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The treatment landscape of chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults, is constantly changing. CLL patients can be divided into three risk categories, based on their IGHV mutational status and the occurrence of TP53 disruption and/or complex karyotype. For the first-line treatment of low- and intermediate-risk CLL, both the BCL2 inhibitor venetoclax plus obinutuzumab and the second generation BTK inhibitors (BTKi), namely acalabrutinib and zanubrutinib, are valuable and effective options. Conversely, venetoclax-based fixed duration therapies have not shown remarkable results in high-risk CLL patients, while continuous treatment with acalabrutinib and zanubrutinib displayed favorable outcomes, similar to those obtained in TP53 wild-type patients. The development of acquired resistance to pathway inhibitors is still a clinical challenge, and the optimal treatment sequencing of relapsed/refractory CLL is not completely established. Covalent BTKi-refractory patients should be treated with venetoclax plus rituximab, whereas venetoclax-refractory CLL may be treated with second generation BTKi in the case of early relapse, while venetoclax plus rituximab might be used if late relapse has occurred. On these grounds, here we provide an overview of the current state-of-the-art therapeutic algorithms for treatment-naïve patients, as well as for relapsed/refractory disease. [ABSTRACT FROM AUTHOR]

Most of the time, the deep analysis of a biological sample requires the acquisition of images at different time points, using different modalities and/or different stainings. This information gives morphological, functional, and physiological insights, but the acquired images must be aligned to be able to proceed with the co-localisation analysis. Practically speaking, according to Aristotle's principle, "The whole is greater than the sum of its parts", multi-modal image registration is a challenging task that involves fusing complementary signals. In the past few years, several methods for image registration have been described in the literature, but unfortunately, there is not one method that works for all applications. In addition, there is currently no user-friendly solution for aligning images that does not require any computer skills. In this work, DS4H Image Alignment (DS4H-IA), an open-source ImageJ/Fiji plugin for aligning multimodality, immunohistochemistry (IHC), and/or immunofluorescence (IF) 2D microscopy images, designed with the goal of being extremely easy to use, is described. All of the available solutions for aligning 2D microscopy images have also been revised. The DS4H-IA source code; standalone applications for MAC, Linux, and Windows; video tutorials; manual documentation; and sample datasets are publicly available. [ABSTRACT FROM AUTHOR]

ETV6::ABL1 rearranged neoplasms are rare hematological diseases. To date, about 80 cases have been reported, including myeloid and lymphoid leukemias. The ETV6 gene codes for an ETS family transcription factor and several fusion partners have been described. When translocated, ETV6 causes the constitutive activation of the partner genes. Here, we report the case of a 54-year-old woman with a cryptic insertion of the 3′ region of ABL1 in the ETV6 gene. The patient was first diagnosed with idiopathic hypereosinophilic syndrome, according to the clinical history, conventional cytogenetics, standard molecular analyses and pathologist description. Next generation sequencing of diagnosis samples unexpectedly detected both ETV6::ABL1 type A and B fusion transcripts, which were then confirmed by FISH. The diagnosis was Myeloid/Lymphoid neoplasm with ETV6::ABL1 fusion, and the patient received imatinib mesylate treatment. In a follow-up after more than one year, the patient still maintained the molecular and complete hematological responses. This case highlights the importance of timely and proper diagnostics and prompt tyrosine kinase inhibitor treatment. [ABSTRACT FROM AUTHOR]

Bottled mineral waters originate from groundwater aquifers, their chemical composition being initially determined by geochemical water-rock interaction processes. The waters used for bottling originate from different parts of the hydrological cycle and have a unique hydro-geochemical fingerprint. As water moves through the water cycle, the isotopic composition of oxygen and hydrogen in the water molecule may change. Determining 18O and 2H can help to characterize the source of bottled water and the natural conditions of the parent water body, of the recharge area, and the influence of various processes during infiltration and water flow within the water body. Usually, the chemical composition is reported on the label of bottled waters, while stable isotopes data are often unreported and are sometimes available from scientific publications. Bottled waters from selected sites of Europe where chemical and stable isotopic composition were available have been considered and accompanying data reinterpreted. The available data have been reinterpreted by obtaining results comparable, within limitations, to traditional sampling and analytical procedures, demonstrating the usefulness of the adopted methodology in emergency cases. Therefore, the utilization of isotopic values of bottled waters should be limited to the observation of general trends in isotopic composition of feeding waters, while more local studies are advised for a better understanding of the hydro-geological circuits. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL), is a hematologic malignancy characterized by the uncontrolled proliferation of mature B lymphocytes. CLL is the most prevalent leukemia in Western countries. Its presentation can range from asymptomatic with the incidental finding of absolute lymphocytosis on a routine blood test, to symptomatic disease requiring immediate intervention. Prognosis of the disease is defined by the presence or absence of specific mutations such as TP53, chromosomal abnormalities such as del(17p), a type of IGHV mutational status, and elevation of B2M and LDH. Treatment of CLL in the United States and Europe has evolved over the recent years thanks to the development of targeted therapies. The standard of care has shifted from traditional chemoimmunotherapy approaches to targeted therapies including Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitors, administered either as monotherapy or in combination with CD20 monoclonal antibodies. Several clinical trials have also recently evaluated combinations of BTKi and venetoclax and showed the combination to be well tolerated and able to induce deep remissions. Targeted therapies have a good safety profile overall; however, they also have unique toxicities that are important to recognize. Diarrhea, fatigue, arthralgia, infections, cytopenias, bleeding, and cardiovascular toxicities (including atrial fibrillation, ventricular arrhythmias, and hypertension) are the adverse events (AEs) commonly associated with BTKis. Initiation of therapy with venetoclax requires close monitoring because of the risk for tumor lysis syndrome associated with this agent, particularly in patients with a high disease burden. Development of newer target therapies is ongoing and the therapeutic landscape in CLL is expanding rapidly. [ABSTRACT FROM AUTHOR]

Simple Summary: This review highlights the role of phospholipase in lung cancer, a topic which should be better elucidated considering that phospholipase signaling plays a crucial role in the regulation of multiple cellular processes and its deregulation can promote lung tumorigenesis, favoring lung cancer cell proliferation, migration, and invasion. Lung cancer (LC) is the second most common neoplasm in men and the third most common in women. In the last decade, LC therapies have undergone significant improvements with the advent of immunotherapy. However, the effectiveness of the available treatments remains insufficient due to the presence of therapy-resistant cancer cells. For decades, chemotherapy and radiotherapy have dominated the treatment strategy for LC; however, relapses occur rapidly and result in poor survival. Malignant lung tumors are classified as either small- or non-small-cell lung carcinoma (SCLC and NSCLC). Despite improvements in the treatment of LC in recent decades, the benefits of surgery, radiotherapy, and chemotherapy are limited, although they have improved the prognosis of LC despite the persistent low survival rate due to distant metastasis in the late stage. The identification of novel prognostic molecular markers is crucial to understand the underlying mechanisms of LC initiation and progression. The potential role of phosphatidylinositol in tumor growth and the metastatic process has recently been suggested by some researchers. Phosphatidylinositols are lipid molecules and key players in the inositol signaling pathway that have a pivotal role in cell cycle regulation, proliferation, differentiation, membrane trafficking, and gene expression. In this review, we discuss the current understanding of phosphoinositide-specific phospholipase enzymes and their emerging roles in LC. [ABSTRACT FROM AUTHOR]

Adenocarcinoma of the esophagus (EAC) and gastroesophageal junction (GEJ-AC) is associated with poor prognosis, treatment resistance and limited systemic therapeutic options. To deeply understand the genomic landscape of this cancer type, and potentially identify a therapeutic target in a neoadjuvant chemotherapy non-responder 48-year-old man, we adopted a multi-omic approach. We simultaneously evaluated gene rearrangements, mutations, copy number status, microsatellite instability and tumor mutation burden. The patient displayed pathogenic mutations of the TP53 and ATM genes and variants of uncertain significance of three kinases genes (ERBB3, CSNK1A1 and RPS6KB2), along with FGFR2 and KRAS high copy number amplification. Interestingly, transcriptomic analysis revealed the Musashi-2 (MSI2)-C17orf64 fusion that has never been reported before. Rearrangements of the RNA-binding protein MSI2 with a number of partner genes have been described across solid and hematological tumors. MSI2 regulates several biological processes involved in cancer initiation, development and resistance to treatment, and deserves further investigation as a potential therapeutic target. In conclusion, our extensive genomic characterization of a gastroesophageal tumor refractory to all therapeutic approaches led to the discovery of the MSI2-C17orf64 fusion. The results underlie the importance of deep molecular analyses enabling the identification of novel patient-specific markers to be monitored during therapy or even targeted at disease evolution. [ABSTRACT FROM AUTHOR]

