Future Therapies Research Articles

Hepatic oxylipin profiles in mouse models of Wilson disease: New insights into early hepatic manifestations

Hepatic inflammation is commonly identified in Wilson disease (WD), a genetic disease of hepatic and brain copper accumulation. Copper accumulation is associated with increased oxidative stress and reactive oxygen species generation which may result in non-enzymatic oxidation of membrane-bound polyunsaturated fatty acids (PUFA). PUFA can be oxidized enzymatically via lipoxygenases (LOX), cyclooxygenases (COX), and cytochrome P450 monooxygenases (CYP). Products of PUFA oxidation are collectively known as oxylipins (OXL) and are bioactive lipids that modulate hepatic inflammation. We examined hepatic OXL profiles at early stages of WD in two mouse models, the toxic milk mouse from The Jackson Laboratory (tx-j) and the Atp7b knockout on a C57Bl/6 background (Atp7b−/−B6). Targeted lipidomic analysis performed by ultra-high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry showed that in both tx-j and Atp7b−/−B6 mice, hepatic OXL profiles were altered with higher thromboxane and prostaglandins levels. The levels of oxidative stress marker, 9-HETE were increased more markedly in tx-j mice. However, both genotypes showed upregulated transcript levels of many genes related to oxidative stress and inflammation. Both genotypes showed higher prostaglandins, thromboxin along with higher PUFA-derived alcohols, diols, and ketones with altered epoxides; the expression of Alox5 was upregulated and many CYP-related genes were dysregulated. Pathway analyses show dysregulation in arachidonic acid and linoleic acid metabolism characterizes mice with WD. Our findings indicate alterations in hepatic PUFA metabolism in early-stage WD and suggest the upregulation of both, non-enzymatic ROS-dependent and enzymatic PUFA oxidation, which could have implications for hepatic manifestations in WD and represent potential targets for future therapies.

Oncolytic viruses improve cancer immunotherapy by reprogramming solid tumor microenvironment.

Immunotherapies using immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T-cell therapy have achieved successful results against several types of human tumors, particularly hematological malignancies. However, their clinical results for the treatment of solid tumors remain poor and unsatisfactory. The immunosuppressive tumor microenvironment (TME) plays an important role by interfering with intratumoral T-cell infiltration, promoting effector T-cell exhaustion, upregulating inhibitory molecules, inducing hypoxia, and so on. Oncolytic viruses are an encouraging biocarrier that could be used in both natural and genetically engineered platforms to induce oncolysis in a targeted manner. Oncolytic virotherapy (OV) contributes to the reprogramming of the TME, thus synergizing the functional effects of current ICIs and CAR T-cell therapy to overcome resistant barriers in solid tumors. Here, we summarize the TME-related inhibitory factors affecting the therapeutic outcomes of ICIs and CAR T cells and discuss the potential of OV-based approaches to alleviate these barriers and improve future therapies for advanced solid tumors.

MiR-195-5p as Regulator of γ-Catenin and Desmosome Junctions in Colorectal Cancer

Desmosomes play a key role in the regulation of cell adhesion and signaling. Dysregulation of the desmosome complex is associated with the loss of epithelial cell polarity and disorganized tissue architecture typical of colorectal cancer (CRC). The aim of this study was to investigate and characterize the effect of miR-195-5p on desmosomal junction regulation in CRC. In detail, we proposed to investigate the deregulation of miR-195-5p and JUP, a gene target that encodes a desmosome component in CRC patients. JUP closely interacts with desmosomal cadherins, and downstream, it regulates several intracellular transduction factors. We restored the miR-195-5p levels by transient transfection in colonic epithelial cells to examine the effects of miR-195-5p on JUP mRNA and protein expression. The JUP regulation by miR-195-5p, in turn, determined a modulation of desmosome cadherins (Desmoglein 2 and Desmocollin 2). Furthermore, we focused on whether the miR-195-5p gain of function was also able to modulate the expression of key components of Wnt signaling, such as NLK, LEF1 and Cyclin D1. In conclusion, we have identified a novel mechanism controlled by miR-195-5p in the regulation of adhesive junctions, suggesting its potential clinical relevance for future miRNA-based therapy in CRC.

