Genetically engineered bacteriophages as novel nanomaterials: applications beyond antimicrobial agents.

Bacteriophages, also known as phages, are viruses that replicate in bacteria and archaea. Phages were initially discovered as antimicrobial agents, and they have been used as therapeutic agents for bacterial infection in a process known as "phage therapy." Recently, phages have been investigated as functional nanomaterials in a variety of areas, as they can function not only as therapeutic agents but also as biosensors and tissue regenerative materials. Phages are nontoxic to humans, and they possess self-assembled nanostructures and functional properties. Additionally, phages can be easily genetically modified to display specific peptides or to screen for functional peptides via phage display. Here, we demonstrated the application of phage nanomaterials in the context of tissue engineering, sensing, and probing.

Correction: Increasing Fusobacterium infections with Fusobacterium varium, an emerging pathogen.

[This corrects the article DOI: 10.1371/journal.pone.0266610.].

Clinical characteristics and risk factors for right-sided infective endocarditis in Korea: a 12-year retrospective cohort study.

Right-sided infective endocarditis (RSIE) is less common than left-sided infective endocarditis (LSIE) and exhibits distinct epidemiological, clinical, and microbiological characteristics. Previous studies have focused primarily on RSIE in patients with intravenous drug use. We investigated the characteristics and risk factors for RSIE in an area where intravenous drug use is uncommon. A retrospective cohort study was conducted at a tertiary hospital in South Korea. Patients diagnosed with infective endocarditis between November 2005 and August 2017 were categorized into LSIE and RSIE groups. Of the 406 patients, 365 (89.9%) had LSIE and 41 (10.1%) had RSIE. The mortality rates were 31.7% in the RSIE group and 31.5% in the LSIE group (P = 0.860). Patients with RSIE had a higher prevalence of infection with Staphylococcus aureus (29.3% vs. 13.7%, P = 0.016), coagulase-negative staphylococci (17.1% vs. 6.0%, P = 0.022), and gram-negative bacilli other than HACEK (12.2% vs. 2.2%, P = 0.003). Younger age (adjusted odds ratio [aOR] 0.97, 95% confidence interval [CI] 0.95-0.99, P = 0.006), implanted cardiac devices (aOR 37.75, 95% CI 11.63-141.64, P ≤ 0.001), and central venous catheterization  (aOR 4.25, 95%  CI 1.14-15.55, P = 0.029) were independent risk factors for RSIE. Treatment strategies that consider the epidemiologic and microbiologic characteristics of RSIE are warranted.

Genetic Inactivation of the ß1 adrenergic receptor prevents Cerebral Cavernous Malformations in zebrafish.

Propranolol reduces experimental murine cerebral cavernous malformations (CCMs) and prevents embryonic caudal venous plexus (CVP) lesions in zebrafish that follow mosaic inactivation of ccm2 . Because morpholino silencing of the ß1 adrenergic receptor ( adrb1 ) prevents the embryonic CVP lesion, we proposed that adrb1 plays a role in CCM pathogenesis. Here we report that adrb1 -/- zebrafish exhibited 86% fewer CVP lesions and 87% reduction of CCM lesion volume relative to wild type brood mates at 2dpf and 8-10 weeks stage, respectively. Treatment with metoprolol, a ß1 selective antagonist, yielded a similar reduction in CCM lesion volume. Adrb1 -/- zebrafish embryos exhibited reduced heart rate and contractility and reduced CVP blood flow. Similarly, slowing the heart and eliminating the blood flow in CVP by administration of 2,3-BDM suppressed the CVP lesion. In sum, our findings provide genetic and pharmacological evidence that the therapeutic effect of propranolol on CCM is achieved through ß1 receptor antagonism.

Disentangling the acute subjective effects of classic psychedelics from their enduring therapeutic properties.

