Successful treatment pure red cell aplasia after ABO major mismatched allogeneic hematopoietic stem cell transplantation with avatrombopag and low dose rituximab.

BACKGROUND: Pure red cell aplasia (PRCA) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) with ABO major incompatibility is characterized by transfusion dependent anemia. No standard treatment existed for PRCA following allo-HSCT yet. STUDY DESIGN AND METHODS: We conducted a retrospective study, and reported our experience with the use of avatrombopag and lower dose rituximab to treat five patients with PRCA subsequent to major ABO-incompatible allo-HSCT. RESULTS: Five cases of PRCA were identified from 72 patients who underwent allo-HSCT with major or bidirectional ABO mismatch. Cumulative incidence at Day +60 was 6.9% (5/72) at our center. All donor and recipient blood groups were A+  and O+ , respectively. In the first three cases we reported, patients received erythropoietin, plasma exchange, and donor lymphocyte infusion, but none of them had any effect. After 4 weeks of treatment with low dose rituximab (100 mg/week) combined with avatrombopag (40 mg/day), favorable outcomes were obtained. According to the aforementioned experience, Cases 4 and 5 were administered low-dose rituximab and avatrombopag in 3 months after transplantation, and erythroid response was observed on 3 weeks after treatment. Our patients tolerated low-dose rituximab and avatrombopag well and experienced rapid efficacy, with a median duration of 3 weeks. Furthermore, no severe infection or thrombocytosis necessitated a dose adjustment. CONCLUSION: Low-dose rituximab and avatrombopag may be an effective treatment for patients with PRCA after major ABO-incompatible allo-HSCT. The patients should be treated at least 90 days post transplantation if conventional erythropoietin therapy fails.

Development and Validation of a Predictive Model for Intraoperative Hypothermia in Elderly Patients Undergoing Craniocerebral Tumor Resection: A Retrospective Cohort Study.

OBJECTIVE: Timely identification of elderly patients who are at risk of developing intraoperative hypothermia (IH) is imperative to enable appropriate interventions. This study aimed to develop a nomogram for predicting the risk of IH in elderly patients undergoing resection of craniocerebral tumor, and to validate its effectiveness. METHODS: Elderly patients who underwent craniocerebral tumor resection at a large tertiary hospital in eastern China between January 2019 and December 2022 were included (n = 988). The study population was divided into a training set and a validation set by time period. Risk factors identified through the Least Absolute Shrinkage and Selection Operator method and logistic regression analysis were used to establish the nomogram. The model was validated internally by Bootstrap method and externally by validation set through receiver operating characteristic curve analysis, Hosmer-Lemeshow test, and decision curve analysis. RESULTS: A total of 273 (27.6%) patients developed IH. Duration of anesthesia (P < 0.001), blood loss (P < 0.001), preoperative temperature (P < 0.001), tumor location (P < 0.001), age (P < 0.05), and mean arterial pressure (P < 0.05) were identified as independent risk factors for IH. A nomogram integrating these 6 factors was constructed. The area under the curve was 0.773 (95% confidence interval: 0.735-0.811) (70.5% specificity and 75.0% sensitivity), indicating good predictive performance. The decision curve analysis demonstrated the clinical benefit of using the nomogram. CONCLUSIONS: Our model showed good performance in identifying elderly patients who are at high risk of developing IH during craniocerebral tumor resection. The nomogram can help inform timely preventive interventions.

Etoposide combined with cytarabine and pegfilgrastim for poorly mobilizing patients with multiple myeloma and lymphoma: A prospective multicentre study.

