The Role of Regulatory T Cells and TH17 Cells in Multiple Myeloma

The development of multiple myeloma (MM) involves a series of genetic alterations and changes in the bone marrow microenvironment, favoring the growth of the tumor and failure of local immune control. Quantitative and functional alterations in CD4+ and CD8+ T cells have been described in MM. The balance between T regulatory cells (Treg) and T helper (Th) 17 cells represents one essential prerequisite for maintaining anti-tumor immunity in MM. Tregs play an important role in the preservation of self-tolerance and modulation of overall immune responses against infections and tumor cells. In MM patients, Tregs seem to contribute to myeloma-related immune dysfunction and targeting them could, therefore, help to restore and enhance vital immune responses. Th17 cells protect against fungal and parasitic infections and participate in inflammatory reactions and autoimmunity. The interplay of TGF-β and IL-6, expressed at high levels in the bone marrow of myeloma patients, may affect generation of Th17 cells both directly or via other pro-inflammatory cytokines and thereby modulate antitumor immune responses. A detailed analysis of the balance between Tregs and Th17 cells seems necessary in order to design more effective and less toxic modes of immunotherapy myeloma which still is an uncurable malignancy

Cancer/Testis Antigen MAGE-C1/CT7: New Target for Multiple Myeloma Therapy

Cancer/Testis Antigens (CTAs) are a promising class of tumor antigens that have a limited expression in somatic tissues (testis, ovary, fetal, and placental cells). Aberrant expression of CTAs in cancer cells may lead to abnormal chromosome segregation and aneuploidy. CTAs are regulated by epigenetic mechanisms (DNA methylation and acetylation of histones) and are attractive targets for immunotherapy in cancer because the gonads are immune privileged organs and anti-CTA immune response can be tumor-specific. Multiple myeloma (MM) is an incurable hematological malignancy, and several CTAs have been detected in many MM cell lines and patients. Among CTAs expressed in MM we must highlight the MAGE-C1/CT7 located on the X chromosome and expressed specificity in the malignant plasma cells. MAGE-C1/CT7 seems to be related to disease progression and functional studies suggests that this CTA might play a role in cell cycle and mainly in survival of malignant plasma cells, protecting myeloma cells against spontaneous as well as drug-induced apoptosis

Modeling Northern Hemisphere ice-sheet distribution during MIS 5 and MIS 7 glacial inceptions

The present manuscript compares Marine Iso- tope Stage 5 (MIS 5, 125–115 kyr BP) and MIS 7 (236– 229 kyr BP) with the aim to investigate the origin of the difference in ice-sheet growth over the Northern Hemi- sphere high latitudes between these last two inceptions. Our approach combines a low resolution coupled atmosphere– ocean–sea-ice general circulation model and a 3-D thermo- mechanical ice-sheet model to simulate the state of the ice sheets associated with the inception climate states of MIS 5 and MIS 7. Our results show that external forcing (orbitals and GHG) and sea-ice albedo feedbacks are the main fac- tors responsible for the difference in the land-ice initial state between MIS 5 and MIS 7 and that our cold climate model bias impacts more during a cold inception, such as MIS 7, than during a warm inception, such as MIS 5. In addition, if proper ice-elevation and albedo feedbacks are not taken into consideration, the evolution towards glacial inception is hardly simulated, especially for MIS 7. Finally, results high- light that while simulated ice volumes for MIS 5 glacial in- ception almost fit with paleo-reconstructions, the lack of pre- cipitation over high latitudes, identified as a bias of our cli- mate model, does not allow for a proper simulation of MIS 7 glacial inception

JNKs function as CDK4-activating kinases by phosphorylating CDK4 and p21

Cyclin D-CDK4/6 are the first cyclin-dependent kinase (CDK) complexes to be activated by mitogenic/oncogenic pathways. They have a central role in the cell multiplication decision and in its deregulation in cancer cells. We identified T172 phosphorylation of CDK4 rather than cyclin D accumulation as the distinctly regulated step determining CDK4 activation. This finding challenges the view that the only identified metazoan CDK-activating kinase, cyclin H-CDK7-Mat1 (CAK), which is constitutively active, is responsible for the activating phosphorylation of all cell cycle CDKs. We previously showed that T172 phosphorylation of CDK4 is conditioned by an adjacent proline (P173), which is not present in CDK6 and CDK1/2. Although CDK7 activity was recently shown to be required for CDK4 activation, we proposed that proline-directed kinases might specifically initiate the activation of CDK4. Here, we report that JNKs, but not ERK1/2 or CAK, can be direct CDK4-activating kinases for cyclin D-CDK4 complexes that are inactivated by p21-mediated stabilization. JNKs and ERK1/2 also phosphorylated p21 at S130 and T57, which might facilitate CDK7-dependent activation of p21-bound CDK4, however, mutation of these sites did not impair the phosphorylation of CDK4 by JNKs. In two selected tumor cells, two different JNK inhibitors inhibited the phosphorylation and activation of cyclin D1-CDK4-p21 but not the activation of cyclin D3-CDK4 that is mainly associated to p27. Specific inhibition by chemical genetics in MEFs confirmed the involvement of JNK2 in cyclin D1-CDK4 activation. Therefore, JNKs could be activating kinases for cyclin D1-CDK4 bound to p21, by independently phosphorylating both CDK4 and p21