Detection of early Alzheimer’s disease at the eye clinic: The BeyeOMARKER study

AbstractBackgroundEarly detection of Alzheimer’s disease (AD) is essential for establishing a patient management plan, and for clinical trial selection and determining who will benefit most from future therapies. Effective screening for early AD will require large‐scale implementation of non‐invasive, scalable, and accessible biomarkers such as blood‐based biomarkers and retinal scans. With a high population throughput and a visually impaired population at increased risk for AD (HR = 1.47 (Kuźma et al., J Alzheimers Dis (2021)), eye clinics provide a prime proof‐of‐concept setting to explore the potential of implementing non‐invasive biomarkers in an alternative clinical setting. The BeyeOMARKER study aims to explore the feasibility of large‐scale screening using non‐invasive tools in eye clinics, with the ultimate goal of providing recommendations for AD screening in alternative clinical settings, and exploring factors underlying the association between eye disease and AD.MethodThe BeyeOMARKER study is a prospective, observational, longitudinal cohort study. At the eye clinic, ∼700 participants (aged ≥45) will be screened for early AD using plasma phospho‐tau181 (p‐tau181) and a short neuropsychological test battery (Montreal Cognitive assessment). After screening, 100 plasma p‐tau181 positive cases and 50 p‐tau181 negative controls (matched based on age, sex and eye disease) will be included into the longitudinal BeyeOMARKER cohort. This cohort will be invited to the memory clinic for a hyperspectral retinal scan, structural magnetic resonance imaging (MRI), and a comprehensive neuropsychological assessment including cortical vision tests (e.g., visuo‐perceptive and visuospatial abilities).ResultMain outcomes of the BeyeOMARKER study are 1) a prevalence estimate of AD in a large, diverse population of visually impaired individuals, 2) the performance of hyperspectral retinal scans to detect AD pathology in this population and its complementary benefit over‐and‐above plasma p‐tau181, and 3) improved understanding on the eye‐brain connection in the context of AD through comparison of cognitive and cortical vision performance, and brain atrophy across visually impaired p‐tau181 positive and negative individuals.ConclusionThe BeyeOMARKER consortium aspires to build a detailed roadmap for the implementation of non‐invasive screening for early AD within the eye clinic.

Abstract B013: Identification of a Notch transcriptomic signature for breast cancer

Abstract Background: Dysregulated Notch signalling contributes to breast cancer development and progression, but validated tools to measure the level of Notch signalling in breast cancer subtypes and in response to systemic therapy are largely lacking. A transcriptomic signature of Notch signalling would thus be warranted, and in this report, we have established such a classifier. Methods: To generate the signature, we first identified Notch-regulated genes from six basal-like breast cancer cell lines subjected to elevated and reduced Notch signalling by culturing on immobilized Notch ligand Jagged1 or blockade of Notch by g-secretase inhibitors, respectively. From this cadre of Notch-regulated genes, we developed candidate transcriptomic signatures that were trained on a breast cancer patient dataset (the TCGA-BRCA cohort) and a broader breast cancer cell line cohort and sought to validate in independent data sets. Results: An optimal 20-gene transcriptomic signature was selected. We validated the signature on two independent patient datasets (METABRIC and Oslo2) and it showed an improved coherence score and tumour specificity compared with previously published signatures. Furthermore, the signature score was particularly high for basal-like breast cancer, indicating an enhanced level of Notch signalling in this subtype. The signature score was increased after neoadjuvant treatment in the PROMIX and BEAUTY patient cohorts, and a lower signature score generally correlated with better clinical outcome. Conclusions: The 20-gene transcriptional signature has the potential to better stratify patients and to evaluate the response of future Notch-based therapies for breast cancer. Citation Format: Eike-Benjamin Braune, Felix Geist, Xiaojia Tang, Krishna Kalari, Judy Boughey, Liewei Wang, Roberto A. Leon-Ferre, Antonino B. D’Assoro, James N. Ingle, Matthew P. Goetz, Kang Wang, Theodoros Foukakis, Anita Seshire, Dirk Wienke, Urban Lendahl. Identification of a Notch transcriptomic signature for breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B013.