A chemotherapy-based mobilization regimen in patients who mobilize poorly, based on etoposide, cytarabine and pegfilgrastim (EAP), has recently been introduced. The aim of this prospective study was to investigate the efficacy and safety of the EAP regimen in patients with poorly mobilizing multiple myeloma (MM) or lymphoma. This single-arm clinical trial was performed at eight public hospitals in China and was registered as a clinical trial (NCT05510089). The inclusion criteria were; (1) diagnosis of MM or lymphoma, (2) defined as a 'poor mobilizer' and (3) aged 18-75 years. The EAP regimen consisted of etoposide 75 mg/m2 /day on days 1-2, cytarabine 300 mg/m2 every 12 h on days 1-2 and pegfilgrastim 6 mg on day 6. The primary endpoint of the study was the ratio of patients achieving adequate mobilization (≥2.0 × 106 CD34+ cells/kg). From 1 September 2022 to 15 August 2023, a total of 58 patients were enrolled, 53 (91.4%) achieved adequate mobilization, while 41 (70.7%) achieved optimal mobilization with a median number of cumulative collected CD34+ cells was 9.2 (range 2.1-92.7) × 106 /kg and the median number of apheresis per patient of 1.2. The median time from administration of the EAP regimen to the first apheresis was 12 days. Approximately 8.6% of patients required plerixa for rescue, which was successful. Twelve (20.7%) of the 58 patients suffered grade 2-3 infections, while 25 (43.1%) required platelet transfusions. The duration of neutrophil and platelet engraftment was 11 days. In conclusion, these results suggest that the EAP mobilization regimen might be a promising option for poorly mobilizing patients with MM or lymphoma.

A transcriptome based molecular classification scheme for cholangiocarcinoma and subtype-derived prognostic biomarker.

Previous studies on the molecular classification of cholangiocarcinoma (CCA) focused on certain anatomical sites, and disregarded tissue contamination biases in transcriptomic profiles. We aim to provide universal molecular classification scheme and prognostic biomarker of CCAs across anatomical locations. Comprehensive bioinformatics analysis is performed on transcriptomic data from 438 CCA cases across various anatomical locations. After excluding CCA tumors showing normal tissue expression patterns, we identify two universal molecular subtypes across anatomical subtypes, explore the molecular, clinical, and microenvironmental features of each class. Subsequently, a 30-gene classifier and a biomarker (called "CORE-37") are developed to predict the molecular subtype of CCA and prognosis, respectively. Two subtypes display distinct molecular characteristics and survival outcomes. Key findings are validated in external cohorts regardless of the stage and anatomical location. Our study provides a CCA classification scheme that complements the conventional anatomy-based classification and presents a promising prognostic biomarker for clinical application.

The Proportion of Myeloid-derived Suppressor Cells in the Graft as a Potential Predictor of Acute Graft-versus-host Disease in Haploid Allogeneic Hematopoietic Stem Cell Transplantation.

Myeloid-derived suppressor cells (MDSC) are powerful immunomodulatory cells that play an important role in infectious and inflammatory disorders, but the correlation between graft MDSC amount and early transplant outcomes remains unknown in allogeneic hematopoietic stem cell transplantation. We collected data from 91 patients with acute leukemia undergoing haploidentical allogeneic hematopoietic stem cell transplantation. The grafts were analyzed in terms of CD34+ cells, CD3+ T cells and subpopulation, and MDSC (HLA-DR -/low CD33 + CD16 - ) by flow cytometry. The cutoff value of the MDSC proportion in the graft on the receiver operating curve was 8.89%, with a sensitivity of 0.833 and specificity of 0.852. Day +100 cumulative incidences of II-IV and III-IV acute graft-versus-host disease (aGVHD) in the low MDSC group were 73.5% and 38.8%, respectively, and that in the high MDSC group were 5.3% and 0%, with a significant difference in incidences of II-IV and III-IV aGVHD ( P <0.001). The overall survival, relapse-free survival, and GVHD-relapse-free survival (GRFS) at 1 year were 66.3% versus 80.5% ( P =0.043), 71.6% versus 71.7% ( P =0.248), and 22.1% versus 62.8% ( P <0.001), respectively. No significant difference in the cumulative incidence of relapse between the 2 groups was observed. Multivariate analysis revealed that higher MDSC proportions were associated with a lower risk of II-IV aGVHD. Graft MDSC proportion exceeding 8.89% was significantly associated with higher overall survival and GRFS. The prophylaxis of antithymocyte globulin+post-transplant cyclophosphamide and higher MDSC proportion in the graft were favorable factors for improving GRFS. In conclusion, graft MDSC proportion may be a significant predictor of aGVHD.

