Sequential treatment escalation improves survival in patients with Waldenstrom macroglobulinemia.

Waldenstrom macroglobulinemia (WM) is a type of incurable, indolent B-cell lymphoma that is prone to relapse. Over time, treatment strategies have progressed from cytotoxic drugs to rituximab (R)- or bortezomib (V)-based regimens, and have now entered into an era of Bruton tyrosine kinase inhibitor (BTKi)-based regimens. However, the optimal treatment for the relapsed patients is still unclear. Herein, we analyzed the outcomes of the first- and second-line therapies in 377 patients with WM to illustrate the optimal choices for second-line therapy. After a median follow-up of 45.4 months, 89 patients received second-line therapy, and 53 patients were evaluated for response. The major response rates (MRR) of first- and second-line treatment were 65.1% and 67.9% (P = 0.678). The median progression-free survival (PFS) for the second-line therapy (PFS2) was shorter than that for the first-line therapy (PFS1) (56.3 vs 40.7 months, P = 0.03). However, PFS2 in targeted drugs group (R-/V-/BTKi-based regimens) was comparable to PFS1 (60.7 months vs 44.7 months, respectively, P = 0.21). Regarding second-line therapy, patients who underwent sequential treatment escalation-such as transitioning from cytotoxic drugs to R-/V-/BTKi-based regimens or from R-/V-based to BTKi-based regimens (escalation group) -had higher MRR (80.6% vs 47.1%, respectively, P = 0.023) and longer PFS2 (50.4 vs 23.5 months, respectively, P < 0.001) compared to the non-escalation group. Patients in the escalation group also had longer post-relapse overall survival compared with the non-escalation group (median, 50.4 vs 23.5 months, respectively, P = 0.039). Our findings indicate that sequential treatment escalation may improve the survival of patients with WM.

The dynamic coupling and spatio-temporal differentiation of green finance and industrial green transformation: Evidence from China regions.

Promoting the development of green finance and industrial green transformation is of great significance for achieving high-quality economic development in China's regions. A deep exploration of the dynamic coupling relationships and interaction mechanisms between green finance development and industrial green transformation has important theoretical value and practical implications. Based on relevant data from 2014 to 2019 for 30 provincial regions in China, this paper selects the Eastern, Central, Western, and Northeastern regions as the subjects of study. It constructs a comprehensive evaluation index system for the levels of green finance development and industrial green transformation. Since sorting out the interactive coupling theoretical mechanisms between the two, the paper employs a coupling coordination model to explore the coupling and coordinating relationships between green finance and industrial green transformation. Furthermore, using the Theil index, Moran's index, and Markov chain algorithms, the paper conducts a comparative analysis of the spatiotemporal differences and patterns in coupling coordination degrees between green finance and industrial green transformation in the four major regions, and identifies their causes. The results show that: overall, there is regional heterogeneity between green finance and industrial green transformation, and the mean coupling coordination degree is east, west, central and northeast in order from high to low. From the perspective of dynamic distribution, the coupling coordination of the four regions is moving to a high level, and it is difficult to achieve leapfrog development. As far as the sources of differences are concerned, intra-regional differences are the main cause of the differences in the coupling and coordinated development of the four regions, but the contribution rate shows a downward trend, and the gap between the four regions is gradually narrowing. To further reduce the coupling and coordination differences between green finance and industrial green transformation and development in the four regions, the region should strengthen mutual penetration and mutual radiation, increase the innovation of green financial products, improve the efficiency of green finance allocation, and provide an important reference for the realization of high-quality development of China's industrial green transformation.

[Genetic analysis of two cases with MYC "negative" Burkitt lymphoma].

OBJECTIVE: To carry out combined genetic analysis on two patients suspected for Burkitt lymphoma to facilitate their diagnosis and treatment. METHODS: G banded karyotyping and interphase and metaphase fluorescence in situ hybridization (FISH) were used to detect the specific sites of chromosomes by using separate and fusion probes. RESULTS: The separate probe showed no presence of MYC gene abnormality, while fusion probe confirmed the IGH::MYC translocation in the samples. Combined with the clinical features and pathological characteristics, the two patients were finally diagnosed with Burkitt lymphoma, which was confirmed by targeted capture next generation sequencing. CONCLUSION: The separate probe for the MYC gene has some shortcomings and should be used together with dual fusion probe to improve the accuracy of diagnosis.

