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Jing-Min Zheng,1,* Han-Xi Zhou,1,* Hong-Yuan Yu,1,* Yu-Hui Xia,2 Qing-Xin Yu,2 Hang-Shuai Qu,1 Jia-Qian Bao1 1Department of Urology, Taizhou Hospital, Wenzhou Medical University, Linhai, Zhejiang, People’s Republic of China; 2Department of Pathology, Taizhou Hospital, Wenzhou Medical University, Linhai, Zhejiang, People’s Republic of China*These authors contributed equally to this work.Correspondence: Jing-Min ZhengDepartment of Urology, Taizhou Hospital, Wenzhou Medical University, 150 Ximen Road, Linhai, Zhejiang, 317000, People’s Republic of ChinaTel +86-576-85133065Fax +86-576-85199800Email zhengjingmin@enzemed.comBackground: Contradictive results about the direct role of C5a/C5aR1 axis in different cancer cells have been reported. The direct effect of C5a on human renal cell carcinoma (RCC) cells and the underlying mechanism are not clear. The aim of this study is to investigate the role of C5a/C5aR1 axis in RCC cells and its working mechanism.Methods: RCC cells were infected with lentivirus Lenti-C5a, which was designed to over-express secretory C5a in the cells, or directly treated with recombinant C5a, the influence of these treatments in the cells and the underlying mechanism were explored.Results: Transfection of RCC cells with Lenti-C5a markedly increased the production of C5a and significantly increased the proliferation, migration, and invasion of RCC cells, but direct addition of C5a to the cell culture medium had no such effects though it indeed induced a transient intracellular calcium rise. RCC cells were found to express carboxypeptidase D and M, which reportedly to inactivate C5a. Also, the RCC cells stably transfected with Lenti-C5a produced larger transgrafted tumors in nude mice compared with the non-transfected or control virus transfected cells. In addition, over-expression of C5a significantly increased the expression and phosphorylation of STAT3 as well as the phosphorylated JNK level. Furthermore, the effect of C5a over-expression on RCC cells’ proliferation, migration, and invasion could be blocked by Stattic, a STAT3-specific inhibitor.Conclusion: Chronic over-activation of C5a/C5aR1 axis could directly increase RCC cells’ proliferation, migration, and invasion and thus contribute directly to the progression of the disease. Over-activation of STAT3 pathway is among the underlying mechanism.Keywords: C5a, C5aR1, renal cell carcinoma, STAT3

Gui-Qian Huang,1,* Hao-Ran Cheng,1,* Yue-Min Wu,1 Qian-Qian Cheng,2 Yu-Min Wang,3 Jia-Li Fu,3 Hui-Xin Zhou,3 Zhen Wang1 1Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, People’s Republic of China; 2School of Mental Health, Wenzhou Medical University, Wenzhou 325000, Zhejiang, People’s Republic of China; 3Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhen WangDepartment of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, People’s Republic of ChinaTel +86 577-555780166Fax +86 577-55578033Email wangzhen_wenzhou@163.comBackground and aim: Stroke-associated pneumonia (SAP) is a common complication in patients with acute ischemic stroke (AIS). This study explored the potential relationship between serum vitamin D levels and SAP.Methods: This study recruited 863 consecutive AIS patients. In-hospital SAP was defined as a complication that occurred after stroke, during hospitalization, that was confirmed radiographically. Serum vitamin D levels were measured within 24 hrs of admission and the patients were divided into vitamin D sufficient (>50 nmol/L), insufficient (25–50 nmol/L), and deficient (Results: In this study, 102 (11.8%) patients were diagnosed with SAP. Compared to the patients without SAP, patients with SAP had significantly lower vitamin D levels (P = 0.023). The incidence of SAP was significantly higher in patients with vitamin D deficiency than in those with vitamin D insufficiency or sufficiency (21.2% vs 16.2% & 9.5%, P = 0.006). After adjusting for confounders, vitamin D deficiency and insufficiency were independently associated with SAP (OR = 3.034, 95% CI = 1.207–7.625, P = 0.018; OR = 1.921, 95% CI = 1.204–3.066, P = 0.006, respectively). In multiple-adjusted spline regression, vitamin D levels showed a linear association with the risk of SAP (P < 0.001 for linearity).Conclusion: Reduced vitamin D is a potential risk factor of in-hospital SAP, which can help clinicians identify high-risk SAP patients.Keywords: acute ischemic stroke, stroke-associated pneumonia, vitamin D

