Small-Cell Lung Cancer: Is Liquid Biopsy a New Tool Able to Predict the Efficacy of Immunotherapy?

Small-cell lung cancer (SCLC) cases represent approximately 15% of all lung cancer cases, remaining a recalcitrant malignancy with poor survival and few treatment options. In the last few years, the addition of immunotherapy to chemotherapy improved clinical outcomes compared to chemotherapy alone, resulting in the current standard of care for SCLC. However, the advantage of immunotherapy only applies to a few SCLC patients, and predictive biomarkers selection are lacking for SCLC. In particular, due to some features of SCLC, such as high heterogeneity, elevated cell plasticity, and low-quality tissue samples, SCLC biopsies cannot be used as biomarkers. Therefore, the characterization of the tumor and, subsequently, the selection of an appropriate therapeutic combination may benefit greatly from liquid biopsy. Soluble factors, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and extracellular vesicles (EVs) are now useful tools in the characterization of SCLC. This review summarizes the most recent data on biomarkers detectable with liquid biopsy, emphasizing their role in supporting tumor detection and their potential role in SCLC treatment choice.

The Complexity of the Tumor Microenvironment in Hepatocellular Carcinoma and Emerging Therapeutic Developments.

This review explores various aspects of the HCC TME, including both cellular and non-cellular components, to elucidate their roles in tumor development and progression. Specifically, it highlights the significance of cancer-associated fibroblasts (CAFs) and their contributions to tumor progression, angiogenesis, immune suppression, and therapeutic resistance. Moreover, this review emphasizes the role of immune cells, such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T-cells (Tregs), in shaping the immunosuppressive microenvironment that promotes tumor growth and immune evasion. Furthermore, we also focused only on the non-cellular components of the HCC TME, including the extracellular matrix (ECM) and the role of hypoxia-induced angiogenesis. Alterations in the composition of ECM and stiffness have been implicated in tumor invasion and metastasis, while hypoxia-driven angiogenesis promotes tumor growth and metastatic spread. The molecular mechanisms underlying these processes, including the activation of hypoxia-inducible factors (HIFs) and vascular endothelial growth factor (VEGF) signaling, are also discussed. In addition to elucidating the complex TME of HCC, this review focuses on emerging therapeutic strategies that target the TME. It highlights the potential of second-line treatments, such as regorafenib, cabozantinib, and ramucirumab, in improving overall survival for advanced HCC patients who have progressed on or were intolerant to first-line therapy. Furthermore, this review explores the implications of the Barcelona Clinic Liver Cancer (BCLC) staging and classification system in guiding HCC management decisions. The BCLC system, which incorporates tumor stage, liver function, and performance status, provides a framework for treatment stratification and prognosis prediction in HCC patients. The insights gained from this review contribute to the development of novel therapeutic interventions and personalized treatment approaches for HCC patients, ultimately improving clinical outcomes in this challenging disease.

Circulating extracellular vesicles are monitoring biomarkers of anti-PD1 response and enhancer of tumor progression and immunosuppression in metastatic melanoma.

