Fluvoxamine prompts the antitumor immune effect via inhibiting the PD-L1 expression on mice-burdened colon tumor.

A colon tumor, one of the digestive tract malignant tumors, is harmful to human health. A potential new treatment still deserves attention. The development of a new drug needs more resources, including time and expense. Therefore, the old drug with new targets has become a current research hotspot. Fluvoxamine, as an antidepressant, could play an effect on inhibiting 5-hydroxytryptamine reuptake. In the present research, the antitumor effects and possible mechanisms of fluvoxamine are validated. The results showed that fluvoxamine significantly suppressed the migration and proliferation of tumor cells, and increased the apoptosis in vitro. Additionally, fluvoxamine significantly delays tumor development, and prompts the apoptosis in tumor tissues of mice-burdened colon tumors in vivo. The tumor suppression might be related with that fluvoxamine inhibits the expression of phosphorylated signal transducer and activator of transcription 3, matrix metalloproteinase 2, and cleaved-caspase 3. Importantly, fluvoxamine significantly reduces the expression level of programmed cell death ligand 1. This could be a possible reason that treatment with fluvoxamine drives the infiltration of T lymphocytes and M1-type macrophages in tumor tissues. Taken together, this research suggests that fluvoxamine might be a promising drug to treat colon cancer by inhibiting the proliferation and migration, inducing apoptosis, and even increasing the immune response of antitumor.

Targeted single-cell RNA sequencing analysis reveals metabolic reprogramming and the ferroptosis-resistant state in hematologic malignancies.

Hematologic malignancies are the most common hematopoietic diseases and a major public health concern. However, the mechanisms underlying myeloid tumors remain unknown owing to the intricate interplay between mutations and diverse clonal evolution patterns, as evidenced by the analysis of bulk cell-derived omics data. Several single-cell omics techniques have been used to characterize the hierarchies and altered immune microenvironments of hematologic malignancies. The comprehensive single-cell atlas of hematologic malignancies provides novel opportunities for personalized combinatorial targeted treatments, avoiding unwanted chemo-toxicity. In the present study, we performed transcriptome sequencing by combining single-cell RNA sequencing (scRNA-seq) with a targeted oncogenic gene panel for acute myeloid leukemia, overcoming the limitations of scRNA-seq in detecting oncogenic mutations. The distribution of oncogenic IDH1, IDH2, and KRAS mutations in each cell type was identified in the bone marrow (BM) samples of each patient. Our findings suggest that ferroptosis and metabolic reprogramming are involved in the tumorigenesis and chemotherapy resistance of oncogenic mutation-carrying cells. Biological progression via IDH1, IDH2, and KRAS mutations arrests hematopoietic maturation. Our study findings provide a rationale for using primary BM cells for personalized treatment in clinical settings.

Dexmedetomidine Attenuates Total Body Radiation-Induced Acute Liver Injury in Mice Through the Nrf2/HO-1 Pathway.

BACKGROUND: The purpose of this study was to investigate the protective effects of dexmedetomidine (DEX) on total body radiation-induced acute liver injury in mice and to explore the possible mechanisms. METHODS: A total of 40 mice were randomly divided into the Control group (Group C), Dexmedetomidine group (Group Dex), Radiation group (Group R), and Group R+Dex. Mice in Group Dex and Group R+Dex were intraperitoneally injected with 10 µg/mL Dex at 50 mg/kg. Both Group C and Group R received normal saline instead of Dex. Mice were treated via continuous administration for 10 days and injection once a day (pre-administration for 3 days and 7 days after radiation). One hour after administration on the third day, the mice in Group R and R+Dex received total body radiation with a total dose of 6 Gy at a rate of 2 Gy/min. Group C received sham radiation. Levels of aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), and liver levels of tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA) were measured. HE staining was employed to evaluate the pathological changes in liver tissues, and the expressions of Nrf2 and HO-1 proteins in the liver were measured by western blot. RESULTS: Compared with group C, serum levels of AST and ALT, liver TNF-α, IL-1ß, MDA, and ROS levels increased, and SOD decreased in Group R. Group R mice had higher liver injury scores, and the protein expressions of Nrf2 and HO-1 proteins were lower (p ＜ 0.05). Compared with Group R, the levels of AST, ALT, TNF-α, IL-1ß, MDA, and ROS decreased, SOD increased, liver injury scores were lower, and the expressions of Nrf2 and HO-1 proteins were higher in the Group R+Dex group (all p ＜ 0.05). CONCLUSIONS: Dex exhibits a protective effect on reducing acute radiation-induced liver injury and oxidative stress, and the mechanism may be associated with the activation of Nrf2/HO-1 pathways.

