RESUMEN
The prognosis of primary plasma cell leukemia (pPCL) is poor, and the relevant prognostic factors are incompletely understood. We aimed to explore the prognostic factors and develop a validated prognostic prediction model for pPCL patients in the new era. This multicenter retrospective study was conducted across 16 hospitals in China. Cox proportional hazards regression analysis was used to develop a prediction model. The predictive performance of the model was assessed using multiple metrics. Internal validation was conducted using bootstrap resampling. A total of 102 pPCL patients were included in this study, and 57 (55.9%) were male. The 12-month, 24-month, and 36-month OS rates for pPCL patients were 75.4%, 58.3%, and 47.6%, respectively. An overall survival prognostic nomogram for pPCL patients was established by integrating independent prognostic factors, including age, B2MG, and del17p. The nomogram exhibited good performance, with a C-index of 0.720 (95% CI 0.642-0.797) and an AUC of 0.653. Bootstrap validation yielded a C-index of 0.721 (95% CI 0.629-0.787) and an AUC of 0.653 (95% CI 0.546-0.759), indicating a relatively good fit of the calibration curve. A nomogram incorporating age, B2MG grade, and del17p were developed and validated to accurately and consistently predict the prognosis of pPCL patients.
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Leucemia de Células Plasmáticas , Nomogramas , Humanos , Estudios Retrospectivos , Masculino , Persona de Mediana Edad , Femenino , Leucemia de Células Plasmáticas/mortalidad , Leucemia de Células Plasmáticas/diagnóstico , Leucemia de Células Plasmáticas/terapia , Leucemia de Células Plasmáticas/tratamiento farmacológico , Anciano , Pronóstico , Adulto , Tasa de Supervivencia , Anciano de 80 o más Años , China/epidemiologíaRESUMEN
In this paper, based on the information entropy and spatio-temporal correlation of sensing nodes in the Internet of Things (IoT), a Spatio-temporal Scope Information Model (SSIM) is proposed to quantify the scope of the valuable information of sensor data. Specifically, the valuable information of sensor data decays with space and time, which can be used to guide the system to make efficient sensor activation scheduling decisions for regional sensing accuracy. A simple sensing and monitoring system with three sensor nodes is investigated in this paper, and a single-step scheduling decision mechanism is proposed for the optimization problem of maximizing valuable information acquisition and efficient sensor activation scheduling in the sensed region. Regarding the above mechanism, the scheduling results and approximate numerical bounds on the node layout between different scheduling results are obtained through theoretical analyses, which are consistent with simulation. In addition, a long-term decision mechanism is also proposed for the aforementioned optimization issues, where the scheduling results with different node layouts are derived by modeling as a Markov decision process and utilizing the Q-learning algorithm. Concerning the above two mechanisms, the performance of both is verified by conducting experiments using the relative humidity dataset; furthermore, the differences in performance and limitations of the model are discussed and summarized.
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Algoritmos , Simulación por Computador , Cadenas de MarkovRESUMEN
The common features shared by primary plasma cell leukemia (pPCL) and multiple myeloma (MM) with circulating plasma cells (CPCs) are peripheral blood invasion and expansion of plasma cells independent of the protective bone marrow (BM) microenvironment niche. However, few studies have addressed the relationship between pPCL and MM with CPCs. Here, we quantitated the number CPCs by conventional morphology in 767 patients with newly diagnosed MM; their clinic features were compared with those of 33 pPCL cases. When the presence of CPCs was defined as more than 2 % plasma cells per 100 nucleated cells on Wright-Giemsa stained peripheral blood smears, the incidence of MM with CPCs was 14.1 % in newly diagnosed MM. Patients with CPCs shared many clinical features with pPCL, especially clinical parameters related to tumor burden. However, no commonalities were found in immunophenotyping and cytogenetics. The prognosis of pPCL was poor, with a median progression free survival (PFS) of 12 months and an overall survival (OS) of 15 months. MM patients with CPCs had a clearly inferior PFS and OS as compared with the control cohort. Most interestingly, although the CPCs were not high enough to meet the diagnostic criteria for pPCL, the survival of MM patients with CPCs was comparable with that of pPCL, with a median PFS of 17 months and an OS of 25 months.