BACKGROUND: Clinical drawback in checkpoint inhibitors immunotherapy (ICI) of metastatic melanoma (MM) is monitoring clinical benefit. Soluble forms of PD1(sPD1) and PD-L1(sPD-L1) and extracellular vesicles (EVs) expressing PD1 and PD-L1 have recently emerged as predictive biomarkers of response. As factors released in the blood, EVs and soluble forms could be relevant in monitoring treatment efficacy and adaptive resistance to ICI. METHODS: We used pre-therapy plasma samples of 110 MM patients and longitudinal samples of 46 patients. Elisa assay and flow cytometry (FCM) were used to measure sPD-L1 and sPD1 concentrations and the percentage of PD1+ EVs and PD-L1+ EVs, released from tumor and immune cells in patients subsets. Transwell assays were conducted to investigate the impact of EVs of each patient subset on MM cells invasion and interaction between tumor cells and macrophages or dendritic cells. Viability assays were performed to assess EVs effect on MM cells and organoids sensitivity to anti-PD1. FCM was used to investigate immunosuppressive markers in EVs and immune cells. RESULTS: The concentrations of sPD1 and sPD-L1 in pre-treatment and longitudinal samples did not correlate with anti-PD1 response, instead only tumor-derived PD1+ EVs decreased in long responders while increased during disease progression in responders. Notably, we observed reduction of T cell derived EVs expressing LAG3+ and PD1+ in long responders and their increase in responders experiencing progression. By investigating the impact of EVs on disease progression, we found that those isolated from non-responders and from patients with progression disease accelerated tumor cells invasiveness and migration towards macrophages, while EVs of long responders reduced the metastatic potential of MM cells and neo-angiogenesis. Additionally, the EVs of non-responders and of progression disease patients subset reduced the sensitivity of MM cells and organoids of responder to anti-PD1 and the recruitment of dendritic cells, while the EVs of progression disease subset skewed macrophages to express higher level of PDL-1. CONCLUSION: Collectively, we suggest that the detection of tumor-derived PD1 + EVs may represent a useful tool for monitoring the response to anti-PD1 and a role for EVs shed by tumor and immune cells in promoting tumor progression and immune dysfunction.

Cervical cancer benefits from trabectedin combination with the ß-blocker propranolol: in vitro and ex vivo evaluations in patient-derived organoids.

Background: Cervical cancer (CC) is characterized by genomic alterations in DNA repair genes, which could favor treatment with agents causing DNA double-strand breaks (DSBs), such as trabectedin. Hence, we evaluated the capability of trabectedin to inhibit CC viability and used ovarian cancer (OC) models as a reference. Since chronic stress may promote gynecological cancer and may hinder the efficacy of therapy, we investigated the potential of targeting ß-adrenergic receptors with propranolol to enhance trabectedin efficacy and change tumor immunogenicity. Methods: OC cell lines, Caov-3 and SK-OV-3, CC cell lines, HeLa and OV2008, and patient-derived organoids were used as study models. MTT and 3D cell viability assays were used for drug(s) IC50 determination. The analysis of apoptosis, JC-1 mitochondrial membrane depolarization, cell cycle, and protein expression was performed by flow cytometry. Cell target modulation analyses were carried out by gene expression, Western blotting, immunofluorescence, and immunocytochemistry. Results: Trabectedin reduced the proliferation of both CC and OC cell lines and notably of CC patient-derived organoids. Mechanistically, trabectedin caused DNA DSBs and S-phase cell cycle arrest. Despite DNA DSBs, cells failed the formation of nuclear RAD51 foci and underwent apoptosis. Under norepinephrine stimulation, propranolol enhanced trabectedin efficacy, further inducing apoptosis through the involvement of mitochondria, Erk1/2 activation, and the increase of inducible COX-2. Notably, trabectedin and propranolol affected the expression of PD1 in both CC and OC cell lines. Conclusion: Overall, our results show that CC is responsive to trabectedin and provide translational evidence that could benefit CC treatment options. Our study pointed out that combined treatment offset trabectedin resistance caused by ß-adrenergic receptor activation in both ovarian and cervical cancer models.

BRAFV600E;K601Q metastatic melanoma patient-derived organoids and docking analysis to predict the response to targeted therapy.

The V600E mutation in BRAF is associated with increased phosphorylation of Erk1/2 and high sensitivity to BRAFi/MEKi combination in metastatic melanoma. In very few patients, a tandem mutation in BRAF, V600 and K601, causes a different response to BRAFi/MEKi combination. BRAFV600E;K601Q patient-derived organoids (PDOs) were generated to investigate targeted therapy efficacy and docking analysis was used to assess BRAFV600E;K601Q interactions with Vemurafenib. PDOs were not sensitive to Vemurafenib and Cobimetinib given alone and sensitive to their combination, although not as responsive as BRAFV600E PDOs. The docking analysis justified such a result showing that the tandem mutation in BRAF reduced the affinity for Vemurafenib. Tumor analysis showed that BRAFV600E;K601Q displayed both increased phosphorylation of Erk1/2 at cytoplasmic level and activation of Notch resistance signaling. This prompted us to inhibit Notch signaling with Nirogacestat, achieving a greater antitumor response and providing PDOs-based evaluation of treatment efficacy in such rare metastatic melanoma.

