Bone Marrow Microenvironment in Multiple Myeloma Progression

Substantial advances have been made in understanding the biology of multiple myeloma (MM) through the study of the bone marrow (BM) microenvironment. Indeed, the BM niche appears to play an important role in differentiation, migration, proliferation, survival, and drug resistance of the malignant plasma cells. The BM niche is composed of a cellular compartment (stromal cells, osteoblasts, osteoclasts, endothelial cells, and immune cells) and a noncellular compartment including the extracellular matrix (ECM) and the liquid milieu (cytokines, growth factors, and chemokines). In this paper we discuss how the interaction between the malignant plasma cell and the BM microenvironment allowed myeloma progression through cell homing and the new concept of premetastatic niche

Bipolar HII regions - Morphology and star formation in their vicinity - I - G319.88++00.79 and G010.32−-00.15

Our goal is to identify bipolar HII regions and to understand their morphology, their evolution, and the role they play in the formation of new generations of stars. We use the Spitzer and Herschel Hi-GAL surveys to identify bipolar HII regions. We search for their exciting star(s) and estimate their distances using near-IR data. Dense clumps are detected using Herschel-SPIRE data. MALT90 observations allow us to ascertain their association with the central HII region. We identify Class 0/I YSOs using their Spitzer and Herschel-PACS emissions. These methods will be applied to the entire sample of candidate bipolar HII regions. This paper focuses on two bipolar HII regions, one interesting in terms of its morphology, G319.88$+$00.79, and one in terms of its star formation, G010.32$-$00.15. Their exciting clusters are identified and their photometric distances estimated to be 2.6 kpc and 1.75 kpc, respectively. We suggest that these regions formed in dense and flat structures that contain filaments. They have a central ionized region and ionized lobes perpendicular to the parental cloud. The remains of the parental cloud appear as dense (more than 10^4 per cm^3) and cold (14-17 K) condensations. The dust in the PDR is warm (19-25 K). Dense massive clumps are present around the central ionized region. G010.32-00.14 is especially remarkable because five clumps of several hundred solar masses surround the central HII region; their peak column density is a few 10^23 per cm^2, and the mean density in their central regions reaches several 10^5 per cm^3. Four of them contain at least one massive YSO; these clumps also contain extended green objects and Class II methanol masers. This morphology suggests that the formation of a second generation of massive stars has been triggered by the central bipolar HII region. It occurs in the compressed material of the parental cloud.Comment: 32 pages, 28 figures, to be published in A&

Characterization of the HD 108236 system with CHEOPS and TESS Confirmation of a fifth transiting planet

Context. The HD 108236 system was first announced with the detection of four small planets based on TESS data. Shortly after, the transit of an additional planet with a period of 29.54 d was serendipitously detected by CHEOPS. In this way, HD 108236 (V = 9.2) became one of the brightest stars known to host five small transiting planets (Rp < 3 R⊕). Aims. We characterize the planetary system by using all the data available from CHEOPS and TESS space missions. We use the flexible pointing capabilities of CHEOPS to follow up the transits of all the planets in the system, including the fifth transiting body. Methods. After updating the host star parameters by using the results from Gaia eDR3, we analyzed 16 and 43 transits observed by CHEOPS and TESS, respectively, to derive the planets’ physical and orbital parameters. We carried out a timing analysis of the transits of each of the planets of HD 108236 to search for the presence of transit timing variations. Results. We derived improved values for the radius and mass of the host star (R★ = 0.876 ± 0.007 R0 and M★ = 0.867-0.046+0.047M⊙). We confirm the presence of the fifth transiting planet f in a 29.54 d orbit. Thus, the HD 108236 system consists of five planets of Rb = 1.587±0.028, Rc = 2.122±0.025, Rd = 2.629 ± 0.031, Re = 3.008 ± 0.032, and Rf = 1.89 ± 0.04 [R⊕]. We refine the transit ephemeris for each planet and find no significant transit timing variations for planets c, d, and e. For planets b and f, instead, we measure significant deviations on their transit times (up to 22 and 28 min, respectively) with a non-negligible dispersion of 9.6 and 12.6 min in their time residuals. Conclusions. We confirm the presence of planet f and find no significant evidence for a potential transiting planet in a 10.9 d orbital period, as previously suggested. Further monitoring of the transits, particularly for planets b and f, would confirm the presence of the observed transit time variations. HD 108236 thus becomes a key multi-planetary system for the study of formation and evolution processes. The reported precise results on the planetary radii – together with a profuse RV monitoring – will allow for an accurate characterization of the internal structure of these planets

Unbiasing the density of TTV-characterised sub-Neptunes: Update of the mass-radius relationship of 34 Kepler planets

