Early predictor for differentiation syndrome in newly diagnosed acute promyelocytic leukaemia patients treated with single-agent arsenic trioxide.

Differentiation syndrome (DS) is the second leading cause of death in acute promyelocytic leukaemia (APL) patients. Few studies have tested predictors of DS events. This study aimed to identify optimized predictors of DS events related to APL. The data of 298 consecutive patients who were newly diagnosed with APL between December 2012 and June 2023 were retrospectively investigated. A systematic review of computer-based patient medical records was conducted to obtain clinical data, including baseline characteristics, routine blood examination findings, biochemical indices and clinical manifestations of DS. Among the 298 patients, 158 were classified into the no-DS group, while 140 had DS. Compared with those of patients without DS, the peripheral blast count, age, and WBC count at each time point were significantly different in patients with DS (P < 0.05 for all time points). Generalized linear mixed models (GLMMs) revealed that WBC Double (Coeff. 0.442, P = 0.000) and WBCPeak (Coeff. 0.879, P = 0.000) were independent risk factors for DS. The frequencies of clinical manifestations of unexplained fever (P = 0.003), dyspnoea (P = 0.002), weight gain of more than 5 kg (P = 0.006), pleural effusion (P = 0.001), pulmonary infiltrates (P < 0.001), pericardial effusion (P = 0.002) and renal failure (P = 0.006) were considerably lower in moderate DS patients than in severe DS patients. The WBCDouble occurs earlier than the WBCpeak occurrence, so WBC Double might be a new indicator of DS.

OXPHOS-targeted nanoparticles for boosting photodynamic therapy against hypoxia tumor.

Hypoxia as an inherent feature in tumors is firmly associated with unsatisfactory clinical outcomes of photodynamic therapy (PDT) since the lack of oxygen leads to ineffective reactive oxygen species (ROS) productivity for tumor eradication. In this study, an oxidative phosphorylation (OXPHOS) targeting nanoplatform was fabricated to alleviate hypoxia and enhance the performance of PDT by encapsulating IR780 and OXPHOS inhibitor atovaquone (ATO) in triphenylphosphine (TPP) modified poly(ethylene glycol) methyl ether-block-poly(L-lactide-co-glycolide) (mPEG-PLGA) nanocarriers (TNPs/IA). ATO by interrupting the electron transfer in OXPHOS could suppress mitochondrial respiration of tumor cells, economising on oxygen for the generation of ROS. Benefiting from the mitochondrial targeting function of TPP, ATO was directly delivered to its site of action to obtain highlighted effect at a lower dosage. Furthermore, positioning the photosensitizer IR780 to mitochondria, a more vulnerable organelle to ROS, was a promising method to attenuate the spatiotemporal limitation of ROS caused by its short half-life and narrow diffusion radius. As a result, TNPs/IA exhibited accurate subcellular localization, lead to the collapse of ATP production by damaging mitochondrion and elicited significant antitumor efficacy via oxygen-augmented PDT in the HeLa subcutaneous xenograft model. Overall, TNPs/IA was a potential strategy in photodynamic eradication of tumors.

Exosomal circRNAs in the plasma serve as novel biomarkers for IPF diagnosis and progression prediction.

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a type of chronic interstitial pneumonia, often fatal, with elusive causes and a bleak prognosis. Its treatment options are limited and largely ineffective. Early detection and precise diagnosis are pivotal in managing the disease effectively and enhancing patient survival rates. Recently, the quest for trustworthy biomarkers for IPF has gained momentum. Notably, emerging studies indicate that circular RNAs (circRNAs) found in exosomes may hold significant potential as valuable diagnostic markers. METHODS: In this study, we initially explored the expression profile of circRNAs in exosomes sourced from the blood of IPF patients and healthy volunteers, employing a human circRNA microarray. We then utilized RT-qPCR to corroborate the dysregulated circRNAs identified by the microarray during the training phase. Next, the circRNAs that displayed a significant increase during the training phase were selected for further validation in a larger cohort encompassing 113 IPF patients and 76 healthy volunteers. Ultimately, the expression level and function of hsa_circ_0044226 were substantiated through a series of in vivo and in vitro experiments. RESULTS: Utilizing a human circRNA microarray, we identified 11 dysregulated circRNAs in the exosomes derived from the blood of IPF patients and control volunteers. Subsequent RT-qPCR analysis revealed significant increases in three circRNAs (hsa_circ_0044226, hsa_circ_0004099, hsa_circ_0008898) within the IPF patients. Notably, hsa_circ_0044226 was markedly elevated in patients experiencing acute exacerbation of IPF (AE-IPF) compared to those with stable IPF (S-IPF). Additionally, an upregulation of hsa_circ_0044226 was observed in the blood exosomes derived from a bleomycin-induced IPF mouse model. CONCLUSION: The expression levels of hsa_circ_0044226, hsa_circ_0004099, and hsa_circ_0008898 in plasma exosomes introduce a new paradigm of biomarkers for the diagnosis and progression of IPF.

