Socioeconomic Status, Stress, and Cancer-related Fatigue among Chinese American Breast Cancer Survivors: The Mediating Roles of Sleep.

Sleep-related issues may be one significant pathway through which socioeconomic disadvantages are associated with worse self-reported states in cancer. The present study examined the relationships between SES (income and education level) and two important biobehavioral factors (cancer-related fatigue and perceived stress), as well as mediation through sleep-related problems (sleep medication use, daytime dysfunction, and sleep quality) among a sample of Chinese American breast cancer survivors. 136 Chinese American breast cancer survivors completed a self-reported questionnaire. We found that relative to those with the lowest annual household income, those with the highest income have lower perceived stress. This relationship was mediated by lower sleep quality. Relative to those with a high school degree or less, those with graduate degrees have lower daytime dysfunction, and in turn lower cancer-related fatigue. Our findings point to the importance of addressing sleep-related issues, perceived stress, and cancer-related fatigue among Chinese American breast cancer survivors with low SES backgrounds.

Safety and immunogenicity of a delayed booster dose of the rVSVΔG-ZEBOV-GP vaccine for prevention of Ebola virus disease: a multicentre, open-label, phase 2 randomised controlled trial.

BACKGROUND: rVSVΔG-ZEBOV-GP is the first approved vaccine with clinical efficacy against Ebola virus disease. Although a seroprotective threshold has not been defined for those at occupational risk of exposure, the current vaccine strategy is to attain a sustained high level of antibody titres. The aim of this trial was to explore the effects of delayed boosting upon both the height and duration of antibody titres following primary immunisation. METHODS: In this open-label phase 2 randomised controlled trial, we compared antibody titres at month 36 in participants who had received a homologous booster dose at month 18 following primary immunisation with those who had received no booster. From Oct 25, 2016, to Jan 29, 2020, healthy adults aged 18 years or older deemed at occupational risk of exposure to Ebola virus due to laboratory work, clinical duties, or travel to an active endemic region were recruited from four hospital clinics in the USA and one hospital clinic in Canada and received primary vaccination with 2×107 plaque-forming unit per mL of VSVΔG-ZEBOV-GP. 18 months later, individuals who consented and were still eligible were randomly assigned 1:1 to receive either a homologous booster dose or no booster. Study visits for safety and serial blood collections for antibody titres were done on enrolled participants at months 0, 1, 3, 6, 12, 18, 19, 24, 30, and 36. Through July, 2021, a web-based application was used for randomisation, including assignments with schedules for each of the five sites using mixed permuted blocks. The trial was not masked to participants or site staff. The primary endpoint was a comparison of geometric mean titres (GMTs) of anti-Ebola virus glycoprotein IgG antibody at month 36 (ie, 18 months after randomisation) for all randomly assigned participants who completed the 36 months of follow-up (primary analysis cohort). Investigators were aware of antibody titres from baseline (enrolment) through month 18 but were masked to summary data by randomisation group after month 18. This study is registered with ClinicalTrials.gov (NCT02788227). FINDINGS: Of the 248 participants who enrolled and received their primary immunisation, 114 proceeded to the randomisation step at month 18. The two randomisation groups were balanced: 57 participants (24 [42%] of whom were female; median age was 42 years [IQR 35-50]) were randomly assigned to the booster group and 57 (24 [42%] of whom were female; median age was 42 years [IQR 36-51]) to the no-booster group. Of those randomly assigned, 92 participants (45 in the booster group and 47 in the no-booster group) completed 36 months of follow-up. At 18 months after primary immunisation, GMTs in the no-booster group increased from a baseline of 10 ELISA units (EU)/mL (95% CI 7-14) to 1451 EU/mL (1118-1882); GMTs in the booster group increased from 9 EU/mL (6-16) to 1769 EU/mL (1348-2321). At month 19, GMTs were 31 408 EU/mL (23 181-42 554) for the booster group and 1406 EU/mL (1078-1833) for the no-booster group; at month 36, GMTs were 10 146 EU/mL (7960-12 933) for the booster group and 1240 EU/mL (984-1563) for the no-booster group. Accordingly, the geometric mean ratio (GMR) of antibody titres had increased almost 21-fold more in the booster versus no-booster group at 1 month after booster administration (GMR 20·6; 95% CI 18·2-23·0; p<0·0001) and was still over 7-fold higher at month 36 (GMR 7·8; 95% CI 5·5-10·2; p<0·0001). Consistent with previous reports of this vaccine's side-effects, transient mono-articular or oligo-articular arthritis was diagnosed in 18 (9%) of 207 primary vaccination recipients; after randomisation, arthritis was diagnosed in one (2%) of 57 participants in the no-booster group. No new cases of arthritis developed after booster administration. Four serious adverse events occurred following randomisation: one (epistaxis) in the booster group and three (gastrointestinal haemorrhage, prostate cancer, and tachyarrhythmia) in the no-booster group. None of the serious adverse events was judged attributable to the booster vaccination assignment. INTERPRETATION: In addition to no new safety concerns and in marked contrast to earlier trials evaluating short-term boosting, delaying a rVSVΔG-ZEBOV-GP booster until month 18 resulted in an increase in GMT that remained several-fold above the no-booster group GMT for at least 18 months. These findings could have implications for defining the optimal timing of booster doses as pre-exposure prophylaxis in populations at ongoing risk for Ebola virus exposure. FUNDING: The Division of Intramural Research and the Division of Clinical Research of the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health, Canadian Immunization Research Network through the Public Health Agency of Canada, Canadian Institutes of Health Research, and the US Defense Threat Reduction Agency.