The Value of Stimulated Thyroglobulin Before the First Radioactive Iodine Treatment in Metastasis for Differentiated Thyroid Carcinoma.

BACKGROUND: To evaluate the value of preablative stimulated thyroglobulin (ps-Tg) before the first radioactive ablation iodine (RAI) treatment to predict the postoperative metastasis of DTC. METHODS: A total of 235 DTC patients, who underwent total thyroidectomy and neck lymph node dissection, were enrolled. On the basis of the presence or absence of metastasis, all patients were divided into metastasis (M1) and non-metastasis (M0) groups. Besides, the patients in the M1 group were further divided into two subgroups according to sites of metastasis. These groups included cervical lymph node metastasis and distant metastasis groups. Subsequently, the level of serum ps-Tg was measured 3 - 4 days before the first RAI ablation treatment, whereas 131I whole-body imaging and SPECT/CT tomography were performed 5 - 7 days after radio ablation. Subsequently, the Mann Whitney U test was used to compare the different levels of ps-Tg between the two groups. Additionally, the relationship between ps-Tg and the metastasis of DTC was analyzed through correlation analysis, regression analysis, and the ROC curve. RESULTS: The ps-Tg level in the M1 group was higher than that in the M0 group. Further analysis discovered that the ps-Tg in the distant metastasis group was higher than that in the cervical lymph node metastasis and non-metastasis groups. Also, the ps-Tg level was positively correlated with distant metastasis (r = 0.599, p = 0.000). Besides, the results of multivariate logistic regression analysis outlined that the level of ps-Tg was an independent risk factor for the development of distant metastasis (OR = 1.008, p = 0.018). Subsequently, the results from the ROC analysis also showed a good diagnostic performance for ps-Tg in treating distant metastasis (AUC = 0.964, p = 0.000), and the optimal cutoff value was 61.87 ng/mL. CONCLUSIONS: The ps-Tg in patients with DTC before the first RAI ablation treatment is an independent risk factor and a meaningful indicator in predicting postoperative distant metastasis.

Clinical characteristics and treatment outcome of type I cryoglobulinemia in Chinese patients: a single-center study of 45 patients.

To explore the clinical characteristics and outcomes in Chinese patients with type I cryoglobulinemia (CG), we retrospectively analyzed the clinical data, management, and outcomes of 45 patients diagnosed with type I CG in our hospital from January 2015 to March 2019. In our study, all type I CGs were secondary to hematologic diseases, and monoclonal gammopathy of unknown significance was the most common primary disease, accounting for 48.9% (n = 22). Additionally, B cell non-Hodgkin lymphoma, Waldenström's macroglobulinemia, and multiple myeloma accounted for 24.4% (n = 11), 20.0% (n = 9), and 6.7% (n = 3), respectively. In patients with type I CG, skin damage was the most common symptom, presenting in 57.8% of the patients, followed by peripheral neuropathy (22.2%) and renal involvement (15.6%). Treatment was initiated in 29 patients (64.4%), and the most common choice was a rituximab-based regimen in 13 patients (44.8%), followed by bortezomib-based regimen in 11 patients (37.9%). Clinical symptoms were significantly improved after treatment, and the clinical remission rate was 86.2%, including 34.5% of complete clinical remission, while the laboratory response rate was 88.9%, including 33.3% of complete response and 55.6% of partial response. The expected 1-year overall survival was 97.8%. In conclusion, for patients with multisystemic involvement, such as skin damage, kidney damage, or peripheral neuropathy, the diagnosis of type I CG should be considered, and the underlying disease needs to be explored. Symptoms and primary diseases should be taken into consideration before choosing initial management.