Achieving health-oriented air pollution control requires integrating unequal toxicities of industrial particles.

Protecting human health from fine particulate matter (PM) pollution is the ambitious goal of clean air actions, but current control strategies  largely ignore the role of source-specific PM toxicity. Here, we proposed health-oriented control strategies by integrating the unequal toxic potencies of the most polluting industrial PMs. Iron and steel industry (ISI)-emitted PM2.5 exhibit about one order of magnitude higher toxic potency than those of cement and power industries. Compared with the current mass-based control strategy (prioritizing implementation of ultralow emission standards in the power sector), the proposed health-oriented control strategy (priority control of the ISI sector) could generate 5.4 times higher reduction in population-weighted toxic potency-adjusted PM2.5 exposure among polluting industries in China. Furthermore, the marginal abatement cost per unit of toxic potency-adjusted mass of ISI-emitted PM2.5 is only a quarter of that of the other two sectors under ultralow emission scenarios. We highlight that a health-oriented air pollution control strategy is urgently required to achieve cost-effective reductions in particulate exposure risks.

Long non-coding ribonucleic acid zinc finger E-box binding homeobox 1 antisense RNA 1 regulates myocardial fibrosis in diabetes through the Hippo-Yes-associated protein signaling pathway.

AIMS/INTRODUCTION: Fibrosis is the principle reason for heart failure in diabetes. Regarding the involvement of long non-coding ribonucleic acid zinc finger E-box binding homeobox 1 antisense 1 (ZEB1-AS1) in diabetic myocardial fibrosis, we explored its specific mechanism. MATERIALS AND METHODS: Human cardiac fibroblasts (HCF) were treated with high glucose (HG) and manipulated with plasmid cloning deoxyribonucleic acid 3.1-ZEB1-AS1/microribonucleic acid (miR)-181c-5p mimic/short hairpin RNA specific to sirtuin 1 (sh-SIRT1). ZEB1-AS1, miR-181c-5p expression patterns, cell viability, collagen I and III, α-smooth muscle actin (α-SMA), fibronectin levels and cell migration were assessed by reverse transcription quantitative polymerase chain reaction, cell counting kit-8, western blot and scratch tests. Nuclear/cytosol fractionation assay verified ZEB1-AS1 subcellular localization. The binding sites between ZEB1-AS1 and miR-181c-5p, and between miR-181c-5p and SIRT1 were predicted and verified by Starbase and dual-luciferase assays. The binding of SIRT1 to Yes-associated protein (YAP) and YAP acetylation levels were detected by co-immunoprecipitation. Diabetic mouse models were established. SIRT1, collagen I, collagen III, α-SMA and fibronectin levels, mouse myocardium morphology and collagen deposition were determined by western blot, and hematoxylin-eosin and Masson trichrome staining. RESULTS: Zinc finger E-box binding homeobox 1 antisense 1 was repressed in HG-induced HCFs. ZEB1-AS1 overexpression inhibited HG-induced HCF excessive proliferation, migration and fibrosis, and diminished collagen I, collagen III, α-SMA and fibronectin protein levels in cells. miR-181c-5p had targeted binding sites with ZEB1-AS1 and SIRT1. SIRT1 silencing/miR-181c-5p overexpression abrogated ZEB1-AS1-inhibited HG-induced HCF proliferation, migration and fibrosis. ZEB1-AS1 suppressed HG-induced HCF fibrosis through SIRT1-mediated YAP deacetylation. ZEB1-AS1 and SIRT1 were repressed in diabetic mice, and miR-181c-5p was promoted. ZEB1-AS1 overexpression improved myocardial fibrosis in diabetic mice, and reduced collagen I, collagen III, α-SMA and fibronectin protein levels in myocardial tissues. CONCLUSION: Long non-coding ribonucleic acid ZEB1-AS1 alleviated myocardial fibrosis through the miR-181c-5p-SIRT1-YAP axis in diabetic mice.

Minimal residual disease status improved the response evaluation in patients with Waldenström's macroglobulinemia.

