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Huntington's Disease as progressive neurological disorders associated with motor, behavioral, and cognitive impairment poses a therapeutic challenge in case of limited responsiveness to established therapeutics. Pallidal deep brain stimulation and neurorestorative strategies (brain grafts) scoping to modulate fronto-striatal circuits have gained increased recognition for the treatment of refractory Huntington's disease (HD). A review (2000–2022) was performed in PubMed, Embase, and Cochrane Library covering clinical trials conceptualized to determine the efficacy and safety of invasive, stereotactic-guided deep-brain stimulation and intracranial brain-graft injection targeting the globus pallidus and adjunct structures (striatum). Stereotactic brain-grafting strategies were performed in few HD patients with inconsistent findings and mild-to-moderate clinical responsiveness with a recently published large, randomized-controlled trial (NCT 00190450) yielding negative results. We identified 19 in-human DBS trials (uncontrolled) targeting the globus pallidus internus/externus along with randomized-controlled trial pending report (NCT 02535884). We did not detect any significant changes in the UHDRS total score after restorative injections, while in contrast, the use of deep-brain stimulation resulted in a significant reduction of chorea. GPi-DBS should be considered in cases where selective chorea is present. However, both invasive therapies remain experimental and are not ready for the implementation in clinical use. [ABSTRACT FROM AUTHOR]

As TNFAIP8 plays an important role in the development of cancer, several studies have analyzed the relationship between potential functional polymorphic loci of the TNFAIP8 gene and cancer risk. However, some results were inconsistent. Therefore, the current study aims to systematically assess the relationship between these genetic polymorphisms and cancer risk using a meta-analysis approach. Relevant studies were obtained from CNKI, Embase, Web of Science, and PubMed databases. RevMan software was used to conduct data analysis. The combined analysis containing four studies with 2786 cancer patients and 2550 control individuals indicated that rs11064 polymorphism was not associated with cancer risk. The pooled analysis containing three studies with 950 cancer patients and 1036 control individuals showed that rs1045241 polymorphism was associated with cancer risk in the heterozygous model (CT vs. CC: OR = 1.34, 95%CI = 1.10‐1.62, Pz=0.003) and dominant model [(TT + CT) vs. CC: OR = 1.38, 95% CI = 1.15-1.66, Pz=0.0006], but not in other models. The pooled analysis containing two studies 436 cancer patients and 479 control individuals showed that rs1045242 polymorphism was associated with cancer risk in the heterozygous model (AG vs. AA: OR = 1.52, 95%CI = 1.14-2.03, Pz=0.005), dominant model [(GG + AG) vs. AA: OR = 1.56, 95% CI = 1.18-2.07, Pz=0.002] and allelic model (G vs. A: OR = 1.48, 95%CI = 1.16-1.90, Pz=0.002). In conclusion, the current findings suggest that the rs1045241 and rs1045242 polymorphisms located on the TNFAIP8 gene were associated with cancer risk in Chinese population, and may serve as valuable genetic susceptibility markers. [ABSTRACT FROM AUTHOR]

In recent years, several case-control studies have explored the association between the rs7763881 locus polymorphism of the HULC gene and cancer risk, however, the findings have been inconsistent. Therefore, a meta-analysis was conducted to clarify the association. Relevant case-control studies were obtained from CNKI, Embase, Web of Science and PubMed databases. RevMan software was used to perform data analysis. A total of 8 case-control studies containing 4036 cases and 5286 controls were included in the current meta-analysis. The overall analysis results showed no significant association between the rs7763881 locus polymorphism and cancer risk. However, stratified analysis based on cancer type showed that the rs7763881 locus polymorphism was associated with the decreased risk of hepatocellular cancer, colorectal cancer and esophageal cancer. In conclusion, the current findings suggest that the rs7763881 polymorphic loci located on the HULC gene may serve as a biomarker for determining an individual's risk of hepatocellular cancer, colorectal cancer and esophageal cancer. [ABSTRACT FROM AUTHOR]

