[Analysis of a patient with Retinitis pigmentosa due to a novel variant of IMPDH1 gene].

OBJECTIVE: To explore the genetic basis for a patient with autosomal dominant retinitis pigmentosa (RP). METHODS: A male patient with RP treated at Gansu Provincial Maternal and Child Health Care Hospital in September 2019 was selected as the study subject. Clinical data was collected. Peripheral blood samples of the patient and his parents were subjected to whole exome sequencing (WES). Candidate variant was validated by Sanger sequencing and bioinformatic analysis. RESULTS: The patient, a 29-year-old male, developed night blindness, amblyopia, visual field defects and optic disc abnormalities since childhood. Gene sequencing revealed that he has harbored a heterozygous c.942G>C (p.Lys314Asn) variant of the IMPDH1 gene, which was inherited from his mother, whilst his father was of the wild type. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.942G>C variant was predicted as likely pathogenic (PM1+PM2_Supporting+PP3+PP1). CONCLUSION: The c.942G>C (p.Lys314Asn) variant in the IMPDH1 gene probably underlay the RP in this patient.

Arthroscopic Medial Bi-portal Extra-articular Debridement for Recalcitrant Medial Epicondylitis.

Medial epicondylitis, or golfer's elbow, is characterized by pain and tenderness at the tendon insertion points of the pronator teres and flexor carpi radialis. Conservative treatment is sufficient for most patients, whereas surgical treatment is the best choice for intractable medial epicondylitis. With open surgery or arthroscopic surgery, good clinical results have been reported. However, there is still no consensus on which surgical technique is more ideal. We describe our technique of arthroscopic medial bi-portal extra-articular debridement, which is a safe and effective technique that allows more accurate debridement and maximum protection of the ulnar nerve while reducing surgical scars, relieving postoperative pain, reducing the probability of elbow infection and ankylosis, and shortening the recovery time.

Discovery of neuroprotective Agents: Potent, brain Penetrating, lipoic acid derivatives for the potential treatment of ischemic stroke by regulating oxidative stress and inflammation - a Preliminary study.

Stroke poses a serious risk to the physical and mental health of patients. Endogenous compounds are widely used to treat ischemic stroke. Lipoic acid, a naturally occurring (R)-5-(1,2-dithiolan-3-yl)pentanoic acid, has therapeutic potential for the treatment of ischemic stroke. However, the direct application of lipoic acid is limited by its relatively low efficacy and instability. Therefore, there is a need to modify the structure of lipoic acid to improve its pharmaceutical capabilities. Currently, 37 lipoic acid derivatives have been synthesized, and compound AA-9 demonstrated optimal therapeutic potential in an in vitro model of induced oxidative damage using tert-butyl hydroperoxide (t-BHP). In addition, in vitro experiments have shown that compound AA-9 has an excellent safety profile. Subsequently, the therapeutic effect of AA-9 was significant in the rat MCAO ischemic stroke model, which may be attributed to the antioxidant and anti-inflammatory effects of compound AA-9 by activating PGC-1α and inhibiting NLRP3. Notably, compound AA-9 exhibited higher stability and better bioavailability properties than ALA in plasma stability and pharmacokinetic properties. In conclusion, AA-9 may be a promising neuroprotective agent for the treatment of ischemic stroke and warrants further investigation.

Assessment of the changes in growth, photosynthetic traits and gene expression in Cynodon dactylon against drought stress.

