Syndromes and Mechanisms of Depression Induced by Second Hit in Mice / 中国实验方剂学杂志

ObjectiveTo explore the syndromes and mechanisms of depression induced by maternal separation （MS） combined with chronic restraint stress （RS） in mice. MethodOn postnatal day 0 （PD0）， the offspring mice were randomized into a blank group （NC） and a modeling group. The mouse model of depression was established by MS+RS for 21 days. After removal of female mice on PD21， the modeled mice were randomized into model， Wenyang， Jieyu， Wenyang Jieyu， and fluoxetine groups， with 15 mice in each group. The sucrose preference， tail suspension， and open field tests were carried out to evaluate the anxiety and depression-like behavior in mice. Enzyme-linked immunosorbent assay was used to measure the adrenocorticotrophic hormone （ACTH） and corticosterone （CORT） levels in mouse plasma. High performance liquid chromatography-electrochemical detector was used to determine the content of monoamine neurotransmitters in the hippocampus. Real-time fluorescence quantitative polymerase chain reaction was employed to determine the mRNA levels of genes in the 5-hydroxytryptamine （5-HT） system， hypothalamic-pituitary-adrenal （HPA） axis， and brain-derived neurotrophic factor （BDNF） signaling pathway in the hippocampus. Immunohistochemistry was employed to determine the expression levels of proteins in the 5-HT system and HPA axis in the hippocampus. The Simple Western system was used to determine the protein levels of BDNF and tyrosine kinase receptor B （TrkB） in the hippocampus. ResultCompared with the NC group， the model group exhibited depression-like behavior， which was significantly relieved by Wenyang Jieyu prescription and fluoxetine. Compared with the NC group， the model group showed elevated levels of CORT and ACTH in the plasma （P<0.01）， which， however， were lowered by Wenyang Jieyu prescription and fluoxetine （P<0.05， P<0.01）. Compared with the NC group， the model group showed inhibited expression of neurotransmitters in the hippocampus （P<0.05， P<0.01）， while Wenyang Jieyu prescription and fluoxetine restored the expression of neurotransmitters （P<0.05， P<0.01）. Compared with NC group， the model group showed inhibition of the 5-HTergic nerve and abnormal activation of the HPA axis， and Wenyang Jieyu prescription and fluoxetine regulated the abnormal state of the 5-HTergic nerve and HPA axis. Compared with NC group， the modeling down-regulated the mRNA and protein levels of BDNF and TrkB in the hippocampus （P<0.05， P<0.01）， which， however， were recovered in Wenyang， Jieyu， Wenyang Jieyu， and fluoxetine groups （P<0.05， P<0.01）. ConclusionThe mouse model of depression induced by MS+RS may present the syndrome of Yang deficiency and liver depression. Wenyang Jieyu prescription may increase the content of hippocampal neurotransmitters by regulating the 5-HT system and the BDNF signaling pathway mediated by the HPA axis， thereby alleviating depression-like behavior in mice.

Discovery of new Schistosoma mansoni aspartyl protease inhibitors by structure-based virtual screening

BACKGROUND Schistosomiasis is a neglected tropical disease caused by trematodes of the genus Schistosoma, with a limited treatment, mainly based on the use of praziquantel (PZQ). Currently, several aspartic proteases genes have already been identified within the genome of Schistosoma species. At least one enzyme encoded from this gene family (SmAP), named SmCD1, has been validated for the development of schistosomicidal drugs, since it has a key role in haemoglobin digestion by worms. OBJECTIVE In this work, we integrated a structure-based virtual screening campaign, enzymatic assays and adult worms ex vivo experiments aiming to discover the first classes of SmCD1 inhibitors. METHODS Initially, the 3D-structures of SmCD1, SmCD2 and SmCD3 were generated using homology modelling approach. Using these models, we prioritised 50 compounds from 20,000 compounds from ChemBridge database for further testing in adult worm aqueous extract (AWAE) and recombinant SmCD1 using enzymatic assays. FINDINGS Seven compounds were confirmed as hits and among them, two compounds representing new chemical scaffolds, named 5 and 19, had IC50 values against SmCD1 close to 100 μM while presenting binding efficiency indexes comparable to or even higher than pepstatin, a classical tight-binding peptide inhibitor of aspartyl proteases. Upon activity comparison against mammalian enzymes, compound 50 was selective and the most potent against the AWAE aspartic protease activity (IC50 = 77.7 μM). Combination of computational and experimental results indicate that compound 50 is a selective inhibitor of SmCD2. Compounds 5, 19 and 50 tested at low concentrations (10 uM) were neither cytotoxic against WSS-1 cells (48 h) nor could kill adult worms ex-vivo, although compounds 5 and 50 presented a slight decrease on female worms motility on late incubations times (48 or 72 h). MAIN CONCLUSION Overall, the inhibitors identified in this work represent promising hits for further hit-to-lead optimisation.

