Shared genetic factors and causal association between chronic hepatitis C infection and diffuse large B cell lymphoma.

BACKGROUND: Epidemiological research and systematic meta-analyses indicate a higher risk of B-cell lymphomas in patients with chronic hepatitis C virus (HCV) compared to non-infected individuals. However, the genetic links between HCV and these lymphomas remain under-researched. METHODS: Mendelian randomization analysis was employed to explore the association between chronic hepatitis C (CHC) and B-cell lymphomas as well as chronic lymphocytic leukemia (CLL). Approximate Bayes Factor (ABF) localization analysis was conducted to find shared genetic variants that might connect CHC with B-cell lymphomas and chronic lymphocytic leukemia (CLL). Furthermore, The Variant Effect Predictor (VEP) was utilized to annotate the functional effects of the identified genetic variants. RESULTS: Mendelian randomization revealed a significant association between CHC and increased diffuse large B cell lymphoma (DLBCL) risk (OR: 1.34; 95% CI: 1.01-1.78; P = 0.0397). Subsequent colocalization analysis pinpointed two noteworthy variants, rs17208853 (chr6:32408583) and rs482759 (chr6:32227240) between these two traits. The annotation of these variants through the VEP revealed their respective associations with the butyrophilin-like protein 2 (BTNL2) and notch receptor 4 (NOTCH4) genes, along with the long non-coding RNA (lncRNA) TSBP1-AS1. CONCLUSION: This research provides a refined genetic understanding of the CHC-DLBCL connection, opening avenues for targeted therapeutic research and intervention.

A review of type 3 Gaucher disease: unique neurological manifestations and advances in treatment.

Gaucher disease (GD) is a rare lysosomal storage disease that is caused by mutations in the GBA gene. It is classified into three main phenotypes according to the patient's clinical presentation. Of these, chronic neuronopathic GD (GD3) is characterized by progressive neurological damage. Understanding the unique neurological manifestations of GD3 has important diagnostic and therapeutic implications. Our article summarizes the neurological symptoms specific to GD3 and related therapeutic advances, and it highlights the relevance of the gene to clinical symptoms, so as to provide a reference for the diagnosis and treatment of GD3.

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.

White spot syndrome virus hijacks host PP2A-FOXO axes to promote its propagation.

Viruses have developed superior strategies to escape host defenses or exploit host components and enable their infection. The forkhead box transcription factor O family proteins (FOXOs) are reportedly utilized by human cytomegalovirus during their reactivation in mammals, but if FOXOs are exploited by viruses during their infection remains unclear. In the present study, we found that the FOXO of kuruma shrimp (Marsupenaeus japonicus) was hijacked by white spot syndrome virus (WSSV) during infection. Mechanistically, the expression of leucine carboxyl methyl transferase 1 (LCMT1) was up-regulated during the early stages of WSSV infection, which activated the protein phosphatase 2A (PP2A) by methylation, leading to dephosphorylation of FOXO and translocation into the nucleus. The FOXO directly promoted transcription of the immediate early gene, wsv079 of WSSV, which functioned as a transcriptional activator to initiate the expression of viral early and late genes. Thus, WSSV utilized the host LCMT1-PP2A-FOXO axis to promote its replication during the early infection stage. We also found that, during the late stages of WSSV infection, the envelope protein of WSSV (VP26) promoted PP2A activity by directly binding to FOXO and the regulatory subunit of PP2A (B55), which further facilitated FOXO dephosphorylation and WSSV replication via the VP26-PP2A-FOXO axis in shrimp. Overall, this study reveals novel viral strategies by which WSSV hijacks host LCMT1-PP2A-FOXO or VP26-PP2A-FOXO axes to promote its propagation, and provides clinical targets for WSSV control in shrimp aquaculture.

Enhanced recovery after surgery in patients after hip and knee arthroplasty: a systematic review and meta-analysis.