Effect of high-dose intravenous methylprednisolone pulse (IVMP) therapy in the survival of patients with anti-melanoma differentiation-associated gene 5-related rapidly progressive interstitial lung disease: a retrospective analysis.

OBJECTIVES: To assess the impacts of high-dose intravenous methylprednisolone pulse (IVMP) therapy in survival and the occurrences of treatment-related infection of patients with anti-melanoma differentiation-associated gene 5 antibody-related rapidly progressive interstitial lung disease (MDA5-RPILD). METHODS: Patients with MDA5-RPILD from June 2017 to August 2022 in our hospital were retrospectively reviewed. IVMP therapy was defined as intravenous methylprednisolone (mPSL) 0.5g/day for 3 consecutive days during hospitalization or 7 days prior to admission and patients were divided into IVMP group and non-IVMP group based on who had ever received IVMP therapy. All-cause mortality and the incidence of adverse events during treatment were compared between the two groups. RESULTS: Sixty-four patients with MDA5-RPILD were enrolled. Among them, twenty-three (35.9%) patients had ever received IVMP therapy. The overall mortality was comparable between IVMP and non-IVMP group (IVMP group: 22/23, 95.7% vs. non-IVMP group: 38/41, 92.7%, p=0.11). And the incidence of treatment-related infections was also close (IVMP group: 21/23, 91.3% vs. non-IVMP group: 32/41, 78.0%, p=0.30). After adjustment for gender, age, smoking history, duration from symptom onset to diagnosis, and combination with steroid-sparing agent treatment, the Cox proportional hazards model showed that IVMP therapy was not associated with an improved survival (adjusted HR 1.10; 95% CI 0.57-2.13; p=0.77). CONCLUSION: Our study showed that the survival benefits and adverse events were comparable between IVMP-treated and untreated MDA5-RPILD patients. Future prospective trials are needed to investigate the optimal treatment regimen in MDA5-RPILD. Key Points • This observational study found that IVMP therapy may be not associated with an improved outcome in patients with MDA5-RPILD. • Treatment-related infections are common; however, the incidence of treatment-related infections had no difference between IVMP and non-IVMP group.

Correction: Li et al. Fabrication of Poly Dopamine@poly (Lactic Acid-Co-Glycolic Acid) Nanohybrids for Cancer Therapy via a Triple Collaboration Strategy. Nanomaterials 2023, 13, 1447.

The authors regret that, in the published article [...].

Associations between urbanization and the home language environment: Evidence from a LENA study in rural and peri-urban China.

In low- and middle-income countries, urbanization has spurred the expansion of peri-urban communities, or urban communities of formerly rural residents with low socioeconomic status. The growth of these communities offers researchers an opportunity to measure the associations between the level of urbanization and the home language environment (HLE) among otherwise similar populations. Data were collected in 2019 using Language Environment Analysis observational assessment technology from 158 peri-urban and rural households with Han Chinese children (92 males, 66 females) aged 18-24 months in China. Peri-urban children scored lower than rural children in measures of the HLE and language development. In both samples, child age, gender, maternal employment, and sibling number were positively correlated with the HLE, which was in turn correlated with language development.

