Thrombopoietin receptor agonists regulate myeloid-derived suppressor cell-mediated immunomodulatory effects in ITP.

TPO receptor agonists (TPO-RAs) are a class of clinical second-line regimens for the treatment of primary immune thrombocytopenia (ITP). It can promote megakaryocyte maturation and increase platelet production, but its effect on immunosuppressive cells in patients with ITP has not been explored. Sixty-two ITP patients and 34 healthy controls (HCs) were included in this study. The proportion and functions of myeloid-derived immunosuppressive cells (MDSCs) in ITP patients and HCs were investigated. We found that the proportion and function of MDSCs in ITP patients treated with TPO-RAs were significantly higher than those treated with glucocorticoids (GCs), which was correlated with the clinical efficacy. The proportion and function of cytotoxic Th1 cells and CD8+T cells decreased, while the proportion and immunosuppressive function of Treg cells increased in ITP patients treated with TPO-RAs. We further proved, through MDSC depletion tests, that the inhibitory effect of MDSCs on Th1 cells and the promotion of Treg cells in the original immune micro-environment of GCs-treated ITP patients were impaired; however, these MDSCs' functions were improved in TPO-RAs-treated patients. Finally, we found that the KLF9 gene in MDSCs cells of ITP patients treated with TPO-RAs was down-regulated, which contribute to the higher mRNA expression of GADD34 gene and improved function of MDSCs. These results demonstrate a novel mechanism of TPO-RAs for the treatment of ITP through the assessment of MDSCs and their subsequent impact on T cells, which provides a new basis for TPO-RAs as first-line treatment approach to the treatment of ITP.

Pegfilgrastim improves the outcomes of mobilization and engraftment in autologous hematopoietic stem cell transplantation for the treatment of multiple myeloma.

Autologous stem cell transplantation (ASCT) is the only curable therapy for multiple myeloma (MM), while its success primarily relies on mobilization to obtain sufficient hematopoietic stem/progenitor cells (HPC). Although the role of Pegfilgrastim (PEG), a novel PEGylated form of the recombinant G-CSF filgrastim (FIL), in mobilization has been demonstrated, it remains unclear whether this approach is cost-effective in MM treatment. Here, we performed a real-world analysis to evaluate the efficacy and cost of PEG for mobilization in a cohort of MM patients, of which 53% carried high-risk cytogenetic abnormalities. A total of 91 patients who received either a single dose of PEG (6 or 12 mg, n = 42) or multiple dosing of 10 µg/kg/day FIL (n = 49) after chemotherapy for HPC mobilization were included. The yield of MNCs and CD34+ cells per milliliter of blood collected via apheresis was significantly greater in the PEG group than that in the FIL group (P = 0.014 and P = 0.038). Mobilization with PEG yielded significantly higher median number of collected CD34+ cells than FIL (5.56 vs. 4.82 × 106/kg; P = 0.038). Moreover, the average time-to-recovery of leukocytes and platelets after transplantation was markedly shorter in the PEG group than that in the FIL group (leukocyte, 11.59 ± 1.98 vs 12.93 ± 2.83 days, P = 0.019; platelet, 12.86 ± 2.62 vs 14.80 ± 5.47, P = 0.085). However, the total cost of mobilization and apheresis using PEG or FIL was comparable (P = 0.486). Of note, mobilization with 12 mg PEG further shortened time-to-recovery of leukocytes (10.64 ± 0.51 vs. 12.04 ± 2.26 days, P = 0.05) and platelets (10.60 ± 2.89 vs. 13.33 ± 2.35 days, P = 0.031) compared with 6 mg PEG. Our results support a notion that PEG (especially 12 mg) combined with chemotherapy is a cost-effective and convenient regimen of mobilization, which might improve the outcome of ASCT in MM.

Amyand's hernia in a neonate: A case report.

Acute appendicitis secondary to hernia incarceration presenting as scrotal swelling is exceptionally rare in neonates. We report a neonate who presented with tender swelling in the right scrotum. Ultrasonography detected features of a rare Amyand's hernia. Surgical exploration and histopathological examination confirmed the diagnosis.

Can COVID-19 Increase Platelet in Adult Immune Thrombocytopenia During the TPO-RA Administration? A Real-World Observational Study.

