[Effect of Recombinant Human Thrombopoietin on Platelet Reconstitution after Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma].

OBJECTIVE: To analyze the effect of recombinant human thrombopoietin (rhTPO) on platelet (PLT) reconstitution after autologous peripheral blood stem cell transplantation (APBSCT) in patients with multiple myeloma (MM). METHODS: The clinical data of 147 MM patients who were diagnosed in the First Affiliated Hospital of Soochow University and received APBSCT as the first-line therapy were retrospectively analyzed. According to whether rhTPO was used during APBSCT, the patients were divided into rhTPO group (80 cases) and control group (67 cases). The time of PLT engraftment, blood product infusion requirements, the proportion of patients with PLT recovery to≥50×109/L and≥100×109/L at +14 days and +100 days after transplantation, and adverse reactions including the incidence of bleeding were compared between the two groups. RESULTS: There were no significant differences between the two groups in sex, age, M protein type, PLT count at the initial diagnosis, median duration of induction therapy before APBSCT, and number of CD34+ cells reinfused (all P >0.05). The median time of PLT engraftment in the rhTPO group was 10 (6-14) days, which was shorter than 11 (8-23) days in the control group (P < 0.001). The median PLT transfusion requirement in the rhTPO group during APBSCT was 15(0-50)U, which was less than 20 (0-80)U in the control group (P =0.001). At +14 days after transplantation, the proportions of patients with PLT≥50×109/L in the rhTPO group and the control group were 66.3% and 52.2%, while the proportions of patients with PLT≥100×109/L were 23.8% and 11.9%, respectively, with no significant differences (all P >0.05). At +100 days after transplantation, the proportion of patients with PLT≥50×109/L in rhTPO group and control group was 96.3% and 89.6%, respectively (P >0.05), but the proportion of patients with PLT≥100×109/L in rhTPO group was higher than that in control group (75.0% vs 55.2%, P =0.012). There was no difference in the overall incidence of bleeding events in different locations during period of low PLT level of patients between the two groups. In rhTPO group, the rhTPO administration was well tolerated, and the incidences of abnormal liver and kidney function and infection were similar to those in the control group. CONCLUSION: When MM patients undergo first-line APBSCT, subcutaneous injection of rhTPO can shorten the time of platelet engraftment, reduce the transfusion volume of blood products, and be well tolerated, moreover, more patients have achieve a high level of PLT recovery after transplantation, which is very important for ensuring the safety of APBSCT and maintenance therapy.

[Changes in Health Risks and Pollution Sources of Atmospheric PM2.5-bound Metals in a Background Site in North China].

To explore the change features of PM2.5-bound metals in a background site of North China in the past ten years, 71 and 160 samples were collected from December 2011 to January 2013 (period Ⅰ) and from September 2019 to November 2021 (period Ⅱ) in Tuoji Island National Atmospheric Monitoring Station, respectively.The concentration of metals sampled was determined using ICP-MS, and the concentrations, sources, and health risks of heavy metals were compared. The results revealed that the average concentration of PM2.5 was (54.06±39.71) µg·m-3during period Ⅱ, which was 3.53 ng·m-3 lower than that during period Ⅰ. The concentrations of Zn, Mn, As, Pb, and V in stage Ⅱ decreased by 54.53, 172.63, 0.8, 79.06, and 3.81 ng·m-3, respectively, whereas the concentrations of Cr, Cu, Cd, and Ni increased by 2.01, 5.42, 3.03, and 3.55 ng·m-3, respectively. The PMF model results indicated that the biggest contributor to PM2.5-bound metal was industrial emissions (32.32%), followed by coal combustion (27.47%), vehicle emissions (23.70%), ship emissions (9.69%), and dust sources (6.83%) during period Ⅱ. The contribution ratio of dust sources and ship emissions decreased by 20.73% and 8.83%, respectively, whereas for coal combustion and industrial emissions it increased by 2.50% and 13.52%, respectively, when compared with that during period Ⅰ. The total carcinogenic risk induced by PM2.5-bound heavy metals of period Ⅱ increased, with the highest contributions by Cr and Cd. The total non-carcinogenic risk decreased, with Mn contributing the most. Therefore, in the process of air pollution control, the control of pollution sources of heavy metals such as Cr and Mn should be reinforced.