Second-line treatments for Advanced Hepatocellular Carcinoma: A Systematic Review and Bayesian Network Meta-analysis.

BACKGROUND & AIMS: A plethora of second-line therapies have been recently introduced for hepatocellular carcinoma (HCC) treatment with promising results. A meta-analysis of second-line treatments for HCC has been performed to better tailor their use based on improved patient stratification and to identify the best available option. METHODS: Pubmed, Scopus, Web of Science, and ClinicalTrials.gov were searched for randomized controlled trials evaluating second-line treatment for advanced HCC in patients already treated with sorafenib. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) and drug withdrawal due to adverse events. Network meta-analyses were performed considering placebo as the basis for comparison in efficacy and safety analyses. Subgroup stratification considered gender, age, sorafenib-responsiveness and drug tolerability, viral infection, macrovascular invasion, HCC extrahepatic spread, performance status, and alpha-fetoprotein levels. RESULTS: Fourteen phase II or III randomized controlled trials, involving 5,488 patients and 12 regimens, were included in the analysis. Regorafenib (hazard ratio (HR) = 0.63, 95% confidence interval (CI) = 0.50-0.79), cabozantinib (HR = 0.76, 95% CI = 0.63-0.92), and ramucirumab (HR = 0.82, 95% CI = 0.70-0.76) significantly prolonged OS compared with placebo. Cabozantinib (HR = 0.44, 95% CI = 0.36-0.52), regorafenib (HR = 0.46, 95% CI = 0.37-0.56), ramucirumab (HR = 0.54, 95% CI = 0.43-0.68), brivanib (HR = 0.56, 95% CI = 0.42-0.76), S-1 (HR = 0.60, 95% CI = 0.46-0.77), axitinib (HR = 0.62, 95% CI = 0.44-0.87), and pembrolizumab (HR = 0.72, 95% CI = 0.57-0.90) significantly improved PFS compared with placebo. None of the compared drugs deemed undoubtedly superior after having performed a patients' stratification. CONCLUSIONS: The results of this network meta-analysis suggest the use of regorafenib and cabozantinib as second-line treatments in HCC.

The importance of immune checkpoints in immune monitoring: A future paradigm shift in the treatment of cancer.

The growth and development of cancer are directly correlated to the suppression of the immune system. A major breakthrough in cancer immunotherapy depends on various mechanisms to detect immunosuppressive factors that inhibit anti-tumor immune responses. Immune checkpoints are expressed on many immune cells such as T-cells, regulatory B cells (Bregs), dendritic cells (DCs), natural killer cells (NKs), regulatory T (Tregs), M2-type macrophages, and myeloid-derived suppressor cells (MDSCs). Immune inhibitory molecules, including CTLA-4, TIM-3, TIGIT, PD-1, and LAG-3, normally inhibit immune responses via negatively regulating immune cell signaling pathways to prevent immune injury. However, the up-regulation of inhibitory immune checkpoints during tumor progression on immune cells suppresses anti-tumor immune responses and promotes immune escape in cancer. It has recently been indicated that cancer cells can up-regulate various pathways of the immune checkpoints. Therefore, targeting immune inhibitory molecules through antibodies or miRNAs is a promising therapeutic strategy and shows favorable results. Immune checkpoint inhibitors (ICIs) are introduced as a new immunotherapy strategy that enhance immune cell-induced antitumor responses in many patients. In this review, we highlighted the function of each immune checkpoint on different immune cells and therapeutic strategies aimed at using monoclonal antibodies and miRNAs against inhibitory receptors. We also discussed current challenges and future strategies for maximizing these FDA-approved immunosuppressants' effectiveness and clinical success in cancer treatment.

