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The subareolar Sappey's plexus was studied using color lymphography and immunohistochemical methods with a panel of antibodies to podoplanin, smooth muscle actin, low molecular weight cytokeratin AE1/AE3, and GATA3 on archival material obtained during radical mastectomies and sectoral resections with lymph node dissection from 86 patients diagnosed with non-special type breast cancer. At the macro- and microscopic levels, the connection between the subareolar lymphatic plexus and the lymphatic system of the breast parenchyma has been demonstrated. In triple negative breast cancer with metastases to the axillary lymph nodes, the involvement of subareolar lymphatic plexus into lymphogenous metastasis to the lymph nodes of the axillary lymphatic collector was shown., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

DNA amplifications in cancer do not only harbor oncogenes. We sought to determine whether passenger coamplifications could create collateral therapeutic vulnerabilities. Through an analysis of >3,000 cancer genomes followed by the interrogation of CRISPR-Cas9 loss-of-function screens across >700 cancer cell lines, we determined that passenger coamplifications are accompanied by distinct dependency profiles. In a proof-of-principle study, we demonstrate that the coamplification of the bona fide passenger gene DEAD-Box Helicase 1 (DDX1) creates an increased dependency on the mTOR pathway. Interaction proteomics identified tricarboxylic acid (TCA) cycle components as previously unrecognized DDX1 interaction partners. Live-cell metabolomics highlighted that this interaction could impair TCA activity, which in turn resulted in enhanced mTORC1 activity. Consequently, genetic and pharmacologic disruption of mTORC1 resulted in pronounced cell death in vitro and in vivo. Thus, structurally linked coamplification of a passenger gene and an oncogene can result in collateral vulnerabilities., Significance: We demonstrate that coamplification of passenger genes, which were largely neglected in cancer biology in the past, can create distinct cancer dependencies. Because passenger coamplifications are frequent in cancer, this principle has the potential to expand target discovery in oncology. This article is featured in Selected Articles from This Issue, p. 384., (©2024 The Authors; Published by the American Association for Cancer Research.)

KRAS is the most frequently mutated oncogene in human cancer, and its activating mutations represent long-sought therapeutic targets. Programmable nucleases, particularly the CRISPR-Cas9 system, provide an attractive tool for genetically targeting KRAS mutations in cancer cells. Here, we show that cleavage of a panel of KRAS driver mutations suppresses growth in various human cancer cell lines, revealing their dependence on mutant KRAS. However, analysis of the remaining cell population after long-term Cas9 expression unmasked the occurence of oncogenic KRAS escape variants that were resistant to Cas9-cleavage. In contrast, the use of an adenine base editor to correct oncogenic KRAS mutations progressively depleted the targeted cells without the appearance of escape variants and allowed efficient and simultaneous correction of a cancer-associated TP53 mutation. Oncogenic KRAS and TP53 base editing was possible in patient-derived cancer organoids, suggesting that base editor approaches to correct oncogenic mutations could be developed for functional interrogation of vulnerabilities in a personalized manner for future precision oncology applications., Significance: Repairing KRAS mutations with base editors can be used for providing a better understanding of RAS biology and may lay the foundation for improved treatments for KRAS-mutant cancers., (©2022 The Authors; Published by the American Association for Cancer Research.)

DNA-methyltransferase 3A ( DNMT3A ) mutations belong to the most frequent genetic aberrations found in adult acute myeloid leukemia (AML). Recent evidence suggests that these mutations arise early in leukemogenesis, marking leukemic progenitors and stem cells, and persist through consolidation chemotherapy, providing a pool for AML relapse. Currently, there are no therapeutic approaches directed specifically against this cell population. To unravel therapeutically actionable targets in mutant DNMT3A -driven AML cells, we have performed a focused RNAi screen in a panel of 30 primary AML samples, all carrying a DNMT3A R882 mutation. As one of the strongest hits, we identified MDM4 as a gene essential for proliferation of primary DNMT3A WT/R882X AML cells. We analyzed a publicly available RNA-Seq dataset of primary normal karyotype (NK) AML samples and found a trend towards MDM4 transcript overexpression particularly in DNMT3A -mutant samples. Moreover, we found that the MDM2/4 inhibitor ALRN-6924 impairs growth of DNMT3A WT/R882X primary cells in vitro by inducing cell cycle arrest through upregulation of p53 target genes. Our results suggest that MDM4 inhibition is a potential target in NK-AML patients bearing DNMT3A R882X mutations.