Introduction: COVID-19 infection has brought new challenges to the treatment of adult patients with immune thrombocytopenia (ITP). In adult ITP patients, there have been no relevant reports exploring the incidence, clinical characteristics, and risk factors of platelet elevation after COVID-19 infection. Materials and Methods: A total of 66 patients with previously diagnosed ITP from December 2022 to February 2023 in a single-center were collected and analyzed for this real-world clinical retrospective observational study. Results: In the platelet count increased group (n = 19), 13 patients (68.4%) were using thrombopoietin receptor agonists (TPO-RA) treatment at the time of COVID-19 infection; the median platelet count was 52 (2-207) ×109/L at the last visit before infection and 108 (19-453) ×109/L at the first visit after infection. In the platelet count stable group (n = 19) and platelet count decreased group (n = 28), 9 (47.4%) and 8 (28.6%) patients were using TPO-RA at the time of infection, respectively. ITP patients treated with TPO-RA had a significantly higher risk of increased platelet count than those not treated with TPO-RA at the time of infection (platelet count increased group vs platelet count decreased group: OR: 5.745, p = 0.009; platelet count increased group vs the non-increased group: OR: 3.616, p = 0.031). In the platelet count increased group, the median platelet count at 6 months post-infection was 67 (14-235) × 109/L, which was significantly higher than the platelet level at the last visit before infection (p = 0.040). Conclusion: This study showed that some adult ITP patients had an increase in platelet count after COVID-19 infection, and this phenomenon was strongly associated with the use of TPO-RA at the time of infection. Although no thrombotic events were observed in this study, it reminds clinicians that they should be alert to the possibility of thrombotic events in the long-term management of adult ITP patients during the COVID-19 pandemic.

An assessment of the vulnerability of carotid plaques: a comparative study between intraplaque neovascularization and plaque echogenicity.

BACKGROUND: Carotid plaque echolucency as detected by Color Doppler ultrasonography (CDUS) has been used as a potential marker of plaque vulnerability. However, contrast-enhanced ultrasound (CEUS) has recently been shown to be a valuable method to evaluate the vulnerability and neovascularization within carotid atherosclerotic plaques. The aim of this study was to compare CEUS and CDUS in the assessment of plaque vulnerability using transcranial color Doppler (TCD) monitoring of microembolic signals (MES) as a reference technique. METHODS: A total of 46 subjects with arterial stenosis (≥ 50%) underwent a carotid duplex ultrasound, TCD monitoring of MES and CEUS (SonoVue doses of 2.0 mL) within a span of 3 days. The agreement between the CEUS, CDUS, and MES findings was assessed with a chi-square test. A p-value less than 0.05 was considered statistically significant. RESULTS: Neovascularization was observed in 30 lesions (44.4%). The vascular risk factors for stroke were similar and there were no age or gender differences between the 2 groups. Using CEUS, MES were identified in 2 patients (12.5%) within class 1 (non-neovascularization) as opposed to 15 patients (50.0%) within class 2 (neovascularization) (p = 0.023). CDUS revealed no significant differences in the appearance of the MES between the 2 groups (hyperechoic and hypoechoic) (p = 0.237). CONCLUSION: This study provides preliminary evidence to suggest that intraplaque neovascularization detected by CEUS is associated with the presence of MESs, where as plaque echogenicity on traditional CDUS does not. These findings argue that CEUS may better identify high-risk plaques.

Selinexor Synergistically Promotes the Antileukemia Activity of Venetoclax in Acute Myeloid Leukemia by Inhibiting Glycolytic Function and Downregulating the Expression of DNA Replication Genes.

Introduction: The BCL-2 inhibitor venetoclax has been widely used in the treatment of acute myeloid leukemia (AML); however, AML patients treated with venetoclax gradually develop resistance. The exportin-1 (XPO1) inhibitor selinexor can synergistically promote the antileukemia activity of venetoclax, but the mechanism remains unclear. Methods and Results: Annexin V/7-aminoactinomycin D assays were used to examine the effects of a combination of venetoclax and selinexor (VEN+SEL) on AML cell lines and primary AML cells. RNA sequencing and oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) determinations by a Seahorse XF analyzer were employed to investigate the molecular mechanism of the toxicity of the VEN+SEL combination to AML cells. The cytotoxicity of NK cell combined with VEN+SEL combination was assessed in vitro using flow cytometry. VEN+SEL enhanced the apoptosis of AML cells (KG-1A and THP-1) and primary AML samples in vitro. The ECAR and OCR results demonstrated that the VEN+SEL combination significantly inhibited glycolytic function. RNA sequencing of THP-1 cells demonstrated that DNA replication-related genes were downregulated after treatment with the VEN+SEL combination. Conclusion: This study indicated that selinexor can synergistically enhance the antileukemia activity of venetoclax in AML cells in vitro by inhibiting glycolytic function and downregulating DNA replication-related genes. Based on our experimental data, combining selinexor with venetoclax is an appropriate advanced treatment option for AML patients.

[Retracted] Synthetic miR­145 mimic inhibits multiple myeloma cell growth in vitro and in vivo.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the flow cytometric and western blotting data shown in Fig. 3A and C respectively, and the tumor images shown in Fig. 7A, bore unexpected similarities to data appearing in different form in other articles by different authors. Owing to the fact that some of the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Oncology Reports 33: 448-456, 2015; DOI: 10.3892/or.2014.3591].

Coexisting and possible primary extra-gastrointestinal stromal tumors of the pancreas and liver: A single case report.