A Systems Evaluation Model for the Development of Companion Diagnostics and Associated Molecularly Targeted Therapies

PurposeMonoclonal antibodies (mAbs) are important active ingredients of molecularly targeted drugs, which are only effective for specific patient groups. Early assessment of their effectiveness is important for more efficient use of time and resources. Companion diagnostics (CDx) are medical devices or tests to identify groups of promising patients based on specific biomarkers. This work offers a systems evaluation model and a comprehensive assessment from multiple stakeholder perspectives.MethodsThis work introduces a new systems model for assessing available treatment options. Process system diagrams, consisting of independently defined unit structures, are applied to represent the expected decision points and outcomes. A sensitivity analysis is conducted to identify the critical requirements for achieving cost-effectiveness. The model was applied to a case of terminal colorectal cancer treatment to compare mAb drugs to standard therapy.ResultsThe results showed that from the payers’ perspective, the cost and response rates of the mAb drug were critical parameters to improve for achieving the target cost-effectiveness. The results give quantitative guidance for the required improvement.ConclusionThis work represents an important step towards a fair and systematic assessment of treatment alternatives and serves as a guideline for future CDx and therapy technology development efforts.

Abstract B001: Harnessing invariant natural killer T cell cytotoxicity for cancer therapy

Abstract Cytotoxic cells are major effectors in adoptive cell transfer (ACT) cancer therapies. Although autologous conventional T cells are commonly used in ACT therapies, other types of cells, such as invariant natural killer T (iNKT) cells, have become attractive for the design of off-the-shelf ACT therapies. Unlike conventional T cells, iNKT cells react to glycolipid antigens presented by CD1d, a non-polymorphic MHC I-like molecule. Based on their cytokine profile and transcription factor expression, three main helper iNKT subsets have been described in mice: iNKT1, iNKT2, and iNKT17. In addition, the cytotoxic response of iNKT cells has been reported, but this function is less characterized. In a previous transcriptomic study, we have shown that the iNKT1 subset is heterogeneous and it comprises two main clusters: iNKT1b, enriched in genes related to T helper 1, and iNKT1c, characterized by a cytotoxic gene profile. Here, we demonstrated that iNKT1c cells exhibit higher in vitro specific killing activity against EL4 tumor cells compared to iNKT1b cells. We identified IL-15 as one of the factors that boosts the cytotoxic functions of iNKT1c cells. Moreover, adoptive cell transfer of iNKT1c cells in mice previously injected with B16F10 melanoma cells resulted in reduced metastatic lung nodules. We also explored the presence of a distinct cytotoxic iNKT cell subset in humans by spectral flow cytometry and clustering analysis. From PBMCs of healthy donors, we identified a population of CD57+Tbethi iNKT cells that show a cytotoxic profile. Interestingly, this population can also be found infiltrating tumors in lung cancer patients. This study unraveled bona fide cytotoxic iNKT cells and provides insights for the design of future cancer therapies. Citation Format: Carolina de Amat Herbozo, Stephanie Wong, Meggie Kuypers, Jessica Matthews, Thomas Baranek, Sarah Crome, Adrian Sacher, Christophe Paget, Thierry Mallevaey. Harnessing invariant natural killer T cell cytotoxicity for cancer therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B001.

