Targeting glycosylated antigens on cancer cells using siglec-7/9-based CAR T-cells

Chimeric antigen receptor (CAR) T-cells treatment demonstrate the increasing and powerful potential of immunotherapeutic strategies, as seen mainly for hematological malignancies. Still, efficient CAR-T cell approaches for the treatment of a broader spectrum of tumors are needed. It has been shown that cancer cells can implement strategies to evade immune response that include the expression of inhibitory ligands, such as hypersialylated proteins (sialoglycans) on their surface. These may be recognized by sialic acid-binding immunoglobulin-type lectins (siglecs) which are surface receptors found primarily on immune cells. In this regard, siglec-7 and -9 are found on immune cells, such as natural killer cells, T-cells, and dendritic cells and they can promote immune suppression when binding to sialic acids expressed on target cells. In the present study, we hypothesized that it is possible to use genetically engineered T-cells expressing siglec-based CARs, enabling them to recognize and eliminate tumor cells, in a non-histocompatibility complex molecule restricted way. Thus, we genetically modified human T-cells with different chimeric receptors based on the exodomain of human siglec-7 and -9 molecules and selected optimal receptors. We then assessed their antitumor activity in vitro demonstrating the recognition of cell lines from different histologies. These results were confirmed in a tumor xenograft model exemplifying the potential of the present approach. Overall, this study demonstrates the benefit of targeting cancer-associated glycosylation patterns using CAR based on native immune receptors and expressed in human primary T-cells.     

Adult-Onset Ligneous Conjunctivitis with Detection of a Novel Plasminogen Gene Mutation and Anti-Plasminogen IgA Antibody: A Clinicopathologic Study and Review of Literature

Purpose: To report a novel plasminogen gene mutation and detection of anti-plasminogen antibodies in a patient with ligneous conjunctivitis successfully treated with 60% fresh frozen plasma (FFP). Methods: Retrospective data collected on a 45-year-old Caucasian female presenting with unilateral chronic membranous lesions. Results: Laboratory investigation demonstrated decreased plasminogen antigen level, plasminogen activity, and rate of plasminogen activation by u-PA or t-PA, and elevated plasminogen activator inhibitor-1. Anti-plasminogen IgG and IgA antibodies were detected. DNA analysis revealed a novel Asp432Asn heterozygous missense mutation in the plasminogen gene (exon 11). The patient was treated with topical 60% FFP, achieved complete remission after four months, and remained membrane-free for over five years of follow-up. Conclusions: A novel plasminogen gene mutation, deficiency of plasminogen antigen and activity, and anti-plasminogen IgG and IgA antibodies were identified in a patient with adult-onset ligneous conjunctivitis. Sixty percent FFP maintained this patient disease-free for over five years.     

Chemotherapy reaction induced by ixabepilone,a microtubule stabilizing agent,mimicking extramammary Paget's disease in a patient with breast carcinoma

The histopathologic characteristics of reactions caused by the many novel anticancer agents are under‐recognized. We report a case of a 67‐year‐old female with locally advanced metastatic breast cancer, who initially presented with an extensive reticulated erythematous patch on the trunk caused by intravascular metastases confirmed by a skin biopsy. Owing to disease progression, she was started on ixabepilone, a mitotic inhibitor. While receiving ixabepilone, another skin biopsy was obtained and initially interpreted as extramammary Paget's disease. However, the biopsy showed metaphase arrest of numerous keratinocytes in the basilar and suprabasilar epidermis. Atypical epithelial cells were only present in the intravascular spaces similar to the initial biopsy. Given the temporal association between the initiation of ixabepilone therapy and the epidermal mitotic arrest, a diagnosis of chemotherapy reaction to ixabepilone was rendered. Ixabepilone is an analog of epothilone, a microtubule stabilizer causing mitotic arrest of the cell cycle approved for the treatment of metastatic and locally advanced treatment‐resistant breast cancer. The demonstration of epidermal mitotic arrest caused by ixabepilone is without precedent. The case emphasizes the importance of considering a chemotherapy reaction in the histologic differential diagnosis of epidermal mitotic arrest in a cancer patient receiving chemotherapy.     

Nanocrystalline TiO2 doped by small amount of pre-synthesized colloidal CdS nanoparticles for photocatalytic degradation of 1,2,4-trichlorobenzene

The chemical stability and hydrophobic nature of chloroarenes make them a persistent environmental hazard. Modeling of 1,2,4-trichlorobenzene (1,2,4-TCB) degradation in alcohol-water solution under UV irradiation was carried out with the aim of probing how the 1,2,4-TCB might behave in the environment. The photocatalytic activity of both bare TiO₂ and TiO₂ doped by colloidal CdS nanoparticles synthesized by the sol-gel method has been investigated in the processes of 1,2,4-TCB photodegradation in the aqueous protic solvent. Non-sensitized TiO₂ cannot be regarded as catalyst for the 1,2,4-TCB photodecomposition. On the contrary, the CdS/TiO₂ composite accelerated the 1,2,4-TCB photodegradation process. The concentration of CdS/TiO₂ was shown to effect on the 1,2,4-TCB photolysis mechanisms, which resulted in the quantitative ratios of the 1,2,4-TCB photolysis products.     