PURPOSE: Enhanced recovery after surgery (ERAS) was characterized as patient-centered, evidence-based, multidisciplinary team-developed routes for a surgical speciality and institution to improve postoperative recovery and attenuate the surgical stress response. However, evidence of their effectiveness in osteoarthroplasty remains sparse. This study aimed to develop an ERAS standard and evaluate the significance of ERAS interventions for postoperative outcomes after primary total hip arthroplasty (THA) or total knee arthroplasty (TKA). METHODS: We searched Medline, Embase, Cochrane databases, and Clinicaltrials.gov for randomized controlled trials, cohort studies, and case-control studies until 24 February 2023. All relevant data were collected from studies meeting the inclusion criteria. Two reviewers independently assessed the risk of bias and extracted data. The primary outcome was the length of stay (LOS), postoperative complications, and readmission rate. The secondary outcomes included transfusion rate, mortality rate, visual analog score (VAS), the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), Short Form 36 (SF-36) bodily pain (SF-36 BP), SF-36 physical function (SF-36 PF), oxford knee score, and range of motion (ROM). RESULTS: A total of 47 studies involving 76 971 patients (ERAS group: 29 702, control group: 47 269) met the inclusion criteria and were included in the meta-analysis. The result showed that ERAS could significantly shorten the LOS (WMD = -2.65, P < .001), reduce transfusion rate (OR = 0.40, P < .001), and lower 30-day postoperative mortality (OR = 0.46, P = .01) without increasing postoperative complications or readmission rate. Apart from that, ERAS may decrease patients' VAS (WMD = -0.88, P = .01) while improving their ROM (WMD = 6.65, P = .004), SF-36 BP (WMD = 4.49, P < .001), and SF-36 PF (WMD = 3.64, P < .001) scores. However, there was no significant difference in WOMAC, oxford knee score between the ERAS and control groups.Furthermore, we determined that the following seven components of the ERAS program are highly advised: avoid bowel preparation, PONV prophylaxis, standardized anesthesia, use of local anesthetics for infiltration analgesia and nerve blocks, tranexamic acid, prevent hypothermia, and early mobilization. CONCLUSION: Our meta-analysis suggested that the ERAS could significantly shorten the LOS, reduce transfusion rate, and lower 30-day postoperative mortality without increasing postoperative complications or readmission rate after THA and TKA. Meanwhile, ERAS could decrease the VAS of patients while improving their ROM, SF-36 BP, and SF-36 PF scores. Finally, we expect future studies to utilize the seven ERAS elements proposed in our meta-analysis to prevent increased readmission rate for patients with THA or TKA.

Towards Optical Information Recording: A Robust Visible-Light-Driven Molecular Photoswitch with the Ring-Closure Reaction Yield Exceeding 96.3 .

Diarylethene molecular photoswitches hold great fascination as optical information materials due to their unique bistability and exceptional reversible photoswitching properties. Conventional diarylethenes, however, rely on UV light for ring-closure reactions, typically with modest yields. For practical application, diarylethenes driven by visible lights are preferred but achieving high ring-closure reaction yield remains a significant challenge. Herein, we synthesized a novel all-visible-light-driven photoswitch, TPAP-DTE, by facilely endcapping the dithienylethene (DTE) core with triphenylamine phenyl (TPAP) groups. Owing to the electron-donating conjugation effect of TPAP, the open-form TPAP-DTE responds strongly to short-wavelength visible lights with considerable photocyclization quantum yields and molar absorption coefficient. Upon 405 nm visible-light irradiation, TPAP-DTE achieves a ring-closure reaction yield exceeding 96.3 % (confirmed by both nuclear magnetic resonance spectroscopy and high-performance liquid chromatography). Its ring-opening reaction yield is 100 % upon irradiation with long-wavelength visible light. TPAP-DTE could be regarded as a bidirectional "quasi"-quantitative conversion molecular switch. Furthermore, TPAP-DTE exhibits robust fatigue resistance over 100 full photoswitching cycles and great anti-aging property under 85 °C and 85 % humidity for at least 1000 h. Consequently, its rewritable QR-code, multilevel data storage, and anti-counterfeiting/encryption applications are successfully demonstrated exclusively using visible lights, positioning TPAP-DTE as a highly promising medium for information recording.

