Rituximab plus chemotherapy provides no clinical benefit in a peripheral T-cell lymphoma not otherwise specified with aberrant expression of CD20 and CD79a. A case report and review of the literature

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is the most common entity of mature T-cell neoplasms. PTCL-NOS generally has an aggressive behavior and is often refractory to standard therapy. Only a few cases of PTCL with aberrant expression of B-cell antigens have been reported so far. This phenotypic aberrancy may lead to misdiagnosis as B-cell non- Hodgkin lymphomas and eventual inappropriate patient management, whereas in an accurately diagnosed PTCL, the presence of CD20 may appear as an appealing therapeutic target. In this setting, response to anti-CD20 monoclonal antibody in combination with chemotherapy has been poorly explored. We describe the case of a 59-year-old male diagnosed by a pathological and molecular approach as PTCL-NOS with aberrant co-expression of the B-cell antigens CD20 and CD79a, which proved non-responsive to the addition of rituximab to standard polychemotherapy. This case highlights that the presence of CD20 in PTCL may be misleading in the diagnosis and also act as a lure for the clinician to adopt a rituximab-based treatment, the effectiveness of which is undefined as the molecular mechanisms underlying B-cell marker expression in PTCL

Asbestos Fibers Enhance the TMEM16A Channel Activity in Xenopus Oocytes

Background: The interaction of asbestos fibers with target cell membranes is still poorly investigated. Here, we detected and characterized an enhancement of chloride conductance in Xenopus oocyte cell membranes induced by exposure to crocidolite (Croc) asbestos fibers. Methods: A two-microelectrode voltage clamp technique was used to test the effect of Croc fiber suspensions on outward chloride currents evoked by step membrane depolarization. Calcium imaging experiments were also performed to investigate the variation of 'resting' oocyte [Ca2+]i following asbestos exposure. Results: The increase in chloride current after asbestos treatment, was sensitive to [Ca2+]e, and to specific blockers of TMEM16A Ca2+-activated chloride channels, MONNA and Ani9. Furthermore, asbestos treatment elevated the 'resting' [Ca2+]i likelihood by increasing the cell membrane permeability to Ca2 in favor of a tonic activation of TMEME16A channels. Western blot analysis confirmed that TMEME16A protein was endogenously present in the oocyte cell membrane and absorbed by Croc. Conclusion: the TMEM16A channels endogenously expressed by Xenopus oocytes are targets for asbestos fibers and represent a powerful tool for asbestos-membrane interaction studies. Interestingly, TMEM16A channels are highly expressed in many types of tumors, including some asbestos-related cancers, suggesting them, for the first time, as a possible early target of crocidolite-mediated tumorigenic effects on target cell membranes

Mechanism of action and therapeutic use of bempedoic acid in atherosclerosis and metabolic syndrome

Bempedoic acid is a new cholesterol-lowering drug, which has recently received US FDA and EMA approval. This drug targets lipid and glucose metabolism as well as inflammation via downregulation of ATP-citrate lyase and upregulation of AMP-activated protein kinase (AMPK). The primary effect is the reduction of cholesterol synthesis in the liver and its administration is generally not associated to unwanted muscle effects. Suppression of hepatic fatty acid synthesis leads to decreased triglycerides and, possibly, improved non-alcoholic fatty liver disease. Bempedoic acid may decrease gluconeogenesis leading to improved insulin sensitivity, glucose metabolism, and metabolic syndrome. The anti-inflammatory action of bempedoic acid is mainly achieved via activation of AMPK pathway in the immune cells, leading to decreased plasma levels of C-reactive protein. Effects of bempedoic acid on atherosclerotic cardiovascular disease, type 2 diabetes and chronic liver disease have been assessed in randomized clinical trials but require further confirmation. Safety clinical trials in phase III indicate that bempedoic acid administration is generally well-tolerated in combination with statins, ezetimibe, or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to achieve low-density lipoprotein cholesterol targets. The aim of this narrative review on bempedoic acid is to explore the underlying mechanisms of action and potential clinical targets, present existing evidence from clinical trials, and describe practical management of patients

Early lean mass sparing effect of high-protein diet with excess leucine during long-term bed rest in women