Introduction: Minimal residual disease (MRD) has been recognized as an important prognostic factor of survival in patients with hematological malignancies. However, the prognostic value of MRD in Waldenström macroglobulinemia (WM) remains unexplored. Methods: We analyzed 108 newly diagnosed WM patients receiving systematic therapy and assessed for MRD by multiparameter flow cytometry (MFC) using bone marrow samples. Results: Of the total patients, 34 (31.5%) achieved undetectable MRD (uMRD). A hemoglobin level of >115 g/L (P=0.03), a serum albumin level of >35 g/L (P=0.01), a ß2-MG level of ≤3 mg/L (P=0.03), and a low-risk International Prognostic Scoring System for WM (IPSSWM) stage (P<0.01) were associated with a higher rate of uMRD. Improvements in monoclonal immunoglobulin (P<0.01) and hemoglobin (P=0.03) levels were more evident in uMRD patients compared with that in MRD-positive patients. The 3-year progression-free survival (PFS) was better in uMRD patients compared with that in MRD-positive patients (96.2% vs. 52.8%; P=0.0012). Landmark analysis also showed that uMRD patients had better PFS compared with MRD-positive patients after 6 and 12 months. Patients who achieved partial response (PR) and uMRD had a 3-year PFS of 100%, which was significantly higher than that of patients with MRD-positive PR (62.6%, P=0.029). Multivariate analysis showed that MRD positivity was an independent factor of PFS (HR: 2.55, P=0.03). Moreover, the combination of the 6th International Workshop on WM assessment (IWWM-6 Criteria) and MRD assessment had a higher 3-year AUC compared with the IWWM-6 criteria alone (0.71 vs. 0.67). Discussion: MRD status assessed by MFC is an independent prognostic factor for PFS in patients with WM, and its determination could improve the precision of response evaluation, especially in patients who achieved PR.

Oligomeric scaffolding for curvature generation by ER tubule-forming proteins.

The reticulons and receptor expression-enhancing proteins (REEPs) in the endoplasmic reticulum (ER) are necessary and sufficient for generating ER tubules. However, the mechanism of curvature generation remains elusive. Here, we systematically analyze components of the REEP family based on AI-predicted structures. In yeast REEP Yop1p, TM1/2 and TM3/4 form hairpins and TM2-4 exist as a bundle. Site-directed cross-linking reveals that TM2 and TM4 individually mediate homotypic dimerization, allowing further assembly into a curved shape. Truncated Yop1p lacking TM1 (equivalent to REEP1) retains the curvature-generating capability, undermining the role of the intrinsic wedge. Unexpectedly, both REEP1 and REEP5 fail to replace Yop1p in the maintenance of ER morphology, mostly due to a subtle difference in oligomerization tendency, which involves not only the TM domains, but also the TM-connecting cytosolic loop and previously neglected C-terminal helix. Several hereditary spastic paraplegia-causing mutations in REEP1 appear at the oligomeric interfaces identified here, suggesting compromised self-association of REEP as a pathogenic mechanism. These results indicate that membrane curvature stabilization by integral membrane proteins is dominantly achieved by curved, oligomeric scaffolding.

Fog-Haze Transition and Drivers in the Coastal Region of the Yangtze River Delta.

Low-visibility events (LVEs) are severe weather phenomena that are closely linked with anthropogenic pollution, which negatively affects traffic, air quality, human health, and the environment. This study conducted a two-month (from October to December 2019) continuous measurement campaign on Chongming Island in Shanghai to characterize the LVEs transition and its drivers. The LVEs accounted for 38% of the time during the campaign, of which mist accounted for 14%, fog-haze for 13%, haze for 6%, and fog for 5%. The fog and mist mainly occurred from midnight to early morning, while haze mostly occurred during the daytime. Different LVEs were interdependent and transitioned from one to another. Fog generally turned into haze after sunrise, while haze turned into fog after sunset. Their formation and evolution were caused by the combined impacts of meteorological conditions and aerosol particles. It was found that temperature difference was the dominant meteorological factor driving the evolution of LVEs. Within the short term, cooling led to a greater increase in relative humidity than humidification. Radiative cooling during the night promoted the formation of fog and mist. During fog and mist events, cloud condensation nuclei (CCN) were mainly internally mixed due to the impact of fog droplet removal and aqueous/heterogeneous aerosol reactions occurring under high humidity. Increased CCN concentration appeared to increase the fog droplet number and liquid water content in fog events. Overall, conditions of high humidity and high particle loading were conducive to LVEs, whereas conditions of sufficient water vapor at a low particle level and sufficient particles at a low humidity level also caused LVEs. This study provided insights into LVEs classification, evolution scheme, and aerosol roles from a micro point of view. The findings could be useful for improving forecasts of local radiative fog and other LVEs.