Yi Kang,1,2,* Han Ding,1,2,* Hengxing Zhou,1,2 Zhijian Wei,1,2 Lu Liu,1,2 Dayu Pan,1,2 Shiqing Feng1,2 1Department of Orthopaedics, Tianjin Medical University General Hospital, 2Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, People’s Republic of China *These authors contributed equally to this work Study design: A literature review of worldwide epidemiology of spinal cord injury (SCI). Objectives: To review the epidemiological indicators of SCI, such as incidence, prevalence, demographic characteristics, etiology, level and severity of injury, complications and mortality. Setting: The Department of Orthopaedics, Tianjin Medical University General Hospital, ­Heping District, Tianjin, People’s Republic of China. Methods: We searched articles published in PubMed, Medline, EMBASE and the Web of ­Science between January 1993 and June 2017 using the key words “spinal cord injury”, “­traumatic spinal cord injury”, “non-traumatic spinal cord injury” and “epidemiology”. The incidence, etiology, prevalence, patient demographics, level and severity of injury, complications and mortality were reviewed from the articles. Results: The epidemiology of SCI has changed. Motor vehicle accidents and falls have become the most common reasons of injury gradually. Incidence of SCI varies by regions or countries, and it has gradually increased with the expansion of human activities. The number of male patients were significantly more than female, the average age of patients with SCI had a tendency to increase gradually. The cervical level of spine was the most common part of injury; there were more number of patients with tetraplegia than patients with paraplegia. Electrolyte disturbances, pulmonary infections, urinary tract infections and bedsores were the four most common complications. Conclusion: We must have a greater understanding of epidemiology to implement more preventative measures. The epidemiology in different regions is of significant difference, which may be resulted from economic, science and technology, medical, geographical and even social conditions. Therefore, we must establish appropriate intervention measures according to the particularity of population. Keywords: spinal cord injury, etiology, incidence, patient demographics, complications

Hui Qi1, Zhen Zhong1, Han-Xin Zhou1, Chun-Yan Deng1, Hai Zhu2, Jin-Feng Li2, Xi-Li Wang2, Fu-Rong Li1,31Clinical Medical Research Center, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 2Shenzhen Bioeasy Biotechnologies Co, Ltd, 3Shenzhen Institute of Gerontology, Shenzhen, People's Republic of ChinaBackground: Escherichia coli O157:H7 (E. coli O157:H7) is an important pathogenic bacterium that threatens human health. A rapid, simple, highly sensitive, and specific method for the detection of E. coli O157:H7 is necessary.Methods: In the present study, immunomagnetic nanoparticles (IMPs) were prepared with nanopure iron as the core, coated with E. coli O157:H7 polyclonal antibodies. These IMPs were used in combination with immunochromatographic assay (ICA) and used to establish highly sensitive and rapid kits (IMPs+ICA) to detect E. coli O157:H7. The kits were then used to detect E. coli O157:H7 in 150 food samples and were compared with conventional ICA to evaluate their efficacy.Results: The average diameter of IMPs was 56 nm and the amount of adsorbed antibodies was 106.0 µg/mg. The sensitivity of ICA and IMPs+ICA was 105 colony-forming units/mL and 103 CFUs/mL, respectively, for purified E. coli O157:H7 solution. The sensitivity of IMPs+ICA was increased by two orders, and its specificity was similar to ICA.Conclusion: The kits have the potential to offer important social and economic benefits in the screening, monitoring, and control of food safety.Keywords: colloidal gold, immunomagnetic nanoparticles, Escherichia coli O157:H7, immunochromatographic assay

Qing Li1, Hui Qi1, Han-Xin Zhou1, Chun-Yan Deng1, Hai Zhu3, Jin-Feng Li3, Xi-Li Wang3, Fu-Rong Li1,21Clinical Medical Research Center, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, People's Republic of China; 2Shenzhen Institute of Gerontology, Shenzhen, People's Republic of China; 3Shenzhen Bioeasy Biotechnologies Co Ltd, Shenzhen, People's Republic of ChinaAbstract: Fe3O4 particles are currently used as the core of immunomagnetic microspheres in the immunomagnetic enrichment assay of circulating tumor cells (CTCs). It is difficult to further improve the sensitivity of CTC detection or to improve tumor cell-type identification and characterization. In the present study, we prepared immunomagnetic nanoparticles with nanopure iron as the core, coated with anti-cytokeratin 7/8 (CK7/8) monoclonal antibody. These immunomagnetic nanoparticles (IMPs) were used in conjunction with immunocytochemistry (ICC) to establish a refined immunomagnetic nanoparticle enrichment assay for CTC detection in non-small cell lung cancer (NSCLC). The assay was compared with nested reverse transcription polymerase chain reaction (RT-PCR) to detect CK19 mRNA and lung specific X protein (LUNX) mRNA. Human lung adenocarcinoma cell line A549 was used for sensitivity and specificity evaluation. Peripheral blood samples were collected from each group for CTC detection. The average diameter of the immunomagnetic nanoparticles was 51 nm, and the amount of adsorbed antibodies was 111.2 µg/mg. We could detect down to one tumor cell in 5 × 107 peripheral blood mononuclear cells. The sensitivity was consistent with that of nested RT-PCR; however, the false positive rate was significantly reduced. The modified assay combined with ICC did not differ from nested RT-PCR in sensitivity, but it had significantly increased specificity. This approach could, therefore, contribute to identification of micrometastases, re-defining clinical staging, and guiding individual postoperative treatments. The technique shows considerable potential clinical value and further clinical trials are warranted.Keywords: NSCLC, circulating tumor cells, nested RT-PCR, immunomagnetic nanoparticles, immunocytochemistry

