bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Rare Case of Primary Amyloidosis, Presenting with Severe Pulmonary Hypertension and Bilateral Pleural Effusion.
Authors: Agheli Aref , Arora Alka , Khalil Maged , Dumlao Theresa , Naik Seema , Steier William , Kalavar Madhumati 
Published: October 2019

Abstract
Pulmonary arterial hypertension secondary to vascular deposition is a rare presentation of Primary Amyloidosis. The natural history of pulmonary hypertension and concomitant right-sided cardiac failure is not very well understood and is associated with a very short median survival. This syndrome is a marker of advanced Amyloidosis Persistent pleural effusion is another much rarer presentation of pulmonary involvement in Primary Amyloidosis and is secondary to pleural infiltration, which sometimes is difficult to distinguish from the cardiomyopathic causes. The incidence of pleural effusion in primary Amyloidosis is 1–2%. This syndrome also has a very poor prognosis, and has limited response to treatment, however, pleurodesis has been temporarily useful in some cases.
Case report: A 74 year old African American female, non-smoker, with history of hypertension, who presented with shortness of breath and persistent productive cough and 18 pounds weight loss for the last six months. The initial chest x-rays showed bilateral pleural effusion and a transudate fluid on analysis. Cardiac workup for an atypical chest pain revealed moderate to severe pulmonary hypertension without myocardial infiltration on 2-D echocardiogram, and normal coronary arteries on cardiac catheterization. Extensive workup did not show any secondary cause of pulmonary hypertension, however, the patient gradually developed nephrotic range proteinuria and kidney biopsy showed infiltration of 10 nm fibrils, involving 3+ segmental mesangium, and 2+ segmental glomerular basement membranes. This was consistent with renal Primary Amyloidosis, AL Lambda type. A random urine and serum sample for immunofixation also revealed an M- spike of 23 mg/dl in gamma region. A concomitant bone marrow biopsy revealed presence of monoclonal IgG lambda plasma cell (CD38 bright) population, without any B-cell or T-cell markers.
Conclusion: Pulmonary hypertension and pleural effusion are two rare and lethal presentations of pulmonary involvements in Primary Amyloidosis, and it should be considered in the differential diagnosis of any patient presenting with pulmonary symptoms. There is no definite treatment of these syndromes, although combinations of steroids and melphalan, along with colchicines, vincristine, adriamycin, and thalidomide have been used with minimum satisfactory outcomes. Autologous stem cell transplantation (SCT) provides the opportunity to give higher doses of chemotherapy and may be of benefit in some cases.
T Cell Acute Lymphoblastic Leukemia Originates from a Differentiation Block in T Cell Development Due to Aberrant Expression of LMO2 and SCL(TAL1).
Authors: Layh-Schmitt Gerlinde , Crable Scott , Crable Kathleen , Kraft Elizabeth , Bailey Jeff , Klanke Charles , von Kalle Christof 
Published: October 2019

Abstract
T cell acute lymphoblastic leukemia (T-ALL) is frequently associated with overexpression of the oncogenes LMO2 and SCL(TAL1) which are normally down regulated following the double negative stage of T cell development. Our goal is to decipher the molecular and cellular mechanisms leading to the onset of LMO2 associated T-ALL. We were able to isolate a complex containing the transcription factors LMO2, SCL(TAL1) and E47 from primary human T-ALL cells with proven aberrant expression of LMO2 and SCL(TAL1) by applying immunoprecipitation and Western blotting techniques. This protein complex regulates the transcription of a truncated form of RALDH2 (retinaldehyde dehydrogenase) in T-ALL cells as shown by gene transcription profiling in conjunction with RT-PCR and siRNA approaches. To monitor the effect of LMO2 expression on T cell development and leukemogenesis, lethally irradiated mice (C57BL/6) were transplanted with bone marrow cells that had been transduced with a retrovirus carrying LMO2 as the transgene. One year later, 88% of the cells in the thymus expressed LMO2 and a shift towards CD3−/CD44+/CD25+ cells was observed (an 88% increase compared to normal thymocytes), suggesting a differentiation block caused by LMO2 leading to an accumulation of immature T cells. To test and identify cooperating genes in T-ALL development, bone marrow cells of LMO2 double transgenic mice in which tet-inducible LMO2 is controlled by a thymic specific promoter, were retrovirally transduced with SCL(TAL1). So far, none of the control animals, transplanted with bone marrow cells transduced with a vector only containing EGFP, developed T-ALL. However, six out of the seven test animals developed T-ALL exhibiting enlargement of the spleen, liver and thymus between seven and nine months after transplantation. Organs and blood of the diseased animals were infiltrated with T-ALL cells of the immature phenotype CD8+/CD4+ in five cases and of the CD3−/CD44+/CD25+ phenotype in one case. This indicates that the differentiation block caused by a lack of down-regulation of LMO2 and SCL(TAL1) in maturing T cells leads to a block in T cell differentiation and precedes T-ALL. These models will be used to examine the involvement of other cooperating genes in T-ALL development as well as downstream target genes of LMO2/SCL(TAL1), such as RALDH2, in the onset of T-ALL. We conclude that aberrant expression of LMO2 in T cells leads to a block in T cell maturation and, in conjunction with up-regulation of secondary genes like SCL(TAL1), triggers deregulation of genes in immature T cells leading to impaired T cell development and the onset of T-ALL. The described model will help to identify cooperating genes in LMO2 associated T-ALL as well as the chain of events leading to malignancy.
Inositol 1,4,5-Trisphosphate Receptors Mediating Spontaneous Ca2+ Oscillation Favors Proliferation in Human Mesenchymal Stem Cells from Bone Marrow.
Authors: Tao Rong , Lau Chu-Pak , Li Gui-Rong 
Published: October 2019