[Myxoid liposarcoma of the testis: A case report and review of the literature].

OBJECTIVE: To investigate the clinicopathological features, diagnosis, differential diagnosis, treatment and prognosis of myxoid liposarcoma (MLPS)of the testis. METHODS: We observed the clinicopathological and immunophenotypic characteristics of primary MLPS of the testis in a male patient and reviewed the relevant literature. RESULTS: The tumor was located in the right testicular parenchyma, of multi-nodular growth microscopically. The tumor cells were stellate, fusiform, foamy and signet ring-like, with abundant mucus and a network of fine branched or plexiform capillaries in the stroma. Immune phenotype-related findings included positive p16 and H3K27ME3 tumor cells and CD34 vascular network, negative CD99, CK, Desmin, FLI agreed-1, S-100, SMA, STAT6, TFE3, α-inhibin and SOX1, and a Ki-67 proliferation index of about 15%. CONCLUSION: Primary MLPS of the testis is rare, which needs to be differentiated from myxosarcoma, rhabdomyosarcoma, myxoma, spindle cell or pleomorphic liposarcoma, and lipophiloma. Immunohistochemical markers Vimentin, s-100 and CD34 can assist in the diagnosis of the tumor.

Atezolizumab-induced anaphylactic shock in a patient with hepatocellular carcinoma undergoing immunotherapy: A case report.

BACKGROUND: Atezolizumab is a programmed death ligand 1 (PD-L1) inhibitor, and its combination with bevacizumab has been proven an effective immunotherapy for unresectable hepatocellular carcinoma (HCC). Treatment with immune checkpoint inhibitors (ICIs) can lead to hypersensitivity reactions; however, anaphylactic shock is rare. We present a case of life-threatening anaphylactic shock during atezolizumab infusion and performed a relevant literature review. CASE SUMMARY: A 75-year-old man was diagnosed with HCC recurrence after hepatectomy. He was administered immunotherapy with atezolizumab plus bevacizumab after an allergy to a programmed death-1 (PD-1) inhibitor. The patient showed a sudden onset of dizziness, numbness, and lack of consciousness with severe hypotension during atezolizumab infusion. The treatment was stopped immediately. The patient's symptoms resolved after 5 mg dexamethasone was administered. Because of repeated hypersensitivity reactions to ICIs, treatment was changed to oral targeted regorafenib therapy. CONCLUSION: Further research is necessary for elucidating the hypersensitivity mechanisms and establishing standardized skin test and desensitization protocols associated with PD-1 and PD-L1 to ensure effective treatment with ICIs.

[Inhibitory effect of KyoT2 overexpression on proliferation and migration of airway smooth muscle cells in mice with asthma].

OBJECTIVE: To investigate the effect of KyoT2 on the proliferation and migration of airway smooth muscle cells (ASMCs) in mice with asthma. METHODS: Ovalbumin (OVA) was used to establish the asthmatic model of airway remodeling in BALB/c mice. ASMCs were isolated and cultured, and primarily cultured ASMCs were used as the control group. The expression of KyoT2 in ASMCs was measured in the control and asthma groups. After the ASMCs from asthmatic mice were transfected with pCMV-Myc (empty vector group) or pCMV-Myc-KyoT2 plasmid with overexpressed KyoT2 (KyoT2 expression group) for 48 hours, RT-PCR and Western blot were used to measure the mRNA and protein expression of KyoT2, the MTT assay and BrdU assay were used to measure the proliferation of ASMCs, and Transwell assay was used to measure the migration of ASMCs. Western blot was used to determine the effect of KyoT2 overexpression on the protein expression of RBP-Jκ, PTEN, and AKT. RESULTS: Compared with the control group, the asthma group had significantly downregulated expression of KyoT2 in ASMCs, and the KyoT2 expression group had significantly upregulated expression of KyoT2 in ASMCs (P<0.05). Compared with the empty vector group, overexpressed KyoT2 significantly inhibited cell proliferation and migration, downregulated the expression of RBP-Jκ and AKT, and upregulated the expression of PTEN. CONCLUSIONS: Overexpressed KyoT2 can inhibit the proliferation and migration of ASMCs through the negative regulation of RBP-Jκ/PTEN/AKT signaling pathway.

