Lymphopenia at diagnosis is highly prevalent in myelodysplastic syndromes and has an independent negative prognostic value in IPSS-R-low-risk patients.

Lymphopenia is associated with an increased mortality in several medical conditions. Its prognostic impact in myelodysplastic syndromes (MDS) is less well studied. Hence, we analyzed 1023 patients from the Düsseldorf MDS-registry with regard to the absolute lymphocyte count (ALC) at diagnosis. An ALC below the median of the population (1.2 × 10 <sup>9</sup> /l) was associated with lower counts of neutrophils (median 1.35 vs. 1.92 × 10 <sup>9</sup> /l, p < 0.001) and platelets (median 100 vs. 138 × 10 <sup>9</sup> /l, p < 0.001) and with a significant lower overall survival in univariate analysis (whole cohort: median 36 vs. 46 months, p = 0.016; 721 patients without hematopoietic stem cell transplantation or induction chemotherapy: median 36 vs. 56 months, p = 0.001). For low-risk MDS according to IPSS-R, an ALC < 1.2 × 10 <sup>9</sup> /l was of additional prognostic value in a multivariate Cox regression model together with age (< or ≥65 years) and LDH (< or ≥normal value of 240 U/l; HR 1.46, 95% CI: 1.03-2.08, p = 0.033). These data support the hypothesis of subtle but clinical relevant changes of the adaptive immune system in MDS. Further studies are necessary to identify the ALC cut-off best suitable for prognostication and the mechanisms responsible for the impairment of lymphoid homeostasis in MDS

The novel beta 2-selective proteasome inhibitor LU-102 synergizes with bortezomib and carfilzomib to overcome proteasome inhibitor resistance of myeloma cells

Bio-organic Synthesi

Loss of the Promyelocytic Leukemia Protein in Gastric Cancer: Implications for IP-10 Expression and Tumor-Infiltrating Lymphocytes

Gastric cancer is one of the most common causes of cancer-related mortality worldwide. Expression of the tumor suppressor, promyelocytic leukemia (PML) protein, is reduced or abolished in gastric carcinomas, in association with an increased level of lymphatic invasion, development of higher pTNM staging, and unfavorable prognosis. Herein, we investigated the relationship between the extent of tumor-infiltrating lymphocytes and the status of PML protein expression in advanced gastric carcinoma. We observed higher numbers of infiltrating T-cells in gastric carcinoma tissues in which PML expression was reduced or abolished, compared to tissues positive for PML. The extent of T-cell migration toward culture supernatants obtained from interferon-gamma (IFN-γ-stimulated gastric carcinoma cell lines was additionally affected by expression of PML in vitro. Interferon-gamma-inducible protein 10 (IP-10/CXCL10) expression was increased in gastric carcinoma tissues displaying reduced PML levels. Moreover, both Pml knockout and knockdown cells displayed enhanced IP-10 mRNA and protein expression in the presence of IFN-γ. PML knockdown increased IFN-γ-mediated Signal Transducer and Activator of Transcription-1 (STAT-1) binding to the IP-10 promoter, resulting in elevated transcription of the IP-10 gene. Conversely, PML IV protein expression suppressed IP-10 promoter activation. Based on these results, we propose that loss of PML protein expression in gastric cancer cells contributes to increased IP-10 transcription via enhancement of STAT-1 activity, which, in turn, promotes lymphocyte trafficking within tumor regions

Magnitude and phase response measurement of headphones at the eardrum

Transfer functions of headphones are measured to verify that they meet certain requirements or to determine what equalization may make them meet an ideal target curve. The present study compares six headphones by physical measurements at the eardrums of six individuals and on a dummy head. For headphone transfer functions we are interested in the variability in the produced sound pressure at the eardrum across individuals, the similarity between dummy head and real-ear measurements, the agreement with the diffuse-field design target and, finally, the prevalence of all-pass phase

Lymphopenia is highly prevalent in overt myelofibrosis at diagnosis but lacks additional prognostic value