Abstract A024: Systemic administration of CD3-redirected lentiviral vector efficiently targets CD19-CAR delivery to human T cells in vivo

Abstract In recent years, there has been a significant increase in interest regarding the generation of CAR-T cells directly within patients using a simple vector injection containing the CAR transgene. This promising technology has the potential to streamline the procedure and decrease its overall cost. To ensure effective in vivo delivery, these vectors must demonstrate resistance to neutralization by human serum, the ability to specifically target and transduce desired cells, and must support their subsequent expansion. Lentiviral vectors (LV) pseudotyped with VSV G-protein (G-WT) have a broad tropism, targeting various cell types through their affinity for the ubiquitously expressed LDL receptor (LDLR). G-WT LV have proven effective in generating therapeutic CAR-T cells ex vivo, however, requiring proper purification and activation of T cells beforehand. To address challenges related to their in vivo delivery, we utilized rational engineering to redesign the G protein, resulting in a modified version termed G-CD3. This redesigned G protein incorporates a CD3-specific single-chain antibody, allowing for targeted recognition of T cells while avoiding LDLR recognition. Upon testing the newly designed G-CD3 LV, we demonstrated its specificity in targeting and infecting both un-activated and activated T cells in peripheral blood monocytic cell cultures. In addition, the G-CD3 LV powerfully activates T cells, evident from their increased CD25 expression, and the infection is not hindered by the presence of human serum (25%). In further experiments, we successfully demonstrated that G-CD3-LV can infect T cells in fresh whole blood. In vivo evaluation of G-CD3-LV efficiency was performed in humanized NSG mice with more than 40 % of human CD45+ cells by intravenous (IV) or intraperitoneal (IP) LV delivery using LV encoding anti-CD19 CAR and GFP transgenes. Both IV and IP delivery of G-CD3-LV led to in vivo CAR T cell generation. However, CAR-T blood levels were higher after IP administration, reaching 13-17% of total circulating human CD45+ cells at the peak on day 21. Anti CD19-CAR-T cell generation coincided with the disappearance of endogenous CD19+ B cells, demonstrating functional in vivo CAR-T generation. Tissue analysis at day 39 after LV injection showed the presence of anti-CD19 CAR-T cells accompanied by the absence or dramatic reduction in CD19+ B cells in spleen, bone marrow and liver. In contrast, no CAR-T cell generation was detected at any time point in the mice injected with G-WT-LV, regardless of whether the virus was administered IV or IP. Taken together these data highlight the potential applicability of newly designed retargeted LV for in vivo gene delivery, offering promising prospects for future human gene therapy applications. Citation Format: Karina Krotova, Gopal Naik Nenavath, Nandakumar Packiriswamy, Rianna Vandergaast, Christopher Ziegler, Melissa Moy, Riya Narjari, Luke Schnebeck, Zachary Larson, Kyle Gromer, Chia-Hsuan Chin, Samantha Reiter, Miguel Muñoz Alía, Kah-Whye Peng, Stephen Russell. Systemic administration of CD3-redirected lentiviral vector efficiently targets CD19-CAR delivery to human T cells in vivo [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A024.

REM sleep behavior disorder: update on diagnosis and management.

REM sleep behavior disorder (RBD) is characterized by a loss of atonia of skeletal muscles during REM sleep, associated with acting out behaviors during dreams. Knowledge of this pathology is important to predict neurodegenerative diseases since there is a strong association of RBD with diseases caused by the deposition of alpha-synuclein in neurons (synucleinopathies), such as Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). Proper diagnosis of this condition will enable the use of future neuroprotective strategies before motor and cognitive symptoms. Diagnostic assessment should begin with a detailed clinical history with the patient and bed partner or roommate and the examination of any recorded home videos. Polysomnography (PSG) is necessary to verify the loss of sleep atonia and, when documented, the behaviors during sleep. Technical recommendations for PSG acquisition and analysis are defined in the AASM Manual for the scoring of sleep and associated events, and the PSG report should describe the percentage of REM sleep epochs that meet the criteria for RWA (REM without atonia) to better distinguish patients with and without RBD. Additionally, PSG helps rule out conditions that may mimic RBD, such as obstructive sleep apnea, non-REM sleep parasomnias, nocturnal epileptic seizures, periodic limb movements, and psychiatric disorders. Treatment of RBD involves guidance on protecting the environment and avoiding injuries to the patient and bed partner/roommate. Use of medications are also reviewed in the article. The development of neuroprotective medications will be crucial for future RBD therapy.

