Synergistic effects of the KDM4C inhibitor SD70 and the menin inhibitor MI-503 against MLL::AF9-driven acute myeloid leukaemia.

MLL-rearranged (MLL-r) leukaemia is observed in approximately 10% of acute myeloid leukaemia (AML) and is associated with a relatively poor prognosis, highlighting the need for new treatment regimens. MLL fusion proteins produced by MLL rearrangements recruit KDM4C to mediate epigenetic reprogramming, which is required for the maintenance of MLL-r leukaemia. In this study, we used a combinatorial drug screen to selectively identify synergistic treatment partners for the KDM4C inhibitor SD70. The results showed that the drug combination of SD70 and MI-503, a potent menin-MLL inhibitor, induced synergistically enhanced apoptosis in MLL::AF9 leukaemia cells without affecting normal CD34+ cells. In vivo treatment with SD70 and MI-503 significantly prolonged survival in AML xenograft models. Differential gene expression analysis by RNA-seq following combined pharmacological inhibition of SD70 and MI-503 revealed changes in numerous genes, with MYC target genes being the most significantly downregulated. Taken together, these data provide preclinical evidence that the combination of SD70 and MI-503 is a potential dual-targeted therapy for MLL::AF9 AML.

Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms.

Despite the identification of driver mutations leading to the initiation of myeloproliferative neoplasms (MPNs), the molecular pathogenesis of MPNs remains incompletely understood. Here, we demonstrate that growth arrest and DNA damage inducible gamma (GADD45g) is expressed at significantly lower levels in patients with MPNs, and JAK2V617F mutation and histone deacetylation contribute to its reduced expression. Downregulation of GADD45g plays a tumor-promoting role in human MPN cells. Gadd45g insufficiency in the murine hematopoietic system alone leads to significantly enhanced growth and self-renewal capacity of myeloid-biased hematopoietic stem cells, and the development of phenotypes resembling MPNs. Mechanistically, the pathogenic role of GADD45g insufficiency is mediated through a cascade of activations of RAC2, PAK1 and PI3K-AKT signaling pathways. These data characterize GADD45g deficiency as a novel pathogenic factor in MPNs.

Immunometabolic reprogramming of macrophages with inhalable CRISPR/Cas9 nanotherapeutics for acute lung injury intervention.

Acute lung injury (ALI) represents a critical respiratory condition typified by rapid-onset lung inflammation, contributing to elevated morbidity and mortality rates. Central to ALI pathogenesis lies macrophage dysfunction, characterized by an overabundance of pro-inflammatory cytokines and a shift in metabolic activity towards glycolysis. This study emphasizes the crucial function of glucose metabolism in immune cell function under inflammatory conditions and identifies hexokinase 2 (HK2) as a key regulator of macrophage metabolism and inflammation. Given the limitations of HK2 inhibitors, we propose the CRISPR/Cas9 system for precise HK2 downregulation. We developed an aerosolized core-shell liposomal nanoplatform (CSNs) complexed with CaP for efficient drug loading, targeting lung macrophages. Various CSNs were synthesized to encapsulate an mRNA based CRISPR/Cas9 system (mCas9/gHK2), and their gene editing efficiency and HK2 knockout were examined at both gene and protein levels in vitro and in vivo. The CSN-mCas9/gHK2 treatment demonstrated a significant reduction in glycolysis and inflammation in macrophages. In an LPS-induced ALI mouse model, inhaled CSN-mCas9/gHK2 mitigated the proinflammatory tumor microenvironment and reprogrammed glucose metabolism in the lung, suggesting a promising strategy for ALI prevention and treatment. This study highlights the potential of combining CRISPR/Cas9 gene editing with inhalation delivery systems for effective, localized pulmonary disease treatment, underscoring the importance of targeted gene modulation and metabolic reprogramming in managing ALI. STATEMENT OF SIGNIFICANCE: This study investigates an inhalable CRISPR/Cas9 gene editing system targeting pulmonary macrophages, with the aim of modulating glucose metabolism to alleviate Acute Lung Injury (ALI). The research highlights the role of immune cell metabolism in inflammation, as evidenced by changes in macrophage glucose metabolism and a notable reduction in pulmonary edema and inflammation. Additionally, observed alterations in macrophage polarization and cytokine levels in bronchoalveolar lavage fluid suggest potential therapeutic implications. These findings not only offer insights into possible ALI treatments but also contribute to the understanding of immune cell metabolism in inflammatory diseases, which could be relevant for various inflammatory and metabolic disorders.