Silencing tumor-intrinsic CD73 enhances the chemosensitivity of NSCLC and potentiates the anti-tumoral effects of cisplatin: An in vitro study.

AIMS: Besides suppressing anti-tumoral immune responses, tumor-intrinsic inhibitory immune checkpoints have been implicated in tumor development. Herein, we aimed to investigate the significance of tumor-intrinsic CD73, as an inhibitory immune checkpoint, in non-small cell lung cancer (NSCLC) development and propose a novel therapeutic approach. MAIN METHODS: We investigated the cell viability, chemosensitivity, apoptosis, migration, and the cell cycle of A-549 and NCI-H1299 following treatment with cisplatin and CD73-small interfering RNA (siRNA) transfection. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to study the viability of studied groups and chemosensitivity of tumoral cells. Flow cytometry and 4',6-diamidino-2-phenylindole (DAPI) staining were used to investigate the apoptosis of NSCLC cells. Flow cytometry and the wound-healing assay were used to investigate the cell cycle and migration of NSCLC cells, respectively. The mRNA expression levels of c-Myc, caspase 3, ROCK, and MMP-9 were investigated to study the underlying molecular mechanism. KEY FINDINGS: CD73-siRNA transfection has significantly decreased the cell viability and enhanced the chemosensitivity of A-549 and NCI-H1299 cells to cisplatin. CD73-siRNA has considerably stimulated apoptosis, arrested the cell cycle, inhibited tumor migration, downregulated the mRNA expression of c-Myc, MMP-9, and ROCK, and upregulated caspase 3 expression in NSCLC cells. Besides, combined cisplatin therapy with CD73-siRNA transfection has potentiated the aforementioned anti-tumoral effects of cisplatin on NSCLC cells. SIGNIFICANCE: Besides suppressing anti-tumoral immune responses, tumor-intrinsic CD73 can facilitate NSCLC development, and the combined cisplatin therapy with CD73-siRNA transfection can substantially enhance the chemosensitivity of NSCLC to cisplatin and potentiates cisplatin-induced anti-tumoral effects on NSCLC.

Immunotherapy for Hepatocellular Carcinoma: New Prospects for the Cancer Therapy.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. HCC patients may benefit from liver transplantation, hepatic resection, radiofrequency ablation, transcatheter arterial chemoembolization, and targeted therapies. The increased infiltration of immunosuppressive immune cells and the elevated expression of immunosuppressive factors in the HCC microenvironment are the main culprits of the immunosuppressive nature of the HCC milieu. The immunosuppressive tumor microenvironment can substantially attenuate antitumoral immune responses and facilitate the immune evasion of tumoral cells. Immunotherapy is an innovative treatment method that has been promising in treating HCC. Immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT), and cell-based (primarily dendritic cells) and non-cell-based vaccines are the most common immunotherapeutic approaches for HCC treatment. However, these therapeutic approaches have not generally induced robust antitumoral responses in clinical settings. To answer to this, growing evidence has characterized immune cell populations and delineated intercellular cross-talk using single-cell RNA sequencing (scRNA-seq) technologies. This review aims to discuss the various types of tumor-infiltrating immune cells and highlight their roles in HCC development. Besides, we discuss the recent advances in immunotherapeutic approaches for treating HCC, e.g., ICIs, dendritic cell (DC)-based vaccines, non-cell-based vaccines, oncolytic viruses (OVs), and ACT. Finally, we discuss the potentiality of scRNA-seq to improve the response rate of HCC patients to immunotherapeutic approaches.

A Promising Role of TGF-ß Pathway in Response to Regorafenib in Metastatic Colorectal Cancer: A Case Report.