Moxibustion Reduces Ovarian Granulosa Cell Apoptosis Associated with Perimenopause in a Natural Aging Rat Model.

In recent years, concerns about the adverse effects of hormone replacement therapy have increased interest in alternative therapies for the management of the symptoms of perimenopause. Here, we investigated the effects of moxibustion, a traditional Chinese practice that is involved in heated Artemisia vulgaris (mugwort) stimulation, on hormonal imbalance and ovarian granulosa cell (GC) apoptosis in a rat model of perimenopause. Our results showed that mild warm moxibustion (MWM) modulated the circulating levels of estradiol and follicle-stimulating hormone and their receptors and inhibited apoptosis in the ovaries of perimenopausal rats, similar to the effect of estrogen. Further investigation revealed that the effects of MWM on ovary tissues and cultured GCs were mediated by the modulation of the activity of Forkhead box protein O1 and involved the JAK2/STAT3 pathway. Our results provide information on the factors and pathways modulated by MWM and shed light on the mechanism underlying the beneficial effect of moxibustion on the symptoms of perimenopause.

Zuo Jin Wan reverses P-gp-mediated drug-resistance by inhibiting activation of the PI3K/Akt/NF-κB pathway.

BACKGROUND: Zuo-Jin-Wan (ZJW), a traditional Chinese medicine formula, has been identified to be effective against drug resistance in cancer. In the present study, we investigated the effect of ZJW on acquired oxaliplatin-resistant and the PI3K/Akt/NF-κB pathway in vitro. METHODS: We tested the dose-response relationship of ZJW on reversing drug-resistance by CCK-8 assay and flow cytometry analysis in vitro. The protein expression of P-gp, MRP-2, LRP, and ABCB1 mRNA expression level were evaluated by Western blot and quantitative RT-PCR. The activities of PI3K/Akt/NF-κB pathway were also examined with or without ZJW, including Akt, IκB, p65 and their phosphorylation expression. RESULTS: We found that ZJW significantly enhanced the sensitivity of chemotherapeutic drugs and increased oxaliplatin (L-OHP)-induced cell apoptosis in a time- and dose-dependent manner. Moreover, both ZJW and a PI3K specific inhibitor (LY294002) suppressed phosphorylation of Akt (Ser473) and NF-κB, which is necessary in the activation of the PI3K/Akt/NF-κB pathway. The effect of ZJW in reversing drug-resistance and suppressing phosphorylation of Akt (Ser473) and NF-κB were weakened after treatment with a PI3K/Akt activator in HCT116/L-OHP cells. CONCLUSIONS: Our study has provided the first direct evidence that ZJW reverses drug-resistance in human colorectal cancer by blocking the PI3K/Akt/NF-κB signaling pathway, and could be considered as a useful drug for cancer therapy.

Angiotensin II facilitates fibrogenic effect of TGF-ß1 through enhancing the down-regulation of BAMBI caused by LPS: a new pro-fibrotic mechanism of angiotensin II.