Clinical features, gene mutation profile and prognosis analysis of diffuse large B-cell lymphoma complicated with follicular lymphoma / 白血病·淋巴瘤

Objective:To investigate the clinicopathologic characteristics, gene mutation profile and prognostic influencing factors of diffuse large B-cell lymphoma (DLBCL) complicated with follicular lymphoma (FL) (DLBCL/FL).Methods:The clinicopathological data of 50 DLBCL/FL patients admitted to Rui Jin Hospital Affiliated of Shanghai Jiao Tong University School of Medicine from February 2018 to November 2021 were retrospectively analyzed. Targeted sequencing was performed to assess the mutation profile of 55 lymphoma-related genes. The clinicopathological characteristics were summarized to evaluate the short-term therapeutic efficacy of all patients. Kaplan-Meier method was used to analyze the overall survival (OS) and progression-free survival (PFS) of patients. Cox regression risk models were used to assess the factors affecting the OS and PFS.Results:Among 50 DLBCL/FL patients, 23 cases (46%) were male, 22 cases (44%) had an international prognosis index (IPI) score ≥ 2 points, 16 cases (32%) were double-expression lymphoma (DEL) and 4 cases (8%) were double-hit lymphoma (DHL). The complete response (CR) and overall response rates were 68% (34/50) and 78% (39/50), respectively after the first-line therapy. The median follow-up time was 23.3 months (5.1-50.9 months). The 2-year OS rate was 82.1% and 2-year PFS rate was 67.1%; and the median OS and PFS were not reached. Targeted sequencing results showed that the mutation frequencies of KMT2D, MYD88, TP53, BTG2, DTX1, EZH2, CD70, CREBBP, DUSP2, HIST1H1C, HIST1H1E and PRDM1 genes in this cohort were more than 15%. Multivariate Cox regression analysis showed that male ( HR = 4.264, 95% CI 1.144-15.896, P = 0.031) and IPI score ≥ 2 points ( HR = 6.800, 95% CI 1.771-37.741, P = 0.007) were independent risk factors of PFS in newly diagnosed DLBCL/FL patients, and TP53 mutation ( HR = 4.992, 95% CI 1.027-24.258, P = 0.046) was an risk influencing factor of OS. Conclusions:The proportion of male and female DLBCL/FL patients is similar, with a small proportion of DHL. Mutations of KMT2D, MYD88 and TP53 genes are commonly found in DLBCL/FL patients. Generally, DLBCL/FL patients can have a high overall response and good prognosis. Male and IPI score ≥ 2 points are the independent risk factors of PFS, and TP53 mutation is an independent risk factor of OS in DLBCL/FL patients.

Application progress of artificial intelligence in the screening and identification of drug targets / 中国药科大学学报

@#In recent years, artificial intelligence (AI) has developed rapidly, with improved computing power and algorithms, which has greatly facilitated the collection and processing of biological, chemical information and clinical data, injecting new vitality into the research and development of new drugs.In this review, we began with a brief overview of the development and the main algorithms of AI in drug discovery.Then we elaborated through several specific cases on the various scenarios of AI application, including target identification, protein structure prediction, hit generation and optimization etc.Finally, we focused on a recent example to discuss the high efficiency of "end-to-end" application of AI.

Analysis of family mutation type and two-hit hypothesis of a familial VHL Syndrome patient / 现代泌尿外科杂志

【Objective】 To explore the mutation type, clinical characteristics, molecular genetics and the two-hit type of a patient with familial Von Hippel Lindau (VHL) syndrome. 【Methods】 The data of the patient were collected. DNA was extracted from the peripheral blood and renal cell carcinoma sample. The VHL gene germline mutation site was detected with high throughput sequencing next generation sequencing (NGS). The two-hit site was identified with UCSCXena database, methylation-specific PCR (MSP) and microsatellite stability detection. 【Results】 The mutation site of the embryo line was located in c.500G>A R167Q mutation. The patient had single nucleotide polymorphism, but no clear loss of heterozygosity, methylation or system mutation. 【Conclusion】 The germline mutation in exon 3 is the basis for the clinical features of this familial renal cell carcinoma proband. The identification of the two-hit site is key to the occurrence of the disease, which is significant for the diagnosis and treatment. The use of the databases can guide the screening of mutations and methylation sites in familial renal cell carcinoma.