Drought stress considered a key restrictive factor for a warm-season bermudagrass growth during summers in China. Genotypic variation against drought stress exists among bermudagrass (Cynodon sp.), but the selection of highly drought-tolerant germplasm is important for its growth in limited water regions and for future breeding. Our study aimed to investigate the most tolerant bermudagrass germplasm among thirteen, along latitude and longitudinal gradient under a well-watered and drought stress condition. Current study included high drought-resistant germplasm, "Tianshui" and "Linxiang", and drought-sensitive cultivars; "Zhengzhou" and "Cixian" under drought treatments along longitude and latitudinal gradients, respectively. Under water deficit conditions, the tolerant genotypes showed over-expression of a dehydrin gene cdDHN4, antioxidant genes Cu/ZnSOD and APX which leads to higher antioxidant activities to scavenge the excessive reactive oxygen species and minimizing the membrane damage. It helps in maintenance of cell membrane permeability and osmotic adjustment by producing organic osmolytes. Proline an osmolyte has the ability to keep osmotic water potential and water use efficiency high via stomatal conductance and maintain transpiration rate. It leads to optimum CO2 assimilation rate, high chlorophyll contents for photosynthesis and elongation of leaf mesophyll, palisade and thick spongy cells. Consequently, it results in elongation of leaf length, stolon and internode length; plant height and deep rooting system. The CdDHN4 gene highly expressed in "Tianshui" and "Youxian", Cu/ZnSOD gene in "Tianshui" and "Linxiang" and APX gene in "Shanxian" and "Linxiang". The genotypes "Zhongshan" and "Xiaochang" showed no gene expression under water deficit conditions. Our results indicate that turfgrass show morphological modifications firstly when subjected to drought stress; however the gene expression is directly associated and crucial for drought tolerance in bermudagrass. Hence, current research has provided excellent germplasm of drought tolerant bermudagrass for physiological and molecular study and future breeding.

[Clinical and genetic analysis of two pedigrees affected with Carnitine-acylcarnitine translocase deficiency due to variant of SLC25A20 gene].

OBJECTIVE: To analyze the clinical phenotype and genotypes of two children with Carnitine-acylcarnitine translocase deficiency (CACTD). METHODS: Two children diagnosed with CACTD at the Gansu Provincial Maternal and Child Health Care Hospital respectively on January 3 and November 19, 2018 were selected as the study subjects. Trio-whole exome sequencing (trio-WES) was carried out, and candidate variants were validated through Sanger sequencing and pathogenicity analysis. RESULTS: Both children were males and had manifested mainly with hypoglycemia. Trio-WES and Sanger sequencing showed that child 1 had harbored compound heterozygous variants of the SLC25A20 gene, namely c.49G>C (p.Gly17Arg) and c.106-2A>G, which were inherited from his father and mother, respectively. Child 2 had harbored homozygous c.199-10T>G variants of the SLC25A20 gene, which were inherited from both of his parents. Among these, the c.106-2A>G and c.49G>C variants were unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.49G>C (p.Gly17Arg), c.106-2A>G, and c.199-10T>G variants were classified as likely pathogenic (PM2_supporting+PP3+PM3_strong+PP4), pathogenic (PVS1+PM2_supporting+PM5+PP3), and pathogenic (PVS1+PM2_supporting+PP3+PP5), respectively. CONCLUSION: Combined with their clinical phenotype and genetic analysis, both children were diagnosed with CACTD. Above finding has provided a basis for their treatment as well as genetic counseling and prenatal diagnosis for their families.

The white matter characteristic of the genu of corpus callosum coupled with pain intensity and negative emotion scores in patients with trigeminal neuralgia: a multivariate analysis.

Background: Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder that not only causes intense pain but also affects the psychological health of patients. Since TN pain intensity and negative emotion may be grounded in our own pain experiences, they exhibit huge inter-individual differences. This study investigates the effect of inter-individual differences in pain intensity and negative emotion on brain structure in patients with TN and the possible pathophysiology mechanism underlying this disease. Methods: T1 weighted magnetic resonance imaging and diffusion tensor imaging scans were obtained in 46 patients with TN and 35 healthy controls. All patients with TN underwent pain-related and emotion-related questionnaires. Voxel-based morphometry and regional white matter diffusion property analysis were used to investigate whole brain grey and white matter quantitatively. Innovatively employing partial least squares correlation analysis to explore the relationship among pain intensity, negative emotion and brain microstructure in patients with TN. Results: Significant difference in white matter integrity were identified in patients with TN compared to the healthy controls group; The most correlation brain region in the partial least squares correlation analysis was the genus of the corpus callosum, which was negatively associated with both pain intensity and negative emotion. Conclusion: The genu of corpus callosum plays an important role in the cognition of pain perception, the generation and conduction of negative emotions in patients with TN. These findings may deepen our understanding of the pathophysiology of TN.

