[The treatment strategies of autoimmune hemolytic anemia].

Autoimmune hemolytic anemia (AIHA) is characterized by the accelerated destruction of erythrocytes due to the presence of antibodies and/or complement that bind to antigens on erythrocytes. It can be subdivided into warm, cold or mixed AIHA based on the type of autoantibody and the optimal temperature of antigen-antibody reaction. Glucocorticoid with or without rituximab is the first-line treatment of warm AIHA (wAIHA), and splenectomy was once the preferred second-line treatment for relapsed or refractory wAIHA. However, due to the various complications of splenectomy, rituximab has gradually become the preferred treatment for patients who have failed glucocorticoid therapy. Other available treatments including immunosuppressants and plasma exchange can be chosen. Rituximab with or without bendamustine is generally taken as the first-line regimen for cold autoimmune hemolytic anemia (cAIHA), while glucocorticoid and splenectomy are ineffective. Sutimlimab, a kind of complement inhibitor, has been approved for the treatment of cold agglutinin disease (CAD). In recent years, many new drugs have emerged as treatment options for AIHA. Emerging therapies, including B-cell-directed therapies, plasma cell-directed therapies, complement inhibitors, and phagocytosis inhibition, provide a new perspective for AIHA therapy, showing great potential for clinical applications.

[Identification of potential biomarkers and immunoregulatory mechanisms of rheumatoid arthritis based on multichip co-analysis of GEO database].

OBJECTIVE: To identify the biomarkers for early rheumatoid arthritis (RA) diagnosis and explore the possible immune regulatory mechanisms. METHODS: The differentially expressed genesin RA were screened and functionally annotated using the limma, RRA, batch correction, and clusterProfiler. The protein-protein interaction network was retrieved from the STRING database, and Cytoscape 3.8.0 and GeneMANIA were used to select the key genes and predicting their interaction mechanisms. ROC curves was used to validate the accuracy of diagnostic models based on the key genes. The disease-specific immune cells were selected via machine learning, and their correlation with the key genes were analyzed using Corrplot package. Biological functions of the key genes were explored using GSEA method. The expression of STAT1 was investigated in the synovial tissue of rats with collagen-induced arthritis (CIA). RESULTS: We identified 9 core key genes in RA (CD3G, CD8A, SYK, LCK, IL2RG, STAT1, CCR5, ITGB2, and ITGAL), which regulate synovial inflammation primarily through cytokines-related pathways. ROC curve analysis showed a high predictive accuracy of the 9 core genes, among which STAT1 had the highest AUC (0.909). Correlation analysis revealed strong correlations of CD3G, ITGAL, LCK, CD8A, and STAT1 with disease-specific immune cells, and STAT1 showed the strongest correlation with M1-type macrophages (R=0.68, P=2.9e-08). The synovial tissues of the ankle joints of CIA rats showed high expressions of STAT1 and p-STAT1 with significant differential expression of STAT1 between the nucleus and the cytoplasm of the synovial fibroblasts. The protein expressions of p-STAT1 and STAT1 in the cell nuclei were significantly reduced after treatment. CONCLUSION: CD3G, CD8A, SYK, LCK, IL2RG, STAT1, CCR5, ITGB2, and ITGAL may serve as biomarkers for early diagnosis of RA. Gene-immune cell pathways such as CD3G/CD8A/LCK-γδ T cells, ITGAL-Tfh cells, and STAT1-M1-type macrophages may be closely related with the development of RA.

MiR-539-3p Alleviates Apoptosis and Extracellular Matrix Degradation in Chondrocytes of Childhood-Onset Osteoarthritis by Targeting RUNX2.

Recent research has identified that miR-539-3p impedes chondrogenic differentiation, yet its specific role and underlying mechanisms in childhood-onset osteoarthritis (OA) remain unclear. This study found that miR-539-3p levels were considerably lower in cartilage samples derived from childhood-onset OA patients compared to the control group. Enhancing miR-539-3p expression or suppressing RUNX2 expression notably reduced apoptosis, inflammation, and extracellular matrix (ECM) degradation in OA chondrocytes. In contrast, reducing miR-539-3p or increasing RUNX2 had the opposite effects. RUNX2 was confirmed as a direct target of miR-539-3p. Further experiments demonstrated that miR-539-3p targeting RUNX2 effectively lessened apoptosis, inflammation, and ECM degradation in OA chondrocytes, accompanied by changes in key molecular markers like reduced caspase-3 and matrix etallopeptidase 13 (MMP-13) levels, and increased B-cell lymphoma 2 (Bcl-2) and collagen type X alpha 1 chain (COL2A1). This study underscores the pivotal role of miR-539-3p in alleviating inflammation and ECM degradation in childhood-onset OA through targeting RUNX2, offering new insights for potential therapeutic strategies against this disease.