Relationship between dust allergen sensitization and cardiac autonomic function in patients with chronic obstructive pulmonary disease.

OBJECTIVE: Cardiac autonomic function predicts cardiovascular disease risk. The aim of this study was to investigate the relationship between sensitization to dust allergens and cardiac autonomic dysfunction in patients with chronic obstructive pulmonary disease (COPD), and to provide new ideas for the prevention of cardiovascular complications in these patients. METHODS: Immunoassays for sensitization to cats/dogs, cockroaches and dust mites were performed in 840 patients with COPD. Indicators of heart rate variability in these patients were used to assess cardiac autonomic function, including standard deviation of normal-to-normal intervals (SDNN), root-mean square of successive differences between normal-to-normal intervals (RMSSD), low-frequency power (LF), high-frequency power (HF), and LF/HF ratios, which were obtained based on ambulatory electrocardiographic monitoring data. The relationship between sensitization to these dust allergens and heart rate variability was explored using multivariate logistic regression. FINDINGS: The multivariate analyses showed that sensitization to total allergens was associated with reduced levels of SDNN, RMSSD, LF and HF and with increased levels of the LF/HF ratio in the patients with COPD (p < .05). CONCLUSION: Dust allergen sensitization may be associated with cardiac autonomic dysfunction in patients with COPD. Whether desensitization can prevent cardiovascular complications in these patients should be further explored.

Value of painless transvaginal four-dimensional hysterosalpingo contrast sonography in reducing venous intravasation: a comparative study.

OBJECTIVE: To investigate the value of painless transvaginal four-dimensional hysterosalpingo contrast sonography (TV 4-D HyCoSy) in reducing venous intravasation and its influencing factors through a retrospective comparative study on conventional TV 4-D HyCoSy. MATERIALS AND METHODS: A total of 451 patients were enrolled in this study from Jan. 2019 to Oct. 2021. There were 249 patients in the painless TV 4-D HyCoSy group and 202 patients in the conventional TV 4-D HyCoSy group. The incidence of venous intravasation and its related influencing factors were analyzed and compared between these two groups. The difficulty of image evaluation for the diagnosis was also compared. RESULTS: There was no significant difference in the baseline characteristics between the painless group and the conventional group (p > 0.05). Compared with the conventional group, the painless group had a lower incidence of venous intravasation (16.9 vs. 24.8%; p = 0.039). Painless TV 4-D HyCoSy was more effective in reducing venous intravasation in patients with primary infertility (p = 0.032) without a history of pelvic surgery (p = 0.008) or ectopic pregnancy (p = 0.018). Logistic regression analysis demonstrated that painless TV 4-D HyCoSy and endometrial thickness > 5 mm were protective factors for venous intravasation. Moreover, the diagnostic procedure was easier in the painless group than in the conventional group (p = 0.002). CONCLUSIONS: Painless TV 4D-HyCoSy may be an effective mode in reducing the incidence of venous intravasation and improving the diagnosis of patency of fallopian tubes.

Twist family BHLH transcription factor 1 is required for the maintenance of leukemia stem cell in MLL-AF9+ acute myeloid leukemia.