Purpose: Dihydroartemisinin (DHA) has recently shown antitumor activity in human pancreatic cancer cells. However, its effect on antiangiogenic activity in pancreatic cancer is unknown, and the mechanism is unclear. This study was aimed to investigate whether DHA would inhibit angiogenesis in human pancreatic cancer.Methods: Cell viability and proliferation, tube formation of human umbilical vein endothelial cells (HUVECs), nuclear factor (NF)-κB DNA-binding activity, expressions of vascular endothelial growth factor (VEGF), interleukin (IL)-8, cyclooxygenase (COX)-2, and matrix metalloproteinase (MMP)-9 were examined in vitro. The effect of DHA on antiangiogenic activity in pancreatic cancer was also assessed using BxPC-3 xenografts subcutaneously established in BALB/c nude mice.Results: DHA inhibited cell proliferation and tube formation of HUVECs in a time- and dose-dependent manner and also reduced cell viability in pancreatic cancer cells. DHA significantly inhibited NF-κB DNA-binding activity, so as to tremendously decrease the expression of NF-κB-targeted proangiogenic gene products: VEGF, IL-8, COX-2, and MMP-9 in vitro. In vivo studies, DHA remarkably reduced tumor volume, decreased microvessel density, and down-regulated the expression of NF-κB-related proangiogenic gene products.Conclusions: Inhibition of NF-κB activation is one of the mechanisms that DHA inhibits angiogenesis in human pancreatic cancer. We also suggest that DHA could be developed as a novel agent against pancreatic cancer. [ABSTRACT FROM AUTHOR]

The low-complexity domain of hnRNPA1 (A1-LCD) phase separates in a salt-dependent manner. Unlike many intrinsically disordered proteins (IDPs) whose phase separation is suppressed by increasing salt concentrations, the phase separation of A1-LCD is promoted by >100 mM NaCl. To investigate the atypical salt effect on A1-LCD phase separation, we carried out all-atom molecular dynamics simulations of systems comprising multiple A1-LCD chains at NaCl concentrations from 50 to 1000 mM NaCl. The ions occupy first shell as well as more distant sites around the IDP chains, with Arg sidechains and backbone carbonyls the favored partners of Cl - and Na + , respectively. They play two direct roles in driving A1-LCD condensation. The first is to neutralize the high net charge of the protein (+9) by an excess of bound Cl - over Na + ; the second is to bridge between A1-LCD chains, thereby fortifying the intermolecular interaction networks in the dense phase. At high concentrations, NaCl also indirectly strengthens π-π, cation-π, and amino-π interactions, by drawing water away from the interaction partners. Therefore, at low salt, A1-LCD is prevented from phase separation by net charge repulsion; at intermediate concentrations, NaCl neutralizes enough of the net charge while also bridging IDP chains to drive phase separation. This drive becomes even stronger at high salt due to strengthened π-type interactions. Based on this understanding, four classes of salt dependence of IDP phase separation can be predicted from amino-acid composition., Competing Interests: MM, SD, HZ No competing interests declared, (© 2024, MacAinsh et al.)

Objective: To explore the relevant factors associated with poor prognosis in patients suffering from chronic obstructive pulmonary disease (COPD) combined with pulmonary embolism (PE), and investigate the predictive value of the simplified pulmonary embolism severity index (sPESI) score on adverse outcomes in these patients. Methods: A total of 168 patients with COPD and PE who were treated at West China Hospital of Sichuan University from January 1, 2018, to December 30, 2020 were retrospectively included. Patients were divided into adverse outcome group and control group based on the occurrence of adverse outcomes [any of the following events: in-hospital death, intensive care unit (ICU) admission, and endotracheal intubation]. Correlation factors for poor prognosis were explored using multivariate logistic regression analysis. Receiver operating characteristic (ROC) curve was employed to assess the predictive value of the sPESI score for adverse outcomes in COPD patients with PE. Results: A total of 168 patients were studied, with an age of (73.4±10.4) years and 119 male (70.8%). In the adverse outcome group, there were 18 cases (10.7%), including 12 in-hospital deaths, 6 ICU admission, and 1 endotracheal intubation. The control group comprised 150 cases (89.3%). Statistically significant differences were observed between two groups regarding the proportion of patients with diabetes, nephrotic syndrome, severe pneumonia, respiratory failure and lower extremity edema, and the pulse, diastolic blood pressure, pulse oxygen saturation, lactate dehydrogenase and cholesterol levels (all P <0.05). Multivariate logistic regression analysis revealed that severe pneumonia, respiratory failure, lower extremity edema, and diastolic blood pressure<60 mmHg (1 mmHg=0.133 kPa) are correlative factors of adverse outcomes in patients with COPD complicated by PE [ OR (95% CI ) were 7.363 (1.053-51.772), 4.077 (1.030-16.133), 4.490 (1.131-17.832), and 8.060 (1.209-53.918), respectively, all P <0.05]. The sPESI score in the adverse outcome group was higher than that in the control group [ M ( Q 1 , Q 3 ), 2 (2, 2) vs 1 (1, 2) score, P =0.006]; the optimal cutoff value for sPESI score was 2 score, the sensitivity was 77.8%, the specificity was 54.0%, and the area under the curve (AUC) and 95% CI were 0.681 (0.554-0.809) based on the ROC curve analysis. Patients with sPESI≥2 score exhibited a 4.109-fold (95% CI : 1.292-13.063, P =0.017) increased risk of adverse prognosis compared to those with sPESI<2 score. Conclusions: Patients with COPD combined with PE have a higher incidence of adverse prognostic outcomes. Severe pneumonia, respiratory failure, lower limb edema, and diastolic pressure<60 mmHg are associated factors for poor prognosis. The sPESI score has some value in predicting adverse outcomes in COPD patients with PE.

