Recent advances in cancer therapeutics, such as targeted therapy and immunotherapy, have raised the hope for cures for many cancer types. However, there are still ongoing challenges to the pursuit of ...novel therapeutic approaches, including high toxicity to normal tissue and cells, difficulties in treating deep tumor tissue, and the possibility of drug resistance in tumor cells. The use of live tumor-targeting bacteria provides a unique therapeutic option that meets these challenges. Compared with most other therapeutics, tumor-targeting bacteria have versatile capabilities for suppressing cancer. Bacteria preferentially accumulate and proliferate within tumors, where they can initiate antitumor immune responses. Bacteria can be further programmed via simple genetic manipulation or sophisticated synthetic bioengineering to produce and deliver anticancer agents based on clinical needs. Therapeutic approaches using live tumor-targeting bacteria can be applied either as a monotherapy or in combination with other anticancer therapies to achieve better clinical outcomes. In this review, we introduce and summarize the potential benefits and challenges of this anticancer approach. We further discuss how live bacteria interact with tumor microenvironments to induce tumor regression. We also provide examples of different methods for engineering bacteria to improve efficacy and safety. Finally, we introduce past and ongoing clinical trials involving tumor-targeting bacteria.
Objective
The purpose of this study was to present the results of our investigation of the prognostic value of adipopenia and sarcopenia in patients with amyotrophic lateral sclerosis (ALS).
Methods
...Consecutive patients with ALS with abdominal computed tomography (CT) were retrospectively identified at a single tertiary hospital between January 2010 and July 2021. Deep learning‐based volumetric CT body composition analysis software was used to obtain abdominal waist fat volume, fat attenuation, and skeletal muscle area at the L3 level, then normalized to the fat volume index (FVI) and skeletal muscle index (SMI). Adipopenia and sarcopenia were defined as the sex‐specific lowest quartile and SMI reference values, respectively. The associations of CT‐derived body composition parameters with clinical variables, such as body mass index (BMI) and creatinine, were evaluated by Pearson correlation analyses, and associations with survival were assessed using the multivariable Cox regression analysis.
Results
Eighty subjects (40 men, 65.5 ± 9.4 years of age) were investigated (median interval between disease onset and CT examination = 25 months). The mean BMI at the CT examination was 20.3 ± 4.3 kg/m2. The BMI showed a positive correlation with both FVI (R = 0.70, p < 0.001) and SMI (R = 0.63, p < 0.001), and the serum creatinine level was associated with SMI (R = 0.68, p < 0.001). After adjusting for sex, age, King's stage, BMI, creatinine, progression rate, and sarcopenia, adipopenia was associated with shorter survival (hazard ratio HR = 5.94, 95% confidence interval CI = 1.01, 35.0, p = 0.049). In a subgroup analysis for subjects with nutritional failure (stage 4a), the HR of adipopenia was 15.1 (95% CI = 2.45, 93.4, p = 0.003).
Interpretation
Deep learning‐based CT‐derived adipopenia in patients with ALS is an independent poor prognostic factor for survival. ANN NEUROL 2023;94:1116–1125
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•Metal–organic frameworks composed of hydroxo ligands (MOF-HLs) are firstly reviewed.•MOF-HLs are advantageous because of no expensive linker or functionalization required.•Hydroxo ...ligands are useful in adsorption and catalysis due to polarity or acidity of –OH sites.•Analysis, functionalization, and preparation of MOF-HLs are also summarized.•A prospect on MOF-HLs is provided for a future study in the relevant fields.
Metal-organic frameworks (MOFs) are popular porous materials prepared from metallic species and organic linkers via the formation of coordination bonds. The applications and potentiality of MOFs can be further improved by their functionalization, such as the introduction of functional groups into pristine MOFs. Among these functional groups, the –OH group is interesting because of its polarity and weak acidity for hydrogen bonding and acid catalysis, respectively, for example. The hydroxyl group can be loaded onto both the linker and metal sites. In this review, the –OH groups on the metallic species of MOFs are discussed because various MOFs contain hydroxo groups as ligands. MOFs bearing hydroxo ligands (MOF-HLs) are attractive because no functionalized linker (that is useful for MOFs with –OH on the linkers) or modification/functionalization is required during their preparation, unlike MOFs composed of other functional groups, such as –NH2, –SO3H, and –COOH. In this work, MOF-HLs have been reviewed for the first time in terms of their preparation, analysis, and applications (in adsorption, catalysis, and further functionalization). After a summary of this discussion, the future prospects for MOF-HLs are provided for further study in their relevant fields.