[Clinical characteristics of perimenopausal female patients with rheumatoid arthritis].

Objective: To explore the menopause status of patients with rheumatoid arthritis (RA) and clinical characteristics of perimenopausal RA patients. Methods: A cross-sectional study. Female RA patients were recruited retrospectively in the Sun Yat-Sen Memorial Hospital from August 2015 to August 2023. Clinical data were collected, including onset age, disease duration, RA disease activity indicators, functional assessment, and radiographic scores. According to menopausal status, the patients were categorized as pre-menopausal, perimenopausal and post-menopausal groups to explore their menopausal and clinical characteristics. Results: A total of 1 151 female patients were enrolled, with a mean age of (50.2±13.0) years. At enrollment, there were 470 (40.8%), 140 (12.2%) and 541 (47.0%) patients in pre-menopause, perimenopause and post-menopause status, respectively. The mean age of menopause was (49.0±4.2) years. Compared with pre-menopausal group, perimenopausal RA patients had higher disease activity indicators [clinical disease activity index (CDAI) 17 (6, 26) vs 10 (3, 19) ], higher levels of inflammation [erythrocyte sedimentation rate (ESR) 35 (21, 65) vs 26 (14, 44) mm/1h, C-reactive protein (CRP) 6.2 (3.2, 16.8) vs 3.3 (3.2, 13.6) mg/L], and a higher proportion of functional limitation [25.0%(35/140) vs 10.4%(49/470)] (all P<0.016 7); while there was no significant differences in disease activity[M(Q1, Q3)] [CDAI 17 (6, 26) vs 14 (6, 25)], levels of inflammation [ESR 35(21, 65) vs 42 (23, 72) mm/1h, CRP 6.2 (3.2, 16.8) vs 6.2 (3.3, 23.9) mg/L] and functional limitation [25.0%(35/140) vs 28.8%(156/541)] when compared with those in post-menopausal group (all P>0.016 7). In RA patients during the perimenopausal period, 49 cases (35.0%) developed RA during this period. Compared with patients with RA onset during reproductive age, patients with RA onset during the perimenopausal period had higher numbers of 28-joint tender joints [7 (2, 10) vs 4 (0, 8)], higher CDAI [20 (12, 29) vs 14 (4, 24)], and higher ESR [45 (25, 72) vs 32 (18, 56) mm/1h] (all P<0.05). Conclusion: Perimenopausal patients with RA have severe disease activity and functional limitation.

[Guillain-Barre syndrome after allogeneic hematopoietic stem cell transplantation: a case report and literature review].

Guillain-Barre syndrome rarely develops after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and only a few reports exist in China. Guillain-Barre syndrome is an acute and life-threatening condition that requires early diagnosis and treatment. A patient with acute myeloid leukemia underwent allogeneic HSCT for >5 months and gradually developed limb muscle weakness and limited eye movement after coexisting with delayed acute intestinal graft-versus-host disease. After the examination of cerebrospinal fluid and electromyography, the diagnosis of Guillain-Barre syndrome was confirmed. After a high-dose intravenous immunoglobulin (IVIg) treatment, muscle strength gradually recovered, and the prognosis was good.

Effects of Repetitive Mild Traumatic Brain Injury on Corticotropin-Releasing Factor Modulation of Lateral Habenula Excitability and Motivated Behavior.