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Leucemia de Células Plasmáticas/patología , Mieloma Múltiple/patología , Células Plasmáticas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Aberraciones Cromosómicas , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/terapia , Células Plasmáticas/metabolismo , Pronóstico , Estudios Retrospectivos , Trasplante Autólogo , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate the correlation of peripheral blood T lymphocyte subsets with overall survival (OS) and clinical baseline characteristics in mantle cell lymphoma (MCL). METHODS: The clinical data of 55 MCL patients who were newly diagnosed in the Department of Hematology, Second Hospital of Shanxi Medical University from January 2012 to July 2022 were analyzed retrospectively. The percentages of T lymphocyte subsets and CD4+/CD8+ ratio in peripheral blood were detected by flow cytometry, and their correlation with clinical characteristics of patients were analyzed. Kaplan-Meier method was used for survival analysis and survival curves were drawn. Log-rank test was used for univariate analysis, while Cox proportional hazards model was used for multivariate analysis. RESULTS: The median follow-up was 40(1-68) months, and the median overall survival (OS) was 47 months. Among the 55 patients, 30(54.5%) patients had a decrease in peripheral blood CD4+T lymphocyte, while 17(30.9%) patients had a increase in peripheral blood CD8+T lymphocyte, and 20(36.4%) patients had a decrease in CD4+/CD8+ ratio. There were no significant correlations between CD4+/CD8+ ratio and sex, age, Ki-67, B symptoms, leukocytes, hemoglobin, lymphocytes, platelets, albumin, lactate dehydrogenase (LDH), ß2-microglobulin, splenomegaly, bone marrow invasion, primary site and MIPI score. Survival analysis showed that patients with CD4+T cell >23.3%, CD8+T cell ≤33.4% and CD4+/CD8+ ratio >0.6 had longer OS (P =0.020, P <0.001, P <0.001). Univariate analysis showed that Ki-67>30%, LDH>250 U/L, splenomegaly, bone marrow involvement, CD4+T cells ≤23.3%, CD8+ T cells >33.4%, CD4+/CD8+ ratio ≤0.6 were adverse prognostic factors affecting OS of MCL patients. Multivariate analysis showed that CD4+/CD8+ ratio ≤0.6 (HR =4.382, P =0.005) was an independent adverse prognostic factor for OS of MCL patients. CONCLUSIONS: Low CD4+/CD8+ ratio is associated with poor prognosis in MCL, and the CD4+/CD8+ ratio can be used as an important indicator to evaluate the prognosis risk in MCL patients.
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Relación CD4-CD8 , Linfoma de Células del Manto , Humanos , Linfoma de Células del Manto/sangre , Pronóstico , Estudios Retrospectivos , Linfocitos T CD8-positivos , Modelos de Riesgos Proporcionales , Masculino , Femenino , Subgrupos de Linfocitos T , Persona de Mediana EdadRESUMEN
OBJECTIVE: To analyze the dynamic changes in hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HBsAg) levels in chronic hepatitis B (CHB) patients following treatment by antiviral nucleotide drugs over a 5-year follow-up period and to assess the clinical significance of quarterly and annual quantitative measurements. METHODS: One-hundred-and-ten patients with CHB were enrolled in the study and administered on-going standard mono-therapy with various antiviral nucleotide drugs. Over a 5-year period, the HBV DNA level was measured by quantitative PCR every three months and the HBsAg levels were measured by chemiluminescence once a year. The dynamic changes in HBV DNA and HBsAg levels were assessed by Chi-squared test and ANOVA. RESULTS: Only 90 of the CHB patients completed the 5-year follow-up and were included in the analysis. The patients who showed HBeAg-positivity at baseline (study start) had higher levels of HBV DNA and HBsAg than the patients showing HBeAg-negativity. In general, the antiviral nucleotide drug therapy induced downward trends in HBsAg and HBV DNA level over time (F = 17.1, 151.53, all P less than 0.05). However, the most robust reduction in HBV DNA occurred during the first year. The HBsAg level followed an opposite trend, with the most robust reductions occurring in the 3rd, 4th and 5th years of treatment. CONCLUSION: Long-term antiviral nucleotide mono-therapies induced decreases in HBV DNA and HBsAg levels in CHB patients, with the former being most reduced in the short-term and the latter in the long-term.