Muscle inactivity leads to muscle atrophy. Leucine is known to inhibit protein degradation and to promote protein synthesis in skeletal muscle. We tested the ability of a high-protein diet enriched with branched-chain amino acids (BCAAs) to prevent muscle atrophy during long-term bed rest (BR). We determined body composition (using dual energy x-ray absorptiometry) at baseline and every 2-weeks during 60 days of BR in 16 healthy young women. Nitrogen (N) balance was assessed daily as the difference between N intake and N urinary excretion. The subjects were randomized into two groups: one received a conventional diet (1.1 ± 0.03 g protein/kg, 4.9 ± 0.3 g leucine per day) and the other a high protein, BCAA-enriched regimen (1.6 ± 0.03 g protein-amino acid/kg, 11.4 ± 0.6 g leucine per day). There were significant BR and BR × diet interaction effects on changes in lean body mass (LBM) and N balance throughout the experimental period (repeated measures ANCOVA). During the first 15 days of BR, lean mass decreased by 4.1 ± 0.9 and 2.4 ± 2.1% (p < 0.05) in the conventional and high protein-BCAA diet groups, respectively, while at the end of the 60-day BR, LBM decreased similarly in the two groups by 7.4 ± 0.7 and 6.8 ± 2.4%. During the first 15 days of BR, mean N balance was 2.5 times greater (p < 0.05) in subjects on the high protein-BCAA diet than in those on the conventional diet, while we did not find significant differences during the following time intervals. In conclusion, during 60 days of BR in females, a high protein-BCAA diet was associated with an early protein-LBM sparing effect, which ceased in the medium and long term

Homologous Recombination Deficiency in Ovarian Cancer: from the Biological Rationale to Current Diagnostic Approaches

The inability to efficiently repair DNA double-strand breaks using the homologous recombination repair pathway is defined as homologous recombination deficiency (HRD). This molecular phenotype represents a positive predictive biomarker for the clinical use of poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors and platinum-based chemotherapy in ovarian cancers. However, HRD is a complex genomic signature, and different methods of analysis have been developed to introduce HRD testing in the clinical setting. This review describes the technical aspects and challenges related to HRD testing in ovarian cancer and outlines the potential pitfalls and challenges that can be encountered in HRD diagnostics

Platelet Activation in Ovarian Cancer Ascites: Assessment of GPIIb/IIIa and PF4 in Small Extracellular Vesicles by Nano-Flow Cytometry Analysis

In ovarian cancer, ascites represent the microenvironment in which the platelets extravasate to play their role in the disease progression. We aimed to develop an assay to measure ascites’ platelet activation. We enriched small extracellular vesicles (EVs) (40–200 nm) from ascites of high-grade epithelial ovarian cancer patients (n = 12) using precipitation with polyethylene glycol, and we conducted single-particle phenotyping analysis by nano-flow cytometry after labelling and ultra-centrifugation. Atomic force microscopy single-particle nanomechanical analysis showed heterogeneous distributions in the size of the precipitated particles and their mechanical stiffness. Samples were fluorescently labelled with antibodies specific to the platelet markers GPIIb/IIIa and PF4, showing 2.6 to 18.16% of all particles stained positive for the biomarkers and, simultaneously, the EV membrane labelling. Single-particle phenotyping analysis allowed us to quantify the total number of non-EV particles, the number of small-EVs and the number of platelet-derived small-EVs, providing a platelet activation assessment independent of the ascites volume. The percentage of platelet-derived small-EVs was positively correlated with platelet distribution width to platelet count in sera (PDW/PLT). Overall, we presented a high-throughput method that can be helpful in future studies to determine the correlation between the extent of platelet activation in ascites and disease status

SARS-CoV-2 modulates virus receptor expression in placenta and can induce trophoblast fusion, inflammation and endothelial permeability

SARS-CoV-2 is a devastating virus that induces a range of immunopathological mechanisms including cytokine storm, apoptosis, inflammation and complement and coagulation pathway hyperactivation. However, how the infection impacts pregnant mothers is still being worked out due to evidence of vertical transmission of the SARS-CoV-2, and higher incidence of preeclampsia, preterm birth, caesarian section, and fetal mortality. In this study, we assessed the levels of the three main receptors of SARS-CoV-2 (ACE2, TMPRSS2 and CD147) in placentae derived from SARS-CoV-2 positive and negative mothers. Moreover, we measured the effects of Spike protein on placental cell lines, in addition to their susceptibility to infection. SARS-CoV-2 negative placentae showed elevated levels of CD147 and considerably low amount of TMPRSS2, making them non-permissive to infection. SARS-CoV-2 presence upregulated TMPRSS2 expression in syncytiotrophoblast and cytotrophoblast cells, thereby rendering them amenable to infection. The non-permissiveness of placental cells can be due to their less fusogenicity due to infection. We also found that Spike protein was capable of inducing proinflammatory cytokine production, syncytiotrophoblast apoptosis and increased vascular permeability. These events can elicit pre-eclampsia-like syndrome that marks a high percentage of pregnancies when mothers areinfected with SARS-CoV-2. Our study raises important points relevant to SARSCoV- 2 mediated adverse pregnancy outcomes