Landscape of immunoglobulin heavy chain gene repertoire and its clinical relevance to LPL/WM.

Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) is a heterogeneous disease in which the role of immunoglobulin heavy-chain genes (IGHs) remains unknown. To determine the clinical relevance of the IGH repertoire in patients with LPL/WM, we performed immunoglobulin gene rearrangement and complementarity determining region 3 (CDR3) analysis. The IGH variable gene (IGHV) repertoire was remarkably biased in LPL/WM. IGHV3-23, IGHV4-34, IGHV3-30, IGHV3-7, and IGHV3-74 accounted for one-half of the cohort's repertoire. Most cases (97.1%) were found to carry mutated IGHV genes, based on a 98% IGHV germline homology cutoff. IGHV3-30 was associated with long heavy chain CDR3, indicating there was specific antigen selection in LPL/WM. Patients with IGHV3-7 were significantly more likely to harbor the 6q deletion (P < .001) and an abnormal karyotype (P = .004). The IGHV hypermutation rate in patients with the MYD88 L265P mutation was significantly higher than that of wild-type patients (P = .050). IGHV3-23 and IGHV3-74 segments were more frequently detected in patients with MYD88-mutated LPL/WM (P = .050), whereas IGHV3-7 presented more frequently in MYD88 wild-type patients (P = .042). Patients with IGHV4, especially IGHV4-34, had higher levels of lactate dehydrogenase, and IGHV4 was a predictive marker of shorter progression-free survival. These results showed for the first time that the IGHV repertoire has clinical relevance in LPL/WM.

Anti-Epileptic Effect of Crocin on Experimental Temporal Lobe Epilepsy in Mice.

Temporal lobe epilepsy (TLE) is a common kind of refractory epilepsy. More than 30% TLE patients were multi-drug resistant. Some patients may even develop into status epilepticus (SE) because of failing to control seizures. Thus, one of the avid goals for anti-epileptic drug development is to discover novel potential compounds to treat TLE or even SE. Crocin, an effective component of Crocus sativus L., has been applied in several epileptogenic models to test its anti-epileptic effect. However, it is still controversial and its effect on TLE remains unclear. Therefore, we investigated the effects of crocin on epileptogenesis, generalized seizures (GS) in hippocampal rapid electrical kindling model as well as SE and spotaneous recurrent seizure (SRS) in pilocarpine-induced TLE model in ICR mice in this study. The results showed that seizure stages and cumulative afterdischarge duration were significantly depressed by crocin (20 and 50 mg/kg) during hippocampal rapid kindling acquisition. And crocin (100 mg/kg) significantly reduced the incidence of GS and average seizure stages in fully kindled animals. In pilocarpine-induced TLE model, the latency of SE was significantly prolonged and the mortality of SE was significantly decreased by crocin (100 mg/kg), which can also significantly suppress the number of SRS. The underlying mechanism of crocin may be involved in the protection of neurons, the decrease of tumor necrosis factor-α in the hippocampus and the increase of brain derived neurotrophic factor in the cortex. In conclusion, crocin may be a potential and promising anti-epileptic compound for treatment of TLE.

Purine nucleoside analogs plus rituximab are an effective treatment choice for hairy cell leukemia-variant.