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Antivirales/uso terapéutico , Antígenos de Superficie de la Hepatitis B/sangre , Hepatitis B Crónica/sangre , Hepatitis B Crónica/tratamiento farmacológico , Adolescente , Adulto , Anciano , ADN Viral/sangre , Femenino , Estudios de Seguimiento , Virus de la Hepatitis B , Humanos , Masculino , Persona de Mediana Edad , Nucleótidos/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To investigate the clinical characteristics, therapeutic response and prognosis of patients with plasma cell leukemia (PCL) and improve the understanding of this disease. METHODS: The clinical manifestations, laboratory tests and treatment response of 27 patients with plasma cell leukemia treated in The Second Hospital of Shanxi Medical University from December 2010 to August 2019 were analyzed retrospectively, and their clinical characteristics were summarized. Kaplan-Meier method was used for survival analysis. RESULTS: There were 18 cases of primary plasma cell leukemia (pPCL) and 9 cases of secondary plasma cell leukemia (sPCL). The male to female ratio was 1.7â¶1. The median age was 62 years old. The first manifestations were bone pain, fatigue, fever, splenomegaly and bleeding, and a large number of plasma cell infiltration was observed in the morphological examination of peripheral blood and bone marrow cells. 13 cases were detected by immunotyping and all of them expressed CD38/CD138. 8 cases underwent karyotype analysis, and 3 cases were normal, clonal abnormalities occurred in 5 cases. FISH detection was performed in 12 cases, of which 8 cases were abnormal. In 17 cases of bortezomib based chemotherapy, the ovevall response rate was 52.9%, which was higher than that in the non-bortezomib group, but there was no significant difference between the two groups (P =0.242). The overall median survival time of 27 patients was 6.4 months, the median progression-free survival time was 3.5 months, and the median survival time of patients with pPCL and sPCL was 8.2 months and 2.4 months, respectively, the difference between the two groups was statistically significant (P =0.031). CONCLUSION: PCL is highly invasive and has diverse clinical manifestations, and is not sensitive to traditional chemotherapy. The median survival time of patients with pPCL is relatively longer than that of patients with sPCL. The chemotherapy regimen based on bortezomib improves the treatment effectiveness and prolongs the survival time of PCL patients.
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Leucemia de Células Plasmáticas , Masculino , Femenino , Humanos , Leucemia de Células Plasmáticas/diagnóstico , Estudios Retrospectivos , Bortezomib/uso terapéutico , Pronóstico , Análisis de SupervivenciaRESUMEN
The release of highly toxic beryllium in sludge (BCS) produced by physico-chemical treatment of beryllium-containing wastewater from Be smelting production has become a growing concern with the widespread use of Be in the defense industry. This work investigated the potential mobility of Be in BCS. The toxicity characteristic leaching procedure (TCLP) of BCS showed that the amount of leached Be was up to 202 mg L-1, which exceeded the regulated limit by nearly 10,000 times. The chemical fractionation analysis further revealed that the excessive amount of Be leached from BCS was contributed to the high content of acid-soluble fraction and reducible fraction of Be, which accounted for over 70% of the Be content. The results obtained from mineralogical automatic analyzer (MLA) showed that gypsum (23.23%) and epidote (19.55%) were the two major mineralogical phases of BCS. Both were small and loosely structured agglomerated particles with a D50 of 6.61 µm and 3.31 µm. ToF-SIMS results revealed that the Be distribution on the surface of BCS particles was relatively dispersed, with no aggregation or encapsulation. Be co-precipitated with gypsum and chlorite in the form of unstable Be(OH)2, which attached to the surface of these small particles. The unstable state of Be and the small size, loose structure and high liberation of the host material phases are the main reasons for the high leaching mobility of Be. The results of the risk assessment indicated that BCS posed an extremely high potential ecological risk, with Be being the most significant contributor.