ZLN005 improves the protective effect of mitochondrial function on alveolar epithelial cell aging by upregulating PGC-1α.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal pulmonary interstitial disease that usually occurs in the elderly. The senescence of alveolar epithelial cells (AECs) is an important mechanism of IPF. The AECs of patients with IPF have lower expression of peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α), which has been shown to play an important role in maintaining mitochondrial morphology and energy metabolism. This study sought to explore the mechanism by which ZLN005 improves mitochondrial function by upregulating PGC-1α to protect AECs from aging. Methods: Western blot was used to detect the expression of PGC-1α, mitochondrial synthesis protein nuclear respiratory factor-1 (NRF-1), and p21WAF1 in the lung tissue of the IPF patients and the mice with bleomycin (BLM)-induced pulmonary fibrosis. A549 cells and mice AEC2 cells were treated with hydrogen peroxide (H2O2) to construct cell senescence models. Cell senescence was detected by senescence-associated beta-galactosidase staining. The mitochondrial respiratory function was measured, including the adenosine triphosphate (ATP) generation, reactive oxygen species (ROS) level, changes in cell membrane potential, and energy metabolism. Using lentivirus as a vector and using gene editing technology to over express (upPGC-1α) and knockdown PGC-1α (shPGC-1α) in the A549 cells. The PGC-1α agonist ZLN005 was used to pretreat the A549 and shPGC-1α A549 cells, and cell aging and mitochondrial respiratory function were observed. Results: The Western blot and immunofluorescence assays showed that the expression of PGC-1α and NRF-1 was decreased in the lung tissues of the IPF patients and BLM-induced mice pulmonary fibrosis model, while the expression of p21WAF1 was increased. The results of the immunofluorescence and mitochondrial function experiments also indicated that the expression of PGC-1α and mitochondrial synthesis protein NRF-1 were decreased in the senescent cells. Further, the mitochondrial morphology was abnormal and the mitochondrial function was impaired. PGC-1α was involved in the AEC senescence by regulating mitochondrial morphology and function. Treatment with the agonist of PGC-1α (i.e., ZLN005) blocked the H2O2-induced cell senescence by enhancing the expression of PGC-1α. Conclusions: These results provide preliminary insights into the potential clinical application of ZLN005 as a novel therapeutic agent for the treatment of IPF.

[Effect of Circulating Plasma Cells on the Prognosis of Patients with Multiple Myeloma].

OBJECTIVE: to analyze the effect of circulating plasma cells(CPC) on the prognosis of patients with multiple myeloma(MM) in the era of new drugs, and to explore the new definition standard of primary plasma cell leukemia(pPCL). METHODS: The clinical data of 321 patients with newly diagnosed MM and 21 patients with pPCL admitted to our hospital from January 2014 to May 2022 were retrospectively analyzed. According to the proportion of CPC in peripheral blood smears, all patients were divided into 4 groups: CPC 0% group(211 cases), CPC 1%-4% group(69 cases), CPC 5%-19% group(41 cases) and CPC≥20% group(21 cases). The clinical features of patients in each group were compared and the prognosis fators was analyzed. RESULTS: The median OS of the four groups were 44.5,21.3,24.6 and 12.8 months, respectively. Among them, 295 patients(86.3%) were treated with new drugs, and the median OS of the four groups were not reached, 26.7, 24.6 and 14.9 months, respectively. As the survival curves of CPC 5%-19% group and CPC≥20% group were similar, the patients were divided into CPC<5% group and CPC≥5% group, the median OS of CPC<5% group was better than that in CPC≥5% (43.5 vs 22.3 months, P<0.001). In addition, the median OS of patients in the CPC 1%-4% group was also significantly lower than that in the CPC 0% group and similar to that in the CPC≥5% group. Multivariate analysis showed that 1%-4% CPC was an independent risk factor for the OS of patients with CPC<5%. The patients with CPC<5% were stratified by R-ISS staging, and the OS of R-ISS stage Ⅰ or stage Ⅱ with 1%-4% CPC was similar to that of R-ISS stage Ⅲ. The newly defined pPCL patients showed increased tumor load and obvious invasive characteristics. Multivariate analysis showed no independent prognostic factors for pPCL, and high-risk cytogenetic abnormalities(HRCA) had no significant effect on the prognosis. CONCLUSION: The validity of IMWG's new pPCL definition standard was verified, and it was found that the survival of MM with 1%-4% CPC also is poor and the prognosis is very close to pPCL. In addition, the newly defined pPCL has unique clinical and biological characteristics.

Periostin-targeted SDSSD peptide decorated calcium phosphate nanocomposites incorporation with simvastatin for osteoporosis treatment.