Molecular mechanism and therapeutic potential of HDAC9 in intervertebral disc degeneration.

BACKGROUND: Intervertebral disc degeneration (IVDD) is the major cause of low-back pain. Histone deacetylase 9 (HDAC9) was dramatically decreased in the degenerative nucleus pulposus (NP) samples of patients with intervertebral disc degeneration (IVDD) according to bioinformatics analysis of Gene Expression Omnibus (GEO) GSE56081 dataset. This study aims to investigate the role of HDAC9 in IVDD progression. METHODS: The contribution of HDAC9 to the progression of IVDD was assessed using HDAC9 knockout (HDAC9KO) mice and NP-targeted HDAC9-overexpressing mice by IVD injection of adenovirus-mediated HDAC9 under a Col2a1 promoter. Magnetic resonance imaging (MRI) and histological analysis were used to examine the degeneration of IVD. NP cells were isolated from mice to investigate the effects of HDAC9 on apoptosis and viability. mRNA-seq and coimmunoprecipitation/mass spectrometry (co-IP/MS) analysis were used to analyze the HDAC9-regulated factors in the primary cultured NP cells. RESULTS: HDAC9 was statistically decreased in the NP tissues in aged mice. HDAC9KO mice spontaneously developed age-related IVDD compared with wild-type (HDAC9WT) mice. In addition, overexpression of HDAC9 in NP cells alleviated IVDD symptoms in a surgically-induced IVDD mouse model. In an in vitro assay, knockdown of HDAC9 inhibited cell viability and promoted cell apoptosis of NP cells, and HDAC9 overexpression had the opposite effects in NP cells isolated from HDAC9KO mice. Results of mRNA-seq and co-IP/MS analysis revealed the possible proteins and signaling pathways regulated by HDAC9 in NP cells. RUNX family transcription factor 3 (RUNX3) was screened out for further study, and RUNX3 was found to be deacetylated and stabilized by HDAC9. Knockdown of RUNX3 restored the effects of HDAC9 silencing on NP cells by inhibiting apoptosis and increasing viability. CONCLUSION: Our results suggest that HDAC9 plays an important role in the development and progression of IVDD. It might be required to protect NP cells against the loss of cell viability and apoptosis by inhibiting RUNX3 acetylation and expression during IVDD. Together, our findings suggest that HDAC9 may be a potential therapeutic target in IVDD.

Molecular mechanisms of ferroptosis and its roles in leukemia.

Cell death is a complex process required to maintain homeostasis and occurs when cells are damage or reach end of life. As research progresses, it is apparent that necrosis and apoptosis do not fully explain the whole phenomenon of cell death. Therefore, new death modalities such as autophagic cell death, and ferroptosis have been proposed. In recent years, ferroptosis, a new type of non-apoptotic cell death characterized by iron-dependent lipid peroxidation and reactive oxygen species (ROS) accumulation, has been receiving increasing attention. Ferroptosis can be involved in the pathological processes of many disorders, such as ischemia-reperfusion injury, nervous system diseases, and blood diseases. However, the specific mechanisms by which ferroptosis participates in the occurrence and development of leukemia still need to be more fully and deeply studied. In this review, we present the research progress on the mechanism of ferroptosis and its role in leukemia, to provide new theoretical basis and strategies for the diagnosis and treatment of clinical hematological diseases.

Causal relationships between circulating inflammatory cytokines and diffuse large B cell lymphoma: a bidirectional Mendelian randomization study.