Research on the Application Value of Serum and Urine ß2-Microglobulin in Immunoglobulin a Nephropathy.

BACKGROUND: To compare the application value of serum and urinary ß2-microglobulin in immunoglobulin A nephropathy (IgAN). METHODS: Two hundred thirteen patients were hospitalized at the First Affiliated Hospital of Bengbu Medical College in China because of physical abnormalities and diagnosed with IgAN by means of renal biopsy between January 2010 and December 2018. ß2-MG levels in serum and urine were detected through immunoturbidimetric methods. The renal histopathology was quantified according to Katafuchi semi-quantitative standards and Lee's grading. RESULTS: One hundred twenty-four patients were male and 89 cases were female, for a 1.39:1 male to female ratio. The average age was 38.25 ± 12.48 years old when patients received their first renal biopsy. The levels of serum ß2-MG and urine ß2-MG increased gradually with the aggravation of tubulointerstitial lesions. Results of correlation analysis showed that serum ß2-MG had higher application value. Serum ß2-MG levels were positively correlated with SCr and tubulointerstitial lesions (r = 0.840, 0.652, p = 0.000), negatively correlated with CG-eGFR (r = -0.680, p = 0.000). The results of multivariate logistic regression analysis showed that serum ß2-MG was a marker of independent risk factor for the score of tubulointerstitial lesions ≥ 3 (OR = 6.649, p = 0.000). ROC analysis showed better diagnostic performance for serum ß2-MG, with the optimal cutoffs in predicting tubulointerstitial score ≥ 1, score ≥ 4 and score ≥ 7 of 1.905 mg/L, 2.13 mg/L, and 4.49 mg/L, respectively. CONCLUSIONS: Serum ß2-MG is valuable in evaluating renal function and pathological lesions in IgAN patients and has significant predictive value in evaluating tubulointerstitial lesions. Serum ß2-MG may be used as a non-invasive diagnostic indicator for predicting renal function and tubulointerstitial lesions in IgAN.

Outcome of Cardiac Light-Chain Amyloidosis in the Era of Novel Therapy　- A Single-Center Cohort Study of 227 Patients.

BACKGROUND: Cardiac involvement occurs in more than half of the patients with light-chain amyloidosis (AL), but the characteristics, treatment and prognosis of cardiac AL (CAL) are not fully described. Methods and Results: A total of 227 patients with CAL diagnosis between January 2009 and March 2017 at Peking Union Medical College Hospital were included. Patients with Mayo stages I, II and III AL accounted for 0.9%, 49.8% and 49.3%, respectively. Autologous stem cell transplantation, bortezomib combinations, non-bortezomib regimens and palliative treatment were given as first line therapy in 3.1%, 44.1%, 30.8% and 22.0% of patients, respectively. Overall hematological response and cardiac response were achieved in 60.6% and 37.2% of evaluable patients, respectively. The median overall survival (OS) was 17 months in all patients, and 10 months in those with Mayo stage III. In patients with Mayo stage III disease who survived for >1 month, the bortezomib group survived significantly longer than the non-bortezomib group (median OS, not reached vs. 12 months, P=0.019). Three independent prognostic factors for survival were identified: N-terminal fragment of B-type natriuretic peptide (NT-proBNP) ≥5,000 pg/mL, bone marrow plasma cells ≥10%, and systolic blood pressure <100 mmHg. CONCLUSIONS: CAL patients had poor prognosis, but those treated with bortezomib combinations had a better outcome than the non-bortezomib group.

The Value of Serum IgA in the Diagnosis, Clinical and Pathological Evaluation of Patients with IgA Nephropathy Found During Physical Examination in China.