Anesthesia management for giant pulmonary bullae during emergency intracranial aneurysm embolization: a case report.

INTRODUCTION: An intracranial aneurysm with an acute subarachnoid hemorrhage is an acute neurosurgical disease that often requires emergency surgical intervention. A patient with giant pulmonary bullae is usually elderly and has consistently resisted any surgery, so general anesthesia is required. However, anesthesia management in patients with pulmonary bullae is challenging due to the possibility of spontaneous pneumothorax, a serious complication. Thus, these patients require careful preoperative evaluation and intraoperative management to ensure rapid recovery and minimize adverse effects from anesthesia. CASE DESCRIPTION: A 76-year-old female patient had giant pulmonary bullae and resisted emergency intracranial aneurysm embolization. The patient underwent rapid anesthesia induction after breathing normally through the mask for 5 minutes. A left dual-lumen tracheal catheter No. 33 was quickly inserted and positioned using an electronic fiber bronchoscope. The tracheal catheter was removed under deep anesthesia and replaced with a 3.0 laryngeal mask after the operation. The patient was fully awake and her laryngeal mask was removed. The patient reported no discomfort and was sent back to the ward. CONCLUSIONS: We report the case of a patient with giant pulmonary bullae who underwent emergency non-lung surgery associated with a possible serious complication who was successfully treated with general anesthesia. This approach can be used for patients with similar conditions.

The Role of Iron Metabolism in Sepsis-associated Encephalopathy: a Potential Target.

Sepsis-associated encephalopathy (SAE) is an acute cerebral dysfunction secondary to infection, and the severity can range from mild delirium to deep coma. Disorders of iron metabolism have been proven to play an important role in a variety of neurodegenerative diseases by inducing cell damage through iron accumulation in glial cells and neurons. Recent studies have found that iron accumulation is also a potential mechanism of SAE. Systemic inflammation can induce changes in the expression of transporters and receptors on cells, especially high expression of divalent metal transporter1 (DMT1) and low expression of ferroportin (Fpn) 1, which leads to iron accumulation in cells. Excessive free Fe2+ can participate in the Fenton reaction to produce reactive oxygen species (ROS) to directly damage cells or induce ferroptosis. As a result, it may be of great help to improve SAE by treatment of targeting disorders of iron metabolism. Therefore, it is important to review the current research progress on the mechanism of SAE based on iron metabolism disorders. In addition, we also briefly describe the current status of SAE and iron metabolism disorders and emphasize the therapeutic prospect of targeting iron accumulation as a treatment for SAE, especially iron chelator. Moreover, drug delivery and side effects can be improved with the development of nanotechnology. This work suggests that treating SAE based on disorders of iron metabolism will be a thriving field.

Effectiveness of single-dose 6 mg pegfilgrastim in mobilizing peripheral blood stem cells in allogeneic hematopoietic cell transplantation donors.