The limited options of anabolic drugs restrict their application potential in osteoporosis treatment, despite their theoretical superiority in therapeutic efficacy over antiresorptive drugs. As a prevailing strategy, nano-delivery systems could offer a wider choice of anabolic drugs. In this study, calcium phosphate nanocomposites incorporated with simvastatin (Sim) with periostin-targeting ability were designed and prepared for osteoporosis treatment. Carboxymethyl dextran (CMD) as an anionic and hydrophilic dextran derivative was used to stabilize CaP. In addition, periosteum-targeted peptide (SDSSD) was further grafted on CMD to achieve the bone targeting function. In a one-step coordination assembly strategy, hydrophobic anabolic agent Sim and SDSSD-CMD graft (SDSSD-CMD) were incorporated into the CaP nanoparticles forming SDSSD@CaP/Sim nanocomposites. The resulting SDSSD@CaP/Sim possesses uniform size, great short-term stability and excellent biocompatibility. Moreover, SDSSD@CaP/Sim exhibited a reduced release rate of Sim and showed slow-release behaviour. As anticipated, the nanocomposites exhibited bone bonding capacity in both cellular and animal studies. Besides, SDSSD@CaP/Sim achieved obviously enhanced osteoporosis treatment effect compared to direct injection of Simin vivo. Therefore, our findings highlight the potential of SDSSD-incorporated and CaP-based nanocomposites as a viable strategy to enhance the therapeutic efficacy of anabolic drugs for osteoporosis treatment.

[Correlation between D-Dimer/Fibrinogen Ratio and Bleeding in Patients with Newly Diagnosed Acute Promyelocytic Leukemia].

OBJECTIVE: To further explore the better indicators for predicting the degree of bleeding associated with newly diagnosed acute promyelocytic leukemia (APL). METHODS: A total of 131 patients with newly diagnosed APL were classified according to WHO bleeding scales before treatment and divided into two groups: scales 0, 1 and 2 were included in no severe bleeding group, scales 3 and 4 were included in severe bleeding group. The information of the patients were collected, including sex, age, hemoglobin (Hb), white blood cell (WBC) count and platelet (PLT) count, peripheral blood lymphocyte percentage (LYMPH%), peripheral blood monocyte percentage (MONO%), percentage of leukemic cells in pripheral blood and bone marrow, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB) levels, D-dimer (D-D), D-dimer/fibrinogen ratio (DFR). RESULTS: Among 131 patients, 110 were classified as no severe bleeding, and 21 were severe bleeding. The results of univariate analysis showed that patients with severe bleeding had significantly higher percentage of leukemic cells in pripheral blood, WBC, D-D, and DFR, as well as longer PT and lower LYMPH%, compared to those with no severe bleeding. Multivariate analysis revealed that DFR (OR =1.054, 95%CI : 1.024-1.084, P < 0.001) and percentage of peripheral blood leukemic cells (OR=1.026, 95%CI: 1.002-1.051, P =0.033) were independent risk factors for severe bleeding. The area under ROC curve (AUC) of peripheral blood leukemic cells, D-D and DFR were 0.748, 0.736 and 0.809, respectively. There was no statistical difference between the peripheral blood leukemic cells and D-D in diagnostic efficacy (P =0.8708). Compared with D-D, DFR had a higher predictive value (P =0.0302). The optimal cut-off value of DFR was 16.50, with a sensitivity of 90.5% and a specificity of 70.0%. CONCLUSION: DFR has a significant advantage in predicting the degree of bleeding associated with newly diagnosed APL. The greater the DFR value, the heavier the degree of bleeding. The risk of severe or fatal bleeding increases when DFR is greater than 16.50.

Diagnostic finding on high-resolution computed tomography (HRCT) predicts a good response to pirfenidone in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a debilitating condition, with a life expectancy of 2 to 5 years after diagnosis. Pirfenidone is a drug that has been shown to reduce the decline in forced vital capacity (FVC). We sought to identify whether different patterns on high-resolution computed tomography (HRCT) have different clinical effects through a retrospective comparison of baseline values and changes in pulmonary function tests (PFTs) after treatment with pirfenidone. We retrospectively analyzed data from IPF patients treated with pirfenidone at Nanjing Drum Tower Hospital in Jiangsu Province, China. According to the HRCT pattern, the patients were divided into usual interstitial pneumonitis (UIP) and possible UIP groups. Baseline clinical characteristics and changes every 6 months in the PFTs during the follow-up period were compared between the 2 groups. A total of 65 consecutive patients were enrolled. According to the HRCT pattern, patients were clustered into the UIP group (n = 46) and possible UIP group (n = 19). No difference was observed in the baseline PFTs ratio between the 2 groups. The FVC values of the 2 groups were not significantly different at the initial treatment and at 6 and 12 months after pirfenidone treatment (P = .081, 0.099, and 0.236, respectively). The improvement in % diffusion capacity of the lung for carbon monoxide (%DLCO) was higher in the possible UIP group after 6 and 12 months of pirfenidone treatment (P = .149, 0.026, and 0.025, respectively). The annual decrease in FVC was not significantly different between the 2 groups, and the annual decrease in %DLCO in the UIP group was significantly higher than that in patients with the possible UIP type (-7.767 ±â€…12.797 vs 0.342 ±â€…20.358, P < .05). These results indicate that patients with IPF with a possible UIP pattern on HRCT showed indications of a good response to pirfenidone.