Comparative proteomic analysis of saliva from chewing tobacco users and oral cancer patients reveals shared biomarkers: A case control observational study.

OBJECTIVE: The aim of this study was to compare the salivary proteomic profile of smokeless tobacco users with that of non-users and oral cancer patients using Liquid Chromatography-Mass Spectrometry/ Mass Spectrometry (LC-MS/MS). METHODS: Saliva samples from 65 participants were collected in three groups: control (25 participants), smokeless tobacco users (25 participants), and oral cancer (15 participants). RESULTS: The analysis revealed 343 protein groups with significantly altered abundance in the saliva samples (P < 0.05). Among these, 43 out of 51 dysregulated proteins in the smokeless tobacco group were also dysregulated in the oral cancer group. Notably, Apolipoprotein A1 (ApoA1) and Pon1 were found to be significantly increased in both smokeless tobacco users and oral cancer patients (p < 0.05). Furthermore, six out of the 20 most significantly altered proteins were mitochondrial proteins, and all of these were decreased relative to controls in both smokeless tobacco users and cancer samples. CONCLUSION: The proteomic profile of users of chewing (smokeless) tobacco (SLT) shows substantial overlap in the altered pathways and dysregulated proteins with those altered in oral cancer samples, suggesting that SLT use induces a shift toward an oncogenic state. Specifically indicated pathways included blood microparticles, platelet α-granules and protease inhibitors as well as indicators of oxidative stress and exogenous compound processing. What differentiates oral cancer samples from SLT users is enrichment of alterations related to cytoskeletal organisation and tissue remodelling. CLINICAL SIGNIFICANCE: The findings emphasize the importance of salivary proteomic profiles because changes in certain proteins may be indicators for early oral cancer identification and risk assessment in smokeless tobacco users.

Applying the Unified Theory of Acceptance and Use of Technology to Identify Factors Associated With Intention to Use Teledelivered Supportive Care Among Recently Diagnosed Breast Cancer Survivors During COVID-19 in Hong Kong: Cross-Sectional Survey.