A single injection of 12 mg pegfilgrastim was used to mobilize peripheral blood progenitor cells (PBPCs) from healthy donors in some studies. The purpose of this study was to determine if 6 mg of pegfilgrastim was effective and safe for mobilizing CD34+ cells in donors for allogeneic hematopoietic stem cell transplantation. We conducted a retrospective case-matched design. A single dosage of 6 mg pegfilgrastim was used to mobilize PBPCs from 60 healthy donors. Granulocyte colony-stimulating factor (G-CSF, 10 µg/kg) was administered daily to the matched donors. Leukapheresis was scheduled to commence on day 4 of the mobilization regimen. The median yielded CD34+ cell in the pegfilgrastim group was higher than those in the G-CSF group, at 5.06 × 106/kg recipient weight. The 73.3% of donors mobilized with pegfilgrastim yielded >4 × 106 cells/kg CD34+ cells in a single apheresis procedure when compared to the 33.3% of donors mobilized with G-CSF (P < 0.001). The myeloid-derived suppressor cells (MDSC) proportion in the pegfilgrastim group was significantly higher than that in the G-CSF group (P < 0.001). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was higher in the G-CSF group than that in the pegfilgrastim group (26.7% vs. 11.7%), without statistical difference. In comparison to the G-CSF group, the pegfilgrastim group had a reduced median pain intensity numerical rating scale score (1 vs. 2). A single 6 mg dosage of pegfilgrastim is effective and safe for allogeneic PBPCs collection from healthy donors. Pegfilgrastim may decrease the incidence of aGVHD by boosting MDSCs, which need further investigation.

SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53.

Pancreatic cancer cells undergo intricate metabolic reprogramming to sustain their survival and proliferation. p53 exhibits a dual role in tumor cell ferroptosis. However, the precise role and mechanisms underlying wild-type p53 activation in promoting ferroptosis in pancreatic cancer cells remain obscure. In this study, we applied bioinformatics tools and performed an analysis of clinical tissue sample databases and observed a significantly upregulated expression of solute carrier family 35 member F2 (SLC35F2) in pancreatic cancer tissues. Our clinical investigations indicated that elevated SLC35F expression was related to adverse survival outcomes. Through multi-omics analyses, we discerned that SLC35F2 influences the transcriptome and inhibits ferroptosis in pancreatic cancer cells. Moreover, our findings reveal the pivotal involvement of p53 in mediating SLC35F2-mediated ferroptosis, both in vitro and in vivo. SLC35F2 inhibits ferroptosis by facilitating TRIM59-mediated p53 degradation. Further mechanistic investigations demonstrated that SLC35F2 competitively interacts with the E3 ubiquitin ligase SYVN1 of TRIM59, thereby stabilizing TRIM59 expression and consequentially promoting p53 degradation. Utilizing protein 3D structure analysis and drug screening, we identified irinotecan hydrochloride and lapatinib ditosylate as compounds targeting SLC35F2, augmenting the antitumor effect of imidazole ketone erastin (IKE) in a wild-type p53 patient-derived xenograft (PDX) model. However, in the p53 mutant PDX model, irinotecan hydrochloride and lapatinib ditosylate did not alter the sensitivity of the tumor xenograft model to IKE-triggered ferroptosis. In summary, our work establishes a novel mechanism wherein the SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Thus, SLC35F2 emerges as a promising therapeutic target for treating pancreatic cancer.

From clinical variables to multiomics analysis: a margin morphology-based gross classification system for hepatocellular carcinoma stratification.

OBJECTIVE: Selecting interventions for patients with solitary hepatocellular carcinoma (HCC) remains a challenge. Despite gross classification being proposed as a potential prognostic predictor, its widespread use has been restricted due to inadequate studies with sufficient patient numbers and the lack of established mechanisms. We sought to investigate the prognostic impacts on patients with HCC of different gross subtypes and assess their corresponding molecular landscapes. DESIGN: A prospective cohort of 400 patients who underwent hepatic resection for solitary HCC was reviewed and analysed and gross classification was assessed. Multiomics analyses were performed on tumours and non-tumour tissues from 49 patients to investigate the mechanisms underlying gross classification. Inverse probability of treatment weight (IPTW) was used to control for confounding factors. RESULTS: Overall 3-year survival rates varied significantly among the four gross subtypes (type I: 91%, type II: 80%, type III: 74.6%, type IV: 38.8%). Type IV was found to be independently associated with poor prognosis in both the entire cohort and the IPTW cohort. The four gross subtypes exhibited three distinct transcriptional modules. Particularly, type IV tumours exhibited increased angiogenesis and immune score as well as decreased metabolic pathways, together with highest frequency of TP53 mutations. Patients with type IV HCC may benefit from adjuvant intra-arterial therapy other than the other three subtypes. Accordingly, a modified trichotomous margin morphological gross classification was established. CONCLUSION: Different gross types of HCC showed significantly different prognosis and molecular characteristics. Gross classification may aid in development of precise individualised diagnosis and treatment strategies for HCC.