Impact of stressors and stress responses on the daily life of college students with migraine / 四川精神卫生

BackgroundStress is closely related to migraine attacks， however， previous studies on stressors， stress responses and their impact on the daily life of college students with migraine remain unclear. ObjectiveTo explore the impact of stressors and stress responses on the daily life of college students with migraine， in order to provide references for improving daily life of this population. MethodsFrom August 2018 to August 2019， 458 students from North Sichuan Medical College who met the International Classification of Headache Diseases third edition （ICHD-3）， were selected using random sampling method. General data and headache characteristics were collected. The 6-item Headache Impact Test Questionnaire （HIT-6） was used to assess the impact of migraine on daily life. Student-Life Stress Inventory （SLSI） was used to assess the stressors and stress responses. Hamilton Anxiety Scale （HAMA） and Hamilton Depression Scale-24 item （HAMD-24） were used to assess anxiety and depressive symptoms. Pearson correlation analysis were used to examine the relationship between HIT-6 score and scores on various scales. Multiple linear regression was used to analyze the influencing factors on daily life in college students with migraine. ResultsIn the SLSI， stressors in the dimensions of frustration （r=0.138， P<0.01）， conflict （r=0.168， P<0.01）， pressure （r=0.157， P<0.01）， change （r=0.148， P<0.01）， self-imposed （r=0.158， P<0.01） ， as well as physiological response （r=0.256， P<0.01）， emotional response （r=0.241， P<0.01）， behavioral response （r=0.164， P<0.01）， HAMA total score （r=0.192， P<0.01）， dHAMD-24 total score （r=0.250， P<0.01）， and SLSI total score （r=0.250， P<0.01）， were positively correlated with HIT-6 score. Cognitive response （r=-0.104， P<0.05） was negatively correlated with HIT-6 score. Stepwise multiple linear regression revealed that physiological response （β=0.140， P<0.05）， anxiety （β=0.159， P<0.05）， and cognitive response （β=-0.091， P<0.05） could predict the impact on daily life of college students with migraine. ConclusionPhysiological response， cognitive response and anxiety may be the independent influencing factors on the daily life of college students with migraine. ［Funded by Nanchong City University Science and Technology Strategic Cooperation Project （number， NSMC20170420）］

Cefalea por abuso de medicamentos y sus marcadores clínicos / Medication overuse headache and its specific clinical markers

Resumen Introducción: Los marcadores clínicos de la cefalea por uso excesivo de medicación (CMA) se basan en la clasificación de las cefaleas desarrollada por la Sociedad Internacional de Cefaleas (IHS). Esta clasificación incluye sólo dos criterios: la frecuencia de los días de cefalea debe ser de 15 o más días al mes durante al menos tres o más meses; - y el número de días de uso excesivo de la medicación debe ser de 10 o 15 días al mes dependiendo del tipo de medicación. Sin embargo, los pacientes suelen tener otros marcadores clínicos asociados distintos, que la mayoría de los médicos pasan por alto durante la evaluación inicial. Metodología: Este estudio es un estudio prospectivo, longitudinal y observacional de 76 pacientes ingresados en la Unidad de Cefaleas del hospital DIPRECA. Todos ellos fueron diagnosticados de HMO según los criterios establecidos por su ICHD III beta.(1) Los pacientes recibieron un tratamiento estándar que incluía desintoxicación y medicación preventiva y fueron seguidos durante 6 meses. Se registraron los síntomas de interés en cada visita de seguimiento clínico y se administraron escalas de evaluación como Zung, MIDAS, HIT-6. Resultados: Los medicamentos sobreutilizados incluyeron antiinflamatorios no esteroideos (AINE), triptanes y cornezuelos. Los síntomas clínicos más significativos asociados fueron: despertar por la mañana con dolor de cabeza, despertar al paciente al amanecer por dolor de cabeza, dificultades de atención, depresión, dolor cervical y síndrome de dolor miofascial. Todos los síntomas mejoraron significativamente al iniciar el tratamiento, al igual que la calidad de vida medida por las escalas MIDAS y HIT-6. Discusión: Al evaluar a los pacientes con HMO, hay que tener en cuenta tanto los criterios diagnósticos de la ICHD III beta como los síntomas comunes y específicos que se observan en la mayoría de los casos de HMO.

Introduction: Clinical markers of medication overuse headache (MOH) are based on headache classification developed by the International Headache Society (IHS). This classification include only two criteria: frequency of headache days must be 15 or more days per month for at least three or more months; - and the number of days of overuse medication must be either 10 or 15 days per month depending on the type of medication. However, patients often have others distinct associated clinical markers, which are overlooked by most physicians during the initial evaluation. Methodology: This study is a prospective, longitudinal and observational study of 76 patients admitted to DIPRECA´s hospital Headache Unit. They were all diagnosed with, MOH according to the criteria established by the his ICHD III beta.(1) Patients were given standard treatment including detoxification and preventive medications and followed for 6 months. Symptoms of interest were recorded in at each clinical monitoring visit and assessment scales such as Zung, MIDAS, HIT-6 were administered. Results: Overused medications included nonsteroidal anti-inflammatory drugs (NSAIDs), triptans and ergots. The most significant clinical symptoms associated were: awaking in the morning with headache, awaking the patient at dawn by headache, attention difficulties, depression, cervical pain and myofascial pain syndrome. All symptoms significantly improved when treatment began, as did quality of life as measured by MIDAS and HIT-6 scales. Discussion: In evaluating patients with MOH consider both the ICHD III beta diagnostic criteria and the common and specific symptoms seen in most cases of MOH.