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Metales Pesados , Aguas del Alcantarillado , Aguas del Alcantarillado/química , Aguas Residuales , Metales Pesados/análisis , Berilio , Sulfato de CalcioRESUMEN
OBJECTIVE: To explore the association of C20orf54 gene rs3746804 position single nucleotide polymorphism and susceptibility to esophageal squamous cell carcinoma (ESCC). METHODS: Purification of genomic DNA from whole blood was used the Maxwell(16) System. rs3746804 in C20orf54 was detected by direct sequencing in 434 ESCC patients from Changzhi (Shanxi province) and Linzhou (Henan province) and 554 healthy controls from Changzhi, Linzhou and including immigrators from Linzhou to Changzhi. RESULTS: For rs3746804, the genotypic frequencies of CT (37.5% vs 51.0%, 37.5% vs 52.0%), CC (44.2% vs 34.8%, 44.2% vs 33.0%) in Changzhi ESCC patients showed significant differences with healthy Changzhi controls and the healthy immigrator controls (all P < 0.05), and the frequencies of TT (18.3% vs 4.1%) and CC (44.2% vs 54.6%) in Changzhi ESCC patients showed significant differences with Linzhou ESCC patients (all P < 0.05). The genotypic frequencies of TT (4.1% vs 15.0%), CT (41.2% vs 52.0%) and CC(54.6% vs 33.0%) showed significant differences between Linzhou ESCC patients and the healthy immigrator controls (all P < 0.05), and the frequencies of TT (4.1% vs 14.1%) and CC(54.6% vs 34.8%) showed significant differences between Linzhou ESCC patients and Changzhi healthy controls (all P < 0.01). Meanwhile, there were significant differences between ESCC patients (including Changzhi and Linzhou ESCC patients) and healthy controls (including the healthy Changzhi, Linzhou and immigrator controls) in genotypic frequencies of CT (39.2% vs 48.7%) and CC (48.8% vs 38.2%) (all P < 0.01). CT and CT + TT genotype could decrease the risk of ESCC compared with the CC genotype (OR = 0.630, 95%CI 0.481 - 0.826; OR = 0.654, 95%CI 0.507 - 0.844). CONCLUSION: There is a closed relationship between SNP rs3746804 in C20orf54 and susceptibility to ESCC.
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Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Predisposición Genética a la Enfermedad , Proteínas de Transporte de Membrana/genética , Polimorfismo de Nucleótido Simple , Adulto , Estudios de Casos y Controles , Carcinoma de Células Escamosas de Esófago , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Riboflavina/metabolismoRESUMEN
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.
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Mieloma Múltiple , Aberraciones Cromosómicas , Humanos , Hibridación Fluorescente in Situ , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Recurrencia Local de Neoplasia , FilogeniaRESUMEN
OBJECTIVE: To study the relationship between plasma riboflavin levels and esophageal squamous cell carcinoma. METHODS: We detected and compared plasma concentrations of riboflavin in patients with esophageal squamous cell carcinoma (ESCC) and immigrants of Linzhou living in Changzhi. Plasma riboflavin levels were quantified in 445 ESCC patients, 689 healthy control subjects and 347 immigrants of Linzhou living in Changzhi by using enzyme-linked immunosorbent assay. RESULTS: The plasma riboflavin levels in patients with ESCC were significantly lower than those in the healthy controls and immigrants of Linzhou living in Changzhi [(731.69 ± 330.67) µg/L vs (1090.43 ± 445.08) µg/L, (731.69 ± 330.67) µg/L vs (897.58 ± 177.78) µg/L, respectively, all P < 0.05], and the plasma riboflavin levels of the healthy controls were higher than those in the immigrants of Linzhou living in Changzhi (P < 0.05). CONCLUSION: Patients with ESCC have decreased plasma riboflavin levels as compared with the healthy controls and immigrants of Linzhou living in Changzhi, there exists a lack of riboflavin in ESCC patients, but the specific mechanism needs further study.