Fabrication of Poly Dopamine@poly (Lactic Acid-Co-Glycolic Acid) Nanohybrids for Cancer Therapy via a Triple Collaboration Strategy.

Breast cancer is a common malignant tumor among women and has a higher risk of early recurrence, distant metastasis, and poor prognosis. Systemic chemotherapy is still the most widely used treatment for patients with breast cancer. However, unavoidable side effects and acquired resistance severely limit the efficacy of treatment. The multi-drug combination strategy has been identified as an effective tumor therapy pattern. In this investigation, we demonstrated a triple collaboration strategy of incorporating the chemotherapeutic drug doxorubicin (DOX) and anti-angiogenesis agent combretastatin A4 (CA4) into poly(lactic-co-glycolic acid) (PLGA)-based co-delivery nanohybrids (PLGA/DC NPs) via an improved double emulsion technology, and then a polydopamine (PDA) was modified on the PLGA/DC NPs' surface through the self-assembly method for photothermal therapy. In the drug-loaded PDA co-delivery nanohybrids (PDA@PLGA/DC NPs), DOX and CA4 synergistically induced tumor cell apoptosis by interfering with DNA replication and inhibiting tumor angiogenesis, respectively. The controlled release of DOX and CA4-loaded PDA@PLGA NPs in the tumor region was pH dependent and triggered by the hyperthermia generated via laser irradiation. Both in vitro and in vivo studies demonstrated that PDA@PLGA/DC NPs enhanced cytotoxicity under laser irradiation, and combined therapeutic effects were obtained when DOX, CA4, and PDA were integrated into a single nanoplatform. Taken together, the present study demonstrates a nanoplatform for combined DOX, CA4, and photothermal therapy, providing a potentially promising strategy for the synergistic treatment of breast cancer.

Soluble CD206 levels correlate with disease deterioration and predict prognosis of anti-MDA5 antibody-positive dermatomyositis related interstitial lung disease.

INTRODUCTION: The prognosis of anti-MDA5 antibody-positive dermatomyositis/clinically amyopathic dermatomyositis-associated interstitial lung disease (MDA5-DM/CADM-ILD) is poor. This study was to evaluate the effect of serum soluble CD206 (sCD206), a biomarker of macrophage activation, on predicting the interstitial lung disease (ILD) deterioration and prognosis for MDA5-DM/CADM-ILD. METHODS: Forty-one patients diagnosed with MDA5-DM/CADM-ILD were retrospectively included. The clinical data were analyzed. Serum sCD206 levels were measured in 41 patients and 30 healthy controls. The relation between sCD206 levels and ILD deterioration was assessed. Receiver operating characteristic (ROC) curve was generated to determine the optimal cut-off value of sCD206 for predicting outcome. The association between sCD206 and survival was examined. RESULTS: The median serum sCD206 level in patients was significantly higher than healthy controls (464.1 ng/mL vs. 349.1 ng/mL, P = 0.002). In DM/CADM patients, the sCD206 level was significantly higher in patients with acute/subacute interstitial lung disease (AILD/SILD) than those with chronic interstitial lung disease (CILD) (539.2 ng/mL vs. 309.4 ng/mL, P = 0.005). The AUC of sCD206 was 0.885 for predicting mortality (95% CI 0.779-0.990). Patients were divided into two groups: sCD206 high level group (≥400 ng/mL) and sCD206 low level group (<400 ng/mL). Patients with sCD206 high level had significantly decreased survival rate than those with low level (25% vs. 88%, P < 0.001). The adjusted hazard ratio of sCD206 for mortality was 1.003 (adjusted for age and gender, P < 0.001), with sCD206 high level associated with higher death risk (HR 4.857, P = 0.006). CONCLUSION: Serum sCD206 might be a potential predictor of ILD deterioration and prognosis for Chinese patients with MDA5-DM/CADM-ILD.