The Inflammatory Feed-Forward Loop Triggered by the Complement Component C3 as a Potential Target in Endometriosis

The complement system is a major component of humoral innate immunity, acting as a first line of defense against microbes via opsonization and lysis of pathogens. However, novel roles of the complement system in inflammatory and immunological processes, including in cancer, are emerging. Endometriosis (EM), a benign disease characterized by ectopic endometrial implants, shows certain unique features of cancer, such as the capacity to invade surrounding tissues, and in severe cases, metastatic properties. A defective immune surveillance against autologous tissue deposited in the peritoneal cavity allows immune escape for endometriotic lesions. There is evidence that the glandular epithelial cells found in endometriotic implants produce and secrete the complement component C3. Here, we show, using immunofluorescence and RT-qPCR, the presence of locally synthesized C3 in the ectopic endometriotic tissue, but not in the eutopic tissue. We generated a murine model of EM via injection of minced uterine tissue from a donor mouse into the peritoneum of recipient mice. The wild type mice showed greater amount of cyst formation in the peritoneum compared to C3 knock-out mice. Peritoneal washings from the wild type mice with EM showed more degranulated mast cells compared to C3 knock-out mice, consistent with higher C3a levels in the peritoneal fluid of EM patients. We provide evidence that C3a participates in an auto-amplifying loop leading to mast cell infiltration and activation, which is pathogenic in EM. Thus, C3 can be considered a marker of EM and its local synthesis can promote the engraftment of the endometriotic cysts

A Spatially Resolved Dark- versus Light-Zone Microenvironment Signature Subdivides Germinal Center-Related Aggressive B Cell Lymphomas

We applied digital spatial profiling for 87 immune and stromal genes to lymph node germinal center (GC) dark- and light-zone (DZ/LZ) regions of interest to obtain a differential signature of these two distinct microenvironments. The spatially resolved 53-genes signature, comprising key genes of the DZ mutational machinery and LZ immune and mesenchymal milieu, was applied to the transcriptomes of 543 GC-related diffuse large B cell lymphomas and double-hit (DH) lymphomas. According to the DZ/LZ signature, the GC-related lymphomas were subclassified into two clusters. The subgroups differed in the distribution of DH cases and survival, with most DH displaying a distinct DZ-like profile. The clustering analysis was also performed using a 25-genes signature composed of genes positively enriched in the non-B, stromal sub-compartments, for the first time achieving DZ/LZ discrimination based on stromal/immune features. The report offers new insight into the GC microenvironment, hinting at a DZ microenvironment of origin in DH lymphomas

Integrative molecular analysis of combined small-cell lung carcinomas identifies major subtypes with different therapeutic opportunities

Background: Combined small-cell lung cancer (C-SCLC) is composed of SCLC admixed with a non-small-cell cancer component. They currently receive the same treatment as SCLC. The recent evidence that SCLC may belong to either of two lineages, neuroendocrine (NE) or non-NE, with different vulnerability to specific cell death pathways such as ferroptosis, opens new therapeutic opportunities also for C-SCLC. Materials and methods: Thirteen C-SCLCs, including five with adenocarcinoma (CoADC), five with large-cell neuroendocrine carcinoma (CoLCNEC) and three with squamous cell carcinoma (CoSQC) components, were assessed for alterations in 409 genes and transcriptomic profiling of 20&nbsp;815 genes. Results: All 13 cases harbored TP53 (12 cases) and/or RB1 (7 cases) inactivation, which was accompanied by mutated KRAS in 4 and PTEN in 3 cases. Potentially targetable alterations included two KRAS G12C, two PIK3CA and one EGFR mutations. Comparison of C-SCLC transcriptomes with those of 57 pure histology lung cancers (17 ADCs, 20 SQCs, 11 LCNECs, 9 SCLCs) showed that CoLCNEC and CoADC constituted a standalone group of NE tumors, while CoSQC transcriptional setup was overlapping that of pure SQC. Using transcriptional signatures of NE versus non-NE SCLC as classifier, CoLCNEC was clearly NE while CoSQC was strongly non-NE and CoADC exhibited a heterogeneous phenotype. Similarly, using ferroptosis sensitivity/resistance markers, CoSQC was classified as sensitive (as expected for non-NE), CoLCNEC as resistant (as expected for NE) and CoADC showed a heterogeneous pattern. Conclusions: These data support routine molecular profiling of C-SCLC to search for targetable driver alterations and to precisely classify them according to therapeutically relevant subgroups (e.g. NE versus non-NE)