BACKGROUND: The goal was to study the role of serum IgA in patients with IgA nephropathy (IgAN) found during physical examination, and to explore its value in diagnosis, assessment of pathological injury, and clinical prediction of IgAN. METHODS: The study included 457 patients who were hospitalized between January 2010 and June 2018 due to physical abnormalities and diagnosed with kidney disease via renal biopsy. Renal histopathology was quantified according to Katafuchi semi-quantitative standards, while the IgAN patients were also scored according to Lee's grading system. RESULTS: The average age of the 457 patients was 39.62 ± 13.52 years when abnormalities were found during physical examination. IgAN (202 cases, 46.12%) was the most common type of primary glomerulonephritis in the 457 patients. Of the IgAN patients, 75.25% (152 cases) were under 45 years old at the time of abnormal physical examination and IgAN patients were significantly younger than non-IgAN patients. There was a significant difference in the gender ratio between IgAN patients and non-IgAN patients (χ2 = 4.24, p = 0.039). In IgAN patients, the proportion of male patients, serum creatinine (SCr), the glomerular lesion and tubulointerstitial scores, and serum IgA were statistically higher than in non-IgAN patients with other types of primary glomerulonephritis; however, MDRD-GFR was lower. The ROC curve of serum IgA in the diagnosis of IgAN showed the AUC was 0.602. One hundred forty-seven cases (72.77%) were Lee's III - V grade. The proportion of patients who were at Lee's III - V grades in the normal serum IgA group (184 cases) was higher than that of the elevated serum IgA group (18 cases). There were no significant differences in gross hematuria, proteinuria, MDRD-GFR, SCr, and hypertension between the two groups. CONCLUSIONS: Serum IgA may be of little value in the diagnosis of patients with IgA nephropathy detected via physical examination. The level of serum IgA may have predictive value in evaluating Lee's pathological damage in IgAN patients.

Clinical presentation and prognosis of light-chain amyloidosis patients with unmeasurable free light-chain levels.

To summarize distinct clinical characteristics and prognoses associated with and validate the novel hematologic response criteria in Chinese light-chain amyloidosis patients with a difference between involved and uninvolved free light chain (dFLC) < 50 mg/L. We retrospectively compared clinical features and outcomes between patients in the dFLC < 50 mg/L group (n = 74) and the ≥ 50 mg/L group (n = 248). Patients with dFLC < 50 mg/L presented less frequent and less severe cardiac involvement, but higher renal involvement. Additionally, more patients in the dFLC < 50 mg/L group showed intact immunoglobulin monoclonal protein and high immunoglobulin monoclonal protein levels. Moreover, patients in the dFLC < 50 mg/L group had significantly superior progression-free survival (PFS; not reached vs. 16.0 months; p < 0.001) and overall survival (OS; not reached vs. 41.0 months; p < 0.001) as compared with those in the dFLC ≥ 50 mg/L group. Furthermore, we confirmed that achieving complete response (CR) or low dFLC partial response (PR) predicted better OS in patients with initial dFLC ≥ 20 mg/L (not reached vs. 19 months; p = 0.005). Patients with initial dFLC < 50 mg/L represented distinct clinical manifestations and outcomes. Achieving CR or low dFLC PR might represent potential therapy goals allowing better survival and organ response in patients with dFLC between 20 and 50 mg/L.

Detection of MYD88 L265P and WHIM-like CXCR4 mutation in patients with IgM monoclonal gammopathy related disease.