Leukemia stem cells (LSC) are a rare population capable of limitless self-renewal and are responsible for the initiation, maintenance, and relapse of leukemia. Elucidation of the mechanisms underlying the regulation of LSC function could provide novel treatment strategies. Here, we show that TWIST1 is extremely highly expressed in the LSC of MLL-AF9+ acute myeloid leukemia (AML), and its upregulation is positively regulated by KDM4C in a H3K9me3 demethylation-dependent manner. We further demonstrate that TWIST1 is essential for the viability, dormancy, and self-renewal capacities of LSC, and that it promotes the initiation and maintenance of MLL-AF9-mediated AML. In addition, TWIST1 directly interacts and collaborates with HOXA9 in inducing AML in mice. Mechanistically, TWIST1 exerts its oncogenic function by activating the WNT5a/RAC1 axis. Collectively, our study uncovers a critical role of TWIST1 in LSC function and provides new mechanistic insights into the pathogenesis of MLL-AF9+ AML.

PI3K inhibitors in trastuzumab-resistant HER2-positive breast cancer cells with PI3K pathway alterations.

The activation of the PI3K signaling pathway resulting from genetic alterations induces carcinogenesis and resistance to anticancer therapies. Breast cancer is a major malignancy that is associated with dysregulation of the PI3K signaling pathway. PIK3CA mutations and PTEN loss occur in every subtype of breast cancer. PI3K inhibitors are being evaluated in breast cancer after the success of an alpha isoform-specific PI3K inhibitor in estrogen receptor (ER)-positive/HER2-negative metastatic breast cancer. Some preclinical data indicate the potential for PI3K/mTOR targeting in combination with trastuzumab for HER2-positive breast cancer with or without expression of the estrogen receptor. However, the role of this therapy in HER2-positive breast cancer with PIK3CA mutations and/or PTEN loss remains unclear. We examined three HER2-positive, ER-negative breast cancer cell lines to determine the efficacy of a novel alpha isoform-specific PI3K inhibitor in combination with trastuzumab. The results indicated that this combination was effective in PIK3CA-mutant or PTEN-deficient breast cancer cells by inducing apoptosis and inhibiting the expression of downstream proteins. PTEN loss by siRNA modulation in parental HER2-positive cancer cells with PI3K signaling pathway alterations could not confer resistance to alpelisib or GDC-0077 plus trastuzumab. We selected the CK-MB-1 cell line without alterations in the PI3K pathway to demonstrate that PI3K inhibitors plus trastuzumab represented a biomarker-specific treatment. In vivo effects of alpelisib plus trastuzumab were tested and confirmed in a mouse model, showing the combination strategy offered the best opportunity to achieve tumor volume reduction. With known safety profiles, this cytotoxic chemotherapy-free regimen warrants further attention as a biomarker-driven strategy for treating HER2-positive breast cancer.

Structural characterization and fluidness analysis of lactose/whey protein isolate composite hydrocolloids as printing materials for 3D printing.

In this study, the lactose/Whey Protein Isolate (WPI) composite hydrocolloids were prepared as an printing material for subsequent 3D printing. The results showed that the rheological, viscoelastic, thermal and mechanical properties of the studied hydrocolloids were composition dependent, which was directly linked to the printing fidelity of printed objects. The morphology of all printed objects showed a porous microstructure, and their porosity was changed by lactose addition. This outcome resulted from lactose-derived co-solvation discouraging WPI aggregation during the printing process, which was necessary for improving printing performance. Moreover, an innovative Fluidness concept (F), using material-specific WLF analysis of relaxation times, was introduced to quantify the fluidness of lactose/WPI composite hydrocolloids at a certain decay of timescales (from 102 to 10-3 s). This F concept was superior for the description and control of printing fidelity, dimensional deviation, and textural properties of 3D-printed objects. Therefore, the F concept is a "printable indicator" for dairy by-products that may possess proper printability and provides an alternative approach to make attractive designs for 3D printing foods.

Mutation profiling of circulating tumor DNA identifies distinct mutation patterns in non-Hodgkin lymphoma.