Angiotensin II has progressively been considered to play an important role in the development of liver fibrosis, although the mechanism isn't fully understood. The aim of this study was to investigate a possible pro-fibrotic mechanism, by which angiotensin II would enhance the pro-fibrotic effect of transforming growth factor beta 1 (TGF-ß1) through up-regulation of toll-like receptor 4 (TLR4) and enhancing down-regulation of TGF-ß1 inhibitory pseudo-receptor-BAMBI caused by LPS in hepatic stellate cells (HSCs). Firstly, the synergistic effects of angiotensin II, TGF-ß1 and LPS on collagen 1α production were confirmed in vitro by ELISA, in which angiotensin II, LPS and TGF-ß1 were treated sequentially, and in vivo by immunofluorescence, in the experiments single or multiple intra-peritoneally implanted osmotic mini-pumps administrating angiotensin II or LPS combined with intra-peritoneal injections of TGF-ß1 were used. We also found that only LPS and TGF-ß1 weren't enough to induce obvious fibrogenesis without angiotensin II. Secondly, to identify the reason of why angiotensin II is so important, the minute level of TLR4 in activated HSCs - T6 and primary quiescent HSCs of rat, up-regulation of TLR4 by angiotensin II and blockage by different angiotensin II receptor type 1 (AT1) blockers in HSCs were assayed by western blotting in vitro and immunofluorescence in vivo. Finally, BAMBI expression level, which is regulated by LPS-TLR4 pathway, was detected by qRT-PCR and results showed angiotensin II enhanced the down-regulation of BAMBI mRNA caused by LPS in vitro and in vivo, and TLR4 neutralization antibody blocked this interactive effect. These data demonstrated that angiotensin II enhances LPS-TLR4 pathway signaling and further down-regulates expression of BAMBI through up-regulation of TLR4, which results in facilitation of pro-fibrotic activity of TGF-ß1. Angiotensin II, LPS and TGF-ß1 act synergistically during hepatic fibrogenesis, showing crosstalks between angiotensin II-AT1, LPS-TLR4 and TGF-ß1-BAMBI signal pathways in rat HSCs.

[Impact of disease status on outcomes of allogeneic hematopoietic stem cell transplantation in patients with refractory and relapsed acute myeloid leukemia].

The study was aimed to evaluate the impact of disease status on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with refractory and relapsed acute myeloid leukemia (AML). 32 patients with refractory and relapsed AML received allo-HSCT after myeloablative conditioning regimen, including 17 patients in no-remission (NR) and 15 patients in complete remission (CR) at the time of transplant. Treatment related adverse events, relapse rate and leukemia free survival (LFS) were analyzed. The results showed that the parameters of sex, age, cytogenetic risk and transplant procedures were comparable between the two groups. 30 patients had successful engraftment, except one had graft failure and one died from severe veno-occlusive disease in the NR group. The incidences of aGVHD in NR group and CR group were 47.1% (8 patients) and 33.5% (5 patients) respectively. Out of comparable patients, 5 from 9 patients in NR group developed with cGVHD, and 4 from 11 patients in CR group were subjected to cGVHD. There were no statistic difference in incidences of aGVHD and cGVHD between two group. Compa-red with CR group, NR group had a higher treatment-related mortality (29.4% vs 14.3%, P = 0.392) and relapse rate (42.9% vs 26.7% P = 0.300), but there was no significant difference. With a median follow-up of 13 (1 - 124) months, 6 patients remained alive in both of the two groups, and the 2 year LFS of them were parallel (35.3% vs 40.0%, P = 0.267). Among these 32 patients, overall survival (OS) was better in patients with age < 35 years (P = 0.044) and with the appearance of cGVHD (P = 0.046). It is concluded that allo-HSCT is an effective salvage therapy for patients with refractory and relapsed AML, and the overall outcome seems unrelated to the disease status (NR or CR) before transplantation. As such, for refractory and relapsed AML patients in non-remission, performance of allo-HSCT to achieve long-term survival is feasible.

[Correlation between clinical outcome and WT1 detection after hematopoietic stem cell transplantation in acute leukemia].