Impact of estrogen receptor α on the tamoxifen response and prognosis in luminal-A-like and luminal-B-like breast cancer

Clinical and Experimental Medicine - The luminal-A-like and luminal-B-like breast cancer groups have distinct biological features that lead to differences in the treatment response and clinical...     

Attitudes of incoming dental students toward tobacco cessation promotion in the dental setting

Dentists can play an important role in helping patients quit using tobacco. The aim of this study was to investigate incoming dental students' attitudes toward tobacco cessation promotion in the dental setting. Such attitudes can impact students' receptivity to training and subsequent involvement in tobacco cessation promotion. A twenty-six-item written survey was administered to freshman students at a midwestern dental school during orientation weeks 2002 and 2003. Questions focused on students' attitudes toward the dental professional's responsibilities and scope of practice in promotion of tobacco cessation. Response rate was 99 percent (139/140). Respondents were 75 percent male, 25 percent female. Mean age was 24.8 +/- 3.0 years. Ninety-nine percent agreed that it is the dental professional's responsibility to educate patients about the oral health risks of tobacco use. Eighty-five percent agreed that it is within the scope of dental practice to advise patients to quit using tobacco, but fewer agreed that it is within the scope of practice to discuss specific strategies for stopping (70 percent) or to prescribe nicotine gum (45 percent). Sixty-nine percent agreed that tobacco cessation counseling in the dental office could impact patients' quitting. Seventy-one percent anticipated that patient resistance could be a barrier to tobacco cessation promotion. Nearly one quarter (23 percent) were only slightly or not interested in receiving tobacco cessation training. Attitudes of incoming dental students appear to be positive regarding the dental professional's responsibility to educate patients about the risks of tobacco use. However, some students may have reservations about the extent to which tobacco cessation services fit within the scope of dental practice, the efficacy of such services, and patient receptiveness. These reservations should be addressed if dental school curricula in tobacco cessation are to be effective.     

Region‐specific impairments in striatal synaptic transmission and impaired instrumental learning in a mouse model of Angelman syndrome

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation and impaired speech. Because patients with this disorder often exhibit motor tremor and stereotypical behaviors, which are associated with basal ganglia pathology, we hypothesized that AS is accompanied by abnormal functioning of the striatum, the input nucleus of the basal ganglia. Using mutant mice with maternal deficiency of AS E6‐AP ubiquitin protein ligase Ube3a (Ube3a^m?/p+), we assessed the effects of Ube3a deficiency on instrumental conditioning, a striatum‐dependent task. We used whole‐cell patch‐clamp recording to measure glutamatergic transmission in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS). Ube3a^m?/p+ mice were severely impaired in initial acquisition of lever pressing. Whereas the lever pressing of wild‐type controls was reduced by outcome devaluation and instrumental contingency reversal, the performance of Ube3a^m?/p+ mice were more habitual, impervious to changes in outcome value and action–outcome contingency. In the DMS, but not the DLS, Ube3a^m?/p+ mice showed reduced amplitude and frequency of miniature excitatory postsynaptic currents. These results show for the first time a selective deficit in instrumental conditioning in the Ube3a deficient mouse model, and suggest a specific impairment in glutmatergic transmission in the associative corticostriatal circuit in AS.     

Clinical evaluation of hyponatremia and hypovolemia in critically ill adult neurologic patients: contribution of the use of cumulative balance of sodium

Purpose

Knowledge of the cumulative balance of sodium (CBS) is important for the diagnosis of salt disorders and water homeostasis and has the potential to predict hypovolemic status in acute neurological patients. However, an extensive application of the use of CBS is still lacking in the intensive care setting, where salt and water homeostasis represents a priority.

Methods

Records of consecutive series of acute neurological patients admitted to a neurointensive care unit over a 6-month period were retrospectively reviewed. CBS was calculated at the admission to the Emergency Department. Discrimination between cerebral salt-wasting syndrome (CSWS) and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) was performed on the basis of the classical criteria. Additionally, we used the findings of a negative CBS exceeding 2 mEq/kg for the diagnosis of CSWS. Two independent clinicians who were blinded to the CBS results performed diagnosis of the causes of hyponatremia and estimated the daily volemic status of the patients on the basis of clinical parameters. Logistic regression analysis was used to determine the independent prognostic factors of hypovolemia.

Results

Thirty-five patients were studied for a total of 418 days. Four patients (11.4 %) fitted the criteria of CSWS and three patients (8.5 %) had SIADH. The unavailability of the CBS led to a wrong diagnosis in three of the eight hyponatremic patients (37.5 %). The risk of developing hypovolemia in patients with negative CBS was 7.1 times higher (CI 3.86–13.06; p < 0.001). Multivariate analysis revealed that negative cumulative fluid balance, negative CBS >2 mEq/kg, and CVP ≤5 cmH₂O were independent prognostic factors for hypovolemia.

Conclusions

CBS is likely to be a useful parameter in the diagnosis of CSWS and a surrogate parameter for estimating hypovolemia in acute neurological patients.