Induced pluripotent stem cells and cerebral organoids from the critically endangered Sumatran rhinoceros

Less than 80 Sumatran rhinos (SR, Dicerorhinus sumatrensis) are left on earth. Habitat loss and limited breeding possibilities are the greatest threats to the species and lead to a continuous population decline. To stop the erosion of genetic diversity, reintroduction of genetic material is indispensable. However, as the propagation rate of captive breeding is far too low, innovative technologies have to be developed. Induced pluripotent stem cells (iPSCs) are a powerful tool to fight extinction. They give rise to each cell within the body including gametes and provide a unique modality to preserve genetic material across time. Additionally, they enable studying species-specific developmental processes. Here, we generate iPSCs from the last male Malaysian SR Kertam, who died in 2019, and characterize them comprehensively. Differentiation in cells of the three germ layers and cerebral organoids demonstrate their high quality and great potential for supporting the rescue of this critically endangered species

Embryos and embryonic stem cells from the white rhinoceros

The northern white rhinoceros (NWR, Ceratotherium simum cottoni) is the most endangered mammal in the world with only two females surviving. Here we adapt existing assisted reproduction techniques (ART) to fertilize Southern White Rhinoceros (SWR) oocytes with NWR spermatozoa. We show that rhinoceros oocytes can be repeatedly recovered from live SWR females by transrectal ovum pick-up, matured, fertilized by intracytoplasmic sperm injection and developed to the blastocyst stage in vitro. Next, we generate hybrid rhinoceros embryos in vitro using gametes of NWR and SWR. We also establish embryonic stem cell lines from the SWR blastocysts. Blastocysts are cryopreserved for later embryo transfer. Our results indicate that ART could be a viable strategy to rescue genes from the iconic, almost extinct, northern white rhinoceros and may also have broader impact if applied with similar success to other endangered large mammalian species

Outcomes of special histotypes of breast cancer after adjuvant endocrine therapy with letrozole or tamoxifen in the monotherapy cohort of the BIG 1-98 trial

In the BIG 1-98 clinical trial of 4922 postmenopausal women treated with 5 years of letrozole or tamoxifen for endocrine-responsive breast cancer, 183 had the rare histotypes mucinous or tubular/cribriform. These women had better outcomes than those with other histotypes. The magnitude of the letrozole advantage compared with tamoxifen may not be as large in patients with these rare histotype

Association of VEGFA-2578 C > A polymorphism with clinicopathological aspects and outcome in follicular lymphoma patients

Univ Estadual Campinas, Fac Med Sci, Campinas, BrazilAC Camargo Canc Ctr, Dept Pathol, Sao Paulo, BrazilUniv Estadual Campinas, Hematol & Hemotherapy Ctr, Campinas, BrazilUniv Fed Sao Paulo, Dept Clin & Expt Oncol, Sao Paulo, BrazilUniv Estadual Campinas, Fac Med Sci, Lab Mol & Investigat Pathol, Campinas, BrazilUniv Fed Sao Paulo, Dept Clin & Expt Oncol, Sao Paulo, BrazilWeb of Scienc

Collisionless Shock Acceleration of protons in a plasma slab produced in a gas jet by the collision of two laser-driven hydrodynamic shockwaves

We recently proposed a new technique of plasma tailoring by laser-driven hydrodynamic shockwaves generated on both sides of a gas jet [J.-R. Marqu\`es et al., Phys. Plasmas 28, 023103 (2021)]. In the continuation of this numerical work, we studied experimentally the influence of the tailoring on proton acceleration driven by a high-intensity picosecond-laser, in three cases: without tailoring, by tailoring only the entrance side of the ps-laser, or both sides of the gas jet. Without tailoring the acceleration is transverse to the laser axis, with a low-energy exponential spectrum, produced by Coulomb explosion. When the front side of the gas jet is tailored, a forward acceleration appears, that is significantly enhanced when both the front and back sides of the plasma are tailored. This forward acceleration produces higher energy protons, with a peaked spectrum, and is in good agreement with the mechanism of Collisionless Shock Acceleration (CSA). The spatio-temporal evolution of the plasma profile was characterized by optical shadowgraphy of a probe beam. The refraction and absorption of this beam was simulated by post-processing 3D hydrodynamic simulations of the plasma tailoring. Comparison with the experimental results allowed to estimate the thickness and near-critical density of the plasma slab produced by tailoring both sides of the gas jet. These parameters are in good agreement with those required for CSA