Nuevo índice de desempeño global de una prueba diagnóstica: el índice T / New global performance index of a diagnostic test: the T index

Introducción. En el presente artículo se propone un nuevo índice de desempeño global de una prueba diagnóstica: el índice T, que corresponde a la proporción de aciertos (Pa) menos la proporción de error (Pe) dividido entre la proporción de aciertos (Pa). Métodos. Describir los fundamentos teóricos y prácticos del índice T. Comparar el índice T frente al índice de Youden para poder establecer si dos o más modalidades diagnósticas difieren en su capacidad de discriminar, correctamente, entre los individuos verdaderamente enfermos de los sanos. Comparar el índice T frente al índice de Youden para poder establecer si el índice T puede ser utilizado para escoger "el mejor punto de corte" cuando la prueba diagnóstica de interés expresa sus resultados en forma cuantitativa continua.Resultados. Comparado frente al índice de Youden, el índice T permite distinguir entre las pruebas diagnósticas con alto desempeño diagnóstico de aquellas con pobre desempeño diagnóstico. Además, el índice T, de manera confiable, permite escoger "el mejor punto de corte" cuando una prueba diagnóstica utiliza una variable cuantitativa continua para expresar sus resultados.Conclusiones. Al contrastar los resultados del índice T versusel índice de Youden y los resultados del índice T versus la curva COR, podemos afirmar que el índice T es un índice exacto y eficiente.

Introduction. In this article, a new global performance index of a diagnostic test is proposed: the T Index, which corresponds to the proportion of the hit ratio (Hr) minus the error ratio (Er) divided by the hit ratio (Hr).Methods. To describe the theoretical and practical foundations of the T index; to compare the T index against the Youden index in order to establish whether two or more diagnostic modalities differ in their ability to correctly discriminate between truly ill and healthy individuals; and to compare the T index with the Youden index in order to establish whether the T index can be used to choose the "best cut-off point" when the diagnostic test of interest expresses its results in a continuous quantitative way.Results. Compared with the Youden index, the T index allows us to differentiate between diagnostic tests with high diagnostic performance and those with poor diagnostic performance. In addition, the T index, reliably, allows choosing "the best cut-off point" when a diagnostic test uses a continuous quantitative variable to express its results.Conclusions. By contrasting the results of the T index versus the Youden index and the results of the T index versus the COR curve, we can affirm that the T index is an accurate and efficient index.

Effects of therapeutic and aerobic exercise programs in temporomandibular disorder-associated headaches

Abstract Objective To assess the effects of three 8-week exercise programs on the frequency, intensity, and impact of headaches in patients with headache attributed to temporomandibular disorder (TMD). Methodology Thirty-six patients diagnosed with headache attributed to TMD participated in the study and were divided into three groups of 12 patients: a therapeutic exercise program (G1, mean age: 26.3±5.6 years), a therapeutic and aerobic exercise program (G2, mean age: 26.0±4.6 years), and an aerobic exercise program (G3, 25.8±2.94 years). Headache frequency and intensity were evaluated using a headache diary, and the adverse headache impact was evaluated using the Headache Impact Test (HIT-6). The intensity was reported using the numerical pain rating scale. These parameters were evaluated twice at baseline (A01/A02), at the end of the 8-week intervention period (A1), and 8-12 weeks after the end of the intervention (A2). Results At A1, none of the G2 patients reported having headaches, in G1, only two patients reported headaches, and in G3, ten patients reported headache. The headache intensity scores (0.3 [95% CI: -0.401, 1.068]), (0.0 [95% CI: -0.734, 0.734]) and HIT-6 (50.7 [95% CI: 38.008, 63.459]), (49.5 [95% CI: 36.808, 62.259]), significantly decreased in G1 and G2 at A1. At A2 headache intensity scores (0.5 [95% CI: -0.256, 1.256]), (0.0 [95% CI: -0.756, 0.756]) and HIT-6 (55.1 [95% CI: 42.998, 67.268]), (51.7 [95% CI: 39.532, 63.802]) in G1 and G2 haven't change significantly. The effects obtained immediately after the completion of the intervention programs were maintained until the final follow-up in all groups. Conclusion The programs conducted by G1 (therapeutic exercises) and G2 (therapeutic and aerobic exercise) had significant results at A1 and A2.

