Increased TMEM166 Level in Patients with Postoperative Stroke after Carotid Endarterectomy.

Postoperative stroke is a challenging and potentially devastating complication after elective carotid endarterectomy (CEA). We previously demonstrated that transmembrane protein 166 (TMEM166) levels were directly related to neuronal damage after cerebral ischemia-reperfusion injury in rats. In this subsequent clinical study, we aimed to evaluate the prognostic value of TMEM166 in patients suffering from post-CEA strokes. Thirty-five patients undergoing uncomplicated elective CEA and 8 patients who suffered ischemic strokes after CEA were recruited. We evaluated the protein level and expression of TMEM166 in patients diagnosed with postoperative strokes and compared it to those in patients who underwent uncomplicated elective CEA. Blood samples and carotid artery plaques were collected and analyzed. High expressions of TMEM166 were detected by immunofluorescence staining and Western Blot in carotid artery plaques of all patients who underwent CEA. Furthermore, circulating TMEM166 concentrations were statistically higher in post-CEA stroke patients than in patients allocated to the control group. Mean plasma concentrations of inflammatory markers, including interleukin 6 (IL-6) and C-reactive protein (CRP), were also elevated in patients with postoperative strokes. Therefore, based on these findings, we hypothesize that elevated TMEM166 levels, accompanied by a strong inflammatory response, serve as a useful biomarker for risk assessment of postoperative stroke following CEA.

Minimal residual disease monitoring in childhood Philadelphia chromosome-positive acute lymphoblastic leukemia: prognostic significance and correlation between multiparameter flow cytometry and real-time quantitative polymerase chain reaction

Not available.

Gene expression prognostic of early relapse risk in low-risk B-cell acute lymphoblastic leukaemia in children.

ETV6::RUNX1 is the most common fusion gene in childhood acute lymphoblastic leukaemia (ALL) and is associated with favorable outcomes, especially in low-risk children. However, as many as 10% of children relapse within 3 years, and such early relapses have poor survival. Identifying children at risk for early relapse is an important challenge. We interrogated data from 87 children with low-risk ETV6::RUNX1-positive B-cell ALL and with available preserved bone marrow samples (discovery cohort). We profiled somatic point mutations in a panel of 559 genes and genome-wide transcriptome and single-nucleotide variants. We found high TIMD4 expression (> 85th-percentile value) at diagnosis was the most important independent prognostic factor of early relapse (hazard ratio [HR] = 5.07 [1.76, 14.62]; p = 0.03). In an independent validation cohort of low-risk ETV6::RUNX1-positive B-cell ALL (N = 68) high TIMD4 expression at diagnosis had an HR = 4.78 [1.07, 21.36] (p = 0.04) for early relapse. In another validation cohort including 78 children with low-risk ETV6::RUNX1-negative B-cell ALL, high TIMD4 expression at diagnosis had an HR = 3.93 [1.31, 11.79] (p = 0.01). Our results suggest high TIMD4 expression at diagnosis in low-risk B-cell ALL in children might be associated with high risk for early relapse.

Rationally engineered novel AAV capsids for intra-articular gene delivery.

Intra-articular adeno-associated virus (AAV) gene therapy has been explored as a potential strategy for joint diseases. However, concerns of low transduction efficacy, off-target expression, and neutralizing antibodies (Nabs) still need to be addressed. In this study, we demonstrated that AAV6 was the best serotype to transduce joints after screening serotypes 1 to 9. To develop a more effective AAV vector, a set of novel AAV capsids were rationally engineered. The mutant AAV62 created by swapping variable region I (VRI) of AAV2 into AAV6 induced a higher transduction efficiency per AAV genome copy number. To further investigate the roles of specific amino acids in the transduction of AAV62 and AAV6, we found out that AAV6D with the deletion of threonine at residue 265 induced a 2-fold higher transduction than AAV6, while the transduction efficiency from AAV6M with the mutation of alanine to glutamine at residue 263 was 10-fold lower. AAV6D efficiently transduced both synoviocytes and chondrocytes with low AAV genome copy numbers in other tissues and less Nab formation. This study demonstrates that novel AAV mutants with rational engineering may enhance joint transduction after intra-articular administration in mice, with the potential to evade AAV Nabs and minimize off-target effects in the liver.

Nonintubated spontaneous ventilation versus intubated mechanical ventilation anesthesia for video-assisted thoracic surgery in terms of perioperative complications and practitioners' workload assessments: a pilot randomized control study.