A broad spectrum of diseases are associated with IgM monoclonal gammopathy, including Waldenstrom macroglobulinemia (WM), various types of B cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), primary amyloidosis (AL), and monoclonal gammopathy of undetermined significance (MGUS); these are called IgM monoclonal gammopathy related diseases (IgM-RD). We investigated MYD88 L265P and WHIM-like CXCR4 mutations in various IgM-RD. Patients with serum immunofixation electrophoresis confirmed IgM monoclonal gammopathy who had enough material for DNA extraction and presented between January 2008 and October 2016 at Peking Union Medical College Hospital were enrolled in this cohort. We performed real-time allele-specific-polymerase chain reaction and Sanger sequencing to explore the presence of MYD88 L265P and WHIM-like CXCR4 mutations. One hundred and twelve patients (64 male and 48 female patients) were included in this retrospective study. The median age at diagnosis was 62 years (range, 30-84 years). In total, 64 patients (57.1%) carried the MYD88 L265P mutation and 14 patients (12.5%) carried the CXCR4 WHIM-like mutation. We identified the MYD88 L265P somatic variant in cases with WM (39/42), MGUS (8/18), NHL (14/41, including 4/13 diffuse large B cell lymphoma (DLBCL), 1/8 mucosa-associated lymphoid tissue, 3/6 splenic marginal zone lymphoma (SMZL), 1/4 chronic lymphocytic leukemia, 2/3 nodal marginal zone lymphoma (NMZL), 1/2 mantle cell lymphoma, 1 Burkitt lymphoma, and 1 B cell NHL that could not be classified), primary AL (2/2), and IgM-PN (1/1). The mutation was absent in five patients with Cryoglobulinemia, two with primary cold agglutinin disease and one with MM. The CXCR4 WHIM-like mutation was present in 10/42 patients with WM, 3/41 with NHL (1 DLBCL, 1 SMZL, and 1 NMZL), and 1/18 patients with IgM MGUS. Among the patients with NHL, those with the mutated MYD88 L265P genotype were younger and had lower level of IgG and IgA than the patients with the wild-type genotype. Patients with the mutated MYD88 L265P genotype with WM and MZL were compared. More male patients, higher levels of IgM and lower levels of LDH were found in the WM group. There was no significant difference in overall survival between the two groups. We present a study of the prevalence of the MYD88 L265P mutation and CXCR4 WHIM-like mutation in IgM RD. The MYD88 L265P mutation may play a key role in the pathogenesis of IgM monoclonal gammopathies. It would be interesting in the future to use MYD88 mutation status to differentiate among diseases.

At least partial hematological response after first cycle of treatment predicts organ response and long-term survival for patients with AL amyloidosis receiving bortezomib-based treatment.

AL amyloidosis is a rare plasma cell dyscrasia characterized by multi-organ involvement and poor prognosis. We retrospectively evaluated the organ response (OR) and long-term survival of newly diagnosed AL amyloidosis patients who received first-line bortezomib-containing induction therapy, aiming to identify the clinical indication of a 50% reduction in the difference between involved and uninvolved free light chains (dFLC) after first cycle of treatment. Among the 89 patients included, 78.7% had cardiac involvement and 42.7% were diagnosed with 2004 Mayo stage III disease, while 75.3% of patients achieved a hematological response, including 37.1% with complete response and a median response time of 1 month. Cardiac and renal responses were observed in 44.3 and 53.1% of patients, respectively. Sixty-one (68.5%) patients achieved at least 50% reduction in dFLC after the first cycle of therapy. After a median follow-up duration of 12 months, the estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 61.3 and 61.7% respectively. At least 50% reduction in dFLC after the first cycle of therapy was predictive of achieving an OR (p = 0.002), as well as superior PFS (HR = 0.119; 95% CI = 0.045-0.313; p < 0.001) and OS (HR = 0.206; 95% CI = 0.078-0.541; p = 0.001). Additionally, the median PFS and OS were not reached for patients with rapid reduction of dFLC. These results demonstrated that early reduction of dFLC after the first cycle of treatment is predictive of achieving an OR and long-term survival in AL patients receiving bortezomib.

Selection of Biopsy Site for Patients with Systematic Amyloidosis.

Objective To evaluate the sensitivities of various biopsy methods for the diagnosis of systematic amyloidosis (SA). Methods The clinical data and biopsy results of 194 SA patients who were treated in Peking Union Medical College Hospital from January 2009 to June 2015 were retrospectively analyzed. Results The highest sensitivity was achieved by biopsy of affected organs,with renal biopsy 97.4%,heart biopsy 95.0% and liver biopsy 87.5%. Among non-invasive biopsy methods,tongue biopsy was found to be 75% sensitive,followed by gingiva biopsy at 57%,abdominal fat pad aspiration at 57%,rectum biopsy at 16%,and bone marrow examination at 8%. Combination of tongue and abdominal fat pad biopsy yielded a detection rate of 93.1%. Conclusions Biopsy of the involved organ has the highest sensitivity. However,combination of multiple non-invasive biopsy methods may has sensitivity comparable to organ biopsy and is safer and more convenient.