Sequential-delivery nanocomplex for combined anti-angiogenesis and gene therapy against colorectal cancer.

Neovascularization can provide tumors with essential nutrients and oxygen, as well as maintain a microenvironment for tumor cell growth. In this study, we combined anti-angiogenic therapy and gene therapy for synergistic anti-tumor therapy. We co-delivered the vascular endothelial growth factor receptor inhibitor fruquintinib (Fru) and small interfering RNA CCAT1 (siCCAT1) inhibiting epithelial-mesenchymal transition using 1,2-distearoyl-snglycero-3-phosphoethanolamine-N- [methoxy (polyethylene glycol)] with a pH-responsive benzoic imine linker bond (DSPE-Hyd-mPEG) and polyethyleneimine-poly (d, l-lactide) (PEI-PDLLA) nanocomplex (Fru and siCCAT1 co-delivery NP, FCNP). Due to the characteristics of pH-response, DSPE-Hyd-mPEG removed from FCNP after enrichment at the tumor site, which had a protective effect in the body. Meanwhile, Fru acting on the peritumor blood vessels was rapidly released, and then the nanoparticles loaded with siCCAT1 (CNP) was engulfed by cancer cells and facilitate the successful lysosomal escape of siCCAT1 in, playing the role of silencing CCAT1. Efficient silencing of CCAT1 by FCNP was observed, and simultaneously, the expression of VEGFR-1 was also down-regulated. Furthermore, FCNP elicited significant synergistic antitumor efficacy via anti-angiogenesis and gene therapy in the SW480 subcutaneous xenograft model with favorable biosafety and biocompatibility during the treatment. Overall, FCNP was considered a promising strategy for the combined anti-angiogenesis-gene treatment against colorectal cancer.

Self-assembled nanocomposites of carboxymethyl ß-dextran/protamine sulfate for enhanced chemotherapeutic drug sensitivity of triple-negative breast cancer by autophagy inhibition via a ternary collaborative strategy.

Drug resistance in cancer chemotherapy is a major confounding factor affecting the effectiveness of chemotherapeutic agents, thereby leading to poor clinical outcomes. Most chemotherapeutic drugs can induce protective autophagy and increase the resistance of tumors to chemotherapeutic drugs and reduce effective drug delivery to tumor cells. In this study, a tri-drug nanocomposite (NP) delivery system was devised using carboxymethyl ß-dextran (CMD) and protamine sulfate (PS), two natural materials with good bio-compatibility. They were designed to carry the chemotherapeutic drug docetaxel (DTX), the autophagy inhibitor chloroquine (CQ), and Atg5 siRNA to cancer cells. The CQ + DTX + Atg5 siRNA NPs was driven by electrostatic interaction and self-assembly methods. The breast cancer cell line MDA-MB-231 was used for both cell culture and establishing mouse xenograft model. Our findings demonstrated that CQ and Atg5 siRNA encapsulated in NPs could enhance the sensitivity of tumor cells to DTX. The NPs exhibited remarkable considerable therapeutic effects for treating triple-negative breast cancer (TNBC) and good biosafety. Therefore, we established a novel multifunctional nanoplatform based on CMD and PS that enhances chemotherapeutic drug sensitivity through an autophagy inhibition strategy, providing new opportunities to overcome conventional drug resistance and enhance therapeutic efficiency against TNBC.

Value of the FDP/FIB ratio in predicting early severe bleeding events in patients with newly diagnosed acute promyelocytic leukemia.