Targeted therapy based on protein–drug conjugates has attracted significant attention owing to its high efficacy and low side effects. However, efficient and stable drug conjugation to a protein ...binder remains a challenge. Herein, a chemoenzymatic method to generate highly stable and homogenous drug conjugates with high efficiency is presented. The approach comprises the insertion of the CaaX sequence at the C‐terminal end of the protein binder, prenylation using farnesyltransferase, and drug conjugation through an oxime ligation reaction. MMAF and an EGFR‐specific repebody are used as the antitumor agent and protein binder, respectively. The method enables the precisely controlled synthesis of repebody–drug conjugates with high yield and homogeneity. The utility of this approach is illustrated by the notable stability of the repebody–drug conjugates in human plasma, negligible off‐target effects, and a remarkable antitumor activity in vivo. The present method can be widely used for generating highly homogeneous and stable PDCs for targeted therapy.
A chemoenzymatic conjugation method that is based on enzymatic prenylation and oxime ligation is a simple and efficient means for generating highly stable and homogeneous protein–drug conjugates in a site‐specific manner. It can be generally applied to the conjugation of drugs to a wide range of protein binders, facilitating the development of targeted therapies with high efficacies and low off‐target effects.
As persistent elevation of transforming growth factor-β (TGF-β) promotes fibrosis of muscles and joints and accelerates disease progression in amyotrophic lateral sclerosis (ALS), we investigated ...whether inhibition of TGF-β would be effective against both exacerbations. The effects of TGF-β and its inhibitor on myoblasts and fibroblasts were tested in vitro and confirmed in vivo, and the dual action of a TGF-β inhibitor in ameliorating the pathogenic role of TGF-β in ALS mice was identified. In the peripheral neuromuscular system, fibrosis in the muscles and joint cavities induced by excessive TGF-β causes joint contracture and muscular degeneration, which leads to motor dysfunction. In an ALS mouse model, an increase in TGF-β in the central nervous system (CNS), consistent with astrocyte activity, was associated with M1 microglial activity and pro-inflammatory conditions, as well as with neuronal cell death. Treatment with the TGF-β inhibitor halofuginone could prevent musculoskeletal fibrosis, resulting in the alleviation of joint contracture and delay of motor deterioration in ALS mice. Halofuginone could also reduce glial cell-induced neuroinflammation and neuronal apoptosis. These dual therapeutic effects on both the neuromuscular system and the CNS were observed from the beginning to the end stages of ALS; as a result, treatment with a TGF-β inhibitor from the early stage of disease delayed the time of symptom exacerbation in ALS mice, which led to prolonged survival.
We investigated the clinical characteristics and outcomes of myelin oligodendrocyte glycoprotein (MOG) antibody-associated autoimmune encephalitis (MOGAE) in adult patients.
From an institutional ...cohort, we analysed adult patients with MOGAE followed-up for more than 1 year. Disease severity was assessed using the modified Rankin scale (mRS) and Clinical Assessment Scale in Autoimmune Encephalitis scores. Immunotherapy profiles, outcomes and disease relapses were evaluated along with serial brain MRI data.
A total of 40 patients were enrolled and categorised into cortical encephalitis (18 patients), limbic encephalitis (LE, 5 patients) and acute disseminated encephalomyelitis (ADEM, 17 patients). 80.0% of patients achieved good clinical outcomes (mRS 0‒2) and 40.0% relapsed. The LE subtype was associated with an older onset age (p=0.004) and poor clinical outcomes (p=0.014) than the other subtypes but with a low rate of relapse (0.0%). 21/25 (84.0%) relapse attacks were associated with an absence or short (≤6 months) immunotherapy maintenance. On MRI, the development of either diffuse cerebral or medial temporal atrophy within the first 6 month was correlated with poor outcomes. MOG-antibody (MOG-Ab) was copresent with anti-N-methyl-D-aspartate receptor (NMDAR)-antibody in 13 patients, in whom atypical clinical presentation (cortical encephalitis or ADEM, p
0.001) and disease relapse (46.2% vs 0.0%, p
0.001) were more frequent compared with conventional NMDAR encephalitis without MOG-Ab.
Outcomes are different according to the three phenotypes in MOGAE. Short immunotherapy maintenance is associated with relapse, and brain atrophy was associated with poor outcomes. Patients with dual antibodies of NMDAR and MOG have a high relapse rate.