Gastrointestinal stromal tumors (GIST) are mesenchymal neoplasms of the gastrointestinal tract (GI) that are defined, in part, by the expression of CD117, a c-Kit proto-oncogene protein. GISTs emerge outside of the GI at a very low frequency, typically in a single organ or location. GISTs that occasionally emerge outside of the GI are classified as extra-gastrointestinal stromal tumors (EGIST). The present study reports an extremely rare case of EGIST detected in the pancreas and the liver. The pancreatic and liver tumors were 4.5×2.5 cm and 2.0×1.5 cm in size, respectively. Both tumors consisted of CD117-positive spindle cells with a similar mitotic rate of 1-2 per 50 high power fields. The pancreatic and the hepatic EGISTs were at a low risk of malignancy, and both tumors were proposed to be primary stromal tumors. To the best of our knowledge, this is the first report of likely primary EGIST identified in the pancreas and liver of the same patient.

Synthetic miR-145 mimic inhibits multiple myeloma cell growth in vitro and in vivo.

Multiple myeloma (MM) is a disease with an adverse outcome and new therapeutic strategies are required to combat this disease. It is well known that tumor­suppressor microRNA (miRNA) acts as a new potential anticancer agent. Accumulating evidence showed that microRNA-145 (miR-145) is a candidate tumor suppressor miRNA. However, whether miR-145 is involved in the development and progression of MM reamins to be determined. In the present study, we investigated the therapeutic potential of synthetic miR-145 against human MM cells in vitro and in vivo. The results showed that miR-145 was reduced in MM tissues and cell lines. Enforced expression of miR-145 by transfection with miR-145 mimics inhibited cell proliferation, migration, and the invasion abilities of H929 cells. Furthermore, our results demonstrated that the enforced expression of miR-145 in H929 cells profoundly decreased the levels of p-AKT and p-PI3K, which may contribute to some extent to the inhibition of MM cell proliferation and survival. The enforced expression of miR-145 in a xenograft mouse model suppressed tumor growth. In conclusion, our findings suggested that miR-145 may act as a tumor suppressor and contributes to the progression of MM. Additionally, miR-145 mimics is a potential therapeutic agent for the treatment of MM.

Repeated formaldehyde inhalation impaired olfactory function and changed SNAP25 proteins in olfactory bulb.

BACKGROUND: Formaldehyde inhalation exposure, which can occur through occupational exposure, can lead to sensory irritation, neurotoxicity, mood disorders, and learning and memory impairment. However, its influence on olfactory function is unclear. OBJECTIVES: To investigate the mechanism and the effect of repeated formaldehyde inhalation exposure on olfactory function. METHODS: Rats were treated with formaldehyde inhalation (13·5±1·5 ppm, twice 30 minutes/day) for 14 days. Buried food pellet and locomotive activity tests were used to detect olfactory function and locomotion. Western blots were used to evaluate synaptosomal-associated protein 25 (SNAP25) protein levels in the olfactory bulb (OB) lysate and synaptosome, as well as mature and immature olfactory sensory neuron markers, olfactory marker protein (OMP), and Tuj-1. Real-time polymerase chain reaction (PCR) was used to detect SNAP25 mRNA amounts. RESULTS: Repeated formaldehyde inhalation exposure impaired olfactory function, whereas locomotive activities were unaffected. SNAP25 protein decreased significantly in the OB, but not in the occipital lobe. SNAP25 also decreased in the OB synaptosome when synaptophysin did not change after formaldehyde treatment. mRNA levels of SNAP25A and SNAP25B were unaffected. Mature and immature olfactory sensory neuron marker, OMP, and Tuj-1, did not change after formaldehyde treatment. CONCLUSION: Repeated formaldehyde exposure impaired olfactory function by disturbing SNAP25 protein in the OB.

Synergistic antitumor effects of endostar in combination with oxaliplatin via inhibition of HIF and CXCR4 in the colorectal cell line SW1116.

Combination treatment with endostar, a novel modified endostatin, and cytotoxic chemotherapies showed a survival benefit in Chinese clinical trials. However, the exact mechanism for this synergism remains unclear. In this study, we report for the first time that the chemokine receptor CXCR4 and the hypoxia-inducible transcription factors (HIF)-1α and HIF-2α are involved in these synergistic antitumor effects in human colorectal cancer SW1116 cells in vitro when endostar treatment is combined with the cytotoxic drug oxaliplatin. Under normoxia, we demonstrate that endostar and oxaliplatin treatments synergize to inhibit SW1116 cell proliferation, Matrigel adhesion and invasion by reduction of CXCR4 expression. Consistently, these antitumor abilities of endostar and oxaliplatin were markedly reduced by silencing of CXCR4 in SW1116 cells. Under low oxygen conditions (hypoxia, 1% oxygen), enhanced proliferation of SW1116 cells exposed to oxaliplatin was observed due to the emergence of drug resistance. Strikingly, endostar overcame oxaliplatin-resistance, most likely as a consequence of reduced HIF-2α and CXCR4 levels. CXCR4, is only dependent on HIF-2α, which promotes more aggressive phenotype and more significant for oxaliplatin resistance in SW1116 cells. Our data not only provide clues to aid understanding of the mechanism of the synergism of endostar and chemotherapy under either normoxia or hypoxia, but also suggests a new strategy of combination endostar and chemotherapy treatments which might potentiate therapeutic efficacies and/or counteract chemotherapy resistance.