BACKGROUND: Many supportive cancer care (SCC) services were teledelivered during COVID-19, but what facilitates patients' intentions to use teledelivered SCC is unknown. OBJECTIVE: The study aimed to use the unified theory of acceptance and use of technology to investigate the factors associated with the intentions of breast cancer survivors (BCS) in Hong Kong to use various types of teledelivered SCC (including psychosocial care, medical consultation, complementary care, peer support groups). Favorable telehealth-related perceptions (higher performance expectancy, lower effort expectancy, more facilitating conditions, positive social influences), less technological anxiety, and greater fear of COVID-19 were hypothesized to be associated with higher intentions to use teledelivered SCC. Moreover, the associations between telehealth-related perceptions and intentions to use teledelivered SCC were hypothesized to be moderated by education level, such that associations between telehealth-related perceptions and intentions to use teledelivered SCC would be stronger among those with a higher education level. METHODS: A sample of 209 (209/287, 72.8% completion rate) women diagnosed with breast cancer since the start of the COVID-19 outbreak in Hong Kong (ie, January 2020) were recruited from the Hong Kong Breast Cancer Registry to complete a cross-sectional survey between June 2022 and December 2022. Participants' intentions to use various types of teledelivered SCC (dependent variables), telehealth-related perceptions (independent variables), and sociodemographic variables (eg, education, as a moderator variable) were measured using self-reported, validated measures. RESULTS: Hierarchical regression analysis results showed that greater confidence using telehealth, performance expectancy (believing telehealth helps with daily tasks), social influence (important others encouraging telehealth use), and facilitating conditions (having resources for telehealth use) were associated with higher intentions to use teledelivered SCC (range: ß=0.16, P=.03 to ß=0.34, P<.001). Moreover, 2-way interactions emerged between education level and 2 of the telehealth perception variables. Education level moderated the associations between (1) performance expectancy and intention to use teledelivered complementary care (ß=0.34, P=.04) and (2) facilitating conditions and intention to use teledelivered peer support groups (ß=0.36, P=.03). The positive associations between those telehealth perceptions and intentions were only significant among those with a higher education level. CONCLUSIONS: The findings of this study implied that enhancing BCS' skills at using telehealth, BCS' and their important others' perceived benefits of telehealth, and providing assistance for telehealth use could increase BCS' intentions to use teledelivered SCC. For intentions to use specific types of SCC, addressing relevant factors (performance expectancy, facilitating conditions) might be particularly beneficial for those with a higher education level.

Soluble Plasma Proteins of Tumor Necrosis Factor and Immunoglobulin Superfamilies Reveal New Insights into Immune Regulation in People with HIV and Opioid Use Disorder.

People with HIV (PWH) frequently suffer from Opioid (OP) Use Disorder (OUD). In an investigation of the impact of OUD on underlying immune dysfunction in PWH, we previously reported that OP use exacerbates inflammation in virally controlled PWH followed in the Infectious Diseases Elimination Act (IDEA) Syringe Services Program (SSP). Unexpectedly, Flu vaccination-induced antibody responses in groups with OUD were superior to PWH without OUD. Here, we investigated the profile of 48 plasma biomarkers comprised of TNF and Ig superfamily (SF) molecules known to impact interactions between T and B cells in 209 participants divided into four groups: (1) HIV+OP+, (2) HIV-OP+, (3) HIV+OP-, and (4) HIV-OP-. The differential expression of the top eight molecules ranked by median values in individual Groups 1-3 in comparison to Group 4 was highly significant. Both OP+ groups 1 and 2 had higher co-stimulatory TNF SF molecules, including 4-1BB, OX-40, CD40, CD30, and 4-1BBL, which were found to positively correlate with Flu Ab titers. In contrast, HIV+OP- exhibited a profile dominant in Ig SF molecules, including PDL-2, CTLA-4, and Perforin, with PDL-2 showing a negative correlation with Flu vaccine titers. These findings are relevant to vaccine development in the fields of HIV and OUD.

Unlocking the Therapeutic Potential of BCL-2 Associated Protein Family: Exploring BCL-2 Inhibitors in Cancer Therapy.

Apoptosis, programmed cell death pathway, is a vital physiological mechanism that ensures cellular homeostasis and overall cellular well-being. In the context of cancer, where evasion of apoptosis is a hallmark, the overexpression of anti-apoptotic proteins like Bcl2, Bcl-xL and Mcl-1 has been documented. Consequently, these proteins have emerged as promising targets for therapeutic interventions. The BCL-2 protein family is central to apoptosis and plays a significant importance in determining cellular fate serving as a critical determinant in this biological process. This review offers a comprehensive exploration of the BCL-2 protein family, emphasizing its dual nature. Specifically, certain members of this family promote cell survival (known as anti-apoptotic proteins), while others are involved in facilitating cell death (referred to as pro-apoptotic and BH3-only proteins). The potential of directly targeting these proteins is examined, particularly due to their involvement in conferring resistance to traditional cancer therapies. The effectiveness of such targeting strategies is also discussed, considering the tumor's propensity for anti-apoptotic pathways. Furthermore, the review highlights emerging research on combination therapies, where BCL-2 inhibitors are used synergistically with other treatments to enhance therapeutic outcomes. By understanding and manipulating the BCL-2 family and its associated pathways, we open doors to innovative and more effective cancer treatments, offering hope for resistant and aggressive cases.