OBJECTIVE: Circulating tumor DNA (ctDNA) is emerging as a versatile biomarker for noninvasive genotyping and response monitoring in specific B-cell lymphomas; however, few studies have been conducted to explore ctDNA-based mutation profiling across non-Hodgkin lymphomas (NHLs) and genomic changes after initiation of chemotherapy. METHODS: A targeted sequencing of 362 genes was performed to detect the mutation profiles in paired blood and tissue samples from 42 NHL patients. Genomic alterations were explored in 11 diffuse large B-cell lymphoma (DLBCL) patients using paired blood samples collected pre- and post-R-CHOP chemotherapy. RESULTS: The frequencies of PIM1, MYD88, MYC, ZNF292, JAK, and MAF mutations were higher in aggressive than in indolent B-cell lymphoma and NK/T subtypes. Tumor mutation burden in blood samples was higher in aggressive than in indolent B-cell lymphomas and higher in patients who progressed than in those who responded to treatments. Our data also revealed significant enhance of concordance index through integrating mutated genes that were significantly associated with prognosis into International Prognostic Index-based prognostic model. Moreover, acquisition of mutations such as PCLO_p.L1220Tfs*3 was associated with resistance to R-CHOP in DLBCL patients. CONCLUSIONS: Our findings illustrated distinct mutation patterns across various NHL subtypes and suggested the association of genomic alterations in ctDNA with treatment outcomes.

The Prediction Analysis of Autistic and Schizotypal Traits in Attentional Networks.

OBJECTIVE: Empirical findings confirmed that autistic and schizotypal traits are associated with attentional function as well as include various dimensions. So far, no study has reported which dimension of these traits relates to attentional networks. This study aimed to find out whether there are associations between attentional networks and autistic traits; and between attentional networks and schizotypal traits. METHODS: A total of 449 volunteers was included in this study, and autism-spectrum quotient (AQ), schizotypal personality questionnaire (SPQ), and attention network test (ANT) were used to measure autistic traits and schizotypal traits. The three independent attentional networks, including alerting network, orienting network, and executive control network, were also measured. RESULTS: Autistic traits were associated with the orienting network, whereas schizotypal traits were associated with the orienting network and executive control network. Furthermore, attentional networks could be predicted by specific dimensions of autistic and schizotypal traits. AQ-attention switching [0.104 (-1.175- -0.025), p=0.041] and AQ-attention to detail [-0.097 (-0.798- -0.001), p=0.049] were significant predictors of orienting network and gender were significant predictor of executive network (Beta=0.107; 95% CI=-0.476-10.139; p=0.031). Whereas, schizotypal dimension "interpersonal" was a significant predictor of all three attentional networks [Alerting: 0.147 (-0.010-0.861), p=0.045; Orienting: 0.147 (0.018-0.733), p=0.040; Executive: 0.198 (0.215-1.309), p=0.006]. CONCLUSION: This study demonstrated that autistic and schizotypal traits were associated with attentional networks. The specific dimensions of autistic and schizotypal traits could predict attentional networks. Nevertheless, the attentional networks predicted with these two traits were different.

Common variants of the autism-associated CNTNAP2 gene contribute to the modulatory effect of social function mediated by temporal cortex.

Autistic traits are highly heritable and characterized by social deficits. Common genetic variants of the autism-related CNTNAP2 gene have been linked with social impairments, but the neural substrates are poorly understood. In the present study, we investigated the genetic effect of common variants of CNTNAP2 (rs2710102 and rs7794745) on gray matter volume and its association with social performance among 442 healthy participants. Our results showed that individuals with rs2710102 GG homozygotes had smaller left superior temporal gyrus (STG)/insular volume than A-allele carriers (AA and AG), while individuals with rs7794745 TT and AT showed smaller right parahippocampal, right STG/insular, and left inferior parietal lobule (IPL) cortex volume than those with rs7794745 AA. Smaller volume of the STG/insular and parahippocampal cortex was associated with poorer social performance. An indirect effect of CNTNAP2 rs7794745 and rs2710102 genotype on the social performance was mediated by the STG/insular cortex and parahippocampal cortex volume. These findings provided insight into the genetic effect of CNTNAP2 variants on social behavior, which may be moderated by the temporal cortex.