Mild traumatic brain injury (mTBI) is a significant health burden due to mTBI-related chronic debilitating cognitive and psychiatric morbidities. Recent evidence from our laboratory suggests a possible dysregulation within reward/motivational circuit function at the level of a subcortical structure, the lateral habenula (LHb), where we demonstrated a causal role for hyperactive LHb in mTBI-induced motivational deficits in self-care grooming behavior in young adult male mice when exposed to mTBI during late adolescence (at ∼8 weeks old). In this study, we extended this observation by further characterizing neurobehavioral effects of this repetitive closed head injury model of mTBI in both young adult male and female mice on LHb excitability, corticotropin releasing factor (CRF) modulation of LHb activity, and behavioral responses of motivation to self-care behavior and approach versus avoidance behavior in the presence of a social- or threat-related stimulus. We show that mTBI increases LHb spontaneous tonic activity in female mice similar to what we previously observed in male mice, as well as promoting LHb neuronal hyperexcitability and hyperpolarization-induced LHb bursting in both male and female mice. Interestingly, mTBI only increases LHb intrinsic excitability in male mice coincident with higher levels of the hyperpolarization-activated cation currents (HCN/Ih) and reduces levels of the M-type potassium currents while potentiating M-currents without altering intrinsic excitability in LHb neurons of female mice. Because persistent dysregulation of brain CRF systems is suggested to contribute to chronic psychiatric morbidities and that LHb neurons are highly responsive to CRF, we tested whether the LHb CRF subsystem becomes engaged following mTBI. We found that in vitro inhibition of CRF receptor type 1 (CRFR1) within the LHb reverses mTBI-induced enhancement of LHb tonic activity and hyperexcitability in both sexes, suggesting that an augmented intra-LHb CRF-CRFR1-mediated signaling contributes to the overall LHb hyperactivity following mTBI. Behaviorally, mTBI diminishes motivation for self-care grooming in female mice as in male mice. mTBI also alters defensive behaviors in the looming shadow task by shifting the innate defensive behaviors toward more passive action locking rather than escape behaviors in response to an aerial threat in both male and female mice, as well as prolonging the latency to escape responses in female mice. While this model of mTBI reduces social preference in male mice, it induces higher social novelty seeking during the novel social encounters in both male and female mice. Overall, our study provides further translational validity for the use of this pre-clinical model of mTBI for investigation of mTBI-related reward circuit dysfunction and mood/motivation-related behavioral deficits in both sexes while uncovering a few sexually dimorphic neurobehavioral effects of this model that may differentially affect young males and females when exposed to this type of mTBI during late adolescence.

[An observational and Mendelian randomization study of the associations of body mass index with plasma amino acids and acylcarnitines in Chinese adults].

Objective: To explore the relationship between BMI and levels of plasma amino acids and acylcarnitines in Chinese adults. Methods: Based on 2 182 individuals with targeted mass spectrometry metabolomic measurements from the first resurvey of the China Kadoorie Biobank, we assessed the linear and nonlinear associations between BMI and plasma levels of 20 amino acids and 40 acylcarnitines using linear regression models and restricted cubic spline models, and identified BMI-related metabolic pathways. We conducted one-sample Mendelian randomization (MR) with BMI genetic risk scores as the instrumental variable further to explore the potential causal relationships between BMI and 20 amino acids and 40 acylcarnitines, and tested for horizontal pleiotropy using the MR-Egger method. Results: Observational analyses found that BMI was associated with increased plasma levels of 3 branched-chain amino acids (isoleucine, leucine, and valine), 2 aromatic amino acids (phenylalanine and tyrosine), 3 other amino acids (cysteine, glutamate, lysine), and 7 acylcarnitines (C3, C4, C5, C10, C10:1, C14, and C16), and with decreased circulating levels of asparagine, serine, and glycine. Pathway analysis identified 7 BMI-related amino acids metabolic pathways (false discovery rate corrected all P<0.05), including branched-chain amino acids and aromatic amino acids biosynthesis, glutathione metabolism, etc. BMI showed a nonlinear relationship with leucine, valine, and threonine, and a linear relationship with other amino acids and acylcarnitines. One-sample MR analyses revealed that BMI was associated with elevated levels of tyrosine and 4 acylcarnitines [C5-DC(C6-OH), C5-M-DC, C12-DC, and C14], with tyrosine and acylcarnitine C14 positively correlated with BMI in both observational [the ß values (95%CIs) were 0.057 (0.044-0.070) and 0.018 (0.005-0.032), respectively] and One-sample MR analyses [the ß values (95%CIs) were 0.102 (0.035-0.169) and 0.104 (0.036-0.173), respectively]. The MR analyses of the current study satisfied the 3 core assumptions of instrumental variable. Conclusions: BMI was associated with circulating 11 amino acids and 7 acylcarnitines in Chinese adults, involving several pathways such as branched-chain amino acid and aromatic amino acid metabolism, fatty acid metabolism, and oxidative stress. There may be a causal relationship between BMI and tyrosine and acylcarnitine C14.

Effects of Repetitive Mild Traumatic Brain Injury on Corticotropin-Releasing Factor Modulation of Lateral Habenula Excitability and Motivated Behavior.