Simple Summary: To date, different therapeutic strategies, including immunotherapies, have been shown to prolong survival in breast cancer patients, representing one of the most common malignancies. Our article deals with chimeric antigen receptor-based immunotherapy in breast cancer. Breast cancer represents one of the most common tumor histologies. To date, based on the specific histotype, different therapeutic strategies, including immunotherapies, capable of prolonging survival are used. More recently, the astonishing results that were obtained from CAR-T cell therapy in haematological neoplasms led to the application of this new therapeutic strategy in solid tumors as well. Our article will deal with chimeric antigen receptor-based immunotherapy (CAR-T cell and CAR-M therapy) in breast cancer. [ABSTRACT FROM AUTHOR]

Approximately 7% of cancers arising in children and 1% of those arising in adults are soft tissue sarcomas (STS). Of these malignancies, rhabdomyosarcoma (RMS) is the most common. RMS survival rates using current therapeutic protocols have remained largely unchanged in the past decade. Thus, it is imperative that the main molecular drivers in RMS tumorigenesis are defined so that more precise, effective, and less toxic therapies can be designed. Curcumin, a common herbal supplement derived from plants of the Curcuma longa species, has an exceptionally low dietary biotoxicity profile and has demonstrated anti-tumorigenic benefits in vitro. In this study, the anti-tumorigenic activity of curcumin was assessed in rhabdomyosarcoma cell lines and used to identify the major pathways responsible for curcumin's anti-tumorigenic effects. Curcumin treatment resulted in cell cycle arrest, inhibited cell migration and colony forming potential, and induced apoptotic cell death. Proteome profiler array analysis demonstrated that curcumin treatment primarily influenced flux through the AKT-mammalian target of rapamycin (mTOR), signal transducer and activator of transcription (STAT), AMP-dependent kinase (AMPK), and p53 associated pathways in a rhabdomyosarcoma subtype-specific manner. Thus, the strategic, combinational therapeutic targeting of these pathways may present the best option to treat this group of tumors. [ABSTRACT FROM AUTHOR]

Uncontrolled proliferative signals and cell cycle dysregulation due to genomic or functional alterations are important drivers of the expansion of undifferentiated blast cells in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells. Therefore, they are largely studied as potential therapeutic targets in the field. We here present the most recent advancements in the evaluation of novel compounds targeting cell cycle proteins or oncogenic mechanisms, including those showing an antiproliferative effect in acute leukemia, independently of the identification of a specific target. Several new kinase inhibitors have been synthesized that showed effectiveness in a nanomolar to micromolar concentration range as inhibitors of FLT3 and its mutant forms, a highly attractive therapeutic target due to its driver role in a significant fraction of AML cases. Moreover, we introduce novel molecules functioning as microtubule-depolymerizing or P53-restoring agents, G-quadruplex-stabilizing molecules and CDK2, CHK1, PI3Kδ, STAT5, BRD4 and BRPF1 inhibitors. We here discuss their mechanisms of action, including the downstream intracellular changes induced by in vitro treatment, hematopoietic toxicity, in vivo bio-availability and efficacy in murine xenograft models. The promising activity profile demonstrated by some of these candidates deserves further development towards clinical investigation. [ABSTRACT FROM AUTHOR]

The treatment landscape for hematologic malignancies has changed since the recent approval of highly effective chimeric antigen receptor T-cell therapies (CAR-T). Moreover, more than 600 active trials are currently ongoing. However, early enthusiasm should be tempered since several issues are still unsolved and represent the challenges for the coming years. The lack of initial responses and early relapse are some hurdles to be tackled. Moreover, new strategies are needed to increase the safety profile or shorten the manufacturing process during CAR-T cells therapy production. Nowadays, most clinically evaluated CAR-T cells products are derived from autologous immune cells. The use of allogeneic CAR-T cells products generated using cells from healthy donors has the potential to change the scenario and overcome many of these limitations. In addition, CAR-T cells carry a high price tag, and there is an urgent need to understand how to pay for these therapies as many of today's current payment systems do not feature the functionality to address the reimbursement gap. Finally, the clinical experience with CAR-T cells for solid tumors has been less encouraging, and development in this setting is desirable. [ABSTRACT FROM AUTHOR]

Simple Summary: Pegfilgrastim, the pegylated form of filgrastim (recombinant human GCSF) is widely adopted as supportive care for preventing neutropenia or febrile neutropenia episodes during chemotherapy. Neutropenia is directly cause of potentially severe infections and indirectly cause of treatment delivery delay. No guidelines address the pegfilgrastim role in the specific setting of Hodgkin lymphoma (HL). Since HL is a young-adult disease and shows mostly a very a favorable outcome after chemotherapy, treatment delay or dose reduction could potentially affect negatively the outcome. The aim of our review is to explore the current scientific literature on pegfilgratim use in HL, evaluating both observational than prospective trial. Moreover, analyzing the latter, we aim to define some practical suggestion about primary prophylaxis with pegfilgrastim in HL. Neutropenia and febrile neutropenia are common and potentially life-threating events associated with chemotherapy treatment in Hodgkin lymphoma (HL). Neutropenia-related infectious events could be an issue both for direct clinical consequences and for delay in treatment delivery, affecting final outcomes in a potentially highly curable disease. Pegfilgrastim is the pegylated form of filgrastim, the recombinant form of human G-CSF, capable of prevent and mitigate neutropenic effects of chemotherapy, when adopted as primary prophylaxis in several hematological malignancies. No updated version of major international guidelines provides clear indication on prophylaxis use of pegfilgrastim in HL to prevent febrile neutropenia episodes in HL. Moreover, to date, scarce and non-uniform clinical experiences evaluating pegfilgrastim as prophylaxis in HL are present in the literature. Herein, we propose a brief summary of the literature data about efficacy and safety of the use of pegfilgrastim as primary prophylaxis in HL during chemotherapy treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Circulating tumor cells (CTCs) are rare cells found in the bloodstream of oncologic patients with a central role in the metastatic spread. In this study, we aim at exploring their heterogeneity levels in metastatic breast cancer patients focusing on single cell single nucleotide variant (SNV) and copy number aberration (CNA) analyses. Our results show high levels of heterogeneity, especially concerning SNVs. Further analysis revealed the presence of CNAs associated with breast tumorigenesis, while longitudinal CNA profiling was demonstrated to track clonal selection of CTCs during treatment. Despite this heterogeneity, we found a group of CTCs from different patients sharing common genomic aberrations, such as losses on 15q. Collectively, our findings demonstrate that single-cell molecular analyses could be exploited in future to better address therapeutic strategies. Further investigations to better characterize this mixed population are needed to understand its role in MBC. Circulating tumor cells' (CTCs) heterogeneity contributes to counteract their introduction in clinical practice. Through single-cell sequencing we aim at exploring CTC heterogeneity in metastatic breast cancer (MBC) patients. Single CTCs were isolated using DEPArray NxT. After whole genome amplification, libraries were prepared for copy number aberration (CNA) and single nucleotide variant (SNV) analysis and sequenced using Ion GeneStudio S5 and Illumina MiSeq, respectively. CTCs demonstrate distinctive mutational signatures but retain molecular traces of their common origin. CNA profiling identifies frequent aberrations involving critical genes in pathogenesis: gains of 1q (CCND1) and 11q (WNT3A), loss of 22q (CHEK2). The longitudinal single-CTC analysis allows tracking of clonal selection and the emergence of resistance-associated aberrations, such as gain of a region in 12q (CDK4). A group composed of CTCs from different patients sharing common traits emerges. Further analyses identify losses of 15q and enrichment of terms associated with pseudopodium formation as frequent and exclusive events. CTCs from MBC patients are heterogeneous, especially concerning their mutational status. The single-cell analysis allows the identification of aberrations associated with resistance, and is a candidate tool to better address treatment strategy. The translational significance of the group populated by similar CTCs should be elucidated. [ABSTRACT FROM AUTHOR]