The CRISPR-Cas9 technology has revolutionized the scope and pace of biomedical research, enabling the targeting of specific genomic sequences for a wide spectrum of applications. Here we describe assays to functionally interrogate mutations identified in cancer cells utilizing both CRISPR-Cas9 nuclease and base editors. We provide guidelines to interrogate known cancer driver mutations or functionally screen for novel vulnerability mutations with these systems in characterized human cancer cell lines. The proposed platform should be transferable to primary cancer cells, opening up a path for precision oncology on a functional level., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

The purpose of this paper was to study theoretically and experimentally clinical and electrophysiological correlates of the human abilities to recognize emotions in speech. It was shown that the disorder of the recognition of emotions in speech occurred following the lesion of the right temporal region, however the most serious defect of recognition manifested itself at the frontal temporal localization of the lesion. The comparison of the EEG characteristics between two groups of subjects with high and low indices of recognition of emotions in speech revealed a higher level of activation in the posterior temporal regions of the right hemisphere and in the frontal regions of the left hemisphere in the group with the low index of recognition. Clinical data and findings obtained in electrophysiological studies permitted us to make a conclusion that the recognition of emotions in speech involved not only temporal regions of the right hemisphere, but also speech centers in the left hemisphere.

The efficiency of emotion recognition by verbal and facial samples was tested in 81 persons (25 healthy subjects and 56 patients with focal pathology of premotor and temporal areas of brain hemispheres). The involvement of some cortical structures in the recognition of the basic emotional states (joy, anger, grief, and fear) and the neutral state was compared. It was shown that the damage to both right and left hemispheres impaired the recognition of emotional states by not only facial but also verbal samples. Damage to the right premotor area and to the left temporal area impaired the efficiency of the emotion recognition by both kinds of samples to the highest degree.

To assess the involvement of different structures of the human brain into successive stages of the recognition of the principal emotions by facial expression, we examined 48 patients with local brain lesions and 18 healthy adult subjects. It was shown that at the first (intuitive) stage of the recognition, premotor areas of the right hemisphere and temporal areas of the left hemisphere are of considerable importance in the recognition of both positive and negative emotions. In this process, the left temporal areas are substantially involved into the recognition of anger, and the right premotor areas predominantly participate in the recognition of fear. In patients with lesions of the right and left brain hemispheres, at the second (conscious) stage of recognition, the critical attitude to the assessment of emotions drops depending on the sign of the detected emotion. We have confirmed the hypothesis about a correlation between the personality features of the recognition of facial expressions and the dominant emotional state of a given subject.

Voluntary components of the emotion perception were shown to be related to the left hemisphere temporal area in patients with focal lesions of postero-frontal and temporal areas of both hemispheres, whereas the involuntary components required involvement of the right hemisphere temporal area. The voluntary components of the emotion reproduction are associated with involvement of the left hemisphere postero-frontal area, whereas involuntary components of perception are related to work of the right hemisphere postero-frontal area. The data obtained suggest that the voluntary (conscious) recognition and reproduction of emotions are mainly related to the sensory and motor speech centres of the left hemisphere, whereas involuntary those involve symmetrical areas of the opposite hemisphere.

Nonlinear dependence between the emotion intensity and main emotion components: the value of need and probability of its satisfaction is confirmed by the analysis of subjective and objective indices during mental reproduction of emotional situations. The dependence suggests a possibility of application of some its linear analogs in a certain range of changes in the intensity of need and possibility of its satisfaction.

The psychophysiological correlates of recognition and reproduction of emotional states were studied in patients with differently localized lesions of the brain cortex. It was shown that the effect of different lesions are anisotropic. The cross and reciprocal interaction between the posteriofrontal and temporal regions of the left and right hemispheres was described. A relation was revealed between the emotion sign and different autonomic indices. A quantitative estimation of physiological reactions of healthy persons and patients with focal brain pathology was carried out.