Recent research with classic psychedelics suggests significant therapeutic potential, particularly for neuropsychiatric disorders. A mediating influence behind symptom resolution is thought to be the personal insight - at times, bordering on the mystical - one acquires during the acute phase of a psychedelic session. Indeed, current clinical trials have found strong correlations between the acute subjective effects (ASE) under the influence of psychedelics and their enduring therapeutic properties. However, with potential barriers to widespread clinical implementation, including the healthcare resource-intensive nature of psychedelic sessions and the exclusion of certain at-risk patient groups, there is an active search to determine whether ASE elimination can be accompanied by the retention of persisting therapeutic benefits of these class of compounds. Recognizing the aberrant underlying neural circuitry that characterizes a range of neuropsychiatric disorders, and that classic psychedelics promote neuroplastic changes that may correct abnormal circuitry, investigators are rushing to design and discover compounds with psychoplastogenic, but not hallucinogenic (i.e., ASE), therapeutic potential. These efforts have paved the discovery of 'non-psychedelic/subjective psychedelics', or compounds that lack hallucinogenic activity but with therapeutic efficacy in preclinical models. This review aims to distill the current evidence - both clinical and preclinical - surrounding the question: can the ASE of classic psychedelics be dissociated from their sustained therapeutic properties? Several plausible clinical scenarios are then proposed to offer clarity on and potentially answer this question.

Rhamnogalacturonan lyase 1 (RGL1), as a suppressor of E3 ubiquitin ligase Arabidopsis thaliana ring zinc finger 1 (AtRZF1), is involved in dehydration response to mediate proline synthesis and pectin rhamnogalacturonan-I composition.

Proline metabolism plays a crucial role in both environmental stress responses and plant growth. However, the specific mechanism by which proline contributes to abiotic stress processes remains to be elucidated. In this study, we utilized atrzf1 (Arabidopsis thaliana ring zinc finger 1) as a parental line for T-DNA tagging mutagenesis and identified a suppressor mutant of atrzf1, designated proline content alterative 31 (pca31). The pca31 mutant suppressed the insensitivity of atrzf1 to dehydration stress during early seedling growth. Using Thermal Asymmetric Interlaced-PCR, we found that the T-DNA of pca31 was inserted into the promoter region of the At2g22620 gene, which encodes the cell wall enzyme rhamnogalacturonan lyase 1 (RGL1). Enzymatic assays indicated that RGL1 exhibited rhamnogalacturonan lyase activity, influencing cell wall pectin composition. The decrease in RGL1 gene expression suppressed the transcriptomic perturbation of the atrzf1 mutant. Silencing of the RGL1 gene in atrzf1 resulted in a sensitive phenotype similar to pca31 under osmotic stress conditions. Treatment with mannitol, salt, hydrogen peroxide, and abscisic acid induced RGL1 expression. Furthermore, we uncovered that RGL1 plays a role in modulating root growth and vascular tissue development. Molecular, physiological, and genetic experiments revealed that the positive modulation of RGL1 during abiotic stress was linked to the AtRZF1 pathway. Taken together, these findings establish that pca31 acts as a suppressor of atrzf1 in abiotic stress responses through proline and cell wall metabolisms.

Clinical efficacy of prophylactic intravenous immunoglobulin for elderly DLBCL patients with hypogammaglobulinemia in the COVID-19 pandemic era.

Background: Elderly patients diagnosed with diffuse large B-cell lymphoma (DLBCL) undergoing reduced intensity R-CHOP therapy are at a heightened risk of acquiring infections, notably coronavirus disease 2019 (COVID-19) infection. This study aimed to evaluate the efficacy of intravenous immunoglobulin (IVIG) as prophylaxis against COVID-19 in this vulnerable population. Methods: A total of 125 elderly patients with DLBCL undergoing reduced intensity R-CHOP therapy were analyzed in this prospective, multicenter study. Patients with hypogammaglobulinemia were categorized into IVIG and non-IVIG groups, while those with normal immunoglobulin levels constituted the observation group. The study evaluated COVID-19 infection rates, therapy response, and safety outcomes. Results: Among the enrolled patients (median age: 77 years), 89 patients (71.2%) presented with hypogammaglobulinemia at diagnosis, and 56 patients enrolled in the IVIG administration group. IVIG administration remarkably reduced COVID-19 infection rates compared to non-IVIG recipients (8.9% vs. 24.6%; p =0.040). Notably, patients over 80 years old were more susceptible to COVID-19. Patients on IVIG exhibited good tolerance with manageable adverse events. Among patients with hypogammaglobulinemia who received IVIG, 40.5% of patients developed additional immunoglobulin deficiencies during chemotherapy. One or more new hypogammaglobulinemia occurred during chemotherapy in 72% of patients with hypogammaglobulinemia who did not receive IVIG, and in 61.3% of patients who did not have hypogammaglobulinemia at diagnosis. Conclusion: IVIG showed promise in reducing COVID-19 infections among elderly patients with DLBCL receiving reduced intensity R-CHOP therapy. This highlights IVIG's potential as a prophylactic measure, necessitating further investigation to optimize dosing, administration schedules, and potential interactions with vaccination strategies.