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Studies indicated that inflammatory cytokines involved in the occurrence and progression of DLBCL and it is challenging to discern causality from the effects due to the presence of feedback loops. We conducted a bidirectional Mendelian randomization (MR) study to investigate the potential causal relationship between DLBCL and inflammatory cytokines. The genetic variants associated with inflammatory cytokines were obtained from a genome-wide association study (GWAS) involving 8293 European participants, and the data on 1010 individuals with DLBCL were sourced from the FinnGen consortium. The primary method employed in this study was the inverse-variance weighted (IVW) method, with supplementary analyses conducted using the MR-Egger, weighted median, and MR-PRESSO approaches. Based on the IVW method, genetically predicted that increasing level of Monokine induced by interferon gamma (MIG/CXC chemokine ligand 9, CXCL9) [OR: 1.31; 95% CI: 1.05-1.62; P = 0.01] and interferon gamma-induced protein 10(IP-10/CXC chemokine ligand 10, CXCL10) [OR: 1.30; 95% CI: 1.02-1.66; P = 0.03] showed suggestive associations with DLBCL risk. DLBCL may increase the level of macrophage colony-stimulating factor (M-CSF) [OR: 1.12; 95% CI: 1.01-1.2; P = 0.03], tumor necrosis factor beta (TNF-ß) [OR: 1.16; 95% CI: 1.02-1.31; P = 0.02] and TNF-related apoptosis-inducing ligand (TRAIL) [OR: 1.07; 95% CI: 1.01-1.13; P = 0.02]. This study presents evidence supporting a causal relationship between inflammation cytokines and DLBCL. Specifically, MIG/CXCL9 and IP-10/CXCL10 were identified as indicators of upstream causes of DLBCL; while, DLBCL itself was found to elevate the levels of M-CSF, TNF-ß, and TRAIL. These findings suggest that targeting specific inflammatory factors through regulation and intervention could serve as a potential approach for the treatment and prevention of DLBCL.

Extensive genetic diversity of severe fever with thrombocytopenia syndrome virus circulating in Hubei Province, China, 2018-2022.

Severe fever with thrombocytopenia syndrome virus (SFTSV), an etiological agent causing febrile human disease was identified as an emerging tick-borne bunyavirus. The clinical disease characteristics and case fatality rates of SFTSV may vary across distinct regions and among different variant genotypes. From 2018 to 2022, we surveyed and recruited 202 severe fever with thrombocytopenia syndrome (SFTS) patients in Hubei Province, a high-incidence area of the epidemic, and conducted timely and systematic research on the disease characteristics, SFTSV diversity, and the correlation between virus genome variation and clinical diseases. Our study identified at least 6 genotypes of SFTSV prevalent in Hubei Province based on the analysis of the S, M, and L genome sequences of 88 virus strains. Strikingly, the dominant genotype of SFTSV was found to change during the years, indicating a dynamic shift in viral genetic diversity in the region. Phylogenetic analysis revealed the genetic exchange of Hubei SFTSV strains was relatively frequent, including 3 reassortment strains and 8 recombination strains. Despite the limited sample size, SFTSV C1 genotype may be associated with higher mortality compared to the other four genotypes, and the serum amyloid A (SAA) level, an inflammatory biomarker, was significantly elevated in these patients. Overall, our data summarize the disease characteristics of SFTSV in Hubei Province, highlight the profound changes in viral genetic diversity, and indicate the need for in-depth monitoring and exploration of the relationship between viral mutations and disease severity.

Targeting HSP90 with picropodophyllin suppresses gastric cancer tumorigenesis by disrupting the association of HSP90 and AKT.

