Multi-Base Station Cooperative Sensing with AI-Aided Tracking

In this work, we investigate the performance of a joint sensing and communication (JSC) network consisting of multiple base stations (BSs) that cooperate through a fusion center (FC) to exchange information about the sensed environment while concurrently establishing communication links with a set of user equipments (UEs). Each BS within the network operates as a monostatic radar system, enabling comprehensive scanning of the monitored area and generating range-angle maps that provide information regarding the position of a group of heterogeneous objects. The acquired maps are subsequently fused in the FC. Then, a convolutional neural network (CNN) is employed to infer the category of the targets, e.g., pedestrians or vehicles, and such information is exploited by an adaptive clustering algorithm to group the detections originating from the same target more effectively. Finally, two multi-target tracking algorithms, the probability hypothesis density (PHD) filter and multi-Bernoulli mixture (MBM) filter, are applied to estimate the state of the targets. Numerical results demonstrated that our framework could provide remarkable sensing performance, achieving an optimal sub-pattern assignment (OSPA) less than 60 cm, while keeping communication services to UEs with a reduction of the communication capacity in the order of 10% to 20%. The impact of the number of BSs engaged in sensing is also examined, and we show that in the specific case study, 3 BSs ensure a localization error below 1 m

The prognostic value of 18F-FDG PET-CT in the management of Hodgkin’s lymphoma: preliminary results of a prospective study

BACKGROUND: To date, Hodgkin’s lymphoma (HL) patients have achieved long-term survival of more than 80%. Unfortunately, longer follow-up has shown serious adverse effects of the treatments used. For this reason, therapeutic strategies are becoming more tailored to the individual patient´s prognosis. Pre-treatment risk factors for early-stage and advanced-stage HL are well known indicators of prognosis. Recently, early interim 18F-FDG PET has been shown as a strong and independent predictor of progression-free survival in HL. Our aim was to assess response to therapy by repeating 18F-FDG-PET/CT after four and six chemotherapy cycles. MATERIAL AND METHODS: We evaluated 21 consecutive patients affected by (HL) and presenting for assessment over a period of three years. All patients underwent initial staging with 18F-FDG-PET/CT along with standard staging procedures. We tailored an individual treatment plan dependent on pre-treatment risk factors and initial 18F-FDG-PET/CT. With the aim of the best definition of response to treatment, we repeated 18F-FDG-PET/CT after two (FDG-PET 2), four (FDG-PET 4) and six (FDG-PET 6) chemotherapy cycles. Chemotherapy was typically given for four cycles in early disease stages and was prolonged to six to eight cycles in advanced disease stages, depending on PET findings. RESULTS: Our results showed a strong negative predictive value in detecting responders in early stage HL and a positive predictive value in advanced-stage patients. Clinical stage, extra-nodal sites and the positivity of the 18F-FDG-PET/CT performed during chemotherapy were also noted as strong determinants of response to treatment. Moreover, in our series the 18F-FDG-PET/CT data obtained after only two chemotherapy cycles (FDG-PET 2) were the same of those obtained after FDGPET 4 and FDG-PET 6 controls. CONCLUSION: The preliminary data of the present study confirm those of previous published studies about the negative predictive value of 18F-FDG-PET/CT performed after four and six chemotherapy cycles, which contributed to the decision to stop treatment and to avoid radiotherapy in HL patients. Nonetheless, our preliminary data seems to suggest that only the 18F-FDG-PET/CT performed after two cycles of chemotherapy (FDG-PET 2) is able to provide the same prognostic information of the FDG-PET 4 and FDG-PET 6 earlier

The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma

Immunomodulatory drugs (IMiDs) have potent anti-tumor activities in multiple myeloma (MM) and are able to enhance the cytotoxic function of natural killer (NK) cells, important effectors of the immune response against MM. Here, we show that these drugs can enhance the expression of the NKG2D and DNAM-1 activating receptor ligands MICA and PVR/CD155 in human MM cell lines and primary malignant plasma cells. Depletion of cereblon (CRBN) by shRNA interference strongly impaired upregulation of these ligands and, more interestingly, IMiDs/CRBN-mediated downregulation of the transcription factors Ikaros (IKZF1), Aiolos (IKZF3) and IRF4 was critical for these regulatory mechanisms. Indeed, shRNA knockdown of IKZF1 or IKZF3 expression was both necessary and sufficient for the upregulation of MICA and PVR/CD155 expression, suggesting that these transcription factors can repress these genes; accordingly, the direct interaction and the negative role of IKZF1 and IKZF3 proteins on MICA and PVR/CD155 promoters were demonstrated. Finally, MICA expression was enhanced in IRF4-silenced cells, indicating a specific suppressive role of this transcription factor on MICA gene expression in MM cells. Taken together, these findings describe novel molecular pathways involved in the regulation of MICA and PVR/CD155 gene expression and identify the transcription factors IKZF-1/IKZF-3 and IRF4 as repressors of these genes in MM cells