In sperm cells, protamine replaces histones to compact DNA 10-20 times more than in somatic cells. To characterize the extreme compaction, we employed confocal microscopy and optical tweezers to determine the conformations and stability of protamine-bound λ-DNA. Confocal images show increasing compaction of λ-DNA at increasing protamine concentration. In the presence of protamine, single λ-DNA molecules form tangles that withstand forces strong enough (∼55 pN) for strand separation and shorten the contour length by up to 40% even at high forces, as well as bends and loops that rupture at 10-40 pN forces. Strand separation nucleates tangles, implicating protamine interactions with DNA bases. Molecular dynamics simulations show that Arg sidechains of protamine each form hydrogen bonds with multiple bases, frequently in the form of a wedge between the two strands of DNA. Protamine may participate in both local and higher-order chromatin organization, leading to extreme compaction and global transcription silencing.

How the sequences of intrinsically disordered proteins (IDPs) code for functions is still an enigma. Dynamics, in particular residue-specific dynamics, holds crucial clues. Enormous efforts have been spent to characterize residue-specific dynamics of IDPs, mainly through NMR spin relaxation experiments. Here, we present a sequence-based method, SeqDYN, for predicting residue-specific backbone dynamics of IDPs. SeqDYN employs a mathematical model with 21 parameters: one is a correlation length and 20 are the contributions of the amino acids to slow dynamics. Training on a set of 45 IDPs reveals aromatic, Arg, and long-branched aliphatic amino acids as the most active in slow dynamics whereas Gly and short polar amino acids as the least active. SeqDYN predictions not only provide an accurate and insightful characterization of sequence-dependent IDP dynamics but may also serve as indicators in a host of biophysical processes, including the propensities of IDP sequences to undergo phase separation., Competing Interests: SQ, HZ No competing interests declared, (© 2023, Qin and Zhou.)

The rules of how amino acids dictate the physical properties of biomolecular condensates are still incomplete. Here, we study condensates formed by tetrapeptides of the form XXssXX. Eight peptides form four types of condensates at different concentrations and pHs: droplets (X = F, L, M, P, V, and A), amorphous dense liquids (X = L, M, P, V, and A), amorphous aggregates (X = W), and gels (X = I, V, and A). The peptides exhibit differences in phase equilibrium and material properties, including a 368-fold range in the threshold concentration for phase separation and a 3,856-fold range in viscosity. All-atom molecular dynamics simulations provide physical explanations of these results. The present work also reveals widespread critical behaviors-including critical slowing down manifested by amorphous dense liquids and critical scaling obeyed by fusion speed-with broad implications for condensate functions., Competing Interests: DECLARATION OF INTERESTS The authors declare that they have no competing interests.