Severe bleeding is the leading cause of early death in patients with newly diagnosed acute promyelocytic leukemia (APL). However, there are no means for hemorrhagic risk stratification in APL. This study aimed to identify optimized predictors of severe bleeding events related to APL. A total of 109 consecutive patients with newly diagnosed APL from January 2015 to April 2022 were retrospectively investigated. A systematic review of computer-based patient medical records was conducted to obtain clinical date, including baseline characteristics, routine blood examination findings, coagulation and fibrinolysis indexes, and bleeding events. Among the 109 patients, 89 were classified into the no-severe bleeding group, while 20 had severe bleeding. Compared with the patients with no severe bleeding, the patients with severe bleeding had significantly higher circulating leukemic cell percentages, disseminated intravascular coagulation (DIC) scores, D-dimer (D-D) levels, and fibrin degradation product (FDP) levels. They also had lower fibrinogen (FIB) levels and a longer prothrombin time. Multivariate analysis revealed that the circulating leukemic cell percentage (OR = 1.040, CI = 1.008-1.072, P = 0.012), FIB level (OR = 0.101, CI = 0.011-0.896, P = 0.040), and FDP level (OR = 1.012, CI = 1.000-1.024, P = 0.047) were independent risk factors for severe bleeding. FDP/FIB, D-D/FIB, and seven meaningful indicators in the single-factor analysis were included in the receiver operating characteristic (ROC) curve analysis. The results showed that FDP/FIB was the best indicator for predicting severe bleeding related to newly diagnosed APL. The area under the ROC curve of FDP/FIB was 0.915, and the best cutoff value was 61.77, with 100% sensitivity and 74.2% specificity. Statistical analysis showed a higher incidence of severe bleeding and higher DIC scores when FDP/FIB was >61.77 in APL patients. FDP/FIB has obvious advantages in predicting the degree of bleeding associated with primary promyelocytic leukemia; the greater the FDP/FIB value, the more severe the bleeding. The risk of severe bleeding was the highest when FDP/FIB > 61.77.

Elevated serum human epididymis protein 4 is associated with disease severity and worse survival in idiopathic pulmonary fibrosis: a cohort study.

Background: Elevated expression of human epididymis protein 4 (HE4) was previously described in connective tissue disease-associated interstitial lung diseases (CTD-ILDs) and cystic fibrosis (CF), but the clinical significance of HE4 has remained unknown in idiopathic pulmonary fibrosis (IPF), which is a progressive fibrosing ILD with a heterogeneous course that is in urgent need of reliable biomarkers in its clinical practice. Methods: A total of 27 IPF patients with acute exacerbation status (AE-IPF), 32 IPF patients with stable status (S-IPF), and 29 sex-age matched healthy controls were retrospectively included. The levels of serum HE4 and Krebs von den Lungen-6 (KL-6) of the 3 cohorts were measured. In addition, the pulmonary expression of HE4 was evaluated in lung transplant specimens of IPF using immunohistochemistry and Western blot, and noncancerous lung tissue resected from early-stage lung cancer patients as controls. The endpoint of follow-up was March 1st, 2022, and the Cox regression model was used to analyze the prognostic value of HE4. Results: The levels of HE4 and KL-6 were obviously elevated in AE-IPF patients compared to S-IPF (296.4 vs. 178.1 pmol/L for HE4, P<0.001; 2,007.0 vs. 990.5 IU/mL for KL-6, P<0.001) or healthy controls (296.4 vs. 51.8 pmol/L for HE4, P<0.001; 2,007.0 vs. 181.0 IU/mL for KL-6, P<0.001). Significant correlations were observed between serum HE4 levels and percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%) (r=-0.526, P<0.001), percent predicted forced vital capacity (FVC%) (r=-0.344, P=0.024), gender-age-physiology (GAP) index (r=0.535, P<0.001), and oxygenation index (r=-0.550, P<0.001) in IPF patients. In histological analysis, overexpression of HE4 in mucosal epithelium of dilated bronchi was observed in IPF patients compared with controls. Multivariate cox regression revealed that serum levels of HE4 [hazard ratio (HR) =1.004, P=0.042] and GAP index (HR =1.374, P=0.010) were associated with worse survival in IPF patients. Conclusions: The expression of serum HE4 was obviously elevated in IPF patients, especially in AE-IPF patients. In addition, serum HE4 could be utilized as a biomarker of disease severity and poor prognosis of IPF patients. These findings warrant further validation in larger, multi-center, and longitudinal cohorts.

Case report: biotin-thiamine-responsive basal ganglia disease with severe subdural hematoma on magnetic resonance imaging.

