A diagnostic analysis reveals that on the interannual time scale the southeast–northwest movement is a dominant feature of the South Asian high (SAH), and it is closely related to the Indian and East ...Asian summer monsoon rainfall. The southeastward (northwestward) shift of the SAH is closely related to less (more) Indian summer monsoon rainfall and more (less) rainfall in the Yangtze River valley (YRV) over the East Asian summer monsoon region. An anomalous AGCM is utilized to examine the effect of latent heat anomalies associated with the Asian summer monsoon rainfall on the SAH. The negative latent heat anomalies over the northern Indian Subcontinent associated with a weak Indian summer monsoon stimulates an anomalous cyclone to its northwest and an anticyclone to its northeast over the eastern Tibetan Plateau and eastern China in the upper troposphere, which is responsible for the east–west shift of the SAH and more rainfall in the YRV. The positive latent heat release associated with rainfall anomalies in the YRV excites a southward-located anticyclone over eastern China, exerting a feedback effect on the SAH and leading to a southeast–northwest shift of the SAH.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Multiple myeloma (MM) is a hematological cancer causing from accumulated abnormal plasma cells. STAT3 overexpression in MM appears to be mediated by a variety of factors, and it may be associated ...with an adverse prognosis and play a role in microenvironment-dependent treatment resistance. Unfortunately, MM remains an incurable disease, as relapse is very common. Therefore, there is urgent need to develop new treatment options for MM. Radotinib is a novel anti-cancer drug, currently approved in South Korea for the treatment of chronic myeloid leukemia patients. It is an oral, multitargeted inhibitor of receptor tyrosine kinases, including BCR-ABL, c-KIT, PDGFR, and Src family kinases. However, little is known about the effects of radotinib on multiple myeloma cells. However, little is known about the effects of radotinib on multiple myeloma cells. But even tinip almost not known about the impact of multiple myeloma cells. Moreover, nothing is known about how it affects STAT3 and JAK2. In this study, we analyzed the effect of radotinib on multiple myeloma cells. Herein, Moreover, nothing is known about how it. Moreover, not all is known about how the affects STAT3 and JAK2. We investigated the effect of radotinib on the STAT3 signaling pathway in MM cells, including several MM cell lines and mouse models. So we investigated the effect of radotinib on MM cells, including several MM cell lines and mouse models. Interestingly, radotinib induced apoptosis, and inhibited cell proliferation in MM cells including RPMI-8226, MM.1S, U266B1, and IM-9 cells. Moreover, radotinib treatment significantly increased the number Annexin V-positive cells and G0/G1-phase cells. In addition, radotinib treatment in various MM cells strongly suppressed the activity and expression of STAT3 and JAK2 proteins. We also observed that diverse proteins related to the STAT3 signaling pathway, including c-Myc, Bcl-xL, Mcl-1, cyclin D1 and cyclin D3, were powerfully inhibited by radotinib treatment in MM cells. Furthermore, radotinib significantly suppressed MM cell growth in a xenograft animal model using IM-9 cells. In conclusion, radotinib may play an important role as a candidate agent for MM treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The number of elderly people is rapidly growing, and the proportion of elderly patients with multiple myeloma (MM) continues to increase. This study aimed to develop a frailty assessment tool based ...on clinical data and to estimate its feasibility in elderly patients with MM. This study analyzed data from 728 elderly transplant-ineligible patients with newly diagnosed MM who were treated between January 2010 and October 2019. Our clinical frailty index included age (< 75, and ≥ 75 years), Charlson comorbidity index (CCI; < 3 and ≥ 3), and Eastern Cooperative Oncology Group performance status score (ECOG score; 0, 1-2, and ≥ 3). Patients were classified as fit, intermediate, or frail if they had a score of 0, 1, or ≥ 2, respectively. The overall survival rates differed significantly according to frailty (fit vs. intermediate: hazard ratio HR = 2.41; 95% confidence interval CI = 1.43-4.06; P = 0.001; fit vs. frail: HR = 4.61; 95% CI = 2.74-7.77; P < 0.001 and intermediate vs. frail: HR = 1.91, 95% CI = 1.49-2.45, P < 0.001, respectively). The frail had significantly shorter EFS compared with the fit and intermediate group in our frailty index (fit vs. intermediate: HR = 1.34, 95% CI = 0.92-1.96, P = 0.132; fit vs. frail: HR = 2.06, 95% CI = 1.40-3.02, P < 0.001; and intermediate vs. frail: HR = 1.53, 95% CI = 1.22-1.92, P < 0.001, respectively). The new clinical frailty index, which is based on age, CCI, and ECOG PS, can easily assess frailty in elderly patients with MM and can be helpful in predicting survival outcomes in real world clinical setting.