BACKGROUND: The use of nonintubated video-assisted thoracoscopic surgery (NI-VATS) has been increasingly reported to yield favourable outcomes. However, this technology has not been routinely used because its advantages and safety have not been fully confirmed. The aim of this study was to assess the safety and feasibility of nonintubated spontaneous ventilation (NI-SV) anesthesia compared to intubated mechanical ventilation (I-MV) anesthesia in VATS by evaluating of perioperative complications and practitioners' workloads. METHODS: Patients who underwent uniportal VATS were randomly assigned at a 1:1 ratio to receive NI-SV or I-MV anesthesia. The primary outcome was the occurrence of intraoperative airway intervention events, including transient MV, conversion to intubation and repositioning of the double-lumen tube. The secondary outcomes included perioperative complications and modified National Aeronautics and Space Administration Task Load Index (NASA-TLX) scores from anesthesiologists and surgeons. RESULTS: Thirty-five patients in each group were enrolled in the intention-to-treat analysis. The incidence of intraoperative airway intervention events was greater in the NI-SV group than in the I-MV group (12 [34.3%] vs. 3 [8.6%]; OR = 0.180; 95% CI = 0.045-0.710; p = 0.009). No significant difference was found in the postoperative pulmonary complications between the groups (p > 0.05). The median of the anesthesiologists' overall NASA-TLX score was 37.5 (29-52) when administering the NI-SV, which was greater than the 25 (19-34.5) when the I-MV was administered (p < 0.001). The surgeons' overall NASA-TLX score was comparable between the two ventilation strategies (28 [21-38.5] vs. 27 [20.5-38.5], p = 0.814). CONCLUSION: The NI-SV anesthesia was feasible for VATS in the selected patients, with a greater incidence of intraoperative airway intervention events than I-MV anesthesia, and with more surgical effort required by anesthesiologists. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2200055427. https://www.chictr.org.cn/showproj.html?proj=147872 was registered on January 09, 2022.

Fully human anti-B7-H3 recombinant antibodies inhibited tumor growth by increasing T cell infiltration.

Mortality due to malignant tumors is one of the major factors affecting the life expectancy of the global population. Therapeutic antibodies are a cutting-edge treatment method for restricting tumor growth. B7-H3 is highly expressed in tumor tissues, but rarely in normal tissues. B7-H3 is closely associated with poor prognosis in patients with tumors. B7-H3 is an important target for antitumor therapy. In this study, the fully human anti-B7H3 single-chain antibodies (scFvs) were isolated and screened from the fully human phage immune library with B7H3 as the target. The antibodies screened from a fully human phage library had low immunogenicity and high affinity, which was more beneficial for clinical application. Leveraging B7-H3 scFvs as a foundation, we constructed two distinct recombinant antibody formats, scFv-Fc and IgG1, characterized by elevated affinity and a prolonged half-life. The results demonstrated that the recombinant antibodies had high specificity and affinity for the B7-H3 antigen and inhibited tumor cell growth by enhancing the ADCC. After treatment with anti-B7H3 recombinant antibody, the number of infiltrating T cells in the tumor increased and the secretion of IFN- γ by infiltrating T cells increased in vivo. Additionally, the use of pleural fluid samples obtained from tumor-afflicted patients revealed the ability of anti-B7-H3 recombinant antibodies to reverse CD8+ T cell exhaustion. In summary, we screened the fully human anti-B7H3 recombinant antibodies with specificity and high affinity that increase immune cell infiltration and IFN-γ secretion, thereby inhibiting tumor cell growth to a certain extent. This finding provides a theoretical basis for the development of therapeutic tumor antibodies and could help promote further development of antibody-based drugs.

Addressing psychosomatic symptom distress with mindfulness-based cognitive therapy in somatic symptom disorder: mediating effects of self-compassion and alexithymia.