Colorectal cancer (CRC) is one of the most common cancer types around the world. The prognosis of patients with advanced diseases is still poor in spite of currently available therapeutic options. Regorafenib is an oral tyrosine kinase inhibitor (TKI) approved to treat refractory metastatic colorectal cancer (mCRC). We investigated Somatic mutations in several genes involved in immunological response and cancer progression in both long/short responder mCRC patients who underwent third-line therapy with regorafenib to identify predictive biomarkers of response using Ion Torrent PGM sequencing and bioinformatic tools. We found Somatic mutations in TGFBR1, TGFBR2, and TGFBR3 genes in primary tumor and metastases samples of long-responder patients. Furthermore, our bioinformatic results show that they were mainly enriched in immune response, cell junction, and cell adhesion in long responder patients, particularly in primary tumor and metastatic sites. These data suggest that the TGF-b pattern could be the leading actor of a prolonged response to this drug.

A Systematic Review and Meta-Analysis on the Significance of TIGIT in Solid Cancers: Dual TIGIT/PD-1 Blockade to Overcome Immune-Resistance in Solid Cancers.

Preclinical studies have indicated that T-cell immunoglobulin and ITIM domain (TIGIT) can substantially attenuate anti-tumoral immune responses. Although multiple clinical studies have evaluated the significance of TIGIT in patients with solid cancers, their results remain inconclusive. Thus, we conducted the current systematic review and meta-analysis based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to determine its significance in patients with solid cancers. We systematically searched the Web of Science, Embase, PubMed, and Scopus databases to obtain peer-reviewed studies published before September 20, 2020. Our results have shown that increased TIGIT expression has been significantly associated with inferior overall survival (OS) (HR = 1.42, 95% CI: 1.11-1.82, and p-value = 0.01). Besides, the level of tumor-infiltrating TIGIT+CD8+ T-cells have been remarkably associated inferior OS and relapse-free survival (RFS) of affected patients (HR = 2.17, 95% CI: 1.43-3.29, and p-value < 0.001, and HR = 1.89, 95% CI: 1.36-2.63, and p-value < 0.001, respectively). Also, there is a strong positive association between TIGIT expression with programmed cell death-1 (PD-1) expression in these patients (OR = 1.71, 95% CI: 1.10-2.68, and p-value = 0.02). In summary, increased TIGIT expression and increased infiltration of TIGIT+CD8+ T-cells can substantially worsen the prognosis of patients with solid cancers. Besides, concerning the observed strong association between TIGIT and PD-1, ongoing clinical trials, and promising preclinical results, PD-1/TIGIT dual blockade can potentially help overcome the immune-resistance state seen following monotherapy with a single immune checkpoint inhibitor in patients with solid cancers.

Antibiotics or No Antibiotics, That Is the Question: An Update on Efficient and Effective Use of Antibiotics in Dental Practice.

The antimicrobial resistance (AMR) phenomenon is an emerging global problem and is induced by overuse and misuse of antibiotics in medical practice. In total, 10% of antibiotic prescriptions are from dentists, usually to manage oro-dental pains and avoid postsurgical complications. Recent research and clinical evaluations highlight new therapeutical approaches with a reduction in dosages and number of antibiotic prescriptions and recommend focusing on an accurate diagnosis and improvement of oral health before dental treatments and in patients' daily lives. In this article, the most common clinical and operative situations in dental practice, such as endodontics, management of acute alveolar abscesses, extractive oral surgery, parodontology and implantology, are recognized and summarized, suggesting possible guidelines to reduce antibiotic prescription and consumption, maintaining high success rates and low complications rates. Additionally, the categories of patients requiring antibiotic administration for pre-existing conditions are recapitulated. To reduce AMR threat, it is important to establish protocols for treatment with antibiotics, to be used only in specific situations. Recent reviews demonstrate that, in dentistry, it is possible to minimize the use of antibiotics, thoroughly assessing patient's conditions and type of intervention, thus improving their efficacy and reducing the adverse effects and enhancing the modern concept of personalized medicine.