Autoimmune nodopathy (AN) is a group of peripheral neuropathies caused by antibodies targeting the nodes of Ranvier or paranodes. It typically presents with sensory ataxia, distal limb weakness, and ...tremor, and often has a subacute onset, with limited response to immunoglobulin or corticosteroids. We report a case of anti-contactin-1 neuropathy initially manifesting as isolated superior oblique palsy, aiming to broaden the clinical spectrum of the disease. A 68-year-old male with well-controlled diabetes, hypertension, and hyperlipidemia developed acute binocular vertical diplopia, progressing over two months to include distal paresthesia, sensory ataxia, ageusia, and dysarthria. Concurrent nephrotic syndrome was identified. Nerve conduction studies supported demyelination. Despite treatment with intravenous methylprednisolone followed by long-term immunosuppression, some disability persisted. Serum archived during his admission tested positive for anti-contactin-1 IgG, with IgG4 as the predominant subclass, in the flow cytometry assay for AN. This case extends the clinical spectrum of AN. Some cases of isolated cranial nerve palsies, especially in the relevant context like nephrotic syndrome, may be attributed to AN. Prompt initiation of more effective therapies, such as rituximab, could significantly improve outcomes.
•The clinical spectrum of autoimmune nodopathy (AN) is not fully known.•We describe a case of anti-contactin-1 IgG AN presenting with superior oblique palsy.•Physicians should be aware of the diverse presentations of anti-contactin-1 IgG AN.•Prompt initiation of more effective therapies may optimize therapeutic outcomes.
Aberrant nucleocytoplasmic localization of proteins has been implicated in many neurodegenerative diseases. Evidence suggests that cytoplasmic mislocalization of nuclear proteins such as transactive ...response DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS) may be associated with neurotoxicity in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. This study investigated the changes in nucleocytoplasmic distributions of the proteome and transcriptome in an in vitro model of ALS. After subcellular fractionation of motor neuron-like cell lines expressing wild-type or G93A mutant hSOD1, quantitative mass spectrometry and next-generation RNA sequencing (RNA-seq) were performed for the nuclear and cytoplasmic compartments. A subset of the results was validated via immunoblotting. A total of 1,925 proteins were identified in either the nuclear or cytoplasmic fractions, and 32% of these proteins were quantified in both fractions. The nucleocytoplasmic distribution of 37 proteins was significantly changed in mutant cells with nuclear and cytoplasmic shifts in 13 and 24 proteins, respectively (p<0.05). The proteins shifted towards the nucleus were enriched regarding pathways of RNA transport and processing (Dhx9, Fmr1, Srsf3, Srsf6, Tra2b), whereas protein folding (Cct5, Cct7, Cct8), aminoacyl-tRNA biosynthesis (Farsb, Nars, Txnrd1), synaptic vesicle cycle (Cltc, Nsf), Wnt signalling (Cltc, Plcb3, Plec, Psmd3, Ruvbl1) and Hippo signalling (Camk2d, Plcb3, Ruvbl1) pathways were over-represented in the proteins shifted to the cytoplasm. A weak correlation between the changes in protein and mRNA levels was found only in the nucleus, where mRNA was relatively abundant in mutant cells. This study provides a comprehensive dataset of the nucleocytoplasmic distribution of the proteome and transcriptome in an in vitro model of ALS. An integrated analysis of the nucleocytoplasmic distribution of the proteome and transcriptome demonstrated multiple candidate pathways including RNA processing/transport and protein synthesis and folding that may be relevant to the pathomechanism of ALS.
Machine learning approaches using intravascular optical coherence tomography (OCT) to predict fractional flow reserve (FFR) have not been investigated. Both OCT and FFR data were obtained for left ...anterior descending artery lesions in 125 patients. Training and testing groups were partitioned in the ratio of 5:1. The OCT-based machine learning-FFR was derived for the testing group and compared with wire-based FFR in terms of ischemia diagnosis (FFR ≤ 0.8). The OCT-based machine learning-FFR showed good correlation (r = 0.853, P < 0.001) with the wire-based FFR. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the OCT-based machine learning-FFR for the testing group were 100%, 92.9%, 87.5%, 100%, and 95.2%, respectively. The OCT-based machine learning-FFR can be used to simultaneously acquire information on both image and functional modalities using one procedure, suggesting that it may provide optimized treatments for intermediate coronary artery stenosis.
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