Gastric cancer (GC) is one of the most common malignant tumors worldwide. Thus, the development of safe and effective therapeutic compounds for GC treatment is urgently required. Here, we aimed to examine the role of picropodophyllin (PPP), a compound extracted from the rhizome of Dysosma versipellis (Hance) M. Cheng ex Ying, on the proliferation of GC cells. Our study revealed that PPP inhibits the proliferation of GC cells in a dose-dependent manner by inducing apoptosis. Moreover, our study elucidated that PPP suppresses the growth of GC tumor xenografts with no side effects of observable toxicity. Mechanistically, PPP exerts its effects by blocking the AKT/mammalian target of rapamycin (mTOR) signaling pathway; these effects are markedly abrogated by the overexpression of constitutively active AKT. Furthermore, drug affinity responsive target stability (DARTS) and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) revealed that heat shock protein 90 (HSP90) may be a potential target of PPP. Surface plasmon resonance and immunoprecipitation assay validated that PPP directly targets HSP90 and disrupts the binding of HSP90 to AKT, thereby suppressing GC cell proliferation. Thus, our study revealed that PPP may be a promising therapeutic compound for GC treatment.

Scavenger receptor B2, a type III membrane pattern recognition receptor, senses LPS and activates the IMD pathway in crustaceans.

The immune deficiency (IMD) pathway is critical for elevating host immunity in both insects and crustaceans. The IMD pathway activation in insects is mediated by peptidoglycan recognition proteins, which do not exist in crustaceans, suggesting a previously unidentified mechanism involved in crustacean IMD pathway activation. In this study, we identified a Marsupenaeus japonicus B class type III scavenger receptor, SRB2, as a receptor for activation of the IMD pathway. SRB2 is up-regulated upon bacterial challenge, while its depletion exacerbates bacterial proliferation and shrimp mortality via abolishing the expression of antimicrobial peptides. The extracellular domain of SRB2 recognizes bacterial lipopolysaccharide (LPS), while its C-terminal intracellular region containing a cryptic RHIM-like motif interacts with IMD, and activates the pathway by promoting nuclear translocation of RELISH. Overexpressing shrimp SRB2 in Drosophila melanogaster S2 cells potentiates LPS-induced IMD pathway activation and diptericin expression. These results unveil a previously unrecognized SRB2-IMD axis responsible for antimicrobial peptide induction and restriction of bacterial infection in crustaceans and provide evidence of biological diversity of IMD signaling in animals. A better understanding of the innate immunity of crustaceans will permit the optimization of prevention and treatment strategies against the arising shrimp diseases.

Analysis of genetic test results in 378 patients suspected of thalassaemia.

OBJECTIVE: To analyze the genetic test results of 378 patients suspected of thalassemia. METHODS: 378 suspected thalassemia patients in Shaoxing People's Hospital from 2014 to 2020 were selected and venous blood was tested using Gap-PCR and PCR-reversed dot blottin. The distribution of genotypes and other information of gene-positive patients was observed. RESULTS: Thalassemia genes were detected in 222 cases, with an overall detection rate of 58.7%, of which 41.4% were α deletion type, 1.35% were α dot, 52.7% were α thalassemia, and 4.5% were αß complex type. Among the 86 people with provincial household registration, the α-thalassemia gene accounted for 65.1% and the ß-thalassemia gene accounted for 25.6%. Follow-up found that Shaoxing nationality accounted for 53.1% of positive patients, of which ß-thalassemia gene accounted for 72.9% and α-thalassemia gene accounted for 25.4%; other cities in the province accounted for 8.1% of the total. Other provinces and cities accounted for 38.7%, most of which were from Guangxi and Guizhou. Among all positive patients, the most common α-thalassemia genotypes were --sea / αα, --α / αα,--α 3.7 4.2 / αα , --α3.7 / --sea. The most common mutations in ß-thalassemia were IVS-II-654, CD41-42, CD17 and CD14-15. CONCLUSION: The thalassemia gene carrier status was sporadically distributed outside the traditional thalassemia high prevalence areas. The local population in Shaoxing has a high detection rate of thalassemia genes, and the genetic composition is different from the traditional high prevalence area of thalassemia in the south.

Epidemiological Investigation of Pediatric Fractures-A Retrospective Cohort Study of 1129 Patients.