Inhibition of bromodomain and extra-terminal (BET) proteins increases NKG2D ligand MICA expression and sensitivity to NK cell-mediated cytotoxicity in multiple myeloma cells. role of cMYC-IRF4-miR-125b interplay

Background: Anticancer immune responses may contribute to the control of tumors after conventional chemotherapy and different observations have indicated that chemotherapeutic agents can induce immune responses resulting in cancer cell death and immune-stimulatory side effects. Increasing experimental and clinical evidence highlight the importance of Natural Killer (NK) cells in immune responses toward Multiple Myeloma (MM) and combination therapies able to enhance the activity of NK cells against MM are showing promise in treating this hematologic cancer. The epigenetic readers of acetylated histones Bromodomain and Extra-Terminal (BET) proteins are critical regulators of gene expression. In cancer, they can upregulate transcription of key oncogenes such as cMYC, IRF4, BCL-2 and others. In addition, the activity of these proteins can regulate the expression of osteoclastogenic cytokines during cancer progression. Here, we investigated the effect of BET-bromodomain proteins inhibition, on the expression of Natural Killer (NK) cell-activating ligands in Multiple Myeloma (MM) cells. Methods: Five MM cell lines [SKO-007(J3), U266, RPMI-8226, ARP-1, JJN3] and CD138+ MM cells isolated from MM patients were used to investigate the activity of BET bromodomain inhibitors (BETi) (JQ1 and I-BET-151) and of the selective BRD4-degrader PROTAC (Proteolysis Targeting Chimera) (ARV-825), on the expression and function of several NK cell activating ligands (NKG2DLs and DNAM-1Ls), using Flow Cytometry, Real-Time PCR, transient transfections and degranulation assays. Results: Our results indicate that inhibition of BET proteins via small molecule inhibitors or their degradation via a hetero-bifunctional Proteolysis Targeting Chimera (PROTAC) probe can enhance the expression of MICA, a ligand of the NKG2D receptor, in human MM cell lines and primary malignant plasma cells, rendering myeloma cells more efficient to activate NK cell degranulation. Noteworthy, similar results were obtained using selective CBP/EP300 bromodomain inhibition. Mechanistically, we found that BETi-mediated inhibition of cMYC correlates with the upregulation of miR-125b-5p and the downregulation of the cMYC/miR-125b-5p target gene IRF4, a transcriptional repressor of MICA. Conclusions: These findings provide new insights on the immuno-mediated antitumor activities of BETi and further elucidate the molecular mechanisms that regulate NK cell-activating ligand expression in MM

plasma matrix metalloprotease 9 correlates with blood lymphocytosis leukemic cell invasiveness and prognosis in b cell chronic lymphocytic leukemia

The complex biology underlying chronic lymphocytic leukemia cell migration and tissue invasiveness is not yet completely understood and might provide novel predictive markers and therapeutic targets. A total of 36 patients out of treatment from at least 3 months were enrolled and followed up for a median period of 44.2 months (range: 4.4-99.2). Matrix metalloprotease 9 and tissue inhibitor of metalloproteases 1 plasma levels and production/release from lymphoid cells were measured by zymography and enzyme-linked immunosorbent assay (ELISA) analysis. Malignant and normal lymphocyte mobility and matrix-degradation capability were studied using a Boyden chamber system, with and without autologous plasma. Free matrix metalloprotease 9 plasma levels were related with blood lymphocytosis, especially in more advanced stages (p = 0.003), and higher concentrations were associated with an increased disease progression risk (hazard ratio = 9.0, 95% confidence interval = 1.5-13.8). Leukemic cells expressed and secreted very little matrix metalloprotease 9. On the contrary, normal lymphocytes derived from the same leukemic patients showed matrix metalloprotease 9 intracellular levels that were lower in subjects with higher blood lymphocytosis (p = 0.024) and more advanced stages (p = 0.03); the released quantities were inversely associated with matrix metalloprotease 9 plasma concentrations (p = 0.035). Leukemic cells had a reduced spontaneous mobility and matrix-degradation capability that were stimulated by autologous plasma (p = 0.001) and normal lymphocytes (p = 0.005), respectively. Matrix metalloprotease 9 affected cell invasiveness depending on concentration and disease stage. In conclusion, chronic lymphocytic leukemia cells have a reduced mobility, matrix-degradation capability, and matrix metalloprotease 9 production compared to their own autologous normal lymphocytes. They are exposed to matrix metalloprotease 9 of prevalently systemic origin whose higher levels are associated with both leukemic and normal lymphocyte accumulation in the peripheral blood and have a negative prognostic value

Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: role of HSP70/TLR2/NF-kB axis

Exosomes are a class of nanovesicles formed and released through the late endosomal compartment and represent an important mode of intercellular communication. The ability of anticancer chemotherapy to enhance the immunogenic potential of malignant cells mainly relies on the establishment of the immunogenic cell death (ICD) and the release of damage-associated molecular patterns (DAMPs). Here, we investigated whether genotoxic stress could promote the release of exosomes from multiple myeloma (MM) cells and studied the immunomodulatory properties they exert on NK cells, a major component of the antitumor immune response playing a key role in the immunosurveillance of MM. Our findings show that melphalan, a genotoxic agent used in MM therapy, significantly induces an increased exosome release from MM cells. MM cell-derived exosomes are capable of stimulating IFNg production, but not the cytotoxic activity of NK cells through a mechanism based on the activation of NF-kB pathway in a TLR2/ HSP70-dependent manner. Interestingly, HSP70 positive exosomes are primarily found in the bone marrow (BM) of MM patients suggesting that they might have a crucial immunomodulatory action in the tumor microenvironment. We also provide evidence that the CD56high NK cell subset is more responsive to exosome-induced IFNg production mediated by TLR2 engagement. All together, these findings suggest a novel mechanism of synergism between chemotherapy and antitumor innate immune responses based on the drug-promotion of nanovesicles exposing DAMPs for innate receptors

Residual matrix from different separation techniques impacts exosome biological activity

Exosomes are gaining a prominent role in research due to their intriguing biology and several therapeutic opportunities. However, their accurate purification from body fluids and detailed physicochemical characterization remain open issues. We isolated exosomes from serum of patients with Multiple Myeloma by four of the most popular purification methods and assessed the presence of residual contaminants in the preparations through an ad hoc combination of biochemical and biophysical techniques - including Western Blot, colloidal nanoplasmonics, atomic force microscopy (AFM) and scanning helium ion microscopy (HIM). The preparations obtained by iodixanol and sucrose gradients were highly pure. To the contrary, those achieved with limited processing (serial centrifugation or one step precipitation kit) resulted contaminated by a residual matrix, embedding the exosomes. The contaminated preparations showed lower ability to induce NfkB nuclear translocation in endothelial cells with respect to the pure ones, probably because the matrix prevents the interaction and fusion of the exosomes with the cell membrane. These findings suggest that exosome preparation purity must be carefully assessed since it may interfere with exosome biological activity. Contaminants can be reliably probed only by an integrated characterization approach aimed at both the molecular and the colloidal length scales

Designing a novel tomato ideotype for future cultivation in space manned missions

Introduction: Methods for production of fresh, health food are needed in view of long-term, deep-space manned missions. To this end, crops tailored for better performance under non-terrestrial conditions may be obtained by the exploitation of biochemical patterns related to specialized metabolites known to confer protection against environmental challenges and to be beneficial to human health.Methods: In this work, for the first time, MicroTom plants have been engineered specifically for agrospace applications to express PhAN4, a MYB-like transcription factor able to regulate the biosynthesis of anthocyanins that influence tomato genes possibly involved in agrospace-relevant functions. Results:PhAN4 engineering underpinned the genetic background of the dwarf tomato MicroTom while maintaining yield and photosynthetic capacity. PhAN4 expression resulted in the accumulation of anthocyanins and polyphenols, a differential carotenoid profile, increased antioxidant scavenging capacities of fruits compared to the original genotype. Improved ability to counteract ROS generation and to preserve plant protein folding after ex-vivo gamma irradiation was observed.Discussion: These results highlights that the manipulation of specific metabolic pathways is a promising approach to design novel candidate varieties for agrospace applications

Circulating functional T cells specific to human herpes virus 6 (HHV6) antigens in individuals with chromosomally integrated HHV6

Circulating functional T cells specific to human herpes virus 6 (HHV6) antigens in individuals with chromosomally integrated HHV

All-trans retinoic acid (ATRA) in non-promyelocytic acute myeloid leukemia (AML): results of combination of ATRA with low-dose Ara-C in three elderly patients with NPM1-mutated AML unfit for intensive chemotherapy and review of the literature

Based upon the clinical behavior of three patients, we suggest that the combination of low-dose Ara-C and all-trans retinoic acid may potentially be effective in some elderly patients, unfit for intensive chemotherapy, affected with NPM1-mutated acute myeloid leukemia without FLT3 mutations, warranting perspective clinical studies in these selected patients