Primary central nervous system Hodgkin's lymphoma: a case report.

Primary central nervous system Hodgkin's lymphoma (CNS-HL) is extremely rare. This current case report describes a 60-year-old male patient that presented with numbness of the left lower extremity and worsening headache. After a full range of investigations and a partial resection of the right cerebellum, external ventricular drainage reservoir placement and cranioplasty, he was diagnosed with primary CNS-HL. The patient was treated with 3 g/m2 methotrexate (intravenous [i.v.], once a day, day 1) and 1 g/m2 cytarabine (i.v., every 12 h, days 2 + 3), followed by anti-programmed cell death protein 1 antibodies (200 mg sintilimab, i.v., once a day, day 1, every 3 weeks). After six courses of treatment with intrathecal injections of 50 mg cytarabine (once a day, day 1) and 5 mg dexamethasone (once a day, day 1), there was no residual lesion on cranial magnetic resonance imaging. No significant drug-related adverse events were observed. The patient has been followed up every 3 months and no relapse has occurred.

Development of the CK-MB-1 trastuzumab-resistant HER2-positive breast cancer cell line and xenograft animal models.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who fail to respond to anti-HER2 treatments have poor prognoses. Most trastuzumab-resistant breast cancer cell lines available from biobanks feature either phosphoinositide-3-kinase, catalytic, alpha (PIK3CA) mutation or the loss of phosphatase and tensin homolog (PTEN). However, PIK3CA mutations and/or PTEN loss do not account for most trastuzumab-resistant tumors in humans. METHODS: Breast cancer cells were collected from one patient's malignant ascites. These cells were cultured and maintained to develop a stable cell line, which we named CK-MB-1. We used western blotting to evaluate protein expression. The PIK3CA status of CK-MB-1 cells was analyzed using Sanger sequencing and validated using next-generation sequencing. In vivo, CK-MB-1 xenograft tumor models were developed in zebrafish and immunodeficient mice. RESULTS: CK-MB-1 cells maintained the major characteristics of the parental tumor including HER2 positivity and estrogen receptor negativity. The HER2 gene amplification of CK-MB-1 cells was detected by fluorescence in situ hybridization. The integrity of PTEN was confirmed by its positive protein expression and the absence of gene mutations. No common PIK3CA mutation was detected. Compared with the findings in two other HER2-positive trastuzumab-resistant cell lines, CK-MB-1 cells exhibited greater resistance to trastuzumab, chemotherapeutics, and small-molecule drugs. Trastuzumab resistance in CK-MB-1 cells was confirmed in vivo using the NOD SCID mouse model. CONCLUSIONS: CK-MB-1 cells represent a stable HER2-positive trastuzumab-resistant breast cancer cell line. The resistance of CK-MB-1 cells does not originate from the PTEN or phosphoinositide 3-kinase signaling pathway, which can provide an alternative approach for potential drugs.

Preliminary investigation of the diagnostic value of shear wave elastography in evaluating the testicular spermatogenic function in patients with azoospermia.

To assess the diagnostic value of shear wave elastography (SWE) for evaluating the histological spermatogenic function of azoospermic males, 91 patients with azoospermia who underwent standardised greyscale ultrasound and SWE examinations followed by testicular biopsy were retrospectively recruited. Spermatogenic function was classified by biopsy as normal testicular spermatogenesis (n = 61), hypospermatogenesis (n = 18), spermatogenesis arrest (n = 6) and Sertoli cell-only syndrome (n = 6). Significant differences in testicular size and SWE values were observed between these 4 groups (p < .01). The mean SWE value had good discrimination power (AUC = 0.79) with a cut-off value of 1.55 KPa, a sensitivity of 0.58, specificity of 0.85, positive predictive value (PPV) of 0.36 and negative predictive value (NPV) of 0.93. Testicular volume had an AUC of 0.75. With a cut-off value of 8.41 ml, the testicular volume had a sensitivity of 0.58, specificity of 0.92, PPV of 0.54 and NPV of 0.93. The mean SWE value and testicular volume efficiently discriminated patients with normal spermatogenesis and hypospermatogenesis from patients with Sertoli cell-only syndrome and spermatogenesis arrest.