The immune system is a dynamic feature of each individual and a footprint of our unique internal and external exposures. Indeed, the type and level of exposure to physical and biological agents shape the development and behavior of this complex and diffuse system. Many pathological conditions depend on how our immune system responds or does not respond to a pathogen or a disease or on how the regulation of immunity is altered by the disease itself. T-cells are important players in adaptive immunity and, together with B-cells, define specificity and monitor the internal and external signals that our organism perceives through its specific receptors, TCRs and BCRs, respectively. Today, high-throughput sequencing (HTS) applied to the TCR repertoire has opened a window of opportunity to disclose T-cell repertoire development and behavior down to the clonal level. Although TCR repertoire sequencing is easily accessible today, it is important to deeply understand the available technologies for choosing the best fit for the specific experimental needs and questions. Here, we provide an updated overview of TCR repertoire sequencing strategies, providers and applications to infectious diseases and cancer to guide researchers' choice through the multitude of available options. The possibility of extending the TCR repertoire to HLA characterization will be of pivotal importance in the near future to understand how specific HLA genes shape T-cell responses in different pathological contexts and will add a level of comprehension that was unthinkable just a few years ago. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroendocrine tumors (NETs) are rare neoplasms that often present upregulation of the mammalian rapamycin targeting pathway (mTOR) with consequent uncontrolled growth and proliferation. This pathway is also involved in the metabolism of adipose tissue and in the regulation of skeletal muscle synthesis. The mTOR therefore represents an attractive therapeutic target. Everolimus acts by selectively inhibiting the mTOR pathway with an antiproliferative effect. The aim of this study is to investigate the prognostic and predictive role of body composition indices (muscle and adipose) in metastatic NETs patients treated with everolimus. Neuroendocrine tumors (NETs) are rare neoplasms frequently characterized by an upregulation of the mammalian rapamycin targeting (mTOR) pathway resulting in uncontrolled cell proliferation. The mTOR pathway is also involved in skeletal muscle protein synthesis and in adipose tissue metabolism. Everolimus inhibits the mTOR pathway, resulting in blockade of cell growth and tumor progression. The aim of this study is to investigate the role of body composition indexes in patients with metastatic NETs treated with everolimus. The study population included 30 patients with well-differentiated (G1-G2), metastatic NETs treated with everolimus at the IRCCS Romagnolo Institute for the Study of Tumors (IRST) "Dino Amadori", Meldola (FC), Italy. The body composition indexes (skeletal muscle index [SMI] and adipose tissue indexes) were assessed by measuring on a computed tomography (CT) scan the cross-sectional area at L3 at baseline and at the first radiological assessment after the start of treatment. The body mass index (BMI) was assessed at baseline. The median progression-free survival (PFS) was 8.9 months (95% confidence interval [CI]: 3.4–13.7 months). The PFS stratified by tertiles was 3.2 months (95% CI: 0.9–10.1 months) in patients with low SMI (tertile 1), 14.2 months (95% CI: 2.3 months-not estimable [NE]) in patients with intermediate SMI (tertile 2), and 9.1 months (95% CI: 2.7 months-NE) in patients with high SMI (tertile 3) (p = 0.039). Similarly, the other body composition indexes also showed a statistically significant difference in the three groups on the basis of tertiles. The median PFS was 3.2 months (95% CI: 0.9–6.7 months) in underweight patients (BMI ≤ 18.49 kg/m2) and 10.1 months (95% CI: 3.7–28.4 months) in normal-weight patients (p = 0.011). There were no significant differences in terms of overall survival. The study showed a correlation between PFS and the body composition indexes in patients with NETs treated with everolimus, underlining the role of adipose and muscle tissue in these patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The world of small molecules in solid tumors as cancer stem cells (CSCs), circulating tumor cells (CTCs) and cancer-associated fibroblasts (CAFs) continues to be under-debated, but not of minor interest in recent decades. One of the main problems in regard to cancer is the development of tumor recurrence, even in the early stages, in addition to drug resistance and, consequently, ineffective or an incomplete response against the tumor. The findings behind this resistance are probably justified by the presence of small molecules such as CSCs, CTCs and CAFs connected with the tumor microenvironment, which may influence the aggressiveness and the metastatic process. The mechanisms, connections, and molecular pathways behind them are still unknown. Our review would like to represent an important step forward to highlight the roles of these molecules and the possible connections among them. The importance of defining new molecules to fight cancer is of significant interest to the scientific community. In particular, it has been shown that cancer stem cells (CSCs) are a small subpopulation of cells within tumors with capabilities of self-renewal, differentiation, and tumorigenicity; on the other side, circulating tumor cells (CTCs) seem to split away from the primary tumor and appear in the circulatory system as singular units or clusters. It is becoming more and more important to discover new biomarkers related to these populations of cells in combination to define the network among them and the tumor microenvironment. In particular, cancer-associated fibroblasts (CAFs) are a key component of the tumor microenvironment with different functions, including matrix deposition and remodeling, extensive reciprocal signaling interactions with cancer cells and crosstalk with immunity. The settings of new markers and the definition of the molecular connections may present new avenues, not only for fighting cancer but also for the definition of more tailored therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Molecular characterization of advanced non-small-cell lung cancer (NSCLC) is mandatory before any treatment decision making. Next-generation sequencing (NGS) approaches represent the best strategy in this context. In our study, we analyzed a case series of young (under 65 years old) NSCLC patients with a wide NGS gene panel assay. The most frequent altered genes were TP53 (64.55%), followed by KRAS (44.1%), STK11 (26.9%), CDKN2A (21.5%), CDKN2B (14.0%), EGFR (16.1%), and RB1 (10.8%). Tumor mutational burden (TMB) was also evaluated considering different cut-offs, and we found a significant association between TMB and STK11 and KRAS mutations. Conversely, EGFR and EML4-ALK alterations were more frequently found in tumors with low TMB. We compared results obtained from this approach with those obtained from a single or few genes approach, observing perfect concordance of the results. Molecular characterization of advanced non-small-cell lung cancer (NSCLC) is mandatory before any treatment decision making. Next-generation sequencing (NGS) approaches represent the best strategy in this context. The turnaround time for NGS methodologies and the related costs are becoming more and more adaptable for their use in clinical practice. In our study, we analyzed a case series of young (under 65 years old) NSCLC patients with a wide NGS gene panel assay. The most frequent altered genes were TP53 (64.55%), followed by KRAS (44.1%), STK11 (26.9%), CDKN2A (21.5%), CDKN2B (14.0%), EGFR (16.1%), and RB1 (10.8%). Tumor mutational burden (TMB) was also evaluated. Considering the cut-off of 10 mut/Mb, 62 (68.9%) patients showed a TMB < 10 mut/Mb, whereas 28 (31.1%) showed a TMB ≥ 10 mut/Mb. STK11 and KRAS mutations were significantly associated with a higher TMB (p = 0.019 and p = 0.004, respectively). Conversely, EGFR and EML4-ALK alterations were more frequently found in tumors with low TMB (p = 0.019 and p < 0.001, respectively). We compared results obtained from this approach with those obtained from a single or few genes approach, observing perfect concordance of the results. [ABSTRACT FROM AUTHOR]

Leukemia-initiating cells of core binding factor (CBF) acute myeloid leukemia (AML) likely derive from early committed hematopoietic precursors expressing CD33. As such, targeting CD33 could ameliorate the chance of cure of CBF AML patients. We compared 12 CBF AML patients treated with Fludarabine, Cytarabine, Idarubicin and Gemtuzumab Ozogamicin (FLAI-GO regimen) with 25 CBF AML patients treated with the same schedule, but without GO. With the limit of small numbers, we observed a consistent trend toward better overall survival, disease free survival and event free survival in the FLAI-GO group. We also demonstrated the ability of GO to induce the disappearance in vitro of the AML1-ETO molecular transcript in a polymerase chain reaction-positive graft without decreasing the clonogenic potential of CD34+/CD38- cells. This represent the proof of principle for using GO in a purging strategy before autologous stem cell transplantation. Therefore, our data argue in favor of the reinstitution of GO in the therapy of CBF AML. [ABSTRACT FROM AUTHOR]