Mucosa color and size may indicate malignant transformation of chicken skin mucosa-positive colorectal neoplastic polyps.

BACKGROUND: Lipid metabolism reprogramming is suspected to exist in pre-cancerous lesions, including colorectal adenoma. Screening colonoscopy frequently reveals chicken skin mucosa (CSM; white or yellow-white speckled mucosa) surrounding colorectal polyps, caused by macrophages engulfing and accumulating the lipids decomposed by colon cells or adjacent tumors. CSM-positive colorectal polyps are associated with various diseases; however, their prognosis varies greatly. Cold snare polypectomy is commonly used to resect lesions up to 10 to 15 mm in diameter without signs of submucosal invasion but is controversial for CSM-positive colorectal polyps. Improved imaging is required to diagnose and treat CSM-positive colorectal polyps. AIM: To highlight the clinical significance of CSM surrounding colorectal polyps and clarify the associated treatment for endoscopists. METHODS: This retrospective cohort study included 177 patients with CSM-positive colorectal polyps diagnosed using endoscopy. All patient-related information was extracted from the Goldisc soft-clinic DICOM system or electronic medical record system. Based on the pathological results, patients were classified as non-neoplastic polyps (five juvenile polyps), neoplastic polyps, non-invasive high-grade neoplasia (NHGN), or submucosal invasive carcinoma (SM stage cancer). We analyzed and compared the clinical features, suspected risk factors for malignant transformation of neoplastic polyps, and early infiltration of submucosal carcinoma. RESULTS: The diameters of NHGN and SM polyps were much smaller than those of neoplastic polyps. Most NHGN polyps had a deeper red mucosal color. On logistic regression analyses, diameter and deeper red mucosal color were independent risk factors for malignant transformation of neoplastic polyps. Type 1 CSM was more common in high-grade intraepithelial neoplasia and SM; type 2 CSM was more common in neoplastic polyps. Logistic regression analyses revealed no significant differences in the malignant transformation of neoplastic polyps or early submucosal invasion of CSM-positive colorectal cancer. Changes in the CSM mucosa surrounding neoplastic polyps and submucosal invasion of colorectal cancer disappeared within 12 months. No tumor recurrence was found during either partial or complete endoscopic resection of the CSM. CONCLUSION: CSM-positive colorectal polyps > 1 cm in diameter or with deeper red mucosa may be related to NHGN. Resection of CSM surrounding colorectal adenomas did not affect tumor recurrence.

Complete genome analysis of a novel narnavirus in sweet viburnum (Viburnum odoratissimum).

Trees and shrubs provide important ecological services. However, few studies have surveyed the virome in trees and shrubs. In this study, we discovered a new positive-sense RNA virus originating from Viburnum odoratissimum, which we named "Vo narna-like virus". The complete genome of Vo narna-like virus is 3,451 nt in length with an open reading frame (ORF) encoding the RNA-dependent RNA polymerase (RdRP) protein. Phylogenetic analysis placed this virus within the betanarnavirus clade, sharing 53.63% amino acid sequence identity with its closest relative, Qingdao RNA virus 2. The complete sequence of the virus was confirmed by rapid amplification of cDNA ends (RACE) and Sanger sequencing. Small interfering RNA (siRNA) analysis indicated that this virus interacts with the RNA interference (RNAi) pathway of V. odoratissimum. This is the first report of a narnavirus in V. odoratissimum.

Development and field evaluation of a novel sugar bait device for controlling residential vector mosquitoes in Zhejiang Province, China.