LIGHT (HVEM-L, TNFSF14, or CD258), an entity homologous to lymphotoxins, with inducible nature and the ability to compete with herpes simplex virus glycoprotein D for herpes virus entry mediator ...(HVEM)/tumor necrosis factor (TNF)-related 2, is a member of the TNF superfamily. It is expressed as a homotrimer on activated T cells and dendritic cells (DCs), and has three receptors: HVEM, LT-β receptor (LTβR), and decoy receptor 3 (DcR3). So far, three receptors with distinct cellular expression patterns are known to interact with LIGHT. Follicular DCs and stromal cells bind LIGHT through LTβR. We monitored the effects of LIGHT on human bone marrow-derived mesenchymal stem cells (BM-MSCs). At first, we checked the negative and positive differentiation markers of BM-MSCs. And we confirmed the quality of MSCs by staining cells undergoing adipogenesis (Oil Red O staining), chondrogenesis (Alcian blue staining), and osteogenesis (Alizarin red staining). After rhLIGHT treatment, we monitored the count, viability, and proliferation of cells and cell cycle distribution. PDGF and TGFβ production by rhLIGHT was examined by ELISA, and the underlying biological mechanisms were studied by immunoblotting by rhLIGHT treatment. LTβR was constitutively expressed on the surface of human BM-MSCs. Cell number and viability increased after rhLIGHT treatment. BM-MSC proliferation was induced by an increase in the S/G2/M phase. The expression of not only diverse cyclins such as cyclin B1, D1, D3, and E, but also CDK1 and CDK2, increased, while that of p27 decreased, after rhLIGHT treatment. RhLIGHT-induced PDGF and TGFβ production mediated by STAT3 and Smad3 activation accelerated BM-MSC proliferation. Thus, LIGHT and LTβR interaction increases the survival and proliferation of human BM-MSCs, and therefore, LIGHT might play an important role in stem cell therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
Allogeneic hematopoietic stem‐cell transplantation (HCT) is the only curative option for most hematologic malignancies. However, HSCT can cause early menopause and various complications in ...premenopausal women. Therefore, we aimed to investigate risk factors predicting early menopause and its clinical implications among survivors post HCT.
Methods
We retrospectively analyzed 30 adult women who had received HCT at premenopausal status between 2015 and 2018. We excluded patients who had received autologous stem cell transplantation, had relapsed, or died of any cause within 2 years of HCT.
Results
The median age at HCT was 41.6 years (range, 22–53). Post‐HCT menopause was identified in 90% of myeloablative conditioning (MAC) HCT and 55% of reduced‐intensity conditioning (RIC) HCT (p = .101). In the multivariate analysis, the post‐HCT menopausal risk was 21 times higher in a MAC regimen containing 4 days of busulfan (p = .016) and 9.3 times higher in RIC regimens containing 2–3 days of busulfan (p = .033) than that of non‐busulfan‐based conditioning regimens.
Conclusions
Higher busulfan dose in conditioning regimens is the most significant risk factor affecting post‐HCT early menopause. Considering our data, we need to decide on conditioning regimens and individualized fertility counseling before HCT for premenopausal women.
Background
In East Asia, S-1 plus cisplatin (SP) is one of the standard first-line chemotherapy regimens for metastatic or recurrent gastric cancer (MRGC). Oxaliplatin is generally less toxic and ...more convenient to administer than cisplatin.