Both characteristics and optimal treatment strategy for hairy cell leukemia-variant (HCL-v) remain elusive due to its rarity. We retrospectively analyzed the clinical features of HCL-v and the efficacy of first-line treatment options in a large Chinese cohort. In this study, we recruited 33 HCL-v patients (23 males and 10 females) with a median age of 59 years (range, 34-79 years). The chief complaints included abdominal mass and relative signs (67%) and abnormal complete blood count (27%). Immunophenotyping showed monoclonal B-cells positive for pan B-cell antigens and CD11c, weakly positive for CD103 and CD200, while negative for CD5, CD10, CD25, CD123, and annexin A1. No BRAF V600E mutation was detected, but TP53 abnormality was recurrent. Treatment choices included interferon-α (IFN-α) in 11 patients, chlorambucil (CLB) in 5 patients, single purine nucleoside analogs (PNA) in 3 patients, PNA plus rituximab (PNA + R) in 9 patients, and others in 3 patients. Four patients who received IFN-α or CLB treatment also underwent splenectomy. Patients who received PNA + R had a higher complete response rate (88% versus 5%, P < 0.001) and longer progression-free survival (PFS, 3-year PFS rate 42% [95% CI 1-84] vs. 16% [95% CI 3-40], P = 0.042) than those who received other regimens. Overall, HCL-v is an indolent lymphoma with unique characteristics. The PNA + R regimen is the preferred choice in the first-line treatment for HCL-v.

Small molecule peptidomimetic trypsin inhibitors: validation of an EKO binding mode, but with a twist.

Examination of a series of naturally-occurring trypsin inhibitor proteins, led to identification of a set of three residues (which we call the "interface triplet") to be determinant of trypsin binding affinity, hence excellent templates for small molecule mimicry. Consequently, we attempted to use the Exploring Key Orientation (EKO) strategy developed in our lab to evaluate small molecules that mimic the interface triplet regions of natural trypsin inhibitors, and hence potentially might bind and inhibit the catalytic activity of trypsin. A bis-triazole scaffold ("TT-mer") was the most promising of the molecules evaluated in silico. Twelve such compounds were synthesized and assayed against trypsin, among which the best showed a Kd of 2.1 µM. X-ray crystallography revealed a high degree of matching between an illustrative TT-mer's actual binding mode and that of the mimics that overlaid the interface triplet in the crystal structure. Deviation of the third side chain from the PPI structure seems to be due to alleviation of an unfavorable dipole-dipole interaction in the small molecule's actual bound conformation.

Clonal phylogeny and evolution of critical cytogenetic aberrations in multiple myeloma at single-cell level by QM-FISH.

Single-cell analysis is of significant importance in delineating the exact phylogeny of the subclonal population and in discovering subtle diversification. So far, studies of intratumor heterogeneity and clonal evolution in multiple myeloma (MM) were largely focused on the bulk tumor population level. We performed quantitative multigene fluorescence in situ hybridization (QM-FISH) in 129 longitudinal samples of 57 MM patients. All the patients had newly diagnosed and relapsed paired samples. An expanded cohort of 188 MM patients underwent conventional FISH (cFISH) to validate the cytogenetic evolution in bulk tumor level. Forty-three of 57 patients (75.4%) harbored 3 or 4 cytogenetic clones at diagnosis. We delineated the phylogeny of the subclonal tumor population and derived the evolutionary architecture in each patient. Patients with clonal stabilization had a significantly improved overall survival (OS) than those with other evolutionary patterns (median OS, 71.2 months vs 39.7 months vs 35.2 months vs 25.5 months, for stable, differential, branching, and linear patterns, respectively; P = .001). A high degree of consistency and complementarity across QM-FISH and cFISH was observed in the evaluation of cytogenetic evolution patterns in MM. Survival after relapse was greater influenced by the presence of high-risk aberrations at relapse (hazard ratio = 2.07) rather than present at diagnosis (hazard ratio = 1.55). This study shows that QM-FISH is a valuable tool to elucidate the clonal architecture at the single-cell level. Clonal evolution pattern is of prognostic significance, highlighting the need for repeated cytogenetic evaluation in relapsed MM.

The specialized mitotic behavior of human embryonic stem cells.

Human embryonic stem cells (hESCs) are self-renewing and pluripotent cells that originate from the inner cell mass of the blastocyst. Mitosis is fundamental to organism survival and reproduction and is responsible for the equal distribution of duplicated chromosomes into daughter cells. Mitotic dysfunction is associated with a wide variety of human diseases, not least cancer. hESCs have a unique cell cycle distribution, but it is unclear exactly how the mitotic activity of hESCs is related to their proliferation and differentiation. Here, we established a cell line of hESCs stably expressing GFP-α-tubulin and mCherry-H2B by lentiviral infection to analyze and visualize mitosis in detail. During metaphase, the mitotic spindle was smaller and wider and contained a greater proportion of astral microtubules than normal cells. In addition, spindle microtubules were more stable, and chromosome alignment was faster in hESCs than in somatic cells. We also found that the spindle assembly checkpoint was functional in hESCs. These findings thus reveal a specialized mitotic behavior of hESCs.