The Evolving Role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma Treatment.

Hepatocellular carcinoma (HCC) is one of most common cancers and the fourth leading cause of death worldwide. Commonly, HCC development occurs in a liver that is severely compromised by chronic injury or inflammation. Liver transplantation, hepatic resection, radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), and targeted therapies based on tyrosine protein kinase inhibitors are the most common treatments. The latter group have been used as the primary choice for a decade. However, tumor microenvironment in HCC is strongly immunosuppressive; thus, new treatment approaches for HCC remain necessary. The great expression of immune checkpoint molecules, such as programmed death-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activating gene 3 protein (LAG-3), and mucin domain molecule 3 (TIM-3), on tumor and immune cells and the high levels of immunosuppressive cytokines induce T cell inhibition and represent one of the major mechanisms of HCC immune escape. Recently, immunotherapy based on the use of immune checkpoint inhibitors (ICIs), as single agents or in combination with kinase inhibitors, anti-angiogenic drugs, chemotherapeutic agents, and locoregional therapies, offers great promise in the treatment of HCC. This review summarizes the recent clinical studies, as well as ongoing and upcoming trials.

Impact of Antigen Presentation Mechanisms on Immune Response in Autoimmune Hepatitis.

The liver is a very tolerogenic organ. It is continually exposed to a multitude of antigens and is able to promote an effective immune response against pathogens and simultaneously immune tolerance against self-antigens. In spite of strong peripheral and central tolerogenic mechanisms, loss of tolerance can occur in autoimmune liver diseases, such as autoimmune hepatitis (AIH) through a combination of genetic predisposition, environmental factors, and an imbalance in immunological regulatory mechanisms. The liver hosts several types of conventional resident antigen presenting cells (APCs) such as dendritic cells, B cells and macrophages (Kupffer cells), and unconventional APCs including liver sinusoidal endothelial cells, hepatic stellate cells and hepatocytes. By standard (direct presentation and cross-presentation) and alternative mechanisms (cross-dressing and MHC class II-dressing), liver APCs presents self-antigen to naive T cells in the presence of costimulation leading to an altered immune response that results in liver injury and inflammation. Additionally, the transport of antigens and antigen:MHC complexes by trogocytosis and extracellular vesicles between different cells in the liver contributes to enhance antigen presentation and amplify autoimmune response. Here, we focus on the impact of antigen presentation on the immune response in the liver and on the functional role of the immune cells in the induction of liver inflammation. A better understanding of these key pathogenic aspects could facilitate the establishment of novel therapeutic strategies in AIH.

A Systematic Review on PD-1 Blockade and PD-1 Gene-Editing of CAR-T Cells for Glioma Therapy: From Deciphering to Personalized Medicine.

Background: Programmed cell death protein 1 (PD-1) can attenuate chimeric antigen receptor-T (CAR-T) cell-mediated anti-tumoral immune responses. In this regard, co-administration of anti-PD-1 with CAR-T cells and PD-1 gene-editing of CAR-T cells have been suggested to disrupt this inhibitory axis. Herein, we aim to investigate the advantages and disadvantages of these two approaches and propose a novel strategy to ameliorate the prognosis of glioma patients. Methods: Scopus, Embase, and Web of Science were systematically searched to obtain relevant peer-reviewed studies published before March 7, 2021. Then, the current study was conducted based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements. The random-effect model was applied to evaluate the effect size of administrated agents on the survival of animal models bearing gliomas using RevMan version 5.4. The Cochran Q test and I2 were performed to assess the possible between-study heterogeneity. Egger's and Begg and Mazumdar's tests were performed to objectively assess potential asymmetry and publication bias using CMA version 2. Results: Anti-PD-1 can substantially increase the survival of animal models on second-generation CAR-T cells. Also, PD-1 knockdown can remarkably prolong the survival of animal models on third-generation CAR-T cells. Regardless of the CAR-T generations, PD-1 gene-edited CAR-T cells can considerably enhance the survival of animal-bearing gliomas compared to the conventional CAR-T cells. Conclusions: The single-cell sequencing of tumoral cells and cells residing in the tumor microenvironment can provide valuable insights into the patient-derived neoantigens and the expression profile of inhibitory immune checkpoint molecules in tumor bulk. Thus, single-cell sequencing-guided fourth-generation CAR-T cells can cover patient-derived neoantigens expressed in various subpopulations of tumoral cells and inhibit related inhibitory immune checkpoint molecules. The proposed approach can improve anti-tumoral immune responses, decrease the risk of immune-related adverse events, reduce the risk of glioma relapse, and address the vast inter-and intra-heterogeneity of gliomas.