Mild traumatic brain injury (mTBI) is a significant health burden due to mTBI-related chronic debilitating cognitive and psychiatric morbidities. Recent evidence from our laboratory suggests a possible dysregulation within reward/motivational circuit function at the level of a subcortical structure, the lateral habenula (LHb), where we demonstrated a causal role for hyperactive LHb in mTBI-induced motivational deficits in self-care grooming behavior in young adult male mice when exposed to mTBI injury during late adolescence (at ~8 weeks old). Here we extended this observation by further characterizing neurobehavioral effects of this repetitive closed head injury model of mTBI in both young adult male and female mice on LHb excitability, corticotropin releasing factor (CRF) modulation of LHb activity, and behavioral responses of motivation to self-care behavior, and approach versus avoidance behavior in the presence of a social- or threat-related stimulus. We show that mTBI increases LHb spontaneous tonic activity in female mice similar to what we previously observed in male mice as well as promoting LHb neuronal hyperexcitability and hyperpolarization-induced LHb bursting in both male and female mice. Interestingly, mTBI only increases LHb intrinsic excitability in male mice coincident with higher levels of the hyperpolarization-activated cation currents (HCN/Ih) and reduces levels of the M-type potassium currents while potentiating M-currents without altering intrinsic excitability in LHb neurons of female mice. Since persistent dysregulation of brain CRF systems is suggested to contribute to chronic psychiatric morbidities and that LHb neurons are highly responsive to CRF, we then tested whether LHb CRF subsystem becomes engaged following mTBI. We found that in vitro inhibition of CRF receptor type 1 (CRFR1) within the LHb normalizes mTBI-induced enhancement of LHb tonic activity and hyperexcitability in both sexes, suggesting that an augmented intra-LHb CRF-CRFR1-mediated signaling contributes to the overall LHb hyperactivity following mTBI. Behaviorally, mTBI diminishes motivation for self-care grooming in female mice as in male mice. mTBI also alters defensive behaviors in the looming shadow task by shifting the innate defensive behaviors towards more passive action-locking rather than escape behaviors in response to an aerial threat in both male and female mice as well as prolonging the latency to escape responses in female mice. While, this model of mTBI reduces social preference in male mice, it induces higher social novelty seeking during the novel social encounters in both male and female mice. Overall, our study provides further translational validity for the use of this preclinical model of mTBI for investigation of mTBI-related reward circuit dysfunction and mood/motivation-related behavioral deficits in both sexes while uncovering a few sexually dimorphic neurobehavioral effects of this model that may differentially affect young males and females when exposed to this type of mTBI injury during late adolescence.

Dissemination of meticillin-resistant Staphylococcus aureus sequence type 8 (USA300) in Taiwan.

BACKGROUND: In Taiwan, sequence type (ST) 239 and ST59 were two major clones among meticillin-resistant Staphylococcus aureus (MRSA) clinical isolates in the past two decades. USA300 (ST8) prevailed in the Americas but not in outside areas. Recently USA300 (ST8) emerged and was increasingly identified in Taiwan; we thus conducted an island-wide study to explore the role of USA300 among MRSA isolates. METHODS: One hundred MRSA bloodstream isolates identified in 2020 from each of the six participating hospitals in Taiwan were collected and characterized. The first 10 ST8 isolates from each hospital were further analysed by whole-genome sequencing. RESULTS: Of the 590 confirmed MRSA isolates, a total of 22 pulsotypes and 21 STs were identified. The strain of pulsotype AI/ST8 was the most common lineage identified, accounting for 187 isolates (31.7%) and dominating in five of six hospitals, followed by pulsotype A/ST239 (14.7%), pulsotype C/ST59 (13.9%) and pulsotype D/ST59 (9.2%). Of the 187 pulsotype AI/ST8 isolates, 184 isolates were characterized as USA300 and clustered in three major sub-pulsotypes, accounting for 78%. Ninety per cent of the 60 ST8 isolates for whole-genome sequencing were clustered in three major clades. CONCLUSIONS: In 2020, USA300 became the most common clone of MRSA in Taiwan, accounting for >30% of MRSA bloodstream isolates island wide. Most of USA300 isolates circulating in Taiwan might have been imported on multiple occasions and evolved into at least three successful local clades. MRSA USA300 has successfully established its role in Taiwan, an area outside of the Americas.

Network meta-analysis of the risk of dyspepsia and anorexia in patients with type 2 diabetes mellitus induced by glucagon-like peptide 1 receptor agonist hypoglycemic drugs.