Testicular quantitative ultrasound: A noninvasive monitoring method for evaluating spermatogenic function in busulfan-induced testicular injury mouse models.

Busulfan-induced testicular injury mouse models are commonly used for experiments on spermatogonial stem cell transplantation, treatments for azoospermia due to spermatogenic failure and preserving male fertility after chemotherapy. Here, we investigated the value of testicular quantitative ultrasound for evaluating spermatogenic function in this model. In this study, testicular ultrasound was performed on mice from day 0 to 126 after busulfan treatment (n = 48), and quantitative data, including the testicular volume, mean pixel intensity and pixel uniformity, were analysed. The results revealed that from day 0 to 36, the testicular volume was positively associated with the testicle-to-body weight ratio (r = .92). On day 63, the pixel uniformity, which remained stable from day 0 to 36, declined significantly compared with that on day 36 (p < .01). On day 126, when the whole progression of spermatogenesis could be observed in most tubules, the mean pixel intensity also returned to normal (p > .05). In conclusion, testicular quantitative ultrasound could be used as a noninvasive and accurate monitoring method for evaluating spermatogenic function in busulfan-induced testicular injury mouse models.

Rottlerin, BDNF, and the impairment of inhibitory avoidance memory.

RATIONALE AND OBJECTIVE: As a eukaryotic elongation factor 2 kinase (eEF2K) inhibitor and a mitochondrial uncoupler, oncologists have extensively studied rottlerin. Neuroscientists, however, have accumulated scarce data on the role of rottlerin in affective and cognitive functions. Only two prior studies have, respectively, documented its antidepressant-like effect and how it impairs psychostimulant-supported memory. Whether or not rottlerin would affect aversive memory remains unknown. Hence, we sought to investigate the effects of rottlerin on aversive memory in the inhibitory avoidance (IA) task in mice. MATERIALS AND METHODS: Male C57BL/6J mice were trained to acquire the IA task. Rottlerin (5 mg/kg, i.p. or 3 µg bilaterally in the hippocampus) or the vehicle was administered before footshock training (acquisition), after footshock training (consolidation), after the memory reactivation (reconsolidation), and before the test (retrieval) in the IA task. RESULTS: Systemic and intrahippocampal rottlerin impaired the acquisition, consolidation, and retrieval of IA memory, without affecting the reconsolidation process. Rottlerin (5 mg/kg, i.p.) induced a fast-onset and long-lasting increase in the brain-derived neurotrophic factor (BDNF) protein levels in the mouse hippocampus. Systemic injection of 7,8-dihydroxyflavone (7,8-DHF, 30 mg/kg), a BDNF tropomyosin receptor kinase B (TrkB) agonist impaired IA memory consolidation, and treatment with K252a (5 µg/kg), a Trk receptor antagonist, reversed the suppressing effect of rottlerin on IA memory consolidation. CONCLUSION: Rottlerin impairs IA memory consolidation through the enhancement of BDNF signaling in the mouse hippocampus. Excessive brain BDNF levels can be detrimental to cognitive function. Rottlerin is likely to affect the original memory-associated neuroplasticity. Thus, it can be combined with exposure therapy to facilitate the forgetting of maladaptive aversive memory, such as post-traumatic stress disorder (PTSD).

Crystallization and strength analysis of amorphous maltose and maltose/whey protein isolate mixtures.