Actors on the Scene: Immune Cells in the Myeloma Niche.

Two mechanisms are involved in the immune escape of cancer cells: the immunoediting of tumor cells and the suppression of the immune system. Both processes have been revealed in multiple myeloma (MM). Complex interactions between tumor plasma cells and the bone marrow (BM) microenvironment contribute to generate an immunosuppressive milieu characterized by high concentration of immunosuppressive factors, loss of effective antigen presentation, effector cell dysfunction, and expansion of immunosuppressive cell populations, such as myeloid-derived suppressor cells, regulatory T cells and T cells expressing checkpoint molecules such as programmed cell death 1. Considering the great immunosuppressive impact of BM myeloma microenvironment, many strategies to overcome it and restore myeloma immunosurveillance have been elaborated. The most successful ones are combined approaches such as checkpoint inhibitors in combination with immunomodulatory drugs, anti-monoclonal antibodies, and proteasome inhibitors as well as chimeric antigen receptor (CAR) T cell therapy. How best to combine anti-MM therapies and what is the optimal timing to treat the patient are important questions to be addressed in future trials. Moreover, intratumor MM heterogeneity suggests the crucial importance of tailored therapies to identify patients who might benefit the most from immunotherapy, reaching deeper and more durable responses.

Insights into the Regulation of Tumor Angiogenesis by Micro-RNAs.

One of the hallmarks of cancer is angiogenesis, a series of events leading to the formation of the abnormal vascular network required for tumor growth, development, progression, and metastasis. MicroRNAs (miRNAs) are short, single-stranded, non-coding RNAs whose functions include modulation of the expression of pro- and anti-angiogenic factors and regulation of the function of vascular endothelial cells. Vascular-associated microRNAs can be either pro- or anti-angiogenic. In cancer, miRNA expression levels are deregulated and typically vary during tumor progression. Experimental data indicate that the tumor phenotype can be modified by targeting miRNA expression. Based on these observations, miRNAs may be promising targets for the development of novel anti-angiogenic therapies. This review discusses the role of various miRNAs and their targets in tumor angiogenesis, describes the strategies and challenges of miRNA-based anti-angiogenic therapies and explores the potential use of miRNAs as biomarkers for anti-angiogenic therapy response.

Role of Arabidopsis UV RESISTANCE LOCUS 8 in plant growth reduction under osmotic stress and low levels of UV-B.

In high-light environments, plants are exposed to different types of stresses, such as an excess of UV-B, but also drought stress which triggers a common morphogenic adaptive response resulting in a general reduction of plant growth. Here, we report that the Arabidopsis thaliana UV RESISTANCE LOCUS 8 (UVR8) gene, a known regulator of the UV-B morphogenic response, was able to complement a Saccharomyces cerevisiae osmo-sensitive mutant and its expression was induced after osmotic or salt stress in Arabidopsis plants. Under low levels of UV-B, plants overexpressing UVR8 are dwarfed with a reduced root development and accumulate more flavonoids compared to control plants. The growth defects are mainly due to the inhibition of cell expansion. The growth inhibition triggered by UVR8 overexpression in plants under low levels of UV-B was exacerbated by mannitol-induced osmotic stress, but it was not significantly affected by ionic stress. In contrast, uvr8-6 mutant plants do not differ from wild-type plants under standard conditions, but they show an increased shoot growth under high-salt stress. Our data suggest that UVR8-mediated accumulation of flavonoid and possibly changes in auxin homeostasis are the underlying mechanism of the observed growth phenotypes and that UVR8 might have an important role for integrating plant growth and stress signals.