Vascular dysfunction in behavior‐variant frontotemporal dementia

AbstractBackgroundThe vascular disturbance was recently found in a postmortem study of frontotemporal dementia (FTD), but whether vascular dysfunction exists in the early stage of FTD remains elusive. The study aimed to explore whether there was evidence of vascular dysfunction in FTD and its relationship with central neurodegeneration and the clinical outcome.MethodTwenty patients with behavior frontotemporal dementia (bvFTD) were enrolled and underwent assessment of peripheral plasma vascular markers, positron emission tomography/magnetic resonance imaging, and neuropsychological examinations. Group difference was tested using the student’s t‐test and Mann‐Whitney U test. Partial correlation analysis was implemented using age and sex as covariates to explore the association between peripheral vascular markers, neuroimaging, and clinical measures.ResultAll four factors including matrix metalloproteinases‐1(MMP‐1), matrix metalloproteinases‐3 (MMP‐3), Osteopontin, and pentraxin‐3 are increased in the FTD group. The plasma level of MMP‐1 was negatively correlated with the gray matter metabolism of the prefrontal cortex (r = ‐0.5119, p = 0.0210) and the anterior cingulate cortex (r = ‐0.4685, p = 0.0269). MMP‐3 was negatively correlated with the gray matter metabolism of the anterior temporal cortex (r = ‐0.4650, p = 0.0388). Pentraxin‐3 was negatively correlated with age at sampling (r = ‐0.5024, p = 0.0240) and age at onset (r = ‐0.5693, p = 0.0088). No other significant associations were found in other vascular cytokines and clinical measures.ConclusionThe vascular disturbance was found in patients with bvFTD and associated with the disease‐specific neurodegeneration pattern, indicating vascular dysfunction and perturbance of the BBB participation in the pathogenesis of FTD. The vascular pathway might be a promising target for future potential therapy.

SA42 Project SATURN – A Real-World Evidence and Data Collaboration With Existing European Datasets in Osteogenesis Imperfecta to Support Future Therapies

SA42 Project SATURN – A Real-World Evidence and Data Collaboration With Existing European Datasets in Osteogenesis Imperfecta to Support Future Therapies

Education and Experience in Intrathecal Drug Delivery Systems (IDDS) During Pain Medicine Fellowships.

Targeted drug delivery (TDD) via intrathecal drug delivery systems (IDDS) exposure and clinical adoption remains low despite multiple well-designed trials that demonstrate safety, efficacy, reliability, and cost-saving benefits. This study aims to understand the possible contributing factors starting with Pain Medicine fellowship training. An internet-based, anonymous pilot survey was distributed to pain medicine fellows enrolled in an Accreditation Council for Graduate Medical Education (ACGME) accredited pain medicine training program during the 2021-2022 academic year. Fellowship programs were identified using published online ACGME accreditation data. The survey was distributed via email to fellowship program directors and coordinators and was made available through pain medicine societies. Seventy-one of four hundred and twenty-three pain medicine fellows (17% response rate) completed the survey. Nine percent of respondents evidence-informed opinion coincided with the most recent Polyanalgesic Consensus Conference (PACC) guidelines recommendations for IDDS treatment indications. Fifty-one percent of respondents felt there was an unmet need for IDDS training. About one-third of respondents felt that lack of curriculum, faculty, and cases were barriers to IDDS use, respectively. Thirty-one percent of fellows reported sufficient training for IDDS in their fellowship programs. The majority (70%) of respondents somewhat or strongly support direct training by IDDS manufacturers. A wide variability exists surrounding IDDS training during ACGME accredited pain medicine fellowship. Insufficient case exposure and lack of a standardized curriculum may play a role in future therapy adoption. The results from this study call for a more standardized training approach with an emphasis on adequate clinical exposure, utilization of peer reviewed educational curriculum and supplemental material to aid pain medicine fellows' education.