OBJECTIVE: To evaluate preliminarily the significance of detecting the Wilms' tumor (WT1) gene level on monitoring minimal residual disease (MRD) and predicting the clinical outcome in patients of acute leukemia following hematopoietic stem cell transplantation (HSCT). METHODS: The mRNA expression levels of WT1 and house-keeping gene ABL were dynamically measured with Real-time quantitative reverse transcription polymerase chain reaction (RQ-RT-PCR) on 326 bone marrow samples from 63 post-HSCT patients in our hospital from December 2001 to September 2009. After comparing the WT1 levels of patients with different post-transplantation outcomes, the investigators used the receiver operating characteristic (ROC) curve to determine the WT1 threshold so as to predict their clinical relapses. Then different prognoses of WT1 positive and negative patients were analyzed. RESULTS: The levels of WT1 expression showed significant difference between the 19 relapsing and 44 non-relapsing patients with the median expression levels of 1270 (55 - 47 596) and 132 (0 - 2959) respectively (P < 0.01). In 19 relapsing patients, except for 1 patient discontinuing the detection of WT1, 10 mortality cases due to recurrence had higher levels of WT1 expression than other 8 patients (P > 0.05). According to the ROC curve, the cut-off value of WT1 at 585 could separate 63 patients into the WT1-positive group (> 585) and the WT1-negative group (≤ 585). The WT1-negative group was found to have a longer relapse-free survival (RFS) and overall survival (OS) than the positive group (all P < 0.01). Twenty-one WT1-positive patients were followed up for 3, 4 - 6, 7 - 9 and 9 months respectively. The cumulative post-HSCT recurrence rates in those WT1-positive cases were 8/8, 2/4, 2/4 and 3/5 (P = 0.063) respectively. And the intervention was ineffective. CONCLUSION: WTl gene may be an independent factor of monitoring MRD. And WT1 > 585 is a poor post-HSCT prognostic factor for the patients of acute leukemia.

Research progresses in the pathogenesis of anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is a distinct subset of T-cell non-Hodgkin's lymphoma. As a consequence of its low incidence, general pathogenic consideration of ALCL is lacking. In this review, we summarize the pathogenesis, epidemiology, clinical manifestations, and treatment of ALCL, so as to better understand key stages of the development of this disease and provide valuable information for future treatment.

[New concept for ALK negative anaplastic large cell lymphoma].

ALK negative anaplastic large cell lymphoma (ALK(-) ALCL) lacks the specific expression of ALK protein, although it also strongly expresses CD30 and resembles the morphologic characteristics of ALK positive anaplastic large cell lymphoma (ALK(+) ALCL). Recently, some new researches indicate that there exist molecular and genetic differences between these two types of ALCL. Moreover, the treatment response, prognosis, and long-term survival of ALK(-) ALCL are far worse than that of ALK(+) ALCL, such as ALK(-) ALCL is associated with older age persons, B group syndrome, disease advanced stage, high International Prognostic Index (IPI) and poor prognosis (< 49% 5-year survival). As a consequence, some new advances on basis (cell morphology and tissue pathology, immunophenotypes, cell genetics and molecular marker), diagnosis and treatment of ALK(-) ALCL are summarized in this review.

[Detecting minimal residual disease status in allogeneic hematopoietic stem cell transplantation of patients with high-risk acute leukemia].

OBJECTIVE: To explore the relationship between minimal residual disease (MRD) and the outcome of patients with high-risk acute leukemia (AL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: By 4/5-color multi-parameter flow cytometry (MFC, CD45/SSC gating) for detecting MRD at pre-(day-30) and post-transplant (day +30, +60, +100, 6 months, 9 months and 12 months), the investigators retrospectively analyzed the MRD levels and the prognosis of 90 high-risk patients. According to the MRD cutoff value of 0.1%, the low-level and high-level groups were defined. In the high-level group, the patients were divided into two sub groups according to the subsequent treatment (intervention therapy group and non-intervention therapy group). RESULTS: MRD pre-transplant had no predictive value for the clinical outcome. The patients with high levels of MRD post-transplant (+60 d and +100 d) showed higher relapse rates than those of the low-level group. In addition, regarding MRD +100 d post-transplant, differences were significant among 3 groups (high-level MRD and intervention therapy group, high-level MRD and non-intervention therapy group and low-level MRD group) including 1-year relapse-free survival (RFS) (100% vs 60.87% vs 91.30%, P < 0.05) and 3-year RFS (85.71% vs 44.72% vs 68.48%, P < 0.05). The median time from first high level MRD detected to clinical relapse was 2.5 (1 - 26) months. In the high level MRD group (+100 d post-transplant), 7 of 30 patients received intervention therapy without relapse. However another 23 patients had no intervention treatment and 11 of them relapsed latter (P < 0.05). CONCLUSION: The MFC-based quantification of MRD post-transplant reveals important prognostic information in patients with high-risk AL. MRD check point at day +100 (cutoff: 0.1%) may discriminate different risk populations. Those patients with MRD levels ≥ 0.1% should receive early intervention at an early stage and a low tumor burden so as to reduce the relapse rate and boost survival.