The participation of the cortical zones of the brain in the processes of the perception and reproduction of the emotional states of man was investigated by means of a new method of mapping intracortical interaction. During the recognition of emotions the focus of activity was in the left temporal area of the cortex. If the emotions were not recognized, a focus of activity was not observed in the temporal area of the cortex, but was found in the frontal divisions of both hemispheres. Foci of activity were observed primarily in the frontal areas of the cortex during the mental reproduction of emotional states.

The present investigation is devoted to an analysis of the changes in the bioelectrical and vegetative indices during the mental reproduction of emotional states by man. An analysis of the data of the mapping of intracortical interactions as a function of the time course of the changes in the R-R interval was carried out. Two stages in the mental reproduction of emotions were identified which are characterized by the presence of different centers of integration, in the frontal and temporal divisions of the cerebral cortex. It was demonstrated that in the presence of maximal emotional tension the center of integration shifts from the frontal regions to the temporal region of the left hemisphere.

The present study is devoted to the analysis of changes of bioelectrical and vegetative indices at mental reproduction of emotional states by man. Analysis is conducted of the data of mapping of intracortical interactions depending on the dynamics of R-R interval changes. Two stages of mental reproduction of emotions are revealed which are characterized by the presence of different centers of integration--in the frontal and temporal parts of the brain cortex. It is shown that at maximum emotional stress the integration center shifts from the frontal regions to the temporal region of the left hemisphere.

The influence of medium acidity on the intensity of light-dependent antibacterial activity of chlorophyllides isolated from biomass of microscopic green alga Westella botryoides has been studied. This light-dependent antibacterial activity has been shown to be maximum at low pH values. The ability to suppress the bacterial growth under the action of light decreases in neutral and alkaline media. It has been concluded that the reason of increase of light-dependent antibacterial activity of chlorophyllides at low pH values is formation of pheophorbides out of them

The quantity of correct and erroneous identifications of human emotions was compared according to their intonational and mimical cues in the group of healthy persons (31 persons) and in the group of patients with lesions of different cortical parts of the left and right cerebral hemispheres (54 patients). It was established that the intactness of the temporal parts of both hemispheres is important for non-verbal recognition (choosing of appropriate photograph by the observer) of emotions by mimics. Correct verbal identification of emotions by mimics requires the integrity of the fronto-parietal parts of the left hemisphere while verbal identification of emotional intonation needs the intactness of the fronto-parietal parts of the right hemisphere. The significance of the temporal areas (especially of the right hemisphere) increases in case when the emotional colouring of the presented verbal communication does not coincide with its contents.

The frequency of skin-galvanic (SGR) and motor reactions was analyzed at recognition of human emotional state by mimics. 31 healthy persons and 54 patients with lesions of temporal and frontoparietal areas of both cerebral hemispheres were examined. It has been established that the process of recognition takes place by stages: at first - at intuitive level accompanied by SGR, and then at the level of making decision completed by a motor or verbal reaction. Efficiency of recognition at the first stage does not so much depend on lesion localization as at the second stage. Pathology of the left hemisphere affects mainly the stage of making decision, and of the right one - the process of recognition as a whole.

The paper deals with comparative efficiency of emotional state recognition by intonational and mimic information in healthy and ill subjects with organic lesion of one hemisphere. In particular, it is shown, that the analysis of the verbalized mimic information is better in the healthy left hemisphere and of nonverbalized--in the right one; pathology of the right hemisphere significantly worsens the solving of tasks, connected with recognition of intonational information in comparison with a mimic one.

The goal of this work was to study how the acidity of a medium influenced the light-dependent antibacterial activity of fatty acids towards Staphylococcus aureus. The antibacterial activity of arachidonic, linolenic, linoleic and oleic acids increased abruptly (by 1-2 orders of magnitude) under the action of visible light, it became more intensive with a rise in the number of double bonds in a fatty acid molecule, and the maximum shifted from the neutral region to an alkaline one as the aeration was intensified. In the case of saturated fatty acids (palmitic and stearic), the antibacterial activity with a maximum in the alkaline region was detected only in the light. The effect exerted by the number of double bonds in a fatty acid molecule and by the acidity of a medium on the mechanisms of fatty acid photooxidation is discussed.