Cadherin-6 is a novel mediator for the migration of mesenchymal stem cells to glioblastoma cells in response to stromal cell-derived factor-1.

Glioblastoma recruits various nontransformed cells from distant tissues. Although bone marrow-derived mesenchymal stem cells (MSCs) have been observed migrating to glioblastoma, the underlying mechanism driving MSC migration toward glioblastoma remains unclear. Tumor vascularity is critical in the context of recurrent glioblastoma and is closely linked to the expression of stromal cell-derived factor-1 (SDF-1). We demonstrated that cadherin-6 mediated MSC migration both toward SDF-1 and toward glioblastoma cells. Cadherin-6 knockdown resulted in the downregulation of MSCs capacity to migrate in response to SDF-1. Furthermore, MSCs with cadherin-6 knockdown exhibited impaired migration in response to conditioned media derived from glioblastoma cell lines (U87 and U373) expressing SDF-1, thus simulating the glioblastoma microenvironment. Moreover, MSCs enhanced the vasculogenic capacity of U87 cells without increasing the proliferation, cancer stem cell characteristics, or migration of U87. These results suggest that the current strategy of utilizing MSCs as carriers for antiglioblastoma drugs requires careful examination. Furthermore, cadherin-6 may represent a novel potential target for controlling the recruitment of MSCs toward glioblastoma.

Human coronavirus 229E inactivation on porous and nonporous materials using dielectric barrier discharge (DBD) plasma.

Viruses can spread through contaminated aerosols and contaminated surface materials, and effective disinfection techniques are essential for virus inactivation. Nonthermal plasma-generated reactive oxygen and nitrogen species can effectively inactivate the coronavirus. We aim to interpret the coronavirus inactivation level and mechanism of surface interaction with materials with and without dielectric barrier discharge (DBD) plasma treatment. Nonthermal plasma, particularly surface-type DBD plasma, can inactivate human coronavirus 229E (HCoV-229E) on porous (paper, wood, mask) and nonporous (plastic, stainless steel, glass, Cu) materials. Virus inactivation was analyzed using a 50% tissue culture infectivity dose (TCID50) using cell line, flow cytometry, and immunofluorescence. Surfaces contaminated with HCoV-229E were treated at different time intervals (0-5 h) with and without plasma exposure (natural decay in ambient air conditions). HCoV-229E persistence conformed to the following order: plastic > cover glass > stainless steel > mask > wood > paper > Cu with and without plasma exposure. HCoV-229E was more stable in plastic, cover glass, and stainless steel in 5 h, and the viable virus titer gradually decreased from its initial log10 order of 6.892 to 1.72, 1.53, and 1.32 TCID50/mL, respectively, under plasma exposure. No virus was observed in Cu after treatment for 5 h. The use of airflow, ambient nitrogen, and argon did not promote virus inactivation. Flow cytometry and immunofluorescence analysis demonstrated a low expression level of spike protein (fluorescence intensity) during plasma treatment and in E and M genes expression compared with the virus control.

Transient pacing in pigs with complete heart block via myocardial injection of mRNA coding for the T-box transcription factor 18.

The adenovirus-mediated somatic transfer of the embryonic T-box transcription factor 18 (TBX18) gene can convert chamber cardiomyocytes into induced pacemaker cells. However, the translation of therapeutic TBX18-induced cardiac pacing faces safety challenges. Here we show that the myocardial expression of synthetic TBX18 mRNA in animals generates de novo pacing and limits innate and inflammatory immune responses. In rats, intramyocardially injected mRNA remained localized, whereas direct myocardial injection of an adenovirus carrying a reporter gene resulted in diffuse expression and in substantial spillover to the liver, spleen and lungs. Transient expression of TBX18 mRNA in rats led to de novo automaticity and pacemaker properties and, compared with the injection of adenovirus, to substantial reductions in the expression of inflammatory genes and in activated macrophage populations. In rodent and clinically relevant porcine models of complete heart block, intramyocardially injected TBX18 mRNA provided rate-adaptive cardiac pacing for one month that strongly correlated with the animal's sinus rhythm and physical activity. TBX18 mRNA may aid the development of biological pacemakers.

