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Bacterial collagenolytic proteases have drawn increasing attention due to their essential role in the global nitrogen cycling and their virulent role in some diseases. The inhibition of these enzymes is attractive, as it does not attack the pathogen directly but rather blocks the colonization and infiltration of the host by the clostridia. Optically active non-protein α-amino acids have been screened for their ability to inhibit collagenase of Clostridium histolyticum. Both structure-based drug design approach (modeling) and that of determining enzyme activity in the presence of amino acids have been used to identify low molecular weight inhibitors of collagenase. The compounds able to inhibit collagenase activity have been revealed and IC50 values have been estimated.

Purpose There is currently no curative treatment for patients diagnosed with triple-negative breast cancer brain metastases (TNBC-BM). CAR T cells hold potential for curative treatment given they retain the cytolytic activity of a T cell combined with the specificity of an antibody. In this proposal we evaluated the potential of EGFR re-directed CAR T cells as a therapeutic treatment against TNBC cells in vitro and in vivo . Methods We leveraged a TNBC-BM tissue microarray and a large panel of TNBC cell lines and identified elevated epidermal growth factor receptor (EGFR) expression. Next, we designed a second-generation antiEGFR CAR T construct incorporating a clinically relevant mAb806 tumor specific single-chain variable fragment (scFv) and intracellular 4-1BB costimulatory domain and CD3ζ using a lentivirus system and evaluated in vitro and in vivo anti-tumor activity. Results We demonstrate EGFR is enriched in TNBC-BM patient tissue after neurosurgical resection, with six of 13 brain metastases demonstrating both membranous and cytoplasmic EGFR. Eleven of 13 TNBC cell lines have EGFR surface expression ≥85% by flow cytometry. EGFR806 CAR T treated mice effectively eradicated TNBC-BM and enhanced mouse survival (log rank pConclusion Our results demonstrates anti-tumor activity of EGFR CAR T cells against TNBC cells in vitro and in vivo . Given EGFR CAR T cells are currently undergoing clinical trials in primary brain tumor patients without obvious toxicity, our results are immediately actionable against the TNBC-BM patient population.

There is currently no curative treatment for patients diagnosed with triple-negative breast cancer brain metastases (TNBC-BM). CAR T cells hold potential for curative treatment given they retain the cytolytic activity of a T cell combined with the specificity of an antibody. In this proposal we evaluated the potential of EGFR re-directed CAR T cells as a therapeutic treatment against TNBC cells in vitro and in vivo.We leveraged a TNBC-BM tissue microarray and a large panel of TNBC cell lines and identified elevated epidermal growth factor receptor (EGFR) expression. Next, we designed a second-generation anti-EGFR CAR T construct incorporating a clinically relevant mAb806 tumor specific single-chain variable fragment (scFv) and intracellular 4-1BB costimulatory domain and CD3ζ using a lentivirus system and evaluated in vitro and in vivo anti-tumor activity.We demonstrate EGFR is enriched in TNBC-BM patient tissue after neurosurgical resection, with six of 13 brain metastases demonstrating both membranous and cytoplasmic EGFR. Eleven of 13 TNBC cell lines have EGFR surface expression ≥ 85% by flow cytometry. EGFR806 CAR T treated mice effectively eradicated TNBC-BM and enhanced mouse survival (log rank p 0.004).Our results demonstrates anti-tumor activity of EGFR806 CAR T cells against TNBC cells in vitro and in vivo. Given EGFR806 CAR T cells are currently undergoing clinical trials in primary brain tumor patients without obvious toxicity, our results are immediately actionable against the TNBC-BM patient population.

BACKGROUND Intracranial tuberculomas are rare entities commonly seen only in low- to middle-income countries where tuberculosis remains endemic. Furthermore, following adequate treatment, the development of intracranial spread is uncommon in the absence of immunosuppression. OBSERVATIONS A 22-year-old man with no history of immunosuppression presented with new-onset seizures in the setting of miliary tuberculosis status post 9 months of antitubercular therapy. Following a 2-month period of remission, he presented with new-onset tonic-clonic seizures. Magnetic resonance imaging demonstrated interval development of a mass concerning for an intracranial tuberculoma. After resection, pathological analysis of the mass revealed caseating granulomas within the multinodular lesion, consistent with intracranial tuberculoma. The patient was discharged after the reinitiation of antitubercular medications along with a steroid taper. LESSONS To the best of the authors’ knowledge, this case represents the first instance of intracranial tuberculoma occurring after the initial resolution of a systemic tuberculosis infection. The importance of retaining a high level of suspicion when evaluating these patients for seizure etiology is crucial because symptoms are rapidly responsive to resection of intracranial tuberculoma masses. Furthermore, it is imperative for surgeons to recognize the isolation steps necessary when managing these patients within the operating theater and inpatient settings.