Objective: This study explored the association between self-compassion, alexithymia, and psychosomatic symptom distress in a clinical sample of somatic symptom disorder (SSD) patients participating in a mindfulness-based cognitive therapy (MBCT) program. Methods: One hundred sixteen SSD patients who had participated in an MBCT program and completed ≥4 intervention sessions were included in a retrospective study (76.7% women, mean age = 40.0, SD = 9.5). Psychometric measures of psychosomatic symptom distress [Brief Symptom Inventory-18 Global Severity Index (BSI-GSI)], self-compassion [Self-Compassion Scale (SCS)], and alexithymia [Toronto Alexithymia Scale (TAS)] were collected upon admission to the MBCT program and at 6-month follow-up following treatment inclusion. Results: Serial mediation analysis (MBCT→ΔSCS→ΔTAS→ΔBSI-GSI) suggested that changes in both self-compassion and alexithymia had significant indirect effects on improvement in psychosomatic distress [ΔSCS ß = -1.810, 95% bootstrap CI (-2.488, -1.160); ΔTAS ß = -1.615, bootstrap 95% CI (-2.413, -0.896); ΔSCS→ΔTAS ß = -0.621, bootstrap CI (-1.032, -0.315)]. Furthermore, a post-hoc analysis with a reverse sequence (MBCT→ΔTAS→ΔSCS→ΔBSI-GSI) revealed that reduction in alexithymia improved psychosomatic distress and that an increase in self-compassion was a subsequent outcome of alleviation of alexithymia [ΔTAS ß = -2.235, bootstrap 95% CI (-3.305, -1.270); ΔSCS ß = 0.013, 95% bootstrap CI (-0.600, 0.682); ΔTAS→ΔSCS ß = -1.823, bootstrap CI (-2.770, -1.047)]. Conclusion: Both alleviation of alexithymia and improvement in self-compassion play a mediating role in the reduction of psychosomatic distress in SSD patients following an MBCT program. Improvement in self-compassion might be a subsequent outcome of MBCT-related alleviation of alexithymia.

The extraordinary rearrangement of mitochondrial genome of the wheat pest, Aptinothrips stylifer and the mitochondrial phylogeny of Thripidae (Thysanoptera).

The mitochondrial gene order in Thysanoptera is notably distinct and highly rearranged, with each species exhibiting its own unique arrangement. To elucidate the relationship between gene rearrangements and phylogeny, the complete mitochondrial genome (mitogenome) of the wheat pest, Aptinothrips stylifer, was sequenced and assembled, spanning a total length of 16,033 bp. Compared with the ancestral arthropod mitogenome, significant rearrangement differences were evident in A. stylifer, whereas the gene order between A. stylifer and Anaphothrips obscurus was similar. Phylogenetic trees were reconstructed based on all 13 protein-coding gene sequences using Bayesian inference and maximum-likelihood methods, both yielding similar topological structures. Notably, A. stylifer was robustly clustered with A. obscurus, affirming its classification within Anaphothrips genus group. This exemplifies the potential correlation between gene rearrangements and phylogeny in the Thripidae family. Additionally, the mitogenome of A. stylifer exhibited several atypical features, including: (1) Three putative control regions (CRs) in close proximity, with CR2 and CR3 displaying partial similarity, and CR1 differing in base composition; (2) Two transfer RNAs (tRNAs), trnS1 and trnV, lacking the DHU arm; (3) Two ribosomal RNA (rRNA) genes inverted and positioned distant from each other; (4) Negative AT and GC skew (AT skew = -0.001, GC skew = -0.077); (5) One transposition (nad6), one inverse transposition (trnQ), four inversions (trnF, trnH, trnC, and gene block nad1-trnL1-rrnL-trnV-rrnS), and four tandem duplication random loss events; and (6) Two protein-coding genes, nad2 and atp8, terminated with an incomplete stop codon "T".

[Genetic analysis of two cases with MYC "negative" Burkitt lymphoma].

OBJECTIVE: To carry out combined genetic analysis on two patients suspected for Burkitt lymphoma to facilitate their diagnosis and treatment. METHODS: G banded karyotyping and interphase and metaphase fluorescence in situ hybridization (FISH) were used to detect the specific sites of chromosomes by using separate and fusion probes. RESULTS: The separate probe showed no presence of MYC gene abnormality, while fusion probe confirmed the IGH::MYC translocation in the samples. Combined with the clinical features and pathological characteristics, the two patients were finally diagnosed with Burkitt lymphoma, which was confirmed by targeted capture next generation sequencing. CONCLUSION: The separate probe for the MYC gene has some shortcomings and should be used together with dual fusion probe to improve the accuracy of diagnosis.

Asymmetric Synthesis of Axially Chiral Arylpyrazole via an Organocatalytic Arylation Reaction.

Herein, a highly enantioselective arylation reaction of 3-aryl-5-aminopyrazoles and quinone derivatives was realized using a chiral phosphoric acid catalyst under mild conditions. The reaction has a broad scope with respect to both arylation reaction partners and hence offers rapid access to an array of axially chiral arylpyrazoles with pretty outcomes (up to 95% yield and 99% ee). Notably, the reaction is very efficient, as the catalyst loadings for the model reaction can be reduced to 1 mol % and the enantioselectivity is still maintained. Besides, the synthetic utility of the protocol was proven by a gram-scale reaction and the transformation of the product.