Background: Mosquito-borne diseases pose serious public health threats in Zhejiang Province, China, and vector control is believed to be the primary method for reducing transmission. Due to severe resistance problems, effective and sustainable methods without chemical insecticides are urgently required to control mosquito vectors. Attractive toxic sugar baits (ATSB) are newly developed methods to control mosquitoes in recent decades with the core element sugar bait, which was invented according to the sugar-feeding behavior of mosquitoes. In this study, we developed a Novel Sugar Bait Device (NSBD) trap by combining sugar bait and physical adhesive capture technology. The study aimed to evaluate the effect of the NSBD trap on controlling mosquitoes in residential environments and to identify the optimal sugar solution concentration in the sugar bait of the NSBD for real use. Methods: Four residential villages in Ningbo City with similar geographic environments and mosquito densities were selected for field trials in 2022. One village (site 1) was designated as the control group, and three villages (sites 2-4) served as the test groups to assess the effectiveness of NSBD traps with different sugar solution concentrations (6, 8, and 10%) in the sugar bait. Larval and adult mosquito densities were monitored monthly before and semi-monthly after the trials using the CDC light trap and larval pipette method. Results: Before the trials, we monitored mosquito density for 3 months to confirm the baseline mosquito density among the four sites, and no statistical differences in adult and larval mosquitoes were found (adult, F = 3.047, p > 0.05; larvae, F = 0.436, p > 0.05). After the trials, all NCBD traps effectively controlled larval and adult mosquito densities, with the highest standard decrease rates of larval and adult mosquito densities at 57.80 and 86.31%, respectively, observed in site 4. The most suitable sugar solution concentration in the sugar bait was 10%. Conclusion: NSBD traps effectively controlled mosquitoes in residential environments during field trials. Without the use of insecticides, this may be a promising choice for mosquito vector control to prevent mosquito-borne diseases.

Recent developments in ureteral stent: Substrate material, coating polymer and technology, therapeutic function.

The ureteral stent is an effective treatment for clinical ureteral stricture following urological surgery, and the functional coating of the stent could effectively inhibit bacterial colonization and other complications. The present review provides an analysis and description of the materials used in ureteral stents and their coatings. Emphasis is placed on the technological advancements of functional coatings, taking into consideration the characteristics of these materials and the properties of their active substances. Furthermore, recent advances in enhancing the therapeutic efficacy of functional coatings are also reviewed. It is anticipated that this article will serve as a valuable reference providing insights for future research development on new drug-loaded ureteral stents.

Aflibercept combined with triamcinolone acetonide in the treatment of diabetic macular edema: optical coherence tomography and optical coherence tomography angiography.

AIM: To analyze the relationship between optical coherence tomography (OCT) and OCT angiography (OCTA) imaging in patients with diabetic macular edema (DME) who are treated with a combination of aflibercept and triamcinolone acetonide (TA). METHODS: A total of 76 eyes newly diagnosed DME were included in this study. They were randomly assigned to receive either aflibercept or a combination of aflibercept and TA. Injections once a month for a total of three injections. Central macular thickness (CMT), number of hyperreflective foci (HRF), height of subretinal fluid (SRF), and area of foveal avascular zone (FAZ) were evaluated using OCT and OCTA at baseline and after each monthly treatment. RESULTS: Both groups showed improvement in best corrected visual acuity (BCVA) and reduction in macular edema after treatment, and the difference in BCVA between the two groups was statistically significant after each treatment (P<0.05). The difference in CMT between the two groups was statistically significant after the first two injections (P<0.01), but not after the third injection (P=0.875). The number of HRF (1mo: 7.41±8.25 vs 10.86±7.22, P=0.027; 2mo: 5.33±6.13 vs 9.12±8.61, P=0.034; 3mo: 3.58±3.00 vs 6.37±5.97, P=0.007) and height of SRF (1mo: 82.39±39.12 vs 105.77±42.26 µm, P=0.011; 2mo: 36.84±10.02 vs 83.59±37.78 µm, P<0.01; 3mo: 11.57±3.29 vs 45.43±12.60 µm, P<0.01) in combined group were statistically significant less than aflibercept group after each injection, while the area of FAZ showed no significant change before and after treatment in both groups. CONCLUSION: The combination therapy of aflibercept and TA shows more significant effects on DME eyes with decreased HRF and SRF. However, both aflibercept and combination therapy show no significant change in the area of FAZ.