Psychological sexuality features in people living with HIV with and without substance use as a determinant of the HIV epidemic growth were explored. The study involved 136 respondents (2 groups of 50 people with different infection routes: blood-borne infection route and heterosexual transmission; 36 individuals without HIV). The following research methods were used: a specially developed clinical map, an original authors questionnaire Infection risk and the disease situation (allows to register the main characteristics of the life situation of the disease), the incomplete sentences test of Sachs Levy, Freiburgh Personality Inventory, I-structure Ammon test. Data processing included the Fisher criterion (Fisher angular transformation), ANOVA, content analysis. Significant negative effects in sexual sphere related to gender and the presence of HIV were revealed in the study. It has been established that people living with HIV with and without substance use differ in the frequency of concealment of HIV status and the presence of destructive type of sexuality. It has been established that people living with HIV and healthy respondents differ in the frequency of unrealistic way of thinking regarding opposite sex. A frequent occurrence of negatively colored attitude towards opposite sex and positively colored attitude towards sexual relations was noted in all groups. The results of the study determine the need for timely preventive measures in all population groups and psychocorrectional measures among people living with HIV, which will allow to prevent an increase in the number of children and adolescents with HIV. Psychological sexuality features in people living with HIV in the Russian sample were studied for the first time. The results are partially confirmed in foreign literature.

Primitive round- or spindle-cell EWSR1-negative undifferentiated sarcomas harboring CIC-DUX4 gene fusion are the most common form of Ewing-like sarcomas. These tumors primarily occur in peripheral soft tissues, but examples have been described within viscera and the brain. As far as we are aware, CIC-DUX4 positive primary epidural spinal sarcoma has not been reported. Herein, we describe a T5–T6 epidural tumor in a 15-year-old girl in which many neoplastic cells had moderate and focally abundant cytoplasm, including plasmacytoid or rhabdoid cells, rather than the more common Ewing-like morphology described in the majority of such tumors. The diagnosis was confirmed by fluorescent in situ hybridization after the tumor was found to be WT-1 positive, and comprehensive genomic profiling demonstrated breakpoints in exon 20 and exon 1 of the CIC and DUX4 genes, respectively. After treatment with local radiation and systemic chemotherapy, resected recurrent tumor demonstrated more pleomorphic neoplastic cells as well as intracytoplasmic eosinophilic globules and nuclear pseudoinclusions which may reflect therapy-related changes. Unfortunately, there was further progression of tumor including the development of intracranial lesions, and the patient succumbed to her tumor 22 months after the original resection.

Prostate cancer management changed in recent times given the recommendation against prostate-specific antigen screening, adherence to active surveillance, and "cytoreductive" surgery. We hypothesized that radical prostatectomy (RP) findings changed as well. All consecutive RPs (n=1348) and first time prostate needle biopsies (n=1719) in a period of 9 years were reviewed. The cohort was separated into 3 groups: (1) from May 2006 to April 2009, (2) from May 2009 to April 2012, and (3) from May 2012 to April 2015. The number of RPs decreased 15% from 551 in group 1 to 476 in group 2 and decreased a further 35% to 311 in group 3. Pure Gleason 6 (grade group 1) decreased from 46% in group 1 to 24% in group 2 (P

Liquid crystals are a perspective type of materials for application in the field of tactile pressure sensors owning to their unique physical properties. One of such properties is the anisotropic electric conductivity, the value of which can be controlled by the external electric field. In this report we will consider a capacitive method of the measurement of the direct current conductivity in the liquid crystal layer, confined in the cell with blocking electrodes. It will be demonstrated that this technique allows estimating the direct current conductivity of a liquid crystal in a broad temperature range. The retrieved results can be used