The outcome of patients underwent to allogeneic stem cell transplantation (allo- SCT) is closely related to graft versus host disease (GvHD) and graft versus leukemia (GvL) effects which can be mediated by mHAgs. 23 mHAgs have been identified and reported to be differently correlated with GVHD or GVL and the aim of this work was develop a method to genotype the mHAgs described so far. For this study we used MALDI-TOF iPLEX Gold Mass Array technology. We tested 46 donor/recipient matched pairs that underwent allo-SCT because of Philadelphia positive (Ph+) chronic myeloid leukemia (n=29) or Ph+ acute lymphoblastic leukemia (n=17). Our data show that sibling pairs had a lesser number of mHAgs mismatches compared to MUD pairs. Notably, donor/recipient genomic mismatch on DPH1 was correlated with an increased risk of acute GvHD and LB-ADIR-1R mismatch on graft versus host direction was correlated with a better RFS with no increase of GvHD risk. Our work provides a simple, accurate and highly automatable method for mHAgs genotyping and suggest the role of mHAgs in addressing the immune reaction between donor and host. [ABSTRACT FROM AUTHOR]

In the last two decades great improvements have been made in the treatment of childhood acute lymphoblastic leukemia, with 5-year overall survival rates currently approaching almost 90%. In comparison, results reported in adolescents and young adults (AYAs) are relatively poor. In adults, results have improved, but are still lagging behind those obtained in children. Possible reasons for this different pattern of results include an increased incidence of unfavorable and a decreased incidence of favorable cytogenetic abnormalities in AYAs compared with children. Furthermore, in AYAs less intensive treatments (especially lower cumulative doses of drugs such as asparaginase, corticosteroids and methotrexate) and longer gaps between courses of chemotherapy are planned compared to those in children. However, although favorable results obtained in AYAs receiving pediatric protocols have been consistently reported in several international collaborative trials, physicians must also be aware of the specific toxicity pattern associated with increased success in AYAs, since an excess of toxicity may compromise overall treatment schedule intensity. Cooperative efforts between pediatric and adult hematologists in designing specific protocols for AYAs are warranted. [ABSTRACT FROM AUTHOR]

This study sums up the first estimates of the young water fraction (Fyw; here understood as the percentage proportion of groundwater passing through the well's screen and younger than approximately 2–3 months) from groundwater collected in 75 wells from alluvial fans facing the northern Italian Apennines of Italy. The Fyw estimates were based on a monthly dataset of water-stable isotopes (oxygen-18 (18O)) from surficial water (9 rivers), while the dataset of groundwater (75 wells) consisted of three-monthly isotopic data. In the cases of surficial water and stable isotopes, these lasted over the period of January 2003 to December 2007, while in the case of groundwater, the data were collected from January 2005 to December 2007. The values of Fyw were estimated by means of a sine-wave fitting technique; the results made evident the presence of unexpectedly reduced differences between groundwater. In particular, shallower groundwater hosted in aquifers from the apical parts of the alluvial fans (i.e., aquifers characterized by the coarsest materials such as gravels and sands, and closest to the recharge areas) showed similar values of Fyw to the deepest aquifers from the distal parts; however, former studies mentioned here evidenced the existence of poorly recharged old groundwater. Our results seem to confirm a complex behavior of these aquifers compared with what had previously been thought. [ABSTRACT FROM AUTHOR]

Simple Summary: Myelosuppression is a side effect of chemotherapy, in which the production of red and white blood cells and platelets is reduced, increasing risk of infections. Blinatumomab, a bispecific T-cell engager (BiTE®) molecule, is a novel anticancer drug that kills acute lymphoblastic leukemia (ALL) cells while sparing majority of the normal bone marrow cells. Results from our study, which compared the effects of blinatumomab treatment with chemotherapy on bone marrow function in a large number of patients with ALL, indicated that the decrease in blood cell counts was more severe and lasted longer after chemotherapy compared with blinatumomab treatment, in which the effects were transient. Survival in patients treated with blinatumomab achieving complete remission was more similar between those with incomplete recovery of blood cell counts versus those with complete blood cell counts than the corresponding survival outcomes seen with chemotherapy. In conclusion, blinatumomab treatment caused transient myelosuppression when compared with chemotherapy. Association of blinatumomab treatment with myelosuppression was examined in this study. Peripheral blood counts were assessed prior to, during, and after blinatumomab treatment in patients with relapsed/refractory Philadelphia chromosome-negative (Ph−) B-cell precursor (BCP) acute lymphoblastic leukemia (ALL; n = 267) and Ph+ BCP-ALL (n = 45) from the TOWER and ALCANTARA studies, respectively, or chemotherapy in patients with Ph− BCP-ALL (n = 109) from the TOWER study; all the patients with relapsed/refractory BCP-ALL and responders achieving complete remission (CR) or CR with partial/incomplete hematological recovery (CRh/CRi) were evaluated. Event-free survival (EFS) and overall survival (OS) were assessed in patients achieving CR and CRh/CRi. Median leukocyte, neutrophil, and platelet counts increased during two blinatumomab cycles but remained low longer after chemotherapy. Among the responders, there was a trend that a greater proportion of patients achieved CR with blinatumomab (Ph−, 76.5%; Ph+, 77.8%) versus with chemotherapy (Ph−, 63.6%). In the TOWER study, the survival prognosis for patients achieving CRh/CRi versus CR with blinatumomab was more similar (median OS, 11.9 (95% CI, 3.9–not estimable (NE)) vs. 15.0 (95% CI, 10.4–NE) months, p = 0.062) than with chemotherapy (5.2 (95% CI, 1.6–NE) vs. 18.9 (95% CI, 9.3–NE) months, p = 0.013). Blinatumomab treatment, with only temporary and transient myelosuppression, resulted in a greater survival benefit than chemotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The introduction to clinical practice of a treatment-free remission approach in chronic myeloid leukemia patients with a stable deep molecular response highlighted how crucial it is to monitor the molecular levels of BCR–ABL1 as accurately and precisely as possible. In this context, the droplet digital PCR (ddPCR) presents an alternative methodology for such quantification. To hypothesize the introduction of this technology in routine practice, we performed a multicentric study that compares ddPCR with the standard methodology currently used. Our results demonstrate that the use of ddPCR in clinical practice is feasible and could be beneficial. BCR–ABL1 mRNA levels represent the key molecular marker for the evaluation of minimal residual disease (MRD) in chronic myeloid leukemia (CML) patients and real-time quantitative PCR (RT-qPCR) is currently the standard method to monitor it. In the era of tyrosine kinase inhibitors (TKIs) discontinuation, droplet digital PCR (ddPCR) has emerged to provide a more precise detection of MRD. To hypothesize the use of ddPCR in clinical practice, we designed a multicentric study to evaluate the potential value of ddPCR in the diagnostic routine. Thirty-seven RNA samples from CML patients and five from healthy donors were analyzed using both ddPCR QXDxTMBCR-ABL %IS Kit and LabNet-approved RT-qPCR methodologies in three different Italian laboratories. Our results show that ddPCR has a good agreement with RT-qPCR, but it is more precise to quantify BCR–ABL1 transcript levels. Furthermore, we did not find differences between duplicate or quadruplicate analysis in terms of BCR–ABL1% IS values. Droplet digital PCR could be confidently introduced into the diagnostic routine as a complement to the RT-qPCR. [ABSTRACT FROM AUTHOR]