FBXO11 amplifies type I interferon signaling to exert antiviral effects by facilitating the assemble of TRAF3-TBK1-IRF3 complex.

As the key component of host innate antiviral immunity, type I interferons (IFN-Is) exert multiple antiviral effects by inducing hundreds of IFN-stimulated genes. However, the precise mechanism involved in host sensing of IFN-I signaling priming is particularly complex and remains incompletely resolved. This research identified F-box protein 11 (FBXO11), a component of the E3-ubiquitin ligase SKP/Cullin/F-box complex, acted as an important regulator of IFN-I signaling priming and antiviral process against several RNA/DNA viruses. FBXO11 functioned as an essential enhancer of IFN-I signaling by promoting the phosphorylation of TBK1 and IRF3. Mechanistically, FBXO11 facilitated the assembly of TRAF3-TBK1-IRF3 complex by mediating the K63 ubiquitination of TRAF3 in a NEDD8-dependent manner to amplify the activation of IFN-I signaling. Consistently, the NEDD8-activating enzyme inhibitor MLN4921 could act as a blocker for FBXO11-TRAF3-IFN-I axis of signaling. More significantly, examination of clinical samples of chronic hepatitis B virus (HBV) infection and public transcriptome database of severe acute respiratory syndrome coronavirus-2-, HBV-, and hepatitis C virus-infected human samples revealed that FBXO11 expression was positively correlated with the stage of disease course. Taken together, these findings suggest that FBXO11 is an amplifier of antiviral immune responses and might serve as a potential therapeutic target for a number of different viral diseases.

[Clinical Value of Translocator Protein Gene in Evaluating the Efficacy of FLT3-ITD/DNMT3A R882 Double-Mutated Acute Myeloid Leukemia].

OBJECTIVE: To observe the clinical significance of translocator proteins (TSPO) gene in the treatment of FLT3-ITD/DNMT3A R882 double-mutated acute myeloid leukemia (AML). METHODS: Seventy-six patients with AML hospitalized in the Department of Hematology of the Affiliated People's Hospital of Ningbo University from June 2018 to June 2020 were selected, including 34 patients with FLT3-ITD mutation, 27 patients with DNMT3A R882 mutation, 15 patients with FLT3-ITD/DNMT3A R882 double mutation, as well as 19 patients with immune thrombocytopenia (ITP) hospitalized during the same period as control group. RNA was routinely extracted from 3 ml bone marrow retained during bone puncture, and TSPO gene expression was detected by transcriptome sequencing (using 2-deltadeltaCt calculation). RESULTS: The expression of TSPO gene in FLT3-ITD group and DNMT3A R882 group at first diagnosis was 2.02±1.04 and 1.85±0.76, respectively, which were both higher than 1.00±0.06 in control group, but the differences were not statistically significant (P=0.671, P=0.821). The expression of TSPO gene in the FLT3-ITD/DNMT3A R882 group was 3.98±1.07, wich was significantly higher than that in the FLT3-ITD group and DNMT3A R882 group, the differences were statistically significant (P=0.032, P=0.021). The expression of TSPO gene in patients who achieved complete response after chemotherapy in the FLT3-ITD/DNMT3A R882 group was 1.19±0.87, which was significantly lower than that at first diagnosis, and the difference was statistically significant (P=0.011). CONCLUSION: TSPO gene may be used as an indicator of efficacy in FLT3-ITD /DNMT3A R882 double-mutated AML.

FBXO6 regulates the antiviral immune responses via mediating alveolar macrophages survival.