Objective: To analyze the factors affecting delayed chemotherapy in children with Burkitt lymphoma (BL) and their influence on prognosis. Methods: Retrospective cohort study. Clinical data of 591 children aged ≤18 years with BL from May 2017 to December 2022 in China Net Childhood Lymphoma (CNCL) was collected. The patients were treated according to the protocol CNCL-BL-2017. According to the clinical characteristics, therapeutic regimen was divided into group A, group B and group C .Based on whether the total chemotherapy time was delayed, patients were divided into two groups: the delayed chemotherapy group and the non-delayed chemotherapy group. Based on the total delayed time of chemotherapy, patients in group C were divided into non-delayed chemotherapy group, 1-7 days delayed group and more than 7 days delayed group. Relationships between delayed chemotherapy and gender, age, tumor lysis syndrome before chemotherapy, bone marrow involvement, disease group (B/C group), serum lactate dehydrogenase (LDH) > 4 times than normal, grade Ⅲ-Ⅳ myelosuppression after chemotherapy, minimal residual disease in the interim assessment, and severe infection (including severe pneumonia, sepsis, meningitis, chickenpox, etc.) were analyzed. Logistic analysis was used to identify the relevant factors. Kaplan-Meier method was used to analyze the patients' survival information. Log-Rank was used for comparison between groups. Results: Among 591 patients, 504 were males and 87 were females, the follow-up time was 34.8 (18.6,50.1) months. The 3-year overall survival (OS) rate was (92.5±1.1)%,and the 3-year event-free survival (EFS) rate was (90.5±1.2)%. Seventy-three (12.4%) patients were in delayed chemotherapy group and 518 (87.6%) patients were in non-delayed chemotherapy group. The reasons for chemotherapy delay included 72 cases (98.6%) of severe infection, 65 cases (89.0%) of bone marrow suppression, 35 cases (47.9%) of organ dysfunction, 22 cases (30.1%) of tumor lysis syndrome,etc. There were 7 cases of chemotherapy delay in group B, which were seen in COPADM (vincristine+cyclophosphamide+prednisone+daunorubicin+methotrexate+intrathecal injection,4 cases) and CYM (methotrexate+cytarabine+intrathecal injection,3 cases) stages. There were 66 cases of chemotherapy delay in group C, which were common in COPADM (28 cases) and CYVE 1 (low dose cytarabine+high dose cytarabine+etoposide+methotrexate, 12 cases) stages. Multinomial Logistic regression analysis showed that the age over 10 years old ( OR =0.54,95% CI 0.30-0.93), tumor lysis syndrome before chemotherapy ( OR =0.48,95% CI 0.27-0.84) and grade Ⅲ-Ⅳ myelosuppression after chemotherapy ( OR =0.55,95% CI 0.33-0.91)were independent risk factors for chemotherapy delay.The 3-year OS rate and the 3-year EFS rate of children with Burkitt lymphoma in the delayed chemotherapy group were lower than those in the non-delayed chemotherapy group ((79.4±4.9)% vs. (94.2±1.1)%, (80.2±4.8)% vs. (92.0±1.2)%,both P <0.05). The 3-year OS rate of the group C with chemotherapy delay >7 days (42 cases) was lower than that of the group with chemotherapy delay of 1-7 days (22 cases) and the non-delay group (399 cases) ((76.7±6.9)% vs. (81.8±8.2)% vs. (92.7±1.3)%, P =0.002).The 3-year OS rate of the chemotherapy delay group (9 cases) in the COP (vincristine+cyclophosphamide+prednisone) phase was lower than that of the non-chemotherapy delay group (454 cases) ((66.7±15.7)% vs. (91.3±1.4)%, P =0.005). Similarly, the 3-year OS rate of the chemotherapy delay group (11 cases) in the COPADM1 phase was lower than that of the non-chemotherapy delay group (452 cases) ((63.6±14.5)% vs. (91.5±1.3)%, P =0.001). Conclusions: The delayed chemotherapy was related to the age over 10 years old, tumor lysis syndrome before chemotherapy and grade Ⅲ-Ⅳ myelosuppression after chemotherapy in pediatric BL. There is a significant relationship between delayed chemotherapy and prognosis of BL in children.

Alzheimer's disease (AD) is caused by the assembly of amyloid-beta (Aβ) peptides into oligomers and fibrils. Endogenous Aβ aggregation may be assisted by cell membranes, which can accelerate the nucleation step enormously, but knowledge of membrane-assisted aggregation is still very limited. Here we used extensive MD simulations to structurally and energetically characterize key intermediates along the membrane-assisted aggregation pathways of Aβ40. Reinforcing experimental observations, the simulations reveal unique roles of GM1 ganglioside and cholesterol in stabilizing membrane-embedded β-sheets and of Y10 and K28 in the ordered release of a small oligomeric seed into solution. The same seed leads to either an open-shaped or R-shaped fibril, with significant stabilization provided by inter- or intra-subunit interfaces between a straight β-sheet (residues Q15-D23) and a bent β-sheet (residues A30-V36). This work presents the first comprehensive picture of membrane-assisted aggregation of Aβ40, with broad implications for developing AD therapies and rationalizing disease-specific polymorphisms of amyloidogenic proteins.

Background: Multisystem inflammatory syndrome in adults (MIS-A) is a rare but severe disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 infection. It develops in adults with inflammation of different organs including the gastrointestinal tract, heart, kidneys, skin and hematopoietic system., Case Summary: We present a 58-year-old Chinese man diagnosed with MIS-A. His chief complaints were fever, generalized fatigue and anorexia, accompanied with rashes on his back. Further examination showed cardiac, renal and liver injury. He had melena and gastroscopy indicated esophageal ulcer and severe esophagitis. Repeated blood and sputum culture did not show growth of bacteria or fungi. Antibiotic treatment was stopped due to unsatisfactory performance. His condition improved after prednisone and other supportive treatment., Conclusion: Gastrointestinal involvement in MIS-A is not uncommon. Intestinal involvement predominates, and esophageal involvement is rarely reported. Esophageal ulcer with bleeding could also be a manifestation of MIS-A., Competing Interests: Conflict-of-interest statement: All authors declare that they have no competing interests., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: To evaluate the efficacy of avatinib plus allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the treatment of recurrent/refractory RUNX1-RUNX1T1 positive acute myeloid leukemia (AML) with KIT mutations. Method: A retrospective study was conducted on the clinical data of seven relapsed/refractory AML patients containing the RUNX1-RUNX1T1 fusion gene and KIT mutation who received afatinib plus allo-HSCT treatment at the First Affiliated Hospital of Soochow University from June 2019 to June 2023. Results: The seven AML patients included one male and six females with a median age of 37 (18-56) years. All seven patients had KIT mutations (five positive for D816V and two positive for D816Y) . There were two refractory patients and five relapsed patients (all of whom had bone marrow recurrence) . All patients had to complete at least one course of treatment with afatinib before transplantation. Four patients achieved complete remission (CR) after treatment with afatinib, six patients had negative KIT gene mutations, and one had a decreased KIT gene mutational burden. There were three cases of unrelated identical transplantation and four cases of haploidentical transplantation. All patients received the modified Bu/Cy pretreatment regimen. After transplantation, all patients were successfully implanted and a bone marrow examination showed CR and minimal residual disease turned negative. Five patients exhibited negative fusion genes. Two patients died from infection following transplantation. Conclusion: Afatinib plus allo-HSCT may be an effective and safe new treatment strategy for RUNX1-RUNX1T1 positive AML patients with KIT-D816 mutation.