Abstract
Although human mesenchymal stem cells (hMSCs) constitute a very small population of cells in bone marrow, they play an important role in the regulation of hematopoietic microenvironment. The self-renew and/or proliferation of hMSCs is believed to be particularly important in maintaining bone marrow niche; however, the regulation of this process is not fully understood. The present study was designed to investigate whether spontaneous Ca2+ oscillation mediated by inositol 1,4,5-trisphosphate (IP3) receptors participates in the proliferation regulation in cultured hMSCs from bone marrow using RT-PCR, cell proliferation assay, Western-blotting analysis. It was found that no gene expression for ryanodine-sensitive receptors was detected in undifferentiated hMSCs, while three subtypes of IP3 receptor genes (i.e. IP3R1, IP3R2, and IP3R3), and genes for sarco/endoplasmic reticulum Ca2+ ATPases (SERCA) (ATP2A1, ATP2A2, and ATP2A3) were expressed in these cells. The proliferation of hMSCs was reduced by inhibiting Ca2+ oscillation with the IP3 receptor antagonist 2-aminoethyl diphenylborinate (2-APB) or the SERCA inhibitor cyclopiazonic acid (CPA). In addition, inhibition of Mek/Erk and PI-3K/Akt signaling also decreased hMSCs proliferation. The relation of Ca2+ oscillation to the activity of these kinases was revealed by Western blotting analysis. Erk1/2 (Thr185/Tyr187) phosphorylation level was found to be reduced by directly inhibiting Ca2+ oscillation with 2-APB or CPA either in the presence or absence of serum. However, Akt (Thr308) phosphorylation was decreased only in the presence of serum, and serum-free starvation (2 h) eliminated Akt (Thr308) phosphorylation. Finally the calmodulin inhibitors W-7 and SKF-7171A were employed to further investigate whether this ubiquitous Ca2+ sensor is involved in the Ca2+ signal-mediated effect. Similarly, the phosphorylation level of Erk1/2 (Thr185/Tyr187) and Akt (Thr308) reduced upon the inhibition of calmodulin. In conclusion, our results demonstrate that IP3 receptors-mediated spontaneous Ca2+ oscillation and/or Ca2+/calmodulin signaling play(s) a crucial role in the regulation of cell proliferation mediated by multiple pro-proliferation signaling pathways (e.g. Mek/Erk and PI-3K/Akt). Importantly, Erk1/2 phosphorylation is sensitive to spontaneous Ca2+ oscillation, and therefore is responsible for the proliferation induced by Ca2+ oscillation in hMSCs.
The Incidence and Impact of Thrombocytopenia in Myelodysplastic Syndrome (MDS).
Authors: Kantarjian Hagop M. , Giles Francis , List Alan F. , Lyons Roger , Price Sherry , Deuson Robert , Leveque Joseph 
Published: October 2019