Inducing early apoptosis in alveolar macrophages is one of the strategies influenza A virus (IAV) evolved to subvert host immunity. Correspondingly, the host mitochondrial protein nucleotide-binding oligomerization domain-like receptor (NLR)X1 is reported to interact with virus polymerase basic protein 1-frame 2 (PB1-F2) accessory protein to counteract virus-induced apoptosis. Herein, we report that one of the F-box proteins, FBXO6, promotes proteasomal degradation of NLRX1, and thus facilitates IAV-induced alveolar macrophages apoptosis and modulates both macrophage survival and type I interferon (IFN) signaling. We observed that FBXO6-deficient mice infected with IAV exhibited decreased pulmonary viral replication, alleviated inflammatory-associated pulmonary dysfunction, and less mortality. Analysis of the lungs of IAV-infected mice revealed markedly reduced leukocyte recruitment but enhanced production of type I IFN in Fbxo6-/- mice. Furthermore, increased type I IFN production and decreased viral replication were recapitulated in FBXO6 knockdown macrophages and associated with reduced apoptosis. Through gain- and loss-of-function studies, we found lung resident macrophages but not bone marrow-derived macrophages play a key role in the differences FBXO6 signaling pathway brings in the antiviral immune response. In further investigation, we identified that FBXO6 interacted with and promoted the proteasomal degradation of NLRX1. Together, our results demonstrate that FBXO6 negatively regulates immunity against IAV infection by enhancing the degradation of NLRX1 and thus impairs the survival of alveolar macrophages and antiviral immunity of the host.

Evolving roles of CD38 metabolism in solid tumour microenvironment.

Given that plenty of clinical findings and reviews have already explained in detail on the progression of CD38 in multiple myeloma and haematological system tumours, here we no longer give unnecessary discussion on the above progression. Though therapeutic antibodies have been regarded as a greatest breakthrough in multiple myeloma immunotherapies due to the durable anti-tumour responses in the clinic, but the role of CD38 in the immunologic regulation and evasion of non-hematopoietic solid tumours are just initiated and controversial. Therefore, we will focus on the bio-function of CD38 enzymatic substrates or metabolites in the variety of non-hematopoietic malignancies and the potential therapeutic value of targeting the CD38-NAD+ or CD38-cADPR/ADPR signal axis. Though limited, we review some ongoing researches and clinical trials on therapeutic approaches in solid tumour as well.

Fludarabine and antithymocyte globulin-based conditioning regimen combined with post-transplantation cyclophosphamide for haploidentical allogeneic hematopoietic stem cell transplantation in patients with high-risk acute myeloid leukemia and myelodysplastic syndrome.

INTRODUCTION: Relapse and graft-versus-host disease (GVHD) are the important complications influencing mortality for patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). GVHD prophylaxis based on post-transplant cyclophosphamide (PTCy) or antithymocyte globulin (ATG) is widely used in haploidentical HSCT (haplo-HSCT). OBJECTIVE: We developed a modified intensified conditioning regimen including fludarabine (Flu) and investigated the effect of ATG-PTCy combination on transplant outcomes in high-risk AML and MDS compared with those patients who received only ATG as GVHD prophylaxis. METHODS: A total of 80 patients with high-risk AML and MDS were divided into two groups and assigned to one-to-one pairing. RESULTS: The modified ATG-PTCy group had more infused mononuclear cells, CD34-positive cells and CD3-positive cells than those in the ATG group (P < 0.05). The amount of platelet transfusion was higher in the ATG group than the modified ATG-PTCy group [2 (range, 1-6) U vs 2 (range, 1-5) U, P = 0.005]. The median of platelet recovery was better in the modified ATG-PTCy group than in the ATG group (12 days vs 13 days,P = 0.041). The infection rates of bacteria, fungi and virus at 100 days after transplantation were similar in both groups. Compared with the ATG group, individuals who received the modified ATG-PTCy regimen had higher 2-year GVHD- and relapse-free survival(GRFS) [60.0% (95%CI, 44.9-75.1%) vs 34.8% (95%CI, 19.9-49.7%), P = 0.028]; lower 180-day incidence of II-IV acute GVHD (aGVHD) [15.0% (95%CI, 4.0-26.0%) vs 39.8% (95%CI, 23.9-55.7%), P = 0.029]; lower 1-year incidence of moderate to severe chronic GVHD (cGVHD) [2.9% (95%CI, 2.0-3.8%) vs 19.6% (95%CI, 5.3-33.9%), P = 0.039]; and without an increase in the 2-year cumulative incidence of relapse (CIR) [19.5% (95%CI, 6.6-32.4%) vs 30.4% (95%CI, 15.3-45.5%), P = 0.291]. CONCLUSIONS: High-dose stem cells can promote blood cell implantation. The modified ATG-PTCy combination was associated with decreased risk of aGVHD and cGVHD, no increased risk of recurrence, and improved GRFS. It represents an effective strategy for high risk AML and MDS.