Cross-kingdom RNA interference mediated by insect salivary microRNAs may suppress plant immunity.

Communication between insects and plants relies on the exchange of bioactive molecules that traverse the species interface. Although proteinic effectors have been extensively studied, our knowledge of other molecules involved in this process remains limited. In this study, we investigate the role of salivary microRNAs (miRNAs) from the rice planthopper Nilaparvata lugens in suppressing plant immunity. A total of three miRNAs were confirmed to be secreted into host plants during insect feeding. Notably, the sequence-conserved miR-7-5P is specifically expressed in the salivary glands of N. lugens and is secreted into saliva, distinguishing it significantly from homologues found in other insects. Silencing miR-7-5P negatively affects N. lugens feeding on rice plants, but not on artificial diets. The impaired feeding performance of miR-7-5P-silenced insects can be rescued by transgenic plants overexpressing miR-7-5P. Through target prediction and experimental testing, we demonstrate that miR-7-5P targets multiple plant genes, including the immune-associated bZIP transcription factor 43 (OsbZIP43). Infestation of rice plants by miR-7-5P-silenced insects leads to the increased expression of OsbZIP43, while the presence of miR-7-5P counteracts this upregulation effect. Furthermore, overexpressing OsbZIP43 confers plant resistance against insects which can be subverted by miR-7-5P. Our findings suggest a mechanism by which herbivorous insects have evolved salivary miRNAs to suppress plant immunity, expanding our understanding of cross-kingdom RNA interference between interacting organisms.

Molecular and biological characterization of a bunyavirus infecting the brown planthopper (Nilaparvata lugens).

A negative-strand symbiotic RNA virus, tentatively named Nilaparvata lugens Bunyavirus (NLBV), was identified in the brown planthopper (BPH, Nilaparvata lugens). Phylogenetic analysis indicated that NLBV is a member of the genus Mobuvirus (family Phenuiviridae, order Bunyavirales). Analysis of virus-derived small interfering RNA suggested that antiviral immunity of BPH was successfully activated by NLBV infection. Tissue-specific investigation showed that NLBV was mainly accumulated in the fat-body of BPH adults. Moreover, NLBV was detected in eggs of viruliferous female BPHs, suggesting the possibility of vertical transmission of NLBV in BPH. Additionally, no significant differences were observed for the biological properties between NLBV-infected and NLBV-free BPHs. Finally, analysis of geographic distribution indicated that NLBV may be prevalent in Southeast Asia. This study provided a comprehensive characterization on the molecular and biological properties of a symbiotic virus in BPH, which will contribute to our understanding of the increasingly discovered RNA viruses in insects.

Surgical treatment of coronal shear fractures of the distal humerus with an intact lateral epicondyle by the lateral combined approach.

BACKGROUND: Coronal shear fractures of the distal humerus are not only rare and prone to misdiagnosis, but their surgical treatment can be challenging. We aimed to investigate the feasibility of exposing distal humeral coronal shear fractures with a combined lateral approach that preserves the extensors and lateral ulnar collateral ligament (LUCL) and to analyze the clinical efficacy of open reduction and internal fixation (ORIF) in the treatment of these injuries. METHODS: We included 45 patients who sustained coronal shear fractures of the distal humerus with the lateral epicondyle intact and were treated with ORIF from January 2013 to August 2020. The fractures were exposed by the lateral combined approach in which the tendons involving the common extensor, the extensor carpi ulnaris (ECU), and the LUCL were preserved. Two observation windows were formed anterior to and posterior to these tendons and the LUCL was used to achieve fracture reduction. Countersunk screws, with or without a plate placed on the posterior lateral condyle, were used to fix the fragments. The functional outcomes of these patients were reviewed and assessed with physical and radiographic examinations, range of motion (ROM) measurements, and self-evaluation Mayo Elbow Performance Index (MEPI) and Disabilities of the Arm, Shoulder, and Hand (DASH) scores. RESULTS: In total, 40 patients were followed up with for over 1 year and were included in the final analysis. The mean follow-up duration was 42±30 months (range, 12-107 months). The patients' mean age was 42 years (range, 14-74 years). According to the Dubberley Classification, there were 15 type I, 17 type II, and 8 type III fractures. At the final follow-up, the mean flexion-extension arc was 131° (range, 65-150) and mean pronation and supination was 73° (range, 45-80) and 71° (range, 40-80), respectively. The mean MEPI score was 88 (range, 61-97) points; the results were excellent in 21, good in 13, fair in 4, and poor in 2 patients. The mean DASH score was 11 (range, 0-42) points. Neither functional score nor range of movement was associated with age, sex, fracture type, injury type, or surgical timing. CONCLUSION: Reduction and stable fixation with internal fixation for coronal shear fractures of the distal humerus can be achieved by the lateral combined approach. Early functional mobilization allows for satisfactory restoration of elbow function.