Lipid Peroxidation and Type I Interferon Coupling Fuels Pathogenic Macrophage Activation Causing Tuberculosis Susceptibility.

A quarter of human population is infected with Mycobacterium tuberculosis, but less than 10% of those infected develop pulmonary TB. We developed a genetically defined sst1-susceptible mouse model that uniquely reproduces a defining feature of human TB: the development of necrotic lung granulomas and determined that the sst1-susceptible phenotype was driven by the aberrant macrophage activation. This study demonstrates that the aberrant response of the sst1-susceptible macrophages to prolonged stimulation with TNF is primarily driven by conflicting Myc and antioxidant response pathways leading to a coordinated failure 1) to properly sequester intracellular iron and 2) to activate ferroptosis inhibitor enzymes. Consequently, iron-mediated lipid peroxidation fueled IFNß superinduction and sustained the Type I Interferon (IFN-I) pathway hyperactivity that locked the sst1-susceptible macrophages in a state of unresolving stress and compromised their resistance to Mtb. The accumulation of the aberrantly activated, stressed, macrophages within granuloma microenvironment led to the local failure of anti-tuberculosis immunity and tissue necrosis. The upregulation of Myc pathway in peripheral blood cells of human TB patients was significantly associated with poor outcomes of TB treatment. Thus, Myc dysregulation in activated macrophages results in an aberrant macrophage activation and represents a novel target for host-directed TB therapies.

Design, synthesis and mechanistic anticancer activity of new acetylated 5-aminosalicylate-thiazolinone hybrid derivatives.

The development of hybrid compounds has been widely considered as a promising strategy to circumvent the difficulties that emerge in cancer treatment. The well-established strategy of adding acetyl groups to certain drugs has been demonstrated to enhance their therapeutic efficacy. Based on our previous work, an approach of accommodating two chemical entities into a single structure was implemented to synthesize new acetylated hybrids (HH32 and HH33) from 5-aminosalicylic acid and 4-thiazolinone derivatives. These acetylated hybrids showed potential anticancer activities and distinct metabolomic profile with antiproliferative properties. The in-silico molecular docking predicts a strong binding of HH32 and HH33 to cell cycle regulators, and transcriptomic analysis revealed DNA repair and cell cycle as the main targets of HH33 compounds. These findings were validated using in vitro models. In conclusion, the pleiotropic biological effects of HH32 and HH33 compounds on cancer cells demonstrated a new avenue to develop more potent cancer therapies.

Association of proton pump inhibitor use with survival and adverse effects outcomes in patients with multiple myeloma: pooled analysis of three clinical trials.

Proton pump inhibitors (PPIs) are commonly used in cancer patients, but their impact on treatment outcomes in multiple myeloma (MM) patients remains unclear. This study investigated the association of PPI use with survival and adverse effects in MM patients across three randomized-control trials initiating daratumumab, lenalidomide, or bortezomib combination treatments. Cox proportional hazard analysis and logistic regression were employed to assess the associations with treatment outcomes, while adjusting for age, sex, weight, MM international staging system stage, ECOG-performance status, comorbidity count, and presence of gastrointestinal disorders. Pooled data involving 1804 patients revealed that 557 (32%) used PPIs at baseline. PPI use was independently associated with worse overall survival (adjusted HR [95% CI] 1.32 [1.08-1.62], P = 0.007) and grade ≥ 3 adverse events (adjusted OR [95% CI] 1.39 [1.03-1.88], P = 0.030). However, the association with progression-free survival did not reach statistical significance (adjusted HR [95% CI] 1.14 [0.97-1.33], P = 0.112). Findings were consistent across trials and treatment arms. PPI use was identified as a negative prognostic factor in MM patients, potentially enhancing clinical decisions regarding its use. Further research is needed to fully comprehend the impacts and safety of PPI use in MM patients.