Simple Summary: Gemtuzumab Ozogamicin (GO) is a drug approved for the treatment of acute myeloid leukemia (AML). It targets leukemic cells that express the CD33 molecule on their surface and brings the toxic agent calicheamicin inside the cell to kill it. Several studies have shown that AML patients can benefit of the addition of GO to chemotherapy during induction regimens, pre- and post-transplantation. Moreover, some disease features have been addressed or are under investigation for their capacity to predict response to GO, with the future aim of selecting AML patients that can mostly benefit of GO treatment. Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by genetic and clinical heterogeneity and high mortality. Despite the recent introduction of novel pharmaceutical agents in hemato-oncology, few advancements have been made in AML for decades. In the last years, the therapeutic options have rapidly changed, with the approval of innovative compounds that provide new opportunities, together with new challenges for clinicians: among them, on 1 September, 2017 the Food and Drug Administration granted approval for Gemtuzumab Ozogamicin (GO) in combination with daunorubicin and cytarabine for the treatment of adult patients affected by newly diagnosed CD33+ AML. Benefits of GO-based regimens were also reported in the pre- and post-transplantation settings. Moreover, several biomarkers of GO response have been suggested, including expression of CD33 and multidrug resistance genes, cytogenetic and molecular profiles, minimal residual disease and stemness signatures. Among them, elevated CD33 expression on blast cells and non-adverse cytogenetic or molecular risk represent largely validated predictors of good response. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is a disease characterized by high degrees of heterogeneity at morphologic, genomic, and genetic levels, even within the same tumor mass or among patients. As a consequence, different subpopulations coexist and less represented clones may have a selective advantage, significantly influencing the outcome of BC patients. Circulating tumor cells (CTCs) represent a rare population of cells with a crucial role in metastatic cascade, and in recent years have represented a fascinating alternative to overcome the heterogeneity issue as a "liquid biopsy". However, besides the raw enumeration of these cells in advanced epithelial tumors, there are no CTC-based assays applied in the clinical practice to improve personalized medicine. In this review, we report the latest findings in the field of CTCs for intra-tumoral heterogeneity unmasking in BC, supporting the need to deepen their analysis to investigate their role in metastatic process and include the molecular characterization in the clinical practice. In the future, CTCs will be helpful in monitoring patients during treatment, as well as to better address therapeutic strategies. [ABSTRACT FROM AUTHOR]

During the COVID-19 pandemic, there has been a significant increase in the use of non-contact infrared devices for screening the body temperatures of people at the entrances of hospitals, airports, train stations, churches, schools, shops, sports centres, offices, and public places in general. The strong correlation between a high body temperature and SARS-CoV-2 infection has motivated the governments of several countries to restrict access to public indoor places simply based on a person's body temperature. Negating/allowing entrance to a public place can have a strong impact on people. For example, a cancer patient could be refused access to a cancer centre because of an incorrect high temperature measurement. On the other hand, underestimating an individual's body temperature may allow infected patients to enter indoor public places where it is much easier for the virus to spread to other people. Accordingly, during the COVID-19 pandemic, the reliability of body temperature measurements has become fundamental. In particular, a debated issue is the reliability of remote temperature measurements, especially when these are aimed at identifying in a quick and reliable way infected subjects. Working distance, body–device angle, and light conditions and many other metrological and subjective issues significantly affect the data acquired via common contactless infrared point thermometers, making the acquisition of reliable measurements at the entrance to public places a challenging task. The main objective of this work is to sensitize the community to the typical incorrect uses of infrared point thermometers, as well as the resulting drifts in measurements of body temperature. Using several commercial contactless infrared point thermometers, we performed four different experiments to simulate common scenarios in a triage emergency room. In the first experiment, we acquired several measurements for each thermometer without measuring the working distance or angle of inclination to show that, for some instruments, the values obtained can differ by 1 °C. In the second and third experiments, we analysed the impacts of the working distance and angle of inclination of the thermometers, respectively, to prove that only a few cm/degrees can cause drifts higher than 1 °C. Finally, in the fourth experiment, we showed that the light in the environment can also cause changes in temperature up to 0.5 °C. Ultimately, in this study, we quantitatively demonstrated that the working distance, angle of inclination, and light conditions can strongly impact temperature measurements, which could invalidate the screening results. [ABSTRACT FROM AUTHOR]

Simple Summary: Available data on anti-BCMA CART-cell therapy has demonstrated efficacy and manageable toxicity in heavily pretreated R/R MM patients. Despite this, the main issues remain to be addressed. First of all, a significant proportion of patients eventually relapse. The potential strategy to prevent relapse includes sequential or combined infusion with CAR T-cells against targets other than BCMA, CAR T-cells with novel dual-targeting vector design, and BCMA expression upregulation. Another dark side of CAR T therapy is safety. Cytokine release syndrome (CRS) and neurologic toxicity are well-described adverse effects. In MM trials, most CRS events tended to be grade 1 or 2. Another critical point is the extended timeline of the manufacturing process and that only a few academic centers can perform these procedures. Recognizing these issues, the excellent response with BCMA-targeted CAR T-cell therapy makes it a treatment strategy of great promise. Despite the improvement in survival outcomes, multiple myeloma (MM) remains an incurable disease. Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) represents a new strategy for the treatment of relapsed/refractory MM (R/R). In this paper, we describe several recent advances in the field of anti-BCMA CAR T-cell therapy and MM. Currently, available data on anti-BCMA CART-cell therapy has demonstrated efficacy and manageable toxicity in heavily pretreated R/R MM patients. Despite this, the main issues remain to be addressed. First of all, a significant proportion of patients eventually relapse. The potential strategy to prevent relapse includes sequential or combined infusion with CAR T-cells against targets other than BCMA, CAR T-cells with novel dual-targeting vector design, and BCMA expression upregulation. Another dark side of CART therapy is safety. Cytokine release syndrome (CRS) andneurologic toxicity are well-described adverse effects. In the MM trials, most CRS events tended to be grade 1 or 2, with fewer patients experiencing grade 3 or higher. Another critical point is the extended timeline of the manufacturing process. Allo-CARs offers the potential for scalable manufacturing for on-demand treatment with shorter waiting days. Another issue is undoubtedly going to be access to this therapy. Currently, only a few academic centers can perform these procedures. Recognizing these issues, the excellent response with BCMA-targeted CAR T-cell therapy makes it a treatment strategy of great promise. [ABSTRACT FROM AUTHOR]

E-cadherin is a key player in gastric cancer (GC) and germline alterations of CDH1, its encoding gene, are responsible for Hereditary Diffuse Gastric Cancer (HDGC) syndrome. This study aimed at elucidating the role of genetic variants and DNA methylation of CDH1 promoter and enhancers in the regulation of gene expression. For this purpose, we analyzed genetic variants of the CDH1 gene through Next-Generation Sequencing (NGS) in a series of GC cell lines (NCI-N87, KATO-III, SNU-1, SNU-5, GK2, AKG, KKP) and the corresponding CDH1 expression levels. By bisulfite genomic sequencing, we analyzed the methylation status of CDH1 regulatory regions in 8 GC cell lines, in a series of 13 sporadic GC tissues and in a group of 20 HDGC CDH1-negative patients and 6 healthy controls. The NGS analysis on CDH1 coding and regulatory regions detected genetic alterations in 3 out of 5 GC cell lines lacking functional E-cadherin. CDH1 regulatory regions showed different methylation patterns in patients and controls, GC cell lines and GC tissues, expressing different E-cadherin levels. Our results showed that alterations in terms of genetic variants and DNA methylation patterns of both promoter and enhancers are associated with CDH1 expression levels and have a role in its regulation. [ABSTRACT FROM AUTHOR]

Genetic studies in the past decade have improved our understanding of the molecular basis of the BCR-ABL1-negative myeloproliferative neoplasm (MPN) polycythaemia vera (PV). Such breakthroughs include the discovery of the JAK2V617F driver mutation in approximately 95% of patients with PV, as well as some very rare cases of familial hereditary MPN caused by inherited germline mutations. Patients with PV often progress to fibrosis or acute myeloid leukaemia, both associated with very poor clinical outcome. Moreover, thrombosis and major bleeding are the principal causes of morbidity and mortality. As a result of increasingly available and economical next-generation sequencing technologies, mutational studies have revealed the prognostic relevance of a few somatic mutations in terms of thrombotic risk and risk of transformation, helping to improve the risk stratification of patients with PV. Finally, knowledge of the molecular basis of PV has helped identify targets for directed therapy. The constitutive activation of the tyrosine kinase JAK2 is targeted by ruxolitinib, a JAK1/JAK2 tyrosine kinase inhibitor for PV patients who are resistant or intolerant to cytoreductive treatment with hydroxyurea. Other molecular mechanisms have also been revealed, and numerous agents are in various stages of development. Here, we will provide an update of the recent published literature on how molecular testing can improve the diagnosis and prognosis of patients with PV and present recent advances that may have prognostic value in the near future. [ABSTRACT FROM AUTHOR]