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Carcinoma de Células Escamosas/sangre , Neoplasias Esofágicas/sangre , Riboflavina/sangre , Adulto , Anciano , Estudios de Casos y Controles , China , Emigrantes e Inmigrantes , Femenino , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
Autoimmune cytopenia is a general term for all hemocytopenia diseases caused by humoral or cellular immunity abnormalities, and its common immune mechanism determines the importance of immunosuppressive therapy. Sirolimus, as an immunosuppressant against of mTOR, induces immune tolerance by adjusting Treg cells, which has application prospect in the treatment of refractory autoimmune cytopenia. This article reviews the mechanism, application, and possible adverse reactions of sirolimus in the treatment of idiopathic autoimmune cytopenia.
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Sirolimus , Trombocitopenia , Humanos , Inmunosupresores , Linfocitos T ReguladoresRESUMEN
Regular screening for the early detection of common chronic diseases might benefit from the use of deep-learning approaches, particularly in resource-poor or remote settings. Here we show that deep-learning models can be used to identify chronic kidney disease and type 2 diabetes solely from fundus images or in combination with clinical metadata (age, sex, height, weight, body-mass index and blood pressure) with areas under the receiver operating characteristic curve of 0.85-0.93. The models were trained and validated with a total of 115,344 retinal fundus photographs from 57,672 patients and can also be used to predict estimated glomerulal filtration rates and blood-glucose levels, with mean absolute errors of 11.1-13.4 ml min-1 per 1.73 m2 and 0.65-1.1 mmol l-1, and to stratify patients according to disease-progression risk. We evaluated the generalizability of the models for the identification of chronic kidney disease and type 2 diabetes with population-based external validation cohorts and via a prospective study with fundus images captured with smartphones, and assessed the feasibility of predicting disease progression in a longitudinal cohort.
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Aprendizaje Profundo , Diabetes Mellitus Tipo 2/diagnóstico por imagen , Interpretación de Imagen Asistida por Computador/estadística & datos numéricos , Fotograbar/estadística & datos numéricos , Insuficiencia Renal Crónica/diagnóstico por imagen , Retina/diagnóstico por imagen , Área Bajo la Curva , Glucemia/metabolismo , Estatura , Índice de Masa Corporal , Peso Corporal , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Progresión de la Enfermedad , Femenino , Fondo de Ojo , Tasa de Filtración Glomerular , Humanos , Masculino , Metadatos/estadística & datos numéricos , Persona de Mediana Edad , Redes Neurales de la Computación , Fotograbar/métodos , Estudios Prospectivos , Curva ROC , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Retina/metabolismo , Retina/patologíaRESUMEN
Gain-of-function mutations of JAK2 play crucial roles in the development of myeloproliferative neoplasms; however, the underlying downstream events of this activated signaling pathway are not fully understood. Our experiment was designed and performed to address one aspect of this issue. Here we report that AG490, a potent JAK2V617F kinase inhibitor, effectively inhibits the proliferation of HEL cells. Interestingly, AG490 also decreases the expression of PTTG1, a possible target gene of the aberrant signaling pathway, in a dose- and time-dependent manner. Furthermore, the promoter activity analyses reveal that the inhibition of the PTTG1 expression is affected at the transcriptional level. Thus, our results suggest that the JAK2V617F/STAT5 signaling pathway promotes cell proliferation through the transcriptional activation of PTTG1.