Construction of the hit-deficient mutant strain of Streptococcus mutans ATCC25175 / 口腔疾病防治

Objective@#To construct a hit-deficient mutant strain of S. mutans ATCC25175 and verify its cell cycle regulatory function.@*Method @# Genomic DNA was extracted from S. mutans ATCC25175 strains, and then the upstream and downstream DNA fragments of the hit gene were cloned into the pFW5 vector (spectinomycin resistant) to construct recombinant plasmids using PCR amplification. Third, employed by natural genetic transformation in S. mutans ATCC25175 strains, the linearized recombinant plasmids were transformed into their genetic competence, induced by the synthesized competence-stimulating peptide (CSP), and then, homologous recombination was utilized to produce crossover and noncrossover products. Fourth, the hit-deficient mutant strains of S. mutans ATCC25175 were screened through the spectinomycin-resistance marker and identified by the electrophoresis of PCR products and PCR Sanger sequencing. Finally, its growth rate in vegetative BHI medium was also investigated.@* Results @# The upstream (856 bp) and downstream (519 bp) DNA fragments of the hit gene from the genomic DNA materials of S. mutans ATCC25175 were cloned into two multiple cloning sites (MCS-I and MCS-II) of the pFW5 vector, respectively, and the recombinant plasmid pFW5_hit_Up_Down was constructed and identified by double-emzyme digestion and PCR Sanger sequencing. The linearized recombinant plasmids were transformed into their genetic competence, induced by the synthetic CSP, and then, homologous recombination was utilized to produce various products. The hit-deficient mutant strains of S. mutans ATCC25175 were screened through the spectinomycin resistance marker and identified by the electrophoresis of PCR products and Sanger sequencing. The growth rate of the hit-deficient mutant strains versus their parental S. mutans ATCC25175 strains was increased greatly (P<0.001).@* Conclusion@# The hit-deficient mutant strains of S. mutans ATCC25175, having heritable traits, were successfully constructed, and the encoding Hit protein is growth-phase regulated in the cell cycle.

Epidemiological analysis of cytogenetic abnormalities in patients with newly-diagnosed multiple myeloma: a multi-center retrospective study / 中华血液学杂志

Objective@#To analyze the frequency and composition of risk-related cytogenetic abnormalities (CAs) in patients with newly-diagnosed multiple myeloma (NDMM) .@*Methods@#The frequency and composition of risk-related CAs from a cohort of 1 015 Chinese patients with NDMM were determined by interphase fluorescence in situ hybridization (iFISH) , individually or in combination.@*Results@#Of the cohort of 1 015 Chinese patients with NDMM, the frequencies of IgH arrangement, del (13q) /13q14, 1q gain and del (17p) were 54.0%, 46.4%, 46.1% (35.8% and 12. 7% for 3 or more than 3 copies) and 9.9%, respectively. Among 454 patients who had the baseline information for all risk-related CAs [except t (14;20) , which was not covered by the FISH panels performed routinely at all five centers], the frequencies of t (4;14) , t (11;14) or t (14;20) were 14.1%, 11.2% and 4.8%, respectively; of them, 44.3% patients carried 2 or more CAs (28.0%, 13.4% and 2.9% for 2, 3 or ≥4 CAs) ; 83.3%, 95.0% or 68.6% patients with 1q gain, del (17p) or IgH rearrangement had 1 or more additional CA (s) , with del (13q) /13q14 as the most frequently accompanied CA; 57.7% patients carried at least 1 HRCA; the incidences of double-hit (DH) MM (DHMM) (=2 HRCAs) and triple-hit (TH) (THMM) (≥3 HRCAs) were 14.3% and 2.9%, respectively.@*Conclusions@#Our results provided an up-to-date profile of CAs in Chinese NDMM patients, which revealed that approximately 58% patients might carry at least 1 HRCA, and 17% could experience so-called DHMM or THMM who presumably had the worst outcome.

Effect of long non-coding RNA hit on imatinib resistance j in acute lymphoblastic leukemia sup-b15 cell line / 中国药理学通报

Aim To investigate the effect of long non-coding RNA (LncRNA) HIT on the resistance of ima-tinib (IM) in SUP-B15 cell line of acute lymphoblastic leukemia (ALL) and the related mechanisms. Methods SUP-B15 cells were treated with concentration gradient IM and saline as IMR and control groups. The lentivirus transfected LncRNA HIT shRNAl # and 2# vector in IMR group cells to knock down the HIT expression as IMR shHITl # and 2# group cells. CCK-8 assay was used to detect IM half-inhibitory concentration ( ICjo ). Fluorescence quantitative PCR (qPCR) was applied to detect the expression levels of LncRNA HIT, QKI, 0ct4 and Sox2 mRNA. Western blot was employed to detect the expression levels of QKI, 0ct4 and Sox2 protein. Results Compared with those in control cells, there was significantly higher IM ICjq, higher expression of LncRNA HIT, 0ct4 and Sox2, and lower expression of QKI in groups of IMR, IMR shHITl# and 2# cells. Compared with those in IMR cells, there was significantly lower IM IC∗, lower expression of LncRNA HIT, 0ct4 and Sox2, and higher expression of QKI in groups of IMR shHITl# and 2# cells. The difference was statistically significant (P < 0. 05). Conclusions LncRNA HIT can increase the expression of Sox2 and 0ct4 via inhibiting the expression of QKI protein, and mediating the formation of IM resistance in ALL cells.