Background and Objectives: Fractures are common in pediatric trauma, and they are caused by a broad spectrum of factors. Only a few studies have discussed the mechanisms of injury and their relationships to different types of fractures. The most frequent type of fractures in different age groups remains unclear. Therefore, we aim to summarize the epidemiological characteristics of pediatric fractures in a medical center in Zhuhai, China from 2006 to 2021 and analyze the causes of fractures with the highest frequency in different age groups. Materials and Methods: We extracted the information from the Zhuhai Center for Maternal and Child Health Care of those under 14 years old who had fractures from 2006 to 2021. Results: We reviewed the information of 1145 children. The number of patients increased during the 15 years (p < 0.0001). The number of patients was significantly different between genders after Y2 (p = 0.014). In addition, more than two-thirds of patients (71.3%) had upper limb fractures, and all types of falls were the most common cause of fractures (83.6%). The incidence demonstrated an insignificant difference in age groups except for the fractures of humerus and radius. Moreover, we discovered that the prevalence of fall-related injuries decreased with age, while that of sports-related injuries increased with age. Conclusions: Our study demonstrates that the prevalence of fall-related injuries decreases with age, and that of sports-related injuries increases with age. Most patients have upper limb fractures, and all types of falls are the most common cause of fractures. Fracture types with the highest frequency differ in each age group. These findings might supplement current epidemiological knowledge of childhood fracture and provide references for decision-making in children's health policies.

The relation between radiographic manifestation and clinical characteristics of congenital radioulnar synostosis in children: A retrospective study from multiple centers.

Objective: To review the radiographic manifestation and clinical appearance of children with congenital radioulnar synostosis (CRUS) retrospectively. Study design: Retrospective cohort study of children with CRUS from multiple medical centers. Results: A total of 329 patients (male 259, female 70) with an average age of 5.4 years (0.5-16 years old), were included in this study. In particular, 145 patients (145/329, 44.1%) demonstrated bilateral involvement, and 184 patients (left 123, right 61) demonstrated unilateral involvement. As for Clear and Omery (C&O) classification, most patients belonged to Type III, and then followed by Type IV. As for Chinese Multi-center Pediatric Orthopedic Study Group (CMPOS) classification, most patients belonged to Type III, and then followed by Type II and Type I. In C&O Type III, 92.03% patients demonstrated severe pronation. According to CMPOS classification, 92.98% Type I patients demonstrated neutral to mild pronation, 72.17% Type II patients demonstrated moderate pronation, and 92.03% Type III patients demonstrated severe pronation. The age distribution showed no significant difference between C&O Type II and IV (P = 0.96); the pronation ankylosis severity showed no significant difference between C&O Type II and IV (P = 0.387). Conclusion: Although CRUS is a rare forearm deformity, there are certain relation between radiographic manifestation and clinical forearm functional restriction. CRUS patients of C&O or CMPOS Type III classification might suffer severe pronation deformity and warrant early intervention.

Gene Mutations and Targeted Therapies of Myeloid Sarcoma.

OPINION STATEMENT: Myeloid sarcoma, a rare malignant tumor characterized by the invasion of extramedullary tissue by immature myeloid cells, commonly occurs concomitantly with acute myeloid leukemia, myelodysplastic syndromes, or myeloproliferative neoplasms. The rarity of myeloid sarcoma poses challenges for diagnosis and treatment. Currently, treatments for myeloid sarcoma remain controversial and primarily follow protocols for acute myeloid leukemia, such as chemotherapy utilizing multi-agent regimens, in addition to radiation therapy and/or surgery. The advancements in next-generation sequencing technology have led to significant progress in the field of molecular genetics, resulting in the identification of both diagnostic and therapeutic targets. The application of targeted therapeutics, such as FMS-like tyrosine kinase 3(FLT3) inhibitors, isocitrate dehydrogenases(IDH) inhibitors, and the B cell lymphoma 2(BCL2) inhibitors, has facilitated the gradual transformation of traditional chemotherapy into targeted precision therapy for acute myeloid leukemia. However, the field of targeted therapy for myeloid sarcoma is relatively under-investigated and not well-described. In this review, we comprehensively summarize the molecular genetic characteristics of myeloid sarcoma and the current application of targeted therapeutics.