Impact factors of benefiting from initial 131 I ablation in patients with intermediate-risk differentiated thyroid carcinoma: a study based on a re-evaluation of therapeutic response.

OBJECTIVE: This study was carried out to confirm whether patients with intermediate-risk differentiated thyroid cancer (DTC) could benefit from initial 131 I ablation and to identify the factors that impacted the benefit. METHODS: We retrospectively assessed a cohort of 548 patients with intermediate-risk DTC who were classified into structural incomplete response (SIR), biochemical incomplete response (BIR), indeterminate response (IDR), and excellent response (ER) groups according to the ATA guidelines (version 2015). A downgrade in the classification, such as from initial SIR to final BIR, IDR, or ER, from BIR to IDR or ER, and from initial IDR to final ER, was defined as benefiting from initial 131 I ablation (benefit group). Non-downgraded classification meant non-benefit. RESULTS: 64.78% of patients benefited from the initial 131 I ablation in the final re-evaluation. Gender (OR = 0.038, P  = 0.002), interval time (OR = 0.038, P  = 0.002) and serum ps-Tg (OR = 0.961, P  = 0.001) were independent prognostic factors for benefiting from initial 131 I ablation, with the cutoff value were 5 months and 19.08 ng/ml. CONCLUSION: Patients with intermediate-risk DTC could benefit from initial 131 I ablation. Female patients with intermediate-risk DTC whose interval time <5 months and ps-Tg <19.08 ng/ml were more likely to benefit. Early 131 I ablation for such patients is beneficial for achieving a complete therapeutic response.

Predicting the Risk of Postoperative Delirium in Elderly Patients Undergoing Hip Arthroplasty: Development and Assessment of a Novel Nomogram.

OBJECTIVE: To construct and internally validate a nomogram that predicts the likelihood of postoperative delirium in a cohort of elderly individuals undergoing hip arthroplasty. METHODS: Data for a total of 681 elderly patients underwent hip arthroplasty were retrospectively collected and divided into a model (n = 477) and a validation cohort (n = 204) according to the principle of 7:3 distribution temporally. The assessment of postoperative cognitive function was conducted through the utilization of The Confusion Assessment Method (CAM). The nomogram model for postoperative cognitive impairments was established by a combination of Lasso regression and logistic regression. The receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis (DCA) were used to evaluate the performance. RESULTS: The nomogram utilized various predictors, including age, body mass index (BMI), education, preoperative Barthel Index, preoperative hemoglobin level, history of diabetes, and history of cerebrovascular disease, to forecast the likelihood of postoperative delirium in patients. The area under the ROC curves (AUC) for the nomogram, incorporating the aforementioned predictors, was 0.836 (95% CI: 0.797-0.875) for the training set and 0.817 (95% CI: 0.755-0.880) for the validation set. The calibration curves for both sets indicated a good agreement between the nomogram's predictions and the actual probabilities. CONCLUSION: The use of this novel nomogram can help clinicians predict the likelihood of delirium after hip arthroplasty in elderly patients and help prevent and manage it in advance.

Dexmedetomidine mitigates acute kidney injury after coronary artery bypass grafting: a prospective clinical trial.