Clinical prognosis analysis of patients with "double hit" multiple myeloma / 中华血液学杂志

Objective@#To analyze and explore the clinical characteristics and prognosis of patients with "double hit" multiple myeloma (MM) .@*Methods@#We retrospectively analyzed 89 MM patients in our department of Shanghai Changzheng Hospital from 2010-2016. All patients were assayed by fluorescence in situ hybridization (FISH) and TP53 gene sequencing, based on Dr. Walker BA proposed the "double hit" MM concept, and then the clinical features and prognosis were evaluated.@*Results@#In the results, 15 (16.85%) cases harbored "double hit" showed the median PFS of 8.4 months and the median OS 22.2 months, which was significantly lower than non-"double hit" patients with median PFS 14.2 months and the median OS 39.2 months, respectively (P<0.05) . Multivariate analysis displayed that the "double hit" was an independent poor prognostic factor on PFS (HR=2.171, 95%CI 1.206-3.907, P=0.010) and OS (HR=4.106, 95%CI 2.116-7.969, P<0.001) . Moreover, "double hit" MM patients had the higher adverse prognosis risk, which showed the shorter median OS and PFS than stage III of R-ISS patients (PFS 8.4 vs 11.8 months; OS 22.2 vs 24.3 months, P<0.05, respectively) .@*Conclusion@#Patients with "double hit" MM have a very poor clinical prognosis. Prospective clinical studies are urgently needed to improve these extra high risk patients.

Adverse effects of double-hit combining ISS-Ⅲ stage and 1q gain or del (17p) on prognosis of patients with newly diagnosed multiple myeloma / 中华血液学杂志

Objective@#To evaluate the prognostic significance of combining ISS-Ⅲ and high risk cytogenetic abnormalities [HRCAs, including 1q gain/amplification and del (17p) ] in patients with newly-diagnosed multiple myeloma (NDMM) .@*Methods@#The clinical characteristics and relevant variables were retrospectively analyzed in a total of 270 NDMM patients diagnosed between November 2009 and May 2018. ISS-Ⅲ stage and HRCAs [detected by FISH, including 1q gain/amplification and del (17p) ] were defined as risk factors (hit) . Based to the number of hit per case, these patients were divided into four groups carrying 0 to 3 risk factors, respectively. Progress-free survival (PFS) and overall survival (OS) were then analyzed using the Kaplan-Meier estimator.@*Results@#Patients who carried single hit (n=120, 44.4%) had shorter median PFS (23.0 vs 28.9 months; P>0.05) and OS (42.3 vs 53.7 months; P>0.05) than those with no risk factors (n=66, 24.4%) . Of note, the outcome of patients who had two or more risk factors (double/triple, n=84, 31.1%) was much worse than those with either no or one risk factor, indicated by significantly reduced median PFS (14.5 months; HR=1.584, 95%CI 1.082-2.319; P=0.003 for double/triple vs single hit) and OS (18.4 months, HR=2.299, 95%CI 1.485-3.560; P<0.001 for double/triple vs single hit) . Strikingly, patients who had three risk factor (triple hit, n=5, 1.9%) displayed the poorest survival with extraordinarily shorter PFS (0.9-15.1 months) and OS (0.9-18.9 months) compared to those carrying two risk factors (double hit) . Analogous results were obtained when different combinations of ISS stages and HRCAs were analyzed.@*Conclusion@#These results suggest a potential but rather important role of combining multiple (e.g. double or triple) adverse factors determined via the routine ISS staging and FISH detection of cytogenetic abnormalities in risk stratification and prognostic prediction, which might be helpful to identify high risk patients more precisely at diagnosis. It also raised a possibility that a small group of ISS-Ⅲ patients carrying both 1q gain/amplification and del (17p) might represent an "extremely-high risk" subset of MM.