OBJECTIVE: The aim of this study was to investigate and evaluate the risk of dyspepsia and anorexia in patients with type 2 diabetes mellitus (T2DM) induced by glucagon-like peptide 1 receptor agonist (GLP-1 RA) hypoglycemic drugs. MATERIALS AND METHODS: We searched papers in PubMed, Web of Science, Cochrane Library, Google Scholar, CNKI, Wanfang, Embase, and VIP databases, and the retrieval time limit was set from the establishment of the database to May 2023. Randomized Controlled Trials (RCTs) were collected in which the subjects were T2DM patients, the intervention was GLP-1RA compared with placebo or traditional hypoglycemic drugs, and the outcome indicators included dyspepsia and anorexia. A meta-analysis and a network meta-analysis were performed. RESULTS: The results of the traditional meta-analysis showed that the risk of dyspepsia and anorexia of total GLP-1 RA was 3.01 and 2.56 times that of placebo, respectively. All types of GLP-1RA were compared with placebo and the results also showed a trend towards increased risk of digestive system adverse events (DSAEs). Among all interventions included, liraglutide was the one with the highest risk of dyspepsia in patients with T2DM, and dulaglutide was the one with the highest risk of anorexia. CONCLUSIONS: The results of the two meta-analyses are consistent, and both clearly show that GLP-1RA can increase the risk of dyspepsia and anorexia in T2DM patients.

[A survey on the implementation of cardiovascular surgery for congenital heart disease in China between 2017 and 2021].

Objective: To investigate the inplementation of cardiovascular surgery for congenital heart disease (CHD) in China. Methods: A cross-sectional study was carried out. The CHD cardiovascular surgery data collected by the Chinese Society of Extracorporeal Circulation from 2017 to 2021 in 31 provinces (autonomous regions/municipalities) of China were retrospectively reviewed, the implementation of CHD cardiovascular surgery in different provinces, regions, general/specialized hospitals, and different age groups (whether≤18 years old) were summarized, and the correlation analysis between the number of surgeries carried out in each province/region and the gross regional product and the number of the regional population was performed. Results: Between 2017 and 2021, the annual volume of CHD cardiovascular surgery was 77 120, 77 634, 81 161, 62 663 and 71 492, respectively, showing a decreasing trend. Meanwhile, the proportion of CHD patients aged≤18 years who underwent cardiovascular surgery also showed a downward trend, from 79.8% (61 557/77 120) in 2017 to 58.6% (41 871/71 492) in 2021 (P=0.027). The number of surgical cases varied greatly among different provinces, including 4 provinces with≥5 000 cases and 9 provinces with 2 000-5 000 cases. In the five years, the number of CHD cardiovascular surgeries in Central and East China was the largest, accounting for 41.1%-45.5% of the total surgical cases. The proportion of CHD surgery cases≤18 years old was the highest in Southwest China (69.7%-87.4%) and the lowest in Northeast China (28.2%-68.9%). Except for 2021, the number of cases carried out by each region between 2017 and 2020 was correlated with the gross regional product (r=0.929, 0.929, 0.893 and 0.964, respectively, all P<0.05) and the population (r=0.821, 0.893, 0.821 and 0.857, respectively, all P<0.05). Hospitals that performed more than 100 operations (20.5%±1.2% of the total number of hospitals) completed 86.2%±1.2% of the total number of operations in China during the 5-year period. In 2017 and 2021, the number of CHD cardiovascular surgeries preformed in children's/women's and children's specialized hospitals accounted for 24.3% (18 772/77 120) and 23.8% (17 012/71 492) of the total number of cases in China, respectively. Conclusions: From 2017 to 2021, the number of cardiovascular surgery for CHD decreases slightly, but the proportion of surgery for adult CHD patients increases significantly.There is a strong correlation between the number of CHD operations in each region and their economic development status. The scale of CHD cardiovascular surgery performed in children's hospitals/women's and children's hospitals accounts for about a quarter of the total volume in China.

[Long-term outcome of patients with rectal cancer who achieve complete or near complete clinical responses after neoadjuvant therapy: a multicenter registry study of data from the Chinese Watch and Wait Database].