Abstract
Background: MDS is a heterogeneous stem cell malignancy characterized by ineffective hematopoiesis and increased risk of transformation to acute myeloid leukemia. Thrombocytopenia and platelet dysfunction are recognized to contribute to hemorrhagic complications, however, reliable data regarding the frequency and consequences of thrombocytopenia in MDS are lacking.
Objective: To assess thrombocytopenia in MDS based on literature and chart review.
Methods: MDS literature (January 1980 to November 2005) was identified using MEDLINE, EMBASE, and Cochrane databases, society websites, and hand searches of bibliographies. In addition, a retrospective review of all patients referred to the MD Anderson Cancer Center (MDACC) with MDS since 1980 was performed.
Results: A total of 85 references were identified describing clinical consequences of thrombocytopenia, n=16; efficacy and safety of MDS therapies, n=60; guidelines, n=9. Because of variable definitions of thrombocytopenia, a platelet count <100x109/L was applied as the threshold point in the literature analysis. The prevalence of thrombocytopenia in MDS ranged from 40% to 65%. Baseline thrombocytopenia rates were reported in 19/60 (32%) references; the median frequency of thrombocytopenia prior to MDS therapy was 65% (range, 23% to 93%). The MDACC database review identified 1605/2410 (67%) patients with thrombocytopenia (<100x109/L) at referral. Severe thrombocytopenia (<20x109/L) was observed in 425 (18%) patients. Using the International Prognostic Scoring System (IPSS), 399/2410 (17%) patients had intermediate-2 or high risk disease; 83% and 25% of these patients had platelet counts of <100x109/L and <20x109/L, respectively. Corresponding event frequencies decreased to 21% and 3% in patients with low or intermediate-1 risk MDS (264/2410, 11%). The reported incidence of MDS treatment-related thrombocytopenia was >50% in studies involving lenalidomide, azacitidine, or a combination of idarubicin, cytarabine and topotecan. Treatment-related thrombocytopenia was also observed in studies involving tipifarnib, linomide, decitabine, all-trans retinoic acid, and sirolimus. The reported incidence of hemorrhagic complications ranged from 3% to 53%, and the frequency of hemorrhagic deaths ranged from 14% to 24%. At MDACC, 460 patients had a coded cause of death: hemorrhage as a cause of death, 20%; hemorrhage as the only cause of death, 10%.
Conclusions: Thrombocytopenia is common in MDS with a higher prevalence in higher risk IPSS categories. Many approved and investigational MDS therapies cause or exacerbate pre-existing thrombocytopenia. The incidence of severe bleeding in MDS was higher than reported in current guidelines or reviews.
The Novel, Irreversible Proteasome Inhibitor PR-171 Demonstrates Potent Anti-Tumor Activity in Pre-Clinical Models of Multiple Myeloma, and Overcomes Bortezomib Resistance.
Authors: Kuhn Deborah J. , Chen Qing , Voorhees Peter M. , Strader John S. , Shenk Kevin D. , Sun Congcong M. , Demo Susan D. , Bennett Mark K. , van Leeuwen Fred W. , Orlowski Robert Z. 
Published: October 2019

Abstract
Introduction: The ubiquitin-proteasome pathway has been validated as a therapeutic target with the approval of the small molecule proteasome inhibitor, bortezomib (VELCADE®), in multiple myeloma and non-Hodgkin lymphoma. However, the overall response rate of patients with multiple myeloma in phase III clinical trials was 43%, underscoring the need for a next generation of inhibitors with the potential for greater efficacy.
Methods: PR-171 is a novel, tetrapeptide epoxomicin-related inhibitor that binds the proteasome irreversibly, and our objectives were to evaluate its activity and mechanism of action in pre-clinical models of multiple myeloma.
Results: PR-171 potently bound and inhibited the chymotrypsin-like subunit of the proteasome in vitro, in cellulo, and in vivo at low concentrations. At higher concentrations, however, unlike bortezomib, which targeted the chymotrypsin-like and peptidyl-glutamyl peptide hydrolyzing activities in vivo, PR-171 also displayed significant inhibition of the trypsin-like and the peptidyl-glutamyl peptide hydrolyzing activities. PR-171-induced proteasome inhibition was associated with accumulation of polyubiquitinated substrates and pro-apoptotic Bax. Brief pulse PR-171 exposure, which simulates the in vivo pharmacokinetics of bortezomib, led to PR-171-mediated inhibition of cellular proliferation linked to induction of caspase-3-dependent apoptosis through both intrinsic (caspase-9) and extrinsic (caspase-8-dependent) pathways. Pretreatment with caspase-3, -8, and -9 inhibitors rescued the anti-proliferative effect of PR-171. Furthermore, pulse PR-171 treatment activated c-Jun-N-terminal kinase, a key-signaling molecule in proteasome inhibitor-induced apoptosis, and cleavage of poly-ADP-ribose polymerase, while abrogation of c-Jun-N-terminal kinase signaling with a dominant-negative c-Jun inhibited PR-171-induced effects. PR-171 displayed enhanced anti-proliferative activity compared to bortezomib in multiple myeloma cell lines and freshly isolated patient-derived CD138+ plasma cells, associated with enhanced phosphorylation of c-Jun-N-terminal kinase and capase-3, -8, and -9 activation. Lastly, PR-171 was a potent inhibitor of proliferation in a multiple myeloma cell line model resistant to bortezomib and in isolates from two patients, one with primary and the other with acquired bortezomib-resistance.
Conclusions: These data indicate that PR-171 has enhanced activity against preclinical models of multiple myeloma, perhaps owing to its irreversible binding and subunit specificity, and provide a rationale for its translation into the clinic.
Candida tropicalis Arthritis of the Knee in a Patient with Acute Monocytic Leukemia.
Authors: He Jingsong , Ye Xiujin , Zheng Weiyan , Wu Wenjun , Lin Maofang , Huang He 
Published: October 2019