In acute myeloid leukemia (AML), the restoration of p53 activity through MDM2 inhibition proved efficacy in combinatorial therapies. WIP1, encoded from PPM1D, is a negative regulator of p53. We evaluated PPM1D expression and explored the therapeutic efficacy of WIP1 inhibitor (WIP1i) GSK2830371, in association with the MDM2 inhibitor Nutlin-3a (Nut-3a) in AML cell lines and primary samples. PPM1D transcript levels were higher in young patients compared with older ones and in core-binding-factor AML compared with other cytogenetic subgroups. In contrast, its expression was reduced in NPM1-mutated (mut, irrespective of FLT3-ITD status) or TP53-mut cases compared with wild-type (wt) ones. Either Nut-3a, and moderately WIP1i, as single agent decreased cell viability of TP53-wt cells (MV-4-11, MOLM-13, OCI-AML3) in a time/dosage-dependent manner, but not of TP53-mut cells (HEL, KASUMI-1, NOMO-1). The drug combination synergistically reduced viability and induced apoptosis in TP53-wt AML cell line and primary cells, but not in TP53-mut cells. Gene expression and immunoblotting analyses showed increased p53, MDM2 and p21 levels in treated TP53-wt cells and highlighted the enrichment of MYC, PI3K-AKT-mTOR and inflammation-related signatures upon WIP1i, Nut-3a and their combination, respectively, in the MV-4-11 TP53-wt model. This study demonstrated that WIP1 is a promising therapeutic target to enhance Nut-3a efficacy in TP53-wt AML. [ABSTRACT FROM AUTHOR]

Aberrant PI3K/AKT signaling is a hallmark of acute B-lymphoblastic leukemia (B-ALL) resulting in increased tumor cell proliferation and apoptosis deficiency. While previous AKT inhibitors struggled with selectivity, MK-2206 promises meticulous pan-AKT targeting with proven anti-tumor activity. We herein, characterize the effect of MK-2206 on B-ALL cell lines and primary samples and investigate potential synergistic effects with BCL-2 inhibitor venetoclax to overcome limitations in apoptosis induction. MK-2206 incubation reduced AKT phosphorylation and influenced downstream signaling activity. Interestingly, after MK-2206 mono application tumor cell proliferation and metabolic activity were diminished significantly independently of basal AKT phosphorylation. Morphological changes but no induction of apoptosis was detected in the observed cell lines. In contrast, primary samples cultivated in a protective microenvironment showed a decrease in vital cells. Combined MK-2206 and venetoclax incubation resulted in partially synergistic anti-proliferative effects independently of application sequence in SEM and RS4;11 cell lines. Venetoclax-mediated apoptosis was not intensified by addition of MK-2206. Functional assessment of BCL-2 inhibition via Bax translocation assay revealed slightly increased pro-apoptotic signaling after combined MK-2206 and venetoclax incubation. In summary, we demonstrate that the pan-AKT inhibitor MK-2206 potently blocks B-ALL cell proliferation and for the first time characterize the synergistic effect of combined MK-2206 and venetoclax treatment in B-ALL. [ABSTRACT FROM AUTHOR]

Simple Summary: Gynecological cancers represent a group of malignancies with high incidence and mortality, despite their relative sensitivity to platinum-based chemotherapy. This review aims to illustrate the state of research in the field of immunotherapy, and in particular, deals with the development of CAR-T cell therapy, which represents a very promising treatment in the hematological field, but is still taking its first tentative steps in solid tumors. Gynecological tumors are malignancies with both high morbidity and mortality. To date, only a few chemotherapeutic agents have shown efficacy against these cancer types (only ovarian cancer responds to several agents, especially platinum-based combinations). Within this context, the discovery of immune checkpoint inhibitors has led to numerous clinical studies being carried out that have also demonstrated their activity in these cancer types. More recently, following the development of chimeric antigen receptor (CAR)-T cell therapy in hematological malignancies, this strategy was also tested in solid tumors, including gynecological cancers. In this article, we focus on the molecular basis of gynecological tumors that makes them potential candidates for immunotherapy. We also provide an overview of the main immunotherapy studies divided by tumor type and report on CAR technology and the studies currently underway in the area of gynecological malignancies. [ABSTRACT FROM AUTHOR]

Introduction: Treatment of relapsed and refractory (R/R) B acute lymphoblastic leukemia (B-ALL) represents an unmet medical need in children and adults. Adoptive T cells engineered to express a chimeric antigen receptor (CAR-T) is emerging as an effective technique for treating these patients. Areas covered: Efficacy and safety of CAR-T therapy in R/R B-ALL patients. Expert opinion: CD19 CAR-T infusion induce high CR rates in patients with poor prognosis and few therapeutic options, while real-life data demonstrate similar results with an interestingly lower incidence of grade 3/4 toxicity. Nevertheless, despite impressive in-depth responses, more than half of patients will experience a relapse. Therefore, rather than using CAR-T cell therapy as a stand-alone option, consolidation with allogeneic stem-cell transplant (Allo-SCT) after CAR-T treatment might increase long-term outcome. Moreover, CD19 is one target, but several other targets are being examined, such as CD20 and CD22 and dual-targeting CARs or combination therapy. Another issue is the time consuming process of CAR-T engineering. New platforms have shortened the CAR-T cell manufacturing process, and studies are underway to evaluate the effectiveness. Another way to mitigate waiting is the development of allogeneic "off the shelf" therapy. In conclusion, CD19-targeted CAR-modified T-cell therapy has shown unprecedented results in patients without curative options. Future work focusing on target identification, toxicity management and reducing manufacturing time will broaden the clinical applicability and bring this exciting therapy to more patients, with longer-term remissions without additional Allo-SCT. [ABSTRACT FROM AUTHOR]

Seismic hazard reduction policies usually utilize earthquake catalogues and probability evaluations of occurrence. Further geophysical and geochemical parameters could contribute to hazard reduction policies as is currently the case in some countries, such as Iceland, Taiwan, China and Russian Federation. In the past four decades, intense research activity carried out by many different institutions in Italy has allowed us to recognize the most relevant sensitive sites for detecting acceleration in crustal deformation processes by means of geofluids monitoring. All scientific papers published in the period 1976–2020 concerning tectonic-related signals in geofluids have been considered. An in-depth review of previous and present-day research activities, as well as an update of two unpublished time series recorded in Central and Southern Italy, has contributed to identifying areas where an instrumental array is still lacking and the most relevant priority areas for monitoring activities in geofluids. An atlas of all experimental sites utilized in recent decades has been obtained with the purpose of contributing to identifying the most suitable monitoring areas. [ABSTRACT FROM AUTHOR]

We synthesized five novel tryptamine derivatives characterized by the presence of an azelayl chain or of a 1,1,1-trichloroethyl group, in turn connected to another heterocyclic scaffold. The combination of tryptamin-, 1,1,1-trichloroethyl- and 2-aminopyrimidinyl- moieties produced compound 9 identified as the most active compound in hematological cancer cell lines (IC50 = 0.57–65.32 μM). Moreover, keeping constant the presence of the tryptaminic scaffold and binding it to the azelayl moiety, the compounds maintain biological activity. Compound 13 is still active against hematological cancer cell lines and shows a selective effect only on HT29 cells (IC50 = 0.006 µM) among solid tumor models. Compound 14 loses activity on all leukemic lines, while showing a high level of toxicity on all solid tumor lines tested (IC50 0.0015–0.469 µM). [ABSTRACT FROM AUTHOR]

Adult acute lymphoblastic leukemia (ALL) with BCR-ABL1 rearrangement (Philadelphia chromosome, Ph) is a hematological aggressive disease with a fatal outcome in more than 50% of cases. Tyrosine kinase inhibitors (TKIs) targeting the activity of BCR-ABL1 protein have improved the prognosis; however, relapses are frequent because of acquired somatic mutations in the BCR-ABL1 kinase domain causing resistance to first, second and third generation TKIs. Axitinib has shown in vitro and ex vivo activity in blocking ABL1; however, clinical trials exploring its efficacy in ALL are missing. Here, we presented a 77-year-old male with a diagnosis of Ph positive ALL resistant to ponatinib and carrying a rare threonine to leucine (T315L) mutation on BCR-ABL1 gene. The patient was treated with axitinib at 5 mg/twice daily as salvage therapy showing an immediate although transient benefit with an overall survival of 9.3 months. Further dose-finding and randomized clinical trials are required to assess the real efficacy of axitinib for adult Ph positive ALL resistant to third generation TKIs. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a hematological disease characterized by the proliferation and accumulation of malignant plasmacells (PCs) in the bone marrow (BM). Despite widespread use of high-dose chemotherapy in combination with autologous stem cell transplantation (ASCT) and the introduction of novel agents (immunomodulatory drugs, IMiDs, and proteasome inhibitors, PIs), the prognosis of MM patients is still poor. CD38 is a multifunctional cell-surface glycoprotein with receptor and ectoenzymatic activities. The very high and homogeneous expression of CD38 on myeloma PCs makes it an attractive target for novel therapeutic strategies. Several anti-CD38 monoclonal antibodies have been, or are being, developed for the treatment of MM, including daratumumab and isatuximab. Here we provide an in-depth look at CD38 biology, the role of CD38 in MM progression and its complex interactions with the BM microenvironment, the importance of anti-CD38 monoclonal antibodies, and the main mechanisms of antibody resistance. We then review a number of multiparametric flow cytometry techniques exploiting CD38 antigen expression on PCs to diagnose and monitor the response to treatment in MM patients. [ABSTRACT FROM AUTHOR]

