCNF1) was up-regulated in non-small cell lung cancer (NSCLC). Silencing of KCNF1 in NSCLC cell lines reduced cell proliferation and tumor progression in mouse xenografts, re-established the integrity of the basement membrane, and enhanced cisplatin sensitivity. KCNF1 was predominately localized in the nucleoplasm and likely mediated its functions in an ion-independent manner. We identified integrin ß4 subunit (ITGB4) as a downstream target for KCNF1. Our findings suggest that KCNF1 promotes lung cancer by enhancing ITGB4 signaling and implicate KCNF1 as a novel therapeutic target for lung cancer.

Downregulation of Salt-Inducible Kinase 3 Enhances CCL24 Activation in the Placental Environment with Preeclampsia.

Preeclampsia (PE) remains one of the leading causes of maternal and perinatal morbidity and mortality. However, the exact pathophysiology of PE is still unclear. The recent widely accepted notion that successful pregnancy relies on maternal immunological adaptation is of utmost importance. Moreover, salt-inducible kinase 3 (SIK3) is an AMP-activated protein kinase-related kinase, and it has reported a novel regulator of energy and inflammation, and its expression related with some diseases. To explore whether SIK3 expression correlated with PE, we analyzed SIK3 gene expression and its association with PE through GEO datasets. We identified that SIK3 was significantly downregulated in PE across four datasets (p < 0.05), suggesting that SIK3 participated in the pathogenesis of PE. We initially demonstrated the significant downregulation of SIK3 in trophoblast cells of PE. SIK3 downregulation was positively correlated with the increased number of CD204(+) cells in in vivo and in vitro experiments. The increased number of CD204(+) cells could inhibit the migration and invasion of trophoblast cells. We then clarified the potential mechanism of PE with SIK3 downregulation: M2 skewing was triggered by trophoblast cells derived via the CCL24/CCR3 axis, leading to an increase in CD204(+) cells, a decrease in phagocytosis, and the production of IL-10 at the maternal-fetal interface of the placenta with PE. IL-10 further contributed to a reduction in the migration and invasion of trophoblast cells. It also established a feedback loop wherein trophoblast cells increased CCL24 production to maintain M2 dominance in the placental environments of PE.

Evolution of anti-SARS-CoV-2 spike protein titers after two-dose of COVID-19 vaccination among people living with HIV.

Background: A community COVID-19 outbreak caused by the B.1.1.7 SARS-CoV-2 variant occurred in Taiwan in May 2021. High-risk populations such as people living with HIV (PLWH) were recommended to receive two doses of COVID-19 vaccines. While SARS-CoV-2 vaccines have demonstrated promising results in general population, real-world information on the serological responses remains limited among PLWH. Methods: PLWH receiving the first dose of SARS-CoV-2 vaccine from 2020 to 2021 were enrolled. Determinations of anti-SARS-CoV-2 spike IgG titers were performed every one to three months, the third dose of the SARS-CoV-2 vaccine or confirmed SARS-CoV-2 infection. All serum samples were tested for anti-nucleocapsid antibody and those tested positive were excluded from analysis. Results: A total of 1189 PLWH were enrolled: 829 (69.7%) receiving two doses of the AZD1222 vaccine, 232 (19.5%) of the mRNA-1273 vaccine, and 128 (10.8%) of the BNT162b2 vaccine. At all time-points, PLWH receiving two doses of mRNA vaccines had consistently higher antibody levels than those receiving the AZD1222 vaccine (p <0.001 for all time-point comparisons). Factors associated with failure to achieve an anti-spike IgG titer >141 BAU/mL within 12 weeks, included type 2 diabetes mellitus (DM) (adjusted odds ratio [aOR], 2.24; 95% CI, 1.25-4), a CD4 T cell count <200 cells/mm3 upon receipt of the first dose of vaccination (aOR, 3.43; 95% CI, 1.31-9) and two homologous AZD1222 vaccinations (aOR, 16.85; 95%CI, 10.13-28). For those receiving two doses of mRNA vaccines, factors associated with failure to achieve an anti-spike IgG titer >899 BAU/mL within 12 weeks were a CD4 T cell count <200 cells/mm3 on first-dose vaccination (aOR, 3.95; 95% CI, 1.08-14.42) and dual BNT162b2 vaccination (aOR, 4.21; 95% CI, 2.57-6.89). Conclusions: Two doses of homologous mRNA vaccination achieved significantly higher serological responses than vaccination with AZD1222 among PLWH. Those with CD4 T cell counts <200 cells/mm3 and DM had consistently lower serological responses.

Low-level viraemia and virologic failure among people living with HIV who received maintenance therapy with co-formulated bictegravir, emtricitabine and tenofovir alafenamide versus dolutegravir-based regimens.

Real-world experience with low-level viraemia (LLV) and its impact remain less reported among people living with HIV (PLWH) who receive antiretroviral therapy (ART) containing second-generation integrase strand transferase inhibitors, including dolutegravir and bictegravir. This retrospective cohort study included virally suppressed PLWH who achieved plasma HIV-RNA viral load (PVL) <50 copies/mL for ≥6 months and were switched to either dolutegravir- or bictegravir-based ART. Incidence rates of developing LLV events (PVL, 50-200 copies/mL) and virologic failure (VF) (PVL ≥1000 copies/mL) were compared between the dolutegravir and bictegravir cohorts. A total of 623 and 862 PLWH switched to dolutegravir-based and bictegravir-based ART, respectively, were included. The incidence rate of developing LLV was 6.2 per 100 person-years of follow-up (PYFU) in the bictegravir cohort and 3.8 per 100 PYFU in the dolutegravir cohort [incidence rate ratio (IRR) = 1.63, 95% confidence interval (CI), 0.90-2.95; P = 0.08], while rates of VF were 0.69 per 100 PYFU and 0.95 per 100 PYFU, respectively, in the bictegravir and dolutegravir cohorts (IRR = 0.72, 95% CI 0.12-3.39; P = 0.34). Presence of LLV events was not associated with subsequent VF in multivariate analysis. Secondary analysis also demonstrated that resistance-associated mutations (RAMs) to nucleoside reverse transcriptase inhibitors (NRTIs) before switch were not associated with adverse virologic outcomes in either cohort. In conclusion, among virally suppressed PLWH, the incidences of developing LLV or VF were similar after switch to dolutegravir- or bictegravir-based ART. Pre-existing RAMs to NRTIs or LLV events were not associated with subsequent VF.

Effectiveness of COVID-19 vaccination among people living with HIV during a COVID-19 outbreak.

COVID-19 vaccination is recommended for at-risk populations, but the vaccine effectiveness in people living with HIV (PLWH) remains incompletely understood. Here we demonstrate that COVID-19 vaccination was clinically effective among PLWH during the outbreak setting with a low endemicity of COVID-19 where non-pharmaceutical interventions were strictly implemented.