Laboratory Evaluation of Storage Stability for Asphalt Binder Modified with Crumb Rubber and Styrene-Isoprene-Styrene Depending on Evaluation Factors and Blending Condition.

Modified asphalt binders are still considered important in asphalt pavement. However, the comprehensive use of various modifiers is limited due to storage stability issues. Moreover, there is a scarcity of detailed analyses regarding the degree of separation for asphalt binders among each method despite the utilization of various methods to assess the storage stability of binders. Therefore, a comprehensive analysis was conducted to assess the storage stability of asphalt binder modified with a crumb rubber modifier (CRM) and styrene-isoprene-styrene (SIS), utilizing five evaluation factors following the ASTM D7173 guidelines based on four mixing methods (A: high-shear mixing method, B: low-speed agitating method, C: high-shear mixing method + low mixing method, D: low-speed agitating method + low mixing method). To produce the modified asphalt binder, the proportions of the CRM were 5% and 10% for each binder, and 10% SIS was added to all binders. The results in this study convey that (1) the addition of the modifier led to an increase in G*/sin δ with different mixing methods, but using mixing methods (C and D) for a relatively long time resulted in a lower G*/sin δ, indicating suboptimal performance; (2) through the multiple stress creep recovery (MSCR), rheological properties of Jnr and % rec exhibited trends similar to G*/sin δ evaluation, highlighting an improved elastic recovery with a higher modifier content; (3) storage stability assessment revealed consistent trends in high-shear mixing groups (A and C), while low-speed mixing groups (B and D) exhibited an elevated separation index (SI), suggesting a sensitivity to modification conditions; (4) evaluation using the MSCR method indicated that % rec with a 3.2 kPa load is effective for the sensitive assessment of binder storage stability and Jnr showed a limited sensitivity across varying loads, advocating for % rec for precise evaluation; and (5) despite permitting various tests, achieving consistent results remains challenging. Future research should explore diverse modifiers and optimal evaluation methods to enhance knowledge of binder behavior and separation dynamics.

Radiopharmaceuticals for Skeletal Muscle PET Imaging.

The skeletal muscles account for approximately 40% of the body weight and are crucial in movement, nutrient absorption, and energy metabolism. Muscle loss and decline in function cause a decrease in the quality of life of patients and the elderly, leading to complications that require early diagnosis. Positron emission tomography/computed tomography (PET/CT) offers non-invasive, high-resolution visualization of tissues. It has emerged as a promising alternative to invasive diagnostic methods and is attracting attention as a tool for assessing muscle function and imaging muscle diseases. Effective imaging of muscle function and pathology relies on appropriate radiopharmaceuticals that target key aspects of muscle metabolism, such as glucose uptake, adenosine triphosphate (ATP) production, and the oxidation of fat and carbohydrates. In this review, we describe how [18F]fluoro-2-deoxy-D-glucose ([18F]FDG), [18F]fluorocholine ([18F]FCH), [11C]acetate, and [15O]water ([15O]H2O) are suitable radiopharmaceuticals for diagnostic imaging of skeletal muscles.

Clinical outcomes and challenges of surgical extirpation for carotid body paraganglioma in South Korea: a single-center retrospective study.