BACKGROUND: Maltose is an essential derivative of starch. To understand the processability and stability of maltose-containing foods, material characterization of the phase and state transition from its amorphous state is required. Although the crystallization of amorphous maltose is well understood, few studies have reported the relationship between the crystallization and the glass transition temperature (Tg )-related molecular mobility. In this study, water sorption, crystallization, Tg -related α-relaxation, and the corresponding time factor for amorphous maltose and maltose / whey protein isolate (WPI) mixtures are measured at various water activity (aw ) levels and 25 °C. RESULTS: The water-additive principle for maltose / WPI mixtures was observed at aw ≤ 0.440 at the molecular level, whereas the crystallization of amorphous maltose occurred at high aw values (≥0.534). The crystal formation and crystallization kinetics of amorphous maltose were affected by water and WPI at aw ≥ 0.534 and 25 °C, as determined by X-ray diffraction. The relationship between Tg and the water content was fitted by the Gordon-Taylor model, and its constant showed a compositional dependence for the maltose / WPI mixtures. The α-relaxation temperature of the amorphous samples decreased due to water plasticization, but increased with an increase in the WPI quantity. The Strength (S) value for amorphous maltose, which was a quantitative estimate of the compositional effects on molecular mobility, was based on the William-Landel-Ferry (WLF) equation. CONCLUSION: The S concept exhibits considerable potential for application in controlling the crystallization of amorphous maltose and improving the processability and stability of maltose-containing foods. © 2020 Society of Chemical Industry.

Clinical characteristics and survival of extranodal natural killer/T-cell lymphoma: a single-center 12-year retrospective analysis.

The characteristics and survival of 218 patients with extranodal natural killer/T-cell lymphoma (ENKTCL) were analyzed in this retrospective study. The median progression-free survival (PFS) and overall survival (OS) were 10.9 months and 50.5 months, respectively. Sequential chemoradiotherapy achieved a 74.5% overall response rate (ORR) and a 30.9% 5-year PFS rate in patients with localized stage. Asparaginase-containing protocols demonstrated superior prognosis in advanced cases, with a median FPS at 5.7 months, compared to 1.9 months without asparaginase. Initial treatment with P-GEMOX regimens showed superior ORR and PFS compared to the SMILE regimen, with lower toxicities. Hematopoietic stem cell transplantation (HSCT) improved the PFS and OS of refractory or relapsed (R/R) cases. PD-1/PD-L1 antibody could achieve a median PFS at 4.0 months and a median OS at 14.6 months in R/R patients for whom salvage therapies failed. High-risk PINK-E score was the only independent adverse prognostic factor for PFS and OS.

Chlorination of soil-derived dissolved organic matter: Long term nitrogen deposition does not increase terrestrial precursors of toxic disinfection byproducts.

Terrestrial dissolved organic matter (DOM) in forested watersheds is a known precursor of disinfection byproducts (DBPs) in drinking water. Although the characteristics of terrestrial DOM may change with increasing nitrogen (N) deposition in forests, how these changes alter formation potential and toxicity of DBPs remains unexplored. We analyzed the speciation and toxicity of DBPs from chlorination of DOM derived from soils (O, A, and B horizons) in an experimental temperate forest with 22 years of N addition. With long-term N addition, the DOM reactivity toward the formation of trihalomethanes (from 27.7-51.8 to 22.8-31.1 µg/mg-dissolved organic carbon (DOC)) and chloral hydrate (from 1.25-1.63 to 1.14-1.36 µg/mg-DOC) decreased, but that toward the formation of haloketones increased (from 0.23-0.26 to 0.26-0.33 µg/mg-DOC). The DOM reactivity toward the formation of haloacetonitriles was increased in the deeper soil but reduced in the surface soil. The DBP formation potential of DOM draining from a certain area of forest soils (in µg-DBP/m2-soil) was estimated to be reduced by 20.3% for trihalomethanes and increased by 37.5% for haloketones and have minor changes for haloacetonitriles and chloral hydrate (both <7%). Furthermore, the DBPs from chlorination of the soil-derived DOM showed lowered microtoxicity with N addition possibly due to reduced brominated DBP formation. Overall, this study highlights that N deposition may not increase drinking water toxicity through altering terrestrial DOM characteristics.