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Proliferación Celular , Janus Quinasa 2/metabolismo , Proteínas de Neoplasias/genética , Factor de Transcripción STAT5/metabolismo , Activación Transcripcional , Línea Celular , Humanos , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/genética , Inhibidores de Proteínas Quinasas/farmacología , Securina , Transcripción Genética , Tirfostinos/farmacologíaRESUMEN
OBJECTIVE: To investigate whether combination of urine sediment and urine protein can predict the renal pathological changes. METHODS: We prepared 146 specimens of routine fresh fasting morning urine. Sediment analysis was performed with phase-contrast microscopy and 24-hour urine protein was measured. Both urine protein and sediment data were integrated to form three urine analysis groups. Urine group I: proteinuria, hematuira, urine white blood cells, red/white cell casts. Urine group II: proteinuria, few cell hyaline/fine granular casts. Urine group III: minor proteinuira, epithelial cells of tubule, granular/cell casts. The renal pathological lesions were predicted before and then confirmed by renal biopsy. Statistical analyses were performed using kappa test, chi-square test, and significance was accepted at P<0.05. RESULTS: After renal biopsy, we identified 95 cases of glomerular lesion with proliferation, 46 cases of glomerular disease without obvious proliferation and 5 cases of tubular interstitial lesion. According to the sediment analysis, only 67 cases (46%) could be attributed to urine group I. When combined with urine protein, we could pick out another 75 cases from urine groups I and II, and 8 cases from urine group III. The combined urine analysis could predict glomerular disease (77.7%). CONCLUSION: Clinically we can take advantage of the combined urine analysis to predict the pathological lesion of kidney disease, which is especially suitable for primary care doctor, who can not perform renal biopsy.
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Enfermedades Renales/diagnóstico , Enfermedades Renales/orina , Proteinuria/diagnóstico , Urinálisis , Adulto , Biomarcadores , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To explore whether the analyses of urine sediment spectrum contribute to the diagnosis of crescentic nephritis and whether special cells in urine could be a biomarker for the early stage crescentic nephritis. METHODS: Thirty-five patients diagnosed as crescentic nephritis with renal biopsy were recruited. The phase-contrast microscope was used to observe the early morning urine and offer comprehensive descriptions of urine sediment spectrum. And podocalyxin antibody was utilized to detect podocytes in urine and renal specimens by immunohistochemistry. RESULTS: Marked hematuria and casts were present in the urine of crescentic nephritis and "special cells" appeared in over 50% subjects. The detection rates of "special cells" were 75%, 41% and 0 respectively in early, middle and later stages of crescentic nephritis. Podocytes were identified in the urine of 8/9 subjects. CONCLUSIONS: The urine sediment spectrum contributes to the diagnosis of crescentic nephritis. And special cells in urine are helpful to gauge the stage of crescentic nephritis.
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Glomerulonefritis/orina , Hematuria/orina , Urinálisis , Adulto , Biopsia , Femenino , Glomerulonefritis/patología , Hematuria/patología , Humanos , Riñón/patología , Masculino , Persona de Mediana EdadRESUMEN
Multiple myeloma (MM) is the second most prevalent hematologic malignancy. Although the use of bortezomib (BTZ) significantly improves MM therapy, intrinsic and acquired drug resistance to BTZ remains a major clinical problem. In this study, we find that Cdc37, a key co-chaperone of Hsp90, is downregulated in relapsed MM patients, especially after BTZ treatment, suggesting a link between Cdc37 and BTZ resistance. Suppression of Cdc37 or inhibition of Cdc37/Hsp90 association induces plasma cell dedifferentiation, quiescence of MM cells, and BTZ resistance in MM. Furthermore, we discover that Cdc37 expression correlates positively with Xbp1s, a critical transcription factor for plasma cell differentiation in MM samples. Depletion/inhibition of Cdc37 downregulates Xbp1s, while overexpression of Xbp1s in MM cell lines partially rescues plasma immaturation and BTZ resistance. It is suggested that Xbp1s may act as a key downstream effector of Cdc37. Experiments with a mouse model also demonstrate that Cdc37 inhibition promotes plasma cell immaturation, confers BTZ resistance, and increases MM progression in vivo. Together, we identify a critical factor and a new signaling mechanism that regulate plasma cell immaturation and BTZ resistance in MM cells. Our findings may constitute a novel strategy that overcomes BTZ resistance in MM therapy.