In vitro antiproliferative and apoptotic effects of thiosemicarbazones based on (-)-camphene and R-(+)-limonene in human melanoma cells.

A series of 38 thiosemicarbazone derivatives based on camphene and limonene were evaluated for their antiproliferative activity. Among them, 19 were synthesized and characterized using proton and carbon-13 nuclear magnetic resonance (1H and 13C NMR). For initial compound selection, human melanoma cells (SK-MEL-37) were exposed to a single concentration of a compound (100 μM) for 24, 48, and 72 hours, and cell detachment was visually observed. Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Nineteen compounds (4, 6, 8, 11, 13, 14, 15, 16, 17, 18, 20, 22, 25, 26, 31, 3', 4', 6', and 9') yielded cell viability below 20%. Subsequently, IC50 values for these compounds were determined, ranging from 11.56 to 55.38 μM, after 72 hours of treatment. Compound 17 (o-hydroxybenzaldehyde (-)-camphene-based thiosemicarbazone) demonstrated the lowest IC50 value, followed by compound 4 (benzaldehyde (-) camphene-based thiosemicarbazone) at 12.84 μM. Regarding compound 4, we observed the induction of a characteristic ladder pattern of DNA fragmentation through gel electrophoresis. Furthermore, fluorescence, flow cytometry and scanning microscopy assays revealed morphological changes consistent with apoptosis induction. Additionally, the measurement of caspase 6 and 8 activity in cellular extracts after treatment for 2, 4, 6, and 24 hours suggested the potential involvement of the extrinsic apoptosis pathway in the mechanism of action of compound 4. Further investigations, including molecular docking studies, are required to fully explore the potential of compound 4 and the other selected compounds, highlighting their promising role in future melanoma therapy research.

Mesenchymal stem cell therapy modulates macrophage dynamics in ARDS-associated liver injury in rats

Acute Respiratory Distress Syndrome (ARDS) is a life-threatening pulmonary condition characterized by severe hypoxemia and respiratory failure. Beyond its devastating impact on the lungs, ARDS often triggers systemic responses affecting vital organs throughout the body. One such organ commonly affected is the liver, which experiences various degrees of injury during the course of ARDS. Pathophysiological changes in liver during ARDS, particularly polarization of Kupffer cells during the disease and its treatment, have drawn increasing attention. Purpose. To explore the macrophage transformation in liver injury associated with ARDS and investigate the potential of mesenchymal stem cell (MSC) therapy as a means to modulate macrophage responses and mitigate liver injury. Materials and methods. 72 mature male Wistar rats were randomly allocated to nine experimental groups as follows: the control group, groups assessed at 3 days, 7 days, and 28 days following intranasal LPS administration, groups that received 24 hours of LPS followed by 2 days of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs), groups exposed to 4 days of LPS and 3 days of hUC-MSCs, groups subjected to 14 days of LPS and 14 days of hUC-MSCs, groups treated with LPS 21 days and 7 days with hUC-MSCs injection, and a control group assessed 3 days after hUC-MSCs injection. For the administration of hUC-MSCs, intraperitoneal injections were performed at a dose of 1∙106 cells/kg body weight. Immunohistochemistry was employed to analyze macrophage subpopulations in liver tissues. Animal experiments adhered to ethical guidelines. Results. Early ARDS stages showed increased M1 macrophages, indicating pro-inflammatory responses, while later stages showed M2 macrophage activation, suggestive of anti-inflammatory and tissue repair roles. MSC administration facilitated the transition from M1 to M2 macrophages, promoting an anti-inflammatory milieu. Conclusions. MSCs demonstrate the potential to modulate macrophage polarization into M2 anti-inflammatory phenotype. Such findings reflect one of the mechanisms of MSC action which holds practical significance for future ARDS therapies, aiming to mitigate excessive inflammation and enhance tissue repair.