Objective: To explore the prognostic factors of primary plasma cell leukemia (pPCL) in the era of novel agents. Methods: The clinical data of 66 patients with pPCL treated at the Department of Haematology, Beijing Chao-Yang Hospital, Capital Medical University from 2011 to 2022 were retrospectively collected to analyze their prognostic factors. Results: Among the 66 patients with pPCL, the median age was 59 (range: 29-79) years. The median overall survival (OS) duration was 19.0 (95% CI 10.4-27.6) months, and the median progression-free survival (PFS) duration was 11.0 (95% CI 6.5-15.6) months. The median OS and PFS were significantly longer in patients with the best post-treatment response of very good partial remission (VGPR) or better than in patients with a response of partial remission (PR) or worse (median OS: 33.0 months vs 6.0 months, P <0.001; median PFS: 16.0 months vs 3.0 months, P <0.001). OS was significantly longer in patients who underwent autologous hematopoietic stem cell transplantation than in those who did not undergo transplantation (49.0 months vs 6.0 months, P =0.002), and there was a trend toward a longer PFS in patients who underwent transplantation than in those who did not undergo transplantation (19.0 months vs 8.0 months, P =0.299). The median OS and PFS were significantly longer in patients who received maintenance therapy than in those who did not receive maintenance therapy (median OS: 56.0 months vs 4.0 months, P <0.001; median PFS: 20.0 months vs 2.0 months, P <0.001). Multivariate analysis showed that hypercalcemia was an independent risk factor ( HR =3.204, 95% CI 1.068-9.610, P =0.038) for patients with pPCL, while receiving maintenance therapy ( HR =0.075, 95% CI 0.022-0.253, P <0.001) and post-treatment response of VGPR or better ( HR =0.175, 95% CI 0.048-0.638, P =0.008) were independent protective factors for patients with pPCL. Conclusions: In the era of novel agents, hypercalcemia, receiving maintenance therapy, and post-treatment response of VGPR or better are independent prognostic factors for pPCL.

Biomolecular condensates, formed through phase separation, are upending our understanding in much of molecular, cell, and developmental biology. There is an urgent need to elucidate the physicochemical foundations of the behaviors and properties of biomolecular condensates. Here we aim to fill this need by writing a comprehensive, critical, and accessible review on the fundamental aspects of phase-separated biomolecular condensates. We introduce the relevant theoretical background, present the theoretical basis for the computation and experimental measurement of condensate properties, and give mechanistic interpretations of condensate behaviors and properties in terms of interactions at the molecular and residue levels.

We present a method, FMAPS(q), for calculating the structure factor, S ( q ) , of a protein solution, by extending our f ast Fourier transform-based m odeling of a tomistic p rotein-protein interactions (FMAP) approach. The interaction energy consists of steric, nonpolar attractive, and electrostatic terms that are additive among all pairs of atoms between two protein molecules. In the present version, we invoke the free-rotation approximation, such that the structure factor is given by the Fourier transform of the protein center-center distribution function g C ( R ) . At low protein concentrations, g C ( R ) can be approximated as e - β W ( R ) , where W ( R ) is the potential of mean force along the center-center distance R . We calculate W ( R ) using FMAPB2, a member of the FMAP class of methods that is specialized for the second virial coefficient [Qin and Zhou, J Phys Chem B 123 (2019) 8203-8215]. For higher protein concentrations, we obtain S ( q ) by a modified random-phase approximation, which is a perturbation around the steric-only energy function. Without adjusting any parameters, the calculated structure factors for lysozyme and bovine serum albumin at various ionic strengths, temperatures, and protein concentrations are all in reasonable agreement with those measured by small-angle X-ray or neutron scattering. This initial success motivates further developments, including removing approximations and parameterizing the interaction energy function.