Light as stress factor to plant roots - case of root halotropism.

Despite growing underground, largely in darkness, roots emerge to be very sensitive to light. Recently, several important papers have been published which reveal that plant roots not only express all known light receptors but also that their growth, physiology and adaptive stress responses are light-sensitive. In Arabidopsis, illumination of roots speeds-up root growth via reactive oxygen species-mediated and F-actin dependent process. On the other hand, keeping Arabidopsis roots in darkness alters F-actin distribution, polar localization of PIN proteins as well as polar transport of auxin. Several signaling components activated by phytohormones are overlapping with light-related signaling cascade. We demonstrated that the sensitivity of roots to salinity is altered in the light-grown Arabidopsis roots. Particularly, light-exposed roots are less effective in their salt-avoidance behavior known as root halotropism. Here we discuss these new aspects of light-mediated root behavior from cellular, physiological and evolutionary perspectives.

A study of biochemical and functional interactions of Htl1p, a putative component of the Saccharomyces cerevisiae, Rsc chromatin-remodeling complex.

HTL1, a small gene of Saccharomyces cerevisiae, encodes a 78-aminoacid peptide that influences the performance of a wide range of cellular processes [Lanzuolo, C., Ederle, S., Pollice, A., Russo, F., Storlazzi, A., Pulitzer, J.F., 2001. The HTL1 gene,YCR020W-b of Saccharomyces cerevisiae is necessary for growth at 37 degrees C, and for the conservation of chromosome stability and fertility. Yeast, 18, 1317-1330]. Genetic interactions and co-immunoprecipitation experiments indicate a role for Htl1p in functions controlled by RSC, a multiprotein, ATP-dependent, chromatin-remodeling complex [Lu, Y.M., Lin, Y.R., Tsai, A., Hsao, Y.S., Li, C.C., Cheng, M.Y., 2003. Dissecting the pet18 mutation in Saccharomyces cerevisiae: HTL1 encodes a 7-kDa polypeptide that interacts with components of the RSC complex. Mol. Genet. Genomics., 269, 321-330] [Romeo, M.J., Angus-Hill, M.L., Sobering, A.K., Kamada, Y., Cairns, B.R., Levin, D.E., 2002. HTL1 encodes a novel factor that interacts with the Rsc chromatin-remodeling complex in Saccharomyces cerevisiae. Mol. Cell. Biol., 22, 8165-8174]. Htl1p and RSC components, share the property of associating with TBP a component of general multiprotein transcription factor TFIID [Sanders, S.L., Jennings, J., Canutescu, A., Link, A.J., Weil, P.A., 2002. Proteomics of the eukaryotic transcription machinery: identification of proteins associated with components of yeast TFIID by multidimensional mass spectrometry. Mol. Cell. Biol. 22, 4723-4738]. We confirm, by integrating genetic and biochemical experiments, that Htl1p binding to the RSC complex is direct and physiologically relevant and show that it is mediated by Rsc8p, a core component of the RSC complex. Deletion of HTL1, like depletion of RSC core subunits [Moreira, J.M., Holmberg, S., 1999. Transcriptional repression of the yeast CHA1 gene requires the chromatin-remodeling complex Rsc. Embo J., 18, 2836-2844], leads to constitutive transcription of the CHA1 locus. This transcriptional phenotype exhibits variable penetrance. Deletion of HTL1 also leads to hydroxyurea hypersensitivity at 30 degrees C, suggesting a defect in replication/repair. This defect leads, during cell growth, to selection of mutations at the SIR3 locus that suppress hydroxyurea sensitivity.