Objective: To report the long-term outcomes of Chinese rectal cancer patients after adopting a Watch and Wait (W&W) strategy following neoadjuvant therapy (NAT). Methods: This multicenter, cross-sectional study was based on real-world data. The study cohort comprised rectal cancer patients who had achieved complete or near complete clinical responses (cCRs, near-cCRs) after NAT and were thereafter managed by a W&W approach, as well as a few patients who had achieved good responses after NAT and had then undergone local excision for confirmation of pathological complete response. All participants had been followed up for ≥2 years. Patients with distant metastases at baseline or who opted for observation while living with the tumor were excluded. Data of eligible patients were retrospectively collected from the Chinese Wait-and-Watch Data Collaboration Group database. These included baseline characteristics, type of NAT, pre-treatment imaging results, evaluation of post-NAT efficacy, salvage measures, and treatment outcomes. We herein report the long-term outcomes of Chinese rectal cancer patients after NAT and W&W and the differences between the cCR and near-cCR groups. Results: Clinical data of 318 rectal cancer patients who had undergone W&W for over 2 years and been followed up were collected from eight medical centers (Peking University Cancer Hospital, Fudan University Shanghai Cancer Center, Sun Yat-sen University Cancer Center, Shanghai Changhai Hospital, Peking Union Medical College Hospital, Liaoning Cancer Hospital, the First Hospital of Jilin University, and Yunnan Cancer Hospital.) The participants comprised 221 men (69.4%) and 107 women (30.6%) of median age 60 (26-86) years. The median distance between tumor and anal verge was 3.4 (0-10.4) cm. Of these patients, 291 and 27 had achieved cCR or near-cCR, respectively, after NAT. The median duration of follow-up was 48.4 (10.2-110.3) months. The 5-year cumulative overall survival rate was 92.4% (95%CI: 86.8%-95.7%), 5-year cumulative disease-specific survival (CSS) rate 96.6% (95%CI: 92.2%-98.5%), 5-year cumulative organ-preserving disease-free survival rate 86.6% (95%CI: 81.0%-90.7%), and 5-year organ preservation rate 85.3% (95%CI: 80.3%-89.1%). The overall 5-year local recurrence and distant metastasis rates were 18.5% (95%CI: 14.9%-20.8%) and 8.2% (95%CI: 5.4%-12.5%), respectively. Most local recurrences (82.1%, 46/56) occurred within 2 years, and 91.0% (51/56) occurred within 3 years, the median time to recurrence being 11.7 (2.5-66.6) months. Most (91.1%, 51/56) local recurrences occurred within the intestinal lumen. Distant metastases developed in 23 patients; 60.9% (14/23) occurred within 2 years and 73.9% (17/23) within 3 years, the median time to distant metastasis being 21.9 (2.6-90.3) months. Common sites included lung (15/23, 65.2%), liver (6/23, 26.1%), and bone (7/23, 30.4%) The metastases involved single organs in 17 patients and multiple organs in six. There were no significant differences in overall, cumulative disease-specific, or organ-preserving disease-free survival or rate of metastases between the two groups (all P>0.05). The 5-year local recurrence rate was higher in the near-cCR than in the cCR group (41.6% vs. 16.4%, P<0.01), with a lower organ preservation rate (69.2% vs. 88.0%, P<0.001). The success rates of salvage after local recurrence and distant metastasis were 82.1% (46/56) and 13.0% (3/23), respectively. Conclusion: Rectal cancer patients who achieve cCR or near-cCR after NAT and undergo W&W have favorable oncological outcomes and a high rate of organ preservation. Local recurrence and distant metastasis during W&W follow certain patterns, with a relatively high salvage rate for local recurrence. Our findings highlight the importance of close follow-up and timely intervention during the W&W process.

Arginine-linked HPV-associated E7 displaying bacteria-derived outer membrane vesicles as a potent antigen-specific cancer vaccine.

BACKGROUND: Bacteria-based cancer therapy have demonstrated innovative strategies to combat tumors. Recent studies have focused on gram-negative bacterial outer membrane vesicles (OMVs) as a novel cancer immunotherapy strategy due to its intrinsic properties as a versatile carrier. METHOD: Here, we developed an Human Papillomavirus (HPV)-associated E7 antigen displaying Salmonella-derived OMV vaccine, utilizing a Poly(L-arginine) cell penetrating peptide (CPP) to enhance HPV16 E7 (aa49-67) H-2 Db and OMV affinity, termed SOMV-9RE7. RESULTS: Due to OMV's intrinsic immunogenic properties, SOMV-9RE7 effectively activates adaptive immunity through antigen-presenting cell uptake and antigen cross-presentation. Vaccination of engineered OMVs shows immediate tumor suppression and recruitment of infiltrating tumor-reactive immune cells. CONCLUSION: The simplicity of the arginine coating strategy boasts the versatility of immuno-stimulating OMVs that can be broadly implemented to personalized bacterial immunotherapeutic applications.