BACKGROUND: Carotid body paraganglioma (CBP) is a rare, highly vascularized, and slow-growing neuroendocrine tumor. Surgical resection is the definitive treatment for CBP, however, it remains challenging due to the tumor's proximity to critical blood vessels and cervical cranial nerves. This study aimed to document the characteristics of CBP and examine the clinical outcomes of patients following surgical extirpation of CBP. METHODS: This is a single-center retrospective review analyzed patients who underwent CBP extirpation. We examined the patient demographics, preoperative clinical features, tumor characteristics, levels of catecholamines and their metabolites in the serum and urine. Surgeries were performed by one vascular surgeon with follow-ups at 1,3,6 months and yearly thereafter. Logistic regression analysis was conducted to identify risk factors associated with the occurrence of either permanent or temporary cervival cranial nerve palsy (CNP). RESULTS: From September 2020 to February 2023, this study examined 21 cases of CBP removal surgeries that were carried out in 19 patients. The mean age of the patients was 38.9 ± 10.9 years and the percentage of males was 57.1% (n = 12). The most common preoperative clinical feature was painless neck mass (n = 12; 57.1%). Complete resection was achieved in 20 cases; excluding one case with pathologically proven sclerosing paraganglioma. Vascular procedures were performed in four cases (ECA resection, n = 2; primary repair of ICA tear without carotid shunting, n = 1; and ICA patch angioplasty with carotid shunting, n = 1). Temporary cranial neurologic complications, specifically aspiration and hoarseness occurred in four (19.0%), and three (14.3%) cases, respectively. Hoarseness associated with permanent CNP persisted for more than 6 months in two cases (9.5%). No recurrence or mortality was observed during the follow-up period. CONCLUSIONS: Surgical resection is the primay treatment approach for CBP; however, it poses risks of vascular or cervical CNP. The intraoperative estimated blood loss was the only identified risk factor for CNP.

Ethnic discrimination, asking for fair treatment, and poor self-rated health: a gender stratified analysis of 13,443 Korean Chinese waged workers in South Korea.

BACKGROUND: In South Korea, Korean Chinese workers experience ethnic discrimination although they share physical similarities and ethnic heritage with native-born Koreans. This study aimed to examine whether perceived ethnic discrimination is associated with poor self-rated health and whether the association differs by gender among Korean Chinese waged workers in South Korea. METHODS: We conducted a pooled cross-sectional analysis using data of 13,443 Korean Chinese waged workers from the Survey on Immigrants' Living Conditions and Labor Force conducted in 2018, 2020, and 2022. Based on perceived ethnic discrimination, asking for fair treatment, and subsequent situational improvement, respondents were classified into the following four groups: "Not experienced," "Experienced, not asked for fair treatment," "Experienced, asked for fair treatment, not improved," and "Experienced, asked for fair treatment, improved." Poor self-rated health was assessed using a single question "How is your current overall health?" We applied logistic regression to examine the association between perceived ethnic discrimination and poor self-rated health, with gender-stratified analyses. RESULTS: We found an association between ethnic discrimination and poor self-rated health among Korean Chinese waged workers. In the gender-stratified analysis, the "Experienced, not asked for fair treatment" group was more likely to report poor self-rated health compared to the "Not experienced" group, regardless of gender. However, gender differences were observed in the group stratified by situational improvements. For male workers, no statistically significant association was found in the "Experienced, asked for fair treatment, improved" group with poor self-rated health (odd ratios: 0.87, 95% confidence intervals: 0.30-2.53). Conversely, among female workers, a statistically significant association was observed (odd ratios: 2.63, 95% confidence intervals: 1.29-5.38). CONCLUSIONS: This study is the first to find an association between perceived ethnic discrimination and poor self-rated health, along with gender differences in the association between situational improvements after asking for fair treatment and poor self-rated health among Korean Chinese waged workers in South Korea.

Carbapenem-resistant Acinetobacter baumannii Outbreak in a COVID-19 Isolation Ward and Successful Outbreak Control with Infection Control Measures.

BACKGROUND: Even amid the coronavirus disease-19 (COVID-19) pandemic, the spread of multidrug-resistant bacteria and infection control are still important tasks. After recognizing the carbapenem-resistant Acinetobacter baumannii (CRAB) outbreak that occurred in the isolation room for COVID-19, we would like to introduce what infection control measures were implemented to eradicate it. MATERIALS AND METHODS: All COVID-19 patients with CRAB in any specimen admitted to the COVID-19 isolation ward of the tertiary hospital in South Korea from October to November 2021 were analyzed. RESULTS: During the outbreak, 23 patients with COVID-19 and CRAB infections were identified. The index case was an 85-year-old female referred from a long-term care facility. CRAB was identified in sputum culture in most patients (91.3%). The CRAB outbreak occurred mainly in the rooms around the index case. Environmental cultures on the floor, air inlet, air outlet, and window frame of the rooms were performed. The antimicrobial resistance patterns of CRAB from patients and the environment were identical; whole-genome sequencing analyses revealed isolated clonality. Infection control measures with enhanced environmental cleaning using 1,000 ppm sodium hypochlorite and phenolic compounds, enhanced hand hygiene, additional education, and mandatory additional gowning and gloving of COVID-19 personal protective equipment (PPE) were applied on 29 October. No CRAB infection cases occurred from 2 November for two weeks. CONCLUSION: In addition to applying PPE and COVID-19 precautions in COVID-19 isolation wards, adhering to strict contact precautions along with environmental control can help prevent the spread of multidrug-resistant bacteria.