Targeted, safe, and efficient gene delivery to human hematopoietic stem and progenitor cells in vivo using the engineered AVID adenovirus vector platform.

Targeted delivery and cell-type-specific expression of gene-editing proteins in various cell types in vivo represent major challenges for all viral and non-viral delivery platforms developed to date. Here, we describe the development and analysis of artificial vectors for intravascular delivery (AVIDs), an engineered adenovirus-based gene delivery platform that allows for highly targeted, safe, and efficient gene delivery to human hematopoietic stem and progenitor cells (HSPCs) in vivo after intravenous vector administration. Due to a set of refined structural modifications, intravenous administration of AVIDs did not trigger cytokine storm, hepatotoxicity, or thrombocytopenia. Single intravenous administration of AVIDs to humanized mice, grafted with human CD34+ cells, led to up to 20% transduction of CD34+CD38-CD45RA- HSPC subsets in the bone marrow. Importantly, targeted in vivo transduction of CD34+CD38-CD45RA-CD90-CD49f+ subsets, highly enriched for human hematopoietic stem cells (HSCs), reached up to 19%, which represented a 1,900-fold selectivity in gene delivery to HSC-enriched over lineage-committed CD34-negative cell populations. Because the AVID platform allows for regulated, cell-type-specific expression of gene-editing technologies as well as expression of immunomodulatory proteins to ensure persistence of corrected HSCs in vivo, the HSC-targeted AVID platform may enable development of curative therapies through in vivo gene correction in human HSCs after a single intravenous administration.

DCUN1D1 Is an Essential Regulator of Prostate Cancer Proliferation and Tumour Growth That Acts through Neddylation of Cullin 1, 3, 4A and 5 and Deregulation of Wnt/Catenin Pathway.

Defective in cullin neddylation 1 domain containing 1 (DCUN1D1) is an E3 ligase for the neddylation, a post-translational process similar to and occurring in parallel to ubiquitin proteasome pathway. Although established as an oncogene in a variety of squamous cell carcinomas, the precise role of DCUN1D1 in prostate cancer (PCa) has not been previously explored thoroughly. Here, we investigated the role of DCUN1D1 in PCa and demonstrated that DCUN1D1 is upregulated in cell lines as well as human tissue samples. Inhibition of DCUN1D1 significantly reduced PCa cell proliferation and migration and remarkably inhibited xenograft formation in mice. Applying both genomics and proteomics approaches, we provide novel information about the DCUN1D1 mechanism of action. We identified CUL3, CUL4B, RBX1, CAND1 and RPS19 proteins as DCUN1D1 binding partners. Our analysis also revealed the dysregulation of genes associated with cellular growth and proliferation, developmental, cell death and cancer pathways and the WNT/ß-catenin pathway as potential mechanisms. Inhibition of DCUN1D1 leads to the inactivation of ß-catenin through its phosphorylation and degradation which inhibits the downstream action of ß-catenin, reducing its interaction with Lef1 in the Lef1/TCF complex that regulates Wnt target gene expression. Together our data point to an essential role of the DCUN1D1 protein in PCa which can be explored for potential targeted therapy.

Unraveling the immune and metabolic changes associated with metritis in dairy cows.

The objective was to unravel the peripartum immune and metabolic changes associated with metritis in Holstein cows. Holstein cows (n = 128) had blood collected at -14, 0, 3, and 7 d relative to parturition (DRP). Flow cytometry was used to evaluate blood leukocyte counts, proportions, and activation. Total cells, live cells, single cells, monocytes (CD172α+/CD14+), polymorphonuclears (CD172α+/CD14-/SSChigh), B-cells (CD21+/MHCII+), CD4+ T-cells (CD4+), CD8+ T-cells (CD8+), and γδ T-cells (γδTCR+) were evaluated. Both CD62L and CD11b were used as markers of cell activation. Major histocompatibility complex class II was used as a marker of antigen presentation in monocytes. A Milliplex Bovine Cytokine/Chemokine 08-plex kit was used to evaluate plasma concentrations of IFN-γ, IL-1α, IL-1ß, IL-4, IL-6, IL-8, IL-10, and tumor necrosis factor-α. The body weight (BW) change prepartum was calculated as the difference between calving BW and prepartum BW divided by the number of days between measurements. Plasma fatty acids (FA) were measured at -14 and 0 DRP using untargeted gas chromatography with time-of-flight mass spectrometry. Data were analyzed by ANOVA for repeated measures. Cows that developed metritis (n = 57) had greater prepartum BW, prepartum BW loss, and greater FA concentrations at calving. Plasma FA at calving was positively correlated with IL-1ß. Cows that developed metritis had persistent systemic inflammation, which was demonstrated by greater B-cell activation, greater pro-inflammatory cytokine concentrations, and greater cell damage pre- and postpartum. Postpartum, we observed greater polymorphonuclear cell activation and extravasation but lesser monocytes and CD4+ T-cells activation and extravasation, which suggests postpartum immune tolerance. Greater prepartum adiposity in cows that developed metritis may lead to systemic inflammation pre- and postpartum and immune tolerance postpartum, which may lead to failure to prevent bacterial infection, and development of puerperal metritis.