Abstract
The patients with malignant hematopathy are the high-risk group of invasive fungal infections (IFI). Candidemia and IFI caused by Candidas in patients with a hematological malignancy are common but Candida arthritis is rare. Here, we reported a case of Candida tropicalis arthritis of the knee that occurred with acute monocytic leukemia during the recovery period of post chemotherapy myelosuppression and agranulocytosis.
Case report: A 45-year-old Chinese woman was diagnosed with acute monocytic leukemia with normal caryotype in november 2004. Complete remission was achieved upon completion of 2 courses of induction chemotherapy. Treatment was administered via a Hickman catheter in the left elbow. Two days after phase V consolidation chemotherapy, the patient experienced high fever accompanied by the development of arthritis in the right knee. The diagnosis of Candida tropicalis arthritis of the knee was confirmed by the appearance of Candida tropicalis isolated from the synovial fluid, but no leukemic cells and acid-fast bacilli were found. According to the susceptibility test in vitro, itraconazole and amphotericin B injection were used sequentially for therapy for 4–5 weeks, which effectively inhibited bacterial growth. However, the arthritis relapsed after 4–6 weeks of drug withdrawal. The arthritis was fully resolved after 8 weeks of therapy with fluconazol injection at a dose of 400mg/d and douching articular cavity with amphotericin B once a week. And then sequential therapy with oral fluconazole was commenced. There was no any adverse effect occurrence during the course of treatment.
Discussion: Although Candida arthritis in patient with a hematological malignancy is rare, it still occurred in patient with hypoimmunity. Early diagnosis is difficult due to no distinctive clinical manifestation and hysteresis of pathogenic organism detection. It was found that the knee was the sole joint affected according to the review of fourteen other reports of Candida arthritis in patients with a hematological malignancy but the reason remains unclear. Fungal arthritis must be taken into consideration when dealing with patients with immune deficiency accompanied by arthritis, especially gonarthritis. We emphasize that the most important factors for the successful treatment of fungal arthritis are identified diagnosis and adequate dosage through out the course of treatment.
Preclinical Research on Idiotype Vaccine Against B Cell Lymphoma.
Authors: Wang Fuxu , Zhao Bing , Pan Ling , Zhang Xuejun , Luo Jianmin , Dong Zuoren 
Published: October 2019

Abstract
The idiotype (Id) of immunoglobulin expressed by B cell lymphoma can serve as the only widely accepted tumor associated antigen. But the Id vaccines have failed to elicit anti-tumor immunity for its weak immunogenic. Monocyte chemoattractant protein-3 (MCP3) can recruit various subsets of immune cells, such as DCs, which would uptake and properly process and present Id, activating both arms of the immune system, humoral and cellular. So the Id-MCP3 fusion proteins are potential vaccines for immunotherapy of B cell lymphoma. In this study, two vaccine candidates were constructed by fusing allogeneous MCP3 to the amino-(MCP3-scFv) or carboxyl-(scFv-MCP3) terminus of the A20 (BABL/c murine B-lymphocyte) Id scFv with a flexible polypeptide spacer encoding NDAQAPKS to prevent dissociation and keep their respective natural construction and function. And VH and VL domains were linked with a current linker encoding (Gly4Ser)3. Firstly, the cDNAs of Ig VH and Ig VL were amplified by RT-PCR from A20 mRNA, and then assembled into scFv by recombinant PCR method. Secondly the fusion genes of scFv/MCP3 were formed using the same method. After sequencing, MCP3/scFv fusion genes were cloned into pET-39b vector. Lastly MCP3/scFv fusion proteins were expressed in E.coli BL21. And the fusion protein is about 62 kD. We found that, under the same condition, MCP3-scFv fusion protein was expressed successfully and accounted for 40% of the total protein of the bacteria but not scFv-MCP3. Our result indicated that fusing MCP3 to carboxyl-terminus of scFv protein may have cytotoxicity to the host cells or maybe not stable inside the host cells. Next we will determine the activity of the fusion protein MCP3-scFv with cell-chemotatic-experiment in vitro and bearing-tumor mice experiment in vivo. Once the results would suggest that there may be an anti-tumor effect, we can make individual vaccines to lead to a better survival.
Increased Fatty Acid Synthase Is a Therapeutic Target in Multiple Myeloma.
Authors: Wang Weiqin , Zhao Xiaoying , Wang Haiyan , Xu Gengbo , Zhang Xiaohong 
Published: October 2019