Denosumab biosimilar (LY06006) in Chinese postmenopausal osteoporotic women: A randomized, double-blind, placebo-controlled, multicenter phase III study.

Objectives: This study assessed the efficacy, safety, pharmacokinetics (PK), and immunogenicity profiles of a denosumab biosimilar (LY06006) in Chinese postmenopausal osteoporotic women with a high risk of fracture. Methods: In this multicenter, randomized, double-blind, placebo-controlled, phase 3 trial, 448 postmenopausal women aged 50-85 years with osteoporosis were enrolled at 49 centers in China and were randomly assigned (3:1) to receive 60 â€‹mg of the denosumab biosimilar (LY06006) or placebo subcutaneously every 6 months for 1 year. Lumbar spine bone mineral density (BMD) change was the primary endpoint. Results: Of the 448 randomized patients, 409 (LY06006, n â€‹= â€‹311; placebo, n â€‹= â€‹98) completed the study. All 448 (100.0%) subjects were included in the intent-to-treat (ITT) trial, 427 (95.3%) were included in the full analysis set (FAS), 408 (91.1%) were included in the per protocol set (PPS), 446 (99.6%) were included in the safety set (SS), and 336 (75.0%) were included in the pharmacokinetics concentration set (PKCs). For the primary endpoint, a 4.71% (95% CI, 3.81%, 5.60%) treatment difference in percent change in lumbar spine BMD from baseline to month 12 was observed in the LY06006 group compared with the placebo group (P â€‹< â€‹0.0001). For the secondary endpoints, LY06006 was associated with increased lumbar spine BMD levels measured at month 6, BMD levels at the femoral neck, total hip, and trochanter measured at months 6 and 12 and reduced serum C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 â€‹N-peptide (P1NP) levels at months 1, 6, and 12. Safety analysis was based on the safety analysis set (SS), and 264 (78.6%) subjects in the LY06006 group and 83 (75.5%) in the placebo group experienced adverse events (AEs). Most events were mild or moderate and not related to the study drugs. Conclusion: In postmenopausal women with a high risk of fracture, LY06006 increased the BMD and decreased bone resorption; thus, LY06006 might be an effective treatment for osteoporosis. LY06006 was generally safe and well tolerated without unexpected adverse reactions, similar to the reference drug Prolia®. The characteristics of effectiveness and safety were similar to those reported in previous studies. The translational potential of this article: In this multi-center, randomized, double-blind, placebo-controlled phase 3 study, LY06006 showed substantially efficacy to increase BMD and well tolerance without unexpected adverse reactions, which is comparable to the reference drug Prolia ®. The presented results are encouraging and can offer some valuable evidence for the clinical practice.

Future directions in ventilator-induced lung injury associated cognitive impairment: a new sight.