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OBJECTIVE: The aim of this study is to investigate the changes of expression of estrogen receptors (ER), progesterone receptors (PR), Her-2, Ki-67 and histological grade after neoadjuvant chemotherapy in breast cancer. METHODS: Sixty-seven patients with histopathalogically confirmed breast cancer by core needle biopsy received neoadjuvant chemotherapy. The effect of neoadjuvant chemotherapy was assessed according to the criteria of the Japanese Breast Cancer Society: non-effective (G1), mildly effective (G2), moderately effective (G3), markedly effective (G4) and completely effective (G5). All pathological slides were retrospectively reviewed. Immunohistochemical staining (EnVision method) was used to detect the expression of ER and PR, Her-2 and Ki-67. The pre- and post-neoadjuvant chemotherapy status of tumor histological grade, ER and PR, Her-2 and Ki-67 expression in the 49 cases were compared. RESULTS: The effect of neoadjuvant chemotherapy was assessed in 67 patients. There were 5 cases (7.5%) in G1, 19 in G2 (28.4%), 20 in G3 (29.9%), 17 in G4 (25.4%) and 6 in G5 (9.0%), respectively. PR positive rate was 71.4% after chemotherapy versus 91.8% before chemotherapy, with a statistically significant reduction (P = 0.021). However, the ER and Her-2 expression before and after neoadjuvant chemotherapy was stable. Of the patients with invasive ductal carcinoma, 28.6% had histological grade change after neoadjuvant chemotherapy, and 85.7% of patients decreased one grade. The proportion of histological grade change in the G1, G2, G3, G4 were 0, 5.9%, 41.2% and 54.5%, respectively (P = 0.013). The average rate of Ki-67 expression decreased from 28.3% pre-chemotherapy to 11.0% post-chemotherapy (P = 0.011). After the neoadjuvant chemotherapy, the Ki-67 expression rate decreased by > 10%, > 20%, > 30%, > 40% and > 50% in 3 groups (G1 and G2, group G3, group G4 and G5) showed a tendency to be increased, with a significant difference (P < 0.05). CONCLUSION: PR expression in breast cancer decreases after neoadjuvant chemotherapy, while ER and Her-2 expressions remain stable. After neoadjuvant chemotherapy, the histological grade and proliferation index are decreased and correlated with the response to chemotherapy. Therefore, histological grade and proliferation index may be effective complementary factors in assessment of the effectiveness of neoadjuvant chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama , Carcinoma Ductal de Mama , Terapia Neoadyuvante/métodos , Adulto , Anciano , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/tratamiento farmacológico , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patología , Docetaxel , Epirrubicina/administración & dosificación , Femenino , Humanos , Antígeno Ki-67/metabolismo , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos , Taxoides/administración & dosificaciónRESUMEN
OBJECTIVE: To investigate the safety and efficacy of autologous peripheral blood hematopoietic stem cell transplantation (auto-PBHSCT) using modified BU/CY conditioning regimen for young AML patients of low and middle risk in the first complete remission (CR1). METHODS: Ten young AML patients of low and middle risk who did not want to accept allogeneic hematopoietic stem cell transplantationï¼allo-HSCTï¼and underwent auto-PBHSCT in CR1 during May 2013 to December 2016 were retrospectively analyzed. From 3 months after auto-PBHSCT, the maintenance therapy with interleukin-2 (IL-2) or IL-2 combined with histamine dihydrochloride was performed for these patients in the next 18 months. The side effects of the conditioning regimen, hematopoietic recovery time, transplant-related mortality (TRM) within 100 days and 1 year after auto-PBHSCT, relapse