BACKGROUND Human and animal poxvirus infections are being reported with increasing frequency. We describe a challenging case history and treatment of a previously unknown poxvirus rash illness in a renal transplant patient. METHODS A combination of classical microbiology techniques, including viral culture and electron microscopy, were used to provide initial clinical diagnosis. Subsequent standard polymerase chain reaction assays available in 2001 were noncontributory. Next generation sequencing was used to provide definitive diagnosis. RESULTS Retrospectively, next generation sequencing methods were used to ultimately provide the definitive diagnosis of a novel poxvirus infection initially identified by electron microscopy. The closest relative of this poxvirus, identified in North America, is a poxvirus collected from a mosquito pool from Central Africa in 1972. CONCLUSIONS This diagnostic quandary was ultimately solved using next generation DNA sequencing. This article describes the use of classical and next generation diagnostic strategies to identify etiologic agents of emerging infectious diseases and once again demonstrates the susceptibility of immunossupressed patients to novel pathogens. The virus identified is closely related to Yoka virus; these viruses appear to have independently diverged from a common ancestor of all known orthopoxviruses.

Insulin-like 3 (INSL3) is a hormone produced by Leydig cells (LCs) and leads to physiological testicular descent during embryonic development. We investigated the expression of INSL3 by immunohistochemistry in normal LCs, in Leydig cell tumor (LCT) (n=17 including 15 testes and 2 ovaries) and in Leydig cell hyperplasia (LCH) (n=10). Normally distributed LCs showed strong immunostaining in the cytoplasm in all cases. All 10 cases (100%) of LCH were strongly and diffusely positive in the intertubular areas. Six cases of LCH had nodules raging in size from 0.2 to 0.9 cm with variable INSL3 staining. Fifteen of 17 (88.2%) LCTs showed marked decrease INSL3 staining, 10/17 (58.8%) were completely negative, and 5/17 (29.4%) were only focally positive. Two cases with multifocal LCTs showed strong and diffuse cytoplasmic staining of LCs around seminiferous tubules while the LCTs were negative. Two cases diagnosed as LCT were strongly positive for INSL3. Other sex cord stromal tumors tested were consistently negative including Sertoli-cell tumor (n=4), granulosa cell tumor (n=2), and fibrothecoma (n=1). In conclusion, our results contrast with those of previously published studies, and show that the great majority of LCTs are negative or have decreased expression of INSL3 while its expression is retained in LCH. INSL3 negative nodules within LCH may represent early LCTs. INSL3 immunostaining could be helpful to highlight LCs in cases where it is difficult to identify them (ie, small testicular biopsies performed for infertility workup) and in the differential diagnosis between florid LCH and LCT.

We present a theoretical and empirical analysis of the links between the gender of an entrepreneur, access to finance, occupational choice, and business performance. Our theoretical model predicts that, when lenders discriminate against women entrepreneurs, the average entrepreneurial skill of women who become entrepreneurs or enter paid employment as managers is higher than that of their men counterparts. This suggests that the firms owned or managed by women should perform better than the firms owned or managed by men, ceteris paribus. We find empirical support for the assumptions and the predictions of our model using firm-level data for 28 emerging economies in Europe and Asia; the effect is especially strong in the small and medium enterprises, possibly, because in large firms borrowing is a less essential source of finance. An important policy implication of our findings is that discrimination in the capital market spills over to the labour market, leading to the distortion of occupational choice and inefficiency in allocation of physical and human resources.

Collision tumors or metastasis from an extracranial tumor to a primary brain neoplasm are rare but do occur. The majority involve metastases to meningiomas. This case presents the second documented collision of a systemic chronic lymphocytic leukemia (CLL) to a glioblastoma multiforme (GBM). Lymphomas tend to coalesce in perivascular locations, and the characteristic vascularity of glioblastomas may present a very inviting milieu for lymphoma cells.

