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The aim of this study is to analyze the clinical characteristics and outcomes of Chinese patients with progressive multifocal leukoencephalopathy (PML) who were treated with programmed cell death protein 1 (PD1) blockade therapies. We retrospectively analyzed patients who were admitted to our hospital between October 1, 2020, and October 1, 2022, diagnosed with PML and treated with PD1 blockade therapies. Four patients with PML who were treated with PD1 blockade therapies were identified. All patients were male, and their ages ranged from 19 to 54 years old. One patient (Case 2) exhibited mild pleocytosis, while three patients (Cases 2–4) had markedly reduced T lymphocyte cell counts prior to treatment. The time interval between symptom onset and treatment initiation ranged from six to 54 weeks. All patients received pembrolizumab treatment, with a total of two to four doses administered. Three patients who responded to pembrolizumab treatment showed clinical improvement starting around 8 weeks after the initiation of therapy. Although one patient did not show clinical improvement, they ultimately survived until the last follow-up. None of the patients in this study exhibited immune-related adverse events or immune reconstitution inflammatory syndrome. PD1 blockade appears to be a promising novel therapeutic option for PML; additional prospective studies are necessary to confirm its efficacy. [ABSTRACT FROM AUTHOR]

Heterogeneous defect prediction (HDP) refers to identifying more likely defect-proneness of software modules in a target project using heterogeneous metric data from other source projects, which solves the heterogeneous metric problem in cross-project defect prediction. Recently, several mixed-project HDP methods have been presented. However, these models neglect to address the linear inseparability and cross-project class imbalance issues simultaneously. These limitations usually lead to the unsatisfactory performance of HDP. In this paper, we propose an improved transfer learning approach for mixed-project HDP to deal with the above limitations, called data sampling and kernel manifold discriminant alignment (DSKMDA). DSKMDA firstly applies data sampling technique to handle the class imbalance issue. Then it uses kernel manifold discriminant alignment technique to handle the linear inseparability issue. Extensive experiments on 13 projects from three public benchmark datasets with four evaluation measures demonstrate that DSKMDA can produce better or comparable results against a range of competing methods. [ABSTRACT FROM AUTHOR]

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is one of the most common autoimmune peripheral neuropathies in adults. Membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and other nephropathy have been reported in CIDP patients and are possibly correlated to CIDP pathogenesis. This study reviewed the previously described cases of patients with CIDP and nephropathy in order to provide comprehensive evidence on the diagnosis and treatment regarding CIDP patients in the context of renal diseases.Method: We reviewed our database to identify patients with CIDP and nephropathy. Online database including PubMed, EMBASE, and OVID were searched for relevant cases.Results: We identified a total of 18 cases with CIDP and nephropathy, including 2 cases from our database and 16 ones from online searching. A predominance of male was observed [14 (77.8%)] with the mean age of 53.3 (standard deviation, SD: 16.6) years old. Almost all patients complained paresthesia in distal limbs (94.4%), except one only presented weakness of four extremities. Corticosteroids were prescribed for 14 (77.8%) patients, and 10 showed responsiveness. Three patients experienced relapses during the gradual tapering of steroids.Conclusion: The same immune-mediated pathogenesis may be involved in CIDP and concomitant nephropathy. Male and sensory-predominant CIDP are red flags for complications of renal diseases in CIDP patients. Corticosteroids remain the first-line treatment for CIDP when complicated with renal diseases. Slower tapering or long-term maintenance of steroids may be beneficial for the prognosis of patients with CIDP and nephropathy. [ABSTRACT FROM AUTHOR]

Backgrounds: Nerve ultrasound has been proven to be an accurate tool in diagnosing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). However, its value in guiding treatment has not been well evaluated. The aim of this study was to explore whether nerve ultrasound and its changing trend could predict the response to immune treatment in CIDP. Methods: Eighty-nine therapy-naive CIDP patients were recruited prospectively and treated with steroids and/or intravenous immunoglobulin (IVIG). Ultrasonographic and electrophysiological studies were performed on the median and ulnar nerves before treatment in all patients and followed up in 45 patients. The cross-sectional area (CSA) was measured at ten sites on both the median and ulnar nerves. Results: The response rate to steroids (95%) was significantly higher than that to IVIG (70%) (P = 0.001) in patients with normal or moderately enlarged CSA, while there was no significant difference in the response rate between steroid therapy (84%) and IVIG (75%) (P = 0.653) in patients with markedly enlarged CSA. CSAs decreased in 15 patients during follow-up, most of whom had good IVIG and steroid responses (83%) and no need for immune suppressant treatment (82%). Conclusions: Nerve ultrasonography could help guide treatment strategies in patients with CIDP. Patients with normal or moderately enlarged CSA may respond better to steroids than to IVIG. The decrease in CSA after treatment may also indicate better prognosis. [ABSTRACT FROM AUTHOR]