Background: Lymphopenia is prognostically relevant in several malignancies. Little is known about its role in myelofibrosis (MF). Aim: To evaluate the prevalence of lymphopenia at diagnosis and its prognostic impact in MF. Methods: Patients diagnosed between 2010-2020 at the Cantonal Hospitals St. Gallen and Muensterlingen with primary MF [PMF], MF secondary to essential thrombocytopenia or polycythemia vera [MF- post] and prefibrotic primary MF [pre- PMF] were evaluated for the absolute lymphocyte count (ALC) at diagnosis. Results: 80 patients with overt MF (PMF n = 59, MF-post n = 21) and 28 with pre-PMF were included. The ALC was lower in overt MF compared to pre-PMF (median 1.5x109/l versus 2.0x109/l, p = 0.039). In MF-post (evaluable post-ET n = 8, post-PV n = 10), a drop of the ALC was documented at MF-diagnosis compared to the diagnosis of the preceeding disorder (median 1.35x109/l versus 2.05x109/l, p = 0.009). An ALC <1.5x109/l was associated with lower hemoglobin concentration and neutrophil-counts (median 100 vs. 115g/l and 5.5 vs. 8 G/l, p = 0.009 and p = 0.023). For cases with fibrosis grade 3 versus grade 2, a trend towards a lower ALC was noted (median 1.3x109/l versus 1.6x109/l, p = 0.07). The DIPSS-groups did not differ with regard to the ALC. Neither an ALC <1.0x109/l nor <1.5x1.0x109/l was associated with a survival difference (median 65 versus 73 months, p = 0.879 and 66 versus 89 months, p = 0.823). Conclusions: Lymphopenia in MF is highly prevalent at diagnosis, but offers no additional prognostic information. Its association with lower hemoglobin values and the development of fibrosis in cases of MF-post points towards a possible relationship of lymphopenia with MF-pathophysiology

Nelfinavir interacts with mitochondrial VDACs and disrupts oxidative phosphorylation in proteasome inhibitor resistant myeloma

Venetoclax is an oral BCL2 inhibitor undergoing investigation for use in relapsed or refractory multiple myeloma (RRMM), particularly in combination with proteasome inhibitors (VPI)[1,2]. An interim analysis of a current phase 2 trial of venetoclax with carfilzomib in RRMM demonstrated an overall response rate of 78% with a very good partial response rate of 56%[3,4]. However, a separate ongoing phase 3 trial of venetoclax with bortezomib found a decrease in overall survival due to increased fatal infections in the venetoclax arm compared to placebo. Better describing these infections may give insight into the pathophysiology and prove useful in mitigating strategies for use with VPI therapy in RRMM. Bio-organic Synthesi

Fibroblast α11β1 Integrin Regulates Tensional Homeostasis in Fibroblast/A549 Carcinoma Heterospheroids

We have previously shown that fibroblast expression of α11β1 integrin stimulates A549 carcinoma cell growth in a xenograft tumor model. To understand the molecular mechanisms whereby a collagen receptor on fibroblast can regulate tumor growth we have used a 3D heterospheroid system composed of A549 tumor cells and fibroblasts without (α11+/+) or with a deletion (α11-/-) in integrin α11 gene. Our data show that α11-/-/A549 spheroids are larger than α11+/+/A549 spheroids, and that A549 cell number, cell migration and cell invasion in a collagen I gel are decreased in α11-/-/A549 spheroids. Gene expression profiling of differentially expressed genes in fibroblast/A549 spheroids identified CXCL5 as one molecule down-regulated in A549 cells in the absence of α11 on the fibroblasts. Blocking CXCL5 function with the CXCR2 inhibitor SB225002 reduced cell proliferation and cell migration of A549 cells within spheroids, demonstrating that the fibroblast integrin α11β1 in a 3D heterospheroid context affects carcinoma cell growth and invasion by stimulating autocrine secretion of CXCL5. We furthermore suggest that fibroblast α11β1 in fibroblast/A549 spheroids regulates interstitial fluid pressure by compacting the collagen matrix, in turn implying a role for stromal collagen receptors in regulating tensional hemostasis in tumors. In summary, blocking stromal α11β1 integrin function might thus be a stroma-targeted therapeutic strategy to increase the efficacy of chemotherapy