INTRODUCTION AND OBJECTIVES: To evaluate the impact of dexmedetomidine impact on cardiac surgery-associated acute kidney injury (CSA-AKI), kidney function, and metabolic and oxidative stress in patients undergoing coronary artery bypass grafting with heart-lung machine support. METHODS: A randomized double-masked trial with 238 participants (50-75 years) undergoing coronary artery bypass grafting was conducted from January 2021 to December 2022. The participants were divided into Dex (n=119) and NS (n = 119) groups. Dex was administered at 0.5 mcg/kg over 10minutes, then 0.4 mcg/kg/h until the end of surgery; the NS group received equivalent saline. Blood and urine were sampled at various time points pre- and postsurgery. The primary outcome measure was the incidence of CSA-AKI, defined as the occurrence of AKI within 96hours after surgery. RESULTS: The incidence of CSA-AKI was significantly lower in the Dex group than in the NS group (18.26% vs 32.46%; P=.014). Substantial increases were found in estimated glomerular filtration rate value at T4-T6 (P<.05) and urine volume 24hours after surgery (P<.01). Marked decreases were found in serum creatinine level, blood glucose level at T1-T2 (P<.01), blood urea nitrogen level at T3-T6 (P<.01), free fatty acid level at T2-T3 (P<.01), and lactate level at T3-T4 (P<.01). CONCLUSIONS: Dex reduces CSA-AKI, potentially by regulating metabolic disorders and reducing oxidative stress.

Prognostic value of circulating plasma cells detected by flow cytometry in newly diagnosed multiple myeloma patients: a systematic review and meta-analysis.

OBJECTIVES: Multiple myeloma (MM) is a malignant plasma cell disorder. The most widely accepted staging system for MM is the revised International Staging System based on cytogenetic and clinical biomarkers. The circulating clonal plasma cells (CPCs) were reported to have potential prognostic impact on MM. Among various diagnostic approaches, multiparametric flow cytometry (FCM) offers heightened sensitivity, minimal invasiveness and reproducibility. We conducted a meta-analysis to evaluate the prognostic value of quantifying CPCs via FCM in newly diagnosed symptomatic MM (NDMM) patients. DESIGN: Systematic review and meta-analysis. DATA SOURCE: PubMed, Web of Science, Embase and references of included studies. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included observational studies that evaluated the prognostic value of CPCs detected by FCM in NDMM. DATA EXTRACTION AND SYNTHESIS: Data were screened and extracted independently by two investigators. The pooled results originated from random effects models. The primary endpoint was overall survival (OS). The secondary endpoint was progression-free survival (PFS). To evaluate the prognostic value of CPCs in NDMM, HRs and their 95% CI for both OS and PFS were derived using COX multivariable models. These values were then used to compute the pooled estimated effect. RESULTS: Our meta-analysis encompassed a total of 2704 NDMM patients from 11 studies up to 27 August 2022. The pooled HR for OS and PFS in CPC-positive (CPCs+) group and CPC-negative group were 1.95 (95% CI 1.24 to 3.07) and 2.07 (95% CI 1.79 to 2.39), respectively. The autologous stem cell transplantation (ASCT) failed to eliminate the adverse impact on OS and PFS. The heterogeneity may stem from the use of novel agents or traditional chemotherapy as initial treatment. CONCLUSION: This meta-analysis indicates CPCs+ had an adverse impact on the prognosis of NDMM patients in the total population, and the adverse impact could not be eliminated by ASCT. PROSPERO REGISTRATION NUMBER: CRD42021272381.

Nifuroxazide suppresses PD-L1 expression and enhances the efficacy of radiotherapy in hepatocellular carcinoma.

Radiation therapy is a primary treatment for hepatocellular carcinoma (HCC), but its effectiveness can be diminished by various factors. The over-expression of PD-L1 has been identified as a critical reason for radiotherapy resistance. Previous studies have demonstrated that nifuroxazide exerts antitumor activity by damaging the Stat3 pathway, but its efficacy against PD-L1 has remained unclear. In this study, we investigated whether nifuroxazide could enhance the efficacy of radiotherapy in HCC by reducing PD-L1 expression. Our results showed that nifuroxazide significantly increased the sensitivity of tumor cells to radiation therapy by inhibiting cell proliferation and migration while increasing apoptosis in vitro. Additionally, nifuroxazide attenuated the up-regulation of PD-L1 expression induced by irradiation, which may be associated with increased degradation of PD-L1 through the ubiquitination-proteasome pathway. Furthermore, nifuroxazide greatly enhanced the efficacy of radiation therapy in H22-bearing mice by inhibiting tumor growth, improving survival, boosting the activation of T lymphocytes, and decelerating the ratios of Treg cells in spleens. Importantly, nifuroxazide limited the increased expression of PD-L1 in tumor tissues induced by radiation therapy. This study confirms, for the first time, that nifuroxazide can augment PD-L1 degradation to improve the efficacy of radiation therapy in HCC-bearing mice.