Fine mapping and analysis of a candidate gene controlling Phytophthora blight resistance in cucumber.

Cucumber blight is a destructive disease. The best way to control this disease is resistance breeding. This study focuses on disease resistance gene mapping and molecular marker development. We used the resistant cucumber, JSH, and susceptible cucumber, B80, as parents to construct F2 populations. Bulked segregant analysis (BSA) combined with specific length amplified fragment sequencing (SLAF-seq) were used, from which we developed cleaved amplified polymorphic sequence (CAPs) markers to map the resistance gene. Resistance in F2 individuals showed a segregation ratio of resistance:susceptibility close to 3:1. The gene in JSH resistant cucumber was mapped to an interval of 9.25 kb, and sequencing results for the three genes in the mapped region revealed three mutations at base sites 225, 302, and 591 in the coding region of Csa5G139130 between JSH and B80, but no mutations in coding regions of Csa5G139140 and Csa5G139150. The mutations caused changes in amino acids 75 and 101 of the protein encoded by Csa5G139130, suggesting that Csa5G139130 is the most likely resistance candidate gene. We developed a molecular marker, CAPs-4, as a closely linked marker for the cucumber blight resistance gene. This is the first report on mapping of a cucumber blight resistance gene and will provideg a useful marker for molecular breeding of cucumber resistance to Phytophthora blight.

[Propensity score matching analysis of the short-term efficacy of Kamikawa versus double- tract reconstruction in laparoscopic proximal gastric cancer surgery].

Objective: To compare the short-term efficacy of Kamikawa anastomosis and double-tract reconstruction (DTR) after proximal gastrectomy. Methods: This was a propensity score matched, retrospective, cohort study. Inclusion criteria comprised age 20-70 years, diagnosis of gastric cancer by pathological examination of preoperative endoscopic biopsies, tumor diameter ≤4 cm, and location in the upper 1/3 of the stomach (including the gastroesophageal junction), and TNM stage IA, IB, or IIA. The study cohort comprised 73 patients who had undergone laparoscopic proximal gastric cancer radical surgery in the Department of Gastroenterology, Tangdu Hospital, Air Force Medical University between June 2020 and February 2023, 19 of whom were in the Kamikawa group and 54 in the DTR group. After using R language to match the baseline characteristics of patients in a ratio of 1:2, there were 17 patients in the Kamikawa group and 34 in the DTR group. Surgery-related conditions, postoperative quality of life, and postoperative complications were compared between the two groups. Results: After propensity score matching, there were no statistically significant differences in baseline data between the two groups (P>0.05). Compared with the DTR group, the Kamikawa group had longer operative times (321.5±15.7 minutes vs. 296.8±26.1 minutes, t=32.056, P<0.001), longer anastomosis times (93.0±6.8 minutes vs. 45.3±7.7 minutes, t=56.303, P<0.001), and less bleeding (76 [54~103] mL vs.112 [82~148) mL, Z=71.536, P<0.001); these differences are statistically significant. There were no statistically significant differences between the two groups in tumor size, time to first postoperative passage of gas, postoperative hospital stay, number of lymph nodes removed, duration of lymph node dissection, or total hospitalization cost (all P>0.05). The median follow-up time was 6.1 ± 1.8 months. As to postoperative quality of life, the Kamikawa group had a lower rate of upper gastrointestinal contrast reflux than did the DTR group (0 vs. 29.4% [10/34], χ2=6.220, P=0.013); this difference is statistically significant. However, differences between the two groups in quality of life score on follow-up of 3 months and 6 months on the Gastroesophageal Reflux Disease (GERD) scale were not statistically significant (all P>0.05). The incidence of postoperative complications was 2/17 in the Kamikawa group, which is significantly lower than the 41.2% (14/34) in the DTR group (χ2=4.554, P=0.033). Conclusion: Kamikawa anastomosis and DTR are equally safe and effective procedures for reconstructing the digestive tract after proximal gastric surgery. Although Kamikawa anastomosis takes slightly longer and places higher demands on the surgical team, it is more effective at preventing postoperative reflux.

[Analysis of the efficacy and safety of hepatic arterial infusion chemotherapy for unresectable hepatitis B-related intrahepatic cholangiocarcinoma].