Modulation of gut microbiota and metabolites by Flammulina velutipes polysaccharides during in vitro human fecal fermentation: Unveiling Bacteroides as a potential primary degrader.

Flammulina velutipes, a widely cultivated species of edible fungus, exhibits diverse functional activities attributed to its polysaccharides. In this study, we employed an in vitro model to investigate the impact of F. velutipes polysaccharides (FVP) fermentation on gut microbiota, with a particular focus on Bacteroides. FVP fermentation resulted in the proliferation of microbiota associated with short-chain fatty acid (SCFA) metabolism and suppression of Escherichia-Shigella. Bacteroides emerged as potential primary degraders of FVP, with species-level analysis identifying the preference of B. thetaiotaomicron and B. intestinalis in FVP degradation. Metabolomics analysis revealed significant increases in hypoxanthine and 7-methyladenine contents, with histidine metabolism emerging as the most enriched pathway. B. nordii and B. xylanisolvens exhibited the most influence on amino acid and SCFA metabolism. Understanding the mechanisms by which gut microbiota metabolize FVP can provide valuable insights into the potential of FVP to promote intestinal health and disease prevention.

Analysis of spinal muscular atrophy carrier screening results in 32,416 pregnant women and 7,231 prepregnant women.

Objectives: Spinal muscular atrophy (SMA) is an autosomal recessive disease that is one of the most common in childhood neuromuscular disorders. Our screenings are more meaningful programs in preventing birth defects, providing a significant resource for healthcare professionals, genetic counselors, and policymakers involved in designing strategies to prevent and manage SMA. Method: We screened 39,647 participants from 2020 to the present by quantitative real-time PCR, including 7,231 pre-pregnancy participants and 32,416 pregnancy participants, to detect the presence of SMN1 gene EX7 and EX8 deletion in the DNA samples provided by the subjects. To validate the accuracy of our findings, we also utilized the Multiplex Ligation-dependent Probe Amplification (MLPA) to confirm the reliability of screening results obtained by quantitative real-time PCR. Result: Among the 39,647 participants who were screened, 726 participants were the carriers of SMN1. The overall carrier rate was calculated to be 1.83% (95% confidence interval: 0.86-2.8%). After undergoing screening, a total of 592 pregnancy carriers were provided with genetic counseling and only 503 of their spouses (84.97, 95% confidence interval: 82.09-87.85%) voluntarily underwent SMA screening. Conclusion: This study provides crucial insights into the prevalence and distribution of SMA carriers among the female population. The identification of 726 asymptomatic carriers highlights the necessity of comprehensive screening programs to identify at-risk individuals and ensure appropriate interventions are in place to minimize the impact of SMA-related conditions.

The genomic history and global migration of a windborne pest.