Predicting In-Hospital Acute Heart Failure Worsening in the Oldest Old: Insights from Point-of-Care Ultrasound

The decompensation trajectory check is a basic step to assess the clinical course and to plan future therapy in hospitalized patients with acute decompensated heart failure (ADHF). Due to the atypical presentation and clinical complexity, trajectory checks can be challenging in older patients with acute HF. Point-of-care ultrasound (POCUS) has proved to be helpful in the clinical decision-making of patients with dyspnea; however, to date, no study has attempted to verify its role in predicting determinants of ADHF in-hospital worsening. In this single-center, cross-sectional study, we consecutively enrolled patients aged 75 or older hospitalized with ADHF in a tertiary care hospital. All of the patients underwent a complete clinical examination, blood tests, and POCUS, including Lung Ultrasound and Focused Cardiac Ultrasound. Out of 184 patients hospitalized with ADHF, 60 experienced ADHF in-hospital worsening. By multivariable logistic analysis, total Pleural Effusion Score (PEFs) [aO.R.: 1.15 (CI95% 1.02–1.33), p = 0.043] and IVC collapsibility [aO.R.: 0.90 (CI95% 0.83–0.95), p = 0.039] emerged as independent predictors of acute HF worsening after extensive adjustment for potential confounders. In conclusion, POCUS holds promise for enhancing risk assessment, tailoring diuretic treatment, and optimizing discharge timing for older patients with ADHF.

The molecular landscape of oculocutaneous albinism in India and its therapeutic implications.

Oculocutaneous albinism is an inherited disorder of melanin biosynthesis, characterized by absent or reduced pigmentation of the skin, hair, and eyes. Molecular alterations of genes that cause non-syndromic albinism in Asian Indians are poorly characterized. This information would be useful for developing therapies for this disorder. We analyzed 164 persons with non-syndromic albinism, belonging to unrelated families from all parts of India, for molecular changes in the causative genes. Subjects with white hair, white skin, and red iris had their tyrosinase gene sequenced and were also tested by MLPA for deletions/duplications. Subjects with negative results or with darker skin, golden/brown or darker hair had sequencing of TYR, P, TYRP1, SLC45A2 and GPR143 genes. Pathogenic variants in TYR (OCA1) were observed in 139 (84.7%) patients, in the P gene (OCA2) in 20 (12.2%), in TYRP1 (OCA3) in two (1.2%), in SLC45A2 (OCA 4) in one (0.61%), and in GPR143 (X-linked ocular albinism) in two (1.2%) patients. Of 278 alleles with variants in TYR, 179 (64.3%) alleles had (p.R278*) alteration, suggesting the possibility of therapy with a stop codon readthrough molecule. We report 20 patients with 13 disease associated variants in the P gene and 18 novel pathogenic variants in TYR, P, TYRP1, SLC45A2 and GPR143 genes. The data are compared with those reported from India, Pakistan and rest of the world. The therapeutic options in albinism are briefly described, opening this field for future therapies.