Fitness sensors and health systems are paving the way toward improving the quality of medical care by exploiting the benefits of new technology. For example, the great amount of patient-generated health data available today gives new opportunities to measure life parameters in real time and create a revolution in communication for professionals and patients. In this work, we concentrated on the basic parameter typically measured by fitness applications and devices—the number of steps taken daily. In particular, the main goal of this study was to compare the accuracy and precision of smartphone applications versus those of wearable devices to give users an idea about what can be expected regarding the relative difference in measurements achieved using different system typologies. In particular, the data obtained showed a difference of approximately 30%, proving that smartphone applications provide inaccurate measurements in long-term analysis, while wearable devices are precise and accurate. Accordingly, we challenge the reliability of previous studies reporting data collected with phone-based applications, and besides discussing the current limitations, we support the use of wearable devices for mHealth. [ABSTRACT FROM AUTHOR]

This study assesses the correlations between the intensity of stress undergone by crystals and the morphological characteristics of particles and fracturing products. The effects of the fractures on the microstructure of quartz are also studied. Alpha quartz, subjected to shear stress, is quickly crushed according to a fracturing sequence, with a total fracture length that is correlated to the stress rate. The shear stress generates a sequence of macro and microstructural events, in particular localized melting phenomena, never highlighted before on quartz and the formation of different polymorphs, such as cristobalite and tridymite together with amorphous silica. [ABSTRACT FROM AUTHOR]

Simple Summary: Circulating tumor cells (CTCs) are crucial for the identification of patients with a higher risk of relapse, including those diagnosed with breast cancer (BC). The aim of this study was to explore their molecular aspects in 11 early-stage BC patients during patient management, focusing on copy number alterations (CNAs) and exploiting a single-CTC next-generation sequencing approach. CTCs showed different degrees of aberration based on access time. Moreover, CTCs, in particular those persisting even months after tumor resection, shared CNAs with matched tumor tissue. Enrichment analyses of CNAs on CTCs highlighted peculiar aberrations, especially associated with interferon (IFN)-associated terms. The study of CTCs CNAs can provide information about the molecular mechanisms involving CTC-related processes and their survival ability in occult niches, supporting the goal of exploiting their application in patients' surveillance and follow-up. Circulating tumor cells (CTCs) are a rare population of cells representing a key player in the metastatic cascade. They are recognized as a validated tool for the identification of patients with a higher risk of relapse, including those diagnosed with breast cancer (BC). However, CTCs are characterized by high levels of heterogeneity that also involve copy number alterations (CNAs), structural variations associated with gene dosage changes. In this study, single CTCs were isolated from the peripheral blood of 11 early-stage BC patients at different time points. A label-free enrichment of CTCs was performed using OncoQuick, and single CTCs were isolated using DEPArray. Libraries were prepared from single CTCs and DNA extracted from matched tumor tissues for a whole-genome low-coverage next-generation sequencing (NGS) analysis using the Ion Torrent S5 System. The analysis of the CNA burden highlighted that CTCs had different degrees of aberration based on the time point and subtype. CTCs were found even six months after surgery and shared CNAs with matched tumor tissue. Tumor-associated CNAs that were recurrent in CTCs were patient-specific, and some alterations involved regions associated with BC and survival (i.e., gains at 1q21-23 and 5p15.33). The enrichment analysis emphasized the involvement of aberrations of terms, associated in particular with interferon (IFN) signaling. Collectively, our findings reveal that these aberrations may contribute to understanding the molecular mechanisms involving CTC-related processes and their survival ability in occult niches, supporting the goal of exploiting their application in patients' surveillance and follow-up. [ABSTRACT FROM AUTHOR]

Nowadays, climate changes and increased water demand for human and agricultural purposes pose important questions for the groundwater management of alluvial aquifers facing the northern Italian Apennines. The large groundwater withdrawals, coupled with an overall worsening of the water quality, requires a detailed knowledge of the recharge mechanisms of these aquifers that can be useful for further adaptation measures. Concerning the recharge area of the alluvial aquifers (i.e., apices made up of gravelly materials), the present study investigates a dataset made up of 282 water samples for which stable isotopes oxygen-18 (18O) and deuterium (2H) are available. The latter involves precipitations (three rain gauges), surface water (five rivers) and groundwater (twenty wells) from five selected alluvial fans. The study confirms that the different isotopic signatures characterizing rain and river water from this area can be exploited for preliminary characterization of their significance on groundwater recharge. These results lay the foundations for the further use of a suite of environmental tracers (in which a primary role is that of water stable isotopes) at the event-scale (i.e., that of rainfall and/or flood) for eventually estimating the effective quota of recharge linked to precipitation and surface water. [ABSTRACT FROM AUTHOR]

Hazard reduction policies include seismic hazard maps based on probabilistic evaluations and the evaluation of geophysical parameters continuously recorded by instrumental networks. Over the past 25 centuries, a large amount of information about earthquake precursory phenomena has been recorded by scholars, scientific institutions, and civil defense agencies. In particular, hydrogeologic measurements and geochemical analyses have been performed in geofluids in search of possible and reliable earthquake precursors. Controlled experimental areas have been set up to investigate physical and chemical mechanisms originating possible preseismic precursory signals. The main test sites for such research are located in China, Iceland, Japan, the Russian Federation, Taiwan, and the USA. The present state of the art about the most relevant scientific achievements has been described. Future research trends and possible development paths have been identified and allow for possible improvements in policies oriented to seismic hazard reduction by geofluid monitoring. [ABSTRACT FROM AUTHOR]

This paper presents the results of measurements performed on α-quartz subjected to shear stress in dry conditions, to understand the relationship between the shear intensity and the resulting physical and chemical effects. If a shear stress of intensity higher than 100 MPa is applied continuously to alpha quartz crystals, they will tend to lose their crystallinity, progressively reduce their friction coefficient (Cof) and change into a low-order material, apparently amorphous under X-ray diffraction, but with a structure different from silica glass. Raman and Pair Distribution Function analyses suggested a structure like cristobalite, a silica polymorph well-known for its auxetic behavior, i.e., having a negative Poisson ratio. This elastic parameter pre-eminently controls the friction coefficient of the material and, if it is negative, the Cof lowering. As a result, the increase in low crystallinity cristobalite is sufficientto explain the lowering of the quartz friction coefficient up to values able to contribute, in principle, to the triggering processes of active faults. This allows hypothesizing a slip induction mechanism that does not include the need to have the interposition of layers of hydrated silica, as invoked by many authors, to justify the low friction coefficients that are achieved in shear stress tests on rocks abundant in quartz. [ABSTRACT FROM AUTHOR]

Male breast cancer (MBC) is a rare tumor, accounting for less than 1% of all breast cancers. In MBC, genetic predisposition plays an important role; however, only a few studies have investigated in depth the role of genes other than BRCA1 and BRCA2. We performed a Next-Generation Sequencing (NGS) analysis with a panel of 94 cancer predisposition genes on germline DNA from an Italian case series of 70 patients with MBC. Moreover, we searched for large deletions/duplications of BRCA1/2 genes through the Multiplex Ligation-dependent Probe Amplification (MLPA) technique. Through the combination of NGS and MLPA, we identified three pathogenic variants in the BRCA1 gene and six in the BRCA2 gene. Besides these alterations, we found six additional pathogenic/likely-pathogenic variants in PALB2, CHEK2, ATM, RAD51C, BAP1 and EGFR genes. From our study, BRCA1 and BRCA2 emerge as the main genes associated with MBC risk, but also other genes seem to be associated with the disease. Indeed, some of these genes have already been implicated in female breast cancer predisposition, but others are known to be involved in other types of cancer. Consequently, our results suggest that novel genes could be involved in MBC susceptibility, shedding new light on their role in cancer development. [ABSTRACT FROM AUTHOR]