Integrating Proteomics and Lipidomics for Evaluating the Risk of Breast Cancer Progression: A Pilot Study.

Metastasis is a serious and often life-threatening condition, representing the leading cause of death among women with breast cancer (BC). Although the current clinical classification of BC is well-established, the addition of minimally invasive laboratory tests based on peripheral blood biomarkers that reflect pathological changes in the body is of utmost importance. In the current study, the serum proteome and lipidome profiles for 50 BC patients with (25) and without (25) metastasis were studied. Targeted proteomic analysis for concertation measurements of 125 proteins in the serum was performed via liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM MS) using the BAK 125 kit (MRM Proteomics Inc., Victoria, BC, Canada). Untargeted label-free lipidomic analysis was performed using liquid chromatography coupled to tandem mass-spectrometry (LC-MS/MS), in both positive and negative ion modes. Finally, 87 serum proteins and 295 lipids were quantified and showed a moderate correlation with tumor grade, histological and biological subtypes, and the number of lymph node metastases. Two highly accurate classifiers that enabled distinguishing between metastatic and non-metastatic BC were developed based on proteomic (accuracy 90%) and lipidomic (accuracy 80%) features. The best classifier (91% sensitivity, 89% specificity, AUC = 0.92) for BC metastasis diagnostics was based on logistic regression and the serum levels of 11 proteins: alpha-2-macroglobulin, coagulation factor XII, adiponectin, leucine-rich alpha-2-glycoprotein, alpha-2-HS-glycoprotein, Ig mu chain C region, apolipoprotein C-IV, carbonic anhydrase 1, apolipoprotein A-II, apolipoprotein C-II and alpha-1-acid glycoprotein 1.

Integrated multi-omics analysis reveals unique signatures of paclitaxel-loaded poly(lactide-co-glycolide) nanoparticles treatment of head and neck cancer cells.

The use of poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) as carriers for chemotherapeutic drugs is regarded as an actively targeted nano-therapy for the specific delivery of anti-cancer drugs to target cells. However, the exact mechanism by which PLGA NPs boost anticancer cytotoxicity at the molecular level remains largely unclear. This study employed different molecular approaches to define the response of carcinoma FaDu cells to different types of treatment, specifically: paclitaxel (PTX) alone, drug free PLGA NPs, and PTX-loaded PTX-PLGA NPs. Functional cell assays revealed that PTX-PLGA NPs treated cells had a higher level of apoptosis than PTX alone, whereas the complementary, UHPLC-MS/MS (TIMS-TOF) based multi-omics analyses revealed that PTX-PLGA NPs treatment resulted in increased abundance of proteins associated with tubulin, as well as metabolites such as 5-thymidylic acid, PC(18:1(9Z)/18:1(9Z0), vitamin D, and sphinganine among others. The multi-omics analyses revealed new insights about the molecular mechanisms underlying the action of novel anticancer NP therapies. In particular, PTX-loaded NPs appeared to exacerbate specific changes induced by both PLGA-NPs and PTX as a free drug. Hence, the PTX-PLGA NPs' molecular mode of action, seen in greater detail, depends on this synergy that ultimately accelerates the apoptotic process, resulting in cancer cell death.

Serum interleukin-6 level predicts the prognosis for patients with alcohol-related acute-on-chronic liver failure.