Multifunctional Nanoplatform for NIR-II Imaging-Guided Synergistic Oncotherapy

Tumors are a major public health issue of concern to humans, seriously threatening the safety of people’s lives and property. With the increasing demand for early and accurate diagnosis and efficient treatment of tumors, noninvasive optical imaging (including fluorescence imaging and photoacoustic imaging) and tumor synergistic therapies (phototherapy synergistic with chemotherapy, phototherapy synergistic with immunotherapy, etc.) have received increasing attention. In particular, light in the near-infrared second region (NIR-II) has triggered great research interest due to its penetration depth, minimal tissue autofluorescence, and reduced tissue absorption and scattering. Nanomaterials with many advantages, such as high brightness, great photostability, tunable photophysical properties, and excellent biosafety offer unlimited possibilities and are being investigated for NIR-II tumor imaging-guided synergistic oncotherapy. In recent years, many researchers have tried various approaches to investigate nanomaterials, including gold nanomaterials, two-dimensional materials, metal sulfide oxides, polymers, carbon nanomaterials, NIR-II dyes, and other nanomaterials for tumor diagnostic and therapeutic integrated nanoplatform construction. In this paper, the application of multifunctional nanomaterials in tumor NIR-II imaging and collaborative therapy in the past three years is briefly reviewed, and the current research status is summarized and prospected, with a view to contributing to future tumor therapy.

Immune modulation of gut microbiota and its metabolites in chronic hepatitis B

The gut microbiota is a diverse ecosystem consisting of 100 trillion microbiomes. The interaction between the host’s gut and distal organs profoundly impacts various functions such as metabolism, immunity, neurology, and nutrition within the human body. The liver, as the primary immune organ, plays a crucial role in maintaining immune homeostasis by receiving a significant influx of gut-derived components and toxins. Perturbations in gut microbiota homeostasis have been linked to a range of liver diseases. The advancements in sequencing technologies, such as 16S rRNA and metagenomics, have opened up new avenues for comprehending the intricate physiological interplay between the liver and the intestine. Metabolites produced by the gut microbiota function as signaling molecules and substrates, influencing both pathological and physiological processes. Establishing a comprehensive host-bacterium-metabolism axis holds tremendous potential for investigating the mechanisms underlying liver diseases. In this review, we have provided a summary of the detrimental effects of the gut-liver axis in chronic liver diseases, primarily focusing on hepatitis B virus-related chronic liver diseases. Moreover, we have explored the potential mechanisms through which the gut microbiota and its derivatives interact with liver immunity, with implications for future clinical therapies.

Pectin based hydrogel with covalent coupled doxorubicin and limonin loading for lung tumor therapy

Self-healing hydrogels have shown great application potential in drug delivery for anti-tumor therapy and tissue engineering. In this research, Doxorubicin (DOX) was coupled onto the oxidized pectin (pec-Ald) to prepare DOX grafted pec-AD and used to fabricate self-healing hydrogel for lung cancer therapy combined with novel herbal medicine extract limonin targeting lung cancer cells. The hydrogel was prepared with P(NIPAM195-co-AH54) cross-linking and the hydrazone bond cross-linked hydrogel showed good mechanical property and self-healing behavior. With pectin composition, the hydrogel was still biodegradable catalyzed by enzyme and in vivo. The hydrogel formed fast fit for injectable application and the hydrogel itself showed moderate lung cancer inhibition activity. With limonin loading, the hydrogel showed synergistic lung cancer therapy with the tumor growth greatly inhibited. The covalent coupling of DOX and loaded limonin in the hydrogel decreased in vivo toxicity and the hydrogel degraded on time. With biodegradability and improved lung cancer therapy efficiency, this DOX grafted self-healing hydrogel could find great potential application in cancer therapy in near future.

Pharmacokinetics and safety evaluation of intravenously administered Pseudomonas phage PA_LZ7 in a mouse model.

Phage therapy is gaining traction as an alternative to antibiotics due to the rise of multi-drug-resistant (MDR) bacteria. This study assessed the pharmacokinetics and safety of PA_LZ7, a phage targeting MDR Pseudomonas aeruginosa, in mice. After intravenous administration, the phage showed an exponential decay in plasma and its concentration dropped significantly within 24 h for all dosage groups. Although there was a temporary increase in certain plasma cytokines and spleen weight at higher dosages, no significant toxicity was observed. Therefore, PA_LZ7 shows potential as an effective and safe candidate for future phage therapy against MDR P. aeruginosa infections.