Comparing Day 5 versus Day 6 euploid blastocyst in frozen embryo transfer and developing a predictive model for optimizing outcomes: a retrospective cohort study.

Background: Optimal protocols for frozen-thawed embryo transfer (FET) after preimplantation genetic testing (PGT) remain unclear. This study compared Day 5 (D5) and Day 6 (D6) blastocysts and evaluated predictors of FET success. Methods: A total of 870 patients with genetic diseases or chromosomal translocations who received PGT at the First Affiliated Hospital of Zhengzhou University from January 2015 to December 2019 were recruited. All patients underwent at least one year of follow-up. Patients were divided into groups according to the blastocyst development days and quality. Univariate and multivariate logistic regression were applied to identify risk factors that affect clinical outcomes and to construct a predictive nomogram model. Area under the curve (AUC) of the subject's operating characteristic curve and GiViTI calibration belt were conducted to determine the discrimination and fit of the model. Results: D5 blastocysts, especially high-quality D5, resulted in significantly higher clinical pregnancy (58.4% vs 49.2%) and live birth rates (52.5% vs 45%) compared to D6. Multivariate regression demonstrated the number of blastocysts, endometrial preparation protocol, days of embryonic development and the quality of blastocysts independently affected live birth rates (P<0.05). A nomogram integrating these factors indicated favorable predictive accuracy (AUC=0.598) and fit (GiViTI, P=0.192). Conclusions: Transferring high-quality D5 euploid blastocysts after PGT maximizes pregnancy outcomes. Blastocyst quality, blastocyst development days, endometrial preparation protocols, and number of blastocysts, independently predicted outcomes. An individualized predictive model integrating these factors displayed favorable accuracy for counseling patients and optimizing clinical management.

CLEC12A plays an important role in immunomodulatory function and prognostic significance of patients with acute myeloid leukemia.

The physiological function and prognostic significance of C-type lectin domain family 12 member A (CLEC12A) in acute myeloid leukemia (AML) patients are unclear. CLEC12A transcriptional expression in a variety of tumors from several public databases was collected and compared. We found that CLEC12A was highly expressed in AML cell lines and in tissues from AML patients and a higher CLEC12A expression in leukemia stem cells. CLEC12A low expression was associated with poor prognosis in the chemotherapy-only group and high CLEC12A expression may benefit from autologous or allogeneic hematopoietic stem cell transplantation (HSCT). CLEC12A expression was positively correlated with infiltrating levels of type 2 macrophages and monocytes and negatively associated with NK cells and regulatory T cells in AML. CLEC12A high was positively associated with immune checkpoint genes as well as macrophage associated genes. CLEC12A is an ideal chimeric antigen receptor T-cell (CAR-T) therapy target for AML and its expression level was closely linked to treatment response and patients' survival outcome. CLEC12A plays an important immunomodulatory role in AML.

Posttreatment dFLC less than 10 mg/L predicts superior organ response and longer time to next treatment in newly diagnosed light-chain amyloidosis patients treated with bortezomib.

Recently, a difference between involved and uninvolved free light chains (dFLC) less than 10 mg/L after treatment (stringent dFLC response) was reported to be associated with superior survival in light-chain (AL) amyloidosis. We conducted a retrospective study of AL amyloidosis patients treated with bortezomib to investigate the predictive value of a stringent dFLC response. Two hundred and thirty-five patients were included. The cardiac and renal responses were much higher in patients achieving a stringent dFLC response (86.5% versus 42.7% and 75.9% versus 38.2%, p < .001). Patients with a stringent dFLC response had significantly longer overall survival and time to next treatment (TNT). Among the very good partial response (VGPR) patients, the TNT of stringent dFLC responders was superior to those of the remaining VGPR patients (p = .045) and comparable to those of complete response patients. In conclusion, a stringent dFLC response might be added to current response criteria for AL amyloidosis.