Adverse events of bevacizumab for triple negative breast cancer and HER-2 negative metastatic breast cancer: A meta-analysis.

Background: Triple-negative breast cancer (TNBC) and HER-2 negative metastatic breast cancer (HER-2 negative MBC) are intractable to various treatment schemes. Bevacizumab as a novel anti-VEGF drug, its safety for these two high-risk breast cancers remains controversial. Therefore, we conducted this meta-analysis to assess the safety of Bevacizumab for TNBC and HER-2 negative MBC. Methods: We searched Medline, Embase, Web of science and Cochrane databases updated to 1 Oct 2022 for relevant randomized controlled trials (RCTs). In all, 18 RCTs articles with 12,664 female patients were included. We used any grade Adverse Events (AEs) and grade ≥3 AEs to assess the AEs of Bevacizumab. Results: Our study demonstrated that the application of Bevacizumab was associated with increased incidence of grade ≥3 AEs (RR = 1.37, 95% CI 1.30-1.45, Rate: 52.59% vs. 41.32%). Any grade AEs (RR = 1.06, 95% CI 1.04-1.08, Rate: 64.55% vs. 70.59%) did not show a significant statistical difference in both overall results and among the subgroups. In subgroup analysis, HER-2 negative MBC (RR = 1.57, 95% CI 1.41-1.75, Rate: 39.49% vs. 25.6%), dosage over 15 mg/3w (RR = 1.44, 95% CI 1.07-1.92, Rate: 28.67% vs. 19.93%) and endocrine therapy (ET) (RR = 2.32, 95% CI 1.73-3.12, Rate: 31.17% vs. 13.42%) were associated with higher risk of grade ≥3 AEs. Of all graded ≥3 AEs, proteinuria (RR = 9.22, 95%CI 4.49-18.93, Rate: 4.22% vs. 0.38%), mucosal inflammation (RR = 8.12, 95%CI 2.46-26.77, Rate: 3.49% vs. 0.43%), palmar-plantar erythrodysesthesia syndrome (RR = 6.95, 95%CI 2.47-19.57, Rate: 6.01% vs. 0.87%), increased Alanine aminotransferase (ALT) (RR = 6.95, 95%CI 1.59-30.38, Rate: 3.13% vs. 0.24%) and hypertension (RR = 4.94, 95%CI 3.84-6.35, Rate: 9.44% vs. 2.02%) had the top five risk ratios. Conclusion: The addition of Bevacizumab for TNBC and HER-2 negative MBC patients showed an increased incidence of AEs especially for grade ≥3 AEs. The risk of developing different AEs varies mostly dependent on the type of breast cancer and combined therapy. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/#recordDetails], identifier [CRD42022354743].

Is abaloparatide more efficacious on increasing bone mineral density than teriparatide for women with postmenopausal osteoporosis? An updated meta-analysis.