Prospective evaluation of heparin-induced thrombocytopenia expert probability and 4T scores in Chinese patients with suspected heparin-induced thrombocytopenia / 中华医学杂志(英文版)

Background@#Diagnosis of heparin-induced thrombocytopenia (HIT) is challenging. This study aimed to compare the diagnostic performance of HIT expert probability (HEP) and 4T scores, and to evaluate the inter-observer reliability for the 4T score in a clinical setting.@*Methods@#This prospective study included HIT-suspected patients between 2016 and 2018. Three hematologists assessed the HEP and 4T scores. Correlations between scores and anti-platelet factor 4 (anti-PF4)/heparin antibodies were evaluated. Receiver operating characteristic curves and area under the curve (AUC) were used to assess the predictive accuracy of these two scoring models. The intraclass correlation coefficient (ICC) was used to assess the inter-observer agreement of 4T scores between residents and hematologists.@*Results@#Of the 89 subjects included, 22 (24.7%) were positive for anti-PF4/heparin antibody. The correlations between antibody titer and either HEP or 4T scores were similar (r = 0.392, P < 0.01 for the HEP score; r = 0.444, P < 0.01 for the 4T score). No significant difference in the diagnostic performance was displayed between these two scores (AUC for the HEP score: 0.778 vs. AUC for the 4T score: 0.741, P = 0.357). Only 72 4T scores were collected from the residents, with a surprisingly low percentage of observers (43.1%) presenting the four individual item scores which made up their 4T score. The AUC of 4T score assessed by residents and hematologists was 0.657 (95% confidence interval [CI]: 536–0.765) and 0.780 (95% CI: 0.667–0.869, P < 0.05), respectively. The ICC of 4T score between residents and hematologists was 0.49 (95% CI: 0.29–0.65, P < 0.01), demonstrating a fair inter-observer agreement.@*Conclusions@#The HEP score does not display a better performance for predicting HIT than the 4T score. With the unsatisfactory completion rate, the inter-observer agreement of 4T score in a tertiary hospital is fair, underscoring the necessity for continuing education for physicians.

Clinical prognosis analysis of patients with "double hit" multiple myeloma / 中华血液学杂志

Objective: To analyze and explore the clinical characteristics and prognosis of patients with "double hit" multiple myeloma (MM) . Methods: We retrospectively analyzed 89 MM patients in our department of Shanghai Changzheng Hospital from 2010-2016. All patients were assayed by fluorescence in situ hybridization (FISH) and TP53 gene sequencing, based on Dr. Walker BA proposed the "double hit" MM concept, and then the clinical features and prognosis were evaluated. Results: In the results, 15 (16.85%) cases harbored "double hit" showed the median PFS of 8.4 months and the median OS 22.2 months, which was significantly lower than non-"double hit" patients with median PFS 14.2 months and the median OS 39.2 months, respectively (P<0.05) . Multivariate analysis displayed that the "double hit" was an independent poor prognostic factor on PFS (HR=2.171, 95%CI 1.206-3.907, P=0.010) and OS (HR=4.106, 95%CI 2.116-7.969, P<0.001) . Moreover, "double hit" MM patients had the higher adverse prognosis risk, which showed the shorter median OS and PFS than stage III of R-ISS patients (PFS 8.4 vs 11.8 months; OS 22.2 vs 24.3 months, P<0.05, respectively) . Conclusion: Patients with "double hit" MM have a very poor clinical prognosis. Prospective clinical studies are urgently needed to improve these extra high risk patients.

Adverse effects of double-hit combining ISS-Ⅲ stage and 1q gain or del (17p) on prognosis of patients with newly diagnosed multiple myeloma / 中华血液学杂志

Objective: To evaluate the prognostic significance of combining ISS-Ⅲ and high risk cytogenetic abnormalities [HRCAs, including 1q gain/amplification and del (17p) ] in patients with newly-diagnosed multiple myeloma (NDMM) . Methods: The clinical characteristics and relevant variables were retrospectively analyzed in a total of 270 NDMM patients diagnosed between November 2009 and May 2018. ISS-Ⅲ stage and HRCAs [detected by FISH, including 1q gain/amplification and del (17p) ] were defined as risk factors (hit) . Based to the number of hit per case, these patients were divided into four groups carrying 0 to 3 risk factors, respectively. Progress-free survival (PFS) and overall survival (OS) were then analyzed using the Kaplan-Meier estimator. Results: Patients who carried single hit (n=120, 44.4%) had shorter median PFS (23.0 vs 28.9 months; P>0.05) and OS (42.3 vs 53.7 months; P>0.05) than those with no risk factors (n=66, 24.4%) . Of note, the outcome of patients who had two or more risk factors (double/triple, n=84, 31.1%) was much worse than those with either no or one risk factor, indicated by significantly reduced median PFS (14.5 months; HR=1.584, 95%CI 1.082-2.319; P=0.003 for double/triple vs single hit) and OS (18.4 months, HR=2.299, 95%CI 1.485-3.560; P<0.001 for double/triple vs single hit) . Strikingly, patients who had three risk factor (triple hit, n=5, 1.9%) displayed the poorest survival with extraordinarily shorter PFS (0.9-15.1 months) and OS (0.9-18.9 months) compared to those carrying two risk factors (double hit) . Analogous results were obtained when different combinations of ISS stages and HRCAs were analyzed. Conclusion: These results suggest a potential but rather important role of combining multiple (e.g. double or triple) adverse factors determined via the routine ISS staging and FISH detection of cytogenetic abnormalities in risk stratification and prognostic prediction, which might be helpful to identify high risk patients more precisely at diagnosis. It also raised a possibility that a small group of ISS-Ⅲ patients carrying both 1q gain/amplification and del (17p) might represent an "extremely-high risk" subset of MM.