AIM: Heavy alcohol consumption is the most common etiology of acute-on-chronic liver failure (ACLF) in Japan. In some patients, ACLF is associated with a fatal outcome in less than 6 months. We evaluated the prognosis of patients with alcohol-related ACLF in our cohort and explored the prognostic factors. METHODS: Forty-six patients with alcoholic liver cirrhosis who fulfilled the Japanese diagnostic criteria for ACLF, including those classified as extended and/or probable, were enrolled in this study. Serum concentrations of inflammatory cytokines (interleukin [IL]-1ß, IL-6, IL-8, IL-10, IL-12p70 and TNFα) were measured. We assessed prognosis and identified factors associated with survival. RESULTS: During the median 33-day observation period, 19 patients died, and 3 patients underwent living donor liver transplantation. Cumulative survival rates of patients treated without liver transplantation were 69, 48, 41, and 36% at 1, 3, 6, and 12 months, respectively. Eighteen of the 19 deceased patients died within 6 months after ACLF diagnosis. Serum concentrations of inflammatory cytokines were significantly elevated, and patients who underwent liver transplantation or who died within 6 months after admission had significantly higher serum IL-6 levels than the survival group. Multivariate analysis identified IL-6 > 23.3 pg/mL at admission and model for end-stage liver disease (MELD) score ≥ 25 on day 4 of admission as significant independent factors for mortality within 6 months. CONCLUSION: Serum IL-6 level and Day-4 MELD were prognostic factors for alcohol-related ACLF. Early liver transplantation is a potential treatment option for patients whose prognosis is expected to be poor.

Selected Gut Bacteria from Water Monitor Lizard Exhibit Effects against Pathogenic Acanthamoeba castellanii Belonging to the T4 Genotype.

Water monitor lizards (WMLs) reside in unhygienic and challenging ecological surroundings and are routinely exposed to various pathogenic microorganisms. It is possible that their gut microbiota produces substances to counter microbial infections. Here we determine whether selected gut bacteria of water monitor lizards (WMLs) possess anti-amoebic properties using Acanthamoeba castellanii of the T4 genotype. Conditioned media (CM) were prepared from bacteria isolated from WML. The CM were tested using amoebicidal, adhesion, encystation, excystation, cell cytotoxicity and amoeba-mediated host cell cytotoxicity assays in vitro. Amoebicidal assays revealed that CM exhibited anti-amoebic effects. CM inhibited both excystation and encystation in A. castellanii. CM inhibited amoebae binding to and cytotoxicity of host cells. In contrast, CM alone showed limited toxic effects against human cells in vitro. Mass spectrometry revealed several antimicrobials, anticancer, neurotransmitters, anti-depressant and other metabolites with biological functions. Overall, these findings imply that bacteria from unusual places, such as WML gut, produce molecules with anti-acanthamoebic capabilities.

Optical Coherence Tomography Angiographic Evaluation of Macular Vessel Density in Diabetic Macular Edema After Intravitreal Dexamethasone Implants: A Prospective Interventional Trial.

BACKGROUND AND OBJECTIVE: The goal of this study was to assess macular vascular density evolution, macular thickness, and functional outcomes after intravitreal dexamethasone implants for diabetic macular edema. PATIENTS AND METHODS: Vascular density was evaluated with optical coherence tomography (OCT) angiography in 21 eyes. Macular thickness was evaluated with structural OCT. Visual acuity and contrast sensitivity were evaluated before and after treatment, and these functional outcomes were analyzed for association with anatomic outcomes. Macular vessel density in the superficial capillary plexus was evaluated with OCT angiography and quantified in areas with no fluid, allowing a more accurate measurement and eliminating the segmentation bias in areas with intra-retinal fluid. Such a methodology was possible by positioning the scans only in areas with no fluid before and after the implant. The absence of fluid in these areas was confirmed by three experienced evaluators using both the B-scan and the en face. Visual acuity and contrast sensitivity were evaluated before and after treatment, and these functional outcomes were analyzed for association with anatomic outcomes. RESULTS: At 30, 60, and 90 days after implantation, there was improvement in macular perfusion in areas without fluid after intravitreal dexamethasone implantation, accompanied by reduced macular thickness and improved visual acuity (P < .001). However, there was no improvement in contrast sensitivity after treatment. CONCLUSIONS: Improved macular perfusion after treatment with intravitreal dexamethasone implantation may be associated with modulation of leukostasis, when the release of cytokines leads to capillary endothelial damage and obstruction of the micro-vasculature, leading to impaired capillary perfusion and ischemic damage. Despite the anatomical and functional findings demonstrated, further studies are needed to prove the relationship between the inflammatory mechanisms of diabetic macular edema and its relationship with macular perfusion and functional aspects. [Ophthalmic Surg Lasers Imaging Retina 2023;54(3):174-182.].