Undetectable minimal residual disease is an independent prognostic factor in splenic marginal zone lymphoma.

The role of minimal residual disease (MRD) in splenic marginal zone lymphoma (SMZL) has not been well studied. We prospectively designed a study to evaluate undetectable MRD (uMRD) by multiparameter flow cytometry as a prognostic factor. Residual disease level of <0·01% was defined as uMRD. A total of 71 newly diagnosed patients with bone marrow involvement were enrolled and all received rituximab-based therapy. The overall response rate (ORR) was 98·5% (70/71), with a complete remission (CR) rate of 54·9% (39/71). There were a total of 295 MRD detections in bone marrow and 77·4% patients (55/71) had uMRD. The 5-year progression-free survival (PFS) [(74·8 ± 6·5)% vs. (31·4 ± 12·6)%, P < 0·001] and 5-year overall survival (OS) [(87·2 ± 5·6)% vs. (68·9 ± 13·4)%, P = 0·035] were significantly higher in uMRD patients than in MRD-positive patients. The 5-year PFS in partial remission (PR) patients with positive MRD was significantly poorer than that of PR patients with uMRD [(21·1 ± 12·9)% vs. (83·3 ± 8·8)%, P = 0·005]. Multivariate prognostic analysis revealed that uMRD was an independent good prognostic factor for PFS (hazard ratio 0·162, 95% confidence interval 0·041-0·635; P = 0·009). All these results highlight uMRD as an independent prognostic factor in patients with SMZL, especially for patients who only achieve PR.

FIT2 organizes lipid droplet biogenesis with ER tubule-forming proteins and septins.

Lipid droplets (LDs) are critical for lipid storage and energy metabolism. LDs form in the endoplasmic reticulum (ER). However, the molecular basis for LD biogenesis remains elusive. Here, we show that fat storage-inducing transmembrane protein 2 (FIT2) interacts with ER tubule-forming proteins Rtn4 and REEP5. The association is mainly transmembrane domain based and stimulated by oleic acid. Depletion of ER tubule-forming proteins decreases the number and size of LDs in cells and Caenorhabditis elegans, mimicking loss of FIT2. Through cytosolic loops, FIT2 binds to cytoskeletal protein septin 7, an interaction that is also required for normal LD biogenesis. Depletion of ER tubule-forming proteins or septins delays nascent LD formation. In addition, FIT2-interacting proteins are up-regulated during adipocyte differentiation, and ER tubule-forming proteins, septin 7, and FIT2 are transiently enriched at LD formation sites. Thus, FIT2-mediated nascent LD biogenesis is facilitated by ER tubule-forming proteins and septins.

Effects of shipping emissions on cloud physical properties over coastal areas near Shanghai.

To investigate the effects of shipping aerosols on radiation, cloud physical properties, and near-surface PM2.5, four sensitive experiments with the WRF-Chem model were performed over coastal areas near Shanghai for July 2014. In general, the direct effect of shipping aerosols resulted in negative shortwave (SW) radiation forcing at the land surface. However, when considering the indirect effect, the downward SW radiation at the sea surface declined significantly. By the direct effect, shipping aerosols could modify cloud structure, resulting in a higher cloud base, lower cloud top, and shallower cloud depth. With the indirect effect included, both the cloud base and cloud top showed a declining trend over sea areas. The indirect effect of shipping aerosols was relatively more significant in influencing clouds. For example, the results revealed a 1.2% change of low cloud coverage from the indirect effect but only a 0.1% change due to the direct effect. Through their direct and indirect effects, shipping aerosols cause non-negligible impacts on precipitation, which are concentrated within light precipitation (<0.1 mm h-1). Finally, we concluded that after considering the shipping aerosols, the peak of the cloud droplet spectrum increases by about 50 cm-3/µm. It can be found that when the average volume radius of the cloud droplet is less than 2 µm, the number concentration of cloud droplets increases sharply, and when the average radius of the cloud drop is greater than 2 µm and less than 5 µm, the cloud droplet number concentration drops sharply.