[Surgical treatment and pathological findings of hematological malignancies patients complicated with lung diseases.].

OBJECTIVE: To determine the pulmonary pathological changes in hematological malignancy patients with pulmonary complications. METHODS: 17 hematological malignancy patients underwent surgical treatment were evaluated retrospectively. The pathological changes of all the surgical specimens were examined postoperatively by standard hematoxylin and eosin (HE) staining. RESULTS: Pathological examination confirmed: aspergillus infection in 9 patients, sub-acute inflammation (fibrosis and hematoma formation) in 3, and each in 1 of pulmonary infarction with granulomatous tissue in the periphery; granulomatous inflammation with calcified tubercle; alveolar dilation and hemorrhage, interstitial fibrosis and focal vasculitis; intercostal neurilemmoma; and moderate-differentiated adenocarcinoma accompanied by intrapulmonary metastasis. And several operative complications (1 case of fungal implantation, 3 pleural effusion and adhesions and 2 pulmonary hematoma) were occurred. The coincidence rate of pre- and post-operative diagnosis was 9/14 (64.3%). After surgery, 8 patients were received hematopoietic stem cell transplantation (HSCT, allo-gene or autologous), with 7 succeeded. On effective secondary antifungal prophylaxis, 4 of 5 patients of aspergillosis succeeded in transplantation with free from mycotic relapse, one patient died from fungal relapse. CONCLUSION: Hematological malignancies with persistent and/or resistant pulmonary infection, hemoptysis, or unexplained lung diseases, should be treated in time by surgery operation to effectively eliminate residual disease and obtain a definitive diagnosis, so as to create a prerequisite condition for the following treatments. Moreover, the secondary antifungal prophylaxis can provide active roles for patients scheduled for chemotherapy and/or HSCT.

[Clinical study on needle-pricking therapy for treatment of polycystic ovarial syndrome].

OBJECTIVE: To probe into the clinical effect of needle-pricking therapy for treatment of polycystic ovarial syndrome. METHODS: One hondred and twenty-one cases of polycystic ovarial syndrome were divided into a needle-pricking therapy group of 61 cases and a medication group of 60 cases with randomized and controlled method. The needle-pricking therapy group were treated by needle-pricking therapy at sacral plexus stimulating points on both sides of the spine and lateral points of Dazhui (CV 14), and the medication group by oral administration of domiphen and intramuscular injection of chorionic gonadotropin (HCG). Levels of hormones and symptoms in the patients before treatment, after treatment of 3 cycles and at the sixth cycle after treatment were investigated. RESULTS: After treatment of 3 cycles, the level of hormone and B type ultrasound examination were significantly improved in the two groups (P < 0.01). At the sixth cycle after treatment, the conditions of the patients in the medication group were returned to the original levels before treatment, while the conditions in the needle-pricking therapy group still kept at the post-therapeutic level, and their menstruation and ovulation restored to normal state, and the ovulation mucosa and the pregnancy rate were significantly higher than those in the medication group (all P < 0.01). CONCLUSION: Needle-pricking therapy has obvious effect on polycystic ovarial syndrome, and has a good long-term therapeutic effect.