Objective: To explore the efficacy and safety of hepatic arterial infusion chemotherapy(HAIC) for unresectable hepatitis B-related intrahepatic cholangiocarcinoma(ICC). Methods: This is a retrospective controlled study. Data from 140 unresectable ICC patients who received HAIC treatment at Sun Yat-sen University Cancer Center from March 2015 to June 2023 were retrospectively collected, including 72 patients in the hepatitis B surface antigen(HBsAg)negative group (43 males and 29 females, aged (59.6±9.5)years(range: 34 to 81 years)), 68 cases in the HBsAg-positive group (48 males, 20 females, aged (53.4±11.4)years(range: 29 to 82 years)). HAIC treatment used the FOLFOX regimen combined with oxaliplatin, leucovorin,and fluorouracil. The differences in effects, prognosis,and adverse reactions between the two groups of patients after HAIC treatment were analyzed. All variables were expressed as categorical data. The χ2 test or Fisher's exact probability method was used to compare between groups. The Kaplan-Meier method was used to draw survival curves. The difference of survival curve between groups were compared through the Log-rank test. Results: According to the Response Evaluation Criteria in Solid Tumors(RECIST) version 1.1,the objective response rate(ORR) of the HBsAg-negative group was 23.2%(16/69),and the ORR of the HBsAg-positive group was 40.3%(25/62). The difference in ORR between the two groups was statistically significant(χ2=4.459,P=0.035). According to the modified RECIST(mRECIST) criteria,the ORR of the HBsAg-negative group was 27.5%(19/69), and the ORR of the HBsAg-positive group was 45.2%(28/62). The difference in ORR between the two groups was statistically significant(χ2=4.410,P=0.036). The median progression-free survival(PFS) of the HBsAg-negative group and the positive group were 7.1 months(95%CI: 5.8 to 13.2 months) and 7.3 months (95%CI: 5.7 to 10.3 months), respectively, and the median overall survival(OS) were 16.3 months (95%CI: 12.5 to 33.9 months) and 15.9 months (95%CI: 9.2 to 20.7 months) respectively. There were no statistically significant differences in PFS and OS between the two groups (both P>0.05). The main serious adverse reactions of the two groups of patients included increased AST, increased ALT, thrombocytopenia,and neutropenia. There were no statistically significant differences in various adverse reactions between the two groups after HAIC treatment (all P>0.05). Conclusion: Patients with HBsAg-positive unresectable ICC are more likely to benefit from HAIC treatment.

Chronically stressed male and female mice show a similar peripheral and central pro-inflammatory profile after an immune challenge.

Although acute stressors are known for stimulating the production of glucocorticoids and pro-inflammatory cytokines in rodents, the effects of chronic stressors on cytokine levels and the activation of the hypothalamic-pituitary-adrenal (HPA) axis, especially in response to a subsequent challenge, are less clear. In this study, male and female mice were exposed to 6 weeks of chronic variable stress (CVS) and the peripheral and central levels of IL-1ß, IL-6, and TNF-α, as well as the HPA axis reactivity, were measured after an acute injection of LPS. The findings indicate that the pro-inflammatory profile in the plasma, regardless of stress exposure, was similar between male and female animals, whereas there was a region-, sex-, and stress-dependent pattern in the brain. Exposure to chronic stressors blunted the HPA reactivity to the LPS challenge, indicating a modulatory effect on the stress axis responsiveness.

The timing of intravenous antibiotics and clinical outcomes of Mycobacterium abscessus complex lung diseases.

BACKGROUND: The importance of early intravenous (IV) antibiotic use for Mycobacterium abscessus complex lung diseases (MABC-LD) treatment remains unknown. METHODS: A retrospective multi-centre observational study was conducted in Taiwan. Patients who were diagnosed with and received treatment for MABC-LD from January 2007 to April 2021 were included. Treatment outcome was defined as modified microbiological cure of MABC-LD.RESULTS: Of the 89 enrolled patients, 34 (38.2%) received IV antibiotics as part of the treatment regimen. The median time to IV initiation was 1 day (IQR 1???49); 24 (70.6%) of these patients received IV agents within 4 weeks, defined as early-use. Forty-two (47.2%) patients achieved modified microbiological cure. In the multivariable logistic analysis, early IV antibiotic use was an independent factor associated with modified microbiological cure (aOR 5.32, 95% CI 1.66???17.00), whereas high radiological score (aOR 0.86, 95% CI 0.73???1.00) demonstrated negative association.CONCLUSIONS: In the present study, early use of effective IV antibiotic was prescribed in a low percentage (27%) for MABC-LD. By contrast, early IV antibiotic use was correlated with higher microbiological cure than were late or non-use. Future larger and prospective studies are needed to validate the association.