Exposure to fine particulate matter (PM 2.5 ) during pregnancy has been inversely associated with neonatal neurological development. However, the associations of exposure to specific PM 2.5 constituents with neonatal neurological development remain unclear. We investigated these associations and examined the mediating role of meconium metabolites in a Chinese birth cohort consisting of 294 mother-infant pairs. Our results revealed that exposure to PM 2.5 and its specific constituents (i.e., organic matter, black carbon, sulfate, nitrate, and ammonium) in the second trimester, but not in the first or third trimester, was inversely associated with the total neonatal behavioral neurological assessment (NBNA) scores. The PM 2.5 constituent mixture in the second trimester was also inversely associated with NBNA scores, and sulfate was identified as the largest contributor. Furthermore, meconium metabolome analysis identified four metabolites, namely, threonine, lysine, leucine, and saccharopine, that were associated with both PM 2.5 constituents and NBNA scores. Threonine was identified as an important mediator, accounting for a considerable proportion (14.53-15.33%) of the observed inverse associations. Our findings suggest that maternal exposure to PM 2.5 and specific constituents may adversely affect neonatal behavioral development, in which meconium metabolites may play a mediating role.

Over the past two decades, metronomic chemotherapy has gained considerable attention and has demonstrated remarkable success in the treatment of cancer. Through chronic administration and low-dose regimens, metronomic chemotherapy is associated with fewer adverse events but still effectively induces disease control. The identification of its antiangiogenic properties, direct impact on cancer cells, immunomodulatory effects on the tumour microenvironment, and metabolic reprogramming ability has established the intrinsic multitargeted nature of this therapeutic approach. Recently, the utilization of metronomic chemotherapy has evolved from salvage treatment for metastatic disease to adjuvant maintenance therapy for high-risk cancer patients, which has been prompted by the success of several substantial phase III trials. In this review, we delve into the mechanisms underlying the antitumour effects of metronomic chemotherapy and provide insights into potential combinations with other therapies for the treatment of various malignancies. Additionally, we discuss health-economic advantages and candidates for the utilization of this treatment option., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The geographical and ecological patterns of morphological disparity are crucial to understand how species are assembled within communities in the context of the evolutionary history, morphological evolution and ecological interactions. However, with limited exceptions, rather few studies have been conducted on the global pattern of disparity, particularly in early land plants. Here we explored the spatial accumulation of disparity in a morphologically variable and species rich liverwort genus Frullania in order to test the hypothesis of latitude disparity gradient. We compiled a morphological data set consisting of eight continuous traits for 244 currently accepted species, and scored the species distribution into 19 floristic regions worldwide. By reconstructing the morphospace of all defined regions and comparisons, we identified a general Gondwana-Laurasia pattern of disparity in Frullania. This likely results from an increase of ecological opportunities and / or relaxed constraints towards low latitudes. The lowest disparity occurred in arid tropical regions, largely due to a high extinction rate as a consequence of paleoaridification. There was weak correlation between species diversity and disparity at different spatial scales. Furthermore, long-distance dispersal may have partially shaped the present-day distribution of Frullania disparity, given its frequency and the great contribution of widely distributed species to local morphospace. This study not only highlighted the crucial roles of paleoenvironmental changes, ecological opportunities, and efficient dispersal on the global pattern of plant disparity, but also implied its dependence on the ecological and physiological function of traits., (© 2024. The Author(s).)

Fatty acids (FAs) are essential molecules in all organisms and are involved in various physiological and pathophysiological processes. Pentafluorobenzyl bromide (PFBBr) is commonly used for FA derivatization for gas chromatography-mass spectrometry (GC-MS) quantification by chemical ionization (CI). While CI is the conventional ionization mode for PFBBr derivatization, the electron ionization (EI) source has also demonstrated efficacy in achieving satisfactory analytical performance for the analysis of PFB esters. In this study, we present a novel approach utilizing PFBBr-derivatization on a GC-EI-MS platform to quantitatively analyze a comprehensive range of 44 fatty acids (FAs) spanning from C2 to C24. The method's sensitivity, precision, accuracy, linearity, recovery, and matrix effect were rigorously validated against predetermined acceptance criteria. In comparison to the conventional CI ionization mode, the utilization of PFBBr-derivatization in GC-EI-MS exhibits a wider range of applications and achieves comparable sensitivity levels to the conventional CI platform. By using this method, we successfully quantified 44 FAs in plasma and feces samples from the mice with deoxynivalenol (DON)-induced kidney injury. Among these, the levels of most FA species were increased in the DON-exposure group compared with the control group. The orthogonal partial least squares discriminant analysis (OPLS-DA) of all the tested FAs showed a visual separation of the two groups, indicating DON exposure resulted in a disturbance of the FA profile in mice. These results indicate that the established method by integration of GC-MS with PFBBr derivatization is an efficient approach to quantify the comprehensive FA profile, which includes short-, medium- and long-chain FAs. In addition, our study provides new insights into the mechanism underlying DON exposure-induced kidney injury.

With the rapid iteration of multiple myeloma therapeutics over the last two decades, as well as increasing remission rates and depth of remission in patients, traditional methods for monitoring disease response are insufficient to meet the clinical needs of new drugs. Minimal residual disease (MRD) is a more sensitive test for determining the depth of response, and data from multiple clinical trials and meta-analyses show that a negative MRD correlates with a better prognosis than a traditional complete response. MM is at the forefront of MRD evaluation and treatment. MRD detection methods have been continuously updated. The current MRD assessment has three dimensions: bone marrow-based MRD testing, MRD testing based on images of residual metabolic of focal lesions, and peripheral blood-based MRD testing. The various MRD assessment methods complement one another. The goal of this article is to discuss the currently used MRD assays, the progress, and challenges of MRD in MM, and to provide a reference for clinicians to better use the techniques.