Shear tests on quartz rocks and single quartz crystals have been conducted to understand the possible relationship between the intensity of detectable stress in fault areas and the energy released in the form of electromagnetic waves in the range 30 KHz-1 MHz (LF–MF). For these tests, a new type of piston-cylinder has been developed, instrumented to collect the electromagnetic signals generated by the quartz during shear stress tests and that allows energy measurements on electromagnetic emissions (EMR) to be performed. The data obtained indicate that shear-stressed quartz crystals can generate electromagnetic emissions in the LF–MF range. These emissions represent a tiny fraction of the total energy dissipated in the fracturing process. The spectrum of radio emissions consists of continuous radiation and overlapping peaks. For the first time, a characteristic migration of peak frequencies was observed, proportional to the evolution of the fracturing process. In particular, the continuous recording of the radio emission spectra shows a migration of the peaks toward higher frequencies, as stress continues over time and smaller and larger fractures form. This migration could be used to distinguish possible natural signals emitted by quartz in tectonically active environments from possible signals of other geophysical and possibly anthropogenic origin. [ABSTRACT FROM AUTHOR]

Bone marrow aspiration and biopsy (BMAB) is a painful procedure, and the routinely used local infiltration anesthesia (LIA) with lidocaine is unable to provide pain relief during the most uncomfortable phases. The primary endpoint of the present randomized, patient-blinded trial was to evaluate the efficacy of an opioid and benzodiazepine combination plus LIA (sedoanalgesia) in patients undergoing BMAB for hematological malignancies. The secondary endpoint was the safety of the procedure in an outpatient setting. Ancillary assessments were anticipatory anxiety related to pain recall in the event of re-biopsy, and adequacy of bone tissue harvested. Patients were randomly assigned to one of 2 arms to receive either sedoanalgesic placebo plus LIA (standard group) or oral fentanyl citrate 200 μg plus oral midazolam 5 mg plus LIA (combo group) during BMAB. Pre-procedural anxiety and procedural pain were assessed according to the Numerical Rating Scale (NRS: 0–10), dividing the time of the procedure into five intervals (T0, T1, T2a, T2b and T3) and evaluating the degree of discomfort at each time (T) in both groups. One hundred and sixteen patients were eligible for the study. At T2b (time of biopsy) and T3 (time after biopsy), a significantly lower perception of pain was registered in the combo group. Moreover, there were no significant sedoanalgesia-related side-effects. Finally, histological specimens were higher in quality in the combo group. Sedoanalgesia was highly effective in reducing pain during biopsy, diminished anticipatory anxiety in patients undergoing re-biopsy and led to fewer non-diagnostic specimens being harvested. [ABSTRACT FROM AUTHOR]

Introduction: Screening for synthetic lethality markers has demonstrated that the inhibition of the cell cycle checkpoint kinases WEE1 together with CHK1 drastically affects stability of the cell cycle and induces cell death in rapidly proliferating cells. Exploiting this finding for a possible therapeutic approach has showed efficacy in various solid and hematologic tumors, though not specifically tested in acute lymphoblastic leukemia. Methods: The efficacy of the combination between WEE1 and CHK1 inhibitors in B and T cell precursor acute lymphoblastic leukemia (B/T-ALL) was evaluated in vitro and ex vivo studies. The efficacy of the therapeutic strategy was tested in terms of cytotoxicity, induction of apoptosis, and changes in cell cycle profile and protein expression using B/T-ALL cell lines. In addition, the efficacy of the drug combination was studied in primary B-ALL blasts using clonogenic assays. Results: This study reports, for the first time, the efficacy of the concomitant inhibition of CHK1/CHK2 and WEE1 in ALL cell lines and primary leukemic B-ALL cells using two selective inhibitors: PF-0047736 (CHK1/CHK2 inhibitor) and AZD-1775 (WEE1 inhibitor). We showed strong synergism in the reduction of cell viability, proliferation and induction of apoptosis. The efficacy of the combination was related to the induction of early S-phase arrest and to the induction of DNA damage, ultimately triggering cell death. We reported evidence that the efficacy of the combination treatment is independent from the activation of the p53-p21 pathway. Moreover, gene expression analysis on B-ALL primary samples showed that Chek1 and Wee1 are significantly co-expressed in samples at diagnosis (Pearson r = 0.5770, p = 0.0001) and relapse (Pearson r= 0.8919; p = 0.0001). Finally, the efficacy of the combination was confirmed by the reduction in clonogenic survival of primary leukemic B-ALL cells. Conclusion: Our findings suggest that the combination of CHK1 and WEE1 inhibitors may be a promising therapeutic strategy to be tested in clinical trials for adult ALL. [ABSTRACT FROM AUTHOR]

The main gene involved in gastric cancer (GC) predisposition is CDH1, the pathogenic variants of which are associated with diffuse-type gastric cancer (DGC) and lobular breast cancer (LBC). CDH1 only explains a fraction (10–50%) of patients suspected of DGC/LBC genetic predisposition. To identify novel susceptibility genes, thus improving the management of families at risk, we performed a multigene panel testing on selected patients. We searched for germline pathogenic variants in 94 cancer-related genes in 96 GC or LBC Italian patients with early-onset and/or family history of GC. We found CDH1 pathogenic variants in 10.4% of patients. In 11.5% of cases, we identified loss-of-function variants in BRCA1, BRCA2, PALB2, and ATM breast/ovarian cancer susceptibility genes, as well as in MSH2, PMS2, BMPR1A, PRF1, and BLM genes. In 78.1% of patients, we did not find any variants with clear-cut clinical significance; however, 37.3% of these cases harbored rare missense variants predicted to be damaging by bioinformatics tools. Multigene panel testing decreased the number of patients that would have otherwise remained genetically unexplained. Besides CDH1, our results demonstrated that GC pathogenic variants are distributed across a number of susceptibility genes and reinforced the emerging link between gastric and breast cancer predisposition. [ABSTRACT FROM AUTHOR]

This study discusses a dataset of water stable isotopes from precipitation (4 rain gauges) and surficial water (9 rivers) from the northern Italian Apennines, an area in which clay-rich bedrocks widely outcrop and the runoff response to precipitation events is very rapid. The dataset has been compiled starting from existing data that had previously been published in the literature and consists of monthly values of stable isotopes oxygen-18 (18O) and deuterium (2H) lasting over the period from January 2003 to December 2006 (precipitation) and from January 2006 to December 2007 (surficial water). For this period, mean residence times estimated by means of a sine-wave fitting technique make evident the significant differences over time spent by water molecules within the 9 catchments. Moreover, isotopic compositions of rivers deviated from those of precipitations revealing the influence of some catchment characteristics in differentiating the isotopic composition in rivers. Further correlations between mean residence times of river water and selected catchment characteristics reveal the role of orography and bedrocks in delaying the water molecules during their flow-paths. In addition, time series and cross–correlation analyses indicate a certain control by the main watershed divide on the isotopic composition of river waters, which is reflected in a progressive isotopic variation with longitude. The study shows that, despite using a short-time dataset (2-years for surficial water) of sparse stable isotopes can provide remarkable indications for depicting hydrological processes in large catchments made up of clay-rich bedrocks. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a complex hematological disease characterized by genetic and clinical heterogeneity. Recent advances in the understanding of AML pathogenesis have paved the way for the development of new agents targeting specific molecules or mechanisms that contribute to finally move beyond the current standard of care, which is "3 + 7" regimen. In particular, new therapeutic options such as targeted therapies (midostaurin and enasidenib), monoclonal antibodies (gemtuzumab ozogamicin), and a novel liposomal formulation of cytarabine and daunorubicin (CPX-351) have been recently approved, and will be soon available for the treatment of adult patients with AML. In this review, we will present and describe these recently approved drugs as well as selected novel agents against AML that are currently under investigation, and show the most promising results as monotherapy or in combination with chemotherapy. The selection of these emerging treatments is based on the authors' opinion. [ABSTRACT FROM AUTHOR]