Linfoma primario de bazo difuso de células grandes B doble hit: un subtipo de mal pronóstico / Primary splenic diffuse large B-cell lymphoma double hit: A subtype of poor prognosis

Resumen El linfoma difuso de células grandes B (LDCGB) es el tipo de linfoma más frecuente, constituyendo un 35% de todos los casos de linfoma no Hodgkin (LNH). El linfoma no-Hodgkin primario de bazo (LNHPB) presenta una incidencia menor al 1% de todos los linfomas. Los linfomas doble hit están relacionados con el reordenamiento del gen MYC asociado a otra alteración molecular. Tienden a presentarse en varones de edad avanzada y se caracterizan principalmente por su comportamiento agresivo.

Abstract Diffuse Large-cell Lymphoma B (DLCLB) is the most common type of lymphoma, constituting 35% of all cases of Non-Hodgkin's Lymphoma (NHL). Primary Splenic Non-Hodgkin Lymphoma (PS-NHL) has an incidence of less than 1% of all lymphomas. The ''double hit'' lymphomas are related to the rearrangement of the MYC gene associated with another molecular alteration. They used to appear in older men and are mainly characterised by their aggressive behaviour.

Saquinavir plus methylprednisolone ameliorates experimental acute lung injury

Glucocorticoid insensitivity is an important barrier to the treatment of several inflammatory diseases, including acute lung injury (ALI). Saquinavir (SQV) is an inhibitor of the human immunodeficiency virus protease, and the therapeutic effects of SQV in ALI accompanied with glucocorticoid insensitivity have not been previously investigated. In this study, the effects of SQV on lipopolysaccharide (LPS)-mediated injury in human pulmonary microvascular endothelial cells (HPMECs), human type I alveolar epithelial cells (AT I), and alveolar macrophages were determined. In addition, the effects of SQV on an LPS-induced ALI model with or without methylprednisolone (MPS) were studied. In LPS-stimulated HPMECs, SQV treatment resulted in a decrease of high mobility group box 1 (HMGB1), phospho-NF-κB (p-NF-κB), and toll-like receptor 4 (TLR4), and an increase of VE-cadherin. Compared to MPS alone, MPS plus SQV attenuated the decrease of glucocorticoid receptor alpha (GRα) and IκBα in LPS-stimulated HPMECs. HMGB1, TLR4, and p-NF-κB expression were also lessened in LPS-stimulated alveolar macrophages with SQV treatment. In addition, SQV reduced the injury in human AT I with a decrease of HMGB1 and p-NF-κB, and with an increase of aquaporin 5 (AQP 5). SQV ameliorated the lung injury caused by LPS in rats with reductions in vascular permeability, myeloperoxidase activity (MPO) and histopathological scores, and with lowered HMGB1, TLR4, and p-NF-κB expression, but with enhanced VE-cadherin expression. By comparison, SQV plus MPS increased GRα and IκBα in lung tissues of rats with ALI. This study demonstrated that SQV prevented experimental ALI and improved glucocorticoid insensitivity by modulating the HMGB1/TLR4 pathway.

Delayed-Onset Heparin-Induced Thrombocytopenia Following Aortic Valve Replacement / 日本心臓血管外科学会雑誌

Some 50% of patients who undergo cardiac surgery will have heparin-induced thrombocytopenia (HIT) antibodies, only 1% will develop typical clinical HIT. Especially delayed-onset HIT is not well-known and extremely rare. A 83-year-old man underwent aortic valve replacement (AVR) with a bioprosthetic valve (Mitroflow 21 mm) and pulmonary vein isolation (PVI). Intravenous unfractionated heparin (8,000 I.U./day) was administered for 5 days after surgery. He had a good recovery and was discharged to home with a platelet count of 100,600/μl on POD 15 on warfarin. On POD 18, he was readmitted to our hospital due to cerebral infarction with hemiparesis. As MRI revealed a multiple left hemispheric infarction, the presence of cardiogenic cerebral infarction was suspected. Continuous intravenous administration of unfractionated heparin (15,000 I.U./day) was started. On POD 24, the platelet count fell to 27,000/μl, and a contrast CT scan revealed a giant thrombus in the aortic arch. He was found to have HIT antibodies, supporting a diagnosis of HIT. After cessation of heparin therapy and administration of vitamin K antagonist, argatroban was administered. He recovered neurologically and was discharged on POD 58. He remains well at 3 years follow up. If a patient has an unexplained and severe thrombocytopenia after cardiovascular surgery, delayed-onset HIT should be taken into consideration.