Effects of medwakh smoking on salivary metabolomics and its association with altered oral redox homeostasis among youth.

The use of alternative tobacco products, particularly medwakh, has expanded among youth in the Middle East and around the world. The present study is conducted to investigate the biochemical and pathophysiological changes caused by medwakh smoking, and to examine the salivary metabolomics profile of medwakh smokers. Saliva samples were collected from 30 non-smokers and 30 medwakh smokers and subjected to metabolomic analysis by UHPLC-ESI-QTOF-MS. The CRP and Glutathione Peroxidase 1 activity levels in the study samples were quantified by ELISA and the total antioxidant capacity (TAC) by TAC assay kits. Statistical measurements and thorough validation of data obtained from untargeted metabolomics identified 37 uniquely and differentially abundant metabolites in saliva of medwakh smokers. The levels of phthalate, L-sorbose, cytosine, uridine, alpha-hydroxy hippurate, and L-nicotine were noticeably high in medwakh smokers. Likewise, 20 metabolic pathways were differentially altered in medwakh smokers. This study identified a distinctive saliva metabolomics profile in medwakh smokers associated with altered redox homeostasis, metabolic pathways, antioxidant system, and CRP levels. The impact of the altered metabolites in medwakh smokers and their diagnostic utility require further research in large cohorts.

Nicotinamide riboside kinase-2 regulates metabolic adaptation in the ischemic heart.

Ischemia-induced metabolic remodeling plays a critical role in the pathogenesis of adverse cardiac remodeling and heart failure however, the underlying molecular mechanism is largely unknown. Here, we assess the potential roles of nicotinamide riboside kinase-2 (NRK-2), a muscle-specific protein, in ischemia-induced metabolic switch and heart failure through employing transcriptomic and metabolomic approaches in ischemic NRK-2 knockout mice. The investigations revealed NRK-2 as a novel regulator of several metabolic processes in the ischemic heart. Cardiac metabolism and mitochondrial function and fibrosis were identified as top dysregulated cellular processes in the KO hearts post-MI. Several genes linked to mitochondrial function, metabolism, and cardiomyocyte structural proteins were severely downregulated in the ischemic NRK-2 KO hearts. Analysis revealed significantly upregulated ECM-related pathways which was accompanied by the upregulation of several key cell signaling pathways including SMAD, MAPK, cGMP, integrin, and Akt in the KO heart post-MI. Metabolomic studies identified profound upregulation of metabolites mevalonic acid, 3,4-dihydroxyphenylglycol, 2-penylbutyric acid, and uridine. However, other metabolites stearic acid, 8,11,14-eicosatrienoic acid, and 2-pyrrolidinone were significantly downregulated in the ischemic KO hearts. Taken together, these findings suggest that NRK-2 promotes metabolic adaptation in the ischemic heart. The aberrant metabolism in the ischemic NRK-2 KO heart is largely driven by dysregulated cGMP and Akt and mitochondrial pathways. KEY MESSAGES: Post-myocardial infarction metabolic switch critically regulates the pathogenesis of adverse cardiac remodeling and heart failure. Here, we report NRK-2 as a novel regulator of several cellular processes including metabolism and mitochondrial function post-MI. NRK-2 deficiency leads to downregulation of genes important for mitochondrial pathway, metabolism, and cardiomyocyte structural proteins in the ischemic heart. It was accompanied by upregulation of several key cell signaling pathways including SMAD, MAPK, cGMP, integrin, and Akt and dysregulation of numerous metabolites essential for cardiac bioenergetics. Taken together, these findings suggest that NRK-2 is critical for metabolic adaptation of the ischemic heart.