PURPOSE: Osteoporosis poses a challenge to public health, causing fragility fractures, especially in postmenopausal women. Abaloparatide (ABL) is an effective anabolic agent to improve bone formation and resorption among postmenopausal women with osteoporosis. Our meta-analysis aims to assess the effectiveness and safety of ABL versus teriparatide (TPTD) in improving bone mineral density (BMD). METHODS: We searched Medline, Embase, Web of Science, Cochrane databases and Clinicaltrial.gov until September 2, 2022. We included data from randomized controlled trials (RCTs) and post hoc analyses of RCTs. Outcomes included BMD change from baseline and risks of adverse events. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tool was used to evaluate the quality of outcomes. RESULTS: Four studies including 16 subgroups were included in this study. In particular, RCTs with head-to-head comparisons of ABL and TPTD were used in the meta-analysis, and all were from manufacturer-sponsored trials. All parameters in 24 weeks except lumbar spine (versus TPTD) showed significant advantages in the ABL group. Only the results of two subgroups in ABL versus TPTD demonstrated High GRADE quality (femoral neck: weighted mean difference (WMD) = 1.58 [0.52, 2.63]; Total hip: WMD = 1.46 [0.59, 2.32]). However, our fracture data were insufficient. Besides, we found no evident difference in serious adverse events or deaths in either group and the incidence of hypercalcemia in the ABL group lessened by 51% compared with the TPTD group. Nevertheless, compared with placebo, ABL demonstrated higher risks of nausea and palpitations. CONCLUSION: ABL demonstrated a beneficial effect on BMD compared to both placebo and TPTD for postmenopausal women with osteoporosis. ABL also had insignificantly lowered adverse event risk than TPTD. ABL is an alternative for patients with postmenopausal osteoporosis.

A Combination of Ilizarov Frame, Externalized Locking Plate and Tibia Bridging for an Adult with Large Tibial Defect and Severe Varus Deformity Due to Chronic Osteomyelitis in Childhood: A Case Report.

Background: Various techniques have been reported to treat large, segmental tibial defects, such as autogenous bone graft, vascularized free fibula transfer and bone transport. We present a case of a 24-year-old male with a 17-year history of chronic osteomyelitis with obvious lower limb length discrepancy and severe varus deformity of the tibia secondary to osteomyelitis in childhood. Aim: The aim of this work is to provide an alternative choice for treating patients in developing countries with severe lower limb deformity caused by chronic osteomyelitis. Case Presentations: Without surgical intervention for a prolonged period of time, the patient was admitted in our institute for corrective surgery. Corrective surgery consisted of three stages: lengthening with Ilizarov frame, removal of Ilizarov frame and fixation with externalized locking plate, and removal of externalized locking plate. Tibia bridging was achieved at the distal and proximal junction. The range of motion (ROM) of the knee joint was nearly normal, but the stiffness of the ankle joint was noticeable. The remaining leg discrepancy of 0.1 cm required no application of a shoe lift. Moreover, the patient could engage in daily activities without noted limping. Conclusions: Distraction-compression osteogenesis using the Ilizarov apparatus is a powerful tool to lengthen the shortened long bone and adjust the deformity of the lower limbs. Externalized locking plates provide an alternative to the traditional bulky external fixator, as its low profile makes it more acceptable to patients without compromising axial and torsional stiffness. In all, a combination of Ilizarov frame, externalized locking plate and tibia bridging is an alternative for patients in similar conditions.

MALAT-1 regulates the AML progression by promoting the m6A modification of ZEB1.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) is abnormally upregulated in various human cancers. However, the role of MALAT-1 in acute myeloid leukemia (AML) remains unclear. This study investigated the expression and function of MALAT-1 in AML. MTT assay was used to determine cell viability, qRT-PCR was applied to determine the RNA levels. Western blot was performed to detect the protein expression. Flow cytometry was conducted to measure cell apoptosis. RNA pull-down assay was carried out to detect the interaction between MALAT-1 and METTL14. RNA FISH assay was performed to determine the localization of MALAT-1 and METTL14 in AML cells. Our results have revealed the key role of MEEL14 and m6A modification in AML. Besides, MALAT-1 was significantly up-regulated in AML patients. MALAT-1 knockdown inhibited the proliferation, migration and invasion of AML cells, and induced cell apoptosis; additionally, MALAT-1 binding to METTL14 promoted the m6A modification of ZEB1. Besides, ZEB1 overexpression partially reversed the effect of MALAT-1 knockdown on the cellular functions of AML cells. Taken together, MALAT-1 promoted the aggressiveness of AML through regulating m6A modification of ZEB1.