rate, leukemia-free survival (LFS) rate at 2 years and 3 years, overall survival (OS) were evaluated at 3 years and 4 years. RESULTS: Gastrointestinal side effects were the major non-hematologic toxicity reaction, among which, 7 cases relatively mild and 3 cases displayed moderate, just one case suffered from severe reaction. In 4 cases, the mild liver damage occurred, but no hemorrhagic cystitis occurred. All the patients experienced different kinds of infection, including 5 cases of bloodstream infection, 2 cases of gastrointestinal infection, 3 cases of crissum infection and 2 cases of oral infection. The myeloablative effect occurred in all ten patients. The median times for absolute neutrophil count (ANC)<0.5×109/L and for platelet count <20.0×109/L were 1.5 (0-3) days and 3 (2-5) days after transplantation, respectively. The patients achieved ANC>0.5×109/L at 10 to 19 days, median was 13 days after auto-PBHSCT. The patients achieved platelet count >20×109/L at 10 to 72 days; median was 32 days after auto-PBHSCT. The TRM within 100 days and 1 year after transplantation was 0. The relapse occurred in 2 cases at 6 and 14 months after auto-PBHSCT raspectively. The median follow-up time was 48.1 months, and the median survival time was 54.7 months after transplantation. The 2-year and 3-year LFS were 100% (10 cases) and 80% (8 cases), respectively. The 3-year and 4-year OS were 80% (8 cases) and 70% (7 cases), respectively. CONCLUSION: Modified BU/CY as conditioning regimen for auto-PBHSCT can achieve the myeloablative effect without raising TRM and obtain good LFS and OS. As for young AML patients without high risk, it is a valuable therapeutic option, especially for those lacking the chance of allo-HSCT.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Supervivencia sin Enfermedad , Humanos , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Trasplante Autólogo , Resultado del TratamientoRESUMEN
The treatment of multiple myeloma (MM) with proteasome inhibitor (PI) bortezomib has significantly improved the survival of patients with MM. The 26S proteasome inhibitor targets the unfolded protein response (UPR) by inhibiting proteasome degradation of ubiquitinated paraprotein, subsequently leading to the lethal accumulation of paraprotein within the endoplasmic reticulum. According to secretory status of monoclonal immunoglobulin, newly diagnosed MM (NDMM) is divided into measurable and unmeasurable disease, which includes oligosecretory, nonsecretory, and nonproducer myeloma. The present study analyzed the clinical characteristics of 822 patients with NDMM who had either measurable or unmeasurable diseases and received bortezomib- or thalidomide-based therapies. Our results showed that the median progression-free survival (PFS) and overall survival (OS) of patients with MM was significantly longer in patients with measurable disease than those in oligosecretory, nonsecretory, and nonproducer MM (PFS: 27, 18, 19, and 2.0 months, respectively [P < .001]; OS: 51, 30, 22, and 2.0 months, respectively [P < .001]). Within the unmeasurable group, patients with nonproducer myeloma showed the shortest PFS and OS. Importantly, compared with thalidomide treatment, bortezomib significantly improved the PFS and OS of patients with MM with measurable disease (PFS: 25 and 33 months [P = .022], respectively; OS: 41 and 58 months [P < .001], respectively), but not those with unmeasurable disease (PFS: 18 and 16 months [P = .617], respectively; OS: 22 and 27 months [P = .743], respectively). Our results indicate that bortezomib-based therapy performed no better than thalidomide-based treatment in patients with unmeasurable MM. The results need to be confirmed in other patient cohorts, preferably in the context of a prospective trial.