Regulators of G protein signaling (RGSs) are proteins that negatively regulate G protein signal transduction. In this study, seven putative RGSs were characterized in the nematode-trapping (NT) fungus, Arthrobotrys oligospora. Deleting Rgs genes significantly increased intracellular cAMP levels, and caused defects in mycelia growth, stress resistance, conidiation, trap formation, and nematocidal activity. In particular, the ΔAoFlbA mutant was unable to produce conidia and traps. Transcriptomic analysis showed that amino acid metabolic and biosynthetic processes were significantly enriched in the ΔAoFlbA mutant compared to WT. Interestingly, Gas1 family genes are significantly expanded in A. oligospora and other NT fungi that produce adhesive traps, and are differentially expressed during trap formation in A. oligospora. Disruption of two Gas1 genes resulted in defective conidiation, trap formation, and pathogenicity. Our results indicate that RGSs play pleiotropic roles in regulating A. oligospora mycelial growth, development, and pathogenicity. Further, AoFlbA is a prominent member and required for conidiation and trap formation, possibly by regulating amino acid metabolism and biosynthesis. Our results provide a basis for elucidating the signaling mechanism of vegetative growth, lifestyle transition, and pathogenicity in NT fungi. [ABSTRACT FROM AUTHOR]

CD16a (FcγRIIIa) mediates the antibody dependent cellular cytotoxicity (ADCC) and is important for anti-tumor activities of many therapeutic antibodies. Bispecific antibody targeting natural killer (NK) cells has been studied for cancer therapy. In this work, anti-CD16a single-domain antibodies were identified from hCD16a immunized camel. Bispecific antibodies are then constructed by fusing these single domain antibodies with an anti-CEA single domain antibody. These bispecific antibodies can recruite NK cells to kill CEA-positive tumor cells, and inhibit tumor growth in vivo, suggesting that these anti-CD16a single domain antibodies are powerful tools to engaging NK cells for cancer therapy. [ABSTRACT FROM AUTHOR]

Pneumococcal meningitis (PM), caused by Streptococcus pneumonia, remains a high-burden disease in developing countries. Antibiotic therapy has been limited due to the inefficiency of drug transport across the blood-brain barrier (BBB) and the emergence of drug-resistant strains. In our preliminary study, PEGylated nano-self-assemblies of bacitracin A (PEGylated Nano-BA12K) demonstrated a strong antibacterial potency against S. pneumonia. In this study, the potential application of this micelle for the treatment of both Penicillin-sensitive and -resistant PM was studied. To address BBB-targeting and -crossing issues, PEGylated Nano-BA12K was formulated with a specific brain-targeting peptide (rabies virus glycopeptide-29, RVG29) and a P-glycoprotein inhibitor (Pluronic® P85 unimers) to construct a mixed micellar system (RVG29-Nano-BAP85). RVG29-Nano-BAP85 demonstrated a strong antibacterial potency against 13 clinical isolates of S. pneumonia, even higher than that of Penicillin G, a conventional anti-PM agent. RVG29-Nano-BAP85 had more cellular uptake in brain capillary endothelial cells (BCECs) and higher BBB-crossing efficiency than single formulated Nano-BAs as shown in an in vitro BBB model. The enhanced BBB-permeability was attributed to the synergetic effect of RVG29 and P85 unimers through receptor-mediated transcytosis, exhaustion of ATP, and reduction in membrane microviscosity. In vivo results further demonstrated that RVG29-Nano-BAP85 was able to accumulate in brain parenchyma as confirmed by in vivo optical imaging. In addition, RVG29-Nano-BAP85 exhibited high therapeutic efficiencies in both Penicillin-sensitive and -resistant PM mouse models with negligible systemic toxicity. Collectively, RVG29-Nano-BAP85 could effectively overcome BBB barriers and suppressed the growth of both drug-sensitive and -resistant S. pneumonia in the brain tissues, which demonstrated its potential for the treatment of PM. [ABSTRACT FROM AUTHOR]