Background: Schizophrenia (SZ) patients have been reported to have comorbid suicidal behavior (SB) and impaired glucose metabolism in early psychosis, but it is unclear whether impaired glucose metabolism plays a role in the occurrence of SB in patients with first-episode drug-naïve (FEDN) SZ. Therefore, our main aim was to examine the relationship between SB and glucose metabolism in FEDN SZ patients., Methods: We recruited 319 FEDN SZ patients and collected information on their sociodemographic characteristics, clinical data, and glucose metabolism parameters. Participants' psychotic and depressive symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Hamilton Depression Rating Scale (HAMD), respectively. Fasting plasma glucose and insulin levels were also measured., Results: The percentage of FEDN SZ patients with SB was 45.5% (145/319). Compared to SZ patients without SB, SZ patients with SB exhibited higher scores on HAMD, PANSS positive subscale, as well as higher levels of fasting plasma glucose, fasting plasma insulin, and homeostasis model assessment of insulin resistance index (all p<0.05). Logistic regression analysis indicated that increased levels of insulin resistance (adjusted OR = 1.920), body mass index (adjusted OR = 0.931), and PANSS general psychopathology (adjusted OR = 1.041) were independently associated with SB. The Receiver Operating Characteristic Curve showed an Area Under Curve value of 0.732 for the combination of three factors in regression model to distinguish between SB and non-SB., Conclusions: Our results indicate that fasting glucose, fasting insulin, and insulin resistance are strongly associated with SB in FEDN SZ patients, suggesting that glucose metabolism abnormalities may be potential biomarkers of SB in SZ patients. Regular monitoring of glucose metabolism variables is essential for suicide prevention., Competing Interests: Declaration of Competing Interest No conflict of interest was disclosed for each author., (Copyright © 2023. Published by Elsevier Inc.)

Phase separation has emerged as an important mechanism explaining the formation of certain biomolecular condensates. Biological phase separation is often driven by the multivalent interactions of modular protein domains. Beyond valency, the physical features of folded domains that promote phase separation are poorly understood. We used a model system─the small ubiquitin modifier (SUMO) and its peptide ligand, the SUMO interaction motif (SIM)─to examine how domain surface charge influences multivalency-driven phase separation. Phase separation of polySUMO and polySIM was altered by pH via a change in the protonation state of SUMO surface histidines. These effects were recapitulated by histidine mutations, which modulated SUMO solubility and polySUMO-polySIM phase separation in parallel and were quantitatively explained by atomistic modeling of weak interactions among proteins in the system. Thus, surface charge can tune the phase separation of multivalent proteins, suggesting a means of controlling phase separation biologically, evolutionarily, and therapeutically.

Background: Transcranial alternating current stimulation (tACS) has proven to be an effective treatment for improving cognition, a crucial factor in motor learning. However, current studies are predominantly focused on the motor cortex, and the potential brain mechanisms responsible for the therapeutic effects are still unclear. Given the interconnected nature of motor learning within the brain network, we have proposed a novel approach known as multi-target tACS. This study aims to ascertain whether multi-target tACS is more effective than single-target stimulation in stroke patients and to further explore the potential underlying brain mechanisms by using techniques such as transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI)., Methods: This study employs a double-blind, sham-controlled, randomized controlled trial design with a 2-week intervention period. Both participants and outcome assessors will remain unaware of treatment allocation throughout the study. Thirty-nine stroke patients will be recruited and randomized into three distinct groups, including the sham tACS group (SS group), the single-target tACS group (ST group), and the multi-target tACS group (MT group), at a 1:1:1 ratio. The primary outcomes are series reaction time tests (SRTTs) combined with electroencephalograms (EEGs). The secondary outcomes include motor evoked potential (MEP), central motor conduction time (CMCT), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), magnetic resonance imaging (MRI), Box and Block Test (BBT), and blood sample RNA sequencing. The tACS interventions for all three groups will be administered over a 2-week period, with outcome assessments conducted at baseline (T0) and 1 day (T1), 7 days (T2), and 14 days (T3) of the intervention phase., Discussion: The study's findings will determine the potential of 40-Hz tACS to improve motor learning in stroke patients. Additionally, it will compare the effectiveness of multi-target and single-target approaches, shedding light on their respective improvement effects. Through the utilization of techniques such as TMS and MRI, the study aims to uncover the underlying brain mechanisms responsible for the therapeutic impact. Furthermore, the intervention has the potential to facilitate motor learning efficiency, thereby contributing to the advancement of future stroke rehabilitation treatment., Trial Registration: Chinese Clinical Trial Registry ChiCTR2300073465. Registered on 11 July 2023., (© 2024. The Author(s).)