Atr is a serine/threonine kinase, known to sense single-stranded DNA breaks and activate the DNA damage checkpoint by phosphorylating Chek1, which inhibits Cdc25, causing cell cycle arrest. This pathway has not been implicated in neuroregeneration. We show that in Drosophila sensory neurons removing Atr or Chek1, or overexpressing Cdc25 promotes regeneration, whereas Atr or Chek1 overexpression, or Cdc25 knockdown impedes regeneration. Inhibiting the Atr-associated checkpoint complex in neurons promotes regeneration and improves synapse/behavioral recovery after CNS injury. Independent of DNA damage, Atr responds to the mechanical stimulus elicited during regeneration, via the mechanosensitive ion channel Piezo and its downstream NO signaling. Sensory neuron-specific knockout of Atr in adult mice, or pharmacological inhibition of Atr-Chek1 in mammalian neurons in vitro and in flies in vivo enhances regeneration. Our findings reveal the Piezo-Atr-Chek1-Cdc25 axis as an evolutionarily conserved inhibitory mechanism for regeneration, and identify potential therapeutic targets for treating nervous system trauma. The Atr-Check1 pathway is involved in cell cycle and the DNA damage response. Here, the authors show that the Atr-Check1 pathway can inhibit axon regeneration in response to Piezo-mediated mechanosensation, affecting functional recovery. [ABSTRACT FROM AUTHOR]

Aim: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an inherited rare disease affecting young adults. We present the clinical, imaging, and neuropathological results of our case series, emphasizing biopsy histology combined with clinical information will increase the accuracy of early diagnosis.Methods: In total, 4 females and 2 male ALSP patients with onset at ages 24-45 years were enrolled. Clinical manifestations, neuroimaging, and histopathology as well as gene mutation were analyzed and compared with literature.Results: Clinical manifestations include cognitive decline with/without psycho-behavior problems and movement disorders including paralysis, hemiplegia, parkinsonism, and pyramidal tract injury, as well as dysarthria, dysphagia, and sensory disturbances. MRI showed multiple periventricular and subcortical white matter lesions, involving the corpus callosum, with no enhancement, but with persistent hyperintensity on diffuse-weighted imaging. Histology showed widespread white matter damage and pale stain, especially destroyed axons with spheroids and funicular axons which were stained with neurofilament and ubiquitin. Foamy and pigmented macrophages were another typical change. CSF1R mutation was found in 4 of them. All of the patients were misdiagnosed and treated for a long time for multiple sclerosis, cerebral infarction, normal pressure hydrocephalus, etc. CONCLUSION: ALSP will cause rapidly progressing dementia with/without movement disorders in young adults. The definite diagnosis should be based on a comprehensive analysis of clinical manifestations, and neuroimaging, histology, and genetic results. Early biopsy will add to the accuracy of the diagnosis. [ABSTRACT FROM AUTHOR]

To compose some happy melodies which have hierarchical structures, this paper proposes an automatic melody composition algorithm based on relations. First, various types of melody structure are formalized and saved into a database, so the melody structure form preferred by a user can be elected by human-computer interaction. Second, some sequences of trunk-note and several algorithms of splitting note are constructed by means of the pitch interval features of happy melody, and the theme phrase of happy melody is generated by splitting some trunk notes of the trunk-note-sequence. Third, several types of operators for developing the theme phrase, which include pitch offsetting, phrase inversing and repeating-developing, are constructed using relationship methods. Finally, under the guidance of the elected melody structure, some happy melodies of songs are produced automatically by the interreaction of the theme phrase and these operators. Experimental results demonstrate that this algorithm can make the obtained melodies have musically meaningful structures, and it is not easy to distinguish these machine-generated melodies from human-generated melodies. [ABSTRACT FROM AUTHOR]

The newly developed TALENs and emerging CRISPR/Cas9 have spurred interests in the field of genome engineering because of their ease of customization and high-efficient site-specific cleavages. Although these novel technologies have been successfully used in many types of cells, it is of great importance to apply them in human-derived cells to further observe and evaluate their clinical potentials in gene therapy. Here, we review the working mechanism of TALEN and CRISPR/Cas9, their effectiveness and specificity in human cells, and current methods to enhance efficiency and reduce off-target effects. Besides, CCR5 gene was chosen as a target example to illustrate their clinical potentials. Finally, some questions are raised for future research and for researchers to consider when making a proper choice bases on different purposes. [ABSTRACT FROM AUTHOR]

The original version of this Article contained an error in the spelling of the author Brett L. Ecker, which was incorrectly given as Brett Ecker. This has now been corrected in both the PDF and HTML versions of the Article. [ABSTRACT FROM AUTHOR]

Prolyl hydroxylase domain protein 2 (PHD2) is a well-known master oxygen sensor. However, the role of PHD2 in tumor initiation remains controversial. We find that during the transition of human nevi to melanoma, the expression of PHD2 protein is significantly decreased and lower expression PHD2 in melanoma is associated with worse clinical outcome. Knockdown of PHD2 leads to elevated Akt phosphorylation in human melanocytes. Mice with conditional melanocyte-specific expression of Phd2lox/lox (Tyr::CreER;Phd2lox/lox) fail to develop pigmented lesions. However, deletion of Phd2 in combination with expression of BRafV600E in melanocytes (Tyr::CreER;Phd2lox/lox;BRafCA) leads to the development of melanoma with 100% penetrance and frequent lymph node metastasis. Analysis of tumor tissues using reverse phase protein arrays demonstrates that Phd2 deletion activates the AKT-mTOR-S6 signaling axis in the recovered tumors. These data indicate that PHD2 is capable of suppressing tumor initiation largely mediated through inhibiting of the Akt-mTOR signaling pathway in the melanocyte lineage. Prolyl hydroxylase domain protein 2 (PHD2) regulates cellular response to hypoxia. Here the authors show that PHD2 is downregulated in melanoma and that PHD2 depletion, in a mouse model, promotes the progression of benign melanocytic lesions into melanoma, via activation of the Akt/mTOR signaling cascade. [ABSTRACT FROM AUTHOR]