Treatment of hard-to-heal wounds in ischaemic lower extremities with a novel fish skin-derived matrix.

OBJECTIVE: To evaluate the efficacy of treatment of hard-to-heal wounds of patients with ischaemia of the lower extremities, and compare an omega-3 wound matrix product (Kerecis, Iceland) with a standard dressing. METHOD: A single-centre, prospective, randomised, controlled clinical trial of patients with hard-to-heal wounds following three weeks of standard care was undertaken. The ischaemic condition of the wound was confirmed as a decreased transcutaneous oxygen pressure (TcPO2) of <40mmHg. After randomising patients into either a case (omega-3 dressing) or a control group (standard dressing), the weekly decrease in wound area over 12 weeks and the number of patients that achieved complete wound closure were compared between the two groups. Patients with a TcPO2 of ≤32mmHg were taken for further analysis of their wound in a severe ischaemic context. RESULTS: A total of 28 patients were assigned to the case group and 22 patients to the control group. Over the course of 12 weeks, the wound area decreased more rapidly in the case group than the control group. Complete wound healing occurred in 82% of patients in the case group and 45% in the control group. Even in patients with a severe ischaemic wound with a TcPO2 value of <32 mmHg, wound area decreased more rapidly in the case group than the control group. The proportions of re-epithelialised area in the case and control groups were 80.24% and 57.44%, respectively. CONCLUSION: Considering the more rapid decrease in wound area and complete healing ratio in the case group, application of a fish skin-derived matrix for treating lower-extremity hard-to-heal wounds, especially with impaired vascularity, would appear to be a good treatment option.

Napyradiomycin B4 Suppresses RANKL-Induced Osteoclastogenesis and Prevents Alveolar Bone Destruction in Experimental Periodontitis.

The unique structure and beneficial biological properties of marine natural products have drawn interest in drug development. Here, we examined the therapeutic potential of napyradiomycin B4 isolated from marine-derived Streptomyces species for osteoclast-related skeletal diseases. Bone marrow-derived macrophages were treated with napyradiomycin B4 in an osteoclast-inducing medium, and osteoclast formation, osteoclast-specific gene expression, and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) localization were evaluated using tartrate-resistant acid phosphatase staining, real-time PCR, and immunostaining, respectively. Phosphorylation levels of signaling proteins were assessed by immunoblot analysis to understand the molecular action of napyradiomycin B4. The in vivo efficacy of napyradiomycin B4 was examined under experimental periodontitis, and alveolar bone destruction was evaluated by microcomputed tomography (micro-CT) and histological analyses. Among the eight napyradiomycin derivatives screened, napyradiomycin B4 considerably inhibited osteoclastogenesis. Napyradiomycin B4 significantly suppressed the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation and disrupted the expression of NFATc1 and its target genes. Mitogen-activated extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK) phosphorylation levels were reduced by napyradiomycin B4 in response to RANKL. Under in vivo experimental periodontitis, napyradiomycin B4 significantly attenuated osteoclast formation and decreased the distance between the cementoenamel junction and alveolar bone crest. Our findings demonstrate the antiosteoclastogenic activity of napyradiomycin B4 by inhibiting the RANKL-induced MEK-ERK signaling pathway and its protective effect on alveolar bone destruction.

Poor visual prognosis of Asian patients with 3460 mitochondrial DNA mutation in Leber's hereditary optic neuropathy.