Patients and methods
This was a multicenter, phase III study assessing whether S-1/oxaliplatin (SOX) was non-inferior/superior to SP in terms of progression-free survival (PFS). Patients with MRGC were randomized 1:1 to receive either SOX (S-1 80 mg/m
2
/day on days 1–14; oxaliplatin 130 mg/m
2
on day 1; every 3 weeks) or SP (S-1 80 mg/m
2
/day on days 1–14; cisplatin 60 mg/m
2
on day 1; every 3 weeks SP3).
Results
Between October 2012 and October 2014, 338 patients were randomized. The median age was 56 years, and 51% of patients had measurable lesions. SOX was significantly non-inferior but not superior to SP3 in terms of PFS median 5.6 versus 5.7 months; hazard ratio (HR) 0.85; 95% confidence interval (CI) 0.67–1.07. In patients with measurable disease, objective response rates were similar between SOX and SP3 (58% versus 60%). Overall, the survival in both groups did not differ (median 12.9 versus 11.4 months; HR 0.86; 95% CI 0.66–1.11). Treatment was well tolerated in both arms. Anemia, leucopenia, neutropenia, febrile neutropenia, and oral mucositis were more common with SP3. In contrast, thrombocytopenia, nausea, vomiting, and peripheral neuropathy were more common with SOX.
Conclusions
SOX was non-inferior to SP3. The two regimens were well tolerated with different toxicity profiles. The SOX regimen can be recommended as a first-line treatment for MRGC.
Trial registration
ClinicalTrials.gov: NCT01671449
Background Severe graft versus host disease (GVHD) is the main reason for non-relapse mortality following allogeneic hematopoietic cell transplantation (HCT). We investigated the serum protein ...profiles of patients who had undergone HCT to identify predictive biomarkers of severe acute GVHD (aGVHD). Methods Serum samples were collected for 30 patients from day - 7 to day + 14 of HCT. The serum levels of plasma beta2-microglobulin (beta2-MG), soluble vascular cell adhesion molecule-1 (sVCAM-1), platelet factor 4, and TNFSF-14 were measured by ELISA as potential biomarkers following 310 cytokine profiling array. Results The median age of the study patients was 53.5 years (range, 19-69). All grade and grade 2-4 aGVHD developed in 21 (70.0%) and 17 (56.7%) patients, respectively. Compared with their baseline levels on day - 7, beta2-MG and sVCAM-1 were significantly increased on day + 14 of the HCT procedure (P = 0.028 and P < 0.001, respectively). Patients with a grade 2-4 severe aGVHD showed a significantly higher sVCAM-1 level at baseline (day-7) and at day + 14, compared with the other group with a grade 1 aGVHD or no aGVHD (P = 0.028 and P = 0.035, respectively). Conclusion Higher sVCAM- levels at baseline and on day + 14 in HCT patients could be a significant predictive biomarker of severe aGVHD. Keywords: Soluble VCAM-1, Acute graft versus host disease, Biomarker, Allogeneic stem cell transplantation
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Liver transplantation is the most effective treatment option for patients with acute or chronic liver failure. However, the applicability and effectiveness of this modality are often limited by a ...shortage of donors, surgical complications, high medical costs, and the need for continuing immunosuppressive therapy. An alternative approach is liver cell transplantation. LIGHT (a member of the tumor necrosis factor superfamily) could be a promising candidate for promoting the differentiation of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) into hepatocyte-like cells. In this study, we investigated the effect of LIGHT on hBM-MSC differentiation into hepatocyte-like cells. Our previous results showed that LIGHT receptor lymphotoxin-β receptor (LTβR) is constitutively expressed on the surface of hBM-MSCs. Upon treatment with recombinant human LIGHT (rhLIGHT), the phenotype of hBM-MSCs changed to round or polygonal cells. In addition, the cells exhibited high levels of hepatocyte-specific markers, including albumin, cytokeratin-18 (CK-18), CK-19, cytochrome P450 family 1 subfamily A member 1 (CYP1A1), CYP1A2, CYP3A4, SRY-box transcription factor 17 (SOX17), and forkhead box A2 (FOXA2). These results indicate that rhLIGHT enhances the differentiation of hBM-MSCs into functional hepatocyte-like cells. Furthermore, rhLIGHT-induced hepatocyte-like cells showed a higher ability to store glycogen and uptake indocyanine green compared with control cells, indicating functional progression. Additionally, treatment with rhLIGHT increased the number, viability, and proliferation of cells by inducing the S/G2/M phase and upregulating the expression of various cyclin and cyclin dependent kinase (CDK) proteins. We also found that the hepatogenic differentiation of hBM-MSCs induced by rhLIGHT was mediated by the activation of signal transducer and activator of transcription 3 (STAT3) and STAT5 pathways. Overall, our findings suggest that LIGHT plays an essential role in promoting the hepatogenic differentiation of hBM-MSCs. Hence, LIGHT may be a valuable factor for stem cell therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) are new therapeutic targets in cancer immunotherapy. The aim of this study was to investigate the clinicopathological ...characteristics of PD-1 and PD-L1 expression in extranodal natural killer/T‑cell lymphoma, nasal type (ENKTL). We performed PD-1 and PD-L1 immunostaining in 79 ENKTL biopsy samples and retrospectively analyzed medical records of all 79 patients from four tertiary referral hospitals. The expression of PD-1 and PD-L1 by tumor cells and/or infiltrating immune cells was evaluated. The expression rates of PD-L1 in tumor cells and infiltrating immune cells were 79.7 and 78.5 %, respectively, whereas PD-1 in tumor cells and infiltrating immune cells were 1.3 and 11.4 %. The PD-L1 positivity in tumor cells and infiltrating immune cells was significantly associated with low international prognostic index (IPI) (
P
= 0.044 and 0.037, respectively). Patients with normal range of serum lactate dehydrogenase demonstrated a significantly higher PD-L1 positivity in tumor cells (
P
= 0.020). PD-L1-positive patients had a trend toward better overall survival compared with that in patients with PD-L1-negative in tumor cells and infiltrating immune cells (
P
= 0.498 and 0.435, respectively). The expression rate of PD-L1 was up to 79.7 % in ENKTL, while PD-1 expression rate was very low. This is the first report describing the clinicopathological features and survival outcome according to expression of PD-1 and PD-L1 in ENKTL.
Background
Current guidelines recommend using filgrastim or tbo‐filgrastim to mobilize hematopoietic progenitor cells in an autologous setting. However, previous studies have suggested other forms of ...granulocyte colony‐stimulating factor (G‐CSF) are equally efficacious, possibly with fewer leukaphereses required. Thus, we prospectively studied the efficacy of lenograstim, a glycosylated recombinant form of G‐CSF, in multiple myeloma (MM) patients.
Methods
From November 2011 to January 2020, 98 MM patients undergoing autologous stem cell transplant (ASCT) from five academic centers in Korea were enrolled. Patients were mobilized with subcutaneous lenograstim (Neutrogin®) with fixed doses of 10 μg/kg for 4 days.
Results
Most of the patients ( N = 90, 91.8%) achieved at least the targets of 2 × 106 CD34+ cells/kg body weight, and more than half of MM patients ( N = 57, 58.2%) reached a target of 5 × 106 CD34+ cells/kg body weight. The mobilization failure rate was 8.2% ( N = 8). The median number of CD34 + cell/kg using G‐CSF only was 5.25 × 106/kg (range 0.49–13.47). Adverse events included transfusion (TF, N = 53, 54.1%), bone pain ( N = 6, 6.1%), fever ( N = 2, 2.0%), and gastrointestinal troubles ( N = 2, 2.0%). There were no grade 3 or 4 adverse events during mobilization. Body surface area (BSA) at mobilization and platelet TF were factors associated with CD34+ collection. Most patients achieved neutrophil ( N = 93, 98.9%) and platelet ( N = 89, 95.7%) engraftment.
Conclusion
Lenograstim can safely and effectively mobilize stem cells in MM autologous settings.
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