Mechanical ventilation is a widely used short-term life support technique, but an accompanying adverse consequence can be pulmonary damage which is called ventilator-induced lung injury (VILI). Mechanical ventilation can potentially affect the central nervous system and lead to long-term cognitive impairment. In recent years, many studies revealed that VILI, as a common lung injury, may be involved in the central pathogenesis of cognitive impairment by inducing hypoxia, inflammation, and changes in neural pathways. In addition, VILI has received attention in affecting the treatment of cognitive impairment and provides new insights into individualized therapy. The combination of lung protective ventilation and drug therapy can overcome the inevitable problems of poor prognosis from a new perspective. In this review, we summarized VILI and non-VILI factors as risk factors for cognitive impairment and concluded the latest mechanisms. Moreover, we retrospectively explored the role of improving VILI in cognitive impairment treatment. This work contributes to a better understanding of the pathogenesis of VILI-induced cognitive impairment and may provide future direction for the treatment and prognosis of cognitive impairment.

Diabetic peripheral neuropathy: pathogenetic mechanisms and treatment.

Diabetic peripheral neuropathy (DPN) refers to the development of peripheral nerve dysfunction in patients with diabetes when other causes are excluded. Diabetic distal symmetric polyneuropathy (DSPN) is the most representative form of DPN. As one of the most common complications of diabetes, its prevalence increases with the duration of diabetes. 10-15% of newly diagnosed T2DM patients have DSPN, and the prevalence can exceed 50% in patients with diabetes for more than 10 years. Bilateral limb pain, numbness, and paresthesia are the most common clinical manifestations in patients with DPN, and in severe cases, foot ulcers can occur, even leading to amputation. The etiology and pathogenesis of diabetic neuropathy are not yet completely clarified, but hyperglycemia, disorders of lipid metabolism, and abnormalities in insulin signaling pathways are currently considered to be the initiating factors for a range of pathophysiological changes in DPN. In the presence of abnormal metabolic factors, the normal structure and function of the entire peripheral nervous system are disrupted, including myelinated and unmyelinated nerve axons, perikaryon, neurovascular, and glial cells. In addition, abnormalities in the insulin signaling pathway will inhibit neural axon repair and promote apoptosis of damaged cells. Here, we will discuss recent advances in the study of DPN mechanisms, including oxidative stress pathways, mechanisms of microvascular damage, mechanisms of damage to insulin receptor signaling pathways, and other potential mechanisms associated with neuroinflammation, mitochondrial dysfunction, and cellular oxidative damage. Identifying the contributions from each pathway to neuropathy and the associations between them may help us to further explore more targeted screening and treatment interventions.

Multiple-day administration of fosaprepitant combined with tropisetron and olanzapine improves the prevention of nausea and vomiting in patients receiving chemotherapy prior to autologous hematopoietic stem cell transplant: a retrospective study.

Chemotherapy-induced nausea and vomiting (CINV) is common in patients with lymphoma and multiple myeloma (MM) receiving high-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT). Despite a standard triple antiemetic regimen of a neurokinin-1 (NK1) receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone is recommended, how to control the protracted CINV in ASCT setting remains an intractable problem. Here, we retrospectively analyze CINV data of 100 patients who received either SEAM (semustine, etoposide, cytarabine, melphalan) or MEL140-200 (high-dose melphalan) before ASCT, evaluate the efficacy and safety of multiple-day administration of fosaprepitant combined with tropisetron and olanzapine (FTO), and compare the results to those of patients who received a standard regimen of aprepitant, tropisetron, and dexamethasone (ATD). The overall rate of complete response (CR), defined as no emesis and no rescue therapy, is 70% in the FTO group compared to 36% in the ATD group. Although CR rates are comparable in the acute phase between the two groups, significantly more patients treated by FTO achieve CR in the delayed phase than those treated by ATD (74% vs. 38%, p < 0.001). Moreover, FTO treatment significantly reduced the percentage of patients who are unable to eat, as well as the requirement for rescue medications. Both regimens are well tolerated and most adverse events (AEs) were generally mild and transient. In conclusion, the antiemetic strategy containing multiple-day administration of fosaprepitant is safe and effective for preventing CINV in lymphoma and MM patients, particularly in the delayed phase.