Transit Timing Variations (TTVs) can provide useful information on compact multi-planetary systems observed by transits, by putting constraints on the masses and eccentricities of the observed planets. This is especially helpful when the host star is not bright enough for radial velocity follow-up. However, in the past decades, numerous works have shown that TTV-characterised planets tend to have a lower densities than RV-characterised planets. Re-analysing 34 Kepler planets in the super-Earth to sub-Neptunes range using the RIVERS approach, we show that at least part of these discrepancies was due to the way transit timings were extracted from the light curve, which had a tendency to under-estimate the TTV amplitudes. We recover robust mass estimates (i.e. low prior dependency) for 23 of the planets. We compare these planets the RV-characterised population. A large fraction of these previously had a surprisingly low density now occupy a place of the mass-radius diagram much closer to the bulk of the known planets, although a slight shift toward lower densities remains, which could indicate that the compact multi-planetary systems characterised by TTVs are indeed composed of planets which are different from the bulk of the RV-characterised population. These results are especially important for obtaining an unbiased view of the compact multi-planetary systems detected by Kepler, TESS, and the upcoming PLATO mission

Multicenter analysis of sputum microbiota in tuberculosis patients.

The impact of tuberculosis and of anti-tuberculosis therapy on composition and modification of human lung microbiota has been the object of several investigations. However, no clear outcome has been presented so far and the relationship between M. tuberculosis pulmonary infection and the resident lung microbiota remains vague. In this work we describe the results obtained from a multicenter study of the microbiota of sputum samples from patients with tuberculosis or unrelated lung diseases and healthy donors recruited in Switzerland, Italy and Bangladesh, with the ultimate goal of discovering a microbiota-based biomarker associated with tuberculosis. Bacterial 16S rDNA amplification, high-throughput sequencing and extensive bioinformatic analyses revealed patient-specific flora and high variability in taxon abundance. No common signature could be identified among the individuals enrolled except for minor differences which were not consistent among the different geographical settings. Moreover, anti-tuberculosis therapy did not cause any important variation in microbiota diversity, thus precluding its exploitation as a biomarker for the follow up of tuberculosis patients undergoing treatment

Anti-CD38 antibody therapy for patients with relapsed/refractory multiple myeloma: differential mechanisms of action and recent clinical trial outcomes.

CD38 is a transmembrane glycoprotein that functions both as a receptor and an ectoenzyme, playing key roles in the regulation of calcium signaling and migration of immune cells to tumor microenvironments. High expression on multiple myeloma (MM) cells and limited expression on normal cells makes CD38 an ideal target for the treatment of MM patients. Two monoclonal antibodies directed at CD38, isatuximab and daratumumab, are available for use in patients with relapsed and/or refractory MM (RRMM); daratumumab is also approved in newly diagnosed MM and light-chain amyloidosis. Clinical experience has shown that anti-CD38 antibody therapy is transforming treatment of MM owing to its anti-myeloma efficacy and manageable safety profile. Isatuximab and daratumumab possess similarities and differences in their mechanisms of action, likely imparted by their binding to distinct, non-overlapping epitopes on the CD38 molecule. In this review, we present the mechanistic properties of these two antibodies and outline available evidence on their abilities to induce adaptive immune responses and modulate the bone marrow niche in MM. Further, we discuss differences in regulatory labeling between these two agents and analyze recent key clinical trial results, including evidence in patients with underlying renal impairment and other poor prognostic factors. Finally, we describe the limited existing evidence for the use of isatuximab or daratumumab after disease progression on prior anti-CD38 mono- or combination therapy, highlighting the need for additional clinical evaluations to define optimal anti-CD38 antibody therapy selection and sequencing in RRMM

Isatuximab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma patients with renal impairment: ICARIA-MM subgroup analysis

The randomized, phase 3 ICARIA-MM study investigated isatuximab (Isa) with pomalidomide and dexamethasone (Pd) versus Pd in patients with relapsed/refractory multiple myeloma and ≥2 prior lines. This prespecified subgroup analysis examined efficacy in patients with renal impairment (RI; estimated glomerular filtration rate <60 mL/min/1.73 m²). Isa 10 mg/kg was given intravenously once weekly in cycle 1, and every 2 weeks in subsequent 28-day cycles. Patients received standard doses of Pd. Median progression-free survival (PFS) for patients with RI was 9.5 months with Isa-Pd (n = 55) and 3.7 months with Pd (n = 49; hazard ratio [HR] 0.50; 95% confidence interval [CI], 0.30–0.85). Without RI, median PFS was 12.7 months with Isa-Pd (n = 87) and 7.9 months with Pd (n = 96; HR 0.58; 95% CI, 0.38–0.88). The overall response rate (ORR) with and without RI was higher with Isa-Pd (56 and 68%) than Pd (25 and 43%). Complete renal response rates were 71.9% (23/32) with Isa-Pd and 38.1% (8/21) with Pd; these lasted ≥60 days in 31.3% (10/32) and 19.0% (4/21) of patients, respectively. Isa pharmacokinetics were comparable between the subgroups, suggesting no need for dose adjustment in patients with RI. In summary, the addition of Isa to Pd improved PFS, ORR and renal response rates