Abstract
Multiple myeloma is a malignancy arising from postgerminal nature B cells. The estimated incidence of multiple myeloma accounts for 10% of hematological malignancies and 1% of all malignancies. Despite therapeutic advance, the disease is essentially incurable. Fatty acid synthase (FAS), the principle enzyme in the endogenous synthsis of fatty acid, is highly expressed in a wide variety of human malignancies and their presursor lesions, including carcinoma of the colon, prostate, ovary, endometrium and breast. One therapeutic target that has not previously been considered for multiple myeloma treatment is the pathway of the endogenous synthesis of fatty acid. For this purpose, we first evaluated a series of human multiple myeloma cases, bone marrow samples for FAS expression by immunohistochemistry, then established FAS mRNA and protein expression in multiple myeloma cell lines and human multiple myeloma plasma cells by RT-PCR and immunoblot analysis. Our results showed that 19 of the 27(70.37%) MM cases were scored as FAS positive by immunohistochemistry, whereas 8 of the 27 (29.64%) were scored negative. FAS mRNA was highly expressed in U266, RPMI8226 cells and 22 of the 27 MM patients, but wasn’t detected in healthy donor PBMNCs by RT-PCR. Immunoblot analysis found that FAS protein was detected in 16 of the 27 patients(59.25%) and two above myeloma cell lines but not detected in healthy donor PBMNCs. Encouraged by these findings that human multiple myeloma bone marrow samples and cell lines overexpress FAS, we treated human multiple myeloma cell lines (U266, RPMI8226) in vitro with cerulenin, a native inhibitor of FAS. Cells proliferation was measured by methyl thiazolyl tetrazolium(MTT) analysis and apoptosis was evaluated by flow cytometry. Treat with 5ug/ml—640ug/ml of cerelenin for 24h, the proliferation of U266 cells was obviously inhibited with dosage related effect. The inhibition rate of human skin fibroblast cells are all lower than 30%. When U266 cells are treated for 12h with 20ug/ml of cerulenin, the early stage apoptosis rate revealed by Annxin V/PI using FCM are 56,9%. Our findings suggest that FAS may be an effective target for pharmacological therapy in human multiple myeloma.
In Vivo Radiaprotective Effects of Growth Hormone.
Authors: Chen Benny J. , Deoliveira Divino , Chao Nelson J. 
Published: October 2019

Abstract
Ionizing irradiation can cause bone marrow failure and death. Very few effective therapeutic agents are currently available for this condition. It was previously published that human recombinant growth hormone promotes hematopoietic and immune reconstitution after stem cell transplantation. In this study, we investigated the effects of growth hormone on radiation-induced injury. In a sublethally irradiated model (BALB/c mice, 5 Gy), the recovery of platelets in peripheral blood was significantly accelerated after treatment with human recombinant growth hormone at a dose of 20 μg, i.p., once a day, for 35 days starting within one hour after irradiation. Similar trends were also observed in total white blood cells and all lymphocyte subsets tested (T, B, NK cells). These data suggest that growth hormone can promote hematopoietic and immune recovery after irradiation. We then tested whether growth hormone can rescue animals from lethal irradiation. BALB/c mice were irradiated with 7.5 Gy and treated with growth hormone using the same regimen as that used in the sublethal model. As demonstrated in the figure, 5 out of 10 mice in the growth hormone treated group survived more than 80 days after irradiation, whereas 9 out of 10 mice died by day 25 in the saline control group. Growth hormone was still effective when tested using higher dose of radiation (8.5 Gy). These findings demonstrate that human recombinant growth hormone has significant radioprotective effects even when given after total body irradiation.
Figure Figure