BACKGROUND: Among the 3 primary mutations of Leber's hereditary optic neuropathy (LHON), the incidence of LHON with a mutation at nucleotide position 3460 is the lowest in Asians. Therefore, information about the clinical manifestations of LHON mutations in Asians with the 3460 mutation is limited. OBJECTIVE: To determine the clinical manifestations including visual prognosis of Asians with the LHON 3460 mutation. METHODS: We performed a retrospective study of 5 Korean LHON patients with the 3460 mutation. RESULTS: All patients were male, and the age of onset for visual impairment varied from 17 to 35 years, with an average of 25.4 ± 7.16 years. Among the 10 affected eyes, only 1 eye of 1 patient showed visual improvement to 20/50 at 2 years after onset. The remaining patients had a visual acuity of worse than 20/200. CONCLUSION: The visual prognosis of Korean patients with the LHON 3460 mutation was generally poor. Further studies regarding Asian patients with the LHON 3460 mutation are necessary.

The obesity paradox in younger adult patients with sepsis: analysis of the MIMIC-IV database.

BACKGROUND: The obesity paradox suggests that individuals with obesity may have a survival advantage against specific critical illnesses, including sepsis. However, whether this paradox occurs at younger ages remains unclear. Therefore, we aimed to investigate whether obesity could improve survival in younger adult patients with sepsis. METHODS: We used clinical data sourced from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Patients with Sequential Organ Failure Assessment score ≥2 and suspected infection at the time of ICU admission were identified as having sepsis, following the Sepsis-3 definition. Individuals were classified into the obesity (BMI ≥30 kg/m²) and non-obesity (BMI <30 kg/m²) groups. Patients aged <50 and ≥50 years were categorized as younger adult patients and older patients, respectively. RESULTS: Of 73,181 patients in the MIMIC-IV ICU database, 18,120 satisfied the inclusion criteria: 2642 aged <50 years and 15,478 aged ≥50 years. The Kaplan-Meier curve showed that obesity was not associated with an improved mortality rate among younger adult patients with sepsis (log-rank test: P = 0.197), while obesity exhibited a survival benefit in older patients with sepsis (log-rank test: P < 0.001). After propensity score matching, in-hospital mortality did not differ significantly between the obesity and non-obesity groups (13.3% vs. 12.2%; P = 0.457) in the younger adult patients with sepsis. Multivariate logistic regression analysis revealed that BMI was not an independent risk factor for in-hospital mortality in younger adult patients with sepsis (underweight: adjusted odds ratio [aOR] 1.72, P = 0.076; overweight: aOR 0.88, P = 0.437; obesity: aOR 0.93, P = 0.677; and severe obesity: aOR 1.22, P = 0.580, with normal weight as the reference). CONCLUSION: Contrary to findings regarding older patients with sepsis, our findings suggest that the obesity paradox does not apply to younger adult patients with sepsis.

BET inhibition induces synthetic lethality in PTEN deficient colorectal cancers via dual action on p21CIP1/WAF1.

Loss of PTEN tumor suppressor is an important event during colorectal cancer (CRC) development and is a target for therapeutic exploitation. This study reports that bromodomain and extra-terminal motif (BET) is a synthetic lethal partner of PTEN in CRC. BET inhibition (BETi) selectively induced G1 cell cycle arrest and apoptosis in PTEN-/- CRC. Further, BETi selectively and dose-dependently suppressed the growth of PTEN-/- CRC tumor xenografts in mice and patient-derived organoids. Mechanistically, PTEN-deficient CRC cells elevated the level of cytoplasmic p21CIP1/WAF1 that is hyper-phosphorylated at Thr145 by AKT. BETi suppressed AKT activation in PTEN-deficient CRC cells, followed by the reduction in p21 phosphorylation at Thr145, thereby promoting its nuclear translocation. In addition, BETi suppressed MYC level and this in turn increased the total p21 level in the nuclei. Over-expression of a phospho-mimetic p21 mutant (T145D) significantly rescued the BETi effect on PTEN-deficient CRC. These results suggest that BETi has a dual action on p21: elevating the level of p21 by inhibiting MYC and converting the oncogenic (cytoplasmic) p21 into the tumor-suppressive (nuclear) p21 by inhibiting AKT. Taken together, this study identified the synthetic lethal interaction between PTEN and BET, and provides a potential actionable target for CRC with PTEN loss.