Background: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare, treatable autosomal recessive neurometabolic disorder. This condition eventually leads to severe disability and death if not treated correctly. The clinical features of BTBGD, especially those with unusual complications, are not widely known by neurologists or pediatricians.Case presentation: A 4-month-old male infant was admitted to the hospital with a history of cough for the past 7 days and convulsions of 6 h duration. Physical examination showed confusion, bilateral pupillary light reflex delays, hypertonia of limbs, and brisk tendon reflexes of the limbs. Brain magnetic resonance imaging (MRI) showed multiple abnormal signals in the bilateral basal ganglia, lobes, corpus callosum, brainstem, and brain atrophy. However, his condition continued to worsen. Computed tomography performed 3 months later showed severe subdural hematoma and effusion. Subsequently, he underwent puncture drainage; however, his condition did not improve postoperatively. Repeated MRIs showed increasing subdural hematoma and effusion, and brain atrophy. The patient was diagnosed with BTBGD following whole-genome sequencing, which identified a novel compound heterozygous mutation of SLC19A3 gene. He was treated with biotin and thiamine, and the symptoms gradually improved. Subsequent MRIs showed a decrease in the subdural hematoma and effusion and partial improvement in brain atrophy.Conclusion: To the best of our knowledge, this is the first reported case of BTBGD, complicated by severe subdural hematoma. These observations extend our understanding of the clinical features, neuroimaging spectrum, and gene mutation spectrum of BTBGD. The phenotypic spectrum and pathophysiology of BTBGD are not completely understood and need to be studied further.

Human epididymis protein 4 is associated with severity and poor prognosis of connective tissue disease-associated interstitial lung disease with usual interstitial pneumonia pattern.

BACKGROUND: Overexpression of human epididymis protein 4 (HE4) was previously described in idiopathic pulmonary fibrosis (IPF), but whether serum HE4 can be considered as a potential biomarker in connective tissue disease-associated interstitial lung disease (CTD-ILD) with usual interstitial pneumonia (UIP) pattern was still unknown. METHOD: A total of 55 CTD-ILD patients with UIP pattern (UIP-CTD) and 52 healthy controls were enrolled in this study. The serum levels of HE4 and Krebs von den Lungen-6 (KL-6) were evaluated in both cohorts. In addition, immunohistochemistry analysis for HE4 was performed on the lung sections of 6 patients with rheumatoid arthritis-associated UIP (UIP-RA) and 6 patients with early-stage lung cancer as normal control. RESULTS: The levels of serum HE4 and KL-6 were higher in patients with UIP-CTD than in healthy controls (292.3 pmol/L versus 79.5 pmol/L for HE4, p < 0.001; 1091.0 IU/mL versus 171.5 IU/mL for KL-6, p < 0.001). Significant correlations between serum HE4 levels and percentpredicted forced vital capacity (FVC%) (r = -0.425, p = 0.004), percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%) (r = -0.447, p = 0.003), and Gender-Age-Physiology (GAP) index (r = 0.494, p < 0.001) were observed in UIP-CTD patients. In immunohistochemistry analysis, elevated expression of HE4 in bronchiolar epithelium and mesenchyme was observed in patients with UIP-RA compared with controls. The serum levels of HE4 (≥277.5 pmol/L) and GAP index were related to an increased risk of mortality (HR = 3.884, p = 0.034; HR = 1.480, p = 0.028, respectively). CONCLUSION: The expression of HE4 in serum and lung specimens was significantly elevated in UIP-CTD patients. Moreover, serum HE4 may be utilized as a biomarker to evaluate the severity of disease and predict the prognosis of UIP-CTD patients.

Mitochondria-Targeted Self-Assembly of Peptide-Based Nanomaterials.

Mitochondria are well known to serve as the powerhouse for cells and also the initiator for some vital signaling pathways. A variety of diseases are discovered to be associated with the abnormalities of mitochondria, including cancers. Thus, targeting mitochondria and their metabolisms are recognized to be promising for cancer therapy. In recent years, great efforts have been devoted to developing mitochondria-targeted pharmaceuticals, including small molecular drugs, peptides, proteins, and genes, with several molecular drugs and peptides enrolled in clinical trials. Along with the advances of nanotechnology, self-assembled peptide-nanomaterials that integrate the biomarker-targeting, stimuli-response, self-assembly, and therapeutic effect, have been attracted increasing interest in the fields of biotechnology and nanomedicine. Particularly, in situ mitochondria-targeted self-assembling peptides that can assemble on the surface or inside mitochondria have opened another dimension for the mitochondria-targeted cancer therapy. Here, we highlight the recent progress of mitochondria-targeted peptide-nanomaterials, especially those in situ self-assembly systems in mitochondria, and their applications in cancer treatments.