Many insect pests, including the brown planthopper (BPH), undergo windborne migration that is challenging to observe and track. It remains controversial about their migration patterns and largely unknown regarding the underlying genetic basis. By analyzing 360 whole genomes from around the globe, we clarify the genetic sources of worldwide BPHs and illuminate a landscape of BPH migration showing that East Asian populations perform closed-circuit journeys between Indochina and the Far East, while populations of Malay Archipelago and South Asia undergo one-way migration to Indochina. We further find round-trip migration accelerates population differentiation, with highly diverged regions enriching in a gene desert chromosome that is simultaneously the speciation hotspot between BPH and related species. This study not only shows the power of applying genomic approaches to demystify the migration in windborne migrants but also enhances our understanding of how seasonal movements affect speciation and evolution in insects.

Anlotinib for Metastatic Progressed Pheochromocytoma and Paraganglioma: A Retrospective Study of Real-World Data.

Introduction: Pheochromocytomas (PCC) and paragangliomas (PGL) (collectively PPGL) are a type of rare hypervascular neuroendocrine tumors that are very challenging to treat. This study aimed to determine the efficacy and safety of the multi-tyrosine kinase inhibitor anlotinib for the treatment of locally advanced or metastatic (LA/M) PPGL. Methods: A total of 37 eligible patients with unresectable or progressive LA/M PPGL were enrolled. Of them, 27 patients received anlotinib alone (n = 19) or in combination (n = 8) with radionuclide therapies, including peptide receptor radionuclide therapy (PRRT) and iodine 131 meta-iodobenzylguanidine (131I-MIBG). The primary endpoints included objective response rate (ORR), defined as partial response (PR) or complete response (CR), and disease-control rate, defined as PR, CR, or stable disease (SD). The secondary endpoints were progression-free survival (PFS), duration of response, and drug safety. Results: In the efficacy evaluation for all 27 patients, the ORR was 44.44% (95% CI: 24.4%-64.5%) and disease-control rate was 96.29% (95% CI: 88.7%-100%). Twelve cases (44.44%) achieved PR, 14 (51.85%) SD. The median PFS was 25.2 months (95% CI: 17.2 months to not reached). PFS was shorter in the anlotinib monotherapy group than in the group receiving anlotinib in combination with radionuclide therapy (P = .2). There were no serious treatment-related AEs. Conclusion: Anlotinib monotherapy or in combination with radionuclide therapies shows promising efficacy and safety for the treatment of LA/M PCC and PGL. Multi-tyrosine kinase inhibitors might represent a novel therapeutic strategy for patients with PPGL; however, large-scale prospective randomized, blinded, controlled clinical research studies are required.

Gene replacement therapy in Bietti crystalline corneoretinal dystrophy: an open-label, single-arm, exploratory trial.

Bietti crystalline corneoretinal dystrophy is an inherited retinal disease caused by mutations in CYP4V2, which results in blindness in the working-age population, and there is currently no available treatment. Here, we report the results of the first-in-human clinical trial (NCT04722107) of gene therapy for Bietti crystalline corneoretinal dystrophy, including 12 participants who were followed up for 180-365 days. This open-label, single-arm exploratory trial aimed to assess the safety and efficacy of a recombinant adeno-associated-virus-serotype-2/8 vector encoding the human CYP4V2 protein (rAAV2/8-hCYP4V2). Participants received a single unilateral subretinal injection of 7.5 × 1010 vector genomes of rAAV2/8-hCYP4V2. Overall, 73 treatment-emergent adverse events were reported, with the majority (98.6%) being of mild or moderate intensity and considered to be procedure- or corticosteroid-related; no treatment-related serious adverse events or local/systemic immune toxicities were observed. Compared with that measured at baseline, 77.8% of the treated eyes showed improvement in best-corrected visual acuity (BCVA) on day 180, with a mean ± standard deviation increase of 9.0 ± 10.8 letters in the 9 eyes analyzed (p = 0.021). By day 365, 80% of the treated eyes showed an increase in BCVA, with a mean increase of 11.0 ± 10.6 letters in the 5 eyes assessed (p = 0.125). Importantly, the patients' improvement observed using multifocal electroretinogram, microperimetry, and Visual Function Questionnaire-25 further supported the beneficial effects of the treatment. We conclude that the favorable safety profile and visual improvements identified in this trial encourage the continued development of rAAV2/8-hCYP4V2 (named ZVS101e).