A 52-year-old man presented following a motor vehicle collision. Examination revealed a Glasgow Coma Scale score of 15, with right lower extremity paresis. Noncontrast CT demonstrated a left frontal lesion. MRI further characterized the mass within the left superior frontal gyrus, suspicious for high-grade glioma (figure 1). Intraoperatively, the mass exhibited invasive margins, gross hypervascularity, and hemorrhage, without apparent dural attachment. Preliminary diagnosis was glial neoplasm. Final pathology was consistent with meningioma with focal brain invasion and rhabdoid differentiation, without anaplastic features, World Health Organization (WHO) grade II (figure 2). Outcome is correlated with WHO grade.1 Brain invasion is a new WHO diagnostic criterion of atypical meningioma.2 Acknowledgment: The authors thank Glenn Tung, MD, for his preparation of the neuroimaging in this report.

This article is devoted to current issues of labor migrants' adaptation. The research is based on questioning 210 labor migrants from Uzbekistan aged 17 to 49, at present living in Saint Petersburg. It should be mentioned that Uzbekistan labor migrants constitute a considerable part of the entire labor-migrant flow to Russia, Saint Petersburg, in particular. The research targets the analysis of personal characteristics contributing to effective adaptation by labor migrants. The research contains an analysis of the system of personality “I”-structures interrelation, their constructive, destructive, and deficient components as well as the analysis of life-meaning guidelines and the system of migrants' family and interpersonal relationships. The outcomes obtained make it possible to examine labor migrants' unique personality characteristics, depending on their attitude toward whether to stay in Russia or return to Uzbekistan, as well as to provide an analysis of migrants' mental health or psychological well-being and to forecast the effectiveness of migrants' adaptation. Two groups of labor migrants those intending to stay in Russia and those wishing to return to Uzbekistan differ in a number of indicators. The forecast of mental health or psychological well-being of labor migrants intending to stay in Russia is more favorable. A rather high personal level of mental health and adaptation resources are based on a strong potential of activity, ability to achieve definite goals, and capacity to establish and maintain interpersonal relationships. The outcomes of migrants wishing to return to Uzbekistan give us grounds to assume that there exist both threats to their psychological well-being and emergence of psychopathological symptoms. Thus, the forecast of this group's adaptation appears less favorable. Following up, it is reasonable to sort out some groups at risk among migrants wishing to return to Uzbekistan and develop relevant programs of mental-disorder prevention. Nonetheless, we consider the status of both groups to be marginal, that, in its turn, undoubtedly affects the process of their adaptation. The latter is an extremely complex process because, even under quite favorable conditions, it includes many attendant factors.

In the current study we implemented ICV IGF-1 gene therapy in very old rats (28 months) and assessed the motor performance pre and 17-days after surgery. Glial immunoreactivity in striatum was evaluated by Iba1 and GFAP markers., Facultad de Ciencias Médicas

Tetrapyrrolic compounds such as porphyrins are known to be prospective chemotherapeutics and photosensitizers for cancer treatment and diagnosis. In this work, water-soluble, meso-substituted cationic pyridyl-porphyrins and their metallocomplexes bearing various central metal atoms ( Ag , Zn , Co , and Fe ) in the porphine ring and various functional groups (allyl, oxyethyl, butyl, and methallyl) at the nitrogen atom in the pyridine ring were synthesized and characterized by1H and13C NMR and UV-visible spectroscopy. Cytotoxic and photodynamic activities of new porphyrins and their metal derivatives were investigated in vitro (KCL-22 cancer cell line of human chronic myeloid leukemia). The cytotoxicity of porphyrins was shown to be dependent on the presence and type of the central metal atom in the porphine ring. Ag -derivatives were more cytotoxic than Co −, Zn −, and Fe − metallocomplexes. The porphyrins bearing allyl-functional groups were evidenced to be more cytotoxic than those which included butyl-, oxyethyl-, and methallyl-groups. The change of nitrogen position in the pyridine ring of Ag -metalloporphyrins from 3(3-N-pyridylporphyrins) to 4(4-N-pyridylporphyrins) induced an increase in the cytotoxic activity of metallocomplexes. All synthesized Ag-metalloporphyrins, except, the oxyethyl-containing one were more cytotoxic than cisplatin. Allyl containing free porphyrin and its Zn -metallocomplex had higher phototoxicity than Ag −, Co −, and Fe -metalloporphyrins. The results obtained can be useful for further investigation of new porphyrins as potential chemotherapeutics and photosensitizers.